Hepatitis C Virus Treatment and Solid Organ Transplantation
This article reviewed the data on HCV treatment prior to and after organ transplantation.
Introduction:
HCV infection is one of leading causes for liver transplantation. There have been signifcant advancements in the science of HCV therapy (eg: direct-acting antiviral (DAA) therapy) and in the use of HCV-positive
organs, thereby substantially increasing the number of
organ transplants and decreasing waitlist mortality.
Hepatitis C Virus Infection and Direct Acting Antiviral Therapy The availability of safe and highly effective therapy has led to the delicate consideration of treating HCV infection prior to transplant or deferring therapy until after transplant.
DAA therapy has been shown to improve liver function in patients with decompensated cirrhosis.
Pretransplant DAA therapy decrease the risk of reinfection of the allograft. Clinical features associated with meaningful improvement in liver function from pretransplant therapy:
Low baseline Model for End-Stage Liver Disease score (<16)
Low baseline Child-Pugh score
The absence of portal hypertension complications.
Direct-Acting Antiviral Therapy and Liver Transplantation The use of DAA therapy following liver transplant has demonstrated excellent outcomes.
Treatment of HCV infection in patients who undergo simultaneous liver-kidney transplant is safe and effective.
Defining Hepatitis C Virus–Positive Donors HCV-positive donors encompass any stage of HCV infection.
Serologic tests detect antibodies within 2 to 6 months after exposure, but nucleic acid testing (NAT) detects RNA 5 to 7 days after exposure and provides a
more accurate assessment of transmission risk.
There are 3 types of donors:
HCV positive by serologic testing but NAT negative(nonviremic) these are not considered to transmit HCV infection.
HCV-seropositive that is NAT positive is considered to have an active infection and poses a high risk for disease transmission.
HCV-negative that is NAT positive is considered to have an
acute infection and poses a high risk for disease transmission.
Conclusion Transplantation of HCV-viremic organs into HCV-naive recipients followed
by the use of DAA agents provides excellent patient and allograft survival.
In carefully selected patients, the use of HCV-viremic grafts appears to be well tolerated.
Securing DAA therapy posttransplant is essential and patients should be fully informed of the associated risks.
It remains unclear whether HCV infection in posttransplant patients may lead to lasting changes to the immune system or inadvertent interactions with immunosuppressive therapy.
Introduction:
End-stage liver disease from HCV infection is one of the leading causes of liver disease and leading indications for liver transplantation.
Several strategies to expand the donor pool have been implemented,
Including donation after cardiac death, use of living donors, and increased utilization of high-risk donors to mitigate the global shortage.
Organs categorized as high risk by the public health service are those associated with an increased risk for the transmission of blood-borne viruses, including HIV, hepatitis B virus, and HCV.
There have been significant advancements in the science of HCV therapy and in the use of HCV-positive organs, thereby substantially increasing the number of organ transplants and decreasing waitlist mortality. Hepatitis C Virus Infection and Direct Acting Antiviral Therapy: Cure rates defined as sustained virologic response 12 weeks after treatment (SVR12) of greater than 98%.
The combination of ledipasvir (LDV) and SOF (LDV/SOF, 90 mg/400 mg; Harvoni, Gilead), administered once daily, is well tolerated and produces high SVR12 rates in HCV genotype (GT) 1, 4, 5, and 6 infection.
The combination of SOF and NS5A inhibitor velpatasvir (SOF/VEL; Epclusa, Gilead), administered once daily, provides SVR12 rates of greater than 95% across all GTs and has a favorable safety profile.
The combination of NS3/4A protease inhibitor glecaprevir and NS5A inhibitor pibrentasvir (GLE/PIB; Mavyret, AbbVie) was first approved in 2017 for the treatment of HCV infection without cirrhosis or with mild cirrhosis.GLE/PIB is well tolerated and results in SVR12 rates greater than 97% across all GTs. Direct-Acting Antiviral Therapy and Liver Transplantation:
Persistence of HCV infection after liver transplant results in a variable clinical course ranging from mild fibrosis to severe graft damage. With the increasing use of DAA therapy, significant HCV-related progression of liver disease post-transplant is now uncommon. Defining Hepatitis C Virus–Positive Donors: Donors identified as HCV positive by serologic testing but NAT negative (nonviremic) are considered to have undergone spontaneous clearance or successful treatment of infection, or have a false-positive antibody result, and these donors have not been documented to transmit HCV infection.
HCV-seropositive donor that is NAT positive (viremia) is considered to have an active infection and poses a high risk for disease transmission.
An HCV-negative donor that is NAT positive (viremia) is considered to have an acute infection and poses a high risk for disease transmission.
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients:
DAA therapy has increased the utilization of HCVviremic donor organs.
Early data have demonstrated favorable long-term graft outcomes in patients transplanted with HCV-seropositive donors. Liver Transplantation:
Two large retrospective studies evaluated HCV-viremia donors in nonviremic liver transplant recipients and demonstrated no differences in patient or graft survival when compared with nonviremic donors.
Immediate treatment with GLE/PIB for HCV-viremia liver transplant into uninfected recipients is both safe and efficacious.
A later study demonstrated that initiation of DAA therapy within 90 days of transplant, rather than preemptively or immediately following transplant, has also demonstrated favorable outcomes. Renal Transplantation:
The prevalence of HCV among end-stage renal disease patients is 0.2% to 6%, and HCV infection traditionally has been a common complication after renal transplant.
Studies in the past decade have demonstrated promising long-term outcomes of HCV-seropositive recipients transplanted with kidneys from HCV-positive donors.
Furthermore, the availability of DAA therapy and its administration around the time of transplant minimizes the risk of chronic HCV infection in the transplant recipient and thus has led to the recent growth of transplant of kidneys from HCV-infected donors into HCV-naive recipients. Thoracic Transplantation:
Few studies have evaluated the safety of using lungs from HCV-viremia donors for transplantation. In a single-center prospective study of 22 HCV-naive recipients of HCV-viremia lungs treated with 12 weeks of SOF/VEL, 6-month HCV-free survival was 86%.
Preemptive administration of GLE/ PIB in HCV-viremia cardiac transplant into HCV-naive recipients has demonstrated rapid HCV suppression (median time to clearance, 3-5 days; interquartile range, 0.0-8.3), prevention of chronic HCV infection (SVR12 rate of 100%), and excellent early allograft function (100% at a median follow-up of 10.7 months) in patients receiving HCV-viremia donor hearts. Pancreas Transplantation;
The data on utilizing HCV-viremia organs in pancreas transplantation are limited. Conclusion:
Transplantation of HCV-viremia organs into HCV-naive recipients followed by the use of DAA agents provides excellent patient and allograft survival
Hepatitis C virus treatment and SOT. Summary; Introduction; This article discus the data on HCV treatment prior, and after transplantation. Around 30 to 150 million people are affected worldwide by HCV, due to shortage of organ the new strategies is to expend the pool of donor and to include also the high risk donors like HBV/ HCV and HIV infected donors. DAA therapy; With new DAAs the cure rate is around 98%, and with high SVR rates. These can used with decompensated liver disease. DAAs and liver transplantation; The outcomes has improved after discovery and treatment with DAAs. Simultaneous liver-kidney transplant is safe and efficacious with good survival of 90% to 96.6%. Also the MAGELLAN-2 study confirmed the safety and efficacy of DAAs of pan-Genotyps. Hepatitis C Virus positive Donor transplantation in Hepatitis C Virus negative recipients. The outcomes has improved after evolving the treatment of HCV with utilization of vireamic donor organs. According to literature two large RCTs shows there is no difference in donors with vireamic and non-vireamic donor in survival of recipient and graft. Renal transplantation. HCV positive donor with kidney D+/R+ HCV has higher mortality and graft loss. D+/R+ survival at 5- 10 years 84.6%- 72.7% respectively. While D+/R- its 86.6- 76.5% respectively. Pancreas transplantation. HCV infected donor can used safely. Conclusion. SOT with HCV+ organs into HCV+ recipient has good outcomes and could decrease the waitlist gaps and morbidity and mortality.
Hepatitis C Virus Treatment and Solid Organ Transplantation Its review article (evidence V) published in Gastroenterology & Hepatology Journal 2022 about HCV treatment post solid organ transplant.
Please summarize this article.
Introduction: 9.7% of total deceased donor livers are HCV-positive organs. Because of organ shortage and the availability of direct-acting antiviral (DAA) therapy, HCV organs have been accepted to expand the donor pool. HCV and DAA therapy: Selection of DAA is related to multiple factors including previous history of HCV treatment (naive or experienced), kidney functions, HCV genotype and liver cirrhosis. For HCV genotypes 1,4,5, and 6 infections, a combination of ledipasvir and sofosbuvir (LED/SOF) has been associated with >98% SVR12 rates. Pan-genotypes HCV DAA includes SOF/velpatasvir (SOF/VEL) or Gelcaprevir and Pibrentasvir (GLE/PIB) combination with >95% SVR12 rates in patients without cirrhosis or mild cirrhosis. in the case of HCV viremic donors, there is still no generalized agreement regarding the timing of starting DAA pre, peri or post-transplant and the decision should be done on an individualized basis. According to the organ procurement and transplantation network (OPTN) data, DAA initiation pre-emptively, immediately following transplantation or even 90 days post-liver transplant has been shown to be associated with favorable outcomes. 1. DAA therapy in liver transplantation: Multiple trials addressed such subjects like the HCV-TARGET trial, MAGELLAN-1,2 trial, and SOLAR-1,2 trial in which pre-transplant DAA use was associated with high SVR12, reduced the incidence of significant HCV-related liver disease progression (20.5% versus 65.5%) and mortality post-transplant. Also, Perioperative DAA use was associated with comparable survival rates in HCV-positive recipients who received either HCV-negative or HCV-positive organs. 2. Renal transplantation: Multiple trials addressed such subjects as THINKER 1,2 trial, EXPANDER trial, and MYTHIC trial which showed utilizing HCV-positive donor kidney in HCV-positive/negative recipients has shown comparable results with excellent graft function and high SVR12 almost 100%. 3. thoracic transplantation (heart and lung): Multiple trials addressed such subjects as the USHER trial and the DONATE-HCV trial and showed the same results. 4. Pancreas transplantation or simultaneous pancreas-kidney transplantation (SPK): has been shown to be effective with 100% SVR12. Conclusion: under the umbrella of DAA drugs, HCV-positive organs can be utilized in all solid organ transplants with favorable results as regard patient and graft outcomes and it looks reasonable to accept such organs after proper patient counseling about the risks, HCV treatment failure and immunosuppressive drug interactions.
Long queue lengths and high waitlist mortality as a result of organ scarcity have a detrimental impact on organ transplantation in the United States. DAA medications are used when HCV-viremic organs are transplanted into HCV-naive recipients to give excellent patient and allograft survival.The use of HCV-viremic grafts seems to be effective and well tolerated in carefully chosen patients. This procedure has shown to produce respectable short-term results and has the potential to considerably reduce morbidity and mortality while reducing waiting gaps. The need of getting DAA therapy posttransplant, along with the hazards involved, including the possibility of HCV treatment failure, should be made clear to patients. It is yet unknown whether HCV infection in posttransplant patients may result in long-term immune system alterations or unintentional interactions.
Infection with the hepatitis C virus (HCV) affects 130–150 million people worldwide. One of the most common causes of end-stage liver disease and the main justification for liver transplantation is HCV infection. Yet, there is a significant waitlist mortality rate since the demand for organs continues to outstrip the supply of organ donation. Organs with HCV remain more readily available, accounting for 9.7% of livers from dead donors in 2019. Previously, HCV-infected organs from deceased donors were discarded due to the high risk of reperfusion-related transmission and the possibility of considerable posttransplant morbidity and mortality. The science of HCV therapy and the utilization of HCV-positive organs have made considerable strides, leading to a major rise in organ transplantation and a decline in waitlist mortality. In this paper, the research on HCV treatment both before and after organ transplantation is reviewed. Direct acting antiviral therapy Over the past several years, a succession of pangenotypic DAA therapies for the treatment of chronic HCV infection has been introduced, with cure rates defined as sustained virologic response 12 weeks after treatment (SVR12) of greater than 98%.16 Nonstructural protein. Over the past several years, a succession of pangenotypic DAA therapies for the treatment of chronic HCV infection has been introduced, with cure rates defined as sustained virologic response 12 weeks after treatment (SVR12) of greater than 98%.16. The MAGELLAN-2 study was a phase 3 open-label trial that confirmed the safety and efficacy of GLE/PIB once daily for 12 weeks in patients with treatment-naive HCV GT1 to GT6 infection or treatment-experienced HCV GT1, GT2, or GT4 to GT6 who had received a liver or kidney transplant. Treatment with SOF/VEL for 12 weeks in 14 liver transplant recipients with HCV GT1 to GT4 infection and cirrhosis resulted in an SVR12 rate of. HCV antibody HCV NAT clinical interpretation transmission risk No active HCV infection, cleared or treated HCV infection, or false-positive antibody Low. HCV, hepatitis C virus; NAT, nucleic acid testing. Donors identified as HCV positive by serologic testing but NAT negative are considered to have undergone spontaneous clearance or successful treatment of infection, or have a false-positive antibody result, and these donors have not been documented to transmit HCV infection. An. HCV-seropositive donor that is NATpositive is considered to have an active infection and poses a high risk for disease transmission. An HCV-negative donor that is NAT positive is considered to have an acute infection and poses a high risk for disease transmission. Risk of HCV transmission remains during the 1-week eclipse period between viral exposure and positive NAT results, in persons who inject drugs. Risk of HCV transmission remains during the 1-week eclipse period between viral exposure and positive NAT results, in persons who inject drugs. Negative recipients DAA therapy, transplantation of organs from HCV-positive donors into uninfected recipients was not routinely considered owing to low efficacy, high rates of HCV transmission, decreased patient and graft survival, and complications associated with interferon-based therapy in the posttransplant setting. The lack of effective and well-tolerated treatments for HCV had curtailed utilization of HCV-infected organs in transplant recipients. DAA therapy, transplantation of organs from HCV-positive donors into uninfected recipients was not routinely considered owing to low efficacy, high rates of HCV transmission, decreased patient and graft survival, and complications associated with interferon-based therapy in the posttransplant setting. The lack of effective and well-tolerated treatments for HCV had curtailed utilization of HCV-infected organs in transplant recipients. Data have demonstrated favorable long-term graft outcomes in patients transplanted with HCV-seropositive donors. In a study published in 1998, 22 patients with HCV received HCV-seropositive grafts and had excellent 4-year patient and graft survival, 83.9% and. In a larger study that included 2923 transplant recipients with HCV, 96 and 2827 received HCV-positive and -negative organs, respectively, and had comparable Liver transplantation Two large retrospective studies evaluated HCV-viremic donors in nonviremic liver transplant recipients and demonstrated no differences in patient or graft survival when compared with nonviremic donors. 54,55 Data from 2015 to 2017 from the Organ Procurement and Transplantation Network (OPTN) Two large retrospective studies evaluated HCV-viremic donors in nonviremic liver transplant recipients and demonstrated no differences in patient or graft survival when compared with nonviremic donors. HCV-seropositive but NAT-negative and nonviremic livers (92% vs 92% vs 92%; P=NS). 2016 to 2020 data from OPTN, comparable 2-year graft survival rates were seen in 568 liver transplant recipients with and without HCV infection (n=753 and n=87, respectively) who received HCV-viremic organs Antiviral therapy GLE/PIB, glecaprevir/pibrentasvir; KT, kidney transplant; LDV/SOF, ledipasvir/sofosbuvir; LT, liver transplant; SOF/DAC, sofosbuvir/daclatasvir; SOF/VEL, sofosbuvir/velpatasvir; SVR12, sustained virologic response 12 weeks after treatment. The first prospective study included 10 HCV-negative patients who received HCV-viremic livers, 7 of which had been cured of HCV infection prior to transplant. GLE/PIB has been used successfully in HCV-naive patients who receive HCV-viremic livers. In a trial of 14 patients who received HCV-viremic livers, 9 patients developed viremia with SVR12 and 46-week survival rates of 100% and 100%, respectively. The administration of SOF/VEL or GLE/PIB once daily for 12 weeks in HCV-naive patients who received viremic livers (n=51). In a multicenter study evaluating the kinetics of early HCV infection, SOF/VEL once daily for 12 weeks when viremia was confirmed resulted in SVR12 in all patients (13 liver, 11 kidney SVR12 was reported in a prospective multicenter study evaluating outcomes in HCV-naive liver transplant and dual liver-kidney transplant. 60 all HCV-viremic organ recipients (n=20) achieved SVR12, the development of HCV-related complications suggests that careful and longer-term follow-up is still warranted Renal transplantation The prevalence of HCV among end-stage renal disease patients is 0.2% to 6%, and HCV infection traditionally has been a common complication after renal transplant. In 2017, the THINKER trial was the first open-label, single-group pilot study that sought to determine the safety and efficacy of the transplant of kidneys from HCV GT1–viremic donors into HCV-negative recipients followed by treatment with elbasvir/grazoprevir (EBR/GZR; Zepatier, Merck) for 12 weeks (n=10). In a study of 7 HCV-naive kidney recipients receiving HCV GT1– and HCV GT3–viremic kidneys, antiviral treatment with LDV/SOF (n=4) and SOF/VEL (n=3) for 8 to 12 weeks resulted in SVR12 and stable renal allograft function. 70 In a subsequent, larger, single-center, observational study, use of SOF/VEL or LDV/SOF resulted in SVR12 rates of 100% and stable allograft function in 53 HCV-naive recipients who received SOF/VEL or LDV/SOF for 8 to 12 weeks following HCV-viremic kidney transplant.[71]. Of the 6 patients who required treatment, 5 patients achieved SVR12, with 1 patient requiring the addition of ribavirin owing to resistance and 2 patients requiring retreatment with second-line DAA agents owing to relapse. Thoracic transplantation The reported prevalence of HCV infection is as high as 12%. 76 Early studies demonstrated reduced survival in recipients with HCV infection, regardless of acquisition of HCV pre– or post–. The first prospective study utilizing HCV-viremic hearts included 11 HCV-naive recipients, 9 of whom developed HCV viremia after transplant and 8 of whom achieved SVR12 through treatment with either. PIB in HCV-viremic cardiac transplant into HCV-naive recipients (n=20) has demonstrated rapid HCV suppression, prevention of chronic HCV infection (SVR12 rate of 100%), and excellent early allograft function (100% at a median follow-up of 10.7 months) in patients receiving HCV-viremic donor hearts. In the largest-to-date prospective single-center study of 80 patients who underwent heart transplant with HCV-positive donors (70 NAT-positive, GT1-GT3 donors and 10 antibody-positive, NAT-negative donors), 67 of 70 (96%) recipients developed viremia following transplant and started treatment with LDV/. Shorter duration of DAA treatment with GLE/PIB for 8 weeks following cardiac transplant was evaluated in 22 HCV-naive patients who received HCV-viremic organs. At 6 months posttransplant, there was no difference between HCV-viremic and HCV-negative recipients when comparing mortality (6.3% vs 3.9%; P=1), primary graft dysfunction (0.0% vs 11.5%; P=.275), clinically significant rejection requiring treatment (31.8% vs 37%; P=.769), or acute cellular rejection (90.9% vs 100%; P=.196). Pancreas transplantation The data on utilizing HCV-viremic organs in pancreas transplantation are limited. In 2021, the first reported series included 8 HCV-naive patients who received either deceased donor simultaneous pancreas-kidney transplant or pancreas transplant after living donor kidney transplant. Length of stay (16 days vs 10 days; P=.06) was similar between those who received HCV-viremic organs and those who did not, respectively. These preliminary findings suggest that HCV-viremic pancreas transplant may be safely used for potential pancreas recipients; further study regarding morbidity and mortality of pancreas transplantation with HCV-positive donors is needed. Short-term outcomes for solid organ transplantation appear to be comparable for HCV-viremic and -nonviremic donors, based on the previously discussed preliminary data. Promising data are most robust in kidney followed by liver transplant but offer limited results past 1 year Findings Have led to greater utilization of HCV‐positive livers, increasing from 7% to 17% between 2010 and. With cure rates defined as sustained virologic response 12 weeks after treatment (SVR12) of greater than 98%.16. Recipients who achieve SVR12 posttransplant have lower rates of liver fibrosis progression (20.5% vs 65.5%; P<.001) and lower mortality rates compared with patients who do not receive or fail treatment. Treatment with GLE/PIB for 3 months or longer posttransplant in 80 liver transplant and 20 kidney transplant patients resulted in an SVR12 rate of 98%. In posttransplant patients with HCV GT4 infection, SVR12 was achieved by 78% of patients who received 12 weeks of treatment and 94% of patients who received 24 weeks of treatment. Produced similar 1-year patient and graft survival when compared with HCV-naive patients who received nonviremic livers (n=231), at 93.4% vs 93.9% (P=.89) and. HCV seropositivity was reported to be an independent risk factor for increased mortality when matched with controls (2.8-fold greater; 95% CI, 1.3-5.7; P=.006) and for the development of accelerated allograft vasculopathy when compared with matched controls, with a hazard ratio of 9.4 vs 3.08 Conclusion Organ transplantation in the United States is negatively impacted by long waitlist times and high waitlist mortality owing to organ shortages. The use of HCV-viremic grafts appears to be efficacious and well tolerated. This practice has demonstrated acceptable short-term outcomes and has the potential to significantly close waitlist gaps and decrease morbidity and mortality. DAA therapy posttransplant is essential and patients should be fully informed of the associated risks, including the potential of HCV treatment failure. It remains unclear whether HCV infection in posttransplant patients may lead to lasting changes to the immune system or inadvertent interactions with immunosuppressive therapy.
Kidney transplantation is the treatment of choice for end stage chronic kidney disease.
However, owing to dearth of organ supply, an extended donor criteria was adopted. Therefore, HCV infected patient was considered an acceptable potential donor for solid organ transplantation.
This forwards step stemmed from the successful outcome and high reversal rate of infection after treatment with the administration of direct acting antiviral therapy DAAT. Incidence :of HCV infection 150 million worldwide. Chronic hepatitis :
The persistence of HCV genome detected by PCR for more than 6 months.
Positive viremia: the detection of HCV RNA in plasma of patients who is serologically positive.
Seroconversion:
The presence of anti-HCV antibodies. DAAT:
The combination of more than one anti HCV medications protocol was successful for a duration of 12 weeks was liked to a success rate of more than 98% success in establishing sustained virologic remission SVR of 12 moths. This observation was noted with predominantly with genotype 1,4,5 and 6. DAAT types:
1] Non structural protein 5 B inhibitor NS5Bi Sofosbuvir.
2] Nonstructural protein 5A inhibitor. NSP5A ledipasvir and velpatasvir
3] Protease inhibitor.
4] Ribavirin.
the combination of both in one tab formula of LED/SOF 90/400 revolutionized the treatment of HCV infection resultant in a unprecedented recovery rate with SVR12 in more than 98% of the genotypes mentioned earlier. However, VEL/SOF combination is successful in all genotypes with success rate of more than 95%.
The success rate of DAAT administered peri-transplantation paved the acceptance of organs donation from HCV infected donors with different protocols pre-donation, pre-emptive post donation or after seroconversion of recipients, with variable success of organ transplantation without transmitting HCV.
Hepatitis C Virus Treatment and Solid Organ Transplantation
SUMMARY Introduction: · 30-150 million people worldwide are affected by HCV. · With global shortage of organs, strategies to expand the donor pool include donation after cardiac death, increased utilization of high-risk donors like HBV+/ HCV+ / HIV+ donors and use of HCV+ living donors. · The opioid epidemic has caused an increase in HCV transmission. · DAA therapy has led to greater utilization of HCV+ livers, increasing from 7% to 17% between 2010 and 2015, · This article reviews the data on HCV treatment prior to and after organ transplantation. Hepatitis C Virus Infection and Direct- Acting Antiviral Therapy · Pan-genotypic DAA therapies in treatment of chronic HCV infection, confers cure rates of 98% and high SVR12 rates. · It has shown to improve liver function in patients with decompensated cirrhosis, reducing the risk of reinfection of the allograft, but not all patients with end-stage liver disease from HCV infection will benefit. Direct-Acting Antiviral Therapy and Liver Transplantation · HCV infection after liver transplant can have variable course – ranging from mild fibrosis to severe graft damage, advanced fibrosis and graft cirrhosis in up to 45% of posttransplant patients. · DAA therapy following liver transplant has improved outcomes, with lower rates of liver fibrosis progression, mortality, and SVR12 rates compared to those who do not receive or fail treatment. · Treatment of HCV infection in patients undergoing simultaneous liver-kidney transplant is safe and efficacious, with 96.6% and 90.9% SVR12 rates. · The MAGELLAN-2 study confirmed the safety and efficacy of a pan-genotypic, ribavirin-free regimen in posttransplant patients without cirrhosis, with an SVR12 rate of 98%. No patients experienced virologic failure or discontinued GLE/PIB due to adverse events unrelated to treatment. · HCV infection posttransplant has a negative long-term impact, leading to the use of HCV-positive organs in HCV-negative recipients. Defining Hepatitis C Virus–Positive Donors · HCV-positive donors encompass any stage of HCV infection, and serologic tests such as chemiluminescence assays and enzyme immunoassays detect antibodies within 2 to 6 months after exposure. · Nucleic acid testing (NAT) detects RNA 5 to 7 days after exposure and provides a more accurate assessment of transmission risk. · It is important to distinguish between a seropositive and viremic donor when discussing organ transplants from an HCV-positive donor, as the risks of disease transmission vastly differ. · Despite improvements in testing, the risk of HCV transmission remains during the 1-week eclipse period between viral exposure and positive NAT results. Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients · Before the availability of DAA therapy, transplantation of organs from HCV-positive donors into uninfected recipients was not routinely considered due to low efficacy, high rates of HCV transmission, decreased patient and graft survival, and complications associated with interferon-based therapy. · However, the rapidly evolving treatments for HCV have improved outcomes and increased the utilization of HCV-viraemic donor organs. Liver Transplantation · 2 large retrospective studies evaluated HCV-viraemic donors in nonviremic liver transplant recipients and found no differences in patient or graft survival. · HCV treatment within 3 months of transplantation increases the probability of successful graft function and reduces waitlist mortality. · GLE/PIB has been used successfully in HCV-naive patients who receive HCV-viraemic livers, with 9 patients developing viremia with SVR12 and 46-week survival rates of 100% and 100%, respectively. · Immediate treatment is safe and efficacious, and initiation of DAA therapy within 90 days of transplant has also demonstrated favourable outcomes. · A pre-emptive antiviral strategy using SOF/VEL is also successful in achieving SVR12, but serious adverse events include biliary sclerosis, cardiomyopathy, and graft-vs-host disease. Renal Transplantation · HCV infected donor kidney in HCV-seropositive renal recipients is associated with higher all-cause mortality and graft loss. · Studies have shown promising long-term outcomes of HCV-seropositive recipients transplanted with kidneys from HCV-positive donors, with 5- and 10-year patient survival of 84.8% and 72.7%, respectively, compared to 86.6% and 76.5% for HCV-negative recipients. · The THINKER trial was the first open-label, single-group pilot study to evaluate the safety and efficacy of the transplant of kidneys from HCV GT1–viremic donors into HCV-negative recipients (donor positive, recipient negative [D+/R-]) followed by treatment with elbasvir/grazoprevir (EBR/GZR). All recipients had detectable HCV RNA immediate post-transplant, and all attained SVR12. · The EXPANDER trial examined the tolerability and feasibility of DAA prophylaxis before and after renal transplant in HCV-naive patients who received HCV-viremic kidneys. GLE/PIB once daily for 12 weeks has been shown to be well tolerated in patients with chronic HCV GT1 to GT6 infection who have undergone kidney transplantation. · In the MYTHIC trial, 30 HCV-naive patients achieved SVR12 and no severe adverse events were noted. · In the DAPPER trial, a single pretransplant dose of SOF/ VEL followed by 1 or 3 posttransplant doses reduced viral transmission to 7.5% but did result in detectable viremia in 17 of 50 (34%) patients by posttransplant day 14. · Short-course DAA regimens have also been evaluated with promising results. Thoracic Transplantation – Donor HCV seropositivity is an independent risk factor for increased mortality and accelerated allograft vasculopathy in heart transplant recipients. – Pre-emptive administration of GLE/PIB has demonstrated rapid HCV suppression, prevention of chronic HCV infection, and improved allograft function.1 – The largest-to-date prospective single-centre study of 80 patients of heart transplant with HCV-positive donors, revealed viremia in 67 of 70 (96%) following transplant and received treatment with LDV/ SOF, SOF/VEL, or GLE/PIB for 12 weeks. – Most common adverse events were respiratory complications and infections, – 45% requiring hospitalization. – The DONATE-HCV trial evaluated transplanting HCV-viremic organs into 8 cardiac and 36 lung HCV-naive recipients, with 95% of recipients achieving SVR12 with excellent graft function. Pancreas Transplantation – HCV-viremic pancreas transplant may be safely used for potential pancreas recipients, but further study is needed to determine morbidity and mortality. – Short-term outcomes for solid organ transplantation appear to be comparable for HCV-Viremic and nonviremic donors, with promising results past 1 year. Conclusion · Organ transplantation in the US is impacted by long waitlist times and high mortality due to organ shortages. · Transplantation of HCV+ organs into HCV-naive recipients provides excellent patient and allograft survival and has the potential to close waitlist gaps and decrease morbidity and mortality.
Hepatitis C Virus Treatment and Solid Organ Transplantation
The development of safe and highly effective HCV therapy with direct-acting antiviral agents has revolutionized the management of liver transplant candidates and transplant recipients This article reviews the data on HCV treatment prior to and after organ transplantation.
The high success rate of DAA therapy, have led to greater utilization of HCV‐positive livers from 7% to 17% between 2010 and 2015. Major strides in HCV eradication paved the way for use of HCV-positive organs, first in HCV-viremic recipients and now in HCV-negative recipients.
Hepatitis C Virus Infection and Direct Acting Antiviral Therapy
The combination of potent NS5A inhibitor ledipasvir (LDV) and sofosbuvir (SOF) is well tolerated and produces high SVR12 rates in HCV genotype (GT) 1, 4, 5, and 6 infection.
The combination of SOF and NS5A inhibitor velpatasvir provides SVR12 rates of greater than 95% across all GTs and has a favorable safety pro file.
The combination of NS3/4A protease inhibitor glecaprevir and NS5A inhibitor pibrentasvir is well tolerated and results in SVR12 rates greater than 97% across all GT.
Pretransplant DAA therapy reduces the risk of reinfection of the allograft.
Will benefit from treatment prior to liver transplantation.
Clinical features associated with meaningful improve ment in liver function from pretransplant therapy include low baseline Model for End-Stage Liver Disease score (<16), low baseline Child-Pugh score, and the absence of portal hypertension complications.
Direct-Acting Antiviral Therapy and Liver Transplantation
Recipients who achieve SVR12 posttransplant have lower rates of liver fibrosis progression and lower mortality rates compared with patients who do not receive or fail treatment.
Treatment of HCV infection in patients who undergo simultaneous liver-kidney transplant is both safe and efficacious.
The HCV-TARGET trial used the Hepatitis C Therapeutic Registry and Research Network database to evaluate liver transplant and dual liver-kidney transplant recipients with HCV infection treated with LDV/SOF, ombitasvir/paritaprevir/ritonavir plus dasabuvir or SOF plus daclatasvir. SVR12 rates among liver transplant and dual liver-kidney transplant recipi ents were 96.6% and 90.9%, respectively. Successful outcomes from the real-world data of the large HCV-TARGET cohort provided confidence in treating liver transplant patients with a ribavirin-free regimen.
The MAGELLAN-2 study was a phase 3 open-label trial that confirmed the safety and efficacy of GLE/PIB once daily for 12 weeks in patients with treatment-naive HCV GT1 to GT6 infection or treatment-experienced HCV GT1, GT2, or GT4 to GT6 who had received a liver or kidney transplant.
SOLAR-1 and SOLAR-2 were 2 large trials that evaluated LDV/SOF plus ribavirin in liver transplant recipients with HCV GT1 to GT4 infection and liver disease.
In SOLAR-1, SVR12 was achieved in 96% promising data on the safety and effi cacy of DAA therapy for the treatment of HCV infection posttransplant led to a paradigm shift.
Defining Hepatitis C Virus–Positive Donors
Serologic tests such as chemiluminescence assays and enzyme immunoassays detect antibodies within 2 to 6 months after exposure,
Nucleic acid testing (NAT) detects RNA 5 to 7 days after exposure and provides a more accurate assessment of transmission risk. HCV NAT has a sensitivity of 85% to 100% and a specificity of 99% to 100%.
HCV positive by serologic testing but NAT negative (nonviremic) are considered to have undergone spontaneous clearance or successful treatment of infection, or have a false-positive antibody result, and these donors have not been documented to transmit HCV infection.
An HCV-seropositive donor that is NAT positive (viremic) is considered to have an active infection and poses a high risk for disease transmission.
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients
In a study published in 1998, 22 patients with HCV received HCV-seropositive grafts and had excellent 4-year patient and graft survival compare with HCV-seronegative donor grafts.
In a larger study that included 2923 transplant recipients with HCV, 96 and 2827 received HCV-positive and -negative organs, respectively, and had comparable 2-year survival rates (90% vs 77%)
Liver Transplantation
Two large retrospective studies evaluated HCV-viremic donors in nonviremic liver transplant recipients and demonstrated no differences in patient or graft survival when compared with nonviremic donors.
Renal Transplantation
The availability of DAA therapy and its administration around the time of transplant minimizes the risk of chronic HCV infection in the transplant recipient and thus has led to the recent growth of transplant of kidneys from HCV-infected donors into HCV-naive recipients.
THINKER trial (2017) was the first open-label, single-group pilot study that sought to determine the safety and efficacy of the transplant of kid neys from HCV GT1–viremic donors into HCV-negative recipients followed by treatment with elbasvir/grazoprevir for 12 weeks (n=10). All recipients had detectable HCV RNA, and all attained SVR12
THINKER-2 trial (n=20), HCV-negative recipients of HCV-viremic kidneys experienced HCV cure and excellent renal allograft function with estimated glomerular filtration rates (eGFRs) not significantly different from those of matched recipients of HCV-negative kidneys at 6 months and 12 months
The EXPANDER trial was an open-label single center study (n=10) that examined the tolerability and feasibility of DAA prophylaxis before and after renal transplant in HCV-naive patients (n=10) who received HCV-viremic kidneys (GT1-GT3).In this study, all recipients received a dose of EBR/GZR immediately before transplant, and recipients of kidneys from donors with GT1 infection continued receiving EBR/GZR for 12 weeks after transplant; those receiving organs from donors with GT2 or GT3 infection received SOF along with EBR/GZR for 12 weeks of triple therapy. Preemptive use of EBR/GZR for 12 weeks in HCV-naive recipients who received HCV-infected kidneys (n=8) led to SVR12 with no study-related adverse events
SOF-based regimens are safe and effective in HCV-naive recipients undergoing HCV-viremic kidney transplant.
MYTHIC trial, 30 HCV-naive patients received HCV-viremic kidneys across 7 transplant centers. All 30 recipients achieved SVR12, and no severe adverse events related to HCV infection or GLE/PIB were noted in any patient. Although all recipients had good allograft function
In a large, prospective, real-world study, 64 HCV-naive patients underwent HCV-viremic kidney transplant followed by posttransplant NAT to determine the need for treatment. 61 patients developed viremia, of which 41 patients achieved SVR12, 10 reached undetectable viral loads, and 7 remained on treatment. There was 1 nonre sponder owing to NS5A resistance. At a median 8-month follow-up, patient and graft survival were both 98%
The DAPPER trial treated patients with a single pretransplant dose of SOF/ VEL followed by 1 or 3 posttransplant doses. The 4-day strategy reduced viral transmission to 7.5% but did result in detectable viremia in 17 of 50 (34%) patients by posttransplant day 14, of which only 6 of 50 (12%) required treatment; the remaining 11 recipients had self-limited, low-level vire mia. Of the 6 patients who required treatment, 5 patients achieved SVR12, with 1 patient requiring the addition of ribavirin owing to resistance and 2 patients requiring retreatment with second-line DAA agents owing to relapse. Friebus-Kardash et al (2019):Cohort Size: 7, Antiviral Therapy: LDV/SOF, Therapy Duration: 8-12 weeks SVR12: 7/7 (100%) Molnar et al (2019):Cohort Size: 53, Antiviral Therapy: GLE/PIB, SOF/VEL, or LDV/SOF, Therapy Duration: 12 weeks SVR12: 53/53 (100%) Sise et al (2020):Cohort Size: 8, Antiviral Therapy: EBR/GZR, Therapy Duration: 12 weeks SVR12: 8/8 (100%) Thoracic Transplantation:
Among heart transplant recipients, the reported prevalence of HCV infection is as high as 12%.
Donor HCV seropositivity was reported to be an independent risk factor for increased mortality when matched with controls (2.8-fold) and for the development of accelerated allograft vasculopathy.
In the largest RCT study of 80 patients who underwent heart transplant with HCV-positive donors, 67 of 70 (96%) recipients developed viremia following transplant and started treatment with LDV/ SOF, SOF/VEL, or GLE/PIB for 12 weeks. Of those who started DAA treatment (n=55), 37 achieved SVR12 with 17 recipients pending, and 1 recipient died prior to achieving SVR12.
Although there were higher rates of severe primary graft dysfunction, there was no difference regarding the hospital length of stay, rejection requiring treatment, survival at 30 days, or 1-year patient survival.
Short course(8weeks)DAA in heart transplant associated with high SVR12 with out survival difference.
In lung transplant & HCV D+/R- treated with SOF/VEL for 12 weeks show HCV free survival at 6 months 86%, but risk of infection & rate of hospital admission was higher than D-/R- HCV transplant. Pancreas Transplantation:
The data on utilizing HCV-viremic organs in pancreas transplantation are limited.
In 2021, the first reported series included 8 HCV-naive patients who received either deceased donor simultaneous pancreas-kidney transplant or pancreas transplant after living donor kidney transplant.
All patients developed viremia and were treated with either GLE/PIB or SOF/VEL and all achieved SVR12.
All recipients had excellent pancreas graft function and rates of rejection with no difference in hospital stay.
Conclusion:
Transplantation of HCV-viremic organs into HCV-naive recipients followed using DAA agents provides excellent patient and allograft survival.
Introduction:
HCV infection affects 130 million to 150 million people worldwide.
End-stage liver disease is the indications for liver transplantation
DAA therapy has led to greater utilization of HCV-positive livers, increasing from 7% to 17% between 2010 and 2015,
This article reviews the data on HCV treatment prior to and after organ transplantation.
Although the pretransplant DAA therapy reduces the risk of reinfection of the allograft but not all patients benefits from it.
. Hepatitis C Virus Infection and Direct Acting Antiviral therapy:
pangenotypic DAA therapies for chronic HCV infection is introduced, with cure rates greater than 98%
Improvement in liver function from pretransplant therapy include low baseline Model for End-Stage Liver Disease score
Patients with advance liver disease dose not improve with DAA therapy. Direct-Acting Antiviral Therapy and Liver Transplantation:
Post liver transplantation HCV infection cause a variable clinical course ranging from mild fibrosis to severe graft damage, with advanced fibrosis and graft cirrhosis in up to 45% of posttransplant patients.
Improve outcome of liver transplant after DAA therapy following liver transplant by lowering the rate of liver fibrosis progression, mortality, and SVR12 rates compared to those who do not receive or fail treatment of DAA.
Treatment of HCV infection in patients undergoing simultaneous liver-kidney transplant is safe and efficacious, with 96.6% and 90.9% SVR12 rates.
HCV infection has a negative long-term impact on both patient and graft survival. Defining Hepatitis C Virus–Positive Donors:
HCV-positive donors encompass any stage of HCV infection, and serologic tests such as chemiluminescence assays and enzyme immunoassays detect antibodies within 2 to 6 months after exposure.
Nucleic acid testing (NAT) detects RNA 5 to 7 days after exposure and provides a more accurate assessment of transmission risk with sensitivity of 85-100% and specificity of 99-100%.
It is important to distinguish between a seropositive and viremic donor when discussing organ transplants from an HCV-positive donor, as the risks of disease transmission vastly differ.
Despite improvements in testing, the risk of HCV transmission remains during the 1-week eclipse period between viral exposure and positive NAT results. Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients:
Transplantation of organs from HCV-positive donors into uninfected recipients was not routinely till DAA therapy is available due to low efficacy, high rates of HCV transmission, decreased patient and graft survival, and complications associated with interferon-based therapy. Liver Transplantation:
2 large retrospective studies evaluated HCV-viremic donors in nonviremic liver transplant recipients and found no differences in patient or graft survival in compared with nonviremic donors.
GLE/PIB has been used successfully in HCV-naive patients who receive HCV-viremic livers. In a trial of 14 patients who received HCV-viremic livers, 9 patients developed viremia with SVR12 and 46-week survival rates of 100% and 100%, respectively
A preemptive antiviral strategy using SOF/VEL is also successful in achieving SVR12. Renal Transplantation:
Some studies found that DAA therapy are safe and very effective in the treatment of recipients of kidney transplant with HCV.
In compare the outcomes for untreated HCV infection in HCV-seropositive renal recipients are strongly worse than in their HCV-negative counterparts. Thoracic Transplantation:
In comparison between patients who received HCV-viremic heart transplant and who received transplants from HCV-negative donors during the same period.
We found that there was no difference regarding the hospital stay, rejection, survival at 30 days, or 1-year patient survival. Pancreas Transplantation:
HCV-viremic pancreas transplant may be safely used for potential pancreas recipients, but further studies about morbidity and mortality of pancreas transplantation with HCV-positive donors is needed. Conclusion:
Transplantation of HCV-viremic organs into HCV-naive recipients followed using DAA agents provides excellent patient and allograft survival.
In carefully selected patients, the use of HCV-viremic grafts appears to be efficacious and well tolerated.
DAA therapy posttransplant is essential and patients should be informed of associated risks.
· HCV infection affects 130-150 million people worldwide, leading to a global shortage of organs. Strategies to expand the donor pool include donation after cardiac death, the use of living donors, and increased utilization of high-risk donors.
· DAA therapy has led to greater utilization of HCV-positive livers, increasing from 7% to 17% between 2010 and 2015, and the opioid epidemic has caused an increase in HCV transmission. This article reviews the data on HCV treatment prior to and after organ transplantation.
Hepatitis C Virus Infection and Direct- Acting Antiviral Therapy
· Pangeno-typic DAA therapies have been introduced to treat chronic HCV infection, with cure rates of 98% and high SVR12 rates.
· DAA therapy has been shown to improve liver function in patients with decompensated cirrhosis, reducing the risk of reinfection of the allograft, but not all patients with end-stage liver disease from HCV infection will benefit.
Direct-Acting Antiviral Therapy and Liver Transplantation
· HCV infection after liver transplant can cause a variable clinical course ranging from mild fibrosis to severe graft damage, with advanced fibrosis and graft cirrhosis in up to 45% of posttransplant patients.
· DAA therapy following liver transplant has been found to have improved outcomes, with lower rates of liver fibrosis progression, mortality, and SVR12 rates compared to those who do not receive or fail treatment.
· Treatment of HCV infection in patients undergoing simultaneous liver-kidney transplant is safe and efficacious, with 96.6% and 90.9% SVR12 rates.
· The MAGELLAN-2 study confirmed the safety and efficacy of a pan-genotypic, ribavirin-free regimen in posttransplant patients without cirrhosis, with an SVR12 rate of 98%. No patients experienced virologic failure or discontinued GLE/PIB due to adverse events unrelated to treatment.
· HCV infection posttransplant has a negative long-term impact, leading to the use of HCV-positive organs in HCV-negative recipients.
Defining Hepatitis C Virus–Positive Donors
· HCV-positive donors encompass any stage of HCV infection, and serologic tests such as chemiluminescence assays and enzyme immunoassays detect antibodies within 2 to 6 months after exposure.
· Nucleic acid testing (NAT) detects RNA 5 to 7 days after exposure and provides a more accurate assessment of transmission risk.
· It is important to distinguish between a seropositive and viremic donor when discussing organ transplants from an HCV-positive donor, as the risks of disease transmission vastly differ.
· Despite improvements in testing, the risk of HCV transmission remains during the 1-week eclipse period between viral exposure and positive NAT results.
Hepatitis C Virus–Positive DonorTransplantation in Hepatitis C Virus– Negative Recipients
· Before the availability of DAA therapy, transplantation of organs from HCV-positive donors into uninfected recipients was not routinely considered due to low efficacy, high rates of HCV transmission, decreased patient and graft survival, and complications associated with interferon-based therapy.
· However, the rapidly evolving treatments for HCV have improved outcomes and increased the utilization of HCV-viremic donor organs.
Liver Transplantation
· Two large retrospective studies evaluated HCV-viremic donors in nonviremic liver transplant recipients and found no differences in patient or graft survival.
· HCV treatment within 3 months of transplantation increases the probability of successful graft function and reduces waitlist mortality.
· GLE/PIB has been used successfully in HCV-naive patients who receive HCV-viremic livers, with 9 patients developing viremia with SVR12 and 46-week survival rates of 100% and 100%, respectively.
· Immediate treatment is safe and efficacious, and initiation of DAA therapy within 90 days of transplant has also demonstrated favorable outcomes.
· A preemptive antiviral strategy using SOF/VEL is also successful in achieving SVR12, but serious adverse events include biliary sclerosis, cardiomyopathy, and graft-vs-host disease.
Renal Transplantation
· HCV infection in HCV-seropositive renal recipients is associated with higher all-cause mortality and graft loss.
· Studies have shown promising long-term outcomes of HCV-seropositive recipients transplanted with kidneys from HCV-positive donors, with 5- and 10-year patient survival of 84.8% and 72.7%, respectively, compared to 86.6% and 76.5% for HCV-negative graft recipients.
· The THINKER trial was the first open-label, single-group pilot study to evaluate the safety and efficacy of the transplant of kidneys from HCV GT1–viremic donors into HCV-negative recipients (donor positive, recipient negative [D+/R-]) followed by treatment with elbasvir/grazoprevir (EBR/GZR). All recipients had detectable HCV RNA, and all attained SVR12.
· The EXPANDER trial examined the tolerability and feasibility of DAA prophylaxis before and after renal transplant in HCV-naive patients who received HCV-viremic kidneys. GLE/PIB once daily for 12 weeks has been shown to be well tolerated in patients with chronic HCV GT1 to GT6 infection who have undergone kidney transplantation.
· In the MYTHIC trial, 30 HCV-naive patients achieved SVR12 and no severe adverse events were noted.
· In the DAPPER trial, a single pretransplant dose of SOF/ VEL followed by 1 or 3 posttransplant doses reduced viral transmission to 7.5% but did result in detectable viremia in 17 of 50 (34%) patients by posttransplant day 14.
· Short-course DAA regimens have also been evaluated with promising results.
Thoracic Transplantation
· Donor HCV seropositivity is an independent risk factor for increased mortality and accelerated allograft vasculopathy in heart transplant recipients.
· Preemptive administration of GLE/PIB has demonstrated rapid HCV suppression, prevention of chronic HCV infection, and improved allograft function.1
· The largest-to-date prospective single-center study of 80 patients who underwent heart transplant with HCV-positive donors found that 67 of 70 (96%) developed viremia following transplant and started treatment with LDV/ SOF, SOF/VEL, or GLE/PIB for 12 weeks.
· The most common adverse events were respiratory complications and infections, with 45% requiring admission to the hospital.
· The DONATE-HCV trial evaluated transplanting HCV-viremic organs into 8 cardiac and 36 lung HCV-naive recipients, with 95% of recipients achieving SVR12 with excellent graft function.
Pancreas Transplantation
· HCV-viremic pancreas transplant may be safely used for potential pancreas recipients, but further study is needed to determine morbidity and mortality.
· Short-term outcomes for solid organ transplantation appear to be comparable for HCV-Viremic and nonviremic donors, with promising results past 1 year.
Conclusion
Organ transplantation in the US is impacted by long waitlist times and high mortality due to organ shortages, but transplantation of HCV-viremic organs into HCV-naive recipients provides excellent patient and allograft survival and has the potential to close waitlist gaps and decrease morbidity and mortality.
Hepatitis C virus (HCV) infection affects approximately 130 million to 150 million people worldwide.
Historically, organs from deceased donors infected with HCV were discarded because of high transmission risk during reperfusion and risk of significant posttransplant morbidity and mortality. Several strategies to expand the donor pool have been implemented, including donation after cardiac death, use of living donors, and increased utilization of high-risk donors to mitigate the global shortage.
Renal Transplantation
The prevalence of HCV among end-stage renal disease patients is 0.2% to 6%, and HCV infection traditionally has been a common complication after renal transplant.61 Outcomes for untreated HCV infection in HCV-seropositive renal recipients are significantly worse than in their HCV-negative counterparts.
In a study of 545 kidney transplants performed in HCV-positive recipients, 5- and 10-year patient survival was 84.8% and 72.7%, respectively, for HCV-positive graft recipients compared with 86.6% and 76.5%, respectively (P=.25), for HCV-negative graft recipients.
Furthermore, the availability of DAA therapy and its administration around the time of transplant minimizes the risk of chronic HCV infection in the transplant recipient and thus has led to the recent growth of transplant of kidneys from HCV-infected donors into HCV-naive recipients.
In 2017, the THINKER trial was the first open-label, single-group pilot study that sought to determine the safety and efficacy of the transplant of kidneys from HCV GT1–viremic donors into HCV-negative recipients (donor positive, recipient negative [D+/R-]) followed by treatment with elbasvir/grazoprevir (EBR/GZR; Zepatier, Merck) for 12 weeks (n=10).
All recipients had detectable HCV RNA, and all attained SVR12. In the THINKER-2 trial (n=20), which included THINKER participants, HCV-negative recipients of HCV-viremic kidneys experienced HCV cure and excellent renal allograft function with estimated glomerular filtration rates (eGFRs) not significantly different from those of matched recipients of HCV-negative kidneys at 6 months and 12 months.
SOF-based regimens are safe and effective in HCV-naive recipients undergoing HCV-viremic kidney transplant. In a study of 7 HCV-naive kidney recipients receiving HCV GT1– and HCV GT3–viremic kidneys, antiviral treatment with LDV/SOF (n=4) and SOF/VEL (n=3) for 8 to 12 weeks resulted in SVR12 and stable renal allograft function.
In a subsequent, larger, single-center, observational study, use of SOF/VEL or LDV/SOF resulted in SVR12 rates of 100% and stable allograft function in 53 HCV-naive recipients who received SOF/VEL or LDV/SOF for 8 to 12 weeks following HCV-viremic kidney transplant. 71 Four recipients developed acute rejection.
Shorter-course DAA regimens have also been evaluated with promising results. In a study of 10 HCV D+/R- kidney transplants, 4-week GLE/PIB prophylaxis resulted in undetectable HCV RNA after day 7 and stable allograft function with eGFR of 54.5 mL/min/1.73 m 2(range, 30-79 mL/min/1.73 m2)
Conclusion
Organ transplantation in the United States is negatively impacted by long waitlist times and high waitlist mortality owing to organ shortages. Transplantation of HCV-viremic organs into HCV-naive recipients followed by the use of DAA agents provides excellent patient and allograft survival. In carefully selected patients, the use of HCV-viremic grafts appears to be efficacious and well tolerated. This practice has demonstrated acceptable short-term outcomes and has the potential to significantly close waitlist gaps and decrease morbidity and mortality. However, securing DAA therapy posttransplant is essential and patients should be fully informed of the associated risks, including the potential of HCV treatment failure. It remains unclear whether HCV infection in posttransplant patients may lead to lasting changes to the immune system or inadvertent interactions with immunosuppressive therapy. Understanding long-term outcomes of HCVviremic organ utilization remains on the near horizon.
HCV organ transplant is now increasing specially after the dicovery of DAA therapy which increase the chance of cure and less resistence .
No HCV positive donor reached 9.7% with succesful stories .,and this increase the risk of transplant and reduce the waiting list mortality .
DAA therapy has been shown to improve liver function in patients with decompensated cirrhosis. The DAA showed great respose with SVRof 12 weeks more than 97% in the different type .
DAA making the transplant possible so we can proceed with HCV + donor to negative reciepent but is essential that patients should be fully informed about risks, including possible failure of treatment.
What type of HCV positive we need to accept as the donor ???
In case of AntiHCV Ab positive this is meana clearance of the infection or treated and dose not mean infectivity .But the patient with high HCV PCR is infective and need to be on DAA before transplantation .
Hepatitis C Virus Treatment and Solid Organ Transplantation
· HCV-positive organs are increasing and represented 9.7% of deceased-donor livers in 2019.
· After the discovery of direct-acting antiviral (DAA) therapy, the acceptance of HCV‐positive livers is increasing.
· The use of HCV-positive organs, lead to increase number of organ transplants and decrease waitlist mortality.
Hepatitis C Virus Infection and DirectActing Antiviral Therapy
· DAA therapies have a cure rate defined as sustained virologic response 12 weeks after treatment (SVR12) of greater than 98%.
· The combination of ledipasvir and SOF (LDV/SOF, 90 mg/400 mg; Harvoni, Gilead), given once daily, is well tolerated and produces high SVR12 rates in HCV genotype 1, 4, 5, and 6 infection.
· The combination of SOF and velpatasvir (SOF/VEL; Epclusa, Gilead), given once daily, provides SVR12 rates of > 95% across all GTs and has a favorable safety profile.
· The combination of glecaprevir and pibrentasvir (GLE/PIB; Mavyret, AbbVie) was first approved in 2017 for the treatment of HCV infection without cirrhosis or with mild cirrhosis.GLE/PIB is well tolerated and results in SVR12 rates greater than 97% across all GTs
· DAA therapy has been shown to improve liver function in patients with decompensated cirrhosis.
· pretransplant DAA therapy reduces the risk of reinfection of the allograft.
· Patients with advanced liver disease are unlikely to improve with DAA therapy and those with Child-Pugh class C cirrhosis have lower SVR12 rates.
Direct-Acting Antiviral Therapy and Liver Transplantation
· Use of DAA therapy following liver transplant has excellent outcomes, as it reduces rates of liver fibrosis progression and mortality
· Treatment of HCV infection in patients who undergo simultaneous liver-kidney transplant is both safe and efficacious.
Defining Hepatitis C Virus–Positive Donors
· Serologic tests and enzyme immunoassays detect antibodies within 2 – 6 months after exposure
· Nucleic acid testing (NAT) detects RNA 5 to 7 days after exposure and provides a more accurate assessment of transmission risk.
· HCV NAT has a sensitivity of 85% to 100% and a specificity of 99% to 100%.
· Donors identified as HCV positive by serologic testing but NAT negative have:
spontaneous clearance or successful treatment of infection, or have a false-positive antibody result, and they do not transmit HCV infection.
· An HCV-seropositive donor that is NAT positive, have an active infection and a high risk for disease transmission.
· An HCV-negative donor that is NAT positive, have an acute infection and poses a high risk for disease transmission.
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients
· perioperative intake of DAA therapy has increased the use of HCV viremic donor organs Liver Transplantation
· Two large retrospective studies found that there are no differences in patient or graft survival in HCV-viremic donors in nonviremic liver transplant recipients compared with nonviremic donors.
· HCV treatment within 3 months of transplantation increases the probability of successful graft function and reduces waitlist mortality Renal Transplantation
· Outcomes for untreated HCV infection in HCV-seropositive renal recipients are significantly worse than in their HCV-negative counterparts.
· Many studies found that DAA therapy are safe and very effective in the treatment of recipients of kidney transplant with HCV. Thoracic Transplantation
· among patients who received HCV-viremic heart transplant, there was no difference regarding the hospital stay, rejection, survival at 30 days, or 1-year patient survival compared with patients who received transplants from HCV-negative donors during the same period.
Pancreas Transplantation
· HCV-viremic pancreas transplant may be safely used for potential pancreas recipients, but further studies about morbidity and mortality of pancreas transplantation with HCV-positive donors is needed.
Conclusion
· Transplantation of HCV-viremic organs into HCV-naive recipients followed by the use of DAA agents provides excellent patient and allograft survival
· securing DAA therapy posttransplant is essential and patients should be fully informed about risks, including possible failure of treatment.
Hepatitis C Virus Treatment and Solid Organ Transplantation Article Summary Introduction Hepatitis C virus (HCV) infection is a common indication for liver transplantation. If the patient’s HCV is untreated prior to liver transplant, infection of the allograft is nearly universal and can lead to graft failure. The development of direct-acting antiviral agents has revolutionized the management of liver transplant candidates and transplant recipients. The newer antiviral therapies have paved the road for use of HCV-viremic organs, effectively expanding the donor pool and changing the landscape of solid organ transplantation.
Hepatitis C Virus Infection and DirectActing Antiviral Therapy Sofosbuvir has been approved for HCV treatment in combination with a nonstructural protein 5A (NS5A) inhibitor, nonstructural protein 3/4A (NS3/4A) protease inhibitor, and ribavirin. Pretransplant DAA therapy reduces the risk of reinfection of the allograft. Successful therapy-Model for End-Stage Liver Disease score <16, low baseline Child-Pugh score, and the absence of portal hypertension complications.
Direct-Acting Antiviral Therapy and Liver Transplantation Persistence of HCV infection after liver transplant results in a variable clinical course ranging from mild fibrosis to severe graft damage. DAA therapy following liver transplant has demonstrated excellent outcomes. HCV infection has a negative long-term impact on both patient and graft survival, promising data on the safety and efficacy of DAA therapy for the treatment of HCV infection posttransplant led to a paradigm shift
Defining Hepatitis C Virus–Positive Donors Donors identified as HCV positive by serologic testing but NAT negative (nonviremic) are considered to have undergone spontaneous clearance or successful treatment of infection, or have a false-positive antibody result, and these donors have not been documented to transmit HCV infection HCV-seropositive donor that is NAT positive (viremic) is considered to have an active infection and poses a high risk for disease transmission. An HCV-negative donor that is NAT positive (viremic) is considered to have an acute infection and poses a high risk for disease transmission
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients Immediate treatment with GLE/PIB for HCV-viremic liver transplant into uninfected recipients is both safe and efficacious. A preemptive antiviral strategy using SOF/VEL is also successful in achieving SVR12.
Renal Transplantation Outcomes for untreated HCV infection in HCV-seropositive renal recipients are significantly worse than in their HCV-negative counterparts. In a study of 545 kidney transplants performed in HCV-positive recipients, 5- and 10-year patient survival was 84.8% and 72.7%, respectively, for HCV-positive graft recipients compared with 86.6% and 76.5%, respectively. In THINKER trial the safety and efficacy of the transplant of kidneys from HCV GT1–viremic donors into HCV-negative recipients (donor positive, recipient negative [D+/R-]) followed by treatment with elbasvir/grazoprevir (EBR/GZR for 12 weeks. Excellent graft function was shown.
Pancreatic transplantation HCV-viremic pancreas transplant may be safely used for potential pancreas recipients; however, further study regarding morbidity and mortality of pancreas transplantation with HCV-positive donors is needed.
Conclusions Transplantation of HCV-viremic organs into HCV-naive recipients followed by the use of DAA agents provides excellent patient and allograft survival In carefully selected patients, the use of HCV-viremic grafts appears to be efficacious and well tolerated. T DAA therapy posttransplant is essential and patients should be fully informed of the associated risks
Hepatitis C Virus Treatment and Solid Organ Transplantation
The development of safe and highly effective HCV therapy with direct-acting antiviral agents has revolutionized the management of liver transplant candidates and transplant recipients This article reviews the data on HCV treatment prior to and after organ transplantation.
The high success rate of DAA therapy, have led to greater utilization of HCV‐positive livers from 7% to 17% between 2010 and 2015. Major strides in HCV eradication paved the way for use of HCV-positive organs, first in HCV-viremic recipients and now in HCV-negative recipients.
Hepatitis C Virus Infection and Direct Acting Antiviral Therapy
The combination of potent NS5A inhibitor ledipasvir (LDV) and sofosbuvir (SOF) is well tolerated and produces high SVR12 rates in HCV genotype (GT) 1, 4, 5, and 6 infection.
The combination of SOF and NS5A inhibitor velpatasvir provides SVR12 rates of greater than 95% across all GTs and has a favorable safety pro file.
The combination of NS3/4A protease inhibitor glecaprevir and NS5A inhibitor pibrentasvir is well tolerated and results in SVR12 rates greater than 97% across all GT.
Pretransplant DAA therapy reduces the risk of reinfection of the allograft.
Will benefit from treatment prior to liver transplantation.
Clinical features associated with meaningful improve ment in liver function from pretransplant therapy include low baseline Model for End-Stage Liver Disease score (<16), low baseline Child-Pugh score, and the absence of portal hypertension complications.
Direct-Acting Antiviral Therapy and Liver Transplantation
Recipients who achieve SVR12 posttransplant have lower rates of liver fibrosis progression and lower mortality rates compared with patients who do not receive or fail treatment.
Treatment of HCV infection in patients who undergo simultaneous liver-kidney transplant is both safe and efficacious.
The HCV-TARGET trial used the Hepatitis C Therapeutic Registry and Research Network database to evaluate liver transplant and dual liver-kidney transplant recipients with HCV infection treated with LDV/SOF, ombitasvir/paritaprevir/ritonavir plus dasabuvir or SOF plus daclatasvir. SVR12 rates among liver transplant and dual liver-kidney transplant recipi ents were 96.6% and 90.9%, respectively. Successful outcomes from the real-world data of the large HCV-TARGET cohort provided confidence in treating liver transplant patients with a ribavirin-free regimen.
The MAGELLAN-2 study was a phase 3 open-label trial that confirmed the safety and efficacy of GLE/PIB once daily for 12 weeks in patients with treatment-naive HCV GT1 to GT6 infection or treatment-experienced HCV GT1, GT2, or GT4 to GT6 who had received a liver or kidney transplant.
SOLAR-1 and SOLAR-2 were 2 large trials that evaluated LDV/SOF plus ribavirin in liver transplant recipients with HCV GT1 to GT4 infection and liver disease.
In SOLAR-1, SVR12 was achieved in 96% promising data on the safety and effi cacy of DAA therapy for the treatment of HCV infection posttransplant led to a paradigm shift.
Defining Hepatitis C Virus–Positive Donors
Serologic tests such as chemiluminescence assays and enzyme immunoassays detect antibodies within 2 to 6 months after exposure,
Nucleic acid testing (NAT) detects RNA 5 to 7 days after exposure and provides a more accurate assessment of transmission risk. HCV NAT has a sensitivity of 85% to 100% and a specificity of 99% to 100%.
HCV positive by serologic testing but NAT negative (nonviremic) are considered to have undergone spontaneous clearance or successful treatment of infection, or have a false-positive antibody result, and these donors have not been documented to transmit HCV infection.
An HCV-seropositive donor that is NAT positive (viremic) is considered to have an active infection and poses a high risk for disease transmission.
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients
In a study published in 1998, 22 patients with HCV received HCV-seropositive grafts and had excellent 4-year patient and graft survival compare with HCV-seronegative donor grafts.
In a larger study that included 2923 transplant recipients with HCV, 96 and 2827 received HCV-positive and -negative organs, respectively, and had comparable 2-year survival rates (90% vs 77%)
Liver Transplantation
Two large retrospective studies evaluated HCV-viremic donors in nonviremic liver transplant recipients and demonstrated no differences in patient or graft survival when compared with nonviremic donors.
Renal Transplantation
The availability of DAA therapy and its administration around the time of transplant minimizes the risk of chronic HCV infection in the transplant recipient and thus has led to the recent growth of transplant of kidneys from HCV-infected donors into HCV-naive recipients.
THINKER trial (2017) was the first open-label, single-group pilot study that sought to determine the safety and efficacy of the transplant of kid neys from HCV GT1–viremic donors into HCV-negative recipients followed by treatment with elbasvir/grazoprevir for 12 weeks (n=10). All recipients had detectable HCV RNA, and all attained SVR12
THINKER-2 trial (n=20), HCV-negative recipients of HCV-viremic kidneys experienced HCV cure and excellent renal allograft function with estimated glomerular filtration rates (eGFRs) not significantly different from those of matched recipients of HCV-negative kidneys at 6 months and 12 months
The EXPANDER trial was an open-label single center study (n=10) that examined the tolerability and feasibility of DAA prophylaxis before and after renal transplant in HCV-naive patients (n=10) who received HCV-viremic kidneys (GT1-GT3).In this study, all recipients received a dose of EBR/GZR immediately before transplant, and recipients of kidneys from donors with GT1 infection continued receiving EBR/GZR for 12 weeks after transplant; those receiving organs from donors with GT2 or GT3 infection received SOF along with EBR/GZR for 12 weeks of triple therapy. Preemptive use of EBR/GZR for 12 weeks in HCV-naive recipients who received HCV-infected kidneys (n=8) led to SVR12 with no study-related adverse events
SOF-based regimens are safe and effective in HCV-naive recipients undergoing HCV-viremic kidney transplant.
MYTHIC trial, 30 HCV-naive patients received HCV-viremic kidneys across 7 transplant centers. All 30 recipients achieved SVR12, and no severe adverse events related to HCV infection or GLE/PIB were noted in any patient. Although all recipients had good allograft function
In a large, prospective, real-world study, 64 HCV-naive patients underwent HCV-viremic kidney transplant followed by posttransplant NAT to determine the need for treatment. 61 patients developed viremia, of which 41 patients achieved SVR12, 10 reached undetectable viral loads, and 7 remained on treatment. There was 1 nonre sponder owing to NS5A resistance. At a median 8-month follow-up, patient and graft survival were both 98%
The DAPPER trial treated patients with a single pretransplant dose of SOF/ VEL followed by 1 or 3 posttransplant doses. The 4-day strategy reduced viral transmission to 7.5% but did result in detectable viremia in 17 of 50 (34%) patients by posttransplant day 14, of which only 6 of 50 (12%) required treatment; the remaining 11 recipients had self-limited, low-level vire mia. Of the 6 patients who required treatment, 5 patients achieved SVR12, with 1 patient requiring the addition of ribavirin owing to resistance and 2 patients requiring retreatment with second-line DAA agents owing to relapse.
Friebus-Kardash et al (2019):Cohort Size: 7, Antiviral Therapy: LDV/SOF, Therapy Duration: 8-12 weeks SVR12: 7/7 (100%)
Molnar et al (2019):Cohort Size: 53, Antiviral Therapy: GLE/PIB, SOF/VEL, or LDV/SOF, Therapy Duration: 12 weeks SVR12: 53/53 (100%)
Sise et al (2020):Cohort Size: 8, Antiviral Therapy: EBR/GZR, Therapy Duration: 12 weeks SVR12: 8/8 (100%)
Thoracic Transplantation:
Among heart transplant recipients, the reported prevalence of HCV infection is as high as 12%.
Donor HCV seropositivity was reported to be an independent risk factor for increased mortality when matched with controls (2.8-fold) and for the development of accelerated allograft vasculopathy.
In the largest RCT study of 80 patients who underwent heart transplant with HCV-positive donors, 67 of 70 (96%) recipients developed viremia following transplant and started treatment with LDV/ SOF, SOF/VEL, or GLE/PIB for 12 weeks. Of those who started DAA treatment (n=55), 37 achieved SVR12 with 17 recipients pending, and 1 recipient died prior to achieving SVR12.
Although there were higher rates of severe primary graft dysfunction, there was no difference regarding the hospital length of stay, rejection requiring treatment, survival at 30 days, or 1-year patient survival.
Short course(8weeks)DAA in heart transplant associated with high SVR12 with out survival difference.
In lung transplant & HCV D+/R- treated with SOF/VEL for 12 weeks show HCV free survival at 6 months 86%, but risk of infection & rate of hospital admission was higher than D-/R- HCV transplant.
Pancreas Transplantation:
The data on utilizing HCV-viremic organs in pancreas transplantation are limited.
In 2021, the first reported series included 8 HCV-naive patients who received either deceased donor simultaneous pancreas-kidney transplant or pancreas transplant after living donor kidney transplant.
All patients developed viremia and were treated with either GLE/PIB or SOF/VEL and all achieved SVR12.
All recipients had excellent pancreas graft function and rates of rejection with no difference in hospital stay.
Conclusion:
Transplantation of HCV-viremic organs into HCV-naive recipients followed using DAA agents provides excellent patient and allograft survival.
II. Hepatitis C Virus Treatment and Solid Organ Transplantation
Summarise the article
Introduction
– the demand for organs continues to surpass the supply resulting in significant waitlist mortality
– previously, HCV-positive organs were discarded due to the high risk of transmission during reperfusion and the risk of significant post-transplant morbidity and mortality
– high risk organs are those associated with an increased risk for transmission of blood-borne viruses e.g., HIV, HBV, HCV
– emergence of direct-acting antiviral (DAA) therapy has led to greater utilization of HCV-positive organs thereby increasing the number of organ transplants as well as decreasing the waitlist mortality
Hepatitis C virus infection and direct-acting antiviral therapy
– DAAs are used in the treatment of chronic HCV infection
– DAAs are associated with cure rates defined as sustained virologic response 12weeks after treatment (SVR12) of >98%
– with the availability of safe and highly effective DAAs, HCV infection treatment can be offered prior to the transplant or deferred until after transplant
Direct-acting antiviral therapy and liver transplantation
– persistent HCV infection following liver transplantation results in a variable course ranging from mild fibrosis to severe graft damage/ cirrhosis
– HCV-related progression of liver disease post-transplant is not common due to the increasing use of DAAs
– DAAs are associated with excellent outcomes post-liver transplant as evidenced by lower rates of liver fibrosis progression and lower mortality rates
– HCV infection treatment in patients undergoing simultaneous liver-kidney transplant has been found to be safe and efficacious
– DAA therapy post-transplant is considered safe and efficacious among transplant recipients with compensated liver cirrhosis
– with DAAs, HCV-positive organs can now be used in both HCV-positive and HCV-negative recipients
Defining Hepatitis C virus-positive donors
– HCV-positive donors include any stage of HCV infection
– serologic tests e.g., chemiluminescence assays and enzyme immunoassays detect antibodies within 2-6months
– nucleic acid tests (NAT) detect RNA 5-7days after exposure and provide a more precise assessment of the risk of transmission
– HCV NAT sensitivity is 85-100% and specificity is 99-100%
– despite the advances in HCV infection testing, risk of HCV transmission still remains during the 1-week period between viral exposure and positive NAT results especially among intravenous drug users
– the risk of HCV disease transmission differs between a seropositive donor and a viremic donor i.e.,
HCV Ab positive, HCV NAT positive: indicates active HCV infection hence the transmission risk is high
HCV Ab negative, positive HCV NAT: suggests acute HCV infection in the Ab window period or a false positive NAT, the risk of HCV transmission is still high
HCV Ab positive, negative HCV NAT: indicates no active HCV infection, cleared or treated HCV infection or a false positive Ab, has a low transmission risk
HCV ab negative, HCV NAT: suggests absence of HCV infection hence there is no risk of HCV transmission
Hepatitis C virus-positive donor transplantation in Hepatitis C virus-negative recipients
– prior to the advent of DAAs, donation of HCV-positive organs to HCV-negative individuals was discouraged due to the low efficacy, high rates of HCV transmission, decreased graft and patient survival and the complications associated with IFN-based therapy in the post-transplant setting
– DAAs have now increased the utilization of HCV-positive organs with demonstration of favourable long-term graft outcomes
Liver transplantation
– multiple studies have demonstrated no differences in patient and graft survival among HCV-negative liver transplant recipients who had HCV-positive donors compared to those who had a HCV-negative donor
– HCV treatment within 3 months of transplantation reduces waitlist mortality and increases the chances of successful graft function
– despite achieving SVR with DAAs, HCV-related complications do still occur suggesting the need for careful and long-term follow-up e.g., development of HCV-related membranous nephropathy
Kidney transplantation
– HCV is a common complication post-kidney transplant
– HCV seropositivity is associated with higher all-cause graft loss and mortality
– the long-term outcomes of HCV-seropositive recipients who received kidneys from HCV-positive donors are promising
– administration of DAA therapy in the peri-transplant period minimizes the risk of chronic HCV infection in the transplant recipient
– this has led to an increase in the number of transplants between HCV-positive donors and HCV-negative recipients
– the THINKER Trial revealed that it is safe and efficacious to transplant kidneys from HCV-positive donors to HCV-negative recipients followed by treatment with DAAs (Elbasvir/ Grazoprevir) which led to achievement of SVR12
– THINKER-2 trial included the THINKER participants and HCV-negative recipients of HCV-positive kidneys; HCV cure and excellent graft function was noted and it was comparable to those of matched HCV-negative kidneys
– several trials revealed that among HCV-negative recipients, pre-emptive DAA therapy was tolerable and feasible, and it led to SVR12 with no adverse events, the patients had stable graft function
– shorter-course DAA regimens have also been evaluated and the results are promising
Thoracic transplantation
– among heart transplant recipients, donor HCV seropositivity is an independent risk factor for increased mortality, development of severe and rapidly progressive liver disease, and development of accelerated graft vasculopathy
– preemptive DAA therapy in HCV-naïve recipients receiving HCV-viremic cardiac transplants is associated with rapid HCV suppression, prevention of chronic HCV infection and excellent graft function
– among HCV-naïve lung transplant receiving HCV-viremic organs, DAA therapy was associated with SVR12 and excellent graft function, the most common adverse events were respiratory complications and infections
Pancreas transplantation
– there is limited data regarding utilization of HCV-viremic organs
– from reported case series, use of DAA therapy among HCV-naïve pancreas transplant recipients receiving HCV-viremic organs
resulted in SVR12 and excellent pancreas graft function
– more studies evaluating the morbidity and mortality of pancreas transplantation with HCV-positive donors are needed
Conclusion
– transplantation of HCV-viremic organs into HCV-naïve recipients followed by DAA therapy results in excellent patient and graft survival
– use of HCV-viremic grafts is safe, efficacious and well-tolerated
– this helps reduce the long waitlist times and also reduces morbidity and mortality
– DAA therapy post-transplant is essential, however, potential recipients of HCV-viremic organs should be informed about the risks involved including the likelihood of HCV treatment failure
– the long-term outcomes of HCV-viremic organ utilization are yet to be understood
Introduction: Hepatitis C virus (HCV) infection is associated with liver disease leading to liver transplantation. HCV-positive organs comprise 9.7% of total deceased donor livers. Strategies to expand donor pool include using such organs for transplantation, which has become possible due to availability of direct-acting antiviral (DAA) therapy. HCV-viremic donors are usually young, healthier with low co-morbidities, leading to lower complications post-transplant.
HCV and DAA therapy: Introduction of many pan-genotypic DAA therapies with sustained virologic response at 12 weeks (SVR12) of >98% has changed the landscape of HCV infection. Pre-transplant DAA therapy use reduces the risk of re-infection post-transplant. Combination of ledipasvir and sofosbuvir (LED/SOF) has been associated with high SVR12 rates in HCV genotype 1,4,5, and 6 HCV infection. SOF and velpatasvir (SOF/VEL) has >95% SVR12 rates for all genotypes. Gelcaprevir and Pibrentasvir (GLE/PIB) combination has >97% SVR12 for all genotype infection in patients without cirrhosis or mild cirrhosis. DAA use pre-transplant leads to improvement in liver function in presence of model for end-stage liver disease (MELD) score <16, low Child-Pugh score, and absence of portal hypertension. Treatment should be deferred in presence of Child-Pugh class C cirrhosis, and in case of HCV viremic-donors, the decision to treat pre-transplant should be individualized.
DAA therapy and liver transplantation: Pre-transplant DAA use leading to SVR12 has reduced the incidence of significant HCV-related liver disease progression (20.5% versus 65.5%) and mortality post-transplant. HCV infection treatment in simultaneous liver-kidney transplant recipients is safe and efficacious, with SVR12 rates of 90.9% in the HCV-TARGET trial. MAGELLAN-2 trial showed SVR12 of 98% with GLE/PIB use in transplant recipients without cirrhosis. SOLAR-1 trial showed that SOF/VEL use in transplant recipients had SVR12 of 96% in patients without cirrhosis, and 98% in patients with compensated cirrhosis. SOLAR-2 trial showed high SVR12 rates in transplant recipients across spectrum of cirrhosis using LDV/SOF with ribavirin.
Defining HCV-positive donors: Serologic assays detect antibodies within 2-6 months post-exposure, while nucleic acid testing (NAT), having sensitivity of 85-100% and specificity of 99-100%, can detect RNA within 5-7 days of exposure. NAT negative but positive serologic testing in donor indicate either spontaneous clearance or treatment of the patient, or a false-positive serological test, indicating a low risk of transmission. Active infection is characterized by positive NAT and positive antibody test, indicating high risk of transmission.
HCV-positive donor transplantation in HCV-negative recipient: Peri-operative DAA use has increased utilization of HCV-viremic donor organs. Comparable survival rates have been observed in HCV-positive recipients receiving either HCV-negative or HCV-positive organs.
Liver transplantation of HCV-viremic organs in nonviremic recipients had no difference in patient or graft survival as compared to non-viremic donors, according to the organ procurement and transplantation network (OPTN) data. DAA initiation pre-emptively, immediately following transplantation, or even 90 days post-liver-transplant has been shown to be associated with favorable outcomes. Close monitoring of post-transplant adverse immunological events is necessary.
Renal transplantation utilizing HCV-positive donor kidney in HCV-positive recipients has shown comparable results with respect to 5- and 10-year patient survival with use of DAA therapy further reducing the risk of chronic HCV infection in the recipients. THINKER trial used elbasvir/grazoprevir (EBR/GZR) post-transplant of HCV-viremic kidneys with SVR12 attainment in 100%. THINKER-2 trial showed excellent graft function in the THINKER-1 trail patients at 6 and 12 months. EXPANDER trial used EBR/GZR, started immediately prior to the transplant of HCV-viremic kidneys with addition of SOF in genotype 2 and 3, leading to SVR12 in 100% patients. MYTHIC trial showed GLE/PIB use achieved 100% SVR12.
DAA therapy has been used in thoracic transplantation, with GLE/PIB use in heart transplant showing rapid HCV suppression, prevention of chronic HCV infection, and excellent early graft function. USHER trial utilized HCV-viremic hearts in HCV-naïve recipients, treated with EBR/GZR, with SVR12 of 90%. 8 week duration GLE/PIB use in heart transplants have also been associated with 100% SVR12. DAA therapy in lung transplantation has also shown encouraging results. DONATE-HCV trial used SOF/VEL for HCV-viremic cardiac and lung transplant in HCV-naïve recipients with 100% SVR12 and excellent graft function.
DAA therapy in HCV-viremic Pancreas transplantation or simultaneous pancreas-kidney transplantation (SPK) has been shown to effective with 100% SVR12.
Conclusion: Excellent patient and graft outcomes have been achieved by using HCV-viremic organs for transplant in carefully selected HCV-naïve recipients and using DAA therapy. The patients should be fully informed about the risks of HCV treatment failure and immunosuppressive drug interactions before proceeding with such transplants.
Hepatitis C Virus Treatment and Solid Organ Transplantation
Introduction:
HCV infection is highly prevalent worldwide infects 130–150 million individuals globally causing end-stage liver damage, and it is leading indications for liver transplantation. Waitlist mortality is high because organ demand exceeds availability, In 2019, 9.7% of deceased-donor livers were HCV-positive.
The availability of HCV-positive organs continues to increase, representing 9.7% of deceased-donor livers in 2019.
Utilizations of organs from hepatitis C infected individuals significantly increased to mitigate the global organ shortage. This change occurs after the availability of effective direct-acting antiviral (DAA) therapy.
Opioid-related deaths more frequently occur in young donors, who are generally healthier and have fewer comorbidities than older donors, and therefore their HCV-viremic donor organs are often of relatively high quality. Hepatitis C Virus Infection and Direct Acting Antiviral Therapy:
The combination of potent NS5A inhibitor ledipasvir (LDV) and SOF (LDV/SOF, 90 mg/400 mg) administered once daily, is well tolerated, and produces high SVR12 rates in HCV genotype (GT) 1, 4, 5, and 6 infections.
The combination of SOF and NS5A inhibitor velpatasvir (SOF/VEL) administered once daily, provides SVR12 rates of greater than 95% across all GTs and has a favorable safety profile.
The combination of NS3/4A protease inhibitor glecaprevir and NS5A inhibitor pibrentasvir (GLE/PIB) was first approved in 2017 for the treatment of HCV infection without cirrhosis or with mild cirrhosis.
GLE/PIB is well tolerated and results in SVR12 rates greater than 97% across all GTs. Defining Hepatitis C Virus–Positive Donors:
Nucleic acid testing (NAT) detects RNA 5 to 7 days after exposure and provides a more accurate assessment of transmission risk.
HCV NAT has a sensitivity of 85% to 100% and a specificity of 99% to 100%.
Risk of HCV transmission remains during the 1-week eclipse period between viral exposure and positive NAT results, particularly in persons who inject drugs. It is important to distinguish between a seropositive and viremic donor when discussing organ transplant from an HCV-positive donor, as the risks of disease transmission vastly differ.
Donor with HCV Ab + & HCV NAT positive, has active hepatitis and high risk of transmission.
Those with only positive HCV NAT, has acute HCV in Ab window or false positive NAT and considered with high risk for transmission.
Donor with only positive HCV Ab, NAT -ve = no active infection and has low risk of transmission.
Donor with negative both tests, is not infected with no risk of transmission. Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients:
The rapidly evolving treatments for HCV have improved outcomes, and perioperative use of DAA therapy has increased the utilization of HCV-viremic donor organs.
Early data have demonstrated favorable long-term graft outcomes in patients transplanted with HCV-seropositive donors. Renal Transplantation:
The prevalence of HCV among ESRD patients is 0.2% to 6%, and HCV infection traditionally has been a common complication after renal transplant.
Outcomes for untreated HCV infection in HCV-seropositive renal recipients are significantly worse than in their HCV-negative counterparts.
HCV seropositivity is associated with higher all-cause mortality and higher all-cause graft loss.
The availability of DAA therapy and its administration around the time of transplant minimizes the risk of chronic HCV infection in the transplant recipient and thus has led to the recent growth of transplant of kidneys from HCV-infected donors into HCV-naive recipients.
Only a few prospective trials have evaluated the use of DAA therapy in renal transplant recipients with HCV infection. Trials of DAA in kidney transplant: THINKER (2017):
Reported that HCV-negative recipients of HCV-viremic kidneys experienced HCV cure and excellent renal allograft function with eGFRs not significantly different from those of matched recipients of HCV-negative kidneys at 6 months and 12 months.
SOF-based regimens are safe and effective in HCV-naive recipients undergoing HCV-viremic kidney transplant.
GLE/PIB once daily for 12 weeks has been shown to be well tolerated in patients with chronic HCV GT1 to GT6 infection who have undergone kidney transplantation. Shorter-course DAA regimens 9 4wks of GLE/PIB) have also been evaluated with promising results. EXPANDER (2018):
Among heart transplant recipients, the reported prevalence of HCV infection is as high as 12%.
Early studies demonstrated reduced survival in recipients with HCV infection, regardless of acquisition of HCV pre– or post– heart transplant.
Donor HCV seropositivity was reported to be an independent risk factor for increased mortality when matched with controls (2.8-fold) and for the development of accelerated allograft vasculopathy.
In the largest RCT study of 80 patients who underwent heart transplant with HCV-positive donors, 67 of 70 (96%) recipients developed viremia following transplant and started treatment with LDV/ SOF, SOF/VEL, or GLE/PIB for 12 weeks. Of those who started DAA treatment (n=55), 37 achieved SVR12 with 17 recipients pending, and 1 recipient died prior to achieving SVR12.
Although there were higher rates of severe primary graft dysfunction, there was no difference regarding the hospital length of stay, rejection requiring treatment, survival at 30 days, or 1-year patient survival. Pancreas Transplantation:
The data on utilizing HCV-viremic organs in pancreas transplantation are limited. In 2021, the first reported series included 8 HCV-naive patients who received either deceased donor simultaneous pancreas-kidney transplant or pancreas transplant after living donor kidney transplant. All patients developed viremia and were treated with either GLE/PIB or SOF/VEL and all achieved SVR12. All recipients had excellent pancreas graft function and rates of rejection with no difference in hospital stay. Liver Transplantation Two large retrospective studies evaluated HCV-viremic donors in non-viremic liver transplant recipients and demonstrated no differences in patient or graft survival when compared with non-viremic donors.
GLE/PIB has been used successfully in HCV-naive patients who receive HCV-viremic livers.
The administration of SOF/VEL or GLE/PIB once daily for 12 weeks in HCV-naive patients who received viremic livers (n=51) produced similar 1-year patient and graft survival when compared with HCV-naive patients who received nonviremic livers. DAA Therapy & Liver Transplantation:
Significant HCV-related progression of liver disease post-TX is no longer common due to the increased use of DAA therapy.
Compared to those who do not get treatment or who do not respond to it, recipients who reach SVR12 post-TX have lower rates of liver fibrosis progression & mortality. HCV infection treatment in patients undergoing simultaneous liver-kidney transplant is both safe & effective.
The HCV-TARGET trial:
Compared LDV/SOF, ombitasvir/paritaprevir/ritonavir plus dasabuvir, & SOF plus daclatasvir in liver TX & dual liver-kidney TX recipients with HCV infection.
SVR12 rates were 96.6% & 90.9% for recipients of liver transplants & dual liver-kidney transplants, respectively. The huge HCV-TARGET cohort’s real-world data showed promising results, giving doctors confidence to treat liver transplant patients with a ribavirin-free regimen.
HCV-TARGET cohort provided confidence in treating liver TX patients with a ribavirin-free regimen.
The MAGELLAN-2 study (phase 3 open-label trial):
Confirmed the safety & efficacy of GLE/PIB for 12 weeks in patients with treatment-naive HCV GT1 to GT6 infection or treatment-experienced HCV GT1, GT2, or GT4 to GT6 who had received a liver or KTx.
Other studies:
Treatment with SOF/VEL for 12 weeks in 14 liver TX recipients with HCV GT1 to GT4 infection & cirrhosis resulted in an SVR12 rate of 93%. SOLAR-1 (a large trial):
Assessed LDV/SOF plus ribavirin in liver TX recipients with HCV GT1- GT4 infection & liver disease.
SVR12 achieved in 96% – 98% of TX recipients without cirrhosis or with compensated cirrhosis. SOLAR-2 (a multicenter open-label study):
SVR12 rates of 100%, 96%, 95%, & 100% in CTP-A patients with 12 weeks of treatment, CTP-A patients with 24 weeks of treatment, CTP-B patients with 12 weeks of treatment, & CTP-B patients with 24 weeks of treatment, respectively, were seen in HCV GT1 liver transplant recipients who had no cirrhosis, CTP-A, CTP-B, or CTP-C cirrhosis. Conclusion:
Transplantation of HCV-viremic organs into HCV-naive recipients followed using DAA agents provides excellent patient and allograft survival.
In carefully selected patients, the use of HCV-viremic grafts appears to be efficacious and well tolerated.
This practice has demonstrated acceptable short-term outcomes and has the potential to significantly close waitlist gaps and decrease morbidity and mortality.
However, securing DAA therapy post-transplant is essential and patients should be fully informed of the associated risks, including the potential of HCV treatment failure.
Shortage of donor supply has dictated the use of high-risk donors such as those who are HCV positive.
The decision of treating HCV infection prior to TX or delaying it until after TX has arisen because of the availability of safe & highly effective therapy.
DAAs improves liver function in decompensated cirrhosis to the extent that some may no longer require liver TX.
Moreover, pretransplant DAA medication lowers the likelihood of the allograft being reinfected.
Not all HCV-infected individuals with ESLD will, however, benefit from treatment before a liver TX; advanced liver disease is unlikely to improve by DAA therapy, & SVR rates are lower in Child-Pugh class C cirrhosis.
Marked improvement in liver function from pre-TX therapy is expected in the following: 1. Low baseline Model for ESLD score (<16) 2. Low baseline Child-Pugh score 3. Absence of portal hypertension complications.
Understanding long-term outcomes of HCV-viremic organ utilization needs further studies.
Hepatitis C Virus Treatment and Solid Organ Transplantation.
HCV infection is one of the leading cause of liver decompensation, and leading indications for liver transplantation, before direct-acting antiviral (DAA) therapy, transplantation from HCV donor was challengeable due to high risk of infection but with high success rate of DAA, donor pool has been expanded, and the main upside is the possibility to use DAA before and after transplantation. Hepatitis C Virus Infection and Direct-Acting Antiviral Therapy.
The combination of SOF and NS5A inhibitor velpatasvir ,administered once daily, provides SVR12 rates of greater than 95% across all GTs and has a favorable safety profile which could be used before transplantation such as in low baseline Model for End-Stage Liver Disease score (<16), low baseline Child-Pugh score, and the absence of portal hypertension complications, or post transplantation in advanced liver disease. Direct-Acting Antiviral Therapy and Liver Transplantation.
Persistent HCV infection post liver transplant is associated with many morbidity and mortality risk, but using of DAA therapy following liver transplant has demonstrated excellent outcomes such as lower rates of liver fibrosis progression and lower mortality rates compared with patients who do not receive or fail treatment. HCV infection has a negative long-term impact on both patient and graft survival, studies proved the safety and efficacy of DAA therapy for the treatment of HCV infection post-transplant led to a paradigm shift and so HCV eradication paved the way for use of HCV-positive organs. Defining Hepatitis C Virus–Positive Donors.
1-Donors identified as HCV positive by serologic testing but NAT negative (nonviremic) are considered to have undergone spontaneous clearance or successful treatment of infection, or have a false-positive antibody result, and these donors have not been documented to transmit HCV infection.
2-An HCV-seropositive donor that is NAT positive (viremic) is considered to have an active infection and poses a high risk for disease transmission. Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients. Liver transplant:
Immediate treatment with GLE/PIB for HCV-viremic liver transplant into uninfected recipients is both safe and efficacious and some studies shown that administration of SOF/VEL or GLE/PIB once daily for 12 weeks in HCV-naive patients who received viremic livers produced similar 1-year patient and graft survival when compared with HCV-naive patients who received nonviremic livers. Renal Transplantation.
HCV seropositive recipient is associated with higher all-cause mortality relative risk and higher all-cause graft loss, THINKER trial determine the safety and efficacy of the transplant of kidneys from HCV GT1–viremic donors into HCV-negative recipients, followed by treatment with elbasvir/grazoprevir for 12 week and shown HCV cure and excellent renal allograft function, The EXPANDER trial shown that preemptive use of EBR/GZR for 12 weeks in HCV-naive recipients who received HCV-infected kidneys led to SVR12, many protocols for using DAA in prophylactic pre and post-transplant shown great graft and recipient survival outcomes. Pancreas Transplantation
Recipients who developed viremia and were treated with either GLE/PIB or SOF/VEL and all achieved SVR12. All recipients had excellent pancreas graft function and low rates of rejection .These preliminary findings suggest that HCV-viremic pancreas transplant may be safely used for potential pancreas recipients; however, still further study regarding morbidity and mortality of pancreas transplantation with HCV-positive donors is needed. Conclusion.
One of the major solution to expand donor pool for transplantation is using of HCV-viremic organs into HCV-naive recipients followed by the use of DAA agents which shown a great result of SVR12 and provides excellent patient and allograft survival. However, securing DAA therapy post-transplant is essential and patients should be fully informed of the associated risks, including the potential of HCV treatment failure.
The availability of HCV-positive organs continues to increase, representing 9.7% of deceased-donor livers in 2019
direct-acting antivirals (DAAs), which are medications targeted at specific steps within the HCV life cycle results in disruption of viral replication and infection.
There are four classes of DAAs, which are defined by their mechanism of action and therapeutic target. The four classes are
– Non-structural proteins 3/4A (NS3/4A) protease inhibitors (PIs)
– NS5B nucleoside polymerase inhibitors (NPIs)
– NS5B non-nucleoside polymerase inhibitors (NNPIs)
– NS5A inhibitors SVR12: cure rates defined as sustained virologic response 12 weeks after treatment several combinations had more than 95% SVR Therefore, it is considered as a treatment of HCV infection prior to transplant or deferring therapy until after transplant.
DAA therapy has been shown to improve liver function in patients with decompensated cirrhosis and it is use shows excellent outcome in liver transplant populations and simultaneous liver and kidney transplant.
Hepatitis C Virus–Positive Donors:
1) Serologic tests such as an enzyme immunoassays detect antibodies within 2 to 6 months after exposure,
2) HCV nucleic acid test (NAT) detects RNA 5 to 7 days after exposure and provides a more accurate assessment of transmission risk with sensitivity more than 85% and a specificity of 99%.
### Donors identified as HCV positive by serologic testing but NAT negative (nonviremic) are considered to have = undergone spontaneous clearance
= or successful treatment of infection,
= or have a false-positive antibody result,
###HCV-seropositive/negative donor that is NAT positive (viremic) is considered to have
= an active infection and poses a high risk for disease transmission.
Renal Transplantation: The prevalence of HCV among ESRD patients up to 6% and had bad prognosis. DAA therapy and its administration around the time of transplant minimizes the risk of chronic HCV infection. Multiple trials (table 3) shows good sustained virological response in Hepatitis C Virus–Viraemic, Nonhaptic Solid Organ Transplantation in Nonviremic Recipients
This is a review article looking at HCV treatment and solid organ transplantation
Introduction:
HCV affects approximately 130-150 million people worldwide and is one of the leading causes of liver disease and liver failure requiring liver transplant.
However, the demand continues to outmatch the supply resulting in an increase in waiting time for the organs
The availability of HCV positive organs continue to increase especially after the national opioid epidemic. The number of HCV infections more than doubled between 2012 and 2019 and the number of deaths from opioid overdose increased more than 13 fold. The opioid related deaths generally occur in the younger population who are generally healthier with high quality organs even with HCV
With the advent of the DAAs, the landscape of HCV treatment as well as the use of HCV positive donors has changed.
HCV Treatment and DAAs
With the introduction of DAAs, the SVRs have been more than 98% when treated for 12 weeks.
There are several DAAs introduced into the market and several combinations have been tested:
Sofosbuvir with NS3/4A protease inhibitor with ribavirin
Lepidasvir/Sofosbuvir against HCV GT 1, 4, 5 and 6
Sofosbuvir/Velpatasvir – against pangenotyic
Glecaprevir/Pibrentasvir – Used for treatment in patients without cirrhosis or mild cirrhosis and has activity against all GTs
Pretansplant DAA therapy has been shown to reduce infection in the allograft.
In patients with advanced liver disease and Child-Pugh C score, it is preferred to defer treatment until after transplant
DAA and Liver Transplantation:
The risk of HCV infection post-transplant increases the risks of liver damage ranging from mild fibrosis to severe allograft damage.
Progressive centrilobular ballooning, bridging fibrosis and cholestasis are seen in 20-40% of post-transplant patients whose HCV infection is not cured. Advanced fibrosis can occur in up to 45% of post-transplant patients and graft cirrhosis can develop within as little as 5 years post-transplant
Use of DAA therapy following liver transplant has demonstrated excellent outcomes. Recipients who have achieved SVR12 post-transplant have lower rates of liver fibrosis progression.
Several studies have looked at the outcomes of liver transplants and dual kidney/liver transplants with good SVR12 and good graft outcomes:
Use of SOF/VEL in 79 patients with HCV GT 1-4 resulted in SVR12 of 96%. No liver transplant rejection episodes or death occurred during the study period
HCV-TARGET trial – looked at liver transplants and dual kidney/liver transplant recipients with HCV infection using LDV/SOF, ombitasvir/paritaprevir/ritonavir plus dasabuvir or SOF/DAC. SVR12 among liver transplant and dual liver-kidney transplant were 96.6% and 90.9%. 4 episodes of acute rejection occurred in the liver transplant group.
MAGELLAN-2 study – Use of GLE/PIB once daily for 12 weeks in treatment naive HCV GTs 1-6 patients or treatment experienced HCV GTS 1,2,4,5 and 6 resulted in SVR12 of 98%
Treatment with SOF/VEL in patients with HCV GTs 1-4 and cirrhosis resulted in SVR12 rate of 93%
Most of the studies have shown very good SVR12 rates and very few A/Es leading to drug discontinuation and very few rejection rates
Defining Hepatitis C Virus Positive Donors:
HCV Ab become positive 2-6 months after exposure but the HCV RNA can be detected within 5-7 days by the NAT.
HCV NAT has a sensitivity of 85-100% and a specificity of 99-100%
It is important to distinguish a seropositive donor from an HCV viremic donor when discussing organ transplantation from an HCV donor
Donors who are HCV Ab positive but HCV RNA negative are considered to have either cleared the virus spontaneously or has had successful treatment or has a false Ab result
An HCV seropositive donor that is NAT positive is considered to have an active infection and poses a high risk for transmission
An HCV seronegative donor that is NAT positive is considered to have an acute infection and poses a high risk for disease transmission
Hepatitis C Virus -Positive Donor Transplantation In Hepatitis C Virus Negative Recipients:
Before the advent of DAAs the use of HCV positive patients as donors due to the high risk of transmitting the virus to the recipient and subsequent decreased patient and graft survival and complications after using INF therapy. Liver Transplant:
2 large retrospective studies evaluated HCV viremic donors in non-viremic liver transplant recipients and demonstrated no differences in patient or graft survival when compared with non-viremic donors.
Data from OPTN also showed comparable one year patient survival and 2 year graft survival
The first prospective study included 10 HCV negative patients who received HCV viremic livers, 7 of which had been cured prior to transplant. All 10 recipients developed viremia and received DAAs and achieved SVR12. 2 patients developed acute rejection.
GLE/PIB has been successfully used in HCV patients receiving HCV viremic livers.
Careful and longer term follow up is required for these patients due to the potential of developing complications
Kidney Transplant:
The prevalence of HCV among ESKD patients is 0.2 – 6% and HCV infection traditionally has been a common complication after renal transplant. Outcomes for untreated HCV infection in HCV positive renal recipients are significantly worse than in their HCV negative counterparts.
Historically, kidneys from HCV infected donors have been underutilized. However, studies in the past decade have demonstrated promising long-term outcomes of HCV seropositive recipients transplanted with kidneys from HCV positive donors.
Only a few prospective have evaluated the use of DAA therapy in renal transplant recipients with HCV infection.
The THINKER trial was the first open label, single group pilot study that sought to determine the safety and efficacy of the transplant of kidneys from HCV GT1 viremic donors into HCV negative recipients followed by treatment with EBV/GZR. All recipients had detectable HCV RNA and all attained SVR12.
In the THINKER-2 trial, which included THINKER participants, HCV negative recipients of HCV viremic kidneys experienced HCV cure and excellent renal allograft function.
The EXPANDER trial was an open label single center study that examined the tolerability and feasibility of DAA prophylaxis before and after renal transplant in HCV naive patients who received HCV viremic kidneys. In this study, all recipients received a dose of EBR/GZR immediately before transplant and recipients of kidneys from donors with GT1 infection continued receiving EBR/GZR for 12 weeks after transplant; those receiving organs from donors with GT2 and GT3 infection received SOF along with EBR/GZR for 12 weeks of triple therapy. There was no study related adverse events and the patients had SVR12
GLE/PIB once daily for 12 weeks has been well tolerated in patients with HCV GTs1-6
Thoracic Transplantation:
Among heart transplant recipients, the reported prevalence of HCV infection is as high as 12%. Pre-DAA era, there was reduced survival in recipients with HCV infection. Donor HCV seropositivity was reported to be an independent risk factor for increased mortality when matched with controls.
With the advent of DAA, several studies have demonstrated good safety and efficacy with patients achieving SVR12 of between 74-100% for heart, lung and heart-lung donors
Pancreas transplantation:
The data on utilizing HCV viremic organs in pancreas transplantation are limited. In 2021, the first reported series included HCV naive patients who either received deceased donor simultaneous pancreas-kidney transplant or pancreas transplant after living donor kidney transplant. All patients developed viremia and were treated with either GLE/PIB or SOF/VEL and all achieved SVR12. All recipients had excellent pancreas graft function and rates of rejection. LOS was similar between those who received HCV viremic organs versus those who did not. These preliminary findings suggest that HCV viremic pancreas donors may be safely used. However, more studies are needed to assess morbidity and mortality pancreas transplants
Conclusion:
The transplant waiting time is increasing significantly leading to increased morbidity and mortality for the patients on the waiting list. The era of DAA has opened up a new venue of increasing the donor pool by including HCV viremic donors. The use of DAAs either pre- or post-transplant has been shown to achieve SVR12 in kidney and liver and dual liver-kidney recipients with comparable graft survival and patient survival. More data is needed for thoracic and pancreas transplantation. The transplant team needs to ensure the availability of the DAAs for the patients receiving them post-transplant.
There have been significant advancements in the science of HCV therapy and in the use of HCV-positive organs, thereby substantially increasing the number of organ transplants and decreasing waitlist mortality.
This article reviews the data on HCV treatment prior to and after organ transplantation.
Hepatitis C Virus Infection and Direct-Acting Antiviral Therapy
DAA therapies for the treatment of chronic HCV infection has been introduced, with cure rates defined as sustained virologic response 12 weeks after treatment (SVR12) of greater than 98%.
The combination of potent NS5A inhibitor ledipasvir (LDV) and SOF, administered once daily, is well tolerated and produces high SVR12 rates in HCV genotype (GT) 1,4, 5, and 6 infection.
The combination of SOF and NS5A inhibitor velpatasvir (SOF/VEL), administered once daily, provides SVR12 rates of greater than 95% across all GTs and has a favorable safety profile.
The availability of safe and highly effective therapy has led to the delicate consideration of treating HCV infection prior to transplant or deferring therapy until after transplantation.
Pretransplant DAA therapy reduces the risk of reinfection of the allograft.However, not all patients with end-stage liver disease from HCV infection will benefit from treatment prior to liver transplantation.
Patients with advanced liver disease are unlikely to improve with DAA therapy and those with Child-Pugh class C cirrhosis have lower SVR12 rates; therefore, deferring treatment in such situations may be preferred.
Direct-Acting Antiviral Therapy and Liver Transplantation
Progressive centrilobular ballooning degeneration, bridging fibrosis, and cholestasis are seen in 20% to 40% of posttransplant patients whose HCV infection has not been cured.
With the increasing use of DAA therapy, significant HCV-related progression of liver disease posttransplant is now uncommon.
Use of DAA therapy following liver transplant has demonstrated excellent outcomes.
Treatment of HCV infection in patients who undergo simultaneous liver-kidney transplant is both safe and efficacious.
The use of a pangenotypic, ribavirin-free regimen in posttransplant patients without cirrhosis has demonstrated similar overall success.
In transplant recipients who have compensated cirrhosis, DAA therapy following transplant is safe and efficacious.
Although historical data demonstrate that HCV infection has a negative long-term impact on both patient and graft survival, promising data on the safety and efficacy of DAA therapy for the treatment of HCV infection posttransplant led to a paradigm shift.
Defining Hepatitis C Virus–Positive Donors
It is important to distinguish between a seropositive and viremic donor when discussing organ transplant from an HCV-positive donor, as the risks of disease transmission vastly differ.
donor with HCV ab + and HCV NAT positive, has active hepatitis and high risk of transmission
Those with only postive HCV NAT, has acute HCV in Ab window or false positive NAT and considered with high risk for transmission
Donor with only positive Ab, no active infection and has low risk of transmission
Donor with negative both tests, is not infected with no risk of transmission.
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients:
The rapidly evolving treatments for HCV have improved outcomes, and perioperative use of DAA therapy has increased the utilization of HCV-viremic donor organs.
Early data have demonstrated favorable long-term graft outcomes in patients transplanted with HCV-seropositive donors.
Liver Transplantation
Two large retrospective studies evaluated HCV-viremic donors in non-viremic liver transplant recipients and demonstrated no differences in patient or graft survival when compared with non-viremic donors.
GLE/PIB has been used successfully in HCV-naive patients who receive HCV-viremic livers.
The administration of SOF/VEL or GLE/PIB once daily for 12 weeks in HCV-naive patients who received viremic livers (n=51) produced similar 1-year patient and graft survival when compared with HCV-naive patients who received nonviremic livers.
Renal Transplantation
The prevalence of HCV among end-stage renal disease patients is 0.2% to 6%, and HCV infection traditionally has been a common complication after renal transplant.
Outcomes for untreated HCV infection in HCV-seropositive renal recipients are significantly worse than in their HCV-negative counterparts.
HCV seropositivity is associated with higher all-cause mortality and higher all-cause graft loss.
The availability of DAA therapy and its administration around the time of transplant minimizes the risk of chronic HCV infection in the transplant recipient and thus has led to the recent growth of transplant of kidneys from HCV-infected donors into HCV-naive recipients.
Only a few prospective trials have evaluated the use of DAA therapy in renal transplant recipients with HCV infection.
THINKER study reported that HCV-negative recipients of HCV-viremic kidneys experienced HCV cure and excellent renal allograft function with eGFRs not significantly different from those of matched recipients of HCV-negative kidneys at 6 months and 12 months.
SOF-based regimens are safe and effective in HCV-naive recipients undergoing HCV-viremic kidney transplant.
GLE/PIB once daily for 12 weeks has been shown to be well tolerated in patients with chronic HCV GT1 to GT6 infection who have undergone kidney transplantation.
Shorter-course DAA regimens 9 4wks of GLE/PIB) have also been evaluatedwith promising results.
Thoracic Transplantation
Among heart transplant recipients, the reported prevalence of HCV infection is as high as 12%.
Early studies demonstrated reduced survival in recipients with HCV infection, regardless of acquisition of HCV pre– or post– heart transplant.
Donor HCV seropositivity was reported to be an independent risk factor for increased mortality when matched with controls (2.8-fold) and for the development of accelerated allograft vasculopathy.
In the largest RCT study of 80 patients who underwent heart transplant with HCV-positive donors , 67 of 70 (96%) recipients developed viremia following transplant and started treatment with LDV/ SOF, SOF/VEL, or GLE/PIB for 12 weeks. Of those who started DAA treatment (n=55), 37 achieved SVR12 with 17 recipients pending, and 1 recipient died prior to achieving SVR12.
Although there were higher rates of severe primary graft dysfunction, there was no difference regarding the hospital length of stay, rejection requiring treatment, survival at 30 days, or 1-year patient survival.
Pancreas Transplantation
The data on utilizing HCV-viremic organs in pancreas transplantation are limited
In 2021, the first reported series included 8 HCV-naive patients who received either deceased donor simultaneous pancreas-kidney transplant or pancreas transplant after living donor kidney transplant.
All patients developed viremia and were treated with either GLE/PIB or SOF/VEL and all achieved SVR12.
All recipients had excellent pancreas graft function and rates of rejection with no difference in hospital stay.
Conclusion:
Transplantation of HCV-viremic organs into HCV-naive recipients followed by the use of DAA agents provides excellent patient and allograft survival.
with acceptable short-term outcomes and has the potential to significantly close waitlist gaps and decrease morbidity and mortality
Understanding long-term outcomes of HCV-viremic organ utilization remains on the near horizon.
background
long waitlist times and high waitlist mortality can be addressed with expanding donor pool
HCV positive organ use is a step to increase donor pool
DAA are effective and AE are managable so more HCV positive organs are available for KT
Young opiod addict with positive HCV are available as DBD
DAA and HCV
SRV of 12 weeks OF 98%
SOF and LDV for gt1, 4, 5, 6
SOF and VEL for all gt — 95%
GLE and PIB for all gt – 97 % of SVR12 mainly for mild cirrhosis
Recipient with advanced liver disease are unlikely to improve with DAA therapy
TREATMENT WITH DAA
Treatment of HCV infection in patients who
undergo simultaneous liver-kidney transplant is both
safe and efficacious
The use of a pangenotypic, ribavirin-free regimen
in posttransplant patients without cirrhosis has demonstrated good overall success
Although graft survival is less in HCV positive recipient ,safety and efficacy of DAA therapy for the treatment of HCV infection
posttransplant led to a paradigm shift.
HCV positive donor means
HCV antibody positive or HCV NAT positive
ONLY NAT positive donor with or without positive antibody are known to transmit HCV
NAT positive means VIREMIC DONOR
HCV positive liver to HCV negative recipient
it is possibel with SOF/LDV or SOF/VEL combination
HCV positive kidney in HCV positive recipient
THINKR trial
kidneys from HCV GT1–viremic donors into HCV-negative recipients
elbasvir/grazoprevir (EBR/GZR;
all 10 patient werehad SVR
EXPANDER trial
DAA before and after renal transplant in HCV positive to HCV negative pair
GLE/PIB once daily for 12 weeks is also effective
GLE/PIB once daily for 4 weeks is also effective
heart and to lesser extent lung transplant has been shown to be effective in D+/R- pair like kidneys
This article focus on HCV treatment prior and post transplant:
HCV infection is the leading cause of liver failure and needs to liver transplant.
Improving of advanced HCV therapy lead to eradication of HCV infection and donor with treated hepatitis C is not contraindicated to transplant.
Liver transplant is associated with lower rates of biliary complications and improved rejection rates, graft survival, and overall survival. Hepatitis C Virus Infection and Direct- Acting Antiviral Therapy:
ledipasvir
Harvoni
Epclusa
Those given once per day
Those associated with sustained virologic response 12 weeks after treatment (SVR12) of greater than 95 to 98%.
The combination of NS3/4A protease inhibitor glecaprevir and NS5A inhibitor pibrentasvir (GLE/PIB; ) used for the treatment of HCV infection without cirrhosis or with mild cirrhosis.
DAA therapy used to improve liver function in patients with decompensated cirrhosis. Direct-Acting Antiviral Therapy and Liver Transplantation:
Use of DAAT has excellent results prior and post transplant with good outcome for allograft survival and low rate of chronic hepatitis and fibrosis.
The rate of transmission is high in donor and recipient with positive HCV with low rate of sustained virology response post treatment with DAAT.
LDV/SOF is highly of recommended fallow transplant with nice for SVR12 reach to 96%.
LDV/SOF has risk of hyperglycaemia as side effects, so should be monitoring blood sugar during treatment. Diagnosis of donor HCV:
Enzyme immune assays occur within 2-6 months after exposure.
The nucleic acid testing (NAT) can detect RNA within 7 days after exposure.
HCV NAT had sensitivity 85-100% and specificity 99-100%.
Presence of nucleic acid testing (NAT) means virema.
HCV positive donor detected by serology and NAT negative indicates clearance or successful treatment of infection.
Positive NAT indicates active infection and high risk of disease transmission. Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients:
In the past It’s not considered transplant because it’s associated with interferon therapy complications.
Now with improvements of DAA; it’s possible transplant from positive HCV donor to negative recipient with good survival and graft outcome in 2 years post transplant. Renal Transplantation:
The prevalence of HCV among end stage renal disease patients is 0.2% to 6%.
HCV infection is common in ESRD because hazardous of dialysis. HCV seropositiv
However the availability of DAA therapy lead to transplant from donor with HCV can happen with no risk of chronic HCV infection in the transplant recipient.
Some studies done on role of DAAT therapy in renal transplant recipients with HCV infection.
HCV donors into HCV negative recipients (donor positive, recipient negative followed by treatment with elbasvir/grazoprevir (EBR/GZR; Zepatier,) for 12 weeks .
All recipients had detectable HCV RNA responded well to ADDT and this study shows no significant difference in graft survival between positive and negative recipient with HCV whether donor positive or negative and this results happen due to improving of ADD in eradication of HCV.
I like your clinical approach and well-structured extensively detailed summary quoting a number of trials related to HCV and various types of transplants demonstrating a promising approach with DAA in HCV infections
Introduction: · HCV affects 150 million people worldwide, and it is a leading cause of end stage liver disease. · A high risk for transmission and morbidity and mortality associated with HCV +ve donor transplants. · Direct acting antiviral (DAA) and its effect in reaching SVR, increased the utilization of HCV + donors, and subsequently reduced mortality in waiting list. Hepatitis C Virus Infection and Direct Acting Antiviral Therapy: · Cure rate of 98% with the direct acting antiviral therapy revolution for 12 weeks called sustained viral response. · Nonstructural protein 5B inhibitor sofosbuvir+NS5A inhibitor ledipasvir produces high SVR12 rates in HCV genotype (GT) 1, 4, 5, and 6 infection. · SOF + NS5A inhibitor velpatasvir produces response rate of 95%. · NS3/4A protease inhibitor glecaprevir and NS5A inhibitor pibrentasvir in patients with no cirrhosis or mild cirrhosis with response rate reaching 97%. · Presence of these therapies, with high response rate make it worth to treat HCV patients before transplantation, or deferring until after transplantation, improve liver function in patients with cirrhosis, reduce the reinfection after transplantation · Clinical features associated with meaningful improvement in liver function from pretransplant therapy include low baseline Model for End-Stage Liver Disease score (<16), low baseline Child-Pugh score, and the absence of portal hypertension complications. · Patients with advanced liver disease are unlikely to improve with DAA therapy and those with Child-Pugh class C cirrhosis have lower SVR12 rates; therefore, deferring treatment in such situations may be preferred Direct-Acting Antiviral Therapy and Liver Transplantation
· A variable clinical course ranging from mild fibrosis to severe graft damage. Progressive centrilobular ballooning degeneration, bridging fibrosis, and cholestasis are seen in 20% to 40% of posttransplant persistent HCV infection. And graft cirrhosis developed within 5 years post-transplantation, almost 5-10% of posttransplant patients will develop severe progressive cholestatic hepatitis, With the increasing use of DAA therapy, significant HCV-related progression of liver disease posttransplant is now uncommon. · HCV-TARGET cohort provided confidence in treating liver transplant patients with a ribavirin-free regimen, with a very high SVR12 reaching 96%. · MAGELLAN-2 study, demonstrated SVR12 rate of 98% (95% CI, 95.3%-100%). No patients discontinued therapy because of treatment-related adverse events. · SOLAR-1 and SOLAR-2 studies demonstrated 96% and 98% SVR12 rate with or without cihrrosis. HCV GT4 infection, SVR12 was achieved by 78% of patients who received 12 weeks of treatment and 94% of patients who received 24 weeks of treatment. Defining Hepatitis C Virus–Positive Donors · Serologic tests such as chemiluminescence assays and enzyme immunoassays detect antibodies within 2 to 6 months after exposure. · Nucleic acid testing (NAT) detects RNA 5 to 7 days after exposure and provides a more accurate assessment of transmission risk.( sensitivity of 85% to 100% and a specificity of 99% to 100%) · Tests interpretation:- HCV positive by serologic testing but NAT negative = spontaneous clearance or successful treatment of infection, or a false-positive result. (Not transmitting infection). HCV-seropositive donor that is NAT positive (viremic) = active infection and poses a high risk for disease transmission. HCV-negative donor that is NAT positive = acute infection and poses a high risk for disease transmission.
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients perioperative use of DAA therapy has increased the utilization of HCV viremic donor organs, with good long term graft outcomes. Liver Transplantation HCV treatment within 3 months of liver transplantation increases the probability of successful graft function and reduces waitlist mortality. biliary sclerosis, cardiomyopathy, and graft-vs-host disease, membranous nephropathy resulting in end-stage kidney disease, multiorgan failure and death. Renal Transplantation Prevalence of HCV among ESRD patients is 0.2-6%, and HCV associated with poor survival and graft function post transplantation.Thoracic Transplantation THINKER1 &THINKER2 demonstrated almost 98% SVR with an excellent patient and graft survival. EXPANDER trial demonstrated SVR12 rates of 100% and stable allograft function. Thoracic transplantation The prevalence of HCV among heart recipients is 12% DONATE-HCV = Pre-emptive DAA resulted in 100% SVR12 , with good patient and graft survival. Pancreas transplantation Showed same results seen in other solid organ transplantations as mentioned above.
Conclusion: The use of HCV+ donor organs demonstrated acceptable short-term outcomes and has the potential to significantly close waitlist gaps and decrease morbidity and mortality. DAA therapy posttransplant is essential and patients should be fully informed of the associated risks, including the potential of HCV treatment failure.
I like your clinical approach and well-structured extensively detailed summary quoting a number of trials related to HCV and various types of transplants
Summary:
Hepatitis C virus (HCV) infection is a common indication for liver transplantation. If the patient’s HCV is untreated prior to liver transplant, infection of the allograft is nearly universal and can lead to graft failure. Hepatitis C virus infection and Direct-acting antiviral therapy
DAA therapies for the treatment of chronic HCV infection has been introduced, with cure rates defined as sustained virologic response 12 weeks after treatment (SVR12) of greater than 98%.
The availability of DAA has made treatment of HCV infection to be possible pre or post-organ transplantation
Patients with advanced liver disease or Child-Pugh score C are unlikely to respond to the use of DAA
Defining Hepatitis C virus-positive donor
Serological tests can be detected HCV antibodies within 2 to 6 months after exposure while the NAT can be detected within 5-7 days
Potential donors who are serologically positive but had NAT test negative can donate as the chance of transmitting infection is low.
The risk of transmission of HCV infection is still possible during the one week it takes for a NAT test to be possible
The Hepatitis C-positive donor for a negative recipient
The organs form HCV positive diseased donors are usually discarded before the era of DAA
There favorable data are available toward receiving organs from HCV positive donor by a negative recipient with a good outcome for both the patient and the graft
Liver transplantation · One study published in 1998, 22 patients with HCV received HCV-seropositive grafts and had excellent 4-year patient and graft survival, 83.9% and 71.9%, respectively, vs 79.1% and 76.2%, respectively, with HCV-seronegative donor.
Data OPTN showed that 30 HCV-naive patients received HCV-viremic livers and had similar 1-year patient survival rates when compared with HCV-seropositive but NAT-negative and nonviremic livers
The first trial of giving HCV D+/R- where the recipient received SOF/ VEL-based LDV/SOF-based, or SOF/DAC-based therapy and they achieved SVR12
HCV-induced acute MN was observed in a multi-center study of dual liver-kidney transplant
Renal transplant
The prevalence of HCV among end-stage renal disease patients is 0.2% to 6%, and HCV infection traditionally has been a common complication after renal transplant.
Outcomes for untreated HCV infection in HCV-seropositive renal recipients are significantly worse than in their HCV-negative counterparts.
HCV seropositivity is associated with higher all-cause mortality (adjusted relative risk [aRR], 1.85; 95% CI, 1.49-2.31; P<.0001) and higher all-cause graft loss (aRR, 1.76; 95% CI, 1.46-2.11; P><.0001).
Studies have shown good response in HCV infection D+/R+ (Kidney) with long-term outcomes of 82% and 74% after 5 and 10 years respectively
Trials like THINKER, THINKER-2, and EXPANDER have gone as far as using D+/R- kidney transplantation with good outcomes
All the trial has been successful with the use of DAA either before or after kidney transplantation
Conclusion:
Transplantation of HCV-viremic organs into HCV-naive recipients followed by the use of DAA agents provides excellent patient and allograft survival. In carefully selected patients, the use of HCV-viremic grafts appears to be efficacious and well tolerated.
I like your clinical approach and well-structured extensively detailed summary quoting a number of trials related to HCV and various types of transplants
Hepatitis C Virus Infection and Direct Acting Antiviral Therapy
●Over the past several years, a succession of pangenotypic DAA therapies for the treatment of chronic HCV infection has been introduced,
●cure rates defined as (SVR12) of greater than 98%
○NS5B inhibitor sofosbuvir has been approved for HCV treatment in combination with a (NS5A) inhibitor , (NS3/4A) protease inhibitor, and ribavirin.
○T he combination of potent NS5A inhibitor ledipasvir (LDV) and SOF (LDV/SOF, 90 mg/400 mg; Harvoni, Gilead), administered once daily, is well tolerated and produces high SVR12 rates in HCV genotype (GT) 1, 4, 5, and 6 infection.
○The combination of SOF and NS5A inhibitor velpatasvir, administered once daily, provides SVR12 rates of greater than 95% across all GTs and has a favorable safety prof ile.
○The combination of NS3/4A protease inhibitor glecaprevir and NS5A inhibitor pibrentasvir was first approved in 2017 for the treatment of HCV infection without cirrhosis or with mild cirrhosis.
○GLE/PIB is well tolerated and results in SVR12 rates greater than 97% across all GTs.
Therefore, it is considered as a treatment of HCV infection prior to transplant or deferring therapy until after transplant.
●DAA therapy has been shown to improve liver function in patients with decompensated cirrhosis
Direct-Acting Antiviral Therapy and Liver Transplantation
○20% to 40% of posttransplant patients whose HCV infection has not been cured can progress ●centrilobular ballooning degeneration,
●bridging fibrosis,
● cholestasis
○Advanced fibrosis can occur in up to 45% of posttransplant patients,
○5 to 10% of posttransplant patients will develop severe progressive cholestatic hepatitis leading to liver failure.
■Use of DAA therapy following liver transplant has demonstrated excellent outcomes.
Recipients who achieve SVR12 posttransplant have lower rates of liver fibrosis progression (20.5% vs 65.5%; P<.001) and lower mortality (chi2=6.9; P<.01) rates compared with patients who do not receive or fail treatment.
■In a multicenter phase 2 study, 17 patients with chronic HCV GT1 who received an HCV-negative liver followed by treatment with single-dose LDV/SOF for 4 weeks achieved SVR12.
■In a study of 79 patients with chronic HCV GT1 to GT4 infection of whom 59% were treatment-experienced, use of SOF/VEL following liver transplant resulted in an SVR12 rate of 96%.
■Treatment of HCV infection in patients who undergo simultaneous liver-kidney transplant is both safe and efficacious.
■The HCV-TARGET trial SVR12 rates among liver transplant and dual liver-kidney transplant recipients were 96.6% and 90.9%, respectively.
■The MAGELLAN-2 study SVR12 rate of 98% (95% CI, 95.3%-100%). No patients discontinued therapy because of treatment-related adverse events.
■SOLAR-2, a multicenter open-label study demonstrated SVR12 rates of 100% (90% CI, 91%-100%), 96% (90% CI, 84%-100%), 95% (90% CI, 78%-100%), and 100% (90% CI, 86%-100%) in CTP-A patients with 12 weeks of treatment, CTP-A patients with 24 weeks of treatment, CTP-B patients with 12 weeks of treatment, and CTP-B patients with 24 weeks of treatment, respectively.31
■In the entire cohort studied (n=333), 7 patients (2%) discontinued LDV/SOF prematurely because of adverse events and 17 patients (5%) died, mainly from complications of hepatic decompensation.
■In transplant recipients who have compensated cirrhosis, DAA therapy following transplant is safe and efficacious.
■ In SOLAR-1, SVR12 was achieved in 96% Although historical data demonstrate that HCV infection has a negative long-term impact on both patient and graft survival
Hepatitis C Virus–Positive Donors
○Serologic tests such as and enzyme immunoassays detect antibodies within 2 to 6 months after exposure,
○ (NAT) detects RNA 5 to 7 days after exposure and provides a more accurate assessment of transmission risk.
○HCV NAT has a sensitivity of 85% to 100% and a specificity of 99% to 100%.
Donors identified as HCV positive by serologic testing but NAT negative (nonviremic) are considered to have
●undergone spontaneous clearance
●or successful treatment of infection,
●or have a false-positive antibody result,
●and these donors have not been documented to transmit HCV infection.
An HCV-seropositive donor that is NAT positive (viremic) is considered to have
■an active infection
■and poses a high risk for disease transmission.
An HCV-negative donor that is NAT positive (viremic) is considered to have
♤an acute infection
♤ and poses a high risk for disease transmission
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus Negative Recipients
Renal Transplantation
●The prevalence of HCV among ESRD patients is 0.2% to 6%
●Outcomes for untreated HCV infection are significantly worse
●HCV seropositivity is associated with higher all-cause mortality [aRR], 1.85; 95% CI, 1.49-2.31; P<.0001) and higher all-cause graft loss (aRR, 1.76; 95% CI, 1.46-2.11; P<.0001).
♡Historically, kidneys from HCV-infected donors have been underutilized.
○In a study of 545 kidney transplants performed in HCV-positive recipients, 5- and 10-year patient survival was 84.8% and 72.7%, respectively, for HCV-positive graft recipients compared with 86.6% and 76.5%, respectively (P=.25), for HCV-negative graft recipients.
DAA therapy and its administration around the time of transplant minimizes the risk of chronic HCV infection
Only a few prospective trials
●In 2017, the THINKER trial was the first open-label, single-group pilot study that sought to determine the safety and efficacy of the transplant of kidneys from [D+/R-]) followed by treatment with elbasvir/grazoprevir for 12 weeks (n=10).
All recipients had detectable HCV RNA, and all attained SVR12.
■ In the THINKER-2 trial (n=20), which included THINKER participants, HCV-negative recipients of HCV-viremic kidneys experienced HCV cure and excellent renal allograft function with (eGFRs) not significantly different from those of matched recipients of HCV-negative kidneys at 6 months (median, 67.5 vs 66.2 mL/min/1.73 m2; 95% CI, -4.2 to 7.5) and 12 months (median, 72.8 vs 67.2 mL/min/1.73 m2; 95% CI, -7.2 to 9.8).
■T he EXPANDER trial was an open-label single- center study (n=10) .
Preemptive use of EBR/GZR for 12 weeks in HCV-naive recipients who received HCV-infected kidneys (n=8) led to SVR12 with no study-related adverse events.
SOF-based regimens are safe and effective in HCV-naive recipients undergoing HCV-viremic kidney transplant.
■In a subsequent, larger, single-center, observational study, use of SOF/VEL or LDV/SOF resulted in SVR12 rates of 100% and stable allograft function in 53 HCV-naive recipients who received SOF/VEL or LDV/SOF for 8 to 12 weeks following HCV-viremic kidney transplant.
■In the MYTHIC trial, 30 HCV-naive patients received HCV-viremic kidneys across 7 transplant centers.
All 30 recipients achieved SVR12, and no severe adverse events related to HCV infection or GLE/PIB were noted in any patient.
Although all recipients had good allograft
■The DAPPER trial treated patients with a single pretransplant dose of SOF/ VEL followed by 1 or 3 posttransplant doses.
The 4-day strategy reduced viral transmission to 7.5% (3/40; 95% CI, 1.8%-20.5%) but did result in detectable viremia in 17 of 50 (34%) patients by posttransplant day 14, of which only 6 of 50 (12%) required treatment; the remaining 11 recipients had self-limited, low-level viremia.
Of the 6 patients who required treatment, 5 patients achieved SVR12, with 1 patient requiring the addition of ribavirin owing to resistance and 2 patients requiring 90 retreatment with second-line DAA agents owing to relapse.
I like your clinical approach and well-structured extensively detailed summary quoting a number of trials related to HCV and various types of transplants
Hepatitis C Virus Treatment and Solid Organ Transplantation Introduction
· The high success rate of Direct Acting Antiviral (DAA) therapy, coupled with a shortage of organ supply, have led to greater utilization of HCV‐positive livers.
· There have been substantial developments in HCV therapy and in the use of HCV-positive organs, thereby considerably increasing the number of organ transplants and decreasing waitlist mortality. Hepatitis C Virus Infection and DAA
· DAA therapies for the treatment of chronic HCV has cure rates of greater than 98%.
· The treatment consist of regimens of oral combination: Sofosbuvir and ledipasvir, the combination of sofosbuvir and velpatasvir and of glecaprevir and pibrentasvir. They are well tolerated and produces high SVR12 rates in HCV therapy.
· HCV infection can be treated prior to transplant or can be delayed to after transplant
· DAA therapy before transplant has been shown to improve liver function in patients with decompensated cirrhosis, to the extent of no longer requiring liver transplant.
· However, not all patients with end-stage liver disease from HCV infection will benefit from treatment prior to liver transplantation.
· Patients with advanced liver disease are unlikely to improve with DAA therapy therefore, delaying treatment in such situations may be ideal.
Direct-Acting Antiviral Therapy and Liver Transplantation
· Use of DAA therapy following liver transplant has demonstrated excellent outcomes.
· Recipients who achieve SVR12 post-transplant have lower rates of liver fibrosis progression and lower mortality rates.
· Treatment of HCV infection in patients who undergo simultaneous liver-kidney transplant is both safe and efficacious.
· This wide efficacy and safety profile of DAA encouraged the use of HCV- positive organs, first in HCV-viremic recipients and now in HCV-negative recipients. Defining Hepatitis C Virus–Positive Donors
· It is important to distinguish between a seropositive and viremic donor in HCV-positive donor, as the risks of disease transmission is much different.
· Donors identified as HCV positive by serologic testing but NAT negative (nonviremic) have not been documented to transmit HCV infection.
· An HCV-seropositive donor that is NAT positive (viremic) is considered to have an active infection and poses a high risk for disease transmission. The same applies to a HCV-negative donor that is NAT positive. Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients Liver Transplantation
· Retrospective studies evaluated HCV-viremic donors in nonviremic liver transplant recipients demonstrated promising outcomes in patient and graft survival.
· Prospective studies demonstrated efficacy of DAA therapy if used preemptively, immediately following transplant or within 90 days and also showed favorable outcomes.
· However in these studies the development of HCV-related complications such as adverse immunologic response suggested that careful and longer-term follow-up is still necessary.
Renal transplantation
· Studies in the past decade have demonstrated promising long-term outcomes of HCV-seropositive recipients transplanted with kidneys from HCV-positive donors.
· Furthermore, the use of DAA therapy around the time of transplant for 8-12 weeks minimizes the risk of chronic HCV infection in the transplant recipient and thus encouraged the use of kidneys from HCV-infected donors into HCV-naive recipients.
· Shorter-course DAA regimens (4 months) have also been evaluated with promising results. Thoracic Transplantation
· Preemptive administration of DAA in HCV-viremic cardiac transplant into HCV-naive recipients has demonstrated rapid HCV suppression.
· In a large prospective study, patients who underwent heart transplant with HCV-positive donors, 96% recipients developed viremia following transplant and started treatment with DAA.
· Shorter duration of DAA treatment for 8 weeks following cardiac transplant was evaluated in HCV-naive patients who received HCV-viremic organs. All patients developed detectable viremia, and all achieved SVR12.
· A few studies have evaluated the safety of using lungs from HCV-viremic donors for transplantation. All those who developed viremia post-transplant and received DAA for 4-6 months, achieved SVR12. Pancreas Transplantation
· The data on utilizing HCV-viremic organs in pancreas transplantation are limited.
· They demonstrated efficacy of DAA in achieving SVR12. Conclusion
· Transplantation of HCV-viremic organs into HCV-naive recipients followed by the use of DAA agents provides excellent patient and allograft survival in the short term.
· Long-term outcomes of HCV- viremic organ utilization are to be demonstrated in the near future.
Introduction
Infection with the hepatitis C virus (HCV) affects 130 to 150 million individuals globally.
Organs from dead donors with HCV positivity are becoming more readily available; they make up 9.7% of the donor pool.
In the past, HCV-infected organs from deceased donors were discarded due to the high risk of transmission and severe post-transplant morbidity and mortality in liver-related transplants.
Direct-acting antiviral (DAA) therapy’s impact on HCV treatment allowed for an increase in the use of HCV-positive livers from 7% to 17% between 2010 and 2015.
Both the science of HCV therapy and the use of HCV-positive organs have made substantial strides.
Hepatitis C Virus Infection and Direct Acting Antiviral Therapy
When they were first introduced, pan-genotype DAA treatments had a 98% cure rate for chronic HCV infection.
The issue of treating HCV infection before or deferring therapy after transplantation has arisen as a result of the availability of safe and very effective therapy.
DAA medication before transplantation lowers the risk of allograft infection.
Low baseline A model for end-stage liver disease score, a low baseline Child-Pugh score, and the absence of portal hypertension problems are indicators of significant improvement in liver function from the pre-transplant era with active treatment.
When choosing the best time to start HCV therapy, the recent practice of using HCV-viremic donors has impacted the general availability of organs.
Direct-Acting Antiviral Therapy and Liver Transplantation
HCV infection after a liver transplant has a heterogeneous clinical course that can range from mild fibrosis to severe graft destruction. It can also result in progressive centrilobular ballooning degeneration, bridging fibrosis, and cholestasis in 20% to 40% of posttransplant patients.
in untreated circumstances Severe fibrosis can occur in 45% of post-transplant patients, and graft cirrhosis can develop within as little as 5 years post-transplant.
DAA medication has made substantial HCV-related liver disease post-transplantation rare. Following a liver transplant, DAA therapy has produced good results.
It is safe and effective to treat HCV infection in patients getting a liver and kidney transplant at the same time.
Similar overall success has been seen when posttransplant patients without cirrhosis adopt a pan-genotypic, ribavirin-free regimen.
In 14 liver transplant recipients who had HCV genotypes 1–4 and cirrhosis, treatment with SOF/VEL for 12 weeks led to an SVR of up to 93%. SVR12 was attained in 96%–98% of transplant recipients in SOLAR-1, whether they had compensated cirrhosis or not.
A paradigm shift occurred as a result of promising findings on the safety and effectiveness of DAA therapy for the treatment of HCV infection post-transplant, despite historical data showing that HCV infection has a detrimental long-term impact on both patient and graft survival.a
Defining Hepatitis C Virus–Positive Donors
Serology methods like chemical and enzyme immune assays can detect antibodies within 2–6 months after exposure, but nucleic acid testing (NAT) can detect RNA 5–7 days after exposure and gives a more accurate assessment of HCV infection. HCV NAT is 85%–100% sensitive and 99%–100% specific.
NAT negativity indicates spontaneous infection clearance or effective therapy.
NAT positivity indicates active infection and disease transmission risk.
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients
DAA medication has enhanced HCV-viremic donor organ use perioperatively. In a 1998 study, 22 HCV patients got HCV-seropositive grafts and had outstanding 4-year patient and graft survival.
96 and 2827 HCV-positive and -negative transplant recipients exhibited equivalent 2-year survival rates (90% vs 77%; P=.01) in a larger analysis of 2923 transplant recipients.
Liver Transplant
Two large retrospective studies found no differences in patient or graft survival between HCV-viremic and nonviremic liver transplant donors.
Thoracic Transplant
12% of cardiac transplant recipients have HCV.
HCV infection pre- or post-heart transplant lowered survival in early studies.
Kidney transplantation
End-stage renal disease patients have a 0.2–6% HCV prevalence.
Renal transplants often result in an HCV infection.
HCV-seropositive kidney recipients have worse untreated HCV infection outcomes than HCV-negative recipients.
The THINKER study (2017) showed the safety and efficacy of kidney transplants from HCV GT1–viremic donors into HCV-negative recipients [D+/R-], followed by 12 weeks of elbasvir/grazoprevir (EBR/GZR; Zepatier, Merck) treatment (n = 10).
Shorter-course DAA regimens have shown promise.
Conclusion
Excellent patient and allograft survival is achieved with the transplantation of HCV-viremic organs into HCV-naive recipients, followed by the administration of DAA drugs, resulting in a reduction in waiting time. The use of HCV-positive grafts appeared to be effective and well tolerated in a subset of patients. Patients must be warned of all hazards, including the possibility of HCV treatment failure.
Hepatitis C Virus Infection and Direct- Acting Antiviral Therapy:
DAA therapies for the treatment of chronic HCV infection has been introduced, with cure rates defined as sustained virologic response 12 weeks after treatment (SVR12) of greater than 98%.
Ø Nonstructural protein 5B inhibitor sofosbuvir (SOF; Sovaldi, Gilead)
Ø Nonstructural protein 5A (NS5A) inhibitor,
Ø Nonstructural protein 3/4A (NS3/4A) protease inhibitor, and ribavirin.
Defining Hepatitis C Virus–Positive Donors:
HCV-positive donors encompass any stage of HCV infection. Serologic tests positive :
Ø Chemiluminescence assays and enzyme immunoassays detect antibodies within 2 to 6 months after exposure.
Ø Nucleic acid testing (NAT) detects RNA 5 to 7 days after exposure and it is accurate assessment of transmission risk.
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients::
Ø In a study published in 1998, 22 patients with HCV received HCV-seropositive grafts and had excellent 4-year patient and graft survival, 83.9% and 71.9%, respectively, vs 79.1% and 76.2%, respectively, with HCV-seronegative donor grafts (P=not significant )
Ø In a larger study that included 2923 transplant recipients with HCV, 96 and 2827 received HCV-positive and -negative organs, respectively, and had comparable 2-year survival rates (90% vs 77%; P=.01).
Renal Transplantation:
The prevalence of HCV among end-stage renal disease
patients is 0.2% to 6%,
the THINKER trial was the first open-label, single-group pilot study that sought to determine the safety and efficacy of the transplant of kidneys
from HCV GT1–viremic donors into HCV-negative recipients (donor positive, recipient negative [D+/R-]) followed by treatment with elbasvir/grazoprevir (EBR/GZR; Zepatier, Merck) for 12 weeks (n=10).
THINKER-2 trial (n=20), which included THINKER participants, HCV-negative recipients of HCV-viremic kidneys experienced HCV cure and excellent renal allograft function with estimated glomerular filtration
rates (eGFRs) not significantly different from those of matched recipients of HCV-negative kidneys at 6 months (median, 67.5 vs 66.2 mL/min/1.73 m2; 95% CI, -4.2 to 7.5) and 12 months (median, 72.8 vs 67.2 mL/min/1.73
m2; 95% CI, -7.2 to 9.8
The EXPANDER trial was an open-label single-center study (n=10) that examined the tolerability and feasibility of DAA prophylaxis before and after renal transplant in HCV-naive patients
SOF-based regimens are safe and effective in HCV-naive recipients undergoing HCV-viremic kidney transplant
Transplantation of HCV-viremic organs into HCV-naive recipients followed
by the use of DAA agents provides excellent patient and allograft survival.
I like your clinical approach and well-structured extensively detailed summary quoting a number of trials related to HCV and various types of transplants
Hepatitis C Virus Treatment and Solid Organ Transplantation
1. Hepatitis C virus (HCV) infection affects approximately 130 million to 150 million people worldwide.
2. The high success rate of direct-acting antiviral (DAA) therapy, have led to greater utilization of HCV‐positive livers, increasing from 7% to 17% between 2010 and 2015.
3. Cure rates is defined as sustained virologic response 12 weeks after treatment (SVR12) of greater than 98%.
4. DAA therapy has been shown to improve liver function in patients with decompensated cirrhosis.
Hepatitis C Virus Infection and Direct- Acting Antiviral Therapy
1. Sofosbuvir (SOF; Sovaldi, Gilead): Nonstructural protein 5B inhibitor has been approved for HCV treatment in combination with a nonstructural protein 5A (NS5A) inhibitor, nonstructural protein 3/4A (NS3/4A) protease inhibitor, and ribavirin.
2. The combination of potent NS5A inhibitor ledipasvir (LDV) and SOF (LDV/SOF, 90 mg/400 mg; Harvoni, Gilead), administered once daily, is well tolerated and produces high SVR12 rates in HCV genotype (GT) 1, 4, 5, and 6 infection.
3. The combination of SOF and NS5A inhibitor velpatasvir(SOF/VEL; Epclusa, Gilead), administered once daily, provides SVR12 rates of greater than 95% across all GTs and has a favorable safety profile.
4. The combination of NS3/4A protease inhibitor glecaprevir and NS5A inhibitor pibrentasvir (GLE/PIB; Mavyret, AbbVie) was first approved in 2017 for the treatment of HCV infection without cirrhosis or with mild cirrhosis. GLE/PIB is well tolerated and results in SVR12 rates greater than 97% across all GTs.
5. Pre-transplant DAA therapy reduces the risk of reinfection of the allograft.
6. Clinical features associated with meaningful improvement in liver function from pretransplant therapy include: low baseline Model for End-Stage Liver Disease score (<16), low baseline Child-Pugh score, and the absence of portal hypertension complications.
7. Patients who are unlikely to improve with DAA therapy are: patients with advanced liver disease are and those with Child-Pugh class C cirrhosis. Direct-Acting Antiviral Therapy and Liver Transplantation
1. With the increasing use of DAA therapy, significant HCV-related progression of liver disease post-transplant is now uncommon.
2. Use of DAA in recipients who achieve SVR12 therapy following liver transplant has demonstrated excellent outcomes.
· lower rates of liver fibrosis progression (20.5% vs 65.5%)
· lower mortality rates.
3. Use of SOF/VEL following liver transplant resulted in an SVR12 rate of 96%.
4. LDV/SOF plus ribavirin in liver transplant recipients with HCV GT1 to GT4 infection and liver disease, SVR12 was achieved in 96% to 98% of transplant recipients without cirrhosis or with compensated cirrhosis. Defining Hepatitis C Virus–Positive Donors
1. HCV-positive donors encompass any stage of HCV infection:
· Serologic tests such as chemiluminescence assays and enzyme immunoassays detect antibodies within 2 to 6 months after exposure.
· Nucleic acid testing (NAT) detects RNA 5 to 7 days after exposure and provides a more accurate assessment of transmission risk.
· HCV NAT has a sensitivity of 85% to 100% and a specificity of 99% to 100%.
2. Non-viremic HCV-seropositive donors: identified by serologic testing positive but NAT negative.
3. Viremic HCV-seropositive donor: identified by NAT positive, considered to have an active infection and poses a high risk for disease transmission. Transplantation in HCV D+/R-
1. The rapidly evolving treatments for HCV and perioperative use of DAA therapy has increased the utilization of HCV- viremic donor organs.
2. Data have demonstrated favorable long-term graft outcomes in patients transplanted with HCV-sero- positive donors.
3. In a recent larger study, the 2-year survival rates were comparable in transplant recipients with HCV that received HCV-positive and -negative organs.
4. No differences in patient or graft survival in liver transplant recipients after donation from HCV-viremic donors in nonviremic liver when compared with nonviremic donors.
5. OPTN,showed that the 2-year graft survival rates in 568 liver transplant recipients with and without HCV infection were comparable.
6. Outcomes for untreated HCV infection in HCV-seropositive renal recipients are significantly worse than in their HCV-negative counterparts.
7. Use of SOF/VEL or LDV/SOF resulted in SVR12 rates of 100% and stable allograft function in 53 HCV-naive recipients who received SOF/VEL or LDV/SOF for 8 to 12 weeks following HCV-viremic kidney transplant.
8. Preemptive administration of GLE/ PIB in HCV-viremic cardiac transplant into HCV-naive recipients has demonstrated rapid HCV suppression, prevention of chronic HCV infection (SVR12 rate of 100%), and excellent early allograft function in patients receiving HCV-viremic donor hearts.
9. Preliminary findings suggest that HCV-viremic pancreas transplant may be safely used for potential pancreas recipients. Conclusion
1. Transplantation of HCV-viremic organs into HCV-naive recipients followed by the use of DAA agents provides excellent patient and allograft survival.
2. Securing DAA therapy post-transplant is essential and patients should be fully informed of the associated risks, including the potential of HCV treatment failure.
· HCV is a common cause of ESLD requiring liver transplantation.
· HCV infection in the recipient; must be treated prior to liver transplantation, as 100 % of cases will have infected graft after transplantation with higher risk of graft failure, patient morbidity and mortality.
· Use of HCV +ve donors to increase availability of organs (increase donor pool), especially in the presence of direct acting anti-viral therapy (DAAV).
· Unfortunately, young donors with less comorbidities, have HCV infection (related to drug abuse), so have HCV viremic organs.
· Risk of transmission from positive donor is determined according to positive PCR (higher transmission).
· The highest risk is with HCV positive PCR (active viremic state).
· The problem in diagnosis with PCR is one-week periodbetween acquiring viral infection and appearance of positive PCR.
· Use of HCV +ve donor to HCV positive recipient has been used successfully, however using D+/R – was not considered in the past (high risk of infection, graft failure, morbidity and mortality, adverse effects of interferon based therapy).
· Nowadays, it is used in HCV – ve recipient with availability of highly effective and relatively safe DAAV, with relatively comparable graft and patient outcomes to use of HCV –ve donors (but still not the standard practice).
· Direct acting antivirals;
o Has many advances.
o Higher success rate (sustained virologic response (SVR12) 12 weeks after treatment of greater than 98%.
o Duration of therapy is about 3 months.
o Combination of sofosbuvir (Sovaldi) + ledipasvir (given once daily, high SVR, effective against genotypes 1, 4,5,6)
o Combination of sofosbuvir (Sovaldi) + velpatasvir (given once daily, SVR > 95% and more safe).
o Combination of GLE/PIB is well tolerated and results in SVR > 97% across all genotypes.
o Timing of treatment in liver transplant recipients;
§ What favors pre-transplant treatment:
1. Improvement of liver function even in those with decompensated cirrhosis up to not needing transplantation.
2. Decrease risk of HCV infection in allograft.
3. Used in cases with low baseline Model for End-Stage Liver Disease score and absent portal hypertension complications.
§ What favors post-transplant treatment:
1. Cases with compensated cirrhosis.
· HCV persist in 20-40 % of cases after liver transplantation, with progressive fibrosis, cirrhosis and graft failure. So use of DAAV is so crucial to improve graft outcome.
· Use of LDV/SOF or SOF/VEL has achieved high SVR that leads to better outcome, less progression of cirrhosis in HCV positive cases (receiving liver from HCV negative donors) without rejection episodes and with minimal side effects.
· Use of pangenotypic, ribavirin-free regimen in post-transplant patients without cirrhosis has demonstrated similar overall success.
· Liver transplantation (either use early treatment in case of +ve PCR or use preemptive therapy starting immediately after tx)
o HCV +ve donor is used nowadays for HCV _ve recipient with comparable outcomes (in presence of perioperative use of DAAV). The recipients developed HCV infection in spite of donor treatment prior to donation. So, those recipients taking allograft from HCV +ve donors must undergo PCR screening and receive early treatment(with DAAV as SOF/VEL or GLE/PIB combinations as once daily therapy for 12 weeks) to preserve the graft function.
o Preemptive antiviral strategy immediately after transplantation using SOF/VEL is also effective to achieve SVR.
o It is importance to take care of immunological adverse effects as sclerosing cholangitis, cardiomyopathy and GVHD. In addition, long term follow-up and monitoring of graft function and complications is essential.
· Kidney transplantation; (treatment with DAAV must be preemptive, starting in the day prior to KT).
o HCV is a common comorbidity in cases with ESKD. The long-term outcomes of HCV-seropositive recipients transplanted with kidneys from HCV +ve donors is promising. In addition, the availability of DAAV has paved the way to use HCV +ve donors (viremic allograft) for HCV naive recipients.
o Although it remains few trial with small sample size, it seems that CMV viremia is the rule in all cases but effective DAAV as EBR/GZR (for G1,3) for 12 weeks, can achieve SVR (HCV cure) and good graft outcome at 6-12 months after kidney transplantation. The therapy was started preemptively (immediately before transplantation and continued for 3 months after the operation).
o Addition of SOF was required in genotypes 2, 3 (use triple therapyEBR/GZR/SOF). In addition, use of SOF/VEL or LDV/SOF for 8 to 12 weeks was effective in treatment of naïve recipients receiving viremic organs with few rejection episodes. Shorter duration as 4 weeks of GLE/PIB or 4 days of SOF/VEL was effective in decreasing viral transmission.
· Ribavirin can be used for resistant cases to 1st line therapy and 2nd line drugs are used in relapsed cases.
· Pancreases transplantation: very limited numbers of cases, use ofGLE/PIB or SOF/VEL achieved SVR (need further trials).
· Lung/heart transplantation; use of EITHER LDV/SOF (GT1) or SOF/VEL (GT3) or GLE/ PIB for 3- 6 months to achieve SVR with excellent graft outcome. Short treatment duration for 8 weeks was also effective to achieve SVR.
· As a conclusion, use of viremic organs for HCV naïve recipients seems applicable with the use of DAAV (for 12 weeks) with > 95 % SVR. The adverse effects of DAAV and occurrence of acute rejection seem acceptable.
· The prognosis of D+/R- transplantation is still better than waiting on dialysis.
· However, patient counseling about the risk of viremia, failure of treatment and availability and importance of strict adherence to DAAV is essential prior to proceeding in D+/R- transplantation.
· In addition, the long term effects on patient immune system and interaction with immunosuppressive therapy remains unclear and needs further evaluation.
Approx -130 -150 million ppl worldwide have HCV infection. In 2019,9.7% of deceased liver donors were HCV +VE. Adoption of DAA therapy has led to an increase in the use of HEPC +VE liver from 7-17% btn 2010-2015.
HCV infection and DAA therapy;
HCV cure rate is sustained virologic response 12/52 of >98%.Option in transplant popn is either tx pre transplant or deferring therapy until after transplant.
Pre transplant tx candidates;
Low baseline model for ESLD score -<16
Low baseline child pugh score.
Absence of portal hypertension and complication.
Post transplant tx candidates;
Advanced liver dx.
Tx options;
SOF +NS5S,NS5A +SOF,NS3/4A + Ribavirin,NSFA + NS3/4A
DAA therapy and liver transplantation;
-Post transplant HCV leads to fibrosis and graft damage of varied degrees .DAA therapy has markedly decreased HCV related progression of liver dx post transplant.
-In HCV TARGET trial, LDF+SOF,Ombitasvir/paritaprevir/ritonavir +dasabuvir or SOF+DAC therapies gave good outcomes and confidence in transplant groups with HCV with a ribavirin free regimen.
-Transplant candidates with decompensated cirrhosis and HCV have shown good results with DAA therapy as evidenced in SOLAR 1 and 2 Trials where SOF/VEL,LDF/SOF +ribavirin were used with good outcomes.
Defining HEP C virus in +VE donors.
-NAT has rapid results in 5-7 days and is more accurate in accessing transmission risk. HCV NAT has a 85-100% sensitivity and 99-100% specificity.
Non viraemic donors (NAT neg) have low risk of transmission in comparison to seropositive donors and those who are viraemic.
-High risk of transmission;
Active HCV infection; HCV ab +VE,HCV NAT +VE.
Acute HCV in window period or false +VE NAT;HCV ab -VE,HCV NAT -VE
-Low risk of transmission;
No active infection/treated HCV/false +VE ab -HCV ab -VE,HCV NAT -VE
-No risk of transmission -No HCV infection,HCV ab -VE,HCV NAT -VE.
Hep C virus +VE donor transplantation in Hep C virus -VE recipients.
Liver transplantation.
–HCV tx within DAA within 3/12 pre transplant is associated with good graft function.
-Tx options;
SOF+VEL/LDV+SOF/SOF +DAC/GLE +PIB +/- Ribavirin depending on whether the pt can tolerate it.
-Main SE that need to be monitored are DI,ACR,ABMR, biliary sclerosis, cardiomyopathy and graft vs host dx.
Renal transplantation.
-HCV prevalence in ESRD is 0.2-6% with HCV being associated with higher mortality than HCV neg popn.
-In THINKER trials, post transplant pts tx with EBR+GZR had good cure rates with excellent graft function.
-In EXPANDER trial, post transplant pt received EBR/GZR/SOF(dual/triple therapy) with good tolerability.
-In MYTHIC trial, post transplant pts received GLE+PIB with good tolerability and graft outcomes.
Thoracic transplantation.
–HCV prevalence is 12% in heart transplant recipients which has poor survival.
-In USHER trial, EBR+GZR tx was associated with good outcomes post cardiac transplant with tolerability and no serious adverse events.
-Shorter duration therapy generally associated with viremia post transplant with fewer studies supporting it.
-In the DONATE HCV trial both cardiac and lung transplant recipients tx with SOF+VEL pre transplant and GLE+PIB post transplant had good graft function and no mortality or significant rejection.
Pancreas transplantation.
-We don’t have much studies on this but preliminary findings support the use of HCV Viremic pancreas transplant with DAA, More studies are needed on this.
Hepatitis C Virus Treatment and Solid Organ Transplantation
Introduction
Hepatitis C virus (HCV) infection affects approximately 130 million to 150 million people worldwide.
The availability of HCV-positive organs continues to increase, representing 9.7% of deceased-donor pool.
Organs from deceased donors infected with HCV were discarded in the past because of high transmission risk and significant post-transplant morbidity and mortality in Liver related Transplants.
HCV treatment changed with the emergence of direct-acting antiviral (DAA) therapy and made possible the greater utilization of HCV‐positive livers, increasing from 7% to 17% between 2010 and 2015.
There have been significant advancements in the science of HCV therapy and in the use of HCV-positive organs.
Hepatitis C Virus Infection and Direct Acting Antiviral Therapy
The pan-genotype DAA therapies when started led to cure rate of chronic HCV infection in about 98% of cases. (With sustained virologic response SVR)
The availability of safe and highly effective therapy has led to the debate of treating HCV infection prior to or delaying therapy after transplantation.
Pretransplant DAA therapy reduces the risk of infection of the allograft.
Substantial improvement in liver function from pretransplant era with active treatment include low baseline Model for End-Stage Liver Disease score (<16), low baseline Child-Pugh score, and the absence of portal hypertensive complications.
Recent practice of utilizing HCV-viremic donors has changed overall availability of organs and should be taken into consideration when deciding optimal timing of HCV treatment.
Direct-Acting Antiviral Therapy and Liver Transplantation
HCV Infection after liver transplant have variable clinical course ranging from mild fibrosis to severe graft damage, HCV infection can cause Progressive centrilobular ballooning degeneration, bridging fibrosis, and cholestasis (20% to 40% of posttransplant patients).
In untreated cases Advanced fibrosis can occur in 45% of post-transplant patients, and graft cirrhosis can develop within as little as 5 years post-transplant.
significant HCV-related progression of liver disease post-transplant is now uncommon because of DAA therapy. Use of DAA therapy following liver transplant has demonstrated excellent outcomes.
Treatment of HCV infection in patients who undergo simultaneous liver-kidney transplant is both safe and efficacious.
The use of a pan-genotypic, ribavirin-free regimen in posttransplant patients without cirrhosis has demonstrated similar overall success.
Treatment with SOF/VEL for 12 weeks in 14 liver transplant recipients with HCV Geno type 1 to 4 and cirrhosis resulted in an SVR in 12 weeks up to 93%. In SOLAR-1, SVR12 was achieved in 96%- 98% of transplant recipients without cirrhosis or with compensated cirrhosis.
Although historical data demonstrate that HCV infection has a negative long-term impact on both patient and graft survival, promising data on the safety and efficacy of DAA therapy for the treatment of HCV infection post-transplant led to a paradigm shift.
Defining Hepatitis C Virus–Positive Donors
Definition of HCV positive donor is infection at any stage which is established through serology tests such as chemistry and enzyme immune assays to detect antibodies within 2 to 6 months after exposure, but nucleic acid testing (NAT) can detect RNA even 5 to 7 days after exposure and provides a more accurate assessment. HCV NAT has a sensitivity of 85%-100% and a specificity of 99%-100%.
If NAT is negative, it means spontaneous clearance/successful treatment of infection.
If NAT is positive, it means active infection and have high risk for disease transmission.
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients
Treatments for HCV have improved outcomes significantly, and perioperative use of DAA therapy has increased the utilization of HCV- viremic donor organs. In a study published in 1998, 22 patients with HCV received HCV-seropositive grafts and had excellent 4-year patient and graft survival ( 83.9% and 71.9%, respectively, vs 79.1% and 76.2%, respectively), with HCV-seronegative donor grafts (P=not significant).
In a larger study that included 2923 transplant recipients with HCV, 96 and 2827 received HCV-positive and -negative organs, respectively, and had comparable 2-year survival rates (90% vs 77%; P=.01). Liver Transplantation
Two large retrospective studies evaluated HCV-viremic donors in nonviremic liver transplant recipients and demonstrated no differences in patient or graft survival when compared with nonviremic donors.
Renal Transplantation
The prevalence of HCV among end-stage renal disease patients is 0.2% to 6%
HCV infection traditionally has been a common complication after renal transplant.
Outcomes for untreated HCV infection in HCV-seropositive renal recipients are significantly worse than in their HCV-negative counterparts.
The THINKER trial (2017) showed the safety and efficacy of Kidney transplant from HCV GT1–viremic donors into HCV-negative recipients [D+/R-] followed by treatment with elbasvir/grazoprevir (EBR/GZR; Zepatier, Merck) for 12 weeks (n=10).
Shorter-course DAA regimens have also been evaluated with promising results
. Thoracic Transplantation
Among heart transplant recipients, the reported prevalence of HCV infection is as high as 12%.
Early studies demonstrated reduced survival in recipients with HCV infection, regardless of acquisition of HCV pre– or post– heart transplant.
Conclusion
Transplantation of HCV-viremic organs into HCV-naive recipients followed by the use of DAA agents provides excellent patient and allograft survival, leading to reduction in waiting time. In selected patients, the utilization of HCV+ve grafts appears to be efficacious and well tolerated. patients should be fully informed of the associated risks, including the potential of HCV treatment failure.
Infection with the hepatitis C virus (HCV) affects 130–150 million people worldwide.
One of the most common causes of end-stage liver disease and the main justification for liver transplantation is HCV infection.
Yet, there is a significant waitlist mortality rate since the demand for organs continues to outstrip the supply of organ donation.
Organs with HCV remain more readily available, accounting for 9.7% of livers from dead donors in 2019.
Previously, HCV-infected organs from deceased donors were discarded due to the high risk of reperfusion-related transmission and the possibility of considerable posttransplant morbidity and mortality.
The science of HCV therapy and the utilization of HCV-positive organs have made considerable strides, leading to a major rise in organ transplantation and a decline in waitlist mortality.
In this paper, the research on HCV treatment both before and after organ transplantation is reviewed. Direct acting antiviral therapy
Over the past several years, a succession of pangenotypic DAA therapies for the treatment of chronic HCV infection has been introduced, with cure rates defined as sustained virologic response 12 weeks after treatment (SVR12) of greater than 98%.16 Nonstructural protein.
Over the past several years, a succession of pangenotypic DAA therapies for the treatment of chronic HCV infection has been introduced, with cure rates defined as sustained virologic response 12 weeks after treatment (SVR12) of greater than 98%.16.
The MAGELLAN-2 study was a phase 3 open-label trial that confirmed the safety and efficacy of GLE/PIB once daily for 12 weeks in patients with treatment-naive HCV GT1 to GT6 infection or treatment-experienced HCV GT1, GT2, or GT4 to GT6 who had received a liver or kidney transplant.
Treatment with SOF/VEL for 12 weeks in 14 liver transplant recipients with HCV GT1 to GT4 infection and cirrhosis resulted in an SVR12 rate of. HCV antibody HCV NAT clinical interpretation transmission risk
No active HCV infection, cleared or treated HCV infection, or false-positive antibody Low. HCV, hepatitis C virus; NAT, nucleic acid testing.
Donors identified as HCV positive by serologic testing but NAT negative are considered to have undergone spontaneous clearance or successful treatment of infection, or have a false-positive antibody result, and these donors have not been documented to transmit HCV infection.
An. HCV-seropositive donor that is NATpositive is considered to have an active infection and poses a high risk for disease transmission.
An HCV-negative donor that is NAT positive is considered to have an acute infection and poses a high risk for disease transmission.
Risk of HCV transmission remains during the 1-week eclipse period between viral exposure and positive NAT results, in persons who inject drugs.
Risk of HCV transmission remains during the 1-week eclipse period between viral exposure and positive NAT results, in persons who inject drugs. Negative recipients
DAA therapy, transplantation of organs from HCV-positive donors into uninfected recipients was not routinely considered owing to low efficacy, high rates of HCV transmission, decreased patient and graft survival, and complications associated with interferon-based therapy in the posttransplant setting. The lack of effective and well-tolerated treatments for HCV had curtailed utilization of HCV-infected organs in transplant recipients.
DAA therapy, transplantation of organs from HCV-positive donors into uninfected recipients was not routinely considered owing to low efficacy, high rates of HCV transmission, decreased patient and graft survival, and complications associated with interferon-based therapy in the posttransplant setting.
The lack of effective and well-tolerated treatments for HCV had curtailed utilization of HCV-infected organs in transplant recipients.
Data have demonstrated favorable long-term graft outcomes in patients transplanted with HCV-seropositive donors.
In a study published in 1998, 22 patients with HCV received HCV-seropositive grafts and had excellent 4-year patient and graft survival, 83.9% and.
In a larger study that included 2923 transplant recipients with HCV, 96 and 2827 received HCV-positive and -negative organs, respectively, and had comparable Liver transplantation
Two large retrospective studies evaluated HCV-viremic donors in nonviremic liver transplant recipients and demonstrated no differences in patient or graft survival when compared with nonviremic donors. 54,55 Data from 2015 to 2017 from the Organ Procurement and Transplantation Network (OPTN)
Two large retrospective studies evaluated HCV-viremic donors in nonviremic liver transplant recipients and demonstrated no differences in patient or graft survival when compared with nonviremic donors.
HCV-seropositive but NAT-negative and nonviremic livers (92% vs 92% vs 92%; P=NS).
2016 to 2020 data from OPTN, comparable 2-year graft survival rates were seen in 568 liver transplant recipients with and without HCV infection (n=753 and n=87, respectively) who received HCV-viremic organs Antiviral therapy
GLE/PIB, glecaprevir/pibrentasvir; KT, kidney transplant; LDV/SOF, ledipasvir/sofosbuvir; LT, liver transplant; SOF/DAC, sofosbuvir/daclatasvir; SOF/VEL, sofosbuvir/velpatasvir; SVR12, sustained virologic response 12 weeks after treatment.
The first prospective study included 10 HCV-negative patients who received HCV-viremic livers, 7 of which had been cured of HCV infection prior to transplant.
GLE/PIB has been used successfully in HCV-naive patients who receive HCV-viremic livers.
In a trial of 14 patients who received HCV-viremic livers, 9 patients developed viremia with SVR12 and 46-week survival rates of 100% and 100%, respectively.
The administration of SOF/VEL or GLE/PIB once daily for 12 weeks in HCV-naive patients who received viremic livers (n=51).
In a multicenter study evaluating the kinetics of early HCV infection, SOF/VEL once daily for 12 weeks when viremia was confirmed resulted in SVR12 in all patients (13 liver, 11 kidney
SVR12 was reported in a prospective multicenter study evaluating outcomes in HCV-naive liver transplant and dual liver-kidney transplant. 60 all HCV-viremic organ recipients (n=20) achieved SVR12, the development of HCV-related complications suggests that careful and longer-term follow-up is still warranted Renal transplantation
The prevalence of HCV among end-stage renal disease patients is 0.2% to 6%, and HCV infection traditionally has been a common complication after renal transplant.
In 2017, the THINKER trial was the first open-label, single-group pilot study that sought to determine the safety and efficacy of the transplant of kidneys from HCV GT1–viremic donors into HCV-negative recipients followed by treatment with elbasvir/grazoprevir (EBR/GZR; Zepatier, Merck) for 12 weeks (n=10).
In a study of 7 HCV-naive kidney recipients receiving HCV GT1– and HCV GT3–viremic kidneys, antiviral treatment with LDV/SOF (n=4) and SOF/VEL (n=3) for 8 to 12 weeks resulted in SVR12 and stable renal allograft function.
70 In a subsequent, larger, single-center, observational study, use of SOF/VEL or LDV/SOF resulted in SVR12 rates of 100% and stable allograft function in 53 HCV-naive recipients who received SOF/VEL or LDV/SOF for 8 to 12 weeks following HCV-viremic kidney transplant.[71].
Of the 6 patients who required treatment, 5 patients achieved SVR12, with 1 patient requiring the addition of ribavirin owing to resistance and 2 patients requiring retreatment with second-line DAA agents owing to relapse. Thoracic transplantation
The reported prevalence of HCV infection is as high as 12%. 76 Early studies demonstrated reduced survival in recipients with HCV infection, regardless of acquisition of HCV pre– or post–.
The first prospective study utilizing HCV-viremic hearts included 11 HCV-naive recipients, 9 of whom developed HCV viremia after transplant and 8 of whom achieved SVR12 through treatment with either.
PIB in HCV-viremic cardiac transplant into HCV-naive recipients (n=20) has demonstrated rapid HCV suppression, prevention of chronic HCV infection (SVR12 rate of 100%), and excellent early allograft function (100% at a median follow-up of 10.7 months) in patients receiving HCV-viremic donor hearts.
In the largest-to-date prospective single-center study of 80 patients who underwent heart transplant with HCV-positive donors (70 NAT-positive, GT1-GT3 donors and 10 antibody-positive, NAT-negative donors), 67 of 70 (96%) recipients developed viremia following transplant and started treatment with LDV/.
Shorter duration of DAA treatment with GLE/PIB for 8 weeks following cardiac transplant was evaluated in 22 HCV-naive patients who received HCV-viremic organs.
At 6 months posttransplant, there was no difference between HCV-viremic and HCV-negative recipients when comparing mortality (6.3% vs 3.9%; P=1), primary graft dysfunction (0.0% vs 11.5%; P=.275), clinically significant rejection requiring treatment (31.8% vs 37%; P=.769), or acute cellular rejection (90.9% vs 100%; P=.196). Pancreas transplantation
The data on utilizing HCV-viremic organs in pancreas transplantation are limited.
In 2021, the first reported series included 8 HCV-naive patients who received either deceased donor simultaneous pancreas-kidney transplant or pancreas transplant after living donor kidney transplant.
Length of stay (16 days vs 10 days; P=.06) was similar between those who received HCV-viremic organs and those who did not, respectively.
These preliminary findings suggest that HCV-viremic pancreas transplant may be safely used for potential pancreas recipients; further study regarding morbidity and mortality of pancreas transplantation with HCV-positive donors is needed.
Short-term outcomes for solid organ transplantation appear to be comparable for HCV-viremic and -nonviremic donors, based on the previously discussed preliminary data.
Promising data are most robust in kidney followed by liver transplant but offer limited results past 1 year Findings
Have led to greater utilization of HCV‐positive livers, increasing from 7% to 17% between 2010 and.
With cure rates defined as sustained virologic response 12 weeks after treatment (SVR12) of greater than 98%.16.
Recipients who achieve SVR12 posttransplant have lower rates of liver fibrosis progression (20.5% vs 65.5%; P<.001) and lower mortality rates compared with patients who do not receive or fail treatment.
Treatment with GLE/PIB for 3 months or longer posttransplant in 80 liver transplant and 20 kidney transplant patients resulted in an SVR12 rate of 98%.
In posttransplant patients with HCV GT4 infection, SVR12 was achieved by 78% of patients who received 12 weeks of treatment and 94% of patients who received 24 weeks of treatment.
Produced similar 1-year patient and graft survival when compared with HCV-naive patients who received nonviremic livers (n=231), at 93.4% vs 93.9% (P=.89) and.
HCV seropositivity was reported to be an independent risk factor for increased mortality when matched with controls (2.8-fold greater; 95% CI, 1.3-5.7; P=.006) and for the development of accelerated allograft vasculopathy when compared with matched controls, with a hazard ratio of 9.4 vs 3.08 Conclusion
Organ transplantation in the United States is negatively impacted by long waitlist times and high waitlist mortality owing to organ shortages.
The use of HCV-viremic grafts appears to be efficacious and well tolerated.
This practice has demonstrated acceptable short-term outcomes and has the potential to significantly close waitlist gaps and decrease morbidity and mortality.
DAA therapy posttransplant is essential and patients should be fully informed of the associated risks, including the potential of HCV treatment failure.
It remains unclear whether HCV infection in posttransplant patients may lead to lasting changes to the immune system or inadvertent interactions with immunosuppressive therapy.
I like your clinical approach and well-structured extensively detailed summary quoting a number of trials related to HCV and various types of transplants
Introduction: HCV is one of the common causes of CLD that necessitates liver transplantation. In the past, organs from HCV deceased donors were discarded. in the era of DAA with good success rates & manageable S/E, the utilization of HCV-positive organs is increasing. Hepatitis C Virus Infection and Direct Acting Antiviral Therapy: With the use of DAA, the cure rates defined as sustained virological response 12 weeks after treatment reach up to 98%. the availability & safety of these drugs gave the choices of ttt of HCV before or after the transplantation. Patients with low baseline child-pugh score, low baseline model for ESLD score<16 & absence of complications of portal HTN will benefit from TTT of HCV before transplantation in the form of improving liver enzymes & reducing the risk of reinfection of the allograft, while patients with advanced liver disease with child-pugh class C cirrhosis will not benefit with low SVR12 rates. Direct-Acting Antiviral Therapy and Liver Transplantation: Persistent HCV infection after a liver transplant is associated with bad outcomes & high rates of graft cirrhosis. With the use of DAA after a liver transplant, the outcomes are excellent in the form of SVR12 rates & low rates of liver fibrosis. The HCV-TARGET trial evaluated liver transplant and dual liver-kidney transplant recipients with HCV infection treated with LDV/SOF, ombitasvir/paritaprevir/ritonavir plus dasabuvir (Viekira Pak, AbbVie), or SOF/DAC (Darvoni, Beacon) using the Hepatitis C Therapeutic Registry and Research Network database. Liver transplant and dual liver-kidney transplant recipients had 96.6% and 90.9% SVR12. Four liver transplant recipients had acute rejection. The large HCV-TARGET cohort’s real-world results supported ribavirin-free liver transplantation. In transplant recipients who have compensated cirrhosis, DAA therapy following transplant is safe and efficacious. Treatment with SOF/VEL for 12 weeks in 14 liver transplant recipients with HCV GT1 to GT4 infection and cirrhosis resulted in an SVR12 rate of 93% Defining Hepatitis C Virus–Positive Donors: When considering organ transplants from an HCV-positive donor, the risks of disease transmission vary greatly between seropositive and viremic donors. Donors who are HCV positive by serologic testing but NAT negative (nonviremic) are thought to have had spontaneous clearance, effective treatment, or a false-positive antibody result and cannot transmit HCV. A viremic HCV-seropositive donor is a high-risk disease transmitter. An acutely infected HCV-negative donor with NAT positivity (viremic) is a high-risk donor. Despite testing advancements, HCV transmission occurs throughout the 1-week eclipse period between virus exposure and positive NAT results. Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus–Negative Recipients: Ø Liver transplantation: Two large retrospective studies evaluated HCV-viremic donors in nonviremic liver transplant recipients and demonstrated no differences in patient or graft survival when compared with nonviremic donors. In a multicenter investigation on early HCV infection, SOF/VEL once daily after 12 weeks after viremia demonstrated SVR12 in all patients (13 liver, 11 kidney). However, major adverse events in this study included biliary sclerosis, cardiomyopathy, and graft-vs-host disease, which caused multiorgan failure and death, necessitating cautious monitoring for unfavorable immunologic events. A prospective multicenter analysis of HCV-naive liver transplant and dual liver-kidney transplant outcomes found HCV-related acute membranous nephropathy resulting in end-stage kidney disease despite SVR12. All HCV-viremic organ recipients (n=20) achieved SVR12, but HCV-related problems require careful and longer-term follow-up. Ø Renal transplanatation: the availability of DAA therapy and its administration around the time of transplant minimizes the risk of chronic HCV infection in the transplant recipient and thus has led to the recent growth of transplant of kidneys from HCV-infected donors into HCV-naive recipients. The first open-label, single-group pilot project, THINKER trial, examined the safety and effectiveness of kidney transplants from HCV GT1–viremic donors into HCV-negative recipients (D+/R-) followed by 12 weeks of treatment with elbasvir/grazoprevir (EBR/GZR; Zepatier, Merck) (n=10). All recipients had HCV RNA and SVR12. In the THINKER-2 trial (n=20), which included THINKER participants, HCV-negative recipients of HCV-viremic kidneys had HCV cure and excellent renal allograft function with estimated glomerular filtration rates (eGFRs) not significantly different from those of matched recipients of HCV-negative kidneys at 6 months. The EXPANDER trial (n=10) assessed the tolerance and feasibility of DAA prevention before and after renal transplant in HCV-naive patients who received HCV-viremic kidneys (GT1-GT3). In this study, all recipients received a dose of EBR/GZR immediately before the transplant, and recipients of kidneys from donors with GT1 infection received EBR/GZR for 12 weeks after the transplant. Those receiving organs from donors with GT2 or GT3 infection received SOF and EBR/GZR for 12 weeks of triple therapy. Preemptive EBR/GZR for 12 weeks in HCV-naive patients who received HCV-infected kidneys (n=8) resulted in SVR12 with no study-related side effects. SOF-based regimens are safe and effective in HCV-naive recipients undergoing HCV-viremic kidney transplant Seven transplant centers gave 30 HCV-naive patients HCV-viremic kidneys in the MYTHIC study. All 30 participants achieved SVR12 without HCV infection or GLE/PIB-related serious adverse effects. Acute cellular rejection (n=3) and polyomavirus (BK) viremia (n=3) occurred despite acceptable allograft function.
In a large, prospective, real-world trial, 64 HCV-naive patients underwent HCV-viremic kidney transplant and posttransplant NAT to identify therapy requirements. 73; 61 patients acquired viremia, 41 achieved SVR12, 10 had undetectable virus levels, and 7 continued treatment. One NS5A-resistant nonresponder. Patients and grafts survived 98% at a median 8-month follow-up. Thoracic transplantation: The single-center pilot DONATE-HCV trial transplanted HCV-viremic organs into 8 heart and 36 lung HCV-naive recipients who preemptively received SOF/VEL for 4 weeks. HCV viremia emerged in 95% of recipients immediately after transplant, and of the first 35 patients who completed 6 months of follow-up, 100% (95% CI, 90%-100%) achieved SVR12 with excellent graft function. HCV-naive patients (16 lung receivers and 22 heart recipients) who received HCV-viremic donor organs and DAA therapy with GLE/PIB for 8 weeks had similar results. 86 11 of 16 lung recipients developed viremia posttransplant and all attained SVR12. At 6 months posttransplant, HCV-viremic and HCV-negative recipients had similar mortality (6.3% vs 3.9%; P=1), primary graft malfunction (0.0% vs 11.5%; P=.275), clinically severe rejection requiring therapy (31.8% vs 37%; P=.769), and acute cellular rejection (90.9% vs 100%). Conclusion: Organ shortages cause long waitlists and significant waitlist mortality in the US. DAA-treated HCV-viremic organ transplantation into HCV-naive recipients improves patient and allograft survival. HCV-viremic grafts are effective and well-tolerated in selected patients. This method has good short-term results and can reduce waiting gaps and morbidity and death. DAA medication posttransplant is essential, but patients should be warned of the risks, including HCV treatment failure. Posttransplant HCV infection may cause immune system alterations or immunosuppressive therapy interactions. HCVviremic organ utilization long-term results are not still fully established.
II. Hepatitis C Virus Treatment and Solid Organ Transplantation
—————————————————————————————————————— Please summarise this article.
HCV infection is a common indication for liver transplantation, and the demand for deceased-donor organ transplantation continues to exceed the available supply.
HCV therapy with direct-acting antiviral agents has revolutionized the management of liver transplant candidates and transplant recipients, and newer antiviral therapies have paved the road for use of HCV-viremic organs.
HCV infection affects 130 million to 150 million people worldwide and is one of the leading causes of liver disease and leading indications for liver transplantation.
The availability of HCV-positive organs continues to increase, representing 9.7% of deceased-donor livers in 2019. Several strategies have been implemented to expand the donor pool, including donation after cardiac death, use of living donors, and increased utilization of high-risk donors.
The emergence of DAA therapy has led to greater utilization of HCV‐positive livers, and the rising national opioid epidemic has resulted in an increase in HCV transmission.
These liver allografts have been associated with lower rates of biliary complications and improved rejection rates, graft survival, and overall survival.
HCV treatment prior to and after organ transplantation has increased the number of organ transplants and decreased waitlist mortality.
Hepatitis C Virus Infection and Direct-Acting Antiviral Therapy
DAA therapies have been introduced to treat chronic HCV infection, with cure rates of greater than 98%.
Nonstructural protein 5B inhibitor sofosbuvir (SOF) has been approved for HCV treatment in combination with a NS5A inhibitor, nonstructural protein 3/4A (NS3/4A) protease inhibitor, and ribavirin.
GLE/PIB was first approved in 2017 for the treatment of HCV infection without cirrhosis or with mild cirrhosis.
Pretransplant DAA therapy reduces the risk of reinfection of the allog.
Direct-Acting Antiviral Therapy and Liver Transplantation
Direct-Acting Antiviral Therapy and Liver Transplantation has demonstrated excellent outcomes, with lower rates of liver fibrosis progression and lower mortality rates compared to those who do not receive or fail treatment.
HCV infection after liver transplant results in a variable clinical course ranging from mild fibrosis to severe graft damage, with progressive centrilobular ballooning degeneration, bridging fibrosis, and cholestasis seen in 20% to 40% of posttransplant patients.
With the increasing use of DAA therapy, significant HCV-related progression of liver disease posttransplant is now uncommon.
Recipients who achieve SVR12 posttransplant have lower rates of liver fibrosis progression and lower mortality than those who do not receive or fail treatment.
Treatment of HCV infection in patients who undergo simultaneous liver-kidney transplant is safe and efficacious, with 96.6% and 90.9% SVR12 rates.
The use of a pangenotypic, ribavirin-free regimen in posttransplant patients without cirrhosis has been successful, with the MAGELLAN-2 study confirming the safety and efficacy of GLE/PIB once daily for 12 weeks in 80 liver transplant and 20 kidney transplant patients.
Treatment with SOF/VEL for 12 weeks resulted in an SVR12 rate of 93%. SOLAR-1 and SOLAR-2 were 2 large trials that evaluated LDV/SOF plus ribavirin in liver transplant recipients with HCV GT1 to GT4 infection and liver disease.
HCV eradication led to use of DAA therapy for HCV infection posttransplant.
=================================================================== Defining Hepatitis C Virus–Positive Donors
HCV-positive donors encompass any stage of HCV infection, and nucleic acid testing (NAT) provides a more accurate assessment of transmission risk.
It is important to distinguish between seropositive and viremic donors when discussing organ transplant from an HCV-positive donor, as the risks of disease transmission vastly differ.
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus Negative Recipients
The availability of DAA therapy has increased the utilization of HCV-infected organs in transplant recipients, and early data have shown favorable long-term graft outcomes.
Liver Transplantation
Two large retrospective studies evaluated HCV-viremic donors in nonviremic liver transplant recipients and showed no differences in patient or graft survival.
HCV treatment within 3 months of transplantation increases the probability of successful graft function and reduces waitlist mortality.
GLE/PIB has been used successfully in HCV-naive patients.
Immediate treatment with GLE/PIB for HCV-viremic liver transplant into uninfected recipients is safe and efficacious, and initiation of DAA therapy within 90 days of transplant has also demonstrated favorable outcomes.
A preemptive antiviral strategy using SOF/VEL is successful in achieving SVR12, but serious adverse events such as biliary scle-rosis, cardiomyopathy, and graft-vs-host disease are still needed.
Renal Transplantation
The prevalence of HCV among end-stage renal disease patients is 0.2% to 6%, and HCV infection is a common complication after renal transplant.
Outcomes for untreated HCV infection in HCV-seropositive renal recipients are significantly worse than in their HCV-negative counterparts, with higher all-cause mortality and graft loss.
However, studies in the past decade have demonstrated promising long-term outcomes, with 5- and 10-year patient survival being 84.8% and 72.7%, respectively, for HCV-positive graft recipients compared with 86.6% and 76.5%, respectively.
DAA therapy and its administration around the time of transplant minimizes the risk of chronic HCV infection, leading to the recent growth of transplant of kidneys from HCV-infected donors into HCV-naive recipients.
Only a few prospective trials have evaluated the use of DAA therapy in renal transplant recipients with HCV infection.
SOF-based regimens are safe and effective in HCV-naive recipients undergoing HCV-viremic kidney transplant, with SVR12 rates of 100% and stable allograft function.
GLE/PIB once daily for 12 weeks has been shown to be well tolerated in patients with chronic HCV GT1-to GT6 infection who have undergone kidney transplantation.
In the MYTHIC trial, 30 patients achieved SVR12 and no severe adverse events related to HCV infection were noted.
In a large prospective, real-world study, 64 patients developed viremia, with 61 patients achieving SVR12, 10 reaching undetectable viral loads, and 7 remaining on treatment.
Short-course DAA regimens have also been evaluated.
Thoracic Transplantation
Thoracic Transplantation of HCV-infected hearts was nearly abandoned in the era of interferon-based HCV treatment regimens due to concerns about virally mediated coronary vasculopathy and development of severe and rapidly progressive liver disease.
Donor HCV seropositivity was reported to be an independent risk factor for increased mortality and accelerated allograft vasculopathy when compared with matched controls.
Preemptive administration of GLE/PIB in HCV-viremic cardiac transplant into HCV-naive recipients has demonstrated rapid HCV suppresion, prevention of chronic HCV infection, and excellent early allograft function.
The USHER trial found that HCV GT1–viremic hearts were transplanted into HCV-naive recipients and received 12-week treatment with EBR/GZR and demonstrated SVR12 rates of 90%.
There were no serious adverse events from HCV transmission or treatment.
The DONATE-HCV trial evaluated the safety of using HCV-viremic organs for transplantation, finding that 6-month HCV-free survival was 86%.
The most common adverse events were respiratory complications and infections, and serious adverse events requiring admission to the hospital occurred in 45% of recipients.
Pancreas Transplantation
HCV-viremic pancreas transplant may be safely used for potential pancreas recipients, but further study is needed to determine morbidity and mortality.
Short-term outcomes for solid organ transplantation appear to be comparable for HCV-Viremic and nonviremic donors, with promising data in kidney followed by liver transplant.
The data on utilizing HCV-viremic organs in pancreas transplantation is limited, with promising results in kidney followed by liver transplant but limited results past 1 year.
Organ transplantation in the US is negatively impacted by long waitlist times and high mortality due to organ shortages, but transplantation of HCV-viremic organs into HCV-naive recipients provides excellent patient and allograft survival and has the potential to close waitlist gaps and decrease morbidity and mortality.
I like your clinical approach and well-structured detailed summary related to HCV and transplant.Typing whole sentence in bold or typing in capitals amounts to shouting.
Hepatitis C Virus Treatment and SOT Summary of the Article Introduction
HCV infection is the leading cause of liver disease and liver failure and the leading indication for liver Tx.
HCV+ organs are increasing with increasing demand for donation, although in the past the HCV + organs were discarded, a new strategy was implemented to keep the increasing demand and to increase the donor pool, by using a high-risk organ (HCV, HBV, and HIV).
With the introduction of the new DAA and its high great success rate led to great utilization of the organs from HCV+ livers which increase from 7% to 17% between 2010 and 2015.
Hepatitis C virus infection and DAA therapy
The new DAA strategy has been introduced with a success rate defined as a sustained virological response of 12 weeks after treatment of greater than 98%, and effectivity and safety profile help in reducing the rate of HCV infection.
The new therapy includes
a) Sofosbuvir (5B inhibitor). b) Ledipasvir (NS5A inhibitor). c) NS3/4A protease inhibitor. d) Ribavirin.
The combination (LDV/SOF 90/400 mg) (Harvoni, Gilead) OD is well tolerated and produces a high SVR12 rate in HCV GT 1, 4, and 6 infections.
The combination (SOF/NS5A), (SOF/VEL), Epclusa, Gilead, and OD, provides an SVR12 rate of greater than 95% across all GTs and has a safety profile.
The combination of NS3/4A (Glecaprevir) and NS5A inhibitor (pibrentasvir) (GLE/PIB), (Mavyret, AbbVie) was approved in 2017 for the treatment of HCV infection without cirrhosis or without mild cirrhosis, and it is well tolerated and results in SVR12 rate greater than 97% across all GTs.
DAA therapy shown to improve liver function in decompensated cirrhosis, some to the extent of no longer requiring liver Tx.
DAA pre-Tx reduces the risk of allograft reinfection.
Interpretation of HCV Diagnostic testing Results
HCV Ab(+) and HCV(+) === Active HCV infection, with high transmission risk.
HCV Ab(-) and HCV(+) === Acute HCV infection in Ab window period or false + NAT, with high transmission risk.
HCV Ab(+) and HCV NAT (-) === No active HCV infection, cleared or treated HCV infection, or false+ Ab, with low transmission risk.
HCV Ab(-) and HCV NAT(-) === No HCV infection, with no transmission risk
DAA and liver Tx
HCV infection post-Tx can result in
a) Mild to advanced fibrosis. b) Severe graft damage. c) Progressive centrilobular ballooning degeneration. d) Bridging fibrosis. e) Cholestasis. f) Graft cirrhosis.
DAA results in a significant reduction in the incidence of the above-mentioned outcomes.
Recipients achieve SVR12 can result in
a) Lower rate of liver fibrosis progression (20.5% vs 65.5%) b) Lower mortality rate, compared to patients who do not receive DAA. HCV-TARGET trial
Evaluate liver Tx and and dual liver-kidney Tx recipients with HCV.
Rceipients treated with (LDV/SOF), plus dasabuvir or SOF plus daclatasvir (SOF/DAC).
SVR12 rates inliver Tx was 96.6%.
SVR12 rates in dual liver/kidney Tx was 90.9%.
4 cases of acute rejection in liver Tx.
Confidence treatment regiment in liver Tx with a ribavirin-free regimen.
MAGELLAN-2 study
A phase 3 open-label trial.
Confirmed the safety and efficacy of GLE/PIB OD for 12 weeks in patients receive a liver or kidney Tx with
a)HCV GT1 to GT6. b) HCV GT1, GT2. c) HCV GT4 to GT6.
SVR12 rate was 98%.
No patient D/C treatment because of the side effects.
1 virologic failure.
1 adverse effect not related to treatment.
SOLAR-1 and SOLAR-2
2 large trials evaluate LDV/SOF plus ribavirin in liver Tx recipients with HCV GT1 to GT4 infection and liver disease.
SVR12 achieves 96% to 98% in (SOLAR-1) recipients without cirrhosis or with decompensated cirrhosis.
13n patients D/C treatment because of the adverse effects.
10 patients died, mainly due to hepatic decompensation.
SOLAR-2, a large multicenter open-label study that included HCV GT1 liver Tx with
a) No cirrhosis. b) Child-Turcotte-Pugh (CTP)-A, CTP-B, or CTP-C cirrhosis. c) Fibrosing cholestatic hepatitis.
Treatment was 12 or 24 weeks of LDV/SOF plus ribavirin OD demonstrate
a) SVR12 rate of 100% in CTP-A, 12 weeks. b) SVR12 rate of 96% in CTP-A 24 weeks. c) SVR12 rate of 95% in CTP-B, 12 weeks. d) SVR12 rate of 100% in CTP-B 24 weeks.
7 patients D/C LDV/SOF because of the adverse effects.
17 patients died, mainly due to hepatic compensation.
Defining Hepatitis C virus-positive Donors
HCV NAT detects antibodies within 2 to 6 months after exposure.
HCV NAT has a sensitivity of 85% to 100% and a specificity of 99% to 100%.
HCV seropositive (NAT negative) is a non-viremic donor.
HCV seropositive (NAT positive) is a viremic donor.
Liver transplantation
Two large retrospective trials show no difference in patients and graft survival between a group of a viremic donor to a non-viremic recipient compared to a non-viremic donor/recipient.
OPTN data (2016-2020), comparing 568 liver Tx recipients, showed that there is no difference in graft survival in recipients with or without HCV infection who received HCV-viremic organs in 2 years duration.
Renal transplantation
HCV infection is common post renal Tx.
The outcome of untreated HCV infection is worse than in HCV seronegative recipients.
HCV+ recipients are associated with higher all-cause mortality and graft loss.
In a study of 545 kidney transplant recipients with HCV+, a 5 to 10 years patient survival was
a) 84.8% and 72.7%, respectively for HCV+graft. b) 86.6% and 76.5% respectively for HCV-graft.
The availability of DAA at the time of Tx is lead to a great growth of Tx of HCV+ donor grafts.
THINKER trial demonstrated the safety and efficacy of DAA of D+/R- following treatment with (EBR/GZR) for 12 weeks, all recipient has detectable HCV RNA, and all attained SVR12.
THINKER2 trial; included participants of the THINKER1 trial involved HCV-ve recipients of HCV viremic kidneys and showed a cure and excellent renal allograft function with eGFR nearly similar to those of matched recipients of HCV-ev kidneys at 6 months.
EXPANDER trial; showed promising results of using DAA pre-emptively and posy Tx from recipients with HCV-ve and donors with HCV+ve.
Pancreas transplantation
Limited data.
2021 the 1st reported series includes 8 HCV-naive patients who receive either deceased donor simultaneous pancreas/kidney Tx or pancreas Tx in living kidney Tx.
All patients develop viremia and were treated with either GLE/PIB or SOF/VEL and all achieved SVR12.
All recipients had excellent pancreas graft function and rejection rate.
Further study is needed to establish the safety of using HCV + donors to HCV-ve recipients.
Conclusion DAA is available and showing promising results, and open a window of using HCV+ve donor in HCV-ve recipients
II. Hepatitis C Virus Treatment and Solid Organ Transplantation
Please summarise this article.
Introduction
Hepatitis C virus (HCV) infection affects approximately 130 million to 150 million people worldwide.
The availability of HCV-positive organs continues to increase, representing 9.7% of deceased-donor .
In the past , organs from deceased donors infected with HCV were discarded because of high transmission risk during reperfusion and risk of significant post transplant morbidity and mortality livers in 2019.
HCV changed with the emergence of direct-acting antiviral (DAA) therapy, this lead to greater utilization of HCV‐positive livers, increasing from 7% to 17% between 2010 and 2015.
There have been significant advancements in the science of HCV therapy and in the use of HCV-positive organs, thereby substantially increasing the number of organ transplants and decreasing waitlist mortality. Hepatitis C Virus Infection and DirectActing Antiviral Therapy
The pan genotype DAAtherapieswhen started and introduced lead to cure rate of chronic HCV infection about 98%.( sustained virologic response 12 weeks after treatment(SVR12))
The availability of safe and highly effective therapy has led to the delicate consideration of treating HCV infection prior to transplant or deferring therapy until after transplant.
pretransplant DAA therapy reduces the risk of reinfection of the allograft.
The improvement in liver function from pretransplant therapy include low baseline Model for End-Stage Liver Disease score (<16), low baseline Child-Pugh score, and the absence of portal hypertension complications.
more recent practice of utilizing HCV-viremic donors has changed overall access to transplant and should be taken into consideration when deciding optimal timing of HCV treatment. Direct-Acting Antiviral Therapy and Liver Transplantation
The infection after liver transplant causing a variable clinical course ranging from mild fibrosis to severe graft damage, HCV infection can cause Progressive centrilobular ballooning degeneration, bridging fibrosis, and cholestasis are seen in 20% to 40% of posttransplant patients.
Also Advanced fibrosis can occur in up to 45% of post transplant patients, and graft cirrhosis can develop within as little as 5 years post transplant.
Increasing use of DAA therapy, significant HCV-related progression of liver disease post transplant is now uncommon.
Use of DAA therapy following liver transplant has demonstrated excellent outcomes.
Treatment of HCV infection in patients who undergo simultaneous liver-kidney transplant is both safe and efficacious.
The use of a pangenotypic, ribavirin-free regimen in posttransplant patients without cirrhosis has demonstrated similar overall success.
Treatment with SOF/VEL for 12 weeks in 14 liver transplant recipients with HCV GT1 to GT4 infection and cirrhosis resulted in an SVR12 rate of 93%.
In SOLAR-1, SVR12 was achieved in 96% to 98% of transplant recipients without cirrhosis or with compensated cirrhosis.
Although historical data demonstrate that HCV infection has a negative long-term impact on both patient and graft survival, promising data on the safety and efficacy of DAA therapy for the treatment of HCV infection post transplant led to a paradigm shift. Defining Hepatitis C Virus–Positive Donors
Definition of HCV positive donor is infection include any stage of the affection which establish through serology tests such as chemistry assays and enzyme immune assays to detect antibodies within 2 to 6 months after exposure, but nucleic acid testing (NAT) detects RNA 5 to 7 days after exposure and provides a more accurate assessment of transmission risk.
HCV NAT has a sensitivity of 85% to 100% and a specificity of 99% to 100%.
If NAT negative means spontaneous clearance or successful treatment of infection.
If NAT positive means active infection and poses a high risk for disease transmission.
Despite improvements in testing, risk of HCV transmission remains during the 1-week eclipse period between viral exposure and positive NAT results, particularly in persons who inject drugs. Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients
Treatments for HCV have improved outcomes, and perioperative use of(direct acting anti viral therapy) DAA therapy has increased the utilization of HCV- viremic donor organs.
In a study published in 1998, 22 patients with HCV received HCV-seropositive grafts and had excellent 4-year patient and graft survival, 83.9% and 71.9%, respectively, vs 79.1% and 76.2%, respectively, with HCV-seronegative donor grafts (P=not significant [NS]).52 In a larger study that included 2923 transplant recipients with HCV, 96 and 2827 received HCV-positive and -negative organs, respectively, and had comparable 2-year survival rates (90% vs 77%; P=.01). Liver Transplantation
Two large retrospective studies evaluated HCV-viremic donors in nonviremic liver transplant recipients and demonstrated no differences in patient or graft survival when compared with nonviremic donors. Renal Transplantation
The prevalence of HCV among end-stage renal disease patients is 0.2% to 6%, and HCV infection traditionally has been a common complication after renal transplant.61 Outcomes for untreated HCV infection in HCV-seropositive renal recipients are significantly worse than in their HCV-negative counterparts.
The THINKER trial show in 2017 the safety and efficacy of the transplant of kidneys from HCV GT1–viremic donors into HCV-negative recipients (donor positive, recipient negative [D+/R-]) followed by treatment with elbasvir/grazoprevir (EBR/GZR; Zepatier, Merck) for 12 weeks (n=10).
Shorter-course DAA regimens have also been evaluated with promising results. Thoracic Transplantation
Among heart transplant recipients, the reported prevalence of HCV infection is as high as 12%.76 Early studies demonstrated reduced survival in recipients with HCV infection, regardless of acquisition of HCV pre– or post– heart transplant. Conclusion
1.Transplantation of HCV-viremic organs into HCV-naive recipients followed by the use of DAA agents provides excellent patient and allograft survival, this lead to shortage list of waiting.
2.In carefully selected patients, the use of HCV-viremic grafts appears to be efficacious and well tolerated.
3.patients should be fully informed of the associated risks, including the potential of HCV treatment failure.
Summary
HCV infection affects 130-150 million people world wide.
End stage liver disease secondary to HCV infection is leading cause for liver transplant.
DAA have cure rates, defined as sustained virological response at 12 weeks (SVR 12), greater than 98%.
DAA have been shown to improve liver function in patients with decompensated cirrhosis and when given pre-transplant can reduce the risk of allograft reinfection.
Pre-transplant DAA are beneficial in patients with low Child Pugh score and those without portal hypertension.
Patients with advanced liver disease and Child Pugh score class C the SVR12 rates are low thus treatment should be deferred.
HCV antibodies are detected 2-6 months after infection while HCV NAAT is positive within 5-7 days after exposure thus a more accurate assessment for transmission risk.
Donors with HCV antibodies but negative NAAT may indicate past infection that have cleared and have low risk of transmission.
Donors with positive HCV antibodies and NAAT indicates an acute infection and have a high risk of transmission.
Donors with negative antibodies and positive NAAT indicates acute infection in the window period and also have a high risk of transmission.
Use of DAA has allowed transplantation of organs from HCV positive donors to HCV naive recipients with good outcomes.
Post liver transplantation persistence of HCV infection is associated with variable ranges of liver injury from mild fibrosis to severe graft failure. Use DAA has reduced this incidence.
GLE/PIB has been used successfully in HCV naive recipients who receive liver transplants from HCV viremic donors.
In kidney transplant HCV seropositivity is associated with higher all cause mortality and graft loss.
The THINKER trial HCV naive recipients received a kidney froM HCV viremic GT1 donors. EBR/GZR was given for 12 weeks and all had detectable HCV RNA and all attained SVR12.
In the THINKER 2 trial all participants in THINKER trial attained HCV cure with excellent allograft renal function.
GLE/PIB once daily dose for 12 weeks has been well tolerated in kidney transplant recipients with chronic HCV GT1-6. However shorter course regimen (4 weeks) have been evaluated with promising results.
Further studies are also required to determine the long term outcome of utilising HCV viremic organs.
I appreciate your concern that HCV related complications can happen at any time so long term follow up is important. Please use headings and sub-headings to make easier to read your write-up. Please use bold or underline to highlight headings and sub-headings.
Introduction
o The demand for organs continues to rise resulting in considerable waitlist mortality
o Organs categorized as high risk are those associated with an increased risk for the transmission of blood-borne viruses, including HIV, hepatitis B virus, and HCV
o The high success rate of DAA for HCV have led to greater utilization of HCV‐positive livers, increasing from 7% to 17% between 2010 and 2015
o Aim of the study: reviews the data on HCV treatment prior to and after organ transplantation
Hepatitis C Virus Infection and Direct Acting Antiviral Therapy
Pangenotypic DAA treatment of chronic HCV infection leads to cure rates of greater than 98% [sustained virologic response 12 weeks after treatment (SVR12]
The availability of safe and highly effective therapy has led to the treatment of HCV infection prior to transplant or deferring therapy until after transplant
Patients with advanced liver disease are unlikely to improve with DAA therapy and those with Child-Pugh class C cirrhosis have lower SVR12 rates DAA:
1. Nonstructural protein 5B inhibitor: sofosbuvir (SOF)
2. nonstructural protein 5A (NS5A) inhibitor: ledipasvir (LDV) , velpatasvir (VEL), pibrentasvir (PIB)
3. nonstructural protein 3/4A (NS3/4A) protease inhibitor: glecaprevir (GLE)
4. ribavirin
o LDV/SOF combination (90 mg/400 mg): once daily, is well tolerated and produces high SVR12 rates in HCV genotype 1, 4, 5, and 6 infection
o SOF/VEL combination: once daily, provides SVR12 rates of greater than 95% across all genotypes
o GLE/PIB combination: first approved in 2017 for the treatment of HCV infection without cirrhosis or with mild cirrhosis. Is well tolerated and results in SVR12 rates greater than 97% across all genotypes
Direct-Acting Antiviral Therapy and Liver Transplantation
o With the current use of DAA therapy, significant HCV-related progression of liver disease posttransplant is now uncommon
o Recipients who achieve SVR12 posttransplant have lower rates of liver fibrosis progression and lower mortality
o Persistence of HCV infection after liver transplant results in a variable clinical course ranging from mild fibrosis to severe graft damage:
1. Progressive centrilobular ballooning degeneration, bridging fibrosis, and cholestasis (20% to 40%)
2. Advanced fibrosis (45%)
3. graft cirrhosis can develop within 5 years
4. 5-10% will develop severe progressive cholestatic hepatitis leading to liver failure
o DDA in transplant recipients with compensated cirrhosis is safe and efficacious
Defining Hepatitis C Virus–Positive Donors
o Any stage of HCV infection
o Serologic tests detect antibodies within 2-6 months after exposure and NAT detects RNA 5-7 days after exposure
o HCV NAT has a sensitivity of 85-100% and a specificity of 99-100%
Interpretation of HCV Diagnostic Testing Results:
1. HCV Antibody+/HCV NAT+: Active HCV infection and transmission risk is high
2. HCV Antibody-/HCV NAT+: Acute HCV infection in antibody window period or false-positive NAT, transmission risk is high
3. HCV Antibody+/HCV NAT-: No active HCV infection, cleared or treated HCV infection, or false-positive antibody and transmission risk is low
4. HCV Antibody-/HCV NAT-: No HCV infection and no risk of transmission
High – + Acute HCV infection in antibody window period or false-positive NAT High + – No active HCV infection, cleared or treated HCV infection, or false-positive antibody Low – – No HCV infection None
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients
Early data have demonstrated favorable long-term graft outcomes in patients transplanted with HCV-seropositive donors
Liver Transplantation
o Two large retrospective studies evaluated HCV-viremic donors in nonviremic liver transplant recipients and demonstrated no differences in patient or graft survival when compared with nonviremic donors
Renal Transplantation
Prevalence of HCV among ESRD patients is 0.2-6%
Promising long-term outcomes of HCV-seropositive recipients transplanted with kidneys from HCV-positive donors
THINKER trial: transplant of kidneys from HCV GT1–viremic donors into HCV-negative recipients. HCV cure and excellent renal allograft function with eGFR not significantly different from those of matched recipients of HCV-negative kidneys at 6 months The EXPANDER trial: examined the tolerability and feasibility of DAA prophylaxis before and after renal transplant in HCV-naive patients who received HCV-viremic kidneys (GT1-GT3). It concluded that SVR12 was achieved with no study-related adverse events
Thoracic Transplantation
o In heart transplant recipients, donor HCV seropositivity was reported to be an independent risk factor for increased mortality when matched with controls and for the development of accelerated allograft vasculopathy when compared with matched controls
o Only a few studies have evaluated the safety of using lungs from HCV-viremic donors for transplantation
Pancreas Transplantation
Data on utilizing HCV-viremic organs in pancreas transplantation are limited
Conclusion
o Transplantation of HCV-viremic organs into HCV-naive recipients followed by the use of DAA agents provides excellent patient and allograft survival
o In carefully selected patients, HCV-viremic grafts can be used and well tolerated
o Patients should be fully informed of the risks, including the potential of HCV treatment failure
Historically, organs from diseased donors with HCV infection used to be discarded as they are categorized by public health as high risk because of the rate of infectivity to the recipients. Unfortunately, with the growing incidence of HCV infection because of increased abuse of opioids, so also is the need for organs among those on the waiting list. Notably, the discovery of direct-acting antiviral changed this narrative as a cure for HCV infection is now achievable either before or after organ transplantation.
Hepatitis C virus infection and Direct-acting antiviral therapy
There is no availability of pan-genotypic DAA with a sustained virology response 12 weeks after treatment > 98%
The availability of DAA has made treatment of HCV infection to be possible pre or post-organ transplantation
Patients with advanced liver disease or Child-Pugh score C are unlikely to respond to the use of DAA
Defining Hepatitis C virus-positive donor
Serological tests can detect HCV antibodies within 2 to 6 months after exposure while the NAT can detect them within 5-7 days
Potential donors that is serologically positive but had NAT test negative can donate as the chances of transmitting the infection are considered low
The risk of transmission of HCV infection is still possible during the one week it takes for a NAT test to be possible
The hepatitis C-positive donor for a negative recipient
The organs form HCV positive diseased donors are usually discarded before the advent of DAA
There are favorable data now toward receiving organs from HCV positive donor by a negative recipient with a good outcome for both the patient and the graft
Liver transplantation
Data OPTN showed that 30 HCV-naive patients received HCV-viremic livers and had similar 1-year patient survival rates when compared with HCV-seropositive but NAT-negative and nonviremic livers
The first trial of giving HCV D+/R- where the recipient received SOF/ VEL-based LDV/SOF-based, or SOF/DAC-based therapy and they achieved SVR12
HCV-induced acute MN was observed in a multicentre study of dual liver-kidney transplant
Renal transplant
Studies have shown good response in HCV infection D+/R+ (Kidney) with long-term outcomes of 82% and 74% after 5 and 10 years respectively
Trials like THINKER, THINKER-2, and EXPANDER have gone as far as using D+/R- kidney transplantation with good outcomes
All the trial has been successful with the use of DAA either before or after kidney transplantation
The majority of the treatment with DAA is usually for 12 weeks, but shorter course treatment for 4 weeks is also showing promise
Conclusion
The breakthrough obtained in the use of DAA for the treatment of potential recipients about to receive organs from a donor with a positive HCV infection has reduced the waiting list and made more organs available for transplantation. Nevertheless, proper counseling and informed consent must be obtained before the surgical procedure, and care must be taken in watching out for drug-drug interactions
This review article addresses the recent statistics of HCV treatment before and after organ transplantation Introduction
HCV infections account for 130-150million worldwide and it’s one of the leading causes of end-stage liver disease and liver transplantation with the increased shortage of donors, earlier organs from HCV infection donors are discarded due to the risk of infection and complications however with the improvement in the treatment of HCV infection by the DAA therapy with high cure rate nowadays we can use organs from DD with active HCV infection and its one way to expand the donor pool, especially with an increased rate of HCV infection among the opioids addictions and the number of overdose-death donors increased from 1.1% to
13.7% between 2000 and 2017. They usually are young healthier DD with less comorbid compared to old donors. The HCV-viremic donor organs are often
of relatively high quality. These liver allografts have been associated with lower rates of biliary complications and improved rejection rates, graft survival, and overall
survival. Hepatitis C Virus Infection and Direct Acting Antiviral Therapy
The new pan-genotypic Direct antiviral therapy (DAA) with different combinations confirms its efficacy and safety profile and provides a high cure rate of> 98% usually 12 weeks course can be given pre or post-transplantation, DAA therapy has been revealed to recover liver function in patients with decompensated cirrhosis, to the level that delays the need for liver transplantation also pretransplant DAA therapy reduces
the risk of reinfection of the allograft. However, not all patients with end-stage liver disease from HCV infection will benefit from treatment prior to liver transplantation, only those with low baseline Model for End-Stage Liver Disease score (<16), low baseline Child-Pugh score, and the absence of portal hypertension complications. while those with advanced liver cirrhosis are unlikely to improve with DAA
therapy including those with Child-Pugh class C cirrhosis as they have lower SVR12 rates and preferred not to offer DAA therapy. However, the recent trend to accept HCV viremic donors is one way to expand access to transplantation with attention to providing HCV therapy at the ideal time
Direct-Acting Antiviral Therapy and Liver Transplantation
Persistent HCV infection after transplantation can lead to different clinical sequences from mild liver fibrosis to progressive graft failure due to bridging fibrosis, and cholestasis is seen
in 20% to 40% of posttransplant patients Advanced fibrosis can occur in up to 45% of posttransplant patients, and graft
cirrhosis can develop within 5 years post-transplant After liver transplantation, also there is a risk of developing severe progressive cholestatic hepatitis leading to liver failure in about 5-10%
all the above complications are now considered rare after the use of DAA therapy and patients have an excellent outcomes and lower mortality compared to those who did not receive or failed the treatment
most of the recent evidence from multiple studies addressed the efficacy and safety profile of the pan-genotypic DAA with 12-24 weeks SVR and a cure rate of 96-100% of HCV infection after transplantation ( liver, kidney or dual kidney and liver transplantation with lower risk of rejection or graft failure, such data encourage the use of HCV infected donors to HCV negative recipients.
Defining Hepatitis C Virus–Positive Donors HCV NAT has a sensitivity of 85% to 100% and a specificity of 99% to 100%
It is important to distinguish between a seropositive and viremic donor when discussing organ transplants from an HCV-positive donor.
HCV viremia when we have both HCV AB +ve by serology test and HCV NAT positive with a high risk of infection
While HCV AB is positive and negative by NAT this indicates a noninfective (nonviremic) donor due to spontaneous clearance of the infection or after successful treatment, of HCV or a false-positive antibody result
An HCV-negative donor that is NAT-positive (viremic) is considered to have an acute infection and poses a high risk for disease transmission
Conclusion
Transplantation of HCV-viremic organs into HCV-naive recipients followed The use of DAA agents provides excellent patient and allograft survival. In carefully selected patients, the
use of HCV-viremic grafts appears to be efficacious and well tolerated with SVR 12 Weeks based on most of the trials with promising short-term outcomes including better survival and less mortality, and a very well-tolerated safety profile of the new DAA therapy. we need more studies in the future to address the long-term outcome of HCV viremic organ utilization
HCV infection affect 130-150 millions persons worldwide.
It is one of the leading cause of liver disease & subsequent need for liver transplantation.
HCV+ organ constitute 9.7% of deceased lover donors in 2019.
HCV organ categorized as high risk for blood born virus transmission (HIV,HBV, HCV).
Due to use of DAA, deceased HCV+ liver pool increased from 7% to 17%.
Usually HCV viremic donor organ are relatively high quality.
Antiviral & HCV infection:
Pangenotype DAA associated with high cure rate (SVR12)>98%.
combination of LDV/SOF is well tolerated & high SVR12 in GT1,4,5 &6.
SOF/VEL combination associated with SVR12 >95% for all GTs with favorable safety profile.
GLE/PIB combination can be used for patients without liver cirrhosis or with mild cirrhosis & SVR12>97% for all GTs.
HVC infection can be treated pre- or post transplantation.
Pre-transplant use of DAA can improve liver graft outcome if MELD score<16 & low Child-Pugh score and not complicated portal hypertension.
DAA & liver transplantation:
Post liver transplant persistent HCV can result in variable degree of liver injury e.g. mild fibrosis to severe graft damage.
Use of DAA result in uncommon progression of HCV-liver disease with excellent outcome.
Post transplant patients with SVR12 associated with lower fibrosis progression(20.5% vs 65.5%) & lower mortality compared to patient failed to achieve SVR12.
DAA found to be safe & effective in patients with HVC+ simultaneous liver/kidney transplantation.
HCV-TARGET study provide evidence of safety & efficacy of ribavirin free regimen in treatment of HCV+ liver transplant recipients.
Pangenotype ribavirin free regimen found to be effective & safe in patients without cirrhosis & compensated cirrhosis
Defining HCV+ donors:
HCV Abs can be detected 2-6 months after exposure but RNA can be rejected by NAT 5-7 days after exposure (sensitivity 85%-100% & specificity 99%-100%).
Distinguishing between seropositive & viremic patient is important in determination risk of transmission.
Seropositive & NAT negative patients mean spontaneous viral clearance, successful treatment or false positive Abs (no risk of transmission documented).
Viremic patient(NAT+) mean acute infection & high risk of transmission.
HCV+ donors to HCV- recipient:
After introduction of DAA, long term graft outcome of HCV+ organ improved.
HCV – & HCV+ organs have comparable 2 year survival.
Liver transplantation:
No difference in patient or graft survival found between viremic & non viremic donors.
Treatment of HCV within 3 month post transplant associated with improve graft survival & reduce waiting list mortality.
GLE/PIB is safe & effective without noticeable drug interaction when used in HCV D+/R-.
DAA with 90 days of transplantation or pre-emptive treatment are effective in treatment but life long follow up needed.
Kidney transplantation:
HCV prevalece in ESRD patients 0.2-6%.
HCV viremic RTR associated with poor prognosis with out treatment.
Several studies results show improved patient & graft survival in HCV D+/R- with use of DAA e.g. EBR/PIB & SOF based regimen.
Short course of DAA was effective treatment in D+/R- HCV Rena transplant.
Thoracic transplantation:
HCV prevalence in heart transplantation 12%.
Pre-emptive use of GLE/PIB in HCV D+/R- heart transplant associated with rapid viral suppression, prevention of chronic infection & excellent early graft function.
Short course(8weeks)DAA in heart transplant associated with high SVR12 with out survival difference.
In lung transplant & HCV D+/R- treated with SOF/VEL for 12 weeks show HCV free survival at 6 months 86%, but risk of infection & rate of hospital admission was higher than D-/R- HCV transplant.
Pancreatic transplantation:
Data are limited.
Available data show excellent graft function.
Low experience with treatment delay, failure & relapse.
Introduction
· Hepatitis C virus infection had resulted in 130 to 150 million infections across the globe. It is a leading cause of liver cirrhosis and hence the need for liver transplantation. In past the HCV infected organs were rejected due fear of transmitting the virus but now days these organs are widely use due shortages of donors and the development of direct -acting antiviral therapy (DAA). Hepatitis C virus Infection and Direct -Acting Antiviral therapy (DAA)
· DAA therapy cure rates or sustained virological response 12 weeks (SVR12) after treatment of chronic HCV is > 98%. These drugs also improve liver functions in decompensated liver disease and liver transplant was not required for some patients because of improvment.
· DAA includes several drug combinations drugs such as: sofosbuvir (SOF)/ Ledipasvir (LDV), SOF/velpatasvir (VEL), and glecaprevir (GLE)/pibrentasvir (PIB)
Direct-Acting Antiviral therapy and liver transplantation
· After introduction DAA therapy, burden of HCV related liver disease post transplantation is no longer a big problem
· These drugs are well tolerated, safe, and efficacious
· The eradication of HCV opened an avenue for the use of HCV-positive organ, first in HCV positive recipients and at the moment in HCV negative recipients
Defining HCV positive donors
1. HCV positive by serology and negative Nucleic Acid Testing (NAT): This may be spontaneous clearance of the virus, previous HCV treatment or false-positive test
2. HCV positive by serology and positive NAT: this is viremic donor with active infection and high risk of transmission
3. HCV negative by serology and positive NAT: this is active infection, high risk donor or false- positive
HCV-positive Donor Transplantation in HCV-negative Recipients Liver transplantation
· Data from the Organ Procurement and Transplantation network (OPTN) from 2016 to 2020, comparable 2 years graft survival rates were seen in 568 liver transplant recipients with and without HCV infection (n= 753, n = 87 respectively) who received viremic organs (90 versus 86% respectively)
· Almost all recipients developed viremia
· The protocol for DAA therapy varies between studies and they were given preemptively, immediately or within 3 months of transplantation Renal transplantation
· In a study of 545 kidney transplants done in HCV-positive recipients, 5-and 10-years survival patient survival were 85 to 73% for HCV-positive recipients compared to 87 to 76.5% for HCV-negative recipients. Similar findings were demonstrated in many other studies for the same topic (THINKER, and THINKER2 trial)
· DAA therapy is tolerated as prophylaxis before and after transplantation, with no study-related adverse events (EXPANDER trial)
Thoracic Transplantation 1.Heart
· At the early phase the program was challenged by HCV induced coronary vasculopathy and severe rapidly progressive live disease and it was nearly abandoned. How ever, the first study utilizing HCV-viremic heart to 11 HCV naïve recipients showed that 9 of the recipients became positive after transplantation and 8 of whom were treated successfully by LDV/SOF or SOF/VEL (G3). One patient died due pulmonary embolism but DAA therapy was well tolerated in all treated recipients. Later studies confirmed demonstrated the same. 2.Lung
· In a study of 22 HCV-negative recipients of HCV-viremic lung, 6 months survival of HCV-viremic and non-viremic lung was 95 versus 94% respectively. HCV positive group had more chest complications and infections compared to non-viremic group 23 versus 18%. Two patients developed HCV relapse after treatment and 10 patients were admitted to the hospital due to serious adverse events.
Pancreas Transplantation
· The preliminary data showed that, HCV-viremic pancreas transplant may be possible for a potential recipient but more studies are needed to understand the outcome of this procedure
Conclusion
· The emergence of DAA therapy led to more utilization of HCV infected donor organs with excellent short post-transplant outcomes. However, longitudinal studies are required to
conceptualized the long-term outcomes of this type of treatment.
Sustained virological response at 12 weeks after treatment (SVR12)
Reduced HCV-related progression of liver disease post-transplantation among positive recipients
Reduces the risk of allograft re-infection among positive recipients
The utility of using Hepatitis C positive donors
When to start treatment
Pre-transplant and achieved SVR before transplantation
Immediate pre-transplant and continued for 12 weeks post-transplant
Within 90 days post-transplant
Duration of treatment
90 days/12 weeks
Hepatitis C virus-positive donor transplantation in hepatitis C-negative recipient (clinical trial)
Liver transplantation
1.OPTN
HCV-viremic donors vs non viremic donors in non-viremic liver transplant recipient
No difference in patients and allograft survival
2.10-HCV negative received HCV viremic donors
HCV treatments within three months post-transplantation increases probability of successful graft function and reduces waitlist mortality
Kidney transplantation
1.THINKER trial (2017)
Open-label, single group, pilot study
HCV-viremic donors to HCV-negative recipients
Post-transplant treatment with EBR/GZR
All had detectable HCV RNA and achieved SVR12
2.THINKER-2 trial
HCV-viremic donors vs HCV-negative kidneys in HCV-negative recipients
Similar renal allograft function and no significance difference
3.EXPANDER trial
Open-label, single centre
DAA {Elbasvir (EBR) + Grazoprevir (GZR)} before and after kidney transplantation among those received HCV-viremic donors-immediately before and continued post-transplantation.
No major adverse events
4.MYTHIC trial
30 HCV naive patients received HCV-viremic donors (7 transplant centres)
Glecaprevir (GLE) + Pibrentasvir (PIB)
Acieved SVR12 with no major AE
Thoracic transplantation
One largest prospective study showed higher rate of graft dysfunction but no differences in the other outcomes inclusive rejection requiring treatment and patients survival.
HCV infection is highly prevalent worldwide causing liver damage, and it is leading indications for liver transplantation.
Utilizations of organs from hepatitis C infected individuals significantly increased to mitigate the global organ shortage. This change occurs after the availability of effective direct-acting antiviral (DAA) therapy
Hepatitis C Virus Infection and Direct-Acting Antiviral Therapy
– Pan-genotypic DAA therapies successfully used or the treatment of chronic HCV infection.
– It increase the cure rate with sustained virologic response after 12 weeks (SVR12) > 98%.
-Approved treatment: Nonstructural protein 5B inhibitor sofosbuvir (SOF) in combination with a nonstructural protein 5A (NS5A) inhibitor, nonstructural protein 3/4A (NS3/4A) protease inhibitor, and ribavirin.
-The combination of SOF and NS5A inhibitor ledipasvir (LDV) and produces high SVR12 rates in HCV genotype (GT) 1,4, 5, and 6 infection.
-The combination of SOF and NS5A inhibitor velpatasvir provides SVR12 rates of > 95% across all GTs and has a favorable safety profile.
-The combination of NS3/4A PI glecaprevir and NS5A inhibitor pibrentasvir results in SVR12 rates > 97% across all GTs.
DAA therapy reduces the risk of reinfection of the allograft. Also, it has been shown to improve liver function in patients with decompensated cirrhosis, however, those with advanced liver disease are unlikely to improve.
DAA Therapy and Liver Transplantation
-Persistence of HCV infection after liver transplant may results in progressive liver damage and fibrosis and eventually liver failure – The use of DAA therapy following liver transplant has decreases HCV- related progression and demonstrated excellent outcomes if SVR achieved.
– Treatment of HCV infection in patients who undergo simultaneous liver-kidney transplant, or those who have compensated cirrhosis is both safe and efficacious.
Defining Hepatitis C Virus–Positive Donors – Serologic antibodies testing: detected within 2 to 6 months after exposure.
– HCV NAT: detected 5 to 7 days post-exposure, more accurate assessment of transmission risk, sensitivity of 85% to 100% and a specificity of 99% to 100%.
-The risks of disease transmission varies if donor is seropositive or viremic.
–Nonviremic: HCV Ab positive but NAT negative, donors have not been documented to transmit HCV infection.
–Viremic: NAT positive with HCV either seropositive or negative, carries high risk of transmission.
-HCV transmission may occurs during the 1-week window period between viral exposure and positive NAT results.
HCV–Positive Donor Transplantation in HCV–Negative Recipients –Previously was not consideredwith availability of DAA therapy the utilization of HCV-viremic donor organs has increased with favorable long-term graft outcomes.
Liver Transplantation – Studies demonstrated no differences in patient or graft survival when compared with nonviremic donors
– SOF/VEL or GLE/PIB has been used successfully in HCV-naïve patients who receive HCV-viremic livers with high SVR
– Initiation of DAA therapy within 90 days of transplant, rather than preemptively or immediately following transplant, has also demonstrated favorable outcomes.
– A preemptive antiviral strategy using SOF/VEL is also successful in achieving SVR12.
– HCV-related acute MN resulting in ESRD despite achieving SVR12 was reported.
Renal Transplantation
-The prevalence of HCV among ESRD is 0.2% to 6%.
-Untreated HCV seropositivity is associated with higher all-cause mortality aRR:1.85 and higher all-cause graft loss aRR:1.76
– Studies have demonstrated promising long-term outcomes of HCV-seropositive recipients transplanted with kidneys from HCV-positive donors.
-The availability of DAA therapy minimizes the risk of transmission has led to the recent growth of transplant of kidneys from HCV-infected donors into HCV-naive recipients. Major trials in HCV naïve KTR: -THINKER trial: (n=10), [D+/R-], treated with EBR/GZR for 12 weeks. All recipients attained SVR12. -THINKER-2 trial (n=20), expansion of trial 1, outcome: HCV cure and excellent renal allograft function with eGFRs not significantly different from those of matched recipients of HCV-negative kidneys. -EXPANDER trial (n=10), EBR/GZR +/- SOF for 12 weeks, SVR12 achieved with no study-related adverse events.
–MYTHIC trial, (n=30) treated with GLE/PIB, All achieved SVR12, and no severe adverse events related to HCV infection. Although all recipients had good allograft function, adverse events included ACR and BKPyV.
Thoracic Transplantation – earlier studies showed donor HCV seropositivity was reported to be an independent risk factor for increased mortality, virally mediated coronary vasculopathy and development of severe and rapidly progressive liver disease.
-Preemptive administration of GLE/PIB in HCV-viremic cardiac transplant into HCV-naïve recipients (n=20) has demonstrated SVR12 rate of 100%, and excellent early allograft function 100%
– Shorter duration of DAA treatment with GLE/PIB for 8 weeks following cardiac transplant, all achieved SVR12.
Conclusion
-Transplantation of HCV-viremic organs into HCV-naive recipients followed by the use of DAA agents provides excellent patient and allograft survival.
– The use of AAD appears to be efficacious and well tolerated.
-Utilization of HCV infected organs is an acceptable option to close waitlist gaps and decrease morbidity and mortality.
– Understanding long-term outcomes of HCV-viremic organ utilization needs further studies.
1- HCV infection is indication of liver transplantation.
2- There is increase numbers of opioid addict and death related to it hence increase number of HCV.
3- Treatment of HCV by directly acting antiviral therapy DAA makes an organ donation from HCV donors acceptable than before.
4- It is important to widen or enlarge the donor pool for transplantation to accept the donor who were not acceptable before, and addition of DAA is the key for that point. 5- Hepatitis C Virus Infection and DirectActing Antiviral Therapy:
a- Sustained virologic response by DAA 12 weeks after treatment (SVR12) of greater than 98% is the cure rate.
b- Nonstructural protein 5B inhibitor sofosbuvir (SOF; Sovaldi, Gilead) has been approved for HCV treatment in combination with a nonstructural protein 5A (NS5A) inhibitor, nonstructural protein 3/4A (NS3/4A) protease inhibitor, and ribavirin.
c- The combination of potent NS5A inhibitor ledipasvir (LDV) and SOF (LDV/SOF, 90 mg/400 mg; Harvoni, Gilead), administered once daily, is well tolerated and produces high SVR12 rates in HCV genotype (GT) 1, 4, 5, and 6 infection.
d- The combination of SOF and NS5A inhibitor velpatasvir (SOF/VEL; Epclusa, Gilead), administered once daily, provides SVR12 rates of greater than 95% across all GTs and has a favorable safety profile.
e- The combination of NS3/4A protease inhibitor glecaprevir and NS5A inhibitor pibrentasvir (GLE/PIB; Mavyret, AbbVie) was first approved in 2017 for the treatment of HCV infection without cirrhosis or with mild cirrhosis. GLE/PIB is well tolerated and results in SVR12 rates greater than 97% across all GTs.
f- DAA can change decision and treat HCV and not require liver transplant, and in some cases treatment prior to liver transplant can decrease post transplant morbidity and complications, but in some cases of advanced liver disease has no benefit over transplant and prior to it. 6- Direct-Acting Antiviral Therapy and Liver Transplantation:
a- Presence or persistence of HCV viremia after liver transplant can leads to variable clinical picture with multiple comorbidities and may ends by graft failure, but after introduction of DAA , this story became uncommon.
b- Introduction of DAA post liver transplant decreased morbidity and mortality compared to patient who did not receive DAA.
c- Safe and effective introduction of DAA in the patient with simultaneous liver-kidney transplant. 7- Defining Hepatitis C Virus–Positive Donors:
a- Donors identified as HCV positive by serologic testing but NAT negative (nonviremic) are considered to have undergone spontaneous clearance or successful treatment of infection, or have a false-positive antibody result, and these donors have not been documented to transmit HCV infection.
b- An HCV-seropositive donor that is NAT positive (viremic) is considered to have an active infection and poses a high risk for disease transmission.
c- An HCV-negative donor that is NAT positive (viremic) is considered to have an acute infection and poses a high risk for disease transmission.
d- Despite improvements in testing, risk of HCV transmission remains during the 1-week eclipse period between viral exposure and positive NAT results, particularly in persons who inject drugs.
e- Antibodies can be detected by serology within 2-6 months after exposure but NAT becomes positive in 5-7 days from exposure. 8- Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients:
a- HCV seropositive donors were not accepted as a donor because of high risk of viral transmission and complications related to interferon post transplant and increased morbidity and mortality but now after perioperative introduction of DAA , it was easy to accept HCV donors with favorable outcome post transplant.
b- There was favorable outcome which is also similar between HCV viremic and non viremic donors
c- Initiation of DAA can be preemptive or immediately post transplant or even within 90 days post transplant , all have similar outcomes.
d- In spite of SVR12 and clearance of viremia, but HCV related complications can happen at any time so long term follow up is important.
Hepatitis C Virus Treatment and Solid Organ Transplantation Introduction: HCV infection affects 130-150 million people worldwide, leading to a global shortage of liver transplantation. HCV transmission has increased with the opioid epidemic but DAA therapy has led to greater utilization of HCV-positive livers.
Hepatitis C Virus Infection and Direct Acting Antiviral Therapy
DAA therapies ( pangenotypic ) have been introduced to treat chronic HCV infection, with cure rates of greater than 98%. Nonstructural protein 5B inhibitor sofosbuvir (SOF) has been approved for HCV treatment in combination with a NS5A inhibitor, nonstructural protein 3/4A (NS3/4A) protease inhibitor, and ribavirin. GLE/PIB is well tolerated and results in SVR12 rates greater than 97%. Pretransplant DAA therapy reduces the risk of reinfection of the allograft, but not all patients with end-stage liver disease from HCV infection benefit from it.
Direct-Acting Antiviral Therapy and Liver Transplantation (DAA)
DAA is an effective treatment for HCV infection after liver transplantation, which can lead to a variable clinical course ranging from mild fibrosis to severe graft damage; this is uncommon now with the increasing use of DAA therapy . Recipients who achieve SVR12 posttransplant have lower rates of liver fibrosis progression (20.5% vs 65.5%; P<.001) and lower mortality (chi2=6.9; P<.01) rates compared with those who do not receive or fail treatment. Treatment of HCV with DAA therapy in transplant recipients who have compensated cirrhosis or underwent simultaneous liver-kidney is safe and efficacious with 96.6% and 90.9% SVR12 rates. SVR12 was achieved in 96% to 98% of transplant recipients without cirrhosis or compensated cirrhosis, but 13 patients discontinued prematurely due to adverse events and 10 died, mainly from complications related to hepatic decompensation.
Defining Hepatitis C Virus–Positive Donors:
HCV-positive donors are considered to have an active infection and pose a high risk for disease transmission, particularly in persons who inject drugs.
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients: DAA therapy has improved outcomes and increased utilization of HCV-infected organs in transplant recipients, leading to favourable long-term graft outcomes.
Liver Transplantation: There is no difference in graft and patient survival between HCV-viremic donors in non viremic liver transplant recipients intwo large retrospective studies . VEL-based, LDV/SOF-based, or SOF/DAC-based therapy has been successful in HCV-viremic livers, with no treatment-related or HCV-attributable adverse events and no GLE/PIB drug reactions or interactions.
Renal Transplantation:
HCV infection is a common complication after renal transplant with the prevalence of 0.2% to 6% in end stage renal disease . HCV-seropositive renal recipients, if untreated, will end with significant mortality and morbidity compared with their HCV-negative counterparts. However, the long-term outcomes of kidney transplants from HCV-infected donors is promising in many studies . Thoracic Transplantation:
HCV infection is high among heart transplant recipients, with reduced survival and increased risk of accelerated allograft vasculopathy. Preemptive administration of GLE/PIB in HCV-viremic cardiac transplant into HCV-naive recipients has demonstrated rapid HCV suppression, prevention of chronic HCV infection, and excellent early allograft function. Pancreas Transplantation: HCV-viremic pancreas transplant may be safely used for potential pancreas recipients, but further study is needed to determine morbidity and mortality. Short-term outcomes for solid organ transplantation are comparable for HCV-virmic and nonviremic donors, but promising data are most robust in kidney followed by liver transplant.
Conclusion:
Organ transplantation in the US is negatively impacted by long waitlist times and high mortality due to organ shortages, but transplantation of HCV-viremic organs into HCV-naive recipients provides excellent patient and allograft survival and has the potential to close waitlist gaps and decrease morbidity and mortality.
HCV-positive organs continue to increase, representing 9.7% of deceased-donor livers in 2019 ,those organs were discarded before duet to risk of HCV infection transmission , high morbidity and mortality transmission risk.
Due to the global shortage of organs available for transplantation ,HCV positive organs became included but categorised as high risk organs.
The introduction of DAAT with high cure rate and acceptable side effects enabled more usage of HCV positive livers for transplantion, thereby decreasing waiting lists mortality Hepatitis C Virus Infection and Direct Acting Antiviral Therapy DAAT
DAAT for HCV infection have a SVR after 12 weeks post transplantion more than 98%.
The combination of NS5A inhibitor ledipasvir (LDV) and sofosbuvir SOF(LDV/SOF, 90 mg/400 mg; Harvoni, Gilead), once daily dose achieves high SVR12 rates in HCV genotype 1, 4, 5, and 6 infection.
The combination of SOF and NS5A inhibitor velpatasvir (SOF/VEL;Epclusa, Gilead) once daily dose leads to SVR12 95% across all genotypes.
The combination of NS3/4A protease inhibitor glecaprevir and NS5A inhibitor pibrentasvir (GLE/PIB; Mavyret, AbbVie) for treatment of HCV infection without cirrhosis or with mild cirrhosis, achieving SVR12 rates > 97% across all genotypes.
DAAT improved liver function in decompensated cirrhosis, also DAAT before transplantation decreased the risk of reinfection of the allograft but therapy before transplantation is not always beneficial .
Model for End-Stage Liver Disease score (MELD)<16, low baseline Child-Pugh score, and the absence of portal hypertension complications indicate improvement of liver functions response to pretransplant therapy.
On the other hand ,cases with advanced liver disease and those with Child-Pugh class C cirrhosis are less likely to attain good response with DAA therapy . DAAT and liver transplantation
HCV infection persistence after liver transplant results in variable outcomes ranging from mild fibrosis to severe graft damage.
DAAT use decreased HCV-related progression of liver disease posttransplant improving the outcomes.
Cases who achieve SVR 12 weeks have lower rates of liver fibrosis progression and lower mortality.
HCV infection treatment in patients having simultaneous liver-kidney transplant is both safe and effective.
HCV-TARGET trial assessed liver transplant and dual liver-kid[1]ney transplant recipients with HCV infection treated with LDV/SOF, ombitasvir/paritaprevir/ritonavir plus dasabuvir (Viekira Pak, AbbVie), or SOF plus daclatasvir (SOF/DAC; Darvoni, Beacon). SVR12 rates among liver transplant and dual liver-kidney transplant recipients were 96.6% and 90.9%, respectively.Liver transplant cases experienced 4 attacks of acute rejection.
This study enabled treatment of liver transplant cases with ribavirin free regimen .
Pangenotypic, ribavirin-free regimen use in posttransplant patients without cirrhosis showed favourable outcomes
MAGELLAN-2 study demonstrated the efficacy of GLE/PIB once daily for 12 weeks in patients with treatment-naive HCVgenotype GT1 to GT6 infection or treatment-experienced HCV GT1, GT2, or GT4 to GT6 who had received a liver or kidney transplant ,DAAT after transplant is safe and effective.
Treatment with SOF/VEL for 12 weeks in liver transplant recipients with HCV GT1 to GT4 infection and cirrhosis lead to SVR12 rate of 93%.
SOLAR-1 and SOLAR-2 trials demonstrated that LDV/SOF plus ribavirin regimen in liver transplant recipients with HCV GT1 to GT4 infection and liver disease achieved acceptable SVR and better outcomes.
DAAT enabled the use of HCV-positive organs in HCV-viremic recipients and currently in HCV-negative recipients. HCV positive donor definition
HCV NAT has a sensitivity of 85% – 100% and a specificity of 99% – 100% ,NAT is an accurate test because differentiating seropositive from viremic HCV positive donors is mandatory.
HCV positive donors detected by serologic testing but have negative NAT indicates either spontaneous clearance or successful therapy or
have a false-positive antibody result, and they donot transmit HCV infection.
HCV-seropositive donors having positive NAT have active infection and harbours a high risk for disease transmission while HCV-negative donor with positive NAT have acute infection and highly transmissibility of infection. HCV positive donor transplant to HCV negative recipient
Before DAAT introduction such transplant was not performed .
DAA therapy introduction increased the usage of HCV viremic donor organs.
Multiple studies demonstrated favourable long-term prognosis in patients transplanted with HCV-seropositive donors. Liver Transplantation
2studies assessed HCV-viremic donors in nonviremic liver transplant recipients and showed no variation in patient or graft survival compared to nonviremic donors.
A study showed that HCV treatment within 3 months of transplantation increases the possibility of acceptable graft function and decreases waitlist mortality.
Immediate treatment with GLE/PIB for HCV-viremic liver transplant into seronegative recipients is safe and effective.
A later study revealed that initiation of DAA therapy within 90 days of transplant, instead of preemptively or immediately after transplantation, has favourable outcomes.
Another study demonstrated that in early HCV infection, SOF/VEL use once daily for 12 weeks when viremia was confirmed lead to SVR12 but extensive side effects occurred as biliary sclerosis, cardiomyopathy, and graft-vs-host disease, that can lead to multiorgan failure and death.
A prospective multicenter study assessed outcomes in HCV-naive liver transplant and dual liver-kidney transplant showed that inspite of achieving SVR12 ,HCV-related acute membranous nephropathy can happen leading to ESRD. Renal transplantation
Untreated HCV infection in HCV-seropositive renal recipients experience worse outcomes when compared to HCV seronegative cases.
HCV infected donors’ organs were not used.
Studies showed acceptable long-term outcomes of HCV-seropositive recipients transplanted with kidneys from HCV-positive donors.
DAAT enhanced transplant of kidneys from HCV-infected donors into HCV-naive recipients.
THINKER trial evaluated the efficacy and safety of transplanting of kidneys from HCV GT1–viremic donors into HCV-negative
recipients the treated with elbasvir/grazoprevir (EBR/GZR;
Zepatier)for 12 weeks,the recipients had SVR12 and graft function was comparable to matched HCV seronegative recipients at 6 and 12 months.
EXPANDER trial assessed the applicability of DAA prophylaxis (EBR/GZR only for GT 1 and added to it SOF for GT 2 ,GT3) before and after renal transplant in HCV-naive patients who received HCV-viremic kidneys (GT1-GT3) and SVR 12 was attained without significant side effects.
Studies concluded that SOF-based regimens are safe and efficient in HCV-naive recipients having HCV-viremic kidney transplant.
GLE/PIB once daily for 12 weeks was endured by renal transplant recipients with chronic HCV GT1 to GT6 infection .
Shorter DAA regimens courses expressed favourable outcomes . Thoracic Transplantation
Previous studies demonstrated increased mortality in recipients with HCV infection either acquired pre or post heart transplant.
HCV infected cases where not considered for cardiac transplant in INF era due to viral coronary vasculopathy and progressive hepatic disease occurrence
Multiple studies concluded no difference between the overall outcomes for cardiac transplant recipients receiving hearts from HCV positive donors and were treated with DAA from on side and the other side for recipients receiving hearts from HCV negative donors.
Shorter courses of DAA treatment with GLE/PIB for 8 weeks after heart transplant was assessed in HCV-naive recipients who received HCV-viremic organs, the recipients had detectable viremia, and SVR12.
Not many studies assessed transplanting lungs from HCV infected donors .A study evaluated that using 12 weeks of SOF/VEL, 6-month HCV-free survival was 86% and 6month survival post transplant of HCV-viremic and -nonviremic donors was 95% vs 94%, respectively meanwhile side effects occurred including respiratory complications, infections and HCV relapse in need of therapy.
DONATE-HCV study demonstrated comparable results for recipients whom received hearts and lungs from HCV positive donors and those whom received those organs from HCV negative donors Pancreas Transplantation
There is limited studies on HCV-viremic organs in pancreas transplantation .
One study carried on in 2021 demonstrated preliminary acceptable outcomes for HCV-viremic pancreas transplant meanwhile further studies are needed. Conclusion
HCV-viremic organs transplant into HCV-naive recipients followed
by adminstering DAAT agents resulted in favourable patient
and allograft survival.
On the other hand the long-term consequences of HCV viremic organ transplantion needs further evaluation
This article is about Hepatitis C virus treatment in the setting of solid organ transplantation. This is especially important in terms of liver transplant. Untreated HCV infection in a liver transplant recipient can lead to graft failure.
Discussion
Liver transplant setting
Liver transplant recipients need to be checked for HCV infection and treated prior to transplant. In the case of persistence of infection post transplant it can lead to fibrosis of liver and ultimately graft failure. Other clinical characteristics include progressive centrilobular ballooning degeneration, bridging fibrosis, and cholestasis. Usage of DAA therapy post liver transplant can give good outcome with lower rate of liver fibrosis progression and lower mortality.
Patients undergoing simultaneous kidney liver transplant can be treated for HCV infection safely. Ribavirin free regimen can be used in posttransplant recipients without cirrhosis.
Donors who are seropositive for HCV, but NAT negative do not transmit infection and can be used for the recipient. HCV negative donor who is NAT positive is considered to have acute infection, and can transmit disease.
Kidney transplant setting
HCV infection is a common complication post kidney transplant. Outcome for HCV seropositive renal recipients is worse than seronegative recipients. HCV seropositivity is associated with all cause mortality.
HCV positive donors can be used safely for HCV seropositive recipients. Using DAA therapy can reduce the risk of chronic HCV infection in these patients.
SOF based regimen are safe and efficacious in HCV naive recipients undergoing HCV viremic kidney transplant.
GLE/PIB once daily for 12 weeks can be used for patients with chronic HCV infection who have undergone kidney transplant.
Short course DAA regimen can have good results in terms of prophylaxis. 4 weeks of GLE/PIB therapy can cause undetectable HCV RNA and stable allograft function.
Thoracic transplant setting
The incidence of HCV infection is high among heart transplant recipients, at 12%. Whether the patient acquired HCV before or after the transplant, these recipients have reduced rates of survival.
Donor HCV seropositivity can be an independent risk factor of HCV in recipients. DAA therapy is well tolerated in these patients, but short course does not have a significant impact in any way.
Pancreas transplant setting
There is limited data regarding HCV infection in pancreas transplant. HCV viremic pancreas can be used safely for recipients, however, further study is needed regarding the effects it has on morbidity and mortality of said recipients.
Conclusion
Due to high wait times and numerous people requiring transplantation, using HCV viremic organs may need to be done even into HCV naive recipients. However, use of DAA agents can give good graft and patient survival. This can decrease mortality and morbidity among the recipient population. Further understanding long term outcome and standardized regimen formulation is required in the near future to progress in this therapy.
This is a narrative review study on Hepatitis C virus infection in the context of solid organ transplantation.
Introduction
Hepatitis C affects 130 to 150 million people worldwide and was a limiting factor for donations because we do not have effective medications available, as well as their consequences (liver cirrhosis and hepatocellular carcinoma).
Direct-acting antiviral therapies have changed the prognosis and goals for proceeding with transplantation.
Infection and targeted therapy
New oral medications capable of maintaining sustained viral suppression above 95% (previous treatments were no more than 40%) and with only 12 weeks of therapy have modified HCV treatment. Sofosbuvir + Ledispavir are used for genotypes 1, 4, 5, and 6. Sofosbuvir and velpastavir can cover all genotypes. These treatments improve liver function even in patients with organ involvement and decrease the risk of graft reinfection.
Liver transplant
Persistence of viral load after liver transplantation leads to fibrosis and cholestasis with graft loss. The use of new therapies considerably reduces the risk of viral load persistence, showing excellent results.
Even in transplants associated with other organs, the outcome is favorable.
Several studies show the result of sustainably suppressed viral load and concomitant improvement in liver function, even in ribavirin-free regimens (ClCr < 30, withholding ribavirin is mandatory).
HCV positive donors
Serological tests show exposure to the virus, while the viral load suggests disease activity. When both are present, the disease may be cured, but there is a risk of reactivation depending on immunosuppression.
A positive viral load determines a high risk of transmission.
D+/R-
With the new therapies, it is possible to perform the transplant and proceed with the appropriate treatment, maintaining excellent survival results for the recipient and the graft.
Liver transplant
Two studies showed safety in transplanting D+R- with the new therapies and reducing the waiting time for an organ. Another study that started therapy within the first 90 days of transplantation showed excellent results.
Kidney transplant
It used to be a contraindication, but nowadays it is authorized. Care is taken to avoid ribavirin in patients with CrCl lower than 30. Few studies compare the use of new therapies and their impact with different treatment times (if the viral load is positive, 12 hours before or at time zero of the transplant), but always when the therapy has performed the result was better.
Sofosbuvir-based regimens are safe and have low drug interactions and do not require correction for renal function. Four-week prophylaxis has been evaluated, but further studies are needed.
Thoracic transplant
Not unlike the other transplants, the results with interferon were quite low and discouraging and with the intervention of the new treatments there was primary dysfunction but with numbers similar to the seronegative ones in terms of length of hospital stay, organ rejection, survival on day 30 and after one transplant year.
An eight-week prophylactic protocol, it was successful in controlling viral load and protecting the graft.
For lung transplantation, there is little data to generate statistical conclusions, but they must comply with the findings of other organs.
Conclusion
Transplantation of HCV-positive patients can be done safely and decrease waiting time in the transplant queue. New therapies are safe and well tolerated, including the possibility of shorter therapies for prophylaxis.
Low interaction with immunosuppressants and sustained viral response brings a promising horizon.
II. Hepatitis C Virus Treatment and Solid Organ Transplantation Please summarize this article.
Shortage of donor supply has dictated the use of high-risk donors such as those who are HCV positive.
The decision of treating HCV infection prior to TX or delaying it until after TX has arisen as a result of the availability of safe & highly effective therapy.
DAAs improves liver function in decompensated cirrhosis to the extent that some may no longer require liver TX.
Moreover, pretransplant DAA medication lowers the likelihood of the allograft being reinfected.
Not all HCV-infected individuals with ESLD will, however, benefit from treatment before a liver TX; advanced liver disease is unlikely to improve by DAA therapy, & SVR rates are lower in Child-Pugh class C cirrhosis.
Marked improvement in liver function from pre-TX therapy is expected in the following:
Low baseline Model for ESLD score (<16)
Low baseline Child-Pugh score
Absence of portal hypertension complications.
DAA Therapy & Liver Transplantation
Significant HCV-related progression of liver disease post-TX is no longer common due to the increased use of DAA therapy.
Compared to those who do not get treatment or who do not respond to it, recipients who reach SVR12 post-TX have lower rates of liver fibrosis progression & mortality.
HCV infection treatment in patients undergoing simultaneous liver-kidney transplant is both safe & effective.
The HCV-TARGET trial:
Compared LDV/SOF, ombitasvir/paritaprevir/ritonavir plus dasabuvir, & SOF plus daclatasvir in liver TX & dual liver-kidney TX recipients with HCV infection.
SVR12 rates were 96.6% & 90.9% for recipients of liver transplants & dual liver-kidney transplants, respectively. The huge HCV-TARGET cohort’s real-world data showed promising results, giving doctors confidence to treat liver transplant patients with a ribavirin-free regimen.
HCV-TARGET cohort provided confidence in treating liver TX patients with a ribavirin-free regimen.
The MAGELLAN-2 study (phase 3 open-label trial):
Confirmed the safety & efficacy of GLE/PIB for 12 weeks in patients with treatment-naive HCV GT1 to GT6 infection or treatment-experienced HCV GT1, GT2, or GT4 to GT6 who had received a liver or KTX.
Other studies
Treatment with SOF/VEL for 12 weeks in 14 liver TX recipients with HCV GT1 to GT4 infection & cirrhosis resulted in an SVR12 rate of 93%.
SOLAR-1 (a large trial):
Assessed LDV/SOF plus ribavirin in liver TX recipients with HCV GT1- GT4 infection & liver disease.
SVR12 achieved in 96% – 98% of TX recipients without cirrhosis or with compensated cirrhosis.
SOLAR-2 (a multicenter open-label study):
SVR12 rates of 100%, 96%, 95%, & 100% in CTP-A patients with 12 weeks of treatment, CTP-A patients with 24 weeks of treatment, CTP-B patients with 12 weeks of treatment, & CTP-B patients with 24 weeks of treatment, respectively, were seen in HCV GT1 liver transplant recipients who had no cirrhosis, CTP-A, CTP-B, or CTP-C cirrhosis.
Defining Hepatitis C Virus–Positive Donors
NAT detects RNA 5–7 days after exposure & more precisely evaluate transmission risk than serologic tests (chemiluminescence assay & enzyme immunoassays) that detect antibodies 2–6 months after exposure.
The sensitivity & specificity of HCV NAT are 85% to 100% & 99% to 100%, respectively.
When considering organ donation from HCV+ve donors, it is crucial to differentiate a seropositive donor from a viremic one since they greatly vary in the risk of disease transmission.
Donors positive by serology but NAT negative (non-viremic) have successfully treated their disease, cleared up on their own, or had a false-positive antibody result. These donors do not transmit the HCV virus.
A NAT-positive (viremic) HCV-seropositive donor has an active infection & carries a significant risk for disease transmission.
A NAT positive (viremic) HCV-negative donor has an acute infection & presents a significant risk for disease transmission.
Despite advances in testing, there is still a danger of HCV transmission within the 1-week window between virus exposure & a positive NAT result, especially for drug injectors.
HCV+ve Donor TX in HCV–ve Recipients
Before DAA era, the low efficacy, high rates of HCV transmission, decreased patient & graft survival, & complications related to interferon-based therapy in the post-TX setting prevented the routine use of organ TX from HCV+ve donors into uninfected recipients.
Use of HCV-infected organs was also hampered by the lack of safe & efficient HCV therapies.
Now, as HCV treatments quickly advance & improve, the use of HCV-viremic donor organs has grown due to the perioperative use of DAA medication.
Early research showed that patients transplanted from donors positive for HCV have good long-term graft results.
Liver Transplantation
There was no difference in patient or graft survival between HCV-viremic donors & nonviremic donors (2 large retrospective studies).
OPTN data (2015 to 2017): 30 HCV-naive patients who received HCV-viremic livers had 1-year patient survival rates that were comparable to those of HCV-seropositive but NAT-negative & nonviremic liver recipients.
Comparable 2-year graft survival rates were observed in 568 liver TX recipients +/- HCV infection who received HCV-viremic organs (OPTN, 2016 to 2020).
The first prospective study (10 HCV-ve patients received HCV-viremic livers) showed that HCV treatment within 3 months of TX increases the chances of successful graft function & reduces waitlist mortality.
In HCV-naive patients who received HCV-viremic livers, GLE/PIB has been used successfully (safe & efficacious).
In a trial (14 patients received HCV-viremic livers), 9 patients developed viremia with SVR12 & 46-week survival rates of 100% & 100%, respectively.
A subsequent trial showed that DAA within 90 days of TX, as opposed to preventively or after transplant, also showed positive results.
In HCV-naive patients who received viremic livers (n = 51), the use of SOF/VEL or GLE/PIB once daily for 12 weeks had similar 1-year patient & graft survival rates as HCV-naive patients who got nonviremic livers (n = 231).
A prospective multicenter study examining outcomes in HCV-naive liver TX & dual liver-kidney TX found HCV-related acute membranous nephropathy leading to ESRD despite achieving SVR12.
The emergence of HCV-related comorbidities indicates that careful & prolonged follow-up is still necessary.
Renal Transplantation
Patients with ESRD have an HCV frequency of 0.2% to 6%, & HCV infection has historically been a prevalent post-KTX complication.
HCV-seropositive kidney recipients have much worse outcomes (greater all-cause mortality & worse graft loss) from untreated HCV infection than do HCV-negative recipients.
Donor kidneys with HCV infection have not been used as much in the past. Yet, research from the last ten years has shown positive long-term results & the availability of DAA therapy and its use around the time of TX reduces the risk of chronic HCV infection in the recipient & thus has led to the recent rise of TX of kidneys from HCV-infected donors into HCV-naive recipients.
THINKER trial (2017):
The first open-label, single-group pilot prospective study examining the safety & efficacy of the TX of kidneys from HCV GT1–viremic donors into HCV-ve recipients (D+/R-) followed by treatment with elbasvir/grazoprevir (EBR/GZR) for 12 weeks (n=10). All recipients had detectable HCV RNA, and all attained SVR12.
THINKER-2 trial (n=20):
HCV-ve recipients of HCV-viremic kidneys had HCV cure & excellent renal allograft function with eGFRs not significantly different from those of matched recipients of HCV-ve kidneys at 6 months & 12 months.
EXPANDER trial (n=10):
Evaluated the tolerability & feasibility of DAA prophylaxis before & KTX in HCV-naive patients who received HCV-viremic kidneys (GT1-GT3).
SOF-based regimens are safe & effective in HCV-naive recipients undergoing HCV-viremic KTX.
MYTHIC trial (30 HCV-naive patients received HCV-viremic kidneys across 7 transplant centers):
All recipients achieved SVR12, & no severe adverse events related to HCV infection or GLE/PIB were noted in any patient.
The DAPPER trial:
A single pre-TX dose of SOF/VEL was followed by 1 or 3 post-TX doses.
Viral transmission was reduced to 7.5% but did result in detectable viremia in 17 of 50 (34%) patients by post-TX day 14, of which only 6 of 50 (12%) required treatment. The remaining 11 recipients had self-limited, low-level viremia.
Thoracic Transplantation
Due to worries about virally induced coronary vasculopathy & the emergence of severe & rapidly progressing liver disease, the TX of HCV-infected hearts was almost completely abandoned in the period of interferon-based HCV treatment regimens.
In patients receiving hearts from HCV-viremic donors, preemptive use of GLE/PIB showed rapid HCV suppression, avoidance of chronic HCV infection, & excellent early allograft function (n = 20).
Conclusions
Long waitlist wait times & high waiting mortality caused by organ shortages have a negative impact on organ transplantation,
DAAs are used when HCV-viremic organs are transplanted into HCV-naive recipients to give excellent patient & allograft survival.
The use of HCV-viremic grafts seems to be effective & well tolerated in carefully chosen patients.
This practice showed acceptable short-term outcomes & potentially to narrow waitlist time & decrease morbidity & mortality.
The need of getting DAA therapy post-TX & the hazards involved, including the possibility of HCV treatment failure, should be made clear to patients.
It is yet unknown if HCV infection in post-TX patients may result in immune system modifications that last a lifetime or unintended interactions with IS medications.
The long-term effects of using HCV-infected organs is still unknown.
Hepatitis C Virus Treatment and Solid Organ Transplantation Introduction;
-Hepatitis C virus (HCV) infection affects approximately 130 million to 150 million people worldwide.
-The availability of HCV-positive organs continues to increase, representing 9.7% of deceased-donor livers in 2019.
-There have been significant advancements in the science of HCV therapy and in the use of HCV-positive organs, thereby substantially increasing the number of organ transplants and decreasing waitlist mortality. Hepatitis C Virus Infection and Direct Acting Antiviral Therapy;
-Over the past several years, a succession of pangenotypic DAA therapies for the treatment of chronic HCV infection has been introduced, with cure rates defined as sustained virologic response 12 weeks after treatment (SVR12) of greater than 98%.
-The combination of potent NS5A inhibitor ledipasvir (LDV) and SOF (LDV/SOF, 90 mg/400 mg; administered once daily, is well tolerated and produces high SVR12 rates in HCV genotype (GT) 1, 4, 5, and 6 infection.
-The combination of SOF and NS5A inhibitor velpatasvir (SOF/VEL) administered once daily, provides SVR12 rates of greater than 95% across all GTs and has a favorable safety profile.
-The combination of NS3/4A protease inhibitor glecaprevir and NS5A inhibitor pibrentasvir (GLE/PIB) was first approved in 2017 for the treatment of HCV infection without cirrhosis or with mild cirrhosis, and results in SVR12 rates greater than 97% across all GTs.
-DAA therapy has been shown to improve liver function in patients with decompensated cirrhosis.
-Pre-transplant DAA therapy reduces the risk of reinfection of the allograft.
-Patients with advanced liver disease are unlikely to improve with DAA therapy and those with Child-Pugh class C cirrhosis have lower SVR12 rates; therefore, deferring treatment in such situations may be preferred. Direct-Acting Antiviral Therapy and Liver Transplantation;
-Persistence of HCV infection after liver transplant results in a variable clinical course ranging from mild fibrosis to severe graft damage.
-Advanced fibrosis can occur in up to 45% of posttransplant patients, and graft cirrhosis can develop within as little as 5 years post-transplant.
-5-10% of post-transplant patients will develop severe progressive cholestatic hepatitis leading to liver failure.
-With the increasing use of DAA therapy, significant HCV-related progression of liver disease post-transplant is now uncommon.
-Use of DAA therapy following liver transplant has demonstrated excellent outcomes.
-Treatment of HCV infection in patients who undergo simultaneous liver-kidney transplant is both safe and efficacious.
-In transplant recipients who have compensated cirrhosis, DAA therapy following transplant is safe and efficacious. Defining Hepatitis C Virus–Positive Donors;
-HCV-positive donors involved any stage of HCV infection. Serologic tests detect antibodies within 2 to 6 months after exposure, but nucleic acid testing (NAT) detects RNA 5 to 7 days after exposure and provides a more accurate assessment of transmission risk.
-Donors identified as HCV positive by serologic testing but NAT negative (nonviremic) are considered to have undergone spontaneous clearance or successful treatment of infection, or have a false-positive antibody result, and these donors have not been documented to transmit HCV infection.
-An HCV-seropositive donor that is NAT positive (viremic) is considered to have an active infection and poses a high risk for disease transmission.
-An HCV-negative donor that is NAT positive (viremic) is considered to have an acute infection and poses a high risk for disease transmission. Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients.
-Before the availability of DAA therapy, transplantation of organs from HCV-positive donors into uninfected recipients was not routinely considered owing to low efficacy, high rates of HCV transmission, decreased patient and graft survival, and complications associated with interferon-based therapy in the post-transplant setting. Liver Transplantation;
-Two large retrospective studies evaluated HCV-viremic donors in nonviremic liver transplant recipients and demonstrated no differences in patient or graft survival when compared with nonviremic donors.
-GLE/PIB has been used successfully in HCV-naive patients who receive HCV-viremic livers.
-A later study demonstrated that initiation of DAA therapy within 90 days of transplant, rather than preemptively or immediately following transplant, has also demonstrated favorable outcomes.
-The administration of SOF/VEL or GLE/PIB once daily for 12 weeks in HCV-naive patients who received viremic livers produced similar 1-year patient and graft survival when compared with HCV-naive patients who received nonviremic livers. Renal Transplantation
-The prevalence of HCV among end-stage renal disease patients is 0.2% to 6%, and HCV infection traditionally has been a common complication after renal transplant.
-Outcomes for untreated HCV infection in HCV-seropositive renal recipients are significantly worse than in their HCV-negative counterparts.
-THINKER trial was the first open-label, single-group pilot study that sought to determine the safety and efficacy of the transplant of kidneys from HCV GT1–viremic donors into HCV-negative recipients (donor positive, recipient negative [D+/R-]) followed by treatment with elbasvir/grazoprevir (EBR/GZR; Zepatier, Merck) for 12 weeks.
-EXPANDER trial was an open-label single center study that examined the tolerability and feasibility of DAA prophylaxis before and after renal transplant in HCV-naive patients who received HCV-viremic kidneys (GT1-GT3).
-SOF-based regimens are safe and effective in HCV-naive recipients undergoing HCV-viremic kidney transplant. Thoracic Transplantation;
-Among heart transplant recipients, the reported prevalence of HCV infection is as high as 12%.
-Early studies demonstrated reduced survival in recipients with HCV infection, regardless of acquisition of HCV pre– or post– heart transplant.
-Preemptive administration of GLE/ PIB in HCV-viremic cardiac transplant into HCV-naive recipients has demonstrated rapid HCV suppression (median time to clearance, 3-5 days , prevention of chronic HCV infection (SVR12 rate of 100%), and excellent early allograft function (100% at a median follow-up of 10.7 months) Pancreas Transplantation;
-The data on utilizing HCV-viremic organs in pancreas transplantation are limited.
-In 2021, the first reported series included 8 HCV-naive patients who received either deceased donor simultaneous pancreas-kidney transplant or pancreas transplant after living donor kidney transplant.
-All patients developed viremia and were treated with either GLE/PIB or SOF/VEL and all achieved SVR12, and had excellent pancreas graft function. Conclusion;
-Transplantation of HCV-viremic organs into HCV-naive recipients followed by the use of DAA agents provides excellent patient and allograft survival.
-The use of HCV-viremic grafts in carefully selected patients appears to be efficacious and well tolerated, and this practice has demonstrated acceptable short-term outcomes and has the potential to significantly close waitlist gaps and decrease morbidity and mortality.
-However, securing DAA therapy post-transplant is essential and patients should be fully informed of the associated risks, including the potential of HCV treatment failure.
-The availability of highly effective pangnomic DAA has allowed the use of HCV infected donors ,however it should be considered as experimental therapy to be studied.
The availability of HCV-positive organs continues to increase, representing 9.7% of deceased-donor livers in 2019.
Opioid-related deaths more frequently occur in young donors, who are generally healthier and have fewer comorbidities than older donors, and therefore their HCV-viremic donor organs are often of relatively high quality
Hepatitis C Virus Infection and Direct Acting Antiviral Therapy:
The combination of potent NS5A inhibitor ledipasvir (LDV) and SOF (LDV/SOF, 90 mg/400 mg) administered once daily, is well tolerated and produces high SVR12 rates in HCV genotype (GT) 1, 4, 5, and 6 infection.
The combination of SOF and NS5A inhibitor velpatasvir (SOF/VEL) administered once daily, provides SVR12 rates of greater than 95% across all GTs and has a favorable safety profile.
The combination of NS3/4A protease inhibitor glecaprevir and NS5A inhibitor pibrentasvir (GLE/PIB) was first approved in 2017 for the treatment of HCV infection without cirrhosis or with mild cirrhosis.
GLE/PIB is well tolerated and results in SVR12 rates greater than 97% across all GTs.
Defining Hepatitis C Virus–Positive Donors:
Nucleic acid testing (NAT) detects RNA 5 to 7 days after exposure and provides a more accurate assessment of transmission risk.
HCV NAT has a sensitivity of 85% to 100% and a specificity of 99% to 100%.
Risk of HCV transmission remains during the 1-week eclipse period between viral exposure and positive NAT results, particularly in persons who inject drugs
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients:
In a larger study that included 2923 transplant recipients with HCV, 96 and 2827 received HCV-positive and -negative organs, respectively, and had comparable 2-year survival rates (90% vs 77%; P=.01).
The prevalence of HCV among end-stage renal disease patients is 0.2% to 6%
SOF-based regimens are safe and effective in HCV-naive recipients undergoing HCV-viremic kidney transplant
GLE/PIB once daily for 12 weeks has been shown to be well tolerated in patients with chronic HCV GT1 to GT6 infection who have undergone kidney transplantation.
Trials of DAA in kidney transplant
THINKER(2017)
Cohort Size: 10
Antiviral Therapy : EBR/GZR
Therapy Duration : 12 weeks
SVR12: 10/10 (100%)
THINKER-2(2018)
Cohort Size: 20
Antiviral Therapy : EBR/GZR
Therapy Duration : 12 weeks
SVR12: 20/20 (100%)
EXPANDER (2018)
Cohort Size: 10
Antiviral Therapy : EBR/GZR ± sofosbuvir
Therapy Duration : 12 weeks
SVR12: 10/10 (100%)
Friebus-Kardash et al (2019)
Cohort Size: 7
Antiviral Therapy : LDV/SOF
Therapy Duration : 8-12 weeks
SVR12: 7/7 (100%)
Molnar et al (2019)
Cohort Size: 53
Antiviral Therapy : GLE/PIB, SOF/VEL, or LDV/SOF
Therapy Duration : 12 weeks
SVR12: 53/53 (100%)
Sise et al (2020)
Cohort Size: 8
Antiviral Therapy : EBR/GZR
Therapy Duration : 12 weeks
SVR12: 8/8 (100%)
Conclusion :
Transplantation of HCV-viremic organs into HCV-naive recipients followed by the use of DAA agents provides excellent patient and allograft survival.
In carefully selected patients, the use of HCV-viremic grafts appears to be efficacious and well tolerated.
This practice has demonstrated acceptable short-term outcomes and has the potential to significantly close waitlist gaps and decrease morbidity and mortality.
However, securing DAA therapy posttransplant is essential and patients should be fully informed of the associated risks, including the potential of HCV treatment failure
HCV infects 130–150 million individuals globally. HCV infection is a primary cause of end-stage liver disease and liver transplantation. 2. Waitlist mortality is high because organ demand exceeds availability. 3,4 In 2019, 9.7% of deceased-donor livers were HCV-positive.
Due to increased reperfusion risk and posttransplant morbidity and death, organs from dead HCV-infected donors were rejected.
5-7 To address the worldwide scarcity, donation after cardiac death, live donors, and high-risk donors have been used. The public health agency classifies organs as high risk for HIV, hepatitis B, and HCV transmission.
Antiviral Treatment:
During the last several years, a number of pan-genotypic DAA treatments for chronic HCV infection have been launched, with SVR12 rates of over 98%.
HCV therapy with the nonstructural protein 5B inhibitor sofosbuvir (SOF; Sovaldi, Gilead) and NS5A, NS3/4A, and ribavirin is authorized.
In HCV genotype (GT) 1, 4, 5, and 6 infections, the once-daily combination of powerful NS5A inhibitor ledipasvir (LDV) and SOF (LDV/SOF, 90 mg/400 mg; Harvoni, Gilead) is well tolerated and yields significant SVR12 rates.
SOF and NS5A inhibitor velpatasvir (SOF/VEL) given once daily had SVR12 rates of over 95% across all GTs and a good safety profile. GLE/PIB was originally licensed in 2017 to treat HCV infection without cirrhosis or moderate cirrhosis. 21 GLE/PIB is well-tolerated and has SVR12 rates of 97% across all GTs.
Liver transplantation and direct-acting Antivirals:
HCV persistence after liver transplant causes moderate fibrosis to severe graft destruction. In 20% to 40% of posttransplant HCV-positive individuals, centrilobular ballooning degeneration, bridging fibrosis, and cholestasis progress.
45% of posttransplant patients have advanced fibrosis, and graft cirrhosis may develop within 5 years.
32,33,5%–10% of posttransplant individuals suffer severe progressive cholestatic hepatitis and liver failure. DAA treatment has made HCV-related liver disease progression post-transplant rare.
HCV-Positive Donors:
HCV-positive donors include all stages of infection. Serologic techniques like chemiluminescence assays and enzyme immunoassays identify antibodies 2–6 months after exposure, whereas nucleic acid testing (NAT) identifies RNA 5–7 days after exposure and gives a more accurate estimate of the transmission risk. HCV NAT has 85%–100% sensitivity and 99%–100% specificity.
When contemplating organ donation from an HCV-positive donor, the risks of disease transmission vary greatly between seropositive and viremic donors. Donors who are HCV positive by serologic testing but NAT negative (nonviremic) are thought to have had spontaneous clearance, effective treatment, or a false-positive antibody result and cannot transmit HCV.
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus–Negative Recipients
Before DAA treatment, organ transplantation from HCV-positive donors to uninfected recipients was seldom contemplated due to its limited effectiveness, high HCV transmission rates, lower patient and graft survival rates, and posttransplant problems from interferon-based therapy.
HCV-infected organs were seldom transplanted due to a lack of efficient and well-tolerated therapies. Nonetheless, rapidly improving HCV therapies have improved outcomes, and perioperative DAA medication has boosted HCV-viremic donor organ usage.
Liver Transplantation:
Two large retrospective investigations found no differences in patient or graft survival between HCV-viremic and nonviremic liver transplant donors. The Organ Procurement and Transplantation Network (OPTN) found that 30 HCV-naive patients who received HCV-viremic livers had equal 1-year patient survival rates.
In a subsequent analysis utilizing 2016–2020 OPTN data, 568 liver transplant patients with and without HCV infection who received HCV-viremic organs had similar 2-year graft survival rates. Successes of HCV-Viremic Liver Transplantation in Nonviremic Patients, Organ Type
Renal Transplantation:
Few prospective studies have examined DAA treatment in HCV-infected renal transplant patients. The THINKER experiment was the first open-label, single-group pilot research to assess the safety and effectiveness of transplanting kidneys from HCV GT1–viremic donors into HCV-negative recipients (D+/R-) and treating them for 12 weeks with elbasvir/grazoprevir (EBR/GZR; Zepatier, Merck).
The open-label, single-center EXPANDER trial (n=10) assessed the tolerance and feasibility of DAA prevention before and after renal transplant in HCV-naive patients who received HCV-viremic kidneys (GT1-GT3).
12 weeks after transplant, GT2 or GT3-infected organ recipients got SOF and EBR/GZR for triple treatment. Preemptive EBR/GZR for 12 weeks in HCV-naive patients who received HCV-infected kidneys (n=8) resulted in SVR12 with no study-related side effects.
Thoracic Transplant:
HCV infection pre- or post-heart transplant lowered survival in early trials. In the period of interferon-based HCV treatment regimens, worries regarding virally induced coronary vasculopathy and severe and fast-increasing liver disease almost halted heart transplantation. Donor HCV seropositivity was an independent risk factor for increased mortality when matched with controls and accelerated allograft vasculopathy.
Conclusion:
Organ shortages cause lengthy waitlists and significant backlog mortality in the US. DAA-treated HCV-viremic organ transplantation into HCV-naive recipients improves patient and allograft survival. HCV-viremic grafts are effective and well-tolerated in certain individuals. This method has good short-term results and can reduce waiting gaps, morbidity, and death.
After a transplant, it’s important to take DAA drugs, but patients should be aware of the risks, such as failing HCV treatment. Posttransplant HCV infection may cause immune system alterations or immunosuppressive treatment interactions. HCV-viremic organ utilization results are yet unknown.
Hepatitis C Virus Treatment and Solid
Organ Transplantation
This article reviewed the data on HCV treatment prior to and after organ transplantation.
Introduction:
HCV infection is one of leading causes for liver transplantation. There have been signifcant advancements in the science of HCV therapy (eg: direct-acting antiviral (DAA) therapy) and in the use of HCV-positive
organs, thereby substantially increasing the number of
organ transplants and decreasing waitlist mortality.
Hepatitis C Virus Infection and Direct Acting Antiviral Therapy
The availability of safe and highly effective therapy has led to the delicate consideration of treating HCV infection prior to transplant or deferring therapy until after transplant.
DAA therapy has been shown to improve liver function in patients with decompensated cirrhosis.
Pretransplant DAA therapy decrease the risk of reinfection of the allograft. Clinical features associated with meaningful improvement in liver function from pretransplant therapy:
Direct-Acting Antiviral Therapy and Liver Transplantation
The use of DAA therapy following liver transplant has demonstrated excellent outcomes.
Treatment of HCV infection in patients who undergo simultaneous liver-kidney transplant is safe and effective.
Defining Hepatitis C Virus–Positive Donors
HCV-positive donors encompass any stage of HCV infection.
Serologic tests detect antibodies within 2 to 6 months after exposure, but nucleic acid testing (NAT) detects RNA 5 to 7 days after exposure and provides a
more accurate assessment of transmission risk.
There are 3 types of donors:
acute infection and poses a high risk for disease transmission.
Conclusion
Transplantation of HCV-viremic organs into HCV-naive recipients followed
by the use of DAA agents provides excellent patient and allograft survival.
In carefully selected patients, the use of HCV-viremic grafts appears to be well tolerated.
Securing DAA therapy posttransplant is essential and patients should be fully informed of the associated risks.
It remains unclear whether HCV infection in posttransplant patients may lead to lasting changes to the immune system or inadvertent interactions with immunosuppressive therapy.
Introduction:
End-stage liver disease from HCV infection is one of the leading causes of liver disease and leading indications for liver transplantation.
Several strategies to expand the donor pool have been implemented,
Including donation after cardiac death, use of living donors, and increased utilization of high-risk donors to mitigate the global shortage.
Organs categorized as high risk by the public health service are those associated with an increased risk for the transmission of blood-borne viruses, including HIV, hepatitis B virus, and HCV.
There have been significant advancements in the science of HCV therapy and in the use of HCV-positive organs, thereby substantially increasing the number of organ transplants and decreasing waitlist mortality.
Hepatitis C Virus Infection and Direct Acting Antiviral Therapy:
Cure rates defined as sustained virologic response 12 weeks after treatment (SVR12) of greater than 98%.
The combination of ledipasvir (LDV) and SOF (LDV/SOF, 90 mg/400 mg; Harvoni, Gilead), administered once daily, is well tolerated and produces high SVR12 rates in HCV genotype (GT) 1, 4, 5, and 6 infection.
The combination of SOF and NS5A inhibitor velpatasvir (SOF/VEL; Epclusa, Gilead), administered once daily, provides SVR12 rates of greater than 95% across all GTs and has a favorable safety profile.
The combination of NS3/4A protease inhibitor glecaprevir and NS5A inhibitor pibrentasvir (GLE/PIB; Mavyret, AbbVie) was first approved in 2017 for the treatment of HCV infection without cirrhosis or with mild cirrhosis.GLE/PIB is well tolerated and results in SVR12 rates greater than 97% across all GTs.
Direct-Acting Antiviral Therapy and Liver Transplantation:
Persistence of HCV infection after liver transplant results in a variable clinical course ranging from mild fibrosis to severe graft damage. With the increasing use of DAA therapy, significant HCV-related progression of liver disease post-transplant is now uncommon.
Defining Hepatitis C Virus–Positive Donors:
Donors identified as HCV positive by serologic testing but NAT negative (nonviremic) are considered to have undergone spontaneous clearance or successful treatment of infection, or have a false-positive antibody result, and these donors have not been documented to transmit HCV infection.
HCV-seropositive donor that is NAT positive (viremia) is considered to have an active infection and poses a high risk for disease transmission.
An HCV-negative donor that is NAT positive (viremia) is considered to have an acute infection and poses a high risk for disease transmission.
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients:
DAA therapy has increased the utilization of HCVviremic donor organs.
Early data have demonstrated favorable long-term graft outcomes in patients transplanted with HCV-seropositive donors.
Liver Transplantation:
Two large retrospective studies evaluated HCV-viremia donors in nonviremic liver transplant recipients and demonstrated no differences in patient or graft survival when compared with nonviremic donors.
Immediate treatment with GLE/PIB for HCV-viremia liver transplant into uninfected recipients is both safe and efficacious.
A later study demonstrated that initiation of DAA therapy within 90 days of transplant, rather than preemptively or immediately following transplant, has also demonstrated favorable outcomes.
Renal Transplantation:
The prevalence of HCV among end-stage renal disease patients is 0.2% to 6%, and HCV infection traditionally has been a common complication after renal transplant.
Studies in the past decade have demonstrated promising long-term outcomes of HCV-seropositive recipients transplanted with kidneys from HCV-positive donors.
Furthermore, the availability of DAA therapy and its administration around the time of transplant minimizes the risk of chronic HCV infection in the transplant recipient and thus has led to the recent growth of transplant of kidneys from HCV-infected donors into HCV-naive recipients.
Thoracic Transplantation:
Few studies have evaluated the safety of using lungs from HCV-viremia donors for transplantation. In a single-center prospective study of 22 HCV-naive recipients of HCV-viremia lungs treated with 12 weeks of SOF/VEL, 6-month HCV-free survival was 86%.
Preemptive administration of GLE/ PIB in HCV-viremia cardiac transplant into HCV-naive recipients has demonstrated rapid HCV suppression (median time to clearance, 3-5 days; interquartile range, 0.0-8.3), prevention of chronic HCV infection (SVR12 rate of 100%), and excellent early allograft function (100% at a median follow-up of 10.7 months) in patients receiving HCV-viremia donor hearts.
Pancreas Transplantation;
The data on utilizing HCV-viremia organs in pancreas transplantation are limited.
Conclusion:
Transplantation of HCV-viremia organs into HCV-naive recipients followed by the use of DAA agents provides excellent patient and allograft survival
Hepatitis C virus treatment and SOT.
Summary;
Introduction;
This article discus the data on HCV treatment prior, and after transplantation.
Around 30 to 150 million people are affected worldwide by HCV, due to shortage of organ the new strategies is to expend the pool of donor and to include also the high risk donors like HBV/ HCV and HIV infected donors.
DAA therapy;
With new DAAs the cure rate is around 98%, and with high SVR rates.
These can used with decompensated liver disease.
DAAs and liver transplantation;
The outcomes has improved after discovery and treatment with DAAs.
Simultaneous liver-kidney transplant is safe and efficacious with good survival of 90% to 96.6%.
Also the MAGELLAN-2 study confirmed the safety and efficacy of DAAs of pan-Genotyps.
Hepatitis C Virus positive Donor transplantation in Hepatitis C Virus negative recipients.
The outcomes has improved after evolving the treatment of HCV with utilization of vireamic donor organs.
According to literature two large RCTs shows there is no difference in donors with vireamic and non-vireamic donor in survival of recipient and graft.
Renal transplantation.
HCV positive donor with kidney D+/R+ HCV has higher mortality and graft loss.
D+/R+ survival at 5- 10 years 84.6%- 72.7% respectively.
While D+/R- its 86.6- 76.5% respectively.
Pancreas transplantation.
HCV infected donor can used safely.
Conclusion.
SOT with HCV+ organs into HCV+ recipient has good outcomes and could decrease the waitlist gaps and morbidity and mortality.
Hepatitis C Virus Treatment and Solid Organ Transplantation
Its review article (evidence V) published in Gastroenterology & Hepatology Journal 2022 about HCV treatment post solid organ transplant.
Introduction: 9.7% of total deceased donor livers are HCV-positive organs. Because of organ shortage and the availability of direct-acting antiviral (DAA) therapy, HCV organs have been accepted to expand the donor pool.
HCV and DAA therapy:
Selection of DAA is related to multiple factors including previous history of HCV treatment (naive or experienced), kidney functions, HCV genotype and liver cirrhosis. For HCV genotypes 1,4,5, and 6 infections, a combination of ledipasvir and sofosbuvir (LED/SOF) has been associated with >98% SVR12 rates. Pan-genotypes HCV DAA includes SOF/velpatasvir (SOF/VEL) or Gelcaprevir and Pibrentasvir (GLE/PIB) combination with >95% SVR12 rates in patients without cirrhosis or mild cirrhosis. in the case of HCV viremic donors, there is still no generalized agreement regarding the timing of starting DAA pre, peri or post-transplant and the decision should be done on an individualized basis. According to the organ procurement and transplantation network (OPTN) data, DAA initiation pre-emptively, immediately following transplantation or even 90 days post-liver transplant has been shown to be associated with favorable outcomes.
1. DAA therapy in liver transplantation: Multiple trials addressed such subjects like the HCV-TARGET trial, MAGELLAN-1,2 trial, and SOLAR-1,2 trial in which pre-transplant DAA use was associated with high SVR12, reduced the incidence of significant HCV-related liver disease progression (20.5% versus 65.5%) and mortality post-transplant. Also, Perioperative DAA use was associated with comparable survival rates in HCV-positive recipients who received either HCV-negative or HCV-positive organs.
2. Renal transplantation: Multiple trials addressed such subjects as THINKER 1,2 trial, EXPANDER trial, and MYTHIC trial which showed utilizing HCV-positive donor kidney in HCV-positive/negative recipients has shown comparable results with excellent graft function and high SVR12 almost 100%.
3. thoracic transplantation (heart and lung): Multiple trials addressed such subjects as the USHER trial and the DONATE-HCV trial and showed the same results.
4. Pancreas transplantation or simultaneous pancreas-kidney transplantation (SPK): has been shown to be effective with 100% SVR12.
Conclusion: under the umbrella of DAA drugs, HCV-positive organs can be utilized in all solid organ transplants with favorable results as regard patient and graft outcomes and it looks reasonable to accept such organs after proper patient counseling about the risks, HCV treatment failure and immunosuppressive drug interactions.
Long queue lengths and high waitlist mortality as a result of organ scarcity have a detrimental impact on organ transplantation in the United States. DAA medications are used when HCV-viremic organs are transplanted into HCV-naive recipients to give excellent patient and allograft survival. The use of HCV-viremic grafts seems to be effective and well tolerated in carefully chosen patients. This procedure has shown to produce respectable short-term results and has the potential to considerably reduce morbidity and mortality while reducing waiting gaps. The need of getting DAA therapy posttransplant, along with the hazards involved, including the possibility of HCV treatment failure, should be made clear to patients. It is yet unknown whether HCV infection in posttransplant patients may result in long-term immune system alterations or unintentional interactions.
Please summarise this article.
Infection with the hepatitis C virus (HCV) affects 130–150 million people worldwide.
One of the most common causes of end-stage liver disease and the main justification for liver transplantation is HCV infection.
Yet, there is a significant waitlist mortality rate since the demand for organs continues to outstrip the supply of organ donation.
Organs with HCV remain more readily available, accounting for 9.7% of livers from dead donors in 2019.
Previously, HCV-infected organs from deceased donors were discarded due to the high risk of reperfusion-related transmission and the possibility of considerable posttransplant morbidity and mortality.
The science of HCV therapy and the utilization of HCV-positive organs have made considerable strides, leading to a major rise in organ transplantation and a decline in waitlist mortality.
In this paper, the research on HCV treatment both before and after organ transplantation is reviewed.
Direct acting antiviral therapy
Over the past several years, a succession of pangenotypic DAA therapies for the treatment of chronic HCV infection has been introduced, with cure rates defined as sustained virologic response 12 weeks after treatment (SVR12) of greater than 98%.16 Nonstructural protein.
Over the past several years, a succession of pangenotypic DAA therapies for the treatment of chronic HCV infection has been introduced, with cure rates defined as sustained virologic response 12 weeks after treatment (SVR12) of greater than 98%.16.
The MAGELLAN-2 study was a phase 3 open-label trial that confirmed the safety and efficacy of GLE/PIB once daily for 12 weeks in patients with treatment-naive HCV GT1 to GT6 infection or treatment-experienced HCV GT1, GT2, or GT4 to GT6 who had received a liver or kidney transplant.
Treatment with SOF/VEL for 12 weeks in 14 liver transplant recipients with HCV GT1 to GT4 infection and cirrhosis resulted in an SVR12 rate of.
HCV antibody HCV NAT clinical interpretation transmission risk
No active HCV infection, cleared or treated HCV infection, or false-positive antibody Low. HCV, hepatitis C virus; NAT, nucleic acid testing.
Donors identified as HCV positive by serologic testing but NAT negative are considered to have undergone spontaneous clearance or successful treatment of infection, or have a false-positive antibody result, and these donors have not been documented to transmit HCV infection.
An. HCV-seropositive donor that is NAT positive is considered to have an active infection and poses a high risk for disease transmission.
An HCV-negative donor that is NAT positive is considered to have an acute infection and poses a high risk for disease transmission.
Risk of HCV transmission remains during the 1-week eclipse period between viral exposure and positive NAT results, in persons who inject drugs.
Risk of HCV transmission remains during the 1-week eclipse period between viral exposure and positive NAT results, in persons who inject drugs.
Negative recipients
DAA therapy, transplantation of organs from HCV-positive donors into uninfected recipients was not routinely considered owing to low efficacy, high rates of HCV transmission, decreased patient and graft survival, and complications associated with interferon-based therapy in the posttransplant setting. The lack of effective and well-tolerated treatments for HCV had curtailed utilization of HCV-infected organs in transplant recipients.
DAA therapy, transplantation of organs from HCV-positive donors into uninfected recipients was not routinely considered owing to low efficacy, high rates of HCV transmission, decreased patient and graft survival, and complications associated with interferon-based therapy in the posttransplant setting.
The lack of effective and well-tolerated treatments for HCV had curtailed utilization of HCV-infected organs in transplant recipients.
Data have demonstrated favorable long-term graft outcomes in patients transplanted with HCV-seropositive donors.
In a study published in 1998, 22 patients with HCV received HCV-seropositive grafts and had excellent 4-year patient and graft survival, 83.9% and.
In a larger study that included 2923 transplant recipients with HCV, 96 and 2827 received HCV-positive and -negative organs, respectively, and had comparable
Liver transplantation
Two large retrospective studies evaluated HCV-viremic donors in nonviremic liver transplant recipients and demonstrated no differences in patient or graft survival when compared with nonviremic donors. 54,55 Data from 2015 to 2017 from the Organ Procurement and Transplantation Network (OPTN)
Two large retrospective studies evaluated HCV-viremic donors in nonviremic liver transplant recipients and demonstrated no differences in patient or graft survival when compared with nonviremic donors.
HCV-seropositive but NAT-negative and nonviremic livers (92% vs 92% vs 92%; P=NS).
2016 to 2020 data from OPTN, comparable 2-year graft survival rates were seen in 568 liver transplant recipients with and without HCV infection (n=753 and n=87, respectively) who received HCV-viremic organs
Antiviral therapy
GLE/PIB, glecaprevir/pibrentasvir; KT, kidney transplant; LDV/SOF, ledipasvir/sofosbuvir; LT, liver transplant; SOF/DAC, sofosbuvir/daclatasvir; SOF/VEL, sofosbuvir/velpatasvir; SVR12, sustained virologic response 12 weeks after treatment.
The first prospective study included 10 HCV-negative patients who received HCV-viremic livers, 7 of which had been cured of HCV infection prior to transplant.
GLE/PIB has been used successfully in HCV-naive patients who receive HCV-viremic livers.
In a trial of 14 patients who received HCV-viremic livers, 9 patients developed viremia with SVR12 and 46-week survival rates of 100% and 100%, respectively.
The administration of SOF/VEL or GLE/PIB once daily for 12 weeks in HCV-naive patients who received viremic livers (n=51).
In a multicenter study evaluating the kinetics of early HCV infection, SOF/VEL once daily for 12 weeks when viremia was confirmed resulted in SVR12 in all patients (13 liver, 11 kidney
SVR12 was reported in a prospective multicenter study evaluating outcomes in HCV-naive liver transplant and dual liver-kidney transplant. 60 all HCV-viremic organ recipients (n=20) achieved SVR12, the development of HCV-related complications suggests that careful and longer-term follow-up is still warranted
Renal transplantation
The prevalence of HCV among end-stage renal disease patients is 0.2% to 6%, and HCV infection traditionally has been a common complication after renal transplant.
In 2017, the THINKER trial was the first open-label, single-group pilot study that sought to determine the safety and efficacy of the transplant of kidneys from HCV GT1–viremic donors into HCV-negative recipients followed by treatment with elbasvir/grazoprevir (EBR/GZR; Zepatier, Merck) for 12 weeks (n=10).
In a study of 7 HCV-naive kidney recipients receiving HCV GT1– and HCV GT3–viremic kidneys, antiviral treatment with LDV/SOF (n=4) and SOF/VEL (n=3) for 8 to 12 weeks resulted in SVR12 and stable renal allograft function.
70 In a subsequent, larger, single-center, observational study, use of SOF/VEL or LDV/SOF resulted in SVR12 rates of 100% and stable allograft function in 53 HCV-naive recipients who received SOF/VEL or LDV/SOF for 8 to 12 weeks following HCV-viremic kidney transplant.[71].
Of the 6 patients who required treatment, 5 patients achieved SVR12, with 1 patient requiring the addition of ribavirin owing to resistance and 2 patients requiring retreatment with second-line DAA agents owing to relapse.
Thoracic transplantation
The reported prevalence of HCV infection is as high as 12%. 76 Early studies demonstrated reduced survival in recipients with HCV infection, regardless of acquisition of HCV pre– or post–.
The first prospective study utilizing HCV-viremic hearts included 11 HCV-naive recipients, 9 of whom developed HCV viremia after transplant and 8 of whom achieved SVR12 through treatment with either.
PIB in HCV-viremic cardiac transplant into HCV-naive recipients (n=20) has demonstrated rapid HCV suppression, prevention of chronic HCV infection (SVR12 rate of 100%), and excellent early allograft function (100% at a median follow-up of 10.7 months) in patients receiving HCV-viremic donor hearts.
In the largest-to-date prospective single-center study of 80 patients who underwent heart transplant with HCV-positive donors (70 NAT-positive, GT1-GT3 donors and 10 antibody-positive, NAT-negative donors), 67 of 70 (96%) recipients developed viremia following transplant and started treatment with LDV/.
Shorter duration of DAA treatment with GLE/PIB for 8 weeks following cardiac transplant was evaluated in 22 HCV-naive patients who received HCV-viremic organs.
At 6 months posttransplant, there was no difference between HCV-viremic and HCV-negative recipients when comparing mortality (6.3% vs 3.9%; P=1), primary graft dysfunction (0.0% vs 11.5%; P=.275), clinically significant rejection requiring treatment (31.8% vs 37%; P=.769), or acute cellular rejection (90.9% vs 100%; P=.196).
Pancreas transplantation
The data on utilizing HCV-viremic organs in pancreas transplantation are limited.
In 2021, the first reported series included 8 HCV-naive patients who received either deceased donor simultaneous pancreas-kidney transplant or pancreas transplant after living donor kidney transplant.
Length of stay (16 days vs 10 days; P=.06) was similar between those who received HCV-viremic organs and those who did not, respectively.
These preliminary findings suggest that HCV-viremic pancreas transplant may be safely used for potential pancreas recipients; further study regarding morbidity and mortality of pancreas transplantation with HCV-positive donors is needed.
Short-term outcomes for solid organ transplantation appear to be comparable for HCV-viremic and -nonviremic donors, based on the previously discussed preliminary data.
Promising data are most robust in kidney followed by liver transplant but offer limited results past 1 year
Findings
Have led to greater utilization of HCV‐positive livers, increasing from 7% to 17% between 2010 and.
With cure rates defined as sustained virologic response 12 weeks after treatment (SVR12) of greater than 98%.16.
Recipients who achieve SVR12 posttransplant have lower rates of liver fibrosis progression (20.5% vs 65.5%; P<.001) and lower mortality rates compared with patients who do not receive or fail treatment.
Treatment with GLE/PIB for 3 months or longer posttransplant in 80 liver transplant and 20 kidney transplant patients resulted in an SVR12 rate of 98%.
In posttransplant patients with HCV GT4 infection, SVR12 was achieved by 78% of patients who received 12 weeks of treatment and 94% of patients who received 24 weeks of treatment.
Produced similar 1-year patient and graft survival when compared with HCV-naive patients who received nonviremic livers (n=231), at 93.4% vs 93.9% (P=.89) and.
HCV seropositivity was reported to be an independent risk factor for increased mortality when matched with controls (2.8-fold greater; 95% CI, 1.3-5.7; P=.006) and for the development of accelerated allograft vasculopathy when compared with matched controls, with a hazard ratio of 9.4 vs 3.08
Conclusion
Organ transplantation in the United States is negatively impacted by long waitlist times and high waitlist mortality owing to organ shortages.
The use of HCV-viremic grafts appears to be efficacious and well tolerated.
This practice has demonstrated acceptable short-term outcomes and has the potential to significantly close waitlist gaps and decrease morbidity and mortality.
DAA therapy posttransplant is essential and patients should be fully informed of the associated risks, including the potential of HCV treatment failure.
It remains unclear whether HCV infection in posttransplant patients may lead to lasting changes to the immune system or inadvertent interactions with immunosuppressive therapy.
Kidney transplantation is the treatment of choice for end stage chronic kidney disease.
However, owing to dearth of organ supply, an extended donor criteria was adopted. Therefore, HCV infected patient was considered an acceptable potential donor for solid organ transplantation.
This forwards step stemmed from the successful outcome and high reversal rate of infection after treatment with the administration of direct acting antiviral therapy DAAT.
Incidence :of HCV infection 150 million worldwide.
Chronic hepatitis :
The persistence of HCV genome detected by PCR for more than 6 months.
Positive viremia: the detection of HCV RNA in plasma of patients who is serologically positive.
Seroconversion:
The presence of anti-HCV antibodies.
DAAT:
The combination of more than one anti HCV medications protocol was successful for a duration of 12 weeks was liked to a success rate of more than 98% success in establishing sustained virologic remission SVR of 12 moths. This observation was noted with predominantly with genotype 1,4,5 and 6.
DAAT types:
1] Non structural protein 5 B inhibitor NS5Bi Sofosbuvir.
2] Nonstructural protein 5A inhibitor. NSP5A ledipasvir and velpatasvir
3] Protease inhibitor.
4] Ribavirin.
the combination of both in one tab formula of LED/SOF 90/400 revolutionized the treatment of HCV infection resultant in a unprecedented recovery rate with SVR12 in more than 98% of the genotypes mentioned earlier. However, VEL/SOF combination is successful in all genotypes with success rate of more than 95%.
The success rate of DAAT administered peri-transplantation paved the acceptance of organs donation from HCV infected donors with different protocols pre-donation, pre-emptive post donation or after seroconversion of recipients, with variable success of organ transplantation without transmitting HCV.
Hepatitis C Virus Treatment and Solid Organ Transplantation
SUMMARY
Introduction:
· 30-150 million people worldwide are affected by HCV.
· With global shortage of organs, strategies to expand the donor pool include donation after cardiac death, increased utilization of high-risk donors like HBV+/ HCV+ / HIV+ donors and use of HCV+ living donors.
· The opioid epidemic has caused an increase in HCV transmission.
· DAA therapy has led to greater utilization of HCV+ livers, increasing from 7% to 17% between 2010 and 2015,
· This article reviews the data on HCV treatment prior to and after organ transplantation.
Hepatitis C Virus Infection and Direct- Acting Antiviral Therapy
· Pan-genotypic DAA therapies in treatment of chronic HCV infection, confers cure rates of 98% and high SVR12 rates.
· It has shown to improve liver function in patients with decompensated cirrhosis, reducing the risk of reinfection of the allograft, but not all patients with end-stage liver disease from HCV infection will benefit.
Direct-Acting Antiviral Therapy and Liver Transplantation
· HCV infection after liver transplant can have variable course – ranging from mild fibrosis to severe graft damage, advanced fibrosis and graft cirrhosis in up to 45% of posttransplant patients.
· DAA therapy following liver transplant has improved outcomes, with lower rates of liver fibrosis progression, mortality, and SVR12 rates compared to those who do not receive or fail treatment.
· Treatment of HCV infection in patients undergoing simultaneous liver-kidney transplant is safe and efficacious, with 96.6% and 90.9% SVR12 rates.
· The MAGELLAN-2 study confirmed the safety and efficacy of a pan-genotypic, ribavirin-free regimen in posttransplant patients without cirrhosis, with an SVR12 rate of 98%. No patients experienced virologic failure or discontinued GLE/PIB due to adverse events unrelated to treatment.
· HCV infection posttransplant has a negative long-term impact, leading to the use of HCV-positive organs in HCV-negative recipients.
Defining Hepatitis C Virus–Positive Donors
· HCV-positive donors encompass any stage of HCV infection, and serologic tests such as chemiluminescence assays and enzyme immunoassays detect antibodies within 2 to 6 months after exposure.
· Nucleic acid testing (NAT) detects RNA 5 to 7 days after exposure and provides a more accurate assessment of transmission risk.
· It is important to distinguish between a seropositive and viremic donor when discussing organ transplants from an HCV-positive donor, as the risks of disease transmission vastly differ.
· Despite improvements in testing, the risk of HCV transmission remains during the 1-week eclipse period between viral exposure and positive NAT results.
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients
· Before the availability of DAA therapy, transplantation of organs from HCV-positive donors into uninfected recipients was not routinely considered due to low efficacy, high rates of HCV transmission, decreased patient and graft survival, and complications associated with interferon-based therapy.
· However, the rapidly evolving treatments for HCV have improved outcomes and increased the utilization of HCV-viraemic donor organs.
Liver Transplantation
· 2 large retrospective studies evaluated HCV-viraemic donors in nonviremic liver transplant recipients and found no differences in patient or graft survival.
· HCV treatment within 3 months of transplantation increases the probability of successful graft function and reduces waitlist mortality.
· GLE/PIB has been used successfully in HCV-naive patients who receive HCV-viraemic livers, with 9 patients developing viremia with SVR12 and 46-week survival rates of 100% and 100%, respectively.
· Immediate treatment is safe and efficacious, and initiation of DAA therapy within 90 days of transplant has also demonstrated favourable outcomes.
· A pre-emptive antiviral strategy using SOF/VEL is also successful in achieving SVR12, but serious adverse events include biliary sclerosis, cardiomyopathy, and graft-vs-host disease.
Renal Transplantation
· HCV infected donor kidney in HCV-seropositive renal recipients is associated with higher all-cause mortality and graft loss.
· Studies have shown promising long-term outcomes of HCV-seropositive recipients transplanted with kidneys from HCV-positive donors, with 5- and 10-year patient survival of 84.8% and 72.7%, respectively, compared to 86.6% and 76.5% for HCV-negative recipients.
· The THINKER trial was the first open-label, single-group pilot study to evaluate the safety and efficacy of the transplant of kidneys from HCV GT1–viremic donors into HCV-negative recipients (donor positive, recipient negative [D+/R-]) followed by treatment with elbasvir/grazoprevir (EBR/GZR). All recipients had detectable HCV RNA immediate post-transplant, and all attained SVR12.
· The EXPANDER trial examined the tolerability and feasibility of DAA prophylaxis before and after renal transplant in HCV-naive patients who received HCV-viremic kidneys. GLE/PIB once daily for 12 weeks has been shown to be well tolerated in patients with chronic HCV GT1 to GT6 infection who have undergone kidney transplantation.
· In the MYTHIC trial, 30 HCV-naive patients achieved SVR12 and no severe adverse events were noted.
· In the DAPPER trial, a single pretransplant dose of SOF/ VEL followed by 1 or 3 posttransplant doses reduced viral transmission to 7.5% but did result in detectable viremia in 17 of 50 (34%) patients by posttransplant day 14.
· Short-course DAA regimens have also been evaluated with promising results.
Thoracic Transplantation
– Donor HCV seropositivity is an independent risk factor for increased mortality and accelerated allograft vasculopathy in heart transplant recipients.
– Pre-emptive administration of GLE/PIB has demonstrated rapid HCV suppression, prevention of chronic HCV infection, and improved allograft function.1
– The largest-to-date prospective single-centre study of 80 patients of heart transplant with HCV-positive donors, revealed viremia in 67 of 70 (96%) following transplant and received treatment with LDV/ SOF, SOF/VEL, or GLE/PIB for 12 weeks.
– Most common adverse events were respiratory complications and infections, – 45% requiring hospitalization.
– The DONATE-HCV trial evaluated transplanting HCV-viremic organs into 8 cardiac and 36 lung HCV-naive recipients, with 95% of recipients achieving SVR12 with excellent graft function.
Pancreas Transplantation
– HCV-viremic pancreas transplant may be safely used for potential pancreas recipients, but further study is needed to determine morbidity and mortality.
– Short-term outcomes for solid organ transplantation appear to be comparable for HCV-Viremic and nonviremic donors, with promising results past 1 year.
Conclusion
· Organ transplantation in the US is impacted by long waitlist times and high mortality due to organ shortages.
· Transplantation of HCV+ organs into HCV-naive recipients provides excellent patient and allograft survival and has the potential to close waitlist gaps and decrease morbidity and mortality.
Summary:
Hepatitis C Virus Treatment and Solid Organ Transplantation
The development of safe and highly effective HCV therapy with direct-acting antiviral agents has revolutionized the management of liver transplant candidates and transplant recipients This article reviews the data on HCV treatment prior to and after organ transplantation.
The high success rate of DAA therapy, have led to greater utilization of HCV‐positive livers from 7% to 17% between 2010 and 2015. Major strides in HCV eradication paved the way for use of HCV-positive organs, first in HCV-viremic recipients and now in HCV-negative recipients.
Hepatitis C Virus Infection and Direct Acting Antiviral Therapy
The combination of potent NS5A inhibitor ledipasvir (LDV) and sofosbuvir (SOF) is well tolerated and produces high SVR12 rates in HCV genotype (GT) 1, 4, 5, and 6 infection.
The combination of SOF and NS5A inhibitor velpatasvir provides SVR12 rates of greater than 95% across all GTs and has a favorable safety pro file.
The combination of NS3/4A protease inhibitor glecaprevir and NS5A inhibitor pibrentasvir is well tolerated and results in SVR12 rates greater than 97% across all GT.
Pretransplant DAA therapy reduces the risk of reinfection of the allograft.
Will benefit from treatment prior to liver transplantation.
Clinical features associated with meaningful improve ment in liver function from pretransplant therapy include low baseline Model for End-Stage Liver Disease score (<16), low baseline Child-Pugh score, and the absence of portal hypertension complications.
Direct-Acting Antiviral Therapy and Liver Transplantation
Recipients who achieve SVR12 posttransplant have lower rates of liver fibrosis progression and lower mortality rates compared with patients who do not receive or fail treatment.
Treatment of HCV infection in patients who undergo simultaneous liver-kidney transplant is both safe and efficacious.
The HCV-TARGET trial used the Hepatitis C Therapeutic Registry and Research Network database to evaluate liver transplant and dual liver-kidney transplant recipients with HCV infection treated with LDV/SOF, ombitasvir/paritaprevir/ritonavir plus dasabuvir or SOF plus daclatasvir. SVR12 rates among liver transplant and dual liver-kidney transplant recipi ents were 96.6% and 90.9%, respectively. Successful outcomes from the real-world data of the large HCV-TARGET cohort provided confidence in treating liver transplant patients with a ribavirin-free regimen.
The MAGELLAN-2 study was a phase 3 open-label trial that confirmed the safety and efficacy of GLE/PIB once daily for 12 weeks in patients with treatment-naive HCV GT1 to GT6 infection or treatment-experienced HCV GT1, GT2, or GT4 to GT6 who had received a liver or kidney transplant.
SOLAR-1 and SOLAR-2 were 2 large trials that evaluated LDV/SOF plus ribavirin in liver transplant recipients with HCV GT1 to GT4 infection and liver disease.
In SOLAR-1, SVR12 was achieved in 96% promising data on the safety and effi cacy of DAA therapy for the treatment of HCV infection posttransplant led to a paradigm shift.
Defining Hepatitis C Virus–Positive Donors
Serologic tests such as chemiluminescence assays and enzyme immunoassays detect antibodies within 2 to 6 months after exposure,
Nucleic acid testing (NAT) detects RNA 5 to 7 days after exposure and provides a more accurate assessment of transmission risk. HCV NAT has a sensitivity of 85% to 100% and a specificity of 99% to 100%.
HCV positive by serologic testing but NAT negative (nonviremic) are considered to have undergone spontaneous clearance or successful treatment of infection, or have a false-positive antibody result, and these donors have not been documented to transmit HCV infection.
An HCV-seropositive donor that is NAT positive (viremic) is considered to have an active infection and poses a high risk for disease transmission.
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients
In a study published in 1998, 22 patients with HCV received HCV-seropositive grafts and had excellent 4-year patient and graft survival compare with HCV-seronegative donor grafts.
In a larger study that included 2923 transplant recipients with HCV, 96 and 2827 received HCV-positive and -negative organs, respectively, and had comparable 2-year survival rates (90% vs 77%)
Liver Transplantation
Two large retrospective studies evaluated HCV-viremic donors in nonviremic liver transplant recipients and demonstrated no differences in patient or graft survival when compared with nonviremic donors.
Renal Transplantation
The availability of DAA therapy and its administration around the time of transplant minimizes the risk of chronic HCV infection in the transplant recipient and thus has led to the recent growth of transplant of kidneys from HCV-infected donors into HCV-naive recipients.
THINKER trial (2017) was the first open-label, single-group pilot study that sought to determine the safety and efficacy of the transplant of kid neys from HCV GT1–viremic donors into HCV-negative recipients followed by treatment with elbasvir/grazoprevir for 12 weeks (n=10). All recipients had detectable HCV RNA, and all attained SVR12
THINKER-2 trial (n=20), HCV-negative recipients of HCV-viremic kidneys experienced HCV cure and excellent renal allograft function with estimated glomerular filtration rates (eGFRs) not significantly different from those of matched recipients of HCV-negative kidneys at 6 months and 12 months
The EXPANDER trial was an open-label single center study (n=10) that examined the tolerability and feasibility of DAA prophylaxis before and after renal transplant in HCV-naive patients (n=10) who received HCV-viremic kidneys (GT1-GT3).In this study, all recipients received a dose of EBR/GZR immediately before transplant, and recipients of kidneys from donors with GT1 infection continued receiving EBR/GZR for 12 weeks after transplant; those receiving organs from donors with GT2 or GT3 infection received SOF along with EBR/GZR for 12 weeks of triple therapy. Preemptive use of EBR/GZR for 12 weeks in HCV-naive recipients who received HCV-infected kidneys (n=8) led to SVR12 with no study-related adverse events
SOF-based regimens are safe and effective in HCV-naive recipients undergoing HCV-viremic kidney transplant.
MYTHIC trial, 30 HCV-naive patients received HCV-viremic kidneys across 7 transplant centers. All 30 recipients achieved SVR12, and no severe adverse events related to HCV infection or GLE/PIB were noted in any patient. Although all recipients had good allograft function
In a large, prospective, real-world study, 64 HCV-naive patients underwent HCV-viremic kidney transplant followed by posttransplant NAT to determine the need for treatment. 61 patients developed viremia, of which 41 patients achieved SVR12, 10 reached undetectable viral loads, and 7 remained on treatment. There was 1 nonre sponder owing to NS5A resistance. At a median 8-month follow-up, patient and graft survival were both 98%
The DAPPER trial treated patients with a single pretransplant dose of SOF/ VEL followed by 1 or 3 posttransplant doses. The 4-day strategy reduced viral transmission to 7.5% but did result in detectable viremia in 17 of 50 (34%) patients by posttransplant day 14, of which only 6 of 50 (12%) required treatment; the remaining 11 recipients had self-limited, low-level vire mia. Of the 6 patients who required treatment, 5 patients achieved SVR12, with 1 patient requiring the addition of ribavirin owing to resistance and 2 patients requiring retreatment with second-line DAA agents owing to relapse.
Friebus-Kardash et al (2019):Cohort Size: 7, Antiviral Therapy: LDV/SOF, Therapy Duration: 8-12 weeks SVR12: 7/7 (100%)
Molnar et al (2019):Cohort Size: 53, Antiviral Therapy: GLE/PIB, SOF/VEL, or LDV/SOF, Therapy Duration: 12 weeks SVR12: 53/53 (100%)
Sise et al (2020):Cohort Size: 8, Antiviral Therapy: EBR/GZR, Therapy Duration: 12 weeks SVR12: 8/8 (100%)
Thoracic Transplantation:
Among heart transplant recipients, the reported prevalence of HCV infection is as high as 12%.
Donor HCV seropositivity was reported to be an independent risk factor for increased mortality when matched with controls (2.8-fold) and for the development of accelerated allograft vasculopathy.
In the largest RCT study of 80 patients who underwent heart transplant with HCV-positive donors, 67 of 70 (96%) recipients developed viremia following transplant and started treatment with LDV/ SOF, SOF/VEL, or GLE/PIB for 12 weeks. Of those who started DAA treatment (n=55), 37 achieved SVR12 with 17 recipients pending, and 1 recipient died prior to achieving SVR12.
Although there were higher rates of severe primary graft dysfunction, there was no difference regarding the hospital length of stay, rejection requiring treatment, survival at 30 days, or 1-year patient survival.
Short course(8weeks)DAA in heart transplant associated with high SVR12 with out survival difference.
In lung transplant & HCV D+/R- treated with SOF/VEL for 12 weeks show HCV free survival at 6 months 86%, but risk of infection & rate of hospital admission was higher than D-/R- HCV transplant.
Pancreas Transplantation:
The data on utilizing HCV-viremic organs in pancreas transplantation are limited.
In 2021, the first reported series included 8 HCV-naive patients who received either deceased donor simultaneous pancreas-kidney transplant or pancreas transplant after living donor kidney transplant.
All patients developed viremia and were treated with either GLE/PIB or SOF/VEL and all achieved SVR12.
All recipients had excellent pancreas graft function and rates of rejection with no difference in hospital stay.
Conclusion:
Transplantation of HCV-viremic organs into HCV-naive recipients followed using DAA agents provides excellent patient and allograft survival.
Introduction:
HCV infection affects 130 million to 150 million people worldwide.
End-stage liver disease is the indications for liver transplantation
DAA therapy has led to greater utilization of HCV-positive livers, increasing from 7% to 17% between 2010 and 2015,
This article reviews the data on HCV treatment prior to and after organ transplantation.
Although the pretransplant DAA therapy reduces the risk of reinfection of the allograft but not all patients benefits from it.
. Hepatitis C Virus Infection and Direct Acting Antiviral therapy:
pangenotypic DAA therapies for chronic HCV infection is introduced, with cure rates greater than 98%
Improvement in liver function from pretransplant therapy include low baseline Model for End-Stage Liver Disease score
Patients with advance liver disease dose not improve with DAA therapy.
Direct-Acting Antiviral Therapy and Liver Transplantation:
Post liver transplantation HCV infection cause a variable clinical course ranging from mild fibrosis to severe graft damage, with advanced fibrosis and graft cirrhosis in up to 45% of posttransplant patients.
Improve outcome of liver transplant after DAA therapy following liver transplant by lowering the rate of liver fibrosis progression, mortality, and SVR12 rates compared to those who do not receive or fail treatment of DAA.
Treatment of HCV infection in patients undergoing simultaneous liver-kidney transplant is safe and efficacious, with 96.6% and 90.9% SVR12 rates.
HCV infection has a negative long-term impact on both patient and graft survival.
Defining Hepatitis C Virus–Positive Donors:
HCV-positive donors encompass any stage of HCV infection, and serologic tests such as chemiluminescence assays and enzyme immunoassays detect antibodies within 2 to 6 months after exposure.
Nucleic acid testing (NAT) detects RNA 5 to 7 days after exposure and provides a more accurate assessment of transmission risk with sensitivity of 85-100% and specificity of 99-100%.
It is important to distinguish between a seropositive and viremic donor when discussing organ transplants from an HCV-positive donor, as the risks of disease transmission vastly differ.
Despite improvements in testing, the risk of HCV transmission remains during the 1-week eclipse period between viral exposure and positive NAT results.
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients:
Transplantation of organs from HCV-positive donors into uninfected recipients was not routinely till DAA therapy is available due to low efficacy, high rates of HCV transmission, decreased patient and graft survival, and complications associated with interferon-based therapy.
Liver Transplantation:
2 large retrospective studies evaluated HCV-viremic donors in nonviremic liver transplant recipients and found no differences in patient or graft survival in compared with nonviremic donors.
GLE/PIB has been used successfully in HCV-naive patients who receive HCV-viremic livers. In a trial of 14 patients who received HCV-viremic livers, 9 patients developed viremia with SVR12 and 46-week survival rates of 100% and 100%, respectively
A preemptive antiviral strategy using SOF/VEL is also successful in achieving SVR12.
Renal Transplantation:
Some studies found that DAA therapy are safe and very effective in the treatment of recipients of kidney transplant with HCV.
In compare the outcomes for untreated HCV infection in HCV-seropositive renal recipients are strongly worse than in their HCV-negative counterparts.
Thoracic Transplantation:
In comparison between patients who received HCV-viremic heart transplant and who received transplants from HCV-negative donors during the same period.
We found that there was no difference regarding the hospital stay, rejection, survival at 30 days, or 1-year patient survival.
Pancreas Transplantation:
HCV-viremic pancreas transplant may be safely used for potential pancreas recipients, but further studies about morbidity and mortality of pancreas transplantation with HCV-positive donors is needed.
Conclusion:
Transplantation of HCV-viremic organs into HCV-naive recipients followed using DAA agents provides excellent patient and allograft survival.
In carefully selected patients, the use of HCV-viremic grafts appears to be efficacious and well tolerated.
DAA therapy posttransplant is essential and patients should be informed of associated risks.
Introduction:
· HCV infection affects 130-150 million people worldwide, leading to a global shortage of organs. Strategies to expand the donor pool include donation after cardiac death, the use of living donors, and increased utilization of high-risk donors.
· DAA therapy has led to greater utilization of HCV-positive livers, increasing from 7% to 17% between 2010 and 2015, and the opioid epidemic has caused an increase in HCV transmission. This article reviews the data on HCV treatment prior to and after organ transplantation.
Hepatitis C Virus Infection and Direct- Acting Antiviral Therapy
· Pangeno-typic DAA therapies have been introduced to treat chronic HCV infection, with cure rates of 98% and high SVR12 rates.
· DAA therapy has been shown to improve liver function in patients with decompensated cirrhosis, reducing the risk of reinfection of the allograft, but not all patients with end-stage liver disease from HCV infection will benefit.
Direct-Acting Antiviral Therapy and Liver Transplantation
· HCV infection after liver transplant can cause a variable clinical course ranging from mild fibrosis to severe graft damage, with advanced fibrosis and graft cirrhosis in up to 45% of posttransplant patients.
· DAA therapy following liver transplant has been found to have improved outcomes, with lower rates of liver fibrosis progression, mortality, and SVR12 rates compared to those who do not receive or fail treatment.
· Treatment of HCV infection in patients undergoing simultaneous liver-kidney transplant is safe and efficacious, with 96.6% and 90.9% SVR12 rates.
· The MAGELLAN-2 study confirmed the safety and efficacy of a pan-genotypic, ribavirin-free regimen in posttransplant patients without cirrhosis, with an SVR12 rate of 98%. No patients experienced virologic failure or discontinued GLE/PIB due to adverse events unrelated to treatment.
· HCV infection posttransplant has a negative long-term impact, leading to the use of HCV-positive organs in HCV-negative recipients.
Defining Hepatitis C Virus–Positive Donors
· HCV-positive donors encompass any stage of HCV infection, and serologic tests such as chemiluminescence assays and enzyme immunoassays detect antibodies within 2 to 6 months after exposure.
· Nucleic acid testing (NAT) detects RNA 5 to 7 days after exposure and provides a more accurate assessment of transmission risk.
· It is important to distinguish between a seropositive and viremic donor when discussing organ transplants from an HCV-positive donor, as the risks of disease transmission vastly differ.
· Despite improvements in testing, the risk of HCV transmission remains during the 1-week eclipse period between viral exposure and positive NAT results.
Hepatitis C Virus–Positive DonorTransplantation in Hepatitis C Virus– Negative Recipients
· Before the availability of DAA therapy, transplantation of organs from HCV-positive donors into uninfected recipients was not routinely considered due to low efficacy, high rates of HCV transmission, decreased patient and graft survival, and complications associated with interferon-based therapy.
· However, the rapidly evolving treatments for HCV have improved outcomes and increased the utilization of HCV-viremic donor organs.
Liver Transplantation
· Two large retrospective studies evaluated HCV-viremic donors in nonviremic liver transplant recipients and found no differences in patient or graft survival.
· HCV treatment within 3 months of transplantation increases the probability of successful graft function and reduces waitlist mortality.
· GLE/PIB has been used successfully in HCV-naive patients who receive HCV-viremic livers, with 9 patients developing viremia with SVR12 and 46-week survival rates of 100% and 100%, respectively.
· Immediate treatment is safe and efficacious, and initiation of DAA therapy within 90 days of transplant has also demonstrated favorable outcomes.
· A preemptive antiviral strategy using SOF/VEL is also successful in achieving SVR12, but serious adverse events include biliary sclerosis, cardiomyopathy, and graft-vs-host disease.
Renal Transplantation
· HCV infection in HCV-seropositive renal recipients is associated with higher all-cause mortality and graft loss.
· Studies have shown promising long-term outcomes of HCV-seropositive recipients transplanted with kidneys from HCV-positive donors, with 5- and 10-year patient survival of 84.8% and 72.7%, respectively, compared to 86.6% and 76.5% for HCV-negative graft recipients.
· The THINKER trial was the first open-label, single-group pilot study to evaluate the safety and efficacy of the transplant of kidneys from HCV GT1–viremic donors into HCV-negative recipients (donor positive, recipient negative [D+/R-]) followed by treatment with elbasvir/grazoprevir (EBR/GZR). All recipients had detectable HCV RNA, and all attained SVR12.
· The EXPANDER trial examined the tolerability and feasibility of DAA prophylaxis before and after renal transplant in HCV-naive patients who received HCV-viremic kidneys. GLE/PIB once daily for 12 weeks has been shown to be well tolerated in patients with chronic HCV GT1 to GT6 infection who have undergone kidney transplantation.
· In the MYTHIC trial, 30 HCV-naive patients achieved SVR12 and no severe adverse events were noted.
· In the DAPPER trial, a single pretransplant dose of SOF/ VEL followed by 1 or 3 posttransplant doses reduced viral transmission to 7.5% but did result in detectable viremia in 17 of 50 (34%) patients by posttransplant day 14.
· Short-course DAA regimens have also been evaluated with promising results.
Thoracic Transplantation
· Donor HCV seropositivity is an independent risk factor for increased mortality and accelerated allograft vasculopathy in heart transplant recipients.
· Preemptive administration of GLE/PIB has demonstrated rapid HCV suppression, prevention of chronic HCV infection, and improved allograft function.1
· The largest-to-date prospective single-center study of 80 patients who underwent heart transplant with HCV-positive donors found that 67 of 70 (96%) developed viremia following transplant and started treatment with LDV/ SOF, SOF/VEL, or GLE/PIB for 12 weeks.
· The most common adverse events were respiratory complications and infections, with 45% requiring admission to the hospital.
· The DONATE-HCV trial evaluated transplanting HCV-viremic organs into 8 cardiac and 36 lung HCV-naive recipients, with 95% of recipients achieving SVR12 with excellent graft function.
Pancreas Transplantation
· HCV-viremic pancreas transplant may be safely used for potential pancreas recipients, but further study is needed to determine morbidity and mortality.
· Short-term outcomes for solid organ transplantation appear to be comparable for HCV-Viremic and nonviremic donors, with promising results past 1 year.
Conclusion
Organ transplantation in the US is impacted by long waitlist times and high mortality due to organ shortages, but transplantation of HCV-viremic organs into HCV-naive recipients provides excellent patient and allograft survival and has the potential to close waitlist gaps and decrease morbidity and mortality.
Hepatitis C virus (HCV) infection affects approximately 130 million to 150 million people worldwide.
Historically, organs from deceased donors infected with HCV were discarded because of high transmission risk during reperfusion and risk of significant posttransplant morbidity and mortality. Several strategies to expand the donor pool have been implemented, including donation after cardiac death, use of living donors, and increased utilization of high-risk donors to mitigate the global shortage.
Renal Transplantation
The prevalence of HCV among end-stage renal disease patients is 0.2% to 6%, and HCV infection traditionally has been a common complication after renal transplant.61 Outcomes for untreated HCV infection in HCV-seropositive renal recipients are significantly worse than in their HCV-negative counterparts.
In a study of 545 kidney transplants performed in HCV-positive recipients, 5- and 10-year patient survival was 84.8% and 72.7%, respectively, for HCV-positive graft recipients compared with 86.6% and 76.5%, respectively (P=.25), for HCV-negative graft recipients.
Furthermore, the availability of DAA therapy and its administration around the time of transplant minimizes the risk of chronic HCV infection in the transplant recipient and thus has led to the recent growth of transplant of kidneys from HCV-infected donors into HCV-naive recipients.
In 2017, the THINKER trial was the first open-label, single-group pilot study that sought to determine the safety and efficacy of the transplant of kidneys from HCV GT1–viremic donors into HCV-negative recipients (donor positive, recipient negative [D+/R-]) followed by treatment with elbasvir/grazoprevir (EBR/GZR; Zepatier, Merck) for 12 weeks (n=10).
All recipients had detectable HCV RNA, and all attained SVR12. In the THINKER-2 trial (n=20), which included THINKER participants, HCV-negative recipients of HCV-viremic kidneys experienced HCV cure and excellent renal allograft function with estimated glomerular filtration rates (eGFRs) not significantly different from those of matched recipients of HCV-negative kidneys at 6 months and 12 months.
SOF-based regimens are safe and effective in HCV-naive recipients undergoing HCV-viremic kidney transplant. In a study of 7 HCV-naive kidney recipients receiving HCV GT1– and HCV GT3–viremic kidneys, antiviral treatment with LDV/SOF (n=4) and SOF/VEL (n=3) for 8 to 12 weeks resulted in SVR12 and stable renal allograft function.
In a subsequent, larger, single-center, observational study, use of SOF/VEL or LDV/SOF resulted in SVR12 rates of 100% and stable allograft function in 53 HCV-naive recipients who received SOF/VEL or LDV/SOF for 8 to 12 weeks following HCV-viremic kidney transplant. 71 Four recipients developed acute rejection.
Shorter-course DAA regimens have also been evaluated with promising results. In a study of 10 HCV D+/R- kidney transplants, 4-week GLE/PIB prophylaxis resulted in undetectable HCV RNA after day 7 and stable allograft function with eGFR of 54.5 mL/min/1.73 m 2(range, 30-79 mL/min/1.73 m2)
Conclusion
Organ transplantation in the United States is negatively impacted by long waitlist times and high waitlist mortality owing to organ shortages. Transplantation of HCV-viremic organs into HCV-naive recipients followed by the use of DAA agents provides excellent patient and allograft survival. In carefully selected patients, the use of HCV-viremic grafts appears to be efficacious and well tolerated. This practice has demonstrated acceptable short-term outcomes and has the potential to significantly close waitlist gaps and decrease morbidity and mortality. However, securing DAA therapy posttransplant is essential and patients should be fully informed of the associated risks, including the potential of HCV treatment failure. It remains unclear whether HCV infection in posttransplant patients may lead to lasting changes to the immune system or inadvertent interactions with immunosuppressive therapy. Understanding long-term outcomes of HCVviremic organ utilization remains on the near horizon.
HCV organ transplant is now increasing specially after the dicovery of DAA therapy which increase the chance of cure and less resistence .
No HCV positive donor reached 9.7% with succesful stories .,and this increase the risk of transplant and reduce the waiting list mortality .
DAA therapy has been shown to improve liver function in patients with decompensated cirrhosis. The DAA showed great respose with SVRof 12 weeks more than 97% in the different type .
DAA making the transplant possible so we can proceed with HCV + donor to negative reciepent but is essential that patients should be fully informed about risks, including possible failure of treatment.
What type of HCV positive we need to accept as the donor ???
In case of AntiHCV Ab positive this is meana clearance of the infection or treated and dose not mean infectivity .But the patient with high HCV PCR is infective and need to be on DAA before transplantation .
Hepatitis C Virus Treatment and Solid Organ Transplantation
· HCV-positive organs are increasing and represented 9.7% of deceased-donor livers in 2019.
· After the discovery of direct-acting antiviral (DAA) therapy, the acceptance of HCV‐positive livers is increasing.
· The use of HCV-positive organs, lead to increase number of organ transplants and decrease waitlist mortality.
Hepatitis C Virus Infection and DirectActing Antiviral Therapy
· DAA therapies have a cure rate defined as sustained virologic response 12 weeks after treatment (SVR12) of greater than 98%.
· The combination of ledipasvir and SOF (LDV/SOF, 90 mg/400 mg; Harvoni, Gilead), given once daily, is well tolerated and produces high SVR12 rates in HCV genotype 1, 4, 5, and 6 infection.
· The combination of SOF and velpatasvir (SOF/VEL; Epclusa, Gilead), given once daily, provides SVR12 rates of > 95% across all GTs and has a favorable safety profile.
· The combination of glecaprevir and pibrentasvir (GLE/PIB; Mavyret, AbbVie) was first approved in 2017 for the treatment of HCV infection without cirrhosis or with mild cirrhosis.GLE/PIB is well tolerated and results in SVR12 rates greater than 97% across all GTs
· DAA therapy has been shown to improve liver function in patients with decompensated cirrhosis.
· pretransplant DAA therapy reduces the risk of reinfection of the allograft.
· Patients with advanced liver disease are unlikely to improve with DAA therapy and those with Child-Pugh class C cirrhosis have lower SVR12 rates.
Direct-Acting Antiviral Therapy and Liver Transplantation
· Use of DAA therapy following liver transplant has excellent outcomes, as it reduces rates of liver fibrosis progression and mortality
· Treatment of HCV infection in patients who undergo simultaneous liver-kidney transplant is both safe and efficacious.
Defining Hepatitis C Virus–Positive Donors
· Serologic tests and enzyme immunoassays detect antibodies within 2 – 6 months after exposure
· Nucleic acid testing (NAT) detects RNA 5 to 7 days after exposure and provides a more accurate assessment of transmission risk.
· HCV NAT has a sensitivity of 85% to 100% and a specificity of 99% to 100%.
· Donors identified as HCV positive by serologic testing but NAT negative have:
spontaneous clearance or successful treatment of infection, or have a false-positive antibody result, and they do not transmit HCV infection.
· An HCV-seropositive donor that is NAT positive, have an active infection and a high risk for disease transmission.
· An HCV-negative donor that is NAT positive, have an acute infection and poses a high risk for disease transmission.
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients
· perioperative intake of DAA therapy has increased the use of HCV viremic donor organs
Liver Transplantation
· Two large retrospective studies found that there are no differences in patient or graft survival in HCV-viremic donors in nonviremic liver transplant recipients compared with nonviremic donors.
· HCV treatment within 3 months of transplantation increases the probability of successful graft function and reduces waitlist mortality
Renal Transplantation
· Outcomes for untreated HCV infection in HCV-seropositive renal recipients are significantly worse than in their HCV-negative counterparts.
· Many studies found that DAA therapy are safe and very effective in the treatment of recipients of kidney transplant with HCV.
Thoracic Transplantation
· among patients who received HCV-viremic heart transplant, there was no difference regarding the hospital stay, rejection, survival at 30 days, or 1-year patient survival compared with patients who received transplants from HCV-negative donors during the same period.
Pancreas Transplantation
· HCV-viremic pancreas transplant may be safely used for potential pancreas recipients, but further studies about morbidity and mortality of pancreas transplantation with HCV-positive donors is needed.
Conclusion
· Transplantation of HCV-viremic organs into HCV-naive recipients followed by the use of DAA agents provides excellent patient and allograft survival
· securing DAA therapy posttransplant is essential and patients should be fully informed about risks, including possible failure of treatment.
Hepatitis C Virus Treatment and Solid Organ Transplantation
Article Summary
Introduction
Hepatitis C virus (HCV) infection is a common indication for liver transplantation. If the patient’s HCV is untreated prior to liver transplant, infection of the allograft is nearly universal and can lead to graft failure. The development of direct-acting antiviral agents has revolutionized the management of liver transplant candidates and transplant recipients. The newer antiviral therapies have paved the road for use of HCV-viremic organs, effectively expanding the donor pool and changing the landscape of solid organ transplantation.
Hepatitis C Virus Infection and DirectActing Antiviral Therapy
Sofosbuvir has been approved for HCV treatment in combination with a nonstructural protein 5A (NS5A) inhibitor, nonstructural protein 3/4A (NS3/4A) protease inhibitor, and ribavirin. Pretransplant DAA therapy reduces the risk of reinfection of the allograft.
Successful therapy-Model for End-Stage Liver Disease score <16, low baseline Child-Pugh score, and the absence of portal hypertension complications.
Direct-Acting Antiviral Therapy and Liver Transplantation
Persistence of HCV infection after liver transplant results in a variable clinical course ranging from mild fibrosis to severe graft damage. DAA therapy following liver transplant has demonstrated excellent outcomes. HCV infection has a negative long-term impact on both patient and graft survival, promising data on the safety and efficacy of DAA therapy for the treatment of HCV infection posttransplant led to a paradigm shift
Defining Hepatitis C Virus–Positive Donors
Donors identified as HCV positive by serologic testing but NAT negative (nonviremic) are considered to have undergone spontaneous clearance or successful treatment of infection, or have a false-positive antibody result, and these donors have not been documented to transmit HCV infection
HCV-seropositive donor that is NAT positive (viremic) is considered to have an active infection and poses a high risk for disease transmission.
An HCV-negative donor that is NAT positive (viremic) is considered to have an acute infection and poses a high risk for disease transmission
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients
Immediate treatment with GLE/PIB for HCV-viremic liver transplant into uninfected recipients is both safe and efficacious. A preemptive antiviral strategy using SOF/VEL is also successful in achieving SVR12.
Renal Transplantation
Outcomes for untreated HCV infection in HCV-seropositive renal recipients are significantly worse than in their HCV-negative counterparts. In a study of 545 kidney transplants performed in HCV-positive recipients, 5- and 10-year patient survival was 84.8% and 72.7%, respectively, for HCV-positive graft recipients compared with 86.6% and 76.5%, respectively.
In THINKER trial the safety and efficacy of the transplant of kidneys from HCV GT1–viremic donors into HCV-negative recipients (donor positive, recipient negative [D+/R-]) followed by treatment with elbasvir/grazoprevir (EBR/GZR for 12 weeks. Excellent graft function was shown.
Pancreatic transplantation
HCV-viremic pancreas transplant may be safely used for potential pancreas recipients; however, further study regarding morbidity and mortality of pancreas transplantation with HCV-positive donors is needed.
Conclusions
Transplantation of HCV-viremic organs into HCV-naive recipients followed by the use of DAA agents provides excellent patient and allograft survival
In carefully selected patients, the use of HCV-viremic grafts appears to be efficacious and well tolerated. T
DAA therapy posttransplant is essential and patients should be fully informed of the associated risks
Summary
Hepatitis C Virus Treatment and Solid Organ Transplantation
The development of safe and highly effective HCV therapy with direct-acting antiviral agents has revolutionized the management of liver transplant candidates and transplant recipients This article reviews the data on HCV treatment prior to and after organ transplantation.
The high success rate of DAA therapy, have led to greater utilization of HCV‐positive livers from 7% to 17% between 2010 and 2015. Major strides in HCV eradication paved the way for use of HCV-positive organs, first in HCV-viremic recipients and now in HCV-negative recipients.
Hepatitis C Virus Infection and Direct Acting Antiviral Therapy
The combination of potent NS5A inhibitor ledipasvir (LDV) and sofosbuvir (SOF) is well tolerated and produces high SVR12 rates in HCV genotype (GT) 1, 4, 5, and 6 infection.
The combination of SOF and NS5A inhibitor velpatasvir provides SVR12 rates of greater than 95% across all GTs and has a favorable safety pro file.
The combination of NS3/4A protease inhibitor glecaprevir and NS5A inhibitor pibrentasvir is well tolerated and results in SVR12 rates greater than 97% across all GT.
Pretransplant DAA therapy reduces the risk of reinfection of the allograft.
Will benefit from treatment prior to liver transplantation.
Clinical features associated with meaningful improve ment in liver function from pretransplant therapy include low baseline Model for End-Stage Liver Disease score (<16), low baseline Child-Pugh score, and the absence of portal hypertension complications.
Direct-Acting Antiviral Therapy and Liver Transplantation
Recipients who achieve SVR12 posttransplant have lower rates of liver fibrosis progression and lower mortality rates compared with patients who do not receive or fail treatment.
Treatment of HCV infection in patients who undergo simultaneous liver-kidney transplant is both safe and efficacious.
The HCV-TARGET trial used the Hepatitis C Therapeutic Registry and Research Network database to evaluate liver transplant and dual liver-kidney transplant recipients with HCV infection treated with LDV/SOF, ombitasvir/paritaprevir/ritonavir plus dasabuvir or SOF plus daclatasvir. SVR12 rates among liver transplant and dual liver-kidney transplant recipi ents were 96.6% and 90.9%, respectively. Successful outcomes from the real-world data of the large HCV-TARGET cohort provided confidence in treating liver transplant patients with a ribavirin-free regimen.
The MAGELLAN-2 study was a phase 3 open-label trial that confirmed the safety and efficacy of GLE/PIB once daily for 12 weeks in patients with treatment-naive HCV GT1 to GT6 infection or treatment-experienced HCV GT1, GT2, or GT4 to GT6 who had received a liver or kidney transplant.
SOLAR-1 and SOLAR-2 were 2 large trials that evaluated LDV/SOF plus ribavirin in liver transplant recipients with HCV GT1 to GT4 infection and liver disease.
In SOLAR-1, SVR12 was achieved in 96% promising data on the safety and effi cacy of DAA therapy for the treatment of HCV infection posttransplant led to a paradigm shift.
Defining Hepatitis C Virus–Positive Donors
Serologic tests such as chemiluminescence assays and enzyme immunoassays detect antibodies within 2 to 6 months after exposure,
Nucleic acid testing (NAT) detects RNA 5 to 7 days after exposure and provides a more accurate assessment of transmission risk. HCV NAT has a sensitivity of 85% to 100% and a specificity of 99% to 100%.
HCV positive by serologic testing but NAT negative (nonviremic) are considered to have undergone spontaneous clearance or successful treatment of infection, or have a false-positive antibody result, and these donors have not been documented to transmit HCV infection.
An HCV-seropositive donor that is NAT positive (viremic) is considered to have an active infection and poses a high risk for disease transmission.
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients
In a study published in 1998, 22 patients with HCV received HCV-seropositive grafts and had excellent 4-year patient and graft survival compare with HCV-seronegative donor grafts.
In a larger study that included 2923 transplant recipients with HCV, 96 and 2827 received HCV-positive and -negative organs, respectively, and had comparable 2-year survival rates (90% vs 77%)
Liver Transplantation
Two large retrospective studies evaluated HCV-viremic donors in nonviremic liver transplant recipients and demonstrated no differences in patient or graft survival when compared with nonviremic donors.
Renal Transplantation
The availability of DAA therapy and its administration around the time of transplant minimizes the risk of chronic HCV infection in the transplant recipient and thus has led to the recent growth of transplant of kidneys from HCV-infected donors into HCV-naive recipients.
THINKER trial (2017) was the first open-label, single-group pilot study that sought to determine the safety and efficacy of the transplant of kid neys from HCV GT1–viremic donors into HCV-negative recipients followed by treatment with elbasvir/grazoprevir for 12 weeks (n=10). All recipients had detectable HCV RNA, and all attained SVR12
THINKER-2 trial (n=20), HCV-negative recipients of HCV-viremic kidneys experienced HCV cure and excellent renal allograft function with estimated glomerular filtration rates (eGFRs) not significantly different from those of matched recipients of HCV-negative kidneys at 6 months and 12 months
The EXPANDER trial was an open-label single center study (n=10) that examined the tolerability and feasibility of DAA prophylaxis before and after renal transplant in HCV-naive patients (n=10) who received HCV-viremic kidneys (GT1-GT3).In this study, all recipients received a dose of EBR/GZR immediately before transplant, and recipients of kidneys from donors with GT1 infection continued receiving EBR/GZR for 12 weeks after transplant; those receiving organs from donors with GT2 or GT3 infection received SOF along with EBR/GZR for 12 weeks of triple therapy. Preemptive use of EBR/GZR for 12 weeks in HCV-naive recipients who received HCV-infected kidneys (n=8) led to SVR12 with no study-related adverse events
SOF-based regimens are safe and effective in HCV-naive recipients undergoing HCV-viremic kidney transplant.
MYTHIC trial, 30 HCV-naive patients received HCV-viremic kidneys across 7 transplant centers. All 30 recipients achieved SVR12, and no severe adverse events related to HCV infection or GLE/PIB were noted in any patient. Although all recipients had good allograft function
In a large, prospective, real-world study, 64 HCV-naive patients underwent HCV-viremic kidney transplant followed by posttransplant NAT to determine the need for treatment. 61 patients developed viremia, of which 41 patients achieved SVR12, 10 reached undetectable viral loads, and 7 remained on treatment. There was 1 nonre sponder owing to NS5A resistance. At a median 8-month follow-up, patient and graft survival were both 98%
The DAPPER trial treated patients with a single pretransplant dose of SOF/ VEL followed by 1 or 3 posttransplant doses. The 4-day strategy reduced viral transmission to 7.5% but did result in detectable viremia in 17 of 50 (34%) patients by posttransplant day 14, of which only 6 of 50 (12%) required treatment; the remaining 11 recipients had self-limited, low-level vire mia. Of the 6 patients who required treatment, 5 patients achieved SVR12, with 1 patient requiring the addition of ribavirin owing to resistance and 2 patients requiring retreatment with second-line DAA agents owing to relapse.
Friebus-Kardash et al (2019):Cohort Size: 7, Antiviral Therapy: LDV/SOF, Therapy Duration: 8-12 weeks SVR12: 7/7 (100%)
Molnar et al (2019):Cohort Size: 53, Antiviral Therapy: GLE/PIB, SOF/VEL, or LDV/SOF, Therapy Duration: 12 weeks SVR12: 53/53 (100%)
Sise et al (2020):Cohort Size: 8, Antiviral Therapy: EBR/GZR, Therapy Duration: 12 weeks SVR12: 8/8 (100%)
Thoracic Transplantation:
Among heart transplant recipients, the reported prevalence of HCV infection is as high as 12%.
Donor HCV seropositivity was reported to be an independent risk factor for increased mortality when matched with controls (2.8-fold) and for the development of accelerated allograft vasculopathy.
In the largest RCT study of 80 patients who underwent heart transplant with HCV-positive donors, 67 of 70 (96%) recipients developed viremia following transplant and started treatment with LDV/ SOF, SOF/VEL, or GLE/PIB for 12 weeks. Of those who started DAA treatment (n=55), 37 achieved SVR12 with 17 recipients pending, and 1 recipient died prior to achieving SVR12.
Although there were higher rates of severe primary graft dysfunction, there was no difference regarding the hospital length of stay, rejection requiring treatment, survival at 30 days, or 1-year patient survival.
Short course(8weeks)DAA in heart transplant associated with high SVR12 with out survival difference.
In lung transplant & HCV D+/R- treated with SOF/VEL for 12 weeks show HCV free survival at 6 months 86%, but risk of infection & rate of hospital admission was higher than D-/R- HCV transplant.
Pancreas Transplantation:
The data on utilizing HCV-viremic organs in pancreas transplantation are limited.
In 2021, the first reported series included 8 HCV-naive patients who received either deceased donor simultaneous pancreas-kidney transplant or pancreas transplant after living donor kidney transplant.
All patients developed viremia and were treated with either GLE/PIB or SOF/VEL and all achieved SVR12.
All recipients had excellent pancreas graft function and rates of rejection with no difference in hospital stay.
Conclusion:
Transplantation of HCV-viremic organs into HCV-naive recipients followed using DAA agents provides excellent patient and allograft survival.
II. Hepatitis C Virus Treatment and Solid Organ Transplantation
Summarise the article
Introduction
– the demand for organs continues to surpass the supply resulting in significant waitlist mortality
– previously, HCV-positive organs were discarded due to the high risk of transmission during reperfusion and the risk of significant post-transplant morbidity and mortality
– high risk organs are those associated with an increased risk for transmission of blood-borne viruses e.g., HIV, HBV, HCV
– emergence of direct-acting antiviral (DAA) therapy has led to greater utilization of HCV-positive organs thereby increasing the number of organ transplants as well as decreasing the waitlist mortality
Hepatitis C virus infection and direct-acting antiviral therapy
– DAAs are used in the treatment of chronic HCV infection
– DAAs are associated with cure rates defined as sustained virologic response 12weeks after treatment (SVR12) of >98%
– with the availability of safe and highly effective DAAs, HCV infection treatment can be offered prior to the transplant or deferred until after transplant
Direct-acting antiviral therapy and liver transplantation
– persistent HCV infection following liver transplantation results in a variable course ranging from mild fibrosis to severe graft damage/ cirrhosis
– HCV-related progression of liver disease post-transplant is not common due to the increasing use of DAAs
– DAAs are associated with excellent outcomes post-liver transplant as evidenced by lower rates of liver fibrosis progression and lower mortality rates
– HCV infection treatment in patients undergoing simultaneous liver-kidney transplant has been found to be safe and efficacious
– DAA therapy post-transplant is considered safe and efficacious among transplant recipients with compensated liver cirrhosis
– with DAAs, HCV-positive organs can now be used in both HCV-positive and HCV-negative recipients
Defining Hepatitis C virus-positive donors
– HCV-positive donors include any stage of HCV infection
– serologic tests e.g., chemiluminescence assays and enzyme immunoassays detect antibodies within 2-6months
– nucleic acid tests (NAT) detect RNA 5-7days after exposure and provide a more precise assessment of the risk of transmission
– HCV NAT sensitivity is 85-100% and specificity is 99-100%
– despite the advances in HCV infection testing, risk of HCV transmission still remains during the 1-week period between viral exposure and positive NAT results especially among intravenous drug users
– the risk of HCV disease transmission differs between a seropositive donor and a viremic donor i.e.,
Hepatitis C virus-positive donor transplantation in Hepatitis C virus-negative recipients
– prior to the advent of DAAs, donation of HCV-positive organs to HCV-negative individuals was discouraged due to the low efficacy, high rates of HCV transmission, decreased graft and patient survival and the complications associated with IFN-based therapy in the post-transplant setting
– DAAs have now increased the utilization of HCV-positive organs with demonstration of favourable long-term graft outcomes
– multiple studies have demonstrated no differences in patient and graft survival among HCV-negative liver transplant recipients who had HCV-positive donors compared to those who had a HCV-negative donor
– HCV treatment within 3 months of transplantation reduces waitlist mortality and increases the chances of successful graft function
– despite achieving SVR with DAAs, HCV-related complications do still occur suggesting the need for careful and long-term follow-up e.g., development of HCV-related membranous nephropathy
– HCV is a common complication post-kidney transplant
– HCV seropositivity is associated with higher all-cause graft loss and mortality
– the long-term outcomes of HCV-seropositive recipients who received kidneys from HCV-positive donors are promising
– administration of DAA therapy in the peri-transplant period minimizes the risk of chronic HCV infection in the transplant recipient
– this has led to an increase in the number of transplants between HCV-positive donors and HCV-negative recipients
– the THINKER Trial revealed that it is safe and efficacious to transplant kidneys from HCV-positive donors to HCV-negative recipients followed by treatment with DAAs (Elbasvir/ Grazoprevir) which led to achievement of SVR12
– THINKER-2 trial included the THINKER participants and HCV-negative recipients of HCV-positive kidneys; HCV cure and excellent graft function was noted and it was comparable to those of matched HCV-negative kidneys
– several trials revealed that among HCV-negative recipients, pre-emptive DAA therapy was tolerable and feasible, and it led to SVR12 with no adverse events, the patients had stable graft function
– shorter-course DAA regimens have also been evaluated and the results are promising
– among heart transplant recipients, donor HCV seropositivity is an independent risk factor for increased mortality, development of severe and rapidly progressive liver disease, and development of accelerated graft vasculopathy
– preemptive DAA therapy in HCV-naïve recipients receiving HCV-viremic cardiac transplants is associated with rapid HCV suppression, prevention of chronic HCV infection and excellent graft function
– among HCV-naïve lung transplant receiving HCV-viremic organs, DAA therapy was associated with SVR12 and excellent graft function, the most common adverse events were respiratory complications and infections
– there is limited data regarding utilization of HCV-viremic organs
– from reported case series, use of DAA therapy among HCV-naïve pancreas transplant recipients receiving HCV-viremic organs
resulted in SVR12 and excellent pancreas graft function
– more studies evaluating the morbidity and mortality of pancreas transplantation with HCV-positive donors are needed
Conclusion
– transplantation of HCV-viremic organs into HCV-naïve recipients followed by DAA therapy results in excellent patient and graft survival
– use of HCV-viremic grafts is safe, efficacious and well-tolerated
– this helps reduce the long waitlist times and also reduces morbidity and mortality
– DAA therapy post-transplant is essential, however, potential recipients of HCV-viremic organs should be informed about the risks involved including the likelihood of HCV treatment failure
– the long-term outcomes of HCV-viremic organ utilization are yet to be understood
Introduction: Hepatitis C virus (HCV) infection is associated with liver disease leading to liver transplantation. HCV-positive organs comprise 9.7% of total deceased donor livers. Strategies to expand donor pool include using such organs for transplantation, which has become possible due to availability of direct-acting antiviral (DAA) therapy. HCV-viremic donors are usually young, healthier with low co-morbidities, leading to lower complications post-transplant.
HCV and DAA therapy: Introduction of many pan-genotypic DAA therapies with sustained virologic response at 12 weeks (SVR12) of >98% has changed the landscape of HCV infection. Pre-transplant DAA therapy use reduces the risk of re-infection post-transplant. Combination of ledipasvir and sofosbuvir (LED/SOF) has been associated with high SVR12 rates in HCV genotype 1,4,5, and 6 HCV infection. SOF and velpatasvir (SOF/VEL) has >95% SVR12 rates for all genotypes. Gelcaprevir and Pibrentasvir (GLE/PIB) combination has >97% SVR12 for all genotype infection in patients without cirrhosis or mild cirrhosis. DAA use pre-transplant leads to improvement in liver function in presence of model for end-stage liver disease (MELD) score <16, low Child-Pugh score, and absence of portal hypertension. Treatment should be deferred in presence of Child-Pugh class C cirrhosis, and in case of HCV viremic-donors, the decision to treat pre-transplant should be individualized.
DAA therapy and liver transplantation: Pre-transplant DAA use leading to SVR12 has reduced the incidence of significant HCV-related liver disease progression (20.5% versus 65.5%) and mortality post-transplant. HCV infection treatment in simultaneous liver-kidney transplant recipients is safe and efficacious, with SVR12 rates of 90.9% in the HCV-TARGET trial. MAGELLAN-2 trial showed SVR12 of 98% with GLE/PIB use in transplant recipients without cirrhosis. SOLAR-1 trial showed that SOF/VEL use in transplant recipients had SVR12 of 96% in patients without cirrhosis, and 98% in patients with compensated cirrhosis. SOLAR-2 trial showed high SVR12 rates in transplant recipients across spectrum of cirrhosis using LDV/SOF with ribavirin.
Defining HCV-positive donors: Serologic assays detect antibodies within 2-6 months post-exposure, while nucleic acid testing (NAT), having sensitivity of 85-100% and specificity of 99-100%, can detect RNA within 5-7 days of exposure. NAT negative but positive serologic testing in donor indicate either spontaneous clearance or treatment of the patient, or a false-positive serological test, indicating a low risk of transmission. Active infection is characterized by positive NAT and positive antibody test, indicating high risk of transmission.
HCV-positive donor transplantation in HCV-negative recipient: Peri-operative DAA use has increased utilization of HCV-viremic donor organs. Comparable survival rates have been observed in HCV-positive recipients receiving either HCV-negative or HCV-positive organs.
Liver transplantation of HCV-viremic organs in nonviremic recipients had no difference in patient or graft survival as compared to non-viremic donors, according to the organ procurement and transplantation network (OPTN) data. DAA initiation pre-emptively, immediately following transplantation, or even 90 days post-liver-transplant has been shown to be associated with favorable outcomes. Close monitoring of post-transplant adverse immunological events is necessary.
Renal transplantation utilizing HCV-positive donor kidney in HCV-positive recipients has shown comparable results with respect to 5- and 10-year patient survival with use of DAA therapy further reducing the risk of chronic HCV infection in the recipients. THINKER trial used elbasvir/grazoprevir (EBR/GZR) post-transplant of HCV-viremic kidneys with SVR12 attainment in 100%. THINKER-2 trial showed excellent graft function in the THINKER-1 trail patients at 6 and 12 months. EXPANDER trial used EBR/GZR, started immediately prior to the transplant of HCV-viremic kidneys with addition of SOF in genotype 2 and 3, leading to SVR12 in 100% patients. MYTHIC trial showed GLE/PIB use achieved 100% SVR12.
DAA therapy has been used in thoracic transplantation, with GLE/PIB use in heart transplant showing rapid HCV suppression, prevention of chronic HCV infection, and excellent early graft function. USHER trial utilized HCV-viremic hearts in HCV-naïve recipients, treated with EBR/GZR, with SVR12 of 90%. 8 week duration GLE/PIB use in heart transplants have also been associated with 100% SVR12. DAA therapy in lung transplantation has also shown encouraging results. DONATE-HCV trial used SOF/VEL for HCV-viremic cardiac and lung transplant in HCV-naïve recipients with 100% SVR12 and excellent graft function.
DAA therapy in HCV-viremic Pancreas transplantation or simultaneous pancreas-kidney transplantation (SPK) has been shown to effective with 100% SVR12.
Conclusion: Excellent patient and graft outcomes have been achieved by using HCV-viremic organs for transplant in carefully selected HCV-naïve recipients and using DAA therapy. The patients should be fully informed about the risks of HCV treatment failure and immunosuppressive drug interactions before proceeding with such transplants.
Hepatitis C Virus Treatment and Solid Organ Transplantation
Introduction:
HCV infection is highly prevalent worldwide infects 130–150 million individuals globally causing end-stage liver damage, and it is leading indications for liver transplantation.
Waitlist mortality is high because organ demand exceeds availability, In 2019, 9.7% of deceased-donor livers were HCV-positive.
The availability of HCV-positive organs continues to increase, representing 9.7% of deceased-donor livers in 2019.
Utilizations of organs from hepatitis C infected individuals significantly increased to mitigate the global organ shortage. This change occurs after the availability of effective direct-acting antiviral (DAA) therapy.
Opioid-related deaths more frequently occur in young donors, who are generally healthier and have fewer comorbidities than older donors, and therefore their HCV-viremic donor organs are often of relatively high quality.
Hepatitis C Virus Infection and Direct Acting Antiviral Therapy:
The combination of potent NS5A inhibitor ledipasvir (LDV) and SOF (LDV/SOF, 90 mg/400 mg) administered once daily, is well tolerated, and produces high SVR12 rates in HCV genotype (GT) 1, 4, 5, and 6 infections.
The combination of SOF and NS5A inhibitor velpatasvir (SOF/VEL) administered once daily, provides SVR12 rates of greater than 95% across all GTs and has a favorable safety profile.
The combination of NS3/4A protease inhibitor glecaprevir and NS5A inhibitor pibrentasvir (GLE/PIB) was first approved in 2017 for the treatment of HCV infection without cirrhosis or with mild cirrhosis.
GLE/PIB is well tolerated and results in SVR12 rates greater than 97% across all GTs.
Defining Hepatitis C Virus–Positive Donors:
Nucleic acid testing (NAT) detects RNA 5 to 7 days after exposure and provides a more accurate assessment of transmission risk.
HCV NAT has a sensitivity of 85% to 100% and a specificity of 99% to 100%.
Risk of HCV transmission remains during the 1-week eclipse period between viral exposure and positive NAT results, particularly in persons who inject drugs.
It is important to distinguish between a seropositive and viremic donor when discussing organ transplant from an HCV-positive donor, as the risks of disease transmission vastly differ.
Donor with HCV Ab + & HCV NAT positive, has active hepatitis and high risk of transmission.
Those with only positive HCV NAT, has acute HCV in Ab window or false positive NAT and considered with high risk for transmission.
Donor with only positive HCV Ab, NAT -ve = no active infection and has low risk of transmission.
Donor with negative both tests, is not infected with no risk of transmission.
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients:
The rapidly evolving treatments for HCV have improved outcomes, and perioperative use of DAA therapy has increased the utilization of HCV-viremic donor organs.
Early data have demonstrated favorable long-term graft outcomes in patients transplanted with HCV-seropositive donors.
Renal Transplantation:
The prevalence of HCV among ESRD patients is 0.2% to 6%, and HCV infection traditionally has been a common complication after renal transplant.
Outcomes for untreated HCV infection in HCV-seropositive renal recipients are significantly worse than in their HCV-negative counterparts.
HCV seropositivity is associated with higher all-cause mortality and higher all-cause graft loss.
The availability of DAA therapy and its administration around the time of transplant minimizes the risk of chronic HCV infection in the transplant recipient and thus has led to the recent growth of transplant of kidneys from HCV-infected donors into HCV-naive recipients.
Only a few prospective trials have evaluated the use of DAA therapy in renal transplant recipients with HCV infection.
Trials of DAA in kidney transplant:
THINKER (2017):
Cohort Size: 10, Antiviral Therapy: EBR/GZR, Therapy Duration: 12 weeks
SVR12: 10/10 (100%)
THINKER-2(2018):
Cohort Size: 20, Antiviral Therapy: EBR/GZR, Therapy Duration: 12 weeks
SVR12: 20/20 (100%)
Reported that HCV-negative recipients of HCV-viremic kidneys experienced HCV cure and excellent renal allograft function with eGFRs not significantly different from those of matched recipients of HCV-negative kidneys at 6 months and 12 months.
SOF-based regimens are safe and effective in HCV-naive recipients undergoing HCV-viremic kidney transplant.
GLE/PIB once daily for 12 weeks has been shown to be well tolerated in patients with chronic HCV GT1 to GT6 infection who have undergone kidney transplantation.
Shorter-course DAA regimens 9 4wks of GLE/PIB) have also been evaluated with promising results.
EXPANDER (2018):
Cohort Size: 10, Antiviral Therapy: EBR/GZR ± sofosbuvir, Therapy Duration: 12 weeks
SVR12: 10/10 (100%)
Friebus-Kardash et al (2019):
Cohort Size: 7, Antiviral Therapy: LDV/SOF, Therapy Duration: 8-12 weeks
SVR12: 7/7 (100%)
Molnar et al (2019):
Cohort Size: 53, Antiviral Therapy: GLE/PIB, SOF/VEL, or LDV/SOF, Therapy Duration: 12 weeks
SVR12: 53/53 (100%)
Sise et al (2020):
Cohort Size: 8, Antiviral Therapy: EBR/GZR, Therapy Duration: 12 weeks
SVR12: 8/8 (100%)
Thoracic Transplantation:
Among heart transplant recipients, the reported prevalence of HCV infection is as high as 12%.
Early studies demonstrated reduced survival in recipients with HCV infection, regardless of acquisition of HCV pre– or post– heart transplant.
Donor HCV seropositivity was reported to be an independent risk factor for increased mortality when matched with controls (2.8-fold) and for the development of accelerated allograft vasculopathy.
In the largest RCT study of 80 patients who underwent heart transplant with HCV-positive donors, 67 of 70 (96%) recipients developed viremia following transplant and started treatment with LDV/ SOF, SOF/VEL, or GLE/PIB for 12 weeks. Of those who started DAA treatment (n=55), 37 achieved SVR12 with 17 recipients pending, and 1 recipient died prior to achieving SVR12.
Although there were higher rates of severe primary graft dysfunction, there was no difference regarding the hospital length of stay, rejection requiring treatment, survival at 30 days, or 1-year patient survival.
Pancreas Transplantation:
The data on utilizing HCV-viremic organs in pancreas transplantation are limited.
In 2021, the first reported series included 8 HCV-naive patients who received either deceased donor simultaneous pancreas-kidney transplant or pancreas transplant after living donor kidney transplant.
All patients developed viremia and were treated with either GLE/PIB or SOF/VEL and all achieved SVR12.
All recipients had excellent pancreas graft function and rates of rejection with no difference in hospital stay.
Liver Transplantation
Two large retrospective studies evaluated HCV-viremic donors in non-viremic liver transplant recipients and demonstrated no differences in patient or graft survival when compared with non-viremic donors.
GLE/PIB has been used successfully in HCV-naive patients who receive HCV-viremic livers.
The administration of SOF/VEL or GLE/PIB once daily for 12 weeks in HCV-naive patients who received viremic livers (n=51) produced similar 1-year patient and graft survival when compared with HCV-naive patients who received nonviremic livers.
DAA Therapy & Liver Transplantation:
Significant HCV-related progression of liver disease post-TX is no longer common due to the increased use of DAA therapy.
Compared to those who do not get treatment or who do not respond to it, recipients who reach SVR12 post-TX have lower rates of liver fibrosis progression & mortality.
HCV infection treatment in patients undergoing simultaneous liver-kidney transplant is both safe & effective.
The HCV-TARGET trial:
Compared LDV/SOF, ombitasvir/paritaprevir/ritonavir plus dasabuvir, & SOF plus daclatasvir in liver TX & dual liver-kidney TX recipients with HCV infection.
SVR12 rates were 96.6% & 90.9% for recipients of liver transplants & dual liver-kidney transplants, respectively. The huge HCV-TARGET cohort’s real-world data showed promising results, giving doctors confidence to treat liver transplant patients with a ribavirin-free regimen.
HCV-TARGET cohort provided confidence in treating liver TX patients with a ribavirin-free regimen.
The MAGELLAN-2 study (phase 3 open-label trial):
Confirmed the safety & efficacy of GLE/PIB for 12 weeks in patients with treatment-naive HCV GT1 to GT6 infection or treatment-experienced HCV GT1, GT2, or GT4 to GT6 who had received a liver or KTx.
Other studies:
Treatment with SOF/VEL for 12 weeks in 14 liver TX recipients with HCV GT1 to GT4 infection & cirrhosis resulted in an SVR12 rate of 93%.
SOLAR-1 (a large trial):
Assessed LDV/SOF plus ribavirin in liver TX recipients with HCV GT1- GT4 infection & liver disease.
SVR12 achieved in 96% – 98% of TX recipients without cirrhosis or with compensated cirrhosis.
SOLAR-2 (a multicenter open-label study):
SVR12 rates of 100%, 96%, 95%, & 100% in CTP-A patients with 12 weeks of treatment, CTP-A patients with 24 weeks of treatment, CTP-B patients with 12 weeks of treatment, & CTP-B patients with 24 weeks of treatment, respectively, were seen in HCV GT1 liver transplant recipients who had no cirrhosis, CTP-A, CTP-B, or CTP-C cirrhosis.
Conclusion:
Transplantation of HCV-viremic organs into HCV-naive recipients followed using DAA agents provides excellent patient and allograft survival.
In carefully selected patients, the use of HCV-viremic grafts appears to be efficacious and well tolerated.
This practice has demonstrated acceptable short-term outcomes and has the potential to significantly close waitlist gaps and decrease morbidity and mortality.
However, securing DAA therapy post-transplant is essential and patients should be fully informed of the associated risks, including the potential of HCV treatment failure.
Shortage of donor supply has dictated the use of high-risk donors such as those who are HCV positive.
The decision of treating HCV infection prior to TX or delaying it until after TX has arisen because of the availability of safe & highly effective therapy.
DAAs improves liver function in decompensated cirrhosis to the extent that some may no longer require liver TX.
Moreover, pretransplant DAA medication lowers the likelihood of the allograft being reinfected.
Not all HCV-infected individuals with ESLD will, however, benefit from treatment before a liver TX; advanced liver disease is unlikely to improve by DAA therapy, & SVR rates are lower in Child-Pugh class C cirrhosis.
Marked improvement in liver function from pre-TX therapy is expected in the following:
1. Low baseline Model for ESLD score (<16)
2. Low baseline Child-Pugh score
3. Absence of portal hypertension complications.
Understanding long-term outcomes of HCV-viremic organ utilization needs further studies.
Hepatitis C Virus Treatment and Solid Organ Transplantation.
HCV infection is one of the leading cause of liver decompensation, and leading indications for liver transplantation, before direct-acting antiviral (DAA) therapy, transplantation from HCV donor was challengeable due to high risk of infection but with high success rate of DAA, donor pool has been expanded, and the main upside is the possibility to use DAA before and after transplantation.
Hepatitis C Virus Infection and Direct-Acting Antiviral Therapy.
The combination of SOF and NS5A inhibitor velpatasvir ,administered once daily, provides SVR12 rates of greater than 95% across all GTs and has a favorable safety profile which could be used before transplantation such as in low baseline Model for End-Stage Liver Disease score (<16), low baseline Child-Pugh score, and the absence of portal hypertension complications, or post transplantation in advanced liver disease.
Direct-Acting Antiviral Therapy and Liver Transplantation.
Persistent HCV infection post liver transplant is associated with many morbidity and mortality risk, but using of DAA therapy following liver transplant has demonstrated excellent outcomes such as lower rates of liver fibrosis progression and lower mortality rates compared with patients who do not receive or fail treatment. HCV infection has a negative long-term impact on both patient and graft survival, studies proved the safety and efficacy of DAA therapy for the treatment of HCV infection post-transplant led to a paradigm shift and so HCV eradication paved the way for use of HCV-positive organs.
Defining Hepatitis C Virus–Positive Donors.
1-Donors identified as HCV positive by serologic testing but NAT negative (nonviremic) are considered to have undergone spontaneous clearance or successful treatment of infection, or have a false-positive antibody result, and these donors have not been documented to transmit HCV infection.
2-An HCV-seropositive donor that is NAT positive (viremic) is considered to have an active infection and poses a high risk for disease transmission.
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients.
Liver transplant:
Immediate treatment with GLE/PIB for HCV-viremic liver transplant into uninfected recipients is both safe and efficacious and some studies shown that administration of SOF/VEL or GLE/PIB once daily for 12 weeks in HCV-naive patients who received viremic livers produced similar 1-year patient and graft survival when compared with HCV-naive patients who received nonviremic livers.
Renal Transplantation.
HCV seropositive recipient is associated with higher all-cause mortality relative risk and higher all-cause graft loss, THINKER trial determine the safety and efficacy of the transplant of kidneys from HCV GT1–viremic donors into HCV-negative recipients, followed by treatment with elbasvir/grazoprevir for 12 week and shown HCV cure and excellent renal allograft function, The EXPANDER trial shown that preemptive use of EBR/GZR for 12 weeks in HCV-naive recipients who received HCV-infected kidneys led to SVR12, many protocols for using DAA in prophylactic pre and post-transplant shown great graft and recipient survival outcomes.
Pancreas Transplantation
Recipients who developed viremia and were treated with either GLE/PIB or SOF/VEL and all achieved SVR12. All recipients had excellent pancreas graft function and low rates of rejection .These preliminary findings suggest that HCV-viremic pancreas transplant may be safely used for potential pancreas recipients; however, still further study regarding morbidity and mortality of pancreas transplantation with HCV-positive donors is needed.
Conclusion.
One of the major solution to expand donor pool for transplantation is using of HCV-viremic organs into HCV-naive recipients followed by the use of DAA agents which shown a great result of SVR12 and provides excellent patient and allograft survival. However, securing DAA therapy post-transplant is essential and patients should be fully informed of the associated risks, including the potential of HCV treatment failure.
The availability of HCV-positive organs continues to increase, representing 9.7% of deceased-donor livers in 2019
direct-acting antivirals (DAAs), which are medications targeted at specific steps within the HCV life cycle results in disruption of viral replication and infection.
There are four classes of DAAs, which are defined by their mechanism of action and therapeutic target. The four classes are
– Non-structural proteins 3/4A (NS3/4A) protease inhibitors (PIs)
– NS5B nucleoside polymerase inhibitors (NPIs)
– NS5B non-nucleoside polymerase inhibitors (NNPIs)
– NS5A inhibitors
SVR12: cure rates defined as sustained virologic response 12 weeks after treatment several combinations had more than 95% SVR Therefore, it is considered as a treatment of HCV infection prior to transplant or deferring therapy until after transplant.
DAA therapy has been shown to improve liver function in patients with decompensated cirrhosis and it is use shows excellent outcome in liver transplant populations and simultaneous liver and kidney transplant.
Hepatitis C Virus–Positive Donors:
1) Serologic tests such as an enzyme immunoassays detect antibodies within 2 to 6 months after exposure,
2) HCV nucleic acid test (NAT) detects RNA 5 to 7 days after exposure and provides a more accurate assessment of transmission risk with sensitivity more than 85% and a specificity of 99%.
### Donors identified as HCV positive by serologic testing but NAT negative (nonviremic) are considered to have
= undergone spontaneous clearance
= or successful treatment of infection,
= or have a false-positive antibody result,
###HCV-seropositive/negative donor that is NAT positive (viremic) is considered to have
= an active infection and poses a high risk for disease transmission.
Renal Transplantation: The prevalence of HCV among ESRD patients up to 6% and had bad prognosis. DAA therapy and its administration around the time of transplant minimizes the risk of chronic HCV infection. Multiple trials (table 3) shows good sustained virological response in Hepatitis C Virus–Viraemic, Nonhaptic Solid Organ Transplantation in Nonviremic Recipients
This is a review article looking at HCV treatment and solid organ transplantation
Introduction:
HCV affects approximately 130-150 million people worldwide and is one of the leading causes of liver disease and liver failure requiring liver transplant.
However, the demand continues to outmatch the supply resulting in an increase in waiting time for the organs
The availability of HCV positive organs continue to increase especially after the national opioid epidemic. The number of HCV infections more than doubled between 2012 and 2019 and the number of deaths from opioid overdose increased more than 13 fold. The opioid related deaths generally occur in the younger population who are generally healthier with high quality organs even with HCV
With the advent of the DAAs, the landscape of HCV treatment as well as the use of HCV positive donors has changed.
HCV Treatment and DAAs
With the introduction of DAAs, the SVRs have been more than 98% when treated for 12 weeks.
There are several DAAs introduced into the market and several combinations have been tested:
Sofosbuvir with NS3/4A protease inhibitor with ribavirin
Pretansplant DAA therapy has been shown to reduce infection in the allograft.
In patients with advanced liver disease and Child-Pugh C score, it is preferred to defer treatment until after transplant
DAA and Liver Transplantation:
The risk of HCV infection post-transplant increases the risks of liver damage ranging from mild fibrosis to severe allograft damage.
Progressive centrilobular ballooning, bridging fibrosis and cholestasis are seen in 20-40% of post-transplant patients whose HCV infection is not cured. Advanced fibrosis can occur in up to 45% of post-transplant patients and graft cirrhosis can develop within as little as 5 years post-transplant
Use of DAA therapy following liver transplant has demonstrated excellent outcomes. Recipients who have achieved SVR12 post-transplant have lower rates of liver fibrosis progression.
Several studies have looked at the outcomes of liver transplants and dual kidney/liver transplants with good SVR12 and good graft outcomes:
Most of the studies have shown very good SVR12 rates and very few A/Es leading to drug discontinuation and very few rejection rates
Defining Hepatitis C Virus Positive Donors:
HCV Ab become positive 2-6 months after exposure but the HCV RNA can be detected within 5-7 days by the NAT.
HCV NAT has a sensitivity of 85-100% and a specificity of 99-100%
It is important to distinguish a seropositive donor from an HCV viremic donor when discussing organ transplantation from an HCV donor
Donors who are HCV Ab positive but HCV RNA negative are considered to have either cleared the virus spontaneously or has had successful treatment or has a false Ab result
An HCV seropositive donor that is NAT positive is considered to have an active infection and poses a high risk for transmission
An HCV seronegative donor that is NAT positive is considered to have an acute infection and poses a high risk for disease transmission
Hepatitis C Virus -Positive Donor Transplantation In Hepatitis C Virus Negative Recipients:
Before the advent of DAAs the use of HCV positive patients as donors due to the high risk of transmitting the virus to the recipient and subsequent decreased patient and graft survival and complications after using INF therapy.
Liver Transplant:
2 large retrospective studies evaluated HCV viremic donors in non-viremic liver transplant recipients and demonstrated no differences in patient or graft survival when compared with non-viremic donors.
Data from OPTN also showed comparable one year patient survival and 2 year graft survival
The first prospective study included 10 HCV negative patients who received HCV viremic livers, 7 of which had been cured prior to transplant. All 10 recipients developed viremia and received DAAs and achieved SVR12. 2 patients developed acute rejection.
GLE/PIB has been successfully used in HCV patients receiving HCV viremic livers.
Careful and longer term follow up is required for these patients due to the potential of developing complications
Kidney Transplant:
The prevalence of HCV among ESKD patients is 0.2 – 6% and HCV infection traditionally has been a common complication after renal transplant. Outcomes for untreated HCV infection in HCV positive renal recipients are significantly worse than in their HCV negative counterparts.
Historically, kidneys from HCV infected donors have been underutilized. However, studies in the past decade have demonstrated promising long-term outcomes of HCV seropositive recipients transplanted with kidneys from HCV positive donors.
Only a few prospective have evaluated the use of DAA therapy in renal transplant recipients with HCV infection.
The THINKER trial was the first open label, single group pilot study that sought to determine the safety and efficacy of the transplant of kidneys from HCV GT1 viremic donors into HCV negative recipients followed by treatment with EBV/GZR. All recipients had detectable HCV RNA and all attained SVR12.
In the THINKER-2 trial, which included THINKER participants, HCV negative recipients of HCV viremic kidneys experienced HCV cure and excellent renal allograft function.
The EXPANDER trial was an open label single center study that examined the tolerability and feasibility of DAA prophylaxis before and after renal transplant in HCV naive patients who received HCV viremic kidneys. In this study, all recipients received a dose of EBR/GZR immediately before transplant and recipients of kidneys from donors with GT1 infection continued receiving EBR/GZR for 12 weeks after transplant; those receiving organs from donors with GT2 and GT3 infection received SOF along with EBR/GZR for 12 weeks of triple therapy. There was no study related adverse events and the patients had SVR12
GLE/PIB once daily for 12 weeks has been well tolerated in patients with HCV GTs1-6
Thoracic Transplantation:
Among heart transplant recipients, the reported prevalence of HCV infection is as high as 12%. Pre-DAA era, there was reduced survival in recipients with HCV infection. Donor HCV seropositivity was reported to be an independent risk factor for increased mortality when matched with controls.
With the advent of DAA, several studies have demonstrated good safety and efficacy with patients achieving SVR12 of between 74-100% for heart, lung and heart-lung donors
Pancreas transplantation:
The data on utilizing HCV viremic organs in pancreas transplantation are limited. In 2021, the first reported series included HCV naive patients who either received deceased donor simultaneous pancreas-kidney transplant or pancreas transplant after living donor kidney transplant. All patients developed viremia and were treated with either GLE/PIB or SOF/VEL and all achieved SVR12. All recipients had excellent pancreas graft function and rates of rejection. LOS was similar between those who received HCV viremic organs versus those who did not. These preliminary findings suggest that HCV viremic pancreas donors may be safely used. However, more studies are needed to assess morbidity and mortality pancreas transplants
Conclusion:
The transplant waiting time is increasing significantly leading to increased morbidity and mortality for the patients on the waiting list. The era of DAA has opened up a new venue of increasing the donor pool by including HCV viremic donors. The use of DAAs either pre- or post-transplant has been shown to achieve SVR12 in kidney and liver and dual liver-kidney recipients with comparable graft survival and patient survival. More data is needed for thoracic and pancreas transplantation. The transplant team needs to ensure the availability of the DAAs for the patients receiving them post-transplant.
Hepatitis C Virus Infection and Direct-Acting Antiviral Therapy
Direct-Acting Antiviral Therapy and Liver Transplantation
Defining Hepatitis C Virus–Positive Donors
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients:
Liver Transplantation
Renal Transplantation
Thoracic Transplantation
Pancreas Transplantation
Conclusion:
background
long waitlist times and high waitlist mortality can be addressed with expanding donor pool
HCV positive organ use is a step to increase donor pool
DAA are effective and AE are managable so more HCV positive organs are available for KT
Young opiod addict with positive HCV are available as DBD
DAA and HCV
SRV of 12 weeks OF 98%
SOF and LDV for gt1, 4, 5, 6
SOF and VEL for all gt — 95%
GLE and PIB for all gt – 97 % of SVR12 mainly for mild cirrhosis
Recipient with advanced liver disease are unlikely to improve with DAA therapy
TREATMENT WITH DAA
Treatment of HCV infection in patients who
undergo simultaneous liver-kidney transplant is both
safe and efficacious
The use of a pangenotypic, ribavirin-free regimen
in posttransplant patients without cirrhosis has demonstrated good overall success
Although graft survival is less in HCV positive recipient ,safety and efficacy of DAA therapy for the treatment of HCV infection
posttransplant led to a paradigm shift.
HCV positive donor means
HCV antibody positive or HCV NAT positive
ONLY NAT positive donor with or without positive antibody are known to transmit HCV
NAT positive means VIREMIC DONOR
HCV positive liver to HCV negative recipient
it is possibel with SOF/LDV or SOF/VEL combination
HCV positive kidney in HCV positive recipient
THINKR trial
kidneys from HCV GT1–viremic donors into HCV-negative recipients
elbasvir/grazoprevir (EBR/GZR;
all 10 patient werehad SVR
EXPANDER trial
DAA before and after renal transplant in HCV positive to HCV negative pair
GLE/PIB once daily for 12 weeks is also effective
GLE/PIB once daily for 4 weeks is also effective
heart and to lesser extent lung transplant has been shown to be effective in D+/R- pair like kidneys
LONG TERM results are awaited
Thanks
This article focus on HCV treatment prior and post transplant:
HCV infection is the leading cause of liver failure and needs to liver transplant.
Improving of advanced HCV therapy lead to eradication of HCV infection and donor with treated hepatitis C is not contraindicated to transplant.
Liver transplant is associated with lower rates of biliary complications and improved rejection rates, graft survival, and overall survival.
Hepatitis C Virus Infection and Direct- Acting Antiviral Therapy:
ledipasvir
Harvoni
Epclusa
Those given once per day
Those associated with sustained virologic response 12 weeks after treatment (SVR12) of greater than 95 to 98%.
The combination of NS3/4A protease inhibitor glecaprevir and NS5A inhibitor pibrentasvir (GLE/PIB; ) used for the treatment of HCV infection without cirrhosis or with mild cirrhosis.
DAA therapy used to improve liver function in patients with decompensated cirrhosis.
Direct-Acting Antiviral Therapy and Liver Transplantation:
Use of DAAT has excellent results prior and post transplant with good outcome for allograft survival and low rate of chronic hepatitis and fibrosis.
The rate of transmission is high in donor and recipient with positive HCV with low rate of sustained virology response post treatment with DAAT.
LDV/SOF is highly of recommended fallow transplant with nice for SVR12 reach to 96%.
LDV/SOF has risk of hyperglycaemia as side effects, so should be monitoring blood sugar during treatment.
Diagnosis of donor HCV:
Enzyme immune assays occur within 2-6 months after exposure.
The nucleic acid testing (NAT) can detect RNA within 7 days after exposure.
HCV NAT had sensitivity 85-100% and specificity 99-100%.
Presence of nucleic acid testing (NAT) means virema.
HCV positive donor detected by serology and NAT negative indicates clearance or successful treatment of infection.
Positive NAT indicates active infection and high risk of disease transmission.
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients:
In the past It’s not considered transplant because it’s associated with interferon therapy complications.
Now with improvements of DAA; it’s possible transplant from positive HCV donor to negative recipient with good survival and graft outcome in 2 years post transplant.
Renal Transplantation:
The prevalence of HCV among end stage renal disease patients is 0.2% to 6%.
HCV infection is common in ESRD because hazardous of dialysis. HCV seropositiv
However the availability of DAA therapy lead to transplant from donor with HCV can happen with no risk of chronic HCV infection in the transplant recipient.
Some studies done on role of DAAT therapy in renal transplant recipients with HCV infection.
HCV donors into HCV negative recipients (donor positive, recipient negative followed by treatment with elbasvir/grazoprevir (EBR/GZR; Zepatier,) for 12 weeks .
All recipients had detectable HCV RNA responded well to ADDT and this study shows no significant difference in graft survival between positive and negative recipient with HCV whether donor positive or negative and this results happen due to improving of ADD in eradication of HCV.
I like your clinical approach and well-structured extensively detailed summary quoting a number of trials related to HCV and various types of transplants demonstrating a promising approach with DAA in HCV infections
Introduction:
· HCV affects 150 million people worldwide, and it is a leading cause of end stage liver disease.
· A high risk for transmission and morbidity and mortality associated with HCV +ve donor transplants.
· Direct acting antiviral (DAA) and its effect in reaching SVR, increased the utilization of HCV + donors, and subsequently reduced mortality in waiting list.
Hepatitis C Virus Infection and Direct Acting Antiviral Therapy:
· Cure rate of 98% with the direct acting antiviral therapy revolution for 12 weeks called sustained viral response.
· Nonstructural protein 5B inhibitor sofosbuvir+NS5A inhibitor ledipasvir produces high SVR12 rates in HCV genotype (GT) 1, 4, 5, and 6 infection.
· SOF + NS5A inhibitor velpatasvir produces response rate of 95%.
· NS3/4A protease inhibitor glecaprevir and NS5A inhibitor pibrentasvir in patients with no cirrhosis or mild cirrhosis with response rate reaching 97%.
· Presence of these therapies, with high response rate make it worth to treat HCV patients before transplantation, or deferring until after transplantation, improve liver function in patients with cirrhosis, reduce the reinfection after transplantation
· Clinical features associated with meaningful improvement in liver function from pretransplant therapy include low baseline Model for End-Stage Liver Disease score (<16), low baseline Child-Pugh score, and the absence of portal hypertension complications.
· Patients with advanced liver disease are unlikely to improve with DAA therapy and those with Child-Pugh class C cirrhosis have lower SVR12 rates; therefore, deferring treatment in such situations may be preferred
Direct-Acting Antiviral Therapy and Liver Transplantation
· A variable clinical course ranging from mild fibrosis to severe graft damage. Progressive centrilobular ballooning degeneration, bridging fibrosis, and cholestasis are seen in 20% to 40% of posttransplant persistent HCV infection. And graft cirrhosis developed within 5 years post-transplantation, almost 5-10% of posttransplant patients will develop severe progressive cholestatic hepatitis, With the increasing use of DAA therapy, significant HCV-related progression of liver disease posttransplant is now uncommon.
· HCV-TARGET cohort provided confidence in treating liver transplant patients with a ribavirin-free regimen, with a very high SVR12 reaching 96%.
· MAGELLAN-2 study, demonstrated SVR12 rate of 98% (95% CI, 95.3%-100%). No patients discontinued therapy because of treatment-related adverse events.
· SOLAR-1 and SOLAR-2 studies demonstrated 96% and 98% SVR12 rate with or without cihrrosis. HCV GT4 infection, SVR12 was achieved by 78% of patients who received 12 weeks of treatment and 94% of patients who received 24 weeks of treatment.
Defining Hepatitis C Virus–Positive Donors
· Serologic tests such as chemiluminescence assays and enzyme immunoassays detect antibodies within 2 to 6 months after exposure.
· Nucleic acid testing (NAT) detects RNA 5 to 7 days after exposure and provides a more accurate assessment of transmission risk.( sensitivity of 85% to 100% and a specificity of 99% to 100%)
· Tests interpretation:-
HCV positive by serologic testing but NAT negative = spontaneous clearance or successful treatment of infection, or a false-positive result. (Not transmitting infection).
HCV-seropositive donor that is NAT positive (viremic) = active infection and poses a high risk for disease transmission.
HCV-negative donor that is NAT positive = acute infection and poses a high risk for disease transmission.
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients
perioperative use of DAA therapy has increased the utilization of HCV viremic donor organs, with good long term graft outcomes.
Liver Transplantation
HCV treatment within 3 months of liver transplantation increases the probability of successful graft function and reduces waitlist mortality.
biliary sclerosis, cardiomyopathy, and graft-vs-host disease, membranous nephropathy resulting in end-stage kidney disease, multiorgan failure and death.
Renal Transplantation
Prevalence of HCV among ESRD patients is 0.2-6%, and HCV associated with poor survival and graft function post transplantation.Thoracic Transplantation
THINKER1 &THINKER2 demonstrated almost 98% SVR with an excellent patient and graft survival.
EXPANDER trial demonstrated SVR12 rates of 100% and stable allograft function.
Thoracic transplantation
The prevalence of HCV among heart recipients is 12%
DONATE-HCV = Pre-emptive DAA resulted in 100% SVR12 , with good patient and graft survival.
Pancreas transplantation
Showed same results seen in other solid organ transplantations as mentioned above.
Conclusion:
The use of HCV+ donor organs demonstrated acceptable short-term outcomes and has the potential to significantly close waitlist gaps and decrease morbidity and mortality.
DAA therapy posttransplant is essential and patients should be fully informed of the associated risks, including the potential of HCV treatment failure.
I like your clinical approach and well-structured extensively detailed summary quoting a number of trials related to HCV and various types of transplants
Summary:
Hepatitis C virus (HCV) infection is a common indication for liver transplantation. If the patient’s HCV is untreated prior to liver transplant, infection of the allograft is nearly universal and can lead to graft failure.
Hepatitis C virus infection and Direct-acting antiviral therapy
Defining Hepatitis C virus-positive donor
The Hepatitis C-positive donor for a negative recipient
Liver transplantation
· One study published in 1998, 22 patients with HCV received HCV-seropositive grafts and had excellent 4-year patient and graft survival, 83.9% and 71.9%, respectively, vs 79.1% and 76.2%, respectively, with HCV-seronegative donor.
Renal transplant
Conclusion:
Transplantation of HCV-viremic organs into HCV-naive recipients followed by the use of DAA agents provides excellent patient and allograft survival. In carefully selected patients, the use of HCV-viremic grafts appears to be efficacious and well tolerated.
I like your clinical approach and well-structured extensively detailed summary quoting a number of trials related to HCV and various types of transplants
Hepatitis C Virus Infection and Direct Acting Antiviral Therapy
●Over the past several years, a succession of pangenotypic DAA therapies for the treatment of chronic HCV infection has been introduced,
●cure rates defined as (SVR12) of greater than 98%
○NS5B inhibitor sofosbuvir has been approved for HCV treatment in combination with a (NS5A) inhibitor , (NS3/4A) protease inhibitor, and ribavirin.
○T he combination of potent NS5A inhibitor ledipasvir (LDV) and SOF (LDV/SOF, 90 mg/400 mg; Harvoni, Gilead), administered once daily, is well tolerated and produces high SVR12 rates in HCV genotype (GT) 1, 4, 5, and 6 infection.
○The combination of SOF and NS5A inhibitor velpatasvir, administered once daily, provides SVR12 rates of greater than 95% across all GTs and has a favorable safety prof ile.
○The combination of NS3/4A protease inhibitor glecaprevir and NS5A inhibitor pibrentasvir was first approved in 2017 for the treatment of HCV infection without cirrhosis or with mild cirrhosis.
○GLE/PIB is well tolerated and results in SVR12 rates greater than 97% across all GTs.
Therefore, it is considered as a treatment of HCV infection prior to transplant or deferring therapy until after transplant.
●DAA therapy has been shown to improve liver function in patients with decompensated cirrhosis
Direct-Acting Antiviral Therapy and Liver Transplantation
○20% to 40% of posttransplant patients whose HCV infection has not been cured can progress ●centrilobular ballooning degeneration,
●bridging fibrosis,
● cholestasis
○Advanced fibrosis can occur in up to 45% of posttransplant patients,
○5 to 10% of posttransplant patients will develop severe progressive cholestatic hepatitis leading to liver failure.
■Use of DAA therapy following liver transplant has demonstrated excellent outcomes.
Recipients who achieve SVR12 posttransplant have lower rates of liver fibrosis progression (20.5% vs 65.5%; P<.001) and lower mortality (chi2=6.9; P<.01) rates compared with patients who do not receive or fail treatment.
■In a multicenter phase 2 study, 17 patients with chronic HCV GT1 who received an HCV-negative liver followed by treatment with single-dose LDV/SOF for 4 weeks achieved SVR12.
■In a study of 79 patients with chronic HCV GT1 to GT4 infection of whom 59% were treatment-experienced, use of SOF/VEL following liver transplant resulted in an SVR12 rate of 96%.
■Treatment of HCV infection in patients who undergo simultaneous liver-kidney transplant is both safe and efficacious.
■The HCV-TARGET trial SVR12 rates among liver transplant and dual liver-kidney transplant recipients were 96.6% and 90.9%, respectively.
■The MAGELLAN-2 study SVR12 rate of 98% (95% CI, 95.3%-100%). No patients discontinued therapy because of treatment-related adverse events.
■SOLAR-2, a multicenter open-label study demonstrated SVR12 rates of 100% (90% CI, 91%-100%), 96% (90% CI, 84%-100%), 95% (90% CI, 78%-100%), and 100% (90% CI, 86%-100%) in CTP-A patients with 12 weeks of treatment, CTP-A patients with 24 weeks of treatment, CTP-B patients with 12 weeks of treatment, and CTP-B patients with 24 weeks of treatment, respectively.31
■In the entire cohort studied (n=333), 7 patients (2%) discontinued LDV/SOF prematurely because of adverse events and 17 patients (5%) died, mainly from complications of hepatic decompensation.
■In transplant recipients who have compensated cirrhosis, DAA therapy following transplant is safe and efficacious.
■ In SOLAR-1, SVR12 was achieved in 96% Although historical data demonstrate that HCV infection has a negative long-term impact on both patient and graft survival
Hepatitis C Virus–Positive Donors
○Serologic tests such as and enzyme immunoassays detect antibodies within 2 to 6 months after exposure,
○ (NAT) detects RNA 5 to 7 days after exposure and provides a more accurate assessment of transmission risk.
○HCV NAT has a sensitivity of 85% to 100% and a specificity of 99% to 100%.
Donors identified as HCV positive by serologic testing but NAT negative (nonviremic) are considered to have
●undergone spontaneous clearance
●or successful treatment of infection,
●or have a false-positive antibody result,
●and these donors have not been documented to transmit HCV infection.
An HCV-seropositive donor that is NAT positive (viremic) is considered to have
■an active infection
■and poses a high risk for disease transmission.
An HCV-negative donor that is NAT positive (viremic) is considered to have
♤an acute infection
♤ and poses a high risk for disease transmission
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus Negative Recipients
Renal Transplantation
●The prevalence of HCV among ESRD patients is 0.2% to 6%
●Outcomes for untreated HCV infection are significantly worse
●HCV seropositivity is associated with higher all-cause mortality [aRR], 1.85; 95% CI, 1.49-2.31; P<.0001) and higher all-cause graft loss (aRR, 1.76; 95% CI, 1.46-2.11; P<.0001).
♡Historically, kidneys from HCV-infected donors have been underutilized.
○In a study of 545 kidney transplants performed in HCV-positive recipients, 5- and 10-year patient survival was 84.8% and 72.7%, respectively, for HCV-positive graft recipients compared with 86.6% and 76.5%, respectively (P=.25), for HCV-negative graft recipients.
DAA therapy and its administration around the time of transplant minimizes the risk of chronic HCV infection
Only a few prospective trials
●In 2017, the THINKER trial was the first open-label, single-group pilot study that sought to determine the safety and efficacy of the transplant of kidneys from [D+/R-]) followed by treatment with elbasvir/grazoprevir for 12 weeks (n=10).
All recipients had detectable HCV RNA, and all attained SVR12.
■ In the THINKER-2 trial (n=20), which included THINKER participants, HCV-negative recipients of HCV-viremic kidneys experienced HCV cure and excellent renal allograft function with (eGFRs) not significantly different from those of matched recipients of HCV-negative kidneys at 6 months (median, 67.5 vs 66.2 mL/min/1.73 m2; 95% CI, -4.2 to 7.5) and 12 months (median, 72.8 vs 67.2 mL/min/1.73 m2; 95% CI, -7.2 to 9.8).
■T he EXPANDER trial was an open-label single- center study (n=10) .
Preemptive use of EBR/GZR for 12 weeks in HCV-naive recipients who received HCV-infected kidneys (n=8) led to SVR12 with no study-related adverse events.
SOF-based regimens are safe and effective in HCV-naive recipients undergoing HCV-viremic kidney transplant.
■In a subsequent, larger, single-center, observational study, use of SOF/VEL or LDV/SOF resulted in SVR12 rates of 100% and stable allograft function in 53 HCV-naive recipients who received SOF/VEL or LDV/SOF for 8 to 12 weeks following HCV-viremic kidney transplant.
■In the MYTHIC trial, 30 HCV-naive patients received HCV-viremic kidneys across 7 transplant centers.
All 30 recipients achieved SVR12, and no severe adverse events related to HCV infection or GLE/PIB were noted in any patient.
Although all recipients had good allograft
■The DAPPER trial treated patients with a single pretransplant dose of SOF/ VEL followed by 1 or 3 posttransplant doses.
The 4-day strategy reduced viral transmission to 7.5% (3/40; 95% CI, 1.8%-20.5%) but did result in detectable viremia in 17 of 50 (34%) patients by posttransplant day 14, of which only 6 of 50 (12%) required treatment; the remaining 11 recipients had self-limited, low-level viremia.
Of the 6 patients who required treatment, 5 patients achieved SVR12, with 1 patient requiring the addition of ribavirin owing to resistance and 2 patients requiring 90 retreatment with second-line DAA agents owing to relapse.
I like your clinical approach and well-structured extensively detailed summary quoting a number of trials related to HCV and various types of transplants
Hepatitis C Virus Treatment and Solid Organ Transplantation
Introduction
· The high success rate of Direct Acting Antiviral (DAA) therapy, coupled with a shortage of organ supply, have led to greater utilization of HCV‐positive livers.
· There have been substantial developments in HCV therapy and in the use of HCV-positive organs, thereby considerably increasing the number of organ transplants and decreasing waitlist mortality.
Hepatitis C Virus Infection and DAA
· DAA therapies for the treatment of chronic HCV has cure rates of greater than 98%.
· The treatment consist of regimens of oral combination: Sofosbuvir and ledipasvir, the combination of sofosbuvir and velpatasvir and of glecaprevir and pibrentasvir. They are well tolerated and produces high SVR12 rates in HCV therapy.
· HCV infection can be treated prior to transplant or can be delayed to after transplant
· DAA therapy before transplant has been shown to improve liver function in patients with decompensated cirrhosis, to the extent of no longer requiring liver transplant.
· However, not all patients with end-stage liver disease from HCV infection will benefit from treatment prior to liver transplantation.
· Patients with advanced liver disease are unlikely to improve with DAA therapy therefore, delaying treatment in such situations may be ideal.
Direct-Acting Antiviral Therapy and Liver Transplantation
· Use of DAA therapy following liver transplant has demonstrated excellent outcomes.
· Recipients who achieve SVR12 post-transplant have lower rates of liver fibrosis progression and lower mortality rates.
· Treatment of HCV infection in patients who undergo simultaneous liver-kidney transplant is both safe and efficacious.
· This wide efficacy and safety profile of DAA encouraged the use of HCV- positive organs, first in HCV-viremic recipients and now in HCV-negative recipients.
Defining Hepatitis C Virus–Positive Donors
· It is important to distinguish between a seropositive and viremic donor in HCV-positive donor, as the risks of disease transmission is much different.
· Donors identified as HCV positive by serologic testing but NAT negative (nonviremic) have not been documented to transmit HCV infection.
· An HCV-seropositive donor that is NAT positive (viremic) is considered to have an active infection and poses a high risk for disease transmission. The same applies to a HCV-negative donor that is NAT positive.
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients
Liver Transplantation
· Retrospective studies evaluated HCV-viremic donors in nonviremic liver transplant recipients demonstrated promising outcomes in patient and graft survival.
· Prospective studies demonstrated efficacy of DAA therapy if used preemptively, immediately following transplant or within 90 days and also showed favorable outcomes.
· However in these studies the development of HCV-related complications such as adverse immunologic response suggested that careful and longer-term follow-up is still necessary.
Renal transplantation
· Studies in the past decade have demonstrated promising long-term outcomes of HCV-seropositive recipients transplanted with kidneys from HCV-positive donors.
· Furthermore, the use of DAA therapy around the time of transplant for 8-12 weeks minimizes the risk of chronic HCV infection in the transplant recipient and thus encouraged the use of kidneys from HCV-infected donors into HCV-naive recipients.
· Shorter-course DAA regimens (4 months) have also been evaluated with promising results.
Thoracic Transplantation
· Preemptive administration of DAA in HCV-viremic cardiac transplant into HCV-naive recipients has demonstrated rapid HCV suppression.
· In a large prospective study, patients who underwent heart transplant with HCV-positive donors, 96% recipients developed viremia following transplant and started treatment with DAA.
· Shorter duration of DAA treatment for 8 weeks following cardiac transplant was evaluated in HCV-naive patients who received HCV-viremic organs. All patients developed detectable viremia, and all achieved SVR12.
· A few studies have evaluated the safety of using lungs from HCV-viremic donors for transplantation. All those who developed viremia post-transplant and received DAA for 4-6 months, achieved SVR12.
Pancreas Transplantation
· The data on utilizing HCV-viremic organs in pancreas transplantation are limited.
· They demonstrated efficacy of DAA in achieving SVR12.
Conclusion
· Transplantation of HCV-viremic organs into HCV-naive recipients followed by the use of DAA agents provides excellent patient and allograft survival in the short term.
· Long-term outcomes of HCV- viremic organ utilization are to be demonstrated in the near future.
I appreciate limitations of promising approach with DAA in HCV infections but long-term data being unavailable.
Introduction
Infection with the hepatitis C virus (HCV) affects 130 to 150 million individuals globally.
Organs from dead donors with HCV positivity are becoming more readily available; they make up 9.7% of the donor pool.
In the past, HCV-infected organs from deceased donors were discarded due to the high risk of transmission and severe post-transplant morbidity and mortality in liver-related transplants.
Direct-acting antiviral (DAA) therapy’s impact on HCV treatment allowed for an increase in the use of HCV-positive livers from 7% to 17% between 2010 and 2015.
Both the science of HCV therapy and the use of HCV-positive organs have made substantial strides.
Hepatitis C Virus Infection and Direct Acting Antiviral Therapy
When they were first introduced, pan-genotype DAA treatments had a 98% cure rate for chronic HCV infection.
The issue of treating HCV infection before or deferring therapy after transplantation has arisen as a result of the availability of safe and very effective therapy.
DAA medication before transplantation lowers the risk of allograft infection.
Low baseline A model for end-stage liver disease score, a low baseline Child-Pugh score, and the absence of portal hypertension problems are indicators of significant improvement in liver function from the pre-transplant era with active treatment.
When choosing the best time to start HCV therapy, the recent practice of using HCV-viremic donors has impacted the general availability of organs.
Direct-Acting Antiviral Therapy and Liver Transplantation
HCV infection after a liver transplant has a heterogeneous clinical course that can range from mild fibrosis to severe graft destruction. It can also result in progressive centrilobular ballooning degeneration, bridging fibrosis, and cholestasis in 20% to 40% of posttransplant patients.
in untreated circumstances Severe fibrosis can occur in 45% of post-transplant patients, and graft cirrhosis can develop within as little as 5 years post-transplant.
DAA medication has made substantial HCV-related liver disease post-transplantation rare. Following a liver transplant, DAA therapy has produced good results.
It is safe and effective to treat HCV infection in patients getting a liver and kidney transplant at the same time.
Similar overall success has been seen when posttransplant patients without cirrhosis adopt a pan-genotypic, ribavirin-free regimen.
In 14 liver transplant recipients who had HCV genotypes 1–4 and cirrhosis, treatment with SOF/VEL for 12 weeks led to an SVR of up to 93%. SVR12 was attained in 96%–98% of transplant recipients in SOLAR-1, whether they had compensated cirrhosis or not.
A paradigm shift occurred as a result of promising findings on the safety and effectiveness of DAA therapy for the treatment of HCV infection post-transplant, despite historical data showing that HCV infection has a detrimental long-term impact on both patient and graft survival.a
Defining Hepatitis C Virus–Positive Donors
Serology methods like chemical and enzyme immune assays can detect antibodies within 2–6 months after exposure, but nucleic acid testing (NAT) can detect RNA 5–7 days after exposure and gives a more accurate assessment of HCV infection. HCV NAT is 85%–100% sensitive and 99%–100% specific.
NAT negativity indicates spontaneous infection clearance or effective therapy.
NAT positivity indicates active infection and disease transmission risk.
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients
DAA medication has enhanced HCV-viremic donor organ use perioperatively. In a 1998 study, 22 HCV patients got HCV-seropositive grafts and had outstanding 4-year patient and graft survival.
96 and 2827 HCV-positive and -negative transplant recipients exhibited equivalent 2-year survival rates (90% vs 77%; P=.01) in a larger analysis of 2923 transplant recipients.
Liver Transplant
Two large retrospective studies found no differences in patient or graft survival between HCV-viremic and nonviremic liver transplant donors.
Thoracic Transplant
12% of cardiac transplant recipients have HCV.
HCV infection pre- or post-heart transplant lowered survival in early studies.
Kidney transplantation
End-stage renal disease patients have a 0.2–6% HCV prevalence.
Renal transplants often result in an HCV infection.
HCV-seropositive kidney recipients have worse untreated HCV infection outcomes than HCV-negative recipients.
The THINKER study (2017) showed the safety and efficacy of kidney transplants from HCV GT1–viremic donors into HCV-negative recipients [D+/R-], followed by 12 weeks of elbasvir/grazoprevir (EBR/GZR; Zepatier, Merck) treatment (n = 10).
Shorter-course DAA regimens have shown promise.
Conclusion
Excellent patient and allograft survival is achieved with the transplantation of HCV-viremic organs into HCV-naive recipients, followed by the administration of DAA drugs, resulting in a reduction in waiting time. The use of HCV-positive grafts appeared to be effective and well tolerated in a subset of patients. Patients must be warned of all hazards, including the possibility of HCV treatment failure.
I like your well-structured extensively detailed summary quoting a number of trials related to HCV and various types of transplants
Hepatitis C Virus Infection and Direct- Acting Antiviral Therapy:
DAA therapies for the treatment of chronic HCV infection has been introduced, with cure rates defined as sustained virologic response 12 weeks after treatment (SVR12) of greater than 98%.
Ø Nonstructural protein 5B inhibitor sofosbuvir (SOF; Sovaldi, Gilead)
Ø Nonstructural protein 5A (NS5A) inhibitor,
Ø Nonstructural protein 3/4A (NS3/4A) protease inhibitor, and ribavirin.
Defining Hepatitis C Virus–Positive Donors:
HCV-positive donors encompass any stage of HCV infection. Serologic tests positive :
Ø Chemiluminescence assays and enzyme immunoassays detect antibodies within 2 to 6 months after exposure.
Ø Nucleic acid testing (NAT) detects RNA 5 to 7 days after exposure and it is accurate assessment of transmission risk.
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients::
Ø In a study published in 1998, 22 patients with HCV received HCV-seropositive grafts and had excellent 4-year patient and graft survival, 83.9% and 71.9%, respectively, vs 79.1% and 76.2%, respectively, with HCV-seronegative donor grafts (P=not significant )
Ø In a larger study that included 2923 transplant recipients with HCV, 96 and 2827 received HCV-positive and -negative organs, respectively, and had comparable 2-year survival rates (90% vs 77%; P=.01).
Renal Transplantation:
The prevalence of HCV among end-stage renal disease
patients is 0.2% to 6%,
the THINKER trial was the first open-label, single-group pilot study that sought to determine the safety and efficacy of the transplant of kidneys
from HCV GT1–viremic donors into HCV-negative recipients (donor positive, recipient negative [D+/R-]) followed by treatment with elbasvir/grazoprevir (EBR/GZR; Zepatier, Merck) for 12 weeks (n=10).
THINKER-2 trial (n=20), which included THINKER participants, HCV-negative recipients of HCV-viremic kidneys experienced HCV cure and excellent renal allograft function with estimated glomerular filtration
rates (eGFRs) not significantly different from those of matched recipients of HCV-negative kidneys at 6 months (median, 67.5 vs 66.2 mL/min/1.73 m2; 95% CI, -4.2 to 7.5) and 12 months (median, 72.8 vs 67.2 mL/min/1.73
m2; 95% CI, -7.2 to 9.8
The EXPANDER trial was an open-label single-center study (n=10) that examined the tolerability and feasibility of DAA prophylaxis before and after renal transplant in HCV-naive patients
SOF-based regimens are safe and effective in HCV-naive recipients undergoing HCV-viremic kidney transplant
Transplantation of HCV-viremic organs into HCV-naive recipients followed
by the use of DAA agents provides excellent patient and allograft survival.
I like your clinical approach and well-structured extensively detailed summary quoting a number of trials related to HCV and various types of transplants
Summary of the article
Hepatitis C Virus Treatment and Solid Organ Transplantation
1. Hepatitis C virus (HCV) infection affects approximately 130 million to 150 million people worldwide.
2. The high success rate of direct-acting antiviral (DAA) therapy, have led to greater utilization of HCV‐positive livers, increasing from 7% to 17% between 2010 and 2015.
3. Cure rates is defined as sustained virologic response 12 weeks after treatment (SVR12) of greater than 98%.
4. DAA therapy has been shown to improve liver function in patients with decompensated cirrhosis.
Hepatitis C Virus Infection and Direct- Acting Antiviral Therapy
1. Sofosbuvir (SOF; Sovaldi, Gilead): Nonstructural protein 5B inhibitor has been approved for HCV treatment in combination with a nonstructural protein 5A (NS5A) inhibitor, nonstructural protein 3/4A (NS3/4A) protease inhibitor, and ribavirin.
2. The combination of potent NS5A inhibitor ledipasvir (LDV) and SOF (LDV/SOF, 90 mg/400 mg; Harvoni, Gilead), administered once daily, is well tolerated and produces high SVR12 rates in HCV genotype (GT) 1, 4, 5, and 6 infection.
3. The combination of SOF and NS5A inhibitor velpatasvir (SOF/VEL; Epclusa, Gilead), administered once daily, provides SVR12 rates of greater than 95% across all GTs and has a favorable safety profile.
4. The combination of NS3/4A protease inhibitor glecaprevir and NS5A inhibitor pibrentasvir (GLE/PIB; Mavyret, AbbVie) was first approved in 2017 for the treatment of HCV infection without cirrhosis or with mild cirrhosis. GLE/PIB is well tolerated and results in SVR12 rates greater than 97% across all GTs.
5. Pre-transplant DAA therapy reduces the risk of reinfection of the allograft.
6. Clinical features associated with meaningful improvement in liver function from pretransplant therapy include: low baseline Model for End-Stage Liver Disease score (<16), low baseline Child-Pugh score, and the absence of portal hypertension complications.
7. Patients who are unlikely to improve with DAA therapy are: patients with advanced liver disease are and those with Child-Pugh class C cirrhosis.
Direct-Acting Antiviral Therapy and Liver Transplantation
1. With the increasing use of DAA therapy, significant HCV-related progression of liver disease post-transplant is now uncommon.
2. Use of DAA in recipients who achieve SVR12 therapy following liver transplant has demonstrated excellent outcomes.
· lower rates of liver fibrosis progression (20.5% vs 65.5%)
· lower mortality rates.
3. Use of SOF/VEL following liver transplant resulted in an SVR12 rate of 96%.
4. LDV/SOF plus ribavirin in liver transplant recipients with HCV GT1 to GT4 infection and liver disease, SVR12 was achieved in 96% to 98% of transplant recipients without cirrhosis or with compensated cirrhosis.
Defining Hepatitis C Virus–Positive Donors
1. HCV-positive donors encompass any stage of HCV infection:
· Serologic tests such as chemiluminescence assays and enzyme immunoassays detect antibodies within 2 to 6 months after exposure.
· Nucleic acid testing (NAT) detects RNA 5 to 7 days after exposure and provides a more accurate assessment of transmission risk.
· HCV NAT has a sensitivity of 85% to 100% and a specificity of 99% to 100%.
2. Non-viremic HCV-seropositive donors: identified by serologic testing positive but NAT negative.
3. Viremic HCV-seropositive donor: identified by NAT positive, considered to have an active infection and poses a high risk for disease transmission.
Transplantation in HCV D+/R-
1. The rapidly evolving treatments for HCV and perioperative use of DAA therapy has increased the utilization of HCV- viremic donor organs.
2. Data have demonstrated favorable long-term graft outcomes in patients transplanted with HCV-sero- positive donors.
3. In a recent larger study, the 2-year survival rates were comparable in transplant recipients with HCV that received HCV-positive and -negative organs.
4. No differences in patient or graft survival in liver transplant recipients after donation from HCV-viremic donors in nonviremic liver when compared with nonviremic donors.
5. OPTN,showed that the 2-year graft survival rates in 568 liver transplant recipients with and without HCV infection were comparable.
6. Outcomes for untreated HCV infection in HCV-seropositive renal recipients are significantly worse than in their HCV-negative counterparts.
7. Use of SOF/VEL or LDV/SOF resulted in SVR12 rates of 100% and stable allograft function in 53 HCV-naive recipients who received SOF/VEL or LDV/SOF for 8 to 12 weeks following HCV-viremic kidney transplant.
8. Preemptive administration of GLE/ PIB in HCV-viremic cardiac transplant into HCV-naive recipients has demonstrated rapid HCV suppression, prevention of chronic HCV infection (SVR12 rate of 100%), and excellent early allograft function in patients receiving HCV-viremic donor hearts.
9. Preliminary findings suggest that HCV-viremic pancreas transplant may be safely used for potential pancreas recipients.
Conclusion
1. Transplantation of HCV-viremic organs into HCV-naive recipients followed by the use of DAA agents provides excellent patient and allograft survival.
2. Securing DAA therapy post-transplant is essential and patients should be fully informed of the associated risks, including the potential of HCV treatment failure.
Yes, I appreciate the need for proper informed consent in light of long-term data being unavailable.
HCV Treatment and SOT
Summary:
· HCV is a common cause of ESLD requiring liver transplantation.
· HCV infection in the recipient; must be treated prior to liver transplantation, as 100 % of cases will have infected graft after transplantation with higher risk of graft failure, patient morbidity and mortality.
· Use of HCV +ve donors to increase availability of organs (increase donor pool), especially in the presence of direct acting anti-viral therapy (DAAV).
· Unfortunately, young donors with less comorbidities, have HCV infection (related to drug abuse), so have HCV viremic organs.
· Risk of transmission from positive donor is determined according to positive PCR (higher transmission).
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· The highest risk is with HCV positive PCR (active viremic state).
· The problem in diagnosis with PCR is one-week period between acquiring viral infection and appearance of positive PCR.
· Use of HCV +ve donor to HCV positive recipient has been used successfully, however using D+/R – was not considered in the past (high risk of infection, graft failure, morbidity and mortality, adverse effects of interferon based therapy).
· Nowadays, it is used in HCV – ve recipient with availability of highly effective and relatively safe DAAV, with relatively comparable graft and patient outcomes to use of HCV –ve donors (but still not the standard practice).
· Direct acting antivirals;
o Has many advances.
o Higher success rate (sustained virologic response (SVR12) 12 weeks after treatment of greater than 98%.
o Duration of therapy is about 3 months.
o Combination of sofosbuvir (Sovaldi) + ledipasvir (given once daily, high SVR, effective against genotypes 1, 4,5,6)
o Combination of sofosbuvir (Sovaldi) + velpatasvir (given once daily, SVR > 95% and more safe).
o Combination of GLE/PIB is well tolerated and results in SVR > 97% across all genotypes.
o Timing of treatment in liver transplant recipients;
§ What favors pre-transplant treatment:
1. Improvement of liver function even in those with decompensated cirrhosis up to not needing transplantation.
2. Decrease risk of HCV infection in allograft.
3. Used in cases with low baseline Model for End-Stage Liver Disease score and absent portal hypertension complications.
§ What favors post-transplant treatment:
1. Cases with compensated cirrhosis.
· HCV persist in 20-40 % of cases after liver transplantation, with progressive fibrosis, cirrhosis and graft failure. So use of DAAV is so crucial to improve graft outcome.
· Use of LDV/SOF or SOF/VEL has achieved high SVR that leads to better outcome, less progression of cirrhosis in HCV positive cases (receiving liver from HCV negative donors) without rejection episodes and with minimal side effects.
· Use of pangenotypic, ribavirin-free regimen in post-transplant patients without cirrhosis has demonstrated similar overall success.
· Liver transplantation (either use early treatment in case of +ve PCR or use preemptive therapy starting immediately after tx)
o HCV +ve donor is used nowadays for HCV _ve recipient with comparable outcomes (in presence of perioperative use of DAAV). The recipients developed HCV infection in spite of donor treatment prior to donation. So, those recipients taking allograft from HCV +ve donors must undergo PCR screening and receive early treatment (with DAAV as SOF/VEL or GLE/PIB combinations as once daily therapy for 12 weeks) to preserve the graft function.
o Preemptive antiviral strategy immediately after transplantation using SOF/VEL is also effective to achieve SVR.
o It is importance to take care of immunological adverse effects as sclerosing cholangitis, cardiomyopathy and GVHD. In addition, long term follow-up and monitoring of graft function and complications is essential.
· Kidney transplantation; (treatment with DAAV must be preemptive, starting in the day prior to KT).
o HCV is a common comorbidity in cases with ESKD. The long-term outcomes of HCV-seropositive recipients transplanted with kidneys from HCV +ve donors is promising. In addition, the availability of DAAV has paved the way to use HCV +ve donors (viremic allograft) for HCV naive recipients.
o Although it remains few trial with small sample size, it seems that CMV viremia is the rule in all cases but effective DAAV as EBR/GZR (for G1,3) for 12 weeks, can achieve SVR (HCV cure) and good graft outcome at 6-12 months after kidney transplantation. The therapy was started preemptively (immediately before transplantation and continued for 3 months after the operation).
o Addition of SOF was required in genotypes 2, 3 (use triple therapy EBR/GZR/SOF). In addition, use of SOF/VEL or LDV/SOF for 8 to 12 weeks was effective in treatment of naïve recipients receiving viremic organs with few rejection episodes. Shorter duration as 4 weeks of GLE/PIB or 4 days of SOF/VEL was effective in decreasing viral transmission.
· Ribavirin can be used for resistant cases to 1st line therapy and 2nd line drugs are used in relapsed cases.
· Pancreases transplantation: very limited numbers of cases, use of GLE/PIB or SOF/VEL achieved SVR (need further trials).
· Lung/heart transplantation; use of EITHER LDV/SOF (GT1) or SOF/VEL (GT3) or GLE/ PIB for 3- 6 months to achieve SVR with excellent graft outcome. Short treatment duration for 8 weeks was also effective to achieve SVR.
· As a conclusion, use of viremic organs for HCV naïve recipients seems applicable with the use of DAAV (for 12 weeks) with > 95 % SVR. The adverse effects of DAAV and occurrence of acute rejection seem acceptable.
· The prognosis of D+/R- transplantation is still better than waiting on dialysis.
· However, patient counseling about the risk of viremia, failure of treatment and availability and importance of strict adherence to DAAV is essential prior to proceeding in D+/R- transplantation.
· In addition, the long term effects on patient immune system and interaction with immunosuppressive therapy remains unclear and needs further evaluation.
Yes, I appreciate the need for proper counselling and informed consent in light of long-term data being unavailable.
HEPATITIS C VIRUS TX IN SOT.
Introduction.
Approx -130 -150 million ppl worldwide have HCV infection. In 2019,9.7% of deceased liver donors were HCV +VE. Adoption of DAA therapy has led to an increase in the use of HEPC +VE liver from 7-17% btn 2010-2015.
HCV infection and DAA therapy;
HCV cure rate is sustained virologic response 12/52 of >98%.Option in transplant popn is either tx pre transplant or deferring therapy until after transplant.
Pre transplant tx candidates;
Post transplant tx candidates;
Tx options;
DAA therapy and liver transplantation;
-Post transplant HCV leads to fibrosis and graft damage of varied degrees .DAA therapy has markedly decreased HCV related progression of liver dx post transplant.
-In HCV TARGET trial, LDF+SOF,Ombitasvir/paritaprevir/ritonavir +dasabuvir or SOF+DAC therapies gave good outcomes and confidence in transplant groups with HCV with a ribavirin free regimen.
-Transplant candidates with decompensated cirrhosis and HCV have shown good results with DAA therapy as evidenced in SOLAR 1 and 2 Trials where SOF/VEL,LDF/SOF +ribavirin were used with good outcomes.
Defining HEP C virus in +VE donors.
-NAT has rapid results in 5-7 days and is more accurate in accessing transmission risk. HCV NAT has a 85-100% sensitivity and 99-100% specificity.
Non viraemic donors (NAT neg) have low risk of transmission in comparison to seropositive donors and those who are viraemic.
-High risk of transmission;
-Low risk of transmission;
-No risk of transmission -No HCV infection,HCV ab -VE,HCV NAT -VE.
Hep C virus +VE donor transplantation in Hep C virus -VE recipients.
Liver transplantation.
–HCV tx within DAA within 3/12 pre transplant is associated with good graft function.
-Tx options;
-Main SE that need to be monitored are DI,ACR,ABMR, biliary sclerosis, cardiomyopathy and graft vs host dx.
Renal transplantation.
-HCV prevalence in ESRD is 0.2-6% with HCV being associated with higher mortality than HCV neg popn.
-In THINKER trials, post transplant pts tx with EBR+GZR had good cure rates with excellent graft function.
-In EXPANDER trial, post transplant pt received EBR/GZR/SOF(dual/triple therapy) with good tolerability.
-In MYTHIC trial, post transplant pts received GLE+PIB with good tolerability and graft outcomes.
Thoracic transplantation.
–HCV prevalence is 12% in heart transplant recipients which has poor survival.
-In USHER trial, EBR+GZR tx was associated with good outcomes post cardiac transplant with tolerability and no serious adverse events.
-Shorter duration therapy generally associated with viremia post transplant with fewer studies supporting it.
-In the DONATE HCV trial both cardiac and lung transplant recipients tx with SOF+VEL pre transplant and GLE+PIB post transplant had good graft function and no mortality or significant rejection.
Pancreas transplantation.
-We don’t have much studies on this but preliminary findings support the use of HCV Viremic pancreas transplant with DAA, More studies are needed on this.
I like your well-structured detailed summary quoting a number of trials related to HCV and various types of transplants.
Thanks.
Hepatitis C Virus Treatment and Solid Organ Transplantation
Introduction
Hepatitis C Virus Infection and Direct Acting Antiviral Therapy
Direct-Acting Antiviral Therapy and Liver Transplantation
Defining Hepatitis C Virus–Positive Donors
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients
Treatments for HCV have improved outcomes significantly, and perioperative use of DAA therapy has increased the utilization of HCV- viremic donor organs. In a study published in 1998, 22 patients with HCV received HCV-seropositive grafts and had excellent 4-year patient and graft survival ( 83.9% and 71.9%, respectively, vs 79.1% and 76.2%, respectively), with HCV-seronegative donor grafts (P=not significant).
In a larger study that included 2923 transplant recipients with HCV, 96 and 2827 received HCV-positive and -negative organs, respectively, and had comparable 2-year survival rates (90% vs 77%; P=.01).
Liver Transplantation
Two large retrospective studies evaluated HCV-viremic donors in nonviremic liver transplant recipients and demonstrated no differences in patient or graft survival when compared with nonviremic donors.
Renal Transplantation
.
Thoracic Transplantation
Among heart transplant recipients, the reported prevalence of HCV infection is as high as 12%.
Early studies demonstrated reduced survival in recipients with HCV infection, regardless of acquisition of HCV pre– or post– heart transplant.
Conclusion
Transplantation of HCV-viremic organs into HCV-naive recipients followed by the use of DAA agents provides excellent patient and allograft survival, leading to reduction in waiting time. In selected patients, the utilization of HCV+ve grafts appears to be efficacious and well tolerated. patients should be fully informed of the associated risks, including the potential of HCV treatment failure.
I like your clinical approach and well-structured detailed summary quoting a number of trials related to HCV and transplant.
Infection with the hepatitis C virus (HCV) affects 130–150 million people worldwide.
One of the most common causes of end-stage liver disease and the main justification for liver transplantation is HCV infection.
Yet, there is a significant waitlist mortality rate since the demand for organs continues to outstrip the supply of organ donation.
Organs with HCV remain more readily available, accounting for 9.7% of livers from dead donors in 2019.
Previously, HCV-infected organs from deceased donors were discarded due to the high risk of reperfusion-related transmission and the possibility of considerable posttransplant morbidity and mortality.
The science of HCV therapy and the utilization of HCV-positive organs have made considerable strides, leading to a major rise in organ transplantation and a decline in waitlist mortality.
In this paper, the research on HCV treatment both before and after organ transplantation is reviewed.
Direct acting antiviral therapy
Over the past several years, a succession of pangenotypic DAA therapies for the treatment of chronic HCV infection has been introduced, with cure rates defined as sustained virologic response 12 weeks after treatment (SVR12) of greater than 98%.16 Nonstructural protein.
Over the past several years, a succession of pangenotypic DAA therapies for the treatment of chronic HCV infection has been introduced, with cure rates defined as sustained virologic response 12 weeks after treatment (SVR12) of greater than 98%.16.
The MAGELLAN-2 study was a phase 3 open-label trial that confirmed the safety and efficacy of GLE/PIB once daily for 12 weeks in patients with treatment-naive HCV GT1 to GT6 infection or treatment-experienced HCV GT1, GT2, or GT4 to GT6 who had received a liver or kidney transplant.
Treatment with SOF/VEL for 12 weeks in 14 liver transplant recipients with HCV GT1 to GT4 infection and cirrhosis resulted in an SVR12 rate of.
HCV antibody HCV NAT clinical interpretation transmission risk
No active HCV infection, cleared or treated HCV infection, or false-positive antibody Low. HCV, hepatitis C virus; NAT, nucleic acid testing.
Donors identified as HCV positive by serologic testing but NAT negative are considered to have undergone spontaneous clearance or successful treatment of infection, or have a false-positive antibody result, and these donors have not been documented to transmit HCV infection.
An. HCV-seropositive donor that is NAT positive is considered to have an active infection and poses a high risk for disease transmission.
An HCV-negative donor that is NAT positive is considered to have an acute infection and poses a high risk for disease transmission.
Risk of HCV transmission remains during the 1-week eclipse period between viral exposure and positive NAT results, in persons who inject drugs.
Risk of HCV transmission remains during the 1-week eclipse period between viral exposure and positive NAT results, in persons who inject drugs.
Negative recipients
DAA therapy, transplantation of organs from HCV-positive donors into uninfected recipients was not routinely considered owing to low efficacy, high rates of HCV transmission, decreased patient and graft survival, and complications associated with interferon-based therapy in the posttransplant setting. The lack of effective and well-tolerated treatments for HCV had curtailed utilization of HCV-infected organs in transplant recipients.
DAA therapy, transplantation of organs from HCV-positive donors into uninfected recipients was not routinely considered owing to low efficacy, high rates of HCV transmission, decreased patient and graft survival, and complications associated with interferon-based therapy in the posttransplant setting.
The lack of effective and well-tolerated treatments for HCV had curtailed utilization of HCV-infected organs in transplant recipients.
Data have demonstrated favorable long-term graft outcomes in patients transplanted with HCV-seropositive donors.
In a study published in 1998, 22 patients with HCV received HCV-seropositive grafts and had excellent 4-year patient and graft survival, 83.9% and.
In a larger study that included 2923 transplant recipients with HCV, 96 and 2827 received HCV-positive and -negative organs, respectively, and had comparable
Liver transplantation
Two large retrospective studies evaluated HCV-viremic donors in nonviremic liver transplant recipients and demonstrated no differences in patient or graft survival when compared with nonviremic donors. 54,55 Data from 2015 to 2017 from the Organ Procurement and Transplantation Network (OPTN)
Two large retrospective studies evaluated HCV-viremic donors in nonviremic liver transplant recipients and demonstrated no differences in patient or graft survival when compared with nonviremic donors.
HCV-seropositive but NAT-negative and nonviremic livers (92% vs 92% vs 92%; P=NS).
2016 to 2020 data from OPTN, comparable 2-year graft survival rates were seen in 568 liver transplant recipients with and without HCV infection (n=753 and n=87, respectively) who received HCV-viremic organs
Antiviral therapy
GLE/PIB, glecaprevir/pibrentasvir; KT, kidney transplant; LDV/SOF, ledipasvir/sofosbuvir; LT, liver transplant; SOF/DAC, sofosbuvir/daclatasvir; SOF/VEL, sofosbuvir/velpatasvir; SVR12, sustained virologic response 12 weeks after treatment.
The first prospective study included 10 HCV-negative patients who received HCV-viremic livers, 7 of which had been cured of HCV infection prior to transplant.
GLE/PIB has been used successfully in HCV-naive patients who receive HCV-viremic livers.
In a trial of 14 patients who received HCV-viremic livers, 9 patients developed viremia with SVR12 and 46-week survival rates of 100% and 100%, respectively.
The administration of SOF/VEL or GLE/PIB once daily for 12 weeks in HCV-naive patients who received viremic livers (n=51).
In a multicenter study evaluating the kinetics of early HCV infection, SOF/VEL once daily for 12 weeks when viremia was confirmed resulted in SVR12 in all patients (13 liver, 11 kidney
SVR12 was reported in a prospective multicenter study evaluating outcomes in HCV-naive liver transplant and dual liver-kidney transplant. 60 all HCV-viremic organ recipients (n=20) achieved SVR12, the development of HCV-related complications suggests that careful and longer-term follow-up is still warranted
Renal transplantation
The prevalence of HCV among end-stage renal disease patients is 0.2% to 6%, and HCV infection traditionally has been a common complication after renal transplant.
In 2017, the THINKER trial was the first open-label, single-group pilot study that sought to determine the safety and efficacy of the transplant of kidneys from HCV GT1–viremic donors into HCV-negative recipients followed by treatment with elbasvir/grazoprevir (EBR/GZR; Zepatier, Merck) for 12 weeks (n=10).
In a study of 7 HCV-naive kidney recipients receiving HCV GT1– and HCV GT3–viremic kidneys, antiviral treatment with LDV/SOF (n=4) and SOF/VEL (n=3) for 8 to 12 weeks resulted in SVR12 and stable renal allograft function.
70 In a subsequent, larger, single-center, observational study, use of SOF/VEL or LDV/SOF resulted in SVR12 rates of 100% and stable allograft function in 53 HCV-naive recipients who received SOF/VEL or LDV/SOF for 8 to 12 weeks following HCV-viremic kidney transplant.[71].
Of the 6 patients who required treatment, 5 patients achieved SVR12, with 1 patient requiring the addition of ribavirin owing to resistance and 2 patients requiring retreatment with second-line DAA agents owing to relapse.
Thoracic transplantation
The reported prevalence of HCV infection is as high as 12%. 76 Early studies demonstrated reduced survival in recipients with HCV infection, regardless of acquisition of HCV pre– or post–.
The first prospective study utilizing HCV-viremic hearts included 11 HCV-naive recipients, 9 of whom developed HCV viremia after transplant and 8 of whom achieved SVR12 through treatment with either.
PIB in HCV-viremic cardiac transplant into HCV-naive recipients (n=20) has demonstrated rapid HCV suppression, prevention of chronic HCV infection (SVR12 rate of 100%), and excellent early allograft function (100% at a median follow-up of 10.7 months) in patients receiving HCV-viremic donor hearts.
In the largest-to-date prospective single-center study of 80 patients who underwent heart transplant with HCV-positive donors (70 NAT-positive, GT1-GT3 donors and 10 antibody-positive, NAT-negative donors), 67 of 70 (96%) recipients developed viremia following transplant and started treatment with LDV/.
Shorter duration of DAA treatment with GLE/PIB for 8 weeks following cardiac transplant was evaluated in 22 HCV-naive patients who received HCV-viremic organs.
At 6 months posttransplant, there was no difference between HCV-viremic and HCV-negative recipients when comparing mortality (6.3% vs 3.9%; P=1), primary graft dysfunction (0.0% vs 11.5%; P=.275), clinically significant rejection requiring treatment (31.8% vs 37%; P=.769), or acute cellular rejection (90.9% vs 100%; P=.196).
Pancreas transplantation
The data on utilizing HCV-viremic organs in pancreas transplantation are limited.
In 2021, the first reported series included 8 HCV-naive patients who received either deceased donor simultaneous pancreas-kidney transplant or pancreas transplant after living donor kidney transplant.
Length of stay (16 days vs 10 days; P=.06) was similar between those who received HCV-viremic organs and those who did not, respectively.
These preliminary findings suggest that HCV-viremic pancreas transplant may be safely used for potential pancreas recipients; further study regarding morbidity and mortality of pancreas transplantation with HCV-positive donors is needed.
Short-term outcomes for solid organ transplantation appear to be comparable for HCV-viremic and -nonviremic donors, based on the previously discussed preliminary data.
Promising data are most robust in kidney followed by liver transplant but offer limited results past 1 year
Findings
Have led to greater utilization of HCV‐positive livers, increasing from 7% to 17% between 2010 and.
With cure rates defined as sustained virologic response 12 weeks after treatment (SVR12) of greater than 98%.16.
Recipients who achieve SVR12 posttransplant have lower rates of liver fibrosis progression (20.5% vs 65.5%; P<.001) and lower mortality rates compared with patients who do not receive or fail treatment.
Treatment with GLE/PIB for 3 months or longer posttransplant in 80 liver transplant and 20 kidney transplant patients resulted in an SVR12 rate of 98%.
In posttransplant patients with HCV GT4 infection, SVR12 was achieved by 78% of patients who received 12 weeks of treatment and 94% of patients who received 24 weeks of treatment.
Produced similar 1-year patient and graft survival when compared with HCV-naive patients who received nonviremic livers (n=231), at 93.4% vs 93.9% (P=.89) and.
HCV seropositivity was reported to be an independent risk factor for increased mortality when matched with controls (2.8-fold greater; 95% CI, 1.3-5.7; P=.006) and for the development of accelerated allograft vasculopathy when compared with matched controls, with a hazard ratio of 9.4 vs 3.08
Conclusion
Organ transplantation in the United States is negatively impacted by long waitlist times and high waitlist mortality owing to organ shortages.
The use of HCV-viremic grafts appears to be efficacious and well tolerated.
This practice has demonstrated acceptable short-term outcomes and has the potential to significantly close waitlist gaps and decrease morbidity and mortality.
DAA therapy posttransplant is essential and patients should be fully informed of the associated risks, including the potential of HCV treatment failure.
It remains unclear whether HCV infection in posttransplant patients may lead to lasting changes to the immune system or inadvertent interactions with immunosuppressive therapy.
I like your clinical approach and well-structured extensively detailed summary quoting a number of trials related to HCV and various types of transplants
Introduction:
HCV is one of the common causes of CLD that necessitates liver transplantation. In the past, organs from HCV deceased donors were discarded. in the era of DAA with good success rates & manageable S/E, the utilization of HCV-positive organs is increasing.
Hepatitis C Virus Infection and Direct Acting Antiviral Therapy:
With the use of DAA, the cure rates defined as sustained virological response 12 weeks after treatment reach up to 98%. the availability & safety of these drugs gave the choices of ttt of HCV before or after the transplantation. Patients with low baseline child-pugh score, low baseline model for ESLD score<16 & absence of complications of portal HTN will benefit from TTT of HCV before transplantation in the form of improving liver enzymes & reducing the risk of reinfection of the allograft, while patients with advanced liver disease with child-pugh class C cirrhosis will not benefit with low SVR12 rates.
Direct-Acting Antiviral Therapy and Liver Transplantation:
Persistent HCV infection after a liver transplant is associated with bad outcomes & high rates of graft cirrhosis. With the use of DAA after a liver transplant, the outcomes are excellent in the form of SVR12 rates & low rates of liver fibrosis.
The HCV-TARGET trial evaluated liver transplant and dual liver-kidney transplant recipients with HCV infection treated with LDV/SOF, ombitasvir/paritaprevir/ritonavir plus dasabuvir (Viekira Pak, AbbVie), or SOF/DAC (Darvoni, Beacon) using the Hepatitis C Therapeutic Registry and Research Network database. Liver transplant and dual liver-kidney transplant recipients had 96.6% and 90.9% SVR12. Four liver transplant recipients had acute rejection.
The large HCV-TARGET cohort’s real-world results supported ribavirin-free liver transplantation.
In transplant recipients who have compensated cirrhosis, DAA therapy following transplant is safe and efficacious. Treatment with SOF/VEL for 12 weeks in 14 liver transplant recipients with HCV GT1 to GT4 infection and cirrhosis resulted in an SVR12 rate of 93%
Defining Hepatitis C Virus–Positive Donors:
When considering organ transplants from an HCV-positive donor, the risks of disease transmission vary greatly between seropositive and viremic donors. Donors who are HCV positive by serologic testing but NAT negative (nonviremic) are thought to have had spontaneous clearance, effective treatment, or a false-positive antibody result and cannot transmit HCV. A viremic HCV-seropositive donor is a high-risk disease transmitter. An acutely infected HCV-negative donor with NAT positivity (viremic) is a high-risk donor. Despite testing advancements, HCV transmission occurs throughout the 1-week eclipse period between virus exposure and positive NAT results.
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus–Negative Recipients:
Ø Liver transplantation:
Two large retrospective studies evaluated HCV-viremic donors in nonviremic liver transplant recipients and demonstrated no differences in patient or graft survival when compared with nonviremic donors.
In a multicenter investigation on early HCV infection, SOF/VEL once daily after 12 weeks after viremia demonstrated SVR12 in all patients (13 liver, 11 kidney). However, major adverse events in this study included biliary sclerosis, cardiomyopathy, and graft-vs-host disease, which caused multiorgan failure and death, necessitating cautious monitoring for unfavorable immunologic events. A prospective multicenter analysis of HCV-naive liver transplant and dual liver-kidney transplant outcomes found HCV-related acute membranous nephropathy resulting in end-stage kidney disease despite SVR12. All HCV-viremic organ recipients (n=20) achieved SVR12, but HCV-related problems require careful and longer-term follow-up.
Ø Renal transplanatation:
the availability of DAA therapy and its administration around the time of transplant minimizes the risk of chronic HCV infection in the transplant recipient and thus has led to the recent growth of transplant of kidneys from HCV-infected donors into HCV-naive recipients.
The first open-label, single-group pilot project, THINKER trial, examined the safety and effectiveness of kidney transplants from HCV GT1–viremic donors into HCV-negative recipients (D+/R-) followed by 12 weeks of treatment with elbasvir/grazoprevir (EBR/GZR; Zepatier, Merck) (n=10). All recipients had HCV RNA and SVR12. In the THINKER-2 trial (n=20), which included THINKER participants, HCV-negative recipients of HCV-viremic kidneys had HCV cure and excellent renal allograft function with estimated glomerular filtration rates (eGFRs) not significantly different from those of matched recipients of HCV-negative kidneys at 6 months.
The EXPANDER trial (n=10) assessed the tolerance and feasibility of DAA prevention before and after renal transplant in HCV-naive patients who received HCV-viremic kidneys (GT1-GT3). In this study, all recipients received a dose of EBR/GZR immediately before the transplant, and recipients of kidneys from donors with GT1 infection received EBR/GZR for 12 weeks after the transplant. Those receiving organs from donors with GT2 or GT3 infection received SOF and EBR/GZR for 12 weeks of triple therapy. Preemptive EBR/GZR for 12 weeks in HCV-naive patients who received HCV-infected kidneys (n=8) resulted in SVR12 with no study-related side effects. SOF-based regimens are safe and effective in HCV-naive recipients undergoing HCV-viremic kidney transplant
Seven transplant centers gave 30 HCV-naive patients HCV-viremic kidneys in the MYTHIC study.
All 30 participants achieved SVR12 without HCV infection or GLE/PIB-related serious adverse effects.
Acute cellular rejection (n=3) and polyomavirus (BK) viremia (n=3) occurred despite acceptable allograft function.
In a large, prospective, real-world trial, 64 HCV-naive patients underwent HCV-viremic kidney transplant and posttransplant NAT to identify therapy requirements.
73; 61 patients acquired viremia, 41 achieved SVR12, 10 had undetectable virus levels, and 7 continued treatment. One NS5A-resistant nonresponder. Patients and grafts survived 98% at a median 8-month follow-up.
Thoracic transplantation:
The single-center pilot DONATE-HCV trial transplanted HCV-viremic organs into 8 heart and 36 lung HCV-naive recipients who preemptively received SOF/VEL for 4 weeks. HCV viremia emerged in 95% of recipients immediately after transplant, and of the first 35 patients who completed 6 months of follow-up, 100% (95% CI, 90%-100%) achieved SVR12 with excellent graft function. HCV-naive patients (16 lung receivers and 22 heart recipients) who received HCV-viremic donor organs and DAA therapy with GLE/PIB for 8 weeks had similar results. 86 11 of 16 lung recipients developed viremia posttransplant and all attained SVR12. At 6 months posttransplant, HCV-viremic and HCV-negative recipients had similar mortality (6.3% vs 3.9%; P=1), primary graft malfunction (0.0% vs 11.5%; P=.275), clinically severe rejection requiring therapy (31.8% vs 37%; P=.769), and acute cellular rejection (90.9% vs 100%).
Conclusion:
Organ shortages cause long waitlists and significant waitlist mortality in the US. DAA-treated HCV-viremic organ transplantation into HCV-naive recipients improves patient and allograft survival. HCV-viremic grafts are effective and well-tolerated in selected patients. This method has good short-term results and can reduce waiting gaps and morbidity and death.
DAA medication posttransplant is essential, but patients should be warned of the risks, including HCV treatment failure. Posttransplant HCV infection may cause immune system alterations or immunosuppressive therapy interactions. HCVviremic organ utilization long-term results are not still fully established.
I like your clinical approach and well-structured detailed summary quoting a number of trials related to HCV and transplant.
II. Hepatitis C Virus Treatment and Solid Organ Transplantation
——————————————————————————————————————
Please summarise this article.
====================================================================
Hepatitis C Virus Infection and Direct-Acting Antiviral Therapy
====================================================================
Direct-Acting Antiviral Therapy and Liver Transplantation
===================================================================
Defining Hepatitis C Virus–Positive Donors
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus Negative Recipients
Liver Transplantation
Renal Transplantation
Thoracic Transplantation
Pancreas Transplantation
====================================================================
Conclusion
I like your clinical approach and well-structured detailed summary related to HCV and transplant.Typing whole sentence in bold or typing in capitals amounts to shouting.
Hepatitis C Virus Treatment and SOT
Summary of the Article
Introduction
Hepatitis C virus infection and DAA therapy
a) Sofosbuvir (5B inhibitor).
b) Ledipasvir (NS5A inhibitor).
c) NS3/4A protease inhibitor.
d) Ribavirin.
Interpretation of HCV Diagnostic testing Results
DAA and liver Tx
a) Mild to advanced fibrosis.
b) Severe graft damage.
c) Progressive centrilobular ballooning degeneration.
d) Bridging fibrosis.
e) Cholestasis.
f) Graft cirrhosis.
a) Lower rate of liver fibrosis progression (20.5% vs 65.5%)
b) Lower mortality rate, compared to patients who do not receive DAA.
HCV-TARGET trial
MAGELLAN-2 study
a)HCV GT1 to GT6.
b) HCV GT1, GT2.
c) HCV GT4 to GT6.
SOLAR-1 and SOLAR-2
a) No cirrhosis.
b) Child-Turcotte-Pugh (CTP)-A, CTP-B, or CTP-C cirrhosis.
c) Fibrosing cholestatic hepatitis.
a) SVR12 rate of 100% in CTP-A, 12 weeks.
b) SVR12 rate of 96% in CTP-A 24 weeks.
c) SVR12 rate of 95% in CTP-B, 12 weeks.
d) SVR12 rate of 100% in CTP-B 24 weeks.
Defining Hepatitis C virus-positive Donors
Liver transplantation
Renal transplantation
a) 84.8% and 72.7%, respectively for HCV+graft.
b) 86.6% and 76.5% respectively for HCV-graft.
Pancreas transplantation
Conclusion
DAA is available and showing promising results, and open a window of using HCV+ve donor in HCV-ve recipients
I like your clinical approach and well-structured detailed summary quoting a number of trials related to HCV and transplant.
II. Hepatitis C Virus Treatment and Solid Organ Transplantation
Please summarise this article.
Introduction
Hepatitis C virus (HCV) infection affects approximately 130 million to 150 million people worldwide.
The availability of HCV-positive organs continues to increase, representing 9.7% of deceased-donor .
In the past , organs from deceased donors infected with HCV were discarded because of high transmission risk during reperfusion and risk of significant post transplant morbidity and mortality livers in 2019.
HCV changed with the emergence of direct-acting antiviral (DAA) therapy, this lead to greater utilization of HCV‐positive livers, increasing from 7% to 17% between 2010 and 2015.
There have been significant advancements in the science of HCV therapy and in the use of HCV-positive organs, thereby substantially increasing the number of organ transplants and decreasing waitlist mortality.
Hepatitis C Virus Infection and DirectActing Antiviral Therapy
The pan genotype DAAtherapieswhen started and introduced lead to cure rate of chronic HCV infection about 98%.( sustained virologic response 12 weeks after treatment(SVR12))
The availability of safe and highly effective therapy has led to the delicate consideration of treating HCV infection prior to transplant or deferring therapy until after transplant.
pretransplant DAA therapy reduces the risk of reinfection of the allograft.
The improvement in liver function from pretransplant therapy include low baseline Model for End-Stage Liver Disease score (<16), low baseline Child-Pugh score, and the absence of portal hypertension complications.
more recent practice of utilizing HCV-viremic donors has changed overall access to transplant and should be taken into consideration when deciding optimal timing of HCV treatment.
Direct-Acting Antiviral Therapy and Liver Transplantation
The infection after liver transplant causing a variable clinical course ranging from mild fibrosis to severe graft damage, HCV infection can cause Progressive centrilobular ballooning degeneration, bridging fibrosis, and cholestasis are seen in 20% to 40% of posttransplant patients.
Also Advanced fibrosis can occur in up to 45% of post transplant patients, and graft cirrhosis can develop within as little as 5 years post transplant.
Increasing use of DAA therapy, significant HCV-related progression of liver disease post transplant is now uncommon.
Use of DAA therapy following liver transplant has demonstrated excellent outcomes.
Treatment of HCV infection in patients who undergo simultaneous liver-kidney transplant is both safe and efficacious.
The use of a pangenotypic, ribavirin-free regimen in posttransplant patients without cirrhosis has demonstrated similar overall success.
Treatment with SOF/VEL for 12 weeks in 14 liver transplant recipients with HCV GT1 to GT4 infection and cirrhosis resulted in an SVR12 rate of 93%.
In SOLAR-1, SVR12 was achieved in 96% to 98% of transplant recipients without cirrhosis or with compensated cirrhosis.
Although historical data demonstrate that HCV infection has a negative long-term impact on both patient and graft survival, promising data on the safety and efficacy of DAA therapy for the treatment of HCV infection post transplant led to a paradigm shift.
Defining Hepatitis C Virus–Positive Donors
Definition of HCV positive donor is infection include any stage of the affection which establish through serology tests such as chemistry assays and enzyme immune assays to detect antibodies within 2 to 6 months after exposure, but nucleic acid testing (NAT) detects RNA 5 to 7 days after exposure and provides a more accurate assessment of transmission risk.
HCV NAT has a sensitivity of 85% to 100% and a specificity of 99% to 100%.
If NAT negative means spontaneous clearance or successful treatment of infection.
If NAT positive means active infection and poses a high risk for disease transmission.
Despite improvements in testing, risk of HCV transmission remains during the 1-week eclipse period between viral exposure and positive NAT results, particularly in persons who inject drugs.
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients
Treatments for HCV have improved outcomes, and perioperative use of(direct acting anti viral therapy) DAA therapy has increased the utilization of HCV- viremic donor organs.
In a study published in 1998, 22 patients with HCV received HCV-seropositive grafts and had excellent 4-year patient and graft survival, 83.9% and 71.9%, respectively, vs 79.1% and 76.2%, respectively, with HCV-seronegative donor grafts (P=not significant [NS]).52 In a larger study that included 2923 transplant recipients with HCV, 96 and 2827 received HCV-positive and -negative organs, respectively, and had comparable 2-year survival rates (90% vs 77%; P=.01).
Liver Transplantation
Two large retrospective studies evaluated HCV-viremic donors in nonviremic liver transplant recipients and demonstrated no differences in patient or graft survival when compared with nonviremic donors.
Renal Transplantation
The prevalence of HCV among end-stage renal disease patients is 0.2% to 6%, and HCV infection traditionally has been a common complication after renal transplant.61 Outcomes for untreated HCV infection in HCV-seropositive renal recipients are significantly worse than in their HCV-negative counterparts.
The THINKER trial show in 2017 the safety and efficacy of the transplant of kidneys from HCV GT1–viremic donors into HCV-negative recipients (donor positive, recipient negative [D+/R-]) followed by treatment with elbasvir/grazoprevir (EBR/GZR; Zepatier, Merck) for 12 weeks (n=10).
Shorter-course DAA regimens have also been evaluated with promising results.
Thoracic Transplantation
Among heart transplant recipients, the reported prevalence of HCV infection is as high as 12%.76 Early studies demonstrated reduced survival in recipients with HCV infection, regardless of acquisition of HCV pre– or post– heart transplant.
Conclusion
1.Transplantation of HCV-viremic organs into HCV-naive recipients followed by the use of DAA agents provides excellent patient and allograft survival, this lead to shortage list of waiting.
2.In carefully selected patients, the use of HCV-viremic grafts appears to be efficacious and well tolerated.
3.patients should be fully informed of the associated risks, including the potential of HCV treatment failure.
Yes, I appreciate the need for proper counselling and informed consent in light of long-term data being unavailable.
Summary
HCV infection affects 130-150 million people world wide.
End stage liver disease secondary to HCV infection is leading cause for liver transplant.
DAA have cure rates, defined as sustained virological response at 12 weeks (SVR 12), greater than 98%.
DAA have been shown to improve liver function in patients with decompensated cirrhosis and when given pre-transplant can reduce the risk of allograft reinfection.
Pre-transplant DAA are beneficial in patients with low Child Pugh score and those without portal hypertension.
Patients with advanced liver disease and Child Pugh score class C the SVR12 rates are low thus treatment should be deferred.
HCV antibodies are detected 2-6 months after infection while HCV NAAT is positive within 5-7 days after exposure thus a more accurate assessment for transmission risk.
Donors with HCV antibodies but negative NAAT may indicate past infection that have cleared and have low risk of transmission.
Donors with positive HCV antibodies and NAAT indicates an acute infection and have a high risk of transmission.
Donors with negative antibodies and positive NAAT indicates acute infection in the window period and also have a high risk of transmission.
Use of DAA has allowed transplantation of organs from HCV positive donors to HCV naive recipients with good outcomes.
Post liver transplantation persistence of HCV infection is associated with variable ranges of liver injury from mild fibrosis to severe graft failure. Use DAA has reduced this incidence.
GLE/PIB has been used successfully in HCV naive recipients who receive liver transplants from HCV viremic donors.
In kidney transplant HCV seropositivity is associated with higher all cause mortality and graft loss.
The THINKER trial HCV naive recipients received a kidney froM HCV viremic GT1 donors. EBR/GZR was given for 12 weeks and all had detectable HCV RNA and all attained SVR12.
In the THINKER 2 trial all participants in THINKER trial attained HCV cure with excellent allograft renal function.
GLE/PIB once daily dose for 12 weeks has been well tolerated in kidney transplant recipients with chronic HCV GT1-6. However shorter course regimen (4 weeks) have been evaluated with promising results.
Further studies are also required to determine the long term outcome of utilising HCV viremic organs.
I appreciate your concern that HCV related complications can happen at any time so long term follow up is important. Please use headings and sub-headings to make easier to read your write-up. Please use bold or underline to highlight headings and sub-headings.
Introduction
o The demand for organs continues to rise resulting in considerable waitlist mortality
o Organs categorized as high risk are those associated with an increased risk for the transmission of blood-borne viruses, including HIV, hepatitis B virus, and HCV
o The high success rate of DAA for HCV have led to greater utilization of HCV‐positive livers, increasing from 7% to 17% between 2010 and 2015
o Aim of the study: reviews the data on HCV treatment prior to and after organ transplantation
Hepatitis C Virus Infection and Direct Acting Antiviral Therapy
Pangenotypic DAA treatment of chronic HCV infection leads to cure rates of greater than 98% [sustained virologic response 12 weeks after treatment (SVR12]
The availability of safe and highly effective therapy has led to the treatment of HCV infection prior to transplant or deferring therapy until after transplant
Patients with advanced liver disease are unlikely to improve with DAA therapy and those with Child-Pugh class C cirrhosis have lower SVR12 rates
DAA:
1. Nonstructural protein 5B inhibitor: sofosbuvir (SOF)
2. nonstructural protein 5A (NS5A) inhibitor: ledipasvir (LDV) , velpatasvir (VEL), pibrentasvir (PIB)
3. nonstructural protein 3/4A (NS3/4A) protease inhibitor: glecaprevir (GLE)
4. ribavirin
o LDV/SOF combination (90 mg/400 mg): once daily, is well tolerated and produces high SVR12 rates in HCV genotype 1, 4, 5, and 6 infection
o SOF/VEL combination: once daily, provides SVR12 rates of greater than 95% across all genotypes
o GLE/PIB combination: first approved in 2017 for the treatment of HCV infection without cirrhosis or with mild cirrhosis. Is well tolerated and results in SVR12 rates greater than 97% across all genotypes
Direct-Acting Antiviral Therapy and Liver Transplantation
o With the current use of DAA therapy, significant HCV-related progression of liver disease posttransplant is now uncommon
o Recipients who achieve SVR12 posttransplant have lower rates of liver fibrosis progression and lower mortality
o Persistence of HCV infection after liver transplant results in a variable clinical course ranging from mild fibrosis to severe graft damage:
1. Progressive centrilobular ballooning degeneration, bridging fibrosis, and cholestasis (20% to 40%)
2. Advanced fibrosis (45%)
3. graft cirrhosis can develop within 5 years
4. 5-10% will develop severe progressive cholestatic hepatitis leading to liver failure
o DDA in transplant recipients with compensated cirrhosis is safe and efficacious
Defining Hepatitis C Virus–Positive Donors
o Any stage of HCV infection
o Serologic tests detect antibodies within 2-6 months after exposure and NAT detects RNA 5-7 days after exposure
o HCV NAT has a sensitivity of 85-100% and a specificity of 99-100%
Interpretation of HCV Diagnostic Testing Results:
1. HCV Antibody+/HCV NAT+: Active HCV infection and transmission risk is high
2. HCV Antibody-/HCV NAT+: Acute HCV infection in antibody window period or false-positive NAT, transmission risk is high
3. HCV Antibody+/HCV NAT-: No active HCV infection, cleared or treated HCV infection, or false-positive antibody and transmission risk is low
4. HCV Antibody-/HCV NAT-: No HCV infection and no risk of transmission
High – + Acute HCV infection in antibody window period or false-positive NAT High + – No active HCV infection, cleared or treated HCV infection, or false-positive antibody Low – – No HCV infection None
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients
Early data have demonstrated favorable long-term graft outcomes in patients transplanted with HCV-seropositive donors
Liver Transplantation
o Two large retrospective studies evaluated HCV-viremic donors in nonviremic liver transplant recipients and demonstrated no differences in patient or graft survival when compared with nonviremic donors
Renal Transplantation
Prevalence of HCV among ESRD patients is 0.2-6%
Promising long-term outcomes of HCV-seropositive recipients transplanted with kidneys from HCV-positive donors
THINKER trial: transplant of kidneys from HCV GT1–viremic donors into HCV-negative recipients. HCV cure and excellent renal allograft function with eGFR not significantly different from those of matched recipients of HCV-negative kidneys at 6 months
The EXPANDER trial: examined the tolerability and feasibility of DAA prophylaxis before and after renal transplant in HCV-naive patients who received HCV-viremic kidneys (GT1-GT3). It concluded that SVR12 was achieved with no study-related adverse events
Thoracic Transplantation
o In heart transplant recipients, donor HCV seropositivity was reported to be an independent risk factor for increased mortality when matched with controls and for the development of accelerated allograft vasculopathy when compared with matched controls
o Only a few studies have evaluated the safety of using lungs from HCV-viremic donors for transplantation
Pancreas Transplantation
Data on utilizing HCV-viremic organs in pancreas transplantation are limited
Conclusion
o Transplantation of HCV-viremic organs into HCV-naive recipients followed by the use of DAA agents provides excellent patient and allograft survival
o In carefully selected patients, HCV-viremic grafts can be used and well tolerated
o Patients should be fully informed of the risks, including the potential of HCV treatment failure
Yes appreciate the need for proper counselling and informed consent in light of long-term data being unavailable.
Historically, organs from diseased donors with HCV infection used to be discarded as they are categorized by public health as high risk because of the rate of infectivity to the recipients. Unfortunately, with the growing incidence of HCV infection because of increased abuse of opioids, so also is the need for organs among those on the waiting list. Notably, the discovery of direct-acting antiviral changed this narrative as a cure for HCV infection is now achievable either before or after organ transplantation.
Hepatitis C virus infection and Direct-acting antiviral therapy
Defining Hepatitis C virus-positive donor
The hepatitis C-positive donor for a negative recipient
Liver transplantation
Renal transplant
Conclusion
The breakthrough obtained in the use of DAA for the treatment of potential recipients about to receive organs from a donor with a positive HCV infection has reduced the waiting list and made more organs available for transplantation. Nevertheless, proper counseling and informed consent must be obtained before the surgical procedure, and care must be taken in watching out for drug-drug interactions
Yes appreciate the need for proper counselling and informed consent in light of long-term data being unavailable.
This review article addresses the recent statistics of HCV treatment before and after organ transplantation
Introduction
HCV infections account for 130-150million worldwide and it’s one of the leading causes of end-stage liver disease and liver transplantation with the increased shortage of donors, earlier organs from HCV infection donors are discarded due to the risk of infection and complications however with the improvement in the treatment of HCV infection by the DAA therapy with high cure rate nowadays we can use organs from DD with active HCV infection and its one way to expand the donor pool, especially with an increased rate of HCV infection among the opioids addictions and the number of overdose-death donors increased from 1.1% to
13.7% between 2000 and 2017. They usually are young healthier DD with less comorbid compared to old donors. The HCV-viremic donor organs are often
of relatively high quality. These liver allografts have been associated with lower rates of biliary complications and improved rejection rates, graft survival, and overall
survival.
Hepatitis C Virus Infection and Direct Acting Antiviral Therapy
The new pan-genotypic Direct antiviral therapy (DAA) with different combinations confirms its efficacy and safety profile and provides a high cure rate of> 98% usually 12 weeks course can be given pre or post-transplantation, DAA therapy has been revealed to recover liver function in patients with decompensated cirrhosis, to the level that delays the need for liver transplantation also pretransplant DAA therapy reduces
the risk of reinfection of the allograft. However, not all patients with end-stage liver disease from HCV infection will benefit from treatment prior to liver transplantation, only those with low baseline Model for End-Stage Liver Disease score (<16), low baseline Child-Pugh score, and the absence of portal hypertension complications. while those with advanced liver cirrhosis are unlikely to improve with DAA
therapy including those with Child-Pugh class C cirrhosis as they have lower SVR12 rates and preferred not to offer DAA therapy. However, the recent trend to accept HCV viremic donors is one way to expand access to transplantation with attention to providing HCV therapy at the ideal time
Direct-Acting Antiviral Therapy and Liver Transplantation
Persistent HCV infection after transplantation can lead to different clinical sequences from mild liver fibrosis to progressive graft failure due to bridging fibrosis, and cholestasis is seen
in 20% to 40% of posttransplant patients Advanced fibrosis can occur in up to 45% of posttransplant patients, and graft
cirrhosis can develop within 5 years post-transplant After liver transplantation, also there is a risk of developing severe progressive cholestatic hepatitis leading to liver failure in about 5-10%
all the above complications are now considered rare after the use of DAA therapy and patients have an excellent outcomes and lower mortality compared to those who did not receive or failed the treatment
most of the recent evidence from multiple studies addressed the efficacy and safety profile of the pan-genotypic DAA with 12-24 weeks SVR and a cure rate of 96-100% of HCV infection after transplantation ( liver, kidney or dual kidney and liver transplantation with lower risk of rejection or graft failure, such data encourage the use of HCV infected donors to HCV negative recipients.
Defining Hepatitis C Virus–Positive Donors
HCV NAT has a sensitivity of 85% to 100% and a specificity of 99% to 100%
It is important to distinguish between a seropositive and viremic donor when discussing organ transplants from an HCV-positive donor.
HCV viremia when we have both HCV AB +ve by serology test and HCV NAT positive with a high risk of infection
While HCV AB is positive and negative by NAT this indicates a noninfective (nonviremic) donor due to spontaneous clearance of the infection or after successful treatment, of HCV or a false-positive antibody result
An HCV-negative donor that is NAT-positive (viremic) is considered to have an acute infection and poses a high risk for disease transmission
Conclusion
Transplantation of HCV-viremic organs into HCV-naive recipients followed The use of DAA agents provides excellent patient and allograft survival. In carefully selected patients, the
use of HCV-viremic grafts appears to be efficacious and well tolerated with SVR 12 Weeks based on most of the trials with promising short-term outcomes including better survival and less mortality, and a very well-tolerated safety profile of the new DAA therapy. we need more studies in the future to address the long-term outcome of HCV viremic organ utilization
Yes, I agree that adequate follow-up is necessary to address the long-term outcome of HCV viremic organ utilization
Introduction:
Antiviral & HCV infection:
DAA & liver transplantation:
Defining HCV+ donors:
HCV+ donors to HCV- recipient:
Liver transplantation:
Kidney transplantation:
Thoracic transplantation:
Pancreatic transplantation:
Yes, I agree HCV and pancreas transplant data is limited.
Summarize this article II
Introduction
· Hepatitis C virus infection had resulted in 130 to 150 million infections across the globe. It is a leading cause of liver cirrhosis and hence the need for liver transplantation. In past the HCV infected organs were rejected due fear of transmitting the virus but now days these organs are widely use due shortages of donors and the development of direct -acting antiviral therapy (DAA).
Hepatitis C virus Infection and Direct -Acting Antiviral therapy (DAA)
· DAA therapy cure rates or sustained virological response 12 weeks (SVR12) after treatment of chronic HCV is > 98%. These drugs also improve liver functions in decompensated liver disease and liver transplant was not required for some patients because of improvment.
· DAA includes several drug combinations drugs such as: sofosbuvir (SOF)/ Ledipasvir (LDV), SOF/velpatasvir (VEL), and glecaprevir (GLE)/pibrentasvir (PIB)
Direct-Acting Antiviral therapy and liver transplantation
· After introduction DAA therapy, burden of HCV related liver disease post transplantation is no longer a big problem
· These drugs are well tolerated, safe, and efficacious
· The eradication of HCV opened an avenue for the use of HCV-positive organ, first in HCV positive recipients and at the moment in HCV negative recipients
Defining HCV positive donors
1. HCV positive by serology and negative Nucleic Acid Testing (NAT): This may be spontaneous clearance of the virus, previous HCV treatment or false-positive test
2. HCV positive by serology and positive NAT: this is viremic donor with active infection and high risk of transmission
3. HCV negative by serology and positive NAT: this is active infection, high risk donor or false- positive
HCV-positive Donor Transplantation in HCV-negative Recipients
Liver transplantation
· Data from the Organ Procurement and Transplantation network (OPTN) from 2016 to 2020, comparable 2 years graft survival rates were seen in 568 liver transplant recipients with and without HCV infection (n= 753, n = 87 respectively) who received viremic organs (90 versus 86% respectively)
· Almost all recipients developed viremia
· The protocol for DAA therapy varies between studies and they were given preemptively, immediately or within 3 months of transplantation
Renal transplantation
· In a study of 545 kidney transplants done in HCV-positive recipients, 5-and 10-years survival patient survival were 85 to 73% for HCV-positive recipients compared to 87 to 76.5% for HCV-negative recipients. Similar findings were demonstrated in many other studies for the same topic (THINKER, and THINKER2 trial)
· DAA therapy is tolerated as prophylaxis before and after transplantation, with no study-related adverse events (EXPANDER trial)
Thoracic Transplantation
1.Heart
· At the early phase the program was challenged by HCV induced coronary vasculopathy and severe rapidly progressive live disease and it was nearly abandoned. How ever, the first study utilizing HCV-viremic heart to 11 HCV naïve recipients showed that 9 of the recipients became positive after transplantation and 8 of whom were treated successfully by LDV/SOF or SOF/VEL (G3). One patient died due pulmonary embolism but DAA therapy was well tolerated in all treated recipients. Later studies confirmed demonstrated the same.
2.Lung
· In a study of 22 HCV-negative recipients of HCV-viremic lung, 6 months survival of HCV-viremic and non-viremic lung was 95 versus 94% respectively. HCV positive group had more chest complications and infections compared to non-viremic group 23 versus 18%. Two patients developed HCV relapse after treatment and 10 patients were admitted to the hospital due to serious adverse events.
Pancreas Transplantation
· The preliminary data showed that, HCV-viremic pancreas transplant may be possible for a potential recipient but more studies are needed to understand the outcome of this procedure
Conclusion
· The emergence of DAA therapy led to more utilization of HCV infected donor organs with excellent short post-transplant outcomes. However, longitudinal studies are required to
conceptualized the long-term outcomes of this type of treatment.
Yes, I agree HCV and pancreas transplant data is limited.
Thanks prof
Hepatitis C Virus Treatment and Solid Organ Transplantation
Pangenotypic Direct-Acting Antiviral (DAA)
Treatment
Aim
When to start treatment
Duration of treatment
Hepatitis C virus-positive donor transplantation in hepatitis C-negative recipient (clinical trial)
Liver transplantation
1.OPTN
2.10-HCV negative received HCV viremic donors
Kidney transplantation
1.THINKER trial (2017)
2.THINKER-2 trial
3.EXPANDER trial
4.MYTHIC trial
Thoracic transplantation
Pancreatic transplantation
I appreciate your advice in HCV infection and various types of transplantation and corresponding mode of treatment indicated.
HCV infection is highly prevalent worldwide causing liver damage, and it is leading indications for liver transplantation.
Utilizations of organs from hepatitis C infected individuals significantly increased to mitigate the global organ shortage. This change occurs after the availability of effective direct-acting antiviral (DAA) therapy
Hepatitis C Virus Infection and Direct-Acting Antiviral Therapy
– Pan-genotypic DAA therapies successfully used or the treatment of chronic HCV infection.
– It increase the cure rate with sustained virologic response after 12 weeks (SVR12) > 98%.
-Approved treatment: Nonstructural protein 5B inhibitor sofosbuvir (SOF) in combination with a nonstructural protein 5A (NS5A) inhibitor, nonstructural protein 3/4A (NS3/4A) protease inhibitor, and ribavirin.
-The combination of SOF and NS5A inhibitor ledipasvir (LDV) and produces high SVR12 rates in HCV genotype (GT) 1,4, 5, and 6 infection.
-The combination of SOF and NS5A inhibitor velpatasvir provides SVR12 rates of > 95% across all GTs and has a favorable safety profile.
-The combination of NS3/4A PI glecaprevir and NS5A inhibitor pibrentasvir results in SVR12 rates > 97% across all GTs.
DAA therapy reduces the risk of reinfection of the allograft. Also, it has been shown to improve liver function in patients with decompensated cirrhosis, however, those with advanced liver disease are unlikely to improve.
DAA Therapy and Liver Transplantation
-Persistence of HCV infection after liver transplant may results in progressive liver damage and fibrosis and eventually liver failure
– The use of DAA therapy following liver transplant has decreases HCV- related progression and demonstrated excellent outcomes if SVR achieved.
– Treatment of HCV infection in patients who undergo simultaneous liver-kidney transplant, or those who have compensated cirrhosis is both safe and efficacious.
Defining Hepatitis C Virus–Positive Donors
– Serologic antibodies testing: detected within 2 to 6 months after exposure.
– HCV NAT: detected 5 to 7 days post-exposure, more accurate assessment of transmission risk, sensitivity of 85% to 100% and a specificity of 99% to 100%.
-The risks of disease transmission varies if donor is seropositive or viremic.
–Nonviremic: HCV Ab positive but NAT negative, donors have not been documented to transmit HCV infection.
–Viremic: NAT positive with HCV either seropositive or negative, carries high risk of transmission.
-HCV transmission may occurs during the 1-week window period between viral exposure and positive NAT results.
HCV–Positive Donor Transplantation in HCV–Negative Recipients
–Previously was not considered with availability of DAA therapy the utilization of HCV-viremic donor organs has increased with favorable long-term graft outcomes.
Liver Transplantation
– Studies demonstrated no differences in patient or graft survival when compared with nonviremic donors
– SOF/VEL or GLE/PIB has been used successfully in HCV-naïve patients who receive HCV-viremic livers with high SVR
– Initiation of DAA therapy within 90 days of transplant, rather than preemptively or immediately following transplant, has also demonstrated favorable outcomes.
– A preemptive antiviral strategy using SOF/VEL is also successful in achieving SVR12.
– HCV-related acute MN resulting in ESRD despite achieving SVR12 was reported.
Renal Transplantation
-The prevalence of HCV among ESRD is 0.2% to 6%.
-Untreated HCV seropositivity is associated with higher all-cause mortality aRR:1.85 and higher all-cause graft loss aRR:1.76
– Studies have demonstrated promising long-term outcomes of HCV-seropositive recipients transplanted with kidneys from HCV-positive donors.
-The availability of DAA therapy minimizes the risk of transmission has led to the recent growth of transplant of kidneys from HCV-infected donors into HCV-naive recipients.
Major trials in HCV naïve KTR:
-THINKER trial: (n=10), [D+/R-], treated with EBR/GZR for 12 weeks. All recipients attained SVR12.
-THINKER-2 trial (n=20), expansion of trial 1, outcome: HCV cure and excellent renal allograft function with eGFRs not significantly different from those of matched recipients of HCV-negative kidneys.
-EXPANDER trial (n=10), EBR/GZR +/- SOF for 12 weeks, SVR12 achieved with no study-related adverse events.
–MYTHIC trial, (n=30) treated with GLE/PIB, All achieved SVR12, and no severe adverse events related to HCV infection. Although all recipients had good allograft function, adverse events included ACR and BKPyV.
Thoracic Transplantation
– earlier studies showed donor HCV seropositivity was reported to be an independent risk factor for increased mortality, virally mediated coronary vasculopathy and development of severe and rapidly progressive liver disease.
-Preemptive administration of GLE/PIB in HCV-viremic cardiac transplant into HCV-naïve recipients (n=20) has demonstrated SVR12 rate of 100%, and excellent early allograft function 100%
– Shorter duration of DAA treatment with GLE/PIB for 8 weeks following cardiac transplant, all achieved SVR12.
Conclusion
-Transplantation of HCV-viremic organs into HCV-naive recipients followed by the use of DAA agents provides excellent patient and allograft survival.
– The use of AAD appears to be efficacious and well tolerated.
-Utilization of HCV infected organs is an acceptable option to close waitlist gaps and decrease morbidity and mortality.
– Understanding long-term outcomes of HCV-viremic organ utilization needs further studies.
I appreciate your advice in relation to the natural history of HCV infection and transplantation and corresponding mode of treatment indicated.
1- HCV infection is indication of liver transplantation.
2- There is increase numbers of opioid addict and death related to it hence increase number of HCV.
3- Treatment of HCV by directly acting antiviral therapy DAA makes an organ donation from HCV donors acceptable than before.
4- It is important to widen or enlarge the donor pool for transplantation to accept the donor who were not acceptable before, and addition of DAA is the key for that point.
5- Hepatitis C Virus Infection and DirectActing Antiviral Therapy:
a- Sustained virologic response by DAA 12 weeks after treatment (SVR12) of greater than 98% is the cure rate.
b- Nonstructural protein 5B inhibitor sofosbuvir (SOF; Sovaldi, Gilead) has been approved for HCV treatment in combination with a nonstructural protein 5A (NS5A) inhibitor, nonstructural protein 3/4A (NS3/4A) protease inhibitor, and ribavirin.
c- The combination of potent NS5A inhibitor ledipasvir (LDV) and SOF (LDV/SOF, 90 mg/400 mg; Harvoni, Gilead), administered once daily, is well tolerated and produces high SVR12 rates in HCV genotype (GT) 1, 4, 5, and 6 infection.
d- The combination of SOF and NS5A inhibitor velpatasvir (SOF/VEL; Epclusa, Gilead), administered once daily, provides SVR12 rates of greater than 95% across all GTs and has a favorable safety profile.
e- The combination of NS3/4A protease inhibitor glecaprevir and NS5A inhibitor pibrentasvir (GLE/PIB; Mavyret, AbbVie) was first approved in 2017 for the treatment of HCV infection without cirrhosis or with mild cirrhosis. GLE/PIB is well tolerated and results in SVR12 rates greater than 97% across all GTs.
f- DAA can change decision and treat HCV and not require liver transplant, and in some cases treatment prior to liver transplant can decrease post transplant morbidity and complications, but in some cases of advanced liver disease has no benefit over transplant and prior to it.
6- Direct-Acting Antiviral Therapy and Liver Transplantation:
a- Presence or persistence of HCV viremia after liver transplant can leads to variable clinical picture with multiple comorbidities and may ends by graft failure, but after introduction of DAA , this story became uncommon.
b- Introduction of DAA post liver transplant decreased morbidity and mortality compared to patient who did not receive DAA.
c- Safe and effective introduction of DAA in the patient with simultaneous liver-kidney transplant.
7- Defining Hepatitis C Virus–Positive Donors:
a- Donors identified as HCV positive by serologic testing but NAT negative (nonviremic) are considered to have undergone spontaneous clearance or successful treatment of infection, or have a false-positive antibody result, and these donors have not been documented to transmit HCV infection.
b- An HCV-seropositive donor that is NAT positive (viremic) is considered to have an active infection and poses a high risk for disease transmission.
c- An HCV-negative donor that is NAT positive (viremic) is considered to have an acute infection and poses a high risk for disease transmission.
d- Despite improvements in testing, risk of HCV transmission remains during the 1-week eclipse period between viral exposure and positive NAT results, particularly in persons who inject drugs.
e- Antibodies can be detected by serology within 2-6 months after exposure but NAT becomes positive in 5-7 days from exposure.
8- Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients:
a- HCV seropositive donors were not accepted as a donor because of high risk of viral transmission and complications related to interferon post transplant and increased morbidity and mortality but now after perioperative introduction of DAA , it was easy to accept HCV donors with favorable outcome post transplant.
b- There was favorable outcome which is also similar between HCV viremic and non viremic donors
c- Initiation of DAA can be preemptive or immediately post transplant or even within 90 days post transplant , all have similar outcomes.
d- In spite of SVR12 and clearance of viremia, but HCV related complications can happen at any time so long term follow up is important.
I appreciate your concern that HCV related complications can happen at any time so long term follow up is important.
Hepatitis C Virus Treatment and Solid Organ Transplantation
Introduction:
HCV infection affects 130-150 million people worldwide, leading to a global shortage of liver transplantation. HCV transmission has increased with the opioid epidemic but DAA therapy has led to greater utilization of HCV-positive livers.
Hepatitis C Virus Infection and Direct Acting Antiviral Therapy
DAA therapies ( pangenotypic ) have been introduced to treat chronic HCV infection, with cure rates of greater than 98%. Nonstructural protein 5B inhibitor sofosbuvir (SOF) has been approved for HCV treatment in combination with a NS5A inhibitor, nonstructural protein 3/4A (NS3/4A) protease inhibitor, and ribavirin. GLE/PIB is well tolerated and results in SVR12 rates greater than 97%. Pretransplant DAA therapy reduces the risk of reinfection of the allograft, but not all patients with end-stage liver disease from HCV infection benefit from it.
Direct-Acting Antiviral Therapy and Liver Transplantation (DAA)
DAA is an effective treatment for HCV infection after liver transplantation, which can lead to a variable clinical course ranging from mild fibrosis to severe graft damage; this is uncommon now with the increasing use of DAA therapy . Recipients who achieve SVR12 posttransplant have lower rates of liver fibrosis progression (20.5% vs 65.5%; P<.001) and lower mortality (chi2=6.9; P<.01) rates compared with those who do not receive or fail treatment.
Treatment of HCV with DAA therapy in transplant recipients who have compensated cirrhosis or underwent simultaneous liver-kidney is safe and efficacious with 96.6% and 90.9% SVR12 rates.
SVR12 was achieved in 96% to 98% of transplant recipients without cirrhosis or compensated cirrhosis, but 13 patients discontinued prematurely due to adverse events and 10 died, mainly from complications related to hepatic decompensation.
Defining Hepatitis C Virus–Positive Donors:
HCV-positive donors are considered to have an active infection and pose a high risk for disease transmission, particularly in persons who inject drugs.
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients:
DAA therapy has improved outcomes and increased utilization of HCV-infected organs in transplant recipients, leading to favourable long-term graft outcomes.
Liver Transplantation:
There is no difference in graft and patient survival between HCV-viremic donors in non viremic liver transplant recipients in two large retrospective studies . VEL-based, LDV/SOF-based, or SOF/DAC-based therapy has been successful in HCV-viremic livers, with no treatment-related or HCV-attributable adverse events and no GLE/PIB drug reactions or interactions.
Renal Transplantation:
HCV infection is a common complication after renal transplant with the prevalence of 0.2% to 6% in end stage renal disease .
HCV-seropositive renal recipients, if untreated, will end with significant mortality and morbidity compared with their HCV-negative counterparts.
However, the long-term outcomes of kidney transplants from HCV-infected donors is promising in many studies .
Thoracic Transplantation:
HCV infection is high among heart transplant recipients, with reduced survival and increased risk of accelerated allograft vasculopathy. Preemptive administration of GLE/PIB in HCV-viremic cardiac transplant into HCV-naive recipients has demonstrated rapid HCV suppression, prevention of chronic HCV infection, and excellent early allograft function.
Pancreas Transplantation:
HCV-viremic pancreas transplant may be safely used for potential pancreas recipients, but further study is needed to determine morbidity and mortality. Short-term outcomes for solid organ transplantation are comparable for HCV-virmic and nonviremic donors, but promising data are most robust in kidney followed by liver transplant.
Conclusion:
Organ transplantation in the US is negatively impacted by long waitlist times and high mortality due to organ shortages, but transplantation of HCV-viremic organs into HCV-naive recipients provides excellent patient and allograft survival and has the potential to close waitlist gaps and decrease morbidity and mortality.
I like your well-structured detailed summary.
HCV-positive organs continue to increase, representing 9.7% of deceased-donor livers in 2019 ,those organs were discarded before duet to risk of HCV infection transmission , high morbidity and mortality transmission risk.
Due to the global shortage of organs available for transplantation ,HCV positive organs became included but categorised as high risk organs.
The introduction of DAAT with high cure rate and acceptable side effects enabled more usage of HCV positive livers for transplantion, thereby decreasing waiting lists mortality
Hepatitis C Virus Infection and Direct Acting Antiviral Therapy DAAT
DAAT for HCV infection have a SVR after 12 weeks post transplantion more than 98%.
The combination of NS5A inhibitor ledipasvir (LDV) and sofosbuvir SOF(LDV/SOF, 90 mg/400 mg; Harvoni, Gilead), once daily dose achieves high SVR12 rates in HCV genotype 1, 4, 5, and 6 infection.
The combination of SOF and NS5A inhibitor velpatasvir (SOF/VEL;Epclusa, Gilead) once daily dose leads to SVR12 95% across all genotypes.
The combination of NS3/4A protease inhibitor glecaprevir and NS5A inhibitor pibrentasvir (GLE/PIB; Mavyret, AbbVie) for treatment of HCV infection without cirrhosis or with mild cirrhosis, achieving SVR12 rates > 97% across all genotypes.
DAAT improved liver function in decompensated cirrhosis, also DAAT before transplantation decreased the risk of reinfection of the allograft but therapy before transplantation is not always beneficial .
Model for End-Stage Liver Disease score (MELD)<16, low baseline Child-Pugh score, and the absence of portal hypertension complications indicate improvement of liver functions response to pretransplant therapy.
On the other hand ,cases with advanced liver disease and those with Child-Pugh class C cirrhosis are less likely to attain good response with DAA therapy .
DAAT and liver transplantation
HCV infection persistence after liver transplant results in variable outcomes ranging from mild fibrosis to severe graft damage.
DAAT use decreased HCV-related progression of liver disease posttransplant improving the outcomes.
Cases who achieve SVR 12 weeks have lower rates of liver fibrosis progression and lower mortality.
HCV infection treatment in patients having simultaneous liver-kidney transplant is both safe and effective.
HCV-TARGET trial assessed liver transplant and dual liver-kid[1]ney transplant recipients with HCV infection treated with LDV/SOF, ombitasvir/paritaprevir/ritonavir plus dasabuvir (Viekira Pak, AbbVie), or SOF plus daclatasvir (SOF/DAC; Darvoni, Beacon). SVR12 rates among liver transplant and dual liver-kidney transplant recipients were 96.6% and 90.9%, respectively.Liver transplant cases experienced 4 attacks of acute rejection.
This study enabled treatment of liver transplant cases with ribavirin free regimen .
Pangenotypic, ribavirin-free regimen use in posttransplant patients without cirrhosis showed favourable outcomes
MAGELLAN-2 study demonstrated the efficacy of GLE/PIB once daily for 12 weeks in patients with treatment-naive HCVgenotype GT1 to GT6 infection or treatment-experienced HCV GT1, GT2, or GT4 to GT6 who had received a liver or kidney transplant ,DAAT after transplant is safe and effective.
Treatment with SOF/VEL for 12 weeks in liver transplant recipients with HCV GT1 to GT4 infection and cirrhosis lead to SVR12 rate of 93%.
SOLAR-1 and SOLAR-2 trials demonstrated that LDV/SOF plus ribavirin regimen in liver transplant recipients with HCV GT1 to GT4 infection and liver disease achieved acceptable SVR and better outcomes.
DAAT enabled the use of HCV-positive organs in HCV-viremic recipients and currently in HCV-negative recipients.
HCV positive donor definition
HCV NAT has a sensitivity of 85% – 100% and a specificity of 99% – 100% ,NAT is an accurate test because differentiating seropositive from viremic HCV positive donors is mandatory.
HCV positive donors detected by serologic testing but have negative NAT indicates either spontaneous clearance or successful therapy or
have a false-positive antibody result, and they donot transmit HCV infection.
HCV-seropositive donors having positive NAT have active infection and harbours a high risk for disease transmission while HCV-negative donor with positive NAT have acute infection and highly transmissibility of infection.
HCV positive donor transplant to HCV negative recipient
Before DAAT introduction such transplant was not performed .
DAA therapy introduction increased the usage of HCV viremic donor organs.
Multiple studies demonstrated favourable long-term prognosis in patients transplanted with HCV-seropositive donors.
Liver Transplantation
2studies assessed HCV-viremic donors in nonviremic liver transplant recipients and showed no variation in patient or graft survival compared to nonviremic donors.
A study showed that HCV treatment within 3 months of transplantation increases the possibility of acceptable graft function and decreases waitlist mortality.
Immediate treatment with GLE/PIB for HCV-viremic liver transplant into seronegative recipients is safe and effective.
A later study revealed that initiation of DAA therapy within 90 days of transplant, instead of preemptively or immediately after transplantation, has favourable outcomes.
Another study demonstrated that in early HCV infection, SOF/VEL use once daily for 12 weeks when viremia was confirmed lead to SVR12 but extensive side effects occurred as biliary sclerosis, cardiomyopathy, and graft-vs-host disease, that can lead to multiorgan failure and death.
A prospective multicenter study assessed outcomes in HCV-naive liver transplant and dual liver-kidney transplant showed that inspite of achieving SVR12 ,HCV-related acute membranous nephropathy can happen leading to ESRD.
Renal transplantation
Untreated HCV infection in HCV-seropositive renal recipients experience worse outcomes when compared to HCV seronegative cases.
HCV infected donors’ organs were not used.
Studies showed acceptable long-term outcomes of HCV-seropositive recipients transplanted with kidneys from HCV-positive donors.
DAAT enhanced transplant of kidneys from HCV-infected donors into HCV-naive recipients.
THINKER trial evaluated the efficacy and safety of transplanting of kidneys from HCV GT1–viremic donors into HCV-negative
recipients the treated with elbasvir/grazoprevir (EBR/GZR;
Zepatier)for 12 weeks,the recipients had SVR12 and graft function was comparable to matched HCV seronegative recipients at 6 and 12 months.
EXPANDER trial assessed the applicability of DAA prophylaxis (EBR/GZR only for GT 1 and added to it SOF for GT 2 ,GT3) before and after renal transplant in HCV-naive patients who received HCV-viremic kidneys (GT1-GT3) and SVR 12 was attained without significant side effects.
Studies concluded that SOF-based regimens are safe and efficient in HCV-naive recipients having HCV-viremic kidney transplant.
GLE/PIB once daily for 12 weeks was endured by renal transplant recipients with chronic HCV GT1 to GT6 infection .
Shorter DAA regimens courses expressed favourable outcomes .
Thoracic Transplantation
Previous studies demonstrated increased mortality in recipients with HCV infection either acquired pre or post heart transplant.
HCV infected cases where not considered for cardiac transplant in INF era due to viral coronary vasculopathy and progressive hepatic disease occurrence
Multiple studies concluded no difference between the overall outcomes for cardiac transplant recipients receiving hearts from HCV positive donors and were treated with DAA from on side and the other side for recipients receiving hearts from HCV negative donors.
Shorter courses of DAA treatment with GLE/PIB for 8 weeks after heart transplant was assessed in HCV-naive recipients who received HCV-viremic organs, the recipients had detectable viremia, and SVR12.
Not many studies assessed transplanting lungs from HCV infected donors .A study evaluated that using 12 weeks of SOF/VEL, 6-month HCV-free survival was 86% and 6month survival post transplant of HCV-viremic and -nonviremic donors was 95% vs 94%, respectively meanwhile side effects occurred including respiratory complications, infections and HCV relapse in need of therapy.
DONATE-HCV study demonstrated comparable results for recipients whom received hearts and lungs from HCV positive donors and those whom received those organs from HCV negative donors
Pancreas Transplantation
There is limited studies on HCV-viremic organs in pancreas transplantation .
One study carried on in 2021 demonstrated preliminary acceptable outcomes for HCV-viremic pancreas transplant meanwhile further studies are needed.
Conclusion
HCV-viremic organs transplant into HCV-naive recipients followed
by adminstering DAAT agents resulted in favourable patient
and allograft survival.
On the other hand the long-term consequences of HCV viremic organ transplantion needs further evaluation
I appreciate your concern that ‘long-term consequences of HCV viremic organ transplantion needs further evaluation’
Summary
Introduction
This article is about Hepatitis C virus treatment in the setting of solid organ transplantation. This is especially important in terms of liver transplant. Untreated HCV infection in a liver transplant recipient can lead to graft failure.
Discussion
Liver transplant setting
Liver transplant recipients need to be checked for HCV infection and treated prior to transplant. In the case of persistence of infection post transplant it can lead to fibrosis of liver and ultimately graft failure. Other clinical characteristics include progressive centrilobular ballooning degeneration, bridging fibrosis, and cholestasis. Usage of DAA therapy post liver transplant can give good outcome with lower rate of liver fibrosis progression and lower mortality.
Patients undergoing simultaneous kidney liver transplant can be treated for HCV infection safely. Ribavirin free regimen can be used in posttransplant recipients without cirrhosis.
Donors who are seropositive for HCV, but NAT negative do not transmit infection and can be used for the recipient. HCV negative donor who is NAT positive is considered to have acute infection, and can transmit disease.
Kidney transplant setting
HCV infection is a common complication post kidney transplant. Outcome for HCV seropositive renal recipients is worse than seronegative recipients. HCV seropositivity is associated with all cause mortality.
HCV positive donors can be used safely for HCV seropositive recipients. Using DAA therapy can reduce the risk of chronic HCV infection in these patients.
SOF based regimen are safe and efficacious in HCV naive recipients undergoing HCV viremic kidney transplant.
GLE/PIB once daily for 12 weeks can be used for patients with chronic HCV infection who have undergone kidney transplant.
Short course DAA regimen can have good results in terms of prophylaxis. 4 weeks of GLE/PIB therapy can cause undetectable HCV RNA and stable allograft function.
Thoracic transplant setting
The incidence of HCV infection is high among heart transplant recipients, at 12%. Whether the patient acquired HCV before or after the transplant, these recipients have reduced rates of survival.
Donor HCV seropositivity can be an independent risk factor of HCV in recipients. DAA therapy is well tolerated in these patients, but short course does not have a significant impact in any way.
Pancreas transplant setting
There is limited data regarding HCV infection in pancreas transplant. HCV viremic pancreas can be used safely for recipients, however, further study is needed regarding the effects it has on morbidity and mortality of said recipients.
Conclusion
Due to high wait times and numerous people requiring transplantation, using HCV viremic organs may need to be done even into HCV naive recipients. However, use of DAA agents can give good graft and patient survival. This can decrease mortality and morbidity among the recipient population. Further understanding long term outcome and standardized regimen formulation is required in the near future to progress in this therapy.
This is a narrative review study on Hepatitis C virus infection in the context of solid organ transplantation.
Introduction
Hepatitis C affects 130 to 150 million people worldwide and was a limiting factor for donations because we do not have effective medications available, as well as their consequences (liver cirrhosis and hepatocellular carcinoma).
Direct-acting antiviral therapies have changed the prognosis and goals for proceeding with transplantation.
Infection and targeted therapy
New oral medications capable of maintaining sustained viral suppression above 95% (previous treatments were no more than 40%) and with only 12 weeks of therapy have modified HCV treatment. Sofosbuvir + Ledispavir are used for genotypes 1, 4, 5, and 6. Sofosbuvir and velpastavir can cover all genotypes. These treatments improve liver function even in patients with organ involvement and decrease the risk of graft reinfection.
Liver transplant
Persistence of viral load after liver transplantation leads to fibrosis and cholestasis with graft loss. The use of new therapies considerably reduces the risk of viral load persistence, showing excellent results.
Even in transplants associated with other organs, the outcome is favorable.
Several studies show the result of sustainably suppressed viral load and concomitant improvement in liver function, even in ribavirin-free regimens (ClCr < 30, withholding ribavirin is mandatory).
HCV positive donors
Serological tests show exposure to the virus, while the viral load suggests disease activity. When both are present, the disease may be cured, but there is a risk of reactivation depending on immunosuppression.
A positive viral load determines a high risk of transmission.
D+/R-
With the new therapies, it is possible to perform the transplant and proceed with the appropriate treatment, maintaining excellent survival results for the recipient and the graft.
Liver transplant
Two studies showed safety in transplanting D+R- with the new therapies and reducing the waiting time for an organ. Another study that started therapy within the first 90 days of transplantation showed excellent results.
Kidney transplant
It used to be a contraindication, but nowadays it is authorized. Care is taken to avoid ribavirin in patients with CrCl lower than 30. Few studies compare the use of new therapies and their impact with different treatment times (if the viral load is positive, 12 hours before or at time zero of the transplant), but always when the therapy has performed the result was better.
Sofosbuvir-based regimens are safe and have low drug interactions and do not require correction for renal function. Four-week prophylaxis has been evaluated, but further studies are needed.
Thoracic transplant
Not unlike the other transplants, the results with interferon were quite low and discouraging and with the intervention of the new treatments there was primary dysfunction but with numbers similar to the seronegative ones in terms of length of hospital stay, organ rejection, survival on day 30 and after one transplant year.
An eight-week prophylactic protocol, it was successful in controlling viral load and protecting the graft.
For lung transplantation, there is little data to generate statistical conclusions, but they must comply with the findings of other organs.
Conclusion
Transplantation of HCV-positive patients can be done safely and decrease waiting time in the transplant queue. New therapies are safe and well tolerated, including the possibility of shorter therapies for prophylaxis.
Low interaction with immunosuppressants and sustained viral response brings a promising horizon.
I like your clinical approach and well-structured detailed summary.
Thank you, Professor
II. Hepatitis C Virus Treatment and Solid Organ Transplantation
Please summarize this article.
DAA Therapy & Liver Transplantation
The HCV-TARGET trial:
The MAGELLAN-2 study (phase 3 open-label trial):
Other studies
SOLAR-1 (a large trial):
SOLAR-2 (a multicenter open-label study):
Defining Hepatitis C Virus–Positive Donors
HCV+ve Donor TX in HCV–ve Recipients
Liver Transplantation
Renal Transplantation
THINKER trial (2017):
THINKER-2 trial (n=20):
EXPANDER trial (n=10):
MYTHIC trial (30 HCV-naive patients received HCV-viremic kidneys across 7 transplant centers):
The DAPPER trial:
Thoracic Transplantation
Conclusions
I like your well-structured detailed summary.
Hepatitis C Virus Treatment and Solid Organ Transplantation
Introduction;
-Hepatitis C virus (HCV) infection affects approximately 130 million to 150 million people worldwide.
-The availability of HCV-positive organs continues to increase, representing 9.7% of deceased-donor livers in 2019.
-There have been significant advancements in the science of HCV therapy and in the use of HCV-positive organs, thereby substantially increasing the number of organ transplants and decreasing waitlist mortality.
Hepatitis C Virus Infection and Direct Acting Antiviral Therapy;
-Over the past several years, a succession of pangenotypic DAA therapies for the treatment of chronic HCV infection has been introduced, with cure rates defined as sustained virologic response 12 weeks after treatment (SVR12) of greater than 98%.
-The combination of potent NS5A inhibitor ledipasvir (LDV) and SOF (LDV/SOF, 90 mg/400 mg; administered once daily, is well tolerated and produces high SVR12 rates in HCV genotype (GT) 1, 4, 5, and 6 infection.
-The combination of SOF and NS5A inhibitor velpatasvir (SOF/VEL) administered once daily, provides SVR12 rates of greater than 95% across all GTs and has a favorable safety profile.
-The combination of NS3/4A protease inhibitor glecaprevir and NS5A inhibitor pibrentasvir (GLE/PIB) was first approved in 2017 for the treatment of HCV infection without cirrhosis or with mild cirrhosis, and results in SVR12 rates greater than 97% across all GTs.
-DAA therapy has been shown to improve liver function in patients with decompensated cirrhosis.
-Pre-transplant DAA therapy reduces the risk of reinfection of the allograft.
-Patients with advanced liver disease are unlikely to improve with DAA therapy and those with Child-Pugh class C cirrhosis have lower SVR12 rates; therefore, deferring treatment in such situations may be preferred.
Direct-Acting Antiviral Therapy and Liver Transplantation;
-Persistence of HCV infection after liver transplant results in a variable clinical course ranging from mild fibrosis to severe graft damage.
-Advanced fibrosis can occur in up to 45% of posttransplant patients, and graft cirrhosis can develop within as little as 5 years post-transplant.
-5-10% of post-transplant patients will develop severe progressive cholestatic hepatitis leading to liver failure.
-With the increasing use of DAA therapy, significant HCV-related progression of liver disease post-transplant is now uncommon.
-Use of DAA therapy following liver transplant has demonstrated excellent outcomes.
-Treatment of HCV infection in patients who undergo simultaneous liver-kidney transplant is both safe and efficacious.
-In transplant recipients who have compensated cirrhosis, DAA therapy following transplant is safe and efficacious.
Defining Hepatitis C Virus–Positive Donors;
-HCV-positive donors involved any stage of HCV infection. Serologic tests detect antibodies within 2 to 6 months after exposure, but nucleic acid testing (NAT) detects RNA 5 to 7 days after exposure and provides a more accurate assessment of transmission risk.
-Donors identified as HCV positive by serologic testing but NAT negative (nonviremic) are considered to have undergone spontaneous clearance or successful treatment of infection, or have a false-positive antibody result, and these donors have not been documented to transmit HCV infection.
-An HCV-seropositive donor that is NAT positive (viremic) is considered to have an active infection and poses a high risk for disease transmission.
-An HCV-negative donor that is NAT positive (viremic) is considered to have an acute infection and poses a high risk for disease transmission.
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients.
-Before the availability of DAA therapy, transplantation of organs from HCV-positive donors into uninfected recipients was not routinely considered owing to low efficacy, high rates of HCV transmission, decreased patient and graft survival, and complications associated with interferon-based therapy in the post-transplant setting.
Liver Transplantation;
-Two large retrospective studies evaluated HCV-viremic donors in nonviremic liver transplant recipients and demonstrated no differences in patient or graft survival when compared with nonviremic donors.
-GLE/PIB has been used successfully in HCV-naive patients who receive HCV-viremic livers.
-A later study demonstrated that initiation of DAA therapy within 90 days of transplant, rather than preemptively or immediately following transplant, has also demonstrated favorable outcomes.
-The administration of SOF/VEL or GLE/PIB once daily for 12 weeks in HCV-naive patients who received viremic livers produced similar 1-year patient and graft survival when compared with HCV-naive patients who received nonviremic livers.
Renal Transplantation
-The prevalence of HCV among end-stage renal disease patients is 0.2% to 6%, and HCV infection traditionally has been a common complication after renal transplant.
-Outcomes for untreated HCV infection in HCV-seropositive renal recipients are significantly worse than in their HCV-negative counterparts.
-THINKER trial was the first open-label, single-group pilot study that sought to determine the safety and efficacy of the transplant of kidneys from HCV GT1–viremic donors into HCV-negative recipients (donor positive, recipient negative [D+/R-]) followed by treatment with elbasvir/grazoprevir (EBR/GZR; Zepatier, Merck) for 12 weeks.
-EXPANDER trial was an open-label single center study that examined the tolerability and feasibility of DAA prophylaxis before and after renal transplant in HCV-naive patients who received HCV-viremic kidneys (GT1-GT3).
-SOF-based regimens are safe and effective in HCV-naive recipients undergoing HCV-viremic kidney transplant.
Thoracic Transplantation;
-Among heart transplant recipients, the reported prevalence of HCV infection is as high as 12%.
-Early studies demonstrated reduced survival in recipients with HCV infection, regardless of acquisition of HCV pre– or post– heart transplant.
-Preemptive administration of GLE/ PIB in HCV-viremic cardiac transplant into HCV-naive recipients has demonstrated rapid HCV suppression (median time to clearance, 3-5 days , prevention of chronic HCV infection (SVR12 rate of 100%), and excellent early allograft function (100% at a median follow-up of 10.7 months)
Pancreas Transplantation;
-The data on utilizing HCV-viremic organs in pancreas transplantation are limited.
-In 2021, the first reported series included 8 HCV-naive patients who received either deceased donor simultaneous pancreas-kidney transplant or pancreas transplant after living donor kidney transplant.
-All patients developed viremia and were treated with either GLE/PIB or SOF/VEL and all achieved SVR12, and had excellent pancreas graft function.
Conclusion;
-Transplantation of HCV-viremic organs into HCV-naive recipients followed by the use of DAA agents provides excellent patient and allograft survival.
-The use of HCV-viremic grafts in carefully selected patients appears to be efficacious and well tolerated, and this practice has demonstrated acceptable short-term outcomes and has the potential to significantly close waitlist gaps and decrease morbidity and mortality.
-However, securing DAA therapy post-transplant is essential and patients should be fully informed of the associated risks, including the potential of HCV treatment failure.
-The availability of highly effective pangnomic DAA has allowed the use of HCV infected donors ,however it should be considered as experimental therapy to be studied.
I appreciate your clinical approach.
Introduction:
Hepatitis C Virus Infection and Direct Acting Antiviral Therapy:
Defining Hepatitis C Virus–Positive Donors:
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus– Negative Recipients:
Trials of DAA in kidney transplant
THINKER(2017)
Cohort Size: 10
Antiviral Therapy : EBR/GZR
Therapy Duration : 12 weeks
SVR12: 10/10 (100%)
THINKER-2(2018)
Cohort Size: 20
Antiviral Therapy : EBR/GZR
Therapy Duration : 12 weeks
SVR12: 20/20 (100%)
EXPANDER (2018)
Cohort Size: 10
Antiviral Therapy : EBR/GZR ± sofosbuvir
Therapy Duration : 12 weeks
SVR12: 10/10 (100%)
Friebus-Kardash et al (2019)
Cohort Size: 7
Antiviral Therapy : LDV/SOF
Therapy Duration : 8-12 weeks
SVR12: 7/7 (100%)
Molnar et al (2019)
Cohort Size: 53
Antiviral Therapy : GLE/PIB, SOF/VEL, or LDV/SOF
Therapy Duration : 12 weeks
SVR12: 53/53 (100%)
Sise et al (2020)
Cohort Size: 8
Antiviral Therapy : EBR/GZR
Therapy Duration : 12 weeks
SVR12: 8/8 (100%)
Conclusion :
Thankyou for the clear description of the trials.
Introduction:
HCV infects 130–150 million individuals globally. HCV infection is a primary cause of end-stage liver disease and liver transplantation. 2. Waitlist mortality is high because organ demand exceeds availability. 3,4 In 2019, 9.7% of deceased-donor livers were HCV-positive.
Due to increased reperfusion risk and posttransplant morbidity and death, organs from dead HCV-infected donors were rejected.
5-7 To address the worldwide scarcity, donation after cardiac death, live donors, and high-risk donors have been used. The public health agency classifies organs as high risk for HIV, hepatitis B, and HCV transmission.
Antiviral Treatment:
During the last several years, a number of pan-genotypic DAA treatments for chronic HCV infection have been launched, with SVR12 rates of over 98%.
HCV therapy with the nonstructural protein 5B inhibitor sofosbuvir (SOF; Sovaldi, Gilead) and NS5A, NS3/4A, and ribavirin is authorized.
In HCV genotype (GT) 1, 4, 5, and 6 infections, the once-daily combination of powerful NS5A inhibitor ledipasvir (LDV) and SOF (LDV/SOF, 90 mg/400 mg; Harvoni, Gilead) is well tolerated and yields significant SVR12 rates.
SOF and NS5A inhibitor velpatasvir (SOF/VEL) given once daily had SVR12 rates of over 95% across all GTs and a good safety profile. GLE/PIB was originally licensed in 2017 to treat HCV infection without cirrhosis or moderate cirrhosis. 21 GLE/PIB is well-tolerated and has SVR12 rates of 97% across all GTs.
Liver transplantation and direct-acting Antivirals:
HCV persistence after liver transplant causes moderate fibrosis to severe graft destruction. In 20% to 40% of posttransplant HCV-positive individuals, centrilobular ballooning degeneration, bridging fibrosis, and cholestasis progress.
45% of posttransplant patients have advanced fibrosis, and graft cirrhosis may develop within 5 years.
32,33,5%–10% of posttransplant individuals suffer severe progressive cholestatic hepatitis and liver failure. DAA treatment has made HCV-related liver disease progression post-transplant rare.
HCV-Positive Donors:
HCV-positive donors include all stages of infection. Serologic techniques like chemiluminescence assays and enzyme immunoassays identify antibodies 2–6 months after exposure, whereas nucleic acid testing (NAT) identifies RNA 5–7 days after exposure and gives a more accurate estimate of the transmission risk. HCV NAT has 85%–100% sensitivity and 99%–100% specificity.
When contemplating organ donation from an HCV-positive donor, the risks of disease transmission vary greatly between seropositive and viremic donors. Donors who are HCV positive by serologic testing but NAT negative (nonviremic) are thought to have had spontaneous clearance, effective treatment, or a false-positive antibody result and cannot transmit HCV.
Hepatitis C Virus–Positive Donor Transplantation in Hepatitis C Virus–Negative Recipients
Before DAA treatment, organ transplantation from HCV-positive donors to uninfected recipients was seldom contemplated due to its limited effectiveness, high HCV transmission rates, lower patient and graft survival rates, and posttransplant problems from interferon-based therapy.
HCV-infected organs were seldom transplanted due to a lack of efficient and well-tolerated therapies. Nonetheless, rapidly improving HCV therapies have improved outcomes, and perioperative DAA medication has boosted HCV-viremic donor organ usage.
Liver Transplantation:
Two large retrospective investigations found no differences in patient or graft survival between HCV-viremic and nonviremic liver transplant donors. The Organ Procurement and Transplantation Network (OPTN) found that 30 HCV-naive patients who received HCV-viremic livers had equal 1-year patient survival rates.
In a subsequent analysis utilizing 2016–2020 OPTN data, 568 liver transplant patients with and without HCV infection who received HCV-viremic organs had similar 2-year graft survival rates. Successes of HCV-Viremic Liver Transplantation in Nonviremic Patients, Organ Type
Renal Transplantation:
Few prospective studies have examined DAA treatment in HCV-infected renal transplant patients. The THINKER experiment was the first open-label, single-group pilot research to assess the safety and effectiveness of transplanting kidneys from HCV GT1–viremic donors into HCV-negative recipients (D+/R-) and treating them for 12 weeks with elbasvir/grazoprevir (EBR/GZR; Zepatier, Merck).
The open-label, single-center EXPANDER trial (n=10) assessed the tolerance and feasibility of DAA prevention before and after renal transplant in HCV-naive patients who received HCV-viremic kidneys (GT1-GT3).
12 weeks after transplant, GT2 or GT3-infected organ recipients got SOF and EBR/GZR for triple treatment. Preemptive EBR/GZR for 12 weeks in HCV-naive patients who received HCV-infected kidneys (n=8) resulted in SVR12 with no study-related side effects.
Thoracic Transplant:
HCV infection pre- or post-heart transplant lowered survival in early trials. In the period of interferon-based HCV treatment regimens, worries regarding virally induced coronary vasculopathy and severe and fast-increasing liver disease almost halted heart transplantation. Donor HCV seropositivity was an independent risk factor for increased mortality when matched with controls and accelerated allograft vasculopathy.
Conclusion:
Organ shortages cause lengthy waitlists and significant backlog mortality in the US. DAA-treated HCV-viremic organ transplantation into HCV-naive recipients improves patient and allograft survival. HCV-viremic grafts are effective and well-tolerated in certain individuals. This method has good short-term results and can reduce waiting gaps, morbidity, and death.
After a transplant, it’s important to take DAA drugs, but patients should be aware of the risks, such as failing HCV treatment. Posttransplant HCV infection may cause immune system alterations or immunosuppressive treatment interactions. HCV-viremic organ utilization results are yet unknown.
Thankyou well done