title: 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.affiliation: Gilead Sciences, Inc., Foster City, California.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Scott
authors.initials: S
authors.lastname: Fung
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Gane
authors.forename: Phillip
authors.initials: P
authors.lastname: Dinh
authors.forename: John F
authors.initials: JF
authors.lastname: Flaherty
authors.forename: Evguenia S
authors.initials: ES
authors.lastname: Svarovskaia
authors.forename: Michael D
authors.initials: MD
authors.lastname: Miller
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Kitrinos
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004279:DNA, Viral / Q000097:blood*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D000068679:Emtricitabine; D056726:Genetic Association Studies; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000097:blood* / Q000188:drug therapy / Q000821:virology; D006801:Humans; D007700:Kinetics; D020125:Mutation, Missense; D063065:Organophosphonates / Q000494:pharmacology* / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D000068698:Tenofovir; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D063065:Organophosphonates; D003841:Deoxycytidine; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine
keywords: LAM-R rtM204V/I; allele-specific PCR (AS-PCR); chronic hepatitis B; tenofovir disoproxil fumarate (TDF); viral load decay