crease the number of organs available for transplantation. An important strategy is the continuous review of organs that have been discarded, to assess whether advances in medicine could enable such organs to be transplanted. It is now apparent that greater use can be made of organs from hepatitis C (HCV) infected donors.
HCV is RNA virus member of the Flaviviridae family. Six genotypes (G1-6).
Acute infection tends to be subclinical, with chronic infection, defined as persistence of HCV RNA in serum for greater than six months in 60%.
The consensus was in favor of considering D+ to R – transplantation across all solid organs within set criteria, and recommended that such practice should take place within prospective research protocols. Why HCV D+ to R- transplantation should be cost effective:
Whilst there are clear morbidity and mortality benefits to increasing organ availability for patients on solid organ transplant waiting lists, there are also sound economic arguments. What are the risks of HCV D+ to R- transplantation?:
fibrosing cholestatic hepatitis.
resistance associated substitution
extra-hepatic manifestations of HCV such as cryoglobulinaemic vasculitis or potential increased rates of blood derived malignancy such as PTLD are also theoretical consequences of HCV infection in the post-transplantation phase. Patient Consent:
consent to receive a HCV D+ organ should be specifically obtained by individual transplanting centrer
Patient and Unit Requirements Pre-Transplant
the working party agreed that HCV D+/R- non-liver transplantation should be avoided in recipients with advanced fibrosis or cirrhosis.
Rather than mandate that every patient being consented to receive an HCV D+ non-liver organ be seen by a liver specialist, a more pragmatic approach of screening patients using AST-to-Platelet Ratio Index (APRI) and ultrasound is suggested. . If the APRI score is >0.8 or the ultrasound suggests significant or advanced liver disease, then an opinion from a hepatologist.
Allocation of HCV D+ Organs on the Waiting List;
Further study for posttransplant outcome is needed before allocation with different transplant groups is arranged. Management of the Recipient of a HCV D+ donors. testing for hepatitis C RNA of the recipient following receipt of either a HCV antibody positive graft, an HCV RNA positive graft or a graft from an increased infectious risk donor, to ensure appropriate and early intervention if HCV transmission and infection occur.
used as first line agents.
These are either the combination of Glecaprevir/Pibrenatasvir or the combination of Sofosbuvir/Velpatasvir.
for 12 weeks in the context of HCV D+/R- transplants.
Both are pan-genotypic, both have very acceptable drug to drug interaction profiles although exposure to the former is increased by ciclosporin, and it may also increase the levels of tacrolimus (CYP3A and P-glycoprotein inhibition); the latter is not recommended in patient with an eGFR less than 30ml.
If not curative evSofosbuvir/Velpatasvir/Voxaleprevir is used for 12weeks.
Donors with failed therapy or therapy of last 6mpnths should not be used, also if engaged in dangerous behavior increased risk of infection or history of multiple HCV infection
Introduction; The newer oral has changed HCV management with cure rate of 50 to 80%. They effective in pan-genomic types. The current UK rates of HCV positive donor’s organ. Currently UK is restricting the use of HCV positive donors to HCV+ recipient. But the revised literature shows that there is no absolute contraindication for donation. Outside UK; The data shows that after considering this the waiting time has decreased to 58 days, and the only issues were delayed draft function, proteinuria with FSGS. What are the risks of HCV D+/ R- transplantation. The potential risk included fibrosing cholestatic hepatitis. But in the setting of DAAs they very effective if FCH+HCV+, with cure rates of 100%. Ideally if started early with four weeks of FHC. BTS, NHSB and transplantation reviewing the entire way of sharing information and gaining consent from recipient including HCV D+/R-. Pre-transplant requirements; The working party has agreed that if a recipient has cirrhosis should not be considered for transplantation other then liver. They made important check list. Should be waited for six month post DAAs treatment, If did not achieved SVR12. Resistant disease.
Kidney transplantation is the modality of choice for chronic kidney disease. However. shortage of donors is an essential hindrance for this program. HCV infected donors represent a potential pool for donation. Particularly after the introduction of direct antiviral agents DAA therapy which achieve a recovery rate of 95%. The serological markers:
Anti HCV antibodies reflects HCV infection which is representing past exposure or infection with recovery of hepatitis or conversion to chronic carrier or chronic hepatitis status. Diagnosis of HCV: HCV infection depend on isolating HCV RNA by PCR. However, performing HCV antibodies positive / RNA negative solid organ transplant SOT to HCV negative recipient was associated with transmitting the infection in significant no. of patients, a finding that might be explained by reinfection of donor in window period or related to the existence of dormant traces of Viral RNA ijn the transplanted tissues.
the major complication of post transplant is fibrosing cholestatic hepatitis in 10% of the patients underwent liver transplantation from D+/R+. However complete recovery of the disease was reported after treatment with DAA. DAA:
Combination of sofosbuvir and ledipasvir for 12-24 weeks is associated with 100% recovery.
The other issue of using DAA after transplantation is the resistance of HCV to commonly used protocol. In this case especially those with HCV NS5A positive protein. in this case triple DAA is indicative Sofosbuvir, velpatasvir and voxilaprivir with great success in reversing those resistant cases.
prophylactic DAA is indicated for HCV D+/R- transplantation which is resulting in transient curable post transplant infection.
the current status is HCV D+/R+ donation with close follow up and treatment accordingly.
Up to 1 in 6 patients listed for solid organ transplantation will die or become too sick for a transplant. So, it needs to continuously explore improving the utilization of organs that are not currently widely used for transplantation. · Organs from donors infected with hepatitis C have been discarded because of the high likelihood of transmitting the infection to the recipient. Older treatment modalities had poor tolerance and were not sufficiently successful in curing transplant recipients of the infection. · Recent advances in the management of hepatitis C infection have changed the scenario as more than 95% of infected individuals can now be cured with directly acting antiviral agents. · Studies have shown that similar outcomes of hepatitis C clearance can be safely achieved in transplant recipients and small trials have shown excellent outcomes in Hepatitis C negative recipients given hepatitis C infected organs who were subsequently treated and cured of the virus. · A recent analysis of the UK Potential Donor Audit has suggested that up to 15 suitable donors are declined every year because of the risk of transmission of hepatitis C. · Using organs from such donors could result in up to 75 extra solid organ transplants being performed every year in the UK. · Following the recent recommendations by the Advisory Committee on the Safety of Blood, Tissues and Organs that, in some clinical situations, organs from hepatitis C infected donors may be transplanted into uninfected recipients. · Selection of appropriate donors, a policy for ensuring the intended recipient gives fully informed consent, guidance for the testing and treatment of recipients as indicated, the formation of a monitoring group to oversee the program in the 6 early phases of implementation as well as consideration of some of the headline operational issues that will arise during successful implementation of the pathway.
UK Position Statement on the use of Organs from Hepatitis C Viraemic Donors and Increased Infectious Risk Donors in Hepatitis C Negative Recipient Introduction:
16.7% of pts listed for SOT in UK die or get sick pre transplant and thus organs not regularly used for transplantation need to be use d ASAP to decrease waiting time and improve quality of life.
· It is now apparent that greater use can be made of organs from hepatitis C (HCV) infected donors, to HCV+ recipients. · With DAA therapy that can cure >95% HCV regardless of genotype, there is a pressing need to assess, whether organs from HCV infected donors may safely be transplanted into HCV uninfected recipients.
Introduction to HCV and Clarification of Nomenclature: · Anti-HCV remain positive for a number of years after spontaneous clearance, or successful treatment of HCV with interferon or DAA therapy. · ‘HCV viraemic’ refers to – active HCV infection with detectable HCV RNA, regardless of HCV antibody status – donors with HCV IgG +ve, if HCV-RNA is not known at the time of organ donation / transplantation. Changes in the treatment of hepatitis C over the past five years: · DAA regimens [Sofosbuvir+Velpatasvir, Glecaprevir+Pibrentasvir (preferred in CKD), or Sofosbuvir+ Velpatasvir+Voxilaprevir], have increased HCV-cure rates to 95-100% regardless of HCV genotype; enabling use HCV RNA+ donor for recipients without HCV-viremia. Current discard rates for hepatitis C positive donor organs in the UK: · HCV infection is not an absolute contraindication to donation of organs for life-saving transplantation, however the net benefit of such transplantation must over way the risk of not receiving that specific transplant. · This risk/benefit analysis allows for the potential use of a transplant from a HCV infected donor to a non-infected recipient. Experience from outside the UK:
· USA (1995 -2015) – 4.1% of all organ donors were anti-HCV antibody positive. Discard rates of anti-HCV antibody positive livers have reduced from 25% to 10%. · EXPANDER-1 trial and HCV-TARGET trial have shown excellent SVR rates in liver and kidney transplant recipients. Why HCV D+ to R- transplantation should be cost effective: · The course of therapy to cure a R- patient receiving a D+ organ would be less than the cost of dialysis for one year. What are the risks of HCV D+ to R- transplantation? – 10% of liver transplants and 1.5% of kidney transplants develop fibrosing cholestatic hepatitis with high mortalitybut the use of DAA in early post- transplant is effective for prevention and treatment. – Other risks are HCV infection and DAA failure. Practicalities Implementing the Policy in UK: 1. Recipient consent is mandatory 2. Patient and Unit Requirements Pre-Transplant:
Ø Hepatologist consultation – liver USG, APRI (AST-to-platelet ratio index) screening Ø APRI>0.8 or significant / advanced liver disease on USG 3. Organ allocation: after sufficient expertise, if decide favourable, HCV D+ Organs can be allocated similar to HCV-neg waiting list
4. Management of the Recipient of HCV D+ Organ: Testing of HCV RNA PCR – day 3-7, day 10-14, then 6 weeks post-transplant Ø Negative RNA even at 6 weeks à recipient can be reassured. Positive HCV RNA, in first 6 weeks à should be treated with DAAs (12 weeks SOF + VEL or Glecaprevir + Pibrentasvir). Ø If viremia not cleared within 10-14 days, add Voxilaprevir to SOF + VEL regimen, which is very effective. 5. Special considerations: HCV antibody positive donors acceptable, if 1) with no h/o HCV treatment or with document SVR post DAA. 2) HCV treatment history is unknown. 3) with h/o exposure to risk not fulfilling unacceptable criteria. Unacceptable donors: 1) HCV treatment in last 6 months, without documented proof of SVR. 2) failed treatment with ongoing viremia. 3) multiple documented HCV re-infections. Conclusions: · The advantage is weighted against harm in transplanted HCV positive donor. · Transplantation of HCV-infected donor-to-non-infected recipient transplant according to risk/benefit. · All HCV-infected kidney transplant candidates must have DAA therapy
Summary
HCV is a single stranded RNA virus member of the Flaviviridae family. Six genotypes (G1-6)
HCV viraemic’ refer to donors or recipients who have active HCV infection with detectable HCV RNA, regardless of HCV antibody status; it also refers to donors that are HCV IgG +ve where the HCV RNA status is not known at the time of organ offering / transplantation. It is important to note however that transmission of infection may still occur from donors during the window period of acute infection.
There is imbalance of organ demand and organ supply. Previously Organ from hepatitis c were discarded. HCV infection in the potential donor does not amount to an absolute contraindication to donation of material for life-preserving transplantation, however the net benefit of transplantation must be considered against the risk of not receiving that specific transplant. This risk/benefit analysis allows for the potential use of a transplant from a HCV infected donor to a non-infected recipient.’
With advance of direct acting antiviral drug, this has been possible, and studies have shown that similar outcomes of hepatitis C clearance and small trials have shown excellent outcomes in Hepatitis C negative recipients given hepatitis C infected organs who were subsequently treated and cured of the virus. Current regimens used in clinical practice are given for between 8 and 16 weeks, and offer cure rates of 95-100% for patients without cirrhosis, regardless of HCV genotype. The second and third generation DAA regimens have also been shown to be highly effective for patients with cirrhosis, and for patients treated after kidney or liver transplantation. Various combination has been use with good success. That includes
Grazoprevir/Elbasvir, Sofosbuvir/ Grazoprevir/Elbasvir /ribavirin , Sofosbuvir and Ledipasvir (an earlier generation combination), with or without ribavirin , Sofosbuvir / Velpatasvir and Glecaprevir/Pibrentasvir, Sofosbuvir/ Velpatasvir/Voxilaprevir
The advantage of Glecaprevir / Pibrentasvir is that it can be given to patients with established renal failure
Post transplantation, Hcv pcr monitoring is done if negative in following days(3-10 days, 10-14 days, 6 weeks)
DAA is start within 3-10 days of Positive PCR
Treatment should be given in liaison with a clinical team with experience of management of HCV but does not necessarily have to be delivered in the transplanting centre.
In the rare (expected to be less than 2%) instances where the first course of treatment of HCV is not curative, recipients should be treated with a 12 week course of the combination of Sofosbuvir/Velpatasvir/Voxaleprevir which, as previously discussed, has high rates of SVR even in those previously exposed to DAA therapy. Acceptable HCV Donor
HCV Ab positive with no history of treatment of HCV
HCV Ab positive with documented SVR after treatment
Any HCV Ab negative donor who has exposed themselves to risk but who does not fulfill any of the unacceptable criteria
Any HCV Ab positive donor whose HCV treatment history is unknown – proceed with caution. Not Recommended HCV Donor
Previously failed DAA therapy with on-going viraemia
DAA therapy within last year without documented SVR (unless the recipient is at imminent risk of death)
Multiple documented re-infection with HCV
Introduction:
Continuous review of organs that have been discarded, to assess whether advances in medicine could enable such organs to be transplanted. It is now apparent that greater use can be made of organs from hepatitis C (HCV) infected donors. With direct-acting antiviral (DAA) therapy that can cure more than 95% of patients infected with HCV, regardless of genotype, there is a pressing need to assess whether organs from HCV infected donors may safely be transplanted into HCV uninfected recipients. Introduction to HCV and Clarification of Nomenclature:
It is important to define the serological and virological status of the donor in a scenario of using HCV-infected donor for transplant. HCV can be transmitted by either intravenous drug or blood products, sexually, or vertically.
HCV is a single stranded RNA virus member of the Flaviviridae family, with six genotypes (G1-6), transmitted parentally, sexually, or vertical.
It can be acute or chronic and serologic tests can detect antibodies to HCV within two to six months of initial infection.
Anti-HCV remain positive for a number of years after spontaneous clearance, or successful treatment of HCV with interferon or DAA therapy.
‘HCV viraemic’ refer to donors or recipients who have active HCV infection with detectable HCV RNA, regardless of HCV antibody status; it also refers to donors that are HCV IgG +ve where the HCV RNA status is not known at the time of organ offering / transplantation. Changes in the treatment of hepatitis C over the past five years:
Introduction of DAAs in last few years have increased the cure rates of HCV-infected patients to 95-100% regardless of HCV genotype. The regimens used include Sofosbuvir/Velpatasvir, Glecaprevir/Pibrentasvir (useful in renal failure), or Sofosbuvir/Velpatasvir/Voxilaprevir. These results make it possible to use HCV RNA viremic donor for recipients without HCV viremia. Current discard rates for hepatitis C positive donor organs in the UK:
HCV infection is not an absolute contraindication to donation of material for life-preserving transplantation, however the net benefit of transplantation must be considered against the risk of not receiving that specific transplant. This risk/benefit analysis allows for the potential use of a transplant from a HCV infected donor to a non-infected recipient. Experience from outside the UK:
In US between 1995 and 2015, 4.1% of all organ donors were anti-HCV antibody positive. Discard rates of anti-HCV antibody positive livers have reduced from 25% to 10%. EXPANDER-1 trial and HCV-TARGET trial have shown excellent SVR rates in liver and kidney transplant recipients. Why HCV D+ to R- transplantation should be cost effective:
The course of therapy to cure a R- patient receiving a D+ organ would be less than the cost of dialysis for one year. What are the risks of HCV D+ to R- transplantation?
10% of liver transplants and 1.5% of kidney transplants develop fibrosing cholestatic hepatitis with high mortalitybut the use of DAA in early post- transplant is effective for prevention and treatment.
Other risks are HCV infection and DAA failure. The Practicalities of Implementing this Policy in the United Kingdom:
These practices include: 1) Patient consent:
Consent is mandatory specially for HCV D+/R- transplantation. 2) Patient and Unit Requirements Pre-Transplant:
These include screening patients with AST-to-platelet ratio index (APRI) and abdominal US and hepatologist consultation in the presence of APRI>0.8 or ultrasound showing significant or advanced liver disease. 3) Allocation of HCV D+ Organs on the Waiting List:
Done for HCV D+ organs once sufficient expertise has accrued. 4) Management of the Recipient of a HCV D+ Organ:
The management achieved by testing of HCV RNA PCR on day 3-7 post-transplant, then on day 10-14, and then 6 weeks post-transplant. If the reports are negative even at 6 weeks, the recipient can be reassured. If the HCV PCR comes out positive during the testing in first 6 weeks, the patient should be treated with DAAs (12 weeks of either Sofosbuvir/Velpatasvir or Glecaprevir/Pibrentasvir, and Sofosbuvir/Velpatasvir/Voxilaprevir if the first 2 regimes are not curative) within 3-10 days. Special additional considerations: Acceptable donors: These include:
1) HCV antibody positive with either no history of HCV treatment or with document SVR post-transplant.
2) HCV antibody positive donor with history of exposure to risk not fulfilling unacceptable criteria.
3) HCV antibody positive patient whose HCV treatment history is unknown. Unacceptable donors: include:
1) prior treatment with DAA for HCV in last 6 months without documentary proof of SVR.
2) failed treatment with ongoing viremia.
3) multiple documented HCV re-infections. Conclusion:
The advantage is weighted against harm in transplanted HCV positive donor.
Transplantation of HCV-infected donor-to-non-infected recipient transplant according to risk/benefit.
All HCV-infected kidney transplant candidates must have DAA therapy
Executive Summary· Organ donation is increasing, but 1 in 6 patients will die or become too sick for transplantation.
· Older treatment modalities have not been successful in curing hepatitis C in transplant recipients.
· Recent advances in hepatitis C management have enabled 95% of infected individuals to be cured with antiviral agents, with similar outcomes in transplant recipients.
· Up to 75 extra solid organ transplants could be performed annually due to potential donors declining due to hepatitis C risk.
· The Advisory Committee on the Safety of Blood, Tissues, and Organs has proposed a UK-wide framework for the appropriate use of organs from HCV-infected donors.
· The guidelines include a selection of donors, policy for informed consent, testing and treatment, monitoring group, and consideration of operational issues.
Introduction· Solid organ transplantation is now well established in routine clinical practice, and the number of patients alive in the UK following a successful transplant has surpassed 50,000.
· However, a significant number of patients still die due to a shortage of donor organs, with 457 patients dying on UK transplant waiting lists in 2016/17 alone.
· An important strategy is the continuous review of organs that have been discarded, to assess whether advances in medicine could enable such organs to be transplanted.
· This strategy could ultimately make more organs available for transplantation, and reduce the morbidity and mortality of patients on solid organ transplant waiting lists.
Introduction to HCV and Clarification of Nomenclature· HCV is a single-stranded RNA virus that is transmitted parenterally, sexually, or vertically, and can lead to sequelae of acute or chronic hepatitis.
· The University of Cincinnati has reported follow-up data of 25 HCV antibody-negative recipients who received donor livers from HCV antibody-positive but HCV RNA-negative “HCV high risk” donors.
Changes in the treatment of hepatitis C over the past five years· The revolution in HCV management began with the licensing of the first-generation protease inhibitors Telaprevir and Boceprevir in 2012, which increased cure rates for G1 HCV from 50% to over 80%.
· The pace of drug development has been rapid, and many agents licensed have now been superseded by better-tolerated and more effective regimens.
· There is already substantial UK experience using two licensed pan-genotypic regimens in the form of Sofosbuvir / Velpatasvir and Glecaprevir/pibrentasvir.
· The second and third-generation DAA regimens have also been shown to be highly effective for patients with cirrhosis, and for patients treated after kidney or liver transplantation.
· This paper seeks to establish a professional consensus to enable the use of HCV RNA viraemic organs for transplantation for recipients without HCV viremia.
Current discard rates for hepatitis C-positive donor organs in the UK· The UK is restricting the use of HCV D+ organs to HCV-positive recipients, but anecdotal evidence suggests poor utilization of non-liver organs even for HCV R+ recipients.· The revised guidance states that HCV infection does not amount to an absolute contraindication to the donation of material for life-preserving transplantation, but the net benefit of transplantation must be considered against the risk of not receiving it. Experience from outside the UK· The US has the best data on D+ donor numbers and discard rates and is leading the way in early clinical trials of D+ to R- transplants.
· Discard rates for HCV D+ livers have reduced from 25% in 2006 to 10% in 2015, but discard rates for other organs are higher due to opiate abuse.
· A conference of the American Transplantation Society recommended that such practice should take place within prospective research protocols.
· The EXPANDER-1 trial (Exploring Renal Transplants Using Hepatitis- C Infected Donors for HCV-Negative Recipients) reported data from 10 patients who underwent kidney transplantation with an HCV D+ organ.
· The median wait time was reduced to 58 days, and the median eGFR at the end of the study was 68 ml/min (51-83).
· The only SAEs noted were delayed graft function, elevated ALT, transient class 1 donor-specific antibody, and proteinuria and focal segmental glomerulosclerosis on renal biopsy.
· Results in a larger cohort of patients were reported by Saxena et al from the HCV-TARGET consortium of
· Academic US centers, with 443 patients treated after organ transplantation.
· The SVR12 rate was 96.3% in liver recipients, 94.6% in kidney recipients, and 90.9% in kidney/liver recipients.
Why HCV D+ to R- transplantation should be cost-effective· Increasing organ availability for patients on solid organ transplant waiting lists has clear morbidity and mortality benefits, but also economic arguments.
· Dialysis is expensive and can reduce the quality of life, but timely transplantation can reduce waiting times and dialysis expenditure, leading to substantial cost savings and improved quality of life for patients.
What are the risks of HCV D+ to R- transplantation?
· The potential risks of HCV D+ to R- transplantation include fibrosing cholestatic hepatitis (FCH), which is an aggressive form of HCV recurrence seen in 10% of D+/R+ liver transplants. · DAA therapy has been found to be very effective in the setting of FCH, with cure rates of 100% in 15 patients with FCH treated after liver transplantation using the combination of Sofosbuvir and Daclatasvir. · Liu et al from Taiwan reported a case of an HCV R- a patient who became viraemic by 1 week post-transplantation and developed FCH by 6 weeks post-transplantation. · Early treatment (ideally within 4 weeks) with DAA therapy should prevent the development of FCH. · Sexual transmission of HCV to a partner is likely low, and Skipton Fund ex gratia payments may be granted to individuals infected through NHS treatment, but the current Special Category Mechanism (SCM) would require clarification before it could proceed in the UK. The Practicalities of Implementing this Policy in the United Kingdom· The working party felt that it was important to provide a framework for transplant units to consider before proceeding with an HCV D+/R- transplant, and recommended an oversight committee for the first 20-30 transplants. Patient Consent· The British Transplantation Society and NHS Blood and Transplant are reviewing the entire pathway of sharing information with and gaining consent from solid organ transplant candidates, including consent for HCV D+/R- transplantation. Patient and Unit Requirements Pre-Transplant· The working party agreed that HCV D+/R- non-liver transplantation should be avoided in recipients with advanced fibrosis or cirrhosis.· To ensure safety, a more pragmatic approach of screening patients using AST-to-Platelet Ratio Index (APRI) and ultrasound is suggested. · If the APRI score is >0.8 or the ultrasound suggests significant or advanced liver disease, an opinion from a suitably qualified liver specialist should be sought before the patient is considered for a transplant. · A checklist of prerequisites must be in place before an individual transplanting center performs its first transplant. Allocation of HCV D+ Organs on the Waiting List· Advisory Groups must decide how best to allocate HCV D+ organs to optimize organ utilization and review post-transplant outcomes to alter offering and allocation policies. Management of the Recipient of an HCV D+ Organ· The working party discussed the need to implement standardized, longitudinal testing for hepatitis C RNA of the recipient following receipt of either an HCV antibody positive graft, an HCV RNA positive graft, or a graft from an increased infectious risk donor. · Two alternative regimens should be used as first-line agents, either the combination of Glecaprevir/Pibrenatasvir or the combination of Sofosbuvir/velpatasvir. · Treatment should be given in liaison with a clinical team with experience in the management of HCV but does not necessarily have to be delivered in the transplanting center. Special Additional Considerations· The use of organs from donors known to have been treated for HCV with DAA within the last 6 months should be avoided unless there is clear documentary proof at the time of donation of an SVR12 result. · Donor and recipient testing should be followed, and any organ from a donor who has not achieved SVR12 for any reason should not be considered for transplantation into a negative recipient unless the benefits outweigh the risks. · Resistance testing of the virus at baseline prior to commencing treatment may be required and the choice of drug regimen tailored in light of this information. Oversight of the Programme in its Early Days· An Oversight Committee should be established to oversee the implementation of the program and receive clinical information on the recipients of HCV D+/R- transplantation, led by BVHG with strong representation from NHSBT and the BRITISH TRANSPLANTATION SOCIETY. Appendix 1 – Patient Information Leaflet for the Use of Hepatitis C Infected Organs in Hepatitis C Negative Recipients· Hepatitis C is a virus that can cause inflammation and scarring of the liver, and it is now possible to cure over 95% of patients with treatment. · Accepting an organ from a hepatitis C virus-infected donor can be beneficial, but there are risks such as jaundice, kidney injury, and a small chance that the virus may not disappear after 12 weeks of treatment. · Studies have shown that it is possible to cure every patient of the hepatitis C virus after kidney transplantation, with a 100% cure rate. · Hepatitis C virus does not damage the heart, lungs, or pancreas, so kidneys from infected donors should work just as well. Appendix 2 – Checklist for Transplant Units to Go Through Prior to Going Ahead with HCV D+ / R- Transplantation· Recipient-specific, pharmacy issues, personnel issues, blood tests post-transplantation, referral pathway to local HCV MDT, and Blueteq access. · The clinical lead must ensure mandatory blood tests are taken post-transplantation and results are actioned within the timelines stipulated, have a formal pathway for the management of potential recipients, and have mechanisms in place to ensure timely testing of potential recipients.
Current discard rates for hepatitis C positive donor organs in the UK
Organs from only 76 (31%) of these donors were transplanted into 93 recipients (63 liver, 27 kidney and 2 heart transplants). The quality of the declined organs did not differ from that of the organs that were used, with positive serological tests reported as the reason for decline in 69% of cases. The declined donors often had good kidney and liver function, and, based on validated UK Donor Risk Indices, if they had been used, 77% of kidneys and 80% of livers from the potential donors would be predicted to be functioning 5 years later. Furthermore, even at the list price of DAAs (the actual prices that the NHS pays are lower) the additional costs of transplanting recipients exposed to HCV with a kidney from a HCV antibody positive donor was cost-neutral in comparison with remaining on dialysis within 5 years following transplantation. In reality, it is likely that this cost effectiveness will manifest earlier. Notably, data were not provided as to whether the donors had detectable HCV RNA by PCR testing, as only a minority had HCV RNA status reported.
HCV infection in the potential donor does not amount to an absolute contraindication to donation of
material for life-preserving transplantation, however the net benefit of transplantation must be considered against the risk of not receiving that specific transplant. This risk/benefit analysis allows for the potential use of a transplant from a HCV infected donor to a non-infected recipient.’
This change in the guidance paves the way for potential D+ to R- transplants.
What are the risks of HCV D+ to R- transplantation?
While there are clear economic and health related benefits to HCV D+ to R- transplantation, it is important to consider the potential risks and how these could be mitigated.
The first and perhaps most feared risk is of fibrosing cholestatic hepatitis (FCH) [34,35]. This is an aggressive form of HCV recurrence seen in 10% of D+/R+ liver transplants. Prior to the advent of DAA therapy FCH was associated with a high mortality. It is also reported in kidney transplantation, with an incidence of 1.5% in the largest series from Spain [36]. However, there are now increasing reports of DAA therapy being very effective in the setting of FCH.
By contrast, HCV D+/R- transplantation followed by early DAA therapy would result in only a transient, usually rapidly curable infection.
In the early days of a HCV D+/R- programme, treatment duration could be extended slightly (from 8 weeks to 12 weeks or from 12 weeks to 16 weeks) to mitigate this risk until more real world data emerges. However, data from the POLARIS-1 trial has shown that 12 weeks of re-treatment with the triple therapy combination of Sofosbuvir, Velpatasvir and Voxilaprevir is highly effective (>95%) in achieving cure of HCV in patients with HCV NS5A RAS at baseline [19]. Thus virtually all HCV D+/R- recipients can be cured with modern DAA therapies, even if this is not achieved at the first attempt at treatment.
Extra-hepatic manifestations of HCV such as cryoglobulinaemic vasculitis or potential increased rates of blood derived malignancy such as PTLD are also theoretical consequences of HCV infection in the post-transplantation phase.
Sexual transmission of HCV to a partner could potentially occur in the HCV D+/R- transplant scenario. The risk can be mitigated by simple lifestyle advice, as well as through the proposed early inception of DAA therapy post transplantation. It is likely this risk will be extremely low (<2% perhaps).
Patient Consent
Although patients are currently routinely consented to receive so-called ‘marginal’ organs including for example CMV-positive organs, it was felt that consent to receive a HCV D+ organ should be specifically obtained by individual transplanting centres. To aid this process, the working group has developed a patient information sheet (see Appendix 1). In addition, the group noted that the British Transplantation Society together with NHS Blood and Transplant is currently reviewing the entire pathway of sharing information with and gaining consent from solid organ transplant candidates, and inclusion of consent for HCV D+/R- transplantation will need to form part of this work.
Summary
HCV is a single stranded RNA virus member of the Flaviviridae family. Six genotypes (G1-6)
HCV viraemic’ refer to donors or recipients who have active HCV infection with detectable HCV RNA, regardless of HCV antibody status; it also refers to donors that are HCV IgG +ve where the HCV RNA status is not known at the time of organ offering / transplantation. It is important to note however that transmission of infection may still occur from donors during the window period of acute infection.
There is imbalance of organ demand and organ supply. Previously Organ from hepatitis c were discarded. HCV infection in the potential donor does not amount to an absolute contraindication to donation of material for life-preserving transplantation, however the net benefit of transplantation must be considered against the risk of not receiving that specific transplant. This risk/benefit analysis allows for the potential use of a transplant from a HCV infected donor to a non-infected recipient.’
With advance of direct acting antiviral drug, this has been possible, and studies have shown that similar outcomes of hepatitis C clearance and small trials have shown excellent outcomes in Hepatitis C negative recipients given hepatitis C infected organs who were subsequently treated and cured of the virus.
Current regimens used in clinical practice are given for between 8 and 16 weeks, and offer cure rates of 95-100% for patients without cirrhosis, regardless of HCV genotype. The second and third generation DAA regimens have also been shown to be highly effective for patients with cirrhosis, and for patients treated after kidney or liver transplantation. Various combination has been use with good success. That includes
Grazoprevir/Elbasvir, Sofosbuvir/ Grazoprevir/Elbasvir /ribavirin , Sofosbuvir and Ledipasvir (an earlier generation combination), with or without ribavirin , Sofosbuvir / Velpatasvir and Glecaprevir/Pibrentasvir, Sofosbuvir/ Velpatasvir/Voxilaprevir
The advantage of Glecaprevir / Pibrentasvir is that it can be given to patients with established renal failure
Post transplantation, Hcv pcr monitoring is done if negative in following days(3-10 days, 10-14 days, 6 weeks)
DAA is start within 3-10 days of Positive PCR
Treatment should be given in liaison with a clinical team with experience of management of HCV but does not necessarily have to be delivered in the transplanting centre.
In the rare (expected to be less than 2%) instances where the first course of treatment of HCV is not curative, recipients should be treated with a 12 week course of the combination of Sofosbuvir/Velpatasvir/Voxaleprevir which, as previously discussed, has high rates of SVR even in those previously exposed to DAA therapy.
Acceptable HCV Donor
HCV Ab positive with no history of treatment of HCV
HCV Ab positive with documented SVR after treatment
Any HCV Ab negative donor who has exposed themselves to risk but who does not fulfill any of the unacceptable criteria
Any HCV Ab positive donor whose HCV treatment history is unknown – proceed with caution.
Not Recommended HCV Donor
Previously failed DAA therapy with on-going viraemia
DAA therapy within last year without documented SVR (unless the recipient is at imminent risk of death)
Multiple documented re-infection with HCV
UK Position Statement on the use of Organs from Hepatitis C Viraemic Donors and Increased Infectious Risk Donors in Hepatitis C Negative Recipients Introduction
· A significant number of patients still die due to a shortage of donor organs
· With the advent of direct-acting antiviral (DAA) therapy organs from hepatitis C (HCV) infected donors can be used.
· HCV is a single stranded RNA virus member of the Flaviviridae family. Six genotypes (G1-6) and a large number of sub-genotypes have been characterised in detail
· Transmission of HCV generally occurs parenterally, sexually or vertically, and can lead to sequelae of acute or chronic hepatitis.
· Acute infection tends to be subclinical, with chronic infection, defined as persistence of HCV RNA in serum for greater than six months after initial infection.
· Serologic tests can detect antibodies to HCV within two to six months of initial infection
· detectable HCV RNA by PCR is indicator for viremia
· HCV antibody continues to remain positive for many years (often indefinitely) after spontaneous clearance, or successful treatment of HCV resulting in undetectable HCV RNA.
· ‘HCV viraemic’ will be used for donors or recipients who have active HCV infection with detectable HCV RNA, regardless of HCV antibody status; or for donors that are HCV IgG +ve where the HCV RNA status is not known at the time of organ offering / transplantation.
Changes in the treatment of hepatitis C over the past five years
· Most of the current regimens used in clinical practice are given for between 8 and 16 weeks, and offer cure rates of 95-100% for patients without cirrhosis, regardless of HCV genotype.
· Most regimens do not rely on the use of ribavirin.
· There is already substantial UK experience of using two licensed pan-genotypic regimens in the form of Sofosbuvir / Velpatasvir and Glecaprevir/Pibrentasvir.
· The pan-genotypic triplet of Sofosbuvir, Velpatasvir and Voxilaprevir was licenced in August 2017.
· The advantage of Glecaprevir / Pibrentasvir is that it can be given to patients with established renal failure.
· These regimens also have high efficacy for the treatment of patients who have previously failed other DAA-containing regimens, with the best data currently available for Sofosbuvir, Velpatasvir and Voxilaprevir.
· The second and third generation DAA regimens have also been shown to be highly effective for patients with cirrhosis, and for patients treated after kidney or liver transplantation.
Current discard rates for hepatitis C positive donor organs in the UK
· ‘HCV infection in the potential donor does not amount to an absolute contraindication to donation of material for life-preserving transplantation, however the net benefit of transplantation must be considered against the risk of not receiving that specific transplant. This risk/benefit analysis allows for the potential use of a transplant from a HCV infected donor to a non-infected recipient.’
Experience from outside the UK
· Discard rates for HCV D+ livers have reduced in the US from 25% in 2006 to 10% in 2015
· A clinical trial at the American Transplant Congress in 2017, the EXPANDER-1 trial (Exploring Renal Transplants Using Hepatitis C Infected Donors for HCV-Negative Recipients).
· Results in a larger cohort of patients were reported by Saxena et al from the HCV-TARGET consortium of Academic US centres.
Why HCV D+ to R- transplantation should be cost effective
· all stakeholders are reassured that a course of therapy to cure a R- patient receiving a D+ organ would be less than the cost of dialysis for one year. What are the risks of HCV D+ to R- transplantation?
· The first and most feared risk is of fibrosing cholestatic hepatitis (FCH), but DAA therapy is very effective in the setting of FCH.
· HCV D+/R- transplantation followed by early DAA therapy would result in only a transient, usually rapidly curable infection.
· Sexual transmission of HCV to a partner will be extremely low with simple lifestyle advice, and early initiation of DAA therapy post transplantation.
Patient and Unit Requirements Pre-Transplant
· If the AST-to-Platelet Ratio Index score is >0.8 or the ultrasound suggests significant or advanced liver disease, then a qualified liver specialist should be consulted before the patient is considered for a HCV D+ organ.
· a checklist of pre-requisites that must be in place before an individual transplanting centre performs its first HCV D+/R- transplant would be valuable Allocation of HCV D+ Organs on the Waiting List
· once sufficient expertise has ensued, HCV D+ organs should be treated in the same way as HCV D- organs within the current allocation rules of the national waiting lists as determined by the individual NHSBT bodies. Management of the Recipient of a HCV D+ Organ
· Regimens should be used as first line agents are either the combination of Glecaprevir/Pibrenatasvir or the combination of Sofosbuvir/Velpatasvir
· Both are pan-genotypic and should be given for 12 weeks for the HCV D+/R- transplants.
· Both have very acceptable drug to drug interaction profiles although exposure to the former is increased by ciclosporin, and it may also increase the levels of tacrolimus.
· The latter is not recommended in patient with a eGFR <30 mL/min/1.73 m2
· If the first course of treatment of HCV is not curative, recipients should be treated with a 12 week course of the combination of Sofosbuvir/Velpatasvir/Voxaleprevir. Special Additional Considerations
· The use of organs from donors known to have been treated for HCV with DAA within the last 6 months should be avoided unless there is clear documentary proof at the time of donation of an SVR12 result.
· Potentially donors engaging in increased infectious risk behaviour are at risk of re-infection post SVR and thus could still transmit HCV.
· any organ from a donor who has been treated for HCV with DAAs but has not achieved SVR12 for any reason should not be considered for transplantation into a negative recipient unless the benefits outweigh the risks
With the need for organs and an increasing waiting list, morbidity and mortality and the emerge of DAA transplants of HCV +Ab can happen with special attention.
HCV is a single-stranded RNA virus of the Flaviviridae family, 6 genotypes have been described. we have two types of hepatitis C infection; Aute which is a subclinical chronic hep Cv with detectable HCV RNA in the serum for more than 6 months and this happened in 60% of the affected person.
HCV Ab remain positive for years, and it denotes to previously treated infection or spontaneous clearance, but generally, DAA plays the main role in this phenomenon.
HCV viremia refers to: –
donors or recipients with active HCV infection with detectable HCV RNA regardless of the HCV Ab status
donors with HCV IgG positive where the HCV RNA status is not known at the time of organ donation or transplantation
– HCV transmission can still occur during the window period of acute infection.
DAA has 95 to 100% cure rate in all genotypic patient, especially if they don’t have cirrhosis.
We have different types of combinations of Antival viral medication.
examples of pan-genotypic regimens include: –
Sofosbuvir / Velpatasvir
Glecaprevir/Pibrentasvir – for patients with established kidney failure
Sofosbuvir, Velpatasvir and Voxilaprevir – this combination has high efficacy for treatment of patients who had previously failed other DAA-containing regimens
2nd and 3rd generation DAA regimens are highly effective for patients with cirrhosis and for patients treated after kidney or liver transplantation
– HCV positive donors (HCV RNA viremic donor) can donate to both HCV positive and HCV negative recipients to reduce the waiting-list morbidity and mortality
IV. UK Position Statement on the use of Organs from Hepatitis C Viraemic Donors and Increased Infectious Risk Donors in Hepatitis C Negative Recipients
Summarise the article
Introduction
– the waiting list is growing by the day and so is the waiting list morbidity and mortality
– previously, HCV-positive organs used to be discarded due to the increased risk of HCV transmission to the recipients
– this has since changed, with the advent of DAA therapy which is associated with favourable outcomes
– HCV is a single stranded RNA virus of the Flaviviridae family, 6 genotypes have been described
– chronic HCV infection is defined as persistence of HCV RNA in the serum for >6months after the initial infection, this develops in ~60% of those infected
– serological tests can detect antibodies to HCV within 2-6 months of initial infection
– HCV Ab (anti-HCV) continues to remain positive for years and often indefinitely after spontaneous clearance, or successful treatment of HCV with DAA therapy resulting in undetectable HCV RNA (SVR)
– the most important thing when assessing the HCV infectivity of an organ donor or recipient is whether or not active HCV replication is present; i.e., whether they are viraemic/ have detectable HCV RNA by doing sensitive genome amplification tests like polymerase chain reaction (PCR) nucleic acid testing (NAT) or antigen testing
– HCV re-infection is defined as detectable HCV RNA by PCR testing in a person who had spontaneous clearance of HCV or had achieved SVR following antiviral therapy
– occult HCV i.e., residual HCV viral genomes in donor tissue – can be a potential means of HCV transmission
– HCV viremia refers to: –
donors or recipients with active HCV infection with detectable HCV RNA regardless of the HCV Ab status
donors with HCV IgG positive where the HCV RNA status is not known at the time of organ donation or transplantation
– HCV transmission can still occur during the window period of acute infection
Advances in the treatment of HCV
– DAAs offer cure rates of 95-100% for patients without cirrhosis regardless of the HCV genotype
– examples of pan-genotypic regimens include: –
Sofosbuvir / Velpatasvir
Glecaprevir/Pibrentasvir – for patients with established kidney failure
Sofosbuvir, Velpatasvir and Voxilaprevir – this combination has high efficacy for treatment of patients who had previously failed other DAA-containing regimens
– 2nd and 3rd generation DAA regimens are highly effective for patients with cirrhosis and for patients treated after kidney or liver transplantation
– HCV positive donors (HCV RNA viremic donor) can donate to both HCV positive and HCV negative recipients to reduce the waiting-list morbidity and mortality
Current discard rates for HCV positive donor organs in the UK
– there is poor utilization of HCV RNA viremic donor non-liver organs even for HCV RNA viremic recipients
– the number of HCV RNA viremic recipients on the waiting list is bound to decrease due to the efficacy of DAA therapy
– organ discard rates will increase unless the current clinical practice changes
– the risk vs benefit analysis allows for the potential use of a transplant from a HCV infected donor to a non-infected recipient
Experience from outside the UK
– the US has the best data on D+ donor numbers as well as on discard rates and is leading in early clinical trials of D+ to R- transplants
Why HCV D+ to R- transplantation should be cost effective
– in the kidney transplantation field, HCV D+ to R- transplantation is considered cost effective since dialysis by itself is expensive compared to DAA therapy
– the cost of dialysis can be mitigated by timely transplantation
– patients on dialysis have a significantly reduced quality of life
– saves costs by reducing waiting times and dialysis expenditure, save lives and improve quality of life for patients
What are the risks of HCV D+ to R- transplantation?
Fibrosing cholestatic hepatitis (FCH):
– FCH is an aggressive form of HCV recurrence seen in 10% of D+/ R+ liver transplant
– prior to DAA therapy, FCH was associated with high mortality
– early treatment with DAA therapy helps prevent the development of FCH
Risk of transmitting an infectious agent
– this poses important ethical issues
– HCV is usually rapidly curable with DAA therapy, unlike other infectious diseases like CMV and EBV, HCV
DAA treatment failure
– may be associated with development of difficult to treat resistance associated substitutions
– 12 weeks of re-treatment with the triple therapy combination of Sofosbuvir, Velpatasvir and Voxilaprevir has been found to be highly effective
Sexual transmission of HCV to a partner
– this can be avoided by simple lifestyle advice, early initiation of DAA therapy post-transplantation
The practicalities of implementing this policy in the UK
– there is need to provide a framework for some of the important practical issues that can be adopted
Patient consent
– provide the patient with the patient information sheet and the consent form
Patient and unit requirements pre-transplant
– avoid HCV D+/ R- non-liver transplantation in recipients with advanced fibrosis and cirrhosis
– screen patients with an APRI score and ultrasound and consult a hepatologist if the APRI score is >0.8 or if the ultrasound suggests significant or advanced liver disease
Allocation of HCV D+ organs on the waiting list
– HCV D+ organs should be treated in the same way as HCV D- organs on the waiting list
– aim is to optimize organ utilisation
Management of the recipient of a HCV D+ organ
– test recipient for HCV RNA to ensure appropriate and early intervention if HCV transmission and infection occurs
– 1st line treatment agents include:
either a combination of Glecaprevir/Pibrenatasvir or
a combination of Sofosbuvir/Velpatasvir
– both should be given for 12 weeks, both are pan-genotypic meaning they can be started as soon as HCV PCR positivity is known, without having to wait for a HCV genotype
– both have acceptable drug-drug interactions
– exposure to Glecaprevir/Pibrenatasvir is increased by cyclosporine and it may also increase tacrolimus levels by inhibiting CYP3A and P-glycoprotein
– Sofosbuvir/Velpatasvir is not recommended in patients with eGFR <30
– in cases of treatment failure, treat the recipient for another 12 weeks with a combination of Sofosbuvir/ Velpatasvir/ Voxaleprevir this combination has high rates of SVR even in those with previous DAA exposure
Special additional considerations
– avoid use of organs from donors previously treated for HCV with DAA within the last 6 months unless there is clear evidence of an SVR12 result at the time of organ donation
– this is due to concerns about transmission of resistant HCV
– acceptable donors include:
HCV Ab positive with no history of treatment of HCV
HCV Ab positive with documented SVR after treatment
any HCV Ab negative donor who has exposed themselves to risk but who does not fulfill any of the unacceptable criteria
any HCV Ab positive donor whose HCV treatment history is unknown – proceed with caution
– unacceptable donors include:
previously failed DAA therapy with on-going viraemia
DAA therapy within last year without documented SVR (unless the recipient is at imminent risk of death)
The article deals with the UK position statement on the use of organs from hepatitis C viraemic donors and increased infectious risk donors in hepatitis C negative recipient, endorsed by 12 different UK organizations.
Introduction: Due to increasing gap between organ demand and supply, continuous review of the organs discarded needs to be done, especially considering >95% cure rate of hepatitis C virus (HCV) infection achieved with direct-acting antivirals (DAAs), which can increase the donor pool.
Introduction to HCV and clarification of nomenclature: It is important to define the serological and virological status of the donor in a scenario of using HCV-infected donor for transplant. HCV can be transmitted by either intravenous drug or blood products, sexually, or vertically. Acute infection could be subclinical. Chronic infection is persistence of HCV RNA in serum for >6 months, and can be seen in 60% of the cases. Serologic tests can detect anti-HCV antibodies within 2-6 months of initial infection. HCV RNA can be detected in serum after 7 days of infection. Re-infection implies detectable HCV RNA in a patient with documented spontaneous HCV clearance or someone who achieved sustained virologic response (SVR) post DAA therapy. Occult HCV is the condition with residual HCV viral genome in donor tissue. So, careful testing of recipients of HCV-infected organs is important. HCV viremic person, for the purpose of the document, is someone with detectable HCV RNA regardless of HCV antibody status as well as a donor who is HCV IgG positive with unknown HCV RNA status at time of organ donation.
Changes in the treatment of HCV over past 5 years: Introduction of DAAs in last few years have increased the cure rates of HCV-infected patients to 95-100% regardless of HCV genotype. The regimens used include Sofosbuvir/Velpatasvir, Glecaprevir/Pibrentasvir (useful in renal failure), or Sofosbuvir/Velpatasvir/Voxilaprevir. These results make it possible to use HCV RNA viremic donor for recipients without HCV viremia.
Current discard rated for HCV positive donor organs in the UK: Upto 15 suitable donors are discarded annually due to HCV transmission (69% due to positive serological tests, D+). Using such organs can increase solid organ transplants by 75 extra transplants in UK annually.
Experience from outside the UK: 4.1% of all organ donors in US between 1995 and 2015 were anti-HCV antibody positive. Discard rates of anti-HCV antibody positive livers have reduced from 25% to 10%. EXPANDER-1 trial and HCV-TARGET trial have shown excellent SVR rates in liver and kidney transplant recipients.
Why HCV D+ to R- transplantation should be cost effective: In addition to morbidity and mortality benefits as well as better quality of life, timely transplant also reduces the costs associated with dialysis, one year of which is much more than the cost of DAAs.
What are the risks of HCV D+ to R- transplantation: The risks in this scenario including fibrosing cholestatic hepatitis (FCH) seen in 10% of liver transplants and 1.5% of kidney transplants with high mortality. Early post-transplant (within 4 weeks) DAA use has shown to be effective in FCH prevention and treatment. Transient, usually rapidly curable with DAA therapy, HCV infection is another risk in such scenario. <5% may develop DAA failure. Other concerns include extrahepatic HCV manifestations like cryoglobulinemic vasculitis, and PTLD as well as sexual transmission to a partner which can be easily prevented by lifestyle advice and early DAA use.
The practicalities of implementing this policy in UK: These include patient consent specifically to be taken in context of HCV D+/R- transplantation. Patient and unit requirements pre-transplant include screening patients with AST-to-platelet ratio index (APRI) and ultrasound abdomen and taking hepatologist opinion in presence of APRI>0.8 or ultrasound showing significant or advanced liver disease. Allocation of HCV D+ organs on the waiting list could be done as for HCV D- organs with sufficient experience. Management of recipient of a HCV D+ organ includes testing of HCV RNA PCR on day 3-7 post-transplant, then on day 10-14, and then 6 weeks post-transplant. If the reports are negative even at 6 weeks, the recipient can be reassured. If the HCV PCR comes out positive during the testing in first 6 weeks, the patient should be treated with DAAs (12 weeks of either Sofosbuvir/Velpatasvir or Glecaprevir/Pibrentasvir, and Sofosbuvir/Velpatasvir/Voxilaprevir if the first 2 regimes are not curative) within 3-10 days.
Special additional considerations:Acceptable donors include HCV antibody positive with either no history of HCV treatment or with document SVR post-treatment, or HCV antibody positive donor with history of exposure to risk not fulfilling unacceptable criteria, or HCV antibody positive patient whose HCV treatment history is unknown (proceed with caution in this scenario). Unacceptable donors include prior treatment with DAA for HCV in last 6 months without documentary proof of SVR, or failed treatment with ongoing viremia (to avoid resistant HCV transmission), or multiple documented HCV re-infections.
The prospective HCV-negative recipient should be provided with an information leaflet providing information regarding HCV-infected organ transplant.
UK Position Statement on the use of Organs from Hepatitis C Viraemic Donors and Increased Infectious Risk Donors in Hepatitis C Negative Recipient
16.7% of pts listed for SOT in UK die or get sick pre transplant and thus organs not regularly used for transplantation need to be use d ASAP to decrease waiting time and improve quality of life.
Most HEP C donor organs are not used due to high transmission risk. Pre DAA therapy, tx had poor tolerance and outcomes. Fibrosing cholestatic hepatitis had high death rate pre DAA therapy an occurrence that has since been reversed.
DAA therapy has led to cure rates of >95% with good outcomes in transplant recipients including Hep C -VE R/ Hep C +VE D pairs.
From a UK donor audit, utilization of HEP C donors at risk of rejection from high transmission risk will lead up to 75 potential SOT being done annually highlighting the importance of using these organs to shorten the waiting list and avail more organs for transplantation.
An MDT of a hepatologist, clinician, virologist and health rep have formulated guidelines for transplanting HEP C + VE to HEP C -VE recipient.
Vital parts of guidelines; Good donor, recipient consent policy, tx and testing guidelines as needed, monitoring group to follow up on the program and address any new issues that might come up once it is initiated.
Avoid D+/R- if APRI score is more than 0.8 or ALD/Cirrhosis on ultrasound.
Tx should be started early possibly within 3-10/7 with DAA in recipients getting organs from +VE donors ;Pangenomic regimen -Glecaprevir/Pibrenatasvir or SOF/VEL for 12/52
UK Position Statement on the use of Organs from Hepatitis C Viraemic Donors and Increased Infectious Risk Donors in Hepatitis C Negative Recipient
Most organs from donors infected with hepatitis C have hitherto been discarded because of the high likelihood of transmitting the infection in past.
95% of infected individuals can now be cured with directly acting antiviral agents and hepatitis C clearance can be safely achieved in transplant recipients after donation from Hepatitis C treated donor.
HVC Treatment
pan-genotypic regimens in the form of Sofosbuvir / Velpatasvir and Glecaprevir/Pibrentasvir
The pan-genotypic triplet of Sofosbuvir, Velpatasvir and Voxilaprevir
The advantage of Glecaprevir / Pibrentasvir is that it can be given to patients with established renal failure. HCV D Positive and Recipient negative transplant
Fibrosing hepatitis and extra hepatic manifestations are high.
There is an aggressive form of HCV recurrence seen in 10% of D+/R+ liver transplants Pre transplant requirements
AST-to-Platelet Ratio Index (APRI) and ultrasound is suggested
HCV D positive organ management
Standardized, longitudinal testing for hepatitis C RNA of the recipient following receipt of either a HCV antibody positive graft, a HCV RNA positive graft or a graft from an increased infectious risk donor
HCV positive organ donors
The exact drug regimens and length of therapy that should be offered to recipients that test positive for HCV after receiving an organ from a HCV D+ donor
Acceptable donors
HCV Ab positive with no history of treatment of HCV
HCV Ab positive with documented SVR after treatment
Any HCV Ab negative donor who has exposed themselves to risk but who does not fulfill any of the unacceptable criteria
Any HCV Ab positive donor whose HCV treatment history is unknown – proceed with caution
Unacceptable donors
Previously failed DAA therapy with on-going viraemia
UK Position Statement on the use of Organs from Hepatitis C Viraemic Donors and Increased Infectious Risk Donors in Hepatitis C Negative Recipient
Summary: Up to One in Six patients scheduled for SOT will die or become too unwell for a transplant despite the rise in organ donation in the UK. So, there is a need to find ways to better utilize organs that are frequently discarded.
Serologic tests can detect antibodies to HCV within two to six months of initial infection.
Chronic infection: defined as persistence of HCV RNA in serum for greater than six months after initial infection. This develops in at least 60% of those infected.
HCV antibody (anti-HCV) continues to remain positive for several years and often indefinitely after spontaneous clearance, or successful treatment of HCV with interferon or DAA therapy resulting in undetectable HCV RNA (SVR; sustained virologic response).
HCV viraemic refer to:
Donors or recipients who have active HCV infection with detectable HCV RNA, regardless of HCV antibody status
Donors that are HCV IgG +ve where the HCV RNA status is not known at the time of organ offering / transplantation.
Earlier treatment options were less effective at curing TX recipients of the virus & had less tolerance.
About > 95% of those with HCV can now be treated with DAAs.
The advantage of Glecaprevir / Pibrentasvir is that it can be given to patients with established renal failure.
These regimens also have high efficacy for the treatment of patients who have previously failed other DAA-containing regimens, with the best data currently available for Sofosbuvir, Velpatasvir and Voxilaprevir.
HCV infection in the potential donor does not amount to an absolute contraindication to donation of material for life-preserving transplantation, however the net benefit of transplantation must be considered against the risk of not receiving that specific transplant.
This risk/benefit analysis allows for the potential use of a transplant from a HCV infected donor to a non-infected recipient.
Why HCV D+ to R- transplantation should be cost effective:
All stakeholders are reassured that a course of therapy to cure a R- patient receiving a D+ organ would be less than the cost of dialysis for one year.
What are the risks of HCV D+ to R- transplantation:
The first and perhaps most feared risk is of fibrosing cholestatic hepatitis (FCH)
This is an aggressive form of HCV recurrence seen in 10% of D+/R+ liver transplants.
There are now increasing reports of DAA therapy being very effective in the setting of FCH.
A minority (in reality <5%) of patients treated after organ transplantation may experience DAA treatment failure, which may be associated with the development of difficult to treat resistance associated substitutions (RAS) especially in the viral NS5A protein, but also, for recipients of a protease inhibitor, in the NS3A region.
Data from the POLARIS-1 trial has shown that 12 weeks of re-treatment with the triple therapy combination of Sofosbuvir, Velpatasvir and Voxilaprevir is highly effective (>95%) in achieving cure of HCV in patients with HCV NS5A RAS at baseline.
Thus, virtually all HCV D+/R- recipients can be cured with modern DAA therapies, even if this is not achieved at the first attempt at treatment.
Extra-hepatic manifestations of HCV such as cryoglobulinaemic vasculitis or potential increased rates of blood derivedmalignancy such as PTLD are also theoretical consequences of HCV infection in the post-transplantation phase.
There are no data in the HCV D+/R+ field to demonstrate an increased risk of these consequences, and early DAA therapy should mitigate against these in any case.
Sexual transmission of HCV to a partner could potentially occur in the HCV D+/R- transplant scenario. The risk can be mitigated by simple lifestyle advice
A proper patient consent should be taken for D+/R- patients
AST-to-Platelet Ratio Index (APRI) and ultrasound is suggested.
APRI scores are easily calculated using on line tools such platelet-ratio-index-apri.
If the APRI score is >0.8 or the ultrasound suggests significant or advanced liver disease, then an opinion from a suitably qualified liver specialist should be sought before the patient is considered for a HCV D+ organ.
It was felt that even cirrhotic patients could potentially receive HCV D+ organs safely but that this was not an appropriate risk for the early phases of a new UK HCV D+/R- programme.
If the APRI score is <0.8, there is no need for the patient to be seen by a liver specialist.
Combination of Glecaprevir/Pibrenatasvir or the combination of Sofosbuvir/Velpatasvir should be given for 12 weeks in the context of HCV D+/R- transplants.
Both are pan-genotypic, which means that they can be started as soon as HCV PCR positivity is known, without having to wait for a HCV genotype, which can take 3-4 weeks in some areas.
Both have very acceptable drug to drug interaction profiles although exposure to the former is increased by ciclosporin, and it may also increase the levels of tacrolimus (CYP3A and P-glycoprotein inhibition); the latter is not recommended in patient with a eGFR <30 mL/min/1.73 m2,
Are rare (expected to be less than 2%) instances where the first course of treatment of HCV is not curative, recipients should be treated with a 12 week course of the combination of Sofosbuvir/Velpatasvir/Voxaleprevir which, as previously discussed, has high rates of SVR even in those previously exposed to DAA therapy.
The acceptability of HCV D+ donors is as follows:
Acceptable Donor :
HCV Ab positive with no history of treatment of HCV
HCV Ab positive with documented SVR after treatment
Any HCV Ab negative donor who has exposed themselves to risk but who does not fulfill any of the unacceptable criteria
Any HCV Ab positive donor whose HCV treatment history is unknown – proceed with caution
Not Recommended Donor Within Proposed Policy:
Previously failed DAA therapy with on-going viraemia
DAA therapy within last year without documented SVR (unless the recipient is at imminent risk of death)
Multiple documented re-infection with HCV
Conclusion:
The advantage of life-saving transplantation must be weighed against the harm of not getting organ donation from HCV positive.
This risk/benefit analysis allows an HCV-infected donor-to-non-infected recipient transplant.
DAA medication is recommended for all HCV-infected kidney transplant candidates.
In recent years, these novel hepatitis C medications have had few adverse effects and are well-tolerated by patients.
UK Position Statement on the use of Organs from Hepatitis C Viraemic Donors and Increased Infectious Risk Donors in Hepatitis C Negative Recipients
Introduction
· With the advent of highly effective and well tolerated direct-acting antiviral (DAA) therapy, that can cure more than 95% of patients infected with HCV, there is a need to assess whether organs from a HCV infected donors may safely be transplanted into HCV uninfected recipients.
· It is important to precisely define the serological and virological status of the donor.
· HCV D+ to R- transplantation is cost effective.
Risks of HCV D+ to R- transplantation
· Fibrosing cholestatic hepatitis, this is an aggressive form of HCV recurrence seen in 10% of D+/R+ liver transplants. There are now increasing reports of DAA therapy being very effective in the setting of FCH.
· Patients treated after organ transplantation may experience DAA treatment failure. However, data has shown that 12 weeks of re-treatment with DAA combination is highly effective in achieving cure of HCV in patients with drug resistance at baseline.
· Risk of Extra-hepatic manifestations of HCV such as cryoglobulinaemic vasculitis or PTLD is a theoretical risk and no reports of an increased risk.
Patient Consent
· Consent to receive a HCV D+ organ should be specifically obtained by individual transplanting centres.
Patient and Unit Requirements Pre-Transplant
· HCV D+/R- non-liver transplantation should be avoided in recipients with advanced fibrosis or cirrhosis.
· Checklist of pre-requisites that must be in place before an individual transplanting centre performs its first HCV D+/R- transplant would be valuable.
Allocation of HCV D+ Organs on the Waiting List
· HCV D+ organs should be treated in the same way as HCV D- organs within the current allocation rules of the national waiting lists.
· But different organ Advisory Groups will need to decide how best to offer and allocate such organs in order to optimise organ utilisation.
Management of the Recipient of a HCV D+ Organ
· Organ donors should be tested for HCV by PCR, if positive check for genotype.
· Recipient should be checked for HCV PCR by day 3-7, 10-14, 6 weeks, post-transplant.
· If HCV PCR is positive give DAA therapy within 3- 10 days of result.
· The combination of Glecaprevir/Pibrenatasvir or the combination of Sofosbuvir/Velpatasvir for 12 weeks.
· Treatment should be given in liaison with a clinical team with experience of management of HCV, but not necessarily have to be delivered in the transplanting centre.
Special Additional Considerations
Donors recommended to use:
· HCV Ab positive with no history of treatment of HCV.
· HCV Ab positive with documented SVR after treatment.
· Any HCV Ab negative donor who has exposed themselves to risk but who does not fulfill any of the unacceptable criteri.
· Any HCV Ab positive donor whose HCV treatment history is unknown – proceed with caution.
Donors not recommended to use:
· Previously failed DAA therapy with on-going viraemia
· DAA therapy within last year without documented SVR (unless the recipient is at imminent risk of death).
· Multiple documented re-infection with HCV.
Next Steps in the Process
· Transplant units should make sure that there is clear provision for DAA therapy in their local areas before implement this proposals.
Two-year-old therapeutic options rejected HCV-infected organs. 3-DAAT for HCV has a 95% cure rate, and transplanting HCV-positive organs from treated donors into HCV-negative recipients was encouraging. After a multidisciplinary team examination, organs from hepatitis C-infected donors can be used for uninfected recipients with restrictions.
DAA-treated HCV D+ to HCV R- transplant recipients are treatment-nave, noncirrhotic, and likely to achieve SVR. HCV; current treatment · Pan-genotypic regimens in the form of Sofosbuvir / Velpatasvir and Glecaprevir/Pibrentasvir. · The pan-genotypic triplet of Sofosbuvir, Velpatasvir and Voxilaprevir was licenced in August 2017. · The advantage of Glecaprevir / Pibrentasvir is that it can be given to patients with established renal failure. The risks of HCV D+ to R- transplantation : Fibrosing cholestatic hepatitis and extra-hepatic manifestations of HCV Consent HCV+ organ recipients must sign a specific consent. Pre-transplant essentials HCV D+ non-liver organ recipients are tested using AST-to-Platelet Ratio Index (APRI) and ultrasonography to determine if a hepatic specialist is needed. HCV D+ organ management Standardized HCV RNA testing of the recipient after receiving an HCV Ab positive, RNA positive, or graft from an enhanced infectious risk donor to detect HCV transmission and infection early. For HCV-positive donor organs The donor PCR must be tested in a central lab. If positive, genotyping testing must be done and all centres must be informed within 2 days. If negative, all centres must be informed. The negatively consenting recipient must undergo an HCV PCR test 3-7 days after transplant, repeated 10-14 days, and retested 6 weeks afterwards. Treatment – DAA should be begun within 3-10 days of a positive HCV PCR test. – Two pan-genotypic, 12-week regimens for HCV D+/R- transplants are Glecaprevir/Pibrenatasvir or Sofosbuvir/Velpatasvir. – After first DAAAT failure, 12-week Sofosbuvir/Velpatasvir/Voxaleprevir has high SVR rates. Accepted donors – HCV Ab positive with no HCV treatment history – HCV Ab positive reaching SVR after treatment – HCV Ab negative donor exposed to risk but does not meet the unacceptable criteria – HCV Ab positive donor with unknown treatment history. Unrecommended donors Include instances with failed DAA therapy and persistent viraemia, DAA therapy within last year without confirmed SVR, and repeated HCV reinfection.
Active donor HCV infection is considered a contraindication to donation, due to the fear of transmission of HCV from the donor to the recipient and this was accepted only if the recipient is HCV positive
D+/R- transplantation is associated with 100% viremia of the recipient detected early after transplantation, so carry the highest risk
On the other hand accepting HCV positive donors will save transplant candidates as in UK a recent analysis found that around 15 suitable donors are excluded per year due to HCV infection and around 20% of waitlisted transplant recipients either die or become unfit for transplantation.
All donors should be screened for HCV using both anti-HCV antibodies and PCR
After infection, HCV Abs appears after 2-6 months of infection and persists for years it denotes previous or current infection, while the PCR needs 5-7 days to be detected and a positive PCR denotes active infection.
Around 60 % of cases infected with HCV will develop chronic HCV infection defined as the detection of HCV PCR after 6 months of infection.
If donor anti-HCV Abs (+), PCR (-) this means either spontaneous resolution of HCV (occur in 42% of cases but not common in immunocompromised individuals) or resolution after treatment, this type of donation is associated with seroconversion but minimal viremia indicating that the donor may has occult infection or has reinfection and is in the window period (assessment of risk behaviors is important) .
If donor anti-HCV Abs (+), PCR (+) this denotes active viremia and this type of donation is associated with high risk of transmission and viremia.
If anti-HCV Abs (-), PCR (+) this indicates early infection in the window period since serology needs 2-6 months while PCR needs 5-7 days to detect infection, and this also denotes active viremia and this type of donation is associated with high risk of transmission and viremia.
HCV viremic donors are referred to donors with either PCR positive regardless of antibodies or HCV Ab positive donors if the PCR status is unknown
In the new era of directly acting drugs which has high efficiency, with more tolerability than previous IFN based therapy, it is applicable to use infected kidney to increase the donor pool and narrow the gap between kidney supply and demand.
Risks associated with transplanting kidney from HCV + donor to HCV – kidney recipient
The most important and feared risk is the development of fibrosing cholestatic hepatitis (FCH) which is associated with high mortality, it occur in up to 1.5 % or renal transplant recipients receiving infected kidneys ( it occurs in 10 % of D+/R+ liver transplants recipients), the use of modern DAA decrease the incidence of this condition and cure it effectively if happen.
Theoretical increase in the risk of cryoglobulinaemic vasculitis and post-transplant malignancy as PTLD which is not proved in practice and even so the use of modern DAA will vanish this risk
Very low risk of sexual transmission of HCV to a the transplant partner (< 2 %) and this can be managed by education, life style modification and early treatment with DAA
Approach for transplanting kidney from HCV + donor to HCV – recipient
The main challenge is transmission of HCV from donor to the recipient with possibility of HCV related hepatic affection and extra hepatic complications including GN, so the following approach should be done in order to improve outcome:
Avoid these types of donors
Donors with history of failed treatment with ongoing viremia.
History of DAA treatment in the previous year without documented SVR.
Donor with history of multiple relapses.
HCV related renal disease should be excluded.
Selecting appropriate recipient
Recipient should be willing to take an infected kidney (consent should be taken)
The recipient should be in urgent need for a graft such as those with no vascular access or those with expected very long time on waiting list.
The recipient should have no advanced fibrosis or cirrhosis, so patients should be screened using AST-to-Platelet Ratio Index (APRI) and ultrasound and if APRI is > 0.8 or the ultrasound is showing fibrosis, consultation of liver specialist is advised before transplanting an infected organ.
Recommended protocol by UK
HCV PCR should be done at 3-7 days post transplantation, if negative it should be repeated at 10-14 days and then at 6 weeks after transplantation, if persistently negative, the patient should be assured.
If HCV RNA is detected at any time antiviral treatment should be started within 3-10 working days of positive result
Antiviral therapy
Pan-genotypic regimens include Sofosbuvir / Velpatasvir, Glecaprevir/Pibrentasvir and Sofosbuvir, Velpatasvir and Voxilaprevir.
All these regimens are highly effective and provide cure rate of > 95%
The recommended duration of therapy is between 2-4 months, 3 months is the preferred duration in renal transplant recipients
These regimens can be started without waiting for the genotype assessment that can take 3-4 weeks since both regimens are pan-genotypic.
All these regimens especially (Sofosbuvir, Velpatasvir and Voxilaprevir ) have the advantage in the successful treatment of resistant HCV infection to other DAA since the resistance to these agents is < 5 %
Glecaprevir / Pibrentasvir regimen (Sofosbuvir-free regimen ) is the only regimen that can be used safely in renal failure
Both regimens have very acceptable drug -drug interaction but the Glecaprevir/Pibrenatasvir may increase tacrolimus level
So … first line therapy includes the use of one of 2 regimens (for 3 months), Glecaprevir/Pibrenatasvir or Sofosbuvir/Velpatasvir and If the first line regimen fail (< 2 %), the patient should be given Sofosbuvir/Velpatasvir/Voxaleprevir for 3 months
introduction: HCV is a single-stranded RNA Flaviviridae virus. Six genotypes (G1-6) and many sub-genotypes have been described. HCV is transmitted parenterally (via IVDU or blood products), sexually (predominantly individuals who have unprotected anal intercourse with several partners), or vertically, from mothers to Newborns, and can cause acute or chronic hepatitis. Acute infection is subclinical, but chronic infection is defined by HCV RNA in serum for more than six months after initial infection. This occurs in at least 60%. During two to six months of infection, serologic testing can identify HCV antibodies. However, the most crucial factor in determining an organ donor or recipient’s HCV infectivity is whether they are viraemic, with detectable HCV RNA by PCR or NAT. After spontaneous clearance or effective treatment with interferon or DAA therapy, HCV antibody (anti-HCV) remains positive for years and often indefinitely. DAA therapy for HCV enhanced the number of HCV antibody-positive patients with undetectable HCV RNA. 25 HCV antibody-negative receivers who got donor livers from anti-HCV antibody-positive but HCV RNA-negative “HCV high risk” donors were followed up by the University of Cincinnati. All patients performed follow-up HCV RNA testing, and 4 (16%) developed HCV viremia within three months of transplantation. These findings suggest HCV transmission from high-risk donors in the reinfection window. Occult HCV, or residual HCV viral genomes, in donor tissue may also transmit HCV. so, rigorous testing of transplant recipients is required. This publication shall utilize the term “HCV viraemic” to refer to donors or recipients who have active HCV infection with detectable HCV RNA, regardless of HCV antibody status, as well as HCV IgG +ve donors whose HCV RNA status is unknown at the time of organ donation or transplantation. Changes in the treatment of hepatitis C over the past five years: Six years ago, HCV management changed greatly. DAAs with interferon and ribavirin increased G1 HCV cure rates from 50% to over 80%. Typically 8-16-week clinical regimens cure 95-100% of non-cirrhotic patients regardless of HCV genotype. Few regimens use ribavirin. Second and third-generation DAA regimens help cirrhosis and kidney/liver transplant patients. This treatment adjustment suggests transplanting HCV RNA viraemic donor (D+) organs to R- recipients to minimize morbidity and mortality on solid organ transplant waiting lists. This article aims consensus to allow HCV-viraemic donor organs for HCV-negative UK recipients. Why HCV D+ to R- transplantation should be cost-effective: A course of therapy to cure an R- patient receiving a D+ organ will cost less than one year of dialysis. Reducing waiting times and dialysis costs will save money most importantly, should save lives and improve patient quality of life. What are the risks of HCV D+ to R- transplantation? HCV D+ to R- transplantation has economic and health benefits, but hazards must be considered. Fibrosing cholestatic hepatitis is the main concern. 10% of D+/R+ liver transplants have aggressive HCV recurrence. FCH was fatal before DAA therapy. In SOLAR-1 and 2, Sofosbuvir plus Ledipasvir for 12 or 24 weeks healed all 11 FCH patients after liver transplantation. In 15 FCH patients treated with Sofosbuvir and Daclatasvir after liver transplantation, Leroy et al. reported 100% cure rates. Many case reports and short case series have successfully managed FCH with LFT normalization. HCV D+/R- transplantation followed by early DAA therapy would cause a brief, easily treatable infection. Another theoretical concern is that a minority (in reality <5%) of patients treated after organ transplantation may fail DAA treatment. To reduce this risk, early HCV D+/R- programs may increase treatment duration from 8 to 12 weeks or 12 to 16 weeks. In patients with HCV NS5A RAS at baseline, 12 weeks of triple therapy with Sofosbuvir, velpatasvir, and Voxilaprevir cures HCV >95%. Hence, current DAA medications can cure most HCV D+/R- recipients. HCV infection post-transplantation may cause extra-hepatic symptoms such as cryoglobulinaemic vasculitis or blood-derived malignancies like PTLD. Early DAA therapy should prevent these outcomes, as HCV D+/R+ studies show no elevated risk. HCV D+/R- transplants may cause sexual transmission of HCV. Lifestyle guidance and early DAA therapy post-transplantation can reduce risk. This risk may be very minimal (<2%). Patient and Unit Requirements Pre-Transplant: HCV D+/R- transplantation is relatively new. The working team recommended avoiding HCV D+/R- non-liver transplantation in recipients with advanced fibrosis or cirrhosis to be safe. Screening patients with AST-to-Platelet Ratio Index (APRI) and ultrasound instead of requiring liver specialists for all HCV D+ non-liver organ recipients is more practical. Before considering an HCV D+ organ, a liver specialist should be consulted if the APRI score is >0.8 or the ultrasound indicates advanced liver illness. Cirrhotic patients could get HCV D+ organs safely, but a new UK HCV D+/R- program should not take this risk at the time being. No liver specialist is needed if the APRI score is <0.8. Allocation of HCV D+ Organs on the Waiting List: The working group decided that, once sufficient expertise has been obtained and outcomes are favorable, HCV D+ organs should be handled the same as HCV D- organs within the current allocation rules of the national waiting lists as determined by the individual NHSBT bodies, such as the Liver Advisory Group, Kidney Advisory Group, and Cardiothoracic Advisory Group. Advisory Groups must decide how to give and assign organs during the initial phase of any HCV D+ to HCV R- program to maximize organ use. Advisory Panels must frequently examine post-transplant outcomes to adjust offering and allocation strategies. Management of the Recipient of HCV D+ Organ:
PCR testing after 3 days, 14 days & 6 weeks, if negative, handle as a standard recipient, but if positive, start DAA within 3 days.
Two alternative regimens should be used as first-line agents. These are either the combination of glecaprevir/Pibrenatasvir or the combination of Sofosbuvir/velpatasvir. Both should be given for 12 weeks in the context of HCV D+/R- transplants.
IV. UK Position Statement on the use of Organs from Hepatitis C Viraemic Donors and Increased Infectious Risk Donors in Hepatitis C Negative Recipient
Please summarise this article
Introduction
Greater use can be made of organs from hepatitis C (HCV) infected donors, With
the advent and licensing of highly effective and well tolerated direct-acting antiviral (DAA) therapy
that can cure more than 95% of patients infected with HCV, regardless of genotype, there is a
pressing need to assess whether organs from HCV infected donors may safely be transplanted into
HCV uninfected recipients. Introduction to HCV and Clarification of Nomenclature
HCV is a single stranded RNA virus member of the Flaviviridae family. Six genotypes (G1-6) and a large
number of sub-genotype.
Transmission of HCV generally occurs:
1.parenterally (through intravenous drug use (IVDU) or blood products).
2.sexually (predominantly those who have unprotected anal sex with multiple partners)
3. vertically, from mothers to infants. Acute infection tends to be subclinical, with chronic infection, defined as persistence of HCV RNA in serum for greater than six months .
the most important parameter to be considered when assessing the HCV infectivity of an organ donor
or recipient is whether or not active HCV replication is present through HCV RNA by sensitive genome amplification methods such as polymerase chain reaction nucleic acid testing. ‘HCV viraemic’ used to refer to donors or recipients who have active HCV infection with detectable HCV RNA, regardless of HCV antibody status; it also refers to donors that are HCV IgG +ve where the HCV RNA status is not known at the time of organ offering / transplantation. Changes in the treatment of hepatitis C over the past five years
There has been a revolution in the management of HCV in the past six years. This began with the
licensing of the first generation protease inhibitors Telaprevir and Boceprevir in 2012. These prototype
direct-acting antiviral (DAA) drugs were combined with interferon and ribavirin, and increased cure
rates for patients with G1 HCV from 50% to over 80%.
Most of the current regimens used in clinical practice are given for between 8 and 16 weeks, and offer cure rates of 95-100% for patients without cirrhosis, regardless of HCV genotype.
This paper seeks to establish a professional consensus to enable the use of HCV viraemic donor organs for HCV negative recipients in the United Kingdom. Current discard rates for hepatitis C positive donor organs in the UK
The most up to date UK data available was published in 2017 by Trotter and colleagues. Using data from the UK Transplant Registry and the National Potential Donor Audit from 2000 to 2015, they identified 244 HCV antibody positive donors during that 16 year time period, The quality of the declined
organs did not differ from that of the organs that were used, with positive serological tests reported
as the reason for decline in 69% of cases. HCV infection in the potential donor does not amount to an absolute contraindication to donation of
material for life-preserving transplantation, however the net benefit of transplantation must be
considered against the risk of not receiving that specific transplant. This risk/benefit analysis allows
for the potential use of a transplant from a HCV infected donor to a non-infected recipient.’
This change in the guidance paves the way for potential D+ to R- transplants. Why HCV D+ to R- transplantation should be cost effective
Although the exact cost of DAAs to the NHS remains commercially confidential, all stakeholders are
reassured that a course of therapy to cure a R- patient receiving a D+ organ would be less than the
cost of dialysis for one year. What are the risks of HCV D+ to R- transplantation?
1.The most risk is of fibrosing cholestatic hepatitis
2.infecting individuals with cytomegalovirus (CMV) or Epstein Barr virus (EBV) at the time of organ transplantation.
3. DAA treatment failure.
4. Extra-hepatic manifestations of HCV such as cryoglobulinaemic vasculitis or potential increased rates
of blood derived malignancy . Patient Consent
obtained by individual transplanting centres.
To do it in working group.
In sharing information with and gaining consent from solid organ transplant candidates, and
inclusion of consent for HCV D+/R- transplantation will need to form part of this work.
Allocation of HCV D+ Organs on the Waiting List
HCV D+ organs should be treated in the same way as HCV D- organs within the current allocation rules . Management of the Recipient of a HCV D+ Organ
Individual units may also wish to consult with their virology laboratories to enhance testing for HIV and HBV.
1.combination of Glecaprevir/Pibrenatasvir .or
2.combination of Sofosbuvir/Velpatasvir.
Recipients should be treated with a 12 week course.
A significant number of patients still die due to a shortage of donor organs, SOT improves patient survival and quality of life.
Greater use can be made of organs from hepatitis C (HCV) infected donors, that was previously discarded, this would not be possible before the highly effective DAA.
HCV is a single stranded RNA virus member of the Flaviviridae family. Six genotypes (G1-6).
Transmission of HCV generally occurs parenterally (through intravenous drug use (IVDU) or blood products), sexually (predominantly those who have unprotected anal sex with multiple partners) or vertically, from mothers to infants, and can lead to sequelae of acute or chronic hepatitis.
Acute infection tends to be subclinical, with chronic infection, defined as persistence of HCV RNA in serum for greater than six months after initial infection. This develops in at least 60% of those infected.
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.
R- patient receiving a D+ organ would be less than the cost of dialysis for one year.
The first and perhaps most feared risk is of fibrosing cholestatic hepatitis (FCH), an aggressive form of HCV recurrence seen in 10% of D+/R+ liver transplants, DAA is an effective therapy preventing FCH.
HCV D+/R- transplantation followed by early DAA therapy would result in only a transient, usually rapidly curable infection, though cryoglobulinaemic vasculitis or potential increased rates of blood derived malignancy such as PTLD are consequences of HCV infection in the post-transplantation phase.
Patient Consent:
– Although patients are currently routinely consented to receive ‘marginal’ organs by individual transplanting centres.
– Patient and Unit Requirements:
– HCV D+/R- non-liver transplantation should be avoided in recipients with advanced fibrosis or cirrhosis. Every patient being consented to receive a HCV D+ non-liver organ be seen by a liver specialist.
– Screening patients using AST-to-Platelet Ratio Index (APRI) and ultrasound is suggested, If the APRI score is >0.8 or the ultrasound suggests significant or advanced liver disease, then an opinion from a suitably qualified liver specialist should be sought before the patient is considered for a HCV D+ organ. Allocation of HCV D+ Organs on the Waiting List:
– HCV D+ organs should be treated in the same way as HCV D- organs within the current allocation rules of the national waiting lists.
– Frequent review of post-transplant outcomes will be needed in order to enable Advisory Groups to alter offering and allocation policies as needed.
– The following donors should be excluded: a) Previously failed DAA therapy with on-going viraemia. b) DAA therapy within last year without documented SVR, except in recipient lifesaving issues. c) Multiple documented re-infection with HCV. Management of the Recipient of a HCV D+ Organ:
– There was consensus on regular testing for hepatitis C RNA of the recipients, of either a HCV antibody positive graft, a HCV RNA positive graft or a graft from an increased infectious risk donor, to ensure appropriate and early intervention if HCV transmission and infection occurs.
– Multidisciplinary team work is needed in those patients (virologist, hepatologist, transplant physician, and pharmacologist).
– Glecaprevir/pibrenatasvir or sofosbuvir/velpatasvir should be given for 12 weeks in HCV D+/R- transplants.
Use oF D+ IN R+ is common for liver and still rare in kidney transplants
With effective DAA , waiting list R+ are going down
use of D+ in R- is the way forward to avoid organ wasting
in UK registry
Organ was decline in 69% of cases only for HCV positive status
in USA
liver is not discarded for HCV positive status but non liver organ are still discarded
COST
in KT , cost of such D+/R- is less than dialysis
RISK
fibrosing cholestatic hepatitis (FCH) is real risk and common in liver transplants
1-2 % of kidney transplant
ETHICAL issue
high mortality on waiting ;list can justify this
In general , D+/R- transplant leads to transient, usually rapidly curable HCV infection.
CONSENT
consent to receive a HCV D+ organ should be
specifically obtained by individual transplanting centers.
HOW TO START D+/R- transplant ?
AVOID If the APRI score is >0.8 or the ultrasound suggests significant or advanced
liver disease
ALLOCATION
HCV D+ organs should be treated in the same way as HCV
D- organs within the current allocation rules
RECIPIENT WITH D+ ORGAN
Tested for HCV PCR ON 3/7 DAY , 10-14 DAY AND 6 WEEK
START DAA within 3-10 days
TREATMENT
Glecaprevir/Pibrenatasvir or the combination of Sofosbuvir/Velpatasvi
Summary
HCV is a single stranded RNA virus that belongs to the flaviviridae family with 6 genotypes.Transmission is through parenteral, sexually and vertical transmission.
Acute infections is subclinical while chronic infection the HCV RNA persists for more 6 months.
Serologic tests can detect antibodies within 2-6 months after infection and they can remain positive indefinitely after clearance or successful treatment. HCV PCR or antigen test determine the infectivity thus are more important.
Most of current DAA treatments are given for 8-16 weeks and have a cure rate of 95-100% in patients without cirrhosis regardless of the genotype. Glecaprevir / Pibrentasvir has advantage of other regimens since it can be used in renal failure.
This current regimens have allowed the use of HCV D+/R- organs that would have otherwise been discarded.
Several trials have looked at outcomes of HCV D+/R- SOT:
Goldberg et al single centre trial of 10 kidney recipients (D+/R-) HCV G1, all were viremic by day 3 and received 12 weeks of Grazoprevir/Elbasvir. All achieved SVR12 after cessation of treatment.
EXPANDER 1 trial 10 kidney recipients D+/R- genotype not known. Grazoprevir/Elbasvir started before transplant and continued for 12 weeks. 8 patients achieved SVR12 and all 10 completed treatment with no adverse events.
Fernades et al and Saxon who had larger patient populations also reported similar results.
For HCV D+/R- to proceed the R must be HCV naive, no liver cirrhosis and likely to achieve SVR12.
The use of HCV donors in kidney transplantation will reduce the waiting time in transplant list and the cost of dialysis.
Risks of HCV D+/R- transplantation are:
Fibrosing cholestatic hepatitis- was associated with high mortality prior to DAA. SOLAR 1 and 2 studies all liver transplant recipients with FCH achieved cure with DAA.
Ethical issue-the high morbidity and mortality of patients on transplant waiting list justify their use.
DAA treatment failure following SOT-POLARIS trial re-treatment for 12weeks with triple therapy achieved cure rates >95%.
Extra hepatic manifestations-theoretical risk no studies have shown an increased risk could also be mitigated by DAA.
Risk of HCV sexual transmission- can be mitigated by early initiation of DAA post-transplant and lifestyle changes.
HCV D+/R- should be avoided in cirrhotic or in advanced fibrosis.
First line DAA agents to be used Glecaprevir/Pibrenatasvir or Sofosbuvir/Velpatasvir for 12 weeks, both are pan-genotypic with acceptable drug-drug interaction.
Organs from donors treated for HCV in the last 6 months should be avoided unless there is proof of an SVR12 results.
Individual transplanting centre should obtain consent from R to use a HCV+ donor.
IntroductionSolid organ transplants help greatly in reducing the mortality and morbidity of the affected patients. Unfortunately, there is a shortage of organ donors. In order to increase the number of organs available for transplantation, there is a continuous review of organs that have been discarded, to assess whether advances in medicine could enable such organs to be transplanted.
It has now been studied that greater use can be made of organs from hepatitis C (HCV) infected donors, due to highly effective and well tolerated direct-acting antiviral (DAA) therapy that can cure more than 95% of patients infected with HCV. There is a need to assess whether organs from HCV infected donors may safely be transplanted into HCV uninfected recipients.
Introduction to HCV and Clarification of NomenclatureHCV is a single stranded RNA virus member of the Flaviviridae family. It has six genotypes (G1-6). Transmission of HCV generally occurs parenterally (through intravenous drug use (IVDU) or blood products), sexually (predominantly those who have unprotected anal sex with multiple partners) or vertically, from mothers to infants, and can lead to sequelae of acute or chronic hepatitis.
Acute infection tends to be subclinical, with chronic infection, defined as persistence of HCV RNA in serum for greater than six months after initial infection. Serologic tests can detect antibodies to HCV within two to six months of initial infection. An important parameter to consider when assessing the HCV infectivity of an organ donor or recipient is whether or not active HCV replication is present.
Current discard rates for hepatitis C positive donor organs in the UKThe current practice is to restrict the use of HCV D+ organs to HCV positive recipients (R+). Data from the UK Transplant Registry and the National Potential Donor Audit from 2000 to 2015 identified 244 HCV antibody positive donors during a 16 year time period. Organs from only 76 (31%) of these donors were transplanted into 93 recipients (63 liver, 27 kidney and 2 heart transplants).
The declined donors often had good kidney and liver function based on validated UK Donor Risk Indices. The UK Advisory Committee on the Safety of Blood, Tissues and Organs (SaBTO) states that ‘HCV infection in the potential donor does not amount to an absolute contraindication to donation of material for life-preserving transplantation, however the net benefit of transplantation must be considered against the risk of not receiving that specific transplant. This risk/benefit analysis allows for the potential use of a transplant from a HCV infected donor to a non-infected recipient.’
Experience from outside the UKThe United States has the best data on D+ donor numbers as well as on discard rates, and is leading the way in early clinical trials of D+ to R- transplants. Utilisation of HCV antibody positive livers has increased with time but these have been transplanted exclusively into HCV R+ patients. A conference of the American Transplantation Society was held in January 2017, it was decided to consider D+ to R- transplantation across all solid organs within set criteria, and recommended that such practice should take place within prospective research protocols.
Part of the rationale for this strong recommendation has been emerging clinical trial data from the renal field. Goldberg et al published a single centre trial at the University of Pennsylvania involving 10 kidney transplant recipients, all were given HCV D+ kidneys from individuals infected with genotype 1 HCV. All recipients became viraemic by day 3 and all received 12 weeks of treatment with Grazoprevir/Elbasvir as soon as the positive result was obtained. These drugs can be used safely in patients with kidney failure. All the recipients were cured 12 weeks after cessation of therapy.
Results in a larger cohort of patients were reported by Saxena et al from the HCV-TARGET consortium of Academic US centres. In this paper 443 patients were treated after organ transplantation. There were 347 liver transplant recipients, 60 kidney transplant recipients and 36 dual transplant recipients included in the study. The majority were treated with Sofosbuvir and Ledipasvir (an earlier generation combination), with or without ribavirin. Overall SVR12 rates were 96.3% in liver recipients, 94.6% in kidney recipients and 90.9% in kidney/liver recipients. There were 6 episodes of rejection in total; 4 in the liver recipients and 2 in kidney recipients. It should be noted that 42% of the recipients had liver cirrhosis and 54% had previously failed HCV treatment. These patients would be classified as difficult to treat in a pre-transplant setting and in that context the SVR12 results are in fact quite impressive.
Why HCV D+ to R- transplantation should be cost effectiveDialysis is expensive and this cost would be mitigated by timely transplantation, particularly in individuals who are highly sensitised or otherwise difficult to transplant and who may spend many years on dialysis. More importantly, despite the fact that patients can survive on dialysis for many years, their quality of life is significantly reduced. A course of therapy to cure a R- patient receiving a D+ organ would be less than the cost of dialysis for one year.
What are the risks of HCV D+ to R- transplantation?
Fibrosing cholestatic hepatitis
The concept of knowingly infecting a patient with an infectious agent
Patients treated after organ transplantation may experience DAA treatment failure
Extra-hepatic manifestations of HCV such as cryoglobulinaemic vasculitis or potential increased rates of blood derived malignancy such as PTLD
Sexual transmission of HCV to a partner could potentially occur
The Practicalities of Implementing this Policy in the United Kingdom
It is required to obtain consent from the recipients, specifically for receiving a HCV D+ organ.
HCV D+/R- non-liver transplantation should be avoided in recipients with advanced fibrosis or cirrhosis
Allocation of HCV D+ organs should be treated in the same way as HCV D- organs
A combination of Glecaprevir/Pibrenatasvir or Sofosbuvir/Velpatasvir should be given for 12 weeks in the context of HCV D+/R- transplants.
Summary:
· Up to 1 in 6 patients listed for solid organ transplantation will die or become too sick for a transplant. So, it needs to continuously explore improving the utilization of organs that are not currently widely used for transplantation.
· Organs from donors infected with hepatitis C have been discarded because of the high likelihood of transmitting the infection to the recipient. Older treatment modalities had poor tolerance and were not sufficiently successful in curing transplant recipients of the infection.
· Recent advances in the management of hepatitis C infection have changed the scenario as more than 95% of infected individuals can now be cured with directly acting antiviral agents.
· Studies have shown that similar outcomes of hepatitis C clearance can be safely achieved in transplant recipients and small trials have shown excellent outcomes in Hepatitis C negative recipients given hepatitis C infected organs who were subsequently treated and cured of the virus.
· A recent analysis of the UK Potential Donor Audit has suggested that up to 15 suitable donors are declined every year because of the risk of transmission of hepatitis C.
· Using organs from such donors could result in up to 75 extra solid organ transplants being performed every year in the UK.
· Following the recent recommendations by the Advisory Committee on the Safety of Blood, Tissues and Organs that, in some clinical situations, organs from hepatitis C infected donors may be transplanted into uninfected recipients.
· Selection of appropriate donors, a policy for ensuring the intended recipient gives fully informed consent, guidance for the testing and treatment of recipients as indicated, the formation of a monitoring group to oversee the program in the 6 early phases of implementation as well as consideration of some of the headline operational issues that will arise during successful implementation of the pathway.
It has been shown that solid organ transplantation has increased the number of people living that would have died if not for the intervention. Unfortunately, the number of those on the wait list is also on the rise, hence necessitating a new and safe way of making available organs from donors with HCV that used to be discarded. In about twelve months in the UK alone, close to 500 people died on the waitlist.
The introduction of DAA has significantly made possible the use of donors with HCV infection not only to HCV-positive recipients but also to those that are negative and willing to accept.
The status of the supposed donor needs to be ascertained through very sensitive tests. Although, even with the PCR the window period could still be missed and this is part of the challenges still holding back the full acceptability of this method of making more organs available for transplantation.
Changes in the treatment of hepatitis C in the last 5 years
The revolution of new medication started in 2012 with the introduction of Telaprevir and Boceprevir
The current regimens used for treatments are given for between 8 and 16 weeks, and offer cure rates of 95-100% for patients without cirrhosis, regardless of HCV genotype
The introduction of the pan-genotypic regimens in the form of Sofosbuvir / Velpatasvir and Glecaprevir/Pibrentasvir has made cure a reality
Current discard rate of HCV-infected organs in UK
The current practice in the UK is the use of HCV D+ /R+organs predominantly accepted in liver transplantation. Anecdotal evidence points
The efficacy of DAA has resulted in the reduction of R+, hence causing a second thought on the possibility of extending this to R-
The conclusion of The UK Advisory Committee on the Safety of Blood, Tissues, and Organs is:
‘HCV infection in the potential donor does not amount to an absolute contraindication to the donation of material for life-preserving transplantation, however, the net benefit of transplantation must be considered against the risk of not receiving that specific transplant. This risk/benefit analysis allows for the potential use of a transplant from an HCV-infected donor to a non-infected recipient.’
Experience from outside the UK
The discarded rate of HCV D+ liver declined from 25% in 2006 to 10% in 2015 and is closely related to HCV D- liver
The conference of the American Transplantation Society made a consensus in favour of considering D+ to R- transplantation across all solid organs within set criteria and recommendations
Some clinical trials done with the use of DAA for 12 weeks have come out with encouraging positive outcomes
What are the risks of HCV D+ to R- transplantation?
Fibrosing cholestatic hepatitis
Ethical issues of infecting a recipient with infection
Risk of DAA treatment failure
Cryoglobulineamic vasculitis
Risk of sexual transmission of HCV to partner
The Practicalities of Implementing this Policy in the United Kingdom
Patient consent: Aside from consenting to receive a marginal kidney while on the waitlist, another consent should be obtained by the transplant centre for HCV D+
Patient and the unit requirement pre-transplant
Allocation of the HCV D+ organs on the waitlisting
Management of the recipient of the HCV D+ organ
Any organ from a donor who has been treated for HCV with DAAs but has not achieved SVR12 for any reason should not be considered for transplantation into a negative recipient except in urgent transplantation
Article Summery
Most organs from donors infected with HCV were discarded for transplantation because of the high risk of transmission of this infection post-Transplant. Recent introduction of DAA led to cure in >95% of HCV related infection. Similarly, the outcomes are even excellent in Hepatitis C negative recipients, given organs from HCV+ Donar, who were subsequently treated and cured of the virus with DAA.
According to recommendations by the Advisory Committee on the Safety of Blood, Tissues and Organs, Different organs from hepatitis C infected donors may be transplanted into uninfected recipients. Appropriate donor might be selected and fully informed consent should be taken from the recipient.
Introduction
Shortage of donor organs because of increase demand have prompted researcher to look for alternate avenue. With the advent of DAA therapy with cure rate >95% of patients regardless of genotype, HCV donors can be used for organ donations.
HCV is a single stranded RNA virus (member of the Flaviviridae family). It has Six genotypes (G1-6) with a large number of sub-genotypes. Transmission is parenterally (through intravenous drug use (IVDU) or blood products), sexually (predominantly those who have unprotected anal sex with multiple partners) or vertically, from mothers to infants.
Acute infection is usually subclinical but Chronic infection (persistence of HCV RNA in serum for six months after initial infection) occurs in at least 60% of cases. Serologic tests can detect antibodies to HCV within 2-6 months of initial infection with the virus. HCV RNA detection should be carried out when assessing the HCV infectivity of an organ donor or recipient. Transmission of infection may occur from donors during the window period of acute infection which can be missed due to absence of HCV antibodies.
Changes in the treatment of hepatitis C over the past five years
DAA are usually given for 8 and 16 weeks and offer cure rates of 95-100% for patients without cirrhosis, regardless of HCV genotype.
Two licensed pan-genotypic regimens (Sofosbuvir / Velpatasvir and Glecaprevir/ Pibrentasvir) are moistly used.
The pan-genotypic triplet of Sofosbuvir, Velpatasvir and Voxilaprevir was licenced in August 2017
Glecaprevir / Pibrentasvir regimen can be given to patients in CKD patients of any stage.
The second and third generation DAA regimens are highly effective for patients even with cirrhosis, and for patients with kidney or liver transplantation.
Current discard rates for hepatitis C positive donor organs in the UK
Current practice in the UK is to restrict the use of HCV D+ organs to HCV positive recipients (R+)
The UK Advisory Committee on the Safety of Blood, Tissues and Organs (SaBTO) guidance: HCV infection in the potential donor does not amount to an absolute contraindication to donation of material for life-preserving transplantation, however the net benefit of transplantation must be considered against the risk of not receiving that specific transplant. This risk/benefit analysis allows for the potential use of a transplant from an HCV infected donor to a non-infected recipient.
Experience from outside the UK
Up to 4.0% of all organ donors in the US between 1995 and 2015 were reported to be HCV antibody positive, thereafter discard rates for HCV D+ livers have reduced in the US from 25% in 2006 to 10% in 2015.
More than 500 HCV positive kidneys are discarded annually in the US. A conference of the American Transplantation Society held in January 2017 was in Favour of considering D+ to R- transplantation across all solid organs within a set criterion.
Goldberg et al published a study in the New England Journal of Medicine: 10 kidney transplant recipients, all were given HCV D+ kidneys from individuals infected with genotype 1 HCV. All recipients became viremic by day 3 and all received 12 weeks of treatment with SVR achievement. EXPANDER-1 trial result was the same.
What are the risks of HCV D+ to R- transplantation?
1. fibrosing cholestatic hepatitis (FCH). It is an aggressive form of HCV related liver complication seen in 10% of D+/R+ liver transplants (1.5% in kidney transplant)
2. infection transmission have good prognosis (DAA therapy led to high cure rate)
3. DAA treatment failure is less than <5%.
4. Extra-hepatic manifestations of HCV (cryoglobulinemic vasculitis) or PTLD
5. Sexual transmission of HCV to a partner (extremely low <2% approximately)
The Practicalities of Implementing this Policy in the United Kingdom Patient Consent:
Consent is specifically obtained by individual transplanting centres (supported by a patient information sheet) Patient and Unit Requirements Pre-Transplant:
In case of HCV D+/R- non-liver transplantation should be avoided in recipients with advanced fibrosis or cirrhosis.
Should consult a liver specialist.
Pre-requisites checklist should be completed.
Screen patients by using AST-to-Platelet Ratio Index (APRI) and ultrasound of Liver.
1- If the APRI score is >0.8 or the ultrasound suggests significant or
advanced liver disease, then an opinion from a liver specialist should be
sought
2- If the APRI score is <0.8, there is no need for the patient to be seen by a
liver specialist
Allocation of HCV D+ Organs on the Waiting List:
HCV+ D organs should be treated in the same way as HCV- D organs within the current allocation rules of the national waiting lists.
Management of the Recipient of an HCV+ D Organ:
Do HCV RNA testing following receipt of either a HCV Ab positive graft, an HCV RNA positive graft or a graft from an increased infectious risk donor, to ensure appropriate and early intervention if HCV transmission and infection occurs.
Test for HIV and HBV in all cases.
Recipient testing by HCV RNA on days between 3-7 day, on 10-14day, and 6 weeks
o If recipient HCV+, two alternative regimens should be used as first line agents, either the combination of Glecaprevir/Pibrenatasvir or the combination of Sofosbuvir/Velpatasvir. Both should be given for 12 weeks in the context of HCV D+/R- transplants and both are pan-genotypic.
o In case of treatment failure, a 12-week course of the combination of Sofosbuvir/Velpatasvir/Voxaleprevir which has a high rate of SVR even in those previously exposed to DAA therapy.
Special Additional Considerations:
Use of organs from donors treated for HCV with DAA within the last 6 months should be avoided unless there is clear documentary proof at the time of donation that an SVR12 was achieved.
Any organ from a donor treated for HCV with DAAs but has not achieved SVR12 for any reason should not be considered for transplantation into a negative recipient unless the benefits outweigh the risks (in a case of urgent transplantation need)
HCV + Donors used for transplant:
1. HCV Ab positive with no history of treatment of HCV
2. HCV Ab positive with documented SVR after treatment
3. Any HCV Ab negative donor who has exposed themselves to risk but who does not fulfill any of the unacceptable criteria
4. Any HCV Ab positive donor whose HCV treatment history is unknown
HCV+ Donors should not use for transplant:
1. Previously failed DAA therapy with on-going viraemia
2. DAA therapy within last year without documented SVR (unless the recipient is at imminent risk of death)
3. Multiple documented re-infection with HCV
UK Position Statement on the use of Organs from Hepatitis C Viremic Donors and Increased Infectious Risk Donors in Hepatitis C Negative Recipients Summary
Despite an increase in organ donation in the UK, up to 1 in 6 patients listed for SOT will die or become too sick for a transplant. There is, therefore, a need to continuously explore improving the utilization of organs that are not currently widely used for transplantation.
Most organs from donors infected with hepatitis C have hitherto been discarded because of the high likelihood of transmitting the infection to the recipient. Older treatment modalities had poor tolerance and were not sufficiently successful in curing transplant recipients of the infection.
Recent advances in the management of hepatitis C infection have meant that more than 95% of infected individuals can now be cured with DAA agents. Studies have shown that similar outcomes of hepatitis C clearance can be safely achieved in transplant recipients and small trials have shown excellent outcomes in hepatitis c negative recipients given hepatitis C-infected organs who were subsequently treated and cured of the virus.
A recent analysis of the UK Potential Donor Audit has suggested that up to 15 suitable donors are declined every year because of the risk of transmission of hepatitis C. Using organs from such donors could result in up to 75 extra SOT being performed every year in the UK.
Following the recent recommendations by the Advisory Committee on the Safetry of Blood, Tissues and Organs that, in some clinical situations, organs from hepatitis C infected donors may be transplanted into uninfected recipients, a group of clinicians, virologist, scientists, health care managers and patients representatives have proposed a UK wide framework for the appropriate use of organs from HCV infected donors.
Key elements of the guidelines include selection of appropriate donors, a policy for ensuring the intended recipient gives fully informed consent, guidance for the testing and treatment of the recipients as indicated, the formation of a monitoring group to oversee the pgramme in the early phases of implementation as well as consideration of some of the headline operational issues that will arise during successful implementation of the pathway.
Summary
Organ donation in the UK has increased, but there are still examples of people dying due to a lack of grafts; therefore, techniques are being found to utilize organs that were previously rejected.
Two-year-old therapeutic options rejected HCV-infected organs.
3-DAAT for HCV has a 95% cure rate, and transplanting HCV-positive organs from treated donors into HCV-negative recipients was encouraging.
The 4-UK registry showed 15 suitable HCV-positive donors were discarded annually, which might increase solid organ transplantation by 75 cases.
After a multidisciplinary team examination, organs from hepatitis C-infected donors can be used for uninfected recipients with restrictions.
Six precautions include qualified donors, fully informed permission, recipient testing and treatment, and a monitoring group.
HCV viraemia, regardless of HCV antibody status, refers to donors with HCV IgG +ve whose HCV RNA status is unclear upon organ transplantation.
Non-UK experience
Transplanting HCV-positive donors to HCV-negative recipients yielded positive results in US studies.
DAA-treated HCV D+ to HCV R- transplant recipients are treatment-nave, noncirrhotic, and likely to achieve SVR.
Why is HCV D+ to R- transplantation cost-effective?
Therapy for an R+ patient with a D+ organ should cost less than a year of dialysis.
HCV D+-to-R- transplantation risks
The biggest danger is fibrosing cholestatic hepatitis (FCH), an aggressive HCV recurrence forum in D+/R+ liver transplants with significant mortality before DAAT.
SOLAR-1 and 2 showed that sofosbuvir and ledipasvir for 12 or 24 weeks treated FHC after liver transplantation.
Additional studies showed encouraging FCH cure results with sofosbuvir, daclatasvir, and ledipasvir.
Early DAAT prevents FCH.
DAAT failure was rare.
No extrahepatic HCV D+/R+ data
Consent
HCV+ organ recipients must sign a specific consent.
Pre-transplant essentials
Advanced fibrosis or cirrhosis recipients should avoid HCV D+/R- non-liver transplantation.
HCV D+ non-liver organ recipients are tested using AST-to-Platelet Ratio Index (APRI) and ultrasonography to determine if a hepatic specialist is needed.
A checklist is needed before a transplanting center performs its first HCV D+/R- transplant.
HCV D+ Waiting List Organs
To promote organ use, national waiting list allocation regulations must treat HCV D+ organs the same as HCV D- organs.
HCV D+ organ management
Standardized HCV RNA testing of the recipient after receiving an HCV Ab positive, RNA positive, or graft from an enhanced infectious risk donor to detect HCV transmission and infection early.
For HCV-positive donor organs
The donor PCR must be tested in a central lab. If positive, genotyping testing must be done and all centers must be informed within 2 days. If negative, all centers must be informed.
The negatively consenting recipient must undergo an HCV PCR test 3-7 days after transplant, repeated 10-14 days, and retested 6 weeks afterwards.
DAA should be begun within 3-10 days of a positive HCV PCR test.
Two pan-genotypic, 12-week regimens for HCV D+/R- transplants are Glecaprevir/Pibrenatasvir or Sofosbuvir/Velpatasvir.
After first DAAAT failure, 12-week Sofosbuvir/Velpatasvir/Voxaleprevir has high SVR rates.
Special issues
Avoid transplanting organs from donors treated for HCV with DAA within the last 6 months unless they have SVR to avoid transmitting HCV-resistant infection.
Accepted donors
Suitable donors include HCV Ab positive with no HCV treatment history, HCV Ab positive reaching SVR after treatment, HCV Ab negative donor exposed to risk but does not meet the unacceptable criteria, and HCV Ab positive donor with unknown treatment history.
Unrecommended donors
Include instances with failed DAA therapy and persistent viraemia, DAA therapy within last year without confirmed SVR, and repeated HCV reinfection.
Unless the advantages outweigh the dangers, DAA-treated HCV donors who fail to achieve SVR12 should not be transplanted into negative recipients.
In conclusion,the net benefit of life-saving transplantation must be weighed against the harm of not getting organ donation from HCV positive.
This risk/benefit analysis allows an HCV-infected donor-to-non-infected recipient transplant.
DAA medication is recommended for all HCV-infected kidney transplant candidates.
In recent years, these novel hepatitis C medications have had few adverse effects and are well-tolerated by patients.
HCV is a singlestranded RNA virus of the Flaviviridae family. Six genotypes (G16). Hepatitis C patients in the last five years: 4,444 There is considerable experience in the UK with two licensed pangenotypic regimens in the form of Sofosbuvir/Velpatasvir and Glecaprevir/Pibrentasvir.
The pangenotypic triplet of Sofosbuvir, Velpatasvir and Voxilaprevir was licensed in August 2017. independent of HCV genotype.
Current rates of processing organs from Hepatitis C positive donors in the UK:
“HCV infection in a potential donor is not an absolute contraindication to the donation of material for lifesaving transplantation, but the net benefits of transplantation must be weighed against the risks of not accepting that specific transplant. This risk/benefit analysis allows for the potential use of transplantation from HCV-infected donors to uninfected recipients.
’Why HCV D+ to R transplantation is cost-effective:
might be the strongest in kidney transplantation. Dialysis is expensive.
What are the risks of a HCV D+ to R transplant?
Ø Cholestatic fibrosing hepatitis (CHF)
Ø Individuals infected with cytomegalovirus (CMV) or Epstein Barr virus (EBV).
Practicality of policy implementation in the UK:
However, it was felt that it would be useful for the group to provide a framework for some of the important practical issues which need to be addressed by every transplant unit wishing to adopt the policy. Consideration
Patient consent prior to D+/R HCV transplantation:While patients currently generally consent to socalled “marginal” organs, including, for example, CMVpositive organs, it is thought HCV D+ specifically should be obtained at individual transplant centers
Patient and unit requirements prior to transplantation:
For safety reasons, the Working Group agrees that nonhepatic transplantation of HCV D+/R should be avoided in recipients with advanced fibrosis or cirrhosis.Allocation of HCV D+ organs on the waiting list:Periodic review of posttransplant outcomes is necessary to allow advisory groups to modify procurement and allocation policies as needed.
Two alternatives should be used as firstline agents. It is a Glecaprevir/Pibrenatasvir combination or a Sofosbuvir/Velpatasvir combination. In case of HCV D+/R transplantation, both must be administered for 12 weeks. Both are pangenotyped, meaning they can startimmediately after a positive HCV PCR result without waiting for the HCV genotype, which can take 34 weeks in some areas.Additional special considerations:
Acceptable in proposed policy:
Ø HCV Ab positive with no history of HCV treatment
Ø HCV Ab positive with documented SVR after treatment
Ø Any HCV negative negative donor at no risk Meeting any of the following unacceptable criteria
Ø Any HCV Ab positive donor with unknown history of HCV treatment – proceed with caution
Not recommended in proposed policy
is at imminent risk of death
Ø Multiple documented HCV re-infections
Early project follow-up:
The working group believes that a review committee should be formed after this position statement is approved, the committee will oversee program execution and next steps in the process clof information on HCV recipients receiving D+/R- transplants:
Transplant Society Annual Conference in Brighton, March 2018. ‘- Program date September 2018. NHSBT will publish further operational details using its standard communication channels.HSBT using its standard communication channels.
Summary of the article UK Position Statement on the use of Organs from Hepatitis C Viraemic Donors and Increased Infectious Risk Donors in Hepatitis C Negative Recipient
Executive Summary
1. Despite the increase in organ donation in the UK, up to 1 in 6 patients listed for solid organ transplantation will die or become too sick for a transplant. There is, therefore, a need to continuously explore improving the utilisation of organs that are not currently widely used for transplantation.
2. Most organs from donors infected with hepatitis C have hitherto been discarded because of the high likelihood of transmitting the infection to the recipient. Older treatment modalities had poor tolerance and were not sufficiently successful in curing transplant recipients of the infection.
3. Recent advances in the management of hepatitis C infection have meant that more than 95% of infected individuals can now be cured with directly acting antiviral agents. Studies have shown that similar outcomes of hepatitis C clearance can be safely achieved in transplant recipients and small trials have shown excellent outcomes in Hepatitis C negative recipients given hepatitis C infected organs who were subsequently treated and cured of the virus.
4. A recent analysis of the UK Potential Donor Audit has suggested that up to 15 suitable donors are declined every year because of the risk of transmission of hepatitis C. Using organs from such donors could result in up to 75 extra solid organ transplants being performed every year in the UK.
5. Following the recent recommendations by the Advisory Committee on the Safety of Blood, Tissues and Organs that, in some clinical situations, organs from hepatitis C infected donors may be transplanted into uninfected recipients, a group of clinicians, virologists, scientists, health care managers and patient representatives have proposed a UK wide framework for the appropriate use of organs from HCV infected donors.
6. Key elements of the guidelines include selection of appropriate donors, a policy for ensuring the intended recipient gives fully informed consent, guidance for the testing and treatment of recipients as indicated, the formation of a monitoring group to oversee the programme in the early phases of implementation as well as consideration of some of the headline operational issues that will arise during successful implementation of the pathway.
HCV; current treatment
1. Pan-genotypic regimens in the form of Sofosbuvir / Velpatasvir and Glecaprevir/Pibrentasvir.
2. The pan-genotypic triplet of Sofosbuvir, Velpatasvir and Voxilaprevir was licenced in August 2017.
3. The advantage of Glecaprevir / Pibrentasvir is that it can be given to patients with established renal failure.
4. The best data currently available for Sofosbuvir, Velpatasvir and Voxilaprevir.
HCV D+ to R- transplantation is cost effective
The course of therapy to cure a R- patient receiving a D+ organ would be less than the cost of dialysis for one year.
The risks of HCV D+ to R- transplantation
1. Fibrosing cholestatic hepatitis (FCH).
2. DAA treatment failure, which may be associated with the development of difficult to treat resistance associated substitutions (RAS) especially in the viral NS5A protein.
3. Extra-hepatic manifestations of HCV such as cryoglobulinaemic vasculiti and PTLD.
4. Sexual transmission of HCV to a partner.
Management of the Recipient of a HCV D+ Organ
1. Either the combination of Glecaprevir/Pibrenatasvir or the combination of Sofosbuvir/Velpatasvir. Both should be given for 12 weeks in the context of HCV D+/R- transplants.
2. In the rare (expected to be less than 2%) instances where the first course of treatment of HCV is not curative, recipients should be treated with a 12 week course of the combination of Sofosbuvir/Velpatasvir/Voxaleprevir.
UK Position Statement on the use of Organs from HCV +ve Donors in HCV -ve Recipients
Summary:
· HCV is transmitted by blood borne, sexual and vertical (trans-placental).
· Serologic tests can detect antibodies to HCV within 2-6 months of initial infection, while PCR is more accurate for diagnosis and detect active viremic state (active viral replication).
· Anti-HCV antibodies continue to be positive for years or indefinitely after spontaneous clearance, or successful treatment with interferon or DAA.
· While undetectable HCV RNA after therapy means SVR; sustained virologic response (no longer ordinarily infectious, but can be re-infected, so FU PCR is recommended).
· Transplantation has better patient survival than prolonged dialysis, so use of extended criteria donor has been raised to increase donor pool and increase chance to get transplanted.
· HCV +ve donor organ were discarded in the past as interferon was unsafe in transplant recipient and risk of infection and viremia ere high with poor graft outcome and higher mortality.
· The current practice is to use HCV D+ organs to HCV positive recipients (R+) only in the field of liver transplantation.
· HCV D+ never used for HCV –R (in any SOT), and positive for positive is applied only in liver transplantation.
· Availability of DAAV (safe, well-tolerated and pangenotypic effective) paved the way to think about the use HCV +ve donor for HCV –ve recipients.
· This strategy is not yet the standard practice and requires certain inquiries:
o Counseling of recipient about risk of viremia and? resistance to treatment.
o Protocol for viral PCR and liver function monitoring.
· As regard the available DAAV:
o 2 licensed pan-genotypic regimens:
1. Sofosbuvir / Velpatasvir.
2. Glecaprevir/Pibrentasvir (can be used in renal failure patients).
3. The triplet of Sofosbuvir, Velpatasvir and Voxilaprevir was licenced in 2017, effective in refractory cases.
4. The 2nd and 3rd generation DAA regimens are effective for patients with cirrhosis, and for patients treated after kidney or liver transplantation.
IV. UK Position Statement on the use of Organs from Hepatitis C Viraemic Donors and Increased Infectious Risk Donors in Hepatitis C Negative Recipient
==================================================================== Please summarise this article.
Executive Summary
Organ donation in the UK is increasing, but up to 1 in 6 patients listed for solid organ transplantation will die or become too sick for a transplant.
Most organs from donors infected with hepatitis C have been discarded due to the high likelihood of transmitting the infection to the recipient.
Recent advances in the management of hepatitis C infection have meant that 95% of infected individuals can now be cured with directly acting antiviral agents.
A recent analysis of the UK Potential Donor Audit has suggested that up to 15 suitable donors are declined every year due to the risk of transmission of hepatitis C.
A group of clinicians, virologists, scientists, health care managers and patient representatives have proposed a UK wide framework for the appropriate use of organs from HCV infected donors, including selection of appropriate donors,.
A policy for ensuring the intended recipient gives fully informed consent, guidance for the testing and treatment of recipients as indicated, the formation of a monitoring group to oversee the programme in the early phases of implementation, and consideration of some of the operational issues that will arise during successful implementation of the pathway.
The United States has the best data on D+ donor numbers and discard rates, and is leading the way in early clinical trials of D+ to R- transplants. 4.1% (6,567/159,552) of all organ donors in the US between 1995 and 2015 were reported to be HCV antibody positive.
Discard rates for HCV D+ livers have reduced from 25% in 2006 to 10% in 2015, but discard rates for other organs are significantly higher despite the fact that they often come from younger donors.
A conference of the American Transplantation Society was held in January 2017 to explore this area, and recommended that such practice should take place within prospective research protocols.
Insurance companies should guarantee funding for DAA therapy for patients knowingly infected with HCV at the time of transplantation.
Goldberg et al. published two clinical trials in the New England Journal of Medicine in which 10 kidney transplant recipients were given HCV D+ kidneys from individuals infected with genotype 1 HCV.
All recipients became viraemic by day 3 and received 12 weeks of treatment with Grazoprevir/Elbasvir as soon as the positive result was obtained. All the recipients were cured 12 weeks after cessation of therapy, with the median wait time reduced to 58 days and the median eGFR at the end of the study being 68 ml/min (51-83).
The only SAEs noted were delayed graft function, elevated ALT, transient class 1 antibodies, and proteinuria and focal segmental glomerulosclerosis.
The most important details are that Grazoprevir/Elbasvir was started immediately before transplantation and continued for 12 weeks, Sofosbuvir was added if HCV resistance associated substitutions (RAS) were identified, and treatment was extended to 16 weeks.
There were no adverse events related to the treatment in the trial, and there are also data emerging on the efficacy and safety of DAA therapy in patients who have undergone organ transplantation and have established HCV.
Why HCV D+ to R- transplantation should be cost effective
Increasing organ availability for HCV D+ to R- transplantation should be cost-effective to reduce waiting times and dialysis expenditure, saving lives and improving quality of life for patients.
DAAs to the NHS would be less than the cost of dialysis for one year, leading to substantial cost savings and improved quality of life.
What are the risks of HCV D+ to R- transplantation?
The risks of HCV D+ to R- transplantation include fibrosing cholestatic hepatitis (FCH), which is an aggressive form of HCV recurrence seen in 10% of D+/R+ liver transplants.
There are increasing reports of DAA therapy being effective in the setting of FCH, with cure rates of 100% in 15 patients with FCH treated after liver transplantation using the combination of Sofosbuvir and Daclatasvir.
Early treatment (ideally within 4 weeks) with DAA therapy should prevent the development of FCH.
The concept of knowingly infecting a patient with an infectious agent poses important ethical issues, but the high morbidity and mortality rates for patients on the waiting list justify the utilisation of D+ organs.
The most important details are that a minority of patients treated after organtransplantation may experience DAA treatment failure, and that 12 weeks of re-treatment with the triple therapy combination of Sofosbuvir, Velpatasvir and Voxilaprevir is highly effective (>95%) in achieving cure of HCV in patients with HCV NS5A RAS at baseline.
Extra-hepatic manifestations of HCV such as cryoglobulinaemic vasculitis or potential increased rates of blood derived malignancy such as PTLD are also theoretical consequences of HCV infection in the post-transplantation phase, but there are no data in the HCV D+/R+ field to demonstrate an increased risk of these consequences.
Sexual transmission of HCV to a partner could potentially occur, but this risk is likely low (<2% perhaps).
The current Special Category Mechanism (SCM) would require clarification before HCVD+/R- transplants could proceed in the UK.
Patient consent for HCV D+/R- transplantation should be specifically obtained by individual transplanting centres, and the British Transplantation Society and NHS Blood and Transplant are reviewing the entire process.
Patient and Unit Requirements Pre-Transplant
The working party agreed that HCV D+/R- non-liver transplantation should be avoided in recipients with advanced fibrosis or cirrhosis, and a more pragmatic approach of screening patients using AST-to-Platelet Ratio Index (APRI) and ultrasound is suggested.
If the APRI score is <0.8 or the ultrasound suggests significant or advanced liver disease, an opinion from a suitably qualified liver specialist should be sought before the patient is considered for a transplant.
A checklist of pre-requisites must be in place before an individual transplanting centre performs its first transplant.
Individual units should ensure that these requirements are met in order to minimise the theoretical risk to any individual recipient.
Allocation of HCV D+ Organs on the Waiting List
Advisory Groups must decide how best to allocate HCV D+ organs to optimise organ utilisation and review post-transplant outcomes to alter offering and allocation policies as needed.
Management of the Recipient of a HCV D+ Organ
The working party recommended standardized, longitudinal testing for hepatitis C RNA of the recipient following receipt of either a HCV antibody positive graft, a HCV RNA positive graft or a graft from an increased infectious risk donor.
The exact drug regimens and length of therapy that should be offered to recipients that test positive
Two alternative regimens should be used as first line agents for HCV D+/R- transplants: Glecaprevir/Pibrenatasvir or Sofosbuvir/Velpatasvir.
Both have acceptable drug to drug interaction profiles, but exposure to the former is increased by ciclosporin and may also increase the levels of tacrolimus.
Treatment should be given in liaison with a clinical team with experience of management of HCV but does not necessarily have to be delivered in the transplanting centre.
Special Additional Considerations
The use of organs from donors known to have been treated for HCV with DAA should be avoided unless there is clear documentary proof.
Oversight of the Programme in its Early Days
An Oversight Committee should be established to oversee the implementation of the programme and receive clinical information on the recipients of HCV D+/R- transplantation, led by BVHG with strong representation from NHSBT and BRITISH TRANSPLANTATION SOCIETY.
A minimal dataset should be collected to aid the Steering Committee.
Executive summary
1-In spite that organ donation has increased in UK yet there are cases dying out of shortage of grafts ,therefore organs that were used to be discarded before ,ways are figured out to get use if it
2-HCV infected organs were discarded due to old treatment options which changed now.
3-DAAT for HCV have 95% cure rate , the outcomes of transplanting HCV positive organs from treated donors into HCV negative recipients were promising.
4-Uk registry showed that 15 suitable HCV positive donors were discarded per year wich can increase solidorgan transplantation to 75 extra cases
5-Recent recommendations after multi disciplinary team evaluation ,stated that organs from hepatitis C infected donors can be used for uninfected recipients with certain precautions
6-Precautions include suitable donors, fully informed consent need to be explained to and signed by the recipient, testing and treatment of recipients as indicated, available of a monitoring group.
HCV viraemia indicate donors or recipients with active HCV infection with detectable HCV RNA, irrespective of HCV Ab state, also refers to donors with HCV IgG +ve whose HCV RNA status is unknown at the organ transplantation time. Experience from outside the UK
Studies from USA revealed favourable results for transplanting HCV positive donors to HCV negative recipients.
If HCV D+ to HCV R- transplants will be done ,those recipients treated with DAAs are treatment naïve and mostly noncirrhotic, and have a high tendency to reach SVR. Why HCV D+ to R- transplantation should be cost effective?
It is supposed that therapy course to cure a R- patient receiving a D+ organ is less than dialysis cost for a year. Risks of HCV D+ to R- transplantation
Fibrosing cholestatic hepatitis (FCH) is the worst risk which is an aggressive forum of HCV recurrence in D+/R+ liver transplant with high mortality before DAAT introduction.
SOLAR-1 and 2 studies demonstrated that the combination
of Sofosbuvir and Ledipasvir for 12 or 24 weeks treated cases with FHC after liver transplantation.
Other studies revealed that Sofosbuvir and Daclatasvir as well as Sofosbuvir and Ledipasvir have promising results in FCH cure .
Also early DAAT can prevent FCH .
DAAT failure was noticed in minority of cases.
No available data on HCV extrahepatic manifestations in the HCV D+/R+ field Patient consent
Recipients who receives organs from HCV + donors have to sign a special consent. Pretransplant requirements
HCV D+/R- non-liver transplantation have to be avoided in recipients with advanced fibrosis or cirrhosis.
Cases consented to receive a HCV D+ non-liver organs are screened using AST-to-Platelet Ratio Index (APRI) and ultrasound then accordingly to decide if a hepatic specialist need to be consulted.
Checklist of requirements before an individual transplanting centre undergo the first HCV D+/R- transplant is essential. Allocation of HCV D+ Organs on the Waiting List
HCV D+ organs have to be dealt with the same as HCV
D- organs regarding the allocation rules of the national waiting lists to maximize the organ utilisation . Recipient of a HCV D+ Organ management
Standardized testing for HCV RNA of the recipient after receiving a HCV Ab positive graft, a HCV RNA positive graft or a graft from an increased infectious risk donor, to attain an early and appropriate intervention if HCV transmission and infection occurs.
Flow chart is as follows
For Organs from HCV Ab positive donors ,
-the donor PCR have to be tested in a central lab if positive result then genotype testing is done then all centers have to be informed within 2 days and if negative result also all centers have to be informed within 2 days .
-the negatively consented recipient has to have HCV PCR test 3-7 days post transplant ,then if negative to be repeated 10-14 days ,if negative 6 weeks retesting post transplant.
If HCV PCR is positive after confirmatory results DAA to be started within 3-10 working days since the first positive test.
There are 2 regimens including combination of Glecaprevir/Pibrenatasvir or the combination of Sofosbuvir/Velpatasvir, both given for 12 weeks with HCV D+/R- transplants and are pan-genotypic with acceptable drug interactions.
Sofosbuvir/Velpatasvir/Voxaleprevir for 12 week can be given after first DAAAT failure having high rates of SVR . Special issues
The fear to transmit HCV resistant infection can be manged by avoiding transplanting organs from donors treated for HCV with DAA within the last 6 months unless there is an evidence of SVR. Acceptable donors
include HCV Ab positive with no HCV treatment history , HCV Ab positive reaching SVR after treatment, HCV Ab negative donor exposed to risk but does not fulfill the unacceptable criteria
and proceed with caution for HCV Ab positive donor whose HCV treatment history is unknown . Unrecommended donors
Include cases with failed DAA therapy and persistence of viraemia, DAA therapy within last year without documented SVR, multiple HCV reinfection.
Donors treated for HCV with DAAs but not achieving SVR12 for any reason should not be considered for transplantation into a negative
recipient unless the benefits outweigh the risks
UK Position Statement on the use of Organs from Hepatitis C Viraemic Donors and Increased Infectious Risk Donors in Hepatitis C Negative Recipient. Introduction : Solid organ transplantation is now well established in routine clinical practice, but a significant number of patients still die due to a shortage of donor organs. An important strategy is to review discarded organs to assess if advances in medicine could enable them to be transplanted, which could make more organs available for transplantation and reduce the morbidity and mortality of patients on waiting lists.
Introduction to HCV and Clarification of Nomenclature
HCV is a single stranded RNA virus with six genotypes and a large number of sub-genotypes, which can lead to acute or chronic infection. The term ‘HCV viraemic’ is used to refer to donors or recipients who have active HCV infection with detectable HCV RNA, regardless of HCV antibody status. Changes in the treatment of hepatitis C over the past five years
The most important details in this text are the changes in the treatment of hepatitis C over the past five years, which began with the licensing of the first generation protease inhibitors Telaprevir and Boceprevir in 2012. These drugs have increased cure rates for patients with G1 HCV from 50% to over 80%. Most current regimens are given for 8-16 weeks and offer cure rates of 95-100% for patients without cirrhosis, regardless of HCV genotype. There is already substantial UK experience of using two licensed pan-genotypic regimens in the form of Sofosbuvir / Velpatasvir and Glecaprevir/Pibrentasvir. The second and third generation DAA regimens have also been shown to be highly effective for patients with cirrhosis and for patients treated after kidney or liver transplantation. Current discard rates for hepatitis C positive donor organs in the UK The UK currently restricts the use of HCV D+ organs to HCV positive recipients, but anecdotal evidence suggests poor utilisation of non-liver organs even for HCV R+ recipients. The revised guidance states that HCV infection does not amount to an absolute contraindication to donation of material for life-preserving transplantation, but the net benefit of transplantation must be considered against the risk of not receiving it.
Experience from outside the UK
The United States has the best data on D+ donor numbers and discard rates, and is leading the way in early clinical trials of D+ to R- transplants. 4.1% of all organ donors between 1995 and 2015 were reported to be HCV antibody positive, but these have been transplanted exclusively into HCV R+ patients. Discard rates for HCV D+ livers have reduced from 25% in 2006 to 10% in 2015, but discard rates for other organs are significantly higher. A conference of the American Transplantation Society recommended that insurance companies should guarantee funding for DAA therapy for patients knowingly infected with HCV at the time of transplantation.
Why HCV D+ to R- transplantation should be cost effective
Increasing organ availability for HCV D+ to R- transplantation should be cost-effective to reduce waiting times and dialysis expenditure, saving lives and improving quality of life for patients. DAAs to the NHS would be less than the cost of dialysis for one year, leading to substantial cost savings and improved quality of life.
What are the risks of HCV D+ to R- transplantation?
Fibrosing cholestatic hepatitis (FCH) is an aggressive form of HCV recurrence seen in 10% of D+/R+ liver transplants. Early treatment with DAA therapy should prevent the development of FCH, and modern DAA therapy provides an excellent chance of cure. However, a minority of patients may experience DAA treatment failure, which could lead to extra-hepatic manifestations of HCV such as cryoglobulinaemic vasculitis or potential increased rates of blood derived malignancy. Treatment duration should be extended slightly to mitigate this risk.
The Practicalities of Implementing this Policy in the United Kingdom:
The working party met on the 2nd of November 2017 to discuss the practicalities of implementing this Policy in the UK. It was felt that it would be useful to provide a framework for some of the important practical issues that transplant units should consider prior to proceeding with a HCV D+/R- transplant. The group also felt strongly that there should be an oversight committee for the first 20-30 transplants, and this will be discussed further.
Patient Consent:
Patient consent for HCV D+/R- transplantation should be specifically obtained by individual transplanting centres, and a patient information sheet has been developed. The British Transplantation Society and NHS Blood and Transplant are reviewing the entire pathway of sharing information with and gaining consent from solid organ transplant candidates.
Patient and Unit Requirements Pre-Transplant:
The working party agreed that HCV D+/R- non-liver transplantation should be avoided in recipients with advanced fibrosis or cirrhosis. Screening patients using AST-to-Platelet Ratio Index (APRI) and ultrasound is suggested to ensure safety, If the APRI score is <0.8 or the ultrasound suggests significant or advanced liver disease, an opinion from a suitably qualified liver specialist should be sought before the patient is considered. A checklist of pre-requisites must be in place before an individual unit performs its first transplant to minimize the theoretical risk.
Allocation of HCV D+ Organs on the Waiting List:
The working group considered the allocation of HCV D+ organs on the waiting list and concluded that they should be treated the same as HCV D- organs within the current allocation rules of the NHSBT bodies. Advisory Groups will need to decide how best to offer and allocate such organs in order to optimise organ utilisation, and frequent review of post-transplant outcomes will be needed to alter offering and allocation policies as needed.
Management of the Recipient of a HCV D+ Organ:
Standardized, longitudinal testing for hepatitis C RNA of the recipient following receipt of either a HCV antibody positive graft, a HCV RNA positive graft or a graft from an increased infectious risk donor is mandatory . Two alternative regimens should be used as first line agents, either Glecaprevir/Pibrenatasvir or Sofosbuvir/Velpatasvir. A clinical team with experience of management of HCV should be included . Organ from a donor who has been treated for HCV with DAAs but has not achieved SVR12 for any reason should not be considered for transplantation unless the benefits outweigh the risks.
Oversight of the Programme in its Early Days: Oversight Committee should be established to oversee implementation of HCV D+/R- transplantation, led by BVHG, with representation from NHSBT and BRITISH TRANSPLANTATION SOCIETY.
UK Position Statement on the use of Organs from Hepatitis C Viraemic Donors and Increased Infectious Risk Donors in Hepatitis C Negative Recipients 1- Despite the increase in organ donation in the UK, up to 1 in 6 patients listed for solid organ transplantation will die or become too sick for a transplant. There is, therefore, a need to continuously explore improving the utilisation of organs that are not currently widely used for transplantation. 2- Most organs from donors infected with hepatitis C have been discarded because of the high likelihood of transmitting the infection to the recipient. 3- Older treatment modalities had poor tolerance and were not sufficiently successful in curing transplant recipients of the infection. 4- Recent advances in the management of hepatitis C infection have meant that more than 95% of infected individuals can now be cured with directly acting antiviral agents. 5- Studies have shown that similar outcomes of hepatitis C clearance can be safely achieved in transplant recipients and small trials have shown excellent outcomes in Hepatitis C negative recipients given hepatitis C infected organs who were subsequently treated and cured of the virus. 6- A recent analysis of the UK Potential Donor Audit has suggested that up to 15 suitable donors are declined every year because of the risk of transmission of hepatitis C. Using organs from such donors could result in up to 75 extra solid organ transplants being performed every year in the UK. 7- Following the recent recommendations by the Advisory Committee on the Safety of Blood, Tissues and Organs that,: in some clinical situations, organs from hepatitis C infected donors may be transplanted into uninfected recipients
8- Key elements of the guidelines include selection of appropriate donors, a policy for ensuring the intended recipient gives fully informed consent, guidance for the testing and treatment of recipients as indicated, the formation of a monitoring group to oversee the programme in the early phases of implementation as well as consideration of some of the headline operational issues that will arise during successful implementation of the pathway. Figure1 : Proposal for Testing of Donors and Management of All Recipients in the UK HCV D+/R- scheme
Treatment of the HCV positive recipient: Regimen:
– First line agents. Either
1- Either the combination of Glecaprevir/Pibrenatasvir
SE: increased by ciclosporin, and it may also increase the levels of tacrolimus 2- The combination of Sofosbuvir/Velpatasvir.
SE: not recommended in patient with a eGFR <30 mL/min/1.73 m2 Duration: – Both should be given for 12 weeks in the context of HCV D+/R- transplants. Both are pan-genotypic, which means that they can be started as soon as HCV PCR positivity is known, without having to wait for a HCV genotype, which can take 3-4 weeks in some areas. – Second line:
After failure of first line
12 week of combined Sofosbuvir/Velpatasvir/Voxaleprevir.
The demand for organs continues to outpace the supply of organ donation. Therefore, there is a constant need to find ways to better utilize organs that are not now frequently used for transplantation.
Historically, organs from deceased donors infected with HCV were discarded because of high transmission risk. The current availability highly effective and well tolerated direct-acting antiviral (DAA) therapy, improve the utilization of HCV infected organs.
Chronic infection: defined as persistence of HCV RNA in serum for greater than six months after initial infection This develops in at least 60% of those infected.
HCV viraemia those with detectable HCV RNA by PCR regardless HCV antibody status. Also, refer to those with HCV IgG +ve where the HCV RNA status is not known at the time of organ offering / transplantation (window period), transmission of infection may still occur from donors during the window period of acute infection.
SVR( sustained virologic response) clearance of the virus with successful treatment of HCV lead to undetectable HCV RNA.
The Changes in the treatment of HCV:
– The first generation protease inhibitors: Telaprevir and Boceprevir. These drugs were combined with interferon and ribavirin.
– Pan-genotypic DAA: Sofosbuvir / Velpatasvir, Voxilaprevir and Glecaprevir/Pibrentasvir.
-The advantage of Glecaprevir / Pibrentasvir is that it can be given to patients with established renal failure.
– Sofosbuvir, Velpatasvir and Voxilaprevir highly effective in those previously failed other DAA-containing regimens.
– The 2nd& 3rd generation: highly effective for patients with cirrhosis, and after kidney or liver transplantation
Advisory Committee on SaBTO stated: ‘HCV infection does not amount to an absolute contraindication to donation of material for life-preserving transplantation, however the net benefit of transplantation must be considered against the risk of not receiving transplant. This allow use of HCV infected donor to a non-infected recipient.
Clinical trials are very encouraging, and data emerging on the efficacy and safety of DAA therapy in patients who have undergone organ transplantation and have established HCV.
Why HCV D+ to R- transplantation should be cost effective
-Dialysis is expensive lead to increase in morbidity and mortality and reduce quality of life. This can be mitigated by transplantation especially for those highly sensitized, DAA is cost effective therapy.
-There are clear economic and health related benefits to HCV D+ to R- transplantation, What are the risks of HCV D+ to R- transplantation?
–Fibrosing cholestatic hepatitis (FCH), an aggressive form of HCV recurrence seen in 10% of D+/R+ liver transplants. DAA is very effective in this setting.
– DAA treatment failure; in minority <5% of patients treated after SOT, may be associated with the development of resistance,modern DAA therapies can cure this, even if this is not achieved at the first attempt at treatment.
– Extra-hepatic manifestations of HCV; cryoglobulinaemic vasculitis or potential increased rates of blood derived malignancy such as PTLD. No data reported an increased risk, however, early DAA should mitigate this risk.
– Sexual transmission of HCV to a partner is very low, early DAA and simple lifestyle advice reduce the risk.
–Patient should be Consented toreceive a HCV D+ organ.
– HCV D+/R- non-liver transplantation should be avoided in recipients with advanced fibrosis or cirrhosis.
– Using AST-to-Platelet Ratio Index (APRI) can help to identify advanced liver disease if score >0.8 liver specialist opinion should be sought.
-If the APRI score is <0.8, there is no need for the patient to be seen by a liver specialist.
– HCV D+ organs should be treated in the same way as HCV D- organs within the current allocation rules
Recipient monitoring with HCV RNA after receiving an organ from HCV+RNA or HCV positive antibodies, to allow early identification and treatment.
At day 3-7 Post-Tx, then day 10-14,then at 6 weeks if all results are negative reassure the recipient & managed as standard recipients. If HCV PCR positive; DAA started within 3-10 days of first positive PCR.
-The combination of either Glecaprevir/Pibrenatasvir or the combination of Sofosbuvir/Velpatasvir, is used as first line agents. For total 12 weeks, both regimen are pan-genomic can be started immediately before knowing the genotype.
– Sofosbuvir/Velpatasvir is not recommended in patient with a eGFR <30 mL/min/1.73 m2
– The combination of Sofosbuvir/Velpatasvir/Voxaleprevir used for 12 weeks in recipients did not respond to first course. As the rates of SVR is high even in those previously exposed to DAA therapy.
Key elements of the guidelines include selection of appropriate donors: Acceptable Within Proposed Policy
HCV Ab positive with no history of treatment of HCV
HCV Ab positive with documented SVR after treatment
Any HCV Ab negative donor who has exposed themselves to risk but who does not fulfill any of the unacceptable criteria
Any HCV Ab positive donor whose HCV treatment history is unknown – proceed with caution
Not Recommended Within Proposed Policy
Previously failed DAA therapy with on-going viraemia
DAA therapy within last year without documented SVR (unless the recipient is at imminent risk of death)
Multiple documented re-infection with HCV
Please summarise this article.
o Most organs from donors infected with HCV discard from transplant because of the high risk of transmitting the infection to the recipient
o Recent DAA cure >95% of HCV infection
o The outcomes is excellent in Hepatitis C negative recipients given hepatitis C infected organs who were subsequently treated and cured of the virus
o According to recommendations by the Advisory Committee on the Safety of Blood, Tissues and Organs that, organs from hepatitis C infected donors may be transplanted into uninfected recipients
o Select the appropriate donor and fully informed consent of the recipient
Introduction
o Due to a shortage of donor organs, there is an increase need for organs
o With the advent DAA therapy which cure >95% of patients infected with HCV, regardless of genotype, HCV donors can be used
o HCV is a single stranded RNA virus member of the Flaviviridae family
o Six genotypes (G1-6) with a large number of sub-genotypes
o Transmission is parenterally (through intravenous drug use (IVDU) or blood products), sexually (predominantly those who have unprotected anal sex with multiple partners) or vertically, from mothers to infants
o Acute infection is usually subclinical
o Chronic infection (persistence of HCV RNA in serum for greater than six months after initial infection) occurs in at least 60% of those infected
o Serologic tests can detect antibodies to HCV within 2-6 months of initial infection
o Use HCV RNA when assessing the HCV infectivity of an organ donor or recipient (active HCV replication or not)
o Transmission of infection may occur from donors during the window period of acute infection
Changes in the treatment of hepatitis C over the past five years
o Now DAA are given for between 8 and 16 weeks, and offer cure rates of 95-100% for patients without cirrhosis, regardless of HCV genotype
o Two licensed pan-genotypic regimens (Sofosbuvir / Velpatasvir and Glecaprevir/Pibrentasvir)
o The pan-genotypic triplet of Sofosbuvir, Velpatasvir and Voxilaprevir was licenced in August 2017
o Glecaprevir / Pibrentasvir regimen can be given to patients with established renal failure
o The second and third generation DAA regimens are highly effective for patients with cirrhosis, and for patients treated after kidney or liver transplantation
Current discard rates for hepatitis C positive donor organs in the UK
o Current practice in the UK is to restrict the use of HCV D+ organs to HCV positive recipients (R+)
o The UK Advisory Committee on the Safety of Blood, Tissues and Organs (SaBTO) guidance: HCV infection in the potential donor does not amount to an absolute contraindication to donation of material for life-preserving transplantation, however the net benefit of transplantation must be considered against the risk of not receiving that specific transplant. This risk/benefit analysis allows for the potential use of a transplant from a HCV infected donor to a non-infected recipient
Experience from outside the UK
o 4.1% of all organ donors in the US between 1995 and 2015 were reported to be HCV antibody positive
o Discard rates for HCV D+ livers have reduced in the US from 25% in 2006 to 10% in 2015 (discard of HCV D-)
o More than 500 HCV positive kidneys are discarded annually in the US (opiate Abuse)
o A conference of the American Transplantation Society held in January 2017 was in favour of considering D+ to R- transplantation across all solid organs within set criteria
o Goldberg et al published a study in the New England Journal of Medicine: 10 kidney transplant recipients, all were given HCV D+ kidneys from individuals infected with genotype 1 HCV. All recipients became viraemic by day 3 and all received 12 weeks of treatment with SVR
o EXPANDER-1 trial result was the same
What are the risks of HCV D+ to R- transplantation?
1. fibrosing cholestatic hepatitis (FCH). It is an aggressive form of HCV recurrence seen in 10% of D+/R+ liver transplants (1.5% in kidnet transplant)
2. infection transmission (DAA therapy results a high cure)
3. DAA treatment failure (<5%)
4. Extra-hepatic manifestations of HCV (cryoglobulinaemic vasculitis) or PTLD
5. Sexual transmission of HCV to a partner [(extremely low (<2% perhaps)]
The Practicalities of Implementing this Policy in the United Kingdom Patient Consent:
o Consent is specifically obtained by individual transplanting centres (supported by a patient information sheet)
Patient and Unit Requirements Pre-Transplant:
o HCV D+/R- non-liver transplantation should be avoided in recipients with advanced fibrosis or cirrhosis
o Seen by a liver specialist
o Screen patients by using AST-to-Platelet Ratio Index (APRI) and ultrasound
o If the APRI score is >0.8 or the ultrasound suggests significant or advanced liver disease, then an opinion from a liver specialist should be sought
o If the APRI score is <0.8, there is no need for the patient to be seen by a liver specialist
o Pre-requisites checklist
Allocation of HCV D+ Organs on the Waiting List:
o HCV D+ organs should be treated in the same way as HCV D- organs within the current allocation rules of the national waiting lists
Management of the Recipient of a HCV D+ Organ:
o Do HCV RNA following receipt of either a HCV antibody positive graft, a HCV RNA positive graft or a graft from an increased infectious risk donor, to ensure appropriate and early intervention if HCV transmission and infection occurs
o Test for HIV and HBV
o Recipient test by HCV RND day 3-7, day 10-14, and 6 weeks
o If recipient HCV+, two alternative regimens should be used as first line agents, either the combination of Glecaprevir/Pibrenatasvir or the combination of Sofosbuvir/Velpatasvir. Both should be given for 12 weeks in the context of HCV D+/R- transplants and both are pan-genotypic
o In treatment failure, a 12 week course of the combination of Sofosbuvir/Velpatasvir/Voxaleprevir which has a high rates of SVR even in those previously exposed to DAA therapy
Special Additional Considerations:
o Use of organs from donors treated for HCV with DAA within the last 6 months should be avoided unless there is clear documentary proof at the time of donation of an SVR12 result
o Any organ from a donor treated for HCV with DAAs but has not achieved SVR12 for any reason should not be considered for transplantation into a negative recipient unless the benefits outweigh the risks (in a clinically urgent transplant candidate)
HCV + Donors used for transplant:
1. HCV Ab positive with no history of treatment of HCV
2. HCV Ab positive with documented SVR after treatment
3. Any HCV Ab negative donor who has exposed themselves to risk but who does not fulfill any of the unacceptable criteria
4. Any HCV Ab positive donor whose HCV treatment history is unknown
HCV+ Donors should not used for transplant:
1. Previously failed DAA therapy with on-going viraemia
2. DAA therapy within last year without documented SVR (unless the recipient is at imminent risk of death)
3. Multiple documented re-infection with HCV
Large number of patients on waiting list died due to shortage of donor organ.
HCV+ donor used to reduce this shortage after introduction of DAA.
It is important to determine serological & virological status of donor (rather than use HCV+).
Prevalence of HCV Ab+/RNA- increased after use of pan genotype DAA.
HCV infection can be transmitted through donor organ if the donor HCV Ab+/RNA-(window period of reinfection) or there was occult infection (residual viral genome in donor tissue).
Viremic patient: mean active infection with detectable HCV RNA regardless antibody status.
Post transplant pangenotypes DAA for 8-12 weeks can cure patient in 95-100%.
GLE/PIB can be used in patient with renal failure.
Second & third generation DAA highly effective for patients with cirrhosis & patients need treatment after kidney & liver transplantation with high rate of cure.
HCVD+/R- SOT can be used with reduced morbidity & mortality.
SaBTO state that HCV donor are not an absolute contraindication of donation, but benefit of transplantation should be considered against the risk of not receiving specific transplantation. The analysis of risk/benefit allow acceptance of HCV D+/R- transplantation.
Experience from outside UK:
US has the beat data on HCV D+number & discarded rate.
America Transplant Society recommend:
use HCV D+/R- transplant across all Sot within set criteria.
This practice should take place within prospective research protocol.
insurance companies guarantee funding for DAA for infected patients at time of transplantation.
Several studies results were encouraging about efficacy & safety of DAA.
HCV D+ to R- transplant cost:
Course of DAA to cure R-/D+ transplant is less costly than dialysis for 1 year.
So using HCV D+/R- transplant will reduce cost of waiting list & dialysis with with improved quality of life.
Risk of HCV /R- transplant:
risk of fibrosing cholestatic hepatitis.
risk of virus transmission which can be cured by early DAA treatment.
DAA treatment failure.
increase risk of blood derived malignancy.
sexual transmission of HCV to a partner occur in HCV D+/R- transplant.
Pr-transplant patient & unite requirement:
HCV D+/R- non liver transplant should be avoided in recipient with advance fibrosis or cirrhosis.
Any patient receive HCV D+ non liver organ should be reviewed by liver specialist & assessment for fibrosis by APRI score
Allocation of HCV D+ organ on waiting list:
HCV D+ organ should be treated as HCV- organ within allocation rules of international waiting list by individualized NHSBT.
Post transplant outcome review needed.
Management of recipients of HCV D+ organ.
Hepatitis C RNA of recipient should be monitored if:
HCV Ab+ graft.
HCV RNA+ graft
graft from increased infectious risk donor.
Monitoring of HCV RNA as follow: 3-7 days post transplant, 10-14 days post transplant, at 6 weeks post transplant if all results are negative reassure the recipient & managed as standard recipients.
If HCV RNA positive during monitoring, DAA started within 3-10 days of first positive PCR.
· Kidney transplantation is the best form of kidney replacement therapy for individuals suffering from end stage kidney disease. Nonetheless, 1 in 6 patients on the waiting list are not able to get transplanted because they either die or deteriorated before transplantation. One reason for this is shortages of donors, hence there should a continuous effort to utilize the organs which have not been used for transplantation such as hepatitis C infected organs.
· Up to now most hepatitis C infected organs were discarded due to fear of transmitting the virus to the recipient. In past hepatitis C treatment was very challenging because of tolerability issues and was not effective to clear the virus in the infected transplant recipient. How ever with new hepatitis C treatment i.e., directly acting antiviral agents most patients are cured with a cure rate exceeding 95%.
· A number of small studies confirmed a very good outcomes of transplanting hepatitis C positive organs to hepatitis C negative recipients after their treatment and clearance of the virus.
· Unfortunately, a recent report of the UK potential donor Audit showed that, 15 suitable hepatitis C infected donors are rejected and the fact is that utilization of these donors may result in 75 additional donor pools available for transplantation every year.
· Thanks to UK Advisory Committee on the Safety of Blood, Tissues and Organs to address this issue and they recommended that, in situations of urgent demand hepatitis C infected organ can be transplanted to hepatitis C negative recipients. The advisory committee consist of a group of professionals consist of: clinicians, virologists, scientists, health care managers & patient representatives. They make reasonable decisions on the use of organs from hepatitis C infected donors.
· The recommendation statements focus on the following areas:
1. Appropriate donor selection
2. A policy for a fully informed recipient consent
3. Guidelines for recipient tests & treatments
4. Monitoring committee to follow up the program
This article is based on the position of the UK on using HCV viremic donors for HCV negative recipients.
Discussion
Organ donors with HIV infection have been discarded due to the risk of transmission of the virus to the recipient.
In recent times HCV infection has been treated well with antiviral agents. Due to this many centers have used HCV infected organs for HCV negative recipients and experienced good results with adequate prophylaxis and treatment as required.
Recent analysis shows that suitable donors are declined due to HCV transmission risk. Due to the already scarce donor pool, this needs to be remedied. Using HCV infected organs with appropriate precautions can increase the number of solid organ transplants done every year and decrease the burden on waiting lists.
A wider UK framework for the use of HCV infected organs has been proposed.
Key guidelines that need to be followed to achieve successful outcome in such transplants would include careful selection of appropriate and suitable donors, applicable policy to ensure that the donor situation is transparent with the recipient so that he/she can give their informed consent for the process, and guidance of the testing, prophylaxis and treatment of the recipient in such situation.
HCV infection in the donor used to be an absolute contraindication in the past, however, in recent times, it has shifted into being a relative contraindication with possible remedial measures. The net benefit of the transplant must be considered over the risk of transmission. This kind of risk/benefit analysis makes it possible for the use of an HCV infected organ for a HCV negative recipient.
Using HCV infected donors decreases the burden on transplant wait lists, but also reduces the economic burden due to time on dialysis until a suitable donor is available. Timely transplantation is more beneficial for the recipient both cost wise and health wise since dialysis is expensive, and reduces the quality of life for the patient significantly. In addition to this, finding suitable donors for highly sensitized recipients can be a struggle, especially in the scarce donor pool. This can be mitigated by the use of HCV donors.
The ethical issue concerning knowingly infecting a patient has to be considered. Even if the high mortality and morbidity rate of patients on waiting list can be justified by using infected donors, transmission risk is real and cannot be overlooked. However, with appropriate prophylactic measures done for suitable period of time, patient may only develop a transient and curable infection, while receiving a life saving organ.
DAA treatment failure is a concern but repeated and modernized therapies may help in eliminating the infection in the recipient post transplant.
Conclusion
Forming a group to monitor and oversee such programs in the early phases of implementation will help in stadandrized protocols being put in place to ensure successful implementation and good outcome for the recipient and all involved.
Serologic tests can detect antibodies to HCV within two to six months of initial infection
the most important parameter to be considered when assessing the HCV infectivity is whether or not active HCV replication is present by PCR or antigen testing..
the term ‘HCV viraemic’
1- donors or recipients who have active HCV infection with detectable HCV RNA, regardless of HCV antibody status
2- donors that are HCV IgG +ve where the HCV RNA status is not known
□Changes in the treatment of hepatitis C over the past five years
□Most of the current regimens used in clinical practice are given for between 8 and 16 weeks, and offer cure rates of 95-100% for patients without cirrhosis, regardless of HCV genotype.
□Most regimens do not rely on the use of ribavirin.
□There is already substantial UK experience of using two licensed pan-genotypic
□regimens in the form of
Sofosbuvir / Velpatasvir
and
Glecaprevir/Pibrentasvir.
□The pan-genotypic triplet of Sofosbuvir, Velpatasvir and Voxilaprevir was licenced in August 2017
□HCV D+ to R- transplantation should be cost effective
——————————————————
What are the risks of HCV D+ to R- transplantation?
○The first and perhaps most feared risk is of fibrosing cholestatic hepatitis (FCH)
●the SOLAR-1 and 2 studies the combination of Sofosbuvir and Ledipasvir for 12 or 24 weeks cured all 11 patients treated after liver transplantation with FCH
●Leroy et al reported similarly impressive cure rates of 100% in 15 patients with FCH
○ This and other studies would suggest that early treatment (ideally within 4 weeks) with DAA therapy should prevent the development of FCH.
○the high morbidity and mortality rates for patients on the waiting list justify the utilisation of D+ organs.
○Infecting individuals with (CMV) or (EBV) is mitigated by giving prophylactic treatment in the case of CMV.
○HCV D+/R- transplantation followed by early DAA therapy would result in only a transient, usually rapidly curable infection.
○ Another theoretical concern is that a minority ( <5%) of patients treated after organ transplantation may experience DAA treatment failure
○POLARIS-1 trial has shown that 12 weeks of re-treatment with the triple therapy combination of Sofosbuvir, Velpatasvir and Voxilaprevir is highly effective (>95%) in achieving cure of HCV in patients with HCV NS5A RAS
○Extra-hepatic manifestations of HCV such as cryoglobulinaemic vasculitis or PTLD are also theoretical there are no data, and early DAA therapy should mitigate against these in any case
————————————————————–
Patient and Unit Requirements
■Pre-Transplant
screening patients using AST-to-Platelet Ratio Index (APRI) and ultrasound is suggested.
■the APRI score is >0.8 or the ultrasound suggests significant or advanced liver disease, then an opinion from a liver specialist before the patient is considered for a HCV D+ organ.
■ If the APRI score is <0.8, there is no need for the patient to be seen by a liver specialist.
————————————————————-
Management
D+ /R – ==> Recipient tested for HCV by PCR day 3-7 post transplant ==> HCV PCR – ==> Recipient tested for HCV by PCR day 10-14 post transplant ==>
HCV PCR – ==> Recipient tested for HCV by PCR 6w post transplant ==> reassure patient as standard recipient
If HCV PCR + at any stage==> start DAA within 3- 7 day after test
Two alternative regime should used as first line agents.
●These are either the combination of
Glecaprevir/Pibrenatasvir or
Sofosbuvir/Velpatasvir.
for 12 weeks in the context of HCV positivity, they can be started as soon as HCV PCR without having to wait for a HCV genotype areas.
■Glecaprevir/Pibrenatasvir is increased by ciclosporin, and it may also increase the levels of tacrolimus)
■ Sofosbuvir/Velpatasvir is not recommended in patient with a eGFR <30 mL/min/1.73 m 2
■Sofosbuvir/Velpatasvir/Voxaleprevir combination for high rates of SVR even in those previously exposed to DAA therapy.
———————————————————–
Special Additional Considerations
Acceptable Within Proposed Policy
●HCV Ab positive with no history of treatment of HCV
●HCV Ab positive with documented SVR after treatment
●Any HCV Ab negative donor who has exposed themselves to risk but who does not fulfill any of the unacceptable criteria
●Any HCV Ab positive donor whose HCV treatment history is unknown – proceed with caution
Not Recommended Within Proposed Policy
●Previously failed DAA therapy with on-going viraemia
●DAA therapy within last year without documented SVR (unless the recipient is at imminent risk of death)
IV. UK Position Statement on the use of Organs from Hepatitis C Viraemic Donors and Increased Infectious Risk Donors in Hepatitis C Negative Recipient Please summarise this article.
Up to 1 in 6 patients scheduled for SOT will die or become too unwell for a TX despite the rise in organ donation in the UK. So, there is a need to find ways to better utilize organs that are frequently discarded.
Because of the high risk to the recipients, the majority of organs from HCV -infected donors have previously been discarded.
Earlier treatment options were less effective at curing TX recipients of the virus & had less tolerance.
> 95% of those with HCV can now be treated with DAAs.
Research indicates that TX recipients can safely reach similar levels of HCV clearance.
Limited studies reported great outcomes in HCV-ve recipients who received HCV+ve organs & went on to get treatment & cured of the virus.
Up to 15 eligible donors may be turned away annually due to the possibility of HCV infection (a recent UK Prospective Donor Audit).
The UK might perform up to 75 more SOTs annually if such donors’ organs were used.
Virologists, scientists, health care managers, & patient representatives have proposed a UK-wide framework for the rationale use of organs from HCV-infected donors in response to the Advisory Committee on the Safety of Blood, Tissues, & Organs’ recent recommendations that, in certain situations, organs from HCV-infected donors may be transplanted into uninfected recipients.
The key components of the guidelines are:
The selection of suitable donors
A policy to guarantee that the intended recipient gives fully informed consent.
Instructions for testing & treating recipients as indicated.
Creation of a monitoring group to oversee the program in its early stages of implementation.
Consideration of some of the major operational issues that will arise during the successful implementation of the pathway.
Changes in the treatment of HCV over years
1stgeneration protease inhibitors Telaprevir & Boceprevir in 2012.
DAAs combined with interferon & ribavirin, increased cure rates for G1 HCV from 50% to > 80%.
Currently, most regimens (8 to 16 weeks), have cure rates 95-100% for patients without cirrhosis, irrespective to HCV genotype.
Most regimens do not contain ribavirin.
Substantial UK experience of using 2 licensed pan-genotypic regimens (Sofosbuvir / Velpatasvir & Glecaprevir /Pibrentasvir).
Pan-genotypic triplet (Sofosbuvir, Velpatasvir & Voxilaprevir) licenced in 2017.
Glecaprevir /Pibrentasvir can be used in kidney failure.
Sofosbuvir, Velpatasvir & Voxilaprevir regimens are highly effective for those who have failed other DAA-containing regimens.
The 2nd& 3rdgeneration DAA regimens are highly effective in cirrhotic patients, & for post-renal or liver TX treatment (majority can be cured post TX).
The realistic possibility of transplanting organs from donors with HCV RNA viremia (D+) into recipients without HCV viremia (R-) is made easy by this shift in the treatment strategies.
This would lower the morbidity & mortality of people on SOT waiting lists.
Current discard rates for HCV+ve donor organs in the UK
Use of HCV D+ organs are restricted to HCV R+ recipients.
There is very poor utilization of HCV D+ non-liver organs even for HCV R+ recipients.
According to validated UK Donor Risk Indices, if discarded donors had been used, 77% of the kidneys & 80% of the livers from the possible donors would have been expected to be functioning 5 years later.
The recently issued revised guidance by the UK Advisory Committee on the Safety of Blood, Tissues and Organs (SaBTO) paves the way for potential D+ to R- transplants.
Experience from outside the UK
In the US, the discard rates for HCV D+ livers decreased from 25% in 2006 to 10% in 2015 & now nearly approches those for HCV D- livers.
Although other organs frequently come from younger donors, their discard rates are greater. The US discards > 500 kidneys/year that have the HCV virus.
The median age of HCV D+ in the US is decreasing as a result of the widespread opiate abuse. Therefore, it is likely that high-quality organs are currently being wasted because a sizable portion of them come from HCV D+ people.
Why HCV D+ to R- TX should be cost effective?
Dialysis is costly & this expense might be reduced by prompt TX.
Reduced waiting times.
Patients’ quality of life is considerably diminished on dialysis.
A course of treatment for an R-receiving a D+ organ would be less expensive than a year’s worth of dialysis.
The risks of HCV D+ to R- TX
Fibrosing cholestatic hepatitis (FCH): 10% of D+/R+ liver transplants develop this severe form of HCV recurrence. It also occurs in 1.5% of KTX. There are reports that DAA therapy is successful in the context of FCH.
Infecting a patient with an infectious agent carries ethical issues. Yet, the use of D+ organs is justified by the high morbidity & mortality rates on the waiting list.
DAA treatment failure (in <5%)
Extra-hepatic manifestations of HCV such as cryo-globulinaemic vasculitis.
introduction
HCV virus is a single-stranded RNA virus with known 6 genotypes, the mode of transmission is through contaminated blood and blood products, IVDA sharing needles, and sexual transmission is rare only in anal sex, with multiple partners, vertical from the mother to the fetus, acute HCV infection usually subclinical, and chronic HCV is the predominate course with persistent positive HCV RNA more than 6 months.
The previous policy of discarded organs including organs from HCV-infected donors and limiting their use only for infected recipients can increase the number of discarded organs An important strategy is a continuous review to assess whether advances in medicine could enable such organs to be transplanted. It is now apparent that
greater use can be made of organs from hepatitis C (HCV) infected donors with the improvement in the screening methods and the use of the new medications with direct antiviral effect (DAA) and a high cure rate of up to 95% with the sustained viral response regardless of the genotype and well-tolerated medications that licensed and approved for the treatment of HCV infection and with such evidence nowadays we can transplant organs from HCV infected donors to HCV negative or positive recipients with a proper serological and virological assessment with the recent use of DAA therapy the prevalence of individuals who are HCV
antibody positive but who have undetectable HCV RNA will increase, Acute HCV infection is usually subclinical, and up to 60% will have chronic infection with persistent positive anti-HCV ABS, but viremia defined by the positive NAT, or HCV PCR positive.
‘HCV viraemic’term
Refer to the status of both recipient or donor with active HCV infection which is confirmed by detectable HCV RNA by PCR test regardless of the HCV antibodies status or to donors that are HCV IgG +ve where the HCV RNA status is not known at the time of organ offer/transplantation( window period ).
In the era of the new medications for HCV infection
The treatment of HCV infection has been evolving over the last six years after the introduction of the DAA therapy in 2012and the current regimens used in clinical practice are given
for between 8 and 16 weeks, with suggested cure rates of 95-100% for patients without cirrhosis, regardless
of HCV genotype. Most regimens do not count on the use of ribavirin. There is already substantial UK
experience of using two licensed pan-genotypic regimens in the form of Sofosbuvir / Velpatasvir and
Glecaprevir/Pibrentasvir Why HCV D+ to R- transplantation should cost-effective
the cost of the DAA therapy to cure R- HCV infection from donor +ve is less than the one-year cost of dialysis, in addition to that have better survival and better quality of life.
compared to waiting on dialysis. What are the risks of HCV D+ to R- transplantation?
One of the serious complications after D+/R- transplantation is the risk of an aggressive form of fibrosing cholangitis hepatitis due to HCV recurrence which was reported in 10% of D+/R+ liver transplants. Prior to the advent of DAA Therapy, FCH was associated with high mortality. It is also reported in kidney transplantation, with an incidence of 1.5% in the largest series from Spain (36). the combination
of Sofosbuvir and Ledipasvir for 12 or 24 weeks cured all patients treated after liver transplantation with FCH In the SOLAR-1 and 2 studies (23,27) similar case series and case reports also confirmed the effectiveness of the DAA therapy especially if started within the first 4 weeks of infection and resulted in 100% cure rate of FCH with a sustained viral response.
However, reported in < 5% failure to respond to the first line DAA therapy but by extension of treatment duration up to 16 weeks or use of the alternative triple DAA protocol improves the cure rate to 95%
Sexual transmission of HCV to a partner could potentially occur in the HCV D+/R- transplant scenario.
The risk can be mitigated by simple lifestyle advice and its rare < 2% The Practicalities of Implementing this Policy in the United Kingdom
HCV D+/R- non-liver transplantation should be avoided in recipients with advanced fibrosis or cirrhosis. Rather than mandate that every
The patient consented to receive an HCV D+ non-liver organ to be seen by a liver specialist.
AST to PLATLET RISK score < 0.8 no need to be seen by a liver specialist but if the score >0.8 with US finding of liver cirrhosis then clearance from a liver specialist needed
Management of the Recipient of an HCV D+ Organ Special consideration
Not recommended to accept donors
1. with Previously failed DAA therapy with on-going
Viremia in the last 6 months without achieving SVR (HCV resistance)
2. DAA therapy within the last year without documented SVR (unless the recipient is at
imminent risk of death)
2. Multiple known re-infection risks with HCV Still, we can accept the donation provide the following
1. HCV Ab positive with no history of treatment
2. HCV Ab positive with documented SVR after treatment
3. Any HCV Ab negative donor who has exposed themselves to risk but who does not fulfill any of the unacceptable criteria
4. use with caution in case of an HCV Ab-positive donor whose HCV treatment history is unknown.
Figure 2. summarize the Proposal for Testing of Donors and Management of All Recipients in the UK HCV D+/R- scheme
All donors with HCV AB positive will be tested for HCV PCR, if negative or positive in addition to the genotype, the results will be informed to the transplant team within two working days, organ transplanted to the HCV-negative recipients after being informed consent signed then the recipient HCVPCR will be frequently tested in first 3-7 days, if negative HCV PCR, then next test in day10-12 if negative, then in week 6 if HCV cpr negative after 6 weeks then reassure the recipient of no transfer f the infection while any HCV PCR turned positive earlier in the first 6 weeks he should receive DAA therapy preferred within 3-10 days from first positive HCV PCR with FU for SVR and cure.
When starting such a proposal need an MDT approach including a transplant physician with good experience, in treating and following such cases with an MDT approach with a hepatologist and pharmacy that is able to provide the treatment and sustained the supply of DAA therapy including the alternative protocol if no response to first-line therapy also virologist to timely screen and Fu for SVR.
This is a UK document to establish criteria for donors with active Hepatitis C virus for negative recipients.
Introduction
Solid organ transplantation is considered routine best practice for replacing failing organs.
The waiting list can take years and several organs are discarded due to positivity for Hepatitis C. In recent years, with the emergence of direct-acting antivirals and adequate viral suppression, the possibility of including this donor profile and reducing the waiting list has arisen.
Immune status
Exposure (Immune window), viremia (RT PCR positive), and serological conversion (Antibody positive).
Change in treatment
Interferon-based regimens with the very low viral response and disease persistence. Drugs with a sustained viral response by acting directly against the virus brought sustained viral response with almost 100% response in oral treatments for twelve weeks.
Currently, there are pan-genotypic drugs with Sofosbuvir without the need to genotype the virus.
Current practice with D+
Discarding is common, with specific acceptance for individualized cases of liver transplantation. With the new therapies, many donors have a negative viral load again. The new drugs improved viral load, liver function, fibrosis, hepatic steatosis and waiting time for transplantation.
With the current structure, it is possible to transplant from positive donors to negative recipients safely and effectively, and this is the purpose of this document.
Experience outside the UK
There has been a reduction in discarding viable organs with HCV+ donors in the US, mainly due to the tragedy of opium and the availability of young patients. But to make it possible the availability of direct-acting antiviral therapy was necessary.
Broad regimens with Grazoprevir/Elbasvir and the addition of sofosbuvir depending on the genotype.
Another study used pan-genotypic treatment with Sofosbuvir/Ledispavir with good post-transplant viral suppression.
Cost-effectiveness
Specific antiviral therapies against the Hepatitis C virus are expensive, but carrying out the treatment together with the transplant would pay for the investment of one year of dialysis. In this way, not only dialysis would be reduced, but also hospitalizations would be reduced, quality of life would be improved, and survival would increase.
Risks
The greatest fear is fibrosing cholestatic hepatitis, an aggressive form of recurrent HCV with high mortality.
The use of antiviral therapy minimizes these risks. In situations of antiviral resistance, triple regimens with Sofosbuvir, Velpatasvir, and Voxilaprevir are highly effective.
Cryoglobulinemia and PTLD vasculitis may occur.
Pre-transplant
Clinical and laboratory markers such as APRI can help when a specialized team is needed, as well as USG with elastase.
Positive and negative HCV donors must follow the same rules in the waiting list, not being a limiting factor anymore.
Pangenotypic treatments such as Sofosbuvir/Velpatasvir and Glecaprevir/Pibrenatasvir for twelve weeks. Monitor calcineurin inhibitors become necessary.
Additional considerations Acceptable
– HCV Ab positive with no history of previous treatment
– HCV Ab positive with the sustained viral response after treatment
– HCV Ab positive with previous treatment history but no description (caution)
Not recommended
– Failure to treat with direct-acting antiviral drugs with present viremia
– No documentation of sustained viral response
– HCV reinfections
New processes must be carried out with the new therapies and experiences in progress.
Chronic infection: defined as persistence of HCV RNA in serum for greater than six months after initial infection. This develops in at least 60% of those infected.
HCV antibody (anti-HCV) continues to remain positive for a number of years and often indefinitely after spontaneous clearance, or successful treatment of HCV with interferon or DAA therapy resulting in undetectable HCV RNA (SVR; sustained virologic response).
‘HCV viraemic: refer to donors or recipients who have active HCV infection with detectable HCV RNA, regardless of HCV antibody status; it also refers to donors that are HCV IgG +ve where the HCV RNA status is not known at the time of organ offering / transplantation.
The advantage of Glecaprevir / Pibrentasvir is that it can be given to patients with established renal failure
These regimens also have high efficacy for the treatment of patients who have previously failed other DAA-containing regimens, with the best data currently available for Sofosbuvir, Velpatasvir and Voxilaprevir.
‘HCV infection in the potential donor does not amount to an absolute contraindication to donation of material for life-preserving transplantation, however the net benefit of transplantation must be considered against the risk of not receiving that specific transplant.
This risk/benefit analysis allows for the potential use of a transplant from a HCV infected donor to a non-infected recipient.
Why HCV D+ to R- transplantation should be cost effective:
all stakeholders are reassured that a course of therapy to cure a R- patient receiving a D+ organ would be less than the cost of dialysis for one year.
What are the risks of HCV D+ to R- transplantation:
The first and perhaps most feared risk is of fibrosing cholestatic hepatitis (FCH)
This is an aggressive form of HCV recurrence seen in 10% of D+/R+ liver transplants.
There are now increasing reports of DAA therapy being very effective in the setting of FCH.
A minority (in reality <5%) of patients treated after organ transplantation may experience DAA treatment failure, which may be associated with the development of difficult to treat resistance associated substitutions (RAS) especially in the viral NS5A protein, but also, for recipients of a protease inhibitor, in the NS3A region.
data from the POLARIS-1 trial has shown that 12 weeks of re-treatment with the triple therapy combination of Sofosbuvir, Velpatasvir and Voxilaprevir is highly effective (>95%) in achieving cure of HCV in patients with HCV NS5A RAS at baseline
Thus virtually all HCV D+/R- recipients can be cured with modern DAA therapies, even if this is not achieved at the first attempt at treatment.
Extra-hepatic manifestations of HCV such as cryoglobulinaemic vasculitis or potential increased rates of blood derived malignancy such as PTLD are also theoretical consequences of HCV infection in the post-transplantation phase.
There are no data in the HCV D+/R+ field to demonstrate an increased risk of these consequences, and early DAA therapy should mitigate against these in any case.
Sexual transmission of HCV to a partner could potentially occur in the HCV D+/R- transplant scenario. The risk can be mitigated by simple lifestyle advice
A proper patient consent should be taken for D+/R- patients
AST-to-Platelet Ratio Index (APRI) and ultrasound is suggested.
APRI scores are easily calculated using on line tools such as https://www.mdcalc.com/ast platelet-ratio-index-apri.
If the APRI score is >0.8 or the ultrasound suggests significant or advanced liver disease, then an opinion from a suitably qualified liver specialist should be sought before the patient is considered for a HCV D+ organ.
It was felt that even cirrhotic patients could potentially receive HCV D+ organs safely but that this was not an appropriate risk for the early phases of a new UK HCV D+/R- programme.
If the APRI score is <0.8, there is no need for the patient to be seen by a liver specialist.
Combination of Glecaprevir/Pibrenatasvir or the combination of Sofosbuvir/Velpatasvir should be given for 12 weeks in the context of HCV D+/R- transplants.
Both are pan-genotypic, which means that they can be started as soon as HCV PCR positivity is known, without having to wait for a HCV genotype, which can take 3-4 weeks in some areas.
Both have very acceptable drug to drug interaction profiles although exposure to the former is increased by ciclosporin, and it may also increase the levels of tacrolimus (CYP3A and P-glycoprotein inhibition); the latter is not recommended in patient with a eGFR <30 mL/min/1.73 m2
e rare (expected to be less than 2%) instances where the first course of treatment of HCV is not curative, recipients should be treated with a 12 week course of the combination of Sofosbuvir/Velpatasvir/Voxaleprevir which, as previously discussed, has high rates of SVR even in those previously exposed to DAA therapy.
The acceptability of HCV D+ donors is as follows:
Acceptable Within Proposed Policy
HCV Ab positive with no history of treatment of HCV
HCV Ab positive with documented SVR after treatment
Any HCV Ab negative donor who has exposed themselves to risk but who does not fulfill any of the unacceptable criteria
Any HCV Ab positive donor whose HCV treatment history is unknown – proceed with caution
Not Recommended Within Proposed Policy
Previously failed DAA therapy with on-going viraemia
DAA therapy within last year without documented SVR (unless the recipient is at imminent risk of death)
In spite of the rise in the number of organs that are donated in the UK, up to one in six people who are on the waiting list for a solid organ transplant will pass away or become too ill to receive one. As a result, there is an ongoing need to investigate ways to improve the use of organs that are not presently utilized on a widespread basis for transplantation.
The vast majority of organs obtained from donors who were infected with hepatitis C had, up until this point, been thrown away because of the significant risk of the virus being passed on to the recipient. The older treatment methods had a low tolerance and were not effective enough in eradicating the virus in transplant patients.
Changes in the treatment of hepatitis C:
Due to recent developments in the treatment of hepatitis C infection, it is now possible to cure more than 95% of people who are afflicted with the C with antiviral medications that work directly on the virus. Studies have demonstrated that similar outcomes of hepatitis C clearance can be safely achieved in transplant recipients. Additionally, small trials have demonstrated excellent outcomes in hepatitis C-negative recipients who were given hepatitis C-infected organs and who were subsequently treated and cured of the virus.
A recent review of the UK prospective donor audit revealed that up to 15 potential donors are denied per year due to the risk of transmission of hepatitis C. The reason for this was cited as the possibility of the transfer of the virus. If organs from these donors were used in transplants, it is possible that an additional 75 solid organ transplants would be conducted each year in the UK.
Following the recent recommendations made by the Advisory Committee on the Safety of Blood, Tissues, and Organs that organs from hepatitis C-infected donors may be transplanted into uninfected recipients in certain clinical situations, a group of clinicians, virologists, scientists, healthcare managers, and patient representatives have proposed a framework for the appropriate use of organs from HCV infected donors that is applicable across the United Kingdom.
The selection of appropriate donors, a policy for ensuring that the intended recipient gives fully informed consent, guidance for the testing and treatment of recipients as indicated, the formation of a monitoring group to oversee the program in the six early phases of implementation, as well as consideration of some of the headline operational issues that will arise during the successful implementation of the pathway, are all key elements of the guidelines.
Indication of which donors should be utilized for transplantation within the framework of the suggested policy, as well as which donors should not be used;
Tolerable Within the Bounds of the New Policy;
HCV antibody positivity without a previous record of HCV therapy.
-HCV antibody positivity with a demonstrated suppression of viral replication after therapy
-Any HCV Ab negative donor who has put themselves in a risky situation but who does not meet any of the criteria that are considered unsuitable.
-Proceed with extreme care in the case of any HCV Ab-positive donor whose previous HCV treatment history is unclear.
Not Suggested Within the Bounds of the Draft Policy
DAA treatment had been tried before but was unsuccessful, and ongoing viremia was present.
Treatment with DAA during the previous year without a confirmed SVR (unless the recipient is at imminent risk of death).
There have been many recorded instances of re-infection with HCV.
Introduction;
-Kidney transplantation, is the best therapeutic option for patients with CKD G5 ,irrespective of presence of HCV infection, however, a significant number of patients still die due to a shortage of donor organs.
-In the twelve month period of 2016/17 alone, 457 patients died on UK transplant waiting lists.
-This confirms the ongoing need to strive to increase the number of organs available for transplantation.
-However, the most important parameter to be considered when assessing the HCV infectivity of an organ donor or recipient is whether or not active HCV replication is present; i.e. whether they are viraemic, with detectable HCV RNA by sensitive genome amplification methods such as polymerase chain reaction nucleic acid testing or, potentially, antigen testing.
-The presence of occult HCV, i.e residual HCV viral genomes, in donor tissue is also a potential means of HCV transmission. Benefits from treatment of HCV infection;
-To reduce the morbidity and mortality of those individuals on solid organ transplant waiting lists.
-Treatments for hepatitis C have changed greatly over recent years. It is now possible to cure over 95% of patients who are infected with the hepatitis C virus.
-Most of the current regimens used in clinical practice are given for between 8 and 16 weeks, and offer cure rates of 95-100% for patients without cirrhosis, regardless of HCV genotype.
-The advantage of Glecaprevir / Pibrentasvir is that it can be given to patients with established renal failure.
-These regimens also have high efficacy for the treatment of patients who have previously failed other DAA-containing regimens, with the best data currently available for Sofosbuvir, Velpatasvir and Voxilaprevir. Why HCV D+ to R- transplantation should be cost effective; –Whilst there are clear morbidity and mortality benefits to increasing organ availability for patients on solid organ transplant waiting lists, there are also economic arguments.
-Thecourse of therapy to cure a R- patient receiving a D+ organ would be less than the cost of dialysis for one year.
-Implementation of the proposal contained within this position statement is likely to lead to substantial cost savings by reducing waiting times and dialysis expenditure.
-More importantly this should save lives and improve quality of life for patients. What are the risks of HCV D+ to R- transplantation? –The most feared risk is of fibrosing cholestatic hepatitis (FCH), which prior to the advent of DAA therapy was associated with a high mortality
-This is an aggressive form of HCV recurrence seen in 10% of D+/R+ liver transplants.
-It is also reported in kidney transplantation, with an incidence of 1.5% in the largest series from Spain, however, there are now increasing reports of DAA therapy being very effective in the setting of FCH.
-In the early days of a HCV D+/R- programme, treatment duration could be extended slightly (from 8 weeks to 12 weeks or from 12 weeks to 16 weeks) to mitigate this risk until more real world data emerges.
-Extra-hepatic manifestations of HCV such as cryoglobulinaemic vasculitis or potential increased rates of blood derived malignancy such as PTLD are also theoretical consequences of HCV infection in the post-transplantation phase.
-However, there are no data in the HCV D+/R+ field to demonstrate an increased risk of these consequences, and early DAA therapy should mitigate against these in any case. Patient and Unit Requirements Pre-Transplant; –HCV D+/R- non-liver transplantation should be avoided in recipients with advanced fibrosis or cirrhosis. –Rather than mandate that every patient being consented to receive a HCV D+ non-liver organ be seen by a liver specialist, a more pragmatic approach of screening patients using AST-to-Platelet Ratio Index (APRI) and ultrasound is suggested. –The exact drug regimens and length of therapy that should be offered to recipients that test positive for HCV after receiving an organ from a HCV D+ donor; two alternative regimens should be used as first line agents.
-These are either the combination of Glecaprevir/Pibrenatasvir or the combination of Sofosbuvir/Velpatasvir. (keep in mind drugs interaction with CNI)
-Both should be given for 12 weeks in the context of HCV D+/R- transplants.
-Both are pan-genotypic, which means that they can be started as soon as HCV PCR positivity is known, without having to wait for a HCV genotype, which can take 3-4 weeks in some areas.
-In the rare (expected to be less than 2%) instances where the first course of treatment of HCV is not curative, recipients should be treated with a 12 week course of the combination of Sofosbuvir/Velpatasvir/Voxaleprevir, has high rates of SVR even in those previously exposed to DAA therapy. UK Practice in treatment HCV D+ to R- transplantation;
-Grazoprevir/Elbasvir was started immediately before transplantation, and continued for 12 weeks.
-If the donor had genotype 2 or genotype 3 HCV, Sofosbuvir was added.
-If HCV resistance associated substitutions (RAS) were identified in donors with G1a HCV, ribavirin was added and treatment was extended to 16 weeks. Indication which donors should and should not be used for transplantation within the proposed policy; Acceptable Within Proposed Policy;
-HCV Ab positive with no history of treatment of HCV.
-HCV Ab positive with documented SVR after treatment.
-Any HCV Ab negative donor who has exposed themselves to risk but who does not fulfill any of the unacceptable criteria.
-Any HCV Ab positive donor whose HCV treatment history is unknown – proceed with caution. Not Recommended Within Proposed Policy
-Previously failed DAA therapy with on-going viraemia.
-DAA therapy within last year without documented SVR (unless the recipient is at imminent risk of death).
-Multiple documented re-infection with HCV. Informations discussed with patient who received a hepatitis C infected ?
-After transplant he will have a specific and very sensitive blood test to look for the presence of hepatitis C virus in his blood.
-The first blood sample will be taken within the first 7 days of his transplant, then again within the first 14 days and the last sample will be taken within the first 6 weeks of his transplant.
-If the virus tests remain negative by that time then his transplant organ has not passed on the infection to him.
-If any of these tests are positive for hepatitis C virus then the doctors looking after he will start him on highly effective treatment within 3-10 days of the result.
-This means that he will be prescribed some specific antiviral tablets that he will need to take for a total of 3 months.
-Once the treatment is finished he will have further blood tests to check that he has been cured of the virus.
-If the virus disappears from his blood and cannot be detected 12 weeks after the treatment has stopped then he has been cured , predicting that more than 95% of patients will be cured.
-If the first course of treatment does not work then a second 12 weeks course of treatment using a different combination of tablets will be used which cures more than 95% of patients whose first course of treatment has not worked. Conclusion;
-HCV infection in the potential donor does not amount to an absolute contraindication to donation of material for life-preserving transplantation, however the net benefit of transplantation must be considered against the risk of not receiving that specific transplant.
-This risk/benefit analysis allows for the potential use of a transplant from a HCV infected donor to a non-infected recipient.
-All HCV-infected patients who are candidates for kidney transplantation are to be considered for DAA therapy, either before or after transplantation.
-It is worth mentioning that these new drugs for hepatitis C have very few side effects in recent world experience and are generally very well tolerated by patients taking them.
crease the number of organs available for transplantation. An important strategy is the continuous review of organs that have been discarded, to assess whether advances in medicine could enable such organs to be transplanted. It is now apparent that greater use can be made of organs from hepatitis C (HCV) infected donors.
HCV is RNA virus member of the Flaviviridae family. Six genotypes (G1-6).
Acute infection tends to be subclinical, with chronic infection, defined as persistence of HCV RNA in serum for greater than six months in 60%.
The consensus was in favor of considering D+ to R – transplantation across all solid organs within set criteria, and recommended that such practice should take place within prospective research protocols.
Why HCV D+ to R- transplantation should be cost effective:
Whilst there are clear morbidity and mortality benefits to increasing organ availability for patients on solid organ transplant waiting lists, there are also sound economic arguments.
What are the risks of HCV D+ to R- transplantation?:
fibrosing cholestatic hepatitis.
resistance associated substitution
extra-hepatic manifestations of HCV such as cryoglobulinaemic vasculitis or potential increased rates of blood derived malignancy such as PTLD are also theoretical consequences of HCV infection in the post-transplantation phase.
Patient Consent:
consent to receive a HCV D+ organ should be specifically obtained by individual transplanting centrer
Patient and Unit Requirements Pre-Transplant
the working party agreed that HCV D+/R- non-liver transplantation should be avoided in recipients with advanced fibrosis or cirrhosis.
Rather than mandate that every patient being consented to receive an HCV D+ non-liver organ be seen by a liver specialist, a more pragmatic approach of screening patients using AST-to-Platelet Ratio Index (APRI) and ultrasound is suggested. . If the APRI score is >0.8 or the ultrasound suggests significant or advanced liver disease, then an opinion from a hepatologist.
Allocation of HCV D+ Organs on the Waiting List;
Further study for posttransplant outcome is needed before allocation with different transplant groups is arranged.
Management of the Recipient of a HCV D+ donors.
testing for hepatitis C RNA of the recipient following receipt of either a HCV antibody positive graft, an HCV RNA positive graft or a graft from an increased infectious risk donor, to ensure appropriate and early intervention if HCV transmission and infection occur.
used as first line agents.
These are either the combination of Glecaprevir/Pibrenatasvir or the combination of Sofosbuvir/Velpatasvir.
for 12 weeks in the context of HCV D+/R- transplants.
Both are pan-genotypic, both have very acceptable drug to drug interaction profiles although exposure to the former is increased by ciclosporin, and it may also increase the levels of tacrolimus (CYP3A and P-glycoprotein inhibition); the latter is not recommended in patient with an eGFR less than 30ml.
If not curative evSofosbuvir/Velpatasvir/Voxaleprevir is used for 12weeks.
Donors with failed therapy or therapy of last 6mpnths should not be used, also if engaged in dangerous behavior increased risk of infection or history of multiple HCV infection
Introduction;
The newer oral has changed HCV management with cure rate of 50 to 80%.
They effective in pan-genomic types.
The current UK rates of HCV positive donor’s organ.
Currently UK is restricting the use of HCV positive donors to HCV+ recipient.
But the revised literature shows that there is no absolute contraindication for donation.
Outside UK;
The data shows that after considering this the waiting time has decreased to 58 days, and the only issues were delayed draft function, proteinuria with FSGS.
What are the risks of HCV D+/ R- transplantation.
The potential risk included fibrosing cholestatic hepatitis.
But in the setting of DAAs they very effective if FCH+HCV+, with cure rates of 100%.
Ideally if started early with four weeks of FHC.
BTS, NHSB and transplantation reviewing the entire way of sharing information and gaining consent from recipient including HCV D+/R-.
Pre-transplant requirements;
The working party has agreed that if a recipient has cirrhosis should not be considered for transplantation other then liver.
They made important check list.
Should be waited for six month post DAAs treatment,
If did not achieved SVR12.
Resistant disease.
Kidney transplantation is the modality of choice for chronic kidney disease. However. shortage of donors is an essential hindrance for this program. HCV infected donors represent a potential pool for donation. Particularly after the introduction of direct antiviral agents DAA therapy which achieve a recovery rate of 95%.
The serological markers:
Anti HCV antibodies reflects HCV infection which is representing past exposure or infection with recovery of hepatitis or conversion to chronic carrier or chronic hepatitis status.
Diagnosis of HCV:
HCV infection depend on isolating HCV RNA by PCR. However, performing HCV antibodies positive / RNA negative solid organ transplant SOT to HCV negative recipient was associated with transmitting the infection in significant no. of patients, a finding that might be explained by reinfection of donor in window period or related to the existence of dormant traces of Viral RNA ijn the transplanted tissues.
the major complication of post transplant is fibrosing cholestatic hepatitis in 10% of the patients underwent liver transplantation from D+/R+. However complete recovery of the disease was reported after treatment with DAA.
DAA:
Combination of sofosbuvir and ledipasvir for 12-24 weeks is associated with 100% recovery.
The other issue of using DAA after transplantation is the resistance of HCV to commonly used protocol. In this case especially those with HCV NS5A positive protein. in this case triple DAA is indicative Sofosbuvir, velpatasvir and voxilaprivir with great success in reversing those resistant cases.
prophylactic DAA is indicated for HCV D+/R- transplantation which is resulting in transient curable post transplant infection.
the current status is HCV D+/R+ donation with close follow up and treatment accordingly.
Please summarise this article.
Up to 1 in 6 patients listed for solid organ transplantation will die or become too sick for a transplant. So, it needs to continuously explore improving the utilization of organs that are not currently widely used for transplantation.
· Organs from donors infected with hepatitis C have been discarded because of the high likelihood of transmitting the infection to the recipient. Older treatment modalities had poor tolerance and were not sufficiently successful in curing transplant recipients of the infection.
· Recent advances in the management of hepatitis C infection have changed the scenario as more than 95% of infected individuals can now be cured with directly acting antiviral agents.
· Studies have shown that similar outcomes of hepatitis C clearance can be safely achieved in transplant recipients and small trials have shown excellent outcomes in Hepatitis C negative recipients given hepatitis C infected organs who were subsequently treated and cured of the virus.
· A recent analysis of the UK Potential Donor Audit has suggested that up to 15 suitable donors are declined every year because of the risk of transmission of hepatitis C.
· Using organs from such donors could result in up to 75 extra solid organ transplants being performed every year in the UK.
· Following the recent recommendations by the Advisory Committee on the Safety of Blood, Tissues and Organs that, in some clinical situations, organs from hepatitis C infected donors may be transplanted into uninfected recipients.
· Selection of appropriate donors, a policy for ensuring the intended recipient gives fully informed consent, guidance for the testing and treatment of recipients as indicated, the formation of a monitoring group to oversee the program in the 6 early phases of implementation as well as consideration of some of the headline operational issues that will arise during successful implementation of the pathway.
UK Position Statement on the use of Organs from Hepatitis C Viraemic Donors and Increased Infectious Risk Donors in Hepatitis C Negative Recipient
Introduction:
· It is now apparent that greater use can be made of organs from hepatitis C (HCV) infected donors, to HCV+ recipients.
· With DAA therapy that can cure >95% HCV regardless of genotype, there is a pressing need to assess, whether organs from HCV infected donors may safely be transplanted into HCV uninfected recipients.
Introduction to HCV and Clarification of Nomenclature:
· Anti-HCV remain positive for a number of years after spontaneous clearance, or successful treatment of HCV with interferon or DAA therapy.
· ‘HCV viraemic’ refers to
– active HCV infection with detectable HCV RNA, regardless of HCV antibody status
– donors with HCV IgG +ve, if HCV-RNA is not known at the time of organ donation / transplantation.
Changes in the treatment of hepatitis C over the past five years:
· DAA regimens [Sofosbuvir+Velpatasvir, Glecaprevir+Pibrentasvir (preferred in CKD), or Sofosbuvir+ Velpatasvir+Voxilaprevir], have increased HCV-cure rates to 95-100% regardless of HCV genotype; enabling use HCV RNA+ donor for recipients without HCV-viremia.
Current discard rates for hepatitis C positive donor organs in the UK:
· HCV infection is not an absolute contraindication to donation of organs for life-saving transplantation, however the net benefit of such transplantation must over way the risk of not receiving that specific transplant.
· This risk/benefit analysis allows for the potential use of a transplant from a HCV infected donor to a non-infected recipient.
Experience from outside the UK:
· USA (1995 -2015) – 4.1% of all organ donors were anti-HCV antibody positive. Discard rates of anti-HCV antibody positive livers have reduced from 25% to 10%.
· EXPANDER-1 trial and HCV-TARGET trial have shown excellent SVR rates in liver and kidney transplant recipients.
Why HCV D+ to R- transplantation should be cost effective:
· The course of therapy to cure a R- patient receiving a D+ organ would be less than the cost of dialysis for one year.
What are the risks of HCV D+ to R- transplantation?
– 10% of liver transplants and 1.5% of kidney transplants develop fibrosing cholestatic hepatitis with high mortality but the use of DAA in early post- transplant is effective for prevention and treatment.
– Other risks are HCV infection and DAA failure.
Practicalities Implementing the Policy in UK:
1. Recipient consent is mandatory
2. Patient and Unit Requirements Pre-Transplant:
Ø Hepatologist consultation – liver USG, APRI (AST-to-platelet ratio index) screening
Ø APRI>0.8 or significant / advanced liver disease on USG
3. Organ allocation: after sufficient expertise, if decide favourable, HCV D+ Organs can be allocated similar to HCV-neg waiting list
4. Management of the Recipient of HCV D+ Organ:
Testing of HCV RNA PCR – day 3-7, day 10-14, then 6 weeks post-transplant
Ø Negative RNA even at 6 weeks à recipient can be reassured.
Positive HCV RNA, in first 6 weeks à should be treated with DAAs (12 weeks SOF + VEL or Glecaprevir + Pibrentasvir).
Ø If viremia not cleared within 10-14 days, add Voxilaprevir to SOF + VEL regimen, which is very effective.
5. Special considerations:
HCV antibody positive donors acceptable, if
1) with no h/o HCV treatment or with document SVR post DAA.
2) HCV treatment history is unknown.
3) with h/o exposure to risk not fulfilling unacceptable criteria.
Unacceptable donors:
1) HCV treatment in last 6 months, without documented proof of SVR.
2) failed treatment with ongoing viremia.
3) multiple documented HCV re-infections.
Conclusions:
· The advantage is weighted against harm in transplanted HCV positive donor.
· Transplantation of HCV-infected donor-to-non-infected recipient transplant according to risk/benefit.
· All HCV-infected kidney transplant candidates must have DAA therapy
Summary
HCV is a single stranded RNA virus member of the Flaviviridae family. Six genotypes (G1-6)
HCV viraemic’ refer to donors or recipients who have active HCV infection with detectable HCV RNA, regardless of HCV antibody status; it also refers to donors that are HCV IgG +ve where the HCV RNA status is not known at the time of organ offering / transplantation. It is important to note however that transmission of infection may still occur from donors during the window period of acute infection.
There is imbalance of organ demand and organ supply. Previously Organ from hepatitis c were discarded. HCV infection in the potential donor does not amount to an absolute contraindication to donation of material for life-preserving transplantation, however the net benefit of transplantation must be considered against the risk of not receiving that specific transplant. This risk/benefit analysis allows for the potential use of a transplant from a HCV infected donor to a non-infected recipient.’
With advance of direct acting antiviral drug, this has been possible, and studies have shown that similar outcomes of hepatitis C clearance and small trials have shown excellent outcomes in Hepatitis C negative recipients given hepatitis C infected organs who were subsequently treated and cured of the virus.
Current regimens used in clinical practice are given for between 8 and 16 weeks, and offer cure rates of 95-100% for patients without cirrhosis, regardless of HCV genotype. The second and third generation DAA regimens have also been shown to be highly effective for patients with cirrhosis, and for patients treated after kidney or liver transplantation. Various combination has been use with good success. That includes
Grazoprevir/Elbasvir, Sofosbuvir/ Grazoprevir/Elbasvir /ribavirin , Sofosbuvir and Ledipasvir (an earlier generation combination), with or without ribavirin , Sofosbuvir / Velpatasvir and Glecaprevir/Pibrentasvir, Sofosbuvir/ Velpatasvir/Voxilaprevir
The advantage of Glecaprevir / Pibrentasvir is that it can be given to patients with established renal failure
Post transplantation, Hcv pcr monitoring is done if negative in following days(3-10 days, 10-14 days, 6 weeks)
DAA is start within 3-10 days of Positive PCR
Treatment should be given in liaison with a clinical team with experience of management of HCV but does not necessarily have to be delivered in the transplanting centre.
In the rare (expected to be less than 2%) instances where the first course of treatment of HCV is not curative, recipients should be treated with a 12 week course of the combination of Sofosbuvir/Velpatasvir/Voxaleprevir which, as previously discussed, has high rates of SVR even in those previously exposed to DAA therapy.
Acceptable HCV Donor
HCV Ab positive with no history of treatment of HCV
HCV Ab positive with documented SVR after treatment
Any HCV Ab negative donor who has exposed themselves to risk but who does not fulfill any of the unacceptable criteria
Any HCV Ab positive donor whose HCV treatment history is unknown – proceed with caution.
Not Recommended HCV Donor
Previously failed DAA therapy with on-going viraemia
DAA therapy within last year without documented SVR (unless the recipient is at imminent risk of death)
Multiple documented re-infection with HCV
Introduction:
Continuous review of organs that have been discarded, to assess whether advances in medicine could enable such organs to be transplanted. It is now apparent that greater use can be made of organs from hepatitis C (HCV) infected donors. With direct-acting antiviral (DAA) therapy that can cure more than 95% of patients infected with HCV, regardless of genotype, there is a pressing need to assess whether organs from HCV infected donors may safely be transplanted into HCV uninfected recipients.
Introduction to HCV and Clarification of Nomenclature:
It is important to define the serological and virological status of the donor in a scenario of using HCV-infected donor for transplant. HCV can be transmitted by either intravenous drug or blood products, sexually, or vertically.
HCV is a single stranded RNA virus member of the Flaviviridae family, with six genotypes (G1-6), transmitted parentally, sexually, or vertical.
It can be acute or chronic and serologic tests can detect antibodies to HCV within two to six months of initial infection.
Anti-HCV remain positive for a number of years after spontaneous clearance, or successful treatment of HCV with interferon or DAA therapy.
‘HCV viraemic’ refer to donors or recipients who have active HCV infection with detectable HCV RNA, regardless of HCV antibody status; it also refers to donors that are HCV IgG +ve where the HCV RNA status is not known at the time of organ offering / transplantation.
Changes in the treatment of hepatitis C over the past five years:
Introduction of DAAs in last few years have increased the cure rates of HCV-infected patients to 95-100% regardless of HCV genotype. The regimens used include Sofosbuvir/Velpatasvir, Glecaprevir/Pibrentasvir (useful in renal failure), or Sofosbuvir/Velpatasvir/Voxilaprevir. These results make it possible to use HCV RNA viremic donor for recipients without HCV viremia.
Current discard rates for hepatitis C positive donor organs in the UK:
HCV infection is not an absolute contraindication to donation of material for life-preserving transplantation, however the net benefit of transplantation must be considered against the risk of not receiving that specific transplant. This risk/benefit analysis allows for the potential use of a transplant from a HCV infected donor to a non-infected recipient.
Experience from outside the UK:
In US between 1995 and 2015, 4.1% of all organ donors were anti-HCV antibody positive. Discard rates of anti-HCV antibody positive livers have reduced from 25% to 10%. EXPANDER-1 trial and HCV-TARGET trial have shown excellent SVR rates in liver and kidney transplant recipients.
Why HCV D+ to R- transplantation should be cost effective:
The course of therapy to cure a R- patient receiving a D+ organ would be less than the cost of dialysis for one year.
What are the risks of HCV D+ to R- transplantation?
10% of liver transplants and 1.5% of kidney transplants develop fibrosing cholestatic hepatitis with high mortality but the use of DAA in early post- transplant is effective for prevention and treatment.
Other risks are HCV infection and DAA failure.
The Practicalities of Implementing this Policy in the United Kingdom:
These practices include:
1) Patient consent:
Consent is mandatory specially for HCV D+/R- transplantation.
2) Patient and Unit Requirements Pre-Transplant:
These include screening patients with AST-to-platelet ratio index (APRI) and abdominal US and hepatologist consultation in the presence of APRI>0.8 or ultrasound showing significant or advanced liver disease.
3) Allocation of HCV D+ Organs on the Waiting List:
Done for HCV D+ organs once sufficient expertise has accrued.
4) Management of the Recipient of a HCV D+ Organ:
The management achieved by testing of HCV RNA PCR on day 3-7 post-transplant, then on day 10-14, and then 6 weeks post-transplant. If the reports are negative even at 6 weeks, the recipient can be reassured. If the HCV PCR comes out positive during the testing in first 6 weeks, the patient should be treated with DAAs (12 weeks of either Sofosbuvir/Velpatasvir or Glecaprevir/Pibrentasvir, and Sofosbuvir/Velpatasvir/Voxilaprevir if the first 2 regimes are not curative) within 3-10 days.
Special additional considerations:
Acceptable donors: These include:
1) HCV antibody positive with either no history of HCV treatment or with document SVR post-transplant.
2) HCV antibody positive donor with history of exposure to risk not fulfilling unacceptable criteria.
3) HCV antibody positive patient whose HCV treatment history is unknown.
Unacceptable donors: include:
1) prior treatment with DAA for HCV in last 6 months without documentary proof of SVR.
2) failed treatment with ongoing viremia.
3) multiple documented HCV re-infections.
Conclusion:
The advantage is weighted against harm in transplanted HCV positive donor.
Transplantation of HCV-infected donor-to-non-infected recipient transplant according to risk/benefit.
All HCV-infected kidney transplant candidates must have DAA therapy
Executive Summary· Organ donation is increasing, but 1 in 6 patients will die or become too sick for transplantation.
· Older treatment modalities have not been successful in curing hepatitis C in transplant recipients.
· Recent advances in hepatitis C management have enabled 95% of infected individuals to be cured with antiviral agents, with similar outcomes in transplant recipients.
· Up to 75 extra solid organ transplants could be performed annually due to potential donors declining due to hepatitis C risk.
· The Advisory Committee on the Safety of Blood, Tissues, and Organs has proposed a UK-wide framework for the appropriate use of organs from HCV-infected donors.
· The guidelines include a selection of donors, policy for informed consent, testing and treatment, monitoring group, and consideration of operational issues.
Introduction· Solid organ transplantation is now well established in routine clinical practice, and the number of patients alive in the UK following a successful transplant has surpassed 50,000.
· However, a significant number of patients still die due to a shortage of donor organs, with 457 patients dying on UK transplant waiting lists in 2016/17 alone.
· An important strategy is the continuous review of organs that have been discarded, to assess whether advances in medicine could enable such organs to be transplanted.
· This strategy could ultimately make more organs available for transplantation, and reduce the morbidity and mortality of patients on solid organ transplant waiting lists.
Introduction to HCV and Clarification of Nomenclature· HCV is a single-stranded RNA virus that is transmitted parenterally, sexually, or vertically, and can lead to sequelae of acute or chronic hepatitis.
· The University of Cincinnati has reported follow-up data of 25 HCV antibody-negative recipients who received donor livers from HCV antibody-positive but HCV RNA-negative “HCV high risk” donors.
Changes in the treatment of hepatitis C over the past five years· The revolution in HCV management began with the licensing of the first-generation protease inhibitors Telaprevir and Boceprevir in 2012, which increased cure rates for G1 HCV from 50% to over 80%.
· The pace of drug development has been rapid, and many agents licensed have now been superseded by better-tolerated and more effective regimens.
· There is already substantial UK experience using two licensed pan-genotypic regimens in the form of Sofosbuvir / Velpatasvir and Glecaprevir/pibrentasvir.
· The second and third-generation DAA regimens have also been shown to be highly effective for patients with cirrhosis, and for patients treated after kidney or liver transplantation.
· This paper seeks to establish a professional consensus to enable the use of HCV RNA viraemic organs for transplantation for recipients without HCV viremia.
Current discard rates for hepatitis C-positive donor organs in the UK· The UK is restricting the use of HCV D+ organs to HCV-positive recipients, but anecdotal evidence suggests poor utilization of non-liver organs even for HCV R+ recipients.· The revised guidance states that HCV infection does not amount to an absolute contraindication to the donation of material for life-preserving transplantation, but the net benefit of transplantation must be considered against the risk of not receiving it.
Experience from outside the UK· The US has the best data on D+ donor numbers and discard rates and is leading the way in early clinical trials of D+ to R- transplants.
· Discard rates for HCV D+ livers have reduced from 25% in 2006 to 10% in 2015, but discard rates for other organs are higher due to opiate abuse.
· A conference of the American Transplantation Society recommended that such practice should take place within prospective research protocols.
· The EXPANDER-1 trial (Exploring Renal Transplants Using Hepatitis- C Infected Donors for HCV-Negative Recipients) reported data from 10 patients who underwent kidney transplantation with an HCV D+ organ.
· The median wait time was reduced to 58 days, and the median eGFR at the end of the study was 68 ml/min (51-83).
· The only SAEs noted were delayed graft function, elevated ALT, transient class 1 donor-specific antibody, and proteinuria and focal segmental glomerulosclerosis on renal biopsy.
· Results in a larger cohort of patients were reported by Saxena et al from the HCV-TARGET consortium of
· Academic US centers, with 443 patients treated after organ transplantation.
· The SVR12 rate was 96.3% in liver recipients, 94.6% in kidney recipients, and 90.9% in kidney/liver recipients.
Why HCV D+ to R- transplantation should be cost-effective· Increasing organ availability for patients on solid organ transplant waiting lists has clear morbidity and mortality benefits, but also economic arguments.
· Dialysis is expensive and can reduce the quality of life, but timely transplantation can reduce waiting times and dialysis expenditure, leading to substantial cost savings and improved quality of life for patients.
What are the risks of HCV D+ to R- transplantation?
· The potential risks of HCV D+ to R- transplantation include fibrosing cholestatic hepatitis (FCH), which is an aggressive form of HCV recurrence seen in 10% of D+/R+ liver transplants. · DAA therapy has been found to be very effective in the setting of FCH, with cure rates of 100% in 15 patients with FCH treated after liver transplantation using the combination of Sofosbuvir and Daclatasvir. · Liu et al from Taiwan reported a case of an HCV R- a patient who became viraemic by 1 week post-transplantation and developed FCH by 6 weeks post-transplantation. · Early treatment (ideally within 4 weeks) with DAA therapy should prevent the development of FCH. · Sexual transmission of HCV to a partner is likely low, and Skipton Fund ex gratia payments may be granted to individuals infected through NHS treatment, but the current Special Category Mechanism (SCM) would require clarification before it could proceed in the UK.
The Practicalities of Implementing this Policy in the United Kingdom· The working party felt that it was important to provide a framework for transplant units to consider before proceeding with an HCV D+/R- transplant, and recommended an oversight committee for the first 20-30 transplants.
Patient Consent· The British Transplantation Society and NHS Blood and Transplant are reviewing the entire pathway of sharing information with and gaining consent from solid organ transplant candidates, including consent for HCV D+/R- transplantation.
Patient and Unit Requirements Pre-Transplant· The working party agreed that HCV D+/R- non-liver transplantation should be avoided in recipients with advanced fibrosis or cirrhosis.· To ensure safety, a more pragmatic approach of screening patients using AST-to-Platelet Ratio Index (APRI) and ultrasound is suggested. · If the APRI score is >0.8 or the ultrasound suggests significant or advanced liver disease, an opinion from a suitably qualified liver specialist should be sought before the patient is considered for a transplant. · A checklist of prerequisites must be in place before an individual transplanting center performs its first transplant.
Allocation of HCV D+ Organs on the Waiting List· Advisory Groups must decide how best to allocate HCV D+ organs to optimize organ utilization and review post-transplant outcomes to alter offering and allocation policies.
Management of the Recipient of an HCV D+ Organ· The working party discussed the need to implement standardized, longitudinal testing for hepatitis C RNA of the recipient following receipt of either an HCV antibody positive graft, an HCV RNA positive graft, or a graft from an increased infectious risk donor. · Two alternative regimens should be used as first-line agents, either the combination of Glecaprevir/Pibrenatasvir or the combination of Sofosbuvir/velpatasvir. · Treatment should be given in liaison with a clinical team with experience in the management of HCV but does not necessarily have to be delivered in the transplanting center.
Special Additional Considerations· The use of organs from donors known to have been treated for HCV with DAA within the last 6 months should be avoided unless there is clear documentary proof at the time of donation of an SVR12 result. · Donor and recipient testing should be followed, and any organ from a donor who has not achieved SVR12 for any reason should not be considered for transplantation into a negative recipient unless the benefits outweigh the risks. · Resistance testing of the virus at baseline prior to commencing treatment may be required and the choice of drug regimen tailored in light of this information.
Oversight of the Programme in its Early Days· An Oversight Committee should be established to oversee the implementation of the program and receive clinical information on the recipients of HCV D+/R- transplantation, led by BVHG with strong representation from NHSBT and the BRITISH TRANSPLANTATION SOCIETY.
Appendix 1 – Patient Information Leaflet for the Use of Hepatitis C Infected Organs in Hepatitis C Negative Recipients· Hepatitis C is a virus that can cause inflammation and scarring of the liver, and it is now possible to cure over 95% of patients with treatment. · Accepting an organ from a hepatitis C virus-infected donor can be beneficial, but there are risks such as jaundice, kidney injury, and a small chance that the virus may not disappear after 12 weeks of treatment. · Studies have shown that it is possible to cure every patient of the hepatitis C virus after kidney transplantation, with a 100% cure rate. · Hepatitis C virus does not damage the heart, lungs, or pancreas, so kidneys from infected donors should work just as well.
Appendix 2 – Checklist for Transplant Units to Go Through Prior to Going Ahead with HCV D+ / R- Transplantation· Recipient-specific, pharmacy issues, personnel issues, blood tests post-transplantation, referral pathway to local HCV MDT, and Blueteq access. · The clinical lead must ensure mandatory blood tests are taken post-transplantation and results are actioned within the timelines stipulated, have a formal pathway for the management of potential recipients, and have mechanisms in place to ensure timely testing of potential recipients.
Current discard rates for hepatitis C positive donor organs in the UK
Organs from only 76 (31%) of these donors were transplanted into 93 recipients (63 liver, 27 kidney and 2 heart transplants). The quality of the declined organs did not differ from that of the organs that were used, with positive serological tests reported as the reason for decline in 69% of cases. The declined donors often had good kidney and liver function, and, based on validated UK Donor Risk Indices, if they had been used, 77% of kidneys and 80% of livers from the potential donors would be predicted to be functioning 5 years later. Furthermore, even at the list price of DAAs (the actual prices that the NHS pays are lower) the additional costs of transplanting recipients exposed to HCV with a kidney from a HCV antibody positive donor was cost-neutral in comparison with remaining on dialysis within 5 years following transplantation. In reality, it is likely that this cost effectiveness will manifest earlier. Notably, data were not provided as to whether the donors had detectable HCV RNA by PCR testing, as only a minority had HCV RNA status reported.
HCV infection in the potential donor does not amount to an absolute contraindication to donation of
material for life-preserving transplantation, however the net benefit of transplantation must be considered against the risk of not receiving that specific transplant. This risk/benefit analysis allows for the potential use of a transplant from a HCV infected donor to a non-infected recipient.’
This change in the guidance paves the way for potential D+ to R- transplants.
What are the risks of HCV D+ to R- transplantation?
While there are clear economic and health related benefits to HCV D+ to R- transplantation, it is important to consider the potential risks and how these could be mitigated.
The first and perhaps most feared risk is of fibrosing cholestatic hepatitis (FCH) [34,35]. This is an aggressive form of HCV recurrence seen in 10% of D+/R+ liver transplants. Prior to the advent of DAA therapy FCH was associated with a high mortality. It is also reported in kidney transplantation, with an incidence of 1.5% in the largest series from Spain [36]. However, there are now increasing reports of DAA therapy being very effective in the setting of FCH.
By contrast, HCV D+/R- transplantation followed by early DAA therapy would result in only a transient, usually rapidly curable infection.
In the early days of a HCV D+/R- programme, treatment duration could be extended slightly (from 8 weeks to 12 weeks or from 12 weeks to 16 weeks) to mitigate this risk until more real world data emerges. However, data from the POLARIS-1 trial has shown that 12 weeks of re-treatment with the triple therapy combination of Sofosbuvir, Velpatasvir and Voxilaprevir is highly effective (>95%) in achieving cure of HCV in patients with HCV NS5A RAS at baseline [19]. Thus virtually all HCV D+/R- recipients can be cured with modern DAA therapies, even if this is not achieved at the first attempt at treatment.
Extra-hepatic manifestations of HCV such as cryoglobulinaemic vasculitis or potential increased rates of blood derived malignancy such as PTLD are also theoretical consequences of HCV infection in the post-transplantation phase.
Sexual transmission of HCV to a partner could potentially occur in the HCV D+/R- transplant scenario. The risk can be mitigated by simple lifestyle advice, as well as through the proposed early inception of DAA therapy post transplantation. It is likely this risk will be extremely low (<2% perhaps).
Patient Consent
Although patients are currently routinely consented to receive so-called ‘marginal’ organs including for example CMV-positive organs, it was felt that consent to receive a HCV D+ organ should be specifically obtained by individual transplanting centres. To aid this process, the working group has developed a patient information sheet (see Appendix 1). In addition, the group noted that the British Transplantation Society together with NHS Blood and Transplant is currently reviewing the entire pathway of sharing information with and gaining consent from solid organ transplant candidates, and inclusion of consent for HCV D+/R- transplantation will need to form part of this work.
Summary
HCV is a single stranded RNA virus member of the Flaviviridae family. Six genotypes (G1-6)
HCV viraemic’ refer to donors or recipients who have active HCV infection with detectable HCV RNA, regardless of HCV antibody status; it also refers to donors that are HCV IgG +ve where the HCV RNA status is not known at the time of organ offering / transplantation. It is important to note however that transmission of infection may still occur from donors during the window period of acute infection.
There is imbalance of organ demand and organ supply. Previously Organ from hepatitis c were discarded. HCV infection in the potential donor does not amount to an absolute contraindication to donation of material for life-preserving transplantation, however the net benefit of transplantation must be considered against the risk of not receiving that specific transplant. This risk/benefit analysis allows for the potential use of a transplant from a HCV infected donor to a non-infected recipient.’
With advance of direct acting antiviral drug, this has been possible, and studies have shown that similar outcomes of hepatitis C clearance and small trials have shown excellent outcomes in Hepatitis C negative recipients given hepatitis C infected organs who were subsequently treated and cured of the virus.
Current regimens used in clinical practice are given for between 8 and 16 weeks, and offer cure rates of 95-100% for patients without cirrhosis, regardless of HCV genotype. The second and third generation DAA regimens have also been shown to be highly effective for patients with cirrhosis, and for patients treated after kidney or liver transplantation. Various combination has been use with good success. That includes
Grazoprevir/Elbasvir, Sofosbuvir/ Grazoprevir/Elbasvir /ribavirin , Sofosbuvir and Ledipasvir (an earlier generation combination), with or without ribavirin , Sofosbuvir / Velpatasvir and Glecaprevir/Pibrentasvir, Sofosbuvir/ Velpatasvir/Voxilaprevir
The advantage of Glecaprevir / Pibrentasvir is that it can be given to patients with established renal failure
Post transplantation, Hcv pcr monitoring is done if negative in following days(3-10 days, 10-14 days, 6 weeks)
DAA is start within 3-10 days of Positive PCR
Treatment should be given in liaison with a clinical team with experience of management of HCV but does not necessarily have to be delivered in the transplanting centre.
In the rare (expected to be less than 2%) instances where the first course of treatment of HCV is not curative, recipients should be treated with a 12 week course of the combination of Sofosbuvir/Velpatasvir/Voxaleprevir which, as previously discussed, has high rates of SVR even in those previously exposed to DAA therapy.
Acceptable HCV Donor
HCV Ab positive with no history of treatment of HCV
HCV Ab positive with documented SVR after treatment
Any HCV Ab negative donor who has exposed themselves to risk but who does not fulfill any of the unacceptable criteria
Any HCV Ab positive donor whose HCV treatment history is unknown – proceed with caution.
Not Recommended HCV Donor
Previously failed DAA therapy with on-going viraemia
DAA therapy within last year without documented SVR (unless the recipient is at imminent risk of death)
Multiple documented re-infection with HCV
UK Position Statement on the use of Organs from Hepatitis C Viraemic Donors and Increased Infectious Risk Donors in Hepatitis C Negative Recipients
Introduction
· A significant number of patients still die due to a shortage of donor organs
· With the advent of direct-acting antiviral (DAA) therapy organs from hepatitis C (HCV) infected donors can be used.
· HCV is a single stranded RNA virus member of the Flaviviridae family. Six genotypes (G1-6) and a large number of sub-genotypes have been characterised in detail
· Transmission of HCV generally occurs parenterally, sexually or vertically, and can lead to sequelae of acute or chronic hepatitis.
· Acute infection tends to be subclinical, with chronic infection, defined as persistence of HCV RNA in serum for greater than six months after initial infection.
· Serologic tests can detect antibodies to HCV within two to six months of initial infection
· detectable HCV RNA by PCR is indicator for viremia
· HCV antibody continues to remain positive for many years (often indefinitely) after spontaneous clearance, or successful treatment of HCV resulting in undetectable HCV RNA.
· ‘HCV viraemic’ will be used for donors or recipients who have active HCV infection with detectable HCV RNA, regardless of HCV antibody status; or for donors that are HCV IgG +ve where the HCV RNA status is not known at the time of organ offering / transplantation.
Changes in the treatment of hepatitis C over the past five years
· Most of the current regimens used in clinical practice are given for between 8 and 16 weeks, and offer cure rates of 95-100% for patients without cirrhosis, regardless of HCV genotype.
· Most regimens do not rely on the use of ribavirin.
· There is already substantial UK experience of using two licensed pan-genotypic regimens in the form of Sofosbuvir / Velpatasvir and Glecaprevir/Pibrentasvir.
· The pan-genotypic triplet of Sofosbuvir, Velpatasvir and Voxilaprevir was licenced in August 2017.
· The advantage of Glecaprevir / Pibrentasvir is that it can be given to patients with established renal failure.
· These regimens also have high efficacy for the treatment of patients who have previously failed other DAA-containing regimens, with the best data currently available for Sofosbuvir, Velpatasvir and Voxilaprevir.
· The second and third generation DAA regimens have also been shown to be highly effective for patients with cirrhosis, and for patients treated after kidney or liver transplantation.
Current discard rates for hepatitis C positive donor organs in the UK
· ‘HCV infection in the potential donor does not amount to an absolute contraindication to donation of material for life-preserving transplantation, however the net benefit of transplantation must be considered against the risk of not receiving that specific transplant. This risk/benefit analysis allows for the potential use of a transplant from a HCV infected donor to a non-infected recipient.’
Experience from outside the UK
· Discard rates for HCV D+ livers have reduced in the US from 25% in 2006 to 10% in 2015
· A clinical trial at the American Transplant Congress in 2017, the EXPANDER-1 trial (Exploring Renal Transplants Using Hepatitis C Infected Donors for HCV-Negative Recipients).
· Results in a larger cohort of patients were reported by Saxena et al from the HCV-TARGET consortium of Academic US centres.
Why HCV D+ to R- transplantation should be cost effective
· all stakeholders are reassured that a course of therapy to cure a R- patient receiving a D+ organ would be less than the cost of dialysis for one year.
What are the risks of HCV D+ to R- transplantation?
· The first and most feared risk is of fibrosing cholestatic hepatitis (FCH), but DAA therapy is very effective in the setting of FCH.
· HCV D+/R- transplantation followed by early DAA therapy would result in only a transient, usually rapidly curable infection.
· Sexual transmission of HCV to a partner will be extremely low with simple lifestyle advice, and early initiation of DAA therapy post transplantation.
Patient and Unit Requirements Pre-Transplant
· If the AST-to-Platelet Ratio Index score is >0.8 or the ultrasound suggests significant or advanced liver disease, then a qualified liver specialist should be consulted before the patient is considered for a HCV D+ organ.
· a checklist of pre-requisites that must be in place before an individual transplanting centre performs its first HCV D+/R- transplant would be valuable
Allocation of HCV D+ Organs on the Waiting List
· once sufficient expertise has ensued, HCV D+ organs should be treated in the same way as HCV D- organs within the current allocation rules of the national waiting lists as determined by the individual NHSBT bodies.
Management of the Recipient of a HCV D+ Organ
· Regimens should be used as first line agents are either the combination of Glecaprevir/Pibrenatasvir or the combination of Sofosbuvir/Velpatasvir
· Both are pan-genotypic and should be given for 12 weeks for the HCV D+/R- transplants.
· Both have very acceptable drug to drug interaction profiles although exposure to the former is increased by ciclosporin, and it may also increase the levels of tacrolimus.
· The latter is not recommended in patient with a eGFR <30 mL/min/1.73 m2
· If the first course of treatment of HCV is not curative, recipients should be treated with a 12 week course of the combination of Sofosbuvir/Velpatasvir/Voxaleprevir.
Special Additional Considerations
· The use of organs from donors known to have been treated for HCV with DAA within the last 6 months should be avoided unless there is clear documentary proof at the time of donation of an SVR12 result.
· Potentially donors engaging in increased infectious risk behaviour are at risk of re-infection post SVR and thus could still transmit HCV.
· any organ from a donor who has been treated for HCV with DAAs but has not achieved SVR12 for any reason should not be considered for transplantation into a negative recipient unless the benefits outweigh the risks
With the need for organs and an increasing waiting list, morbidity and mortality and the emerge of DAA transplants of HCV +Ab can happen with special attention.
HCV is a single-stranded RNA virus of the Flaviviridae family, 6 genotypes have been described.
we have two types of hepatitis C infection;
Aute which is a subclinical
chronic hep Cv with detectable HCV RNA in the serum for more than 6 months and this happened in 60% of the affected person.
HCV Ab remain positive for years, and it denotes to previously treated infection or spontaneous clearance, but generally, DAA plays the main role in this phenomenon.
HCV viremia refers to: –
– HCV transmission can still occur during the window period of acute infection.
DAA has 95 to 100% cure rate in all genotypic patient, especially if they don’t have cirrhosis.
We have different types of combinations of Antival viral medication.
examples of pan-genotypic regimens include: –
2nd and 3rd generation DAA regimens are highly effective for patients with cirrhosis and for patients treated after kidney or liver transplantation
– HCV positive donors (HCV RNA viremic donor) can donate to both HCV positive and HCV negative recipients to reduce the waiting-list morbidity and mortality
IV. UK Position Statement on the use of Organs from Hepatitis C Viraemic Donors and Increased Infectious Risk Donors in Hepatitis C Negative Recipients
Summarise the article
Introduction
– the waiting list is growing by the day and so is the waiting list morbidity and mortality
– previously, HCV-positive organs used to be discarded due to the increased risk of HCV transmission to the recipients
– this has since changed, with the advent of DAA therapy which is associated with favourable outcomes
– HCV is a single stranded RNA virus of the Flaviviridae family, 6 genotypes have been described
– transmission: IVDU, blood products, sexually, vertical transmission
– acute HCV infection is usually subclinical
– chronic HCV infection is defined as persistence of HCV RNA in the serum for >6months after the initial infection, this develops in ~60% of those infected
– serological tests can detect antibodies to HCV within 2-6 months of initial infection
– HCV Ab (anti-HCV) continues to remain positive for years and often indefinitely after spontaneous clearance, or successful treatment of HCV with DAA therapy resulting in undetectable HCV RNA (SVR)
– the most important thing when assessing the HCV infectivity of an organ donor or recipient is whether or not active HCV replication is present; i.e., whether they are viraemic/ have detectable HCV RNA by doing sensitive genome amplification tests like polymerase chain reaction (PCR) nucleic acid testing (NAT) or antigen testing
– HCV re-infection is defined as detectable HCV RNA by PCR testing in a person who had spontaneous clearance of HCV or had achieved SVR following antiviral therapy
– occult HCV i.e., residual HCV viral genomes in donor tissue – can be a potential means of HCV transmission
– HCV viremia refers to: –
– HCV transmission can still occur during the window period of acute infection
Advances in the treatment of HCV
– DAAs offer cure rates of 95-100% for patients without cirrhosis regardless of the HCV genotype
– examples of pan-genotypic regimens include: –
– 2nd and 3rd generation DAA regimens are highly effective for patients with cirrhosis and for patients treated after kidney or liver transplantation
– HCV positive donors (HCV RNA viremic donor) can donate to both HCV positive and HCV negative recipients to reduce the waiting-list morbidity and mortality
Current discard rates for HCV positive donor organs in the UK
– there is poor utilization of HCV RNA viremic donor non-liver organs even for HCV RNA viremic recipients
– the number of HCV RNA viremic recipients on the waiting list is bound to decrease due to the efficacy of DAA therapy
– organ discard rates will increase unless the current clinical practice changes
– the risk vs benefit analysis allows for the potential use of a transplant from a HCV infected donor to a non-infected recipient
Experience from outside the UK
– the US has the best data on D+ donor numbers as well as on discard rates and is leading in early clinical trials of D+ to R- transplants
Why HCV D+ to R- transplantation should be cost effective
– in the kidney transplantation field, HCV D+ to R- transplantation is considered cost effective since dialysis by itself is expensive compared to DAA therapy
– the cost of dialysis can be mitigated by timely transplantation
– patients on dialysis have a significantly reduced quality of life
– saves costs by reducing waiting times and dialysis expenditure, save lives and improve quality of life for patients
What are the risks of HCV D+ to R- transplantation?
– FCH is an aggressive form of HCV recurrence seen in 10% of D+/ R+ liver transplant
– prior to DAA therapy, FCH was associated with high mortality
– early treatment with DAA therapy helps prevent the development of FCH
– this poses important ethical issues
– HCV is usually rapidly curable with DAA therapy, unlike other infectious diseases like CMV and EBV, HCV
– may be associated with development of difficult to treat resistance associated substitutions
– 12 weeks of re-treatment with the triple therapy combination of Sofosbuvir, Velpatasvir and Voxilaprevir has been found to be highly effective
– this can be avoided by simple lifestyle advice, early initiation of DAA therapy post-transplantation
The practicalities of implementing this policy in the UK
– there is need to provide a framework for some of the important practical issues that can be adopted
Patient consent
– provide the patient with the patient information sheet and the consent form
Patient and unit requirements pre-transplant
– avoid HCV D+/ R- non-liver transplantation in recipients with advanced fibrosis and cirrhosis
– screen patients with an APRI score and ultrasound and consult a hepatologist if the APRI score is >0.8 or if the ultrasound suggests significant or advanced liver disease
Allocation of HCV D+ organs on the waiting list
– HCV D+ organs should be treated in the same way as HCV D- organs on the waiting list
– aim is to optimize organ utilisation
Management of the recipient of a HCV D+ organ
– test recipient for HCV RNA to ensure appropriate and early intervention if HCV transmission and infection occurs
– 1st line treatment agents include:
– both should be given for 12 weeks, both are pan-genotypic meaning they can be started as soon as HCV PCR positivity is known, without having to wait for a HCV genotype
– both have acceptable drug-drug interactions
– exposure to Glecaprevir/Pibrenatasvir is increased by cyclosporine and it may also increase tacrolimus levels by inhibiting CYP3A and P-glycoprotein
– Sofosbuvir/Velpatasvir is not recommended in patients with eGFR <30
– in cases of treatment failure, treat the recipient for another 12 weeks with a combination of Sofosbuvir/ Velpatasvir/ Voxaleprevir this combination has high rates of SVR even in those with previous DAA exposure
Special additional considerations
– avoid use of organs from donors previously treated for HCV with DAA within the last 6 months unless there is clear evidence of an SVR12 result at the time of organ donation
– this is due to concerns about transmission of resistant HCV
– acceptable donors include:
– unacceptable donors include:
The article deals with the UK position statement on the use of organs from hepatitis C viraemic donors and increased infectious risk donors in hepatitis C negative recipient, endorsed by 12 different UK organizations.
Introduction: Due to increasing gap between organ demand and supply, continuous review of the organs discarded needs to be done, especially considering >95% cure rate of hepatitis C virus (HCV) infection achieved with direct-acting antivirals (DAAs), which can increase the donor pool.
Introduction to HCV and clarification of nomenclature: It is important to define the serological and virological status of the donor in a scenario of using HCV-infected donor for transplant. HCV can be transmitted by either intravenous drug or blood products, sexually, or vertically. Acute infection could be subclinical. Chronic infection is persistence of HCV RNA in serum for >6 months, and can be seen in 60% of the cases. Serologic tests can detect anti-HCV antibodies within 2-6 months of initial infection. HCV RNA can be detected in serum after 7 days of infection. Re-infection implies detectable HCV RNA in a patient with documented spontaneous HCV clearance or someone who achieved sustained virologic response (SVR) post DAA therapy. Occult HCV is the condition with residual HCV viral genome in donor tissue. So, careful testing of recipients of HCV-infected organs is important. HCV viremic person, for the purpose of the document, is someone with detectable HCV RNA regardless of HCV antibody status as well as a donor who is HCV IgG positive with unknown HCV RNA status at time of organ donation.
Changes in the treatment of HCV over past 5 years: Introduction of DAAs in last few years have increased the cure rates of HCV-infected patients to 95-100% regardless of HCV genotype. The regimens used include Sofosbuvir/Velpatasvir, Glecaprevir/Pibrentasvir (useful in renal failure), or Sofosbuvir/Velpatasvir/Voxilaprevir. These results make it possible to use HCV RNA viremic donor for recipients without HCV viremia.
Current discard rated for HCV positive donor organs in the UK: Upto 15 suitable donors are discarded annually due to HCV transmission (69% due to positive serological tests, D+). Using such organs can increase solid organ transplants by 75 extra transplants in UK annually.
Experience from outside the UK: 4.1% of all organ donors in US between 1995 and 2015 were anti-HCV antibody positive. Discard rates of anti-HCV antibody positive livers have reduced from 25% to 10%. EXPANDER-1 trial and HCV-TARGET trial have shown excellent SVR rates in liver and kidney transplant recipients.
Why HCV D+ to R- transplantation should be cost effective: In addition to morbidity and mortality benefits as well as better quality of life, timely transplant also reduces the costs associated with dialysis, one year of which is much more than the cost of DAAs.
What are the risks of HCV D+ to R- transplantation: The risks in this scenario including fibrosing cholestatic hepatitis (FCH) seen in 10% of liver transplants and 1.5% of kidney transplants with high mortality. Early post-transplant (within 4 weeks) DAA use has shown to be effective in FCH prevention and treatment. Transient, usually rapidly curable with DAA therapy, HCV infection is another risk in such scenario. <5% may develop DAA failure. Other concerns include extrahepatic HCV manifestations like cryoglobulinemic vasculitis, and PTLD as well as sexual transmission to a partner which can be easily prevented by lifestyle advice and early DAA use.
The practicalities of implementing this policy in UK: These include patient consent specifically to be taken in context of HCV D+/R- transplantation. Patient and unit requirements pre-transplant include screening patients with AST-to-platelet ratio index (APRI) and ultrasound abdomen and taking hepatologist opinion in presence of APRI>0.8 or ultrasound showing significant or advanced liver disease. Allocation of HCV D+ organs on the waiting list could be done as for HCV D- organs with sufficient experience. Management of recipient of a HCV D+ organ includes testing of HCV RNA PCR on day 3-7 post-transplant, then on day 10-14, and then 6 weeks post-transplant. If the reports are negative even at 6 weeks, the recipient can be reassured. If the HCV PCR comes out positive during the testing in first 6 weeks, the patient should be treated with DAAs (12 weeks of either Sofosbuvir/Velpatasvir or Glecaprevir/Pibrentasvir, and Sofosbuvir/Velpatasvir/Voxilaprevir if the first 2 regimes are not curative) within 3-10 days.
Special additional considerations: Acceptable donors include HCV antibody positive with either no history of HCV treatment or with document SVR post-treatment, or HCV antibody positive donor with history of exposure to risk not fulfilling unacceptable criteria, or HCV antibody positive patient whose HCV treatment history is unknown (proceed with caution in this scenario). Unacceptable donors include prior treatment with DAA for HCV in last 6 months without documentary proof of SVR, or failed treatment with ongoing viremia (to avoid resistant HCV transmission), or multiple documented HCV re-infections.
The prospective HCV-negative recipient should be provided with an information leaflet providing information regarding HCV-infected organ transplant.
UK Position Statement on the use of Organs from Hepatitis C Viraemic Donors and Increased Infectious Risk Donors in Hepatitis C Negative Recipient
UK Position Statement on the use of Organs from Hepatitis C Viraemic Donors and Increased Infectious Risk Donors in Hepatitis C Negative Recipient
Most organs from donors infected with hepatitis C have hitherto been discarded because of the high likelihood of transmitting the infection in past.
95% of infected individuals can now be cured with directly acting antiviral agents and hepatitis C clearance can be safely achieved in transplant recipients after donation from Hepatitis C treated donor.
HVC Treatment
pan-genotypic regimens in the form of Sofosbuvir / Velpatasvir and Glecaprevir/Pibrentasvir
The pan-genotypic triplet of Sofosbuvir, Velpatasvir and Voxilaprevir
The advantage of Glecaprevir / Pibrentasvir is that it can be given to patients with established renal failure.
HCV D Positive and Recipient negative transplant
Fibrosing hepatitis and extra hepatic manifestations are high.
There is an aggressive form of HCV recurrence seen in 10% of D+/R+ liver transplants
Pre transplant requirements
AST-to-Platelet Ratio Index (APRI) and ultrasound is suggested
HCV D positive organ management
Standardized, longitudinal testing for hepatitis C RNA of the recipient following receipt of either a HCV antibody positive graft, a HCV RNA positive graft or a graft from an increased infectious risk donor
HCV positive organ donors
The exact drug regimens and length of therapy that should be offered to recipients that test positive for HCV after receiving an organ from a HCV D+ donor
Acceptable donors
HCV Ab positive with no history of treatment of HCV
HCV Ab positive with documented SVR after treatment
Any HCV Ab negative donor who has exposed themselves to risk but who does not fulfill any of the unacceptable criteria
Any HCV Ab positive donor whose HCV treatment history is unknown – proceed with caution
Unacceptable donors
Previously failed DAA therapy with on-going viraemia
UK Position Statement on the use of Organs from Hepatitis C Viraemic Donors and Increased Infectious Risk Donors in Hepatitis C Negative Recipient
Summary:
Up to One in Six patients scheduled for SOT will die or become too unwell for a transplant despite the rise in organ donation in the UK. So, there is a need to find ways to better utilize organs that are frequently discarded.
Serologic tests can detect antibodies to HCV within two to six months of initial infection.
Chronic infection: defined as persistence of HCV RNA in serum for greater than six months after initial infection. This develops in at least 60% of those infected.
HCV antibody (anti-HCV) continues to remain positive for several years and often indefinitely after spontaneous clearance, or successful treatment of HCV with interferon or DAA therapy resulting in undetectable HCV RNA (SVR; sustained virologic response).
HCV viraemic refer to:
Donors or recipients who have active HCV infection with detectable HCV RNA, regardless of HCV antibody status
Donors that are HCV IgG +ve where the HCV RNA status is not known at the time of organ offering / transplantation.
Earlier treatment options were less effective at curing TX recipients of the virus & had less tolerance.
About > 95% of those with HCV can now be treated with DAAs.
The advantage of Glecaprevir / Pibrentasvir is that it can be given to patients with established renal failure.
These regimens also have high efficacy for the treatment of patients who have previously failed other DAA-containing regimens, with the best data currently available for Sofosbuvir, Velpatasvir and Voxilaprevir.
HCV infection in the potential donor does not amount to an absolute contraindication to donation of material for life-preserving transplantation, however the net benefit of transplantation must be considered against the risk of not receiving that specific transplant.
This risk/benefit analysis allows for the potential use of a transplant from a HCV infected donor to a non-infected recipient.
Why HCV D+ to R- transplantation should be cost effective:
All stakeholders are reassured that a course of therapy to cure a R- patient receiving a D+ organ would be less than the cost of dialysis for one year.
What are the risks of HCV D+ to R- transplantation:
The first and perhaps most feared risk is of fibrosing cholestatic hepatitis (FCH)
This is an aggressive form of HCV recurrence seen in 10% of D+/R+ liver transplants.
There are now increasing reports of DAA therapy being very effective in the setting of FCH.
A minority (in reality <5%) of patients treated after organ transplantation may experience DAA treatment failure, which may be associated with the development of difficult to treat resistance associated substitutions (RAS) especially in the viral NS5A protein, but also, for recipients of a protease inhibitor, in the NS3A region.
Data from the POLARIS-1 trial has shown that 12 weeks of re-treatment with the triple therapy combination of Sofosbuvir, Velpatasvir and Voxilaprevir is highly effective (>95%) in achieving cure of HCV in patients with HCV NS5A RAS at baseline.
Thus, virtually all HCV D+/R- recipients can be cured with modern DAA therapies, even if this is not achieved at the first attempt at treatment.
Extra-hepatic manifestations of HCV such as cryoglobulinaemic vasculitis or potential increased rates of blood derived malignancy such as PTLD are also theoretical consequences of HCV infection in the post-transplantation phase.
There are no data in the HCV D+/R+ field to demonstrate an increased risk of these consequences, and early DAA therapy should mitigate against these in any case.
Sexual transmission of HCV to a partner could potentially occur in the HCV D+/R- transplant scenario. The risk can be mitigated by simple lifestyle advice
A proper patient consent should be taken for D+/R- patients
AST-to-Platelet Ratio Index (APRI) and ultrasound is suggested.
APRI scores are easily calculated using on line tools such platelet-ratio-index-apri.
If the APRI score is >0.8 or the ultrasound suggests significant or advanced liver disease, then an opinion from a suitably qualified liver specialist should be sought before the patient is considered for a HCV D+ organ.
It was felt that even cirrhotic patients could potentially receive HCV D+ organs safely but that this was not an appropriate risk for the early phases of a new UK HCV D+/R- programme.
If the APRI score is <0.8, there is no need for the patient to be seen by a liver specialist.
Combination of Glecaprevir/Pibrenatasvir or the combination of Sofosbuvir/Velpatasvir should be given for 12 weeks in the context of HCV D+/R- transplants.
Both are pan-genotypic, which means that they can be started as soon as HCV PCR positivity is known, without having to wait for a HCV genotype, which can take 3-4 weeks in some areas.
Both have very acceptable drug to drug interaction profiles although exposure to the former is increased by ciclosporin, and it may also increase the levels of tacrolimus (CYP3A and P-glycoprotein inhibition); the latter is not recommended in patient with a eGFR <30 mL/min/1.73 m2,
Are rare (expected to be less than 2%) instances where the first course of treatment of HCV is not curative, recipients should be treated with a 12 week course of the combination of Sofosbuvir/Velpatasvir/Voxaleprevir which, as previously discussed, has high rates of SVR even in those previously exposed to DAA therapy.
The acceptability of HCV D+ donors is as follows:
Acceptable Donor :
HCV Ab positive with no history of treatment of HCV
HCV Ab positive with documented SVR after treatment
Any HCV Ab negative donor who has exposed themselves to risk but who does not fulfill any of the unacceptable criteria
Any HCV Ab positive donor whose HCV treatment history is unknown – proceed with caution
Not Recommended Donor Within Proposed Policy:
Previously failed DAA therapy with on-going viraemia
DAA therapy within last year without documented SVR (unless the recipient is at imminent risk of death)
Multiple documented re-infection with HCV
Conclusion:
The advantage of life-saving transplantation must be weighed against the harm of not getting organ donation from HCV positive.
This risk/benefit analysis allows an HCV-infected donor-to-non-infected recipient transplant.
DAA medication is recommended for all HCV-infected kidney transplant candidates.
In recent years, these novel hepatitis C medications have had few adverse effects and are well-tolerated by patients.
UK Position Statement on the use of Organs from Hepatitis C Viraemic Donors and Increased Infectious Risk Donors in Hepatitis C Negative Recipients
Introduction
· With the advent of highly effective and well tolerated direct-acting antiviral (DAA) therapy, that can cure more than 95% of patients infected with HCV, there is a need to assess whether organs from a HCV infected donors may safely be transplanted into HCV uninfected recipients.
· It is important to precisely define the serological and virological status of the donor.
· HCV D+ to R- transplantation is cost effective.
Risks of HCV D+ to R- transplantation
· Fibrosing cholestatic hepatitis, this is an aggressive form of HCV recurrence seen in 10% of D+/R+ liver transplants. There are now increasing reports of DAA therapy being very effective in the setting of FCH.
· Patients treated after organ transplantation may experience DAA treatment failure. However, data has shown that 12 weeks of re-treatment with DAA combination is highly effective in achieving cure of HCV in patients with drug resistance at baseline.
· Risk of Extra-hepatic manifestations of HCV such as cryoglobulinaemic vasculitis or PTLD is a theoretical risk and no reports of an increased risk.
Patient Consent
· Consent to receive a HCV D+ organ should be specifically obtained by individual transplanting centres.
Patient and Unit Requirements Pre-Transplant
· HCV D+/R- non-liver transplantation should be avoided in recipients with advanced fibrosis or cirrhosis.
· Checklist of pre-requisites that must be in place before an individual transplanting centre performs its first HCV D+/R- transplant would be valuable.
Allocation of HCV D+ Organs on the Waiting List
· HCV D+ organs should be treated in the same way as HCV D- organs within the current allocation rules of the national waiting lists.
· But different organ Advisory Groups will need to decide how best to offer and allocate such organs in order to optimise organ utilisation.
Management of the Recipient of a HCV D+ Organ
· Organ donors should be tested for HCV by PCR, if positive check for genotype.
· Recipient should be checked for HCV PCR by day 3-7, 10-14, 6 weeks, post-transplant.
· If HCV PCR is positive give DAA therapy within 3- 10 days of result.
· The combination of Glecaprevir/Pibrenatasvir or the combination of Sofosbuvir/Velpatasvir for 12 weeks.
· Treatment should be given in liaison with a clinical team with experience of management of HCV, but not necessarily have to be delivered in the transplanting centre.
Special Additional Considerations
Donors recommended to use:
· HCV Ab positive with no history of treatment of HCV.
· HCV Ab positive with documented SVR after treatment.
· Any HCV Ab negative donor who has exposed themselves to risk but who does not fulfill any of the unacceptable criteri.
· Any HCV Ab positive donor whose HCV treatment history is unknown – proceed with caution.
Donors not recommended to use:
· Previously failed DAA therapy with on-going viraemia
· DAA therapy within last year without documented SVR (unless the recipient is at imminent risk of death).
· Multiple documented re-infection with HCV.
Next Steps in the Process
· Transplant units should make sure that there is clear provision for DAA therapy in their local areas before implement this proposals.
Two-year-old therapeutic options rejected HCV-infected organs.
3-DAAT for HCV has a 95% cure rate, and transplanting HCV-positive organs from treated donors into HCV-negative recipients was encouraging.
After a multidisciplinary team examination, organs from hepatitis C-infected donors can be used for uninfected recipients with restrictions.
DAA-treated HCV D+ to HCV R- transplant recipients are treatment-nave, noncirrhotic, and likely to achieve SVR.
HCV; current treatment
· Pan-genotypic regimens in the form of Sofosbuvir / Velpatasvir and Glecaprevir/Pibrentasvir.
· The pan-genotypic triplet of Sofosbuvir, Velpatasvir and Voxilaprevir was licenced in August 2017.
· The advantage of Glecaprevir / Pibrentasvir is that it can be given to patients with established renal failure.
The risks of HCV D+ to R- transplantation : Fibrosing cholestatic hepatitis and extra-hepatic manifestations of HCV
Consent HCV+ organ recipients must sign a specific consent.
Pre-transplant essentials
HCV D+ non-liver organ recipients are tested using AST-to-Platelet Ratio Index (APRI) and ultrasonography to determine if a hepatic specialist is needed.
HCV D+ organ management
Standardized HCV RNA testing of the recipient after receiving an HCV Ab positive, RNA positive, or graft from an enhanced infectious risk donor to detect HCV transmission and infection early.
For HCV-positive donor organs
The donor PCR must be tested in a central lab.
If positive, genotyping testing must be done and all centres must be informed within 2 days.
If negative, all centres must be informed.
The negatively consenting recipient must undergo an HCV PCR test 3-7 days after transplant, repeated 10-14 days, and retested 6 weeks afterwards.
Treatment
– DAA should be begun within 3-10 days of a positive HCV PCR test.
– Two pan-genotypic, 12-week regimens for HCV D+/R- transplants are Glecaprevir/Pibrenatasvir or Sofosbuvir/Velpatasvir.
– After first DAAAT failure, 12-week Sofosbuvir/Velpatasvir/Voxaleprevir has high SVR rates.
Accepted donors
– HCV Ab positive with no HCV treatment history
– HCV Ab positive reaching SVR after treatment
– HCV Ab negative donor exposed to risk but does not meet the unacceptable criteria
– HCV Ab positive donor with unknown treatment history.
Unrecommended donors
Include instances with failed DAA therapy and persistent viraemia, DAA therapy within last year without confirmed SVR, and repeated HCV reinfection.
Risks associated with transplanting kidney from HCV + donor to HCV – kidney recipient
Approach for transplanting kidney from HCV + donor to HCV – recipient
The main challenge is transmission of HCV from donor to the recipient with possibility of HCV related hepatic affection and extra hepatic complications including GN, so the following approach should be done in order to improve outcome:
Avoid these types of donors
Selecting appropriate recipient
Recommended protocol by UK
Antiviral therapy
introduction:
HCV is a single-stranded RNA Flaviviridae virus. Six genotypes (G1-6) and many sub-genotypes have been described. HCV is transmitted parenterally (via IVDU or blood products), sexually (predominantly individuals who have unprotected anal intercourse with several partners), or vertically, from mothers to Newborns, and can cause acute or chronic hepatitis. Acute infection is subclinical, but chronic infection is defined by HCV RNA in serum for more than six months after initial infection. This occurs in at least 60%.
During two to six months of infection, serologic testing can identify HCV antibodies. However, the most crucial factor in determining an organ donor or recipient’s HCV infectivity is whether they are viraemic, with detectable HCV RNA by PCR or NAT. After spontaneous clearance or effective treatment with interferon or DAA therapy, HCV antibody (anti-HCV) remains positive for years and often indefinitely.
DAA therapy for HCV enhanced the number of HCV antibody-positive patients with undetectable HCV RNA.
25 HCV antibody-negative receivers who got donor livers from anti-HCV antibody-positive but HCV RNA-negative “HCV high risk” donors were followed up by the University of Cincinnati. All patients performed follow-up HCV RNA testing, and 4 (16%) developed HCV viremia within three months of transplantation.
These findings suggest HCV transmission from high-risk donors in the reinfection window. Occult HCV, or residual HCV viral genomes, in donor tissue may also transmit HCV. so, rigorous testing of transplant recipients is required.
This publication shall utilize the term “HCV viraemic” to refer to donors or recipients who have active HCV infection with detectable HCV RNA, regardless of HCV antibody status, as well as HCV IgG +ve donors whose HCV RNA status is unknown at the time of organ donation or transplantation.
Changes in the treatment of hepatitis C over the past five years:
Six years ago, HCV management changed greatly. DAAs with interferon and ribavirin increased G1 HCV cure rates from 50% to over 80%. Typically 8-16-week clinical regimens cure 95-100% of non-cirrhotic patients regardless of HCV genotype. Few regimens use ribavirin. Second and third-generation DAA regimens help cirrhosis and kidney/liver transplant patients.
This treatment adjustment suggests transplanting HCV RNA viraemic donor (D+) organs to R- recipients to minimize morbidity and mortality on solid organ transplant waiting lists. This article aims consensus to allow HCV-viraemic donor organs for HCV-negative UK recipients.
Why HCV D+ to R- transplantation should be cost-effective:
A course of therapy to cure an R- patient receiving a D+ organ will cost less than one year of dialysis. Reducing waiting times and dialysis costs will save money most importantly, should save lives and improve patient quality of life.
What are the risks of HCV D+ to R- transplantation?
HCV D+ to R- transplantation has economic and health benefits, but hazards must be considered.
Fibrosing cholestatic hepatitis is the main concern. 10% of D+/R+ liver transplants have aggressive HCV recurrence. FCH was fatal before DAA therapy. In SOLAR-1 and 2, Sofosbuvir plus Ledipasvir for 12 or 24 weeks healed all 11 FCH patients after liver transplantation. In 15 FCH patients treated with Sofosbuvir and Daclatasvir after liver transplantation, Leroy et al. reported 100% cure rates. Many case reports and short case series have successfully managed FCH with LFT normalization.
HCV D+/R- transplantation followed by early DAA therapy would cause a brief, easily treatable infection.
Another theoretical concern is that a minority (in reality <5%) of patients treated after organ transplantation may fail DAA treatment. To reduce this risk, early HCV D+/R- programs may increase treatment duration from 8 to 12 weeks or 12 to 16 weeks. In patients with HCV NS5A RAS at baseline, 12 weeks of triple therapy with Sofosbuvir, velpatasvir, and Voxilaprevir cures HCV >95%. Hence, current DAA medications can cure most HCV D+/R- recipients.
HCV infection post-transplantation may cause extra-hepatic symptoms such as cryoglobulinaemic vasculitis or blood-derived malignancies like PTLD. Early DAA therapy should prevent these outcomes, as HCV D+/R+ studies show no elevated risk.
HCV D+/R- transplants may cause sexual transmission of HCV.
Lifestyle guidance and early DAA therapy post-transplantation can reduce risk. This risk may be very minimal (<2%).
Patient and Unit Requirements Pre-Transplant:
HCV D+/R- transplantation is relatively new. The working team recommended avoiding HCV D+/R- non-liver transplantation in recipients with advanced fibrosis or cirrhosis to be safe. Screening patients with AST-to-Platelet Ratio Index (APRI) and ultrasound instead of requiring liver specialists for all HCV D+ non-liver organ recipients is more practical. Before considering an HCV D+ organ, a liver specialist should be consulted if the APRI score is >0.8 or the ultrasound indicates advanced liver illness. Cirrhotic patients could get HCV D+ organs safely, but a new UK HCV D+/R- program should not take this risk at the time being. No liver specialist is needed if the APRI score is <0.8.
Allocation of HCV D+ Organs on the Waiting List:
The working group decided that, once sufficient expertise has been obtained and outcomes are favorable, HCV D+ organs should be handled the same as HCV D- organs within the current allocation rules of the national waiting lists as determined by the individual NHSBT bodies, such as the Liver Advisory Group, Kidney Advisory Group, and Cardiothoracic Advisory Group. Advisory Groups must decide how to give and assign organs during the initial phase of any HCV D+ to HCV R- program to maximize organ use. Advisory Panels must frequently examine post-transplant outcomes to adjust offering and allocation strategies.
Management of the Recipient of HCV D+ Organ:
IV. UK Position Statement on the use of Organs from Hepatitis C Viraemic Donors and Increased Infectious Risk Donors in Hepatitis C Negative Recipient
Please summarise this article
Introduction
Greater use can be made of organs from hepatitis C (HCV) infected donors, With
the advent and licensing of highly effective and well tolerated direct-acting antiviral (DAA) therapy
that can cure more than 95% of patients infected with HCV, regardless of genotype, there is a
pressing need to assess whether organs from HCV infected donors may safely be transplanted into
HCV uninfected recipients.
Introduction to HCV and Clarification of Nomenclature
HCV is a single stranded RNA virus member of the Flaviviridae family. Six genotypes (G1-6) and a large
number of sub-genotype.
Transmission of HCV generally occurs:
1.parenterally (through intravenous drug use (IVDU) or blood products).
2.sexually (predominantly those who have unprotected anal sex with multiple partners)
3. vertically, from mothers to infants.
Acute infection tends to be subclinical, with chronic infection, defined as persistence of HCV RNA in serum for greater than six months .
the most important parameter to be considered when assessing the HCV infectivity of an organ donor
or recipient is whether or not active HCV replication is present through HCV RNA by sensitive genome amplification methods such as polymerase chain reaction nucleic acid testing.
‘HCV viraemic’ used to refer to donors or recipients who have active HCV infection with detectable HCV RNA, regardless of HCV antibody status; it also refers to donors that are HCV IgG +ve where the HCV RNA status is not known at the time of organ offering / transplantation.
Changes in the treatment of hepatitis C over the past five years
There has been a revolution in the management of HCV in the past six years. This began with the
licensing of the first generation protease inhibitors Telaprevir and Boceprevir in 2012. These prototype
direct-acting antiviral (DAA) drugs were combined with interferon and ribavirin, and increased cure
rates for patients with G1 HCV from 50% to over 80%.
Most of the current regimens used in clinical practice are given for between 8 and 16 weeks, and offer cure rates of 95-100% for patients without cirrhosis, regardless of HCV genotype.
This paper seeks to establish a professional consensus to enable the use of HCV viraemic donor organs for HCV negative recipients in the United Kingdom.
Current discard rates for hepatitis C positive donor organs in the UK
The most up to date UK data available was published in 2017 by Trotter and colleagues. Using data from the UK Transplant Registry and the National Potential Donor Audit from 2000 to 2015, they identified 244 HCV antibody positive donors during that 16 year time period, The quality of the declined
organs did not differ from that of the organs that were used, with positive serological tests reported
as the reason for decline in 69% of cases. HCV infection in the potential donor does not amount to an absolute contraindication to donation of
material for life-preserving transplantation, however the net benefit of transplantation must be
considered against the risk of not receiving that specific transplant. This risk/benefit analysis allows
for the potential use of a transplant from a HCV infected donor to a non-infected recipient.’
This change in the guidance paves the way for potential D+ to R- transplants.
Why HCV D+ to R- transplantation should be cost effective
Although the exact cost of DAAs to the NHS remains commercially confidential, all stakeholders are
reassured that a course of therapy to cure a R- patient receiving a D+ organ would be less than the
cost of dialysis for one year.
What are the risks of HCV D+ to R- transplantation?
1.The most risk is of fibrosing cholestatic hepatitis
2.infecting individuals with cytomegalovirus (CMV) or Epstein Barr virus (EBV) at the time of organ transplantation.
3. DAA treatment failure.
4. Extra-hepatic manifestations of HCV such as cryoglobulinaemic vasculitis or potential increased rates
of blood derived malignancy .
Patient Consent
obtained by individual transplanting centres.
To do it in working group.
In sharing information with and gaining consent from solid organ transplant candidates, and
inclusion of consent for HCV D+/R- transplantation will need to form part of this work.
Allocation of HCV D+ Organs on the Waiting List
HCV D+ organs should be treated in the same way as HCV D- organs within the current allocation rules .
Management of the Recipient of a HCV D+ Organ
Individual units may also wish to consult with their virology laboratories to enhance testing for HIV and HBV.
1.combination of Glecaprevir/Pibrenatasvir .or
2.combination of Sofosbuvir/Velpatasvir.
Recipients should be treated with a 12 week course.
Acknowledged.
Introduction:
Patient Consent:
– Although patients are currently routinely consented to receive ‘marginal’ organs by individual transplanting centres.
– Patient and Unit Requirements:
– HCV D+/R- non-liver transplantation should be avoided in recipients with advanced fibrosis or cirrhosis. Every patient being consented to receive a HCV D+ non-liver organ be seen by a liver specialist.
– Screening patients using AST-to-Platelet Ratio Index (APRI) and ultrasound is suggested, If the APRI score is >0.8 or the ultrasound suggests significant or advanced liver disease, then an opinion from a suitably qualified liver specialist should be sought before the patient is considered for a HCV D+ organ.
Allocation of HCV D+ Organs on the Waiting List:
– HCV D+ organs should be treated in the same way as HCV D- organs within the current allocation rules of the national waiting lists.
– Frequent review of post-transplant outcomes will be needed in order to enable Advisory Groups to alter offering and allocation policies as needed.
– The following donors should be excluded:
a) Previously failed DAA therapy with on-going viraemia.
b) DAA therapy within last year without documented SVR, except in recipient lifesaving issues.
c) Multiple documented re-infection with HCV.
Management of the Recipient of a HCV D+ Organ:
– There was consensus on regular testing for hepatitis C RNA of the recipients, of either a HCV antibody positive graft, a HCV RNA positive graft or a graft from an increased infectious risk donor, to ensure appropriate and early intervention if HCV transmission and infection occurs.
– Multidisciplinary team work is needed in those patients (virologist, hepatologist, transplant physician, and pharmacologist).
– Glecaprevir/pibrenatasvir or sofosbuvir/velpatasvir should be given for 12 weeks in HCV D+/R- transplants.
Acknowledged.
UK position letter
Use oF D+ IN R+ is common for liver and still rare in kidney transplants
With effective DAA , waiting list R+ are going down
use of D+ in R- is the way forward to avoid organ wasting
in UK registry
Organ was decline in 69% of cases only for HCV positive status
in USA
liver is not discarded for HCV positive status but non liver organ are still discarded
COST
in KT , cost of such D+/R- is less than dialysis
RISK
fibrosing cholestatic hepatitis (FCH) is real risk and common in liver transplants
1-2 % of kidney transplant
ETHICAL issue
high mortality on waiting ;list can justify this
In general , D+/R- transplant leads to transient, usually rapidly curable HCV infection.
CONSENT
consent to receive a HCV D+ organ should be
specifically obtained by individual transplanting centers.
HOW TO START D+/R- transplant ?
AVOID If the APRI score is >0.8 or the ultrasound suggests significant or advanced
liver disease
ALLOCATION
HCV D+ organs should be treated in the same way as HCV
D- organs within the current allocation rules
RECIPIENT WITH D+ ORGAN
Tested for HCV PCR ON 3/7 DAY , 10-14 DAY AND 6 WEEK
START DAA within 3-10 days
TREATMENT
Glecaprevir/Pibrenatasvir or the combination of Sofosbuvir/Velpatasvi
12 weeks
Acknowledged.
Looking forward to read your replies to the scenarios.
Summary
HCV is a single stranded RNA virus that belongs to the flaviviridae family with 6 genotypes.Transmission is through parenteral, sexually and vertical transmission.
Acute infections is subclinical while chronic infection the HCV RNA persists for more 6 months.
Serologic tests can detect antibodies within 2-6 months after infection and they can remain positive indefinitely after clearance or successful treatment. HCV PCR or antigen test determine the infectivity thus are more important.
Most of current DAA treatments are given for 8-16 weeks and have a cure rate of 95-100% in patients without cirrhosis regardless of the genotype. Glecaprevir / Pibrentasvir has advantage of other regimens since it can be used in renal failure.
This current regimens have allowed the use of HCV D+/R- organs that would have otherwise been discarded.
Several trials have looked at outcomes of HCV D+/R- SOT:
For HCV D+/R- to proceed the R must be HCV naive, no liver cirrhosis and likely to achieve SVR12.
The use of HCV donors in kidney transplantation will reduce the waiting time in transplant list and the cost of dialysis.
Risks of HCV D+/R- transplantation are:
HCV D+/R- should be avoided in cirrhotic or in advanced fibrosis.
First line DAA agents to be used Glecaprevir/Pibrenatasvir or Sofosbuvir/Velpatasvir for 12 weeks, both are pan-genotypic with acceptable drug-drug interaction.
Organs from donors treated for HCV in the last 6 months should be avoided unless there is proof of an SVR12 results.
Individual transplanting centre should obtain consent from R to use a HCV+ donor.
Acknowledged.
IntroductionSolid organ transplants help greatly in reducing the mortality and morbidity of the affected patients. Unfortunately, there is a shortage of organ donors. In order to increase the number of organs available for transplantation, there is a continuous review of organs that have been discarded, to assess whether advances in medicine could enable such organs to be transplanted.
It has now been studied that greater use can be made of organs from hepatitis C (HCV) infected donors, due to highly effective and well tolerated direct-acting antiviral (DAA) therapy that can cure more than 95% of patients infected with HCV. There is a need to assess whether organs from HCV infected donors may safely be transplanted into HCV uninfected recipients.
Introduction to HCV and Clarification of NomenclatureHCV is a single stranded RNA virus member of the Flaviviridae family. It has six genotypes (G1-6). Transmission of HCV generally occurs parenterally (through intravenous drug use (IVDU) or blood products), sexually (predominantly those who have unprotected anal sex with multiple partners) or vertically, from mothers to infants, and can lead to sequelae of acute or chronic hepatitis.
Acute infection tends to be subclinical, with chronic infection, defined as persistence of HCV RNA in serum for greater than six months after initial infection. Serologic tests can detect antibodies to HCV within two to six months of initial infection. An important parameter to consider when assessing the HCV infectivity of an organ donor or recipient is whether or not active HCV replication is present.
Current discard rates for hepatitis C positive donor organs in the UKThe current practice is to restrict the use of HCV D+ organs to HCV positive recipients (R+). Data from the UK Transplant Registry and the National Potential Donor Audit from 2000 to 2015 identified 244 HCV antibody positive donors during a 16 year time period. Organs from only 76 (31%) of these donors were transplanted into 93 recipients (63 liver, 27 kidney and 2 heart transplants).
The declined donors often had good kidney and liver function based on validated UK Donor Risk Indices. The UK Advisory Committee on the Safety of Blood, Tissues and Organs (SaBTO) states that ‘HCV infection in the potential donor does not amount to an absolute contraindication to donation of material for life-preserving transplantation, however the net benefit of transplantation must be considered against the risk of not receiving that specific transplant. This risk/benefit analysis allows for the potential use of a transplant from a HCV infected donor to a non-infected recipient.’
Experience from outside the UKThe United States has the best data on D+ donor numbers as well as on discard rates, and is leading the way in early clinical trials of D+ to R- transplants. Utilisation of HCV antibody positive livers has increased with time but these have been transplanted exclusively into HCV R+ patients. A conference of the American Transplantation Society was held in January 2017, it was decided to consider D+ to R- transplantation across all solid organs within set criteria, and recommended that such practice should take place within prospective research protocols.
Part of the rationale for this strong recommendation has been emerging clinical trial data from the renal field. Goldberg et al published a single centre trial at the University of Pennsylvania involving 10 kidney transplant recipients, all were given HCV D+ kidneys from individuals infected with genotype 1 HCV. All recipients became viraemic by day 3 and all received 12 weeks of treatment with Grazoprevir/Elbasvir as soon as the positive result was obtained. These drugs can be used safely in patients with kidney failure. All the recipients were cured 12 weeks after cessation of therapy.
Results in a larger cohort of patients were reported by Saxena et al from the HCV-TARGET consortium of Academic US centres. In this paper 443 patients were treated after organ transplantation. There were 347 liver transplant recipients, 60 kidney transplant recipients and 36 dual transplant recipients included in the study. The majority were treated with Sofosbuvir and Ledipasvir (an earlier generation combination), with or without ribavirin. Overall SVR12 rates were 96.3% in liver recipients, 94.6% in kidney recipients and 90.9% in kidney/liver recipients. There were 6 episodes of rejection in total; 4 in the liver recipients and 2 in kidney recipients. It should be noted that 42% of the recipients had liver cirrhosis and 54% had previously failed HCV treatment. These patients would be classified as difficult to treat in a pre-transplant setting and in that context the SVR12 results are in fact quite impressive.
Why HCV D+ to R- transplantation should be cost effectiveDialysis is expensive and this cost would be mitigated by timely transplantation, particularly in individuals who are highly sensitised or otherwise difficult to transplant and who may spend many years on dialysis. More importantly, despite the fact that patients can survive on dialysis for many years, their quality of life is significantly reduced. A course of therapy to cure a R- patient receiving a D+ organ would be less than the cost of dialysis for one year.
What are the risks of HCV D+ to R- transplantation?
The Practicalities of Implementing this Policy in the United Kingdom
Acknowledged.
Summary:
· Up to 1 in 6 patients listed for solid organ transplantation will die or become too sick for a transplant. So, it needs to continuously explore improving the utilization of organs that are not currently widely used for transplantation.
· Organs from donors infected with hepatitis C have been discarded because of the high likelihood of transmitting the infection to the recipient. Older treatment modalities had poor tolerance and were not sufficiently successful in curing transplant recipients of the infection.
· Recent advances in the management of hepatitis C infection have changed the scenario as more than 95% of infected individuals can now be cured with directly acting antiviral agents.
· Studies have shown that similar outcomes of hepatitis C clearance can be safely achieved in transplant recipients and small trials have shown excellent outcomes in Hepatitis C negative recipients given hepatitis C infected organs who were subsequently treated and cured of the virus.
· A recent analysis of the UK Potential Donor Audit has suggested that up to 15 suitable donors are declined every year because of the risk of transmission of hepatitis C.
· Using organs from such donors could result in up to 75 extra solid organ transplants being performed every year in the UK.
· Following the recent recommendations by the Advisory Committee on the Safety of Blood, Tissues and Organs that, in some clinical situations, organs from hepatitis C infected donors may be transplanted into uninfected recipients.
· Selection of appropriate donors, a policy for ensuring the intended recipient gives fully informed consent, guidance for the testing and treatment of recipients as indicated, the formation of a monitoring group to oversee the program in the 6 early phases of implementation as well as consideration of some of the headline operational issues that will arise during successful implementation of the pathway.
Acknowledged.
SUMMARY
Introduction
It has been shown that solid organ transplantation has increased the number of people living that would have died if not for the intervention. Unfortunately, the number of those on the wait list is also on the rise, hence necessitating a new and safe way of making available organs from donors with HCV that used to be discarded. In about twelve months in the UK alone, close to 500 people died on the waitlist.
The introduction of DAA has significantly made possible the use of donors with HCV infection not only to HCV-positive recipients but also to those that are negative and willing to accept.
The status of the supposed donor needs to be ascertained through very sensitive tests. Although, even with the PCR the window period could still be missed and this is part of the challenges still holding back the full acceptability of this method of making more organs available for transplantation.
Changes in the treatment of hepatitis C in the last 5 years
Current discard rate of HCV-infected organs in UK
‘HCV infection in the potential donor does not amount to an absolute contraindication to the donation of material for life-preserving transplantation, however, the net benefit of transplantation must be considered against the risk of not receiving that specific transplant. This risk/benefit analysis allows for the potential use of a transplant from an HCV-infected donor to a non-infected recipient.’
Experience from outside the UK
What are the risks of HCV D+ to R- transplantation?
The Practicalities of Implementing this Policy in the United Kingdom
Acknowledged.
Article Summery
Most organs from donors infected with HCV were discarded for transplantation because of the high risk of transmission of this infection post-Transplant. Recent introduction of DAA led to cure in >95% of HCV related infection. Similarly, the outcomes are even excellent in Hepatitis C negative recipients, given organs from HCV+ Donar, who were subsequently treated and cured of the virus with DAA.
According to recommendations by the Advisory Committee on the Safety of Blood, Tissues and Organs, Different organs from hepatitis C infected donors may be transplanted into uninfected recipients. Appropriate donor might be selected and fully informed consent should be taken from the recipient.
Introduction
Shortage of donor organs because of increase demand have prompted researcher to look for alternate avenue. With the advent of DAA therapy with cure rate >95% of patients regardless of genotype, HCV donors can be used for organ donations.
HCV is a single stranded RNA virus (member of the Flaviviridae family). It has Six genotypes (G1-6) with a large number of sub-genotypes. Transmission is parenterally (through intravenous drug use (IVDU) or blood products), sexually (predominantly those who have unprotected anal sex with multiple partners) or vertically, from mothers to infants.
Acute infection is usually subclinical but Chronic infection (persistence of HCV RNA in serum for six months after initial infection) occurs in at least 60% of cases. Serologic tests can detect antibodies to HCV within 2-6 months of initial infection with the virus. HCV RNA detection should be carried out when assessing the HCV infectivity of an organ donor or recipient. Transmission of infection may occur from donors during the window period of acute infection which can be missed due to absence of HCV antibodies.
Changes in the treatment of hepatitis C over the past five years
Current discard rates for hepatitis C positive donor organs in the UK
Experience from outside the UK
Up to 4.0% of all organ donors in the US between 1995 and 2015 were reported to be HCV antibody positive, thereafter discard rates for HCV D+ livers have reduced in the US from 25% in 2006 to 10% in 2015.
More than 500 HCV positive kidneys are discarded annually in the US. A conference of the American Transplantation Society held in January 2017 was in Favour of considering D+ to R- transplantation across all solid organs within a set criterion.
Goldberg et al published a study in the New England Journal of Medicine: 10 kidney transplant recipients, all were given HCV D+ kidneys from individuals infected with genotype 1 HCV. All recipients became viremic by day 3 and all received 12 weeks of treatment with SVR achievement. EXPANDER-1 trial result was the same.
What are the risks of HCV D+ to R- transplantation?
1. fibrosing cholestatic hepatitis (FCH). It is an aggressive form of HCV related liver complication seen in 10% of D+/R+ liver transplants (1.5% in kidney transplant)
2. infection transmission have good prognosis (DAA therapy led to high cure rate)
3. DAA treatment failure is less than <5%.
4. Extra-hepatic manifestations of HCV (cryoglobulinemic vasculitis) or PTLD
5. Sexual transmission of HCV to a partner (extremely low <2% approximately)
The Practicalities of Implementing this Policy in the United Kingdom
Patient Consent:
Consent is specifically obtained by individual transplanting centres (supported by a patient information sheet)
Patient and Unit Requirements Pre-Transplant:
1- If the APRI score is >0.8 or the ultrasound suggests significant or
advanced liver disease, then an opinion from a liver specialist should be
sought
2- If the APRI score is <0.8, there is no need for the patient to be seen by a
liver specialist
Allocation of HCV D+ Organs on the Waiting List:
HCV+ D organs should be treated in the same way as HCV- D organs within the current allocation rules of the national waiting lists.
Management of the Recipient of an HCV+ D Organ:
Do HCV RNA testing following receipt of either a HCV Ab positive graft, an HCV RNA positive graft or a graft from an increased infectious risk donor, to ensure appropriate and early intervention if HCV transmission and infection occurs.
Test for HIV and HBV in all cases.
Recipient testing by HCV RNA on days between 3-7 day, on 10-14day, and 6 weeks
o If recipient HCV+, two alternative regimens should be used as first line agents, either the combination of Glecaprevir/Pibrenatasvir or the combination of Sofosbuvir/Velpatasvir. Both should be given for 12 weeks in the context of HCV D+/R- transplants and both are pan-genotypic.
o In case of treatment failure, a 12-week course of the combination of Sofosbuvir/Velpatasvir/Voxaleprevir which has a high rate of SVR even in those previously exposed to DAA therapy.
Special Additional Considerations:
HCV + Donors used for transplant:
1. HCV Ab positive with no history of treatment of HCV
2. HCV Ab positive with documented SVR after treatment
3. Any HCV Ab negative donor who has exposed themselves to risk but who does not fulfill any of the unacceptable criteria
4. Any HCV Ab positive donor whose HCV treatment history is unknown
HCV+ Donors should not use for transplant:
1. Previously failed DAA therapy with on-going viraemia
2. DAA therapy within last year without documented SVR (unless the recipient is at imminent risk of death)
3. Multiple documented re-infection with HCV
Acknowledged.
UK Position Statement on the use of Organs from Hepatitis C Viremic Donors and Increased Infectious Risk Donors in Hepatitis C Negative Recipients
Summary
Acknowledged.
Summary
Organ donation in the UK has increased, but there are still examples of people dying due to a lack of grafts; therefore, techniques are being found to utilize organs that were previously rejected.
Two-year-old therapeutic options rejected HCV-infected organs.
3-DAAT for HCV has a 95% cure rate, and transplanting HCV-positive organs from treated donors into HCV-negative recipients was encouraging.
The 4-UK registry showed 15 suitable HCV-positive donors were discarded annually, which might increase solid organ transplantation by 75 cases.
After a multidisciplinary team examination, organs from hepatitis C-infected donors can be used for uninfected recipients with restrictions.
Six precautions include qualified donors, fully informed permission, recipient testing and treatment, and a monitoring group.
HCV viraemia, regardless of HCV antibody status, refers to donors with HCV IgG +ve whose HCV RNA status is unclear upon organ transplantation.
Non-UK experience
Transplanting HCV-positive donors to HCV-negative recipients yielded positive results in US studies.
DAA-treated HCV D+ to HCV R- transplant recipients are treatment-nave, noncirrhotic, and likely to achieve SVR.
Why is HCV D+ to R- transplantation cost-effective?
Therapy for an R+ patient with a D+ organ should cost less than a year of dialysis.
HCV D+-to-R- transplantation risks
The biggest danger is fibrosing cholestatic hepatitis (FCH), an aggressive HCV recurrence forum in D+/R+ liver transplants with significant mortality before DAAT.
SOLAR-1 and 2 showed that sofosbuvir and ledipasvir for 12 or 24 weeks treated FHC after liver transplantation.
Additional studies showed encouraging FCH cure results with sofosbuvir, daclatasvir, and ledipasvir.
Early DAAT prevents FCH.
DAAT failure was rare.
No extrahepatic HCV D+/R+ data
Consent
HCV+ organ recipients must sign a specific consent.
Pre-transplant essentials
Advanced fibrosis or cirrhosis recipients should avoid HCV D+/R- non-liver transplantation.
HCV D+ non-liver organ recipients are tested using AST-to-Platelet Ratio Index (APRI) and ultrasonography to determine if a hepatic specialist is needed.
A checklist is needed before a transplanting center performs its first HCV D+/R- transplant.
HCV D+ Waiting List Organs
To promote organ use, national waiting list allocation regulations must treat HCV D+ organs the same as HCV D- organs.
HCV D+ organ management
Standardized HCV RNA testing of the recipient after receiving an HCV Ab positive, RNA positive, or graft from an enhanced infectious risk donor to detect HCV transmission and infection early.
For HCV-positive donor organs
The donor PCR must be tested in a central lab. If positive, genotyping testing must be done and all centers must be informed within 2 days. If negative, all centers must be informed.
The negatively consenting recipient must undergo an HCV PCR test 3-7 days after transplant, repeated 10-14 days, and retested 6 weeks afterwards.
DAA should be begun within 3-10 days of a positive HCV PCR test.
Two pan-genotypic, 12-week regimens for HCV D+/R- transplants are Glecaprevir/Pibrenatasvir or Sofosbuvir/Velpatasvir.
After first DAAAT failure, 12-week Sofosbuvir/Velpatasvir/Voxaleprevir has high SVR rates.
Special issues
Avoid transplanting organs from donors treated for HCV with DAA within the last 6 months unless they have SVR to avoid transmitting HCV-resistant infection.
Accepted donors
Suitable donors include HCV Ab positive with no HCV treatment history, HCV Ab positive reaching SVR after treatment, HCV Ab negative donor exposed to risk but does not meet the unacceptable criteria, and HCV Ab positive donor with unknown treatment history.
Unrecommended donors
Include instances with failed DAA therapy and persistent viraemia, DAA therapy within last year without confirmed SVR, and repeated HCV reinfection.
Unless the advantages outweigh the dangers, DAA-treated HCV donors who fail to achieve SVR12 should not be transplanted into negative recipients.
In conclusion,the net benefit of life-saving transplantation must be weighed against the harm of not getting organ donation from HCV positive.
This risk/benefit analysis allows an HCV-infected donor-to-non-infected recipient transplant.
DAA medication is recommended for all HCV-infected kidney transplant candidates.
In recent years, these novel hepatitis C medications have had few adverse effects and are well-tolerated by patients.
Acknowledged.
Introduction:
HCV is a singlestranded RNA virus of the Flaviviridae family. Six genotypes (G16). Hepatitis C patients in the last five years: 4,444 There is considerable experience in the UK with two licensed pangenotypic regimens in the form of Sofosbuvir/Velpatasvir and Glecaprevir/Pibrentasvir.
The pangenotypic triplet of Sofosbuvir, Velpatasvir and Voxilaprevir was licensed in August 2017. independent of HCV genotype.
Current rates of processing organs from Hepatitis C positive donors in the UK:
“HCV infection in a potential donor is not an absolute contraindication to the donation of material for lifesaving transplantation, but the net benefits of transplantation must be weighed against the risks of not accepting that specific transplant. This risk/benefit analysis allows for the potential use of transplantation from HCV-infected donors to uninfected recipients.
’Why HCV D+ to R transplantation is cost-effective:
might be the strongest in kidney transplantation. Dialysis is expensive.
What are the risks of a HCV D+ to R transplant?
Ø Cholestatic fibrosing hepatitis (CHF)
Ø Individuals infected with cytomegalovirus (CMV) or Epstein Barr virus (EBV).
Practicality of policy implementation in the UK:
However, it was felt that it would be useful for the group to provide a framework for some of the important practical issues which need to be addressed by every transplant unit wishing to adopt the policy. Consideration
Patient consent prior to D+/R HCV transplantation:While patients currently generally consent to socalled “marginal” organs, including, for example, CMVpositive organs, it is thought HCV D+ specifically should be obtained at individual transplant centers
Patient and unit requirements prior to transplantation:
For safety reasons, the Working Group agrees that nonhepatic transplantation of HCV D+/R should be avoided in recipients with advanced fibrosis or cirrhosis.Allocation of HCV D+ organs on the waiting list:Periodic review of posttransplant outcomes is necessary to allow advisory groups to modify procurement and allocation policies as needed.
Management of HCV D+ organ recipients:
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Two alternatives should be used as firstline agents. It is a Glecaprevir/Pibrenatasvir combination or a Sofosbuvir/Velpatasvir combination. In case of HCV D+/R transplantation, both must be administered for 12 weeks. Both are pangenotyped, meaning they can startimmediately after a positive HCV PCR result without waiting for the HCV genotype, which can take 34 weeks in some areas.Additional special considerations:
Acceptable in proposed policy:
Ø HCV Ab positive with no history of HCV treatment
Ø HCV Ab positive with documented SVR after treatment
Ø Any HCV negative negative donor at no risk Meeting any of the following unacceptable criteria
Ø Any HCV Ab positive donor with unknown history of HCV treatment – proceed with caution
Not recommended in proposed policy
is at imminent risk of death
Ø Multiple documented HCV re-infections
Early project follow-up:
The working group believes that a review committee should be formed after this position statement is approved, the committee will oversee program execution and next steps in the process clof information on HCV recipients receiving D+/R- transplants:
Transplant Society Annual Conference in Brighton, March 2018. ‘- Program date September 2018. NHSBT will publish further operational details using its standard communication channels.HSBT using its standard communication channels.
Acknowledged.
Summary of the article
UK Position Statement on the use of Organs from Hepatitis C Viraemic Donors and Increased Infectious Risk Donors in Hepatitis C Negative Recipient
Executive Summary
1. Despite the increase in organ donation in the UK, up to 1 in 6 patients listed for solid organ transplantation will die or become too sick for a transplant. There is, therefore, a need to continuously explore improving the utilisation of organs that are not currently widely used for transplantation.
2. Most organs from donors infected with hepatitis C have hitherto been discarded because of the high likelihood of transmitting the infection to the recipient. Older treatment modalities had poor tolerance and were not sufficiently successful in curing transplant recipients of the infection.
3. Recent advances in the management of hepatitis C infection have meant that more than 95% of infected individuals can now be cured with directly acting antiviral agents. Studies have shown that similar outcomes of hepatitis C clearance can be safely achieved in transplant recipients and small trials have shown excellent outcomes in Hepatitis C negative recipients given hepatitis C infected organs who were subsequently treated and cured of the virus.
4. A recent analysis of the UK Potential Donor Audit has suggested that up to 15 suitable donors are declined every year because of the risk of transmission of hepatitis C. Using organs from such donors could result in up to 75 extra solid organ transplants being performed every year in the UK.
5. Following the recent recommendations by the Advisory Committee on the Safety of Blood, Tissues and Organs that, in some clinical situations, organs from hepatitis C infected donors may be transplanted into uninfected recipients, a group of clinicians, virologists, scientists, health care managers and patient representatives have proposed a UK wide framework for the appropriate use of organs from HCV infected donors.
6. Key elements of the guidelines include selection of appropriate donors, a policy for ensuring the intended recipient gives fully informed consent, guidance for the testing and treatment of recipients as indicated, the formation of a monitoring group to oversee the programme in the early phases of implementation as well as consideration of some of the headline operational issues that will arise during successful implementation of the pathway.
HCV; current treatment
1. Pan-genotypic regimens in the form of Sofosbuvir / Velpatasvir and Glecaprevir/Pibrentasvir.
2. The pan-genotypic triplet of Sofosbuvir, Velpatasvir and Voxilaprevir was licenced in August 2017.
3. The advantage of Glecaprevir / Pibrentasvir is that it can be given to patients with established renal failure.
4. The best data currently available for Sofosbuvir, Velpatasvir and Voxilaprevir.
HCV D+ to R- transplantation is cost effective
The course of therapy to cure a R- patient receiving a D+ organ would be less than the cost of dialysis for one year.
The risks of HCV D+ to R- transplantation
1. Fibrosing cholestatic hepatitis (FCH).
2. DAA treatment failure, which may be associated with the development of difficult to treat resistance associated substitutions (RAS) especially in the viral NS5A protein.
3. Extra-hepatic manifestations of HCV such as cryoglobulinaemic vasculiti and PTLD.
4. Sexual transmission of HCV to a partner.
Management of the Recipient of a HCV D+ Organ
1. Either the combination of Glecaprevir/Pibrenatasvir or the combination of Sofosbuvir/Velpatasvir. Both should be given for 12 weeks in the context of HCV D+/R- transplants.
2. In the rare (expected to be less than 2%) instances where the first course of treatment of HCV is not curative, recipients should be treated with a 12 week course of the combination of Sofosbuvir/Velpatasvir/Voxaleprevir.
Acknowledged.
UK Position Statement on the use of Organs from HCV +ve Donors in HCV -ve Recipients
Summary:
· HCV is transmitted by blood borne, sexual and vertical (trans-placental).
· Serologic tests can detect antibodies to HCV within 2-6 months of initial infection, while PCR is more accurate for diagnosis and detect active viremic state (active viral replication).
· Anti-HCV antibodies continue to be positive for years or indefinitely after spontaneous clearance, or successful treatment with interferon or DAA.
· While undetectable HCV RNA after therapy means SVR; sustained virologic response (no longer ordinarily infectious, but can be re-infected, so FU PCR is recommended).
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· Transplantation has better patient survival than prolonged dialysis, so use of extended criteria donor has been raised to increase donor pool and increase chance to get transplanted.
· HCV +ve donor organ were discarded in the past as interferon was unsafe in transplant recipient and risk of infection and viremia ere high with poor graft outcome and higher mortality.
· The current practice is to use HCV D+ organs to HCV positive recipients (R+) only in the field of liver transplantation.
· HCV D+ never used for HCV –R (in any SOT), and positive for positive is applied only in liver transplantation.
· Availability of DAAV (safe, well-tolerated and pangenotypic effective) paved the way to think about the use HCV +ve donor for HCV –ve recipients.
· This strategy is not yet the standard practice and requires certain inquiries:
o Counseling of recipient about risk of viremia and? resistance to treatment.
o Protocol for viral PCR and liver function monitoring.
· As regard the available DAAV:
o 2 licensed pan-genotypic regimens:
1. Sofosbuvir / Velpatasvir.
2. Glecaprevir/Pibrentasvir (can be used in renal failure patients).
3. The triplet of Sofosbuvir, Velpatasvir and Voxilaprevir was licenced in 2017, effective in refractory cases.
4. The 2nd and 3rd generation DAA regimens are effective for patients with cirrhosis, and for patients treated after kidney or liver transplantation.
Acknowledged.
IV. UK Position Statement on the use of Organs from Hepatitis C Viraemic Donors and Increased Infectious Risk Donors in Hepatitis C Negative Recipient
====================================================================
Please summarise this article.
Executive Summary
===================================================================
Experience from outside the UK
====================================================================
Why HCV D+ to R- transplantation should be cost effective
====================================================================
What are the risks of HCV D+ to R- transplantation?
===================================================================
Patient Consent
Patient and Unit Requirements Pre-Transplant
Allocation of HCV D+ Organs on the Waiting List
Management of the Recipient of a HCV D+ Organ
Special Additional Considerations
Oversight of the Programme in its Early Days
====================================================================
Acknowledged.
Executive summary
1-In spite that organ donation has increased in UK yet there are cases dying out of shortage of grafts ,therefore organs that were used to be discarded before ,ways are figured out to get use if it
2-HCV infected organs were discarded due to old treatment options which changed now.
3-DAAT for HCV have 95% cure rate , the outcomes of transplanting HCV positive organs from treated donors into HCV negative recipients were promising.
4-Uk registry showed that 15 suitable HCV positive donors were discarded per year wich can increase solidorgan transplantation to 75 extra cases
5-Recent recommendations after multi disciplinary team evaluation ,stated that organs from hepatitis C infected donors can be used for uninfected recipients with certain precautions
6-Precautions include suitable donors, fully informed consent need to be explained to and signed by the recipient, testing and treatment of recipients as indicated, available of a monitoring group.
HCV viraemia indicate donors or recipients with active HCV infection with detectable HCV RNA, irrespective of HCV Ab state, also refers to donors with HCV IgG +ve whose HCV RNA status is unknown at the organ transplantation time.
Experience from outside the UK
Studies from USA revealed favourable results for transplanting HCV positive donors to HCV negative recipients.
If HCV D+ to HCV R- transplants will be done ,those recipients treated with DAAs are treatment naïve and mostly noncirrhotic, and have a high tendency to reach SVR.
Why HCV D+ to R- transplantation should be cost effective?
It is supposed that therapy course to cure a R- patient receiving a D+ organ is less than dialysis cost for a year.
Risks of HCV D+ to R- transplantation
Fibrosing cholestatic hepatitis (FCH) is the worst risk which is an aggressive forum of HCV recurrence in D+/R+ liver transplant with high mortality before DAAT introduction.
SOLAR-1 and 2 studies demonstrated that the combination
of Sofosbuvir and Ledipasvir for 12 or 24 weeks treated cases with FHC after liver transplantation.
Other studies revealed that Sofosbuvir and Daclatasvir as well as Sofosbuvir and Ledipasvir have promising results in FCH cure .
Also early DAAT can prevent FCH .
DAAT failure was noticed in minority of cases.
No available data on HCV extrahepatic manifestations in the HCV D+/R+ field
Patient consent
Recipients who receives organs from HCV + donors have to sign a special consent.
Pretransplant requirements
HCV D+/R- non-liver transplantation have to be avoided in recipients with advanced fibrosis or cirrhosis.
Cases consented to receive a HCV D+ non-liver organs are screened using AST-to-Platelet Ratio Index (APRI) and ultrasound then accordingly to decide if a hepatic specialist need to be consulted.
Checklist of requirements before an individual transplanting centre undergo the first HCV D+/R- transplant is essential.
Allocation of HCV D+ Organs on the Waiting List
HCV D+ organs have to be dealt with the same as HCV
D- organs regarding the allocation rules of the national waiting lists to maximize the organ utilisation .
Recipient of a HCV D+ Organ management
Standardized testing for HCV RNA of the recipient after receiving a HCV Ab positive graft, a HCV RNA positive graft or a graft from an increased infectious risk donor, to attain an early and appropriate intervention if HCV transmission and infection occurs.
Flow chart is as follows
For Organs from HCV Ab positive donors ,
-the donor PCR have to be tested in a central lab if positive result then genotype testing is done then all centers have to be informed within 2 days and if negative result also all centers have to be informed within 2 days .
-the negatively consented recipient has to have HCV PCR test 3-7 days post transplant ,then if negative to be repeated 10-14 days ,if negative 6 weeks retesting post transplant.
If HCV PCR is positive after confirmatory results DAA to be started within 3-10 working days since the first positive test.
There are 2 regimens including combination of Glecaprevir/Pibrenatasvir or the combination of Sofosbuvir/Velpatasvir, both given for 12 weeks with HCV D+/R- transplants and are pan-genotypic with acceptable drug interactions.
Sofosbuvir/Velpatasvir/Voxaleprevir for 12 week can be given after first DAAAT failure having high rates of SVR .
Special issues
The fear to transmit HCV resistant infection can be manged by avoiding transplanting organs from donors treated for HCV with DAA within the last 6 months unless there is an evidence of SVR.
Acceptable donors
include HCV Ab positive with no HCV treatment history , HCV Ab positive reaching SVR after treatment, HCV Ab negative donor exposed to risk but does not fulfill the unacceptable criteria
and proceed with caution for HCV Ab positive donor whose HCV treatment history is unknown .
Unrecommended donors
Include cases with failed DAA therapy and persistence of viraemia, DAA therapy within last year without documented SVR, multiple HCV reinfection.
Donors treated for HCV with DAAs but not achieving SVR12 for any reason should not be considered for transplantation into a negative
recipient unless the benefits outweigh the risks
Acknowledged.
UK Position Statement on the use of Organs from Hepatitis C Viraemic Donors and Increased Infectious Risk Donors in Hepatitis C Negative Recipient.
Introduction :
Solid organ transplantation is now well established in routine clinical practice, but a significant number of patients still die due to a shortage of donor organs. An important strategy is to review discarded organs to assess if advances in medicine could enable them to be transplanted, which could make more organs available for transplantation and reduce the morbidity and mortality of patients on waiting lists.
Introduction to HCV and Clarification of Nomenclature
HCV is a single stranded RNA virus with six genotypes and a large number of sub-genotypes, which can lead to acute or chronic infection. The term ‘HCV viraemic’ is used to refer to donors or recipients who have active HCV infection with detectable HCV RNA, regardless of HCV antibody status.
Changes in the treatment of hepatitis C over the past five years
The most important details in this text are the changes in the treatment of hepatitis C over the past five years, which began with the licensing of the first generation protease inhibitors Telaprevir and Boceprevir in 2012. These drugs have increased cure rates for patients with G1 HCV from 50% to over 80%. Most current regimens are given for 8-16 weeks and offer cure rates of 95-100% for patients without cirrhosis, regardless of HCV genotype. There is already substantial UK experience of using two licensed pan-genotypic regimens in the form of Sofosbuvir / Velpatasvir and Glecaprevir/Pibrentasvir. The second and third generation DAA regimens have also been shown to be highly effective for patients with cirrhosis and for patients treated after kidney or liver transplantation.
Current discard rates for hepatitis C positive donor organs in the UK
The UK currently restricts the use of HCV D+ organs to HCV positive recipients, but anecdotal evidence suggests poor utilisation of non-liver organs even for HCV R+ recipients. The revised guidance states that HCV infection does not amount to an absolute contraindication to donation of material for life-preserving transplantation, but the net benefit of transplantation must be considered against the risk of not receiving it.
Experience from outside the UK
The United States has the best data on D+ donor numbers and discard rates, and is leading the way in early clinical trials of D+ to R- transplants. 4.1% of all organ donors between 1995 and 2015 were reported to be HCV antibody positive, but these have been transplanted exclusively into HCV R+ patients. Discard rates for HCV D+ livers have reduced from 25% in 2006 to 10% in 2015, but discard rates for other organs are significantly higher. A conference of the American Transplantation Society recommended that insurance companies should guarantee funding for DAA therapy for patients knowingly infected with HCV at the time of transplantation.
Why HCV D+ to R- transplantation should be cost
effective
Increasing organ availability for HCV D+ to R- transplantation should be cost-effective to reduce waiting times and dialysis expenditure, saving lives and improving quality of life for patients. DAAs to the NHS would be less than the cost of dialysis for one year, leading to substantial cost savings and improved quality of life.
What are the risks of HCV D+ to R- transplantation?
Fibrosing cholestatic hepatitis (FCH) is an aggressive form of HCV recurrence seen in 10% of D+/R+ liver transplants. Early treatment with DAA therapy should prevent the development of FCH, and modern DAA therapy provides an excellent chance of cure. However, a minority of patients may experience DAA treatment failure, which could lead to extra-hepatic manifestations of HCV such as cryoglobulinaemic vasculitis or potential increased rates of blood derived malignancy. Treatment duration should be extended slightly to mitigate this risk.
The Practicalities of Implementing this Policy in the
United Kingdom:
The working party met on the 2nd of November 2017 to discuss the practicalities of implementing this Policy in the UK. It was felt that it would be useful to provide a framework for some of the important practical issues that transplant units should consider prior to proceeding with a HCV D+/R- transplant. The group also felt strongly that there should be an oversight committee for the first 20-30 transplants, and this will be discussed further.
Patient Consent:
Patient consent for HCV D+/R- transplantation should be specifically obtained by individual transplanting centres, and a patient information sheet has been developed. The British Transplantation Society and NHS Blood and Transplant are reviewing the entire pathway of sharing information with and gaining consent from solid organ transplant candidates.
Patient and Unit Requirements Pre-Transplant:
The working party agreed that HCV D+/R- non-liver transplantation should be avoided in recipients with advanced fibrosis or cirrhosis. Screening patients using AST-to-Platelet Ratio Index (APRI) and ultrasound is suggested to ensure safety, If the APRI score is <0.8 or the ultrasound suggests significant or advanced liver disease, an opinion from a suitably qualified liver specialist should be sought before the patient is considered. A checklist of pre-requisites must be in place before an individual unit performs its first transplant to minimize the theoretical risk.
Allocation of HCV D+ Organs on the Waiting List:
The working group considered the allocation of HCV D+ organs on the waiting list and concluded that they should be treated the same as HCV D- organs within the current allocation rules of the NHSBT bodies. Advisory Groups will need to decide how best to offer and allocate such organs in order to optimise organ utilisation, and frequent review of post-transplant outcomes will be needed to alter offering and allocation policies as needed.
Management of the Recipient of a HCV D+ Organ:
Standardized, longitudinal testing for hepatitis C RNA of the recipient following receipt of either a HCV antibody positive graft, a HCV RNA positive graft or a graft from an increased infectious risk donor is mandatory . Two alternative regimens should be used as first line agents, either Glecaprevir/Pibrenatasvir or Sofosbuvir/Velpatasvir. A clinical team with experience of management of HCV should be included . Organ from a donor who has been treated for HCV with DAAs but has not achieved SVR12 for any reason should not be considered for transplantation unless the benefits outweigh the risks.
Oversight of the Programme in its Early Days:
Oversight Committee should be established to oversee implementation of HCV D+/R- transplantation, led by BVHG, with representation from NHSBT and BRITISH TRANSPLANTATION SOCIETY.
Acknowledged.
UK Position Statement on the use of Organs from Hepatitis C Viraemic Donors and Increased Infectious Risk Donors in Hepatitis C Negative Recipients
1- Despite the increase in organ donation in the UK, up to 1 in 6 patients listed for solid organ transplantation will die or become too sick for a transplant. There is, therefore, a need to continuously explore improving the utilisation of organs that are not currently widely used for transplantation.
2- Most organs from donors infected with hepatitis C have been discarded because of the high likelihood of transmitting the infection to the recipient.
3- Older treatment modalities had poor tolerance and were not sufficiently successful in curing transplant recipients of the infection.
4- Recent advances in the management of hepatitis C infection have meant that more than 95% of infected individuals can now be cured with directly acting antiviral agents.
5- Studies have shown that similar outcomes of hepatitis C clearance can be safely achieved in transplant recipients and small trials have shown excellent outcomes in Hepatitis C negative recipients given hepatitis C infected organs who were subsequently treated and cured of the virus.
6- A recent analysis of the UK Potential Donor Audit has suggested that up to 15 suitable donors are declined every year because of the risk of transmission of hepatitis C. Using organs from such donors could result in up to 75 extra solid organ transplants being performed every year in the UK.
7- Following the recent recommendations by the Advisory Committee on the Safety of Blood, Tissues and Organs that,:
in some clinical situations, organs from hepatitis C infected donors may be transplanted into uninfected recipients
8- Key elements of the guidelines include selection of appropriate donors, a policy for ensuring the intended recipient gives fully informed consent, guidance for the testing and treatment of recipients as indicated, the formation of a monitoring group to oversee the programme in the early phases of implementation as well as consideration of some of the headline operational issues that will arise during successful implementation of the pathway.
Figure1 : Proposal for Testing of Donors and Management of All Recipients in the UK HCV D+/R- scheme
Treatment of the HCV positive recipient:
Regimen:
– First line agents. Either
1- Either the combination of Glecaprevir/Pibrenatasvir
SE: increased by ciclosporin, and it may also increase the levels of tacrolimus
2- The combination of Sofosbuvir/Velpatasvir.
SE: not recommended in patient with a eGFR <30 mL/min/1.73 m2
Duration:
– Both should be given for 12 weeks in the context of HCV D+/R- transplants. Both are pan-genotypic, which means that they can be started as soon as HCV PCR positivity is known, without having to wait for a HCV genotype, which can take 3-4 weeks in some areas.
– Second line:
After failure of first line
12 week of combined Sofosbuvir/Velpatasvir/Voxaleprevir.
Acknowledged.
The demand for organs continues to outpace the supply of organ donation. Therefore, there is a constant need to find ways to better utilize organs that are not now frequently used for transplantation.
Historically, organs from deceased donors infected with HCV were discarded because of high transmission risk. The current availability highly effective and well tolerated direct-acting antiviral (DAA) therapy, improve the utilization of HCV infected organs.
Chronic infection: defined as persistence of HCV RNA in serum for greater than six months after initial infection This develops in at least 60% of those infected.
HCV viraemia those with detectable HCV RNA by PCR regardless HCV antibody status. Also, refer to those with HCV IgG +ve where the HCV RNA status is not known at the time of organ offering / transplantation (window period), transmission of infection may still occur from donors during the window period of acute infection.
SVR( sustained virologic response) clearance of the virus with successful treatment of HCV lead to undetectable HCV RNA.
The Changes in the treatment of HCV:
– The first generation protease inhibitors: Telaprevir and Boceprevir. These drugs were combined with interferon and ribavirin.
– Pan-genotypic DAA: Sofosbuvir / Velpatasvir, Voxilaprevir and Glecaprevir/Pibrentasvir.
-The advantage of Glecaprevir / Pibrentasvir is that it can be given to patients with established renal failure.
– Sofosbuvir, Velpatasvir and Voxilaprevir highly effective in those previously failed other DAA-containing regimens.
– The 2nd& 3rd generation: highly effective for patients with cirrhosis, and after kidney or liver transplantation
Advisory Committee on SaBTO stated: ‘HCV infection does not amount to an absolute contraindication to donation of material for life-preserving transplantation, however the net benefit of transplantation must be considered against the risk of not receiving transplant. This allow use of HCV infected donor to a non-infected recipient.
Clinical trials are very encouraging, and data emerging on the efficacy and safety of DAA therapy in patients who have undergone organ transplantation and have established HCV.
Why HCV D+ to R- transplantation should be cost effective
-Dialysis is expensive lead to increase in morbidity and mortality and reduce quality of life. This can be mitigated by transplantation especially for those highly sensitized, DAA is cost effective therapy.
-There are clear economic and health related benefits to HCV D+ to R- transplantation,
What are the risks of HCV D+ to R- transplantation?
–Fibrosing cholestatic hepatitis (FCH), an aggressive form of HCV recurrence seen in 10% of D+/R+ liver transplants. DAA is very effective in this setting.
– DAA treatment failure; in minority <5% of patients treated after SOT, may be associated with the development of resistance,modern DAA therapies can cure this, even if this is not achieved at the first attempt at treatment.
– Extra-hepatic manifestations of HCV; cryoglobulinaemic vasculitis or potential increased rates of blood derived malignancy such as PTLD. No data reported an increased risk, however, early DAA should mitigate this risk.
– Sexual transmission of HCV to a partner is very low, early DAA and simple lifestyle advice reduce the risk.
– Patient should be Consented to receive a HCV D+ organ.
– HCV D+/R- non-liver transplantation should be avoided in recipients with advanced fibrosis or cirrhosis.
– Using AST-to-Platelet Ratio Index (APRI) can help to identify advanced liver disease if score >0.8 liver specialist opinion should be sought.
-If the APRI score is <0.8, there is no need for the patient to be seen by a liver specialist.
– HCV D+ organs should be treated in the same way as HCV D- organs within the current allocation rules
Recipient monitoring with HCV RNA after receiving an organ from HCV+RNA or HCV positive antibodies, to allow early identification and treatment.
At day 3-7 Post-Tx, then day 10-14,then at 6 weeks if all results are negative reassure the recipient & managed as standard recipients. If HCV PCR positive; DAA started within 3-10 days of first positive PCR.
-The combination of either Glecaprevir/Pibrenatasvir or the combination of Sofosbuvir/Velpatasvir, is used as first line agents. For total 12 weeks, both regimen are pan-genomic can be started immediately before knowing the genotype.
– Sofosbuvir/Velpatasvir is not recommended in patient with a eGFR <30 mL/min/1.73 m2
– The combination of Sofosbuvir/Velpatasvir/Voxaleprevir used for 12 weeks in recipients did not respond to first course. As the rates of SVR is high even in those previously exposed to DAA therapy.
Key elements of the guidelines include selection of appropriate donors:
Acceptable Within Proposed Policy
HCV Ab positive with no history of treatment of HCV
HCV Ab positive with documented SVR after treatment
Any HCV Ab negative donor who has exposed themselves to risk but who does not fulfill any of the unacceptable criteria
Any HCV Ab positive donor whose HCV treatment history is unknown – proceed with caution
Not Recommended Within Proposed Policy
Previously failed DAA therapy with on-going viraemia
DAA therapy within last year without documented SVR (unless the recipient is at imminent risk of death)
Multiple documented re-infection with HCV
Acknowledged.
Please summarise this article.
o Most organs from donors infected with HCV discard from transplant because of the high risk of transmitting the infection to the recipient
o Recent DAA cure >95% of HCV infection
o The outcomes is excellent in Hepatitis C negative recipients given hepatitis C infected organs who were subsequently treated and cured of the virus
o According to recommendations by the Advisory Committee on the Safety of Blood, Tissues and Organs that, organs from hepatitis C infected donors may be transplanted into uninfected recipients
o Select the appropriate donor and fully informed consent of the recipient
Introduction
o Due to a shortage of donor organs, there is an increase need for organs
o With the advent DAA therapy which cure >95% of patients infected with HCV, regardless of genotype, HCV donors can be used
o HCV is a single stranded RNA virus member of the Flaviviridae family
o Six genotypes (G1-6) with a large number of sub-genotypes
o Transmission is parenterally (through intravenous drug use (IVDU) or blood products), sexually (predominantly those who have unprotected anal sex with multiple partners) or vertically, from mothers to infants
o Acute infection is usually subclinical
o Chronic infection (persistence of HCV RNA in serum for greater than six months after initial infection) occurs in at least 60% of those infected
o Serologic tests can detect antibodies to HCV within 2-6 months of initial infection
o Use HCV RNA when assessing the HCV infectivity of an organ donor or recipient (active HCV replication or not)
o Transmission of infection may occur from donors during the window period of acute infection
Changes in the treatment of hepatitis C over the past five years
o Now DAA are given for between 8 and 16 weeks, and offer cure rates of 95-100% for patients without cirrhosis, regardless of HCV genotype
o Two licensed pan-genotypic regimens (Sofosbuvir / Velpatasvir and Glecaprevir/Pibrentasvir)
o The pan-genotypic triplet of Sofosbuvir, Velpatasvir and Voxilaprevir was licenced in August 2017
o Glecaprevir / Pibrentasvir regimen can be given to patients with established renal failure
o The second and third generation DAA regimens are highly effective for patients with cirrhosis, and for patients treated after kidney or liver transplantation
Current discard rates for hepatitis C positive donor organs in the UK
o Current practice in the UK is to restrict the use of HCV D+ organs to HCV positive recipients (R+)
o The UK Advisory Committee on the Safety of Blood, Tissues and Organs (SaBTO) guidance: HCV infection in the potential donor does not amount to an absolute contraindication to donation of material for life-preserving transplantation, however the net benefit of transplantation must be considered against the risk of not receiving that specific transplant. This risk/benefit analysis allows for the potential use of a transplant from a HCV infected donor to a non-infected recipient
Experience from outside the UK
o 4.1% of all organ donors in the US between 1995 and 2015 were reported to be HCV antibody positive
o Discard rates for HCV D+ livers have reduced in the US from 25% in 2006 to 10% in 2015 (discard of HCV D-)
o More than 500 HCV positive kidneys are discarded annually in the US (opiate Abuse)
o A conference of the American Transplantation Society held in January 2017 was in favour of considering D+ to R- transplantation across all solid organs within set criteria
o Goldberg et al published a study in the New England Journal of Medicine: 10 kidney transplant recipients, all were given HCV D+ kidneys from individuals infected with genotype 1 HCV. All recipients became viraemic by day 3 and all received 12 weeks of treatment with SVR
o EXPANDER-1 trial result was the same
What are the risks of HCV D+ to R- transplantation?
1. fibrosing cholestatic hepatitis (FCH). It is an aggressive form of HCV recurrence seen in 10% of D+/R+ liver transplants (1.5% in kidnet transplant)
2. infection transmission (DAA therapy results a high cure)
3. DAA treatment failure (<5%)
4. Extra-hepatic manifestations of HCV (cryoglobulinaemic vasculitis) or PTLD
5. Sexual transmission of HCV to a partner [(extremely low (<2% perhaps)]
The Practicalities of Implementing this Policy in the United Kingdom
Patient Consent:
o Consent is specifically obtained by individual transplanting centres (supported by a patient information sheet)
Patient and Unit Requirements Pre-Transplant:
o HCV D+/R- non-liver transplantation should be avoided in recipients with advanced fibrosis or cirrhosis
o Seen by a liver specialist
o Screen patients by using AST-to-Platelet Ratio Index (APRI) and ultrasound
o If the APRI score is >0.8 or the ultrasound suggests significant or advanced liver disease, then an opinion from a liver specialist should be sought
o If the APRI score is <0.8, there is no need for the patient to be seen by a liver specialist
o Pre-requisites checklist
Allocation of HCV D+ Organs on the Waiting List:
o HCV D+ organs should be treated in the same way as HCV D- organs within the current allocation rules of the national waiting lists
Management of the Recipient of a HCV D+ Organ:
o Do HCV RNA following receipt of either a HCV antibody positive graft, a HCV RNA positive graft or a graft from an increased infectious risk donor, to ensure appropriate and early intervention if HCV transmission and infection occurs
o Test for HIV and HBV
o Recipient test by HCV RND day 3-7, day 10-14, and 6 weeks
o If recipient HCV+, two alternative regimens should be used as first line agents, either the combination of Glecaprevir/Pibrenatasvir or the combination of Sofosbuvir/Velpatasvir. Both should be given for 12 weeks in the context of HCV D+/R- transplants and both are pan-genotypic
o In treatment failure, a 12 week course of the combination of Sofosbuvir/Velpatasvir/Voxaleprevir which has a high rates of SVR even in those previously exposed to DAA therapy
Special Additional Considerations:
o Use of organs from donors treated for HCV with DAA within the last 6 months should be avoided unless there is clear documentary proof at the time of donation of an SVR12 result
o Any organ from a donor treated for HCV with DAAs but has not achieved SVR12 for any reason should not be considered for transplantation into a negative recipient unless the benefits outweigh the risks (in a clinically urgent transplant candidate)
HCV + Donors used for transplant:
1. HCV Ab positive with no history of treatment of HCV
2. HCV Ab positive with documented SVR after treatment
3. Any HCV Ab negative donor who has exposed themselves to risk but who does not fulfill any of the unacceptable criteria
4. Any HCV Ab positive donor whose HCV treatment history is unknown
HCV+ Donors should not used for transplant:
1. Previously failed DAA therapy with on-going viraemia
2. DAA therapy within last year without documented SVR (unless the recipient is at imminent risk of death)
3. Multiple documented re-infection with HCV
Acknowledged.
Experience from outside UK:
HCV D+ to R- transplant cost:
Risk of HCV /R- transplant:
Pr-transplant patient & unite requirement:
Allocation of HCV D+ organ on waiting list:
Management of recipients of HCV D+ organ.
Acknowledged.
UK Position Statement on the use of Organs from Hepatitis C Viraemic Donors and Increased Infectious Risk Donors in Hepatitis C Negative Recipients
HCV infection test
Serologic test
HCV RNA detected either by PCR NAT or antigen testing
UK practice
Restrict the use of HCV D+ organs to HCV-positive recipients (R+)
Experience outside UK
United state
Pro and Cons of transplanting HCV-positive donor to HCV-negative recipient
Advantages
Concern about the risk of transplanting organs from HCV-positive donors
Acknowledged.
Summarize this article IV
· Kidney transplantation is the best form of kidney replacement therapy for individuals suffering from end stage kidney disease. Nonetheless, 1 in 6 patients on the waiting list are not able to get transplanted because they either die or deteriorated before transplantation. One reason for this is shortages of donors, hence there should a continuous effort to utilize the organs which have not been used for transplantation such as hepatitis C infected organs.
· Up to now most hepatitis C infected organs were discarded due to fear of transmitting the virus to the recipient. In past hepatitis C treatment was very challenging because of tolerability issues and was not effective to clear the virus in the infected transplant recipient. How ever with new hepatitis C treatment i.e., directly acting antiviral agents most patients are cured with a cure rate exceeding 95%.
· A number of small studies confirmed a very good outcomes of transplanting hepatitis C positive organs to hepatitis C negative recipients after their treatment and clearance of the virus.
· Unfortunately, a recent report of the UK potential donor Audit showed that, 15 suitable hepatitis C infected donors are rejected and the fact is that utilization of these donors may result in 75 additional donor pools available for transplantation every year.
· Thanks to UK Advisory Committee on the Safety of Blood, Tissues and Organs to address this issue and they recommended that, in situations of urgent demand hepatitis C infected organ can be transplanted to hepatitis C negative recipients. The advisory committee consist of a group of professionals consist of: clinicians, virologists, scientists, health care managers & patient representatives. They make reasonable decisions on the use of organs from hepatitis C infected donors.
· The recommendation statements focus on the following areas:
1. Appropriate donor selection
2. A policy for a fully informed recipient consent
3. Guidelines for recipient tests & treatments
4. Monitoring committee to follow up the program
Acknowledged.
Summary
Introduction
This article is based on the position of the UK on using HCV viremic donors for HCV negative recipients.
Discussion
Conclusion
Forming a group to monitor and oversee such programs in the early phases of implementation will help in stadandrized protocols being put in place to ensure successful implementation and good outcome for the recipient and all involved.
Acknowledged.
Serologic tests can detect antibodies to HCV within two to six months of initial infection
the most important parameter to be considered when assessing the HCV infectivity is whether or not active HCV replication is present by PCR or antigen testing..
the term ‘HCV viraemic’
1- donors or recipients who have active HCV infection with detectable HCV RNA, regardless of HCV antibody status
2- donors that are HCV IgG +ve where the HCV RNA status is not known
□Changes in the treatment of hepatitis C over the past five years
□Most of the current regimens used in clinical practice are given for between 8 and 16 weeks, and offer cure rates of 95-100% for patients without cirrhosis, regardless of HCV genotype.
□Most regimens do not rely on the use of ribavirin.
□There is already substantial UK experience of using two licensed pan-genotypic
□regimens in the form of
Sofosbuvir / Velpatasvir
and
Glecaprevir/Pibrentasvir.
□The pan-genotypic triplet of Sofosbuvir, Velpatasvir and Voxilaprevir was licenced in August 2017
□HCV D+ to R- transplantation should be cost effective
——————————————————
What are the risks of HCV D+ to R- transplantation?
○The first and perhaps most feared risk is of fibrosing cholestatic hepatitis (FCH)
●the SOLAR-1 and 2 studies the combination of Sofosbuvir and Ledipasvir for 12 or 24 weeks cured all 11 patients treated after liver transplantation with FCH
●Leroy et al reported similarly impressive cure rates of 100% in 15 patients with FCH
○ This and other studies would suggest that early treatment (ideally within 4 weeks) with DAA therapy should prevent the development of FCH.
○the high morbidity and mortality rates for patients on the waiting list justify the utilisation of D+ organs.
○Infecting individuals with (CMV) or (EBV) is mitigated by giving prophylactic treatment in the case of CMV.
○HCV D+/R- transplantation followed by early DAA therapy would result in only a transient, usually rapidly curable infection.
○ Another theoretical concern is that a minority ( <5%) of patients treated after organ transplantation may experience DAA treatment failure
○POLARIS-1 trial has shown that 12 weeks of re-treatment with the triple therapy combination of Sofosbuvir, Velpatasvir and Voxilaprevir is highly effective (>95%) in achieving cure of HCV in patients with HCV NS5A RAS
○Extra-hepatic manifestations of HCV such as cryoglobulinaemic vasculitis or PTLD are also theoretical there are no data, and early DAA therapy should mitigate against these in any case
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Patient and Unit Requirements
■Pre-Transplant
screening patients using AST-to-Platelet Ratio Index (APRI) and ultrasound is suggested.
■the APRI score is >0.8 or the ultrasound suggests significant or advanced liver disease, then an opinion from a liver specialist before the patient is considered for a HCV D+ organ.
■ If the APRI score is <0.8, there is no need for the patient to be seen by a liver specialist.
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Management
D+ /R – ==> Recipient tested for HCV by PCR day 3-7 post transplant ==> HCV PCR – ==> Recipient tested for HCV by PCR day 10-14 post transplant ==>
HCV PCR – ==> Recipient tested for HCV by PCR 6w post transplant ==> reassure patient as standard recipient
If HCV PCR + at any stage==> start DAA within 3- 7 day after test
Two alternative regime should used as first line agents.
●These are either the combination of
Glecaprevir/Pibrenatasvir or
Sofosbuvir/Velpatasvir.
for 12 weeks in the context of HCV positivity, they can be started as soon as HCV PCR without having to wait for a HCV genotype areas.
■Glecaprevir/Pibrenatasvir is increased by ciclosporin, and it may also increase the levels of tacrolimus)
■ Sofosbuvir/Velpatasvir is not recommended in patient with a eGFR <30 mL/min/1.73 m 2
■Sofosbuvir/Velpatasvir/Voxaleprevir combination for high rates of SVR even in those previously exposed to DAA therapy.
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Special Additional Considerations
Acceptable Within Proposed Policy
●HCV Ab positive with no history of treatment of HCV
●HCV Ab positive with documented SVR after treatment
●Any HCV Ab negative donor who has exposed themselves to risk but who does not fulfill any of the unacceptable criteria
●Any HCV Ab positive donor whose HCV treatment history is unknown – proceed with caution
Not Recommended Within Proposed Policy
●Previously failed DAA therapy with on-going viraemia
●DAA therapy within last year without documented SVR (unless the recipient is at imminent risk of death)
●Multiple documented re-infection with HCV
Acknowledged.
IV. UK Position Statement on the use of Organs from Hepatitis C Viraemic Donors and Increased Infectious Risk Donors in Hepatitis C Negative Recipient
Please summarise this article.
The key components of the guidelines are:
Changes in the treatment of HCV over years
Current discard rates for HCV+ve donor organs in the UK
Experience from outside the UK
Why HCV D+ to R- TX should be cost effective?
The risks of HCV D+ to R- TX
Acknowledged.
introduction
HCV virus is a single-stranded RNA virus with known 6 genotypes, the mode of transmission is through contaminated blood and blood products, IVDA sharing needles, and sexual transmission is rare only in anal sex, with multiple partners, vertical from the mother to the fetus, acute HCV infection usually subclinical, and chronic HCV is the predominate course with persistent positive HCV RNA more than 6 months.
The previous policy of discarded organs including organs from HCV-infected donors and limiting their use only for infected recipients can increase the number of discarded organs An important strategy is a continuous review to assess whether advances in medicine could enable such organs to be transplanted. It is now apparent that
greater use can be made of organs from hepatitis C (HCV) infected donors with the improvement in the screening methods and the use of the new medications with direct antiviral effect (DAA) and a high cure rate of up to 95% with the sustained viral response regardless of the genotype and well-tolerated medications that licensed and approved for the treatment of HCV infection and with such evidence nowadays we can transplant organs from HCV infected donors to HCV negative or positive recipients with a proper serological and virological assessment with the recent use of DAA therapy the prevalence of individuals who are HCV
antibody positive but who have undetectable HCV RNA will increase, Acute HCV infection is usually subclinical, and up to 60% will have chronic infection with persistent positive anti-HCV ABS, but viremia defined by the positive NAT, or HCV PCR positive.
‘HCV viraemic’term
Refer to the status of both recipient or donor with active HCV infection which is confirmed by detectable HCV RNA by PCR test regardless of the HCV antibodies status or to donors that are HCV IgG +ve where the HCV RNA status is not known at the time of organ offer/transplantation( window period ).
In the era of the new medications for HCV infection
The treatment of HCV infection has been evolving over the last six years after the introduction of the DAA therapy in 2012and the current regimens used in clinical practice are given
for between 8 and 16 weeks, with suggested cure rates of 95-100% for patients without cirrhosis, regardless
of HCV genotype. Most regimens do not count on the use of ribavirin. There is already substantial UK
experience of using two licensed pan-genotypic regimens in the form of Sofosbuvir / Velpatasvir and
Glecaprevir/Pibrentasvir
Why HCV D+ to R- transplantation should cost-effective
the cost of the DAA therapy to cure R- HCV infection from donor +ve is less than the one-year cost of dialysis, in addition to that have better survival and better quality of life.
compared to waiting on dialysis.
What are the risks of HCV D+ to R- transplantation?
One of the serious complications after D+/R- transplantation is the risk of an aggressive form of fibrosing cholangitis hepatitis due to HCV recurrence which was reported in 10% of D+/R+ liver transplants. Prior to the advent of DAA Therapy, FCH was associated with high mortality. It is also reported in kidney transplantation, with an incidence of 1.5% in the largest series from Spain (36). the combination
of Sofosbuvir and Ledipasvir for 12 or 24 weeks cured all patients treated after liver transplantation with FCH In the SOLAR-1 and 2 studies (23,27) similar case series and case reports also confirmed the effectiveness of the DAA therapy especially if started within the first 4 weeks of infection and resulted in 100% cure rate of FCH with a sustained viral response.
However, reported in < 5% failure to respond to the first line DAA therapy but by extension of treatment duration up to 16 weeks or use of the alternative triple DAA protocol improves the cure rate to 95%
Sexual transmission of HCV to a partner could potentially occur in the HCV D+/R- transplant scenario.
The risk can be mitigated by simple lifestyle advice and its rare < 2%
The Practicalities of Implementing this Policy in the United Kingdom
HCV D+/R- non-liver transplantation should be avoided in recipients with advanced fibrosis or cirrhosis. Rather than mandate that every
The patient consented to receive an HCV D+ non-liver organ to be seen by a liver specialist.
AST to PLATLET RISK score < 0.8 no need to be seen by a liver specialist but if the score >0.8 with US finding of liver cirrhosis then clearance from a liver specialist needed
Management of the Recipient of an HCV D+ Organ
Special consideration
Not recommended to accept donors
1. with Previously failed DAA therapy with on-going
Viremia in the last 6 months without achieving SVR (HCV resistance)
2. DAA therapy within the last year without documented SVR (unless the recipient is at
imminent risk of death)
2. Multiple known re-infection risks with HCV
Still, we can accept the donation provide the following
1. HCV Ab positive with no history of treatment
2. HCV Ab positive with documented SVR after treatment
3. Any HCV Ab negative donor who has exposed themselves to risk but who does not fulfill any of the unacceptable criteria
4. use with caution in case of an HCV Ab-positive donor whose HCV treatment history is unknown.
Figure 2. summarize the Proposal for Testing of Donors and Management of All Recipients in the UK HCV D+/R- scheme
All donors with HCV AB positive will be tested for HCV PCR, if negative or positive in addition to the genotype, the results will be informed to the transplant team within two working days, organ transplanted to the HCV-negative recipients after being informed consent signed then the recipient HCVPCR will be frequently tested in first 3-7 days, if negative HCV PCR, then next test in day10-12 if negative, then in week 6 if HCV cpr negative after 6 weeks then reassure the recipient of no transfer f the infection while any HCV PCR turned positive earlier in the first 6 weeks he should receive DAA therapy preferred within 3-10 days from first positive HCV PCR with FU for SVR and cure.
When starting such a proposal need an MDT approach including a transplant physician with good experience, in treating and following such cases with an MDT approach with a hepatologist and pharmacy that is able to provide the treatment and sustained the supply of DAA therapy including the alternative protocol if no response to first-line therapy also virologist to timely screen and Fu for SVR.
Acknowledged.
This is a UK document to establish criteria for donors with active Hepatitis C virus for negative recipients.
Introduction
Solid organ transplantation is considered routine best practice for replacing failing organs.
The waiting list can take years and several organs are discarded due to positivity for Hepatitis C. In recent years, with the emergence of direct-acting antivirals and adequate viral suppression, the possibility of including this donor profile and reducing the waiting list has arisen.
Immune status
Exposure (Immune window), viremia (RT PCR positive), and serological conversion (Antibody positive).
Change in treatment
Interferon-based regimens with the very low viral response and disease persistence. Drugs with a sustained viral response by acting directly against the virus brought sustained viral response with almost 100% response in oral treatments for twelve weeks.
Currently, there are pan-genotypic drugs with Sofosbuvir without the need to genotype the virus.
Current practice with D+
Discarding is common, with specific acceptance for individualized cases of liver transplantation. With the new therapies, many donors have a negative viral load again. The new drugs improved viral load, liver function, fibrosis, hepatic steatosis and waiting time for transplantation.
With the current structure, it is possible to transplant from positive donors to negative recipients safely and effectively, and this is the purpose of this document.
Experience outside the UK
There has been a reduction in discarding viable organs with HCV+ donors in the US, mainly due to the tragedy of opium and the availability of young patients. But to make it possible the availability of direct-acting antiviral therapy was necessary.
Broad regimens with Grazoprevir/Elbasvir and the addition of sofosbuvir depending on the genotype.
Another study used pan-genotypic treatment with Sofosbuvir/Ledispavir with good post-transplant viral suppression.
Cost-effectiveness
Specific antiviral therapies against the Hepatitis C virus are expensive, but carrying out the treatment together with the transplant would pay for the investment of one year of dialysis. In this way, not only dialysis would be reduced, but also hospitalizations would be reduced, quality of life would be improved, and survival would increase.
Risks
The greatest fear is fibrosing cholestatic hepatitis, an aggressive form of recurrent HCV with high mortality.
The use of antiviral therapy minimizes these risks. In situations of antiviral resistance, triple regimens with Sofosbuvir, Velpatasvir, and Voxilaprevir are highly effective.
Cryoglobulinemia and PTLD vasculitis may occur.
Pre-transplant
Clinical and laboratory markers such as APRI can help when a specialized team is needed, as well as USG with elastase.
Positive and negative HCV donors must follow the same rules in the waiting list, not being a limiting factor anymore.
Pangenotypic treatments such as Sofosbuvir/Velpatasvir and Glecaprevir/Pibrenatasvir for twelve weeks. Monitor calcineurin inhibitors become necessary.
Additional considerations
Acceptable
– HCV Ab positive with no history of previous treatment
– HCV Ab positive with the sustained viral response after treatment
– HCV Ab positive with previous treatment history but no description (caution)
Not recommended
– Failure to treat with direct-acting antiviral drugs with present viremia
– No documentation of sustained viral response
– HCV reinfections
New processes must be carried out with the new therapies and experiences in progress.
Acknowledged.
Introduction:
Why HCV D+ to R- transplantation should be cost effective:
What are the risks of HCV D+ to R- transplantation:
The acceptability of HCV D+ donors is as follows:
Acceptable Within Proposed Policy
Not Recommended Within Proposed Policy
Acknowledged.
Introduction:
In spite of the rise in the number of organs that are donated in the UK, up to one in six people who are on the waiting list for a solid organ transplant will pass away or become too ill to receive one. As a result, there is an ongoing need to investigate ways to improve the use of organs that are not presently utilized on a widespread basis for transplantation.
The vast majority of organs obtained from donors who were infected with hepatitis C had, up until this point, been thrown away because of the significant risk of the virus being passed on to the recipient. The older treatment methods had a low tolerance and were not effective enough in eradicating the virus in transplant patients.
Changes in the treatment of hepatitis C:
Due to recent developments in the treatment of hepatitis C infection, it is now possible to cure more than 95% of people who are afflicted with the C with antiviral medications that work directly on the virus. Studies have demonstrated that similar outcomes of hepatitis C clearance can be safely achieved in transplant recipients. Additionally, small trials have demonstrated excellent outcomes in hepatitis C-negative recipients who were given hepatitis C-infected organs and who were subsequently treated and cured of the virus.
A recent review of the UK prospective donor audit revealed that up to 15 potential donors are denied per year due to the risk of transmission of hepatitis C. The reason for this was cited as the possibility of the transfer of the virus. If organs from these donors were used in transplants, it is possible that an additional 75 solid organ transplants would be conducted each year in the UK.
Following the recent recommendations made by the Advisory Committee on the Safety of Blood, Tissues, and Organs that organs from hepatitis C-infected donors may be transplanted into uninfected recipients in certain clinical situations, a group of clinicians, virologists, scientists, healthcare managers, and patient representatives have proposed a framework for the appropriate use of organs from HCV infected donors that is applicable across the United Kingdom.
The selection of appropriate donors, a policy for ensuring that the intended recipient gives fully informed consent, guidance for the testing and treatment of recipients as indicated, the formation of a monitoring group to oversee the program in the six early phases of implementation, as well as consideration of some of the headline operational issues that will arise during the successful implementation of the pathway, are all key elements of the guidelines.
Indication of which donors should be utilized for transplantation within the framework of the suggested policy, as well as which donors should not be used;
Tolerable Within the Bounds of the New Policy;
HCV antibody positivity without a previous record of HCV therapy.
-HCV antibody positivity with a demonstrated suppression of viral replication after therapy
-Any HCV Ab negative donor who has put themselves in a risky situation but who does not meet any of the criteria that are considered unsuitable.
-Proceed with extreme care in the case of any HCV Ab-positive donor whose previous HCV treatment history is unclear.
Not Suggested Within the Bounds of the Draft Policy
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Introduction;
-Kidney transplantation, is the best therapeutic option for patients with CKD G5 ,irrespective of presence of HCV infection, however, a significant number of patients still die due to a shortage of donor organs.
-In the twelve month period of 2016/17 alone, 457 patients died on UK transplant waiting lists.
-This confirms the ongoing need to strive to increase the number of organs available for transplantation.
-However, the most important parameter to be considered when assessing the HCV infectivity of an organ donor or recipient is whether or not active HCV replication is present; i.e. whether they are viraemic, with detectable HCV RNA by sensitive genome amplification methods such as polymerase chain reaction nucleic acid testing or, potentially, antigen testing.
-The presence of occult HCV, i.e residual HCV viral genomes, in donor tissue is also a potential means of HCV transmission.
Benefits from treatment of HCV infection;
-To reduce the morbidity and mortality of those individuals on solid organ transplant waiting lists.
-Treatments for hepatitis C have changed greatly over recent years. It is now possible to cure over 95% of patients who are infected with the hepatitis C virus.
-Most of the current regimens used in clinical practice are given for between 8 and 16 weeks, and offer cure rates of 95-100% for patients without cirrhosis, regardless of HCV genotype.
-The advantage of Glecaprevir / Pibrentasvir is that it can be given to patients with established renal failure.
-These regimens also have high efficacy for the treatment of patients who have previously failed other DAA-containing regimens, with the best data currently available for Sofosbuvir, Velpatasvir and Voxilaprevir.
Why HCV D+ to R- transplantation should be cost effective;
–Whilst there are clear morbidity and mortality benefits to increasing organ availability for patients on solid organ transplant waiting lists, there are also economic arguments.
-The course of therapy to cure a R- patient receiving a D+ organ would be less than the cost of dialysis for one year.
-Implementation of the proposal contained within this position statement is likely to lead to substantial cost savings by reducing waiting times and dialysis expenditure.
-More importantly this should save lives and improve quality of life for patients.
What are the risks of HCV D+ to R- transplantation?
–The most feared risk is of fibrosing cholestatic hepatitis (FCH), which prior to the advent of DAA therapy was associated with a high mortality
-This is an aggressive form of HCV recurrence seen in 10% of D+/R+ liver transplants.
-It is also reported in kidney transplantation, with an incidence of 1.5% in the largest series from Spain, however, there are now increasing reports of DAA therapy being very effective in the setting of FCH.
-In the early days of a HCV D+/R- programme, treatment duration could be extended slightly (from 8 weeks to 12 weeks or from 12 weeks to 16 weeks) to mitigate this risk until more real world data emerges.
-Extra-hepatic manifestations of HCV such as cryoglobulinaemic vasculitis or potential increased rates of blood derived malignancy such as PTLD are also theoretical consequences of HCV infection in the post-transplantation phase.
-However, there are no data in the HCV D+/R+ field to demonstrate an increased risk of these consequences, and early DAA therapy should mitigate against these in any case.
Patient and Unit Requirements Pre-Transplant;
–HCV D+/R- non-liver transplantation should be avoided in recipients with advanced fibrosis or cirrhosis.
–Rather than mandate that every patient being consented to receive a HCV D+ non-liver organ be seen by a liver specialist, a more pragmatic approach of screening patients using AST-to-Platelet Ratio Index (APRI) and ultrasound is suggested.
–The exact drug regimens and length of therapy that should be offered to recipients that test positive for HCV after receiving an organ from a HCV D+ donor; two alternative regimens should be used as first line agents.
-These are either the combination of Glecaprevir/Pibrenatasvir or the combination of Sofosbuvir/Velpatasvir. (keep in mind drugs interaction with CNI)
-Both should be given for 12 weeks in the context of HCV D+/R- transplants.
-Both are pan-genotypic, which means that they can be started as soon as HCV PCR positivity is known, without having to wait for a HCV genotype, which can take 3-4 weeks in some areas.
-In the rare (expected to be less than 2%) instances where the first course of treatment of HCV is not curative, recipients should be treated with a 12 week course of the combination of Sofosbuvir/Velpatasvir/Voxaleprevir, has high rates of SVR even in those previously exposed to DAA therapy.
UK Practice in treatment HCV D+ to R- transplantation;
-Grazoprevir/Elbasvir was started immediately before transplantation, and continued for 12 weeks.
-If the donor had genotype 2 or genotype 3 HCV, Sofosbuvir was added.
-If HCV resistance associated substitutions (RAS) were identified in donors with G1a HCV, ribavirin was added and treatment was extended to 16 weeks.
Indication which donors should and should not be used for transplantation within the proposed policy;
Acceptable Within Proposed Policy;
-HCV Ab positive with no history of treatment of HCV.
-HCV Ab positive with documented SVR after treatment.
-Any HCV Ab negative donor who has exposed themselves to risk but who does not fulfill any of the unacceptable criteria.
-Any HCV Ab positive donor whose HCV treatment history is unknown – proceed with caution.
Not Recommended Within Proposed Policy
-Previously failed DAA therapy with on-going viraemia.
-DAA therapy within last year without documented SVR (unless the recipient is at imminent risk of death).
-Multiple documented re-infection with HCV.
Informations discussed with patient who received a hepatitis C infected ?
-After transplant he will have a specific and very sensitive blood test to look for the presence of hepatitis C virus in his blood.
-The first blood sample will be taken within the first 7 days of his transplant, then again within the first 14 days and the last sample will be taken within the first 6 weeks of his transplant.
-If the virus tests remain negative by that time then his transplant organ has not passed on the infection to him.
-If any of these tests are positive for hepatitis C virus then the doctors looking after he will start him on highly effective treatment within 3-10 days of the result.
-This means that he will be prescribed some specific antiviral tablets that he will need to take for a total of 3 months.
-Once the treatment is finished he will have further blood tests to check that he has been cured of the virus.
-If the virus disappears from his blood and cannot be detected 12 weeks after the treatment has stopped then he has been cured , predicting that more than 95% of patients will be cured.
-If the first course of treatment does not work then a second 12 weeks course of treatment using a different combination of tablets will be used which cures more than 95% of patients whose first course of treatment has not worked.
Conclusion;
-HCV infection in the potential donor does not amount to an absolute contraindication to donation of material for life-preserving transplantation, however the net benefit of transplantation must be considered against the risk of not receiving that specific transplant.
-This risk/benefit analysis allows for the potential use of a transplant from a HCV infected donor to a non-infected recipient.
-All HCV-infected patients who are candidates for kidney transplantation are to be considered for DAA therapy, either before or after transplantation.
-It is worth mentioning that these new drugs for hepatitis C have very few side effects in recent world experience and are generally very well tolerated by patients taking them.
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