Week 48 resistance surveillance in two phase 3 clinical studies of adefovir dipivoxil for chronic hepatitis B

Abstract

H epatitis B virus (HBV) is a major cause of chronic liver disease with an estimated 400 million chronic carriers worldwide. Treatment of chronic hepatitis B aims to achieve sustained suppression of HBV replication, normalization in alanine aminotransferase levels, loss of serologic markers of hepatitis B e antigen or hepatitis B surface antigen, and improvement in liver histology. Before the recent regulatory approval of adefovir dipivoxil for the treatment of chronic hepatitis B in the United States, lamivudine was the only oral agent indicated for this disease. However, a major drawback to long-term lamivudine therapy is the emergence of lamivudine-resistant HBV mutants in a significant proportion of patients. Resistance to lamivudine occurs in 16% to 32% of patients after 1 year of monotherapy and the incidence progressively increases to 67% at 4 years. 1,2 Single mutations (rtM204V or rtM204I) in the tyrosine-methionine-aspartate-aspartate (YMDD) motif of HBV polymerase were shown to be less fit than wild-type HBV during in vitro studies. 3 However, in the majority of patients, YMDD mutations are accompanied by compensatory mutations. Secondary mutations of rtL180M and rtV173L have been observed in greater than 80% of lamivudine-resistant patients and these mutants are able to restore replication fitness of YMDD mutant HBV in vitro. 4,5 Furthermore, long-term data from patients harboring lamivudine-resistant HBV indicates that viral replica-

Increased risk of adefovir resistance in patients with lamivudine-resistant chronic hepatitis B after 48 weeks of adefovir dipivoxil monotherapy

“…Our data are in agreement with previous studies that show ADV-resistant mutations are infrequent and delayed in treatment-naïve patients. 10,11,22 However, in contrast to previous reports in which no ADV-resistant mutations were detected in LAM-resistant patients after 1 year of ADV therapy, 23,24 our study indicated that the emergence of those mutations in LAM-resistant patients was frequently detected after 1 year of ADV therapy.…”

Outbreak of Infections by Hepatitis B Virus Genotype A and Transmission of Genetic Drug Resistance in Patients Coinfected with HIV-1 in Japan

“…In cases of HBV/HIV-1 coinfection, tenofovir and emtricitabine are also used. We studied whether the viruses have drug resistance mutations against these antiretroviral drugs with or without a history of antiretroviral treatments and confirmed the following resistance mutations: lamivudine/emtricitabine resistance mutations V173L, L180M, and M204I/V; adefovir resistance mutations A181V, I233V, and N236T; entecavir resistance mutations I169T, L180M, T184G, S202I, M204I/V, and M250V; and tenofovir resistance mutation A194T (1,2,24,32,34,35). Furthermore, major drug resistance mutations in HIV-1 were defined according to the criteria of the International AIDS Society (IAS)-USA and Stanford HIV drug resistance database (7,23).…”

The Hepatitis B Virus Polymerase Mutation rtV173L Is Selected during Lamivudine Therapy and Enhances Viral Replication In Vitro

“…In contrast to the situation for lamivudine and famciclovir, the emergence of resistance to adefovir dipivoxil has been infrequent and delayed. No adefovir resistance mutations were identified in 467 chronic hepatitis B patients treated with adefovir dipivoxil for 48 weeks during phase III clinical studies or in a smaller cohort of 27 patients treated for up to 136 weeks (37,39 During enrollment of lamivudine-resistant patients into clinical trials of adefovir dipivoxil, we observed the rtV173L mutation in baseline viral sequences from many patients. Here we report a retrospective examination of lamivudine-resistant patients to determine the frequency of the rtV173L mutation and its association with mutations at positions rt180 and rt204.…”