Among patients with chronic HBV infection, tenofovir DF at a daily dose of 300 mg had superior antiviral efficacy with a similar safety profile as compared with adefovir dipivoxil at a daily dose of 10 mg through week 48. (ClinicalTrials.gov numbers, NCT00116805 and NCT00117676.)

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One major challenge in the treatment of chronic hepatitis B is to maintain long-term viral suppression without promoting the selection of drug-resistant mutations. We analyzed data from 347 hepatitis B e antigen-negative and 238 hepatitis B e antigenpositive patients receiving tenofovir disoproxil fumarate (TDF) in an open-label, longterm extension of two phase 3 studies. To date, resistance analyses have been completed for patients receiving up to 288 weeks (6 years) of TDF. Population sequencing of hepatitis B virus (HBV) polymerase/reverse transcriptase (pol/RT) was attempted for all patients at baseline, and any patient who remained viremic (HBV DNA 400 copies/ mL [69 IU/mL]) at week 288 or at the end of treatment with TDF (n 5 52) or emtricitabine (FTC)/TDF (n 5 7). Phenotypic analyses were performed in HepG2 cells using recombinant HBV containing patient pol/RT sequences. Approximately half of the patients on open-label treatment who qualified for genotyping had pol/RT sequence changes compared to baseline (23/52 [44%] on TDF, 4/7 [57%] on FTC/TDF). Most changes were at polymorphic sites and none were associated with TDF resistance. Virologic breakthrough occurred infrequently and was associated with nonadherence to study medication in the majority of cases (12/16, 75%). Per protocol, 57 patients (10%) were eligible to switch to FTC/TDF; the majority had HBV DNA <400 copies/mL at their last study visit regardless of whether they switched to FTC/TDF (n 5 34) or maintained TDF monotherapy (n 5 17). No patient exhibited persistent viremia (HBV DNA never <400 copies/mL) after week 240. Conclusion: TDF monotherapy maintains effective suppression of HBV DNA through 288 weeks of treatment with no evidence of TDF resistance. (HEPATOLOGY 2014;59:434-442) T he treatment goals for chronic hepatitis B (CHB)-infected patients are to improve quality of life and decrease the risk of life-threatening complications by potent and durable suppression of hepatitis B virus (HBV) replication. [1][2][3][4][5] As most patients with CHB will require long-term treatment with nucleos(t)ide analogs, one of the greatest challenges is to maintain effective viral suppression without the selection of resistance mutations. Long-term treatment with first-generation nucleos(t)ide analogs leads to relatively high cumulative resistance rates, 71% after up to 4 years of treatment with lamivudine (LAM), 6 and 29% in hepatitis B e antigen (HBeAg)-negative patients and 20% in HBeAg-positive patients after up to 5 years of treatment with adefovir (ADV). 7,8 Furthermore, 25% of HBeAg-positive patients and 11% of HBeAg-negative patients developed resistance after up to 2 years of treatment with telbivudine.9 Entecavir (ETV) has a markedly lower rate of resistance: 1.2% among treatment-na€ ıve patients treated for up to 5 years.10 However, ETV resistance develops rapidly in patients with prior resistance to LAM: the 5-year cumulative probability of developing ETV resistance is 51% in patients harboring LAM resistance.

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)