Management of the hepatitis B virus in the liver transplantation setting: A European and an American perspective

A total of 5 to 10% of patients undergoing orthotopic liver transplantation (OLT) have hepatitis B virus (HBV)–associated chronic or fulminant liver disease. Long-term survival depends on the prevention of allograft reinfection or the slowing of disease progression in those who have recurrent disease. In the absence of prophylactic measures, the risk of HBV reinfection after OLT is approximately 80% and is related largely to the level of HBV replication at time of transplantation.1, 2 Recurrent infection in the graft can lead to graft failure, retransplantation, or death and in the past was the most common cause of reduced patient and graft survival.1, 2 Significant improvements in both patient and graft survival in HBV liver transplant recipients have been made during the past 15 years. The first major therapeutic advance was the use of long-term hepatitis B immune globulin (HBIG) to prevent reinfection.3, 4 The second major advance came with the availability of highly effective and well-tolerated antiviral agents against HBV, such as lamivudine and adefovir dipivoxil, which improved the outcomes of both patients with decompensated cirrhosis awaiting transplantation5-7 as well as those transplant recipients who had recurrent HBV disease.7-9 Finally, with the use of HBIG in combination with antivirals (lamivudine and adefovir), the risk of reinfection has been reduced to 10% or less during the first 2 years following transplantation.10-14 As a result of these therapies, the outcomes of patients with acute and chronic HBV-related liver disease undergoing liver transplantation are now similar to or better than those of patients undergoing transplantation for non-HBV indications.15, 16 While the therapeutic advances in the management of HBV in transplant recipients represents a major success story in transplantation in the past decade, there remain important challenges. Long-term prophylaxis with HBIG is expensive and inconvenient and has been associated with the development of surface antigen mutations. Similarly, emergence of lamivudine and adefovir resistance occurs with prolonged therapy in patients awaiting OLT and in those with recurrent disease posttransplantation. Thus, new, more cost-effective strategies to prevent reinfection and new antiviral agents with activity against resistant HBV mutants are needed. Additionally, strategies that would eliminate the need for long-term or indefinite therapy, such as therapeutic vaccination and other immune therapies, would further optimize outcomes in liver transplant recipients with HBV. OLT, orthotopic liver transplantation; HBV, hepatitis B virus; HBIG, hepatitis B immune globulin; anti-HBs, hepatitis B surface antibody; PCR, polymerase chain reaction; HBsAg, hepatitis B surface antigen; IM, intramuscular; IV, intravenous; anti-HBc, hepatitis B core antibody. In the absence of prophylaxis of HBV reinfection, the 5-year survival in transplant recipients is only 40% to 60%.1, 2 Survival significantly improved with use of HBIG prophylaxis. In 206 European patients given long-term HBIG therapy, outcomes of OLT for HBV infection were similar to the results achieved with other indications for OLT, with survival rates at 1, 5 and 10 years of 91%, 81%, and 73%, respectively.15 A similar picture is seen in studies from the United States. In the last 2 decades, the 5-year survival of HBV-infected transplant recipients has increased from 53% in the period of 1987-1991 to 69% in the period of 1992-1996, to 76% in the period of 1997-2002.16 This significant improvement in survival corresponds to the introduction of therapeutic innovations, including HBIG and lamivudine. HBV reinfection is the consequence of either an immediate reinfection of the graft by circulating HBV particles, or reinfection of the graft from HBV particles coming from extrahepatic sites, or both. When HBV reinfection occurs in patients receiving prophylactic therapy with HBIG, there are 2 possible explanations: (1) The titer of hepatitis B surface antibody (anti-HBs) achieved with HBIG was inadequate to protect the graft against reinfection, or (2) escape mutants in the pre-S/S region of the HBV genome have developed, resulting in reduced binding of anti-HBs and loss of protective efficacy.17, 18 When HBV reinfection occurs in compliant patients treated with lamivudine monotherapy, the emergence of mutations in domains B and C of the polymerase, resulting in resistance to lamivudine, is the cause.19 Reinfection in patients receiving combination therapy with HBIG and antivirals, such as lamivudine, is less frequent than with HBIG or lamivudine monotherapies, but in the limited cases reported it appears to be due to combined mutations in both the surface and polymerase genes20 or inadequate protective titers of anti-HBs. A common theme for all studies using prophylactic therapies, is that the level of viral replication pretransplantation (attained naturally or with drug therapy) is an important predictor of prophylactic therapy success, and failure of prophylaxis with all the therapies to date has been more frequent in those with high levels of HBV DNA pretransplantation.17-20 Replicative and nonreplicative HBV infection has been defined by the detection of HBV DNA in serum. Earlier studies used hybridization assays that had a detection limit of ∼105 copies/mL, whereas recent studies use more sensitive assays (polymerase chain reaction [PCR] or branched DNA types), which have detection limits of ∼102-3 copies/mL. Thus the term replicative HBV infection has different meanings in different studies, depending upon the HBV DNA test used. In general, the majority of previously published data on risk of recurrent HBV disease in liver transplant recipients defines "replicators" as those patients with HBV DNA levels of 105 copies/mL or greater. The definition of "replicators" is changing, however, and future studies in transplant recipients are likely to utilize lower levels of HBV DNA to define "replication status." The contribution of HBV from extrahepatic sites to the risk of HBV reinfection remains unclear, but in one report, the HBV strain that predominated posttransplantation was the strain present in the peripheral blood mononuclear cells but not the serum pretransplantation.21 While primarily of historical interest, the experience with HBIG monotherapy highlights the importance of replication status on the efficacy of prophylaxis, the use of anti-HBs titers to guide HBIG dosing to prevent HBV reinfection, and the risk of hepatitis B surface antigen (HBsAg) escape mutations emerging with prolonged therapy. Interestingly, despite the use of HBIG as prophylaxis in transplant patients for the past 15 years, the mechanisms by which HBIG protects the transplanted liver against HBV reinfection are not fully understood. One hypothesis suggests that HBIG protects naive hepatocytes against HBV released from extrahepatic sites through the blocking of a putative HBV receptor. Antibody-dependent cell-mediated cytotoxicity may also contribute to infected target cell lysis. There is evidence for a dose-dependent response to HBIG treatment.3, 22 In 1987, the Hannover group reported that immunoprophylaxis with HBIG, to maintain a serum anti-HBs level >100 IU/L for a minimum of 6 months after OLT, could prevent HBV reinfection in liver transplant recipients.23 These results were substantiated by a large, multicenter European study published in 1993 that demonstrated a dramatic reduction in the rate of HBV recurrence, from 75% in patients receiving no or short-term therapy with HBIG to 33% in those receiving long-term HBIG treatment (P < 0.001).3 Thereafter, the use of HBIG as prophylaxis for HBV-infected patients undergoing liver transplantation became the standard in most transplant programs in Europe, North America, and Australia, although the cost and availability of HBIG were limiting in some centers. While studies from Europe and the United States demonstrated an improvement in survival with long-term immunoprophylaxis with HBIG, HBIG was not equally effective in all HBV patients.4, 24-26 HBV recurrence despite HBIG prophylaxis occurred in 29% to 38% in patients transplanted for nonreplicative HBV cirrhosis vs. 70% to 96% in patients with replicative HBV cirrhosis during follow-up of 2 years or less.3, 22, 24, 27 In these studies HBV DNA detection was based on hybridization assays. These results led some programs to deny liver transplantation to HBsAg-positive patients with active replication pretransplantation. Fortunately, subsequent studies showed that the rate of HBV reinfection among HBV DNA–positive patients could be improved upon by the use of higher HBIG doses and with maintenance of serum anti-HBs levels ≥500 IU/L.25, 28 In those studies using higher doses of HBIG with target anti-HBs titers >500 IU/L, HBV recurrence was 0% to 15% and 16% to 35% of patients transplanted for nonreplicative and replicative HBV cirrhosis, respectively. Pharmacokinetic studies using fixed doses of HBIG showed that anti-HBs titers ≥500 IU/L were necessary within the first 7 days to prevent infection, >250 IU/L for days 8-90 posttransplantation, and >100 IU/L thereafter.25 Taken in total, these studies indicated that HBV reinfection could be prevented in the majority of HBsAg-positive patients with use of high-dose HBIG protocols and close monitoring of anti-HBs titers to prevent prophylaxis failures, especially in replicators.4, 24-26, 28 HBIG has been administered in 2 different ways: (1) at a frequency dictated by the maintenance of specific anti-HBs levels, or (2) on a fixed schedule that generally "overshoots" the target anti-HBs level to provide a wide safety margin. The latter approach is simpler and requires less monitoring but is more expensive, especially after the first year posttransplantation. HBIG has a satisfactory safety record, and adverse events observed have been usually minor.29 Infusion-related reactions are mild and uncommon with most HBIG preparations nowadays. Evaluation of patients failing HBIG prophylaxis indicates that early recurrence of HBV post-OLT is typically related to insufficient dosing of HBIG and is more frequent in replicators, whereas late recurrences are usually caused by the emergence of mutations involving the "a" determinant of the HBV surface protein that alters HBIG binding.4, 24 In an effort to find less costly ways of providing HBIG prophylaxis long-term, alternative approaches have been studied, including the use of intramuscular HBIG, non-HBIG forms of anti-HBs, and low-dose or short-term HBIG in combination with antivirals.4, 27, 30, 31 Intramuscular (IM) injections of HBIG appear to be effective in stable patients initially treated with intravenous (IV) HBIG, although long-term outcomes (beyond 2 years posttransplantation) are lacking. Given the limited volumes that can be given per IM injection, only patients with low HBIG requirements are suited for IM HBIG administration.4, 27 High-titer anti-HBs from plasma donors is an economical form of anti-HBs, but clinical experience is limited, and no approved anti-HBs plasma product is available in the United States or Europe.30, 31 Monoclonal antibodies may offer a safe, readily available alternative form of anti-HBs.32 A phase II study using a mixture of 2 fully human monoclonal antibodies against HBsAg in liver transplant recipients is underway in Europe, Israel, and the United States. Since the current practice is to use HBIG in combination with antivirals for long-term prophylaxis, recent studies have focused on defining the minimal doses and duration of HBIG treatment (see Post-OLT Combination Prophylaxis). High levels of HBV DNA at the time of transplantation are associated with failure of prophylactic therapy in transplant recipients. Consequently, in the not so recent past, the presence of HBV replication by hybridization assays (limits of detection ∼105 copies/mL) was considered a contraindication to OLT by most European centers33 and many U.S. centers. The availability of safe and effective antiviral drugs for use in patients with decompensated cirrhosis allowed many HBV-infected patients to achieve low levels of HBV DNA based on PCR assays prior to transplantation and thereby become eligible for OLT. The current goal of antiviral therapy in patients awaiting transplantation is to achieve low levels of HBV DNA (<102-3 copies/mL) prior to transplantation. Some patients awaiting transplantation have low levels of HBV DNA naturally and do not antiviral therapy started until the time of transplantation. However, these nonreplicators may develop HBV DNA increases prior to transplantation, and monitoring of HBV DNA levels every 2-3 months is useful for identifying those with increased viral replication that warrant initiation of antiviral treatment. An additional advantage of antiviral therapy in replicators can be the reversal of symptoms of decompensation and clinical stabilization in some patients, resulting a delay in the need for transplantation. An ideal antiviral agent for patients with decompensated cirrhosis awaiting transplantation would have a rapid and potent antiviral action without inducing deterioration of liver function. Earlier studies evaluated interferon and famciclovir; both drugs suffered from a modest response rate (at best) and in the case of interferon, a major limitation was poor tolerability in patients with cirrhosis.34 Currently, interferon and famciclovir are not recommended for the treatment of patients with hepatitis B awaiting OLT, as superior and better-tolerated anti-HBV agents are now available. The outcomes of treatment with lamivudine and adefovir are much more positive, and these drugs are the treatments of choice for patients with decompensated cirrhosis awaiting transplantation. Entecavir, the most recently approved HBV agent, is effective against wild-type and lamivudine-resistant HBV. Studies using entecavir in patients with decompensated cirrhosis or liver transplant recipients have not been published, but use of this drug in these populations can be expected, given its efficacy and safety in chronic HBV patients. Experience with tenofovir is more limited, but among liver transplant recipients with HIV-coinfection, tenofovir would be the antiviral treatment of choice. The development of drug resistance due to mutations in the HBV DNA polymerase gene is the main limitation of these antiviral treatments. Lamivudine is well tolerated in patients with decompensated cirrhosis, is effective in both hepatitis B e antigen–positive and hepatitis B e antigen–negative chronic HBV,35 and achieves a loss of HBV DNA by molecular hybridization in 62 to 100% of patients within 2 to 3 months of therapy.5, 6, 10-12, 19, 35-40 However, with discontinuation of lamivudine after 1 year, relapse of HBV DNA levels is common, especially if sustained hepatitis B e antigen seroconversion has not occurred during treatment. The development of mutations in the YMDD motif (domain C) of the HBV DNA polymerase gene is the main limitation of treatment, with a reported incidence of 15% to 20% per year of therapy in patients awaiting OLT.5, 6, 10-12, 19, 35-40 Several studies have highlighted the clinical benefits in patients able to achieve sustained suppression of HBV DNA pretransplantation.5, 19, 37, 40-42 However, these clinical improvements, which lag behind the virological responses, are seen typically only after 6 months of treatment. Patients with severely decompensated disease may not survive long enough to achieve the clinical benefits despite achieving a virological response.19, 41, 42 The only controlled study compared lamivudine-treated cirrhotics with a historical untreated control group, and it found that treatment conferred a survival advantage.5 In a prospective, multicenter U.S. study of 154 patients listed for OLT and receiving lamivudine for a median of 16 months, 32 of the 154 (21%) patients died during the observation period, with most of the deaths (25 of 32; 78%) occurring within the first 6 months of therapy.6 The estimated actuarial 3-year survival of patients who survived at least 6 months was 88% on continued treatment. Virological responses to lamivudine were similar in survivors and nonsurvivors. In multivariate analysis, an elevated serum bilirubin, elevated creatinine, and detectable serum HBV DNA by hybridization assay prior to treatment were strong and independent predictors of 6-month mortality.6 The severity of liver disease at the time of starting therapy was a better predictor of early mortality than the virological response to lamivudine. Thus, for patients with advanced liver failure, OLT remains of critical component of management, irrespective of the antiviral response. In patients with YMDD mutants at the time of transplantation, prophylaxis using HBIG and continued lamivudine has not been consistently successful in preventing reinfection.11, 39, 43, 44 In this setting, use of high-dose HBIG is likely important to maximize success of prophylaxis. Moreover, the addition of another antiviral agent with efficacy against the drug-resistant virus would be expected to further reduce the risk of prophylaxis failure. Thus, for patients with lamivudine-resistant HBV and elevated HBV DNA levels pretransplantation, combination HBIG and adefovir, entecavir, or tenofovir is recommended to prevent posttransplant reinfection. Adefovir dipivoxil, a nucleotide analogue of adenosine monophosphate, is a potent inhibitor of the wild-type45, the e-minus strain.46 and both the famciclovir and lamivudine-resistant HBV mutants.47-49 Thus, adefovir is an effective therapy for patients with wild-type, lamivudine-resistant, and famciclovir-resistant HBV infection. A multicenter study reported 128 U.S. and European patients with decompensated cirrhosis with lamivudine-resistant HBV treated with adefovir 10 mg daily for a median of 19 weeks.7 The median reductions in serum HBV DNA levels were 3.1- and 4.1-log copies/mL after 24 and 48 weeks of therapy, with 81% of patients achieving an undetectable HBV DNA by PCR. Normalization of alanine aminotransferase levels occurred in 76% of patients with abnormal baseline values, and the Child-Turcotte-Pugh score stabilized or improved in over 90% of patients. Like lamivudine, the attainment of clinical benefits required survival of approximately 6 months, so for patients with advanced liver decompensation, concurrent consideration of OLT is important. Survival after 1 year of adefovir treatment was 84%, which compares favorably to historical controls. Dose reductions of adefovir were required for patients with preexisting renal dysfunction (i.e., creatinine clearance <50 mL/minute). No patient developed evidence of viral resistance to adefovir after 48 weeks of therapy. However, recent studies with longer durations of therapy report virologic resistance to adefovir in association with the polymerase mutation N236T (D domain) and A181T/V (B Domain).50, 51 The N236T and A181T/V mutants are sensitive to lamivudine. Compared to lamivudine, the emergence of resistance with adefovir treatment was later in the treatment course and less frequent (2% at 2 years), which may argue for the use of adefovir rather than lamivudine as primary treatment.52 Tolerance of adefovir 10 mg/day in decompensated cirrhotic patients was good with no significant renal toxicity identified. Both lamivudine and adefovir require dose adjustment for renal dysfunction. The timing of initiation of antiviral therapy in HBV-infected patients listed for OLT is important. For patients with high levels of HBV DNA who are expected to undergo transplantation within months, an antiviral agent that achieves a rapid and large magnitude decline in HBV DNA is desirable. The presence of high levels of HBV DNA pretransplantation, whether due to uncontrolled wild-type HBV or to the development of breakthrough viremia with drug resistance, increases the risk of failure of prophylactic therapy posttransplantation.11, 39 For those with decompensated cirrhosis, prolonged antiviral treatment is necessary to obtain the clinical benefits, but the risk for developing drug-resistant mutations also increases with the duration of treatment and may lead to worsening of liver decompensation.6 Thus, in patients expected to be on long-term antiviral therapy prior to transplantation, the decision to start treatment requires careful weighing of the risks of drug resistance versus the potential for clinical Studies the different antiviral agents in patients awaiting liver transplantation have not been of the of potential importance antiviral efficacy against drug-resistant HBV, and risk of drug resistance with prolonged therapy to start treatment and to use be based upon the of therapy reversal of the specific virological of the patient DNA presence of drug-resistant and the time to transplantation. For those on antiviral therapy awaiting transplantation, HBV DNA be (at least every 3 by PCR assay to for antiviral efficacy and the development of viral Patients with primary resistance or response than 10% of the defined by a of HBV DNA level from baseline of less than the be considered for a in antiviral agent or the addition of a second Similarly, patients who developed viral breakthrough of HBV DNA by more than from a different or additional antiviral drug with efficacy against the HBV HBV be to HBV mutations of mutations poor to the Since the discontinuation of one antiviral agent and with another the patient to the risk of hepatitis and decompensation, there is for a second drug to the first drug therapy) rather than However, whether combination therapy is necessary long-term is not least in combination therapy would be expected to reduce the of future emergence of drug As one of the major of using treatment with or nucleotide is the risk of emergence of viral The of of the and for use in especially in patients with liver disease in the of drug-resistant may be and and are potent of the wild-type and HBV and with other or nucleotide can be expected to the of HBV in patients. The importance of antiviral therapy with the goal of viral suppression and the risk of drug resistance is especially critical in this patient Combination therapy be more in some patients. Finally, it is important to that patients who may have liver failure, and transplantation remains the primary treatment for these Virological also remain at risk for and continued is during antiviral treatment until the time of transplantation. Lamivudine has been evaluated as a prophylactic therapy, with the drug started pretransplantation and continued posttransplantation on long-term, indefinite The at 1 year posttransplantation was with only a 10% recurrence However, with longer rates of recurrence at 3 years was due to the emergence of escape mutations in the YMDD motif of the polymerase These mutations were observed in patients with a high level of viral replication prior to drug results were reported in other studies, with HBV recurrence in to of patients The development of HBV recurrence with YMDD mutants was associated with a clinical prophylactic therapy using lamivudine was not effective and associated with high rates of reinfection in replicative patients, most transplant programs in the United Europe, and do not use lamivudine monotherapy for prophylaxis. a combination of HBIG and antivirals is used for prophylaxis (see Combination Prophylaxis). combination therapy is required in all patients is B e antigen–negative patients with undetectable levels of HBV DNA by PCR in the absence of antiviral therapy had a low risk of recurrence with lamivudine that these patients may be for prophylactic treatment using lamivudine or adefovir monotherapy or antivirals with an course of There are no available data on adefovir monotherapy as monotherapy prophylaxis. The use of lamivudine or adefovir pretransplantation by a combination of antivirals and HBIG improved control of viral replication pretransplantation and forms of prophylaxis posttransplantation to risk of reinfection. this combination the HBV recurrence rate at 1 to 2 years posttransplantation has been reduced to 24, 39 In serum HBV DNA is by PCR in most cases years suppression of HBV DNA levels prior to transplantation appears to reduce the of HBIG posttransplantation.11, The results achieved with combination treatment may be the consequence of the of reduced of HBsAg with antiviral therapy as well as a rate of escape mutations in the pre-S/S and polymerase Since the HBV genome of the polymerase the surface Consequently, mutations in the surface gene may cause in the polymerase and or use of HBIG and may lead to the of mutations that the efficacy of HBIG, the antivirals or both. In a case report of a patient with posttransplantation HBV disease who HBIG monotherapy and was treated with famciclovir by lamivudine, a lamivudine-resistant HBV with replication in the presence of lamivudine was HBV of this patient showed both mutations in the "a" determinant of the surface gene and the YMDD motif (domain C) of the Combination protocols are with to the dosing and of of HBIG, the duration of HBIG and the duration of antiviral therapy As with HBIG monotherapy, some use high or low fixed doses of HBIG given at fixed time whereas provide HBIG at defined by anti-HBs The most cost-effective reported to is a low IM HBIG lamivudine used by the and multicenter group results high doses of HBIG are for the majority of patients receiving combination therapy, especially those patients without detectable HBV DNA showed that from to IM HBIG in combination with lamivudine in absence of HBV recurrence in of treated patients but that HBIG was required in of efficacy and IM HBIG lamivudine to be superior to HBIG lamivudine, there may be a of patients replicators with high HBV DNA who may from the higher doses of HBIG by the The HBIG in the antiviral is to be Studies of the efficacy of combination prophylaxis using adefovir and HBIG post-OLT have not been published, but efficacy would be expected to be at least to those achieved with lamivudine and combination therapy with HBIG a analogue may not be required in all liver transplant recipients. The replication status of the patient prior to the initiation of antiviral therapy and at the time of transplantation guide posttransplantation treatment strategies to especially in patients without detectable HBV DNA by sensitive assay prior to transplantation, are the discontinuation of HBIG after some defined and treatment with antivirals or HBsAg or both. the high cost of HBIG long-term and the of consideration of these other treatment Studies of hepatitis B vaccination as an alternative to long-term HBIG in OLT recipients were in patients who were 2 years or more from date of transplantation titers achieved with the vaccination from 10 to IU/L in as well as of and of response these studies