ABSTRACT FINAL ID: 1843
TITLE: No Resistance to Tenofovir Alafenamide Detected Through 48 Weeks of Treatment in Patients with Chronic Hepatitis B
SPONSORSHIP - THIS STUDY WAS SPONSORED BY: (IF THIS ABSTRACT WAS NOT SPONSORED PLEASE INDICATE):
Gilead Sciences, Foster City, Unites States
Aim: Presented herein are the Week 48 resistance analyses for 2 Phase 3 studies (GS-US-320-0108 and GS-US-320-0110) evaluating tenofovir alafenamide (TAF) versus tenofovir disoproxil fumarate (TDF) for the treatment of chronic hepatitis B (CHB) in HBeAg+ and HBeAg- treatment-naïve or treatment-experienced adults. Methods: Patients were randomized 2:1 and stratified by HBV DNA and treatment status to receive TAF or TDF. Baseline (BL) resistance substitutions in HBV pol/RT were assessed using INNO-LiPA Multi-DR v2/3 assay. HBV pol/RT population sequencing was conducted for patients with ≥24 weeks of treatment who experienced virologic breakthrough (VB) at Week 48 or discontinued with viremia (HBV DNA ≥69 IU/mL). VB was defined as HBV DNA ≥69 IU/mL after achieving <69 IU/mL or a ≥1.0-log10 increase from nadir. Deep sequencing was conducted for VB patients with HBV DNA ≥159 IU/mL. Phenotypic analysis using recombinant HBV in HepG2 cells was performed for VB patients who were adherent to study drug (plasma drug levels). Results: 1298 patients were randomized and treated (TAF: n=866; TDF: n=432). At BL, the majority of patients harbored wild type pol/RT (89.2%). Of the patients with resistance substitutions (10.8%), a higher percentage was seen in treatment-experienced patients (21.6%) compared to treatment-naive patients (7.6%). After up to 48 weeks of treatment, a small and similar percentage of patients qualified for sequence analysis (TAF, 2.8%; TDF, 3.2%). In the TAF arm, 24 patients qualified: 15 patients had no change from BL, 4 were unable to be sequenced (UTS), and 5 had polymorphic site substitutions. In the TDF arm, 14 subjects qualified: 6 patients had no change, 4 were UTS, 2 had polymorphic site substitutions, and 2 had conserved site substitutions (rtQ67Q/H, rtQ288Q/stop). VB was often associated with study drug nonadherence (TAF, 44%; TDF, 62%). Of the 16 patients who qualified for deep sequencing; 2 polymorphic substitutions were detected in 2 patients each (rtN123D, TAF n=1, TDF n=1; rtH124D, TAF n=2) and 1 adefovir resistance-associated substitution was detected in 1 patient (rtN236T, TDF n=1). rtN236T was detected at a level of 14.7% at Week 48; however, rtN236T was not observed at BL nor in visits preceding/following Week 48 and the patient resuppressed HBV DNA with continued treatment. No deep sequencing substitutions were associated with sustained VB, and 4 of 4 patients remaining on study achieved HBV DNA <69 IU/mL with continued treatment. Phenotypic analysis of 10 patients (TAF n=6, TDF n=4) showed no reduction in susceptibility to TAF or tenofovir, respectively. Conclusion: No resistance to TAF was detected through Week 48.