Tenofovir alafenamide (TAF) has shown equivalent efficacy and improved safety profiles for patients with chronic hepatitis B (CHB) compared to tenofovir disoproxil fumarate (TDF). However, limited data are available for its resistance profiles. In 2 clinical trials, 1298 HBeAg-positive and HBeAg-negative patients with CHB were randomized 2:1 and treated with TAF (n=866) or TDF (n=432). Baseline nucleos(t)ide analog resistance substitutions in HBV polymerase/reverse transcriptase (pol/RT) were assessed using INNO-LiPA Multi DR v2/v3. Resistance surveillance was conducted for patients with viremia (HBV DNA ≥69IU/mL) by HBV pol/RT sequencing at week 96 or at discontinuation. In vitro phenotypic analysis was performed for patients with conserved site substitutions or virologic breakthrough while adherent to study drug. At baseline, the majority of patients harbored virus with wild type pol/RT (89.2%), with 10.8% harboring resistance associated mutations. A similar percentage of patients in the TAF or TDF groups qualified for sequence analysis through week 96 (TAF 11.1%, TDF 10.9%). Of these, a small percentage of patients experienced virologic breakthrough (TAF: 2.8%, TDF: 3.2%) that was often associated with drug nonadherence (TAF: 30%, TDF: 50%). Across treatment groups, 132 patients qualified for sequence analysis through week 96 with nearly half having no sequence changes from baseline (43.2%). Most sequence changes occurred at polymorphic positions, and no isolates showed a reduction in susceptibility in vitro. After 96 weeks, the proportion of patients achieving virus suppression (HBV DNA <69 IU/mL) was similar across treatment groups and no substitutions associated with resistance to TAF or TDF were detected.
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