Recent advances in highly active antiretroviral therapy (HAART) have dramatically changed the natural history of human immunodeficiency virus (HIV) infection, leading to a 60–80% decline in mortality and a decrease in acquired immune deficiency syndrome (AIDS)-defining illnesses and patient hospitalizations (1). However, patients with HIV infection are frequently coinfected with hepatitis B virus (HBV) or hepatitis C virus (HCV) due to similar modes of transmission, which in turn increases their risk of developing chronic liver disease (2–5). Currently, as many as 30% of HIV-infected individuals may also have HCV infection (6). After the improvement in control of HIV with HAART, cirrhosis, and its complications have replaced opportunistic infections and sepsis as the leading cause of death in the HIV-coinfected population. End-stage liver disease may now account for up to 50% of deaths in the HIV population (7).
In the past, HIV infection had been considered an absolute contraindication to orthotopic liver transplantation (OLT). One major concern was that administering iatrogenic immunosuppression to an already immunocompromised individual would lead to an increased risk of opportunistic infections (OI) and acceleration of HIV-related disease. Prior to the advent of HAART, very poor outcomes and numerous complications after OLT were reported (8–12). Other arguments against OLT for the HIV population included the scarcity of organs, ethical concerns regarding organ allocation, and the fear of decreased public support (12, 13). Recent data have suggested that improved survival and decreased morbidity posttransplant can be achieved in the era of HAART therapy (14–18).
The purpose of this retrospective review was to compare the clinical course, overall survival, and cause-specific mortality after OLT in HIV-infected recipients with that of a period-matched cohort of non-HIV transplant recipients.
PATIENTS AND METHODS
This is a retrospective cohort study of all HIV-infected patients who underwent OLT at the University of Miami from January 1, 1999 (first OLT on an HIV patient at the University of Miami) through May 1, 2006. In order for an HIV-infected patient to be actively waitlisted for OLT, the same standard criteria for listing a non-HIV patient had to be met. In addition, HIV patients were required to have a CD4+ count greater than 100 cells/mm3 and a serum HIV viral load <200 copies/mm3. Placement on the waiting list was decided after discussion by our multidisciplinary team, which included infectious disease specialists, hepatologists, and transplant surgeons.
Demographic and clinical data collected in the HIV cohort included: sex, race, age, etiology of liver disease, last HIV viral load and CD4+ count prior to OLT. Serum albumin level, platelet count, total bilirubin, alanine aminotransferase level, prothrombin time, International Normalized Ratio (INR), serum creatinine, and Model for End-stage Liver Disease (MELD) score were recorded within one day prior to OLT. In addition, the most recent CD4+ count and HIV viral load were documented in the posttransplant setting at the time of last known follow-up. All patients receiving HAART had their therapy recorded before and after OLT. No standard antiretroviral program was used, and each patient received an individualized regimen based on HIV resistance patterns and the physician’s preference. All changes to HAART therapy after OLT were documented.
Immunosuppressive regimens used at the time of OLT were documented for all HIV patients. The standard immunosuppression protocol utilized at the University of Miami consists of tacrolimus, and tapering corticosteroids over a 3-month period. Tacrolimus doses were adjusted to achieve a target trough level of 12–15 ng/ml during the first week postOLT, 10–12 ng/ml thereafter during the first 3 months posttransplant, 8–10 ng/ml during months 4–6, then 6–8 ng/ml during months 7–12, and approximately 5 ng/ml thereafter.
Episodes of rejection were documented and confirmed by histopathology. Any additional immunosuppressive treatment or changes over time in response or adverse effects were noted. When a steroid cycle was used for rejection, it was individualized for each patient. In general, an intravenous bolus of methylprednisolone (250–1000 mg) was followed by oral prednisone (160 mg daily) which was gradually tapered over 1–2 months.
All patients received anti-Pneumocystis carinii pneumonia prophylaxis with dapsone or trimethoprim/sulfamethoxazole after transplantation. Prophylaxis for cytomegalovirus and herpes simplex virus was administered in standard fashion with ganciclovir, acyclovir, and/or cytomegalovirus immune globulin.
For patients afflicted with HBV, viral DNA levels were evaluated just prior to OLT and at the time of most recent follow-up. Anti-HBV therapy was documented both before and after OLT. Although not an absolute contraindication to transplant, our center attempted to achieve undetectable HBV DNA levels prior to transplant.
For patients afflicted with HCV, the viral RNA levels were checked just prior to OLT. After OLT, the RNA levels were periodically checked regardless of aminotransferase levels. Surveillance biopsies were only performed if abnormal hepatic biochemical tests were documented. The decision to start antiviral therapy was tailored to the individual patient and based upon the levels of aminotransferases, severity of inflammation and fibrosis on liver biopsy, genotype, HAART regimen, and patient/physician preferences. The need to individualize antiviral therapy has been acknowledged by others (19).
The study was approved by the University of Miami institutional review board.
The median, range, mean, and standard error were used for the descriptive statistics. Tests of association were performed using t-tests and Pearson (uncorrected) chi-squared tests. A P value of <0.05 was considered statistically significant. Cumulative patient survival and cause-specific mortality rates (20) were compared using the Kaplan-Meier technique and logrank tests along with Cox’s model for multivariable analysis. In each case when analyzing a cause-specific mortality rate (death due to infection vs. death due to noninfection), extraneous causes of death were treated as censored observations. The date of last follow-up for the analysis was May 1, 2006.
A total of 15 HIV infected patients underwent OLT at our center during the study period. All OLTs were first transplants, and all the recipients received a cadaveric graft. During this same period, a total of 947 non-HIV patients received OLT at our center; of these, 90 were second or third transplants and were excluded from the study leaving a total of 857 patients as our control group. The median follow up for the HIV population was 38 months (range: 45 days to 74 months). Median follow-up among the 688 ongoing survivors (both groups combined) was 43 months (range: 1 day to 88 months); median follow-up for all patients (n=872) was 36 months.
The baseline characteristics of the 15 patients who underwent OLT are shown in Table 1. The majority of patients were male and white, and the median age at transplant was 46 years (range: 36–54). The median baseline MELD score was 15 (range: 8–39), and the median CD4+ count was 326 cells/μL (range: 91–575). There was no statistically significant difference in demographic variables (age, race, and sex) between the HIV-infected and non-HIV groups. Among the 15 HIV-infected patients, six (40%) were also infected with HCV alone, five (33%) with chronic HBV alone, and two (13%) with both HCV and HBV. One patient had fulminant hepatic failure secondary to acute HBV. In addition, one female patient had documented cirrhosis and was positive for the HCV antibody. However, the serum HCV RNA level in this patient was undetectable both before and after OLT. She was subsequently considered to have cryptogenic cirrhosis.
Twelve of the HIV infected patients had an undetectable HIV viral load before OLT. Two had very low viral counts, and one had a viral load of 141,000 copies/mm3. All but one patient (93%) were receiving HAART therapy prior to OLT. The single patient not receiving HAART therapy had presented with fulminant hepatic failure secondary to HBV and was not known to have HIV prior to his presentation. The HAART regimens are shown in Table 1. The majority (57%) of patients were on at least two nucleoside reverse transcriptase inhibitors (NRTI) and a protease inhibitor (PI). The HAART regimens were adjusted by the infectious disease team depending on tolerability and genotypic sensitivity of the HIV. One subject was transplanted with a resistant virus and responded to Darunavir (a new investigational PI made available via an expanded access program) reaching a viral load of less than 200 copies/mm3.
Although there appeared to be a trend for poorer survival in the HIV group, the cumulative survival among the HIV-infected recipients was not significantly different from the non-HIV recipients as shown in Figure 1. The actuarial 1-, 2-, and 3-year survival rates posttransplant (±standard error) were 73.3% (±11.4%) for the HIV group (unchanged from 1 to 3 years) versus 86.9% (±1.2%), 82.0% (±1.4%), and 79.4% (±1.5%) for the non-HIV group, respectively (P=0.20, log-rank test). The observed mortality from any cause was 33.3% (5 of 15) in the HIV group vs. 20.9% (179 of 857) in the non-HIV group (Figs. 1 and 2). Age at transplant and pretransplant CD4+ count did not affect patient survival (P=NS). The causes of mortality in the five HIV-infected patients are shown in Table 2. Four of the five deaths (80%), all occurring within 6 months of OLT, were due to infection. One HIV patient died at 63 months after OLT due to posttransplant lymphoproliferative disorder (Burkitt’s lymphoma). Causes of mortality among the 179 deaths in the non-HIV group were infection (39%, n=70), cardiopulmonary event (17%, n=30), recurrent HCV infection (16%, n=29), neurologic event (6%, n=10), cancer (5%, n=9), and other (17%, n=31). Sixty (86%) of the 70 deaths due to infection in the non-HIV group occurred within 18 months after OLT.
Comparison of the mortality rates due to infectious etiologies (i.e., freedom from death due to infection) between HIV-infected and non-HIV patients is shown in Figure 3. The mortality rate due to infection was significantly higher in the HIV-infected group (P=0.006, log rank test). The observed percentage of HIV-infected patients who died of infection was 26.7% (4 of 15) versus only 8.2% (70 of 857) in the non-HIV group. Conversely, the mortality rate due to noninfectious causes was not statistically different between the two groups. The observed percentage of patients who died from noninfectious etiologies was 6.7% (1 of 15) in the HIV group vs. 12.7% (109/857) in the non-HIV group (P=0.57, log-rank test).
Rejection and Immunosuppression
Six of the 15 HIV-infected patients (40%) experienced acute allograft rejection as shown in Table 3. One of these patients also experienced chronic rejection. Acute cellular rejection occurred from approximately 1 week to 4 years after OLT. Two early episodes (1 week postOLT) were treated with monomurab-CD3. Other episodes were treated with steroid cycle and/or increase of tacrolimus dose (Table 3). No patient died of rejection. Only one of the five HIV-infected patients who died experienced a rejection episode, which occurred 5 months postOLT. This episode of rejection was unrelated to his demise which occurred 5.3 years postOLT (Burkitt’s lymphoma).
All 15 HIV-infected patients received immunosuppression with steroids and tacrolimus. Tacrolimus was changed to cyclosporine in a single patient due to neurological manifestations. As discussed above, two patients received monomurab-CD3 for episodes of severe acute rejection occurring approximately 1 week after OLT.
HIV in the Posttransplant Setting
Anti-HIV therapy was continued posttransplant in all HIV-infected patients. In the single patient who had not received HAART before transplantation, it was initiated postOLT. In six patients, no changes to the preOLT, HAART therapy were required. In six patients, PI was changed to a nonnucleoside reverse transcriptase inhibitor (NNRTI) or another PI due to gastrointestinal adverse effects (in two patients), suspected hepatotoxicity (one patient), anemia (one patient), decreased absorption due to initiation of a proton pump inhibitor (one patient), and development of renal stones (one patient).
After OLT, low to undetectable HIV levels were maintained in all patients (undetectable in 14 patients, one with a viral load of 76 copies/mL). The mean CD4+ cell count postOLT was 395 cells/μL range: 7–1,303, median: 368. Each of the five patients who expired had an undetectable HIV viral load; however, two had posttransplant CD4+ counts of less than 100, of 7 and 52 respectively. Both patients died of infectious complications (Table 2).
Clinical Course of HCV and HBV Infection PostOLT
Eight of the HIV-infected patients had detectable HCV viral loads at the time of transplant. Two of these eight patients (25%) had spontaneous loss of HCV RNA after OLT; each patient has remained with an undetectable viral load for more than 3 years. Of the six patients with persistent HCV RNA, three had liver biopsies postOLT consistent with recurrent HCV. Five of the six (83%) received therapy with pegylated interferon and ribavirin after OLT. Anti-HCV therapy was individually tailored to each patient. In general, pegylated interferon and ribavirin were started at low doses and gradually titrated to the maximal tolerated dose. Undetectable HCV RNA levels were achieved in two of the five patients (40%) who received anti-HCV therapy. Recurrent HCV infection was not associated with increased mortality or death due to infection in the eight HCV/HIV-infected patients.
Five of the eight patients (62.5%) transplanted for HBV-related liver disease had undetectable HBV DNA by polymerase chain reaction prior to transplant. One patient presented with acute liver failure due to HBV and was not tested for HBV DNA prior to OLT. One patient had a persistently elevated viral load despite treatment with lamivudine (LAM). Tenofovir (TNF) was added to this patient’s regimen at the time of OLT. After OLT, all but one patient (87.5%) maintained undetectable HBV DNA levels. PostOLT treatment was based on combinations of anti-HBV medications (LAM/TNF in three patients, LAM/emtricitabine in one patient, and LAM/Adefovir in one patient) or on a single medication (LAM) in three of eight patients. One patient receiving monotherapy developed a LAM-resistant mutant posttransplant and was successfully treated with the addition of TNF.
Major advances have been made in the management of HIV-infected patients. HAART has caused a dramatic change in the natural history of HIV infection and AIDS, leading to prolonged survival and decreased incidence of opportunistic infections (1). This change has led to the emergence of liver disease as a major cause of death in HIV patients.
HIV-infected patients often have co-existing liver disease caused by chronic HBV and/or HCV infections. For these patients co-infection with HIV portends a worse prognosis, and they are prone to develop cirrhosis, end-stage liver disease, and hepatocellular carcinoma more rapidly (4, 5, 21–24). Liver-related mortality in HIV patients co-infected with HBV was 14.2 per 1000 versus 1.7 per 1000 in HIV patients without HBV infection (25).
This paper describes the clinical outcomes of 15 HIV-infected patients transplanted at the University of Miami. Although a trend toward poorer overall survival in the HIV-infected recipients was observed, no significant difference in overall survival was found between the HIV- infected and non-HIV patient populations (P=0.20). These findings are in agreement with a previous report in which the cumulative survival among HIV- infected OLT recipients, while trending in disfavor of the HIV group, was not significantly different from age and race-comparable non-HIV recipients (15). One shortcoming of our analysis was the inability to match the non-HIV patient population for race and etiology of end stage liver disease with the HIV-infected cohort. However, as our control population included patients with diseases (e.g., Wilson disease, alcoholic cirrhosis, primary biliary cirrhosis) who generally do well after OLT, the finding that no difference in cumulative survival was observed further strengthens our conclusions.
These results suggest that HIV infection should not be a contraindication to OLT provided that the underlying HIV disease is under control. While criteria vary from institution to institution, there is growing agreement among centers regarding the appropriate selection of candidates for OLT as data amasses. Common indicators of controlled HIV disease preOLT include:
- HIV viral load <200 copies/mm3 or the presence of HIV that is sensitive to a HAART regimen based on resistance testing and agreed upon by the transplant team.
- CD4+ count greater than 100 and, preferably, higher, than 200.
- Absence of active opportunistic infections.
These patients must also meet the standard listing criteria for the non-HIV patient population (12, 14). Our criteria are essentially no different from the recent consensus document from Spain as shown in Appendix 1 (19). It is essential that various transplant centers continue to share and publish their data to provide robust practice guidelines.
Ninety-three percent of our HIV-positive patients were receiving HAART therapy prior to transplant. None of these patients developed anti-retroviral intolerance while awaiting OLT. Furthermore, all patients were able to successfully continue HAART therapy in the postOLT setting with only mild adjustments required. The reasons for postOLT adjustments of HAART in our group were gastrointestinal intolerance, suspected hepatotoxicity, decreased absorption due to initiation of proton pump inhibitors, and development of kidney stones.
When considering the specific antiretroviral regimen, potential drug interactions of HAART and immunosuppression must be taken into account. PIs are a part of most HAART regimens. It is now well known that PIs inhibit CYP3A, a component of the cytochrome P450, which results in markedly prolonged half-lives of the calcineurin inhibitors and sirolimus. HIV patients may therefore be more prone to develop toxicity while on these medications, requiring lower doses (e.g., as low as 1 mg/week of tacrolimus) (26). The patients in our population typically required a dose of tacrolimus of 1.0 mg/week but there was variation among all 15 patients. Conversely, use of an NNRTI, such as efavirenz and nevirapine, are inducers of cytochrome P450 and will lead to a decreased level of the calcineurin inhibitors or sirolimus. In our cohort, if a change in the HAART was made, it commonly involved a therapeutic change from a PI to an NNRTI. Even so, 47% of our patients were able to be successfully treated with a PI and tacrolimus, and six patients (40%) required no change to their therapy.
While the cumulative survival did not differ significantly between the HIV-infected and non-HIV populations after OLT, the mortality rate due to infectious etiologies was significantly greater (P=0.006) in the HIV patient cohort despite well controlled HIV infection. Other publications did not show increased susceptibility to infections postOLT in HIV positive recipients compared to non HIV recipients (8, 11, 12, 17, 27, 28). To our knowledge, no other published articles have described a statistically significant difference in the causes of mortality between the HIV and non-HIV populations after OLT. Interestingly, all of the infection-related deaths occurred within the first 6 months after OLT. Based on the documented pathogens (with the exception of aspergillus), it seems unlikely that any of the patients were harboring an occult infection prior to OLT.
Ragni et al. (15) noted the cumulative survival among HIV-positive recipients was similar to age- and race-comparable HIV-negative recipients (P=0.365, by log-rank test). However, they did note poorer survival among subjects with postOLT antiretroviral intolerance, a postOLT CD4+ count of <200 cells/μL, a postOLT HIV viral load of >400 copies/ml, and hepatitis C virus infection. While Ragni et al. did not discuss the specific causes of mortality in their cohort, all of these factors, especially the CD4+ count, are potential indicators of a greater risk of developing and dying of infection. The only two patients in our cohort with postOLT CD4+ counts less than 100 expired due to infectious causes.
In a recent study examining 58 HIV-infected patients awaiting OLT, 21 of the 58 expired while on the waitlist, 22 survived without OLT, and 15 were successfully transplanted (29). The 21 patients who died did not differ from the survivors (both with and without OLT) in the initial MELD score, CD4+ count, or HIV load. However, more than half (12 of 21, 57.1%) expired due to infection.
In conjunction with our observations, these data suggest that the HIV-infected population is particularly prone to infection as a cause of mortality both before and after OLT despite good control of the HIV disease. We have no clear explanation for the increased rate of infection-related mortality in the HIV infected group. Although, in some mortality cases, the CD4 count was lower than 100/ml, the percentage of CD4+ lymphocytes was usually within normal limits. No difference in immunosuppression protocols was executed in the 15 patients with HIV so there is no reason to suspect that the patients who died were overly immunosuppressed.
The difference in mortality due to infectious causes in our cohort suggests that, with a larger sample size, the difference in cumulative survival rates between the two groups may reach statistical significance. Nevertheless, a mildly reduced cumulative survival for the HIV-infected population should not preclude liver transplantation as long as survival after OLT is significantly superior to that achieved without OLT in this population. This concept has been evaluated in non-HIV transplant recipients and should play a major role in determining transplant benefit (30). A comparison of the survival with and without OLT (as well as cause-specific mortality comparisons) within the HIV-infected group would help clarify this issue.
The long-term results of our HIV-infected cohort appear to be promising; actuarial survival at 3 years was 73%: 8/15 patients survived beyond 3 years and 47% (7 of 15) were alive at last follow-up between 38 and 74 months posttransplant.
Acute cellular rejection was observed in 40% (6 of 15) of the HIV-infected patients. This is not different from current reports in the literature for the non-HIV population, in which incidences of rejection range from 25% to 70% (31, 32). Although HIV patients are considered immunosuppressed, two of the rejection episodes were severe and required treatment with monomurab-3, which has also been described in other series (33, 34). All of the rejection episodes were easily treated with the routine protocols as previously described.
HCV was detected postOLT in six of eight HCV co- infected patients. Two patients experienced spontaneous loss of HCV RNA at the time of OLT, which is an interesting and unexpected finding. This loss of HCV RNA has been maintained for more than 3 years. Other centers performing transplantation for HIV/HCV co-infected patients have also witnessed this phenomenon (35). As the total number of co-infected patients undergoing OLT is still low, more data and further investigation are needed before any meaningful conclusions can be drawn from these observations.
Of the patients who received anti-HCV therapy, all were able to tolerate pegylated interferon and ribavirin at varying doses; however, their long-term benefit remains to be determined. When the decision to initiate HCV therapy is made, the HAART protocol must be considered. Ribavirin increases the phosphorylation of abacavir and didanosine leading to toxic levels of these drugs- increasing the risk of hepatic decompensation or other complications related to mitochondrial toxicity, including pancreatitis, lactic acidosis, and peripheral neuropathy. Zidovudine may increase the risk of hemolytic anemia from ribavirin (36–38). There are no specific interactions between the interferons and HAART. Neither interferon nor ribavirin has any significant interactions with the commonly used immunosuppressive therapies.
None of the deaths in the HIV-infected cohort was attributed to recurrent HCV, whereas it was the third leading cause of death in the non-HIV group, accounting for 16% of deaths.
Management of hepatitis B was very successful in the HIV-coinfected patients. Prior to transplant an attempt was made to achieve undetectable HBV DNA levels, as active replication has been shown to impact negatively on survival (39, 40). This goal has also been advocated by other groups (14–19). Ninety-three percent of the patients had undetectable HBV DNA levels by polymerase chain reaction with the use of nucleoside and/or nucleotide analogs in conjunction with hepatitis B immune globulin (HBIG). An impending controversy is how long should HBIG be administered in the era of nucleoside/nucleotide analogs (20). At our institution, HBIG was successfully discontinued 1 week to 12 months postOLT depending upon the HBV DNA level before transplant.
We did not analyze the financial impact of transplanting a patient with HIV and whether or not there were any significant cost differences between those patients and the non-HIV population. The cost of liver transplantation is variable and complicated to calculate. Among the multiple factors contributing to the final cost are: pretransplant evaluation and diagnostic testing, transplant surgery, organ recovery, in-hospital stay, medications, and follow-up outpatient visits. According to the United Network for Organ Sharing, the estimated charges for liver transplantation are $392,800 for the first year with an annual follow-up charge of $21,900 (41). However, one of the biggest costs is the time spent in the ICU after OLT. The average length of stay in the ICU for the HIV-infected cohort was 20.6 days; the non-HIV population had an average length of stay of 16.3 days (P=NS). It must be noted that if a transplant recipient was on HAART therapy that included a protease inhibitor, the dose of tacrolimus would be greatly reduced which, in turn, would decrease the annual medication costs. Further detailed financial analysis is required to determine whether any true cost differentials exist between the HIV and non-HIV populations.
In summary, the survival of HIV infected patients post OLT was comparable to non-HIV recipients, although HIV-patients had significantly higher mortality from infectious complications in the first 6 months postOLT. This difference occurred despite adequate control of HIV postOLT. These findings suggest that OLT can be safely performed in HIV-infected patients, although with a higher risk of mortality from infectious complications.
Despite this increased risk, it would seem that at this point in time, there is no medical justification to withhold organs from patients whose HIV disease is well controlled, as their cumulative survival does not dramatically differ from the non-HIV population. The challenges involved with the care of these patients require a joint effort by a multidisciplinary team. The results of an ongoing multicenter National Institutes of Health–sponsored study will hopefully further clarify the specific problems of HIV- infected organ transplant recipients and optimize the clinical care of these patients.
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1. Criteria for liver transplant in HIV infection: GESIDA/GESITRA-SEIMC, PNS, and ONT Consensus Document (19).*
A. HIV-infected patients who do not fulfill the criteria for HAART
- CD4 lymphocyte count >350
B. HIV-infected patients who fulfill the criteria for HAART
- Must not have had an AIDS-defining opportunistic infection except tuberculosis, esophageal candidiasis, or Pneumocystis jiroveci pneumonia
- Must have a CD4 lymphocyte count >100 cells/μL
- Must have an undetectable viral load in plasma (HIV-1 RNA) (<50 copies/ml) at the time of transplant or have effective and durable therapeutic options for HIV infection during the posttransplant period
C. General criteria and criteria related to risk behavior
- Abstinence from drugs (heroin, cocaine) for at least 2 years
- No consumption of alcohol for at least 6 months
- Favorable psychological/psychiatric evaluation
- Understanding of the techniques and responsibilities involved in liver transplantation
- Social stability
- Women must not be pregnant
*The local criteria at the University of Miami differ from these guidelines in the following:
- For patients who fulfill the criteria for HAART, HIV viral load must be less than 200 copies/ml or have effective and durable therapeutic options for HIV infection during the posttransplant period.
- Patients who have suffered from tuberculosis, esophageal candidiasis, or Pneumocystis jiroveci pneumonia must have a CD4 lymphocyte count of >200 cells/μL.