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Treatment of pre- and post-liver transplantation HBV infection: Should we aim at combination therapy?
Fabien Zoulim, M.D., Ph.D.
INSERM Unit 271, Lyon, France, Liver Department, Hôtel Dieu Hospital, Lyon, France

Treatment of chronic hepatitis B virus (HBV) infection prior to orthotopic liver transplantation (OLT) is a major clinical challenge. Indeed, most studies have shown the positive impact on viral replication prior to OLT of the prophylactic administration of hepatitis B immune globulins (HBIG) and antivirals.
Interferon alfa administration may be beneficial, but serious side effects that may be encountered in patients with decompensated cirrhosis require careful monitoring in specialized centers. Lamivudine administration has shown a beneficial effect in patients with decompensated cirrhosis, with an improvement of liver function that allows some patients to be withdrawn from the graft waiting list. It was also thought that pre- and post-transplantation administration of lamivudine may allow us to substitute the expensive HBIG administration. However, this turned out not to be superior to HBIG alone or HBIG associated with antivirals. Furthermore, due to the slow kinetics of viral clearance and the requirement of prolonged lamivudine therapy to avoid relapse of viral replication, drug-resistant mutants are progressively selected during the course of lamivudine administration. In turn, the rise of viral load may lead to contraindications for transplantation even though the liver function deteriorates. Until recently, this was a major concern as liver transplantation had to be performed prior to the occurrence of lamivudine resistance, while viral replication was controlled and the clinical situation was improved.
Treatment of HBV recurrence in the liver graft is also a major clinical challenge. Indeed, this may be associated with worsening of liver disease including a rapid development of cirrhosis or an acute deterioration of graft liver function. As interferon alfa is contraindicated in this setting due to a higher risk of graft rejection, the development of lamivudine provided new hope for the treatment of HBV recurrence. The first results were encouraging as the initial control of viral replication was accompanied by an improvement of liver function and histology. The initial enthusiasm has abated with the observation of the frequent emergence of lamivudine-resistant mutants, associated with progression of the liver disease and in some cases with fulminant hepatitis. Clearly, the pre- and post-transplantation treatment of chronic hepatitis B is a major clinical challenge.
The development of adefovir dipivoxil as a new anti-HBV medication is a major advance for the therapy of chronic hepatitis B. Adefovir is a potent inhibitor of the wild-type and both the famciclovir and lamivudine-mutant HBV reverse transcriptases. Adefovir dipivoxil administration for hepatitis B e antigen (HBeAg)-positive or HBe-negative chronic hepatitis B has shown a beneficial effect on the control of viral replication and improvement in liver enzymes and liver histology. It was also shown to decrease HBV load in patients presenting a lamivudine-resistant strain whether or not they were coinfected with human immunodeficiency virus (HIV). A phase III clinical trial also showed that the administration of adefovir dipivoxil in patients with lamivudine resistance, whether or not lamivudine is continued, allows for a significant decrease in viral load as well as alanine aminotransferase (ALT) levels. However, results are available only after 48 weeks of therapy.
In this issue of HEPATOLOGY, Schiff et al. report the results of a large open-label, multicenter, international study in which 324 patients with pre- or post-liver transplantation lamivudine-resistant HBV were treated with adefovir dipivoxil 10 mg once daily for a median duration of 18 and 56 weeks, respectively.Although this was not a controlled study, results in serum showed a significant decrease of viral load. In patients who received 48 weeks of therapy, 81% in the pre-liver transplantation and 34% in the post-liver transplantation cohorts achieved undetectable HBV DNA by quantitative polymerase chain reaction (<400 copies HBV DNA/mL). The liver function, assessed by the Child-Pugh score, improved in more than 90% of patients in both cohorts. The 1-year survival rate was 84% and 93% in the pre- and post-transplantation cohorts, respectively, which compared favorably with historical controls. No adefovir resistance was detected after 48 weeks of therapy. It is noteworthy that in this population of patients with severe liver disease, treatment-related adverse events were mild to moderate, with only a limited number of cases with creatinine elevation. The results of this large study, although not controlled, confirm those of pilot studies, and clearly show the clinical benefit of adefovir dipivoxil administration in the life-threatening situation of lamivudine resistance in pre- and post-liver transplantation settings. One also needs to emphasize that after 48 weeks of therapy not all patients had normalized their ALT levels or synthetic/secretory liver functions. Due to this lag in clinical improvement, adefovir dipivoxil administration should be started early after the diagnosis of lamivudine resistance in this group of patients with severe liver disease.
One of the major problems when dealing with drug resistance is to avoid the occurrence of multiple drug resistance. This major issue has been well characterized in the setting of antiretroviral therapy of HIV infection, where it was shown that sequential treatment with nucleoside analogs led to the emergence of multiresistant viral strains. This was also illustrated in the case of chronic hepatitis B therapy, although at a smaller scale. Indeed, several studies, some of which included a clonal and longitudinal analysis of the HBV polymerase gene, showed that sequential treatment with famciclovir followed by lamivudine was associated with the progressive emergence of L180M mutant resistant to famciclovir followed by the emergence of a double L180M + M204V mutant resistant to lamivudine but also to famciclovir. Recently, one case of resistance to adefovir dipivoxil in a previously naive chronic hepatitis B patient has been described after 80 weeks of adefovir monotherapy for HBeAg-negative HBV infection. This corresponded to the emergence of a new polymerase mutation N236T in the D domain of the reverse transciptase. Viral load decreased again after switching to lamivudine administration. Furthermore, another case of resistance associated with the same HBV polymerase mutation has been described in a transplanted patient who received adefovir dipivoxil monotherapy for 20 months because of resistance to lamivudine that was administered after HBV recurrence in the liver graft. The in vitro analysis of the phenotype of the viral quasispecies showed a decreased susceptibility to adefovir, while the mutant strain remained sensitive to lamivudine, emtricitabine, and entecavir.
Interestingly, these in vitro findings were consistent with the clinical evolution of the patient, as the viral load decreased again when lamivudine was added to adefovir dipivoxil.
This observation suggests that in patients with lamivudine resistance, the addition of adefovir dipivoxil may prevent the emergence of new resistant mutants in the long term. These results also underline that in the case of antiviral therapy of chronic hepatitis B, virologic end points should not be examined only after 48 weeks of treatment, but after longer duration of therapy to clearly analyze the impact of treatment. This should be kept in mind for future analysis of antiviral efficacy of new drugs because, in the case of adefovir dipivoxil, the rate of resistance appears slower than with lamivudine. Furthermore, the lack of cross resistance of the lamivudine- and adefovir-resistant strains to these compounds (Table 1) strongly suggests that long-term therapy of lamivudine-resistant patients should rely on the combination of both drugs, especially in patients with severe liver disease in whom the selection of multiple drug-resistant strains may be detrimental. The first results of the combination trials comparing lamivudine versus adefovir plus lamivudine administration did not show a beneficial effect in terms of decline in viral load after 48 weeks of therapy in the de novo treatment of naive patients. However, the absence of information on the emergence of adefovir-resistant strains after more than 2 years of therapy suggest that de novo combination of nucleoside analogs should be evaluated in clinical trials, with much longer virologic end points and careful examination of the emergence of resistant strains. This is especially true in the group of patients with severe liver disease in whom the use of interferon alfa or other immune modulators remains difficult. The rationale for combination therapy has been recently reviewed and strongly suggests the design of new clinical trials.
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