Introduction:
Accumulating evidence has established SOT as standard of care for PWH with end-stage kidney and liver disease, and more limited but encouraging data has demonstrated feasibility of pancreas, heart, and lung transplantation in PWH. Status of organ transplantation by organ type: With availability of effective ART, PWH are increasingly seeking organ transplantation. Kidney:
800 PWH are diagnosed ESRD) annually, it is estimated that 0.5–1.5% of the United States dialysis population.
Outcomes for PWH are favorable, with transplantation providing a clear survival benefit over renal replacement therapy. Important complications:
Bacterial infections: frequency in Hiv KT recipients who were treated with t ATG) or coinfected with HCV. High rates of delayed allograft function.
Finally, HIV KT patient allograft rejection rates two to three times higher than observed in the general kidney transplant population. Liver:
In the era of highly effective ART, liver disease has become the third leading cause of death in PWH.
The outcomes of liver transplantation in PWH vary by the reason for transplant. Pancreas:
Pancreas transplantation can be successful in HIV-infected patients, but additional experience is need. Heart:
HIV-associated cardiomyopathy was seen in the pre-ART era; coronary artery disease is now a rising concern in PWH.
HIV is no longer considered an absolute contra-indication to advanced heart failure therapies, including heart transplantation. Lung:
There is a paucity of lung transplantation reports in PWH. Clinical management of HIV-infected organ transplant candidates and recipient: Selection of candidates:
Candidacy requirements for transplantation:
Updated guidelines recommend that,
Undetectable HIV viral load.
Known compliance with ART.
No evidence of active opportunistic infections or HIV-associated malignancy,
Ability to have close follow-up for immunosuppression, drug level monitoring and management. CD4þ cell counts at least 200 cells/ml are recommended for transplantation of all organs,
With the exception of liver, where the threshold for transplantation is CD4þ cell count more than 100 cells/ml.
Absence of chronic wasting or severe malnutrition
• Hepatitis B or C infection if no advanced fibrosis/cirrhosis (for organ types other than liver). Antirejection therapy:
The best immunosuppression is not known. Induction:
Choice of induction agent should be individualized in renal transplant.
Induction immunosuppression is not required in the majority of liver transplant recipients.
Data regarding use of induction agents in transplant of other organ types in HIV+ persons is lacking. Maintenance immunosuppressive regimens:
Tacrolimus is associated with lower rejection rates, and for this reason, has emerged as the preferred calcineurin inhibitor.
Mycophenolate is a very common component of maintenance immunosuppression.
Although long-term maintenance prednisone therapy reduces risk for rejection, the benefits of its used should be weighed against the long-term effects of this agent. Medication management:
Protease inhibitors:
Alter the pharmacokinetics of immunosuppressive medications, including CNI (tacrolimus, cyclosporine A) and mTOR inhibitors (sirolimus, everolimus), resulting in drastic alterations in doses and dosing schedules of these drugs. Non-nucleoside reverse transcriptase inhibitors have differing potential for induction of CYP3A4.
Non-boosted integrase strand transfer inhibitors (INSTI):
Have emerged as favored therapies. Raltegravir, dolutegravir, and bictegravir are completely or primarily metabolized through the uridine diphosphate glucuronosyltransferase 1A system, resulting in clinically insignificant interactions with the calcineurin inhibitors. Clinical monitoring and care of HIVR persons before and after organ transplantation:
HIV specialists partner with the transplant team to optimize HIV therapy, with the goal of minimizing pre-transplant toxicities and post-transplant drug interactions while maintaining viral suppression.
Patients should be placed on non-protease inhibitor-based ART regimens.
Frequent dose adjustments, especially early in the post transplant period.
More frequent monitoring of CD4þ cell counts and HIV viral load. HIV-to-HIV transplantation:
As the U.S. trials are ongoing, only preliminary data are available but suggest excellent patient and allograft survivals for both kidney and liver recipient. Conclusion:
Kidney and liver transplantation are the standard of care for HIV-infected persons with end-stage kidney and liver diseases.
Encouraging results with transplantation of other organ types, including pancreas, heart, and lung suggest that persons with other advanced organ disease should also be referred to centers experienced in performing these transplants.
The availability of INSTI, with minimal impact on immunosuppressive drug levels, has greatly simplified the post-transplant management of the HIV+ organ recipient. T
Introduction; Always the transplantation would be the better choic for quality of life compared to dialysis. After the invention of HAARTs therapy it was demonstrated that the prognosis and long term survival of infected patients has improved. The result is the other opportunistic infection and long term complications like HIVAN risk has increased. There multiple risk for progression to HIV associated renal failure. Like. Glomerulopathies like FSGS, Has increased risk of diabetes and hypertension. Co-infection with other viral infection like HCV, and HBV. Drug induced AIN and other GN. CKD and HIV; The prognosis is worse with HIV comparatively with patient with HIV on dialysis. Criteria for accepting the recipient for transplantation; Undetected viral load, CD$+T cells >200, On regular ART medications, No active infections with opportunistic infection. No occult or active maligacy. What is the HOPE act; Patients infected with HIV are permitted to donat to HIV infected recipient.
The outcomes of organ recipients who have received coinfected organs are expected to be improved by their high post-transplant effectiveness. The HOPE Act has now made it possible for PWH to donate organs to HIV-positive people awaiting kidney and liver transplants in a research environment. HIV specialists should actively refer suitable patients for transplantation, inform patients on the results of transplantation and the advantages and disadvantages of using HIV-positive organs, and ensure regular HIV infection surveillance following transplant.
Kidney transplantation is the modality of choice for end stage chronic kidney disease.
After the introduction of anti-retroviral therapy ART, prognosis and long-term survival of HIV infected people improved significantly. This improvement in survival increased the incidence of other non-HIV related diseases, including chronic kidney disease. Risk factors for chronic kidney disease in HIV patients:
1] With the introduction of ART, HIV related diseases featured drop in incidence, such as HIV associated nephropathy HIVAN.
2] Other diseases associated chronic organ damage and failure in escalating, such as diabetes and hypertension related nephropathy.
3] Other glomerular diseases such as FSGS.
4] Co-infection with HBV and HCV portends an increasing risk of chronic kidney disease.
5] Chronic ART use such as tenofovir, abacavir, indinavir, ritonavir-boosted lopinavir is associated with chronic kidney disease.
6] protease inhibitors are generally linked to higher incidence of chronic kidney disease. Peculiar features of chronic kidney disease in HIV patients:
1] The prognosis of HIV patients on hemodialysis HD is grim with higher mortality rate than counterparts’ non-HIV infected patients on HD.
2] Related complications are increasingly reported. On transplantation:
1] Prognosis is much better than HD.
2] Incidence of rejection episodes is elevated. Mainly related to inadequate immune suppression or drug-drug interaction.
3] HIV related immune dysregulation.
4] Higher incidence of bacterial infection.
5] delayer graft function is increasingly reported. Criteria for accepting the patient for transplantation:
1] CD4 lymphocyte count of more than 200 c/ml, except for chronic liver disease patients where CD4 of 100 c/ml is acceptable.
2] undetected viral load.
3]On ART regularly.
4] No complications related to HIV infection such as severe waisting and malnutrition.
5] No opportunistic infection.
6] No malignancy reported. Hope act:
HIV patients are permitted to donate to HIV patients with end organ failure. Therefore, donation pool has increased significantly.
Introduction · HIV infection is now a chronic disease due the availability of antiretroviral therapy which caused a significant reduction in mortality associated with HIV/AIDs · The new problems in person living with HIV (PWH) are cardiovascular diseases, liver diseases, and side effects related to antiretroviral therapies. Therefore, PWH are now at-risk organ damage and failure. How ever, before the age of antiretroviral therapy, transplantation was absolute contraindication for HIV but now the understand has improve significantly. · HIV Organ Policy Equity (HOPE) Act stated that, Person living with HIV (PWH) can now be either donor or recipient for the seek of treatment a failed organ. Status of organ transplantation by organ type Kidney · HIV related kidney diseases account for m 0.5 to 1.5% of dialysis treatment in USA · Causes of ESKD: HIV-associated Nephropathy (HIVAN) was historical, FSGS, DM, co-infections with HBV or HCV & Drug induced · Transplantation outcomes: Stock et al. observational study of 150 patients and revealed 1- and 3-years allograft & patient survivals were 90% and 74% and 95% and 88% respectively. They had more bacterial infections, delayed graft function, and rejection rates. · Transplantation is associated with better outcomes compared dialysis · Challenges: PWH faces barriers for referral, enlisting for transplantation, and some transplant centers in USA are still considering HIV is contraindicated for transplantation Liver · Liver disease is the third leading cause of death in PWH · Causes: co-infection with HBV/HCV, antiretroviral therapy, immune reconstitution syndrome, alcohol, and non-HIV factors. · Outcomes: Allograft and patient survival were 85% to 100% after 3 to 5 years of PWH transplanted due to HIV/HBV co-infection. HIV/HCV versus HCV control 1,3-, and 5-years allograft survivals were 52 to 86%, 45 to 60%, 31 to 45% versus 57 to 88%, 50 to 62%, 33 to 58% respectively. · Challenges: the same as renal transplantation Pancreas · This may be successful in future but at the moment the experience is very limited Heart · Although heart transplantation in PEH is not contraindicated the procedure is not commonly carried on · Outcomes: recent data showed, 1- and 5-years survival are between 86 to 90% and 64 to 67%, coronary artery vasculopathy was the important complications occurring in up to 30% as well as higher rejection rates from 39 to 67% after one year compared to non-HIV individual. Up to 50% required mechanical circulatory support before transplantation Lung · Data from case reports and case series demonstrated the feasibility of this procedure in PWH suffering from advanced pulmonary disease. Clinical management of HIV-infected Organ transplant candidates and recipient · Recommendation for selection of the candidates: 1. Virally suppressed 2. Compliant patient 3. Absence of opportunistic infections 4. Absence of HIV-associated Malignancy 5. CD4 >= 200 cell/microliter 6. Ability to come for follow up · HIV to HIV living donor transplantation: few cases on the literature 1. Donor must be evaluated well and HIV specific risk factors for ESKD ruled out 2. APLO1 haplotype screening? is not clear but those with African American with HIV and high risk APLO1 genotype are at risk for HIVAN and FSGS 3. HIV +ve donor must avoid drugs like TDF and NSAIDS after nephrectomy · HIV positive donor to HIV negative recipient 1. At the moment, this is illegal practice in USA 2. One case report from South Africa: HIV positive mother ton her terminally ill daughter with biliary atresia. The daughter became positive but her HIV antibodies reduced significantly to undetectable level during the first year after transplantation Conclusion · The rate of organ failure is now increasing in PWH and transplantation is best form therapy in this kind of situation. Transplantation had been done successfully in kidney and liver failure but more data are needed for other organs including heart, pancreas, and lung. We also want to understand the reasons for barriers to transplantation for PWH through a well design study.
Organ Transplant in HIV Patients Introduction · Improved survival of patients with HIV (PWH) with use of HAART, similar to general population. · HIVAN has reducing incidence, but CKD is common due to DM , nephrotoxic drugs in PWH. · Once on dialysis, PWH have lower survival rates when compared with uninfected dialysis patients Status of SOT in PWH – Transplant is common in person with HIV (PWH) · Stock et al. reported, outcomes of 150 kidney transplant in HIV-infected patients – 1 and 3-year kidney allograft and patient survival estimates were 90.4 and 73.7 and 94.6 and 88.2%, respectively. · REAL WORLD SCENARIO suggests – SOT is feasible in PWH and is not a contraindication It should be done in centre experienced in doing such work – Bacterial infection is common if ATG is used and coinfected with HCV DGF and rejection is common – HIV is an absolute or relative contraindication for liver transplantation, but the outcomes of liver transplantation vary by the reason for transplant. – Pancreas transplantation can be successful in HIV-infected patients, but additional experience is needed. – Lung transplant is not reported IS in PWH drug interactions are very common and drug levels need strict monitoring HIV-to-HIV Transplantation after HOPE act this is more into consideration and will avoid wastage of organ
Clinical management of HIV-infected organ transplant candidates and recipients:
Selection of candidates · HIV providers should refer any patient with end-organ damage and stable HIV to centres well versed in HIV+ organ transplantation. · candidacy requirements for transplantation: 1) Meet transplant centre-specific eligibility for organ transplantation 2) CD4+ cell count > 200 cells/µl during 3 months prior to transplantation for kidney, pancreas, heart and lung candidates 3) CD4+ cell count > 100 cells/µl during 3 months prior to transplantation for liver candidates only 4) Undetectable plasma HIV viremia (unless unable to tolerate ART prior to liver transplant) 5) Documented adherence with stable ART regimen 6) Absence of active opportunistic infection and malignancy 7) Absence of chronic wasting or severe malnutrition 8) Hepatitis B or C infection if no advanced fibrosis/cirrhosis (for organ types other than liver) 9) Access to immunosuppressive agent therapeutic drug monitoring 10) Ability to regularly follow up with HIV care providers
Antirejection therapy · There is no specific immunosuppressive regimen to use for patients with HIV. · Induction immunosuppression is not required in the majority of liver transplant recipients, and data about induction agents in transplant of other organ types in HIV+ persons is lacking. · For HIV-infected transplant recipients, Tacrolimus is associated with lower rejection rates, and is the preferred CNI. MMF can be used. · Prednisone reduces risk for rejection, but the benefits of its used should be weighed against the long-term effects of this agent. · Sirolimus is known to have anti-HIV effects Medication management · Protease inhibitors inhibit (CYP3A4) enzyme, which alter the pharmacokinetics of CNI and mTORi, resulting in severe alterations in doses with possible rejection or toxicity. · In liver transplant recipients, boosted protease inhibitors regimens were associated with episodes of acute renal failure from high cyclosporine levels. · renal transplant recipients also have poor outcomes for patients on protease inhibitor-based regimens. · In the transplant setting, non-boosted integrase strand transfer inhibitors (INSTI) have emerged as favored therapies. · Raltegravir, dolutegravir, and raltegravir have insignificant interactions with the CNI. Clinical monitoring and care of HIV+ persons before and after organ transplantation · In the pre-transplant phase, HIV therapy needs optimization to minimize pre-transplant toxicities and post-transplant drug interactions while maintaining viral suppression. · Patients should be placed on non-protease inhibitor-based ART regimens if possible. · Avoid use of tenofovir disoproxil fumarate after kidney transplant and abacavir after heart transplantation. · In the early post-transplant period, in the setting of allograft rejection, more frequent monitoring of CD4+ cell counts and HIV viral load is necessary. · many centers may use life-long prophylaxis against Pneumocystis jirovecii HIV-to-HIV transplantation · Was successful in South Africa which inspired the United States transplant community to expand HIV+ to HIV+ transplant to North America. · HOPE Act has put safeguards in place to conduct and monitor outcomes in HIV-to-HIV transplantation by conducting these procedures in a research setting using well defined donor eligibility requirements. · preliminary data suggest excellent patient and allograft survivals for both kidney and liver recipients · An unexpected benefit of HOPE Act is the use of organs that may have otherwise been discarded due to having false-positive HIV test results. · When evaluating potential candidates for donor nephrectomy, the assessment must include the identification HIV-specific risk factors for the development of ESRD such as: low CD4+ cell count and HCV coinfection and other conditions that discard persons from donation ( DM, HTN, and preexisting kidney disease) · HIV+ African American persons with high-risk APOL1 genotypes are at risk for the development of HIVAN and FSGS. · Post-nephrectomy, HIV+ donors should avoid nephrotoxic ART (tenofovir) and NSAIDs. Conclusions:
· Kidney and liver transplantation are the standard of care for HIV-infected persons with end-stage kidney and liver diseases.
· The availability of INSTI, with minimal impact on immunosuppressive drug levels, has greatly simplified the post-transplant management of the HIV+ organ recipient.
· The introduction of DAAs for hepatitis C, with their high efficacy in the post-transplant setting, promise to improve outcomes in coinfected organ recipients.
· With Implementation of HOPE Act, PWH can donate organs to HIV infected persons waiting for kidney and liver transplants under a research setting. · HIV providers should play an active role in referring appropriate patients for transplantation, educating patients regarding transplant outcomes and the potential risks and benefits of pursuing HIV-positive organs for transplant, and ensuring frequent monitoring of HIV infection after transplant.
· Antiretroviral therapy reduced AIDS-related mortality, with increased life expectancy and common medical comorbidities.
· coronary artery disease and nonalcoholic steatohepatitis, are important causes of morbidity and mortality in persons with HIV.
· persons with HIV can now register as organ donors, expanding the donor pool for HIV persons waiting for organs. Status of organ transplantation by organ type
· The most evidence in support of transplantation in HIV persons comes from kidney followed by liver transplantation.
· The number of pancreas, heart, and lung transplantation, is increasing. Kidney
· In spite of declining HIV-associated nephropathy, due to antiretroviral treatment, other causes of renal failure such as FSGS, diabetes mellitus, and hypertension remain prominent.
· Coinfections with hepatitis C virus and hepatitis B virus increase risk for kidney failure.
· Many antiretroviral agents are nephrotoxic and increase risk of DM and dyslipidemia.
· HIV patients on dialysis have lower survival than uninfected dialysis patients, that’s why they need transplantation.
· HIV+ recipients who were given (ATG) or who are coinfected with HCV, have increased incidence of bacterial infections.
· HIV patients have high rates of delayed allograft function.
· HIV+ recipients have allograft rejection rates two to three times higher than seen in the general kidney transplant population.
· Some transplant programs still consider HIV as an absolute or relative contraindication to transplantation, so they remain on dialysis for a long time and have longer waitlist times for organ offers and transplant. Liver
· HIV patients are at risk for end-stage liver disease through a variety of mechanisms:
1) HCV and HBV coinfections
2) HIV infection increases the risk for progressive and advanced liver disease
3) ART can cause advanced liver disease by direct hepatotoxicity, hypersensitivity reactions, mitochondrial toxicity, steatosis and/or steatohepatitis, or immune reconstitution phenomena.
4) Alcohol may increase the risk of end stage liver disease.
5) Hepatocellular carcinoma can further complicate the course of ALD
· The outcomes of liver transplantation in HIV patients vary by the reason for transplant.
· HCV-related progressive liver disease, severe infections, and sepsis contributed to poor outcomes. Pancreas
· In 2018, 836 simultaneous pancreas-kidney transplants were performed in the United States, but this rarely done in type 1 diabetic HIV person.
· complications are: graft thrombosis, rejection, and bacterial infections, including fatal sepsis. Heart
· HIV-associated cardiomyopathy was seen in the pre-ART era, but coronary artery disease is now a rising concern in HIV patients.
· HIV is not an absolute contra-indication to heart transplantation, but is uncommonly performed. Lung
· HIV-experienced centers can consider PWH as candidates in the setting of demonstrated antiretroviral adherence with viral suppression and no recent AIDS-defining illness
· There is a paucity of lung transplantation reports in PWH. Clinical management of HIV-infected organ transplant candidates and recipient Selection of candidates
· HIV providers should refer any patient with end-organ damage and stable HIV to centers well versed in HIV+ organ transplantation.
· candidacy requirements for transplantation:
1) Meet transplant center-specific eligibility for organ transplantation
2) CD4+ cell count > 200 cells/µl during 3 months prior to transplantation for kidney, pancreas, heart and lung candidates
3) CD4+ cell count > 100 cells/µl during 3 months prior to transplantation for liver candidates only
4) Undetectable plasma HIV viremia (unless unable to tolerate ART prior to liver transplant)
5) Documented adherence with stable ART regimen
6) Absence of active opportunistic infection and malignancy
7) Absence of chronic wasting or severe malnutrition
8) Hepatitis B or C infection if no advanced fibrosis/cirrhosis (for organ types other than liver)
9) Access to immunosuppressive agent therapeutic drug monitoring
10) Ability to regularly follow up with HIV care providers Antirejection therapy
· There is no specific immunosuppressive regimen to use for patients with HIV.
· Induction immunosuppression is not required in the majority of liver transplant recipients, and data about induction agents in transplant of other organ types in HIV+ persons is lacking.
· For HIV-infected transplant recipients, Tacrolimus is associated with lower rejection rates, and is the preferred CNI. MMF can be used.
· Prednisone reduces risk for rejection, but the benefits of its used should be weighed against the long-term effects of this agent.
· Sirolimus is known to have anti-HIV effects Medication management
· Protease inhibitors inhibit (CYP3A4) enzyme, which alter the pharmacokinetics of CNI and mTORi, resulting in severe alterations in doses with possible rejection or toxicity.
· In liver transplant recipients, boosted protease inhibitors regimens were associated with episodes of acute renal failure from high cyclosporine levels.
· renal transplant recipients also have poor outcomes for patients on protease inhibitor-based regimens.
· In the transplant setting, non-boosted integrase strand transfer inhibitors (INSTI) have emerged as favored therapies.
· Raltegravir, dolutegravir, and raltegravir have insignificant interactions with the CNI. Clinical monitoring and care of HIV+ persons before and after organ transplantation
· In the pre-transplant phase, HIV therapy needs optimization to minimize pre-transplant toxicities and post-transplant drug interactions while maintaining viral suppression.
· Patients should be placed on non-protease inhibitor-based ART regimens if possible.
· Avoid use of tenofovir disoproxil fumarate after kidney transplant and abacavir after heart transplantation.
· In the early post-transplant period, in the setting of allograft rejection, more frequent monitoring of CD4+ cell counts and HIV viral load is necessary.
· many centers may use life-long prophylaxis against Pneumocystis jirovecii HIV-to-HIV transplantation
· Was successful in South Africa which inspired the United States transplant community to expand HIV+ to HIV+ transplant to North America.
· HOPE Act has put safeguards in place to conduct and monitor outcomes in HIV-to-HIV transplantation by conducting these procedures in a research setting using well defined donor eligibility requirements.
· preliminary data suggest excellent patient and allograft survivals for both kidney and liver recipients
· An unexpected benefit of HOPE Act is the use of organs that may have otherwise been discarded due to having false-positive HIV test results.
· When evaluating potential candidates for donor nephrectomy, the assessment must include the identification HIV-specific risk factors for the development of ESRD such as: low CD4+ cell count and HCV coinfection and other conditions that discard persons from donation ( DM, HTN, and preexisting kidney disease)
· HIV+ African American persons with high-risk APOL1 genotypes are at risk for the development of HIVAN and FSGS.
· Post-nephrectomy, HIV+ donors should avoid nephrotoxic ART (tenofovir) and NSAIDs.
Introduction:
HIV infection has become a chronic illness in the current age of antiretroviral therapy; both overall and AIDS-related mortality has declined With increased life expectancy and an aging demographic.
The current review focuses on the current status of SOT for HIV-infected person highlighting the outcomes, standards of care and aspects of post-transplant management. With availability of effective ART, PWH are increasingly seeking organ transplantation Kidney:
HIV-associated nephropathy (HIVAN) rates is reduced because of early antiretroviral treatment but other causes of renal failure such as focal segmental glomerulosclerosis, diabetes mellitus, and hypertension remain prominent.
Coinfections with hepatitis C virus and hepatitis B virus increase risk for kidney failure.
HIV patients on dialysis have lower survival than uninfected dialysis patients, so transplantation is better.
HIV+ recipients who were given (ATG) or who are coinfected with HCV, have increased incidence of bacterial infections
allograft rejection rates is increased two to three times in HIV+VE recipients than in general kidney transplant population.
Many transplant programs still consider HIV as an absolute or relative contraindication to transplantation, so they remain on dialysis for a long time and have longer waitlist times for organ offers and transplant. Liver:
HIV patients are at risk for end-stage liver disease through a variety of mechanisms include: HCV and HBV coinfections, ART toxicity, Alcohol, and hepatocellular carcinoma.
The outcomes of liver transplantation in HIV patients vary by the reason for transplant.
HCV-related progressive liver disease, severe infections, and sepsis contributed to poor outcomes. Pancreas:
In 2018, 836 simultaneous pancreas-kidney transplants were done in the United State except for type 1 diabetic HIV person
Many complications were found: graft thrombosis, rejection, and bacterial infections, including fatal sepsis
Pancreas transplantation can be successful in HIV-infected patients, but it need experience. Heart:
HIV-associated cardiomyopathy was seen in the pre-ART era; coronary artery disease is now a rising concern in PWH. HIV is not an absolute contra-indication to heart transplantation but not common. Lung:
In 2018, 2530 lung and 32 heart/lung transplants were done in the United States.
HIV infection has become a relative contraindication to lung transplantation, but there is a lack of lung transplantation data. Clinical management of HIV-infected organ transplant candidates and recipient: Selection of candidates:
HIV providers should refer patients with end-organ damage and stable HIV to centers well-versed in HIV organ transplantation. CD4 cell counts of at least 200 cells/ml are recommended for transplantation. Antirejection therapy·
Best HIV immunosuppressive regimen is unknown but it should be individualized based on the organ transplanted, immunologic risk, renal and liver function, and ART regimen Medication management:
HIV providers must be aware of key drug interactions with maintenance immunosuppressive therapies, such as protease inhibitors and non-nucleoside reverse transcriptase inhibitors, to ensure adequate levels of antirejection drugs in transplant recipients. Clinical monitoring and care of HIVR persons before and after organ transplantation:
HIV providers play a vital role in preparing patients for transplant, monitoring HIV infection and potential opportunistic complications, and optimizing HIV therapy.
Post transplant, the same ART regimen may be continued, although clinicians must be cognizant of frequent fluctuation in kidney function that may require frequent dose adjustments, also HIV clinicians should avoid, agents that may compromise organ function,
In the post-transplant period, regular HIV care is essential, and more frequent monitoring of CD4 cell counts and HIV viral load is warranted.
Anti-infective prophylaxis is based on transplant center practices and HIV guidelines. HIV-to-HIV transplantation:
In 1984 the National Organ Transplant Act was enacted, making it illegal to use HIV organs for transplantation
In 2008, four HIV+ to HIV +renal transplants were successfully done in Cape Town, South Africa.
HOPE Act has enabled the utilization of organs that may have otherwise been discarded due to false-positive HIV test results, but few cases of HIV-to-HIV living donor transplants have been reported Conclusion:
Encouraging results with transplantation of other organ types, including pancreas, heart, and lung suggest that persons with other advanced organ disease should also be referred to centers experienced in performing these transplants
SOT IN HIV PATIENTS
HAART is effective leading to better sirvival
HIVAN has reducing incidence, but CKD is common due to DM , nephrotoxic drugs
Once on dialysis, PWH have lower survival rates when compared with uninfected dialysis patients
so SOT is common in person with HIV (PWH)
Stock et al.
reported the outcomes of 150 HIV-infected patients after
kidney transplantation; 1 and 3-year kidney allograft and
patient survival estimates were 90.4 and 73.7 and 94.6 and
88.2%, respectively. REAL WORLD SCENARIO suggest SOT is feasible in PWH and is not a contraindication
It should be done in centre experienced in doing such work
Bacterila infection is comon if ATG is used and coinfected with HCV
DGF and rejection is common
HIV is an absolute or relative contraindication for liver transplantation, but the outcomes of liver transplantation vary by the reason for transplant.
Pancreas transplantation can be successful in HIV-infected patients, but additional experience is needed. Lung transplant is not reported
IS in PWH drug interactions are very common and drug levels need strict monitoring
HIV TO HIV transplantation after HOPE act this is more into consideration and will avoid wastage of organ
Introduction:· HIV infection has become a chronic illness, with increased life expectancy and an aging demographic, leading to increased morbidity and mortality.
· Solid organ transplantation is the standard of care for PWH with end-stage kidney and liver disease, with HOPE Act expanding the donor pool.
· HIV management decisions affect pre- and post-organ transplant care, and post-transplant immunosuppressive practices impact HIV and transplant outcomes.
Status of organ transplantation by organ typeThe American Society of Transplantation has recently published updated guidelines on the management of SOT in HIV-infected persons, but it is important for HIV care providers to understand how HIV management decisions affect pre- and post-organ transplant care and post-transplant immunosuppressive practices. Kidney
· PWH are disproportionately affected by the end-stage renal disease (ESRD) in the US, with HIV-associated nephropathy (HIVAN) rates declining, but other causes of renal failure such as focal segmental glomerulosclerosis, diabetes mellitus, and hypertension.
· Antiretroviral agents can lead to nephrotoxicity and metabolic complications, leading to lower survival rates.
· The largest prospective observational trial of 150 HIV-infected patients after kidney transplantation found that 1 and 3-year kidney allograft and patient survival estimates were 90.7 and 94.2%, respectively.
· However, complications such as bacterial infections and delayed allograft function were observed.
· HIV rejection rates were two to three times higher than observed in the general kidney transplant population. Single and multicenter studies have largely confirmed the results.
· Research is underway to evaluate the role of maraviroc in reducing the HIV reservoir and modulation of the immune response and allograft injury following kidney transplantation.
Liver· PWH are at risk for end-stage liver disease due to a variety of mechanisms, including chronic HCV and HBV coinfections, HIV infection, nonalcoholic fatty liver disease and steatohepatitis, and hepatocellular carcinoma.
· HIV is an absolute or relative contraindication for liver transplantation, but the outcomes of liver transplantation vary by the reason for transplant.
· Before the availability of hepatitis C directly acting antiviral (DAA) agents, transplant outcomes of HIV-HCV coinfected patients were problematic, with significantly lower graft and patient survival rates compared with HCV-mono-infected controls.
Pancreas· Pancreas transplantation can be successful in HIV-infected patients, but additional experience is needed.
Heart· HIV-associated cardiomyopathy is a rising concern in PWH, with 1 and 5-year post-transplant survivals between 85.9-90% and 64-77.3%, and higher rates of rejection. 53.7-57% of patients received mechanical circulatory support prior to transplant.
Lung· HIV infection has become a relative contraindication to lung transplantation, but there is a lack of lung transplantation reports in PWH.
Clinical management of HIV-infected organ transplant candidates and recipients:Selection of candidatesHIV providers should refer patients with end-organ damage and stable HIV to centers well-versed in HIV organ transplantation. CD4 cell counts of at least 200 cells/ml are recommended for transplantation. Antirejection therapy· The best immunosuppressive regimen for HIV-infected transplant recipients should be individualized based on the organ transplanted, immunologic risk, renal and liver function, and ART regimen.
Medication management· HIV providers must be aware of key drug interactions with maintenance immunosuppressive therapies, such as protease inhibitors and non-nucleoside reverse transcriptase inhibitors, to ensure adequate levels of antirejection drugs in transplant recipients.
Clinical monitoring and care of HIVR persons before and after organ transplantation· HIV providers play a vital role in preparing patients for transplant, monitoring HIV infection and potential opportunistic complications, and optimizing HIV therapy.
· After the transplant, patients should be placed on non-protease inhibitor-based ART regimens, and clinicians should avoid agents that may compromise organ function.
· In the post-transplant period, regular HIV care is essential, and more frequent monitoring of CD4 cell counts and HIV viral load is warranted.
· Anti-infective prophylaxis is based on transplant center practices and HIV guidelines.
HIV-to-HIV transplantation · The National Organ Transplant Act was enacted to prevent HIV transmission by transplantation, but the South African experience has inspired action to expand HIV to HIV transplant to North America.
· HOPE Act has enabled the utilization of organs that may have otherwise been discarded due to false-positive HIV test results, but few cases of HIV-to-HIV living donor transplants have been reported.
Conclusion
Kidney and liver transplantation is the standard of care for HIV-infected persons with end-stage kidney and liver diseases, and INSTI and DAAs for hepatitis C promise to improve outcomes.
HIV providers should refer appropriate patients for transplantation and ensure frequent monitoring of HIV infection after transplant.
HIV infection has become a chronic illness in the current age of antiretroviraltherapy; both overall and AIDS-related mortality has declined .
With increased life expectancy and an aging demographic, common medical comorbidities, such as coronary artery disease and nonalcoholic steatohepatitis, are becoming important causes of morbidity and mortality in persons with HIV (PWH).
Over the past decade, accumulating evidence has established solid organ transplantation (SOT) as standard of care for PWH with end-stage kidney and liver disease, and more limited but encouraging data has demonstrated feasibility of pancreas, heart, and lung transplantation in PWH. With the passage and implementation of the HIV Organ Policy Equity (HOPE) Act, PWH can now register as organ donors, effectively expanding the donor pool for PWH waiting for organs and, thus, the organ donation pool as a whole.
With improvements in and earlier initiation of ART, HIVassociated nephropathy (HIVAN) rates have declined, but in antiretroval-treated PWH, other causes of renal failure such as focal segmental glomerulosclerosis, diabetes mellitus, and hypertension remain prominent
Coinfections with hepatitis C virus (HCV) and hepatitis B virus (HBV) increase risk for kidney failure.
Importantly, several antiretroval agents, such as tenofovir, abacavir, indinavir, ritonavir-boosted lopinavir, ritonavirboosted atazanavir, and potentially other boosted protease inhibitors, are associated with nephrotoxicity and/or metabolic complications, including diabetes and dyslipidemias, which can ultimately contribute or lead to the development of chronic kidney disease and ESRD.
Once transplanted, outcomes for PWH are favorable, with transplantation providing a clear survival benefit over renal replacement therapy.
Because all patients had viral suppression and CD4 cell counts at least 200 cells/ml prior to transplant and combination ART and posttransplant anti-infective prophylaxis was employed, HIV control was excellent, and few opportunistic infections were encountered.
HIV recipients experienced allograft rejection rates two to three times higher than observed in the general kidney transplant population, and rejection was a predictor for allograft failure in this study.
HIV providers should refer any patient with end-organ þ damage and stable HIV to centers well versed in HIV organ transplantation. Centers may vary in their candidacy requirements for transplantation, but updated guidelines recommend that, regardless of the organ transplanted, patients have undetectable HIV viral load, known compliance with ART, no evidence of active opportunistic infections or HIV-associated malignancy, and the ability to have close follow-up for immunosuppression, drug level monitoring and management.
CD4 cell counts at least 200 cells/ml are recommended for transplantation of all organs with the exception of liver, where the threshold for transplantation þ is CD4 cell count more than 100 cells/ml, with the rationale that ALD and portal hypertension lead to splenic sequestration of white blood cells, including lymphocytes.
Although the outcomes of organ recipients with HCV coinfection have been problematic in pre-DAA era, HCV should not be considered an exclusion factor for transplant. Specialists can weigh the risks and benefits of treatment prior to transplantation, keeping in mind that if treatment can be safely delayed, the option of þ utilizing HCV organs followed by post-transplant DAA treatment increases the pool of organs available for transplant. In the case of both kidney [74] and liver transplant [75,76], excellent HCV treatment outcomes have been achieved with DAA therapy. When evaluating HCV-coinfected persons for liver transplant, it is important to weigh factors predictive of liver allograft loss such as low BMI (<21 kg/m2 ), need for combined þ liver–kidney transplant, and HCV donor organs.
In the U.S. NIH observational trial, persons who received ATG as opposed to basiliximab, an IL-2 receptor antagonist, experienced significant, prolonged lymphocyte depletion, more frequent and severe infections, and increased risk for allograft loss.
Very few cases of HIV-to-HIV living donor transplantation have been reported in the literature. When evaluating potential candidates for donor nephrectomy, the assessment must include identification HIV-specific þ risk factors for development of ESRD such as low CD4 cell count and HCV coinfection in addition to other conditions that generally exclude persons from donation (e.g. diabetes mellitus, hypertension, and preexisting þ kidney disease).
Post-nephrectomy, HIV donors should avoid nephrotoxic ART (such as tenofovir) in addition to agents such as nonsteroidal anti-inflammatory agents. To date, only two living donor kidney transplants have been reported, one with long-term good outcomes in both the donor and recipient.
Kidney and liver transplantation are the standard of care for HIV-infected persons with end-stage kidney and liver diseases. Encouraging results with transplantation of other organ types, including pancreas, heart, and lung suggest that persons with other advanced organ disease should also be referred to centers experienced in performing these transplants. The availability of INSTI, with minimal impact on immunosuppressive drug levels, has greatly þ simplified the post-transplant management of the HIV organ recipient. The introduction of DAAs for hepatitis C, with their high efficacy in the post-transplant setting, promise to improve outcomes in coinfected organ recipients. Finally, with implementation of the HOPE Act, PWH can donate organs to HIV infected persons waiting for kidney and liver transplants under a research setting. HIV providers should play an active role in referring appropriate patients for transplantation, educating patients regarding transplant outcomes and the potential risks and benefits of pursuing HIV-positive organs for transplant, and ensuring frequent monitoring of HIV infection after transplant.
Introduction
· Antiretroviral therapy reduced AIDS-related mortality, with increased life expectancy and common medical comorbidities.
· coronary artery disease and nonalcoholic steatohepatitis, are important causes of morbidity and mortality in persons with HIV.
· persons with HIV can now register as organ donors, expanding the donor pool for HIV persons waiting for organs.
Status of organ transplantation by organ type
· The most evidence in support of transplantation in HIV persons comes from kidney followed by liver transplantation.
· The number of pancreas, heart, and lung transplantation, is increasing. Kidney
· In spite of declining HIV-associated nephropathy, due to antiretroviral treatment, other causes of renal failure such as FSGS, diabetes mellitus, and hypertension remain prominent.
· Coinfections with hepatitis C virus and hepatitis B virus increase risk for kidney failure.
· Many antiretroviral agents are nephrotoxic and increase risk of DM and dyslipidemia.
· HIV patients on dialysis have lower survival than uninfected dialysis patients, that’s why they need transplantation.
· HIV+ recipients who were given (ATG) or who are coinfected with HCV, have increased incidence of bacterial infections.
· HIV patients have high rates of delayed allograft function.
· HIV+ recipients have allograft rejection rates two to three times higher than seen in the general kidney transplant population.
· Some transplant programs still consider HIV as an absolute or relative contraindication to transplantation, so they remain on dialysis for a long time and have longer waitlist times for organ offers and transplant.
Liver
· HIV patients are at risk for end-stage liver disease through a variety of mechanisms:
1) HCV and HBV coinfections
2) HIV infection increases the risk for progressive and advanced liver disease
3) ART can cause advanced liver disease by direct hepatotoxicity, hypersensitivity reactions, mitochondrial toxicity, steatosis and/or steatohepatitis, or immune reconstitution phenomena.
4) Alcohol may increase the risk of end stage liver disease.
5) Hepatocellular carcinoma can further complicate the course of ALD
· The outcomes of liver transplantation in HIV patients vary by the reason for transplant.
· HCV-related progressive liver disease, severe infections, and sepsis contributed to poor outcomes.
Pancreas
· In 2018, 836 simultaneous pancreas-kidney transplants were performed in the United States, but this rarely done in type 1 diabetic HIV person.
· complications are: graft thrombosis, rejection, and bacterial infections, including fatal sepsis.
Heart
· HIV-associated cardiomyopathy was seen in the pre-ART era, but coronary artery disease is now a rising concern in HIV patients.
· HIV is not an absolute contra-indication to heart transplantation, but is uncommonly performed.
Lung
· HIV-experienced centers can consider PWH as candidates in the setting of demonstrated antiretroviral adherence with viral suppression and no recent AIDS-defining illness
· There is a paucity of lung transplantation reports in PWH.
Clinical management of HIV-infected organ transplant candidates and recipient Selection of candidates
· HIV providers should refer any patient with end-organ damage and stable HIV to centers well versed in HIV+ organ transplantation.
· candidacy requirements for transplantation:
1) Meet transplant center-specific eligibility for organ transplantation
2) CD4+ cell count > 200 cells/µl during 3 months prior to transplantation for kidney, pancreas, heart and lung candidates
3) CD4+ cell count > 100 cells/µl during 3 months prior to transplantation for liver candidates only
4) Undetectable plasma HIV viremia (unless unable to tolerate ART prior to liver transplant)
5) Documented adherence with stable ART regimen
6) Absence of active opportunistic infection and malignancy
7) Absence of chronic wasting or severe malnutrition
8) Hepatitis B or C infection if no advanced fibrosis/cirrhosis (for organ types other than liver)
9) Access to immunosuppressive agent therapeutic drug monitoring
10) Ability to regularly follow up with HIV care providers
Antirejection therapy
· There is no specific immunosuppressive regimen to use for patients with HIV.
· Induction immunosuppression is not required in the majority of liver transplant recipients, and data about induction agents in transplant of other organ types in HIV+ persons is lacking.
· For HIV-infected transplant recipients, Tacrolimus is associated with lower rejection rates, and is the preferred CNI. MMF can be used.
· Prednisone reduces risk for rejection, but the benefits of its used should be weighed against the long-term effects of this agent.
· Sirolimus is known to have anti-HIV effects
Medication management
· Protease inhibitors inhibit (CYP3A4) enzyme, which alter the pharmacokinetics of CNI and mTORi, resulting in severe alterations in doses with possible rejection or toxicity.
· In liver transplant recipients, boosted protease inhibitors regimens were associated with episodes of acute renal failure from high cyclosporine levels.
· renal transplant recipients also have poor outcomes for patients on protease inhibitor-based regimens.
· In the transplant setting, non-boosted integrase strand transfer inhibitors (INSTI) have emerged as favored therapies.
· Raltegravir, dolutegravir, and raltegravir have insignificant interactions with the CNI.
Clinical monitoring and care of HIV+ persons before and after organ transplantation
· In the pre-transplant phase, HIV therapy needs optimization to minimize pre-transplant toxicities and post-transplant drug interactions while maintaining viral suppression.
· Patients should be placed on non-protease inhibitor-based ART regimens if possible.
· Avoid use of tenofovir disoproxil fumarate after kidney transplant and abacavir after heart transplantation.
· In the early post-transplant period, in the setting of allograft rejection, more frequent monitoring of CD4+ cell counts and HIV viral load is necessary.
· many centers may use life-long prophylaxis against Pneumocystis jirovecii
HIV-to-HIV transplantation
· Was successful in South Africa which inspired the United States transplant community to expand HIV+ to HIV+ transplant to North America.
· HOPE Act has put safeguards in place to conduct and monitor outcomes in HIV-to-HIV transplantation by conducting these procedures in a research setting using well defined donor eligibility requirements.
· preliminary data suggest excellent patient and allograft survivals for both kidney and liver recipients
· An unexpected benefit of HOPE Act is the use of organs that may have otherwise been discarded due to having false-positive HIV test results.
· When evaluating potential candidates for donor nephrectomy, the assessment must include the identification HIV-specific risk factors for the development of ESRD such as: low CD4+ cell count and HCV coinfection and other conditions that discard persons from donation ( DM, HTN, and preexisting kidney disease)
· HIV+ African American persons with high-risk APOL1 genotypes are at risk for the development of HIVAN and FSGS.
· Post-nephrectomy, HIV+ donors should avoid nephrotoxic ART (tenofovir) and NSAIDs.
This article is focused on HIV patients and SOT. After HAART therapy, EVERYTHING is possible for HIV patient, even if he has the chance to be on the waiting list.
PWH and after HAART, even HIVAN is decreased, but other causes in PWH like HTN, DM, and FSGN remain the same.
PWH once transplanted the graft, and patient survival is better than on remaining on Dialysis.
Stock et al. showed the 150 transplanted HIV patients showed good graft and patient survival fro 1 , and 3 years, estimates were 90.4 and 73.7 and 94.6 and 88.2%, respectively. Still, PWH experienced high rates of delayed allograft function. High rates of allograft rejection following kidney transplantation may be due to inadequate immunosuppression, either because of under use of immunosuppressive agents or drug interactions that lead to inadequate or inconsistent immunosuppressive drug levels.
SELECTION OF THE CANDIDATE SUPPOSE WITH SPECIAL CRITERIA: CD4 count more than 200 /ml for the last 3 month stable patient with no OI for the last 6 month The patient supposes to be on HAART with good adherence.
Anti Rejection therapy ATG is associated with an increased risk of bacterial infection due to its depleted action on lymphocytes. But on the other hand, PWH has a higher rate of rejection and DGF.
Sirolimus have with HIV effect through the downregulation of CCR5, upregulation of b-chemokines, and blockade of the mammalian target of rapamycin (mTOR).
What type of HAART therapy is the most suiting patient for SOT??
PI has adrastic inhibition effect on cytochrom P450 while non-nucleoside reverse transcriptase inhibitors have differing potential for induction of CYP3A4.
For that thetype of HAARt therapy with CNI andIS need to be adjusted because this is the main point which leads to rejection .On the other hand,boosted the dose of HAART therapy will increase the risk of renal faliuer and AKI.
Raltegravir, dolutegravir, and raltegravir are completely or primarily metabolized through the uridine diphosphate glucuronosyltransferase 1A system, resulting in clinically insignificant interactions with the calcineurin inhibitors. Small case reports evaluating use of raltegravir have found that it is well tolerated and effective to use in the setting of transplantation. Dolutegravir has emerged as the favored INSTI due to its high barrier to resistance and ease of dosing.
How to deal with HIVR : this patient need to be on non PI regiem theraby need to vahe a close follow up to his kidney funtion ,highly recommedned not to use tinofovie for its kidney toxcicty in RTX and to avoid abacavir after heart transplant .
HIV to HIV :
the data showed depite good patient survivla they have relatevely low graft survival as the Data which is puplised in 2008 from Captown ,it showed drop from 93% in years 1 and 3 wo 79% in years 5 , still the infection and carrying the infected organe and the OI is the main problems in these group of patients .
prior to donation, the following data about the HIV positive donor should be made available: – CD4, viral load, HIV genotypic testing, HAART history, history of OIs
– assess for HIV-specific risk factors for development of ESKD e.g., low CD4, HCV co-infection, diabetes, hypertension, pre-existing kidney disease
– HIV positive African-American patients with high-risk APOL1 genotypes are at risk of developing HIVAN and FSGS
– the utility of APOL1 haplotype screening remains unknown
– HIV positive donors should avoid nephrotoxic agents post-nephrectomy e.g., TDF, NSAIDs
– intentional transplantation of HIV positive organs to HIV negative recipients is still not an acceptable practice due to medical and ethical concerns
This review focuses on the current status of SOT for HIV-infected persons, highlighting the outcomes, standards of care and aspects of post-transplant management. With availability of effective ART, PWH are increasingly seeking organ transplantation
Kidney
With earlier initiation of ART, HIV associated nephropathy (HIVAN) rates have been decreasing, but in antiretroviral-treated PWH, other causes of renal failure such as focal segmental glomerulosclerosis, diabetes mellitus, and hypertension remain prominent
Once transplanted, outcomes for PWH are better than dialysis, with transplantation providing a clear survival benefit over other renal replacement therapy
Stock et al. reported the outcomes of 150 HIV-infected patients after kidney transplantation; 1 and 3-year kidney allograft and patient survival estimates were 90.4 and 73.7 and 94.6 and 88.2%, respectively but PWH experienced high rates of delayed allograft functionBacterial infections were observed with increased frequency in HIV recipients who were treated with the lymphocyte depleting agent, antithymocyte globulin (ATG) or coinfected with HCV. HIV recipients experienced allograft rejection rates two to three times higher than observed in the general kidney transplant population, and rejection was a predictor for allograft failure.
High rates of allograft rejection following kidney transplantation may be due to inadequate immunosuppression, either because of under use of immunosuppressive agents or drug interactions that lead to inadequate or inconsistent immunosuppressive drug levels. Another potential explanation invokes immune system dysregulation and heterologous immunoreactivity in response to HIV and other chronic infections.
Liver
HIV itself, and ART medications (direct hepatotoxicity, steatosis, immune reconstitution, or hypersensitivity reactions) being the chief etiology for liver disease
The outcomes of liver transplantation in PWH may vary by the reason for transplant. As an example, in those with HIV-HBV co-infection, in the setting of passive prophylaxis with hepatitis B immunoglobulin and antiviral therapy, both graft and patient survival range from 85 to 100% after 3–5 years of follow-up. Due to the frequency of breakthrough HBV viremia, lifelong prophylaxis is recommended.
Before the availability of hepatitis C directly acting antiviral (DAA) agents, the transplant outcomes of HIV– HCV coinfected patients were problematic, with significantly lower graft and patient survival rates compared with HCV-mono-infected controls.DAA therapy introduction has led to improvement in graft and patient survival rates.
Pancreas
Outcomes have been mixed, with reported complications of graft thrombosis, rejection, and bacterial infections, including fatal sepsis
Heart
In a recent study evaluating 41 HIV heart recipients, indicat that risks of post-transplant vasculopathy was not any higher than HIV uninfected recipients but have also shown higher rates of rejection.
Lung
HIV infection is a relative contraindication to lung transplantation.The guidelines stipulate that HIV experienced centers can consider PWH as candidates in the setting of demonstrated antiretroviral adherence with viral suppression and no recent AIDS-defining illness.
Clinical management of HIV-infected organ transplant candidates and recipient
Selection of candidates
• CD4+ cell count > 200 cells/µl during 3 months prior to transplantation for kidney, pancreas, heart and lung candidates
• CD4+ cell count > 100 cells/µl during 3 months prior to transplantation for liver candidates only
• Undetectable plasma HIV viremia
• Adherence with stable antiretroviral treatment regimen
• Absence of active opportunistic infection and malignancy
• Absence of chronic wasting or severe malnutrition
• Hepatitis B or C infection if no advanced fibrosis/cirrhosis
• Availability immunosuppressive agent therapeutic drug monitoring
Antirejection therapy
In the U.S. persons who received ATG experienced prolonged lymphocyte depletion, more frequent and severe infections, and increased risk for allograft loss. Other investigators, through analysis of registry data, reported lower rejection and infection rates with ATG. Tacrolimus is associated with lower rejection rates. Mycophenolate is a very common component of maintenance immunosuppression. Although long-term maintenance prednisone therapy reduces risk for rejection. Sirolimus is known to have anti-HIV effects through downregulation of CCR5, upregulation of b-chemokines, and blockade of the mammalian target of rapamycin (mTOR). In-vitro studies have shown that HIV-1 transcription can continue in the setting of sirolimus, which, in the setting of immune system activation from transplantation, may result in diminishing the HIV reservoir. Calcineurin inhibitors have been found to decrease HIV-1 DNA transcription.
Medication management
Protease inhibitors, via inhibition of cytochrome P450 3A4 (CYP3A4) enzyme, alter the pharmacokinetics of immunosuppressive medications, including the calcineurin inhibitors and mTOR inhibitors, resulting in drastic alterations in doses and dosing schedules of these drugs. Conversely, non-nucleoside reverse transcriptase inhibitors have differing potential for induction of CYP3A4
In liver transplant recipients, boosted protease inhibitor regimens were associated with episodes of acute renal failure from high cyclosporine levels. Studies in renal transplant recipients have also shown poor outcomes for patients on protease inhibitor-based regimens.
The increased rejection may be related to interactions between calcineurin inhibitors and protease inhibitors, though a clear relationship between mortality and protease inhibitors has not been delineated.
Raltegravir, dolutegravir, and bictegravir are completely or primarily metabolized through the uridine diphosphate glucuronosyltransferase 1A system, resulting in clinically insignificant interactions with the calcineurin inhibitors. Small case reports evaluating use of raltegravir have found that it is well tolerated and effective to use in the setting of transplantation. Dolutegravir has emerged as the favored INSTI due to its high barrier to resistance and ease of dosing.
Clinical monitoring and care of HIVR persons before and after organ transplantation
Whenever feasible, patients should be placed on non-protease inhibitor-based ART regimens.
HIV clinicians should avoid, when possible, agents that may compromise organ function, such as use of tenofovir disoproxil fumarate after kidney transplant or abacavir after heart transplantation.
Use of fixed dose combination regimens require caution, particularly because of fluctuating renal function, or, in the case of formulations containing potent CYP system inhibitors, such as cobicistat, supratherapeutic calcineurin inhibitors levels.
HIV-to-HIV transplantation
In 2008, four HIV to HIV renal transplants were successfully performed in Cape Town, South Africa
Recent follow up data published by the same group notes that of the 51 patients transplanted with HIV organs, the 1, 3, and 5-year patient survivals were 87, 87, and 84% while 1, 3, and 5-year graft survivals 96, 93, and 79%
Risks include transmission of latent or unrecognized opportunistic infections to the recipient and poor organ quality because of prevalent renal, hepatic, and cardiac diseases in the HIV population.
HIV African American persons with high-risk apoprotein L1 (APOL1) genotypes are at risk for development HIVAN and focal segmental glomerulosclerosis [8,113], but it is unknown whether APOL1 haplotype screening may be of utility in this setting. Post-nephrectomy, HIV donors should avoid nephrotoxic ART (such as tenofovir) in addition to agents such as nonsteroidal anti-inflammatory agents. To date, only two living donor kidney transplants have been reported, one with long-term good outcomes in both the donor and recipient.
Conclusion
Encouraging results with transplantation of other organ types, including pancreas, heart, and lung suggest that persons with other advanced organ disease should also be referred to centers experienced in performing these transplants
– in this current era of HAART, HIV infection is now regarded a chronic illness
– both overall and AIDS-related mortality has declined significantly
– common medical comorbidities e.g., coronary artery disease, NASH are now becoming causes of morbidity and mortality in the HIV population due to the increased life expectancy and an aging demographic
– HIV patients are also at increased risk of organ dysfunction and organ failure due to the metabolic side effects of the virus as well as the antiretroviral drugs used
– SOT is the standard of care for HIV positive patients with ESKD and liver disease
– there is data showing the feasibility of pancreas, heart and lung transplant among HIV positive patients
– with the HOPE Act i.e., HIV Organ Policy Equity Act, HIV positive patients can now register as organ donors
Status of organ transplantation by organ type
– with the availability of HAART, HIV positive patients are now seeking SOT
Kidney
– with initiation of HAART, the rates of HIVAN have declined, but other causes of kidney disease e.g., FSGS, DM, hypertension remain eminent
– coinfection with HBV and HCV also increases the risk of kidney disease
– several ARVs e.g., tenofovir, abacavir, indinavir, ritonavir-boosted lopinavir, ritonavir-boosted atazanavir, and other boosted PIs, are associated with nephrotoxicity and/ or metabolic complications like DM, dyslipidemias which can eventually lead to CKD and ESKD
– HIV positive patients on dialysis have lower survival rates compared with their HIV-negative counterparts
– as a result, many HIV positive patients are increasingly undergoing kidney transplantation
– the outcomes following kidney transplantation are favourable, providing an obvious survival benefit over other forms of KRT
– a large prospective observational trial revealed that: –
bacterial infections were greater among HIV positive patients who received ATG or those with HCV co-infection
HIV positive patients also had a higher rate of DGF but this was not predictive of graft failure
the rates of graft rejection were 2-3times higher among the HIV positive patients than in the general kidney transplant population
graft rejection was a predictor for graft failure
– proposed mechanisms for the high rates of graft rejection among HIV positive patients include: –
inadequate immunosuppression due to under-use of the immunosuppressants or drug-drug interactions leading to inadequate or inconsistent immunosuppressive drug levels
immune dysregulation and heterogenous immunoreactivity in response to HIV infection itself and other chronic infections
– the role of maraviroc (a CCR5 inhibitor) in reduction of the HIV reservoir and modulation of the immune response and graft injury in kidney transplantation is still being studied
– HIV positive patients still encounter challenges accessing kidney transplantation despite the great evidence in support of kidney transplantation in the HIV positive ESKD population
– some transplant centers still consider HIV as an absolute or relative contraindication to kidney transplantation
– it has also been noted that HIV positive patients remain on dialysis for longer durations before they get to the transplant waiting list
– HIV positive patients also have longer waitlist times for organs, are more likely to remain inactive on the waitlist, have a lower likelihood of undergoing kidney transplantation compared to their HIV negative counterparts
– more data is needed to understand these disparities
Liver
– in this current age of HAART, liver disease has become the 3rd leading cause of death in HIV positive patients
– HIV positive patients are at increased risk for end-stage liver disease due to various mechanisms, i.e.: –
chronic HBV and HCV co-infections
HIV infection increases risk for progressive and advanced liver disease among patients with viral hepatitis (ALD)
HAART can cause direct hepatotoxicity, mitochondrial toxicity, NAFLD, steatosis/ steatohepatitis, immune reconstitution phenomenon, hypersensitivity reactions
HCC further complicates the course of advanced liver disease (ALD)
– unfortunately, some transplant centers still regard HIV as an absolute or relative contraindication to liver transplantation
– before the advent of DAAs, the transplant outcomes of HIV-HCV coinfected patients were challenging resulting in lower graft and patient survival rates compared with patients with HCV mono-infection
– for HIV-HBV coinfection, the graft and patient survival rates range from 85-100% in the setting of passive prophylaxis with HBIG and antiviral therapy
Pancreas
– pancreas-kidney transplantation is not commonly done in type 1 diabetic patients who are HIV positive, additional experience is required
– the outcomes are mixed, reported complications include graft thrombosis, rejection, bacterial infections, fatal sepsis
Heart
– factors predisposing HIV positive patients to cardiac disease include aging, chronic immune activation state of HIV, metabolic effects of HAART
– currently, coronary artery disease among HIV positive patients is now becoming a major concern, while HIV-associated cardiomyopathy was common in the pre-ART era
– HIV is no longer a contraindication to advanced heart failure therapies like heart transplantation although it is not commonly performed
Lung
– there is a paucity of data on lung transplantation among HIV positive patients
– currently, HIV infection is now considered a relative contraindication to lung transplantation
– the patient should demonstrate adherence to HAART, viral suppression, absence of AIDS-defining illness
Clinical management of HIV-infected organ transplant candidates and recipients
Selection of candidates
– transplant requirements include: – CD4 >200, undetectable HIV viremia, compliance to HAART, absence of opportunistic infections, absence of HIV-associated malignancies, absence of chronic wasting or severe malnutrition, access to immunosuppressive agent therapeutic drug monitoring, availability of regular clinic follow-up for the HIV infection
– CD4 >200 is recommended except in liver transplantation where the threshold is 100 since it is argued that ALD and portal hypertension lead to splenic sequestration of WBCs including lymphocytes
– in the current era of DAAs, HCV should not be considered as an exclusion factor for transplant
– weigh risks vs benefit of treatment prior to transplantation e.g., if treatment can be safely delayed, the pool of organs available will increase since this will allow for donation of HCV positive organs then offering DAA therapy post-transplant
– excellent treatment outcomes have been experienced with DAAs
Antirejection therapy
– immunosuppressive regimens should be individualized based on the organ transplanted, the immunologic risk, HAART regimen, kidney and liver function
– the best immunosuppressive regimen among HIV positive patients remains unknown
– among HIV positive kidney transplant recipients, induction with ATG was associated with prolonged lymphocyte depletion, more frequent and severe infection compared to Basiliximab
– however, some studies reported lower rejection and infection rates with ATG, hence the need for individualized treatment
– the best maintenance immunosuppressive regimen among HIV positive patients is yet to be established
– tacrolimus is the preferred CNI since it is associated with lower rejection rates
– mycophenolate is the commonly used antimetabolite
– long-term prednisone use reduces the risk of rejection but one should weigh the benefits against the long-term effects of prednisone use
– sirolimus has anti-HIV effects via upregulation of ß-chemokines, downregulation of CCR5 and blockade of mTOR
– sirolimus also decreases the HIV reservoir
– CNIs decrease HIV-1 DNA transcription
Medication management
– adequate levels of the antirejection drugs should be maintained
– clinicians should be aware of the possible drug-drug interactions (DDIs) i.e., between HAART and the immunosuppressive agents
– PIs are cytochrome P450 3A4 (CYP3A4) enzyme inhibitors hence alter the pharmacokinetics of CNIs (tacrolimus, cyclosporine A) and mTORi (everolimus, sirolimus) leading to alterations in the doses and dosing schedules of these medications
– these DDIs can result in inconsistent immunosuppressive drug levels hence increasing the risk of rejection (in the case of sub-therapeutic drug levels) or risk of toxicity (in the case of supra-therapeutic drug levels)
– NNRTIs have an enzyme inducing effect on CYP3A4
– studies among HIV positive kidney transplant recipients on PI-based regimens have shown poor outcomes (i.e., graft loss/ rejection and mortality) compared to non-PI based regimens
– so essentially, based on these outcomes, PI-based regimens have fallen out of favour in the transplant setting
– however, non-boosted integrase strand transfer inhibitors (INSTI) are now a favourable option
– dolutegravir, raltegravir, bictegravir are metabolized through uridine diphosphate glucuronosyltransferase 1A system leading to clinically insignificant interactions with CNIs
– from the few case reports in literature, raltegravir has been found to be well tolerated and effective in the transplant setting
– dolutegravir is the most favoured INSTI because of its higher genetic barrier to resistance and the ease of administration
Clinical monitoring and care of HIV+ persons before and after organ transplantation
– HIV providers play a significant role in the care of HIV positive patients pre- and post- transplant
– non-PI based HAART regimens are preferred
– the same HAART regimen is usually continued and the doses should be adjusted accordingly based on the kidney function
– where feasible, avoid agents that would compromise the organs e.g., tenofovir post-kidney transplant, abacavir post-heart transplant
– fixed dose combination regimens should be used with caution due to fluctuations in kidney function
– CD4 and HIV viral load should be monitored closely in the following case scenarios: – early post-transplant period, during graft rejection and when the immunosuppressive regimen is adjusted
– anti-infective prophylaxis is usually offered based on the HIV guidelines as well as transplant center protocols
HIV-to-HIV transplantation
– previously, use of HIV positive organs was illegal and HIV positive patients were not considered as potential transplant candidates
– but this has since changed, and HIV positive to HIV positive kidney transplants are now being performed with excellent graft and patient survival rates
– however, there are concerns over the: –
potential consequences of the superinfection with the donor’s HIV strain
risk of transmission of OIs (latent or unrecognized) to the recipient
poor organ quality due to prevalent hepatic, kidney and cardiac diseases in the HIV positive population
– prior to donation, the following data about the HIV positive donor should be made available: – CD4, viral load, HIV genotypic testing, HAART history, history of OIs
– assess for HIV-specific risk factors for development of ESKD e.g., low CD4, HCV co-infection, diabetes, hypertension, pre-existing kidney disease
– HIV positive African-American patients with high-risk APOL1 genotypes are at risk of developing HIVAN and FSGS
– the utility of APOL1 haplotype screening remains unknown
– HIV positive donors should avoid nephrotoxic agents post-nephrectomy e.g., TDF, NSAIDs
– intentional transplantation of HIV positive organs to HIV negative recipients is still not an acceptable practice due to medical and ethical concerns
Conclusion
– kidney and liver transplantation is the standard of care for HIV positive patients with ESKD and liver disease
– INSTIs have minimal impact on immunosuppressive drug levels and this has greatly simplified the post-transplant care of HIV positive organ transplant recipients
– DAAs are highly efficacious and have improved outcomes in HIV-HCV co-infected organ transplant recipients
-With the passage of HOPE ACT, people living with HIV can register as organ donors. HAART has reduced HIV mortality and improved the quality of life.
-Status of organ transplantation by organ type. Kidney and later liver pts with HIV have been transplanted with the advent of HAART.
Kidney.
In the USA,0.5-1.5% of dialysis pts are HIV +VE ,These pts have lower survival rates in comparison to the non HIV popn but with good outcomes post transplantation in comparison to HD.
Bacterial infection prevalence is more in HIV pts on HD, Tx with ATG and those with HCV co infection.
Equally these pts have x2-3 allograft rejection rates in comparison to general popn. Possible explanations; inadequate immunosuppression and immune system dysregulation.
Despite data showing better outcomes with transplantation, most HIV pts still have longer HD duration, longer waiting time with clinicians having limited knowledge in handling them.
Liver.
Liver dx is 3rd cause of death in HIV pts.
The causes of Liver dx in this cohort; viral hepatitis, ART induced hepatotoxicity, hypersensitivity rxns, mitochondrial toxicity, steatosis or IRIS.
HIV with HEP B and C coinfection have good outcomes post liver transplantation with the advent of potent HAART and DAA therapy.
Pancreas.
Despite a few studies showing good outcomes in pancreas transplantation in HIV popn, more studies are needed for concrete guidelines to be developed and adopted.
Heart.
Heart transplant recipients have more rejection compared to non HIV popn and most get some mechanical circulation support pre transplant. More experience is needed on this.
Lung.
HIV is a relative CI to lung transplantation and those adherent to HAART with good CD4 should be considered.
CLINICAL MGT OF HIV INFECTED SOT CANDIDATES AND RECIPIENTS. Selection of candidates.
Pt with undetectable VL, compliance to HAART, no active OI or HIV associated malignancy with capability of good post op care i.e immunosuppressive meds monitoring and drug trough levels monitoring should be referred for transplantation in experienced centres.
With exception of liver where CD4 >100 cells/ul is recommended, other SOT require CD4 >200 cells/ul.
Antirejection therapy.
Immunosuppressive meds individualized depending on organ transplanted, UECS,LFTS status, HAART regimen and immunological risk.
ATG has been associated with infection and rejection in some studies.
Tac is the preferred CNI with lower rejection rates with MMF being used as the antimetabolite of choice in most pts.
Medication mgt.
Adequate drug levels and DI must be monitored and well managed.
PI inhibit CYP3A4 and affect CNI levels leading to nephrotoxicity and thus must be avoided whenever possible.
DTG is the preferred INSTI as it has a high barrier of resistance and easy dosing.
Clinical monitoring and care of HIV +VE persons pre and post transplantation.
Renal adjust meds post transplant and avoid nephrotoxic meds.
Early post transplant, with change in immunosuppressive meds and in the event of graft rejection,CD4 and VL should be monitored more frequently.
HIV to HIV transplantation.
SA and USA have pioneered thee but still risks to be studied include; superinfection with donor strain, transmission of latent OI and poor organ quality from varied kidney, liver and heart dx in the HIV popn.
HOPE act has allowed HIV-HIV transplantation to be done.
We still don’t have much evidence and experience in HIV +VE to HIV -VE pts.
Summary Introduction With increased life expectancy and an aging demographic, common medical comorbidities, such as coronary artery disease and nonalcoholic steatohepatitis, are becoming important causes of morbidity and mortality in persons with HIV (PWH). In addition, the metabolic side effects of both the virus and antiretroviral drugs place patients at a higher risk for organ dysfunction and, ultimately, organ failure. Over the past decade, accumulating evidence has established solid organ transplantation (SOT) as standard of care for PWH with end-stage kidney and liver disease, and more limited but encouraging data has demonstrated feasibility of pancreas, heart, and lung transplantation in PWH Status of organ transplantation by organ type Kidney In the United States where approximately 800 PWH are diagnosed with end-stage renal disease (ESRD) annually The causes of renal failure include focal segmental glomerulosclerosis, diabetes mellitus, and hypertension Coinfections with hepatitis C virus (HCV) and hepatitis B virus (HBV) increase risk for kidney failure Once transplanted, outcomes for PWH are favorable, with transplantation providing a clear survival benefit over renal replacement therapy A recent survey found that 16.9 and 28.1% of responding U.S. transplant programs still considered HIV as an absolute or relative contraindication to transplantation, respectively Liver PWH are at risk for end-stage liver disease through a variety of mechanisms The outcomes of liver transplantation in PWH vary by the reason for transplant As an example, in those with HIV-HBV co-infection, in the setting of passive prophylaxis with hepatitis B immunoglobulin and antiviral therapy, both graft and patient survivals range from 85 to 100% after 3–5 years Pancreas Outcomes have been mixed, with reported complications of graft thrombosis, rejection, and bacterial infections, including fatal sepsis pancreas transplantation can be successful in HIV-infected patients, but additional experience is needed. Heart PWH are prone to both cardiac diseases associated with aging, as well as those associated with the chronic immune activation state of HIV and metabolic effects In a recent study evaluating 41 HIVþ heart recipients, coronary artery vasculopathy occurred in 32% at 5 years post-transplant, compared with 29.3% in the general heart transplant population, indicating that risks of post-transplant vasculopathy are not any higher than HIV uninfected recipients Lungs A case series of three patients from the United States, as well as a small retrospective cohort study demonstrated feasibility of this approach in persons with advanced lung diseases Clinical management of HIV-infected organ transplant candidates and recipient CD4þ cell counts at least 200 cells/ml are recommended for transplantation of all organs The threshold for transplantation is CD4þ cell count more than 100 cells/ml, with the liver Candidates must also have demonstrated adherence to ART Absence of infections In the case of both kidney and liver transplant excellent HCV treatment outcomes have been achieved with DAA therapy. Antirejection therapy Regimens should be individualized to patients based on the organ transplanted, immunologic risk, renal and liver function, and ART regimen Conclusions Kidney and liver transplantation are the standard of care for HIV-infected persons with end-stage kidney and liver diseases. Encouraging results with transplantation of other organ types, including pancreas, heart, and lung suggest that persons with other advanced organ disease should also be referred to centers experienced in performing these transplants
Introduction: Due to antiretroviral therapy, HIV infection has become a chronic illness, with increased life expectancy, lading to increased morbidity and mortality due to medical co-morbidities like coronary artery disease (CAD) and nonalcoholic steatohepatitis (NASH). Persons with HIV (PWH) can also register as organ donor after the passage of HIV organ policy equity (HOPE) act, expanding the donor pool for HIV-infected patients.
Status of organ transplantation by organ type: PWH have been increasingly offered organ transplantation due to availability of antiretroviral therapy (ART).
Renal failure can occur in PWH due to diabetes mellitus (DM), hypertension, and focal segmental glomerulosclerosis (FSGS) besides HIV associated nephropathy (HIVAN). Co-infections with HBV and HCV as well as nephrotoxicity of certain ART drugs also play a role. Kidney transplantation in PWH has clear survival benefit as compared to remaining on dialysis. Due to viral suppression and good CD4 count pre-transplant, post-transplant opportunistic infection incidence is low, but there is increased bacterial infections, high rates of delayed graft function (DGF), and 2-3 times higher rates of acute rejection. The higher acute rejection rates seen could be due to underuse of immunosuppressives, drug interactions, or due to immune system dysregulation and heterologous immunoreactivity. Barriers to kidney transplantation in PWH include poor referral from their primary physicians for transplant, and longer wait-list times.
Liver disease is the third most common cause of death in PWH, with HBV and HCV infections, HIV itself, and ART medications (direct hepatotoxicity, steatosis, immune reconstitution, or hypersensitivity reactions) being the chief etiology for liver disease. Liver transplantation in PWH has variable outcomes with 3-5 year graft and patient survival ranging from 85-100%. DAA therapy introduction has led to improvement in graft and patient survival rates. Outcomes of pancreas transplantation have been mixed with very small number of transplants being performed till now. Incidence of CAD is increasing in PWH, in addition to HIV associated cardiomyopathy. It has been shown that heart transplant in PWH do not have higher risks of coronary artery vasculopathy as compared to HIV-uninfected recipients. HIV infection is a relative contraindication for lung transplant, with transplant to be considered if no recent AIDS-defining illness and demonstrated ART adherence with viral suppression.
Clinical management of HIV-transplant candidates and recipient: PWH should be referred to centers well versed with HIV-positive transplants. Prior to transplants, patient should have undetectable HIV viral load, CD4 count >200 cell/microL (>100 for liver transplant), comply with ART (except in patients with advanced liver disease), without any active opportunistic infection or malignancy, and should be available for close follow-up post-transplant. HCV infection should not be considered as an exclusion for transplant. If treatment can be safely delayed, such recipients can be offered HCV-viremic donor organs, with treatment using DAAs post-transplant.
Antirejection therapy: The best immunosuppressive regimen for PWH is not known, hence it is prudent to individualize the therapy. A trial showed that anti-thymocyte globulin (ATG) use as induction agent led to more frequent and sever infections and increased risk of graft loss as compared to Basiliximab use. Induction therapy is not required in majority of liver transplant recipients. Likewise, best maintenance immunosuppressive therapy for PWH has not been established and individualization is the key. The preferred combination used is of tacrolimus, mycophenolate and steroids. Calcineurin inhibitors (CNI) have been shown to decrease HIV-1 DNA transcription, leading to increase in HIV reservoir, while sirolimus has been shown to increase HIV-1 transcription, thereby reducing the HIV reservoir.
Medication management: Therapeutic drug monitoring and awareness and vigilance regarding drug interactions is important post-transplant. Protease inhibitors (PI) inhibit CYP3A4 enzyme, leading to increased CNI levels, while non-nucleoside reverse transcriptase inhibitors (NNRTI) reduce CNI levels. Boosted PI in liver transplant recipients lead to nephrotoxicity due to high CNI levels. PI use is associated with higher risk of rejection and mortality than non-PI regimen use. Non-boosted integrase strand transfer inhibitors (INSTI), especially dolutegravir, have emerged as favored ART in transplant recipients.
Clinical monitoring and care of HIV-positive persons:Pre-transplant, PWH should be placed on non-PI ART with the goal of minimizing toxicities and drug interactions. Post-transplant, ART regime would require frequent dose adjustments due to change in creatinine clearance. Agents compromising organ function (like tenofovir in renal transplant and abacavir in liver transplant) should be avoided. Similarly, fixed dose combinations should also be avoided. Any change in ART dose should be communicated to the transplant team. Regular HIV care in post-transplant period is essential with more frequent CD4+ cell count and HIV viral load testing. Post-transplant infective prophylaxis is also important.
HIV to HIV transplantation: HIV positive transplantation was declared illegal in 1984, but in 2008 HIV positive renal donor to HIV positive recipient were performed in South Africa, with good graft and patient outcomes. Theoretical risks of using HIV-positive organs include superinfection with donor HIV strain, transmission of antiviral resistance, risks of opportunistic infections, and risk of poor-quality organs. The HOPE Act (HIV organ policy equity act) laid down eligibility criteria for HIV-positive donors with detailed evaluation including HIV viral load, CD4 count, opportunistic complications, HIV resistance and tropism testing, ART therapy status, and HBV/ HCV co-infection presence. Data from HIV-positive to HIV-positive kidney and liver transplant showed excellent patient and graft outcomes. HIV-positive living donors should be assessed for HIV-specific risk factors for ESRD development like low CD4 count and HCV co-infection in addition to non-HIV-specific factors like hypertension, diabetes mellitus, and preexisting renal disease. Nephrotoxic ART (like tenofovir) and NSAIDs should be avoided post-donor-nephrectomy.
Conclusion: Renal and liver transplant is standard-of-care for HIV-infected patients with ESRD and end stage liver disease. Availability of INSTI and DAAs have simplified the post-operative management and improved patient outcomes. PWH can donate organs to HIV-infected persons in research settings.
The metabolic side effects of both the virus and antiretroviral drugs place patients at a higher risk for organ dysfunction and, ultimately, organ failure. Growing numbers of persons have undergone pancreas, heart, and lung transplantation, demonstrating feasibility.
With improvements in ART, HIV associated nephropathy (HIVAN) rates have declined, but in antiretroval-treated PWH, other causes of renal failure such as focal segmental glomerulosclerosis, diabetes mellitus, and hypertension remain prominent. Additionally, coinfections with hepatitis C virus (HCV) and hepatitis B virus (HBV) increased risk for kidney failure.
Importantly, several antiretroval agents, such as tenofovir, abacavir, indinavir, ritonavir-boosted lopinavir, ritonavir boosted atazanavir, and potentially other boosted protease inhibitors, are associated with nephrotoxicity and/or metabolic complications, including diabetes and dyslipidemias, which can ultimately contribute or lead to the development of chronic kidney disease and ESRD.
Once on dialysis, PWH has lower survival rates when compared with uninfected dialysis patients. Because of this, PWH are increasingly undergoing kidney transplantation.
Because all patients had viral suppression and CD4 cell counts at least 200 cells/ml prior to transplant and combination ART and posttransplant anti-infective prophylaxis was employed, HIV control was excellent, and few opportunistic infections were encountered.
Bacterial infections were observed with increased frequency in HIV recipients who were treated with the lymphocyte depleting agent, antithymocyte globulin (ATG) or coinfected with HCV.
Finally, HIV recipients experienced allograft rejection rates two to three times higher than observed in the general kidney transplant population, and rejection was a predictor for allograft failure. Single and multicenter studies reported in the United States and Europe have largely confirmed these results. Several proposed mechanisms for increased rate of rejections, including inadequate immunosuppression, either because of underuse of immunosuppressive agents or drug interactions that lead to inadequate or inconsistent immunosuppressive drug levels. Another potential explanation invokes immune system dysregulation and heterologous immunoreactivity in response to HIV and other chronic infections.
Barriers to referral and listing HIV patients for and undergoing kidney transplantation still exist. A recent survey found that 16.9 and 28.1% of responding U.S. transplant programs still considered HIV as an absolute or relative contraindication to transplantation, respectively. Clinical management of HIV-infected organ transplant candidates and recipient
Centers may vary in their candidacy requirements for transplantation, but updated guidelines recommend that, regardless of the organ transplanted:
· Patients have undetectable HIV viral load,
· Known compliance with ART,
· No evidence of active opportunistic infections or
· No HIV-associated malignancy, and
· The ability to have close follow-up for immunosuppression, drug level monitoring and management.
· CD4 cell counts at least 200 cells/ml are recommended for transplantation of all organs with the exception of liver.
Antirejection therapy
The best immunosuppressive regimen to use for patients with HIV is unknown. Regimens should be individualized to patients based on the organ transplanted, immunologic risk, renal and liver function, and ART regimen.
In the U.S. NIH observational trial, persons who received ATG as opposed to basiliximab, an IL-2 receptor antagonist, experienced significant, prolonged lymphocyte depletion, more frequent and severe infections, and increased risk for allograft loss. Other investigators, through analysis of registry data, reported lower rejection and infection rates with ATG. Based on this, the choice of induction agent should be individualized.
For HIV-infected transplant recipients, the best maintenance immunosuppressive regimens have not been established. Tacrolimus is associated with lower rejection rates and is the preferred calcineurin inhibitor. Calcineurin inhibitors have been found to decrease HIV-1 DNA transcription. Mycophenolate, an antiproliferative agent, is a very common component of maintenance immunosuppression. Although long-term maintenance prednisone therapy reduces risk for rejection, the benefits of its used should be weighed against the long-term effects of this agent.
Sirolimus is known to have anti-HIV effects through downregulation of CCR5, upregulation of b-chemokines, and blockade of the mammalian target of rapamycin (mTOR).
Medication management
Although immunosuppressive therapeutic drug monitoring is the responsibility of the transplanting center, HIV providers must be aware of key drug interactions with maintenance immunosuppressive therapies.
Protease inhibitors, via inhibition of cytochrome P450 3A4 (CYP3A4) enzyme, alter the pharmacokinetics of immunosuppressive medications, including the calcineurin inhibitors (tacrolimus, cyclosporine A) and mTOR inhibitors (sirolimus, everolimus), resulting in drastic alterations in doses and dosing schedules of these drugs. This increases the potential for inconsistent immunosuppressive levels that may place the patient at risk of rejection or, alternatively, supra-therapeutic levels that result in toxicity. Conversely, non-nucleoside reverse transcriptase inhibitors have differing potential for induction of CYP3A4. Studies in renal transplant recipients have also shown poor outcomes for patients on protease inhibitor-based regimens.
Non-boosted integrase strand transfer inhibitors (INSTI) have emerged as favored therapies. Raltegravir, dolutegravir, and bictegravir are completely or primarily metabolized through the uridine diphosphate glucuronosyltransferase 1A system, resulting in clinically insignificant interactions with the calcineurin inhibitors.
Clinical monitoring and care of HIVR persons before and after organ transplantation:
The HIV specialists’ partner should be present with the transplant team to optimize the required HIV therapy. Whenever feasible, patients should be placed on non-protease inhibitor-based ART regimens.
After transplant, often the same ART regimen may be continued, although clinicians must be cognizant of frequent fluctuation in kidney function that may require frequent dose adjustments, especially early in the post-transplant period.
In addition, HIV clinicians should avoid, when possible, agents that may compromise organ function, such as use of tenofovir disoproxil fumarate after kidney transplant or abacavir after heart transplantation.
in the setting of allograft rejection, and when immunosuppressive therapy is changed, more frequent monitoring of CD4+ cell counts, and HIV viral load is warranted.
HIV-to-HIV transplantation
In 2008, four HIV+ to HIV+ renal transplants were successfully performed in Cape Town, South Africa. Recent follow up data published by the same group notes that of the 51 patients transplanted with HIV+ organs, the 1, 3, and 5-year patient survivals were 87, 87, and 84% while 1, 3, and 5-year graft survivals 96, 93, and 79%. As of December 2018, 100 HIV+ persons have undergone deceased donor organ transplants in the United States with organs allocated under the HOPE Act.
A major concern is the potential consequences of superinfection with the donor HIV strain, including acquisition of CXCR4-tropic or dual/mixed-tropic virus or transmitted antiviral resistance. Other risks include transmission of latent or unrecognized opportunistic infections to the recipient and poor organ quality because of prevalent renal, hepatic, and cardiac diseases in the HIV population.
When evaluating potential candidates for donor nephrectomy, the assessment must include identification HIV-specific risk factors for development of ESRD such as low CD4+ cell count and HCV coinfection in addition to other conditions that generally exclude persons from donation (e.g. diabetes mellitus, hypertension, and preexisting kidney disease).
HIV+ African American persons with high-risk apoprotein L1 (APOL1) genotypes are at risk for development HIVAN and focal segmental glomerulosclerosis, but it is unknown whether APOL1 haplotype screening may be of utility in this setting. Post-nephrectomy, HIV+ donors should avoid nephrotoxic ART (such as tenofovir) in addition to agents such as nonsteroidal anti-inflammatory agents. To date, only two living donor kidney transplants have been reported, one with long-term good outcomes in both the donor and recipient.
The HIV Organ Policy Equality Act’s approval has increased the options available to PWH for organ donation and Transplantation, which is a life-saving treatment for PWH who have organ failure.
The current review focused on the status of SOT for HIV-infected persons, highlighting the outcomes of the current standards of care for, and unique aspects of post-transplant management. Status of organ transplantation by organ type: Kidney: The number of HIV patient with ESRD is increased recently for example in united states 800 patients with HIV ending with ESRD annually.
The earlier initiation of ART, HIV associated nephropathy (HIVAN) rates have decline, in spite of that ESRD increased because of focal segmental glomerulosclerosis, diabetes mellitus, and hypertension and also the side effects of ART which is nephrotoxic.
After transplantation, outcomes for PWH are favorable, with transplantation providing a clear survival benefit over renal replacement therapy. In USA0.5-1.5% of dialysis has HIV
Causes of CKD in HIV:
HIV induce nephropathy (decreased with ART)
FSGS
DM and HTN
Co-infection, HCV and HDV
Drug induced nephropathy
Survival is lesser than those without HIV.
Transplantation provides a clear survival benefit over renal replacement therapy. 1 and 3-year kidney allograft and patient survival estimates were 90.4 and 73.7 and 94.6 and 88.2%, respectively.
Associated with higher arte of bacterial infection especially with ATG, higher rate of DGF and 2 folds of rejection episodes.
A recent survey found that 16.9 and 28.1% of responding U.S. transplant programs still considered HIV as an absolute or relative contraindication to transplantation, respectively. Liver:
Liver disease is now the 3rd biggest cause of death in PWH in the era of HAART. PWH are susceptible to ESLD through different pathways. Chronic HCV and HBV co-infections occur in 2.4 & 6.1% of people worldwide, respectively.
In viral hepatitis, HIV infection increases the risk for advanced and progressive liver disease (ALD). ALD can also be brought on by ART.
ESLD can result from alcohol consumption and other non-HIV-related causes of liver disease, either as its major cause or a contributing component.
HCC can make the progression of ALD much more challenging. The number of HIV+ patients receiving liver TX is rising due to the frequency of ALD in this community, however PWH encounter barriers to liver TX, with HIV being viewed as an absolute or relative contraindication by 28.1 & 31.6% of surveyed U.S. TX centers, respectively. The TX results of HIV-HCV co-infected patients were poor (poorer graft & patient survival rates) compared to HCV-mono-infected controls.
This was due to the lack of hepatitis C DAA medications. Poor outcomes were a result of sepsis, severe infections, and increasing liver damage caused by HCV. Pancreas:
In the US in 2018, 836 SKP TX were carried out. Only 10 cases of this treatment being used on type 1 diabetic PWH have been documented.
Graft thrombosis, rejection, & bacterial infections, including deadly sepsis, were reported as complications. Pancreatic TX in HIV-positive patients is feasible but requires more practice. Heart:
PWH are vulnerable to age-related HD as well as those brought on by HIV’s chronic immunological activation state & the metabolic side-effects of ART. Prior to the development of ART, HIV-associated cardiomyopathy was seen; currently, CAD is a growing issue in PWH.
Heart TX is still uncommon, but HIV is no longer considered a strict contraindication to advanced heart failure therapy. The number of people seeking heart TX is expected to rise as the HIV population ages.
Currently, the 1- & 5-year after TX survival rates range from 64.7% to 77.3% & 85.9% to 90%, respectively.
The risk of post-transplant vasculopathy is not higher than in HIV-uninfected recipients. Rejection rates compared to the overall heart TX is greater. Lung:
There is a shortage of information about TX in PWH. HIV infection is a relative contraindication to lung TX in the 2014 revision of the ISHLT guidelines.
HIV-experienced facilities may consider PWH as candidates if they have a history of ART adherence, viral suppression, & no recent AIDS-defining condition. Few lung TX reports can be found in PWH. Clinical management of HIV-infected organ transplant candidates and recipient Selection of candidates:
Any patient with end-organ failure & stable HIV should be referred to centers experienced in HIV organ TX.
Patients should have undetectable HIV viral loads, known ART compliance, no signs of active opportunistic infections or HIV-associated malignancies, & the ability to have close follow-up for IS, drug level monitoring, & management.
Except for the liver, where a CD4 cell count of at least 100 cells/ml is required for TX, other organs should have CD4 cell counts of at least 200 cells/ml.
Although organ recipients with HCV co-infection had unfavorable outcomes in the pre-DAA era, HCV should not be regarded as a bar to TX.
DAAs have produced good HCV treatment outcomes in both kidney & liver TX. It’s crucial to consider factors like low BMI, the need for a combined liver-kidney TX, & HCV donor organs when assessing HCV-co-infected patients for liver TX. Anti-rejection Therapy:
The ideal IS regimen to administer to HIV patients is unknown.
Patients should have tailored regimens depending on the transplanted organ, immunologic risk, renal , hepatic function and ART regimen.
ATG as opposed to basiliximab, causes significant, extended lymphocyte depletion, more frequent, severe infections and a higher risk for allograft loss.
For most liver transplant recipients, induction IS is not necessary.
The best effective maintenance IS regimens are not yet known.
Tacrolimus is the primary CNI due to associated lower rejection rates. MMF is widely used in maintenance IS.
Prednisone maintenance medication minimizes the likelihood of rejection. Sirolimus has anti-HIV effects via upregulating β-chemokines, downregulating CCR5, & blocking the mTOR.
Sirolimus does not prevent HIV-1 transcription (In-vitro research). CNIs reduce HIV-1 DNA transcription. Medication management:
Anti-rejection medicine levels must be carefully monitored as low & high levels might have harmful effects.
Awareness of drug interactions with maintenance IS medicines is necessary.
Protease inhibitors alter the pharmacokinetics of IS drugs, such as CNIs & mTOR inhibitors, causing significant changes in their doses, dosing schedules and thus putting the patient at risk of rejection or, alternatively, toxicity.
Boosted protease inhibitor regimens were linked to ARF caused by high cyclosporine levels in liver TX recipients. Poor results for patients on protease inhibitor-based regimens have also been shown in renal TX recipients.
Non-boosted integrase strand transfer inhibitors (INSTI) have become popular treatments, but protease inhibitors have lost favor in TX. Raltegravir, dolutegravir, & bictegravir have negligible interactions with CNIs.
Because of its high barrier to resistance & simplicity of use, dolutegravir has become the preferred INSTI. Clinical monitoring, care of HIV +ve persons before and after TX:
The same ART treatment is frequently continued after transplant.
Abacavir use after heart TX or the use of tenofovir disoproxil fumarate after KTX are examples of drugs that HIV physicians should avoid whenever feasible.
Fixed dosage combination regimens should only be used with caution.
If a change in ART is being considered, HIV providers must consult with the TX center. HIV care must be regularly provided during the post-TX period.
More regular monitoring of CD4 cell counts & HIV viral load is necessary in the early post-TX period, in cases of rejection & when IS medication is modified.
Anti-infective prophylaxis is based on HIV recommendations as well as TX center practice. HIV-to-HIV transplantation:
The potential of superinfection with the donor HIV strain, such as the development of CXCR4-tropic or dual/mixed-tropic virus or transmitted antiviral resistance, are a big worry.
Additional hazards include the possibility of transmitting opportunistic infections that are latent or undiagnosed to the recipient as well as decreased organ quality due of the high prevalence of renal, hepatic and cardiac problems in the HIV population. Conclusions:
Standard of care for HIV-infected individuals with ESRD and liver disorders is Transplant . Positive outcomes with the transplant of other organ types (pancreas, heart and lung) imply that patients with other severe organ diseases should also be directed to transplant facilities with experience in these procedures. Treatment of the HIV organ recipient after transplant has been eased by the availability of INSTI, which has little interactions with IS medications. With their strong efficacy in the post-transplant environment, DAAs for hepatitis C promise to enhance outcomes for organ recipients who are also co-infected. The HOPE Act’s implementation allows PWH to donate organs to HIV-positive people awaiting kidney and liver TX in a research setting. HIV specialists should actively refer suitable patients for transplant, inform patients on the results of transplant, the advantages and disadvantages of using HIV-positive organs and ensure regular HIV infection surveillance following transplant.
Introduction
· HIV infection has become a chronic illness in the current era of antiretroviral therapy.
· Over the past decade, accumulating evidence has established solid organ transplantation (SOT) as standard of care for persons with HIV (PWH) who develop end-stage kidney and liver disease.
· Some limited data has shown feasibility of pancreas, heart, and lung transplantation in PWH.
Kidney transplantation in PWH:
· With improvements in and earlier initiation of ART, HIV associated nephropathy (HIVAN) rates have declined, but other causes of renal failure increased risk for kidney failure and ESRD in PWH.
· PWH have lower survival rates when compared with uninfected dialysis patients. This is why PWH are increasingly undergoing kidney transplantation.
· There is a clear survival benefit of renal transplant over dialysis in PWH.
· In the largest prospective observational trial conducted by Stock etal, 1 and 3-year kidney allograft where more than 90 and patients survival estimates at 1 and 3 years was 73.7 and 88.2%.
· However, this study identified, bacterial infections were observed with increased frequency in HIV recipients who were treated with ATG or coinfected with HCV.
· In this study PWH experienced higher rates of delayed allograft and allograft rejection than observed in the general kidney transplant population.
· Other studies reported in the US and Europe have largely confirmed the results of this study.
· In spite of international guideline-based support, PWH are meeting barriers to listing for and undergoing kidney transplantation. Livertransplantation in PWH
· In the era of highly effective ART, liver disease has become the third leading cause of death in PWH.
· The mechanism of this is multifactorial.
· The outcomes of liver transplantation in PWH vary by the reason for transplant.
· In those with HIV-HBV co-infection, passive prophylaxis with hepatitis B immunoglobulin and antiviral therapy, improved both graft and patient survivals after 3–5 years of follow-up.
· Before the availability of hepatitis C DAA agents, the transplant outcomes of HIV– HCV coinfected patients were problematic. Pancreastransplantation in PWH
· Outcomes of simultaneous pancreas-kidney transplants have been mixed with reported complications.
· Pancreas transplantation can be successful in HIV-infected patients, but additional experience is needed. Heart transplantation in PWH
· Based on recent studies, 1 and 5-year post transplant survivals are between 85.9–90% and 64–77.3%, respectively.
· In a recent study, the risks of post-transplant vasculopathy are not any higher than HIV uninfected recipients, but there were higher rates of rejection in PWH compared with the general heart transplant population. Lung transplantation in PWH
· There is a paucity of lung transplantation reports in PWH.
· Reports demonstrated feasibility of lung transplant in persons with advanced lung diseases. Clinical management of HIV-infected organ transplant candidates and recipients Selection of candidates
· Candidacy requirements for transplantation include, undetectable HIV viral load, compliance with ART, no evidence of active opportunistic infections or HIV-associated malignancy.
· CD4 cell counts at least 200 cells/ml are recommended for transplantation of all organs with the exception of liver, where more than 100 cells/ml is accepted.
· HCV co infection should not be considered an exclusion factor for transplant.
· In the case of both kidney and liver transplant, excellent HCV treatment outcomes have been achieved with DAA therapy. Antirejection therapy
· The best immunosuppressive regimen to use for patients with HIV is unknown
· Choice of induction agent should be individualized.
· Induction immunosuppression is not required in the majority of liver transplant recipients.
· For HIV-infected transplant recipients, the best maintenance immunosuppressive regimens have not been established.
· Tacrolimus is preferred as it is associated with lower rejection rates.
· MMF is commonly used.
· The benefits of long term use of prednisolone should be weighed against the long-term effects of this agent.
· There is a possibility of utilizing sirolimus as it is known to have anti-HIV effects. Medication management
· Protease inhibitors are inhibitors of cytochrome P450 thus leading to higher levels of IS medications, including the calcineurin and mTOR inhibitors.
· Non-nucleoside reverse transcriptase inhibitors leads to induction of CYP3A4, thereby lead to higher risk of graft loss.
· Dolutegravir has emerged as the favored non-boosted integrase strand transfer inhibitors (INSTI) due to its high barrier to resistance and ease of dosing. Clinical monitoring and care of HIVR persons before and after organ transplantation
· Whenever feasible, patients should be placed on non-protease inhibitor-based ART regimens.
· After transplant, often the same ART regimen may be continued.
· It is vital that HIV providers communicate with the transplant center whenever a change in ART is being contemplated because of fluctuating renal function and drugs interactions as outlines above.
· In the early post-transplant period, in the setting of AR, and when IS medication are changed, more frequent monitoring of CD4 cell counts and HIV viral load is needed.
· Life-long prophylaxis against Pneumocystis jiroveci is warranted. HIV-to-HIV transplantation Risks
· Super infection with the donor HIV strain, including acquisition of CXCR4-tropic or dual/mixed-tropic virus or transmitted antiviral resistance.
· Transmission of latent or unrecognized opportunistic infections to the recipient
· Poor organ quality because of prevalent renal, hepatic, and cardiac diseases in the HIV population. Data
· The South African experience has been overall promising and inspired action by the United States transplant community to expand HIV+ to HIV+ transplant to North America.
· As the U.S. trials are ongoing, only preliminary data are available but suggest excellent patient and allograft survivals for both kidney and liver recipients.
· Few cases of HIV to HIV living donor transplantation have been reported in the literature. Living donors should be evaluated for HIV-specific risk factors for development of ESRD such as low CD4 cell count and HCV coinfection.
Solid organ transplantation (SOT) is standard of care for PWH with end-stage kidney and liver disease.
· HIV Organ Policy Equity (HOPE) Act has enabled (Person With HIV) PWH to register as organ donors, expanding the donor pool for PWH and the organ donation pool as a whole. Kidney transplantation in PWH
FSGS, DM, hypertension, co-infection with HCV, HBV, and some ART drugs remains among the
Causes of ESRD in PWH: HAVIN (declining), FSGS, DM, HTN, HCV, HBV
Outcomes with kidney transplantation has been demonstrated to be better than remaining on dialysis but they have higher rate of rejection.
Liver transplantation in PWH
The co-infection with HCV, and HBV has contributed to liver failure among PWH, in addition to side effects of ART
The outcome of the PWH varies depending on mono infection, to the coinfection with HCV or HBV. The availability of HBV and HCV ttt have improving the outcome.
Clinical management of HIV-infected organ transplant candidates and recipient
There is no agreed induction therapy for transplantation in PWH/
Induction: IL-2 receptor inhibitor is favoured over ATG that could cause some complications
Maintenance: combination of CNIs, antimetabolites and steroid
Many interaction between ART and immunosuppression in particular CNI and protease inhibitors (associated with up to two fold of graft loss) when compared with non-protease inhibitor regimens.
HIV-to-HIV transplantation A major concern is the potential consequences of superinfection with the donor HIV strain, including acquisition of CXCR4-tropic or dual/mixed-tropic virus or transmitted antiviral resistance The HOPE Act has enabled the utilization of organs that may have otherwise been discarded due to false-positive HIV test results, with almost 50% of HOPE-allocated organs coming from donors with false-positive testing.
This is a review article discussing about organ transplantation in HIV patients Introduction:
HIV patients are now living longer dur to cART. However, this predisposes them to cardiac diseases and NASH. The medications used for HIV also cause metabolic conditions like diabetes and dyslipidemia leading to organ dysfunction. Previously, HIV patients were not considered for organ transplant due to the poor outcomes in the pre-HAART era. However, with the HAART the outcomes are comparable to patients without HIV. Before the HIV Organ Policy Equity (HOPE) Act, HIV patients could not register as organ donors.
Kidney:
With the advent of HAART, the incidence of HIVAN has reduced. However, other causes of CKD like FSGS, DM and hypertension are prominent. Co-infections with Hepatitis B and Hepatitis C increase the risk of kidney failure. There are also some ARVs like tenofovir, atazanavir, abacavir that cause kidney damage. Patients with HIV and who are on dialysis have a higher mortality as compared to non-HIV patients on dialysis.
ESKD patients with HIV have a favorable outcome comparable to the non-HIV patients. Stock et al looked at 150 HIV patients who had ESKD and who underwent kidney transplant and found that the 1 and 3 year graft and patient survival was 90.4 and 73.7% and 94.6 and 88.2% respectively. The HIV control was also excellent as all the patients were on ARVs and had a CD4 count of more than 200 cells/microliter.
However, they also found that in this cohort of patients, bacterial infections were increased especially in those patients who received ATG for induction. These patients also had a higher incidence of DGF and had a rejection rate that was 2-3 times higher than the general kidney population.
The higher rate of allograft rejection has been attributed to:
Underuse of immunosuppressive agents or drug interactions affecting the drug levels
Chronic inflammatory state in the HIV patients
Unfortunately, despite the comparable kidney transplant outcomes, people with HIV (PWH) remain on dialysis for a longer duration of time before transplant listing
Liver:
Liver disease has become the 3rd leading cause of death in HIV patients in the HAART era. PWH are at a higher risk of developing end stage liver disease due to:
Increased prevalence and incidence of HBV and HCV coinfection
Increased incidence of advanced liver disease and its progression due to HIV itself
ART hepatotoxicity
There may also be other contributing factors like alcohol and other non-HIV related factors that contribute to the development of ESLD
The outcomes of liver transplant vary depending on the cause of the liver disease.
In HIV/HBV coinfection with prophylaxis with hepatitis B immunoglobulin and antiviral therapy, both graft and patient survival range from 85-100% after 3-5 years of follow up.
Before the availability of DAA for HCV infection, liver transplant outcomes were not very good with lower patient and graft survival. However, this has changed with the advent of the DAAs
Pancreas:
Only 10 cases of pancreas transplant in PWH have been reported in literature. Outcomes have been mixed with reported complications of graft thrombosis, rejections and bacterial infections including fatal sepsis
Heart:
In the post-HAART era, more and more patients with HIV are developing coronary artery disease and ischemic cardiomyopathy with heart failure. HIV is no longer a contraindication to heart transplant.
The one and five year post transplant survival rates are between 85.9-90% and 64-77.3% respectively. The risks of vasculopathy are comparable to the non-HIV patients. The risk of rejection is higher than in the non-HIV population
Lung:
In the 2014 ISHLT guidelines, HIV has been moved from an absolute contraindication to a relative contraindication for lung transplant. There is a paucity of lung transplantation reports in PWH.
Clinical Management of HIV Infected Organ Transplant Candidates and Recipients:
Selection:
All patients with stable HIV who have end-organ damage should be referred to organ transplant centers well versed with HIV+ organ transplantation.
CD4 cell count of at least 200 cells/microliter are recommended for transplantation of all organs with the exception of liver, where the threshold for transplant is more than 100 cells/microliter for at least 3 months
The other criteria include:
Undetectable HIV viral load
Documented compliance to therapy
Absence of OIs and malignancy
Absence of chronic wasting or severe malnutrition
Access to ISS drug therapies post-transplant
Ability to regularly follow up with HIC care providers
Anti-Rejection Therapy:
The best ISS therapy for PWH who have undergone transplant is unknown
For induction therapy, ATG can cause prolonged lymphocyte depletion and CD4 count depletion. Therefore, basiliximab is the preferred induction agent. However, other studies reported lower rejection and infection rates with ATG.
For PWH who have been transplanted, the best maintenance ISS regimen has not yet been established. Tacrolimus has been associated with lower rejection rates and therefore, is the preferred CNI.
Medication Management:
Close attention needs to be paid to the drug to drug interactions between ARVs and the CNIs
The PIs have been known to increase the CNI levels which can lead to CNI toxicity and graft dysfunction
Clinical Monitoring:
PWH who have been transplanted should be co-managed with the HIV specialist
The same ART regiment the patient was on pre-transplant should be continued unless if it was a PI based regimen
Immediately post-transplant, more frequent HIV VL and CD4 count is warranted
Anti-infective prophylaxis is based on transplant center practices with many centers opting for lifelong PCP prophylaxis
HIV to HIV Transplantation:
In the HAART era the landscape of HIV positive patients receiving transplants has changed
In 2008, 4 HIV + to HIV + renal transplant were successfully performed in Cape Town, South Africa. These transplants were performed in the setting of limited access to dialysis, decreased organ availability and increased HIV deceased donors. The 1,3 and 5 year patient survivals were 87%, 87% and 84%. The graft survival was 96, 93 and 79%.
Very few cases of HIV-HIV living donor transplantation has been reported in the literature. When evaluating potential candidates for donor nephrectomy, the assessment must include identification of HIV specific risk factors for development of ESKD such as low CD4 cell count and HCV co-infection in addition to other conditions
Post-nephrectomy, HIV+ donors should avoid nephrotoxic ART
Conclusion:
Kidney and Liver transplant are the standard of care for PWH and have comparable results to the non-HIV population.
The availability of integrase inhibitors with minimal drug to drug interactions has improved care of the post-transplant patient.
HCV co-infected HIV patients have improved outcomes with the DAAs
The current review focused on the current status of SOT for HIV-infected persons, highlighting the outcomes of, the current standards of care for, and unique aspects of post-transplant management.
Status of organ transplantation by organ type Kidney:
In USA 0.5-1.5% of dialysis has HIV
Causes of CKD in HIV:
1- HIV induce nephropathy (decreased with ART)
2- FSGS
3-DM and HTN
4- co-infection, HCV and HDV
5- drug induced nephropathy
survival is lesser than those without HIV
Transplantation provides a clear survival benefit over renal replacement therapy
1 and 3-year kidney allograft and patient survival estimates were 90.4 and 73.7 and 94.6 and 88.2%, respectively.
Associated with higher arte of bacterial infection especially with ATG, higher rate of DGF and 2 folds of rejection episodes.
A recent survey found that 16.9 and 28.1% of responding U.S. transplant programs still considered HIV as an absolute or relative contraindication to transplantation, respectively.
Liver:
liver disease has become the third leading cause of death in HIV patients
HIV infection increases the risk for progressive and advanced liver disease (ALD) in those with viral hepatitis.
Liver transplantation is increasing but face barriers to liver transplantation, with HIV considered an absolute or relative contraindication by 28.1 and 31.6% of surveyed U.S. transplant centers, respectively.
In patients HIV-HBV co-infection, both graft and patient survivals range from 85 to 100% after 3–5 years of follow-up.
Pancreas:
Simultaneous pancreas-kidney transplantation is not commonly performed in type 1 diabetic HIV patient.
Outcomes have been mixed, with reported complications of graft thrombosis, rejection, and bacterial infections, including fatal sepsis.
Heart:
HIV is no longer considered an absolute contra-indication to advanced heart failure therapies, including heart transplantation.
Based on recent studies, 1 and 5-year post transplant survivals are between 85.9–90% and 64–77.3%, respectively.
Lung:
rare data available
no longer absolute contraindication.
Patient selection:
Updated guidelines recommend for transplantation:
1- patients have undetectable HIV viral load
2- known compliance with ART
3- no evidence of active opportunistic infections or HIV-associated malignancy,
4- the ability to have close follow-up for immunosuppression, drug level monitoring and management.
5- CD4+ cell counts at least 200 cells/ml are recommended for transplantation of all organs with the exception of liver, where the threshold for transplantation is CD4þ cell count more than 100 cells/ml.
Antirejection therapy:
The best immunosuppressive regimen to use for patients with HIV is unknown. Regimens should be individualized to patients based on the organ transplanted immunologic risk, renal and liver function, and ART regimen.
ATG induction, prolonged lymphocyte depletion, more frequent and severe infections, and increased risk for allograft loss. Other investigators, through analysis or registry data, reported lower rejection and infection.
For maintenance:
– Tacrolimus is associated with lower rejection rates.
-CNI have been found to decrease HIV-1 DNA transcription.
– Mycophenolate, is a very common component of maintenance immunosuppression.
-Although long-term maintenance prednisone therapy reduces risk for rejection,
the benefits of its used should be weighed against the long-term effects of this agent.
Medication management:
Close attention is needed to ensure adequate levels of antirejection drugs because of the drug interaction with ART.
Protease inhibitors, via inhibition of cytochrome P450 3A4 (CYP3A4) enzyme, alter the pharmacokinetics of immunosuppressive medications, including the calcineurin inhibitors and mTOR inhibitors (sirolimus, everolimus).
Receiving protease inhibitor-based regimens had a 1.8-fold higher risk of allograft loss and a 1.9-fold higher risk of mortality when compared with non-protease inhibitor regimens.
Clinical monitoring and care of HIVR person
HIV clinicians should avoid, when possible, agents that may compromise organ function, such as use of tenofovir disoproxil fumarate after kidney transplant or abacavir after heart transplantation.
Frequent monitoring of CD4+ cell counts and HIV viral load is warranted.
Anti-infective prophylaxis is based both on transplant center practices and HIV guidelines, with many centers opting for life-long prophylaxis against Pneumocystis jirovecii.
HIV-to-HIV transplantation
Accepted in deceased donors
Transplant specialists must make attempts to acquire as much HIV donor-specific data such as ART history, HIV genotypic testing, CD4+ cell counts, HIV viral load results, and history of opportunistic complications, so that donor suitability can be ascertained.
As the U.S. trials are ongoing, only preliminary data are available but suggest excellent patient and allograft survivals for both kidney and liver recipients.
Very few cases of HIV-to-HIV living donor transplantation have been reported in the literature:
When evaluating potential candidates for donor nephrectomy, the assessment must include identification HIV-specific risk factors for development of ESRD such as low CD4+ cell count and HCV co-infection in addition to other conditions that generally exclude persons from donation (e.g. diabetes mellitus, hypertension, and preexisting kidney disease).
To the date of publication, only two living donor kidney transplants have been reported, one with long-term good outcomes in both the donor and recipient.
Transplantation from HIV+ to HIV – donor is illegal in USA:
However, there is one reported case in the literature involving a partial living donor liver transplant from a South African HIV+ mother to her critically ill HIV-negative child with biliary atresia.
The authors report viral suppression in the ART-treated recipient since the time of transplant, and although there was initial seroconversion in the recipient, the child’s HIV antibody-antigen status declined to low reactive during the first year following the transplant
HIV became a chronic controllable disease by introduction of anti retroviral therapy, cardiovascular, liver steatohepatitis, and metabolic derangements caused by HIV and the ART, keep these patients at higher risk for organ dysfunction and graft loss in solid organ transplantations. The HIV Organ Policy Equity (HOPE) Act, allows HIV patients to be a donor to HIV recipients, increasing the pool of organs, and reducing mortality from end organ damage (kidney, liver, heart, lung ..etc) in those HIV patients. This article discuss the management, pre and post transplantation care, and the impact of the ART on graft and patients outcomes in HIV infected patients. Status of organ transplantation by organ type: There was fear of practicing organ transplantation before the revolution of ART, following data on specific organ transplantations in these patients are now evident:
Kidney: Prevalence of HIV in ESRD on dialysis in USA is 0.5-1.5%, the ART revolution reduces the risk of HIVAN, but FSGS, DM, and HTN are still the cause of ESRD. Co-infection with HCV and HBV, ART and protease inhibitors metabolic effects and nephrotoxicity can lead to development of CKD progressing to ESRD in PWH. Stock et al. 150 patients with controlled HIV by ART (CD4þ cell counts at least 200 cells/ml) underwent transplantation (post transplantation ART+ prophylactic antibiotics) with superior survival benefit from being on RRT, the common complications observed in the study are: – Increased risk of early bacterial infections, especially on those receiving ATG induction and HCV infection. – Higher events of delayed graft function requiring dialysis. – 2-3 fold increased rates of acute rejection due to: 1. Underuse of immunosuppressive medications or drug-drug interaction. 2. Dysregulation of the immune system, and heterologous immunoreactivity in response to HIV and other chronic infections. – Graft failure risk was higher than the general population.
Liver: Liver diseases are the third cause of death among HIV infected people (PWH), and caused by: – The prevalence of HCV and HBV co-infection are 2.4% and 6.1% respectively. – Advanced liver disease by HIV hepatic infection, ART toxicity, steotosis, or immune reconstitution. HIV-HBV co-infection, in the setting of passive prophylaxis with hepatitis B immunoglobulin and antiviral therapy, both graft and patient survivals range from 85 to 100% after 3–5 years of follow-up. Due to the frequency of breakthrough HBV viremia, lifelong prophylaxis is recommended. Before introduction of DAA for HCV, HIV-HCV co-infection was associated with significantly poor patient and graft survival post-transplants, contributed to HCV related progressive liver disease, and sepsis.
Pancreas: No sufficient data, only 10 case reports of kidney-pancreas transplants with variable complications.
Heart: HIV cardiomyopathy, ART induced cardiac toxicity, and coronary artery disease contributing to end stage heart failure in PWH, requiring heart transplantation. Based on recent studies, 1 and 5-year post transplant survivals are between 85.9–90% and 64–77.3%, respectively, higher rates of rejection, ranging from 39.3 to 67% in the one-year period after transplant, and Significantly, 53.7–57% of these patients received some form of mechanical circulatory support prior to transplant.
Lung: Data is lacking. Clinical management of HIV-infected organ transplant candidates and recipient: Candidate selection:
· Meet transplant center-specific eligibility for organ transplantation. · CD4+ cell count > 200 cells/µl during 3 months prior to transplantation for kidney, pancreas, heart and lung candidates. · CD4+ cell count > 100 cells/µl during 3 months prior to transplantation for liver candidates only (because of ALD and portal hypertension lead to splenic sequestration of white blood cells, including lymphocytes). · Undetectable plasma HIV viremia (unless unable to tolerate ART prior to liver transplant). · Documented adherence with stable ART regimen. · Absence of active opportunistic infection and malignancy. · Absence of chronic wasting or severe malnutrition. · HBV or HC V infection if no advanced fibrosis/cirrhosis (for organ types other than liver). · Access to immunosuppressive agent therapeutic drug monitoring. · Ability to regularly follow up with HIV care providers.
HCV co-infection, though problematic should not be considered an exclusion for transplant, in DAA recent very high SVR12 rates.
When evaluating HCV-coinfected persons for liver transplant, it is important to weigh factors predictive of liver allograft loss such as low BMI (21 kg/m2), need for combined liver–kidney transplant, and HCV+ donor organs. Antirejection therapy
Induction therapy should be individualized (basiliximab/ATG) Maintenance therapy: – Tacrolimus showed lower risk of rejection than cyclosporine – Calcineurin inhibitors have been found to decrease HIV-1 DNA transcription. – Prednisolone decreases rejection rate. – Mycophenolate commonly used. – m-TORi (sirolimus) has anti HIV effect through: (a) downregulation of CCR5. (b) upregulation of b-chemokines. (c) and blockade of the mammalian target of rapamycin Medication management
In post transplant HIV patients non-protease inhibitor-based ART regimens recommended.
Avoid tenofovir/disoproxil fumarate after kidney transplant and avoid abacavir after heart transplantation.
Protease inhibitors: are potent cytochrome P450 inhibitors, increasing IS trough level and toxicity.
Non-nucleoside reverse transcriptase inhibitors: CYP3A4 inducer thus decreasing IS trough level -> risk for rejection.
Non-boosted integrase strand transfer inhibitors: (Raltegravir, dolutegravir, and bictegravir), metabolized by uridine diphosphate glucuronosyltransferase, and have no interaction with CNI. (preferred).
Clinical monitoring and care of HIVR persons after organ transplantation
– Frequent and regular HIV viral load monitoring. – Regular kidney function followup and high index of suspecting infections. – PCP lifelong prophylaxis.
HIV-to-HIV transplantation:
Deceased HIV+ kidney and liver donors to HIV+ recipient have a good patient and graft survival.
Very few cases of HIV+ to HIV+living donor transplantation have been reported in the literature, limitations due to:
Frequent comorbidties, DM, HTN, Dyslipidemia.
HCV Co- infection.
HIV+ African American persons with high-risk apoprotein L1 (APOL1) genotypes are at risk for development HIVAN and FSGS.
Post-nephrectomy, HIV+ donors should avoid nephrotoxic ART (such as tenofovir), and NSAIDs .
HIV+ to HIV- is prohibited due high risk of disease transmission, one reported case from mother to her critically ill son with biliary atresia reported.
Conclusion: Kidney and liver transplantation in HIV+ patient is the standard of care for patients with ESRD and ESLD with specific criteria, waiting results on other organ transplantation results. DAA allowed transplant in HCV-HIV co-infection. Non-boosted integrase strand transfer inhibitors (dolutegravir) simplified the post-transplant management of the HIV+ organ recipient.
III. Organ transplantation in persons with HIV Please summarise this article. Status of organ transplantation by organ type
The availability of effective ART, persons with HIV (PWH) are increasingly seeking organ transplantation. The most evidence in support of transplantation in this population comes from kidney followed by liver transplantation. However, growing numbers of persons have undergone pancreas, heart, and lung transplantation, demonstrating feasibility. Kidney
The number of HIV patient with ESRD is increased recently for example in united states 800 patients with HIV ending with ESRD annually .
The earlier initiation of ART, HIV associated nephropathy (HIVAN) rates have decline, inspite of that ESRD increased because of focal segmental glomerulosclerosis, diabetes mellitus, and hypertension and also the side effects of ART which is nephrotoxic.
After transplantation , outcomes for PWH are favorable, with transplantation providing a clear survival benefit over renal replacement therapy. Liver
Because of highly effective ART, liver disease has become the third leading cause of death inpatient with HIV.
PWH are at risk for end-stage liver disease through a variety of mechanisms. The estimated global prevalence of chronic HCV and HBV co infections are 2.4 and 6.1%, respectively, although prevalence may differ regionally or by risk for acquisition( like injections).
Advance liver disease (ALD) can also result from ART whether caused by direct hepatotoxicity, hypersensitivity reactions, mitochondrial toxicity, steatosis and/or steatohepatitis, or immune reconstitution phenomena. Pancreas
Pancreas transplantation can be successful in HIV-infected patients, but additional experience is needed. Heart
HIV-associated cardiomyopathy was seen in the pre-ART, coronary artery disease is now a rising concerning PWH. Lung
The guidelines stipulate that HIVexperienced centers can consider PWH as candidates in the setting of demonstrated antiretroviral adherence with viral suppression and no recent AIDS-defining illness, There is a paucity of lung transplantation reports in PWH. Clinical management of HIV-infected organ transplant candidates and recipient Selection of candidate
HIV providers should refer any patient with end-organ damage and stable HIV to centers well versed in HIV positive organ transplantation.whom are:
1. Undetectable HIV viral load
2. Known compliance with ART.
3. No evidence of active opportunistic infections or HIV-associated malignancy.
4. Ability to have close follow-up for immunosuppression.
5. Drug level monitoring and management .
6. Absence of chronic wasting or severe malnutri!on
7. Hepatitis B or C infection if no advanced fibrosis/cirrhosis (for organ types other than liver)
8, Access to immunosuppressive agent therapeutic drug monitoring.
9. Ability to regularly follow up with HIV care providers. Antirejection therapy
The best immunosuppressive regimen to use for patients with HIV is unknown.
Regimens should be individualized to patients based on the organ transplanted, immunologic risk, renal and liver function, and ART regimen.
choice of induction agent should be individualized.
For HIV-infected transplant recipients, the best maintenance immunosuppressive regimens have not been established. Medication management
HIV providers must be aware of key drug interactions with maintenance immunosuppressive therapies.
Protease inhibitors, via inhibition of cytochrome P450 3A4 (CYP3A4) enzyme, alter the pharmacokinetics of immunosuppressive medications, including the calcineurin inhibitors (tacrolimus, cyclosporine A) and mTOR inhibitors (sirolimus, everolimus), resulting in drastic alterations in doses and dosing schedules of these drug. Clinical monitoring and care of HIV positive persons before and after organ transplantation
In the pre-transplant, HIV specialists partner with the transplant team to optimize HIV therapy, with the goal of minimizing pre-transplant toxicities and post-transplant drug interactions while maintaining viral suppression. After transplant, often the same ART regimen may be continued, although clinicians must be cognizant of frequent fluctuation in kidney function that may require frequent dose adjustments, especially early in the posttransplant period.
In the post-transplant period, regular HIV care is essential,by frequent monitoring of CD4 cell counts and HIV viral load is warranted. HIV-to-HIV transplantation
In the past In 1984 the National Organ Transplant Act the transmission of the disease get the transplantation illegal procedure.
Decades later, the landscapes of both HIV and transplantation have changed, making way for HIV positive to HIV-positive transplant.
In 2008, four HIV positive to HIV positive renal transplants were successfully performed in Cape Town, South Africa . These transplants were performed in the setting of limited access to dialysis, decreased organ availability, and increased HIV among brain-dead donors.
A major concern is the potential consequences of super infection with the donor HIV strain, Other risks include transmission of latent or unrecognized opportunistic infections to the recipient and poor organ quality because of prevalent renal, hepatic, and cardiac diseases in the HIV population.
Very few cases of HIV-to-HIV living donor transplantation have been reported in the literature. Conclusion
1.Kidney and liver transplantation are the standard of care for HIV-infected persons with end-stage kidney and liver diseases.
2. The availability of INSTI, with minimal impact on immunosuppressive drug levels, has greatly simplified the post-transplant management of the HIV positive organ recipient.
3. The introduction of DAAs for HCV, promise to improve outcomes in co infected organ recipients.
4.HIV providers should play an active role in referring appropriate patients for transplantation, educating patients regarding transplant outcomes and the potential risks and benefits of pursuing HIV-positive organs for transplant, and ensuring frequent monitoring of HIV infection after transplant.
· Kidney transplantation: (causes of ESKD in HIV patients)
o HIVAN is declining with early use of ARV therapy, but DM, HTN and FSGS, coexisting HBV and HCV infections are still leading causes of ESRD in HIV patients.
o Adverse effects of anti-retroviral therapy (ART) as nephrotoxicity with tenofovir, abacavir, indinavir, ritonavir-boosted lopinavir, ritonavir boosted atazanavir, and potentially other boosted protease inhibitors. In addition, dyslipidemia and inducing metabolic derangement which eventually leads to ESKD.
o Use of ARTincreased patient survival and hence appearance of complications as ESKD and ESLD and need for transplantation.
o Transplantation has better patient survival compared to dialysis. However, ATG use is associated with increased bacterial infection.
o Transplantation in HIV is associated with higher incidence of DGF and AR than HIV naïve recipients (may be related to immune-dysregulation, under immune-suppression).
o Still, the referral of HIV patients to transplantation and taking an active role on waiting list is underuse.
· Liver transplantation
o ESLD can result from coexisting HBV, HCV, ART hepatotoxicity and immune-reconstitution. In addition, other causes as alcoholism and non-HIV related causes can add on the problem.
o In case of coexisting HBV infection, the use of hepatitis B immunoglobulin, antiviral therapy and life-long prophylaxis can increase patient and graft outcome.
o In case of coexisting HCV infection, poor outcome is witnessed (improved with DAAV).
· Pancreas transplantation:
o only 10 reported cases with poor outcome as graft thrombosis, rejection, and bacterial infections including fatal sepsis. Further experience is required.
· Heart transplantation:
o Heart failure and need to transplantation du2 HIV related cardiomyopathy, aging, antiretroviral therapy induced dyslipidemia and DM.
o Coronary vasculopathy post-transplant and rejection is slightly higher than HIV naïve patients.
· Lung transplantation:
o Very limited data, but HIV changed from absolute to relative contraindication in lung transplantation for advanced lung disease.
· Prerequisites to transplantation in HIV patients:
o Undetectable HIV viral load, adherence to ART, no evidence of active opportunistic infections or HIV-associated malignancy or chronic malnutriotion..
o CD4 T cell counts > 200 cells/ml are recommended for transplantation of all organs, except liver, where the threshold for transplantation > 100 cells/ml.
o No fibrosis/ cirrhosis in case of coexisting HBV or HCV infection (in case of any organ transplantation except the liver).
o Strict follow-up for immunosuppression, drug level monitoring and management.
· Treated cutaneous KS and anal carcinoma in situ were not exclusions in the initial HIV-TR trial. All other treated malignancies with disease-free intervals are considered per center-specific policies.
· Use of DAAV in case of coinfection with HCV can improve the graft and patient outcome.
· Induction with ATG can increase risk of infections after transplantation, generally not required in liver transplantation.
· Maintenance with TAC based triple therapy with (MMF and steroids) is generally recommended.
· ART interaction with CNI and mTORi:
o Protease inhibitors= inhibition of cytochrome P450=increase trough level of IS.
o Non-nucleoside reverse transcriptase inhibitors=induction of CYP3A4= decrease trough level.
o Non-boosted integrase strand transfer inhibitors (INSTI) as (Raltegravir, dolutegravir, and bictegravir) have emerged as favored therapies in transplantation as they are metabolized by uridine diphosphate glucuronosyltransferase (no interaction with CNI).
o Dolutegravir has emerged as the favored INSTI due to its high barrier to resistance and ease of dosing
· Recommendation for HIV patients in transplantation:
o Should be treated with non-protease inhibitor-based ART regimens.
o Follow up of infectious complications and graft function.
o Follow up of HIV viral load and CD4 T cells count.
o Avoid tenofovir disoproxil fumarate after kidney transplant and avoid abacavir after heart transplantation.
· HIV donor used only for HIV recipient (only in case of deceased donor). However, there is fear of superinfection with the donor HIV strain, including acquisition of CXCR4-tropic or dual/mixed-tropic virus or transmitted antiviral resistance or transmission of latent or unrecognized opportunistic infections.
· HIV+ to HIV + transplantation has an excellent patient and allograft survivals for both kidney and liver recipients.
· While HIV donation in living kidney donation is not practiced, just 2 reported cases in kidney transplantation.
o Coexisting conditions generally exclude persons from donation (e.g. diabetes
o HIVþ African American persons with high-risk apoprotein L1 (APOL1) genotypes are at risk for development HIVAN and FSGS.
o Post-nephrectomy, HIVþ donors should avoid nephrotoxic ART (such as tenofovir) in addition to agents as NSAIDS.
Summary: Introduction:
With increased life expectancy and an aging demographic, common medical comorbidities, such as coronary artery disease and nonalcoholic steatohepatitis, are becoming important causes of morbidity and mortality in persons with HIV (PWH). In addition, the metabolic side effects of both the virus and antiretroviral drugs place patients at a higher risk for organ dysfunction and, ultimately, organ failure. Over the past decade, accumulating evidence has established solid organ transplantation (SOT) as standard of care for PWH with end-stage kidney and liver disease, and more limited but encouraging data has demonstrated feasibility of pancreas, heart, and lung transplantation in PWH. Status of organ transplantation by organ type: Kidney:
In the United States where approximately 800 PWH are diagnosed with end-stage renal disease (ESRD) annually, it is estimated that 0.5–1.5% of the United States dialysis population is made up of PWH.
Once transplanted, outcomes for PWH are favorable, with transplantation providing a clear survival benefit over renal replacement therapy.
FSGS, DM, hypertension, co-infection with HCV, HBV, and some ART drugs remains among the common cause of ESRD in PWH.
Stock et al. reported the outcomes of 150 HIV-infected patients after kidney transplantation; 1 and 3-year kidney allograft and patient survival estimates were 90.4 and 73.7 and 94.6 and 88.2%, respectively.
A recent survey found that 16.9 and 28.1% of responding U.S. transplant programs still considered HIV as an absolute or relative contraindication to transplantation, respectively. This is also similar to what was found in France.
Liver:
The co-infection with HCV, and HBV are 2.4 and 6.1%, respectively which causes liver failure among PWH, in addition to adverse effects of ART.
Alcohol and other non-HIV-related causes of liver disease may occur as primary or contributing factors to the development of end stage liver disease.
The outcomes of liver transplantation in PWH vary by the reason for transplant. As an example, in those with HIV-HBV co-infection, in the setting of passive prophylaxis with hepatitis B immunoglobulin and antiviral therapy, both graft and patient survivals range from 85 to 100% after 3–5 years of follow-up
Pancreas:
Outcomes have been mixed, with reported complications of graft thrombosis, rejection, and bacterial infections, including fatal sepsis.
With these findings, pancreas transplantation can be successful in HIV-infected patients, but additional experience is needed.
Heart:
· PWH are prone to both cardiac diseases associated with aging, as well as those associated with the chronic immune activation state of HIV and metabolic effects of ART
· In a recent study evaluating 41 HIVþ heart recipients, coronary artery vasculopathy occurred in 32% at 5 years post-transplant, compared with 29.3% in the general heart transplant population, indicating that risks of post-transplant vasculopathy are not any higher than HIV uninfected recipients Lung:
There is a paucity of lung transplantation reports in PWH.
A case series of three patients from the United States, as well as a small retrospective cohort study demonstrated feasibility of this approach in persons with advanced lung diseases.
Clinical management of HIV-infected organ transplant candidates and recipient: Selection of candidates:
• CD4+ cell count > 200 cells/µl during 3 months prior to transplantaton for kidney, pancreas, heart and lung candidates
• CD4+ cell count > 100 cells/µl during 3 months prior to transplantaton for liver candidates only
• Undetectable plasma HIV viremia (unless unable to tolerate antiretroviral therapy prior to liver transplant
• Documented adherence with stable antiretroviral treatment regimen
• Absence of active opportunistic infection and malignancy
• Absence of chronic wasting or severe malnutrition
• Hepatitis B or C infection if no advanced fibrosis/cirrhosis (for organ types other than liver)
• Access to immunosuppressive agent therapeutic drug monitoring
• Ability to regularly follow up with HIV care providers Conclusion:
Kidney and liver transplantation are the standard of care for HIV-infected persons with end-stage kidney and liver diseases. The availability of INSTI, with minimal impact on immunosuppressive drug levels, has greatly simplified the post-transplant management of the HIV positive organ recipient.
Introduction
Antiretroviral medication has made HIV a chronic illness and reduced overall and AIDS-related mortality. Due to increased life expectancy and an aging population, HIV patients are dying from common medical comorbidities such as coronary artery disease and nonalcoholic steatohepatitis. The metabolic side effects of the virus and antiretrovirals increase the probability of organ malfunction and failure.
Over the past decade, solid organ transplantation has become the standard of care for PWH with end-stage kidney and liver disease, and limited but promising data has shown the feasibility of pancreas, heart, and lung transplantation in PWH. The HIV Organ Policy Equity (HOPE) Act allows PWH to register as organ donors, extending the donor pool for PWH and the organ donation pool as a whole.
This review discusses SOT for HIV-positive patients, including outcomes, standards of care, and specific post-transplant management.
Status of organ transplantation by organ type
In terms of survival, transplantation obviously outperforms dialysis.
Following up on 150 HIV+ patients who underwent KTX, the findings were as follows:
The rates of kidney allograft and patient survival after one and three years were 90.4, 73.7, 94.6, and 88.2%, respectively.
There was very good HIV control.
Opportunistic infections were minimal.
Before TX, CD4 cell levels were at least 200 cells/ml.
Anti-infective post-TX prophylaxis was combined with ART.
Bacterial infections in HIV patients were more common when ATG and HCV were co-infected. Also, DGF rates were high in PWH, although this did not appear to be a reliable predictor of graft failure.
Rejection rates for HIV recipients were 2 to 3 times higher than those for the overall KTX group.
Several single- and multicenter studies have supported the results of this pilot trial.
PWH have challenges when applying for and acquiring a KTX.
More thorough statistics are needed to comprehend the variations in referral and ultimate reception.
Liver transplantation
In the era of HAART, liver disease the 3rd leading cause of death in PWH.
ESLD affects PWH in many ways. 2.4 and 6.1% of people globally have chronic HCV/HBV co-infections.
HIV raises the likelihood of severe and progressive liver damage in viral hepatitis. ART causes ALD.
Alcohol and other non-HIV-related liver diseases can cause ESLD.
HCC can exacerbate ALD. Because to the prevalence of ALD in HIV+ patients, liver TX is becoming more common, however 28.1 and 31.6% of U.S. TX centers see HIV as an absolute or relative contraindication.
HIV-HCV co-infected individuals had lower graft and patient survival rates than HCV-mono-infected controls. Because to hepatitis C DAA shortages. Sepsis, severe infections, and HCV-induced liver damage produced poor outcomes.
Pancreas transplantation
In 2018, 836 SKP TX were performed in the United States. Only ten instances of this treatment being administered to PWH with type 1 diabetes have been documented.
Complications included graft thrombosis, rejection, and bacterial infections, including lethal sepsis. Pancreatic TX in HIV-positive individuals is possible, but more practice is required.
Heart transplantation
PWH are susceptible to age-related HD, HIV-induced chronic immunological activation, and ART-induced metabolic side effects.
HIV-associated cardiomyopathy predated ART, however PWH now have CAD.
HIV no longer precludes sophisticated heart failure therapy, but heart TX is rare. As HIV patients age, more will seek cardiac TX.
1- and 5-year TX survival rates are 64.7%–77.3% and 85.9%–90%, respectively.
Post-transplant vasculopathy risk is comparable to HIV-uninfected recipients. Rejection rates exceed heart TX.
Lung transplantation
There is a lack of knowledge on lung transplantation in PWH.
Under the 2014 version of the ISHLT guidelines, HIV infection is a relative contraindication for lung TX.
If they have a history of ART adherence, viral suppression, and no recent AIDS-defining disease, HIV-experienced facilities may consider PWH as candidates. There are few reports of lung TX in PWH.
Treatment for rejection
Unknown is the optimal immunosuppressive regimen for HIV patients.
According to the transplanted organ, immunologic risk, renal and hepatic function, and antiretroviral therapy (ART) regimen, the patient’s regimen should be individualized.
ATG, as compared to basiliximab, results in considerable and prolonged lymphocyte depletion, more frequent and severe infections, and an increased risk of allograft loss.
The majority of liver transplant recipients do not require induction IS.
The most effective IS maintenance regimes have not yet been determined.
Because of associated decreased rejection rates, Tacrolimus is the predominant CNI.
MMF is widely employed in IS for maintenance.
Prednisone maintenance treatment reduces the risk of rejection.
Sirolimus exerts anti-HIV actions through the upregulation of -chemokines, the downregulation of CCR5, and the inhibition of mTOR.
Sirolimus does not block HIV-1 transcription
CNIs inhibit HIV-1 DNA synthesis.
HIV-to-HIV transplantation
The possibility of superinfection with the donor HIV strain, such as the emergence of CXCR4-tropic or dual/mixed-tropic viruses or the transmission of antiviral resistance, is a major cause for concern.
Further risks include the chance of spreading latent or undiscovered opportunistic infections to the receiver, as well as poor organ quality due to the high prevalence of renal, hepatic, and cardiac issues in the HIV community.
In conclusion, HIV-infected patients with end-stage renal and liver illnesses are optimally treated with kidney and liver transplants. The success of pancreatic, heart, and lung transplants suggests that advanced organ disease patients should also be referred to transplant clinics. INSTI, which has low immunosuppressive medication effects, has substantially simplified HIV-positive organ recipient post-transplant treatment. Coinfected organ recipients may benefit from the introduction of DAAs for hepatitis C, which are highly effective post-transplant. Finally, the HOPE Act allows PWH to donate kidney and liver transplants to HIV-positive patients in research settings. HIV providers should refer appropriate individuals for transplantation, educate patients on transplant outcomes and the risks and advantages of using HIV-positive organs, and monitor HIV infection following transplant.
Organ Transplantation in Persons with HIV Summary of the Article Introduction
With ART both overall and AIDs-related mortality has declined.
HIV and ART are prone patients to at high risk of mortality and organ failure.
SOT has been established as the standard of care for HIV patients with ESKD and liver disease, with the feasibility of pancreas, heart, and lung Tx in PWH.
HOPE act, PWH can be registered as organ donors as a pool for PWH waiting recipients, and it helps expand the donor pool.
Status of Organ Transplantation by Organ type Kidney
Although ART reduces the incidence of HIVAN and hence ESKD, still there is a percentage of patients who develop ESKD as a result of medication side effects (FSGS, DM, and HTN), and coexistence of HCV or HBV infection that may cause kidney failure.
With transplantation the overall outcome is favorable and it has benefits over dialysis.
Stock et al; a prospective observational study, studied 150 HIV-infected patients after kidney Tx; after 1-3 years, resulted in;
a) Allograft and patient survival was 90.4% and 73.7% in 1 year. b) Allogfart and patient survival was 94.6% and 88.2% in 3 years.
Measures to increase grat and patients survival;
a) ART before Tx. b) CD4 cell counts >/200 cells. c) ART and anti-infection plan post-Tx.
Bacterial infection increased in patients;
a) Receive depleting agents. b) HCV co-infection.
PWH experienced a high rate of DGF, and a rejection rate two to three times higher than observed in the general kidney Tx population.
Liver
The outcome of liver transplantation with HIV+ varies according to the reason for transplantation
a) HIV-HBV co-infection, the graft, and patient survivals range from 85 to 100% after 3-5 years of follow-up, due to the frequency of breakthrough HBV viremia, lifelong prophylaxis is recommended. b) HIV-HCV co-infection, before DAA the outcome is significantly lower in graft and patients survival, compared to HCV-mono-infection, with estimated 1,3, and 5-years graft survival 52 to 86%, 45 to 60%, and 31 to 45% respectively, while HCV-mono-infection ranged from 57 to 88, 50 to 62, and 358% respectively. Pancreas Pancreas transplantation can be successfully done in HIV-infected patients, but additional experience is needed. Heart
Coronary artery disease is a rising concern in PWH.
HIV is no longer considered an absolute CI to advanced heart failure, including heart transplantation.
A study of 41 HIV+ heart recipients showed that
a) Coronary artery vasculopathy occurred in 32% at 5 years post Tx compared to 29.3% in the general population. b) Higher rate of rejection, 39.3 to 67% in the 1st year, compared to the general population. Lung
Lacking data in lung transplantation with HIV+ patients.
ISHLT guidelines 2014;
a) HIV infection moves from absolute to relative CI to transplantation. b) HIV experience center can consider HIV as a candidate in the setting of; ART adherence with viral suppression and no clinical AIDS. Clinical management of HIV-infected organ transplant candidates and recipients Selection of candidates
Patient criteria according to the updated guidelines;
a) Undetectable viral load. b) Known compliance with ART. c) No active opportunistic infections. d) No associated malignancy. e) Feasibility to follow up. f) CD4 cell counts >/200 cells/microL, unless in the liver transplant which is >/100 cells/microL.
HCV is not considered as an exclusion of Tx with the availability of DAA.
Low BMI is recommended for combined liver-kidney Tx and HCV+ donor organs.
Antirejection therapy
The recipient who receives ATG is more exposed to (compared to basiliximab);
a) Prolonged lymphocyte depletion. b) More frequent and severe infections. c) Increased risk of allograft rejection.
There is lacking data on the use of induction therapy.
No established IS regimen yet, but the preferred regimen includes (CNIs, MMF, and +/-Prednisolone).
Sirolimus is known to have anti-HIV properties.
CNIs have a to decrease HIV-1 DNA transcription.
MMF has antiproliferative properties.
TAC is associated with a lower rejection rate.
Medication management
Protease inhibitors need an adjusted dose of IS as it is a CYP3A4.
PI has a 1.8-fold higher risk of allograft loss and 1.9-fold higher mortality when compared with a non-PI.
Higher risk of rejection associated with PI-CNIs.
Raltegravir, dolutegravir, and bictegravir are non-reacting with CNIs as they are entirely metabolized through uridine diphosphate.
Clinical monitoring and care of HIV+ persons before and after Tx Pretransplant
HIV specialists and transplant teams should optimize ART therapy to minimize pre-Tx toxicity and post-Tx drug interaction.
Post Tx
Frequent dose monitoring especially early after Tx.
HIV clinicians should avoid where possible agents may compromise graft function.
Early post-Tx, monitoring CD4 cell count and HIV viral load is mandatory.
Anti-infection prophylaxis.
Conclusion
Liver and kidney Tx are the standards of care for HIV-infected persons with end-stage kidney and liver disease.
Transplants should be in specialized centers to ensure a better outcome for Tx.
DAA availability provides a better outcome in end-stage organs failure in patients with coinfection.
HIV infection has become a chronic illness in the current age of antiretroviral therapy; both overall and AIDS-related mortality has declined
In the United States where approximately 800 PWH are diagnosed with end-stage renal disease (ESRD) annually With improvements in and earlier initiation of ART, HIV associated nephropathy (HIVAN) rates have declined, but in anti retroval-treated PWH, other causes of renal failure such as focal segmental glomerulosclerosis, diabetes mellitus, and hypertension remain prominen
Co infections with hepatitis C virus (HCV) and hepatitisB virus (HBV) increase risk for kidney failure
Ant I rejection therapy :
The best immunosuppressive regimen to use for patients with HIV is unknown. Regimens should be individualized to patients based on the organ transplanted, immunologic risk, renal and liver function, and ART regimen.
Persons With HIV (PWH):Status of organ transplantation by organ type
1. Kidney
· PWH have lower survival rates when compared with uninfected dialysis patients.
· Causes of CKD in PWH: HIVAN, co-infection with HBV& HCV, adverse effects of cART beside other causes like DM, HTN and FSGS.
· Transplantation outcomes for PWH are favorable and provide a clear survival benefit over renal replacement therapy.
· Complications that can occur during the post-kidney transplant course of PWH: Bacterial infections, high rates of delayed allograft function, allograft rejection rates two to three times higher than observed in the general kidney transplant population.
2. Liver
· PWH face barriers to liver transplantation, with HIV considered an absolute or relative contraindication by 28.1 and 31.6% of surveyed U.S. transplant centers, respectively.
· The outcomes of liver transplantation in those with HIV-HBV co-infection, in the setting of passive prophylaxis with hepatitis B immunoglobulin and antiviral therapy, both graft and patient survivals range from 85 to 100% after 3–5 years of follow-up.
· Before the availability of hepatitis C directly acting antiviral (DAA) agents, the transplant outcomes of HIV-HCV coinfected patients were problematic, with significantly lower graft and patient survival rates compared with HCV-mono-infected controls.
3. Pancreas
· Outcomes have been mixed, with reported complications of graft thrombosis, rejection, and bacterial infections, including fatal sepsis.
· Only ten cases are reported in the literature, based on these findings, pancreas transplantation can be successful in HIV-infected patients, but additional experience is needed.
4. Heart
· HIV is no longer considered an absolute contra-indication to advanced heart failure therapies, including heart transplantation.
· Based on recent studies, 1 and 5-year post transplant survivals are between 85.9 -90% and 64 -77.3%, respectively.
· The risks of post-transplant vasculopathy are not any higher than HIV uninfected recipients.
5. Lung
· There is a paucity of lung transplantation reports in PWH.
· A case series of three patients from the United States, as well as a small retrospective cohort study demonstrated feasibility of this approach in persons with advanced lung diseases.
Clinical management of HIV-infected organ transplant candidates and recipient
1. Selection of candidates Candidacy requirements for transplantation:
a) undetectable HIV viral load.
b) known compliance with ART.
c) no evidence of active opportunistic infections.
d) No HIV-associated malignancy.
e) The ability to have close follow-up for immunosuppression, drug level monitoring and management.
f) CD4+ cell counts at least 200 cells/ml(the threshold for liver transplantation is CD4+ cell count more than 100 cells/ml, why? The ALD and portal hypertension lead to splenic sequestration of white blood cells, including lymphocytes.
g) Adherence to ART as evidenced by viral suppression.
h) When evaluating HCV-coinfected persons for liver transplant, it is important to weigh factors predictive of liver allograftloss such as: low BMI (<21 kg/m2), need for combined liver-kidney transplant, and HCV+ donor organs.
2. Antirejection therapy
a) The best immunosuppressive regimen to use for patients with HIV is unknown.
b) Regimens should be individualized to patients based on the organ transplanted, immunologic risk, renal and liver function, and ART regimen.
c) For HIV-infected transplant recipients, the best maintenance immunosuppressive regimens have not been established.
· Tacrolimus is associated with lower rejection rates, and for this reason, has emerged as the preferred CNI.
· Calcineurin inhibitors have been found to decrease HIV-1 DNA transcription.
· Sirolimus have anti-HIV effects through downregulation of CCR5, upregulation of b-chemokines, and blockade of the mammalian target of rapamycin (mTOR).
3. Medication management
a) Close attention is needed to ensure adequate levels of antirejection drugs.
b) High awareness of drug interactions with maintenance IS.
· Protease inhibitors, via inhibition of cytochrome P450 3A4 (CYP3A4) enzyme, alter the pharmacokinetics of CNIs and mTOR inhibitors( boosted protease inhibitors regimens were associated with episodes of acute renal failure from high cyclosporine levels).
· Studies in renal transplant recipients have shown poor outcomes for patients on protease inhibitor-based regimens(1.8-fold higher risk of allograft loss and a 1.9-fold higher risk of mortality).
· Non-nucleoside reverse transcriptase inhibitors have differing potential for induction of CYP3A4.
· Non-boosted integrase strand transfer inhibitors (INSTI) have emerged as favored therapies. Raltegravir, dolutegravir, and bictegravir are completely or primarily metabolized through the uridine diphosphate glucuronosyltransferase 1A system, resulting in clinically insignificant interactions with the calcineurin inhibitors.
· Raltegravir have found that it is well tolerated and effective to use in the setting of transplantation.
· Dolutegravir has emerged as the favored INSTI due to its high barrier to resistance and ease of dosing.
4. Clinical monitoring and care of HIV+ persons before and after organ transplantation
a) MDT; including HIV providers, HIV clinician, transplant nephrologist and microbiologist.
b) Monitoring of IS drug level.
c) Monitoring for drug-drug interaction.
d) Frequent monitoring of CD4+ cell counts and HIV viral load.
HIV-to-HIV transplantation
1. In 1984 the National Organ Transplant Act was enacted, making it illegal to use HIV+ organs for transplantation.
2. In 2008, four HIV+ to HIV+ renal transplants were successfully performed in Cape Town, South Africa. These transplants were performed in the setting of limited access to dialysis, decreased organ availability, and increased HIV among brain-dead donors.
3. Follow up data of the 51 patients transplanted with HIV+ organs, the 1, 3, and 5-year patient survivals were 87, 87, and 84% while 1, 3, and 5-year graft survivals 96, 93, and 79%.
4. Very few cases of HIV-to-HIV living donor transplanta- tion have been reported in the literature.
Conclusion
1. Kidney and liver transplantation are the standard of care for HIV-infected persons with end-stage kidney and liver diseases.
2. The availability of INSTI, with minimal impact on immunosuppressive drug levels, has greatly simplified the post-transplant management of the HIV+ organ recipient.
3. The introduction of DAAs for HCV,promise to improve outcomes in coinfected organ recipients.
Introduction: Antiretroviral therapy has made HIV a chronic illness and reduced overall and AIDS-related mortality. With longer life expectancies and an aging population, prevalent medical comorbidities including coronary artery disease and nonalcoholic steatohepatitis are becoming major sources of morbidity and mortality in HIV-positive people. The metabolic side effects of the virus and antiretrovirals increase the probability of organ malfunction and failure. Over the past decade, solid organ transplantation (SOT) has become standard of treatment for PWH with end-stage kidney and liver disease, and promising data has shown that pancreas, heart, and lung transplantation in PWH is feasible. PWH can now register as organ donors thanks to the HIV Organ Policy Equity (HOPE) Act. This review discusses SOT for HIV-positive patients, including outcomes, standards of care, and specific post-transplant management. The American Society of Transplantation recently published updated guidelines on SOT management in PWH, but HIV care providers must understand how HIV management decisions affect pre- and post-organ transplant care and how post-transplant immunosuppressive practices affect HIV and transplant outcomes in this unique patient population. Kidney: 800 PWH are diagnosed with ESRD yearly. ART advancements and earlier initiation have reduced HIV-associated nephropathy (HIVAN) rates, however focal segmental glomerulosclerosis, diabetes, and hypertension still cause renal failure in antiretroviral-treated PWH. HCV/HBV coinfections increase renal failure risk. Notably, tenofovir, abacavir, indinavir, ritonavir-boosted lopinavir, atazanavir, and possibly other boosted protease inhibitors can cause nephrotoxicity and metabolic consequences such diabetes and dyslipidemia, which can progress to chronic kidney disease and ESRD. Non-infected dialysis patients outlive PWH. Transplantation outlives renal replacement treatment for PWH. In the largest prospective observational trial, Stock et al. reported 1- and 3-year renal allograft and patient survival rates of 150 HIV-positive kidney transplant recipients. Because all patients used combination ART and posttransplant anti-infective prophylaxis, HIV control and opportunistic infections were low. PWH had considerable post-kidney transplant problems. Antithymocyte globulin-treated HIV/HCV patients had higher bacterial infections (ATG). Delayed allograft function was common in PWH, although it did not indicate transplant failure. Ultimately, HIV-positive kidney transplant recipients had allograft rejection rates two to three times higher than the general kidney transplant group, which predicted failure. The high rates of allograft rejection after kidney transplantation have various causes, including inadequate immunosuppression due to underuse of immunosuppressive drugs or medication interactions that diminish them. HIV and chronic infections produce immune system dysregulation and heterologous immunoreactivity. Maraviroc, a CCR5 inhibitor, is being researched for its impact on HIV population reduction, immune response, and allograft damage following transplantation. Despite U.S. and international criteria, PWH issue with referral, listing, and kidney transplantation. According to the U.S. Scientific Registry of Transplant Recipients and Organ Procurement and Transplantation Network, PWH remain on dialysis longer before transplant listing, have longer waitlist times for organ offers and transplant, are less likely to remain active on the list, and have 18% lower kidney transplantation chances than noninfected patients. Liver: After highly effective ART, the liver disease kills PWH third. PWH has many end-stage liver disease risk factors. Chronic HCV and HBV coinfections are estimated at 2.4 and 6.1% worldwide, depending on geography and risk factor (e.g., injectable drug use, MSM hemophilia). HIV increases viral hepatitis patients’ risk of ALD. Hepatotoxicity, hypersensitivity, mitochondrial toxicity, steatosis, and immunological reconstitution can develop ALD from ART. In a prospective liver biopsy research, 73 and 55% of PWH on ART with persistently elevated liver tests had nonalcoholic fatty liver disease and steatohepatitis. Alcohol and other liver illnesses can cause end-stage liver disease. Hepatocellular carcinoma worsens ALD. 28.1 and 31.6% of U.S. transplant institutions prohibit liver transplantation for PWH with HIV. Passive prevention with hepatitis B immunoglobulin and antivirals yield 85–100% graft and patient survival after 3–5 years in HIV-HBV co-infected patients. Prevent HBV viremia for life. Before DAAs, HIV–HCV coinfected patients exhibited lower graft and patient survival than HCV-mono-infected controls. Assessing organ transplant eligibility in HIV-infected persons: • Meet transplant center-specific eligibility for organ transplantation • CD4+ cell count > 200 cells/µl during 3 months prior to transplantation for kidney, pancreas, heart, and lung candidates • CD4+ cell count > 100 cells/µl during 3 months prior to transplantation for liver candidates only • Undetectable plasma HIV viremia (unless unable to tolerate antiretroviral therapy prior to liver transplantation • Documented adherence with stable antiretroviral treatment regimen • Absence of active opportunistic infection and malignancy • Absence of chronic wasting or severe malnutrition • Hep B or C infection if no advanced fibrosis/cirrhosis (for organ types other than liver) • Access to immunosuppressive agent therapeutic drug monitoring • Ability to regularly follow up with HIV care providers • With liver failure, patients may not tolerate ART; in this setting care providers must be able to predict HIV suppression with the introduction/reintroduction of ART post-transplant. • In addition to no active opportunistic infections, patients with progressive multifocal leukoencephalopathy, chronic intestinal cryptosporidiosis, visceral Kaposi’s sarcoma (KS), and primary central nervous system lymphoma were excluded. Antirejection therapy: HIV immunosuppression differs. Organ transplanted, immunologic risk, renal and hepatic function, and ART regimen determine patient regimens. disagreement on HIV-positive kidney transplant induction immunosuppression. ATG caused prolonged lymphocyte depletion, more severe infections, and worse allograft loss than basiliximab in the U.S. NIH observational trial. HIV-positive liver transplant recipients rarely need induction immunosuppression. HIV-positive transplants lack immunosuppression. Maintenance immunosuppression commonly includes antiproliferative mycophenolate. Long-term prednisone decreases rejection risk. Immunosuppression affects HIV reservoirs. Sirolimus suppresses HIV by blocking mTOR, downregulating CCR5, and upregulating b-chemokines. Sirolimus can sustain HIV-1 transcription in vitro, reducing the HIV reservoir after immune system activation from transplantation. Calcineurin inhibits HIV-1 DNA transcription. Medication management: Protease inhibitors inhibit CYP3A4, which affects drugs such as calcineurin inhibitors (tacrolimus, cyclosporine A) and mTOR inhibitors (sirolimus, everolimus). Variable immunosuppressive levels raise the risk of rejection or toxicity. Elevated cyclosporine levels induced sudden renal failure in liver transplant recipients on increasing protease inhibitors. Protease inhibitor-based regimens were linked with 1.8-fold increased allograft loss and 1.9-fold higher mortality. Non-boosted INSTIs have replaced protease inhibitors in transplantation. The uridine diphosphate glucuronosyltransferase 1A system completely metabolizes raltegravir, dolutegravir, and bictegravir, resulting in clinically minimal interactions with calcineurin inhibitors. Raltegravir is well-tolerated and effective in transplantation. Dolutegravir is the favored INSTI due to its resistance barrier and easy dose. Clinical monitoring and care of HIVR persons before and after organ transplantation: HIV specialists work with the transplant team to optimize HIV therapy to minimize pre-transplant toxicities and post-transplant drug interactions while maintaining viral suppression. Patients should be placed on non-protease inhibitor-based ART regimens wherever possible. The same ART treatment may be continued after transplant, but clinicians must be aware of frequent kidney function variations that may require frequent dose modifications, especially early posttransplant. HIV physicians should also avoid drugs that may impair organ function, such as tenofovir disoproxil fumarate after kidney transplant or abacavir after heart transplant. Due to changing renal function or supratherapeutic calcineurin inhibitor levels in formulations combining powerful CYP system inhibitors such as cobicistat, fixed-dose combination regimens should be used with caution. While considering ART changes, HIV providers must notify the transplant center. HIV care is crucial post-transplant. CD4 cell counts and HIV viral load should be monitored more often in the early post-transplant period, allograft rejection, and immunosuppressive medication changes. Several transplant centers choose lifelong Pneumocystis jiroveci prophylaxis depending on HIV recommendations and transplant center practices. The US HOPE Act authorizes HIV-to-HIV transplantation in research settings with donor eligibility requirements. ART history, HIV genotypic testing, CD4 cell counts, HIV viral load values, and opportunistic concerns must be collected by transplant specialists to determine donor appropriateness. Many U.S. hospitals do HIV-to-HIV kidney and liver transplants in NIH-sponsored trials. After HIV, HOPE should include pancreatic and thoracic transplantation. 100 HIV-positive Americans received December 2018 HOPE Act dead donor organ transplants. Preliminary U.S. kidney and liver allograft survival data are favorable. Conclusion: HIV-infected patients with end-stage renal and liver diseases receive kidney and liver transplants. The success of pancreatic, heart, and lung transplants suggests that advanced organ disease patients should also be referred to transplant clinics. INSTI, which has low immunosuppressive medication effects, has substantially simplified HIV-positive organ recipient post-transplant treatment. Coinfected organ recipients may benefit from the introduction of DAAs for hepatitis C, which are highly effective post-transplant. Finally, the HOPE Act allows PWH to donate kidney and liver transplants to HIV-positive patients in research settings. HIV providers should refer appropriate individuals for transplantation, educate patients on transplant outcomes and the risks and advantages of using HIV-positive organs, and monitor HIV infection following transplant.
HIV infection has become a chronic illness in the current age of antiretroviral therapy, with increased life expectancy and an aging demographic.
Common medical comorbidities, such as coronary artery disease and nonalcoholic steatohepatitis, are becoming important causes of morbidity and mortality in persons with HIV (PWH).
Solid organ transplantation (SOT) is standard of care for PWH with end-stage kidney and liver disease, and more limited but encouraging data has demonstrated feasibility of pancreas, heart, and lung transplantation.
The HOPE Act has enabled PWH to register as organ donors, expanding the donor pool for PWH and the organ donation pool as a whole.
Status of organ transplantation by organ type
PWH are increasingly seeking organ transplantation, with evidence supporting kidney, liver, pancreas, heart, and lung.
Kidney
PWH are estimated to make up 0.5-1.5% of the US dialysis population, and HIV-associated nephropathy (HIVAN) rates have declined, but other causes of renal failure remain prominent.
Antiretroval agents are associated with nephrotoxicity and metabolic complications, which can lead to chronic kidney disease and ESRD.
PWH outcomes are favorable, with transplantation providing a clear survival benefit over renal replacement therapy.
However, complications can occur, such as bacterial infectionsand delayed allograft function.
HIV rejection rates are higher than in the general kidney transplant population.
Single and multicenter studies have confirmed the results of a pivotal study on the high rates of allograft rejection following kidney transplantation.
Research is currently underway to evaluate the role of the C-Cchemokine receptor type 5 (CCR5) inhibitor, maraviroc, in reducing the HIV reservoir and modulation of the immune response and allograft injury following transplantation.
Despite the evidence and U.S. and international guideline-based support, PWH encounter barriers to referral and listing for and undergoing kidney transplan-tation, such as longer waitlist times for organ offers and transplant, and less likely to remain active on the list.
Liver
Liver disease is the third leading cause of death in PWH due to a variety of mechanisms, including HCV and HBV coinfections, HIV infection, nonalcoholic fatty liver disease, and hepatocellular carcinoma.
HIV is an absolute or relative contraindication in 28.1 and 31.6% of surveyed U.S. transplant centers.
The outcomes of liver transplantation in PWH vary depending on the reason for transplant.
HIV-HCV coinfected patients have significantly lower graft and patient survival rates than HCV-monoinfected controls.
HCV-related progressive liver disease, severe infections, and sepsis contribute to poor outcomes.
Pancreas
Pancreas transplantation can be successful in HIV-infected patients, but additional experience is needed.
Heart
HIV-associated cardiomyopathy is a rising concern in PWH, with 1 and 5-year post-transplant survival rates between 85.9-90% and 64-77.3%.
53.7-57% of patients received mechanical circulatory support prior to transplant.
Lung
HIV-experienced centers can consider PWH as candidates for lung transplantation, but there is a lack of data.
Clinical management of HIV-infected organ transplant candidates and recipient Selection of candidates
HIV providers should refer any patient with end-organ damage and stable HIV to centers well versed in HIV-organ transplantation.
Guidelines recommend that patients have undetectable HIV viral load, known compliance with ART, no evidence of active opportunistic infections or HIV-associated malignancy, and the ability to have close follow-up for immunosup-pression, drug level monitoring and management.
CD4 cell counts at least 200 cells/ml are recommended for transplantation of all organs with the exception of liver, where the threshold for transplantation is CD4 cell count more than 100 cells/ml.
When evaluating HCV-coinfected persons for liver transplant, it is important to weigh factors predictive of liver allograft loss such as low BMI (<21 kg/m2), need for combined liver–kidney transplant, and HCV donor organs.
Antirejection therapy
The best immunosuppressive regimen to use for patients with HIV is unknown and should be individualized based on the organ transplanted, immunologic risk, renal and liver function, and ART regimen.
Tacrolimus is associated with lower rejection rates and mycophenolate is a common component of maintenance immunosuppression.
Sirolimus is known to have anti-HIV effects through downregulation of CCR5, upregulation of b-chemokines, and blockade of the mammalian target of rapamycin (mTOR).
In-vitro studies have shown that HIV-1 transcription can continue in the setting of sirolimus, which may result in diminishing the HIV reservoir.
Medication management
Protease inhibitors, via inhibition of cytochrome P4503A4 (CYP3A4) enzyme, alter the pharmacokinetics of immunosuppressive medications, resulting in inconsistent doses and dosing schedules.
Studies have shown that protease inhibitors have a higher risk of allograft loss and mortality than non-protease inhibitor regimens, which may be related to interactions between calcineurin inhibitors and protease inhibitors.
The National Organ Transplant Act was enacted in 1984 to prevent HIV transmission by transplantation.
In 2008, four HIV-positive to HIV-positive renal transplants were successfully performed in Cape Town, South Africa, with 1, 3, and 5-year patient survivals of 87, 87, and 84%.
Probable donor superinfection was suspected in one patient, but the patient continued to have viral suppression.
The South African experience has inspired action by the US transplant community to expand HIV-to-HIV transplant to North America.
The HOPE Act has enabled the utilization of organs that may have otherwise been discarded due to false-positive HIV test results, with almost 50% of HOPE-allocated organs coming from donors with false-positive testing.
Very few cases of HIV-to-HIV living donor transplanta-tion have been reported in the literature, but two living donor kidney transplants have been reported, one with long-term good outcomes in both the donor and recipient.
Intentional transplantation of HIVþ organs into unin-fected recipients is illegal in the United States, with significant medical and ethical concerns.
Kidney and liver transplantation is the standard of care for HIV-infected persons with end-stage kidney and liver diseases, and INSTI and DAAs for hepatitis C have improved post-transplant management.
HIV providers should play an active role in referring appropriate patients for transplantation, educating patients about transplant outcomes, and monitoring HIV infection after transplant.
The era of antiretroviral therapy has significantly reduced the morbidity and mortality associated with HIV/AID making PWH leave almost like a normal population. However, the metabolic and antiretroviral drugs’ side effects have resulted in organ failure hence making the need for organ transplantation a necessity.
The passage of the HOPE Acts has not only reduced the waiting time but has also expanded the donor pool for SOT. Furthermore, the evidence seen PWH that had successful kidney or liver transplantation because of the advent of ART has removed the fear associated with the procedure
Kidney transplantation in PWH
FSGS, DM, hypertension, co-infection with HCV, HBV, and some ART drugs remains among the common cause of ESRD in PWH.
Outcomes with kidney transplantation has been demonstrated to be better than remaining on dialysis
South African experience shows that, ; 1 and 3-year kidney allograft and patient survival estimates were 90.4 and 73.7 and 94.6 and 88.2%, respectively. However, rate of rejection was seen to be higher compared to general population
A recent survey found that 16.9 and 28.1% of responding U.S. transplant programs still considered HIV as an absolute or relative contraindication to transplantation, respectively. This is also similar to what was found in France.
Liver transplantation in PWH
The co-infection with HCV, and HBV has contributed to liver failure among PWH, in addition to side effects of ART
Liver biopsy done among PWH shows some degree of elevated liver tests with non alcoholic steatosis and ALD can be complicated with HCC
The outcome of the PWH varies depending on monoinfection, to the coinfection with HCV or HBV
The availability of hepatiti B immunoglobulin and DAA has resulted in some degree of good outcomes
Pancrease transplantation in PWH
The outcome of this procedure has been mixed as it is frost with complication like graft thrombosis, rejection, and bacteria infections
Clinical management of HIV-infected organ transplant candidates and recipient
The success of transplantation in PWH will depend greatly of selection of recipient that meet the required criteria
There is no agreed induction therapy for transplantation in PWH, IL-2 recepto inhibitor is favored over ATG that could cause some complications
Maitenance immunosuppression usually used are combination of CNIs, antimetabolites and steroid
Utmost attention must be paid to dru-drug interaction particular use of PI and CNIs together because of effect of PI on cytochrome P450.
HIV-to-HIV transplantation
The success story of South African HIV diseased donor to recipient has provided a possibility of such procedure that was previously feared
A major concern is the potential consequences of superinfection with the donor HIV strain, including acquisition of CXCR4-tropic or dual/mixed-tropic virus or transmitted antiviral resistance
The HOPE Act has brought a safeguard to HIV to HIV transplantation, although many of the procedures are still been registered as a trial
Transplantation of living donor and recipient HIV positive transplantation had been documented, but just two cases
Conclusion
The best available form of care for PWH with ESRD and liver failure is kidney and liver transplantation and good outcomes have been demonstrated. Moreso, encouraging result are also been seen in pancreas, lung, and heart transplant among PWH. However, it is important to carried out this procedure in centre with good experience and close monitoring to the use of various ART medication to avoid graft loss.
HIV infection has become a chronic illness in the current age of antiretroviral therapy, with increased life expectancy and an ageing demographic . Solid organ transplantation (SOT) is the standard of care for PWH with end-stage kidney and liver disease, and more limited but encouraging data has demonstrated feasibility of pancreas, heart, and lung transplantation. The HOPE Act has enabled PWH to register as organ donors, expanding the donor pool for PWH and the organ donation pool as a whole. Status of organ transplantation by organ type : PWH are increasingly seeking organ transplantation, with evidence in support of kidney and liver, but growing numbers of persons have undergone pancreas, heart, and lung transplantation, demonstrating feasibility.
Kidney:
Kidney transplantation provides a clear survival benefit over renal replacement therapy, but antiretroviral agents can lead to nephrotoxicity and metabolic complications. High rates of allograft rejection following kidney transplantation may be due to inadequate immunosuppression, immune system dysregulation, and heterologous immunoreactivity.Other complications may arise in HIV patients is bacterial infections which increased frequently in patients who receive lymphocytes depleting agents like ATG ,also delayed graft function was noticed .
Liver :
PWH are at risk for end-stage liver disease due to a variety of mechanisms, including chronic HCV and HBV coinfections, HIV infection, nonalcoholic fatty liver disease and steatohepatitis, alcohol and other non-HIV-related causes, and hepatocellular carcinoma. HIV is considered an absolute or relative contraindication by 28.1 and 31.6% of surveyed U.S. transplant centers. The outcomes of liver transplantation in PWH vary by the reason for transplant, with graft and patient survivals ranging from 85 to 100% after 3-5 years of follow-up.
Pancreas :
Pancreas transplantation can be successful in HIV-infected patients, but additional experience is needed. Outcomes have been mixed, with reported complications such as graft thrombosis, rejection, and bacterial infections.
Heart :
HIV-associated cardiomyopathy is a rising concern in PWH, with 1 and 5-year post-transplant survival rates between 85.9-90% and 64-77.3%. 53.7-57% of patients received mechanical circulatory support prior to transplant.
Lung :
HIV infection is now a relative contraindication to lung transplantation in PWH, in addition there is a paucity of lung transplantation reports.
Clinical management of HIV-infected organ transplant candidates and recipient: -Selection of candidates:
HIV providers should refer any patient with end-organ damage and stable HIV to centers well versed in HIV-organ transplantation. Guidelines recommend that patients have undetectable HIV viral load, known compliance with ART, no evidence of active opportunistic infections or HIV-associated malignancy, and the ability to have close follow-up for immunosuppression, drug level monitoring and management. CD4 cell counts at least 200 cells/ml are recommended for transplantation of all organs with the exception of liver, where the threshold for transplantation is CD4þ cell count more than 100 cells/ml. When evaluating HCV-coinfected persons for liver transplant, it is important to weigh factors predictive of liver allograft loss such as low BMI (<21 kg/ m2)
Antirejection therapy:
The best immunosuppressive regimen to use for patients with HIV for induction and maintenance of immunosuppression should be individualized to the organ transplanted, immunologic risk, renal and liver function, and ART regimen. Tacrolimus is associated with lower rejection and infection rates, and mycophenolate is a common component of maintenance immunosuppression. In-vitro studies have shown that HIV-1 transcription can continue in the setting of sirolimus, which may result in diminishing the HIV reservoir.
Medication management :
Protease inhibitors may alter the pharmacokinetics of immunosuppressive medications , leading to inconsistent doses and dosing schedules and increased risk of rejection. Guidelines have recently been updated outlining these interactions. Studies have shown poor outcomes for patients on protease inhibitor-based regimens, with a 1.8-fold higher risk of allograft loss and a 1.9-fold increased risk of mortality when compared with non-protease inhibitor regimens. The increased rejection may be related to interactions between calcineurin inhibitors and protease inhibitors.
Clinical monitoring and care of HIVR persons before and after organ transplantation HIV providers play a vital role in pre- and post-transplant care of HIVR persons. Pre-transplant, patients should be placed on non-protease inhibitor-based ART regimens, and after transplant, the same ART regimen may be continued. In the post-post-transplant period, regular HIV care is essential, and more frequent monitoring of CD4 cell counts and HIV viral load is warranted. Anti-infective prophylaxis is based on transplant center practices and HIV guidelines.
HIV-to-HIV transplantation:
The National Organ Transplant Act was enacted in 1984 to prevent HIV transmission by transplantation. In 2008, four HIV-to-HIV renal transplants were successfully performed in Cape Town, South Africa, with 1, 3, and 5-year patient survivals of 87, 87, and 84%. Probable donor superinfection was suspected in one patient, but the patient continued to have viral suppression. The South African experience has inspired action by the US transplant community to expand HIV to HIVþ transplant to North America. The HOPE Act has enabled the utilization of organs that may have otherwise been discarded due to false-positive HIV test results, with almost 50% of HOPE-allocated organs coming from donors with false-positive testing. Very few cases of HIV-to-HIV living donor transplantation have been reported in the literature, but two living donor kidney transplants have been reported, one with long-term good outcomes in both the donor and recipient. Intentional transplantation of HIVþ organs into uninfected recipients is illegal in the US, but there is one reported case in the literature involving a partial living donor liver transplant from a South African HIV-mother to her critically ill HIV-negative child with biliary atresia.
Conclusion: Kidney and liver transplantation is the standard of care for HIV-infected persons with end-stage kidney and liver diseases, INSTI and DAAs for hepatitis C are promising to improve outcomes. HIV providers should play an active role in referring appropriate patients for transplantation, educating patients, and monitoring HIV infection after transplant.
Introduction
With the development of antiretroviral therapy, HIV patients life span increased accompanied with organ failures
SOT is offered for patients with HIV( PWH) having end-stage kidney and liver disease,even on lesser scope pancreas, heart, and lung transplantation.
PWH can be considered as donors increasing the donor pool and decreasing waiting list for PWH as recipients.
This review article demonstrates the current SOT status for HIV-infected persons, including the outcomes of the care standards and post-transplant management in this special group. Status of organ transplantation by organ type
kidney transplantation afterwards liver transplantation are the most evidence supported transplants in this group of patients
but pancreas, heart, and lung transplantation, are becoming more applicable. Kidney
Although HIV associated nephropathy (HIVAN) rates decreased with antiretroviral therapy, but , other causes can lead to renal failure as focal segmental glomerulosclerosis, diabetes mellitus, and hypertension as well as coinfection with HBV and HCV.
However antiretoviral drugs have side effects as nephrotoxicity ,diabetes, hyperlipidemia which in turn can lead to ESRD as well
PWH undergoing transplantation have better outcome than those on RRT.
Stock et al. trial demonstrated the outcomes of 150 HIV-infected patients after kidney transplantation ;with favourable graft and patient survival ,those patients had viral suppression and CD4+cell counts at least 200 cells/ml before transplant and c ART and posttransplant anti-infective prophylaxis lead to HIV control , and less opportunistic infections but bacterial infection was higher in cases exposed to ATG as induction therapy and co HCV infection also higher rates of delayed allograft function was detected rendered to insufficient immunosuppression or immune dysregulation and heterologous immunoreactivity in response to HIV.
Researches access the role of the C–C chemokine receptor type 5 (CCR5) inhibitor in decreasing the HIV reservoir and modulating the immune response and allograft injury after transplantation.
HCV positive recipients are facing prolonged trnasplantion waiting lists more than non infected recipients. Liver
PWH are at risk for liver cell failure via different mechanisms including chronic HCV and HBV coinfections, Anitretroviral therapy (ART) can lead to acute liver disease (ALD)through direct hepatotoxicity, hypersensitivity reactions, mitochondrial toxicity, steatosis and/or steatohepatitis, or immune reconstitution phenomena.
In a study on PWH with high liver enzymes receiving ART , NASH and steatohepatitis were detected in liver biopsies.
Alcohol and other non HIV related factors can lead to liver diseases either primarily or as contributing factor.
ALD can lead to hepatocellular carcinomaHCC .
PWH in need for liver transplant is increasing but many difficulties are faced as HIV positive is considered as absolute or relative contraindication for transplantation.
Liver transplant outcome is variable in this group of patients according to transplant cause .
HCV monoinfected candidates have better patient and graft survival compared to HCV and HIV coinfected ones. Pancreas
Pancreas and kidney transplantation has variable results as complications of graft thrombosis, rejection, and bacterial infections including fatal sepsis which was published, so pancreas transplantation can be successful in HIV-infected patients but more studies is needed. Heart
PWH are liable to cardiac diseases due to aging , chronic HIV immune activation status and ART metabolic effects. CAD affects PWH.
HIV is not an absolute contra-indication for advanced heart failure
Therapies ,as heart transplantation but not commonly done.
Studies demonstrated that post-transplant vasculopathy risks are not much higher than HIV negative recipients but had higher rejection risks. Lung
No enough data is available for lung transplant in HIV cases but it is not considered any more as an absolute contraindication by recent guidelines and turned to a relative contraindication for lung transplantation.
Guidelines recommend performing it in HIV experienced centers including PWH adherent to ART ,having suppression of viral load and no HIV recent illness. Clinical management of HIV-infected organ transplant candidates and recipient Candidates selection
Stable HIV cases with end organ failure need to be referred to transplant centers specialized in HIV cases.
Guidelines suggest that candidates need to have undetectable HIV viral load, ART compliance except ALD cases who cannot tolerate ART, without active opportunistic infections or HIV-associated malignancy, immunosuppression follow up , monitoring drug level and management,CD4 count >200 cells/ml for all organ transplantation and >100 cells/ml for liver transplantation.
HCV is not an exclusion factor for transplantation, HCV organs transplantation can be used , followed by DAA treatment after transplantation to enhance the pool of available grafts. Antirejection therapy
Immunosuppressive regimens have to be individualised as there is not a best immunosuppressive drug available.
Trials demonstrated that cases who revived ATG rather than basiliximab as induction suffered severe infection and allograft loss while other registry revealed the opposite.
Also the optimum maintenance therapy is not known for HIV infected cases.
Tac has low rejection rates, MMF is commonly used and prednisolone use have to be through weighing benefits and side effects particularly on the long term.
Sirolimus have anti-HIV effects, apart on HIV 1 which can be suppressed by CNI. Medication management
HIV drug interactions with maintenance immunosuppressive therapies need to be monitored.
Protease inhibitors inhibit cytochrome P4503A4 (CYP3A4)leading to variation in level of CNI and m TORI which render the patient liable to either rejection or toxicity .
Integrase strand transfer inhibitors (INSTI) therapy has better outcomes and less interactions with immunosuppressives as CNI. Clinical monitoring and care of HIV positive cases before and after organ transplantation.
In pre-transplant period , HIV specialists manage HIV therapy, in a way to decrease pre-transplant toxicities and post-transplant drug interactions while maintaining viral suppression.
Non-protease inhibitor-based ART regimen is preferred.
Same ART regimen is continued post transplant with close monitoring .
Agents compromising organ function need to be avoided ,and caution with combination regimens.
In early post-transplant period, if allograft rejection occurred, and when immunosuppressives are modulated more frequent monitoring ofCD4+ cell counts and HIV viral load will be needed as well as life-long prophylaxis against Pneumocystis jiroveci. HIV-to-HIV transplantation
It is applicable, 4 HIV positive to HIV positive renal transplantation cases were conducted successfully in South Africa.
It has to be performed for donors with specific eligibility criteria including donors’ ART history, HIVgenotypic testing, CD4+ cell counts, HIV viral load and history of opportunistic complications
The major concerns were superinfection with the donor HIV strain or antiviral resistant strain transmission or latent or unrecognized opportunistic infections to the recipient and poor organ quality.
In USA the patient and allograft survivals for both kidney and liver recipients in the Hope Act have favourable results.
HIV related risk factors for ESRD occurrence have to be addressed as APO1 genotype association development HIVAN and focal segmental glomerulosclerosis in Afro- American patients but the benefit of APO1 screening is unconfirmed.
Post transplant nephrotoxic ART have to be avoided.
Transplantation of HIV+ organs into HIV negative recipients is unauthorised in USA. Conclusion
The favourable results of kidney and liver transplant for HIV cases encouraged involving pancreas ,heart and lung transplantation which has to be carried out in specialised centers
INSTI, with less effect on immunosuppressives levels, has positively affected post-transplant management of the HIV positive organ recipient.
DAAA introduction improved the outcome for HCVhepatitis post transplant
HOPE Act demonstrated that PWH can be donors to HIV infected persons on kidney and liver transplant waiting lists .
SUMMARY
This Editorial review’s attention to the existing status of SOT for HIV-infected persons, stresses the outcomes of, the current standards of care for, and exceptional aspects of post-transplant management of this particular group of patients with HIV-related CKD including ESRD. the improved life expectancy and aging, comorbid with the metabolic effect of the virus and the antiretroviral medication on persons with retroviral infection (PWH) lead to increased risk of end-organ damage like kidney failure and liver disease In the US around 800 / year of PWH have ESRD and 0.5-1.5% on Dialysis HIV-related nephropathy (HIVAN ) decreased in numbers with the improvement and effectiveness of anti-retroviral medications(HAART ), However, protease inhibitors are associated with nephrotoxicity and/or metabolic complications, including diabetes and dyslipidemias, which can ultimately contribute to or lead to the development of chronic kidney disease in addition to comorbid diseases like DM dyslipidemia.
Kidneys
PWH have higher mortality on dialysis compared to non-HIV infected patients, SOT still can be offered for PWH, especially with the improvement of the antiretroviral medications and the approval of the HIV Organ Policy Equity (HOPE) Act has opened and expanded opportunities for PWH to donate and receive organs. with better patient survival and outcome compared to dialysis, some centers in US and Europe consider HIV to be an absolute or relative contraindication for transplantation, however, there is growing evidence from studies to encourage the PWH to get SOT to provide they are medically fit with undetectable viral load and CD4 count > 200ml for > 6 months, no recent opportunistic infection for > 6 months and no evidence of malignancy or co-infection with HCV, one large prospective cohort study confirms improved patient and graft survival in 1&3 years after kidney transplantation in PWH with a higher risk of DGF and acute rejection and also a more bacterial infection, especially in those received ATG (T- cell depleting agents
Increased risk of graft rejection can be explained in part by the use of lower immunosuppression medications, drug-drug interaction ART with CNI interaction lead to underdosing of the CNI and inconsistency of the trough level, immune dysregulation like CCR5A inhibitor, CCR5 is widely expressed by T lymphocytes and macrophages and a costimulatory molecule for Th1 activation and recruitment inflammatory cells [28]; therefore, CCR5 blockade may dampen the alloimmune response Previous studies in HIV-negative, CCR5Δ3 homozygous persons have demonstrated less rejection and better allograft survival after liver and kidney transplantation.
Liver
Liver disease is the 3rd leading cause of death in PWH especially co-infection with HCV, or HBV which is reported in around 2.4 and -6% respectively
Advanced liver disease in PWH is also related to ART hepatotoxicity hypersensitivity reactions, mitochondrial toxicity, steatosis and/or steatohepatitis, or immune reconstitution phenomena, HCC.PWH face many barriers to liver transplantation, with HIV, considered an absolute or relative contraindication by 28.1 and 31.6% of surveyed U.S. transplant centers, and also have a long waitlist
However, the patient and graft outcome of transplantation of PWH and HBV coinfection varies in the range of 80-100%, with passive HBV Ig and antiviral medication, antiviral prophylaxis recommended lifelong While HCV-related progressive liver disease, severe infections, and sepsis contributed to poor outcomes before the era of DAA therapy. Pancreas
Limited experience for PWH underwent SKP transplantation, not with type 1 DM, and the outcome from 10 cases reported from the US with many complications including graft thrombosis, rejection, bacterial infection including fatal sepsis.
HEART
Heart transplantation in PWH is associated with better 1, 5 years graft and patient survival and the risk of post-transplant vasculopathy is comparable to the non-HIV recipient, but again the rejection risk in one year is higher based on recent evidence. Lung
updated ISHLT guidelines, HIV infection has moved from an absolute to a relative contraindication to lung transplantation in 2014
however, the recent data from the US was limited to case series or reports of feasible lung transplantation for PWH under disease control and no recent infection with advanced lung disease clinical management of HIV -infected organ transplant candidates and recipient
PWH candidates for organ transplantation should meet the following center eligibility criteria
1. Undetectable HIV viral load
2. C4D count > 200 cells /ml except for liver transplant c4d count > 100 cells / ml
3. known compliance with ART
4.No evidence of active opportunistic infections for at least the last 6 months
5.No evidence of HIV-associated malignancy
6. Ability to have a close follow-up for immunosuppression, drug-level monitoring, and management
Antirejection choice No clear guidelines or evidence for choosing induction IS and maintenance IS and this should be guided based on the type of organ transplant, the patient’s immunological risk and the type of antiretroviral therapy, preferred for induction IS to choose IL2 inhibitor in low immunological risk ( basiliximab ) as ATG can lead to T cell depletion however the guidelines still recommend the use of ATG as induction IS once indicated, for liver transplantation no need for induction, regarding maintenance, IS tacrolimus based IS with MMF and steroid took in consideration drug-drug interaction with antiviral therapy Protease inhibitors, via inhibition of cytochrome P4503A4 (CYP3A4) enzyme, alters the pharmacokinetics of immunosuppressive medications, including the calcineurin inhibitors (tacrolimus, cyclosporine A) and
mTOR inhibitors (sirolimus, everolimus), resulting in severe alterations in doses and dosing schedules of these drugs that put the patient at risk of under suppression and risk of rejection or CNI toxicity with overdosing
while non-nucleoside reverse transcriptase inhibitors have the differing potential for induction of CYP3A4. those receiving protease inhibitor-based regimens had a 1.8-fold higher risk of allograft loss and a 1.9-fold higher risk of mortality when compared with non-protease inhibitor regimens based on one registry data, and replaced by non-boosted integrase strand transfer inhibitors (INSTI) as have appeared as favored therapies like Raltegravir, dolutegravir, and bictegravir are completely or primarily metabolized through the uridine diphosphate glucuronosyltransferase 1A system
resultant in trivial interactions with calcineurin inhibitors. Clinical monitoring and care of HIVR persons before and after organ transplantation Both HIV providers and transplant physicians should closely monitor HIV infection recipients for potential opportunistic complications in the post-transplant period. In the pre-transplant phase, HIV specialists partner with the transplant team to optimize HIV therapy, with the goal of minimizing pre-transplant toxicities and post-transplant drug interactions while maintaining viral suppression. , patients should be placed on a non-protease inhibitor-based ART regimen, frequent monitoring for C4D count and viral load especially early post-transplant period or after treatment for acute rejection, or in case of change in immunosuppression avoid fixed drug combination with the risk of acute kidney injury, need lifelong PJP prophylaxis HIV-to-HIV transplantation
HIV-infected donors were absolutely contraindications by law since 1984, however, based on the south African experience of the use of HIV +ve DD to HIV + ve recipients with favored survival outcomes in1, 3, and 5 years such promising results inspired to action by the United States transplant community to expand HIV+ve to HIV+ve transplants to
North America. Keep in mind two major concern is the potential consequences of superinfection with the donor HIV strain, including the acquisition of CXCR4-tropic or dual/mixed-tropic virus or transmitted antiviral resistance. Other risks include the spread of latent or unrecognized opportunistic infections to the recipient and poor organ quality because of widespread renal, hepatic, and cardiac diseases in the
HIV population.With the implementation of the HOPE act, PWH can donate organs to HIV +VE recipients waiting for kidney or liver transplants under a research setting in the US with the delineation of the HIV DD eligibility criteria for a donation. HIV care providers should refer eligible HIV candidates for transplantation. Information about the HIV donor-specific data such as ART history, HIV
genotypic testing, CD4þ cell counts, HIV viral load results, and history of opportunistic complications, so that donor suitability can be ascertained, An unexpected benefit of the HOPE Act is the
utilization of organs that may have otherwise been discarded due to having false-positive HIV test results
], with almost 50% of HOPE-allocated organs coming from donors with false-positive testing.
HIV+ve African American persons with high-risk apoprotein L1 (APOL1) genotypes are at risk for the development of HIVAN and focal segmental glomerulosclerosis
Intentional transplantation of HIV+ve organs into uninfected recipients is uncharted territory (and currently
illegal in the United States), with significant medical and ethical concerns about such a practice.
Conclusion
Organ transplantation is feasible for PWH and ESKD, ESLD and is considered standard of care with better patient and graft survival.
transplantation is even eased for HIV patients with the Introduction of non-protease inhibitors antiviral therapy. The ERA of DAA for HCV co-infection also facilitates the transplantation of PWH and HCV co-infection with better outcomes with the implementation of the HOPE Act, PWH can donate organs to HIV-infected persons waiting for kidney and liver transplants in a research setting. HIV providers should play an active role in referring appropriate patients for transplantation, educating patients regarding transplant outcomes and the potential risks and benefits of following HIV-positive organs for transplant, and ensuring frequent monitoring of HIV infection after transplant.
Introduction
o Now the lifespan of newly diagnosed persons with HIV (PWH) is the same as of uninfected persons (due to advanced antiretroviral therapy)
o Metabolic abnormalities related to both the disease and the virus itself, along with common medical comorbidities (such as CAD and nonalcoholic steatohepatitis)are becoming important causes of morbidity and mortality in persons with HIV (PWH)
o SOT is the standard of care for PWH with ESRD
o HIV Organ Policy Equity (HOPE) Act approved PWH to donate and receive organs
o Aim of the study: review the current status of SOT for PWH
Status of organ transplantation by organ type Kidney
o HIV associated nephropathy (HIVAN) rates have declined due to antiretroviral therapy (ART)
o HCV and HBV coinfections increase risk for kidney failure
o Several antiretroval are associated with nephrotoxicity and/or metabolic complications (diabetes and dyslipidemias) which can contribute to the development of CKD and ESRD
o Survival rate is lower in PMH on dialysis when compared with uninfected dialysis patients
o Transplanted PWH have a clear survival benefit over renal replacement therapy
o In the largest prospective observational study: 1 and 3-year kidney allograft and patient survival estimates were 90.4 and 73.7 and94.6 and 88.2%, respectively (but high risk of bacterial infections, GFF, and allograft rejection)
o Causes of high rates of allograft rejection following kidney transplantation:
1. inadequate immunosuppression (under use of immunosuppressive agents or drug interactions)
2. immune system dysregulation and heterologous immunoreactivity in response to HIVand other chronic infections (C–C chemokine receptor type 5 (CCR5) inhibitor, maraviroc)
Liver
o The prevalence of chronic HCV and HBV coinfections are 2.4 and 6.1%
o Mechanisms of end stage liver disease in PWH:
1. HIV infection increases the risk for progressive and advanced liver disease (ALD) in those with viral hepatitis
2. ALD can also result from ART whether caused by direct hepatotoxicity, hypersensitivity reactions, mitochondrial toxicity, steatosis and/or steatohepatitis, or immune reconstitution phenomena
3. Alcohol and hepatocellular carcinoma
o The outcomes of liver transplantation in PWH vary by the reason for transplant
Pancreas
o Simultaneous pancreas-kidney transplants: reported complications of graft thrombosis, rejection, and bacterial infections, including fatal sepsis
o Needs additional experience
Heart
o HIV is no longer considered an absolute contra-indication to advanced heart failure therapies, including heart transplantation, but is uncommonly performed
o 1 and 5-year post transplant survivals are between 85.9–90% and 64–77.3%, respectively
Lung
o In the 2014 updated ISHLT guidelines, HIV infection has moved from an absolute to a relative contraindication to lung transplantation
o No data of transplantation in PWH
Clinical management of HIV-infected organ transplant candidates and recipient Selection of candidates
o Guidelines recommend that, regardless of the organ transplanted, patients have undetectable HIV viral load, known compliance with ART, no evidence of active opportunistic infections or HIV-associated malignancy, and the ability to have close follow-up for immunosuppression, drug level monitoring and management are candidate for transplant
o CD4+ cell counts at least 200 cells/ml of all organs (more than 100 in liver)
o Adherence to ART as evidenced by viral suppression (exception is ALD who may not be able to tolerate ART and exhibit viremia, with antiretroviral regimen post-transplant)
o HCV coinfection should not be considered an exclusion factor for transplant
o In the case of both kidney and liver transplant, excellent HCV treatment outcomes was achieved with DAA therapy
Meet transplant center-specific eligibility for organ transplantation:
1. CD4+ cell count > 200 cells/µl during 3 months prior to transplanta!on for kidney, pancreas, heart and lung candidates
2. CD4+ cell count > 100 cells/µl during 3 months prior to transplanta!on for liver candidates only
3. Undetectable plasma HIV viremia(unless unable to tolerate an!retroviral therapyprior to liver transplant)
4. Documented adherence with stable antiretroviral treatment regimen
5. Absence of active opportunistic infection and malignancy
6. Absence of chronic wasting or severe malnutrition
7. Hepatitis B or C infection if no advanced fibrosis/cirrhosis (for organ types other than liver)
8. Access to immunosuppressive agent therapeutic drug monitoring
9. Ability to regularly follow up with HIV care providers
Antirejection therapy
o Immunosuppressive regimen should be individualized to patients based on the organ transplanted, immunologic risk, renal and liver function, and ART regimen
o The best maintenance immunosuppressive regimens is not known
o Sirolimus is known to have anti-HIV effects through downregulation of CCR5, upregulation of b-chemokines, and blockade of the mammalian target of rapamycin (mTOR)
Medication management
o Protease inhibitors is an inhibition of cytochrome P450 3A4 (CYP3A4) enzyme
o Non-nucleoside reverse transcriptase inhibitors are CYP3A4 inducer
o Non-boosted integrase strand transfer inhibitors (INSTI): Raltegravir,dolutegravir,andbictegravir. They are completely or primarily metabolized through the uridine diphosphate glucuronosyltransferase 1A system, resulting in clinically insignificant interactions with the calcineurin inhibitors
Clinical monitoring and care of HIVR persons before and after organ transplantation In the pre-transplant phase:
o Optimize HIV therapy, with the goal of minimizing pre-transplant toxicities and post-transplant drug interactions while maintaining viral suppression
After transplant:
o Frequent fluctuation in kidney function may require frequent dose adjustments, especially early in the posttransplant period. Also, avoid, when possible, agents that may compromise organ function, such as use of tenofovir disoproxil fumarate after kidney transplant or abacavir after heart transplantation
o In the early post-transplant period, in the setting of allograft rejection, and when immunosuppressive therapy is changed, more frequent monitoring of CD4 cell counts and HIV viral load is warranted
o Anti-infective prophylaxis (many centers give life-long prophylaxis against PJP
HIV-to-HIV transplantation
o For deceased donor organ transplants, U.S. trials suggest excellent patient and allograft survivals for both kidney and liver recipients
o Very few cases of HIV-to-HIV living donor transplantation have been reported in the literature (only two cases)
o Intentional transplantation of HIV+ organs into uninfected recipients is currently illegal in the United States)
Conclusion
o For HIV-infected persons with end-stage kidney and liver diseases, Kidney and liver transplantation are the standard of care
o As INSTI has minimal drug interaction with immunosuppressions, it facilitates post-transplant management of the HIV+ organ recipient
o DAAs for hepatitis C improve outcomes in coinfected organ recipients
o PWH can donate organs to HIV infected persons waiting for kidney and liver transplants
Overall kidney transplantation is the best solution among the PWH (patients with HIV). The evolution of ART (anti-retroviral therapy) has improved the overall outcome among PWH. However, this vulnerable group required closed monitoring, follow up and ART adjustment to prevent post-transplant complications. It is well documented that this group of patient is at higher risk of bacterial infection, rejection and delayed graft function.
Clinical management of HIV-infected organ transplant candidates and recipients
1.Selection of candidates
CD4+ > 200
Undetectable HIV RNA
Adherence to therapy
Absence of active infection
Absence of malignancy
Absence of chronic wasting or sever malnutrition
2.Anti-rejection therapy
Induction
Anti-thymocyteglobulin vs Basiliximab
Maintainance
Prednisolone (can consider steroid withdrawal in low risk individual)
Tacrolimus or mTORi
Mycophenolate Acid or mTORi
Introduction
HIV infection has become a chronic illness in the current age of antiretroviral therapy; both overall and AIDS-related mortality has declined.
Over the past decade, accumulating evidence has established solid organ transplantation (SOT) as standard of care for PWH with end-stage kidney and liver disease, and more limited but encouraging data has demonstrated feasibility of pancreas, heart, and lung transplantation in PWH.
The current review focuses on the current status of SOT for HIV-infected persons, highlighting the outcomes of, the current standards of care for, and unique aspects of post-transplant management of this highly specialized patient population.
The American Society of Transplantation has recently published updated guidelines on the management of SOT in PWH, but it is important for HIV care providers to have an understanding of how HIV management decisions affect pre and post-organ transplant care and how post-transplant immunosuppressive practices impact HIVand overall transplant outcomes in this unique patient population .
Status of organ transplantation by organ type
Organ transplantation among PWH was initially viewed with trepidation before the current era of antiretroviral a Division of Infectious Diseases, and b Divisions of Infectious Diseases and Organ Transplantation and Comprehensive Transplant.
Associated nephropathy (HIVAN) rates have declined, but in antiretroval-treated PWH, other causes of renal failure such as focal segmental glomerulosclerosis, diabetes mellitus, and hypertension remain prominent .
Reported the outcomes of 150 HIV-infected patients after kidney transplantation; 1 and 3-year kidney allograft and patient survival estimates were 90.4 and 73.7 and 94.6 and.
This study identified important complications that can occur during the post-kidney transplant course of PWH.
HIVþ recipients experienced allograft rejection rates two to three times higher than observed in the general kidney transplant population, and rejection was a predictor for allograft failure in this study
Single and multicentre studies reported on united state
States and Europe have largely confirmed the results of this pivotal study
There has been much scrutiny over the observed high rates of allograft rejection following kidney transplantation with several proposed mechanisms for this, including inadequate immunosuppression, either because of underuse of immunosuppressive agents or drug interactions that lead to inadequate or inconsistent immunosuppressive drug levels
Another potential explanation invokes immune system dysregulation and heterologous immunoreactivity in response to HIV and other chronic infections .
HIV-HBV co-infection, in the setting of passive prophylaxis with hepatitis B immunoglobulin and antiviral therapy, both graft and patient survivals range from 85 to 100% after 3–5 years of follow-up .
With reported complications of graft thrombosis, rejection, and bacterial infections, including fatal sepsis .
Based on these findings, pancreas transplantation can be successful in HIV-infected patients, but additional experience is needed.
A case series of three patients from the United States, as well as a small retrospective cohort study demonstrated feasibility of this approach in persons with advanced lung diseases.
Selection candidates
HIV providers should refer any patient with end-organ damage and stable HIV to centers well versed in HIVþ organ transplantation.
Centers may vary in their candidacy requirements for transplantation, but updated guidelines recommend that, regardless of the organ transplanted, patients have undetectable HIV viral load, known compliance with ART, no evidence of active opportunistic infections or HIV-associated malignancy, and the ability to have close follow-up for immunosuppression, drug level monitoring and management.
Candidates must have demonstrated adherence to ART as evidenced by viral suppression, a notable exception being persons with ALD who may not be able to tolerate ARTand exhibit viremia.
In this situation, the HIV provider must be able to predict viral suppression with an antiretroviral regimen post-transplant. HCV-coinfected persons for liver transplant, it is important to weigh factors predictive of liver allograft loss such as low BMI (<21 kg/m2 ), need for combined liver–kidney transplant, and HCVþ donor organs.
Anti rejection therapy
The best immunosuppressive regimen to use for patients with HIV is unknown.
Regimens should be individualized to patients based on the organ transplanted, immunologic risk, renal and liver function, and ART regimen.
Induction immunosuppression is not required in the majority of liver transplant recipients.
In addi!on to no ac!ve opportunis!c infec!ons, pa!ents with progressive mul!focal leukoencephalopathy, chronic intes!nal cryptosporidiosis, visceral Kaposi’s sarcoma (KS), and primary central nervous system lymphoma were excluded in the ini!al U.S mul!center HIV transplant (HIV-TR) trial.
Persons with liver failure and hepatocellular carcinoma, mee!ng center specific criteria, can be considered for transplanta!on.
And data regarding use of induction agents in transplant of other organ types in HIVþ persons is lacking.
For HIV-infected transplant recipients, the best maintenance immunosuppressive regimens have not been established.
In-vitro studies have shown that HIV-1 transcription can continue in the setting of sirolimus, which, in the setting of immune system activation from transplantation may result in diminishing the HIV reservoir Medical management
Close attention is needed to ensure adequate levels of antirejection drugs in transplant recipients, as both low and high levels can have dire consequences.
3A4 (CYP3A4) enzyme, alter the pharmacokinetics of immunosuppressive medications, including the calcineurin inhibitors and mTOR inhibitors, resulting in drastic alterations in doses and dosing schedules of these drugs.
This increases the potential for inconsistent immunosuppressive levels that may place the patient at risk of rejection or, alternatively, supra-therapeutic levels that result in toxicity .
Studies in renal transplant recipients have shown poor outcomes for patients on protease inhibitor-based regimens.
In the early post-transplant period, in the setting of allograft rejection, and when immunosuppressive therapy is changed, more frequent monitoring of CD4 þ cell counts and HIV viral load is warranted.
As of December 2018, 100 HIVþ persons have undergone deceased donor organ transplants in the
If donor with known HIV infection prior to donation
But proceed with caution if donor has known infection and detectable virus, due to concerns for ART nonadherence, virologic failure, and antiviral resistance.
ART history is especially helpful in this circumstance. Opportunistic complication No invasive of invasive opportunistic complication
Transplant and other care providers should acquire and review prior testing results before transplant.
An unexpected benefit of HOPE Act is the utilization of organs that may have otherwise been discarded due to having false-positive HIV test results [109–111], with almost 50% of HOPE-allocated organs coming from donors with false-positive testing.
Very few cases of HIV-to-HIV living donor transplantation have been reported in the literature.
When evaluating potential candidates for donor nephrectomy, the assessment must include identification HIV-specific risk factors for development of ESRD such as low CD4 þ cell count and HCV coinfection in addition to other conditions that generally exclude persons from donation.
Only two living donor kidney transplants have been reported, one with long-term good outcomes in both the donor and recipient.
There is one reported case in the literature involving a partial living donor liver transplant from a South African HIVþ mother to her critically ill HIV-negative child with biliary atresia.
Treated recipient since the time of transplant, and there was initial seroconversion in the recipient, the child’s HIV antibody-antigen status declined to lowreactive during the first year following the transplant. Findings
When examining data from the U.S Scientific Registry of Transplant Recipients and Organ Procurement and Transplantation Network, even when placed on the waitlist, PWH remain on dialysis for longer durations before transplant listing, have longer waitlist times for organ offers and transplant, are less likely to remain active on the list, and have 18% lower likelihood of undergoing kidney transplantation when compared with their noninfected counterparts .
Conclusion
Kidney and liver transplantation are the standard of care for HIV-infected persons with end-stage kidney and liver diseases.
Encouraging results with transplantation of other organ types, including pancreas, heart, and lung suggest that persons with other advanced organ disease should be referred to centers experienced in performing these transplants.
The introduction of DAAs for hepatitis C, with their high efficacy in the post-transplant setting, promise to improve outcomes in coinfected organ recipients.
Finally, with implementation of the HOPE Act,PWH can donate organs to HIV infected persons waiting for kidney and liver transplants under a research setting.
HIV providers should play an active role in referring appropriate patients for transplantation, educating patients regarding transplant outcomes and the potential risks and benefits of pursuing HIV-positive organs for transplant, and ensuring frequent monitoring of HIV infection after transplantaion
Introduction
· HIV infection is now a chronic disease due the availability of antiretroviral therapy which caused a significant reduction in mortality associated with HIV/AIDs
· The new problems in person living with HIV (PWH) are cardiovascular diseases, liver diseases, and side effects related to antiretroviral therapies. Therefore, PWH are now at-risk organ damage and failure. How ever, before the age of antiretroviral therapy, transplantation was absolute contraindication for HIV but now the understand has improve significantly.
· HIV Organ Policy Equity (HOPE) Act stated that, Person living with HIV (PWH) can now be either donor or recipient for the seek of treatment a failed organ.
Status of organ transplantation by organ type Kidney
· HIV related kidney diseases account for m 0.5 to 1.5% of dialysis treatment in USA
· Causes of ESKD: HIV-associated Nephropathy (HIVAN) was historical, FSGS, DM, co-infections with HBV or HCV & Drug induced
· Transplantation outcomes: Stock et al. observational study of 150 patients and revealed 1- and 3-years allograft & patient survivals were 90% and 74% and 95% and 88% respectively. They had more bacterial infections, delayed graft function, and rejection rates.
· Transplantation is associated with better outcomes compared dialysis
· Challenges: PWH faces barriers for referral, enlisting for transplantation, and some transplant centers in USA are still considering HIV is contraindicated for transplantation Liver
· Liver disease is the third leading cause of death in PWH
· Causes: co-infection with HBV/HCV, antiretroviral therapy, immune reconstitution syndrome, alcohol, and non-HIV factors.
· Outcomes: Allograft and patient survival were 85% to 100% after 3 to 5 years of PWH transplanted due to HIV/HBV co-infection. HIV/HCV versus HCV control 1,3-, and 5-years allograft survivals were 52 to 86%, 45 to 60%, 31 to 45% versus 57 to 88%, 50 to 62%, 33 to 58% respectively.
· Challenges: the same as renal transplantation Pancreas
· This may be successful in future but at the moment the experience is very limited Heart
· Although heart transplantation in PEH is not contraindicated the procedure is not commonly carried on
· Outcomes: recent data showed, 1- and 5-years survival are between 86 to 90% and 64 to 67%, coronary artery vasculopathy was the important complications occurring in up to 30% as well as higher rejection rates from 39 to 67% after one year compared to non-HIV individual. Up to 50% required mechanical circulatory support before transplantation Lung
· Data from case reports and case series demonstrated the feasibility of this procedure in PWH suffering from advanced pulmonary disease. Clinical management of HIV-infected Organ transplant candidates and recipient
· Recommendation for selection of the candidates:
1. Virally suppressed
2. Compliant patient
3. Absence of opportunistic infections
4. Absence of HIV-associated Malignancy
5. CD4 >= 200 cell/microliter
6. Ability to come for follow up
· HIV to HIV living donor transplantation: few cases on the literature
1. Donor must be evaluated well and HIV specific risk factors for ESKD ruled out
2. APLO1 haplotype screening? is not clear but those with African American with HIV and high risk APLO1 genotype are at risk for HIVAN and FSGS
3. HIV +ve donor must avoid drugs like TDF and NSAIDS after nephrectomy
· HIV positive donor to HIV negative recipient
1. At the moment, this is illegal practice in USA
2. One case report from South Africa: HIV positive mother ton her terminally ill daughter with biliary atresia. The daughter became positive but her HIV antibodies reduced significantly to undetectable level during the first year after transplantation
Conclusion
· The rate of organ failure is now increasing in PWH and transplantation is best form therapy in this kind of situation. Transplantation had been done successfully in kidney and liver failure but more data are needed for other organs including heart, pancreas, and lung. We also want to understand the reasons for barriers to transplantation for PWH through a well design study.
●With improvements in and earlier initiation of ART, HIVAN) rates have declined
●Coinfections with (HCV) and (HBV) increase risk for kidney failure
● several ART such as tenofovir, abacavir, indinavir, ritonavir-boosted lopinavir, ritonavirboosted atazanavir, are associated with nephrotoxicity and/or metabolic complications, including diabetes and dyslipidemias
●Once on dialysis, PWH have lower survival rates, Because of this, PWH are increasingly undergoing RTX
○Stock et al. reported the outcomes of 150 HIV-infected patients after kidney transplantation; 1 and 3-year kidney allograft and patient survival estimates were 90.4 and 73.7 and 94.6 and 88.2%, respectively.
○ all patients had viral suppression
CD4cell counts at least 200 cells/ml prior to transplant
○ combination ART and posttransplant anti-infective prophylaxis HIV control was excellent, and few opportunistic infections were encountered.
○, Bacterial infections were observed with increased frequency in HIV recipients who were treated with the (ATG) or coinfected with HCV.
○In addition, PWH experienced high rates of delayed allograft function
○HIV recipients experienced allograft rejection rates two to three times higher
●CCR5D3 homozygous persons have demonstrated less rejection and better allograft survival after liver and kidney transplantation
● A recent survey found that 16.9 and 28.1% of responding U.S. transplant programs still considered HIV as an absolute or relative contraindication to transplantation, respectively
● PWH have 18% lower likelihood of undergoing kidney transplantation when compared with their noninfected counterparts.
Liver
■ liver disease has become the third leading cause of death in PWH
■ The estimated global prevalence of chronic HCVand HBV coinfections are 2.4 and 6.1%, respectively,
■ ALD can also result from ART whether caused by direct hepatotoxicity, hypersensitivity reactions, mitochondrial toxicity, steatosis and/or steatohepatitis, or immune reconstitution phenomena
■hepatocellular carcinoma can further complicate the course of ALD
■HIV considered an absolute or relative contraindication by 28.1 and 31.6% of surveyed U.S. transplant centers, respectively
■The outcomes of liver transplantation in PWH vary by the reason for transplant
■ in the setting of passive prophylaxis with hepatitis B immunoglobulin and antiviral therapy, both graft and patient survivals range from 85 to 100% after 3–5 years of follow-up
■Estimates of 1, 3, and 5-year graft survival for these coinfected patients range from 52 to 86, 45 to 60, and 31 to 45%, respectively,
Pancreas
◇in 2018, 836 simultaneous pancreas-kidney transplants were performed in the United States.
◇additional experience is needed.
Clinical management of HIV-infected organ transplant candidates and recipient
●CD4cell counts at least 200 cells/ml are recommended for transplantation of all organs with the exception of liver, where the threshold for transplantation is CD4cell count more than 100 cells/ml,
●Candidates must also have demonstrated adherence to ART
●HCV should not be considered an exclusion factor for transplant.
●if treatment can be safely delayed, the option of utilizing HCVorgans followed by post-transplant DAA treatment increases the pool of organs available for transplant.
Antirejection therapy
○The best immunosuppressive regimen to use for patients with HIV is unknown.
○In the U.S. NIH observational trial, persons who received ATG as opposed to basiliximab, experienced significant, prolonged lymphocyte depletion, more frequent and severe infections, and increased risk for allograft loss
○Tacrolimus is associated with lower rejection rates
○Mycophenolate, is a very common component of maintenance immunosuppression.
○Sirolimus is known to have anti-HIVeffects through downregulation of CCR5,
Medication management
●Close attention is needed to ensure adequate levels of antirejection drugs
● Protease inhibitors, via inhibition of cytochrome P450 3A4 (CYP3A4) enzyme, alter the pharmacokinetics of immunosuppressive medications such as the calcineurin inhibitors (tacrolimus, cyclosporine A) and mTOR inhibitors (sirolimus, everolimus),
● protease inhibitor-based regimens increases the potential for inconsistent immunosuppressive levels that may place the patient at risk of rejection or, alternatively, supra-therapeutic levels that result in toxicity
●Studies in renal transplant recipients have also shown poor outcomes for patients on protease inhibitor-based regimens.
●those receiving protease inhibitor-based regimens had a 1.8-fold higher risk of allograft loss and a 1.9-fold higher risk of mortality when compared with non-protease inhibitor regimens
●Raltegravir, dolutegravir, and bictegravir are completely or primarily metabolized through the uridine diphosphate glucuronosyltransferase 1A system, resulting in clinically insignificant interactions with the calcineurin inhibitors.
●HIV clinicians should avoid, when possible, agents that may compromise organ function, such as use of tenofovir disoproxil fumarate after kidney transplant or abacavir after heart transplantation.
● In the early post-transplant period, in the setting of allograft rejection, and when immunosuppressive therapy is changed, more frequent monitoring of CD4cell counts and HIV viral load is warranted.
HIV-to-HIV transplantation
■ In 2008, four HIVto HIVrenal transplants were successfully performed
■ of the 51 patients transplanted with HIVorgans, the 1, 3, and 5-year patient survivals were 87, 87, and 84% while 1, 3, and 5-year graft survivals 96, 93, and 79%
■ A major concern is the potential consequences of superinfection with the donor HIV strain
■Other risks include transmission of opportunistic infections and poor organ quality
ART history,
HIV genotypic testing,
CD4cell counts,
HIV viral load results,
and history of opportunistic complications,
■ HIV African American persons with high-risk apoprotein L1 (APOL1) genotypes are at risk for development HIVAN and focal segmental glomerulosclerosis
■HIVdonors should avoid nephrotoxic ART(suchas tenofovir) in addition to agents such as nonsteroidal anti-inflammatory agents.
Introduction
Over the past decade accumulating evidence has established kidney and liver transplantation as a standard of care for PWH with ESKD or liver disease.
Though the evidence for pancreas, heart and lung are promising more data is required.
With passage of the HOPE act, PWH can register as donors thus enlarging the donor pool.
With introduction of HAART the rates of HIVAN have decreased but other causes of ESKD have increased.
PWH on dialysis have lower survival rates than the uninfected population.
Several complications were reported by Stocke et al in a prospective observational trial of 150 KTX PWH:
There was increased incidence of bacterial infections in person induced with lymphocyte depleting agent and those co-infected with HCV
PWH had higher rates of DGF
Allograft rejections rates were twice higher in PWH than general transplant population and they were a predictor of allograft failure.
Allograft rejection has been proposed due to inadequate immunosuppression either due to underuse of the IS or drug interactions that lead to inadequate drug levels.
Liver disease is the 3rd leading cause of death in PWH.
Those with viral hepatitis, HOV co-infection increases the risk for progressive and advanced liver disease.
Selection of candidate
Should have undetectable viral load.
Should be compliant on the cART.
Should have no evidence of opportunistic infection or HIV associated malignancy.
Should be able to be closely followed up for drug level monitoring and management.
Should have at least CD4 counts of 200cells/ul for all organs except liver where the threshold is 100cells/ul.
Anti-rejection therapy
The best IS (induction and maintenance )is not known and should be tailored as per individual patient.
Tacrolimus associated with lower rejection rates thus is the preferred CNI.
Sirolimus has some anti-HIV effect through down regulation of CCR5, and blockade of mTOR.
Medical management
Protease inhibitors are potent inhibitors of cytochrome P450 thus alter the pharmacokinetic of CNIs and mTOR inhibitors.
NNTRI have differing potential of induction of CYP3A4.
Intergrase strand transfer inhibitors (INSTI) are favoured for they have insignificant interactions with CNIs.
HIV+ to HIV+ transplantation
Major potential consequences:
Super infection with donor HIV strain
Acquisition of antiviral resistance or dual/mixed tropic virus
Transmission of latent or unrecognised opportunistic infections
Thus transplant specialist must make attempts to acquire as much of donor HIV history that includes ART history, HIV genomic testing, viral load and history of opportunistic infections.
Very few HIV+ to HIV+ living donation have been reported.
When evaluating living donation donors assessment must include specific HIV risk factors- low CD4 counts, HCV co-infection.
Post-nephrectomy the donors should avoid nephrotoxic drugs eg TDF.
HIV+ to HIV- is currently uncharted waters with significant medical and ethical concerns and currently it is illegal in the USA.
Introduction
-The life expectancy of persons with HIV has been increased with the current availability of antiretroviral therapy.
– The virus and ART drugs may increase the risk for organ dysfunction and, ultimately, organ failure
– SOT are increasingly expanded in PWH as it is a life-saving therapy in those with organ failure , this has opened and expanded opportunities for PWH to donate and receive organs
Status of organ transplantation by organ type Kidney – In US 800 PWH are diagnosed with ESRD and 0.5–1.5% of dialysis population and are PWH
– HIV associated nephropathy (HIVAN) rates have declined.
– However, other causes of renal failure; FSGS, DM, HTN remain prominent, also the risk increase with coinfections with HCV & HBV.
– Several ART associated with nephrotoxicity and/or metabolic complications, which eventually lead to ESRD.
– Transplantation providing a clear survival benefit over renal replacement therapy.
– Pre- transplant viral suppression and the use of combination ART and posttransplant anti-infective prophylaxis improved the outcome.
– The risk of bacterial infections increased if ATG used or coinfected with HCV.
– PWH experienced higher rates of DGF & allograft rejection.
– PWH remain on dialysis for longer durations before transplant listing,have longer waitlist times, and have 18% lower likelihood of undergoing kidney transplantation
Liver – liver disease is the 3rd leading cause of death in PWH.
– The prevalence of chronic HCVand HBV coinfections are 2.4 and 6.1%
– The risk of advanced liver disease (ALD increased in PWH secondary to multiple contributing factors
– The outcomes of liver transplantation in PWH variable.
Pancreas
Only few reported cases for simultaneous pancreas-kidney transplants with mixed, additional experience is needed.
Heart
-HIV-associated cardiomyopathy was seen in the pre-ART era; CAD is now a rising concern in PWH.
-With aging the need for heart transplantation are likely to increase.
– The risks of post-transplant vasculopathy are not any higher than HIV uninfected recipients
– They have higher rates of rejection.
Lung
There is a paucity of lung transplantation reports in PWH.
Clinical management of HIV-infected organ transplant candidates and recipient Selection of candidates: – Any PWH has organ failure and stable HIV to should be referred to experienced transplant center.
– Undetectable HIV viral load. – CD4+ cell count > 200 cells/μl (3 months prior to Tx) for SOT except for liver CD4+ cell count > 100 cells/μl
– Documented adherence with ART
– No evidence of active opportunistic infections or HIV-associated malignancy.
– The ability to have close follow-up for IS, drug level monitoring and management.
– Absence of chronic wasting or severe malnutrition – HBV or HCV infection if no advanced fibrosis/cirrhosis (for organ types other than liver)
Antirejection therapy – The best IS regimen in PWH is unknown, it should be individualized.
– Induction therapy is not required in the majority of liver transplant recipients.
– In KTR, studies showed ATG leads to prolonged lymphocyte depletion, more severe infections, and increased risk for allograft loss while other studies reported lower rejection and infection rates with ATG
– Maintenance IS: Tacrolimus and Mycophenolate, steroids use benefit should be weighed against the long-term effects of this agent.
– Sirolimus has anti-HIV effects.
Medication management
-Protease inhibitors, inhibit cytochrome P4503A4 enzyme; alter CNI & mTOR levels ,does adjustment is required.
In liver Tx; PI regimens were associated with episodes of ARF from high cyclosporine levels
In KTR using PI have 1.8-fold higher risk of allograft loss and a 1.9-fold higher risk of mortality
-NNRT inhibitors have differing potential for induction of CYP3A4.
-INSTI is a favored therapies with clinically insignificant interactions.
Clinical monitoring and care of HIVR persons before and after organ transplantation
-Pre-transplant phase: HIV specialists along with transplant team cooperate to optimize HIV therapy (ideally preTx), with aim to decrease toxicities and drug interactions while maintaining viral suppression.
-Post-transplantation, kidney function fluctuate and frequent dose adjustments may require & to avoid any drug that cause direct organ toxicity (tenofovir disoproxil fumarate in KTR and abacavir after heart Tx.)
-Regular and frequent monitoring of CD4 cell counts and HIV viral load is warranted.
– The use of anti-microbial prophylactic; PCP.
HIV-to-HIV transplantation
-Can be considered in the setting of limited access to dialysis, decreased organ availability, and increased HIV among brain-dead donors
-Good reported outcome: 5-year patient survivals were 87, 87, and 84% while 1, 3, and 5-year graft survivals 96, 93, and 79%.
-Risk of risks include transmission of latent or unrecognized opportunistic or donor HIV strain.
-In LD HIV transplantation; donor should be assessed for risk factors for development of ESRD (low CD4, HCV coinfection & other general conditions exclude donation)
– African American HIV persons with APOL1 genotypes are at risk for development HIVAN and FSGS, APOL1 screening utility to be determine.
-Post-nephrectomy, HIV donors should avoid nephrotoxic ART & NSAID.
HIV positive organs into uninfected recipients
Currently illegal with significant medical and ethical concerns.
This article focusses on the organ transplant in HIV patients, and the outcome of such transplant, along with the post transplant management of this specific population.
Discussion
Transplantation by type
Early initiation of ART helps in reducing rates of HIV associated nephropathy, but confection with HCV and HBV can increase risk of kidney failure.
With respect to kidney transplant, outcomes are favorable with HIV positive patients. However, patients given ATG as part of induction therapy may experience increased incidence of bacterial infection.
Outcome for liver transplantation in PWH vary, with HCV and HBV confection being very common, and requiring lifelong prophylaxis. DAA agents have helped greatly in increasing chances of graft and patient survival.
Pancreas transplant have mixed outcomes, with increased complications of graft thrombosis, rejection, bacterial infections and fatal sepsis.
HIV patients who receive heart transplant have higher rates of rejection within the first year post transplant in comparison with general heart transplant population.
HIV infection used to be an absolute contraindication to lung transplant. However, this has been shifted to a relative contraindication in the recent years, with HIV positive patients with advanced lung disease who adhere to their antiretroviral drug regimen and who do not have any recent AIDS defining illness being considered as potential recipients.
Immunosuppression
There is no perfect immunosuppressive treatment regimen for HIV recipients.
In terms of induction therapy, ATG has been found to cause more lymphocyte depletion resulting in more frequent and severe infection in contrast with Basiliximab. This also means that ATG has a higher rate of leading to graft loss in these patients. However, some centres have found that ATG was associated with lower rates of infection and rejection. Thus it is better to individualize treatment.
In terms of maintenance immunosuppression, Tacrolimus is associated with lower rejection rates. MMF is also a common addition to IS therapy in these patients.
In addition to possibly preventing graft rejection, IS drug therapy may also help in depleting HIV reservoir in the recipient. Sirolimus is a good example of this. Sirolimus down regulates CCR5 and unregulated beta chemokine.
The balance in dosage of IS drugs is very important in HIV patients. Too much immunosuppression can lead to multiple infections developing in the recipient, ultimately endangering the graft as well as the patient survival. Too less immunosuppression may help reduce the incidence of infection but exposes the allograft to the effects of the immune system, thus increasing chances for rejection. The line between these two sides needs to be carefully evaluated and individualized in each recipient to achieve good outcome. This is partly why standardization of IS therapy in HIV recipients is still not possible.
The balance between antiretroviral therapy and IS drug regimen is equally important since some drug interactions can increase or decrease the level of IS drugs in the recipients body and thus, once again, endanger the graft and the patient. An example of this would be protease inhibitors, which alter the levels of IS medications, including CNIs such as tacrolimus, cyclosporine A, and mTORi such as sirolimus, everolimus. This can lead to inconsistent IS levels and increase risk of rejection, or even lead to super therapeutic levels resulting in toxicity. Liver transplant recipients who were on protease inhibitor regimens were associated with episodes of acute renal failure from high cyclosporine levels.
Monitoring before and after organ transplant is crucial and can affect the overall success of the transplant both short term and long term. Infections need to be diagnosed as early as possible and treated to avoid chronicity and recurrence. Non adherence to medication should be dealt with when suspected so that the patient gets the best outcome from the graft.
In most cases, the same ART regimen can be continued post transplant. With this in mind, it is essential to remember that kidney function fluctuations can happen with frequent dose adjustments
HIV to HIV transplantation
HIV positive graft should not be used for HIV negative individuals. Although there has been a case in South Africa where this was done and found to have seroconversion but low reactivity to the infection in the recipient.
When using HIV positive organs, the risk of superinfection with the donor HIV strain and possibly acquiring antiviral resistance is a major drawback and complication.
Conclusion
Kidney and liver transplant can be done with good results in HIV positive recipients. The management of IS and antiretroviral therapy along with close monitoring forms a major part contributing to the outcome of the transplant. Standardization of immunosuppressive regimen has not been possible as yet and it is imperative to find out the best regimen for each recipient on an individual basis with close monitoring. Although HIV positive donors cannot be used for HIV negative recipients, in the case of a crucial life or death situation, it has been attempted and found to be manageable within the first year post transplant. Further studies are essential in this regard to maximize the donor pool. Co infection with HBV and HCV is a major concern in these recipients and adequate dosage of lifelong prophylaxis may be needed in naive recipients. Educating the patient with regards to adherence to medication is an essential part of making sure of good outcome. Frequent monitoring and follow up makes the whole process smoother and more successful in the long term.
After using of ART, HIV became a chronic infection & AIDS-related mortality reduced.
ART & direct effect if HIV increase risk of organ dysfunction & failure.
PWH registered as organ donor & expand donor pool for PWH on waiting list.
Status of organ transplant by organ type Kidney:
In US 0.5-1.5% of dialysis patients are PWH.
HBV & HCV confection with HIV increase risk of renal failure.
PI are nephrotoxic & associated with metabolic complication e.g. DM & dyslipidemia which can lead to CKD & ESRD.
PWH on dialysis have lower survival compared to non HIV dialysis patients.
PWH have better post transplant survival, lower opportunistic infection, but there is increased risk of bacterial infection,DGF, HCV confection & risk of rejection.
Potential mechanism of rejection:
inadequate immunosuppression or inconsistent immunosuppression drug level.
immune system dysregulation & heterogeneous immunreactivity in response to chronic infection including HIV infection.
In US 16.9% of transplant program consider HIV absolute contraindication & 28% of programs considered it as relative contraindication.
Liver:
Liver disease become the third leading cause of death in PWH.
Increased risk of end stage liver disease can be result from:
HBV (6.1%) & HCV (2.4%) coinfection.
HIV infection increased risk of disease progression & ALD in patients with viral hepatitis.
ART are hepatotoxic or may cause hypersensitivity, mitochondria toxicity, steatosis &/or steatohepatitis or immune reconstruction phenomenon .
Alcohol & other non HIV related cause of liver disease & HCC can be a combining factor of ALD development.
PWH consider as contraindication for liver transplantation in 28.1% & relative contraindication in 31.6% of US centers.
Transplant outcome varied according reason e.g. HIV/HBV confection, using prophylaxis (HBIg) & ART use.
Graft & patient survival can reach 85-100% after 3-5 years of flow-up.
HCV related progressive liver disease, sever infection & sepsis associated with poor outcome.
Pancreas:
Pancreatic transplant with HIV infection have mixed outcome , & high rate of complication e.g. graft thrombosis, rejection & bacterial infection.
Pancreatic transplantation can be successful in PWH but need additional experience.
Heart:
Heart disease can be due to aging, chronic immune activation state of HIV & metabolic effect of ART.
HIV is not contraindication for heart transplantation but it is uncommon.
Increased risk of rejection compared to non HIV heart transplant recipients.
Lung:
HIV is a relative contraindication for lung transplantation.
PWH can be considered for transplant if ART adherence confirmed & RNA fully suppressed & no recent AIDS defining illness.
Selection of candidates:
Any PWH can be transplanted if viral load is undetected, ART compliance, no active opportunistic infection or HIV associated malignancy, ability to have close follow up for immunosuppression, drug level monitoring & management & CD4 count>200(liver transplant CD4 count>100).
HCV co-infection is not contraindication to transplant but weigh the risk & benefit of treatment before transplantation.
Anti-rejection therapy:
Best immunosuppression regimen for HIV patients unknown, but regimens should be individualized according organ transplant, immunologic risk, renal & hepatic function & ART.
Data regarding us of induction in transplant other than liver in HIV+ patient is lacking.
Tacrolimus associated with lower risk of rejection s it is the preferred CNI agent.
mTOR-I have anti-HIV effect.
CNI found to reduce HIV-1 DNA transcription.
Drug interaction should be known by HIV providers.
PI (CYP3A4 inhibitor) can alter pharemokinetics of CNI & mTOR-I.
In liver transplan recipients, boosted PI associated with acute renal failure (high level of cyclosporin).
Patients use PI have 1.8 fold increase risk of graft loss & 1.9 fold increase of mortality compared to patients use non PI.
Raltegravir, dolutegravir & bictagravir associated with insignificant interaction with CNI ( effective & well tolerated).
Monitoring of HIV+ patient before & post transplantation:
HIV specialist & transplant stem need co-operation to optimize HIV therapy, minimize pre-transplant toxicity, post transplant drug interaction with maintained viral suppression
Post transplant, kidney function fluctuate so ART dose should be adjusted & HIV clinician should avoid any drug affect organ function.
Communication between HIV provider with transplant center is important during ART dose change.
HIV viral load & CD4 count monitoring essential in early post transplant period, graft rejection & changed immunosuppression dose.
HIV to HIV transplantation:
Patient survival at 1,3, & 5years post transplant is 87,87 &84%, graft survival is 96, 93, & 79%.
There is a fear from transmission of latent unrecognized opportunistic infection w& super infection with donor HIV strain.
Donor suitability assessed by identification of ART history, HIV genotype test, CD4 count, HIV viral load & history of opportunistic infection.
HOPE Act can utilize organ discarded due to false positive HIV result (50% of organs come from donor with false positive test).
HIV donor should be assessed for ESRD risk e.g. low CD4 count, HCV co-infection, & other disease as DM, HT
Afro-American with APOLi genotype at increased risk of HIVAN & FSGS.
Post nephrectomy, HIV+ donor should avoid nephrotoxic drugs & NSAID.
I like your clinical approach and well-structured extensively detailed summary quoting a number of trials related to HIV and various types of transplants
1- After introduction of antiretroviral therapy ART, the possibility of transplantation of persons with HIV PWH and possibility of accepting HIV donor are likely to occur.
2- With introduction of ART, the incidence of HIVAN declines but still PWH have possibility of FSGS, DM and HTN as a causes of renal insult.
3- Also in PWH there is high incidence of co-infection by HCV , HBV with adding risk to renal affection.
4- Most of ART is associated with multiple side effects like DM, dyslipidemia, nephrotoxicity that may leads to ESRD.
5- PWH on dialysis have high mortality rate compared to non-HIV patients, so increasing needs for transplantation.
6- After transplantation, ART together with prophylactic anti-infective therapy, and CD4 cell counts at least 200 cells/ml before transplantation , all these leads to good control of HIV.
7- Bacterial infection can occur in the patient used ATG or if there is co-infection with HCV, also graft rejection is more in HIV patient than non-HIV which may be related to under immunosuppression or inadequate adjustment of the dose or multiple drug interaction.
8- HIV patients remains on dialysis and on the waiting list longer than non-HIV patients.
9- HIV increase the risk of liver disease and its progression because of co-infection by HCV, HBV and due to adverse effects of ART like hepatotoxicity and mitochondrial toxicity in addition to non-HIV related factors.
10- Liver transplant in PWH is varied according to the reason of liver failure.
11- Pancreatic transplantation can be done in PWH but still has multiple complications. 12- Clinical management of HIV-infected organ transplant candidates and recipient:
a- Selection of candidates:
1- Meet transplant center-specific eligibility for organ transplantation
2- CD4+ cell count > 200 cells/µl during 3 months prior to transplantation for kidney, pancreas, heart and lung candidates
3- CD4+ cell count > 100 cells/µl during 3 months prior to transplantation for liver candidates only
4- Undetectable plasma HIV viremia (unless unable to tolerate antiretroviral therapy prior to liver transplant) With liver failure, patients may not tolerate ART; in this setting care providers must be able to predict HIV suppression with introduction/reintroduction of ART post-transplant
5- Documented adherence with stable antiretroviral treatment regimen
6- Absence of active opportunistic infection and malignancy. In addition to no active opportunistic infections, patients with progressive multifocal leukoencephalopathy, chronic intestinal cryptosporidiosis, visceral Kaposi’s sarcoma (KS), and primary central nervous system lymphoma were excluded in the initial U.S. multicenter HIV transplant (HIVTR) trial. Persons with liver failure and hepatocellular carcinoma, meeting center specific criteria, can be considered for transplantation. Treated cutaneous KS and anal carcinoma in situ were not exclusions in the initial HIV-TR trial. All other treated malignancies with disease-free intervals are considered per center-specific policies
7- Absence of chronic wasting or severe malnutrition
8- Hepatitis B or C infection if no advanced fibrosis/cirrhosis (for organ types other than liver)
9- Access to immunosuppressive agent therapeutic drug monitoring. Because of significant drug-drug interactions, persons on protease inhibitor- and some non-nucleoside reverse transcriptase inhibitor-based regimens require ready access to laboratories that perform therapeutic drug monitoring for calcineurin inhibitors with efficient turnaround times.
10- Ability to regularly follow up with HIV care providers.
b- There is no standard induction and maintenance immunosuppressive medication regimen, it is always individualized but it was found that tacrolimus decrease rejection episodes and MMF with long term prednisolone are commonly used in HIV patients and also sirolimus has anti-HIV properties
c- Close monitoring of trough levels is very important to guard against rejection and toxicity because of drug-drug interactions.
d- Post transplant follow up of HIV patient is very important for early detection and management of any complications.
13- HIV-to-HIV transplantation:
a- These transplants were performed in the setting of limited access to dialysis, decreased organ availability, and increased HIV among brain-dead donors.
b- Certain data is required from HIV donor such as ART history, HIV genotypic testing, CD4 cell counts, HIV viral load results, and history of opportunistic complications, so that donor suitability can be ascertained.
c-
Pointwise reply is fine but no 10 (ability to follow-up) be followed by 11 rather than 13 (HIV to HIV). Please use headings and sub-headings to make easier to read your write-up. Please use bold or underline to highlight headings and sub-headings.
In the United States where approximately 800 PWH are diagnosed with end-stage renal disease (ESRD) annually
It is estimated that 0.5–1.5% of the United States dialysis population is made up of PWH
Coinfections with hepatitis C virus (HCV) and hepatitis B virus (HBV) increase risk for kidney failure
Once on dialysis, PWH have lower survival rates when compared with uninfected dialysis patients, thus considering for kidney transplant.
Once transplanted, outcomes for PWH are favorable, with transplantation providing a clear survival benefit over renal replacement therapy
In the largest prospective observational trial conducted, outcomes of 150 HIV-infected patients after kidney transplantation were reported.
1 and 3-year kidney allograft and patient survival estimates were 90.4 and 73.7 and 94.6 and 88.2%, respectively.
Because all patients had viral suppression and CD4 cell counts at least 200 cells/ml prior to transplant and combination ART and posttransplant anti-infective prophylaxis was employed, HIV control was excellent, and few opportunistic infections were encountered
Bacterial infections were observed with increased frequency in HIV recipients who were treated with the lymphocyte-depleting agent, antithymocyte globulin (ATG) or coinfected with HCV
HIV recipients experienced allograft rejection rates two to three times higher than observed in the general kidney transplant population
Causes for rejection:
inadequate immunosuppression,
because of underuse of immunosuppressive agents
drug interactions that lead to inadequate or inconsistent immunosuppressive drug levels
A recent survey found that 16.9 and 28.1% of responding U.S. transplant programs still considered HIV as an absolute or relative contraindication to transplantation, respectively
Transplant eligibility
• CD4+ cell count > 200 cells/µl during 3 months prior to transplantation for kidney, pancreas, heart and lung candidates
• Undetectable plasma HIV viremia
• Documented adherence with stable antiretroviral treatment regimen
• Absence of active opportunistic infection and malignancy
• Absence of chronic wasting or severe malnutrition
• Hepatitis B or C infection if no advanced fibrosis/cirrhosis (for organ types other than liver)
• Access to immunosuppressive agent therapeutic drug monitoring
• Ability to regularly follow up with HIV care providers
Medication management:
Induction agent should be individualized. ATG vs basiliximab
Maintenance : Tacrolimus, steroid, MMF
Calcineurin inhibitors have been found to decrease HIV-1 DNA transcription
Protease inhibitors, via inhibition of cytochrome P450 3A4 (CYP3A4) enzyme, alter the pharmacokinetics of immunosuppressive medications, including the calcineurin inhibitors (tacrolimus, cyclosporine A) and mTOR inhibitors (sirolimus, everolimus)
Non-boosted integrase strand transfer inhibitors (INSTI) have emerged as favored therapies
Raltegravir, dolutegravir, and bictegravir are completely or primarily metabolized through the uridine diphosphate glucuronosyltransferase 1A system, resulting in clinically insignificant interactions with the calcineurin inhibitors
In the early post-transplant period, in the setting of allograft rejection, and when immunosuppressive therapy is changed, more frequent monitoring of CD4 cell counts and HIV viral load is warranted.
life-long prophylaxis against Pneumocystis Jiroveci
HIV to HIV transplant
A major concern is the potential consequences of superinfection with the donor HIV strain, including acquisition of CXCR4-tropic or dual/mixed-tropic virus or transmitted antiviral resistance.
An unexpected benefit of HOPE Act is the utilization of organs that may have otherwise been discarded due to having false-positive HIV test results, with almost 50% of HOPE-allocated organs coming from donors with false-positive testing.
HIV-to-HIV living donor transplantation have been reported in the literature.
When evaluating potential candidates for donor nephrectomy, the assessment must include identification HIV-specific risk factors for development of ESRD such as low CD4 cell count and HCV coinfection in addition to other conditions that generally exclude persons from donation (e.g. diabetes mellitus, hypertension, and preexisting kidney disease)
HIV African American persons with high-risk apoprotein L1 (APOL1) genotypes are at risk for development HIVAN and focal segmental glomerulosclerosis
HIV positive organs should not be transplanted to uninfected recipients.
I like your well-structured detailed summary. I appreciate your comment superinfection with HCV in a HIV patient, and superinfection with another type of genotype of HIV in a HIV positive recipient. Typing whole sentence in bold or typing in capitals amounts to shouting.
This study is a narrative review of solid organ transplantation in patients living with the HIV virus.
Introduction
HIV is a virus that generates human immunodeficiency by reducing the levels of CD4 cells and compromising the cellular response, evolving into AIDS. During the last four decades, it has spread across continents, but disease control and knowledge of immunology have made it possible to perform transplants in this population.
Kidney
In the US, the diagnosis of end-stage renal disease living with HIV can be due to virus-associated nephropathy (high viral loads leading to glomerular damage) or as a result of antiretroviral medications (mainly Tenofovir fumarate and protease inhibitors).
After transplantation, the outcome has been favorable and with clear benefits. As all patients had serum CD4 levels greater than 200 with an undetectable viral load, few opportunistic infections occurred.
Co-infection with HCV and the use of rATG presented greater complications. Acute rejection was more frequent in this group when compared to the HIV-negative group.
Liver
HCV and HBV co-infections, drug interactions, drug hepatotoxicity, metabolic changes and hepatic steatosis, immune reconstitution, and mitochondrial toxicity are some of the mechanisms of both the virus and its treatment. There are still many centers that consider contraindications for the transplant of this organ.
Treatment of Hepatitis B can occur with similar drugs, but it is important in Hepatitis C to have disease control with antivirals that act directly against the virus and its sustained viral suppression to proceed properly with the transplant.
Pancreas
Only ten cases were reported in the literature, in the context of transplantation associated with the kidney, with a lot of associated immunosuppression and little data for the study.
Heart
HIV, metabolic disease, and its drugs can interfere and evolve with cardiomyopathy. They present a higher risk of acute rejection when compared to the HIV-negative population.
Lung
There is little data on this modality.
Patient selection
– Appropriate transplant center
– Serum CD4 above 200 cells for 3 months
– Serum CD4 above 100 cells for 3 months may be considered for liver transplantation
– Negative viral load for HIV
– Adherence to treatment
– Absence of opportunistic infections and malignancy
– Severe malnutrition must be corrected (BMI < 21 or > 35)
– Severe liver disease may exclude from list
– Joint follow-up with the Infectology team
Anti-rejection therapy
There is no well-defined drug of choice. We are aware of the limitation of lymphocyte-depleting drugs such as rATG that can decrease CD4 and induce AIDS, but compared to Basiliximab it still seems to be the best drug. An immunosuppression regimen with MMF tacrolimus and corticosteroids should be considered.
Tacrolimus appears to decrease HIV transcription just as mTOR decreases CCR5 exposure.
Use of Medication
Drug interactions, serum measurement of their values, risk of inadequate immunosuppression, and risk of inadequate rejection. Integrase inhibitors seem to be the most suitable drugs related to HIV control.
Protease inhibitors have a lot of drug interactions with calcineurin inhibitors, statins and other drugs. Negative viral load is mandatory, as well as serum levels of immunosuppressants.
HIV Transplant for HIV
They occurred for the first time in South Africa in the context of limited dialysis, low organ availability, and high rates of HIV. Good response and viral control were promising, but there is a need for a broad study, profile of antiretroviral resistance (genotyping), serum CD4 values, viral load, and complications due to opportunistic infections.
Conclusion
Kidney and liver transplantation are the treatment of choice for patients living with HIV who have failed these organs. These results encourage the possibility of transplantation to other organs in this context.
Organ transplantation in persons with HIV: Introduction;
-With current antiretroviral therapy, the lifespan of newly diagnosed persons with HIV (PWH) approaches that of uninfected persons.
-However, metabolic abnormalities related to both the disease and the virus itself, along with comorbidities of aging, have resulted in end-organ disease and organ failure as a major cause of morbidity and mortality.
-Solid organ transplantation is a life-saving therapy for PWH who have organ failure, and the approval of the HIV Organ Policy Equity Act has opened and expanded opportunities for PWH to donate and receive organs.
-The most evidence in support of transplantation in this population comes from kidney followed by liver transplantation: however, growing numbers of persons have undergone pancreas, heart, and lung transplantation. Kidney
-In the United States where approximately 800 PWH are diagnosed with end-stage renal disease (ESRD) annually, it is estimated that 0.5–1.5% of the United States dialysis population is made up of PWH.
-With improvements in and earlier initiation of ART, HIV associated nephropathy (HIVAN) rates have declined, but in antiretroval-treated PWH, other causes of renal failure such as focal segmental glomerulosclerosis, diabetes mellitus, and hypertension remain prominent.
-Coinfections with hepatitis C virus (HCV) and hepatitis B virus (HBV) increase risk for kidney failure.
-Importantly, several antiretroval agents, such as tenofovir, abacavir, indinavir, ritonavir-boosted lopinavir, ritonavir, boosted atazanavir, and potentially other boosted protease inhibitors, are associated with nephrotoxicity and/or metabolic complications, including diabetes and dyslipidemias, which can ultimately contribute or lead to the development of chronic kidney disease and ESRD.
-PWH experienced high rates of delayed allograft function (i.e. the need for hemodialysis in the immediate post-transplant period), although, ultimately, this did not appear to be predictive of graft failure.
-There is observed high rates of allograft rejection following kidney transplantation with several proposed mechanisms for this, including inadequate immunosuppression, either because of underuse of immunosuppressive agents or drug interactions that lead to inadequate or inconsistent immunosuppressive drug levels. Liver;
-In the era of highly effective ART, liver disease has become the third leading cause of death in PWH.
-PWH are at risk for end-stage liver disease through a variety of mechanisms. The estimated global prevalence of chronic HCV (2.4%) and HBV (6.1%) coinfections, although prevalence may differ regionally or by risk for acquisition.
-ALD can also result from ART whether caused by direct hepatotoxicity, hypersensitivity reactions, mitochondrial toxicity, steatosis and/or steatohepatitis, or immune reconstitution phenomena.
-Finally, hepatocellular carcinoma can further complicate the course of ALD. Pancreas; –In 2018, 836 simultaneous pancreas-kidney transplants were performed in the United States,this procedure is not commonly performed in type 1 diabetic PWH.
-Outcomes have been mixed, with reported complications of graft thrombosis, rejection, and bacterial infections, including fatal sepsis , based on these findings, pancreas transplantation can be successful in HIV-infected patients, but additional experience is needed. Heart;
-PWH are prone to both cardiac diseases associated with aging, as well as those associated with the chronic immune activation state of HIV and metabolic effects of ART.
-HIV-associated cardiomyopathy was seen in the pre-ART era; coronary artery disease is now a rising concern in PWH.
-HIV is no longer considered an absolute contra-indication to advanced heart failure therapies, including heart transplantation , but is uncommonly performed. Lung;
-In 2018, 2530 lung and 32 heart/lung transplants were performed in the United States.
-In the 2014 updated ISHLT guidelines, HIV infection has moved from an absolute to a relative contraindication to lung transplantation. Selection of candidates;
-Updated guidelines recommend that, regardless of the organ transplanted, patients have undetectable HIV viral load, known compliance with ART, no evidence of active opportunistic infections or HIV-associated malignancy, and the ability to have close follow-up for immunosuppression, drug level monitoring and management.
-CD4+ cell counts at least 200 cells/ml are recommended for transplantation of all organs with the exception of liver, where the threshold for transplantation is CD4+ cell count more than 100 cells/ml, with the rationale that ALD and portal hypertension lead to splenic sequestration of white blood cells, including lymphocytes. Antirejection therapy;
-The best immunosuppressive regimen to use for patients with HIV is unknown. Regimens should be individualized to patients based on the organ transplanted, immunologic risk, renal and liver function, and ART regimen.
-Based on this, choice of induction agent should be individualized. Induction immunosuppression is not required in the majority of liver transplant recipients
-For HIV-infected transplant recipients, the best maintenance immunosuppressive regimens have not been established. Tacrolimus is associated with lower rejection rates, and for this reason, has emerged as the preferred calcineurin inhibitor.
-Mycophenolate, an antiproliferative agent, is a very common component of maintenance immunosuppression. Although long-term maintenance prednisone therapy reduces risk for rejection, the benefits of its used should be weighed against the long-term effects of this agent. Medication management;
-Protease inhibitors, via inhibition of cytochrome P450 3A4 (CYP3A4) enzyme, alter the pharmacokinetics of immunosuppressive medications, including the calcineurin inhibitors (tacrolimus, cyclosporine A) and mTOR inhibitors (sirolimus, everolimus), resulting in alterations in doses and dosing schedules of these drugs.
-This increases the potential for inconsistent immunosuppressive levels that may place the patient at risk of rejection or, alternatively, supra-therapeutic levels that result in toxicity.
-Conversely, non-nucleoside reverse transcriptase inhibitors have differing potential for induction of CYP3A4.
-Although protease inhibitors have fallen out of favor in the transplant setting, non-boosted integrase strand transfer inhibitors (INSTI) have emerged as favored therapies. HIV-to-HIV transplantation;
-In 2008, four HIV+ to HIV+ renal transplants were successfully performed in Cape Town, South Africa.
-These transplants were performed in the setting of limited access to dialysis, decreased organ availability, and increased HIV among brain-dead donors.
-Recent follow up data published by the same group notes that of the 51 patients transplanted with HIV+ organs, the 1, 3, and 5-year patient survivals were 87, 87, and 84% while 1, 3, and 5-year graft survivals 96, 93, and 79%.
-As of December 2018, 100 HIV+ persons have undergone deceased donor organ transplants in the United States with organs allocated under the HOPE Act.
-With implementation of the HOPE Act, PWH can donate organs to HIV infected persons waiting for kidney and liver transplants under a research setting. Conclusion;
– Kidney and liver transplantation are the standard of care for HIV-infected persons with end-stage kidney and liver diseases.
-Encouraging results with transplantation of other organ types, including pancreas, heart, and lung suggest that persons with other advanced organ disease should also be referred to centers experienced in performing these transplants.
-The availability of INSTI, with minimal impact on immunosuppressive drug levels, has greatly simplified the post-transplant management of the HIV+ organ recipient.
-The introduction of DAAs for hepatitis C , with their high efficacy in the post-transplant setting, promise to improve outcomes in coinfected organ recipients.
III. Organ transplantation in persons with HIV Please summarize this article.
The HIV Organ Policy Equality Act’s approval has increased the options available to PWH for organ donation & TX, which is a life-saving treatment for PWH who have organ failure.
Current status
TX clearly outperform dialysis in terms of survival.
150 HIV+ve patients who underwent KTX were followed up on by Stock et al.:
CD4 cell counts were at least 200 cells/ml before TX.
Combination ART & post-TX anti-infective prophylaxis were used.
ATG & HCV coinfection were associated with an increased incidence of bacterial infections in HIV patients. Moreover, PWH had high rates of DGF; however, this did not seem to be a reliable indicator of graft failure.
HIV recipients had rejection rates 2 to 3 times greater than general KTX population.
The findings of this pilot study have been confirmed by other single & multicenter studies.
PWH have obstacles on referral & receiving a KTX.
To understand the differences in referral and eventual receipt, more detailed statistics are required.
Liver
Liver disease is now the 3rdbiggest cause of death in PWH in the era of HAART.
PWH are susceptible to ESLD through different pathways. Chronic HCV & HBV co-infections occur in 2.4 & 6.1% of people worldwide, respectively.
In viral hepatitis, HIV infection increases the risk for advanced & progressive liver disease (ALD). ALD can also be brought on by ART.
ESLD can result from alcohol consumption & other non-HIV-related causes of liver disease, either as its major cause or a contributing component.
HCC can make the progression of ALD much more challenging. The number of HIV+ patients receiving liver TX is rising due to the frequency of ALD in this community, however PWH encounter barriers to liver TX, with HIV being viewed as an absolute or relative contraindication by 28.1 & 31.6% of surveyed U.S. TX centers, respectively.
The TX results of HIV-HCV co-infected patients were poor (poorer graft & patient survival rates) compared to HCV-mono-infected controls. This was due to the lack of hepatitis C DAA medications. Poor outcomes were a result of sepsis, severe infections, and increasing liver damage caused by HCV.
Pancreas
In the US in 2018, 836 SKP TX were carried out.
Only 10 cases of this treatment being used on type 1 diabetic PWH have been documented.
Graft thrombosis, rejection, & bacterial infections, including deadly sepsis, were reported as complications. Pancreatic TX in HIV-positive patients is feasible but requires more practice.
Heart
PWH are vulnerable to age-related HD as well as those brought on by HIV’s chronic immunological activation state & the metabolic side-effects of ART.
Prior to the development of ART, HIV-associated cardiomyopathy was seen; currently, CAD is a growing issue in PWH.
Heart TX is still uncommon, but HIV is no longer considered a strict contraindication to advanced heart failure therapy. The number of people seeking heart TX is expected to rise as the HIV population ages.
Currently, the 1- & 5-year after TX survival rates range from 64.7% to 77.3% & 85.9% to 90%, respectively.
The risk of post-transplant vasculopathy is not higher than in HIV-uninfected recipients. Rejection rates compared to the overall heart TX is greater.
Lung
There is a shortage of information about TX in PWH.
HIV infection is a relative contraindication to lung TX in the 2014 revision of the ISHLT guidelines.
HIV-experienced facilities may consider PWH as candidates if they have a history of ART adherence, viral suppression, & no recent AIDS-defining condition. Few lung TX reports can be found in PWH.
Clinical management of HIV-infected organ transplant candidates and recipient Selection of candidates:
Any patient with end-organ failure & stable HIV should be referred to centers experienced in HIV organ TX.
Patients should have undetectable HIV viral loads, known ART compliance, no signs of active opportunistic infections or HIV-associated malignancies, & the ability to have close follow-up for IS, drug level monitoring, & management.
With the exception of the liver, where a CD4 cell count of at least 100 cells/ml is required for TX, other organs should have CD4 cell counts of at least 200 cells/ml.
Although organ recipients with HCV co-infection had unfavorable outcomes in the pre-DAA era, HCV should not be regarded as a bar to TX.
DAAs have produced good HCV treatment outcomes in both kidney & liver TX.
It’s crucial to consider factors like low BMI, the need for a combined liver-kidney TX, & HCV donor organs when assessing HCV-co-infected patients for liver TX.
Antirejection Therapy
The ideal IS regimen to administer to HIV patients is unknown.
Patients should have tailored regimens depending on the transplanted organ, immunologic risk, renal & hepatic function, & ART regimen.
ATG as opposed to basiliximab, causes significant, extended lymphocyte depletion, more frequent &severe infections, & a higher risk for allograft loss.
For the majority of liver transplant recipients, induction IS is not necessary.
The best effective maintenance IS regimens are not yet known.
Tacrolimus is the primary CNI due to associated lower rejection rates.
MMF is widely used in maintenance IS.
Prednisone maintenance medication minimizes the likelihood of rejection.
Sirolimus has anti-HIV effects via upregulating β-chemokines, downregulating CCR5, & blocking the mTOR.
Sirolimus does not prevent HIV-1 transcription (In-vitro research).
CNIs reduce HIV-1 DNA transcription.
Medication management
Anti-rejection medicine levels must be carefully monitored as low & high levels might have harmful effects.
Awareness of drug interactions with maintenance IS medicines is necessary.
Protease inhibitors alter the pharmacokinetics of IS drugs, such as CNIs & mTOR inhibitors, causing significant changes in their doses & dosing schedules, & thus putting the patient at risk of rejection or, alternatively, toxicity.
Boosted protease inhibitor regimens were linked to ARF caused by high cyclosporine levels in liver TX recipients. Poor results for patients on protease inhibitor-based regimens have also been shown in renal TX recipients.
Non-boosted integrase strand transfer inhibitors (INSTI) have become popular treatments, but protease inhibitors have lost favor in TX. Raltegravir, dolutegravir, & bictegravir have negligible interactions with CNIs.
Because of its high barrier to resistance & simplicity of use, dolutegravir has become the preferred INSTI.
Clinical monitoring & care of HIV+ve persons before & after TX
The same ART treatment is frequently continued after transplant.
Abacavir use after heart TX or the use of tenofovir disoproxil fumarate after KTX are examples of drugs that HIV physicians should avoid whenever feasible.
Fixed dosage combination regimens should only be used with caution.
If a change in ART is being considered, HIV providers must consult with the TX center.
HIV care must be regularly provided during the post-TX period.
More regular monitoring of CD4 cell counts & HIV viral load is necessary in the early post-TX period, in cases of rejection, & when IS medication is modified.
Anti-infective prophylaxis is based on HIV recommendations as well as TX center practice.
HIV-to-HIV transplantation
The potential of superinfection with the donor HIV strain, such as the development of CXCR4-tropic or dual/mixed-tropic virus or transmitted antiviral resistance, are a big worry.
Additional hazards include the possibility of transmitting opportunistic infections that are latent or undiagnosed to the recipient as well as decreased organ quality due of the high prevalence of renal, hepatic, & cardiac problems in the HIV population.
Conclusions
Standard of care for HIV-infected individuals with ESRD & liver disorders is TX.
Positive outcomes with the TX of other organ types (pancreas, heart, & lung) imply that patients with other severe organ diseases should also be directed to TX facilities with experience in these procedures.
Treatment of the HIV organ recipient after TX has been eased by the availability of INSTI, which has little interactions with IS medications.
With their strong efficacy in the post-TX environment, DAAs for hepatitis C promise to enhance outcomes for organ recipients who are also co-infected.
The HOPE Act’s implementation allows PWH to donate organs to HIV-positive people awaiting kidney and liver TX in a research setting.
HIV specialists should actively refer suitable patients for TX, inform patients on the results of TX & the advantages & disadvantages of using HIV-positive organs, & ensure regular HIV infection surveillance following TX.
Introduction:
Antiretroviral treatment has made HIV a chronic disease and reduced overall and AIDS-related mortality. With longer life expectancies and an aging population, prevalent medical comorbidities, including coronary artery disease and nonalcoholic steatohepatitis, are becoming major sources of morbidity and death in HIV-positive people. The metabolic side effects of the virus and antiretrovirals increase the probability of organ malfunction and failure.
Kidney:
PWH transplantation improves survival versus renal replacement treatment. HIV control and opportunistic infections were low because all patients had viral suppression and CD4 cell counts of at least 200 cells/ml before transplant and used a combination of ART and posttransplant anti-infective prophylaxis.
This research found significant post-kidney transplant problems in PWH. Bacterial infections were more common in HIV/HCV co-infected patients who received anti-thymocyte globulin (ATG).
PWH also had significant rates of delayed allograft function (hemodialysis in the post-transplant interval), although this did not predict graft failure. Lastly, HIV-positive kidney transplant patients had allograft rejection rates two to three times greater than the overall kidney transplant group, and rejection predicted allograft failure in this research.
Liver:
PWH liver transplant results vary by rationale. In HIV-HBV co-infected patients, passive prophylaxis with hepatitis B immunoglobulin and antiviral treatment results in 85–100% graft and patient survival after 3–5 years.
Lifelong HBV viremia prevention is advised.
HIV–HCV coinfected patients had worse graft and patient survival rates than HCV-monoinfected controls before the availability of DAA medications.
HCV monoinfected controls had 1, 3, and 5-year graft survival rates of 57 to 88, 50 to 62, and 33 to 58%, whereas coinfected patients had 52 to 86, 45 to 60, and 31 to 45%. HCV-related increasing liver damage, severe infections, and sepsis harm results.
Pancreas:
The US conducted 836 simultaneous pancreas-kidney transplants in 2018. Just 10 type 1 diabetic PWH have had this operation.
Graft thrombosis, rejection, and bacterial infections, including deadly sepsis, have caused varied results. These data suggest that HIV-infected individuals may undergo pancreatic transplantation, although more experience is required.
Heart :
PWH are susceptible to heart problems caused by age, HIV, and ART. Pre-ART HIV-associated cardiomyopathy was common, whereas PWH currently has coronary artery disease. HIV is no longer a contraindication to advanced heart failure therapy such as heart transplantation, however, it is seldom done.
Lung:
The US conducted 2530 lung and 32 heart/lung transplants in 2018 [54]. PWH transplantation data is scarce. HIV is now a relative contraindication to lung transplantation under the 2014 ISHLT guidelines.
HIV-infected organ transplant candidates and recipients: clinical treatment Recruitment:
• Meet transplant center-specific organ transplant eligibility.
• CD4+ cell count > 200 cells/μl three months before transplantation for kidney, pancreatic, heart, and lung candidates.
• Liver candidates only: CD4+ cell count > 100 cells/μl 3 months prior to transplantation.
• undetectable plasma HIV viremia (unless unable to tolerate antiretroviral medication before liver transplant).
• Stable antiretroviral therapy adherence
• No chronic wasting or severe malnutrition
• Hepa!!s B or C infection without advanced fibrosis/cirrhosis (for organ types other than liver).
Immunosuppressive medication monitoring.
• Regular HIV care provider follow-up
Antirejection:
The optimum HIV immunosuppressive regimen is uncertain. The organ transplanted, immunologic risk, renal and hepatic function, and ART regimen should determine patient regimens.
Physicians disagree on HIV-positive kidney transplant induction immunosuppression. In the U.S. NIH observational experiment, ATG caused considerable, protracted lymphocyte depletion, more frequent and severe infections, and an increased risk for allograft loss. Basiliximab, an IL-2 receptor antagonist, did not.
Medication management:
Both low and high antirejection medication levels in transplant patients may be dangerous. HIV providers must understand medication interactions with maintenance immunosuppressive medicines, even while the transplant center monitors them.
Protease inhibitors influence the pharmacokinetics of immunosuppressive medicines such as calcineurin inhibitors (tacrolimus, cyclosporine A) and mTOR inhibitors (sirolimus, everolimus) by inhibiting CYP3A4. This raises the danger of variable immunosuppressive levels that might cause rejection or toxicity. Non-nucleoside reverse transcriptase inhibitors induce CYP3A4 differently.
HIV monitoring:
HIV providers prepare patients for transplant and monitor HIV infection and posttransplant opportunistic consequences. HIV experts work with the transplant team to optimize HIV medication before transplant to reduce toxicities and drug interactions and maintain viral suppression.
HIV-to-HIV transplantation:
Four HIV-to-HIV kidney transplants were successful in Cape Town, South Africa, in 2008.
Brain-dead donors had limited access to dialysis, organ availability, and HIV. According to recent follow-up data from the same group, 51 patients transplanted with HIV-positive organs had 1-, 3-, and 5-year patient survival rates of 87, 87, and 84% and graft survival rates of 96, 93, and 79%.
Reverse transcriptase and V3 phylogenetic trees suggested donor superinfection in one instance. The patient’s viral suppression suggests low-level viral inoculum and shedding from the donor’s kidney into the recipient’s blood.
Because of HIV-related renal, hepatic, and cardiac problems, recipients may get latent or undiagnosed opportunistic infections and have poor organ quality.
I appreciate level of recommendation in relation to each advice in relation to the natural history of HIV infection and corresponding mode of treatment indicated.
Introduction:
Accumulating evidence has established SOT as standard of care for PWH with end-stage kidney and liver disease, and more limited but encouraging data has demonstrated feasibility of pancreas, heart, and lung transplantation in PWH.
Status of organ transplantation by organ type:
With availability of effective ART, PWH are increasingly seeking organ transplantation.
Kidney:
800 PWH are diagnosed ESRD) annually, it is estimated that 0.5–1.5% of the United States dialysis population.
Outcomes for PWH are favorable, with transplantation providing a clear survival benefit over renal replacement therapy.
Important complications:
Bacterial infections: frequency in Hiv KT recipients who were treated with t ATG) or coinfected with HCV. High rates of delayed allograft function.
Finally, HIV KT patient allograft rejection rates two to three times higher than observed in the general kidney transplant population.
Liver:
In the era of highly effective ART, liver disease has become the third leading cause of death in PWH.
The outcomes of liver transplantation in PWH vary by the reason for transplant.
Pancreas:
Pancreas transplantation can be successful in HIV-infected patients, but additional experience is need.
Heart:
HIV-associated cardiomyopathy was seen in the pre-ART era; coronary artery disease is now a rising concern in PWH.
HIV is no longer considered an absolute contra-indication to advanced heart failure therapies, including heart transplantation.
Lung:
There is a paucity of lung transplantation reports in PWH.
Clinical management of HIV-infected organ transplant candidates and recipient:
Selection of candidates:
Candidacy requirements for transplantation:
Updated guidelines recommend that,
Undetectable HIV viral load.
Known compliance with ART.
No evidence of active opportunistic infections or HIV-associated malignancy,
Ability to have close follow-up for immunosuppression, drug level monitoring and management. CD4þ cell counts at least 200 cells/ml are recommended for transplantation of all organs,
With the exception of liver, where the threshold for transplantation is CD4þ cell count more than 100 cells/ml.
Absence of chronic wasting or severe malnutrition
• Hepatitis B or C infection if no advanced fibrosis/cirrhosis (for organ types other than liver).
Antirejection therapy:
The best immunosuppression is not known.
Induction:
Choice of induction agent should be individualized in renal transplant.
Induction immunosuppression is not required in the majority of liver transplant recipients.
Data regarding use of induction agents in transplant of other organ types in HIV+ persons is lacking.
Maintenance immunosuppressive regimens:
Tacrolimus is associated with lower rejection rates, and for this reason, has emerged as the preferred calcineurin inhibitor.
Mycophenolate is a very common component of maintenance immunosuppression.
Although long-term maintenance prednisone therapy reduces risk for rejection, the benefits of its used should be weighed against the long-term effects of this agent.
Medication management:
Protease inhibitors:
Alter the pharmacokinetics of immunosuppressive medications, including CNI (tacrolimus, cyclosporine A) and mTOR inhibitors (sirolimus, everolimus), resulting in drastic alterations in doses and dosing schedules of these drugs. Non-nucleoside reverse transcriptase inhibitors have differing potential for induction of CYP3A4.
Non-boosted integrase strand transfer inhibitors (INSTI):
Have emerged as favored therapies. Raltegravir, dolutegravir, and bictegravir are completely or primarily metabolized through the uridine diphosphate glucuronosyltransferase 1A system, resulting in clinically insignificant interactions with the calcineurin inhibitors.
Clinical monitoring and care of HIVR persons before and after organ transplantation:
HIV specialists partner with the transplant team to optimize HIV therapy, with the goal of minimizing pre-transplant toxicities and post-transplant drug interactions while maintaining viral suppression.
Patients should be placed on non-protease inhibitor-based ART regimens.
Frequent dose adjustments, especially early in the post transplant period.
More frequent monitoring of CD4þ cell counts and HIV viral load.
HIV-to-HIV transplantation:
As the U.S. trials are ongoing, only preliminary data are available but suggest excellent patient and allograft survivals for both kidney and liver recipient.
Conclusion:
Kidney and liver transplantation are the standard of care for HIV-infected persons with end-stage kidney and liver diseases.
Encouraging results with transplantation of other organ types, including pancreas, heart, and lung suggest that persons with other advanced organ disease should also be referred to centers experienced in performing these transplants.
The availability of INSTI, with minimal impact on immunosuppressive drug levels, has greatly simplified the post-transplant management of the HIV+ organ recipient. T
Introduction;
Always the transplantation would be the better choic for quality of life compared to dialysis.
After the invention of HAARTs therapy it was demonstrated that the prognosis and long term survival of infected patients has improved.
The result is the other opportunistic infection and long term complications like HIVAN risk has increased.
There multiple risk for progression to HIV associated renal failure.
Like.
Glomerulopathies like FSGS,
Has increased risk of diabetes and hypertension.
Co-infection with other viral infection like HCV, and HBV.
Drug induced AIN and other GN.
CKD and HIV;
The prognosis is worse with HIV comparatively with patient with HIV on dialysis.
Criteria for accepting the recipient for transplantation;
Undetected viral load,
CD$+T cells >200,
On regular ART medications,
No active infections with opportunistic infection.
No occult or active maligacy.
What is the HOPE act;
Patients infected with HIV are permitted to donat to HIV infected recipient.
The outcomes of organ recipients who have received coinfected organs are expected to be improved by their high post-transplant effectiveness. The HOPE Act has now made it possible for PWH to donate organs to HIV-positive people awaiting kidney and liver transplants in a research environment. HIV specialists should actively refer suitable patients for transplantation, inform patients on the results of transplantation and the advantages and disadvantages of using HIV-positive organs, and ensure regular HIV infection surveillance following transplant.
Kidney transplantation is the modality of choice for end stage chronic kidney disease.
After the introduction of anti-retroviral therapy ART, prognosis and long-term survival of HIV infected people improved significantly. This improvement in survival increased the incidence of other non-HIV related diseases, including chronic kidney disease.
Risk factors for chronic kidney disease in HIV patients:
1] With the introduction of ART, HIV related diseases featured drop in incidence, such as HIV associated nephropathy HIVAN.
2] Other diseases associated chronic organ damage and failure in escalating, such as diabetes and hypertension related nephropathy.
3] Other glomerular diseases such as FSGS.
4] Co-infection with HBV and HCV portends an increasing risk of chronic kidney disease.
5] Chronic ART use such as tenofovir, abacavir, indinavir, ritonavir-boosted lopinavir is associated with chronic kidney disease.
6] protease inhibitors are generally linked to higher incidence of chronic kidney disease.
Peculiar features of chronic kidney disease in HIV patients:
1] The prognosis of HIV patients on hemodialysis HD is grim with higher mortality rate than counterparts’ non-HIV infected patients on HD.
2] Related complications are increasingly reported.
On transplantation:
1] Prognosis is much better than HD.
2] Incidence of rejection episodes is elevated. Mainly related to inadequate immune suppression or drug-drug interaction.
3] HIV related immune dysregulation.
4] Higher incidence of bacterial infection.
5] delayer graft function is increasingly reported.
Criteria for accepting the patient for transplantation:
1] CD4 lymphocyte count of more than 200 c/ml, except for chronic liver disease patients where CD4 of 100 c/ml is acceptable.
2] undetected viral load.
3]On ART regularly.
4] No complications related to HIV infection such as severe waisting and malnutrition.
5] No opportunistic infection.
6] No malignancy reported.
Hope act:
HIV patients are permitted to donate to HIV patients with end organ failure. Therefore, donation pool has increased significantly.
Please summarise this article.
Introduction
· HIV infection is now a chronic disease due the availability of antiretroviral therapy which caused a significant reduction in mortality associated with HIV/AIDs
· The new problems in person living with HIV (PWH) are cardiovascular diseases, liver diseases, and side effects related to antiretroviral therapies. Therefore, PWH are now at-risk organ damage and failure. How ever, before the age of antiretroviral therapy, transplantation was absolute contraindication for HIV but now the understand has improve significantly.
· HIV Organ Policy Equity (HOPE) Act stated that, Person living with HIV (PWH) can now be either donor or recipient for the seek of treatment a failed organ.
Status of organ transplantation by organ type
Kidney
· HIV related kidney diseases account for m 0.5 to 1.5% of dialysis treatment in USA
· Causes of ESKD: HIV-associated Nephropathy (HIVAN) was historical, FSGS, DM, co-infections with HBV or HCV & Drug induced
· Transplantation outcomes: Stock et al. observational study of 150 patients and revealed 1- and 3-years allograft & patient survivals were 90% and 74% and 95% and 88% respectively. They had more bacterial infections, delayed graft function, and rejection rates.
· Transplantation is associated with better outcomes compared dialysis
· Challenges: PWH faces barriers for referral, enlisting for transplantation, and some transplant centers in USA are still considering HIV is contraindicated for transplantation
Liver
· Liver disease is the third leading cause of death in PWH
· Causes: co-infection with HBV/HCV, antiretroviral therapy, immune reconstitution syndrome, alcohol, and non-HIV factors.
· Outcomes: Allograft and patient survival were 85% to 100% after 3 to 5 years of PWH transplanted due to HIV/HBV co-infection. HIV/HCV versus HCV control 1,3-, and 5-years allograft survivals were 52 to 86%, 45 to 60%, 31 to 45% versus 57 to 88%, 50 to 62%, 33 to 58% respectively.
· Challenges: the same as renal transplantation
Pancreas
· This may be successful in future but at the moment the experience is very limited
Heart
· Although heart transplantation in PEH is not contraindicated the procedure is not commonly carried on
· Outcomes: recent data showed, 1- and 5-years survival are between 86 to 90% and 64 to 67%, coronary artery vasculopathy was the important complications occurring in up to 30% as well as higher rejection rates from 39 to 67% after one year compared to non-HIV individual. Up to 50% required mechanical circulatory support before transplantation
Lung
· Data from case reports and case series demonstrated the feasibility of this procedure in PWH suffering from advanced pulmonary disease.
Clinical management of HIV-infected Organ transplant candidates and recipient
· Recommendation for selection of the candidates:
1. Virally suppressed
2. Compliant patient
3. Absence of opportunistic infections
4. Absence of HIV-associated Malignancy
5. CD4 >= 200 cell/microliter
6. Ability to come for follow up
· HIV to HIV living donor transplantation: few cases on the literature
1. Donor must be evaluated well and HIV specific risk factors for ESKD ruled out
2. APLO1 haplotype screening? is not clear but those with African American with HIV and high risk APLO1 genotype are at risk for HIVAN and FSGS
3. HIV +ve donor must avoid drugs like TDF and NSAIDS after nephrectomy
· HIV positive donor to HIV negative recipient
1. At the moment, this is illegal practice in USA
2. One case report from South Africa: HIV positive mother ton her terminally ill daughter with biliary atresia. The daughter became positive but her HIV antibodies reduced significantly to undetectable level during the first year after transplantation
Conclusion
· The rate of organ failure is now increasing in PWH and transplantation is best form therapy in this kind of situation. Transplantation had been done successfully in kidney and liver failure but more data are needed for other organs including heart, pancreas, and lung. We also want to understand the reasons for barriers to transplantation for PWH through a well design study.
Organ Transplant in HIV Patients
Introduction
· Improved survival of patients with HIV (PWH) with use of HAART, similar to general population.
· HIVAN has reducing incidence, but CKD is common due to DM , nephrotoxic drugs in PWH.
· Once on dialysis, PWH have lower survival rates when compared with uninfected dialysis patients
Status of SOT in PWH
– Transplant is common in person with HIV (PWH)
· Stock et al. reported, outcomes of 150 kidney transplant in HIV-infected patients – 1 and 3-year kidney allograft and patient survival estimates were 90.4 and 73.7 and 94.6 and 88.2%, respectively.
· REAL WORLD SCENARIO suggests
– SOT is feasible in PWH and is not a contraindication
It should be done in centre experienced in doing such work
– Bacterial infection is common if ATG is used and coinfected with HCV
DGF and rejection is common
– HIV is an absolute or relative contraindication for liver transplantation, but the outcomes of liver transplantation vary by the reason for transplant.
– Pancreas transplantation can be successful in HIV-infected patients, but additional experience is needed.
– Lung transplant is not reported
IS in PWH
drug interactions are very common and drug levels need strict monitoring
HIV-to-HIV Transplantation
after HOPE act this is more into consideration and will avoid wastage of organ
Clinical management of HIV-infected organ transplant candidates and recipients:
Selection of candidates
· HIV providers should refer any patient with end-organ damage and stable HIV to centres well versed in HIV+ organ transplantation.
· candidacy requirements for transplantation:
1) Meet transplant centre-specific eligibility for organ transplantation
2) CD4+ cell count > 200 cells/µl during 3 months prior to transplantation for kidney, pancreas, heart and lung candidates
3) CD4+ cell count > 100 cells/µl during 3 months prior to transplantation for liver candidates only
4) Undetectable plasma HIV viremia (unless unable to tolerate ART prior to liver transplant)
5) Documented adherence with stable ART regimen
6) Absence of active opportunistic infection and malignancy
7) Absence of chronic wasting or severe malnutrition
8) Hepatitis B or C infection if no advanced fibrosis/cirrhosis (for organ types other than liver)
9) Access to immunosuppressive agent therapeutic drug monitoring
10) Ability to regularly follow up with HIV care providers
Antirejection therapy
· There is no specific immunosuppressive regimen to use for patients with HIV.
· Induction immunosuppression is not required in the majority of liver transplant recipients, and data about induction agents in transplant of other organ types in HIV+ persons is lacking.
· For HIV-infected transplant recipients, Tacrolimus is associated with lower rejection rates, and is the preferred CNI. MMF can be used.
· Prednisone reduces risk for rejection, but the benefits of its used should be weighed against the long-term effects of this agent.
· Sirolimus is known to have anti-HIV effects
Medication management
· Protease inhibitors inhibit (CYP3A4) enzyme, which alter the pharmacokinetics of CNI and mTORi, resulting in severe alterations in doses with possible rejection or toxicity.
· In liver transplant recipients, boosted protease inhibitors regimens were associated with episodes of acute renal failure from high cyclosporine levels.
· renal transplant recipients also have poor outcomes for patients on protease inhibitor-based regimens.
· In the transplant setting, non-boosted integrase strand transfer inhibitors (INSTI) have emerged as favored therapies.
· Raltegravir, dolutegravir, and raltegravir have insignificant interactions with the CNI.
Clinical monitoring and care of HIV+ persons before and after organ transplantation
· In the pre-transplant phase, HIV therapy needs optimization to minimize pre-transplant toxicities and post-transplant drug interactions while maintaining viral suppression.
· Patients should be placed on non-protease inhibitor-based ART regimens if possible.
· Avoid use of tenofovir disoproxil fumarate after kidney transplant and abacavir after heart transplantation.
· In the early post-transplant period, in the setting of allograft rejection, more frequent monitoring of CD4+ cell counts and HIV viral load is necessary.
· many centers may use life-long prophylaxis against Pneumocystis jirovecii
HIV-to-HIV transplantation
· Was successful in South Africa which inspired the United States transplant community to expand HIV+ to HIV+ transplant to North America.
· HOPE Act has put safeguards in place to conduct and monitor outcomes in HIV-to-HIV transplantation by conducting these procedures in a research setting using well defined donor eligibility requirements.
· preliminary data suggest excellent patient and allograft survivals for both kidney and liver recipients
· An unexpected benefit of HOPE Act is the use of organs that may have otherwise been discarded due to having false-positive HIV test results.
· When evaluating potential candidates for donor nephrectomy, the assessment must include the identification HIV-specific risk factors for the development of ESRD such as: low CD4+ cell count and HCV coinfection and other conditions that discard persons from donation ( DM, HTN, and preexisting kidney disease)
· HIV+ African American persons with high-risk APOL1 genotypes are at risk for the development of HIVAN and FSGS.
· Post-nephrectomy, HIV+ donors should avoid nephrotoxic ART (tenofovir) and NSAIDs.
Conclusions:
· Kidney and liver transplantation are the standard of care for HIV-infected persons with end-stage kidney and liver diseases.
· The availability of INSTI, with minimal impact on immunosuppressive drug levels, has greatly simplified the post-transplant management of the HIV+ organ recipient.
· The introduction of DAAs for hepatitis C, with their high efficacy in the post-transplant setting, promise to improve outcomes in coinfected organ recipients.
· With Implementation of HOPE Act, PWH can donate organs to HIV infected persons waiting for kidney and liver transplants under a research setting.
· HIV providers should play an active role in referring appropriate patients for transplantation, educating patients regarding transplant outcomes and the potential risks and benefits of pursuing HIV-positive organs for transplant, and ensuring frequent monitoring of HIV infection after transplant.
Introduction:
· Antiretroviral therapy reduced AIDS-related mortality, with increased life expectancy and common medical comorbidities.
· coronary artery disease and nonalcoholic steatohepatitis, are important causes of morbidity and mortality in persons with HIV.
· persons with HIV can now register as organ donors, expanding the donor pool for HIV persons waiting for organs.
Status of organ transplantation by organ type
· The most evidence in support of transplantation in HIV persons comes from kidney followed by liver transplantation.
· The number of pancreas, heart, and lung transplantation, is increasing.
Kidney
· In spite of declining HIV-associated nephropathy, due to antiretroviral treatment, other causes of renal failure such as FSGS, diabetes mellitus, and hypertension remain prominent.
· Coinfections with hepatitis C virus and hepatitis B virus increase risk for kidney failure.
· Many antiretroviral agents are nephrotoxic and increase risk of DM and dyslipidemia.
· HIV patients on dialysis have lower survival than uninfected dialysis patients, that’s why they need transplantation.
· HIV+ recipients who were given (ATG) or who are coinfected with HCV, have increased incidence of bacterial infections.
· HIV patients have high rates of delayed allograft function.
· HIV+ recipients have allograft rejection rates two to three times higher than seen in the general kidney transplant population.
· Some transplant programs still consider HIV as an absolute or relative contraindication to transplantation, so they remain on dialysis for a long time and have longer waitlist times for organ offers and transplant.
Liver
· HIV patients are at risk for end-stage liver disease through a variety of mechanisms:
1) HCV and HBV coinfections
2) HIV infection increases the risk for progressive and advanced liver disease
3) ART can cause advanced liver disease by direct hepatotoxicity, hypersensitivity reactions, mitochondrial toxicity, steatosis and/or steatohepatitis, or immune reconstitution phenomena.
4) Alcohol may increase the risk of end stage liver disease.
5) Hepatocellular carcinoma can further complicate the course of ALD
· The outcomes of liver transplantation in HIV patients vary by the reason for transplant.
· HCV-related progressive liver disease, severe infections, and sepsis contributed to poor outcomes.
Pancreas
· In 2018, 836 simultaneous pancreas-kidney transplants were performed in the United States, but this rarely done in type 1 diabetic HIV person.
· complications are: graft thrombosis, rejection, and bacterial infections, including fatal sepsis.
Heart
· HIV-associated cardiomyopathy was seen in the pre-ART era, but coronary artery disease is now a rising concern in HIV patients.
· HIV is not an absolute contra-indication to heart transplantation, but is uncommonly performed.
Lung
· HIV-experienced centers can consider PWH as candidates in the setting of demonstrated antiretroviral adherence with viral suppression and no recent AIDS-defining illness
· There is a paucity of lung transplantation reports in PWH.
Clinical management of HIV-infected organ transplant candidates and recipient
Selection of candidates
· HIV providers should refer any patient with end-organ damage and stable HIV to centers well versed in HIV+ organ transplantation.
· candidacy requirements for transplantation:
1) Meet transplant center-specific eligibility for organ transplantation
2) CD4+ cell count > 200 cells/µl during 3 months prior to transplantation for kidney, pancreas, heart and lung candidates
3) CD4+ cell count > 100 cells/µl during 3 months prior to transplantation for liver candidates only
4) Undetectable plasma HIV viremia (unless unable to tolerate ART prior to liver transplant)
5) Documented adherence with stable ART regimen
6) Absence of active opportunistic infection and malignancy
7) Absence of chronic wasting or severe malnutrition
8) Hepatitis B or C infection if no advanced fibrosis/cirrhosis (for organ types other than liver)
9) Access to immunosuppressive agent therapeutic drug monitoring
10) Ability to regularly follow up with HIV care providers
Antirejection therapy
· There is no specific immunosuppressive regimen to use for patients with HIV.
· Induction immunosuppression is not required in the majority of liver transplant recipients, and data about induction agents in transplant of other organ types in HIV+ persons is lacking.
· For HIV-infected transplant recipients, Tacrolimus is associated with lower rejection rates, and is the preferred CNI. MMF can be used.
· Prednisone reduces risk for rejection, but the benefits of its used should be weighed against the long-term effects of this agent.
· Sirolimus is known to have anti-HIV effects
Medication management
· Protease inhibitors inhibit (CYP3A4) enzyme, which alter the pharmacokinetics of CNI and mTORi, resulting in severe alterations in doses with possible rejection or toxicity.
· In liver transplant recipients, boosted protease inhibitors regimens were associated with episodes of acute renal failure from high cyclosporine levels.
· renal transplant recipients also have poor outcomes for patients on protease inhibitor-based regimens.
· In the transplant setting, non-boosted integrase strand transfer inhibitors (INSTI) have emerged as favored therapies.
· Raltegravir, dolutegravir, and raltegravir have insignificant interactions with the CNI.
Clinical monitoring and care of HIV+ persons before and after organ transplantation
· In the pre-transplant phase, HIV therapy needs optimization to minimize pre-transplant toxicities and post-transplant drug interactions while maintaining viral suppression.
· Patients should be placed on non-protease inhibitor-based ART regimens if possible.
· Avoid use of tenofovir disoproxil fumarate after kidney transplant and abacavir after heart transplantation.
· In the early post-transplant period, in the setting of allograft rejection, more frequent monitoring of CD4+ cell counts and HIV viral load is necessary.
· many centers may use life-long prophylaxis against Pneumocystis jirovecii
HIV-to-HIV transplantation
· Was successful in South Africa which inspired the United States transplant community to expand HIV+ to HIV+ transplant to North America.
· HOPE Act has put safeguards in place to conduct and monitor outcomes in HIV-to-HIV transplantation by conducting these procedures in a research setting using well defined donor eligibility requirements.
· preliminary data suggest excellent patient and allograft survivals for both kidney and liver recipients
· An unexpected benefit of HOPE Act is the use of organs that may have otherwise been discarded due to having false-positive HIV test results.
· When evaluating potential candidates for donor nephrectomy, the assessment must include the identification HIV-specific risk factors for the development of ESRD such as: low CD4+ cell count and HCV coinfection and other conditions that discard persons from donation ( DM, HTN, and preexisting kidney disease)
· HIV+ African American persons with high-risk APOL1 genotypes are at risk for the development of HIVAN and FSGS.
· Post-nephrectomy, HIV+ donors should avoid nephrotoxic ART (tenofovir) and NSAIDs.
Introduction:
HIV infection has become a chronic illness in the current age of antiretroviral therapy; both overall and AIDS-related mortality has declined With increased life expectancy and an aging demographic.
The current review focuses on the current status of SOT for HIV-infected person highlighting the outcomes, standards of care and aspects of post-transplant management. With availability of effective ART, PWH are increasingly seeking organ transplantation
Kidney:
HIV-associated nephropathy (HIVAN) rates is reduced because of early antiretroviral treatment but other causes of renal failure such as focal segmental glomerulosclerosis, diabetes mellitus, and hypertension remain prominent.
Coinfections with hepatitis C virus and hepatitis B virus increase risk for kidney failure.
HIV patients on dialysis have lower survival than uninfected dialysis patients, so transplantation is better.
HIV+ recipients who were given (ATG) or who are coinfected with HCV, have increased incidence of bacterial infections
allograft rejection rates is increased two to three times in HIV+VE recipients than in general kidney transplant population.
Many transplant programs still consider HIV as an absolute or relative contraindication to transplantation, so they remain on dialysis for a long time and have longer waitlist times for organ offers and transplant.
Liver:
HIV patients are at risk for end-stage liver disease through a variety of mechanisms include: HCV and HBV coinfections, ART toxicity, Alcohol, and hepatocellular carcinoma.
The outcomes of liver transplantation in HIV patients vary by the reason for transplant.
HCV-related progressive liver disease, severe infections, and sepsis contributed to poor outcomes.
Pancreas:
In 2018, 836 simultaneous pancreas-kidney transplants were done in the United State except for type 1 diabetic HIV person
Many complications were found: graft thrombosis, rejection, and bacterial infections, including fatal sepsis
Pancreas transplantation can be successful in HIV-infected patients, but it need experience.
Heart:
HIV-associated cardiomyopathy was seen in the pre-ART era; coronary artery disease is now a rising concern in PWH. HIV is not an absolute contra-indication to heart transplantation but not common.
Lung:
In 2018, 2530 lung and 32 heart/lung transplants were done in the United States.
HIV infection has become a relative contraindication to lung transplantation, but there is a lack of lung transplantation data.
Clinical management of HIV-infected organ transplant candidates and recipient:
Selection of candidates:
HIV providers should refer patients with end-organ damage and stable HIV to centers well-versed in HIV organ transplantation. CD4 cell counts of at least 200 cells/ml are recommended for transplantation.
Antirejection therapy·
Best HIV immunosuppressive regimen is unknown but it should be individualized based on the organ transplanted, immunologic risk, renal and liver function, and ART regimen
Medication management:
HIV providers must be aware of key drug interactions with maintenance immunosuppressive therapies, such as protease inhibitors and non-nucleoside reverse transcriptase inhibitors, to ensure adequate levels of antirejection drugs in transplant recipients.
Clinical monitoring and care of HIVR persons before and after organ transplantation:
HIV providers play a vital role in preparing patients for transplant, monitoring HIV infection and potential opportunistic complications, and optimizing HIV therapy.
Post transplant, the same ART regimen may be continued, although clinicians must be cognizant of frequent fluctuation in kidney function that may require frequent dose adjustments, also HIV clinicians should avoid, agents that may compromise organ function,
In the post-transplant period, regular HIV care is essential, and more frequent monitoring of CD4 cell counts and HIV viral load is warranted.
Anti-infective prophylaxis is based on transplant center practices and HIV guidelines.
HIV-to-HIV transplantation:
In 1984 the National Organ Transplant Act was enacted, making it illegal to use HIV organs for transplantation
In 2008, four HIV+ to HIV +renal transplants were successfully done in Cape Town, South Africa.
HOPE Act has enabled the utilization of organs that may have otherwise been discarded due to false-positive HIV test results, but few cases of HIV-to-HIV living donor transplants have been reported
Conclusion:
Encouraging results with transplantation of other organ types, including pancreas, heart, and lung suggest that persons with other advanced organ disease should also be referred to centers experienced in performing these transplants
SOT IN HIV PATIENTS
HAART is effective leading to better sirvival
HIVAN has reducing incidence, but CKD is common due to DM , nephrotoxic drugs
Once on dialysis, PWH have lower survival rates when compared with uninfected dialysis patients
so SOT is common in person with HIV (PWH)
Stock et al.
reported the outcomes of 150 HIV-infected patients after
kidney transplantation; 1 and 3-year kidney allograft and
patient survival estimates were 90.4 and 73.7 and 94.6 and
88.2%, respectively. REAL WORLD SCENARIO suggest SOT is feasible in PWH and is not a contraindication
It should be done in centre experienced in doing such work
Bacterila infection is comon if ATG is used and coinfected with HCV
DGF and rejection is common
HIV is an absolute or relative contraindication for liver transplantation, but the outcomes of liver transplantation vary by the reason for transplant.
Pancreas transplantation can be successful in HIV-infected patients, but additional experience is needed.
Lung transplant is not reported
IS in PWH
drug interactions are very common and drug levels need strict monitoring
HIV TO HIV transplantation
after HOPE act this is more into consideration and will avoid wastage of organ
Introduction:· HIV infection has become a chronic illness, with increased life expectancy and an aging demographic, leading to increased morbidity and mortality.
· Solid organ transplantation is the standard of care for PWH with end-stage kidney and liver disease, with HOPE Act expanding the donor pool.
· HIV management decisions affect pre- and post-organ transplant care, and post-transplant immunosuppressive practices impact HIV and transplant outcomes.
Status of organ transplantation by organ typeThe American Society of Transplantation has recently published updated guidelines on the management of SOT in HIV-infected persons, but it is important for HIV care providers to understand how HIV management decisions affect pre- and post-organ transplant care and post-transplant immunosuppressive practices.
Kidney
· PWH are disproportionately affected by the end-stage renal disease (ESRD) in the US, with HIV-associated nephropathy (HIVAN) rates declining, but other causes of renal failure such as focal segmental glomerulosclerosis, diabetes mellitus, and hypertension.
· Antiretroviral agents can lead to nephrotoxicity and metabolic complications, leading to lower survival rates.
· The largest prospective observational trial of 150 HIV-infected patients after kidney transplantation found that 1 and 3-year kidney allograft and patient survival estimates were 90.7 and 94.2%, respectively.
· However, complications such as bacterial infections and delayed allograft function were observed.
· HIV rejection rates were two to three times higher than observed in the general kidney transplant population. Single and multicenter studies have largely confirmed the results.
· Research is underway to evaluate the role of maraviroc in reducing the HIV reservoir and modulation of the immune response and allograft injury following kidney transplantation.
Liver· PWH are at risk for end-stage liver disease due to a variety of mechanisms, including chronic HCV and HBV coinfections, HIV infection, nonalcoholic fatty liver disease and steatohepatitis, and hepatocellular carcinoma.
· HIV is an absolute or relative contraindication for liver transplantation, but the outcomes of liver transplantation vary by the reason for transplant.
· Before the availability of hepatitis C directly acting antiviral (DAA) agents, transplant outcomes of HIV-HCV coinfected patients were problematic, with significantly lower graft and patient survival rates compared with HCV-mono-infected controls.
Pancreas· Pancreas transplantation can be successful in HIV-infected patients, but additional experience is needed.
Heart· HIV-associated cardiomyopathy is a rising concern in PWH, with 1 and 5-year post-transplant survivals between 85.9-90% and 64-77.3%, and higher rates of rejection. 53.7-57% of patients received mechanical circulatory support prior to transplant.
Lung· HIV infection has become a relative contraindication to lung transplantation, but there is a lack of lung transplantation reports in PWH.
Clinical management of HIV-infected organ transplant candidates and recipients:Selection of candidatesHIV providers should refer patients with end-organ damage and stable HIV to centers well-versed in HIV organ transplantation. CD4 cell counts of at least 200 cells/ml are recommended for transplantation.
Antirejection therapy· The best immunosuppressive regimen for HIV-infected transplant recipients should be individualized based on the organ transplanted, immunologic risk, renal and liver function, and ART regimen.
Medication management· HIV providers must be aware of key drug interactions with maintenance immunosuppressive therapies, such as protease inhibitors and non-nucleoside reverse transcriptase inhibitors, to ensure adequate levels of antirejection drugs in transplant recipients.
Clinical monitoring and care of HIVR persons before and after organ transplantation· HIV providers play a vital role in preparing patients for transplant, monitoring HIV infection and potential opportunistic complications, and optimizing HIV therapy.
· After the transplant, patients should be placed on non-protease inhibitor-based ART regimens, and clinicians should avoid agents that may compromise organ function.
· In the post-transplant period, regular HIV care is essential, and more frequent monitoring of CD4 cell counts and HIV viral load is warranted.
· Anti-infective prophylaxis is based on transplant center practices and HIV guidelines.
HIV-to-HIV transplantation · The National Organ Transplant Act was enacted to prevent HIV transmission by transplantation, but the South African experience has inspired action to expand HIV to HIV transplant to North America.
· HOPE Act has enabled the utilization of organs that may have otherwise been discarded due to false-positive HIV test results, but few cases of HIV-to-HIV living donor transplants have been reported.
Conclusion
HIV infection has become a chronic illness in the current age of antiretroviraltherapy; both overall and AIDS-related mortality has declined .
With increased life expectancy and an aging demographic, common medical comorbidities, such as coronary artery disease and nonalcoholic steatohepatitis, are becoming important causes of morbidity and mortality in persons with HIV (PWH).
Over the past decade, accumulating evidence has established solid organ transplantation (SOT) as standard of care for PWH with end-stage kidney and liver disease, and more limited but encouraging data has demonstrated feasibility of pancreas, heart, and lung transplantation in PWH. With the passage and implementation of the HIV Organ Policy Equity (HOPE) Act, PWH can now register as organ donors, effectively expanding the donor pool for PWH waiting for organs and, thus, the organ donation pool as a whole.
With improvements in and earlier initiation of ART, HIVassociated nephropathy (HIVAN) rates have declined, but in antiretroval-treated PWH, other causes of renal failure such as focal segmental glomerulosclerosis, diabetes mellitus, and hypertension remain prominent
Coinfections with hepatitis C virus (HCV) and hepatitis B virus (HBV) increase risk for kidney failure.
Importantly, several antiretroval agents, such as tenofovir, abacavir, indinavir, ritonavir-boosted lopinavir, ritonavirboosted atazanavir, and potentially other boosted protease inhibitors, are associated with nephrotoxicity and/or metabolic complications, including diabetes and dyslipidemias, which can ultimately contribute or lead to the development of chronic kidney disease and ESRD.
Once transplanted, outcomes for PWH are favorable, with transplantation providing a clear survival benefit over renal replacement therapy.
Because all patients had viral suppression and CD4 cell counts at least 200 cells/ml prior to transplant and combination ART and posttransplant anti-infective prophylaxis was employed, HIV control was excellent, and few opportunistic infections were encountered.
HIV recipients experienced allograft rejection rates two to three times higher than observed in the general kidney transplant population, and rejection was a predictor for allograft failure in this study.
HIV providers should refer any patient with end-organ þ damage and stable HIV to centers well versed in HIV organ transplantation. Centers may vary in their candidacy requirements for transplantation, but updated guidelines recommend that, regardless of the organ transplanted, patients have undetectable HIV viral load, known compliance with ART, no evidence of active opportunistic infections or HIV-associated malignancy, and the ability to have close follow-up for immunosuppression, drug level monitoring and management.
CD4 cell counts at least 200 cells/ml are recommended for transplantation of all organs with the exception of liver, where the threshold for transplantation þ is CD4 cell count more than 100 cells/ml, with the rationale that ALD and portal hypertension lead to splenic sequestration of white blood cells, including lymphocytes.
Although the outcomes of organ recipients with HCV coinfection have been problematic in pre-DAA era, HCV should not be considered an exclusion factor for transplant. Specialists can weigh the risks and benefits of treatment prior to transplantation, keeping in mind that if treatment can be safely delayed, the option of þ utilizing HCV organs followed by post-transplant DAA treatment increases the pool of organs available for transplant. In the case of both kidney [74] and liver transplant [75,76], excellent HCV treatment outcomes have been achieved with DAA therapy. When evaluating HCV-coinfected persons for liver transplant, it is important to weigh factors predictive of liver allograft loss such as low BMI (<21 kg/m2 ), need for combined þ liver–kidney transplant, and HCV donor organs.
In the U.S. NIH observational trial, persons who received ATG as opposed to basiliximab, an IL-2 receptor antagonist, experienced significant, prolonged lymphocyte depletion, more frequent and severe infections, and increased risk for allograft loss.
Very few cases of HIV-to-HIV living donor transplantation have been reported in the literature. When evaluating potential candidates for donor nephrectomy, the assessment must include identification HIV-specific þ risk factors for development of ESRD such as low CD4 cell count and HCV coinfection in addition to other conditions that generally exclude persons from donation (e.g. diabetes mellitus, hypertension, and preexisting þ kidney disease).
Post-nephrectomy, HIV donors should avoid nephrotoxic ART (such as tenofovir) in addition to agents such as nonsteroidal anti-inflammatory agents. To date, only two living donor kidney transplants have been reported, one with long-term good outcomes in both the donor and recipient.
Kidney and liver transplantation are the standard of care for HIV-infected persons with end-stage kidney and liver diseases. Encouraging results with transplantation of other organ types, including pancreas, heart, and lung suggest that persons with other advanced organ disease should also be referred to centers experienced in performing these transplants. The availability of INSTI, with minimal impact on immunosuppressive drug levels, has greatly þ simplified the post-transplant management of the HIV organ recipient. The introduction of DAAs for hepatitis C, with their high efficacy in the post-transplant setting, promise to improve outcomes in coinfected organ recipients. Finally, with implementation of the HOPE Act, PWH can donate organs to HIV infected persons waiting for kidney and liver transplants under a research setting. HIV providers should play an active role in referring appropriate patients for transplantation, educating patients regarding transplant outcomes and the potential risks and benefits of pursuing HIV-positive organs for transplant, and ensuring frequent monitoring of HIV infection after transplant.
Introduction
· Antiretroviral therapy reduced AIDS-related mortality, with increased life expectancy and common medical comorbidities.
· coronary artery disease and nonalcoholic steatohepatitis, are important causes of morbidity and mortality in persons with HIV.
· persons with HIV can now register as organ donors, expanding the donor pool for HIV persons waiting for organs.
Status of organ transplantation by organ type
· The most evidence in support of transplantation in HIV persons comes from kidney followed by liver transplantation.
· The number of pancreas, heart, and lung transplantation, is increasing.
Kidney
· In spite of declining HIV-associated nephropathy, due to antiretroviral treatment, other causes of renal failure such as FSGS, diabetes mellitus, and hypertension remain prominent.
· Coinfections with hepatitis C virus and hepatitis B virus increase risk for kidney failure.
· Many antiretroviral agents are nephrotoxic and increase risk of DM and dyslipidemia.
· HIV patients on dialysis have lower survival than uninfected dialysis patients, that’s why they need transplantation.
· HIV+ recipients who were given (ATG) or who are coinfected with HCV, have increased incidence of bacterial infections.
· HIV patients have high rates of delayed allograft function.
· HIV+ recipients have allograft rejection rates two to three times higher than seen in the general kidney transplant population.
· Some transplant programs still consider HIV as an absolute or relative contraindication to transplantation, so they remain on dialysis for a long time and have longer waitlist times for organ offers and transplant.
Liver
· HIV patients are at risk for end-stage liver disease through a variety of mechanisms:
1) HCV and HBV coinfections
2) HIV infection increases the risk for progressive and advanced liver disease
3) ART can cause advanced liver disease by direct hepatotoxicity, hypersensitivity reactions, mitochondrial toxicity, steatosis and/or steatohepatitis, or immune reconstitution phenomena.
4) Alcohol may increase the risk of end stage liver disease.
5) Hepatocellular carcinoma can further complicate the course of ALD
· The outcomes of liver transplantation in HIV patients vary by the reason for transplant.
· HCV-related progressive liver disease, severe infections, and sepsis contributed to poor outcomes.
Pancreas
· In 2018, 836 simultaneous pancreas-kidney transplants were performed in the United States, but this rarely done in type 1 diabetic HIV person.
· complications are: graft thrombosis, rejection, and bacterial infections, including fatal sepsis.
Heart
· HIV-associated cardiomyopathy was seen in the pre-ART era, but coronary artery disease is now a rising concern in HIV patients.
· HIV is not an absolute contra-indication to heart transplantation, but is uncommonly performed.
Lung
· HIV-experienced centers can consider PWH as candidates in the setting of demonstrated antiretroviral adherence with viral suppression and no recent AIDS-defining illness
· There is a paucity of lung transplantation reports in PWH.
Clinical management of HIV-infected organ transplant candidates and recipient
Selection of candidates
· HIV providers should refer any patient with end-organ damage and stable HIV to centers well versed in HIV+ organ transplantation.
· candidacy requirements for transplantation:
1) Meet transplant center-specific eligibility for organ transplantation
2) CD4+ cell count > 200 cells/µl during 3 months prior to transplantation for kidney, pancreas, heart and lung candidates
3) CD4+ cell count > 100 cells/µl during 3 months prior to transplantation for liver candidates only
4) Undetectable plasma HIV viremia (unless unable to tolerate ART prior to liver transplant)
5) Documented adherence with stable ART regimen
6) Absence of active opportunistic infection and malignancy
7) Absence of chronic wasting or severe malnutrition
8) Hepatitis B or C infection if no advanced fibrosis/cirrhosis (for organ types other than liver)
9) Access to immunosuppressive agent therapeutic drug monitoring
10) Ability to regularly follow up with HIV care providers
Antirejection therapy
· There is no specific immunosuppressive regimen to use for patients with HIV.
· Induction immunosuppression is not required in the majority of liver transplant recipients, and data about induction agents in transplant of other organ types in HIV+ persons is lacking.
· For HIV-infected transplant recipients, Tacrolimus is associated with lower rejection rates, and is the preferred CNI. MMF can be used.
· Prednisone reduces risk for rejection, but the benefits of its used should be weighed against the long-term effects of this agent.
· Sirolimus is known to have anti-HIV effects
Medication management
· Protease inhibitors inhibit (CYP3A4) enzyme, which alter the pharmacokinetics of CNI and mTORi, resulting in severe alterations in doses with possible rejection or toxicity.
· In liver transplant recipients, boosted protease inhibitors regimens were associated with episodes of acute renal failure from high cyclosporine levels.
· renal transplant recipients also have poor outcomes for patients on protease inhibitor-based regimens.
· In the transplant setting, non-boosted integrase strand transfer inhibitors (INSTI) have emerged as favored therapies.
· Raltegravir, dolutegravir, and raltegravir have insignificant interactions with the CNI.
Clinical monitoring and care of HIV+ persons before and after organ transplantation
· In the pre-transplant phase, HIV therapy needs optimization to minimize pre-transplant toxicities and post-transplant drug interactions while maintaining viral suppression.
· Patients should be placed on non-protease inhibitor-based ART regimens if possible.
· Avoid use of tenofovir disoproxil fumarate after kidney transplant and abacavir after heart transplantation.
· In the early post-transplant period, in the setting of allograft rejection, more frequent monitoring of CD4+ cell counts and HIV viral load is necessary.
· many centers may use life-long prophylaxis against Pneumocystis jirovecii
HIV-to-HIV transplantation
· Was successful in South Africa which inspired the United States transplant community to expand HIV+ to HIV+ transplant to North America.
· HOPE Act has put safeguards in place to conduct and monitor outcomes in HIV-to-HIV transplantation by conducting these procedures in a research setting using well defined donor eligibility requirements.
· preliminary data suggest excellent patient and allograft survivals for both kidney and liver recipients
· An unexpected benefit of HOPE Act is the use of organs that may have otherwise been discarded due to having false-positive HIV test results.
· When evaluating potential candidates for donor nephrectomy, the assessment must include the identification HIV-specific risk factors for the development of ESRD such as: low CD4+ cell count and HCV coinfection and other conditions that discard persons from donation ( DM, HTN, and preexisting kidney disease)
· HIV+ African American persons with high-risk APOL1 genotypes are at risk for the development of HIVAN and FSGS.
· Post-nephrectomy, HIV+ donors should avoid nephrotoxic ART (tenofovir) and NSAIDs.
This article is focused on HIV patients and SOT. After HAART therapy, EVERYTHING is possible for HIV patient, even if he has the chance to be on the waiting list.
PWH and after HAART, even HIVAN is decreased, but other causes in PWH like HTN, DM, and FSGN remain the same.
PWH once transplanted the graft, and patient survival is better than on remaining on Dialysis.
Stock et al. showed the 150 transplanted HIV patients showed good graft and patient survival fro 1 , and 3 years, estimates were 90.4 and 73.7 and 94.6 and 88.2%, respectively. Still, PWH experienced high rates of delayed allograft function.
High rates of allograft rejection following kidney transplantation may be due to inadequate immunosuppression, either because of under use of immunosuppressive agents or drug interactions that lead to inadequate or inconsistent immunosuppressive drug levels.
SELECTION OF THE CANDIDATE SUPPOSE WITH SPECIAL CRITERIA:
CD4 count more than 200 /ml for the last 3 month
stable patient with no OI for the last 6 month
The patient supposes to be on HAART with good adherence.
Anti Rejection therapy
ATG is associated with an increased risk of bacterial infection due to its depleted action on lymphocytes. But on the other hand, PWH has a higher rate of rejection and DGF.
Sirolimus have with HIV effect through the downregulation of CCR5, upregulation of b-chemokines, and blockade of the mammalian target of rapamycin (mTOR).
What type of HAART therapy is the most suiting patient for SOT??
PI has adrastic inhibition effect on cytochrom P450 while non-nucleoside reverse transcriptase inhibitors have differing potential for induction of CYP3A4.
For that thetype of HAARt therapy with CNI andIS need to be adjusted because this is the main point which leads to rejection .On the other hand,boosted the dose of HAART therapy will increase the risk of renal faliuer and AKI.
Raltegravir, dolutegravir, and raltegravir are completely or primarily metabolized through the uridine diphosphate glucuronosyltransferase 1A system, resulting in clinically insignificant interactions with the calcineurin inhibitors. Small case reports evaluating use of raltegravir have found that it is well tolerated and effective to use in the setting of transplantation. Dolutegravir has emerged as the favored INSTI due to its high barrier to resistance and ease of dosing.
How to deal with HIVR :
this patient need to be on non PI regiem theraby
need to vahe a close follow up to his kidney funtion ,highly recommedned not to use tinofovie for its kidney toxcicty in RTX and to avoid abacavir after heart transplant .
HIV to HIV :
the data showed depite good patient survivla they have relatevely low graft survival as the Data which is puplised in 2008 from Captown ,it showed drop from 93% in years 1 and 3 wo 79% in years 5 , still the infection and carrying the infected organe and the OI is the main problems in these group of patients .
prior to donation, the following data about the HIV positive donor should be made available: – CD4, viral load, HIV genotypic testing, HAART history, history of OIs
– assess for HIV-specific risk factors for development of ESKD e.g., low CD4, HCV co-infection, diabetes, hypertension, pre-existing kidney disease
– HIV positive African-American patients with high-risk APOL1 genotypes are at risk of developing HIVAN and FSGS
– the utility of APOL1 haplotype screening remains unknown
– HIV positive donors should avoid nephrotoxic agents post-nephrectomy e.g., TDF, NSAIDs
– intentional transplantation of HIV positive organs to HIV negative recipients is still not an acceptable practice due to medical and ethical concerns
Summary
Organ transplantation in persons with HIV
This review focuses on the current status of SOT for HIV-infected persons, highlighting the outcomes, standards of care and aspects of post-transplant management. With availability of effective ART, PWH are increasingly seeking organ transplantation
Kidney
With earlier initiation of ART, HIV associated nephropathy (HIVAN) rates have been decreasing, but in antiretroviral-treated PWH, other causes of renal failure such as focal segmental glomerulosclerosis, diabetes mellitus, and hypertension remain prominent
Once transplanted, outcomes for PWH are better than dialysis, with transplantation providing a clear survival benefit over other renal replacement therapy
Stock et al. reported the outcomes of 150 HIV-infected patients after kidney transplantation; 1 and 3-year kidney allograft and patient survival estimates were 90.4 and 73.7 and 94.6 and 88.2%, respectively but PWH experienced high rates of delayed allograft functionBacterial infections were observed with increased frequency in HIV recipients who were treated with the lymphocyte depleting agent, antithymocyte globulin (ATG) or coinfected with HCV. HIV recipients experienced allograft rejection rates two to three times higher than observed in the general kidney transplant population, and rejection was a predictor for allograft failure.
High rates of allograft rejection following kidney transplantation may be due to inadequate immunosuppression, either because of under use of immunosuppressive agents or drug interactions that lead to inadequate or inconsistent immunosuppressive drug levels. Another potential explanation invokes immune system dysregulation and heterologous immunoreactivity in response to HIV and other chronic infections.
Liver
HIV itself, and ART medications (direct hepatotoxicity, steatosis, immune reconstitution, or hypersensitivity reactions) being the chief etiology for liver disease
The outcomes of liver transplantation in PWH may vary by the reason for transplant. As an example, in those with HIV-HBV co-infection, in the setting of passive prophylaxis with hepatitis B immunoglobulin and antiviral therapy, both graft and patient survival range from 85 to 100% after 3–5 years of follow-up. Due to the frequency of breakthrough HBV viremia, lifelong prophylaxis is recommended.
Before the availability of hepatitis C directly acting antiviral (DAA) agents, the transplant outcomes of HIV– HCV coinfected patients were problematic, with significantly lower graft and patient survival rates compared with HCV-mono-infected controls.DAA therapy introduction has led to improvement in graft and patient survival rates.
Pancreas
Outcomes have been mixed, with reported complications of graft thrombosis, rejection, and bacterial infections, including fatal sepsis
Heart
In a recent study evaluating 41 HIV heart recipients, indicat that risks of post-transplant vasculopathy was not any higher than HIV uninfected recipients but have also shown higher rates of rejection.
Lung
HIV infection is a relative contraindication to lung transplantation.The guidelines stipulate that HIV experienced centers can consider PWH as candidates in the setting of demonstrated antiretroviral adherence with viral suppression and no recent AIDS-defining illness.
Clinical management of HIV-infected organ transplant candidates and recipient
Selection of candidates
• CD4+ cell count > 200 cells/µl during 3 months prior to transplantation for kidney, pancreas, heart and lung candidates
• CD4+ cell count > 100 cells/µl during 3 months prior to transplantation for liver candidates only
• Undetectable plasma HIV viremia
• Adherence with stable antiretroviral treatment regimen
• Absence of active opportunistic infection and malignancy
• Absence of chronic wasting or severe malnutrition
• Hepatitis B or C infection if no advanced fibrosis/cirrhosis
• Availability immunosuppressive agent therapeutic drug monitoring
Antirejection therapy
In the U.S. persons who received ATG experienced prolonged lymphocyte depletion, more frequent and severe infections, and increased risk for allograft loss. Other investigators, through analysis of registry data, reported lower rejection and infection rates with ATG. Tacrolimus is associated with lower rejection rates. Mycophenolate is a very common component of maintenance immunosuppression. Although long-term maintenance prednisone therapy reduces risk for rejection. Sirolimus is known to have anti-HIV effects through downregulation of CCR5, upregulation of b-chemokines, and blockade of the mammalian target of rapamycin (mTOR). In-vitro studies have shown that HIV-1 transcription can continue in the setting of sirolimus, which, in the setting of immune system activation from transplantation, may result in diminishing the HIV reservoir. Calcineurin inhibitors have been found to decrease HIV-1 DNA transcription.
Medication management
Protease inhibitors, via inhibition of cytochrome P450 3A4 (CYP3A4) enzyme, alter the pharmacokinetics of immunosuppressive medications, including the calcineurin inhibitors and mTOR inhibitors, resulting in drastic alterations in doses and dosing schedules of these drugs. Conversely, non-nucleoside reverse transcriptase inhibitors have differing potential for induction of CYP3A4
In liver transplant recipients, boosted protease inhibitor regimens were associated with episodes of acute renal failure from high cyclosporine levels. Studies in renal transplant recipients have also shown poor outcomes for patients on protease inhibitor-based regimens.
The increased rejection may be related to interactions between calcineurin inhibitors and protease inhibitors, though a clear relationship between mortality and protease inhibitors has not been delineated.
Raltegravir, dolutegravir, and bictegravir are completely or primarily metabolized through the uridine diphosphate glucuronosyltransferase 1A system, resulting in clinically insignificant interactions with the calcineurin inhibitors. Small case reports evaluating use of raltegravir have found that it is well tolerated and effective to use in the setting of transplantation. Dolutegravir has emerged as the favored INSTI due to its high barrier to resistance and ease of dosing.
Clinical monitoring and care of HIVR persons before and after organ transplantation
Whenever feasible, patients should be placed on non-protease inhibitor-based ART regimens.
HIV clinicians should avoid, when possible, agents that may compromise organ function, such as use of tenofovir disoproxil fumarate after kidney transplant or abacavir after heart transplantation.
Use of fixed dose combination regimens require caution, particularly because of fluctuating renal function, or, in the case of formulations containing potent CYP system inhibitors, such as cobicistat, supratherapeutic calcineurin inhibitors levels.
HIV-to-HIV transplantation
In 2008, four HIV to HIV renal transplants were successfully performed in Cape Town, South Africa
Recent follow up data published by the same group notes that of the 51 patients transplanted with HIV organs, the 1, 3, and 5-year patient survivals were 87, 87, and 84% while 1, 3, and 5-year graft survivals 96, 93, and 79%
Risks include transmission of latent or unrecognized opportunistic infections to the recipient and poor organ quality because of prevalent renal, hepatic, and cardiac diseases in the HIV population.
HIV African American persons with high-risk apoprotein L1 (APOL1) genotypes are at risk for development HIVAN and focal segmental glomerulosclerosis [8,113], but it is unknown whether APOL1 haplotype screening may be of utility in this setting. Post-nephrectomy, HIV donors should avoid nephrotoxic ART (such as tenofovir) in addition to agents such as nonsteroidal anti-inflammatory agents. To date, only two living donor kidney transplants have been reported, one with long-term good outcomes in both the donor and recipient.
Conclusion
Encouraging results with transplantation of other organ types, including pancreas, heart, and lung suggest that persons with other advanced organ disease should also be referred to centers experienced in performing these transplants
III. Organ transplantation in persons with HIV
Summarise this article
Introduction
– in this current era of HAART, HIV infection is now regarded a chronic illness
– both overall and AIDS-related mortality has declined significantly
– common medical comorbidities e.g., coronary artery disease, NASH are now becoming causes of morbidity and mortality in the HIV population due to the increased life expectancy and an aging demographic
– HIV patients are also at increased risk of organ dysfunction and organ failure due to the metabolic side effects of the virus as well as the antiretroviral drugs used
– SOT is the standard of care for HIV positive patients with ESKD and liver disease
– there is data showing the feasibility of pancreas, heart and lung transplant among HIV positive patients
– with the HOPE Act i.e., HIV Organ Policy Equity Act, HIV positive patients can now register as organ donors
Status of organ transplantation by organ type
– with the availability of HAART, HIV positive patients are now seeking SOT
– with initiation of HAART, the rates of HIVAN have declined, but other causes of kidney disease e.g., FSGS, DM, hypertension remain eminent
– coinfection with HBV and HCV also increases the risk of kidney disease
– several ARVs e.g., tenofovir, abacavir, indinavir, ritonavir-boosted lopinavir, ritonavir-boosted atazanavir, and other boosted PIs, are associated with nephrotoxicity and/ or metabolic complications like DM, dyslipidemias which can eventually lead to CKD and ESKD
– HIV positive patients on dialysis have lower survival rates compared with their HIV-negative counterparts
– as a result, many HIV positive patients are increasingly undergoing kidney transplantation
– the outcomes following kidney transplantation are favourable, providing an obvious survival benefit over other forms of KRT
– a large prospective observational trial revealed that: –
– proposed mechanisms for the high rates of graft rejection among HIV positive patients include: –
– the role of maraviroc (a CCR5 inhibitor) in reduction of the HIV reservoir and modulation of the immune response and graft injury in kidney transplantation is still being studied
– HIV positive patients still encounter challenges accessing kidney transplantation despite the great evidence in support of kidney transplantation in the HIV positive ESKD population
– some transplant centers still consider HIV as an absolute or relative contraindication to kidney transplantation
– it has also been noted that HIV positive patients remain on dialysis for longer durations before they get to the transplant waiting list
– HIV positive patients also have longer waitlist times for organs, are more likely to remain inactive on the waitlist, have a lower likelihood of undergoing kidney transplantation compared to their HIV negative counterparts
– more data is needed to understand these disparities
– in this current age of HAART, liver disease has become the 3rd leading cause of death in HIV positive patients
– HIV positive patients are at increased risk for end-stage liver disease due to various mechanisms, i.e.: –
– unfortunately, some transplant centers still regard HIV as an absolute or relative contraindication to liver transplantation
– before the advent of DAAs, the transplant outcomes of HIV-HCV coinfected patients were challenging resulting in lower graft and patient survival rates compared with patients with HCV mono-infection
– for HIV-HBV coinfection, the graft and patient survival rates range from 85-100% in the setting of passive prophylaxis with HBIG and antiviral therapy
– pancreas-kidney transplantation is not commonly done in type 1 diabetic patients who are HIV positive, additional experience is required
– the outcomes are mixed, reported complications include graft thrombosis, rejection, bacterial infections, fatal sepsis
– factors predisposing HIV positive patients to cardiac disease include aging, chronic immune activation state of HIV, metabolic effects of HAART
– currently, coronary artery disease among HIV positive patients is now becoming a major concern, while HIV-associated cardiomyopathy was common in the pre-ART era
– HIV is no longer a contraindication to advanced heart failure therapies like heart transplantation although it is not commonly performed
– there is a paucity of data on lung transplantation among HIV positive patients
– currently, HIV infection is now considered a relative contraindication to lung transplantation
– the patient should demonstrate adherence to HAART, viral suppression, absence of AIDS-defining illness
Clinical management of HIV-infected organ transplant candidates and recipients
– transplant requirements include: – CD4 >200, undetectable HIV viremia, compliance to HAART, absence of opportunistic infections, absence of HIV-associated malignancies, absence of chronic wasting or severe malnutrition, access to immunosuppressive agent therapeutic drug monitoring, availability of regular clinic follow-up for the HIV infection
– CD4 >200 is recommended except in liver transplantation where the threshold is 100 since it is argued that ALD and portal hypertension lead to splenic sequestration of WBCs including lymphocytes
– in the current era of DAAs, HCV should not be considered as an exclusion factor for transplant
– weigh risks vs benefit of treatment prior to transplantation e.g., if treatment can be safely delayed, the pool of organs available will increase since this will allow for donation of HCV positive organs then offering DAA therapy post-transplant
– excellent treatment outcomes have been experienced with DAAs
– immunosuppressive regimens should be individualized based on the organ transplanted, the immunologic risk, HAART regimen, kidney and liver function
– the best immunosuppressive regimen among HIV positive patients remains unknown
– among HIV positive kidney transplant recipients, induction with ATG was associated with prolonged lymphocyte depletion, more frequent and severe infection compared to Basiliximab
– however, some studies reported lower rejection and infection rates with ATG, hence the need for individualized treatment
– the best maintenance immunosuppressive regimen among HIV positive patients is yet to be established
– tacrolimus is the preferred CNI since it is associated with lower rejection rates
– mycophenolate is the commonly used antimetabolite
– long-term prednisone use reduces the risk of rejection but one should weigh the benefits against the long-term effects of prednisone use
– sirolimus has anti-HIV effects via upregulation of ß-chemokines, downregulation of CCR5 and blockade of mTOR
– sirolimus also decreases the HIV reservoir
– CNIs decrease HIV-1 DNA transcription
– adequate levels of the antirejection drugs should be maintained
– clinicians should be aware of the possible drug-drug interactions (DDIs) i.e., between HAART and the immunosuppressive agents
– PIs are cytochrome P450 3A4 (CYP3A4) enzyme inhibitors hence alter the pharmacokinetics of CNIs (tacrolimus, cyclosporine A) and mTORi (everolimus, sirolimus) leading to alterations in the doses and dosing schedules of these medications
– these DDIs can result in inconsistent immunosuppressive drug levels hence increasing the risk of rejection (in the case of sub-therapeutic drug levels) or risk of toxicity (in the case of supra-therapeutic drug levels)
– NNRTIs have an enzyme inducing effect on CYP3A4
– studies among HIV positive kidney transplant recipients on PI-based regimens have shown poor outcomes (i.e., graft loss/ rejection and mortality) compared to non-PI based regimens
– so essentially, based on these outcomes, PI-based regimens have fallen out of favour in the transplant setting
– however, non-boosted integrase strand transfer inhibitors (INSTI) are now a favourable option
– dolutegravir, raltegravir, bictegravir are metabolized through uridine diphosphate glucuronosyltransferase 1A system leading to clinically insignificant interactions with CNIs
– from the few case reports in literature, raltegravir has been found to be well tolerated and effective in the transplant setting
– dolutegravir is the most favoured INSTI because of its higher genetic barrier to resistance and the ease of administration
– HIV providers play a significant role in the care of HIV positive patients pre- and post- transplant
– non-PI based HAART regimens are preferred
– the same HAART regimen is usually continued and the doses should be adjusted accordingly based on the kidney function
– where feasible, avoid agents that would compromise the organs e.g., tenofovir post-kidney transplant, abacavir post-heart transplant
– fixed dose combination regimens should be used with caution due to fluctuations in kidney function
– CD4 and HIV viral load should be monitored closely in the following case scenarios: – early post-transplant period, during graft rejection and when the immunosuppressive regimen is adjusted
– anti-infective prophylaxis is usually offered based on the HIV guidelines as well as transplant center protocols
HIV-to-HIV transplantation
– previously, use of HIV positive organs was illegal and HIV positive patients were not considered as potential transplant candidates
– but this has since changed, and HIV positive to HIV positive kidney transplants are now being performed with excellent graft and patient survival rates
– however, there are concerns over the: –
– prior to donation, the following data about the HIV positive donor should be made available: – CD4, viral load, HIV genotypic testing, HAART history, history of OIs
– assess for HIV-specific risk factors for development of ESKD e.g., low CD4, HCV co-infection, diabetes, hypertension, pre-existing kidney disease
– HIV positive African-American patients with high-risk APOL1 genotypes are at risk of developing HIVAN and FSGS
– the utility of APOL1 haplotype screening remains unknown
– HIV positive donors should avoid nephrotoxic agents post-nephrectomy e.g., TDF, NSAIDs
– intentional transplantation of HIV positive organs to HIV negative recipients is still not an acceptable practice due to medical and ethical concerns
Conclusion
– kidney and liver transplantation is the standard of care for HIV positive patients with ESKD and liver disease
– INSTIs have minimal impact on immunosuppressive drug levels and this has greatly simplified the post-transplant care of HIV positive organ transplant recipients
– DAAs are highly efficacious and have improved outcomes in HIV-HCV co-infected organ transplant recipients
ORGAN TRANSPLANTATION IN PERSONS WITH HIV.
INTRODUCTION.
-With the passage of HOPE ACT, people living with HIV can register as organ donors. HAART has reduced HIV mortality and improved the quality of life.
-Status of organ transplantation by organ type. Kidney and later liver pts with HIV have been transplanted with the advent of HAART.
Kidney.
Liver.
Pancreas.
Heart.
Lung.
CLINICAL MGT OF HIV INFECTED SOT CANDIDATES AND RECIPIENTS.
Selection of candidates.
Antirejection therapy.
Medication mgt.
Clinical monitoring and care of HIV +VE persons pre and post transplantation.
HIV to HIV transplantation.
Summary
Introduction
With increased life expectancy and an aging demographic, common medical comorbidities, such as coronary artery disease and nonalcoholic steatohepatitis, are becoming important causes of morbidity and mortality in persons with HIV (PWH). In addition, the metabolic side effects of both the virus and antiretroviral drugs place patients at a higher risk for organ dysfunction and, ultimately, organ failure. Over the past decade, accumulating evidence has established solid organ transplantation (SOT) as standard of care for PWH with end-stage kidney and liver disease, and more limited but encouraging data has demonstrated feasibility of pancreas, heart, and lung transplantation in PWH
Status of organ transplantation by organ type
Kidney
In the United States where approximately 800 PWH are diagnosed with end-stage renal disease (ESRD) annually
The causes of renal failure include focal segmental glomerulosclerosis, diabetes mellitus, and hypertension
Coinfections with hepatitis C virus (HCV) and hepatitis B virus (HBV) increase risk for kidney failure
Once transplanted, outcomes for PWH are favorable, with transplantation providing a clear survival benefit over renal replacement therapy
A recent survey found that 16.9 and 28.1% of responding U.S. transplant programs still considered HIV as an absolute or relative contraindication to transplantation, respectively
Liver
PWH are at risk for end-stage liver disease through a variety of mechanisms
The outcomes of liver transplantation in PWH vary by the reason for transplant
As an example, in those with HIV-HBV co-infection, in the setting of passive prophylaxis with hepatitis B immunoglobulin and antiviral therapy, both graft and patient survivals range from 85 to 100% after 3–5 years
Pancreas
Outcomes have been mixed, with reported complications of graft thrombosis, rejection, and bacterial infections, including fatal sepsis
pancreas transplantation can be successful in HIV-infected patients, but additional experience is needed.
Heart
PWH are prone to both cardiac diseases associated with aging, as well as those associated with the chronic immune activation state of HIV and metabolic effects
In a recent study evaluating 41 HIVþ heart recipients, coronary artery vasculopathy occurred in 32% at 5 years post-transplant, compared with 29.3% in the general heart transplant population, indicating that risks of post-transplant vasculopathy are not any higher than HIV uninfected recipients
Lungs
A case series of three patients from the United States, as well as a small retrospective cohort study demonstrated feasibility of this approach in persons with advanced lung diseases
Clinical management of HIV-infected organ transplant candidates and recipient
CD4þ cell counts at least 200 cells/ml are recommended for transplantation of all organs
The threshold for transplantation is CD4þ cell count more than 100 cells/ml, with the liver
Candidates must also have demonstrated adherence to ART
Absence of infections
In the case of both kidney and liver transplant excellent HCV treatment outcomes have been achieved with DAA therapy.
Antirejection therapy
Regimens should be individualized to patients based on the organ transplanted, immunologic risk, renal and liver function, and ART regimen
Conclusions
Kidney and liver transplantation are the standard of care for HIV-infected persons with end-stage kidney and liver diseases.
Encouraging results with transplantation of other organ types, including pancreas, heart, and lung suggest that persons with other advanced organ disease should also be referred to centers experienced in performing these transplants
Introduction: Due to antiretroviral therapy, HIV infection has become a chronic illness, with increased life expectancy, lading to increased morbidity and mortality due to medical co-morbidities like coronary artery disease (CAD) and nonalcoholic steatohepatitis (NASH). Persons with HIV (PWH) can also register as organ donor after the passage of HIV organ policy equity (HOPE) act, expanding the donor pool for HIV-infected patients.
Status of organ transplantation by organ type: PWH have been increasingly offered organ transplantation due to availability of antiretroviral therapy (ART).
Renal failure can occur in PWH due to diabetes mellitus (DM), hypertension, and focal segmental glomerulosclerosis (FSGS) besides HIV associated nephropathy (HIVAN). Co-infections with HBV and HCV as well as nephrotoxicity of certain ART drugs also play a role. Kidney transplantation in PWH has clear survival benefit as compared to remaining on dialysis. Due to viral suppression and good CD4 count pre-transplant, post-transplant opportunistic infection incidence is low, but there is increased bacterial infections, high rates of delayed graft function (DGF), and 2-3 times higher rates of acute rejection. The higher acute rejection rates seen could be due to underuse of immunosuppressives, drug interactions, or due to immune system dysregulation and heterologous immunoreactivity. Barriers to kidney transplantation in PWH include poor referral from their primary physicians for transplant, and longer wait-list times.
Liver disease is the third most common cause of death in PWH, with HBV and HCV infections, HIV itself, and ART medications (direct hepatotoxicity, steatosis, immune reconstitution, or hypersensitivity reactions) being the chief etiology for liver disease. Liver transplantation in PWH has variable outcomes with 3-5 year graft and patient survival ranging from 85-100%. DAA therapy introduction has led to improvement in graft and patient survival rates. Outcomes of pancreas transplantation have been mixed with very small number of transplants being performed till now. Incidence of CAD is increasing in PWH, in addition to HIV associated cardiomyopathy. It has been shown that heart transplant in PWH do not have higher risks of coronary artery vasculopathy as compared to HIV-uninfected recipients. HIV infection is a relative contraindication for lung transplant, with transplant to be considered if no recent AIDS-defining illness and demonstrated ART adherence with viral suppression.
Clinical management of HIV-transplant candidates and recipient: PWH should be referred to centers well versed with HIV-positive transplants. Prior to transplants, patient should have undetectable HIV viral load, CD4 count >200 cell/microL (>100 for liver transplant), comply with ART (except in patients with advanced liver disease), without any active opportunistic infection or malignancy, and should be available for close follow-up post-transplant. HCV infection should not be considered as an exclusion for transplant. If treatment can be safely delayed, such recipients can be offered HCV-viremic donor organs, with treatment using DAAs post-transplant.
Antirejection therapy: The best immunosuppressive regimen for PWH is not known, hence it is prudent to individualize the therapy. A trial showed that anti-thymocyte globulin (ATG) use as induction agent led to more frequent and sever infections and increased risk of graft loss as compared to Basiliximab use. Induction therapy is not required in majority of liver transplant recipients. Likewise, best maintenance immunosuppressive therapy for PWH has not been established and individualization is the key. The preferred combination used is of tacrolimus, mycophenolate and steroids. Calcineurin inhibitors (CNI) have been shown to decrease HIV-1 DNA transcription, leading to increase in HIV reservoir, while sirolimus has been shown to increase HIV-1 transcription, thereby reducing the HIV reservoir.
Medication management: Therapeutic drug monitoring and awareness and vigilance regarding drug interactions is important post-transplant. Protease inhibitors (PI) inhibit CYP3A4 enzyme, leading to increased CNI levels, while non-nucleoside reverse transcriptase inhibitors (NNRTI) reduce CNI levels. Boosted PI in liver transplant recipients lead to nephrotoxicity due to high CNI levels. PI use is associated with higher risk of rejection and mortality than non-PI regimen use. Non-boosted integrase strand transfer inhibitors (INSTI), especially dolutegravir, have emerged as favored ART in transplant recipients.
Clinical monitoring and care of HIV-positive persons: Pre-transplant, PWH should be placed on non-PI ART with the goal of minimizing toxicities and drug interactions. Post-transplant, ART regime would require frequent dose adjustments due to change in creatinine clearance. Agents compromising organ function (like tenofovir in renal transplant and abacavir in liver transplant) should be avoided. Similarly, fixed dose combinations should also be avoided. Any change in ART dose should be communicated to the transplant team. Regular HIV care in post-transplant period is essential with more frequent CD4+ cell count and HIV viral load testing. Post-transplant infective prophylaxis is also important.
HIV to HIV transplantation: HIV positive transplantation was declared illegal in 1984, but in 2008 HIV positive renal donor to HIV positive recipient were performed in South Africa, with good graft and patient outcomes. Theoretical risks of using HIV-positive organs include superinfection with donor HIV strain, transmission of antiviral resistance, risks of opportunistic infections, and risk of poor-quality organs. The HOPE Act (HIV organ policy equity act) laid down eligibility criteria for HIV-positive donors with detailed evaluation including HIV viral load, CD4 count, opportunistic complications, HIV resistance and tropism testing, ART therapy status, and HBV/ HCV co-infection presence. Data from HIV-positive to HIV-positive kidney and liver transplant showed excellent patient and graft outcomes. HIV-positive living donors should be assessed for HIV-specific risk factors for ESRD development like low CD4 count and HCV co-infection in addition to non-HIV-specific factors like hypertension, diabetes mellitus, and preexisting renal disease. Nephrotoxic ART (like tenofovir) and NSAIDs should be avoided post-donor-nephrectomy.
Conclusion: Renal and liver transplant is standard-of-care for HIV-infected patients with ESRD and end stage liver disease. Availability of INSTI and DAAs have simplified the post-operative management and improved patient outcomes. PWH can donate organs to HIV-infected persons in research settings.
Organ transplantation in persons with HIV
The metabolic side effects of both the virus and antiretroviral drugs place patients at a higher risk for organ dysfunction and, ultimately, organ failure. Growing numbers of persons have undergone pancreas, heart, and lung transplantation, demonstrating feasibility.
With improvements in ART, HIV associated nephropathy (HIVAN) rates have declined, but in antiretroval-treated PWH, other causes of renal failure such as focal segmental glomerulosclerosis, diabetes mellitus, and hypertension remain prominent. Additionally, coinfections with hepatitis C virus (HCV) and hepatitis B virus (HBV) increased risk for kidney failure.
Importantly, several antiretroval agents, such as tenofovir, abacavir, indinavir, ritonavir-boosted lopinavir, ritonavir boosted atazanavir, and potentially other boosted protease inhibitors, are associated with nephrotoxicity and/or metabolic complications, including diabetes and dyslipidemias, which can ultimately contribute or lead to the development of chronic kidney disease and ESRD.
Once on dialysis, PWH has lower survival rates when compared with uninfected dialysis patients. Because of this, PWH are increasingly undergoing kidney transplantation.
Because all patients had viral suppression and CD4 cell counts at least 200 cells/ml prior to transplant and combination ART and posttransplant anti-infective prophylaxis was employed, HIV control was excellent, and few opportunistic infections were encountered.
Bacterial infections were observed with increased frequency in HIV recipients who were treated with the lymphocyte depleting agent, antithymocyte globulin (ATG) or coinfected with HCV.
Finally, HIV recipients experienced allograft rejection rates two to three times higher than observed in the general kidney transplant population, and rejection was a predictor for allograft failure. Single and multicenter studies reported in the United States and Europe have largely confirmed these results. Several proposed mechanisms for increased rate of rejections, including inadequate immunosuppression, either because of underuse of immunosuppressive agents or drug interactions that lead to inadequate or inconsistent immunosuppressive drug levels. Another potential explanation invokes immune system dysregulation and heterologous immunoreactivity in response to HIV and other chronic infections.
Barriers to referral and listing HIV patients for and undergoing kidney transplantation still exist. A recent survey found that 16.9 and 28.1% of responding U.S. transplant programs still considered HIV as an absolute or relative contraindication to transplantation, respectively.
Clinical management of HIV-infected organ transplant candidates and recipient
Centers may vary in their candidacy requirements for transplantation, but updated guidelines recommend that, regardless of the organ transplanted:
· Patients have undetectable HIV viral load,
· Known compliance with ART,
· No evidence of active opportunistic infections or
· No HIV-associated malignancy, and
· The ability to have close follow-up for immunosuppression, drug level monitoring and management.
· CD4 cell counts at least 200 cells/ml are recommended for transplantation of all organs with the exception of liver.
Antirejection therapy
The best immunosuppressive regimen to use for patients with HIV is unknown. Regimens should be individualized to patients based on the organ transplanted, immunologic risk, renal and liver function, and ART regimen.
In the U.S. NIH observational trial, persons who received ATG as opposed to basiliximab, an IL-2 receptor antagonist, experienced significant, prolonged lymphocyte depletion, more frequent and severe infections, and increased risk for allograft loss. Other investigators, through analysis of registry data, reported lower rejection and infection rates with ATG. Based on this, the choice of induction agent should be individualized.
For HIV-infected transplant recipients, the best maintenance immunosuppressive regimens have not been established. Tacrolimus is associated with lower rejection rates and is the preferred calcineurin inhibitor. Calcineurin inhibitors have been found to decrease HIV-1 DNA transcription. Mycophenolate, an antiproliferative agent, is a very common component of maintenance immunosuppression. Although long-term maintenance prednisone therapy reduces risk for rejection, the benefits of its used should be weighed against the long-term effects of this agent.
Sirolimus is known to have anti-HIV effects through downregulation of CCR5, upregulation of b-chemokines, and blockade of the mammalian target of rapamycin (mTOR).
Medication management
Although immunosuppressive therapeutic drug monitoring is the responsibility of the transplanting center, HIV providers must be aware of key drug interactions with maintenance immunosuppressive therapies.
Protease inhibitors, via inhibition of cytochrome P450 3A4 (CYP3A4) enzyme, alter the pharmacokinetics of immunosuppressive medications, including the calcineurin inhibitors (tacrolimus, cyclosporine A) and mTOR inhibitors (sirolimus, everolimus), resulting in drastic alterations in doses and dosing schedules of these drugs. This increases the potential for inconsistent immunosuppressive levels that may place the patient at risk of rejection or, alternatively, supra-therapeutic levels that result in toxicity. Conversely, non-nucleoside reverse transcriptase inhibitors have differing potential for induction of CYP3A4. Studies in renal transplant recipients have also shown poor outcomes for patients on protease inhibitor-based regimens.
Non-boosted integrase strand transfer inhibitors (INSTI) have emerged as favored therapies. Raltegravir, dolutegravir, and bictegravir are completely or primarily metabolized through the uridine diphosphate glucuronosyltransferase 1A system, resulting in clinically insignificant interactions with the calcineurin inhibitors.
Clinical monitoring and care of HIVR persons before and after organ transplantation:
The HIV specialists’ partner should be present with the transplant team to optimize the required HIV therapy. Whenever feasible, patients should be placed on non-protease inhibitor-based ART regimens.
After transplant, often the same ART regimen may be continued, although clinicians must be cognizant of frequent fluctuation in kidney function that may require frequent dose adjustments, especially early in the post-transplant period.
In addition, HIV clinicians should avoid, when possible, agents that may compromise organ function, such as use of tenofovir disoproxil fumarate after kidney transplant or abacavir after heart transplantation.
in the setting of allograft rejection, and when immunosuppressive therapy is changed, more frequent monitoring of CD4+ cell counts, and HIV viral load is warranted.
HIV-to-HIV transplantation
In 2008, four HIV+ to HIV+ renal transplants were successfully performed in Cape Town, South Africa. Recent follow up data published by the same group notes that of the 51 patients transplanted with HIV+ organs, the 1, 3, and 5-year patient survivals were 87, 87, and 84% while 1, 3, and 5-year graft survivals 96, 93, and 79%. As of December 2018, 100 HIV+ persons have undergone deceased donor organ transplants in the United States with organs allocated under the HOPE Act.
A major concern is the potential consequences of superinfection with the donor HIV strain, including acquisition of CXCR4-tropic or dual/mixed-tropic virus or transmitted antiviral resistance. Other risks include transmission of latent or unrecognized opportunistic infections to the recipient and poor organ quality because of prevalent renal, hepatic, and cardiac diseases in the HIV population.
When evaluating potential candidates for donor nephrectomy, the assessment must include identification HIV-specific risk factors for development of ESRD such as low CD4+ cell count and HCV coinfection in addition to other conditions that generally exclude persons from donation (e.g. diabetes mellitus, hypertension, and preexisting kidney disease).
HIV+ African American persons with high-risk apoprotein L1 (APOL1) genotypes are at risk for development HIVAN and focal segmental glomerulosclerosis, but it is unknown whether APOL1 haplotype screening may be of utility in this setting. Post-nephrectomy, HIV+ donors should avoid nephrotoxic ART (such as tenofovir) in addition to agents such as nonsteroidal anti-inflammatory agents. To date, only two living donor kidney transplants have been reported, one with long-term good outcomes in both the donor and recipient.
Organ Transplantation in Persons with HIV
The HIV Organ Policy Equality Act’s approval has increased the options available to PWH for organ donation and Transplantation, which is a life-saving treatment for PWH who have organ failure.
The current review focused on the status of SOT for HIV-infected persons, highlighting the outcomes of the current standards of care for, and unique aspects of post-transplant management.
Status of organ transplantation by organ type:
Kidney:
The number of HIV patient with ESRD is increased recently for example in united states 800 patients with HIV ending with ESRD annually.
The earlier initiation of ART, HIV associated nephropathy (HIVAN) rates have decline, in spite of that ESRD increased because of focal segmental glomerulosclerosis, diabetes mellitus, and hypertension and also the side effects of ART which is nephrotoxic.
After transplantation, outcomes for PWH are favorable, with transplantation providing a clear survival benefit over renal replacement therapy.
In USA 0.5-1.5% of dialysis has HIV
Causes of CKD in HIV:
HIV induce nephropathy (decreased with ART)
FSGS
DM and HTN
Co-infection, HCV and HDV
Drug induced nephropathy
Survival is lesser than those without HIV.
Transplantation provides a clear survival benefit over renal replacement therapy.
1 and 3-year kidney allograft and patient survival estimates were 90.4 and 73.7 and 94.6 and 88.2%, respectively.
Associated with higher arte of bacterial infection especially with ATG, higher rate of DGF and 2 folds of rejection episodes.
A recent survey found that 16.9 and 28.1% of responding U.S. transplant programs still considered HIV as an absolute or relative contraindication to transplantation, respectively.
Liver:
Liver disease is now the 3rd biggest cause of death in PWH in the era of HAART.
PWH are susceptible to ESLD through different pathways. Chronic HCV and HBV co-infections occur in 2.4 & 6.1% of people worldwide, respectively.
In viral hepatitis, HIV infection increases the risk for advanced and progressive liver disease (ALD). ALD can also be brought on by ART.
ESLD can result from alcohol consumption and other non-HIV-related causes of liver disease, either as its major cause or a contributing component.
HCC can make the progression of ALD much more challenging. The number of HIV+ patients receiving liver TX is rising due to the frequency of ALD in this community, however PWH encounter barriers to liver TX, with HIV being viewed as an absolute or relative contraindication by 28.1 & 31.6% of surveyed U.S. TX centers, respectively.
The TX results of HIV-HCV co-infected patients were poor (poorer graft & patient survival rates) compared to HCV-mono-infected controls.
This was due to the lack of hepatitis C DAA medications. Poor outcomes were a result of sepsis, severe infections, and increasing liver damage caused by HCV.
Pancreas:
In the US in 2018, 836 SKP TX were carried out.
Only 10 cases of this treatment being used on type 1 diabetic PWH have been documented.
Graft thrombosis, rejection, & bacterial infections, including deadly sepsis, were reported as complications. Pancreatic TX in HIV-positive patients is feasible but requires more practice.
Heart:
PWH are vulnerable to age-related HD as well as those brought on by HIV’s chronic immunological activation state & the metabolic side-effects of ART.
Prior to the development of ART, HIV-associated cardiomyopathy was seen; currently, CAD is a growing issue in PWH.
Heart TX is still uncommon, but HIV is no longer considered a strict contraindication to advanced heart failure therapy. The number of people seeking heart TX is expected to rise as the HIV population ages.
Currently, the 1- & 5-year after TX survival rates range from 64.7% to 77.3% & 85.9% to 90%, respectively.
The risk of post-transplant vasculopathy is not higher than in HIV-uninfected recipients. Rejection rates compared to the overall heart TX is greater.
Lung:
There is a shortage of information about TX in PWH.
HIV infection is a relative contraindication to lung TX in the 2014 revision of the ISHLT guidelines.
HIV-experienced facilities may consider PWH as candidates if they have a history of ART adherence, viral suppression, & no recent AIDS-defining condition. Few lung TX reports can be found in PWH.
Clinical management of HIV-infected organ transplant candidates and recipient
Selection of candidates:
Any patient with end-organ failure & stable HIV should be referred to centers experienced in HIV organ TX.
Patients should have undetectable HIV viral loads, known ART compliance, no signs of active opportunistic infections or HIV-associated malignancies, & the ability to have close follow-up for IS, drug level monitoring, & management.
Except for the liver, where a CD4 cell count of at least 100 cells/ml is required for TX, other organs should have CD4 cell counts of at least 200 cells/ml.
Although organ recipients with HCV co-infection had unfavorable outcomes in the pre-DAA era, HCV should not be regarded as a bar to TX.
DAAs have produced good HCV treatment outcomes in both kidney & liver TX.
It’s crucial to consider factors like low BMI, the need for a combined liver-kidney TX, & HCV donor organs when assessing HCV-co-infected patients for liver TX.
Anti-rejection Therapy:
The ideal IS regimen to administer to HIV patients is unknown.
Patients should have tailored regimens depending on the transplanted organ, immunologic risk, renal , hepatic function and ART regimen.
ATG as opposed to basiliximab, causes significant, extended lymphocyte depletion, more frequent, severe infections and a higher risk for allograft loss.
For most liver transplant recipients, induction IS is not necessary.
The best effective maintenance IS regimens are not yet known.
Tacrolimus is the primary CNI due to associated lower rejection rates.
MMF is widely used in maintenance IS.
Prednisone maintenance medication minimizes the likelihood of rejection.
Sirolimus has anti-HIV effects via upregulating β-chemokines, downregulating CCR5, & blocking the mTOR.
Sirolimus does not prevent HIV-1 transcription (In-vitro research).
CNIs reduce HIV-1 DNA transcription.
Medication management:
Anti-rejection medicine levels must be carefully monitored as low & high levels might have harmful effects.
Awareness of drug interactions with maintenance IS medicines is necessary.
Protease inhibitors alter the pharmacokinetics of IS drugs, such as CNIs & mTOR inhibitors, causing significant changes in their doses, dosing schedules and thus putting the patient at risk of rejection or, alternatively, toxicity.
Boosted protease inhibitor regimens were linked to ARF caused by high cyclosporine levels in liver TX recipients. Poor results for patients on protease inhibitor-based regimens have also been shown in renal TX recipients.
Non-boosted integrase strand transfer inhibitors (INSTI) have become popular treatments, but protease inhibitors have lost favor in TX. Raltegravir, dolutegravir, & bictegravir have negligible interactions with CNIs.
Because of its high barrier to resistance & simplicity of use, dolutegravir has become the preferred INSTI.
Clinical monitoring, care of HIV +ve persons before and after TX:
The same ART treatment is frequently continued after transplant.
Abacavir use after heart TX or the use of tenofovir disoproxil fumarate after KTX are examples of drugs that HIV physicians should avoid whenever feasible.
Fixed dosage combination regimens should only be used with caution.
If a change in ART is being considered, HIV providers must consult with the TX center.
HIV care must be regularly provided during the post-TX period.
More regular monitoring of CD4 cell counts & HIV viral load is necessary in the early post-TX period, in cases of rejection & when IS medication is modified.
Anti-infective prophylaxis is based on HIV recommendations as well as TX center practice.
HIV-to-HIV transplantation:
The potential of superinfection with the donor HIV strain, such as the development of CXCR4-tropic or dual/mixed-tropic virus or transmitted antiviral resistance, are a big worry.
Additional hazards include the possibility of transmitting opportunistic infections that are latent or undiagnosed to the recipient as well as decreased organ quality due of the high prevalence of renal, hepatic and cardiac problems in the HIV population.
Conclusions:
Standard of care for HIV-infected individuals with ESRD and liver disorders is Transplant .
Positive outcomes with the transplant of other organ types (pancreas, heart and lung) imply that patients with other severe organ diseases should also be directed to transplant facilities with experience in these procedures.
Treatment of the HIV organ recipient after transplant has been eased by the availability of INSTI, which has little interactions with IS medications.
With their strong efficacy in the post-transplant environment, DAAs for hepatitis C promise to enhance outcomes for organ recipients who are also co-infected.
The HOPE Act’s implementation allows PWH to donate organs to HIV-positive people awaiting kidney and liver TX in a research setting.
HIV specialists should actively refer suitable patients for transplant, inform patients on the results of transplant, the advantages and disadvantages of using HIV-positive organs and ensure regular HIV infection surveillance following transplant.
Organ transplantation in persons with HIV
Introduction
· HIV infection has become a chronic illness in the current era of antiretroviral therapy.
· Over the past decade, accumulating evidence has established solid organ transplantation (SOT) as standard of care for persons with HIV (PWH) who develop end-stage kidney and liver disease.
· Some limited data has shown feasibility of pancreas, heart, and lung transplantation in PWH.
Kidney transplantation in PWH:
· With improvements in and earlier initiation of ART, HIV associated nephropathy (HIVAN) rates have declined, but other causes of renal failure increased risk for kidney failure and ESRD in PWH.
· PWH have lower survival rates when compared with uninfected dialysis patients. This is why PWH are increasingly undergoing kidney transplantation.
· There is a clear survival benefit of renal transplant over dialysis in PWH.
· In the largest prospective observational trial conducted by Stock etal, 1 and 3-year kidney allograft where more than 90 and patients survival estimates at 1 and 3 years was 73.7 and 88.2%.
· However, this study identified, bacterial infections were observed with increased frequency in HIV recipients who were treated with ATG or coinfected with HCV.
· In this study PWH experienced higher rates of delayed allograft and allograft rejection than observed in the general kidney transplant population.
· Other studies reported in the US and Europe have largely confirmed the results of this study.
· In spite of international guideline-based support, PWH are meeting barriers to listing for and undergoing kidney transplantation.
Liver transplantation in PWH
· In the era of highly effective ART, liver disease has become the third leading cause of death in PWH.
· The mechanism of this is multifactorial.
· The outcomes of liver transplantation in PWH vary by the reason for transplant.
· In those with HIV-HBV co-infection, passive prophylaxis with hepatitis B immunoglobulin and antiviral therapy, improved both graft and patient survivals after 3–5 years of follow-up.
· Before the availability of hepatitis C DAA agents, the transplant outcomes of HIV– HCV coinfected patients were problematic.
Pancreas transplantation in PWH
· Outcomes of simultaneous pancreas-kidney transplants have been mixed with reported complications.
· Pancreas transplantation can be successful in HIV-infected patients, but additional experience is needed.
Heart transplantation in PWH
· Based on recent studies, 1 and 5-year post transplant survivals are between 85.9–90% and 64–77.3%, respectively.
· In a recent study, the risks of post-transplant vasculopathy are not any higher than HIV uninfected recipients, but there were higher rates of rejection in PWH compared with the general heart transplant population.
Lung transplantation in PWH
· There is a paucity of lung transplantation reports in PWH.
· Reports demonstrated feasibility of lung transplant in persons with advanced lung diseases.
Clinical management of HIV-infected organ transplant candidates and recipients
Selection of candidates
· Candidacy requirements for transplantation include, undetectable HIV viral load, compliance with ART, no evidence of active opportunistic infections or HIV-associated malignancy.
· CD4 cell counts at least 200 cells/ml are recommended for transplantation of all organs with the exception of liver, where more than 100 cells/ml is accepted.
· HCV co infection should not be considered an exclusion factor for transplant.
· In the case of both kidney and liver transplant, excellent HCV treatment outcomes have been achieved with DAA therapy.
Antirejection therapy
· The best immunosuppressive regimen to use for patients with HIV is unknown
· Choice of induction agent should be individualized.
· Induction immunosuppression is not required in the majority of liver transplant recipients.
· For HIV-infected transplant recipients, the best maintenance immunosuppressive regimens have not been established.
· Tacrolimus is preferred as it is associated with lower rejection rates.
· MMF is commonly used.
· The benefits of long term use of prednisolone should be weighed against the long-term effects of this agent.
· There is a possibility of utilizing sirolimus as it is known to have anti-HIV effects.
Medication management
· Protease inhibitors are inhibitors of cytochrome P450 thus leading to higher levels of IS medications, including the calcineurin and mTOR inhibitors.
· Non-nucleoside reverse transcriptase inhibitors leads to induction of CYP3A4, thereby lead to higher risk of graft loss.
· Dolutegravir has emerged as the favored non-boosted integrase strand transfer inhibitors (INSTI) due to its high barrier to resistance and ease of dosing.
Clinical monitoring and care of HIVR persons before and after organ transplantation
· Whenever feasible, patients should be placed on non-protease inhibitor-based ART regimens.
· After transplant, often the same ART regimen may be continued.
· It is vital that HIV providers communicate with the transplant center whenever a change in ART is being contemplated because of fluctuating renal function and drugs interactions as outlines above.
· In the early post-transplant period, in the setting of AR, and when IS medication are changed, more frequent monitoring of CD4 cell counts and HIV viral load is needed.
· Life-long prophylaxis against Pneumocystis jiroveci is warranted.
HIV-to-HIV transplantation
Risks
· Super infection with the donor HIV strain, including acquisition of CXCR4-tropic or dual/mixed-tropic virus or transmitted antiviral resistance.
· Transmission of latent or unrecognized opportunistic infections to the recipient
· Poor organ quality because of prevalent renal, hepatic, and cardiac diseases in the HIV population.
Data
· The South African experience has been overall promising and inspired action by the United States transplant community to expand HIV+ to HIV+ transplant to North America.
· As the U.S. trials are ongoing, only preliminary data are available but suggest excellent patient and allograft survivals for both kidney and liver recipients.
· Few cases of HIV to HIV living donor transplantation have been reported in the literature. Living donors should be evaluated for HIV-specific risk factors for development of ESRD such as low CD4 cell count and HCV coinfection.
· HIV Organ Policy Equity (HOPE) Act has enabled (Person With HIV) PWH to register as organ donors, expanding the donor pool for PWH and the organ donation pool as a whole.
Kidney transplantation in PWH
Liver transplantation in PWH
Clinical management of HIV-infected organ transplant candidates and recipient
HIV-to-HIV transplantation
A major concern is the potential consequences of superinfection with the donor HIV strain, including acquisition of CXCR4-tropic or dual/mixed-tropic virus or transmitted antiviral resistance
The HOPE Act has enabled the utilization of organs that may have otherwise been discarded due to false-positive HIV test results, with almost 50% of HOPE-allocated organs coming from donors with false-positive testing.
This is a review article discussing about organ transplantation in HIV patients
Introduction:
HIV patients are now living longer dur to cART. However, this predisposes them to cardiac diseases and NASH. The medications used for HIV also cause metabolic conditions like diabetes and dyslipidemia leading to organ dysfunction. Previously, HIV patients were not considered for organ transplant due to the poor outcomes in the pre-HAART era. However, with the HAART the outcomes are comparable to patients without HIV. Before the HIV Organ Policy Equity (HOPE) Act, HIV patients could not register as organ donors.
Kidney:
With the advent of HAART, the incidence of HIVAN has reduced. However, other causes of CKD like FSGS, DM and hypertension are prominent. Co-infections with Hepatitis B and Hepatitis C increase the risk of kidney failure. There are also some ARVs like tenofovir, atazanavir, abacavir that cause kidney damage. Patients with HIV and who are on dialysis have a higher mortality as compared to non-HIV patients on dialysis.
ESKD patients with HIV have a favorable outcome comparable to the non-HIV patients. Stock et al looked at 150 HIV patients who had ESKD and who underwent kidney transplant and found that the 1 and 3 year graft and patient survival was 90.4 and 73.7% and 94.6 and 88.2% respectively. The HIV control was also excellent as all the patients were on ARVs and had a CD4 count of more than 200 cells/microliter.
However, they also found that in this cohort of patients, bacterial infections were increased especially in those patients who received ATG for induction. These patients also had a higher incidence of DGF and had a rejection rate that was 2-3 times higher than the general kidney population.
Unfortunately, despite the comparable kidney transplant outcomes, people with HIV (PWH) remain on dialysis for a longer duration of time before transplant listing
Liver:
Liver disease has become the 3rd leading cause of death in HIV patients in the HAART era. PWH are at a higher risk of developing end stage liver disease due to:
There may also be other contributing factors like alcohol and other non-HIV related factors that contribute to the development of ESLD
The outcomes of liver transplant vary depending on the cause of the liver disease.
In HIV/HBV coinfection with prophylaxis with hepatitis B immunoglobulin and antiviral therapy, both graft and patient survival range from 85-100% after 3-5 years of follow up.
Before the availability of DAA for HCV infection, liver transplant outcomes were not very good with lower patient and graft survival. However, this has changed with the advent of the DAAs
Pancreas:
Only 10 cases of pancreas transplant in PWH have been reported in literature. Outcomes have been mixed with reported complications of graft thrombosis, rejections and bacterial infections including fatal sepsis
Heart:
In the post-HAART era, more and more patients with HIV are developing coronary artery disease and ischemic cardiomyopathy with heart failure. HIV is no longer a contraindication to heart transplant.
The one and five year post transplant survival rates are between 85.9-90% and 64-77.3% respectively. The risks of vasculopathy are comparable to the non-HIV patients. The risk of rejection is higher than in the non-HIV population
Lung:
In the 2014 ISHLT guidelines, HIV has been moved from an absolute contraindication to a relative contraindication for lung transplant. There is a paucity of lung transplantation reports in PWH.
Clinical Management of HIV Infected Organ Transplant Candidates and Recipients:
Selection:
All patients with stable HIV who have end-organ damage should be referred to organ transplant centers well versed with HIV+ organ transplantation.
CD4 cell count of at least 200 cells/microliter are recommended for transplantation of all organs with the exception of liver, where the threshold for transplant is more than 100 cells/microliter for at least 3 months
The other criteria include:
Undetectable HIV viral load
Documented compliance to therapy
Absence of OIs and malignancy
Absence of chronic wasting or severe malnutrition
Access to ISS drug therapies post-transplant
Ability to regularly follow up with HIC care providers
Anti-Rejection Therapy:
The best ISS therapy for PWH who have undergone transplant is unknown
For induction therapy, ATG can cause prolonged lymphocyte depletion and CD4 count depletion. Therefore, basiliximab is the preferred induction agent. However, other studies reported lower rejection and infection rates with ATG.
For PWH who have been transplanted, the best maintenance ISS regimen has not yet been established. Tacrolimus has been associated with lower rejection rates and therefore, is the preferred CNI.
Medication Management:
Close attention needs to be paid to the drug to drug interactions between ARVs and the CNIs
The PIs have been known to increase the CNI levels which can lead to CNI toxicity and graft dysfunction
Clinical Monitoring:
PWH who have been transplanted should be co-managed with the HIV specialist
The same ART regiment the patient was on pre-transplant should be continued unless if it was a PI based regimen
Immediately post-transplant, more frequent HIV VL and CD4 count is warranted
Anti-infective prophylaxis is based on transplant center practices with many centers opting for lifelong PCP prophylaxis
HIV to HIV Transplantation:
In the HAART era the landscape of HIV positive patients receiving transplants has changed
In 2008, 4 HIV + to HIV + renal transplant were successfully performed in Cape Town, South Africa. These transplants were performed in the setting of limited access to dialysis, decreased organ availability and increased HIV deceased donors. The 1,3 and 5 year patient survivals were 87%, 87% and 84%. The graft survival was 96, 93 and 79%.
Very few cases of HIV-HIV living donor transplantation has been reported in the literature. When evaluating potential candidates for donor nephrectomy, the assessment must include identification of HIV specific risk factors for development of ESKD such as low CD4 cell count and HCV co-infection in addition to other conditions
Post-nephrectomy, HIV+ donors should avoid nephrotoxic ART
Conclusion:
Kidney and Liver transplant are the standard of care for PWH and have comparable results to the non-HIV population.
The availability of integrase inhibitors with minimal drug to drug interactions has improved care of the post-transplant patient.
HCV co-infected HIV patients have improved outcomes with the DAAs
Status of organ transplantation by organ type
Kidney:
1- HIV induce nephropathy (decreased with ART)
2- FSGS
3-DM and HTN
4- co-infection, HCV and HDV
5- drug induced nephropathy
Liver:
Pancreas:
Heart:
Lung:
Patient selection:
1- patients have undetectable HIV viral load
2- known compliance with ART
3- no evidence of active opportunistic infections or HIV-associated malignancy,
4- the ability to have close follow-up for immunosuppression, drug level monitoring and management.
5- CD4+ cell counts at least 200 cells/ml are recommended for transplantation of all organs with the exception of liver, where the threshold for transplantation is CD4þ cell count more than 100 cells/ml.
Antirejection therapy:
– Tacrolimus is associated with lower rejection rates.
-CNI have been found to decrease HIV-1 DNA transcription.
– Mycophenolate, is a very common component of maintenance immunosuppression.
-Although long-term maintenance prednisone therapy reduces risk for rejection,
the benefits of its used should be weighed against the long-term effects of this agent.
Medication management:
Clinical monitoring and care of HIVR person
HIV-to-HIV transplantation
Very few cases of HIV-to-HIV living donor transplantation have been reported in the literature:
Transplantation from HIV+ to HIV – donor is illegal in USA:
Thanks
Introduction:
HIV became a chronic controllable disease by introduction of anti retroviral therapy, cardiovascular, liver steatohepatitis, and metabolic derangements caused by HIV and the ART, keep these patients at higher risk for organ dysfunction and graft loss in solid organ transplantations.
The HIV Organ Policy Equity (HOPE) Act, allows HIV patients to be a donor to HIV recipients, increasing the pool of organs, and reducing mortality from end organ damage (kidney, liver, heart, lung ..etc) in those HIV patients.
This article discuss the management, pre and post transplantation care, and the impact of the ART on graft and patients outcomes in HIV infected patients.
Status of organ transplantation by organ type:
There was fear of practicing organ transplantation before the revolution of ART, following data on specific organ transplantations in these patients are now evident:
Kidney:
Prevalence of HIV in ESRD on dialysis in USA is 0.5-1.5%, the ART revolution reduces the risk of HIVAN, but FSGS, DM, and HTN are still the cause of ESRD.
Co-infection with HCV and HBV, ART and protease inhibitors metabolic effects and nephrotoxicity can lead to development of CKD progressing to ESRD in PWH.
Stock et al. 150 patients with controlled HIV by ART (CD4þ cell counts at least 200 cells/ml) underwent transplantation (post transplantation ART+ prophylactic antibiotics) with superior survival benefit from being on RRT, the common complications observed in the study are:
– Increased risk of early bacterial infections, especially on those receiving ATG induction and HCV infection.
– Higher events of delayed graft function requiring dialysis.
– 2-3 fold increased rates of acute rejection due to:
1. Underuse of immunosuppressive medications or drug-drug interaction.
2. Dysregulation of the immune system, and heterologous immunoreactivity in response to HIV and other chronic infections.
– Graft failure risk was higher than the general population.
Liver:
Liver diseases are the third cause of death among HIV infected people (PWH), and caused by:
– The prevalence of HCV and HBV co-infection are 2.4% and 6.1% respectively.
– Advanced liver disease by HIV hepatic infection, ART toxicity, steotosis, or immune reconstitution.
HIV-HBV co-infection, in the setting of passive prophylaxis with hepatitis B immunoglobulin and antiviral therapy, both graft and patient survivals range from 85 to 100% after 3–5 years of follow-up. Due to the frequency of breakthrough HBV viremia, lifelong prophylaxis is recommended.
Before introduction of DAA for HCV, HIV-HCV co-infection was associated with significantly poor patient and graft survival post-transplants, contributed to HCV related progressive liver disease, and sepsis.
Pancreas:
No sufficient data, only 10 case reports of kidney-pancreas transplants with variable complications.
Heart:
HIV cardiomyopathy, ART induced cardiac toxicity, and coronary artery disease contributing to end stage heart failure in PWH, requiring heart transplantation.
Based on recent studies, 1 and 5-year post transplant survivals are between 85.9–90% and 64–77.3%, respectively, higher rates of rejection, ranging from 39.3 to 67% in the one-year period after transplant, and Significantly, 53.7–57% of these patients received some form of mechanical circulatory support prior to transplant.
Lung:
Data is lacking.
Clinical management of HIV-infected organ transplant candidates and recipient:
Candidate selection:
· Meet transplant center-specific eligibility for organ transplantation.
· CD4+ cell count > 200 cells/µl during 3 months prior to transplantation for kidney, pancreas, heart and lung candidates.
· CD4+ cell count > 100 cells/µl during 3 months prior to transplantation for liver candidates only (because of ALD and portal hypertension lead to splenic sequestration of white blood cells, including lymphocytes).
· Undetectable plasma HIV viremia (unless unable to tolerate ART prior to liver transplant).
· Documented adherence with stable ART regimen.
· Absence of active opportunistic infection and malignancy.
· Absence of chronic wasting or severe malnutrition.
· HBV or HC V infection if no advanced fibrosis/cirrhosis (for organ types other than liver).
· Access to immunosuppressive agent therapeutic drug monitoring.
· Ability to regularly follow up with HIV care providers.
HCV co-infection, though problematic should not be considered an exclusion for transplant, in DAA recent very high SVR12 rates.
When evaluating HCV-coinfected persons for liver transplant, it is important to weigh factors predictive of liver allograft loss such as low BMI (21 kg/m2), need for combined liver–kidney transplant, and HCV+ donor organs.
Antirejection therapy
Induction therapy should be individualized (basiliximab/ATG)
Maintenance therapy:
– Tacrolimus showed lower risk of rejection than cyclosporine – Calcineurin inhibitors have been found to decrease HIV-1 DNA transcription.
– Prednisolone decreases rejection rate.
– Mycophenolate commonly used.
– m-TORi (sirolimus) has anti HIV effect through:
(a) downregulation of CCR5.
(b) upregulation of b-chemokines.
(c) and blockade of the mammalian target of rapamycin
Medication management
Clinical monitoring and care of HIVR persons after organ transplantation
– Frequent and regular HIV viral load monitoring.
– Regular kidney function followup and high index of suspecting infections.
– PCP lifelong prophylaxis.
HIV-to-HIV transplantation:
Deceased HIV+ kidney and liver donors to HIV+ recipient have a good patient and graft survival.
Very few cases of HIV+ to HIV+living donor transplantation have been reported in the literature, limitations due to:
HIV+ to HIV- is prohibited due high risk of disease transmission, one reported case from mother to her critically ill son with biliary atresia reported.
Conclusion:
Kidney and liver transplantation in HIV+ patient is the standard of care for patients with ESRD and ESLD with specific criteria, waiting results on other organ transplantation results.
DAA allowed transplant in HCV-HIV co-infection.
Non-boosted integrase strand transfer inhibitors (dolutegravir) simplified the post-transplant management of the HIV+ organ recipient.
Thanks
III. Organ transplantation in persons with HIV
Please summarise this article.
Status of organ transplantation by organ type
The availability of effective ART, persons with HIV (PWH) are increasingly seeking organ transplantation. The most evidence in support of transplantation in this population comes from kidney followed by liver transplantation. However, growing numbers of persons have undergone pancreas, heart, and lung transplantation, demonstrating feasibility.
Kidney
The number of HIV patient with ESRD is increased recently for example in united states 800 patients with HIV ending with ESRD annually .
The earlier initiation of ART, HIV associated nephropathy (HIVAN) rates have decline, inspite of that ESRD increased because of focal segmental glomerulosclerosis, diabetes mellitus, and hypertension and also the side effects of ART which is nephrotoxic.
After transplantation , outcomes for PWH are favorable, with transplantation providing a clear survival benefit over renal replacement therapy.
Liver
Because of highly effective ART, liver disease has become the third leading cause of death inpatient with HIV.
PWH are at risk for end-stage liver disease through a variety of mechanisms. The estimated global prevalence of chronic HCV and HBV co infections are 2.4 and 6.1%, respectively, although prevalence may differ regionally or by risk for acquisition( like injections).
Advance liver disease (ALD) can also result from ART whether caused by direct hepatotoxicity, hypersensitivity reactions, mitochondrial toxicity, steatosis and/or steatohepatitis, or immune reconstitution phenomena.
Pancreas
Pancreas transplantation can be successful in HIV-infected patients, but additional experience is needed.
Heart
HIV-associated cardiomyopathy was seen in the pre-ART, coronary artery disease is now a rising concerning PWH.
Lung
The guidelines stipulate that HIVexperienced centers can consider PWH as candidates in the setting of demonstrated antiretroviral adherence with viral suppression and no recent AIDS-defining illness, There is a paucity of lung transplantation reports in PWH.
Clinical management of HIV-infected organ transplant candidates and recipient
Selection of candidate
HIV providers should refer any patient with end-organ damage and stable HIV to centers well versed in HIV positive organ transplantation.whom are:
1. Undetectable HIV viral load
2. Known compliance with ART.
3. No evidence of active opportunistic infections or HIV-associated malignancy.
4. Ability to have close follow-up for immunosuppression.
5. Drug level monitoring and management .
6. Absence of chronic wasting or severe malnutri!on
7. Hepatitis B or C infection if no advanced fibrosis/cirrhosis (for organ types other than liver)
8, Access to immunosuppressive agent therapeutic drug monitoring.
9. Ability to regularly follow up with HIV care providers.
Antirejection therapy
The best immunosuppressive regimen to use for patients with HIV is unknown.
Regimens should be individualized to patients based on the organ transplanted, immunologic risk, renal and liver function, and ART regimen.
choice of induction agent should be individualized.
For HIV-infected transplant recipients, the best maintenance immunosuppressive regimens have not been established.
Medication management
HIV providers must be aware of key drug interactions with maintenance immunosuppressive therapies.
Protease inhibitors, via inhibition of cytochrome P450 3A4 (CYP3A4) enzyme, alter the pharmacokinetics of immunosuppressive medications, including the calcineurin inhibitors (tacrolimus, cyclosporine A) and mTOR inhibitors (sirolimus, everolimus), resulting in drastic alterations in doses and dosing schedules of these drug.
Clinical monitoring and care of HIV positive persons before and after organ transplantation
In the pre-transplant, HIV specialists partner with the transplant team to optimize HIV therapy, with the goal of minimizing pre-transplant toxicities and post-transplant drug interactions while maintaining viral suppression.
After transplant, often the same ART regimen may be continued, although clinicians must be cognizant of frequent fluctuation in kidney function that may require frequent dose adjustments, especially early in the posttransplant period.
In the post-transplant period, regular HIV care is essential,by frequent monitoring of CD4 cell counts and HIV viral load is warranted.
HIV-to-HIV transplantation
In the past In 1984 the National Organ Transplant Act the transmission of the disease get the transplantation illegal procedure.
Decades later, the landscapes of both HIV and transplantation have changed, making way for HIV positive to HIV-positive transplant.
In 2008, four HIV positive to HIV positive renal transplants were successfully performed in Cape Town, South Africa . These transplants were performed in the setting of limited access to dialysis, decreased organ availability, and increased HIV among brain-dead donors.
A major concern is the potential consequences of super infection with the donor HIV strain, Other risks include transmission of latent or unrecognized opportunistic infections to the recipient and poor organ quality because of prevalent renal, hepatic, and cardiac diseases in the HIV population.
Very few cases of HIV-to-HIV living donor transplantation have been reported in the literature.
Conclusion
1.Kidney and liver transplantation are the standard of care for HIV-infected persons with end-stage kidney and liver diseases.
2. The availability of INSTI, with minimal impact on immunosuppressive drug levels, has greatly simplified the post-transplant management of the HIV positive organ recipient.
3. The introduction of DAAs for HCV, promise to improve outcomes in co infected organ recipients.
4.HIV providers should play an active role in referring appropriate patients for transplantation, educating patients regarding transplant outcomes and the potential risks and benefits of pursuing HIV-positive organs for transplant, and ensuring frequent monitoring of HIV infection after transplant.
Thanks, Murwan
Was nice to see you in Sudan
⭐⭐⭐⭐Organ transplantation in persons with HIV
Summary:
· Kidney transplantation: (causes of ESKD in HIV patients)
o HIVAN is declining with early use of ARV therapy, but DM, HTN and FSGS, coexisting HBV and HCV infections are still leading causes of ESRD in HIV patients.
o Adverse effects of anti-retroviral therapy (ART) as nephrotoxicity with tenofovir, abacavir, indinavir, ritonavir-boosted lopinavir, ritonavir boosted atazanavir, and potentially other boosted protease inhibitors. In addition, dyslipidemia and inducing metabolic derangement which eventually leads to ESKD.
o Use of ART increased patient survival and hence appearance of complications as ESKD and ESLD and need for transplantation.
o Transplantation has better patient survival compared to dialysis. However, ATG use is associated with increased bacterial infection.
o Transplantation in HIV is associated with higher incidence of DGF and AR than HIV naïve recipients (may be related to immune-dysregulation, under immune-suppression).
o Still, the referral of HIV patients to transplantation and taking an active role on waiting list is underuse.
· Liver transplantation
o ESLD can result from coexisting HBV, HCV, ART hepatotoxicity and immune-reconstitution. In addition, other causes as alcoholism and non-HIV related causes can add on the problem.
o In case of coexisting HBV infection, the use of hepatitis B immunoglobulin, antiviral therapy and life-long prophylaxis can increase patient and graft outcome.
o In case of coexisting HCV infection, poor outcome is witnessed (improved with DAAV).
· Pancreas transplantation:
o only 10 reported cases with poor outcome as graft thrombosis, rejection, and bacterial infections including fatal sepsis. Further experience is required.
· Heart transplantation:
o Heart failure and need to transplantation du2 HIV related cardiomyopathy, aging, antiretroviral therapy induced dyslipidemia and DM.
o Coronary vasculopathy post-transplant and rejection is slightly higher than HIV naïve patients.
· Lung transplantation:
o Very limited data, but HIV changed from absolute to relative contraindication in lung transplantation for advanced lung disease.
· Prerequisites to transplantation in HIV patients:
o Undetectable HIV viral load, adherence to ART, no evidence of active opportunistic infections or HIV-associated malignancy or chronic malnutriotion..
o CD4 T cell counts > 200 cells/ml are recommended for transplantation of all organs, except liver, where the threshold for transplantation > 100 cells/ml.
o No fibrosis/ cirrhosis in case of coexisting HBV or HCV infection (in case of any organ transplantation except the liver).
o Strict follow-up for immunosuppression, drug level monitoring and management.
· Treated cutaneous KS and anal carcinoma in situ were not exclusions in the initial HIV-TR trial. All other treated malignancies with disease-free intervals are considered per center-specific policies.
· Use of DAAV in case of coinfection with HCV can improve the graft and patient outcome.
· Induction with ATG can increase risk of infections after transplantation, generally not required in liver transplantation.
· Maintenance with TAC based triple therapy with (MMF and steroids) is generally recommended.
· ART interaction with CNI and mTORi:
o Protease inhibitors= inhibition of cytochrome P450=increase trough level of IS.
o Non-nucleoside reverse transcriptase inhibitors=induction of CYP3A4= decrease trough level.
o Non-boosted integrase strand transfer inhibitors (INSTI) as (Raltegravir, dolutegravir, and bictegravir) have emerged as favored therapies in transplantation as they are metabolized by uridine diphosphate glucuronosyltransferase (no interaction with CNI).
o Dolutegravir has emerged as the favored INSTI due to its high barrier to resistance and ease of dosing
· Recommendation for HIV patients in transplantation:
o Should be treated with non-protease inhibitor-based ART regimens.
o Follow up of infectious complications and graft function.
o Follow up of HIV viral load and CD4 T cells count.
o Avoid tenofovir disoproxil fumarate after kidney transplant and avoid abacavir after heart transplantation.
· HIV donor used only for HIV recipient (only in case of deceased donor). However, there is fear of superinfection with the donor HIV strain, including acquisition of CXCR4-tropic or dual/mixed-tropic virus or transmitted antiviral resistance or transmission of latent or unrecognized opportunistic infections.
· HIV+ to HIV + transplantation has an excellent patient and allograft survivals for both kidney and liver recipients.
· While HIV donation in living kidney donation is not practiced, just 2 reported cases in kidney transplantation.
o Coexisting conditions generally exclude persons from donation (e.g. diabetes
o HIVþ African American persons with high-risk apoprotein L1 (APOL1) genotypes are at risk for development HIVAN and FSGS.
o Post-nephrectomy, HIVþ donors should avoid nephrotoxic ART (such as tenofovir) in addition to agents as NSAIDS.
Thanks, Mai.
Summary:
Introduction:
With increased life expectancy and an aging demographic, common medical comorbidities, such as coronary artery disease and nonalcoholic steatohepatitis, are becoming important causes of morbidity and mortality in persons with HIV (PWH). In addition, the metabolic side effects of both the virus and antiretroviral drugs place patients at a higher risk for organ dysfunction and, ultimately, organ failure. Over the past decade, accumulating evidence has established solid organ transplantation (SOT) as standard of care for PWH with end-stage kidney and liver disease, and more limited but encouraging data has demonstrated feasibility of pancreas, heart, and lung transplantation in PWH.
Status of organ transplantation by organ type:
Kidney:
Liver:
Pancreas:
Heart:
· PWH are prone to both cardiac diseases associated with aging, as well as those associated with the chronic immune activation state of HIV and metabolic effects of ART
· In a recent study evaluating 41 HIVþ heart recipients, coronary artery vasculopathy occurred in 32% at 5 years post-transplant, compared with 29.3% in the general heart transplant population, indicating that risks of post-transplant vasculopathy are not any higher than HIV uninfected recipients
Lung:
Clinical management of HIV-infected organ transplant candidates and recipient:
Selection of candidates:
• CD4+ cell count > 200 cells/µl during 3 months prior to transplantaton for kidney, pancreas, heart and lung candidates
• CD4+ cell count > 100 cells/µl during 3 months prior to transplantaton for liver candidates only
• Undetectable plasma HIV viremia (unless unable to tolerate antiretroviral therapy prior to liver transplant
• Documented adherence with stable antiretroviral treatment regimen
• Absence of active opportunistic infection and malignancy
• Absence of chronic wasting or severe malnutrition
• Hepatitis B or C infection if no advanced fibrosis/cirrhosis (for organ types other than liver)
• Access to immunosuppressive agent therapeutic drug monitoring
• Ability to regularly follow up with HIV care providers
Conclusion:
Kidney and liver transplantation are the standard of care for HIV-infected persons with end-stage kidney and liver diseases. The availability of INSTI, with minimal impact on immunosuppressive drug levels, has greatly simplified the post-transplant management of the HIV positive organ recipient.
Thanks
Introduction
Antiretroviral medication has made HIV a chronic illness and reduced overall and AIDS-related mortality. Due to increased life expectancy and an aging population, HIV patients are dying from common medical comorbidities such as coronary artery disease and nonalcoholic steatohepatitis. The metabolic side effects of the virus and antiretrovirals increase the probability of organ malfunction and failure.
Over the past decade, solid organ transplantation has become the standard of care for PWH with end-stage kidney and liver disease, and limited but promising data has shown the feasibility of pancreas, heart, and lung transplantation in PWH. The HIV Organ Policy Equity (HOPE) Act allows PWH to register as organ donors, extending the donor pool for PWH and the organ donation pool as a whole.
This review discusses SOT for HIV-positive patients, including outcomes, standards of care, and specific post-transplant management.
Status of organ transplantation by organ type
In terms of survival, transplantation obviously outperforms dialysis.
Following up on 150 HIV+ patients who underwent KTX, the findings were as follows:
The rates of kidney allograft and patient survival after one and three years were 90.4, 73.7, 94.6, and 88.2%, respectively.
There was very good HIV control.
Opportunistic infections were minimal.
Before TX, CD4 cell levels were at least 200 cells/ml.
Anti-infective post-TX prophylaxis was combined with ART.
Bacterial infections in HIV patients were more common when ATG and HCV were co-infected. Also, DGF rates were high in PWH, although this did not appear to be a reliable predictor of graft failure.
Rejection rates for HIV recipients were 2 to 3 times higher than those for the overall KTX group.
Several single- and multicenter studies have supported the results of this pilot trial.
PWH have challenges when applying for and acquiring a KTX.
More thorough statistics are needed to comprehend the variations in referral and ultimate reception.
Liver transplantation
In the era of HAART, liver disease the 3rd leading cause of death in PWH.
ESLD affects PWH in many ways. 2.4 and 6.1% of people globally have chronic HCV/HBV co-infections.
HIV raises the likelihood of severe and progressive liver damage in viral hepatitis. ART causes ALD.
Alcohol and other non-HIV-related liver diseases can cause ESLD.
HCC can exacerbate ALD. Because to the prevalence of ALD in HIV+ patients, liver TX is becoming more common, however 28.1 and 31.6% of U.S. TX centers see HIV as an absolute or relative contraindication.
HIV-HCV co-infected individuals had lower graft and patient survival rates than HCV-mono-infected controls. Because to hepatitis C DAA shortages. Sepsis, severe infections, and HCV-induced liver damage produced poor outcomes.
Pancreas transplantation
In 2018, 836 SKP TX were performed in the United States. Only ten instances of this treatment being administered to PWH with type 1 diabetes have been documented.
Complications included graft thrombosis, rejection, and bacterial infections, including lethal sepsis. Pancreatic TX in HIV-positive individuals is possible, but more practice is required.
Heart transplantation
PWH are susceptible to age-related HD, HIV-induced chronic immunological activation, and ART-induced metabolic side effects.
HIV-associated cardiomyopathy predated ART, however PWH now have CAD.
HIV no longer precludes sophisticated heart failure therapy, but heart TX is rare. As HIV patients age, more will seek cardiac TX.
1- and 5-year TX survival rates are 64.7%–77.3% and 85.9%–90%, respectively.
Post-transplant vasculopathy risk is comparable to HIV-uninfected recipients. Rejection rates exceed heart TX.
Lung transplantation
There is a lack of knowledge on lung transplantation in PWH.
Under the 2014 version of the ISHLT guidelines, HIV infection is a relative contraindication for lung TX.
If they have a history of ART adherence, viral suppression, and no recent AIDS-defining disease, HIV-experienced facilities may consider PWH as candidates. There are few reports of lung TX in PWH.
Treatment for rejection
Unknown is the optimal immunosuppressive regimen for HIV patients.
According to the transplanted organ, immunologic risk, renal and hepatic function, and antiretroviral therapy (ART) regimen, the patient’s regimen should be individualized.
ATG, as compared to basiliximab, results in considerable and prolonged lymphocyte depletion, more frequent and severe infections, and an increased risk of allograft loss.
The majority of liver transplant recipients do not require induction IS.
The most effective IS maintenance regimes have not yet been determined.
Because of associated decreased rejection rates, Tacrolimus is the predominant CNI.
MMF is widely employed in IS for maintenance.
Prednisone maintenance treatment reduces the risk of rejection.
Sirolimus exerts anti-HIV actions through the upregulation of -chemokines, the downregulation of CCR5, and the inhibition of mTOR.
Sirolimus does not block HIV-1 transcription
CNIs inhibit HIV-1 DNA synthesis.
HIV-to-HIV transplantation
The possibility of superinfection with the donor HIV strain, such as the emergence of CXCR4-tropic or dual/mixed-tropic viruses or the transmission of antiviral resistance, is a major cause for concern.
Further risks include the chance of spreading latent or undiscovered opportunistic infections to the receiver, as well as poor organ quality due to the high prevalence of renal, hepatic, and cardiac issues in the HIV community.
In conclusion, HIV-infected patients with end-stage renal and liver illnesses are optimally treated with kidney and liver transplants. The success of pancreatic, heart, and lung transplants suggests that advanced organ disease patients should also be referred to transplant clinics. INSTI, which has low immunosuppressive medication effects, has substantially simplified HIV-positive organ recipient post-transplant treatment. Coinfected organ recipients may benefit from the introduction of DAAs for hepatitis C, which are highly effective post-transplant. Finally, the HOPE Act allows PWH to donate kidney and liver transplants to HIV-positive patients in research settings. HIV providers should refer appropriate individuals for transplantation, educate patients on transplant outcomes and the risks and advantages of using HIV-positive organs, and monitor HIV infection following transplant.
Thanks
Organ Transplantation in Persons with HIV
Summary of the Article
Introduction
Status of Organ Transplantation by Organ type
Kidney
a) Allograft and patient survival was 90.4% and 73.7% in 1 year.
b) Allogfart and patient survival was 94.6% and 88.2% in 3 years.
a) ART before Tx.
b) CD4 cell counts >/200 cells.
c) ART and anti-infection plan post-Tx.
a) Receive depleting agents.
b) HCV co-infection.
Liver
a) HIV-HBV co-infection, the graft, and patient survivals range from 85 to 100% after 3-5 years of follow-up, due to the frequency of breakthrough HBV viremia, lifelong prophylaxis is recommended.
b) HIV-HCV co-infection, before DAA the outcome is significantly lower in graft and patients survival, compared to HCV-mono-infection, with estimated 1,3, and 5-years graft survival 52 to 86%, 45 to 60%, and 31 to 45% respectively, while HCV-mono-infection ranged from 57 to 88, 50 to 62, and 358% respectively.
Pancreas
Pancreas transplantation can be successfully done in HIV-infected patients, but additional experience is needed.
Heart
a) Coronary artery vasculopathy occurred in 32% at 5 years post Tx compared to 29.3% in the general population.
b) Higher rate of rejection, 39.3 to 67% in the 1st year, compared to the general population.
Lung
a) HIV infection moves from absolute to relative CI to transplantation.
b) HIV experience center can consider HIV as a candidate in the setting of; ART adherence with viral suppression and no clinical AIDS.
Clinical management of HIV-infected organ transplant candidates and recipients
Selection of candidates
a) Undetectable viral load.
b) Known compliance with ART.
c) No active opportunistic infections.
d) No associated malignancy.
e) Feasibility to follow up.
f) CD4 cell counts >/200 cells/microL, unless in the liver transplant which is >/100 cells/microL.
Antirejection therapy
a) Prolonged lymphocyte depletion.
b) More frequent and severe infections.
c) Increased risk of allograft rejection.
Medication management
Clinical monitoring and care of HIV+ persons before and after Tx
Pretransplant
Post Tx
Conclusion
Thanks
HIV infection has become a chronic illness in the current age of antiretroviral therapy; both overall and AIDS-related mortality has declined
In the United States where approximately 800 PWH are diagnosed with end-stage renal disease (ESRD) annually With improvements in and earlier initiation of ART, HIV associated nephropathy (HIVAN) rates have declined, but in anti retroval-treated PWH, other causes of renal failure such as focal segmental glomerulosclerosis, diabetes mellitus, and hypertension remain prominen
Co infections with hepatitis C virus (HCV) and hepatitisB virus (HBV) increase risk for kidney failure
Ant I rejection therapy :
The best immunosuppressive regimen to use for patients with HIV is unknown. Regimens should be individualized to patients based on the organ transplanted, immunologic risk, renal and liver function, and ART regimen.
This is a very short summary Nahla.
Summary of the article
Organ transplantation in persons with HIV
Persons With HIV (PWH):Status of organ transplantation by organ type
1. Kidney
· PWH have lower survival rates when compared with uninfected dialysis patients.
· Causes of CKD in PWH: HIVAN, co-infection with HBV& HCV, adverse effects of cART beside other causes like DM, HTN and FSGS.
· Transplantation outcomes for PWH are favorable and provide a clear survival benefit over renal replacement therapy.
· Complications that can occur during the post-kidney transplant course of PWH: Bacterial infections, high rates of delayed allograft function, allograft rejection rates two to three times higher than observed in the general kidney transplant population.
2. Liver
· PWH face barriers to liver transplantation, with HIV considered an absolute or relative contraindication by 28.1 and 31.6% of surveyed U.S. transplant centers, respectively.
· The outcomes of liver transplantation in those with HIV-HBV co-infection, in the setting of passive prophylaxis with hepatitis B immunoglobulin and antiviral therapy, both graft and patient survivals range from 85 to 100% after 3–5 years of follow-up.
· Before the availability of hepatitis C directly acting antiviral (DAA) agents, the transplant outcomes of HIV-HCV coinfected patients were problematic, with significantly lower graft and patient survival rates compared with HCV-mono-infected controls.
3. Pancreas
· Outcomes have been mixed, with reported complications of graft thrombosis, rejection, and bacterial infections, including fatal sepsis.
· Only ten cases are reported in the literature, based on these findings, pancreas transplantation can be successful in HIV-infected patients, but additional experience is needed.
4. Heart
· HIV is no longer considered an absolute contra-indication to advanced heart failure therapies, including heart transplantation.
· Based on recent studies, 1 and 5-year post transplant survivals are between 85.9 -90% and 64 -77.3%, respectively.
· The risks of post-transplant vasculopathy are not any higher than HIV uninfected recipients.
5. Lung
· There is a paucity of lung transplantation reports in PWH.
· A case series of three patients from the United States, as well as a small retrospective cohort study demonstrated feasibility of this approach in persons with advanced lung diseases.
Clinical management of HIV-infected organ transplant candidates and recipient
1. Selection of candidates Candidacy requirements for transplantation:
a) undetectable HIV viral load.
b) known compliance with ART.
c) no evidence of active opportunistic infections.
d) No HIV-associated malignancy.
e) The ability to have close follow-up for immunosuppression, drug level monitoring and management.
f) CD4+ cell counts at least 200 cells/ml(the threshold for liver transplantation is CD4+ cell count more than 100 cells/ml, why? The ALD and portal hypertension lead to splenic sequestration of white blood cells, including lymphocytes.
g) Adherence to ART as evidenced by viral suppression.
h) When evaluating HCV-coinfected persons for liver transplant, it is important to weigh factors predictive of liver allograft loss such as: low BMI (<21 kg/m2), need for combined liver-kidney transplant, and HCV+ donor organs.
2. Antirejection therapy
a) The best immunosuppressive regimen to use for patients with HIV is unknown.
b) Regimens should be individualized to patients based on the organ transplanted, immunologic risk, renal and liver function, and ART regimen.
c) For HIV-infected transplant recipients, the best maintenance immunosuppressive regimens have not been established.
· Tacrolimus is associated with lower rejection rates, and for this reason, has emerged as the preferred CNI.
· Calcineurin inhibitors have been found to decrease HIV-1 DNA transcription.
· Sirolimus have anti-HIV effects through downregulation of CCR5, upregulation of b-chemokines, and blockade of the mammalian target of rapamycin (mTOR).
3. Medication management
a) Close attention is needed to ensure adequate levels of antirejection drugs.
b) High awareness of drug interactions with maintenance IS.
· Protease inhibitors, via inhibition of cytochrome P450 3A4 (CYP3A4) enzyme, alter the pharmacokinetics of CNIs and mTOR inhibitors( boosted protease inhibitors regimens were associated with episodes of acute renal failure from high cyclosporine levels).
· Studies in renal transplant recipients have shown poor outcomes for patients on protease inhibitor-based regimens(1.8-fold higher risk of allograft loss and a 1.9-fold higher risk of mortality).
· Non-nucleoside reverse transcriptase inhibitors have differing potential for induction of CYP3A4.
· Non-boosted integrase strand transfer inhibitors (INSTI) have emerged as favored therapies. Raltegravir, dolutegravir, and bictegravir are completely or primarily metabolized through the uridine diphosphate glucuronosyltransferase 1A system, resulting in clinically insignificant interactions with the calcineurin inhibitors.
· Raltegravir have found that it is well tolerated and effective to use in the setting of transplantation.
· Dolutegravir has emerged as the favored INSTI due to its high barrier to resistance and ease of dosing.
4. Clinical monitoring and care of HIV+ persons before and after organ transplantation
a) MDT; including HIV providers, HIV clinician, transplant nephrologist and microbiologist.
b) Monitoring of IS drug level.
c) Monitoring for drug-drug interaction.
d) Frequent monitoring of CD4+ cell counts and HIV viral load.
HIV-to-HIV transplantation
1. In 1984 the National Organ Transplant Act was enacted, making it illegal to use HIV+ organs for transplantation.
2. In 2008, four HIV+ to HIV+ renal transplants were successfully performed in Cape Town, South Africa. These transplants were performed in the setting of limited access to dialysis, decreased organ availability, and increased HIV among brain-dead donors.
3. Follow up data of the 51 patients transplanted with HIV+ organs, the 1, 3, and 5-year patient survivals were 87, 87, and 84% while 1, 3, and 5-year graft survivals 96, 93, and 79%.
4. Very few cases of HIV-to-HIV living donor transplanta- tion have been reported in the literature.
Conclusion
1. Kidney and liver transplantation are the standard of care for HIV-infected persons with end-stage kidney and liver diseases.
2. The availability of INSTI, with minimal impact on immunosuppressive drug levels, has greatly simplified the post-transplant management of the HIV+ organ recipient.
3. The introduction of DAAs for HCV, promise to improve outcomes in coinfected organ recipients.
Thanks
Introduction:
Antiretroviral therapy has made HIV a chronic illness and reduced overall and AIDS-related mortality. With longer life expectancies and an aging population, prevalent medical comorbidities including coronary artery disease and nonalcoholic steatohepatitis are becoming major sources of morbidity and mortality in HIV-positive people. The metabolic side effects of the virus and antiretrovirals increase the probability of organ malfunction and failure.
Over the past decade, solid organ transplantation (SOT) has become standard of treatment for PWH with end-stage kidney and liver disease, and promising data has shown that pancreas, heart, and lung transplantation in PWH is feasible. PWH can now register as organ donors thanks to the HIV Organ Policy Equity (HOPE) Act.
This review discusses SOT for HIV-positive patients, including outcomes, standards of care, and specific post-transplant management. The American Society of Transplantation recently published updated guidelines on SOT management in PWH, but HIV care providers must understand how HIV management decisions affect pre- and post-organ transplant care and how post-transplant immunosuppressive practices affect HIV and transplant outcomes in this unique patient population.
Kidney:
800 PWH are diagnosed with ESRD yearly. ART advancements and earlier initiation have reduced HIV-associated nephropathy (HIVAN) rates, however focal segmental glomerulosclerosis, diabetes, and hypertension still cause renal failure in antiretroviral-treated PWH.
HCV/HBV coinfections increase renal failure risk.
Notably, tenofovir, abacavir, indinavir, ritonavir-boosted lopinavir, atazanavir, and possibly other boosted protease inhibitors can cause nephrotoxicity and metabolic consequences such diabetes and dyslipidemia, which can progress to chronic kidney disease and ESRD. Non-infected dialysis patients outlive PWH.
Transplantation outlives renal replacement treatment for PWH. In the largest prospective observational trial, Stock et al. reported 1- and 3-year renal allograft and patient survival rates of 150 HIV-positive kidney transplant recipients. Because all patients used combination ART and posttransplant anti-infective prophylaxis, HIV control and opportunistic infections were low. PWH had considerable post-kidney transplant problems. Antithymocyte globulin-treated HIV/HCV patients had higher bacterial infections (ATG). Delayed allograft function was common in PWH, although it did not indicate transplant failure. Ultimately, HIV-positive kidney transplant recipients had allograft rejection rates two to three times higher than the general kidney transplant group, which predicted failure.
The high rates of allograft rejection after kidney transplantation have various causes, including inadequate immunosuppression due to underuse of immunosuppressive drugs or medication interactions that diminish them. HIV and chronic infections produce immune system dysregulation and heterologous immunoreactivity.
Maraviroc, a CCR5 inhibitor, is being researched for its impact on HIV population reduction, immune response, and allograft damage following transplantation.
Despite U.S. and international criteria, PWH issue with referral, listing, and kidney transplantation.
According to the U.S. Scientific Registry of Transplant Recipients and Organ Procurement and Transplantation Network, PWH remain on dialysis longer before transplant listing, have longer waitlist times for organ offers and transplant, are less likely to remain active on the list, and have 18% lower kidney transplantation chances than noninfected patients.
Liver:
After highly effective ART, the liver disease kills PWH third.
PWH has many end-stage liver disease risk factors. Chronic HCV and HBV coinfections are estimated at 2.4 and 6.1% worldwide, depending on geography and risk factor (e.g., injectable drug use, MSM hemophilia). HIV increases viral hepatitis patients’ risk of ALD. Hepatotoxicity, hypersensitivity, mitochondrial toxicity, steatosis, and immunological reconstitution can develop ALD from ART. In a prospective liver biopsy research, 73 and 55% of PWH on ART with persistently elevated liver tests had nonalcoholic fatty liver disease and steatohepatitis. Alcohol and other liver illnesses can cause end-stage liver disease. Hepatocellular carcinoma worsens ALD. 28.1 and 31.6% of U.S. transplant institutions prohibit liver transplantation for PWH with HIV.
Passive prevention with hepatitis B immunoglobulin and antivirals yield 85–100% graft and patient survival after 3–5 years in HIV-HBV co-infected patients.
Prevent HBV viremia for life.
Before DAAs, HIV–HCV coinfected patients exhibited lower graft and patient survival than HCV-mono-infected controls.
Assessing organ transplant eligibility in HIV-infected persons:
• Meet transplant center-specific eligibility for organ transplantation
• CD4+ cell count > 200 cells/µl during 3 months prior to transplantation for kidney, pancreas, heart, and lung candidates
• CD4+ cell count > 100 cells/µl during 3 months prior to transplantation for liver candidates only
• Undetectable plasma HIV viremia (unless unable to tolerate antiretroviral therapy prior to liver transplantation
• Documented adherence with stable antiretroviral treatment regimen
• Absence of active opportunistic infection and malignancy
• Absence of chronic wasting or severe malnutrition
• Hep B or C infection if no advanced fibrosis/cirrhosis (for organ types other than liver)
• Access to immunosuppressive agent therapeutic drug monitoring
• Ability to regularly follow up with HIV care providers
• With liver failure, patients may not tolerate ART; in this setting care providers must be able to predict HIV suppression with the introduction/reintroduction of ART post-transplant.
• In addition to no active opportunistic infections, patients with progressive multifocal leukoencephalopathy, chronic intestinal cryptosporidiosis, visceral Kaposi’s sarcoma (KS), and primary central nervous system lymphoma were excluded.
Antirejection therapy:
HIV immunosuppression differs. Organ transplanted, immunologic risk, renal and hepatic function, and ART regimen determine patient regimens.
disagreement on HIV-positive kidney transplant induction immunosuppression. ATG caused prolonged lymphocyte depletion, more severe infections, and worse allograft loss than basiliximab in the U.S. NIH observational trial.
HIV-positive liver transplant recipients rarely need induction immunosuppression.
HIV-positive transplants lack immunosuppression. Maintenance immunosuppression commonly includes antiproliferative mycophenolate. Long-term prednisone decreases rejection risk.
Immunosuppression affects HIV reservoirs. Sirolimus suppresses HIV by blocking mTOR, downregulating CCR5, and upregulating b-chemokines.
Sirolimus can sustain HIV-1 transcription in vitro, reducing the HIV reservoir after immune system activation from transplantation.
Calcineurin inhibits HIV-1 DNA transcription.
Medication management:
Protease inhibitors inhibit CYP3A4, which affects drugs such as calcineurin inhibitors (tacrolimus, cyclosporine A) and mTOR inhibitors (sirolimus, everolimus). Variable immunosuppressive levels raise the risk of rejection or toxicity.
Elevated cyclosporine levels induced sudden renal failure in liver transplant recipients on increasing protease inhibitors.
Protease inhibitor-based regimens were linked with 1.8-fold increased allograft loss and 1.9-fold higher mortality.
Non-boosted INSTIs have replaced protease inhibitors in transplantation. The uridine diphosphate glucuronosyltransferase 1A system completely metabolizes raltegravir, dolutegravir, and bictegravir, resulting in clinically minimal interactions with calcineurin inhibitors. Raltegravir is well-tolerated and effective in transplantation.
Dolutegravir is the favored INSTI due to its resistance barrier and easy dose.
Clinical monitoring and care of HIVR persons before and after organ transplantation:
HIV specialists work with the transplant team to optimize HIV therapy to minimize pre-transplant toxicities and post-transplant drug interactions while maintaining viral suppression. Patients should be placed on non-protease inhibitor-based ART regimens wherever possible.
The same ART treatment may be continued after transplant, but clinicians must be aware of frequent kidney function variations that may require frequent dose modifications, especially early posttransplant. HIV physicians should also avoid drugs that may impair organ function, such as tenofovir disoproxil fumarate after kidney transplant or abacavir after heart transplant.
Due to changing renal function or supratherapeutic calcineurin inhibitor levels in formulations combining powerful CYP system inhibitors such as cobicistat, fixed-dose combination regimens should be used with caution. While considering ART changes, HIV providers must notify the transplant center.
HIV care is crucial post-transplant.
CD4 cell counts and HIV viral load should be monitored more often in the early post-transplant period, allograft rejection, and immunosuppressive medication changes.
Several transplant centers choose lifelong Pneumocystis jiroveci prophylaxis depending on HIV recommendations and transplant center practices.
The US HOPE Act authorizes HIV-to-HIV transplantation in research settings with donor eligibility requirements.
ART history, HIV genotypic testing, CD4 cell counts, HIV viral load values, and opportunistic concerns must be collected by transplant specialists to determine donor appropriateness. Many U.S. hospitals do HIV-to-HIV kidney and liver transplants in NIH-sponsored trials. After HIV, HOPE should include pancreatic and thoracic transplantation.
100 HIV-positive Americans received December 2018 HOPE Act dead donor organ transplants. Preliminary U.S. kidney and liver allograft survival data are favorable.
Conclusion:
HIV-infected patients with end-stage renal and liver diseases receive kidney and liver transplants. The success of pancreatic, heart, and lung transplants suggests that advanced organ disease patients should also be referred to transplant clinics. INSTI, which has low immunosuppressive medication effects, has substantially simplified HIV-positive organ recipient post-transplant treatment. Coinfected organ recipients may benefit from the introduction of DAAs for hepatitis C, which are highly effective post-transplant. Finally, the HOPE Act allows PWH to donate kidney and liver transplants to HIV-positive patients in research settings. HIV providers should refer appropriate individuals for transplantation, educate patients on transplant outcomes and the risks and advantages of using HIV-positive organs, and monitor HIV infection following transplant.
Thanks
III. Organ transplantation in persons with HIV
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Please summarise this article.
Introduction
Status of organ transplantation by organ type
Kidney
Liver
Pancreas
Heart
Lung
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Clinical management of HIV-infected organ transplant candidates and recipient
Selection of candidates
Antirejection therapy
Medication management
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Clinical monitoring and care of HIVR persons before and after organ transplantation
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HIV-to-HIV transplantation
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Conclusion
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Thanks
SUMMARY
Introduction
The era of antiretroviral therapy has significantly reduced the morbidity and mortality associated with HIV/AID making PWH leave almost like a normal population. However, the metabolic and antiretroviral drugs’ side effects have resulted in organ failure hence making the need for organ transplantation a necessity.
The passage of the HOPE Acts has not only reduced the waiting time but has also expanded the donor pool for SOT. Furthermore, the evidence seen PWH that had successful kidney or liver transplantation because of the advent of ART has removed the fear associated with the procedure
Kidney transplantation in PWH
Liver transplantation in PWH
Pancrease transplantation in PWH
Clinical management of HIV-infected organ transplant candidates and recipient
HIV-to-HIV transplantation
Conclusion
The best available form of care for PWH with ESRD and liver failure is kidney and liver transplantation and good outcomes have been demonstrated. Moreso, encouraging result are also been seen in pancreas, lung, and heart transplant among PWH. However, it is important to carried out this procedure in centre with good experience and close monitoring to the use of various ART medication to avoid graft loss.
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Organ transplantation in persons with HIV
Summary :
Introduction:
HIV infection has become a chronic illness in the current age of antiretroviral therapy, with increased life expectancy and an ageing demographic . Solid organ transplantation (SOT) is the standard of care for PWH with end-stage kidney and liver disease, and more limited but encouraging data has demonstrated feasibility of pancreas, heart, and lung transplantation. The HOPE Act has enabled PWH to register as organ donors, expanding the donor pool for PWH and the organ donation pool as a whole.
Status of organ transplantation by organ type :
PWH are increasingly seeking organ transplantation, with evidence in support of kidney and liver, but growing numbers of persons have undergone pancreas, heart, and lung transplantation, demonstrating feasibility.
Kidney:
Kidney transplantation provides a clear survival benefit over renal replacement therapy, but antiretroviral agents can lead to nephrotoxicity and metabolic complications. High rates of allograft rejection following kidney transplantation may be due to inadequate immunosuppression, immune system dysregulation, and heterologous immunoreactivity.Other complications may arise in HIV patients is bacterial infections which increased frequently in patients who receive lymphocytes depleting agents like ATG ,also delayed graft function was noticed .
Liver :
PWH are at risk for end-stage liver disease due to a variety of mechanisms, including chronic HCV and HBV coinfections, HIV infection, nonalcoholic fatty liver disease and steatohepatitis, alcohol and other non-HIV-related causes, and hepatocellular carcinoma. HIV is considered an absolute or relative contraindication by 28.1 and 31.6% of surveyed U.S. transplant centers. The outcomes of liver transplantation in PWH vary by the reason for transplant, with graft and patient survivals ranging from 85 to 100% after 3-5 years of follow-up.
Pancreas :
Pancreas transplantation can be successful in HIV-infected patients, but additional experience is needed. Outcomes have been mixed, with reported complications such as graft thrombosis, rejection, and bacterial infections.
Heart :
HIV-associated cardiomyopathy is a rising concern in PWH, with 1 and 5-year post-transplant survival rates between 85.9-90% and 64-77.3%. 53.7-57% of patients received mechanical circulatory support prior to transplant.
Lung :
HIV infection is now a relative contraindication to lung transplantation in PWH, in addition there is a paucity of lung transplantation reports.
Clinical management of HIV-infected organ transplant candidates and recipient:
-Selection of candidates:
HIV providers should refer any patient with end-organ damage and stable HIV to centers well versed in HIV-organ transplantation. Guidelines recommend that patients have undetectable HIV viral load, known compliance with ART, no evidence of active opportunistic infections or HIV-associated malignancy, and the ability to have close follow-up for immunosuppression, drug level monitoring and management. CD4 cell counts at least 200 cells/ml are recommended for transplantation of all organs with the exception of liver, where the threshold for transplantation is CD4þ cell count more than 100 cells/ml. When evaluating HCV-coinfected persons for liver transplant, it is important to weigh factors predictive of liver allograft loss such as low BMI (<21 kg/ m2)
Antirejection therapy:
The best immunosuppressive regimen to use for patients with HIV for induction and maintenance of immunosuppression should be individualized to the organ transplanted, immunologic risk, renal and liver function, and ART regimen. Tacrolimus is associated with lower rejection and infection rates, and mycophenolate is a common component of maintenance immunosuppression. In-vitro studies have shown that HIV-1 transcription can continue in the setting of sirolimus, which may result in diminishing the HIV reservoir.
Medication management :
Protease inhibitors may alter the pharmacokinetics of immunosuppressive medications , leading to inconsistent doses and dosing schedules and increased risk of rejection. Guidelines have recently been updated outlining these interactions. Studies have shown poor outcomes for patients on protease inhibitor-based regimens, with a 1.8-fold higher risk of allograft loss and a 1.9-fold increased risk of mortality when compared with non-protease inhibitor regimens. The increased rejection may be related to interactions between calcineurin inhibitors and protease inhibitors.
Clinical monitoring and care of HIVR persons before and after organ transplantation
HIV providers play a vital role in pre- and post-transplant care of HIVR persons. Pre-transplant, patients should be placed on non-protease inhibitor-based ART regimens, and after transplant, the same ART regimen may be continued. In the post-post-transplant period, regular HIV care is essential, and more frequent monitoring of CD4 cell counts and HIV viral load is warranted. Anti-infective prophylaxis is based on transplant center practices and HIV guidelines.
HIV-to-HIV transplantation:
The National Organ Transplant Act was enacted in 1984 to prevent HIV transmission by transplantation. In 2008, four HIV-to-HIV renal transplants were successfully performed in Cape Town, South Africa, with 1, 3, and 5-year patient survivals of 87, 87, and 84%. Probable donor superinfection was suspected in one patient, but the patient continued to have viral suppression. The South African experience has inspired action by the US transplant community to expand HIV to HIVþ transplant to North America.
The HOPE Act has enabled the utilization of organs that may have otherwise been discarded due to false-positive HIV test results, with almost 50% of HOPE-allocated organs coming from donors with false-positive testing. Very few cases of HIV-to-HIV living donor transplantation have been reported in the literature, but two living donor kidney transplants have been reported, one with long-term good outcomes in both the donor and recipient.
Intentional transplantation of HIVþ organs into uninfected recipients is illegal in the US, but there is one reported case in the literature involving a partial living donor liver transplant from a South African HIV-mother to her critically ill HIV-negative child with biliary atresia.
Conclusion:
Kidney and liver transplantation is the standard of care for HIV-infected persons with end-stage kidney and liver diseases, INSTI and DAAs for hepatitis C are promising to improve outcomes. HIV providers should play an active role in referring appropriate patients for transplantation, educating patients, and monitoring HIV infection after transplant.
Thanks
Introduction
With the development of antiretroviral therapy, HIV patients life span increased accompanied with organ failures
SOT is offered for patients with HIV( PWH) having end-stage kidney and liver disease,even on lesser scope pancreas, heart, and lung transplantation.
PWH can be considered as donors increasing the donor pool and decreasing waiting list for PWH as recipients.
This review article demonstrates the current SOT status for HIV-infected persons, including the outcomes of the care standards and post-transplant management in this special group.
Status of organ transplantation by organ type
kidney transplantation afterwards liver transplantation are the most evidence supported transplants in this group of patients
but pancreas, heart, and lung transplantation, are becoming more applicable.
Kidney
Although HIV associated nephropathy (HIVAN) rates decreased with antiretroviral therapy, but , other causes can lead to renal failure as focal segmental glomerulosclerosis, diabetes mellitus, and hypertension as well as coinfection with HBV and HCV.
However antiretoviral drugs have side effects as nephrotoxicity ,diabetes, hyperlipidemia which in turn can lead to ESRD as well
PWH undergoing transplantation have better outcome than those on RRT.
Stock et al. trial demonstrated the outcomes of 150 HIV-infected patients after kidney transplantation ;with favourable graft and patient survival ,those patients had viral suppression and CD4+cell counts at least 200 cells/ml before transplant and c ART and posttransplant anti-infective prophylaxis lead to HIV control , and less opportunistic infections but bacterial infection was higher in cases exposed to ATG as induction therapy and co HCV infection also higher rates of delayed allograft function was detected rendered to insufficient immunosuppression or immune dysregulation and heterologous immunoreactivity in response to HIV.
Researches access the role of the C–C chemokine receptor type 5 (CCR5) inhibitor in decreasing the HIV reservoir and modulating the immune response and allograft injury after transplantation.
HCV positive recipients are facing prolonged trnasplantion waiting lists more than non infected recipients.
Liver
PWH are at risk for liver cell failure via different mechanisms including chronic HCV and HBV coinfections, Anitretroviral therapy (ART) can lead to acute liver disease (ALD)through direct hepatotoxicity, hypersensitivity reactions, mitochondrial toxicity, steatosis and/or steatohepatitis, or immune reconstitution phenomena.
In a study on PWH with high liver enzymes receiving ART , NASH and steatohepatitis were detected in liver biopsies.
Alcohol and other non HIV related factors can lead to liver diseases either primarily or as contributing factor.
ALD can lead to hepatocellular carcinomaHCC .
PWH in need for liver transplant is increasing but many difficulties are faced as HIV positive is considered as absolute or relative contraindication for transplantation.
Liver transplant outcome is variable in this group of patients according to transplant cause .
HCV monoinfected candidates have better patient and graft survival compared to HCV and HIV coinfected ones.
Pancreas
Pancreas and kidney transplantation has variable results as complications of graft thrombosis, rejection, and bacterial infections including fatal sepsis which was published, so pancreas transplantation can be successful in HIV-infected patients but more studies is needed.
Heart
PWH are liable to cardiac diseases due to aging , chronic HIV immune activation status and ART metabolic effects. CAD affects PWH.
HIV is not an absolute contra-indication for advanced heart failure
Therapies ,as heart transplantation but not commonly done.
Studies demonstrated that post-transplant vasculopathy risks are not much higher than HIV negative recipients but had higher rejection risks.
Lung
No enough data is available for lung transplant in HIV cases but it is not considered any more as an absolute contraindication by recent guidelines and turned to a relative contraindication for lung transplantation.
Guidelines recommend performing it in HIV experienced centers including PWH adherent to ART ,having suppression of viral load and no HIV recent illness.
Clinical management of HIV-infected organ transplant candidates and recipient
Candidates selection
Stable HIV cases with end organ failure need to be referred to transplant centers specialized in HIV cases.
Guidelines suggest that candidates need to have undetectable HIV viral load, ART compliance except ALD cases who cannot tolerate ART, without active opportunistic infections or HIV-associated malignancy, immunosuppression follow up , monitoring drug level and management,CD4 count >200 cells/ml for all organ transplantation and >100 cells/ml for liver transplantation.
HCV is not an exclusion factor for transplantation, HCV organs transplantation can be used , followed by DAA treatment after transplantation to enhance the pool of available grafts.
Antirejection therapy
Immunosuppressive regimens have to be individualised as there is not a best immunosuppressive drug available.
Trials demonstrated that cases who revived ATG rather than basiliximab as induction suffered severe infection and allograft loss while other registry revealed the opposite.
Also the optimum maintenance therapy is not known for HIV infected cases.
Tac has low rejection rates, MMF is commonly used and prednisolone use have to be through weighing benefits and side effects particularly on the long term.
Sirolimus have anti-HIV effects, apart on HIV 1 which can be suppressed by CNI.
Medication management
HIV drug interactions with maintenance immunosuppressive therapies need to be monitored.
Protease inhibitors inhibit cytochrome P4503A4 (CYP3A4)leading to variation in level of CNI and m TORI which render the patient liable to either rejection or toxicity .
Integrase strand transfer inhibitors (INSTI) therapy has better outcomes and less interactions with immunosuppressives as CNI.
Clinical monitoring and care of HIV positive cases before and after organ transplantation.
In pre-transplant period , HIV specialists manage HIV therapy, in a way to decrease pre-transplant toxicities and post-transplant drug interactions while maintaining viral suppression.
Non-protease inhibitor-based ART regimen is preferred.
Same ART regimen is continued post transplant with close monitoring .
Agents compromising organ function need to be avoided ,and caution with combination regimens.
In early post-transplant period, if allograft rejection occurred, and when immunosuppressives are modulated more frequent monitoring ofCD4+ cell counts and HIV viral load will be needed as well as life-long prophylaxis against Pneumocystis jiroveci.
HIV-to-HIV transplantation
It is applicable, 4 HIV positive to HIV positive renal transplantation cases were conducted successfully in South Africa.
It has to be performed for donors with specific eligibility criteria including donors’ ART history, HIVgenotypic testing, CD4+ cell counts, HIV viral load and history of opportunistic complications
The major concerns were superinfection with the donor HIV strain or antiviral resistant strain transmission or latent or unrecognized opportunistic infections to the recipient and poor organ quality.
In USA the patient and allograft survivals for both kidney and liver recipients in the Hope Act have favourable results.
HIV related risk factors for ESRD occurrence have to be addressed as APO1 genotype association development HIVAN and focal segmental glomerulosclerosis in Afro- American patients but the benefit of APO1 screening is unconfirmed.
Post transplant nephrotoxic ART have to be avoided.
Transplantation of HIV+ organs into HIV negative recipients is unauthorised in USA.
Conclusion
The favourable results of kidney and liver transplant for HIV cases encouraged involving pancreas ,heart and lung transplantation which has to be carried out in specialised centers
INSTI, with less effect on immunosuppressives levels, has positively affected post-transplant management of the HIV positive organ recipient.
DAAA introduction improved the outcome for HCVhepatitis post transplant
HOPE Act demonstrated that PWH can be donors to HIV infected persons on kidney and liver transplant waiting lists .
Thanks
SUMMARY
This Editorial review’s attention to the existing status of SOT for HIV-infected persons, stresses the outcomes of, the current standards of care for, and exceptional aspects of post-transplant management of this particular group of patients with HIV-related CKD including ESRD. the improved life expectancy and aging, comorbid with the metabolic effect of the virus and the antiretroviral medication on persons with retroviral infection (PWH) lead to increased risk of end-organ damage like kidney failure and liver disease In the US around 800 / year of PWH have ESRD and 0.5-1.5% on Dialysis HIV-related nephropathy (HIVAN ) decreased in numbers with the improvement and effectiveness of anti-retroviral medications(HAART ), However, protease inhibitors are associated with nephrotoxicity and/or metabolic complications, including diabetes and dyslipidemias, which can ultimately contribute to or lead to the development of chronic kidney disease in addition to comorbid diseases like DM dyslipidemia.
Kidneys
PWH have higher mortality on dialysis compared to non-HIV infected patients, SOT still can be offered for PWH, especially with the improvement of the antiretroviral medications and the approval of the HIV Organ Policy Equity (HOPE) Act has opened and expanded opportunities for PWH to donate and receive organs. with better patient survival and outcome compared to dialysis, some centers in US and Europe consider HIV to be an absolute or relative contraindication for transplantation, however, there is growing evidence from studies to encourage the PWH to get SOT to provide they are medically fit with undetectable viral load and CD4 count > 200ml for > 6 months, no recent opportunistic infection for > 6 months and no evidence of malignancy or co-infection with HCV, one large prospective cohort study confirms improved patient and graft survival in 1&3 years after kidney transplantation in PWH with a higher risk of DGF and acute rejection and also a more bacterial infection, especially in those received ATG (T- cell depleting agents
Increased risk of graft rejection can be explained in part by the use of lower immunosuppression medications, drug-drug interaction ART with CNI interaction lead to underdosing of the CNI and inconsistency of the trough level, immune dysregulation like CCR5A inhibitor, CCR5 is widely expressed by T lymphocytes and macrophages and a costimulatory molecule for Th1 activation and recruitment inflammatory cells [28]; therefore, CCR5 blockade may dampen the alloimmune response Previous studies in HIV-negative, CCR5Δ3 homozygous persons have demonstrated less rejection and better allograft survival after liver and kidney transplantation.
Liver
Liver disease is the 3rd leading cause of death in PWH especially co-infection with HCV, or HBV which is reported in around 2.4 and -6% respectively
Advanced liver disease in PWH is also related to ART hepatotoxicity hypersensitivity reactions, mitochondrial toxicity, steatosis and/or steatohepatitis, or immune reconstitution phenomena, HCC.PWH face many barriers to liver transplantation, with HIV, considered an absolute or relative contraindication by 28.1 and 31.6% of surveyed U.S. transplant centers, and also have a long waitlist
However, the patient and graft outcome of transplantation of PWH and HBV coinfection varies in the range of 80-100%, with passive HBV Ig and antiviral medication, antiviral prophylaxis recommended lifelong While HCV-related progressive liver disease, severe infections, and sepsis contributed to poor outcomes before the era of DAA therapy.
Pancreas
Limited experience for PWH underwent SKP transplantation, not with type 1 DM, and the outcome from 10 cases reported from the US with many complications including graft thrombosis, rejection, bacterial infection including fatal sepsis.
HEART
Heart transplantation in PWH is associated with better 1, 5 years graft and patient survival and the risk of post-transplant vasculopathy is comparable to the non-HIV recipient, but again the rejection risk in one year is higher based on recent evidence.
Lung
updated ISHLT guidelines, HIV infection has moved from an absolute to a relative contraindication to lung transplantation in 2014
however, the recent data from the US was limited to case series or reports of feasible lung transplantation for PWH under disease control and no recent infection with advanced lung disease
clinical management of HIV -infected organ transplant candidates and recipient
PWH candidates for organ transplantation should meet the following center eligibility criteria
1. Undetectable HIV viral load
2. C4D count > 200 cells /ml except for liver transplant c4d count > 100 cells / ml
3. known compliance with ART
4.No evidence of active opportunistic infections for at least the last 6 months
5.No evidence of HIV-associated malignancy
6. Ability to have a close follow-up for immunosuppression, drug-level monitoring, and management
Antirejection choice
No clear guidelines or evidence for choosing induction IS and maintenance IS and this should be guided based on the type of organ transplant, the patient’s immunological risk and the type of antiretroviral therapy, preferred for induction IS to choose IL2 inhibitor in low immunological risk ( basiliximab ) as ATG can lead to T cell depletion however the guidelines still recommend the use of ATG as induction IS once indicated, for liver transplantation no need for induction, regarding maintenance, IS tacrolimus based IS with MMF and steroid took in consideration drug-drug interaction with antiviral therapy Protease inhibitors, via inhibition of cytochrome P4503A4 (CYP3A4) enzyme, alters the pharmacokinetics of immunosuppressive medications, including the calcineurin inhibitors (tacrolimus, cyclosporine A) and
mTOR inhibitors (sirolimus, everolimus), resulting in severe alterations in doses and dosing schedules of these drugs that put the patient at risk of under suppression and risk of rejection or CNI toxicity with overdosing
while non-nucleoside reverse transcriptase inhibitors have the differing potential for induction of CYP3A4. those receiving protease inhibitor-based regimens had a 1.8-fold higher risk of allograft loss and a 1.9-fold higher risk of mortality when compared with non-protease inhibitor regimens based on one registry data, and replaced by non-boosted integrase strand transfer inhibitors (INSTI) as have appeared as favored therapies like Raltegravir, dolutegravir, and bictegravir are completely or primarily metabolized through the uridine diphosphate glucuronosyltransferase 1A system
resultant in trivial interactions with calcineurin inhibitors.
Clinical monitoring and care of HIVR persons before and after organ transplantation
Both HIV providers and transplant physicians should closely monitor HIV infection recipients for potential opportunistic complications in the post-transplant period. In the pre-transplant phase, HIV specialists partner with the transplant team to optimize HIV therapy, with the goal of minimizing pre-transplant toxicities and post-transplant drug interactions while maintaining viral suppression. , patients should be placed on a non-protease inhibitor-based ART regimen, frequent monitoring for C4D count and viral load especially early post-transplant period or after treatment for acute rejection, or in case of change in immunosuppression avoid fixed drug combination with the risk of acute kidney injury, need lifelong PJP prophylaxis
HIV-to-HIV transplantation
HIV-infected donors were absolutely contraindications by law since 1984, however, based on the south African experience of the use of HIV +ve DD to HIV + ve recipients with favored survival outcomes in1, 3, and 5 years such promising results inspired to action by the United States transplant community to expand HIV+ve to HIV+ve transplants to
North America. Keep in mind two major concern is the potential consequences of superinfection with the donor HIV strain, including the acquisition of CXCR4-tropic or dual/mixed-tropic virus or transmitted antiviral resistance. Other risks include the spread of latent or unrecognized opportunistic infections to the recipient and poor organ quality because of widespread renal, hepatic, and cardiac diseases in the
HIV population.With the implementation of the HOPE act, PWH can donate organs to HIV +VE recipients waiting for kidney or liver transplants under a research setting in the US with the delineation of the HIV DD eligibility criteria for a donation. HIV care providers should refer eligible HIV candidates for transplantation. Information about the HIV donor-specific data such as ART history, HIV
genotypic testing, CD4þ cell counts, HIV viral load results, and history of opportunistic complications, so that donor suitability can be ascertained, An unexpected benefit of the HOPE Act is the
utilization of organs that may have otherwise been discarded due to having false-positive HIV test results
], with almost 50% of HOPE-allocated organs coming from donors with false-positive testing.
HIV+ve African American persons with high-risk apoprotein L1 (APOL1) genotypes are at risk for the development of HIVAN and focal segmental glomerulosclerosis
Intentional transplantation of HIV+ve organs into uninfected recipients is uncharted territory (and currently
illegal in the United States), with significant medical and ethical concerns about such a practice.
Conclusion
Organ transplantation is feasible for PWH and ESKD, ESLD and is considered standard of care with better patient and graft survival.
transplantation is even eased for HIV patients with the Introduction of non-protease inhibitors antiviral therapy. The ERA of DAA for HCV co-infection also facilitates the transplantation of PWH and HCV co-infection with better outcomes with the implementation of the HOPE Act, PWH can donate organs to HIV-infected persons waiting for kidney and liver transplants in a research setting. HIV providers should play an active role in referring appropriate patients for transplantation, educating patients regarding transplant outcomes and the potential risks and benefits of following HIV-positive organs for transplant, and ensuring frequent monitoring of HIV infection after transplant.
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Introduction
o Now the lifespan of newly diagnosed persons with HIV (PWH) is the same as of uninfected persons (due to advanced antiretroviral therapy)
o Metabolic abnormalities related to both the disease and the virus itself, along with common medical comorbidities (such as CAD and nonalcoholic steatohepatitis)are becoming important causes of morbidity and mortality in persons with HIV (PWH)
o SOT is the standard of care for PWH with ESRD
o HIV Organ Policy Equity (HOPE) Act approved PWH to donate and receive organs
o Aim of the study: review the current status of SOT for PWH
Status of organ transplantation by organ type
Kidney
o HIV associated nephropathy (HIVAN) rates have declined due to antiretroviral therapy (ART)
o HCV and HBV coinfections increase risk for kidney failure
o Several antiretroval are associated with nephrotoxicity and/or metabolic complications (diabetes and dyslipidemias) which can contribute to the development of CKD and ESRD
o Survival rate is lower in PMH on dialysis when compared with uninfected dialysis patients
o Transplanted PWH have a clear survival benefit over renal replacement therapy
o In the largest prospective observational study: 1 and 3-year kidney allograft and patient survival estimates were 90.4 and 73.7 and94.6 and 88.2%, respectively (but high risk of bacterial infections, GFF, and allograft rejection)
o Causes of high rates of allograft rejection following kidney transplantation:
1. inadequate immunosuppression (under use of immunosuppressive agents or drug interactions)
2. immune system dysregulation and heterologous immunoreactivity in response to HIVand other chronic infections (C–C chemokine receptor type 5 (CCR5) inhibitor, maraviroc)
Liver
o The prevalence of chronic HCV and HBV coinfections are 2.4 and 6.1%
o Mechanisms of end stage liver disease in PWH:
1. HIV infection increases the risk for progressive and advanced liver disease (ALD) in those with viral hepatitis
2. ALD can also result from ART whether caused by direct hepatotoxicity, hypersensitivity reactions, mitochondrial toxicity, steatosis and/or steatohepatitis, or immune reconstitution phenomena
3. Alcohol and hepatocellular carcinoma
o The outcomes of liver transplantation in PWH vary by the reason for transplant
Pancreas
o Simultaneous pancreas-kidney transplants: reported complications of graft thrombosis, rejection, and bacterial infections, including fatal sepsis
o Needs additional experience
Heart
o HIV is no longer considered an absolute contra-indication to advanced heart failure therapies, including heart transplantation, but is uncommonly performed
o 1 and 5-year post transplant survivals are between 85.9–90% and 64–77.3%, respectively
Lung
o In the 2014 updated ISHLT guidelines, HIV infection has moved from an absolute to a relative contraindication to lung transplantation
o No data of transplantation in PWH
Clinical management of HIV-infected organ transplant candidates and recipient
Selection of candidates
o Guidelines recommend that, regardless of the organ transplanted, patients have undetectable HIV viral load, known compliance with ART, no evidence of active opportunistic infections or HIV-associated malignancy, and the ability to have close follow-up for immunosuppression, drug level monitoring and management are candidate for transplant
o CD4+ cell counts at least 200 cells/ml of all organs (more than 100 in liver)
o Adherence to ART as evidenced by viral suppression (exception is ALD who may not be able to tolerate ART and exhibit viremia, with antiretroviral regimen post-transplant)
o HCV coinfection should not be considered an exclusion factor for transplant
o In the case of both kidney and liver transplant, excellent HCV treatment outcomes was achieved with DAA therapy
Meet transplant center-specific eligibility for organ transplantation:
1. CD4+ cell count > 200 cells/µl during 3 months prior to transplanta!on for kidney, pancreas, heart and lung candidates
2. CD4+ cell count > 100 cells/µl during 3 months prior to transplanta!on for liver candidates only
3. Undetectable plasma HIV viremia(unless unable to tolerate an!retroviral therapyprior to liver transplant)
4. Documented adherence with stable antiretroviral treatment regimen
5. Absence of active opportunistic infection and malignancy
6. Absence of chronic wasting or severe malnutrition
7. Hepatitis B or C infection if no advanced fibrosis/cirrhosis (for organ types other than liver)
8. Access to immunosuppressive agent therapeutic drug monitoring
9. Ability to regularly follow up with HIV care providers
Antirejection therapy
o Immunosuppressive regimen should be individualized to patients based on the organ transplanted, immunologic risk, renal and liver function, and ART regimen
o The best maintenance immunosuppressive regimens is not known
o Sirolimus is known to have anti-HIV effects through downregulation of CCR5, upregulation of b-chemokines, and blockade of the mammalian target of rapamycin (mTOR)
Medication management
o Protease inhibitors is an inhibition of cytochrome P450 3A4 (CYP3A4) enzyme
o Non-nucleoside reverse transcriptase inhibitors are CYP3A4 inducer
o Non-boosted integrase strand transfer inhibitors (INSTI): Raltegravir,dolutegravir,andbictegravir. They are completely or primarily metabolized through the uridine diphosphate glucuronosyltransferase 1A system, resulting in clinically insignificant interactions with the calcineurin inhibitors
Clinical monitoring and care of HIVR persons before and after organ transplantation
In the pre-transplant phase:
o Optimize HIV therapy, with the goal of minimizing pre-transplant toxicities and post-transplant drug interactions while maintaining viral suppression
After transplant:
o Frequent fluctuation in kidney function may require frequent dose adjustments, especially early in the posttransplant period. Also, avoid, when possible, agents that may compromise organ function, such as use of tenofovir disoproxil fumarate after kidney transplant or abacavir after heart transplantation
o In the early post-transplant period, in the setting of allograft rejection, and when immunosuppressive therapy is changed, more frequent monitoring of CD4 cell counts and HIV viral load is warranted
o Anti-infective prophylaxis (many centers give life-long prophylaxis against PJP
HIV-to-HIV transplantation
o For deceased donor organ transplants, U.S. trials suggest excellent patient and allograft survivals for both kidney and liver recipients
o Very few cases of HIV-to-HIV living donor transplantation have been reported in the literature (only two cases)
o Intentional transplantation of HIV+ organs into uninfected recipients is currently illegal in the United States)
Conclusion
o For HIV-infected persons with end-stage kidney and liver diseases, Kidney and liver transplantation are the standard of care
o As INSTI has minimal drug interaction with immunosuppressions, it facilitates post-transplant management of the HIV+ organ recipient
o DAAs for hepatitis C improve outcomes in coinfected organ recipients
o PWH can donate organs to HIV infected persons waiting for kidney and liver transplants
Thanks
Organ Transplantation in Person with HIV
Overall kidney transplantation is the best solution among the PWH (patients with HIV). The evolution of ART (anti-retroviral therapy) has improved the overall outcome among PWH. However, this vulnerable group required closed monitoring, follow up and ART adjustment to prevent post-transplant complications. It is well documented that this group of patient is at higher risk of bacterial infection, rejection and delayed graft function.
Clinical management of HIV-infected organ transplant candidates and recipients
1.Selection of candidates
2.Anti-rejection therapy
Induction
Anti-thymocyteglobulin vs Basiliximab
Maintainance
Prednisolone (can consider steroid withdrawal in low risk individual)
Tacrolimus or mTORi
Mycophenolate Acid or mTORi
3.Medication management (ART)
4.Monitoring
Pre-transplantation
Post-transplantation
Thanks
Introduction
HIV infection has become a chronic illness in the current age of antiretroviral therapy; both overall and AIDS-related mortality has declined.
Over the past decade, accumulating evidence has established solid organ transplantation (SOT) as standard of care for PWH with end-stage kidney and liver disease, and more limited but encouraging data has demonstrated feasibility of pancreas, heart, and lung transplantation in PWH.
The current review focuses on the current status of SOT for HIV-infected persons, highlighting the outcomes of, the current standards of care for, and unique aspects of post-transplant management of this highly specialized patient population.
The American Society of Transplantation has recently published updated guidelines on the management of SOT in PWH, but it is important for HIV care providers to have an understanding of how HIV management decisions affect pre and post-organ transplant care and how post-transplant immunosuppressive practices impact HIVand overall transplant outcomes in this unique patient population .
Status of organ transplantation by organ type
Organ transplantation among PWH was initially viewed with trepidation before the current era of antiretroviral a Division of Infectious Diseases, and b Divisions of Infectious Diseases and Organ Transplantation and Comprehensive Transplant.
Associated nephropathy (HIVAN) rates have declined, but in antiretroval-treated PWH, other causes of renal failure such as focal segmental glomerulosclerosis, diabetes mellitus, and hypertension remain prominent .
Reported the outcomes of 150 HIV-infected patients after kidney transplantation; 1 and 3-year kidney allograft and patient survival estimates were 90.4 and 73.7 and 94.6 and.
This study identified important complications that can occur during the post-kidney transplant course of PWH.
HIVþ recipients experienced allograft rejection rates two to three times higher than observed in the general kidney transplant population, and rejection was a predictor for allograft failure in this study
Single and multicentre studies reported on united state
States and Europe have largely confirmed the results of this pivotal study
There has been much scrutiny over the observed high rates of allograft rejection following kidney transplantation with several proposed mechanisms for this, including inadequate immunosuppression, either because of underuse of immunosuppressive agents or drug interactions that lead to inadequate or inconsistent immunosuppressive drug levels
Another potential explanation invokes immune system dysregulation and heterologous immunoreactivity in response to HIV and other chronic infections .
HIV-HBV co-infection, in the setting of passive prophylaxis with hepatitis B immunoglobulin and antiviral therapy, both graft and patient survivals range from 85 to 100% after 3–5 years of follow-up .
With reported complications of graft thrombosis, rejection, and bacterial infections, including fatal sepsis .
Based on these findings, pancreas transplantation can be successful in HIV-infected patients, but additional experience is needed.
A case series of three patients from the United States, as well as a small retrospective cohort study demonstrated feasibility of this approach in persons with advanced lung diseases.
Selection candidates
HIV providers should refer any patient with end-organ damage and stable HIV to centers well versed in HIVþ organ transplantation.
Centers may vary in their candidacy requirements for transplantation, but updated guidelines recommend that, regardless of the organ transplanted, patients have undetectable HIV viral load, known compliance with ART, no evidence of active opportunistic infections or HIV-associated malignancy, and the ability to have close follow-up for immunosuppression, drug level monitoring and management.
Candidates must have demonstrated adherence to ART as evidenced by viral suppression, a notable exception being persons with ALD who may not be able to tolerate ARTand exhibit viremia.
In this situation, the HIV provider must be able to predict viral suppression with an antiretroviral regimen post-transplant.
HCV-coinfected persons for liver transplant, it is important to weigh factors predictive of liver allograft loss such as low BMI (<21 kg/m2 ), need for combined liver–kidney transplant, and HCVþ donor organs.
Anti rejection therapy
The best immunosuppressive regimen to use for patients with HIV is unknown.
Regimens should be individualized to patients based on the organ transplanted, immunologic risk, renal and liver function, and ART regimen.
Induction immunosuppression is not required in the majority of liver transplant recipients.
In addi!on to no ac!ve opportunis!c infec!ons, pa!ents with progressive mul!focal leukoencephalopathy, chronic intes!nal cryptosporidiosis, visceral Kaposi’s sarcoma (KS), and primary central nervous system lymphoma were excluded in the ini!al U.S mul!center HIV transplant (HIV-TR) trial.
Persons with liver failure and hepatocellular carcinoma, mee!ng center specific criteria, can be considered for transplanta!on.
And data regarding use of induction agents in transplant of other organ types in HIVþ persons is lacking.
For HIV-infected transplant recipients, the best maintenance immunosuppressive regimens have not been established.
In-vitro studies have shown that HIV-1 transcription can continue in the setting of sirolimus, which, in the setting of immune system activation from transplantation may result in diminishing the HIV reservoir
Medical management
Close attention is needed to ensure adequate levels of antirejection drugs in transplant recipients, as both low and high levels can have dire consequences.
3A4 (CYP3A4) enzyme, alter the pharmacokinetics of immunosuppressive medications, including the calcineurin inhibitors and mTOR inhibitors, resulting in drastic alterations in doses and dosing schedules of these drugs.
This increases the potential for inconsistent immunosuppressive levels that may place the patient at risk of rejection or, alternatively, supra-therapeutic levels that result in toxicity .
Studies in renal transplant recipients have shown poor outcomes for patients on protease inhibitor-based regimens.
In the early post-transplant period, in the setting of allograft rejection, and when immunosuppressive therapy is changed, more frequent monitoring of CD4 þ cell counts and HIV viral load is warranted.
As of December 2018, 100 HIVþ persons have undergone deceased donor organ transplants in the
If donor with known HIV infection prior to donation
But proceed with caution if donor has known infection and detectable virus, due to concerns for ART nonadherence, virologic failure, and antiviral resistance.
ART history is especially helpful in this circumstance.
Opportunistic complication No invasive of invasive opportunistic complication
Transplant and other care providers should acquire and review prior testing results before transplant.
An unexpected benefit of HOPE Act is the utilization of organs that may have otherwise been discarded due to having false-positive HIV test results [109–111], with almost 50% of HOPE-allocated organs coming from donors with false-positive testing.
Very few cases of HIV-to-HIV living donor transplantation have been reported in the literature.
When evaluating potential candidates for donor nephrectomy, the assessment must include identification HIV-specific risk factors for development of ESRD such as low CD4 þ cell count and HCV coinfection in addition to other conditions that generally exclude persons from donation.
Only two living donor kidney transplants have been reported, one with long-term good outcomes in both the donor and recipient.
There is one reported case in the literature involving a partial living donor liver transplant from a South African HIVþ mother to her critically ill HIV-negative child with biliary atresia.
Treated recipient since the time of transplant, and there was initial seroconversion in the recipient, the child’s HIV antibody-antigen status declined to lowreactive during the first year following the transplant.
Findings
When examining data from the U.S Scientific Registry of Transplant Recipients and Organ Procurement and Transplantation Network, even when placed on the waitlist, PWH remain on dialysis for longer durations before transplant listing, have longer waitlist times for organ offers and transplant, are less likely to remain active on the list, and have 18% lower likelihood of undergoing kidney transplantation when compared with their noninfected counterparts .
Conclusion
Kidney and liver transplantation are the standard of care for HIV-infected persons with end-stage kidney and liver diseases.
Encouraging results with transplantation of other organ types, including pancreas, heart, and lung suggest that persons with other advanced organ disease should be referred to centers experienced in performing these transplants.
The introduction of DAAs for hepatitis C, with their high efficacy in the post-transplant setting, promise to improve outcomes in coinfected organ recipients.
Finally, with implementation of the HOPE Act,PWH can donate organs to HIV infected persons waiting for kidney and liver transplants under a research setting.
HIV providers should play an active role in referring appropriate patients for transplantation, educating patients regarding transplant outcomes and the potential risks and benefits of pursuing HIV-positive organs for transplant, and ensuring frequent monitoring of HIV infection after transplantaion
Thanks
Summarized this article III
Introduction
· HIV infection is now a chronic disease due the availability of antiretroviral therapy which caused a significant reduction in mortality associated with HIV/AIDs
· The new problems in person living with HIV (PWH) are cardiovascular diseases, liver diseases, and side effects related to antiretroviral therapies. Therefore, PWH are now at-risk organ damage and failure. How ever, before the age of antiretroviral therapy, transplantation was absolute contraindication for HIV but now the understand has improve significantly.
· HIV Organ Policy Equity (HOPE) Act stated that, Person living with HIV (PWH) can now be either donor or recipient for the seek of treatment a failed organ.
Status of organ transplantation by organ type
Kidney
· HIV related kidney diseases account for m 0.5 to 1.5% of dialysis treatment in USA
· Causes of ESKD: HIV-associated Nephropathy (HIVAN) was historical, FSGS, DM, co-infections with HBV or HCV & Drug induced
· Transplantation outcomes: Stock et al. observational study of 150 patients and revealed 1- and 3-years allograft & patient survivals were 90% and 74% and 95% and 88% respectively. They had more bacterial infections, delayed graft function, and rejection rates.
· Transplantation is associated with better outcomes compared dialysis
· Challenges: PWH faces barriers for referral, enlisting for transplantation, and some transplant centers in USA are still considering HIV is contraindicated for transplantation
Liver
· Liver disease is the third leading cause of death in PWH
· Causes: co-infection with HBV/HCV, antiretroviral therapy, immune reconstitution syndrome, alcohol, and non-HIV factors.
· Outcomes: Allograft and patient survival were 85% to 100% after 3 to 5 years of PWH transplanted due to HIV/HBV co-infection. HIV/HCV versus HCV control 1,3-, and 5-years allograft survivals were 52 to 86%, 45 to 60%, 31 to 45% versus 57 to 88%, 50 to 62%, 33 to 58% respectively.
· Challenges: the same as renal transplantation
Pancreas
· This may be successful in future but at the moment the experience is very limited
Heart
· Although heart transplantation in PEH is not contraindicated the procedure is not commonly carried on
· Outcomes: recent data showed, 1- and 5-years survival are between 86 to 90% and 64 to 67%, coronary artery vasculopathy was the important complications occurring in up to 30% as well as higher rejection rates from 39 to 67% after one year compared to non-HIV individual. Up to 50% required mechanical circulatory support before transplantation
Lung
· Data from case reports and case series demonstrated the feasibility of this procedure in PWH suffering from advanced pulmonary disease.
Clinical management of HIV-infected Organ transplant candidates and recipient
· Recommendation for selection of the candidates:
1. Virally suppressed
2. Compliant patient
3. Absence of opportunistic infections
4. Absence of HIV-associated Malignancy
5. CD4 >= 200 cell/microliter
6. Ability to come for follow up
· HIV to HIV living donor transplantation: few cases on the literature
1. Donor must be evaluated well and HIV specific risk factors for ESKD ruled out
2. APLO1 haplotype screening? is not clear but those with African American with HIV and high risk APLO1 genotype are at risk for HIVAN and FSGS
3. HIV +ve donor must avoid drugs like TDF and NSAIDS after nephrectomy
· HIV positive donor to HIV negative recipient
1. At the moment, this is illegal practice in USA
2. One case report from South Africa: HIV positive mother ton her terminally ill daughter with biliary atresia. The daughter became positive but her HIV antibodies reduced significantly to undetectable level during the first year after transplantation
Conclusion
· The rate of organ failure is now increasing in PWH and transplantation is best form therapy in this kind of situation. Transplantation had been done successfully in kidney and liver failure but more data are needed for other organs including heart, pancreas, and lung. We also want to understand the reasons for barriers to transplantation for PWH through a well design study.
Thanks
Kidney
●With improvements in and earlier initiation of ART, HIVAN) rates have declined
●Coinfections with (HCV) and (HBV) increase risk for kidney failure
● several ART such as tenofovir, abacavir, indinavir, ritonavir-boosted lopinavir, ritonavirboosted atazanavir, are associated with nephrotoxicity and/or metabolic complications, including diabetes and dyslipidemias
●Once on dialysis, PWH have lower survival rates, Because of this, PWH are increasingly undergoing RTX
○Stock et al. reported the outcomes of 150 HIV-infected patients after kidney transplantation; 1 and 3-year kidney allograft and patient survival estimates were 90.4 and 73.7 and 94.6 and 88.2%, respectively.
○ all patients had viral suppression
CD4cell counts at least 200 cells/ml prior to transplant
○ combination ART and posttransplant anti-infective prophylaxis HIV control was excellent, and few opportunistic infections were encountered.
○, Bacterial infections were observed with increased frequency in HIV recipients who were treated with the (ATG) or coinfected with HCV.
○In addition, PWH experienced high rates of delayed allograft function
○HIV recipients experienced allograft rejection rates two to three times higher
●CCR5D3 homozygous persons have demonstrated less rejection and better allograft survival after liver and kidney transplantation
● A recent survey found that 16.9 and 28.1% of responding U.S. transplant programs still considered HIV as an absolute or relative contraindication to transplantation, respectively
● PWH have 18% lower likelihood of undergoing kidney transplantation when compared with their noninfected counterparts.
Liver
■ liver disease has become the third leading cause of death in PWH
■ The estimated global prevalence of chronic HCVand HBV coinfections are 2.4 and 6.1%, respectively,
■ ALD can also result from ART whether caused by direct hepatotoxicity, hypersensitivity reactions, mitochondrial toxicity, steatosis and/or steatohepatitis, or immune reconstitution phenomena
■hepatocellular carcinoma can further complicate the course of ALD
■HIV considered an absolute or relative contraindication by 28.1 and 31.6% of surveyed U.S. transplant centers, respectively
■The outcomes of liver transplantation in PWH vary by the reason for transplant
■ in the setting of passive prophylaxis with hepatitis B immunoglobulin and antiviral therapy, both graft and patient survivals range from 85 to 100% after 3–5 years of follow-up
■Estimates of 1, 3, and 5-year graft survival for these coinfected patients range from 52 to 86, 45 to 60, and 31 to 45%, respectively,
Pancreas
◇in 2018, 836 simultaneous pancreas-kidney transplants were performed in the United States.
◇additional experience is needed.
Clinical management of HIV-infected organ transplant candidates and recipient
●CD4cell counts at least 200 cells/ml are recommended for transplantation of all organs with the exception of liver, where the threshold for transplantation is CD4cell count more than 100 cells/ml,
●Candidates must also have demonstrated adherence to ART
●HCV should not be considered an exclusion factor for transplant.
●if treatment can be safely delayed, the option of utilizing HCVorgans followed by post-transplant DAA treatment increases the pool of organs available for transplant.
Antirejection therapy
○The best immunosuppressive regimen to use for patients with HIV is unknown.
○In the U.S. NIH observational trial, persons who received ATG as opposed to basiliximab, experienced significant, prolonged lymphocyte depletion, more frequent and severe infections, and increased risk for allograft loss
○Tacrolimus is associated with lower rejection rates
○Mycophenolate, is a very common component of maintenance immunosuppression.
○Sirolimus is known to have anti-HIVeffects through downregulation of CCR5,
Medication management
●Close attention is needed to ensure adequate levels of antirejection drugs
● Protease inhibitors, via inhibition of cytochrome P450 3A4 (CYP3A4) enzyme, alter the pharmacokinetics of immunosuppressive medications such as the calcineurin inhibitors (tacrolimus, cyclosporine A) and mTOR inhibitors (sirolimus, everolimus),
● protease inhibitor-based regimens increases the potential for inconsistent immunosuppressive levels that may place the patient at risk of rejection or, alternatively, supra-therapeutic levels that result in toxicity
●Studies in renal transplant recipients have also shown poor outcomes for patients on protease inhibitor-based regimens.
●those receiving protease inhibitor-based regimens had a 1.8-fold higher risk of allograft loss and a 1.9-fold higher risk of mortality when compared with non-protease inhibitor regimens
●Raltegravir, dolutegravir, and bictegravir are completely or primarily metabolized through the uridine diphosphate glucuronosyltransferase 1A system, resulting in clinically insignificant interactions with the calcineurin inhibitors.
●HIV clinicians should avoid, when possible, agents that may compromise organ function, such as use of tenofovir disoproxil fumarate after kidney transplant or abacavir after heart transplantation.
● In the early post-transplant period, in the setting of allograft rejection, and when immunosuppressive therapy is changed, more frequent monitoring of CD4cell counts and HIV viral load is warranted.
HIV-to-HIV transplantation
■ In 2008, four HIVto HIVrenal transplants were successfully performed
■ of the 51 patients transplanted with HIVorgans, the 1, 3, and 5-year patient survivals were 87, 87, and 84% while 1, 3, and 5-year graft survivals 96, 93, and 79%
■ A major concern is the potential consequences of superinfection with the donor HIV strain
■Other risks include transmission of opportunistic infections and poor organ quality
ART history,
HIV genotypic testing,
CD4cell counts,
HIV viral load results,
and history of opportunistic complications,
■ HIV African American persons with high-risk apoprotein L1 (APOL1) genotypes are at risk for development HIVAN and focal segmental glomerulosclerosis
■HIVdonors should avoid nephrotoxic ART(suchas tenofovir) in addition to agents such as nonsteroidal anti-inflammatory agents.
Thanks, Ghalia
Introduction
Over the past decade accumulating evidence has established kidney and liver transplantation as a standard of care for PWH with ESKD or liver disease.
Though the evidence for pancreas, heart and lung are promising more data is required.
With passage of the HOPE act, PWH can register as donors thus enlarging the donor pool.
With introduction of HAART the rates of HIVAN have decreased but other causes of ESKD have increased.
PWH on dialysis have lower survival rates than the uninfected population.
Several complications were reported by Stocke et al in a prospective observational trial of 150 KTX PWH:
There was increased incidence of bacterial infections in person induced with lymphocyte depleting agent and those co-infected with HCV
PWH had higher rates of DGF
Allograft rejections rates were twice higher in PWH than general transplant population and they were a predictor of allograft failure.
Allograft rejection has been proposed due to inadequate immunosuppression either due to underuse of the IS or drug interactions that lead to inadequate drug levels.
Liver disease is the 3rd leading cause of death in PWH.
Those with viral hepatitis, HOV co-infection increases the risk for progressive and advanced liver disease.
Selection of candidate
Should have undetectable viral load.
Should be compliant on the cART.
Should have no evidence of opportunistic infection or HIV associated malignancy.
Should be able to be closely followed up for drug level monitoring and management.
Should have at least CD4 counts of 200cells/ul for all organs except liver where the threshold is 100cells/ul.
Anti-rejection therapy
The best IS (induction and maintenance )is not known and should be tailored as per individual patient.
Tacrolimus associated with lower rejection rates thus is the preferred CNI.
Sirolimus has some anti-HIV effect through down regulation of CCR5, and blockade of mTOR.
Medical management
Protease inhibitors are potent inhibitors of cytochrome P450 thus alter the pharmacokinetic of CNIs and mTOR inhibitors.
NNTRI have differing potential of induction of CYP3A4.
Intergrase strand transfer inhibitors (INSTI) are favoured for they have insignificant interactions with CNIs.
HIV+ to HIV+ transplantation
Major potential consequences:
Super infection with donor HIV strain
Acquisition of antiviral resistance or dual/mixed tropic virus
Transmission of latent or unrecognised opportunistic infections
Thus transplant specialist must make attempts to acquire as much of donor HIV history that includes ART history, HIV genomic testing, viral load and history of opportunistic infections.
Very few HIV+ to HIV+ living donation have been reported.
When evaluating living donation donors assessment must include specific HIV risk factors- low CD4 counts, HCV co-infection.
Post-nephrectomy the donors should avoid nephrotoxic drugs eg TDF.
HIV+ to HIV- is currently uncharted waters with significant medical and ethical concerns and currently it is illegal in the USA.
Thanks.
Introduction
-The life expectancy of persons with HIV has been increased with the current availability of antiretroviral therapy.
– The virus and ART drugs may increase the risk for organ dysfunction and, ultimately, organ failure
– SOT are increasingly expanded in PWH as it is a life-saving therapy in those with organ failure , this has opened and expanded opportunities for PWH to donate and receive organs
Status of organ transplantation by organ type
Kidney
– In US 800 PWH are diagnosed with ESRD and 0.5–1.5% of dialysis population and are PWH
– HIV associated nephropathy (HIVAN) rates have declined.
– However, other causes of renal failure; FSGS, DM, HTN remain prominent, also the risk increase with coinfections with HCV & HBV.
– Several ART associated with nephrotoxicity and/or metabolic complications, which eventually lead to ESRD.
– Transplantation providing a clear survival benefit over renal replacement therapy.
– Pre- transplant viral suppression and the use of combination ART and posttransplant anti-infective prophylaxis improved the outcome.
– The risk of bacterial infections increased if ATG used or coinfected with HCV.
– PWH experienced higher rates of DGF & allograft rejection.
– PWH remain on dialysis for longer durations before transplant listing,have longer waitlist times, and have 18% lower likelihood of undergoing kidney transplantation
Liver
– liver disease is the 3rd leading cause of death in PWH.
– The prevalence of chronic HCVand HBV coinfections are 2.4 and 6.1%
– The risk of advanced liver disease (ALD increased in PWH secondary to multiple contributing factors
– The outcomes of liver transplantation in PWH variable.
Pancreas
Only few reported cases for simultaneous pancreas-kidney transplants with mixed, additional experience is needed.
Heart
-HIV-associated cardiomyopathy was seen in the pre-ART era; CAD is now a rising concern in PWH.
-With aging the need for heart transplantation are likely to increase.
– The risks of post-transplant vasculopathy are not any higher than HIV uninfected recipients
– They have higher rates of rejection.
Lung
There is a paucity of lung transplantation reports in PWH.
Clinical management of HIV-infected organ transplant candidates and recipient
Selection of candidates:
– Any PWH has organ failure and stable HIV to should be referred to experienced transplant center.
– Undetectable HIV viral load.
– CD4+ cell count > 200 cells/μl (3 months prior to Tx) for SOT except for liver CD4+ cell count > 100 cells/μl
– Documented adherence with ART
– No evidence of active opportunistic infections or HIV-associated malignancy.
– The ability to have close follow-up for IS, drug level monitoring and management.
– Absence of chronic wasting or severe malnutrition
– HBV or HCV infection if no advanced fibrosis/cirrhosis (for organ types other than liver)
Antirejection therapy
– The best IS regimen in PWH is unknown, it should be individualized.
– Induction therapy is not required in the majority of liver transplant recipients.
– In KTR, studies showed ATG leads to prolonged lymphocyte depletion, more severe infections, and increased risk for allograft loss while other studies reported lower rejection and infection rates with ATG
– Maintenance IS: Tacrolimus and Mycophenolate, steroids use benefit should be weighed against the long-term effects of this agent.
– Sirolimus has anti-HIV effects.
Medication management
-Protease inhibitors, inhibit cytochrome P4503A4 enzyme; alter CNI & mTOR levels ,does adjustment is required.
In liver Tx; PI regimens were associated with episodes of ARF from high cyclosporine levels
In KTR using PI have 1.8-fold higher risk of allograft loss and a 1.9-fold higher risk of mortality
-NNRT inhibitors have differing potential for induction of CYP3A4.
-INSTI is a favored therapies with clinically insignificant interactions.
Clinical monitoring and care of HIVR persons before and after organ transplantation
-Pre-transplant phase: HIV specialists along with transplant team cooperate to optimize HIV therapy (ideally preTx), with aim to decrease toxicities and drug interactions while maintaining viral suppression.
-Post-transplantation, kidney function fluctuate and frequent dose adjustments may require & to avoid any drug that cause direct organ toxicity (tenofovir disoproxil fumarate in KTR and abacavir after heart Tx.)
-Regular and frequent monitoring of CD4 cell counts and HIV viral load is warranted.
– The use of anti-microbial prophylactic; PCP.
HIV-to-HIV transplantation
-Can be considered in the setting of limited access to dialysis, decreased organ availability, and increased HIV among brain-dead donors
-Good reported outcome: 5-year patient survivals were 87, 87, and 84% while 1, 3, and 5-year graft survivals 96, 93, and 79%.
-Risk of risks include transmission of latent or unrecognized opportunistic or donor HIV strain.
-In LD HIV transplantation; donor should be assessed for risk factors for development of ESRD (low CD4, HCV coinfection & other general conditions exclude donation)
– African American HIV persons with APOL1 genotypes are at risk for development HIVAN and FSGS, APOL1 screening utility to be determine.
-Post-nephrectomy, HIV donors should avoid nephrotoxic ART & NSAID.
HIV positive organs into uninfected recipients
Currently illegal with significant medical and ethical concerns.
Thanks
Summary
Introduction
This article focusses on the organ transplant in HIV patients, and the outcome of such transplant, along with the post transplant management of this specific population.
Discussion
Transplantation by type
Immunosuppression
HIV to HIV transplantation
Conclusion
Kidney and liver transplant can be done with good results in HIV positive recipients. The management of IS and antiretroviral therapy along with close monitoring forms a major part contributing to the outcome of the transplant. Standardization of immunosuppressive regimen has not been possible as yet and it is imperative to find out the best regimen for each recipient on an individual basis with close monitoring. Although HIV positive donors cannot be used for HIV negative recipients, in the case of a crucial life or death situation, it has been attempted and found to be manageable within the first year post transplant. Further studies are essential in this regard to maximize the donor pool. Co infection with HBV and HCV is a major concern in these recipients and adequate dosage of lifelong prophylaxis may be needed in naive recipients. Educating the patient with regards to adherence to medication is an essential part of making sure of good outcome. Frequent monitoring and follow up makes the whole process smoother and more successful in the long term.
I like you emphasis on adherence to medications in a transplant patient with HIV
Status of organ transplant by organ type
Kidney:
Liver:
Pancreas:
Heart:
Lung:
Selection of candidates:
Anti-rejection therapy:
Monitoring of HIV+ patient before & post transplantation:
HIV to HIV transplantation:
I like your clinical approach and well-structured extensively detailed summary quoting a number of trials related to HIV and various types of transplants
1- After introduction of antiretroviral therapy ART, the possibility of transplantation of persons with HIV PWH and possibility of accepting HIV donor are likely to occur.
2- With introduction of ART, the incidence of HIVAN declines but still PWH have possibility of FSGS, DM and HTN as a causes of renal insult.
3- Also in PWH there is high incidence of co-infection by HCV , HBV with adding risk to renal affection.
4- Most of ART is associated with multiple side effects like DM, dyslipidemia, nephrotoxicity that may leads to ESRD.
5- PWH on dialysis have high mortality rate compared to non-HIV patients, so increasing needs for transplantation.
6- After transplantation, ART together with prophylactic anti-infective therapy, and CD4 cell counts at least 200 cells/ml before transplantation , all these leads to good control of HIV.
7- Bacterial infection can occur in the patient used ATG or if there is co-infection with HCV, also graft rejection is more in HIV patient than non-HIV which may be related to under immunosuppression or inadequate adjustment of the dose or multiple drug interaction.
8- HIV patients remains on dialysis and on the waiting list longer than non-HIV patients.
9- HIV increase the risk of liver disease and its progression because of co-infection by HCV, HBV and due to adverse effects of ART like hepatotoxicity and mitochondrial toxicity in addition to non-HIV related factors.
10- Liver transplant in PWH is varied according to the reason of liver failure.
11- Pancreatic transplantation can be done in PWH but still has multiple complications.
12- Clinical management of HIV-infected organ transplant candidates and recipient:
a- Selection of candidates:
1- Meet transplant center-specific eligibility for organ transplantation
2- CD4+ cell count > 200 cells/µl during 3 months prior to transplantation for kidney, pancreas, heart and lung candidates
3- CD4+ cell count > 100 cells/µl during 3 months prior to transplantation for liver candidates only
4- Undetectable plasma HIV viremia (unless unable to tolerate antiretroviral therapy prior to liver transplant) With liver failure, patients may not tolerate ART; in this setting care providers must be able to predict HIV suppression with introduction/reintroduction of ART post-transplant
5- Documented adherence with stable antiretroviral treatment regimen
6- Absence of active opportunistic infection and malignancy. In addition to no active opportunistic infections, patients with progressive multifocal leukoencephalopathy, chronic intestinal cryptosporidiosis, visceral Kaposi’s sarcoma (KS), and primary central nervous system lymphoma were excluded in the initial U.S. multicenter HIV transplant (HIVTR) trial. Persons with liver failure and hepatocellular carcinoma, meeting center specific criteria, can be considered for transplantation. Treated cutaneous KS and anal carcinoma in situ were not exclusions in the initial HIV-TR trial. All other treated malignancies with disease-free intervals are considered per center-specific policies
7- Absence of chronic wasting or severe malnutrition
8- Hepatitis B or C infection if no advanced fibrosis/cirrhosis (for organ types other than liver)
9- Access to immunosuppressive agent therapeutic drug monitoring. Because of significant drug-drug interactions, persons on protease inhibitor- and some non-nucleoside reverse transcriptase inhibitor-based regimens require ready access to laboratories that perform therapeutic drug monitoring for calcineurin inhibitors with efficient turnaround times.
10- Ability to regularly follow up with HIV care providers.
b- There is no standard induction and maintenance immunosuppressive medication regimen, it is always individualized but it was found that tacrolimus decrease rejection episodes and MMF with long term prednisolone are commonly used in HIV patients and also sirolimus has anti-HIV properties
c- Close monitoring of trough levels is very important to guard against rejection and toxicity because of drug-drug interactions.
d- Post transplant follow up of HIV patient is very important for early detection and management of any complications.
13- HIV-to-HIV transplantation:
a- These transplants were performed in the setting of limited access to dialysis, decreased organ availability, and increased HIV among brain-dead donors.
b- Certain data is required from HIV donor such as ART history, HIV genotypic testing, CD4 cell counts, HIV viral load results, and history of opportunistic complications, so that donor suitability can be ascertained.
c-
Pointwise reply is fine but no 10 (ability to follow-up) be followed by 11 rather than 13 (HIV to HIV). Please use headings and sub-headings to make easier to read your write-up. Please use bold or underline to highlight headings and sub-headings.
Introduction
Causes for rejection:
Transplant eligibility
• CD4+ cell count > 200 cells/µl during 3 months prior to transplantation for kidney, pancreas, heart and lung candidates
• Undetectable plasma HIV viremia
• Documented adherence with stable antiretroviral treatment regimen
• Absence of active opportunistic infection and malignancy
• Absence of chronic wasting or severe malnutrition
• Hepatitis B or C infection if no advanced fibrosis/cirrhosis (for organ types other than liver)
• Access to immunosuppressive agent therapeutic drug monitoring
• Ability to regularly follow up with HIV care providers
Medication management:
HIV to HIV transplant
I like your well-structured detailed summary. I appreciate your comment superinfection with HCV in a HIV patient, and superinfection with another type of genotype of HIV in a HIV positive recipient.
Typing whole sentence in bold or typing in capitals amounts to shouting.
This study is a narrative review of solid organ transplantation in patients living with the HIV virus.
Introduction
HIV is a virus that generates human immunodeficiency by reducing the levels of CD4 cells and compromising the cellular response, evolving into AIDS. During the last four decades, it has spread across continents, but disease control and knowledge of immunology have made it possible to perform transplants in this population.
Kidney
In the US, the diagnosis of end-stage renal disease living with HIV can be due to virus-associated nephropathy (high viral loads leading to glomerular damage) or as a result of antiretroviral medications (mainly Tenofovir fumarate and protease inhibitors).
After transplantation, the outcome has been favorable and with clear benefits. As all patients had serum CD4 levels greater than 200 with an undetectable viral load, few opportunistic infections occurred.
Co-infection with HCV and the use of rATG presented greater complications. Acute rejection was more frequent in this group when compared to the HIV-negative group.
Liver
HCV and HBV co-infections, drug interactions, drug hepatotoxicity, metabolic changes and hepatic steatosis, immune reconstitution, and mitochondrial toxicity are some of the mechanisms of both the virus and its treatment. There are still many centers that consider contraindications for the transplant of this organ.
Treatment of Hepatitis B can occur with similar drugs, but it is important in Hepatitis C to have disease control with antivirals that act directly against the virus and its sustained viral suppression to proceed properly with the transplant.
Pancreas
Only ten cases were reported in the literature, in the context of transplantation associated with the kidney, with a lot of associated immunosuppression and little data for the study.
Heart
HIV, metabolic disease, and its drugs can interfere and evolve with cardiomyopathy. They present a higher risk of acute rejection when compared to the HIV-negative population.
Lung
There is little data on this modality.
Patient selection
– Appropriate transplant center
– Serum CD4 above 200 cells for 3 months
– Serum CD4 above 100 cells for 3 months may be considered for liver transplantation
– Negative viral load for HIV
– Adherence to treatment
– Absence of opportunistic infections and malignancy
– Severe malnutrition must be corrected (BMI < 21 or > 35)
– Severe liver disease may exclude from list
– Joint follow-up with the Infectology team
Anti-rejection therapy
There is no well-defined drug of choice. We are aware of the limitation of lymphocyte-depleting drugs such as rATG that can decrease CD4 and induce AIDS, but compared to Basiliximab it still seems to be the best drug. An immunosuppression regimen with MMF tacrolimus and corticosteroids should be considered.
Tacrolimus appears to decrease HIV transcription just as mTOR decreases CCR5 exposure.
Use of Medication
Drug interactions, serum measurement of their values, risk of inadequate immunosuppression, and risk of inadequate rejection. Integrase inhibitors seem to be the most suitable drugs related to HIV control.
Protease inhibitors have a lot of drug interactions with calcineurin inhibitors, statins and other drugs. Negative viral load is mandatory, as well as serum levels of immunosuppressants.
HIV Transplant for HIV
They occurred for the first time in South Africa in the context of limited dialysis, low organ availability, and high rates of HIV. Good response and viral control were promising, but there is a need for a broad study, profile of antiretroviral resistance (genotyping), serum CD4 values, viral load, and complications due to opportunistic infections.
Conclusion
Kidney and liver transplantation are the treatment of choice for patients living with HIV who have failed these organs. These results encourage the possibility of transplantation to other organs in this context.
I like your well-structured detailed summary. I appreciate your comment regarding relation of drug resistance and genotyping
Thank you, Professor
Organ transplantation in persons with HIV:
Introduction;
-With current antiretroviral therapy, the lifespan of newly diagnosed persons with HIV (PWH) approaches that of uninfected persons.
-However, metabolic abnormalities related to both the disease and the virus itself, along with comorbidities of aging, have resulted in end-organ disease and organ failure as a major cause of morbidity and mortality.
-Solid organ transplantation is a life-saving therapy for PWH who have organ failure, and the approval of the HIV Organ Policy Equity Act has opened and expanded opportunities for PWH to donate and receive organs.
-The most evidence in support of transplantation in this population comes from kidney followed by liver transplantation: however, growing numbers of persons have undergone pancreas, heart, and lung transplantation.
Kidney
-In the United States where approximately 800 PWH are diagnosed with end-stage renal disease (ESRD) annually, it is estimated that 0.5–1.5% of the United States dialysis population is made up of PWH.
-With improvements in and earlier initiation of ART, HIV associated nephropathy (HIVAN) rates have declined, but in antiretroval-treated PWH, other causes of renal failure such as focal segmental glomerulosclerosis, diabetes mellitus, and hypertension remain prominent.
-Coinfections with hepatitis C virus (HCV) and hepatitis B virus (HBV) increase risk for kidney failure.
-Importantly, several antiretroval agents, such as tenofovir, abacavir, indinavir, ritonavir-boosted lopinavir, ritonavir, boosted atazanavir, and potentially other boosted protease inhibitors, are associated with nephrotoxicity and/or metabolic complications, including diabetes and dyslipidemias, which can ultimately contribute or lead to the development of chronic kidney disease and ESRD.
-PWH experienced high rates of delayed allograft function (i.e. the need for hemodialysis in the immediate post-transplant period), although, ultimately, this did not appear to be predictive of graft failure.
-There is observed high rates of allograft rejection following kidney transplantation with several proposed mechanisms for this, including inadequate immunosuppression, either because of underuse of immunosuppressive agents or drug interactions that lead to inadequate or inconsistent immunosuppressive drug levels.
Liver;
-In the era of highly effective ART, liver disease has become the third leading cause of death in PWH.
-PWH are at risk for end-stage liver disease through a variety of mechanisms. The estimated global prevalence of chronic HCV (2.4%) and HBV (6.1%) coinfections, although prevalence may differ regionally or by risk for acquisition.
-ALD can also result from ART whether caused by direct hepatotoxicity, hypersensitivity reactions, mitochondrial toxicity, steatosis and/or steatohepatitis, or immune reconstitution phenomena.
-Finally, hepatocellular carcinoma can further complicate the course of ALD.
Pancreas;
–In 2018, 836 simultaneous pancreas-kidney transplants were performed in the United States,this procedure is not commonly performed in type 1 diabetic PWH.
-Outcomes have been mixed, with reported complications of graft thrombosis, rejection, and bacterial infections, including fatal sepsis , based on these findings, pancreas transplantation can be successful in HIV-infected patients, but additional experience is needed.
Heart;
-PWH are prone to both cardiac diseases associated with aging, as well as those associated with the chronic immune activation state of HIV and metabolic effects of ART.
-HIV-associated cardiomyopathy was seen in the pre-ART era; coronary artery disease is now a rising concern in PWH.
-HIV is no longer considered an absolute contra-indication to advanced heart failure therapies, including heart transplantation , but is uncommonly performed.
Lung;
-In 2018, 2530 lung and 32 heart/lung transplants were performed in the United States.
-In the 2014 updated ISHLT guidelines, HIV infection has moved from an absolute to a relative contraindication to lung transplantation.
Selection of candidates;
-Updated guidelines recommend that, regardless of the organ transplanted, patients have undetectable HIV viral load, known compliance with ART, no evidence of active opportunistic infections or HIV-associated malignancy, and the ability to have close follow-up for immunosuppression, drug level monitoring and management.
-CD4+ cell counts at least 200 cells/ml are recommended for transplantation of all organs with the exception of liver, where the threshold for transplantation is CD4+ cell count more than 100 cells/ml, with the rationale that ALD and portal hypertension lead to splenic sequestration of white blood cells, including lymphocytes.
Antirejection therapy;
-The best immunosuppressive regimen to use for patients with HIV is unknown. Regimens should be individualized to patients based on the organ transplanted, immunologic risk, renal and liver function, and ART regimen.
-Based on this, choice of induction agent should be individualized. Induction immunosuppression is not required in the majority of liver transplant recipients
-For HIV-infected transplant recipients, the best maintenance immunosuppressive regimens have not been established. Tacrolimus is associated with lower rejection rates, and for this reason, has emerged as the preferred calcineurin inhibitor.
-Mycophenolate, an antiproliferative agent, is a very common component of maintenance immunosuppression. Although long-term maintenance prednisone therapy reduces risk for rejection, the benefits of its used should be weighed against the long-term effects of this agent.
Medication management;
-Protease inhibitors, via inhibition of cytochrome P450 3A4 (CYP3A4) enzyme, alter the pharmacokinetics of immunosuppressive medications, including the calcineurin inhibitors (tacrolimus, cyclosporine A) and mTOR inhibitors (sirolimus, everolimus), resulting in alterations in doses and dosing schedules of these drugs.
-This increases the potential for inconsistent immunosuppressive levels that may place the patient at risk of rejection or, alternatively, supra-therapeutic levels that result in toxicity.
-Conversely, non-nucleoside reverse transcriptase inhibitors have differing potential for induction of CYP3A4.
-Although protease inhibitors have fallen out of favor in the transplant setting, non-boosted integrase strand transfer inhibitors (INSTI) have emerged as favored therapies.
HIV-to-HIV transplantation;
-In 2008, four HIV+ to HIV+ renal transplants were successfully performed in Cape Town, South Africa.
-These transplants were performed in the setting of limited access to dialysis, decreased organ availability, and increased HIV among brain-dead donors.
-Recent follow up data published by the same group notes that of the 51 patients transplanted with HIV+ organs, the 1, 3, and 5-year patient survivals were 87, 87, and 84% while 1, 3, and 5-year graft survivals 96, 93, and 79%.
-As of December 2018, 100 HIV+ persons have undergone deceased donor organ transplants in the United States with organs allocated under the HOPE Act.
-With implementation of the HOPE Act, PWH can donate organs to HIV infected persons waiting for kidney and liver transplants under a research setting.
Conclusion;
– Kidney and liver transplantation are the standard of care for HIV-infected persons with end-stage kidney and liver diseases.
-Encouraging results with transplantation of other organ types, including pancreas, heart, and lung suggest that persons with other advanced organ disease should also be referred to centers experienced in performing these transplants.
-The availability of INSTI, with minimal impact on immunosuppressive drug levels, has greatly simplified the post-transplant management of the HIV+ organ recipient.
-The introduction of DAAs for hepatitis C , with their high efficacy in the post-transplant setting, promise to improve outcomes in coinfected organ recipients.
I like your clinical approach and extensively detailed summary related to HIV and various types of transplants.
III. Organ transplantation in persons with HIV
Please summarize this article.
Current status
Liver
Pancreas
Heart
Lung
Clinical management of HIV-infected organ transplant candidates and recipient
Selection of candidates:
Antirejection Therapy
Medication management
Clinical monitoring & care of HIV+ve persons before & after TX
HIV-to-HIV transplantation
Conclusions
I like your clinical approach and extensively detailed summary related to HIV and various types of transplants.
Introduction:
Antiretroviral treatment has made HIV a chronic disease and reduced overall and AIDS-related mortality. With longer life expectancies and an aging population, prevalent medical comorbidities, including coronary artery disease and nonalcoholic steatohepatitis, are becoming major sources of morbidity and death in HIV-positive people. The metabolic side effects of the virus and antiretrovirals increase the probability of organ malfunction and failure.
Kidney:
PWH transplantation improves survival versus renal replacement treatment. HIV control and opportunistic infections were low because all patients had viral suppression and CD4 cell counts of at least 200 cells/ml before transplant and used a combination of ART and posttransplant anti-infective prophylaxis.
This research found significant post-kidney transplant problems in PWH. Bacterial infections were more common in HIV/HCV co-infected patients who received anti-thymocyte globulin (ATG).
PWH also had significant rates of delayed allograft function (hemodialysis in the post-transplant interval), although this did not predict graft failure. Lastly, HIV-positive kidney transplant patients had allograft rejection rates two to three times greater than the overall kidney transplant group, and rejection predicted allograft failure in this research.
Liver:
PWH liver transplant results vary by rationale. In HIV-HBV co-infected patients, passive prophylaxis with hepatitis B immunoglobulin and antiviral treatment results in 85–100% graft and patient survival after 3–5 years.
Lifelong HBV viremia prevention is advised.
HIV–HCV coinfected patients had worse graft and patient survival rates than HCV-monoinfected controls before the availability of DAA medications.
HCV monoinfected controls had 1, 3, and 5-year graft survival rates of 57 to 88, 50 to 62, and 33 to 58%, whereas coinfected patients had 52 to 86, 45 to 60, and 31 to 45%. HCV-related increasing liver damage, severe infections, and sepsis harm results.
Pancreas:
The US conducted 836 simultaneous pancreas-kidney transplants in 2018. Just 10 type 1 diabetic PWH have had this operation.
Graft thrombosis, rejection, and bacterial infections, including deadly sepsis, have caused varied results. These data suggest that HIV-infected individuals may undergo pancreatic transplantation, although more experience is required.
Heart :
PWH are susceptible to heart problems caused by age, HIV, and ART. Pre-ART HIV-associated cardiomyopathy was common, whereas PWH currently has coronary artery disease. HIV is no longer a contraindication to advanced heart failure therapy such as heart transplantation, however, it is seldom done.
Lung:
The US conducted 2530 lung and 32 heart/lung transplants in 2018 [54]. PWH transplantation data is scarce. HIV is now a relative contraindication to lung transplantation under the 2014 ISHLT guidelines.
HIV-infected organ transplant candidates and recipients: clinical treatment
Recruitment:
• Meet transplant center-specific organ transplant eligibility.
• CD4+ cell count > 200 cells/μl three months before transplantation for kidney, pancreatic, heart, and lung candidates.
• Liver candidates only: CD4+ cell count > 100 cells/μl 3 months prior to transplantation.
• undetectable plasma HIV viremia (unless unable to tolerate antiretroviral medication before liver transplant).
• Stable antiretroviral therapy adherence
• No chronic wasting or severe malnutrition
• Hepa!!s B or C infection without advanced fibrosis/cirrhosis (for organ types other than liver).
Immunosuppressive medication monitoring.
• Regular HIV care provider follow-up
Antirejection:
The optimum HIV immunosuppressive regimen is uncertain. The organ transplanted, immunologic risk, renal and hepatic function, and ART regimen should determine patient regimens.
Physicians disagree on HIV-positive kidney transplant induction immunosuppression. In the U.S. NIH observational experiment, ATG caused considerable, protracted lymphocyte depletion, more frequent and severe infections, and an increased risk for allograft loss. Basiliximab, an IL-2 receptor antagonist, did not.
Medication management:
Both low and high antirejection medication levels in transplant patients may be dangerous. HIV providers must understand medication interactions with maintenance immunosuppressive medicines, even while the transplant center monitors them.
Protease inhibitors influence the pharmacokinetics of immunosuppressive medicines such as calcineurin inhibitors (tacrolimus, cyclosporine A) and mTOR inhibitors (sirolimus, everolimus) by inhibiting CYP3A4. This raises the danger of variable immunosuppressive levels that might cause rejection or toxicity. Non-nucleoside reverse transcriptase inhibitors induce CYP3A4 differently.
HIV monitoring:
HIV providers prepare patients for transplant and monitor HIV infection and posttransplant opportunistic consequences. HIV experts work with the transplant team to optimize HIV medication before transplant to reduce toxicities and drug interactions and maintain viral suppression.
HIV-to-HIV transplantation:
Four HIV-to-HIV kidney transplants were successful in Cape Town, South Africa, in 2008.
Brain-dead donors had limited access to dialysis, organ availability, and HIV. According to recent follow-up data from the same group, 51 patients transplanted with HIV-positive organs had 1-, 3-, and 5-year patient survival rates of 87, 87, and 84% and graft survival rates of 96, 93, and 79%.
Reverse transcriptase and V3 phylogenetic trees suggested donor superinfection in one instance. The patient’s viral suppression suggests low-level viral inoculum and shedding from the donor’s kidney into the recipient’s blood.
Because of HIV-related renal, hepatic, and cardiac problems, recipients may get latent or undiagnosed opportunistic infections and have poor organ quality.
I appreciate level of recommendation in relation to each advice in relation to the natural history of HIV infection and corresponding mode of treatment indicated.