Evolution of lamivudine-resistant hepatitis B virus and HIV-1 in co-infected individuals: an analysis of the CAESAR study. CAESAR co-ordinating committee.
ABSTRACT 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.
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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.Drug Resistance Updates 05/2001; 4(2):118-28. DOI:10.1054/drup.2001.0190 · 8.82 Impact Factor
- Medicina Clínica 11/2001; 117(13):518-9. · 1.25 Impact Factor
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ABSTRACT: Shared epidemiological risks have resulted in HIV-infected populations having a high prevalence of hepatitis B virus (HBV) co-infection. Several prospective studies have investigated the impact of HBV co-infection on HIV disease progression; most of them were negative. On the contrary, there is evidence that HIV may modify the natural history of HBV infection. HIV positive subjects have higher rates of HBV chronification, higher HBV replication, lower ALT levels and lower rates of seroconversion to anti-HBe and anti-HBs. The impact of HIV co-infection on the outcome of HBV infection is still controversial, even if some studies have shown an accelerated progression towards decompensated cirrhosis in HIV co-infected subjects. HBV co-infection is a risk factor for severe hepatotoxicity during HAART. Vaccination for HBV is mandatory in nonimmune HIV subjects, however its efficacy in immunosuppressed patients is still controversial. HIV co-infection decreases the effectiveness of Interferon in the treatment of HBV infection. Because of its activity against both HBV and HIV, lamivudine is used in HIV-HBV co-infected patients at doses of 300 mg/daily and as part of an antiretroviral regimen, but the rate of sustained response is poor and HBV strains with mutations associated with lamivudine resistance occur at a rate of 20% per year. Trials of new drugs with activity against HBV, some of them with activity also against HIV, and some of them without cross-resistance with lamivudine, are now underway. Highly Active Anti-Hepatitis B Therapy will probably soon come of age.AIDS reviews 11/2001; 4(1):27-35. · 4.02 Impact Factor