Transplantation in the HIV+ Patient
The historical exclusion from transplantation of HIV-infected people was based on the logical premise that immunosuppression required for organ transplantation would exacerbate an immunocompromised state. However, the prognosis for people with HIV infection has dramatically improved with the clinical use of highly active antiretroviral (ARV) therapy (HAART). Clinical trials of ARV agents have demonstrated significant virologic, immunologic and survival benefits associated with the use of protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) containing regimens, when combined with two nucleoside analogues. The incidence of opportunistic infections and hospitalizations has decreased with the use of HAART. In combination with historical data suggesting that a subpopulation of HIV+ transplant recipients tolerate immunosuppression and have allograft survival comparable to that of HIV– transplant recipients, these results indicate that the medical community should readdress HIV infection as a contraindication to transplantation.
Solid Organ Transplantation in HIV+ Patients during the Pre-HAART Period
Little is known of the outcomes of solid organ transplantation in human immunodeficiency virus positive (HIV+) recipients from the pre-HAART era. There have been a number of anecdotal reports describing both poor and stellar outcomes in HIV+ patients undergoing transplantation during this period. Otherwise, there have only been two single center analyses, which retrospectively chronicle the University of Pittsburgh and the University of Minnesota experience with transplantation in HIV+ patients in the pre-HAART period. In 1990, Erice and colleagues described the University of Minnesota experience with five cases and also reviewed the literature. The authors describe a total of 21 HIV+ recipients of kidney (n = 11) and liver (n = 10) transplants. Among the kidney recipients, graft outcome data were available for eight patients. Six (75%) had normal graft function after a mean follow-up of 30.7 months (range: 2–65 months). Among the entire group of 11 kidney recipients, three (27%) developed AIDS and died at 13 months post-transplant (range: 6–24 months). Of the remaining eight patients, there was no evidence for HIV-related disease. Among the 10 HIV+ liver transplant recipients, the mean follow-up period was 19 months (range: 0–68 months). Four developed AIDS after a mean period of 19.2 months post-transplant. Mortality was 90% (9/10) occurring at 14 months post-transplant. Of the nine deaths, four (44.4%) were the result of an HIV-related cause, occurring at 5.8 months post-transplant (range: 1.5–13 months). The data from the University of Pittsburgh were included in this analysis. However, Tzakis and colleagues also analyzed the AIDS-free time between HIV+ transplant recipients (n = 25) and HIV+ control groups consisting of blood-transfusion recipients (n = 42) and hemophiliacs (n = 28). By Kaplan–Meier analysis, the proportion remaining AIDS-free was not statistically different between the three groups for the five years of retrospective analysis (p = 0.065). When the HIV+ liver recipients (n = 25) were compared with the HIV-liver transplant control group (n = 1303) using Kaplan–Meier analysis, the five-year survival was not statistically different between the two groups. These data suggest that solid organ transplantation in the pre-HAART period was associated with outcomes that were suboptimal, but certainly not dismal.
During this period, investigators also reported a potential association between cyclosporine utilization and improved outcomes in HIV+ transplant recipients. Schwarz and coworkers reviewed the literature in 1993. Life table analysis was performed in a group of 53 patients with HIV-1 infection following transplantation during the period of 1985–1992. They found that the incidence of AIDS was significantly lower in the group of patients treated with cyclosporine (p < 0.001). In cyclosporine-treated HIV+ patients, the cumulative risk of developing AIDS not significantly greater than that noted in HIV+ homosexuals, hemophiliacs and patients receiving blood transfusions. At five years post-transplant, the cumulative risk of developing AIDS in HIV+ transplant recipients receiving cyclosporine was 31% in contrast to that of patients not receiving cyclosporine (90%). In vitro models have demonstrated that cyclophillin A modulates HIV-1 infectivity by forming an essential complex in the virion core with the HIV-1 Gag protein. Cyclosporine blocks nuclear import of HIV-1 DNA in activated CD4+ T cells, presumably by binding to cyclophillin A and preventing its interaction with Gag. In the presence of clinically relevant concentrations of cyclosporine, it has also been demonstrated that HIV does not bind to T lymphocytes and does not replicate in previously infected cells. Although seemingly counter-intuitive, these observations suggest that cyclosporine may attenuate the course of HIV infection by inhibition of HIV replication.
HAART and the Clinical Course of HIV Infection
Beginning in 1996, the generalized use of HAART regimens utilizing three drug combinations of protease inhibitors and non-nucleoside analogue reverse transcriptase inhibitors has significantly altered the clinical course of HIV infection. With laboratory testing to determine CD4+ T-cell count and HIV viral load, the efficacy of specific HAART could also be determined for the individual patient. Palella and colleagues studied 1255 patients treated at nine HIV specialty clinics across the United States during the period 1994–1997. They found that mortality decreased from 29.4/100 patient-yr in 1995 to 8.8/100 patient-yr in 1997. Similarly, the incidence of opportunistic infections (P. carinii pneumonia, MAI complex disease and CMV retinitis) decreased from 21.9/100 patient-yr to 3.7/100 patient-yr. In a failure rate model, intensity of antiretroviral therapy was associated with a stepwise decrease in morbidity and mortality. These authors attribute the decline in AIDS-related morbidity and mortality to the use of intensive HAART. These findings have been duplicated in many other studies, indicating that HAART significantly decreases HIV associated morbidity and mortality. There can be little doubt that HAART has dramatically altered the clinical course of HIV disease.
Interestingly, new clinical syndromes have also appeared in the setting of HAART and reconstituted immune systems. An unanticipated consequence of HAART is an exuberant inflammatory response to an established infection. ‘HAART-induced inflammatory immune response’ or ‘reversal syndromes’ represent unmasking of an undiagnosed opportunistic infection (OI) or exacerbation of a diagnosed OI in the setting of improved immune function. This HAART-associated clinical flare phenomena has been noted with therapy for tuberculosis, CMV retinitis, cryptococossis and leprosy. In this regard, the natural history of hepatitis B and C in the HIV+ patient deserves mention. In many urban series of HIV+ patients, there is > 50% seroprevalence for hepatitis B and at least a 40% prevalence of hepatitis C. As the result of HAART-associated improvement in survival, previously insignificant comorbidities, such as hepatitis B and C, have assumed increasingly significant prominence. In HIV+ patients with chronic hepatitis C receiving HAART, 7/51 patients (14%) developed hepatic decompensation resulting from HAART associated hepatotoxicity. These data exemplify the potential for enhanced morbidity and mortality associated with HAART in HIV+ patients coinfected with hepatitis C and/or hepatitis B.
HIV-Associated Causes of Renal and Liver Disease
People with HIV infection are at significant risk for both end-stage kidney and liver disease. Although these patients can develop organ failure from diseases exclusive of HIV, there are HIV-specific pathophysiologic processes that can result in kidney and/or liver failure. HIV-associated nephropathy (HIVAN), a rapidly progressive disease of uncertain etiology, predominantly affects HIV+ blacks who present with proteinuria, low CD4+ cell counts and normal to enlarged kidneys. Histologically, HIVAN is characterized by a collapsing variant of focal segmental glomerulosclerosis with coexistent global glomerulosclerosis and microcystic tubulointerstitial disease. According to the US Renal Data System (USRDS), the number of cases of HIVAN has increased at a rate of 30% per year from 1991 to 1996. HIVAN is the third leading cause of end-stage renal disease (ESRD) in blacks from the ages of 20–64 yr, accounting for 10% of new cases of ESRD nationally. Its actual prevalence is unknown, but it is 7–10 times more common in men and 30–60% of those affected have a history of injection drug use. Progression to ESRD typically occurs in 6–12 months. In HIV+ Caucasian patients, immune complex glomerulonephropathy (GN) is the most prevalent finding in those with proteinuria and hematuria. Hepatitis C infection, which is a frequent coinfection in HIV+ patients, can be associated with cryoglobulinemic GN-induced renal failure. As a result, the number of HIV+ patients undergoing dialysis continues to increase. In 1994, 1.5% of 3144 patients receiving dialysis were diagnosed with HIV infection, but only 28% of the centers surveyed tested for HIV. As of 1996, 15% of new dialysis patients at San Francisco General Hospital were HIV+. According to the USRDS, AIDS and HIV are listed as comorbidities for 0.4% and 0.7% of the total dialysis population in 1999, respectively.
In a similar fashion, the clinical course of liver disease can be altered in the HIV+ patient. The prevalence of hepatitis C infection in the United States is estimated to be 1.8% (3.9 million). Because of shared routes of transmission, hepatitis C and HIV coinfection is very common. In the US, c. 30% of the estimated 800 000 HIV+ population is thought to be seropositive for hepatitis C. In the EuroSIDA cohort study, the coprevalence of HIV and hepatitis C is 33%. In specific subgroups, more than 90% of HIV+ hemophiliacs and people with a history of injection drug use have hepatitis C infection, with increasing hepatitis C viral RNA levels correlating with decreasing CD4+ T-cell counts. HIV coinfection appears to accelerate the course of progression to hepatitis-C-related cirrhosis. For example, there is a higher proportion of liver failure in hepatitis C infected HIV+ hemophiliacs when compared with hepatitis C infected HIV-hemophiliacs. HIV infection abbreviated the course to hepatitis-C-induced liver failure from 15–20 yr to 10 yr. Indeed, hepatitis-C-related liver disease has already been reported to be a major cause of hospital admissions and deaths among HIV+ patients. Certainly among the larger group of HIV-liver-transplant recipients, 20–25% of liver transplants are presently being performed for hepatitis C infection. The effect of liver disease, in general, and hepatitis C, specifically, on the course of HIV infection is less certain. While the majority of evidence suggests that there is no effect of hepatitis C on the natural history of HIV over the short run, certainly the chronic effects are as yet unknown.
Other related issues are HAART-associated hepatotoxicity, HIV-hepatitis C coinfection, and HIV-hepatitis B coinfection. It is unknown whether there is a role for interferon–ribavirin therapy in post-transplant care of the HIV–hepatitis C coinfected patient undergoing liver or kidney transplantation. In the setting of renal transplantation of HIV–hepatitis C patients, it has been suggested that if interferon–ribavirin therapy is needed, it should be instituted prior to transplantation for fear of initiating an acute rejection if administered post-transplant. However, there is little data to suggest this approach over another. Similarly, it is difficult to determine if subclasses of these HIV–hepatitis C or HIV–hepatitis B patients can be predicted to have favorable outcomes following transplantation. Lamivudine resistance in HIV and hepatitis B coinfected patients will be another issue. As a result, there is little previous data to guide the transplant community in the care of these patients.
Current Outcomes of Liver and Kidney Transplants in HIV+ Patients
Outcome data are lacking regarding liver and/or kidney transplantation in HIV+ patients in the era of HAART. In a recent attempt to query the transplant community regarding this issue, a survey was distributed by the Scientific Studies Committee of the American Society of Transplant Surgeons to its membership with the promise of anonymity. A total of 814 surveys were distributed in October 1999 with 179 respondents (22%). Within the five years preceding the survey (1994–1999), a total of eight transplants (two kidney and six liver) were performed in HIV+ patients. The length of follow-up varied from three years to six months; patient survival was 75% (6/8) with two deaths among the liver recipients resulting from JC virus and VRE sepsis. Uniformly, inclusion criteria included a CD4+ cell count greater than 200 and the presence of an undetectable HIV viral load. Immunosuppression was either cyclosporine- or tacrolimus-based; all recipients remained on HAART following the transplant. [An additional two kidney transplants have been performed since completion of the survey with normal graft function (Peter Stock, UC San Francisco, 2000, personal communication).] Although anecdotal and by no means complete, these data suggest that transplant centers are embarking upon kidney and liver transplantation in select groups of HIV+ patients.
The transplantation of HIV+ patients poses multiple ethical questions. A potential concern revolves around the utilization of a scarce resource for patients who may not have an equivalent survival to HIV– recipients. Preliminary data suggest there is a subgroup of HIV+ patients who have enjoyed equivalent graft outcomes and survival rates as HIV– recipients following transplantation. Some centers are offering ‘high risk’ cadaveric donors for patients who are HIV+, donors that otherwise would not be utilized secondary to concern for disease transmission. Other centers are only utilizing living donors to assure that a scarce resource will not be utilized until the efficacy of the transplantation in the HIV+ can be demonstrated. The use of living donors brings up its own set of ethical concerns, including whether the potential living donor should be informed of the recipients HIV status. If so, who should inform the potential donor? Finally, the issue of insurer payment remains an extremely important issue, with some third-party payers denying payment for a procedure which they consider experimental. The importance of a multicenter trial to demonstrate safety and efficacy will hopefully provide the data necessary to resolve many of these ethical dilemmas.
Additional Considerations in Transplantation of HIV+ Patients
Understanding the drug–drug interactions between immunosuppressive therapy and HAART will be critical to patient management. Although immunosuppression is required for graft maintenance and effective antiretroviral (ARV) therapies are required to suppress HIV replication, it is unknown how and to what extent the antirejection therapies will interact with the antiretroviral medications. All viral aspartyl protease inhibitors that exhibit anti-HIV activity are metabolized by CYP3A4, and these same drugs also act as inhibitors and sometimes inducers of CYP3A4. Because the immunosuppressants cyclosporine, tacrolimus and sirolimus, as well as the ARVs in use, are substrates, inhibitors, and/or inducers of CYP3A4, significant drug–drug interactions may occur when these medications are given concomitantly. Potential drug–drug interactions are listed in Table 1. It is likely that the immunosuppressants will effect the plasma concentrations of the ARVs under study, but it also very likely that the presence of the protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitor (NNRTI) ARVs may act upon the metabolizing enzymes and transport pumps in such a way as to increase immunosuppressant levels as well. It is anticipated there will be an increase in cyclosporine or tacrolimus concentrations, especially with concomitant oral administration of PIs. The development and validation of analytical methods for the specific and sensitive quantification of immunosuppressive drugs and ARV compounds are a prerequisite for the evaluation of the pharmacokinetic interactions between these drugs. Because organ transplant in HIV+ patients is in its nascent stage, describing the long-term pharmacokinetic profiles of concomitant immunosuppressive agents and ARVs in HIV positive transplant recipients will be essential.
Table 1. Potential drug–drug interactions
|NRTI||Didanosine||GI, neuropathy||po GCV, azole, MMF|
|NRTI||Lamivudine||GI, neuropathy||Bactrim, dapsone, MMF, AZA|
|NRTI||Stavudine||Neuropathy, leukopenia, hepatotoxicity||Dapsone, Flagyl|
|NRTI||Zalcitabine||Neuropathy, rash, pancreatitis||CSA, FK506, Bactrim, Flagyl|
|NRTI||Zidovudine||Anemia. neutropenia, GI, myopathy||AZA, Bactrim, dapsone, GCV, azole|
|PI||Indinavir||GI, nephrolithiasis||Azole, CSA, FK506, MMF, AZA|
|PI||Nelfinavir||GI, fatigue||Azole, CSA, FK506, MMF, AZA|
|PI||Ritonavir||GI, asthenia, paresthesias, hepatotoxicity, |
|Azole, CSA, FK506, MMF, AZA,|
|PI||Saquinavir||GI, oral mucoasl ulcers||Azole, CSA, FK506, MMF, AZA|
|NNRTI||Delavirenz||Rash, GI, hepatotoxicity||CSA, FK506, MMF, AZA, nifedipine|
|NNRTI||Efavirenz||Dizziness, GI, hepatotoxicity||Azole, CSA, FK506, MMF, AZA|
|NNRTI||Nevirapine||GI, rash, hepatotoxicity, fever||Azole, CSA, FK506, MMF, AZA|
Additional considerations will include (but certainly not be limited to) the impact of ‘HAART-induced inflammatory immune response’ or ‘reversal syndromes’ in the setting of immunosuppression, appropriate inclusion and exclusion criteria (see sample in Table 2) and postexposure prophylaxis for medical personnel.
Table 2. Potential criteria for kidney and liver transplantation in HIV+ patients
| Inclusion criteria: |
|1.||Documented HIV infection.|
|2.||Kidney: current CD4+ T-cell count ≥ 200/mm3 for ≥ 6 months; Liver: current CD4+ T-cell count ≥ 100/mm3 for ≥ 6 months.|
|3.||HIV-1 RNA ≤ 50 for three months (Amplicor Monitor Ultrasensitive PCR or bDNA Quantiplex version 3.0).|
|4.||Meet standard listing criteria for placement on transplant waiting list for kidney or liver transplantation|
|5.||Able to provide informed consent.|
|6.||On a stable ARV regimen for ≥ 3 months prior to entry.|
|7.||If the patient has HCV infection, must be willing to undergo frequent monitoring, including liver biopsies and treatment of HCV as recommended by the study clinicians.|
|8.||Willing to use PCP prophylaxis, herpes virus and fungal prophylaxis.|
|9.||Males and females of any age. Female subjects of child-bearing potential must have a negative serum beta-HCG pregnancy test within 14 days of screening. All subjects must practice barrier contraception.|
| Exclusion criteria: |
|1.||Any history of any AIDS-defining OI or neoplasm except drug susceptible Candida esophagitis.|
|2.||History of disease caused by aspergillus or aspergillus colonization.|
|3.||History of pulmonary or extrapulmonary tuberculosis.|
|4.||History of pulmonary coccidiodomycosis.|
|5.||History of documented resistant fungal infection (krussii, glabrata, candida).|
|6.||History of documented influenza or RSV in the past 30 days.|
|7.||History of any neoplasm except in situ anogenital carcinoma, adequately treated basal or squamous cell carcinoma of the skin, solid tumors treated with curative therapy and disease free for ≥ 5 years.|
|8.||Inability or unwillingness to comply with immunosuppression protocol, ARV therapy and/or HCV monitoring and therapy if indicated.|
|10.||Advanced cardiac or pulmonary disease.|
|11.||Documented anatomic anomalies precluding transplantation.|
The design of a clinical protocol of transplantation in HIV+ patients has been the recent subject of a conference sponsored by the University of California, San Francisco, CA, USA. Although there are no absolute guidelines available, one potential protocol that addresses toxicologic, immunologic and pharmacologic variables is as follows. (Peter G. Stock, MD, PhD and Michelle Roland, MD, personal communication)
CD4+ and CD8+ T-cell numbers, per cents, and ratios and quantitative HIV-1 RNA by ultrasensitive DNA assays will be monitored at each outpatient clinical visit. In addition to routine post-transplant laboratory tests, patients will be screened at baseline and followed every 6 months for the following markers of past or present infection: syphilis by RPR/VDRL, toxoplasmosis titer, CMV antibody status, hepatitis B surface antigen (HBsAg) and quantitative hepatitis B DNA if surface antigen positive, hepatitis B surface antibody (HBsAb), hepatitis B core antibody (HepBcoreAb), hepatitis C antibody (HCVAb) and quantitative hepatitis C RNA level and quasispecies determination if antibody positive, cervical PAP smear every six months, anal PAP in those with a history of receptive anal intercourse every 6 months, blood and sputum cultures for Mycobacterium avium complex (MAC) if CD4 nadir < 75, magnetic resonance imaging (MRI) of the head at baseline and as needed for evaluation of subsequent alterations in mental status, cerebrospinal fluid (CSF) for JC virus if MRI is suspicious for progressive multifocal leukoencephalopathy (PML), PPD, and the following markers of human herpes virus 8 (HHV8) infection: HHV-8 antibody, HHV-8 quantitative plasma viral load, HHV-8 cell-associated viral load, cellular immunologic studies related to HHV-8 and saliva HHV8 studies. All episodes of potential rejection, marked by increases in tranaminases or creatinine, will require liver or kidney biopsy for confirmation prior to the institution of rejection therapy.
The immunologic consequences of solid organ transplantation and immunosuppression in HIV-1 seropositive recipients will be followed with the following tests pretransplant, then at weeks 4, 28, 52 and years 2 and 5: (1) peripheral blood phenotyping to assess the composition of circulating subpopulations of lymphocytes (e.g. naive vs. memory) and state of cell activation; (2) intracellular cytokine expression following stimulation of recipient lymphocytes with staphylococcal enterotoxin B and CMV; (3) lymphoproliferation assays to assess changes in response to alloantigen (against donor targets), phytohemagglutin, and recall antigens (measles, tetanus, CMV); (4) natural killer (NK) cell function; (5) soluble markers of activation including serum beta-2 microglobulin and neopterin; (6) CD8+ cell suppressing activity (CAF); (7) donor reactivity; (8) chimerism studies; (9) chest computed tomography (CT) to assess thymic index will be obtained pretransplant and at weeks 4 and 52 and year 2. At baseline, P450 genotyping will be performed using a silica chip-based resequencing method that allows genetic sequencing of human cytochrome P450 enzymes (CYPs) and can be used to identify polymorphic expression. The CYPs of primary importance for Phase I/II drug metabolism that display genetic polymorphisms are: CYP2D6, CYP2C19, CYP1A2, CYP2E1, NAT2 and GST. Cyclosporine or tacrolimus levels will be monitored. Pharmacokinetic monitoring will be conducted in the GCRC or during the postoperative hospitalization pretransplant, then at weeks 1 and 4, month 6, year 1, and year 2 and year 5 post-transplant and whenever there is a change in ARVs, a significant change in immunosuppressants, or an episode of organ rejection. Whole blood and/or plasma will be analyzed for immunosuppressant, PI, and NNRTI concentrations using HPLC/MS assays.
People with HIV infection have been traditionally excluded from consideration for solid organ transplantation out of concern about the potential adverse effects of immunosuppressive drugs on HIV progression in a disease characterized by progressive immunocompromise. However, recent medical advances, such as HAART, have improved outcomes in HIV disease and as a result, there is now an increase in death from end-stage organ disease rather than AIDS-associated opportunistic infections and neoplasms. In light of the dramatic improvement in the treatment and survival of people with HIV, the transplant and HIV communities should re-evaluate the policy of HIV as a contraindication to organ transplantation. Although many questions about HIV and transplantation remain unanswered, enough data exist to warrant reconsideration of HIV disease in transplantation.