No Resistance to Tenofovir Disoproxil Fumarate Detected After up to 144 Weeks of Therapy in Patients Monoinfected With Chronic Hepatitis B Virus Δ

Abstract

Tenofovir disoproxil fumarate (TDF) is a nucleotide analogue with potent activity against human immunodeficiency virus type 1 and hepatitis B virus (HBV). To date, no reports of HBV clinical resistance to TDF have been confirmed. In two phase 3 studies (GS-US-174-0102 and GS-US-174-0103), 375 hepatitis B e antigen-negative (HBeAg 2 ) patients and 266 HBeAg 1 patients with chronic hepatitis B (some nucleoside-naive and some lamivudine-experienced) were randomized 2:1 to receive TDF (n 5 426) or adefovir dipivoxil (ADV; n 5 215) for 48 weeks. After week 48, eligible patients received open-label TDF with no interruption. The studies are being continued through week 384/year 8; week 144 data are presented here. Per protocol, viremic patients (HBV DNA level ! 400 copies/mL or 69 IU/mL) had the option of adding emtricitabine (FTC) at or after week 72. Resistance analyses of HBV polymerase/reverse transcriptase (pol/RT) were based on population dideoxy sequencing. Phenotypic analyses were conducted in HepG2 cells with recombinant HBV derived from patient serum. Most patients maintained TDF monotherapy treatment across both studies (607/641, 95%). A resistance analysis of HBV pol/RT was performed at the baseline for all patients, for viremic patients at week 144 or at the last time when they were on TDF monotherapy (34 on TDF and 19 on ADV-TDF), and for patients who remained viremic after the addition of FTC (7/20 on TDF and 5/14 on ADV-TDF). No patient developed amino acid substitutions associated with resistance to TDF. Virological breakthrough on TDF monotherapy was infrequent over 144 weeks (13/426, 3%) and was attributed to documented nonadherence in most cases (11/13, 85%). Persistent viremia (!400 copies/mL) through week 144 was rare (5/641, 0.8%) and was not associated with virological resistance to TDF by population or clonal analyses. Conclusion: No nucleoside-naive or nucleoside-experienced patient developed HBV pol/RT mutations associated with TDF resistance after up to 144 weeks of exposure to TDF monotherapy. (HEPATOLOGY 2011;53:763-773)

Efficacy and Safety of Tenofovir Disoproxil Furmarate for Patients with Lamivudine-Resistant Hepatitis B Virus Infection

“…Tenofovir (TDF) has a potent antiviral activity against both wildtype or LAM-resistant HBV [4] . TDF demonstrated superior antiviral efficacy compared to ADV at 48 weeks and long-term suppression of HBV DAN through 5 years with absence of long-term resistance [14,15] . TDF is currently recommended for the first-line agents for chronic hepatitis B patients [16,17] .…”

Nucleos(t)ide analogue therapy for HBV-related HCC after hepatic resection: clinical benefits and unanswered questions

“…Entecavir monotherapy for long-term treatment of chronic HBV infection led to resistance in 1.2 % of patients in one prospective study [46]. Alone among the five NAs, tenofovir has been associated with a zero rate of resistance among patients with chronic hepatitis B [47]. Given the drug's antiviral potency and minimal toxicity, it may be the most suitable analogue.…”

Authors' reply: Current strategies in the management of hepatitis B virus reactivation

“…4,6 Viral resistance to nucleoside or nucleotide analogues during the long-term treatment of chronic HBV can be a major problem in patient management. 7 The best strategy for treating acute HBV reactivation in a patient who had been on lamivudine would be to add or switch to tenofovir. 8,9 For those patients who develop HBV reactivation (and have never received treatment with nucleoside analogues), entecavir and tenofovir are the drugs of choice given their potent antiviral effect and low levels of resistance.…”