Solid Organ Transplantation in the HIV-Infected Patient
* Corresponding author: E. A. Blumberg, firstname.lastname@example.org
Despite early prohibitions against transplantation in human immunodeficiency virus (HIV) infected individuals, numerous patients with HIV have undergone solid organ transplantation. Before 1984, when HIV testing became available, some of these cases were acquired via transplantation. After 1984, patients with known HIV infection were generally not considered to be candidates either for organ donation or transplantation; since 1987 only three donors with unrecognized HIV have been known to transmit HIV infection (1–3). With the advent of highly active antiretroviral therapy (HAART) and improved outcomes in HIV infected patients due to better control of both HIV infection and opportunistic infections, patients with HIV have been reconsidered for transplantation in some centers (in many cases as part of an ongoing multicenter NIH sponsored clinical trial), although there remains an ongoing prohibition against the use of HIV infected donors. In an unknown number of cases, HIV has been acquired following transplantation.
The interest in transplantation in HIV infected individuals has increased due to the improvements in management of HIV and the associated opportunistic infections and the increasing morbidity and mortality associated with end stage renal and liver diseases in this population (4). Notably HIV associated nephropathy has become an important cause of end-stage renal failure, especially in people of African ancestry. People infected with HIV also have increased incidences of hepatitis-associated glomerulonephritis, membranous nephropathy, IgA nephropathy and drug related nephrotoxicity (5). Due to common infection pathways, HIV often co-exists with both Hepatitis C and Hepatitis B, both of which appear to have accelerated progression to cirrhosis in co-infected individuals with diminished responses and intolerance to therapy.
Historically, outcomes in HIV infected patients prior to HAART were generally poor when compared with patients without HIV infection, although there were some individuals who experienced better outcomes (6). Courses were marked by increased development of opportunistic infections and more rapid progression to AIDS.
Subsequent attempts at transplantation in HIV infected individuals in the HAART era have primarily focused on patients undergoing kidney or liver transplantation and these patients have experienced better outcomes when patients have well-controlled HIV before transplantation. Retrospective review of registry data has revealed conflicting results with one study using the United States Renal Data System (USRDS) database demonstrating comparable survival in HIV patients and the general population and a later study utilizing data collected by the United Network of Organ Sharing (UNOS) revealed diminished renal allograft survival in HIV positive recipients (7,8). However, prospective results from a pilot study of transplantation in HIV infected patients as well as preliminary results of the NIH sponsored trial have suggested that 1 year patient and graft survival following kidney transplantation is comparable to that following transplantation in uninfected individuals >65 years of age (9,10). Additionally, one single center study involving the largest single center experience in HIV infected patients revealed superior survival when compared with maintenance on dialysis (11,12). Results in liver transplantation vary based on the underlying disease. HIV infected individuals transplanted for Hepatitis C have been found to have decreased survival when compared with their HIV infected counterparts transplanted for other indications, whose survival may be comparable to non-HIV infected liver transplant recipients (9,13,14). Information regarding transplantation of other organs has been limited to anecdotal reports and small case series. Based on limited data, successful outcomes have been noted in HIV infected recipients of cardiac transplants and combined kidney–pancreas transplants (14–18). Combined liver and kidney transplants may be more likely to result in worse outcomes (personal communication). Preliminary results of a successful lung transplant in an HIV infected recipient are in press (personal communication).
Regardless of the organ transplanted, outcomes have been notable for the absence of AIDS defining occurrences when standard prophylaxis for opportunistic infections is used. Although outcomes have been generally good, rejection rates have been noted to be at least twice as common in HIV infected individuals. Likewise, HIV infected liver transplant recipients have had significant recurrences of Hepatitis C which have adversely affected patient outcomes (9,10,19).
To limit the potential impact of HIV on transplant outcomes, most centers have required patients to have well-controlled HIV infection before transplantation. Suggested criteria for transplantation in HIV infected individuals are noted in Table 1. In the NIH sponsored collaborative trial of transplantation in HIV infected individuals, patients must have a stable (at least 6 months) CD4+ T-cell count >200 cells/uL for liver transplant candidates with a prior history of an AIDS defining condition and all kidney transplant candidates. In the absence of AIDS defining infections or malignancies, liver transplant candidates may have CD4+ T-cell counts >100 cells/uL. Although a history of opportunistic infection or malignancy was previously a contraindication to transplantation, this exclusion has subsequently been limited to patients in whom the infection or malignancy is ongoing or untreatable (e.g. cryptosporidiosis) (10). Similar requirements have been noted in other centers (11). Additional HIV related criteria include an undetectable viral load on a stable antiretroviral regimen. Though there are no data to establish a time period for which individuals need to sustain these criteria, we recommend a minimum of 3 months. For liver transplant candidates intolerant of antiretroviral agents due to severe liver disease, HIV genotypic and phenotypic testing must be predictive of viral suppression on HAART.
Table 1. Criteria for transplantation in HIV infected individuals
|Must meet center specific inclusion criteria for specific organ transplant|
|HIV related criteria|
| CD4 count >200 cells/ul (kidney patients, liver patients with history of AIDS defining conditions including opportunistic infection or malignancy)|
| CD4 count >100 cells/uL for liver candidates without a history of opportunistic infection|
| Undetectable HIV viral load|
| If intolerant of antiretrovirals due to severe liver disease, must have genotype/phenotype predictive of viral suppression with HAART|
| Stable antiretroviral regimen|
|Absence of active opportunistic infection and malignancy history|
| ○ Patients with history of opportunistic infection and/or malignancy may be considered if all signs/symptoms resolved with appropriate disease free period (period varies with disease)|
| Progressive multifocal leukoencephalopathy|
| Chronic intestinal cryptosporidiosis (>1 month duration)|
| Other neoplasms with exception of resolved Kaposi's sarcoma, squamous cell carcinoma of skin, anogenital carcinoma in situ, other solid tumors that are considered cured, or hepatocellular carcinoma (liver transplant only)|
|Absence of chronic wasting or severe malnutrition|
|Hepatitis C and/or chronic Hepatitis B infection|
| Liver biopsy without evidence of advanced fibrosis or cirrhosis (unless combined liver transplant anticipated)|
|Acceptance of lifelong Pneumocystis prophylaxis|
|Appropriate follow-up by providers experienced in management of HIV infected individuals|
|Ready access to drug level monitoring|
Whether prolonged waiting times may affect outcomes following transplantation is debatable. Early reports suggested that pretransplant survival for liver candidates was diminished in HIV infected individuals when compared with others awaiting liver transplantation, despite equivalent MELD scores (20). Subsequent studies have not confirmed these results, instead demonstrating that MELD was an accurate predictor of wait list mortality in HIV patients, similar to its use in HIV uninfected candidates (21). Following renal transplantation, diminished allograft survival has been noted in recipients of older donor organs, those with delayed graft function and those with prolonged cold ischemia time (8). Significantly increased rejection rates (two to threefold) have been noted throughout the posttransplant period (9,10). The etiology of the higher rejection rates remains unclear. They may be attributed to immune system dysregulation in the HIV infected recipient, or possibly to inadequate exposure to immunosuppressive agents secondary to pharmacokinetic interactions with HAART.
Patient and allograft survival in liver transplantation has been variable; rejection rates have also been increased in recipients and survival appears to be largely affected by the indication for transplant. Those patients transplanted for indications other than Hepatitis C have significantly better outcomes than those patients with hepatitis C-HIV co-infection (9,14,19,22). The biggest impact on patient survival has been the recurrence of Hepatitis C infection with the development of a more rapid progression to cirrhosis. Risk factors for this may include higher pretransplant MELD scores, low pretransplant BMI, African American race and HAART intolerance. Because of the more rapid progression to cirrhosis, current management strategies include the earlier introduction of treatment for Hepatitis C infection (19). Whether this strategy will sufficiently reduce the impact of Hepatitis C on outcome to balance the potential risk of rejection associated with interferon is unknown. Of note, there have been several reports of the spontaneous clearance of Hepatitis C infection following transplantation (23).
Opportunistic infections and other AIDS defining conditions have been uncommonly reported following transplantation. Patients typically experience transient declines in the CD4+ T-cell counts following transplantation, but this does not appear to have an impact on infection risk (9,10). Moreover T-cell responses following transplantation both directed at HIV and at herpesviruses have been shown to be stable or expanded, reflecting an increase in immune reactivity (24). The single exception to this both in vitro and clinically may be related to the administration of thymoglobulin either for induction or treatment of rejection. This has been associated with prolonged declines in CD4+ T-cell counts, loss of polyfunctional T-cell antiviral cytotoxic T lymphocyte responses and in at least one center with the subsequent development of life-threatening bacterial infections (24,25). HIV viremia is generally well controlled with occasional transient episodes of viremia and less frequent persistent HIV viremia (10).
Diagnostic Strategies Posttransplant in the HIV Positive Recipient
As with other transplant recipients, the cause of allograft dysfunction may not be apparent based on clinical presentation or laboratory testing. Medications, rejection, disease recurrence and superinfection may all be contributory. Consequently, it is important to consider allograft biopsy for persistently elevated serum creatinine (for kidney transplant recipients) and liver associated enzymes (for liver recipients) (II-2). Because liver enzymes may not be reflective of ongoing liver damage related to Hepatitis C infection, standard protocol biopsies at 6 month intervals should be considered in liver recipients (III). As liver enzymes may not reflect the degree of damage in renal transplant candidates coinfected with Hepatitis B or C, all candidates for renal transplantation with hepatitis co-infection should undergo liver biopsy before listing and patients with cirrhosis should be excluded unless they could be considered for combined liver and kidney transplant (III).
To maintain virologic control of HIV infection, it is recommended that quantitative HIV RNA and CD4+ T-cell counts be measured regularly, with the first assays at 1 month after transplant and subsequent studies every 2–3 months thereafter (III). If patients have persistent HIV viremia, resistance testing should be carried out (genotypic and phenosense) to determine treatment options (III).
Treatment Considerations in the HIV Positive Transplant Recipient
Before consideration of transplantation for HIV infected individuals, several immunosuppressive agents were considered for control of HIV infection (26). Because of its ability to bind to cyclophilin A, a cytoplasmic protein required for HIV viral replication as well as its inhibition of T cell activation, Cyclosporine A has been studied as part of a treatment regimen in patients with HIV. Mycophenolate has also been demonstrated to suppress HIV replication, especially in combination with nucleoside reverse transcriptase inhibitors such as abacavir (27). Although neither of these agents has been used in standard treatment regimens for patients with HIV, the potential benefit of using them in transplant recipients with HIV is being investigated.
One of the most challenging treatment issues in HIV infected transplant recipients has been managing the numerous drug interactions associated with antiretrovirals and immunosuppressive agents (28). Before transplantation, HIV infected individuals should be on a stable treatment regimen and the composition of the regimen should be noted when planning immunosuppression. Patients receiving protease inhibitors will have significantly slower metabolism of calcineurin inhibitors and sirolimus as a result of potent inhibition of the cytochrome p450 system. As a result, patients on HAART regimens containing protease inhibitors require substantially lower doses of the calcineurin inhibitors and sirolimus, with longer dosing intervals. This will require ongoing monitoring over time as unboosted protease inhibitors may be associated with increased cyclosporine bioavailability with time (28) (II-2). Efavirenz increases the metabolism of the calcineurin inhibitor, thereby necessitating higher doses of calcineurin inhibitors in these patients; nevirapine has minimal effect on immunosuppressive dosing however (28). Consequently, close monitoring of immunosuppressive levels is critical in patients with HIV and should begin on the first day posttransplantation with daily follow-up until levels have stabilized (II-2). A uniform approach to monitoring immunosuppressive drug levels in the face of anticipated drug interactions with antiretroviral agents has not been established and warrants further study.
Choice of antiretrovirals should take into account the potential for increased toxicity or diminished bioavailability following transplantation (III). To diminish the risk of mitochondrial toxicity and lactic acidosis, stavudine and didanosine should be avoided. Zidovudine may be associated with increased risk of anemia in patients receiving interferon. Atazanavir may have diminished absorption in transplant patients, who commonly receive gastric acid suppression and can be associated with hyperbilirubinemia, which may confound posttransplant assessments; consequently it is preferable to avoid this protease inhibitor. The benefits and disadvantages of integrase inhibitors are largely unknown, though one report suggested that raltegravir has little interaction with calcineurin inhibitors (29). Whether it may be advantageous to use a CCR5-coreceptor antagonist is unknown.
Treatment of Hepatitis B before and following transplantation is essential in transplant recipients who are co-infected with Hepatitis B (14) (II-2). Numerous agents, including lamivudine, adefovir, tenofovir and entecavir have all been used successfully. Standard management has also included the use of Hepatitis B immune globulin to maintain titers >200 IU/mL. Lamivudine resistance to hepatitis B has been common in patients co-infected with hepatitis B and HIV as a result of prolonged utilization of lamivudine as a component of HAART therapy. Despite the presence of lamivudine resistance in the majority of HIV-Hepatitis B co-infected patients, outcomes in these patients have been excellent with the administration of anti-retrovirals with appropriate Hepatitis B virus coverage (14). In HIV infected patients who are not undergoing transplantation, combination therapy with tenofovir and a reverse transcriptase inhibitor (lamivudine or emtricitabine) has been noted to decrease the development of resistance (30). Combination therapy may be appropriate following transplantation as well (III). Termination of anti-Hepatitis B therapy should be avoided as it may result in a hepatitis flare (III).
Treatment of Hepatitis C infection has been more difficult. Whenever possible, Hepatitis C infected patients should be assessed for potential treatment before transplant to diminish the Hepatitis C viral load, thereby potentially decreasing the risk of posttransplant recurrence (III). Most patients will probably not tolerate this before transplantation, however. Following transplantation, patients should be considered for treatment based on liver biopsy results revealing early fibrosis and evidence of progression of recurrent Hepatitis C infection (III). Patients on interferon and ribavirin should be closely monitored for rejection (III). The optimal duration of Hepatitis C treatment is currently unknown.
Recommendation for Prophylaxis for Opportunistic Infections
Because HIV infected patients undergoing transplantation were presumed to potentially have an augmented risk of developing opportunistic infections due to the addition of exogenous immunosuppression, prophylactic regimens for prevention of opportunistic infections have been recommended (31) (III). This includes life-long prophylaxis against Pneumocystis jirovecii, preferably with trimethoprim-sulfamethoxazole. Additional prophylactic measures should follow the CDC guidelines and include prophylaxis against toxoplasmosis for CD4 counts <100, Mycobacterium avium complex for CD4 counts <50, and for histoplasmosis and coccidioidomycosis as dictated by exposure risk (31) (I). Secondary prophylaxis regimens for patients with a history of opportunistic infections should be considered following transplantation to prevent reactivation of latent infection (III). For patients at risk for primary toxoplasmosis due to donor infection, trimethoprim-sulfamethoxazole should be considered for primary prevention; dapsone or atovaquone in combination with pyrimethamine can be considered for patients intolerant of trimethoprim-sulfamethoxazole (III).
Vaccination status should be assessed before transplantation and vaccines updated as per regular schedules (31). This includes immunization of all nonimmune individuals against Hepatitis B virus (I). Hepatitis A vaccination should be administered to nonimmune liver transplant candidates, injection drug users, or men who have sex with men (I). Pneumococcal vaccine should be administered to any individual who has not been vaccinated in the prior 5 years and inactivated influenza vaccine administered as seasonally appropriate (I). Human papillomavirus vaccine should be administered to women ages 15–26 years (I). Varicella virus vaccine should be considered for nonimmune individuals who have a CD4 count >200. Following transplantation, it is important to maintain updated vaccination schedules, reimmunizing annually for influenza and every 3–5 years for Streptococcus pneumoniae (II).
All patients should be evaluated for latent tuberculosis before transplantation with either tuberculin skin testing or the interferon gamma release assay (31) (I). Because HIV patients with end stage renal or liver disease may have an increased incidence of anergy, historical information related to potential exposure or past untreated infection as well as chest radiographs should be included in the risk assessment (III). All individuals latently infected with tuberculosis should receive the standard therapy. Because of the significant drug interactions with both immunosuppressives and antiretrovirals, nonrifamycin containing regimens are preferred (III).
Patients with HIV can be appropriate candidates for transplantation. Due to the significant drug interactions and high risk of rejection and recurrent disease (especially Hepatitis C), management of these patients can be complex. Whether there may be differences in the management of adult and pediatric patients is an area that will require future study. An integrated multidisciplinary approach involving health care providers experienced in the care of these patients is recommended for optimal long-term outcomes.
Blumberg E.: Consultant, Roche; Grant Support, Roche, Viropharma. Stock P.: The author has nothing to disclose.