By Liz Highleyman

A 3-D model of the hepatitis B virus. The double-stranded DNA genome (red) is enclosed by a protein capsid shell (blue) contained within a membrane (gold) studded with glycoprotein spikes that bind to liver cells.

Nucleoside/nucleotide analog therapy for chronic hepatitis B virus (HBV) infection has strong antiviral activity, but long-term use is limited by the emergence of drug-resistant virus, especially with monotherapy,

Two recent journal articles looked at HBV drug resistance and its impact on treatment outcomes.

Resistance Mutations

In the first report, investigators looked at the occurrence of amino acid substitutions (mutations) at position 181 of the HBV polymerase, which have been associated with viral breakthrough in patients taking the approved anti-HBV drugs lamivudine (Epivir-HBV) or adefovir (Hepsera). They characterized the main viral variants harboring the rtA181T/V mutation in samples from 10 consecutive patients who developed lamivudine and/or adefovir resistance.

Clonal analysis revealed the co-localization on the same HBV genome of the rtA181T/V mutation with rtN236T -- but not with rtM204V/I -- following viral breakthrough while taking lamivudine, adefovir, or lamivudine plus adefovir.

In a laboratory cell culture, the rtA181T/V mutation induced decreased susceptibility to lamivudine (< 10-fold), adefovir (2- to 8-fold), and tenofovir (2- to 3-fold). The association of rtA181T with rtN236T on 1 clinical isolate genome increased resistance to all 3 drugs. Tenofovir (Viread), a nucleotide analog structurally related to adefovir, is currently approved for HIV and under study for HBV. All the tested HBV mutants remained sensitive to entecavir (Baraclude).

"Our observations suggest that a single amino acid change at position rt181 may induce cross-resistance to lamivudine and adefovir," the study authors concluded. "These data emphasize the clinical relevance of genotypic and phenotypic analysis in the management of antiviral drug resistance."

Effect on Treatment Response

In the second study, researchers assessed the long-term efficacy of adefovir combined with lamivudine in 132 Japanese patients with lamivudine-resistant genotype C-dominant chronic HBV infection.

Participants were followed for a median of 28 months. Virological response (undetectable HBV DNA) and predictors of response were evaluated, as well as emergence of adefovir-resistant mutations during combination therapy.

The investigators found that the cumulative probability of virological response was 69% at 12 months and 81% at 24 months. In a multivariate analysis, identified baseline hepatitis B "e" antigen (HBeAg) status (P=0.0001), aspartate aminotransferase (AST) level (P=0.001), and HBV DNA viral load (P=0.002) were predictors of response.

At the start of adefovir combination therapy, substitutions at HBV positions rtA181 (rtA181T and rtA181S) were identified in 3 patients (2.3%). Among the remaining 129 participants, rtM204 mutations were identified at baseline, and 2 of these individuals (1.6%) developed new adefovir-resistance mutations while on combination therapy (1 with rtA181S, 1 with rtA181T plus rtN236T).

Epivir-HBV Tablet

Hepsera Tablet

Based on these findings, the researchers concluded that, "Adefovir and lamivudine combination therapy effectively suppressed viral replication and maintained the efficacy well in lamivudine-resistant patients with chronic HBV infection. Genotypic analysis indicated that the emergence of adefovir-resistant mutants is rare, at least over a period of 2 years, in patients with combination therapy."

While the first study indicates that some HBV mutations confer cross-resistance to multiple antiviral drugs, the second offers further evidence that combination therapy enables more sustained treatment response compared with monotherapy.

6/24/08

References

H Yatsuji, F Suzuki, H Sezaki, and others. Low risk of adefovir resistance in lamivudine-resistant chronic hepatitis B patients treated with adefovir plus lamivudine combination therapy: Two-year follow-up. Journal of Hepatology 48(6): 923-391. June 2008.

S Villet, C Pichoud, G Billioud, and others. Impact of hepatitis B virus rtA181V/T mutants on hepatitis B treatment failure. Journal of Hepatology 48(5): 747-755. May 2008.