Evaluation of HBV DNA decay kinetics in patients containing both rtM204V/I mutant and wild-type HBV subpopulations during tenofovir DF (TDF) monotherapy or combination therapy with emtricitabine (FTC)/TDF.

Abstract

Tenofovir disoproxil fumarate (TDF) is recommended as treatment for chronic hepatitis B patients harboring lamivudine-associated resistance mutations (LAM-R, rtM204V/I ± rtL180M). This study evaluated the clinical response of rtM204V and rtM204I subpopulations to TDF by comparing their early viral load decay kinetics to wild-type (WT) subpopulations in chronic hepatitis B patients harboring rtM204V/I prior to initiating TDF or emtricitabine (FTC)/TDF therapy. Allele-specific PCR assays capable of detecting rtM204V or rtM204I subpopulations as low as 0.5% were developed and used to assess patient samples from a Phase 3b study evaluating TDF and FTC/TDF treatment in LAM-R patients. Baseline samples (n = 280) were quantified for rtM204V/I subpopulations and rtM204V or rtM204I subpopulations were detected in 269/273 (98.5%) baseline samples with a range of 0.7% to >95%. On-treatment analyses were conducted for seventeen patients (TDF, n = 8; FTC/TDF, n = 9) that harbored baseline WT and either rtM204V or rtM204I (no rtM204V/I mixtures) and HBV DNA ≥1,000 copies/ml at/after week 4. The median change in HBV DNA through week 12 for WT and rtM204V/I subpopulations was similar, -2.64 and -3.30 log10  copies/ml, respectively, with no significant difference between TDF and FTC/TDF treatment. In conclusion, rtM204V/I subpopulations demonstrate similar early HBV DNA decline kinetics to WT subpopulations during treatment with either TDF or FTC/TDF. These results demonstrate that TDF is similarly active against both WT and rtM204V/I subpopulations in vivo.

• Authors: Yang Liu, Scott Fung, Edward J Gane, Phillip Dinh, John F Flaherty, Evguenia S Svarovskaia, Michael D Miller, Kathryn M Kitrinos
• Journal: Journal of medical virology (J Med Virol) Vol. 86 Issue 9 Pg. 1473-81 (Sep 2014) ISSN: 1096-9071 [Electronic] United States
• PMID: 24861361 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 Wiley Periodicals, Inc.

Chemical References

• Antiviral Agents
• DNA, Viral
• Organophosphonates
• Deoxycytidine
• Tenofovir
• Emtricitabine
• Adenine

Topics

• Adenine (analogs & derivatives, pharmacology, therapeutic use)
• Antiviral Agents (pharmacology, therapeutic use)
• DNA, Viral (blood)
• Deoxycytidine (analogs & derivatives, pharmacology, therapeutic use)
• Drug Therapy, Combination
• Emtricitabine
• Genetic Association Studies
• Hepatitis B virus (drug effects, genetics)
• Hepatitis B, Chronic (blood, drug therapy, virology)
• Humans
• Kinetics
• Mutation, Missense
• Organophosphonates (pharmacology, therapeutic use)
• Randomized Controlled Trials as Topic
• Tenofovir
• Treatment Outcome
• Viral Load