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

• Published in: Journal of medical virology 2014-09, Vol.86 (9), p.1473-1481
• Main Authors: Liu, Yang, Fung, Scott, Gane, Edward J., Dinh, Phillip, Flaherty, John F., Svarovskaia, Evguenia S., Miller, Michael D., Kitrinos, Kathryn M.
• Format: Article
• Language: English
• Subjects: Adenine - analogs & derivatives; Adenine - pharmacology; Adenine - therapeutic use; allele-specific PCR (AS-PCR); Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; Antiviral drugs; chronic hepatitis B; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Deoxycytidine - therapeutic use; Deoxyribonucleic acid; DNA; DNA, Viral - blood; Drug therapy; Drug Therapy, Combination; Emtricitabine; Genetic Association Studies; Hepatitis; Hepatitis B virus; Hepatitis B virus - drug effects; Hepatitis B virus - genetics; Hepatitis B, Chronic - blood; Hepatitis B, Chronic - drug therapy; Hepatitis B, Chronic - virology; Humans; Interferon; Kinetics; LAM-R rtM204V/I; Mutation, Missense; Organophosphonates - pharmacology; Organophosphonates - therapeutic use; Randomized Controlled Trials as Topic; Tenofovir; tenofovir disoproxil fumarate (TDF); Treatment Outcome; Viral Load; viral load decay; Virology
• ISSN: 0146-6615; 1096-9071
• DOI: 10.1002/jmv.23982

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. J. Med. Virol. 86:1473–1481, 2014. © 2014 Wiley Periodicals, Inc.