No detectable resistance to tenofovir disoproxil fumarate in HBeAg+ and HBeAg− patients with chronic hepatitis B after 8 years of treatment

Summary A major hurdle in the long‐term treatment of chronic hepatitis B (CHB) patients is to maintain viral suppression in the absence of drug resistance. To date, no evidence of resistance to tenofovir disoproxil fumarate (TDF) has been observed. A cumulative evaluation of CHB patients who qualified for resistance surveillance over 8 years of TDF treatment was conducted. 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 through year 8. Population sequencing of HBV pol/RT was attempted for all TDF‐treated patients at baseline and, annually if viremic, at discontinuation, or with addition of emtricitabine. Overall, 88/641 (13.7%) patients qualified for sequence analysis at one or more time points. The percentage of patients qualifying for sequence analysis declined over time, from 9 to 11% in years 1‐2 to <4% over years 3‐8. Forty‐one episodes of virologic breakthrough (VB) occurred throughout the study, with most ( n =29, 70%) associated with nonadherence to study medication. Fifty‐nine per cent of VB patients with an opportunity to resuppress HBV achieved HBV DNA resuppression. A minority of patients who qualified for sequencing had polymorphic (41/165, 24.8%) or conserved (17/165, 10.3%) site changes in pol/RT, with six patients developing lamivudine and/or ADV resistance‐associated mutations. No accumulation of conserved site changes was detected. The long‐term treatment of CHB with TDF monotherapy maintains effective suppression of HBV DNA through 8 years, with no evidence of TDF resistance or accumulation of conserved site changes.