Evolution of lamivudine-resistant hepatitis B virus and HIV-1 in co-infected individuals: an analysis of the CAESAR study. CAESAR co-ordinating committee.
Division of Immunity and Infection, University of Birmingham Medical School, Edgbaston, UK. AIDS
(Impact Factor: 5.55).
Lamivudine has potent activity against HIV-1 and hepatitis B virus (HBV). Co-infection with these two viruses is common, and this may therefore influence the choice of antiretroviral therapies. A cohort of co-infected patients treated with lamivudine were studied in order to evaluate the differential effects of lamivudine on the two viral populations within the same individual after 44-52 weeks of therapy.
Retrospective virological analysis of an HIV-1/HBV co-infected lamivudine cohort derived from a randomized, placebo-controlled study of lamivudine in HIV infection, the CAESAR study.
Five of thirteen patients with HBV viral load > 10,000 copies/ml after 44-52 weeks of lamivudine therapy had genotypic drug resistance. Four of these five had a rebound of viral replication over the period of study and in one case this was associated with an alanine transaminase serum elevation. Ten of the thirteen patients had a 44-52 week HIV viral load > 1000 copies/ml, all of whom also had HIV reverse transcriptase M184V or M184I mutations.
Extrapolating these results to the population yields an estimated 1-year incidence of drug-resistant HBV of at least 14% in lamivudine-treated HIV-1/HBV co-infected patients. The clinical and virological benefit of HBV lamivudine monotherapy in co-infected patients should be balanced against the potential for emergence of drug resistance. Further, these data suggest that the determinants of HIV and HBV drug resistance are different and that parallel evolution, rather than co-evolution of HBV and HIV-1 in co-infected individuals occurs.
Available from: cid.oxfordjournals.org
- "Decrease in CD4 cell count, high body mass index, and duration of lamivudine therapy have all been associated with an increased risk of the emergence of HBV resistance. The emergence of resistance is characterized by a rise in serum HBV DNA load and a moderate increase in serum ALT levels [17, 19]. At breakthrough, serum HBV DNA levels are lower than levels before lamivudine therapy. "
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ABSTRACT: Among human immunodeficiency virus (HIV)-infected individuals, the prevalence of hepatitis B surface antigen (HBsAg) seropositivity
is ∼10-fold higher than in the general population. HIV/hepatitis B virus (HBV)-coinfected patients have an increased risk
of cirrhosis and liver-disease-related death. The strategy and management of anti-HBV therapy in HIV-infected persons must
take into consideration both viral infections. Among HIV/HBV-coinfected patients, lamivudine promptly inhibits HBV replication.
The emergence of resistance to lamivudine has been documented in HBV strains. Adefovir has been shown to be effective in the
treatment of lamivudine-resistant HBV in HIV/HBV-coinfected patients. Tenofovir has recently been shown to have significant
activity against both HIV and HBV. HBsAg seropositivity has been identified as an independent predictor of highly active antiretroviral
therapy-related hepatotoxicity. However, further research is needed to determine the exact role of HBV and the mechanisms
involved in antiretroviral-associated hepatotoxicity in HBV/HIV-coinfected patients.
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ABSTRACT: Lamivudine (beta-L-(-)-2',3'-dideoxy-3'-thiacytidine) has been a major breakthrough in the care of patients with hepatitis B. With prolonged monotherapy the development of resistance is an increasingly recognized problem that limits the long term efficacy of this nucleoside analogue. The most common mutations associated with lamivudine resistance occur within the highly conserved YMDD motif in the C domain of the viral polymerase and are often associated with a compensatory mutation in the proximal B domain. The structural and functional relationship of resistance mutations is reflected in different in vitro sensitivities to lamivudine and changes in replication capacities. During prolonged lamivudine treatment there can be successive changes of different resistant mutants (genotypic succession) or a single mutant can remain the dominant viral species. In patients treated for chronic hepatitis B infection the cumulative incidence of viral resistance reaches over 50% after 3 years. Most patients will have lower serum HBV DNA levels after the emergence of resistance which is ascribed to the decreased replication capacity of these mutants. Although severe flares and ongoing HBe antigen seroconversion can occur in these patients with lamivudine-resistant HBV, the impact of continued therapy on the long-term outcome is still insufficiently studied. In the setting of liver transplantation for HBV-associated disease the clinical course after the emergence of viral resistance is variable but still may lead to disease progression and graft failure. Analogous to the success of combination therapies to delay the emergence of antiviral-resistant HIV, it will be important to combine anti-HBV agents with additive or synergistic antiviral properties and different resistance profiles for future de novo combination therapies for hepatitis B infection.
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