No Resistance to Tenofovir Alafenamide Detected through 96 Weeks of Treatment in Patients with Chronic Hepatitis B Infection

Abstract

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 two clinical trials, 1,298 hepatitis E antigen-positive and -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 the 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. (These studies have been registered at ClinicalTrials.gov under identifiers NCT01940471 and NCT01940341.).

Keywords: antiviral agents; hepatitis B virus; resistance; tenofovir; tenofovir alafenamide.

Copyright © 2018 American Society for Microbiology.

Figures

FIG 1

Summary of treatment response at week 96 by treatment group. The percentage of patients for either the TAF (left) or TDF (right) treatment group is depicted for each outcome through week 96. Patients that missed their week 96 visit but had suppressed HBV DNA at the previous visit were included in the 10 increase in HBV DNA from nadir. Patients with one visit that met these criteria were classified as viremic in the absence of viral breakthrough.

FIG 2

Baseline HBV genotype and impact on treatment outcomes. (A) The percentages of patients in either the TAF (left) or TDF (right) treatment group are graphed by genotype as a percentage of the whole. Patients with genotypes E, F, H, or unknown are included as “other.” (B) The mean change from the baseline for patients in the TAF (left) or TDF (right) treatment groups is shown for patients with genotypes A through D.

FIG 3

Baseline resistance surveillance and impact on treatment outcomes. (A) The percentage of patients with wild-type HBV (no resistance mutations detected at baseline), primary mutations, or other mutations (defined in methods) detected at baseline by INNO-LiPA in the TAF or TDF treatment group is depicted as a percentage of the group by baseline oral antiviral experience. (B) The mean change of HBV DNA from baseline for patients in the TAF (left) or TDF (right) treatment groups is shown for patients as determined by baseline resistance analysis.

FIG 4

Sequence results for TAF and TDF patients who qualified for resistance analysis through week 96. Sequencing results for patients who qualified for sequencing during resistance surveillance through week 96 in the TAF (A) or TDF (B) are shown. The results are presented as amino acid changes from baseline. The number of patients in each analysis is noted as a percentage of the patients in the corresponding treatment group (n, %).