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Adefovir-resistant Hepatitis B Virus Can Remain Susceptible to Tenofovir

Tenofovir (Viread) continues to be effective for treating chronic hepatitis B patients who have developed resistance to the related drug adefovir (Hepsera), according to a report in the August 14, 2012, online edition of Antiviral Therapy.

Several nucleoside analogs are active against hepatitis B virus (HBV), but the virus can rapidly develop resistance, compromising long-term treatment effectiveness. One of the most effective current drugs, tenofovir, is a nucleotide analog that differs from most earlier agents. However, it is related to another approved nucleotide, adefovir, raising the possibility of cross-resistance.

Florian van Bömmel from the University of Leipzig and colleagues assessed the clinical relevance of HBV polymerase gene variants in people with genotypic resistance to adefovir -- namely the rtN236T and/or rtA181V/T mutations -- who were later treated with tenofovir. In vitro studies show that HBV mutations selected by adefovir confer cross-resistance to tenofovir, the study authors noted as background, but this may not significantly affect tenofovir susceptibility.

The analysis included 10 chronic hepatitis B patients. All but 1 were men, the mean age was 47 years, and 60% were hepatitis B "e" antigen (HBeAg) positive. People with hepatitis C or HIV coinfection were excluded. Participants had experienced virological breakthrough during adefovir treatment associated with the rtN236T and/or rtA181T/V mutations and were later treated with tenofovir.

The researchers analyzed polymerase gene variants during up to 24 months of consecutive tenofovir monotherapy using population sequencing, line probe assays, and clonal analysis.

Results

• In all patients, switching to tenofovir resulted in a continuous reduction in HBV viral load.
• HBV DNA levels fell from a median 7.6 to 3.3 log copies/mL, although viral load remained > 400 copies/mL in 7 patients at 12 months.
• Adefovir resistance mutations remained detectable throughout the entire observation period in most patients.
• Apart from an M204Q mutation in 1 sample, no new tenofovir-associated HBV polymerase gene mutations were identified.
• In 2 participants with continued low-level viral load after 18 weeks on tenofovir, adding lamivudine (3TC or Epivir) led to complete response within a few weeks.

Based on these findings, the study authors concluded, "Adefovir-resistant HBV variants may further become selected during tenofovir treatment, however they cause only a mild decrease in tenofovir susceptibility."

10/2/12

Reference

F Bömmel, J Trojan, K Deterding, et al. Evolution of adefovir-resistant HBV polymerase gene variants after switching to tenofovir disoproxil fumarate monotherapy. Antiviral Therapy 17:1049-1058. August 14, 2012 (Epub ahead of print).