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Background The principal causes of liver enzyme elevation among HIV–hepatitis B virus (HBV) co-infected patients are the hepatotoxic effects of antiretroviral therapy (ART), alcohol abuse, ART-induced immune reconstitution and the exacerbation of chronic HBV infection. Objectives To investigate the incidence and severity of liver enzyme elevation, liver failure and death following lamivudine (3TC) withdrawal in HIV–HBV co-infected patients. Methods Retrospective analysis of the Swiss HIV Cohort Study database to assess the clinical and biological consequences of the discontinuation of 3TC. Variables considered for analysis included liver enzyme, HIV virological and immunological parameters, and medication prescribed during a 6-month period following 3TC withdrawal. Results 3TC was discontinued in 255 patients on 363 occasions. On 147 occasions (109 patients), a follow-up visit within 6 months following 3TC withdrawal was recorded. Among these patients, liver enzyme elevation occurred on 42 occasions (29%), three of them (2%) with severity grade III and five of them (3.4%) with severity grade IV elevations (as defined by the AIDS Clinical Trials Group). Three patients presented with fulminant hepatitis. One death (0.7%) was recorded. Conclusions HBV reactivation leading to liver dysfunction may be an under-reported consequence of 3TC withdrawal in HIV–HBV co-infected patients. Regular monitoring of HBV markers is warranted if active therapy against HBV is discontinued. [ABSTRACT FROM AUTHOR]

Emtricitabine (FTC) and lamivudine (3TC) are deoxycytidine analogues with potent and selective inhibition of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) replication. The K65R mutation in the HIV reverse transcriptase (RT) confers reduced susceptibility to 3TC, ddC, ddI, abacavir, and tenofovir in vitro. The Q151M mutation confers reduced susceptibility to many of the approved anti-HIV nucleoside analogues with the exception of 3TC and tenofovir. The double mutation K65R/Q151M has been shown to be more resistant to many NRTIs than either of the single mutations alone. In this study, we measured the antiviral activity of FTC and 3TC against HIV-1 containing K65R, Q151M, and K65R/Q151M mutations. We also studied the steady-state kinetic properties for the inhibition of dCTP incorporation by FTC 5′-triphosphate (TP) and 3TC-TP. In addition, we measured the incorporation of dCTP, FTC-TP, and 3TC-TP into a random sequence DNA/DNA primer/template by the HIV-1 RTs using pre-steady-state kinetic analysis. Finally, we studied the incorporation of these deoxycytidine analogues into a HIV-1 genomic DNA/DNA primer/template by K65R HIV-1 RT to address certain concerns associated with DNA sequence specificity. Overall, this study demonstrated that K65R and K65R/Q151M related drug resistance to FTC and 3TC was mainly due to a significant decrease in the rate of incorporation. There was little to no effect on the binding affinities of the mutant HIV-1 RTs for the deoxycytidine analogues. The Q151M mutation remained sensitive to both FTC and 3TC in both cell culture and enzymatic assays. At a molecular level, FTC-TP was incorporated at least as efficiently as 3TC-TP for all of the HIV-1 RT and primer/templates tested. [ABSTRACT FROM AUTHOR]

summary. Adefovir is a potent nucleotide analog inhibitor of hepatitis B virus (HBV) DNA polymerase. Its oral prodrug adefovir dipivoxil has been approved for the treatment of chronic HBV infection. In this study, adefovir was characterized for its in vitro effects on mitochondrial DNA (mtDNA) synthesis and compared with the nucleoside analogues lamivudine (3TC), fialuridine (FIAU), and zalcitabine (ddC). No substantial changes in mtDNA content were detected in human hepatoblastoma HepG2 cells and normal human skeletal muscle cells following a 9-day treatment with 0.3–30 μ m adefovir, concentrations up to 500-fold higher than the peak serum levels in patients treated with adefovir dipivoxil. Similarly, mtDNA was unchanged in both cell types following treatment with 3TC. In contrast, 30–55% and > 90% reductions in mtDNA were observed following incubation with 30 μ m FIAU and ddC, respectively. The effects of FIAU on mtDNA became more pronounced following prolonged 18-day treatment of skeletal muscle cells while the effects of other drugs remained unchanged. [ABSTRACT FROM AUTHOR]

Oral adefovir dipivoxil (ADV) reduced viral load in transgenic mice expressing hepatitis B virus (HBV). Liver HBV DNA was reduced to <0.1 pg of viral DNA per μg of total DNA (pg/μg) following oral ADV therapy at a dosage of 100 mg/kg/day twice daily for 10 days as compared to a mean of 3.0 pg/μg for the placebo control group. Oral ADV treatment also reduced serum HBV DNA to 3.5 log10 genomic equivalents (ge)/ml compared to 5.3 log10 ge/ml for the placebo control group. With once daily treatments, ADV antiviral activity reached near maximum viral reduction by day 10 in the liver and reached an endpoint of liver virus inhibition at 1.0 mg/kg/day. The minimum effective dose was less than 0.1 mg/kg/day using inhibition of serum virus. Lamivudine (3TC) given orally at 500 mg/kg/day using the same treatment schedule marginally reduced the serum HBV DNA by 4-fold, but did not significantly reduce HBV liver DNA. Serum titer reduction was also identified in untreated or placebo-treated animals, which may have been caused by the stress of pre-treatment bleeding and multiple oral gavage treatments. This trauma/placebo-effect may have masked the extent of viral reduction in the serum in ADV- and 3TC-treated animals. Liver HBV RNA was not reduced by oral ADV treatments. The lack of RNA reduction was expected, because the HBV transgene is stably integrated into the chromosome and ADV inhibits polymerase activity after transcription of pregenomic RNA. ADV was identified to have potent anti-HBV activity in this HBV transgenic mouse model and could serve as a suitable positive control for future drug discovery experiments. [Copyright &y& Elsevier]

In the past decade, significant progress has been achieved in the battle against hepatitis B virus. In addition to the immunomodulating agents such as interferon-α and thymosin, many novel antiviral agents have been discovered, among which nucleoside analogues are the main-stay. New-generation compounds such as 3TC and famciclovir have shown promise in the treatment of patients chronically infected by this virus, and are on the line for approval. However, viral rebound after cessation of therapy still remains a major problem. Additionally, the reports on the drug resistance to these antiviral agents suggest that combination therapy will be the eventual strategy (Bartholomew et al., 1997; Tipples et al., 1996). Therefore, developments of safe and effective antiviral agents which do not cross-resist with currently available antiviral drugs are still much needed. [ABSTRACT FROM AUTHOR]