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Outcome of patients with hepatitis B virus and HIV referred for liver transplantation
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Liver Transplantation
May 2006, Volume 12, Issue 5, Pages 801-807
Norah A. Terrault 1 *, Jonathan T. Carter 1, Laurie Carlson 1, Michelle E. Roland 1, Peter G. Stock 2
1Department of Medicine, University of California at San Francisco, San Francisco, CA
2Department of Surgery, University of California at San Francisco, San Francisco, CA
This study is the first to assess the outcomes of HBV-HIV coinfected patients referred for liver transplantation.
"......Our study highlights the importance of timely referral for consideration of liver transplantation, the high frequency of lamivudine-resistant HBV infection in these patients...... We found that only 26% of referred patients are eligible candidates. This low rate of ineligibility reflects, in part, a lack of knowledge on the part of referring physicians regarding the indications and appropriate timing for referral for liver transplantation.....
....Ongoing close monitoring of HBV replication status in HBV-HIV coinfected patients will be essential in identifying the emergence of drug-resistant HBV and in making therapeutic decisions to minimize the risk of liver-related complications (so viral breakthrough & severe liver decompensation doesn't occur.....Control of HBV replication in the setting of active liver disease (elevated serum aminotransferase levels and/or presence of necroinflammation on liver histology) has been associated with stabilization of clinical status in those with decompensation...."
Study Funded by:
- UCSF AIDS Research Institute
- University of California University-Wide AIDS Research Program; Grant Number: TP99-SF-001, SF00-SF-154
- The National Institutes of Allergy and Infectious Disease; Grant Number: AI40166-06)
- Solid Organ Transplantation in HIV: Multi-Site Study funded by the National Institute of Allergy and infectious Diseases; Grant Number: AI052748
- UCSF Liver Center Grant; Grant Number: P30 DK-26743
ABSTRACT
The outcome of patients with hepatitis B virus (HBV) and human immunodeficiency virus (HIV) referred for liver transplantation (LT) is unknown.
A high frequency of lamivudine-resistant (LAM-R) HBV infection may increase the risk of liver-related death pre-transplantation and prophylaxis failure post-transplantation.
We evaluated the association of LAM-R HBV on pre-transplant survival and post-transplant outcomes in 35 consecutive HIV-HBV coinfected patients referred for LT between July 2000 and September 2002.
At the time of referral, the median CD4 count was 273/mm, MELD was 14, and LAM-R HBV infection was present in 67%. Among these referred patients, 26% were listed, 29% not listed due to relative/absolute contraindications; 26% not listed as too early for LT; 9% not listed as too sick for LT; and 11% died during transplant evaluation.
Of the 9 listed patients, 4 remained listed, 1 died 18 months post-referral, and 4 were transplanted (11% of total) 3 to 40 months after listing. Of 17 evaluated but not listed patients, 5 died (p=0.38 compared to listed group) and all deaths were liver-related.
All the HBV-HIV coinfected patients, who were transplanted, are HBsAg negative and have undetectable HBV DNA levels on prophylactic therapy using hepatitis B immune globulin (HBIG) plus lamivudine, with and without tenofovir or adefovir, with median 33.1 months follow-up.
Late referral and the presence of LAM-R HBV pre-transplantation are common in referred HIV-HBV patients. In HIV-HBV coinfected patients undergoing LT, HBV recurrence is successfully prevented with combination prophylaxis using HBIG and antivirals.
INTRODUCTION
Liver disease is increasingly recognized as a significant cause of morbidity and mortality among HIV-infected individuals. As deaths due to HIV-related disease have declined, a proportionately greater number of HIV-infected persons are dying of liver-related complications. Both hepatitis C and hepatitis B have emerged as important contributors to liver-related complications.[1-3] In the largest study evaluating the impact of HBV infection on survival, liver-related mortality in HIV-HBV coinfected men was found to be 14.2 per 1000 compared to 1.7 per 1000 (p < 0.001) in men with HIV-1 infection alone.[2] The rate of liver-related mortality was higher in the years since highly active antiretroviral therapy (HAART) was introduced[2][3] and in those with low nadir CD4+ cell counts.[2]
Since the nucleoside analogue lamivudine has both anti-HIV and anti-HBV activity, many HIV-infected patients with HBV coinfection have received prolonged lamivudine therapy as a component of HAART. In HBV/HIV coinfected patients, the incidence of lamivudine-resistant HBV is 50% after two years of therapy[4][5] and approaches nearly 100% after four years. The natural history of HBV disease in coinfected patients is only partially known, but the development of lamivudine-resistant HBV infection may have significant negative consequences. Patients with HIV-HBV coinfection may be more likely to have lamivudine-resistant HBV infection and in patients with cirrhosis, liver decompensation may result in an urgent need for liver transplantation.[6]
Liver transplantation is the treatment of choice for individuals with end-stage liver disease. Historically, HIV infection has been considered a contraindication for liver transplantation due to the theoretical concerns of worsening HIV infection and risk of opportunistic infections in the setting of dual immunosuppression related to HIV and anti-rejection medications. With the advent of HAART and improved ability to prevent HIV-related complications, transplantation of HIV-infected individuals has been undertaken in a selected number of transplant programs. Recent single center reports has been positive,[7-10] but with some concerns regarding patients with hepatitis C infection,[9][10] who are at risk for recurrent disease post-transplantation, like non-HIV transplant recipients. A large NIH-sponsored study of the safety and efficacy of liver and kidney transplantation in HIV-infected individuals is underway and can be expected to provide a more comprehensive evaluation of outcomes in these patients.
In the past decade, the outcomes of patients with chronic HBV infection undergoing liver transplantation has undergone substantial improvements.[11] The availability of effective prophylactic therapies including lamivudine, adefovir and hepatitis B immunoglobulin (HBIG) has resulted in graft and patient survival comparable to those with non-viral diseases. A combination of HBIG and one or more nucleos/tide analogue(s) are commonly used for prophylaxis post-transplantation, and such regimes are effective in 90% of transplant recipients.[12] However, most of these data were generated in patients without preexisting lamivudine-resistant HBV infection and it is unclear whether similar results can be obtained in the setting of drug-resistant HBV. Single center reports suggest the presence of pre-transplant lamivudine-resistant HBV is a risk factor for failure of prophylaxis post-transplantation.[13][14]
In this study, we evaluated the outcomes of HBV-HIV infected patients referred for consideration of liver transplantation, the frequency of lamivudine-resistance among patients presenting for consideration of liver transplantation, and the pre- and post-transplant outcome of coinfected patients undergoing liver transplantation.
DISCUSSION
In the era prior to the development of HAART, HIV-infected patients were largely excluded from consideration of liver transplantation due to relatively high mortality rates.[16][17] However, with continued advances in the understanding of HIV pathogenesis and the recognized benefits of HAART, as well as concurrent advances in immunosuppression and management of post-transplant complications, there are an increasing number of transplant programs undertaking the transplantation of HIV-infected patients.[7][8][10][18-19] Recent reports have highlighted the unique aspects of clinical management in these patients, including the interactions between immunosuppressive agents and antiretroviral drugs,[20-22] the importance of adequate HIV suppression post-transplantation, and the risk of recurrent HCV disease.[7][18][19] HBV coinfection is an important cause of liver failure in HIV-infected patients[2] and a clear understanding of the unique aspects of HBV treatment are essential to optimize pre- and post-transplant outcomes. Our study highlights the importance of timely referral for consideration of liver transplantation, the high frequency of lamivudine-resistant HBV infection in these patients, and the key role of agents such as adefovir and tenofovir in the management of HBV-HIV coinfected patients with decompensated liver disease.
This study is the first to assess the outcomes of HBV-HIV coinfected patients referred for liver transplantation. We found that only 26% of referred patients are eligible candidates. This low rate of ineligibility reflects, in part, a lack of knowledge on the part of referring physicians regarding the indications and appropriate timing for referral for liver transplantation. While 20% of referred patients did not meet minimal listing criteria for liver transplantation and were referred too early, an equal percent were referred too late with liver-related deaths occurring before the transplant evaluation could be completed. Since transplantation in HIV-infected individuals is relatively new as a treatment option for end-stage liver disease, there is a need to educate referring gastroenterologists and infectious disease specialists regarding the indications and contraindications for transplantation in this population.
As anticipated, lamivudine-resistant HBV infection was common among coinfected patients. Adefovir, tenofovir and entecavir are active against lamivudine-resistant HBV and are safe agents in patients with decompensated liver disease.[6][13][23][24] In our study, 30% of patients were on treatment with adefovir or tenofovir for lamivudine-resistant HBV at the time of referral. Those patients on antiviral drugs with efficacy against lamivudine-resistant HBV had a higher likelihood of survival than those not receiving these agents, suggesting that untreated lamivudine-resistant HBV infection can have serious clinical consequences. This argues strongly for regular monitoring of HBV DNA levels in HBV-HIV coinfected patients, so that virological breakthrough can be detected early and new anti-HBV therapies instituted before clinical deterioration. Ongoing control of HBV replication long-term will be of equal importance in maintaining stability of liver disease in coinfected patients. In this regard, the use of anti-HBV drugs (alone or in combination) with goal of minimizing the risk of drug resistance would be the optimal treatment strategy, especially in patients with cirrhosis who may decompensate when drug-resistant HBV infection develops.
Control of HBV replication in the setting of active liver disease (elevated serum aminotransferase levels and/or presence of necroinflammation on liver histology) has been associated with stabilization of clinical status in those with decompensation. In patients with wild-type HBV infection, treatment with lamivudine prior to transplantation has been associated with improvement in survival and delays in the need for transplantation.[25-27] Similarly, treatment of lamivudine-resistant HBV infection in non-HIV infected patients with adefovir results in significant improvements in total bilirubin, prothrombin time and albumin levels and stabilization or improvement in Child-Pugh score in the majority of patients.[23] However, clinical improvements lag behind suppression of HBV DNA replication and patients typically require approximately six months of treatment to derive clinical benefits. In our study, the majority of deaths occurred within three months of referral, suggesting the clinical state of these patients was too advanced to obtain the clinical effects of effective HBV suppressive therapy. However, one listed patient with lamivudine-resistant HBV infection who was treated with adefovir improved significantly to the point that liver transplantation was no longer needed and the patient was removed from the list.
The optimal anti-HBV therapy in patients with HIV coinfection is not known. Several approved anti-HIV agents have anti-HBV activity, including lamivudine, tenofovir, and emtricitabine. The use of one or more agents in the treatment of HIV infection has important implications for control of HBV infection and vice versa. The use of lamivudine as HIV therapy in a patient with unrecognized HBV infection could limit future HBV treatment choices because of the development of lamivudine-resistant HBV. Likewise, the treatment of HBV infection with lamivudine or tenofovir alone in a co-infected patient will lead to HIV resistance to these agents and thereby compromise future anti-HIV treatment options. Both hepatologists and HIV treatment providers need to be aware of the potential impact of nucleos/tide analogue choices in the management of both HBV and HIV infections.
Our limited experience indicates patients with HIV-HBV coinfection can successfully undergo liver transplantation without progression of viral disease, even in the setting of lamivudine resistance. Combination therapy using nucleos/tide analogues plus HBIG was highly effective in the prevention of HBV recurrence post-transplantation. These results add to the evidence of excellent short and longer-term outcomes of HBV-HIV coinfected transplant recipients.[8][9][28]
In summary, we have found the HIV-HBV coinfected individuals referred for liver transplantation had a high prevalence of lamivudine-resistant HBV infection and that use of drugs to suppress HBV replication in these patients (i.e. adefovir and tenofovir) was associated with improved survival. This emphasizes the importance of control of HBV replication in the setting of decompensated liver disease. The availability of an increasing number of drugs with both HIV and HBV activity (e.g. lamivudine, tenofovir, emtricitibine) increases both the opportunities to use drug combinations to control HBV infection pre and post-transplantation, but also may lead to the emergence of multidrug resistant HBV in the future. Ongoing close monitoring of HBV replication status in HBV-HIV coinfected patients will be essential in identifying the emergence of drug-resistant HBV and in making therapeutic decisions to minimize the risk of liver-related complications.
RESULTS
HBV-HIV Coinfected Patients Referred for Liver Transplantation
Baseline Characteristics
A total of 35 HBV-HIV coinfected patients were referred for consideration of liver transplantation during the study period. All but one were male (97%), the majority were Caucasian (93%), and the median age was 46 years (range 28-55 years). The median duration from diagnosis of HBV infection was 11 years (range 1-28 years). The known duration of HIV infection closely mirrored that of HBV infection with a median duration of infection of 12 years (range 1-21 years).
At the time of referral, 83% of patients were receiving HAART with the remaining patients off HAART due to concerns regarding potential hepatotoxicity related to one or more HAART agents. The median duration of lamivudine treatment in those patients who had been on a lamivudine-containing HAART regime was 60 months (range <1-144 months). The median CD4 count was 276/mm3 (range 94-956/mm3) and HIV RNA was undetectable in 79% at the time of referral. The median HIV RNA in those with detectable viral loads was 148 copies/ml (range 140-250,040 copies/ml).
A total of 67% of patients met the criteria for lamivudine-resistant HBV infection based upon review of historical records of HBV DNA levels on lamivudine therapy. In three patients, insufficient virological data were available to determine whether lamivudine-resistance was present. At the time of referral, 48% of all patients were on an additional anti-HBV agent with activity against lamivudine-resistant HBV: 30% on tenofovir, 13% on adefovir and 4% on tenofovir and adefovir.
Outcome of Referred Patients
Of the 35 patients referred for consideration of liver transplantation, nine (26%) were wait-listed, 10 (28%) had contraindications for liver transplantation, nine (26%) were too early for transplantation (did not meet minimal listing criteria), three (9%) were too sick to be considered for transplantation (intubated and/or multi-organ failure) and four (11%) died during the evaluation process (Figure 1). Contraindications for liver transplantation were commonly related to non-HIV issues rather than HIV issues. Only three of the referred patients had conditions related to their HIV infection that were specific contraindications to liver transplantation during the study period: 2 had a history of Kaposi's sarcoma and 1 had a CD4 count less than 100/mm3.
After the initial referral and with a median follow-up of 7.5 months (mean 10, range 0-48 months), 10 patients died, all of liver-related complications. In addition to the four deaths occurring during the evaluation process, all three patients judged to be too sick for liver transplantation at the time of referral died, as well as two patients with contraindications and one patient listed for liver transplantation. The overall 1-year cumulative survival from time of referral was 67%, with the majority of deaths occurring within three months of referral (Figure 2a). Treatment with adefovir or tenofovir prior to or at the time of referral was on the only factor identified as predictive of survival with or without transplantation (Table 1 and Figure 2b).
Of the nine patients who were listed for liver transplantation, four (11% of entire referral population) underwent liver transplantation, two with deceased donors and two with living donors. Two patients were removed from the list, one due to liver-related complications leading to death 18 months post-referral, and one due to significant improvement in the status of his liver disease on adefovir therapy. Five patients remained wait-listed.
Post-Transplant Course of HBV-HIV Coinfected Patients
The pre-transplant features of the four HIV-HBV coinfected liver transplant recipients are shown in Table 2. The median biological MELD score at the time of transplantation ranged from 16 to 28. All patients were on HAART and anti-HBV therapy at the time of transplantation and had undetectable HBV DNA levels by HBV quantitative assay.
Overall cumulative patient and graft survival were 100%. All patients received prophylactic therapy for HBV using HBIG plus lamivudine with or without adefovir or tenofovir. HBV antivirals were started concurrent with reinitiation of HAART post-transplantation. In all patients, the same antivirals used pretransplantation were continued post-transplantation and all patients have remained HBsAg negative, anti-HBs positive and without evidence of HBV recurrence after a median follow-up of 33 months (range 18-48 months) (Figure 3). Changes in anti-HBV therapy post-transplantation were required in two patients. One patient developed a transient low-level increase in HBV DNA at month nine post-transplantation. HBsAg was negative and anti-HBs positive during this period and repeat testing of HBV DNA was undetectable. However, tenofovir was added to lamivudine and HBIG to reduce the possibility of any future virological escape. A second patient developed acute interstitial nephritis and progressive renal dysfunction at month 6 post-transplantation. Tenofovir was discontinued due to concerns of possibly toxicity and adefovir was not considered an option in the setting of new onset renal dysfunction. This patient was maintained on higher dose HBIG infusions (increased from 5000 IU monthly to 10,000 IU monthly) to provide a higher anti-HBs titers and lamivudine was continued. There has been no evidence of HBV infection; HBsAg remains negative and HBV DNA levels undetectable.
HIV viral loads remained undetectable in all patients on continuous HAART. One patient required interruption in HAART due to concerns regarding renal toxicity and HIV RNA levels were transiently positive while the patient was off HAART but became undetectable again once HAART was resumed. There have been no episodes of acute rejection and there have been no emergent opportunistic infections. The median CD4 count on last follow-up was 315/mm3 (range 125 to 505/mm3), which was equal to or higher than pre-transplant values in all patients.
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