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1843
No Resistance to Tenofovir Alafenamide Detected
Through 48 Weeks of Treatment in Patients with Chronic
Hepatitis B
Henry Lik-Yuen Chan1, Scott Fung2, Andrea L. Cathcart3, Yang
Liu3, Karin S. Ku3, John F. Flaherty3, Michael D. Miller3, Anuj
Gaggar3, Kathryn M. Kitrinos3, Young-Suk Lim4, Maria Buti5; 1The
Chinese University of Hong Kong, Hong Kong, China; 2Department
of Medicine, University of Toronto, Toronto, ON, Canada;
3Gilead Sciences, Foster City, CA; 4Asan Medical Center, University
of Ulsan College of Medicine, Seoul, Korea (the Republic
of); 5Hospital Vall Hebron and Ciberehd del Instituto Carlos III,
Barcelona, Spain
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.
Disclosures:
Henry Lik-Yuen Chan - Advisory Committees or Review Panels: Gilead, Janssen,
Bristol-Myers Squibb, Roche, Novartis Pharmaceutical, Abbvie; Speaking and
Teaching: Echosens
Scott Fung - Advisory Committees or Review Panels: Gilead Sciences, Merck,
Abbvie; Speaking and Teaching: BMS, Gilead, AbbVie, Merck
Yang Liu - Employment: Gilead Sciences
Karin S. Ku - Employment: Gilead Sciences, Inc.; Stock Shareholder: Gilead
Sciences, Inc.
John F. Flaherty - Employment: Gilead Sciences; Stock Shareholder: Gilead Sciences
Michael D. Miller - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
Anuj Gaggar - Employment: Gilead Sciences, Inc.
Kathryn M. Kitrinos - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
Young-Suk Lim - Advisory Committees or Review Panels: Bayer Healthcare, Gilead
Sciences; Grant/Research Support: Bayer Healthcare, BMS, Gilead Sciences,
Novartis
Maria Buti - Advisory Committees or Review Panels: Gilead, Janssen, MSD;
Grant/Research Support: Gilead, Janssen; Speaking and Teaching: Gilead,
Janssen, BMS
The following people have nothing to disclose: Andrea L. Cathcart
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