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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.
Survival of Patients Transplanted for HBV Cirrhosis
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.
Mechanisms of HBV Recurrence After Liver Transplantation
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
Prevention of HBV Recurrence
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).
Pre-OLT Antiviral Treatment
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 Treatment Prior to Transplantation
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 Treatment Prior to Transplantation
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.
Considerations With Antiviral Therapy Prior to Transplantation
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 benefits. Studies comparing the different antiviral agents in patients awaiting liver transplantation have not been conducted. Characteristics of the nucleoside/nucleotide analogues of potential importance include antiviral potency, efficacy against drug-resistant HBV, and risk of drug resistance with prolonged therapy (Table 1). Decisions regarding when to start treatment and what antiviral(s) to use should be based upon the desired goals of therapy (viral suppression, reversal of decompensation), the specific virological characteristics of the patient (HBV DNA level, presence of drug-resistant mutations), and the anticipated time to transplantation.
Table 1. Antiviral Therapy Before Transplantation
Abbreviations: HBeAg, hepatitis B e antigen; LAM-R, lamivudine resistance; Drug-R, drug resistance.
Based on studies in chronic HBV patients without liver decompensation.
For those on antiviral therapy awaiting transplantation, HBV DNA should be monitored regularly (at least every 3 months) by quantitative PCR assay to survey for antiviral efficacy and the development of viral resistance. Patients with primary resistance or suboptimal response (less than 10% of the patients) defined by a decrease of HBV DNA level from baseline of less than 2-log10 (by the same testing) should be considered for a change in antiviral agent or the addition of a second drug. Similarly, patients who developed viral breakthrough (increase of HBV DNA by more than 1-log10 from nadir) should receive a different or additional antiviral drug with efficacy against the HBV mutant. Ideally, HBV sequencing should be performed to identify HBV mutations (absence of mutations might reflect poor compliance to the drug). Since the discontinuation of one antiviral agent and replacement with another might expose the patient to the risk of hepatitis flare and decompensation, there is rationale for adding a second drug to the first drug (combination therapy) rather than changing drugs. However, whether combination therapy is necessary long-term is not known. At least in theory, combination therapy would be expected to reduce the likelihood of future emergence of drug resistance.
As emphasized, one of the major problems of using sequential treatment with nucleoside or nucleotide analogues is the risk of emergence of multiresistant viral strains. The lack of cross-resistance of the lamivudine- and adefovir-resistant strains argues strongly for their use in combination, especially in patients with severe liver disease in whom the selection of drug-resistant strains may be deleterious and even life-threatening.53 Entecavir54 and tenofovir55 are potent inhibitors of the wild-type and lamivudine-mutant HBV and together with other nucleoside or nucleotide analogues (e.g., emtricitabine,56 telbivudine,57 clevudine56) can be expected to increase the complexity of HBV mutant viruses in pre-OLT patients. The importance of choosing antiviral therapy with the goal of maximizing viral suppression and minimizing the risk of drug resistance is especially critical in this patient population. Combination therapy might be more appropriate in some patients.
Finally, it is important to emphasize that patients who respond virologically may have persistent liver failure, and transplantation remains the primary treatment for these individuals. Virological responders also remain at risk for hepatocellular carcinoma, and continued surveillance is needed during antiviral treatment until the time of transplantation.
Post-OLT Antiviral Prophylaxis
Lamivudine has been evaluated as a prophylactic therapy, with the drug started pretransplantation and continued posttransplantation on long-term, indefinite basis. The outcome at 1 year posttransplantation was positive with only a 10% recurrence rate.36 However, with longer follow-up, rates of recurrence increased, reaching 50% at 3 years post-OLT. Recurrence was due to the emergence of escape mutations in the YMDD motif of the polymerase gene.58 These mutations were observed mainly in patients with a high level of viral replication prior to drug exposure. Similar results were reported in other studies, with HBV recurrence in 22% to 50% of patients (Table 2).19, 38, 59 The development of HBV recurrence with YMDD mutants was occasionally associated with a severe clinical outcome.60 Since, prophylactic therapy using lamivudine alone was not uniformly effective and associated with unacceptably high rates of reinfection in replicative patients, most transplant programs in the United States, Europe, and Australia do not use lamivudine monotherapy for prophylaxis. Rather, a combination of HBIG and antivirals is used for prophylaxis (see Post-LT Combination Prophylaxis). Whether combination therapy is required in all patients subgroups is unknown. Hepatitis B e antigen–negative patients with undetectable levels of HBV DNA pretransplant by quantitative PCR in the absence of antiviral therapy had a low risk of recurrence with lamivudine monotherapy,19 suggesting that these patients may be candidates for prophylactic treatment using lamivudine or adefovir monotherapy or antivirals with an abbreviated course of HBIG. There are no available data on adefovir monotherapy as monotherapy prophylaxis.
Table 2. Prevention of HBV Recurrence With Lamivudine Monotherapy Before and After Liver Transplantation
Pretreatment Virologic Status of Transplanted Patients
Duration of Treatment Before OLT, Months Median (Range)
HBV DNA Positive at Time of OLT
HBV Recurrence N(%)
Follow-up, Months Median (range)
Death Related to HBV Recurrence
HBV DNA Positive
Abbreviations: HBeAg, hepatitis B e antigen; NA, not available.
These 2 studies report common patients.
6 of these patients were HBsAg positive, HBV DNA negative by polymerase chain reaction.
The use of lamivudine or adefovir pretransplantation followed by a combination of antivirals and HBIG post-OLT, provides improved control of viral replication pretransplantation and complimentary forms of prophylaxis posttransplantation to minimize risk of reinfection. With this combination approach, the HBV recurrence rate at 1 to 2 years posttransplantation has been reduced to <10% (Table 3).10–14, 24, 39 In addition, serum HBV DNA is negative by PCR in most cases several years post-OLT.11–12 Treatment-induced suppression of HBV DNA levels prior to transplantation appears to reduce the overall amount of HBIG needed posttransplantation.11–12, 61 The excellent results achieved with combination treatment may be the consequence of the dual effects of reduced production of HBsAg with antiviral therapy as well as a decreased rate of escape mutations in the pre-S/S and polymerase regions.
Table 3. Prevention of HBV Recurrence after Liver Transplantation with Lamivudine and HBIG
Pretreatment Virologic Status of Transplanted Patients
HBV DNA Positive at OLT
Prevention of HBV Recurrence
HBV Recurrence N(%)
Follow-up, Months Median (Range)
Pre-OLT Duration, Months Median (Range)
Abbreviations: HBeAg, hepatitis B e antigen; LAM, lamivudine; NA, not available; N: number; OLT: Orthotopic liver transplantation.
a: Lamivudine initiated at OLT in 4 patients, HBIG: 80,000 IU first month, then 10,000 IU/month.
b: 7 patients not transplanted: 4 died from liver failure, 3 had improved liver function.
c: 46,500 IU IV first month then 5,000 IU IV/month.
d: 2 patients with YMDD mutation before OLT.
e: 45,000 IU IV first week then reinjection to maintain anti-HBs >500 IU/L until day 14, then >200 IU/L.
f: 80,000 IU IV first month then 10,000 IU IV/month.
g: 80,000 IU IV first week then 10,000 IU IV/month.
h: 80,000 IU IV first week then 1,500-2,000 IU IV to maintain anti-HBs >100 IU/L
Since the HBV genome consists of overlapping reading frames, the polymerase completely overlaps the surface gene. Consequently, mutations in the surface gene may cause changes in the polymerase and vice versa. Sequential or concomitant use of HBIG and nucleoside/nucleotide analogues may lead to the selection of mutations that affect the efficacy of HBIG, the antivirals or both. In a case report of a patient with severe posttransplantation HBV disease who failed HBIG monotherapy and was subsequently treated with famciclovir followed by lamivudine, a lamivudine-resistant HBV mutant with enhanced replication in the presence of lamivudine was described.20 HBV sequence analysis of this patient showed both mutations in the “a” determinant of the surface gene and the YMDD motif (domain C) of the polymerase.
Combination protocols are heterogeneous with regard to the dosing and routes of administration of HBIG, the duration of HBIG administration, and the duration of pretransplant antiviral therapy (Table 3). As with HBIG monotherapy, some centers use high or low fixed doses of HBIG given at fixed time intervals, whereas others provide HBIG at intervals defined by anti-HBs levels. The most cost-effective regimen reported to date, is a very low IM HBIG plus lamivudine regimen used by the Australian and New Zealand multicenter group (Table 3).13 Their results suggest high doses of HBIG are unnecessary for the majority of patients receiving combination therapy, especially those patients without detectable HBV DNA pre-OLT. Han et al. showed that conversion from IV to IM HBIG in combination with lamivudine resulted in absence of HBV recurrence in 58 of 59 (98%) treated patients but that supplemental IV HBIG was required in one-third of patients.62 Taking efficacy and cost-effectiveness into consideration, IM HBIG plus lamivudine seems to be superior to IV HBIG plus lamivudine, though there may be a subset of patients (e.g., replicators with high HBV DNA pretransplantation) who may benefit from the higher doses of HBIG provided by the IV route. The optimal HBIG protocol in the antiviral era is yet to be defined. 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 comparable to those achieved with lamivudine and HBIG.
Indefinite combination therapy with HBIG plus a nucleoside/nucleotide 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 should guide posttransplantation treatment decisions. Alternative strategies to consider, especially in patients without detectable HBV DNA by sensitive quantitative assay prior to transplantation, are the discontinuation of HBIG after some defined interval and continuing treatment with antivirals alone, or adding HBsAg vaccination, or both. Again, the high cost of HBIG long-term and the inconvenience of parenteral administration prompt consideration of these other treatment approaches.
Alternatives to Long-Term Combination HBIG and Antiviral Prophylaxis Vaccination
Studies of hepatitis B vaccination as an alternative to long-term HBIG in OLT recipients were conducted in patients who were 2 years or more from their date of transplantation (Table 4).63–67 Anti-HBs titers achieved with the vaccination series varied from 10 to 83,121 IU/L in responders. Patient populations, as well as vaccine types, doses, schedules of administration, and definitions of response differed across these studies (Table 4). From these data, however, it seems clear that successful hepatitis B vaccination and discontinuation of HBIG are feasible in selected patients. Common features of the transplant recipients included in these vaccination studies were serum HBV DNA negative prior to OLT, prolonged period of time from OLT to the vaccination, low doses of immunosuppression, and HBV DNA negative by PCR at the start of vaccination. The optimal vaccine protocol to induce protective active immunity (i.e., HBsAg dose, number of doses, intervals between each dose, and specific adjuvants needed) have not been established. Additionally, it is noteworthy that postvaccination anti-HBs titers tended to decrease in a proportion of patients, necessitating monitoring of anti-HBs levels and the provision of booster doses of vaccine to maintain protective anti-HBs titers.
Table 4. Studies of Hepatitis B Vaccination in OLT Recipients With Pretransplant HBV Infection
IM recombinant HBV vaccine 40 μg/dose 0, 1, 2 months 1 to 3 coursesCombination with lamivudine, n = 8
Seroconversion cutoff (anti-HBs IU/L)
Vaccination response >10 IU/L anti-HBs (%)
Vaccination response >100 IU/L anti-HBs (%)
Vaccination response >500 IU/L anti-HBs (%)
Maximum anti-HBs IU/L of responders, median (range)
Follow-up after vaccination, months, median (range)
Discontinuation of HBIG
Another strategy used to reduce the total costs related to HBIG therapy is to discontinue HBIG after a defined period of time. Two studies evaluated the efficacy of long-term HBIG monotherapy vs. HBIG followed by lamivudine monotherapy.68, 69 In the U.S. study, 16 patients who were at least 2 years posttransplantation and HBsAg negative on HBIG were transitioned to lamivudine monotherapy.68 All patients remained HBsAg negative at an average 51 months' follow-up. In the European study, 24 patients selected on the basis of low risk of HBV reinfection (i.e., absence of detectable HBV DNA at time of transplantation and no HBV reinfection after a minimal follow-up of 6 months posttransplantation) were randomized to continue HBIG or change to lamivudine monotherapy.69 At 1 year following the discontinuation of HBIG, the HBV reinfection rates were not significantly different: 2/12 and 1/12 patients in the lamivudine and HBIG groups, respectively. However, HBV DNA was detected by PCR in the serum of patients without HBV recurrence (2/11 patients in the HBIG group and in 5/10 patients in the lamivudine group). This latter finding suggests caution with this approach and the need for studies with longer follow-up and other nucleoside/nucleotide analogue(s). Whether the duration of time on HBIG monotherapy before conversion to antiviral monotherapy influences efficacy is unknown.
A final strategy examined in select centers is HBIG withdrawal after a defined period of combination prophylaxis. In a European study of 29 patients who were HBV DNA negative at time of OLT (12 spontaneously and 17 lamivudine induced), high HBIG doses were used in the first month, and then patients were randomized to receive either lamivudine monotherapy (14 patients) or lamivudine plus HBIG at 2000 IU IM monthly (15 patients) until month 18.70 None of the patients developed HBV recurrence during the study period. HBV DNA was positive by PCR at month 18 in 3 patients who received HBIG plus lamivudine and 1 who received lamivudine monotherapy. Polymerase mutations were detected in 3 of these patients. In a U.S. study of HBIG plus lamivudine for 6 months followed by lamivudine monotherapy, treatment failures occurred only in those with HBV DNA–detectable pretransplantation.9 Based upon these results, patients without evidence of HBV replication at the time of transplantation who have received combination therapy for a minimum of 6 months posttransplantation and who are HBV DNA negative by PCR before stopping HBIG may be potential candidates for HBIG withdrawal. With the availability of more HBV antivirals, combination antiviral therapy may be another strategy that would obviate the need for long-term HBIG.
The studies to date highlight several key issues to consider with the discontinuation of HBIG posttransplantation. First, the risk of recurrence of HBV infection after cessation of HBIG may increase with time off HBIG (not apparent in studies to date, as follow-up duration is relatively short). Second, HBV DNA persists in serum, liver, or peripheral blood mononuclear cells in a proportion of HBV transplanted patients who are HBsAg negative on HBIG long-term administration at 10 years24 or on combination prophylaxis with HBIG and lamivudine,12, 69 and these reservoirs may serve as a source of reinfection in the future. Third, currently we lack the ability to identify with certainty patients who may have cleared HBV posttransplantation. For these reasons, if HBIG is stopped and the patient has not seroconverted to anti-HBs, the safest strategy would be to replace HBIG with either antivirals or vaccination.
Guidelines and Future Prospects for Prevention of HBV Reinfection
In considering therapy for HBV-infected patients who are OLT candidates, HBV replication status is critical. Recommendations differ for replicators (HBV DNA positive by quantitative PCR assay) and non-replicators (Fig. 1). For patients without active viral replication pretransplantation, preoperative antiviral therapy is not needed. Antiviral therapy should be started at the time of transplantation and continued indefinitely. These patients should also receive HBIG 10,000 IU in the anhepatic phase and daily HBIG (doses vary) for 7 days, and then every 4 to 8 weeks to maintain anti-HBs titers >100 to 150 IU/L. This is the subgroup of patients potentially eligible for protocols using shorter-term HBIG or vaccination in combination with continued antiviral therapy. However, only patients who are HBV DNA negative by PCR in serum should be considered for this latter prophylactic strategy.
For patients with active viral replication, antiviral therapy should be started before OLT with goal of achieving viral suppression prior to transplantation and improving clinical status. Patients with advanced liver failure should be prioritized for OLT, irrespective of the antiviral response. Patients with resistance to lamivudine should be treated with adefovir or entecavir. Posttransplantation, these higher-risk patients should receive a combination of HBIG 10,000 IU daily for 7 days and then indefinitely every 4 to 8 weeks to maintain anti-HBs titers >500 IU/L, especially during the first month, > 250 IU/L to the third month (and possibly longer), and > 100-150 IU/L thereafter. Antiviral therapy should be continued indefinitely also. There are less data on the risk of recurrent HBV with discontinuation of HBIG therapy in this subgroup of patients. At the present time, discontinuation of HBIG is not recommended for patients with active viral replication due to wild-type or drug-resistant HBV prior to transplantation (Fig. 1). Transplant recipients should be monitored for recurrence using HBsAg and HBV DNA by sensitive quantitative assay every 3 months to detect reinfection and/or the emergence of viral resistance.
Use of Hepatitis B Core Antibody–Positive Donors for Transplantation
Donors previously exposed to HBV but without evidence of chronic infection represent an opportunity to expand the donor pool. However, previous or latent HBV infection in the donor liver may be reactivated in the recipient after OLT. The frequency of organ-donor hepatitis B core antibody (anti-HBc) positivity is approximately 15% in the United States71 and approximately 10% in Europe.72, 73 Indeed, a high false-positive rate of anti-HBc results by enzyme-linked immunoassay has been reported.74 In recipients of anti-HBc–and/or anti-HBs–positive livers, the frequency of HBV transmission ranges from 33% to 100%.71, 75–79 Several studies have shown that recipients positive for anti-HBc and/or anti-HBs have a much lower risk for HBV acquisition than those who have no markers of previous exposure, providing support for routine vaccination of all candidates for transplantation.71, 75, 78 HBV DNA detected in donor liver tissue also has been linked to a greater risk of HBV transmission.79 Absence of HBV DNA in serum cannot be used to determine infectivity of the liver allograft. HBV DNA test results are not currently available at the time of organ retrieval, so decisions regarding the use of anti-HBc positive organs must be made in the absence of HBV DNA results.
Anti-HBc-positive livers should first be offered to suitable HBsAg-positive recipients, and second to anti-HBs-positive recipients. Prophylactic regimens for recipients who are HBV unexposed and unvaccinated remain to be defined. Several prophylactic therapies have been explored in small cohorts, including HBIG alone,78, 80 HBIG plus lamivudine,81 and lamivudine monotherapy.82 Reinfection rates are approximately 10% with each of these prophylactic approaches. From a cost-benefit perspective, lamivudine alone might be most justified. Chang et al.83 reported the results of active immunization following HBIG discontinuation in HBV naïve pediatric recipients of liver grafts from anti-HBc-positive donors. HBV vaccine was administered to 9 recipients 9.9 weeks after discontinuing HBIG (i.e., 11.4 months after OLT) and the overall seroconversion rate (anti-HBs titers >10 IU/L) was 77% (7/9). De novo HBV infection developed 23 months after OLT in 1 vaccine nonresponder. Thus, posttransplant vaccination should be attempted in HBV naïve patients and HBIG discontinued only if a response occurs. However, monitoring of anti-HBs titers would seem prudent to insure persistence of adequate protective titers.
In summary, due to the shortage of grafts, the use of anti-HBc positive organs is likely to continue and seems justifiable. The available data suggests these grafts should be used in selected recipients with low risk of HBV acquisition and with the provision of prophylaxis using HBIG or lamivudine to avoid HBV transmission in those without evidence of HBV immunity.
Treatment of Recurrent HBV Graft Infection
Treatment of recurrent hepatitis B infection in liver transplant recipients is a much less important clinical problem today than it was historically. The availability of safe, effective oral antivirals, including lamivudine, adefovir, entecavir, and tenofovir accounts for the substantial gains made in the past decade. With these gains, however, have come new challenges, as transplant recipients with recurrent HBV disease are now more likely to have progressive disease related to drug-resistant HBV, and treatment options in such individuals can be more limited. The transplant population with recurrent graft infection is a heterogeneous group of patients including those 1) recurrent HBV infection due to an absence of prophylaxis, 2) recurrent HBV infection due to a failure of prophylaxis with HBIG and/or antivirals, and 3) de novo HBV infection. Selection of the optimal therapy for these HBV-infected individuals depends on the treatments previously received (i.e., no therapy, HBIG alone, antivirals alone, or HBIG and antiviral combination) and the presence or absence of drug-resistant HBV species.
The treatment of HBV graft infection is difficult because of the high level of HBV replication and the rapid evolution of histological disease in the setting of ongoing immunosuppressive treatment. Rapid reduction in the immunosuppression, mainly corticosteroids, is common practice in many transplant programs, although the efficacy of this approach has not been proven. Effective antiviral therapy is essential in preventing disease progression.
Interferon is not very efficient in this setting, and there is a potential risk of precipitating allograft rejection.84 Ganciclovir (intravenous)85, 86 and famciclovir87 display modest but inconsistent activity against HBV. Lamivudine,8, 59, 87–93 adefovir, entecavir, and tenofovir are the drugs of choice, since they have potent antiviral effects and are well tolerated.7, 47, 94
Lamivudine is the nucleoside analogue used most widely in liver transplant patients. Lamivudine is well tolerated, results in a decline of HBV DNA in serum within 3-6 months of treatment initiation, and is associated with clinical improvements in the substantial proportion of patients.8, 93 In a multicenter North American study on 52 HBV DNA–positive transplant patients, lamivudine for 1 year resulted in loss of HBV DNA in serum in 60%, anti-HBe seroconversion in 11%, anti-HBs seroconversion in 4%, and histological improvement in the majority.8 Those results were confirmed in other studies showing suppression of HBV DNA to undetectable levels in 68% to 100% of patients, and anti-HBe seroconversion in 3% to 30% of patients treated for periods of 12 to 36 months (Table 5). Prolonged therapy, for more than 6 months, was associated with the emergence of YMDD mutants in 14-62% of patients (Table 5), rise in alanine aminotransferase levels, and clinical deterioration in some cases.8, 93 The development of drug resistance is a major challenge in the management of transplant recipients with recurrent HBV disease. Long-term, usually indefinite, viral suppression is needed to prevent disease progression. With increasing duration of lamivudine therapy, the proportion of patients developing lamivudine resistance and virological breakthrough increases, leading to histological progression and decline in clinical status. If antiviral drugs are stopped once drug resistance develops, the wild-type HBV becomes the dominant viral population again, but retreatment is associated with the development of drug-resistant HBV at an accelerated rate.95 Thus, the recommended strategy when a transplant recipient develops drug-resistant HBV infection is to add or change to an alternative antiviral with efficacy against the drug-resistant HBV strain. For transplant recipients with lamivudine-resistant HBV, adefovir, entecavir, or tenofovir are treatment options. For transplant recipients with adefovir-resistant HBV, lamivudine or entecavir are recommended.
Table 5. Antiviral Treatment of Recurrent Hepatitis B After Transplantation
Treatment Duration, Months Median (Range)
HBV DNA Negative N (%)
Breakthrough N (%)
Time to Breakthrough, Months Median (Range)
HBe N (%)
HBs N (%)
Abbreviations: HBeAg, hepatitis B e antigen; NA, not available.
This study reported treatment of acute HBV reinfection of the graft.
98% (7) to 100% (94) of these patients had lamivudine-resistant mutant HBV.
Median change in serum HBV DNA from baseline (log 10 copies/mL): −4.3.
Time to breakthrough is not applicable for these 2 studies.
Adefovir and tenofovir are effective in viral suppression of lamivudine-resistant variants, and both drugs have been used to treat transplant recipients with recurrent and progressive HBV disease.7, 47, 94 A multinational study of 121 patients treated with adefovir, 10 mg/day, showed a significant decline in HBV DNA levels by 4-log copies/mL after 48 weeks of treatment.7 Successful treatment by adefovir for hepatic failure, such as cholestatic fibrosing hepatitis resulting from lamivudine-resistant HBV, has been also reported.47, 97–98 For these patients, sustained inhibition of replication was not achieved with high-dose lamivudine, ganciclovir, or famciclovir treatment. It is not known if patients treated for lamivudine resistance with adefovir benefit from continued lamivudine treatment, but to minimize the chance of worsening liver enzymes or clinical status, continuation of both drugs for some period after the initiation of adefovir seems prudent. Case reports of patients who developed virologic resistance to adefovir therapy have been described; this adefovir-resistant variant was sensitive to lamivudine. The incidence of adefovir resistance will likely increase with prolonged treatment duration.52 Adefovir is dosed based upon renal function, and close monitoring of renal function for possibly toxicity is recommended.
Given the need of long-term, likely indefinite antiviral therapy, drug combinations that can be safely used in transplant patients and have a very low rate of drug resistance are essential. Prospective studies evaluating the safety and efficacy of the combinations of nucleoside/nucleotide analogues in the posttransplant setting are needed. Experience with tenofovir94 is more limited, but this antiviral appears safe and effective for the treatment of lamivudine-resistant HBV variants in transplanted patients. Recent preliminary data indicate entecavir99 may also be an antiviral option for liver transplant recipients with lamivudine-resistant infection. A higher dose of entecavir is needed for patients with preexisting lamivudine-resistant mutations, and the risk of entecavir resistance is higher (6% at 1 year) in those with preexisting lamivudine resistance. Thus, the choice of an antiviral drug requires consideration of the cause of graft reinfection and of the previously received antiviral treatments.
During the past 15 years, major advances have been made in the management of HBV in the transplant setting. The advent of long-term HBIG administration as a prophylaxis for HBV recurrence was a major breakthrough. Pre-OLT antiviral treatment using lamivudine to suppress HBV replication and induce clinical improvement in a subset of patients was also a major advance. Adefovir and new antiviral drugs, such as entecavir and tenofovir, will be additional antiviral alternatives for cirrhotic patients awaiting transplantation and serve as “rescue” therapy for those with lamivudine-resistant HBV infection. Combination prophylaxis with antivirals and HBIG after transplantation has been highly effective in reducing the rate of HBV recurrence, even in “replicative” patients with cirrhosis.
Treatment of liver transplant recipients with recurrent disease due to hepatitis B is also much improved today compared to a decade ago. However, the presence of drug-resistant HBV infection is increasing among cirrhotic patients undergoing transplantation, and this can increase the risk of prophylaxis failure and the subsequent development of recurrent disease posttransplantation. The need for long-term suppressive therapy makes the development of antiviral resistance posttransplantation a major concern, especially when single agents are used for treatment. Newer HBV antivirals, such as adefovir, entecavir, or tenofovir, are effective in suppressing lamivudine-resistant variants and have served well as “rescue” therapy for these patients. However, more complex multidrug-resistant HBV is a potential future challenge in the management of transplant recipients with recurrent HBV infection. Combinations of antivirals need to be considered in this setting to minimize the emergence of viral resistance.
Thus, despite the tremendous progress of the past 15 years in the management of HBV in transplant recipients, there remain several issues that warrant further study. These include 1) testing of prophylactic protocols that utilize lower HBIG doses given IV or IM, alone or in combination with antiviral agents; 2) identification of safe HBIG alternatives that are less costly and easy to administer long-term; 3) evaluation of new antiviral combinations that have low rates of drug-resistance pre- and post-transplantation; and 4) identification of patients in whom HBIG and/or antiviral therapy can be safely discontinued posttransplantation.