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Survival of HIV-Infected Liver Transplant Recipients
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The Journal of Infectious Diseases 2003;188:1412-1420
Margaret V. Ragni,1 Steven H. Belle,4 KyungAh Im,4 Guy Neff,5 Michelle Roland,6 Peter Stock,7 Nigel Heaton,9 Abhi Humar,8 and John F. Fung2,3
Departments of 1Medicine and 2Surgery and 3Starzl Transplantation Institute, School of Medicine, and 4Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania; 5Department of Surgery, University of Miami Medical Center, Miami, Florida; Departments of 6Medicine and 7Surgery, University of California, San Francisco, San Francisco, California; 9University of Minnesota Medical Center, Minneapolis, Minnesota; 9King's College, London, United Kingdom
ABSTRACT
Human immunodeficiency virus (HIV) infection has been considered an absolute contraindication to solid-organ transplantation. With immune function restoration possible with highly active antiretroviral therapy (HAART), we evaluated 24 HIV-positive subjects with end-stage liver disease who were undergoing orthotopic liver transplantation (OLTX) after the availability of HAART.
The cumulative survival among HIV-positive recipients was similar to that among age- and race-comparable HIV-negative recipients (P = .365, by log-rank test). At 12, 24, and 36 months after OLTX, survival was, respectively, 87.1%, 72.8%, and 72.8% among HIV-positive patients, versus 86.6%, 81.6%, and 77.9% among HIV-negative patients.
Survival was poorer among subjects with post-OLTX antiretroviral intolerance (P = .044), a post-OLTX CD4+ cell count of <200 cells/L (P = .005), a post-OLTX HIV load of >400 copies/mL (P = .016), and hepatitis C virus infection (P=.023).
These findings suggest that survival of HIV-positive liver transplant recipients does not differ from that of HIV-negative liver transplant recipients, and they suggest that HIV infection should no longer be a contraindication to OLTX. Further prospective studies are warranted.
Survival was significantly poorer among the HIV-positive subjects with ESLD caused by HCV infection than among those without HCV infection (50.0% vs. 100.0%; P = .023). Of note, a comparison of survival in the HCV-positive UNOS HIV-negative cohort to that among HCV-positive HIV-positive transplant recipients revealed no significant difference (P = .058), although the small sample size limits statistical power. The proportions of subjects surviving at 12, 24, and 36 months after OLTX were 80.0%, 56.9%, and 56.9%, respectively, for the HCV+ HIV+ recipients. This did not differ from the cumulative survival among the UNOS HCV+ HIV- liver transplant recipients (P = .058): survival at 12, 24, and 36 months after OLTX among UNOS HCV+ HIV- transplant recipients was 86.5%, 80.8%, and 77.0%, respectively.
Although the small sample size, short follow-up, and subsequent small number of deaths limit both the long-term projection of survival after liver transplantation and the elimination of confounders that might explain survival differences among recipient subgroups, these findings warrant further large prospective studies of HIV-infected subjects undergoing liver transplantation.
Background
Despite advances in highly-active antiretroviral therapy (HAART), which suppresses HIV replication, enhances immune function, slows disease progression, and reduces mortality, some individuals with HIV infection are surviving such infection to die of end-stage liver disease (ESLD), especially those with coinfection with hepatitis C virus (HCV) or hepatitis B virus (HBV). In the United States, as many as 30% of individuals with HIV infection are coinfected with HCV, although, in some groups (e.g., individuals with hemophilia), 80% are coinfected with HCV. Moreover, the risk of ESLD among hemophiliacs who are HIV positive is nearly 4-fold greater than that among hemophiliacs who are HIV negative, and liver disease has become the second leading cause of death in this group, after HIV infection
Although the mechanism by which HIV increases progression to ESLD is not known, HIV up-regulates cytokines, which may increase liver fibrosis and lead to liver disease progression. Treatment with HAART may contribute to hepatotoxicity, yet, in some studies, HAART appears to protect against liver disease progression. Because the increasing duration of HIV infection is an independent marker for liver disease progression, it is likely that ESLD will continue to be a growing problem among a significant number of coinfected individuals.
Historically, HIV infection has been considered an absolute contraindication to transplantation because of the high mortality rate of opportunistic infection associated with HIV infection and antirejection immunosuppression. However, the improvement in both immune system function and survival among individuals with HIV infection, which was made possible by the introduction of HAART in 1996, led us to hypothesize that the use of postoperative HAART therapy for HIV-positive subjects with ESLD who are undergoing orthotopic liver transplantation (OLTX) would result in survival comparable to that seen among HIV-negative liver transplant recipients. We therefore prospectively evaluated the outcome of OLTX performed, after the availability of HAART, for 24 HIV-positive subjects with ESLD.
Subjects. Twenty-four subjects with HIV infection and ESLD who fulfilled standard listing criteria for liver transplantation underwent OLTX at 5 institutions (10 subjects underwent OLTX at the University of Pittsburgh [Pittsburgh, PA]; 6 at the University of Miami [Miami, FL]; 4 at the University of California, San Francisco [San Francisco, CA]; 3 at King's College [London, United Kingdom]; and 1 at the University of Minnesota [Minneapolis, MN]) between 1997 and 2001, after the 1996 introduction and licensure of HAART. Although active opportunistic infection was considered a contraindication for transplantation surgery, past opportunistic infection was not considered a contraindication, nor was any level of CD4+ cell count or HIV load. All but 2 of the 24 subjects received preoperative antiretroviral therapy, and all but 1 subject received postoperative antiretroviral therapy. Institutional review board approval was obtained for the research protocols at each institution.
Methods. Liver transplantation was performed by standard orthotopic placement of the donor allograft liver into the recipient. Twenty-three subjects received a cadaveric liver, and 1 subject received a liver from a living donor. The latter subject experienced early graft failure resulting from a "small-for-size" mismatch; this led to a second transplantation with a cadaveric liver. Although all donors were HIV negative, some were HCV positive; however, their organs were used only in HCV-positive recipients, which is a safe and common practice in transplantation. Survival was measured from the time of the first transplantation. The method of reconstruction was institution specific and generally included anastomosis of the allograft portal vein to the recipient portal vein and anastomosis of the allograft hepatic artery to the recipient hepatic artery, with bile duct reconstruction or roux-en-Y choledochojejunostomy. Packed RBCs, fresh frozen plasma, platelets, and clotting factor were transfused as needed during and after the procedure.
Within the first 2448 h after transplantation, antirejection immunosuppression was begun with tacrolimus (FK506) or cyclosporine and with 1 of the following: mycophenolate mofetil, prednisone, and OKT3 monoclonal antibody. Antiretroviral therapy was begun within the first 3 postoperative weeks, after extubation, resumption of oral intake, and correction of liver-function test results toward the range considered to be normal. "Antiretroviral intolerance" was defined as the permanent discontinuation of antiretroviral drugs because of toxicity; antiretroviral intolerance occurred in 4 subjects during the pretransplantation period and in 6 subjects during the posttransplantation period. The 4 subjects who discontinued receiving antiretroviral drugs because of toxicity in the pretransplantation period did not receive any antiretroviral drugs up to the time of transplantation. The 6 subjects who discontinued antiretroviral drugs postoperatively still were not receiving drugs at the time of death or last contact. Interferon therapy with or without ribavirin was given empirically to subjects with chronic HCV infection, either within the first 4 weeks after transplantation or after biopsy evidence of HCV infection recurrence, on the basis of institutional preference.
RESULTS
The majority of HIV-positive subjects were white (21 [87.5%] of 24 subjects) and male (20 [83.3%] of 24 subjects). Among 24 subjects, the cause of ESLD was HCV infection in 15 subjects (62.5%), HBV infection in 7 subjects (29.2%), and fulminant hepatic failure in 3 subjects (13%), in association with nevirapine-induced acute hepatic necrosis, acute hepatitis A infection, and acute hepatitis B infection. After OLTX, 14 transplant recipients received a regimen including protease inhibitors (PIs), 5 received a regimen including nonnucleoside reverse-transcriptase inhibitors (NNRTIs), and 4 received a regimen including only nucleoside reverse-transcriptase inhibitors (NRTIs). One recipient died within 1 month and received no postoperative regimen. Median follow-up was 17.0 months. The posttransplantation values used in the analyses were the last available results.
The median pretransplantation CD4+ lymphocyte count and the HIV load (values were those obtained closest in time to OLTX): median age 46 (15-66); <400 HIV-RNA (<400-179,000); CD4 count 188 (76-973). At the time of the last follow-up after transplantation for each subject, the median CD4+ cell count was 281 cells/L (range, 871084 cells/L), and the median HIV load was <400 copies/mL (range, <400 to 9600 copies/mL). Six subjects (26.1%) experienced postoperative antiretroviral intolerance. Of these subjects, 4 (66.7%) died (table 2); all 4 had hepatitis C and developed antiretroviral intolerance, 2 in association with interferon and/or ribavirin therapy received for recurrence of hepatitis C. Antiretroviral intolerance in the 2 subjects who survived (neither of whom was hepatitis C positive) was associated with early post-OLTX liver dysfunction, which subsequently resolved. By contrast, among the 4 subjects who died, antiretroviral intolerance that preceded death by 0-10 months was associated with recurrence of hepatitis C treated with interferon and/or ribavirin: in 1 of the 4 subjects who died, superimposed parenteral antifungal therapy was also required for invasive aspergillosis.
Table 2. Characteristics of human immunodeficiency virus (HIV)positive subjects after orthotopic liver transplantation (OLTX).
Received ART
With protease inhibitors 14 (58%)
With NNRTIs 5 (21%)
With NRTIs 4 (16%)
Did not receive ART 1 (4%)
Had ART intolerance 6 (25%)
Hepatitis C 14 (58%)
--recurrence 7 (50%): treated 4 (57%), not treated 3 (42%)
--received interferon/ribavirin 7 (50%): at recurrence 4 (57%); empirically at OLTX 3 (43%)
Received antirejection therapy
--tacrolimus 20 (83%)
--cyclosporine 4 (16%)
Experienced transplant rejection 12 (50%): acute 10 (83%); chronic 2 (16%)
CD4 count <200 4 (18%)
HIV-RNA >400 2 (8%)
Cause of death
--ESLD 5 (83%): due to hepatotoxicity and ART intolerance 3 (60%); complicated by recurrent HCV infection 3 (60%); complicated by rejection 2 (40%); complicated by pancreatitis and sepsis 1 (20%); complicated by renal failure 1 (20%).
Cumulative survival after orthotopic liver transplantation (OLTX) among human immunodeficiency virus (HIV)positive (HIV+) liver transplant recipients. The proportions of subjects surviving at 12, 24, and 36 months after OLTX were 87.1%, 72.8%, and 72.8%, respectively. This finding did not differ from the cumulative survival among the cohort of United Network of Organ Sharing (UNOS) HIV-negative (HIV-) liver transplant recipients (dotted line), who were comparable to HIV+ transplant recipients with regard to age, race, and time of transplantation (P = .365): survival at 12, 24, and 36 months in the UNOS HIV-negative cohort was 86.6%, 81.6%, and 77.9%, respectively.
Survival was significantly poorer among transplant recipients with post-OLTX antiretroviral intolerance (P = .044) but not among transplant recipients with pre-OLTX antiretroviral intolerance (P = .239). Although these data suggest an association between poorer survival and post-OLTX antiretroviral intolerance, the sample size of this cohort is inadequate to allow us to examine whether antiretroviral intolerance is an independent risk factor for death in the HIV-positive OLTX cohort or to determine the explanation for this finding.
There was a trend toward poorer survival among transplant recipients receiving regimens including NRTIs, compared with those receiving regimens including PIs or NNRTIs, although this was not statistically different (P = .091). On the basis of the last available posttransplantation values, survival was poorer among transplant recipients with a post-OLTX CD4+ cell count of <200 cells/L than among those with a post-OLTX CD4+ cell count of 200 cells/L (P = .005), and survival was also poorer among those with a post-OLTX HIV load of >400 copies/mL than among those with a post-OLTX HIV load of 400 copies/mL (P = .016), which suggests the importance that post-OLTX viral suppression and an increase in the CD4+ cell count have for survival.
Survival was significantly poorer among the HIV-positive subjects with ESLD caused by HCV infection than among those without HCV infection (50.0% vs. 100.0%; P = .023). All 6 of the HIV-positive transplant recipients who died, including 3 hemophiliacs and 1 transfusion recipient, had received blood products in the past. Again, the small sample size precludes determination of whether poorer survival among HCV-positive subjects is the result of a confounding variable. It should be noted that, among those with ESLD due to HCV, the decrease in survival after 2 years was the result of a single, late death of an HCV-positive subject who developed a fatal opportunistic infection 57 months after OLTX. Of note, a comparison of survival in the HCV-positive UNOS HIV-negative cohort to that among HCV-positive HIV-positive transplant recipients revealed no significant difference (P = .058), although the small sample size limits statistical power.
The proportions of subjects surviving at 12, 24, and 36 months after OLTX were 80.0%, 56.9%, and 56.9%, respectively, for the HCV+ HIV+ recipients. This did not differ from the cumulative survival among the UNOS HCV+ HIV- liver transplant recipients (P = .058): survival at 12, 24, and 36 months after OLTX among UNOS HCV+ HIV- transplant recipients was 86.5%, 80.8%, and 77.0%, respectively.
Conclusion by Authors
The results of this study demonstrate that 1-year survival after liver transplantation is 87.1% among HIV-positive subjects, which is comparable to 1-year survival among age- and race-comparable HIV-negative liver transplant recipients in the United States during the same period. Although they are preliminary, these data suggest that HIV infection should no longer be considered an absolute contraindication for liver transplantation. Although the small sample size, short follow-up, and subsequent small number of deaths limit both the long-term projection of survival after liver transplantation and the elimination of confounders that might explain survival differences among recipient subgroups, these findings warrant further large prospective studies of HIV-infected subjects undergoing liver transplantation.
The optimal antiretroviral regimen after organ transplantation is not known. Although survival was worse among subjects receiving a regimen including only NRTIs than among subjects receiving a regimen including PIs or NNRTIs, the differences were not statistically significant. A larger prospective study will be necessary to determine whether the latter regimens are superior in suppressing the HIV load and/or restoring sufficient immune function to improve survival after transplantation. It is not known whether the antirejection drugs tacrolimus and cyclosporine contribute to HIV suppression through their known inhibition of HIV growth and replication, reduction in HIV cell-to-cell transmission and infectivity, and/or suppression of the growth of HIV-infected cells. Future clinical trials and clinical experience will be necessary before specific recommendations can be made regarding optimal post-OLTX antiretroviral therapy.
A detectable preoperative HIV load of >400 copies/mL and a low CD4+ cell count of <200 cells/L constitute criteria by which some institutions exclude potential candidates for transplantation. Data from this study, however, suggest that pre-OLTX antiretroviral drug intolerance (e.g., that due to liver failure) does not adversely affect post-OLTX survival. Three subjects with pre-OLTX antiretroviral drug intolerance and a detectable HIV load demonstrated effective virus load suppression after postoperative resumption of HAART, despite previous antiretroviral-induced virus load suppression. By contrast, post-OLTX antiretroviral intolerance was associated with shorter survival. Because liver failure may prevent tolerance of antiretroviral treatment before OLTX, these data suggest that strict criteria related to pre-OLTX HIV load and CD4+ cell count may be less important in the selection of transplant candidates than evidence of adequate HIV suppression and an increase in CD4+ cells with antiretroviral therapy before the development of ESLD.
Although hepatitis C recurrence is a nearly universal complication among HCV-positive transplant recipients, there is no standard approach to prevention or treatment of HCV infection among HCV-positive subjects undergoing organ transplantation. In this study, 3 institutions prescribed interferon with or without ribavirin only after biopsy evidence of hepatitis C recurrence was obtained, whereas 2 institutions treated HCV infection empirically. The development of antiretroviral intolerance in some subjects after the post-OLTX initiation of antiviral treatment for HCV infection suggests that adverse drug interactions may contribute to shortened survival after transplantation. Moreover, given the poor prognosis associated with post-OLTX antiretroviral intolerance, these data suggest that consideration should be given to delaying HCV treatment until after there is clear evidence of post-OLTX HAART tolerance.
The shorter posttransplantation survival among HCV-infected transplant recipients, compared with posttransplantation survival among HCV-negative transplant patients, is well documented and is not unique to HIV-positive transplant recipients. Our observation that post-OLTX survival among HIV-positive HCV-positive transplant recipients was similar to that among HIV-negative HCV-positive recipients argues against exclusion of HIV-positive transplantation candidates on the basis of their HCV status, and it further underscores the need for HCV drug development, given the high rate of recurrence of HCV infection.
Late invasive fungal opportunistic infection developed in 2 subjects after OLTX, despite adequate HIV suppression and a CD4+ cell count of >200 cells/L with post-OLTX antiretroviral therapy. Such infection was fatal in one subject. Because the latter subject was HCV positive and was the longest-surviving patient in this cohort (survival time, 57 months), his death accounts for the abrupt decrease in survival among HCV-infected subjects after 48 months. It is known that fungal infections may occur in up to 40% of HIV-negative liver transplant recipients with associated high mortality, and, thus, the death of the longest-surviving patient was not an unanticipated event in the transplantation setting.
In summary, in contrast to the finding of past inferior survival observed among HIV-infected transplant recipients (few, if any, of whom received antiretroviral therapy and all of whom had opportunistic infections), the major finding of this study is that successful liver transplantation is possible for HIV-infected subjects and that, for HIV-infected subjects, post-OLTX survival with antiretroviral therapy is similar to that for HIV-negative subjects. These data provide a scientific rationale to justify that HIV infection should no longer be considered an absolute contraindication to transplantation, which is consistent with recent transplantation arguments based on ethical considerations.
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