No Detectable Resistance to Tenofovir Disoproxil Fumarate (TDF) Following up to 240 Weeks of Treatment in Patients with HBeAg+ and HBeAg- Chronic Hepatitis B Virus Infection
P. Marcellin1; E. Heathcote2; A. Corsa3; Y. Liu3; M. D. Miller3; K. M. Kitrinos3
1. Hopital Beaujon, University of Paris, Clichy, France.
2. Toronto General Hospital, Toronto, ON, Canada.
3. Gilead Sciences, Inc., Foster City, CA, United States.
Aim: To evaluate amino acid changes within HBV pol/RT after up to 240 weeks of tenofovir disoproxil fumarate (TDF) treatment and determine their potential association with resistance to TDF. No TDF resistance has been detected through 192 weeks of TDF treatment. Methods: Patients in Studies GS-US-174-0102 (HBeAg-) and GS-US-174-0103 (HBeAg+) were randomized 2:1 to receive TDF or adefovir dipivoxil (ADV) for 48 weeks followed by open-label TDF. Patients with HBV DNA >400 copies/mL at/after Week 72 could add emtricitabine (FTC) as a fixed-dose combination tablet upon investigator’s discretion. Virologic breakthrough was defined as confirmed HBV DNA either >1 log10 from nadir or HBV DNA ≥400 copies/mL after 77% retention). In the TDF arm, 9/323 (2.8%) patients were viremic at Week 240/last visit, with four patients on TDF and 5 patients on FTC/TDF. For the 4 TDF patients, 1 had no change in pol/RT with virologic breakthrough and 3 had unique polymorphic site changes (1 with virologic breakthrough). One patient had a resolution to wild-type from a baseline mixture at a conserved site (rtK/Q154K) in addition to a polymorphic site change. For the 5 FTC/TDF patients, 2 had no change in pol/RT (1 with virologic breakthrough), 1 was unable to be genotyped, and 2 had unique polymorphic site changes. In the ADV to open-label TDF arm, 3/171 (1.8%) patients were viremic at Week 240/last visit. Two patients were on TDF while 1 was on FTC/TDF. Both TDF patients were unable to be genotyped, likely due to low viral loads (~3.0 copies/mL) and 1 FTC/TDF patient developed a conserved site change (rtK168N) along with a unique polymorphic site change during virologic breakthrough coincident with transient nonadherence. Overall, 4/494 (0.8%) patients had virologic breakthrough defined during Year 5; 3 of these patients had documented nonadherence during breakthrough and HBV DNA began to return to <400 copies/mL in all 4 patients while continuing on study. Phenotypic analysis of HBV from these patients is currently underway. Conclusions: In these long term studies of TDF for chronic hepatitis B where patient retention has remained high, virologic breakthrough during Year 5 was rare (0.8%), transient, and typically associated with nonadherence. No cases of viral resistance to TDF have been documented to date. Resistance surveillance continues through Year 8 of both studies.