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)
The combination of TFV with FTC, 3TC, ETV, LdT or AFV had additive to slightly synergistic anti-HBV effects in vitro. These results support the use of TDF as a component in combination regimens with currently available anti-HBV nucleoside analogues.
An isoleucine-to-valine change at position 233 (rtI233V) of hepatitis B virus (HBV) polymerase was recently reported to cause decreased in vitro susceptibility to, and treatment failure of, adefovir dipivoxil (ADV). To further evaluate these findings, we screened our ADV clinical-study sequence database of 853 patients and identified 4 who, at baseline, had HBV with this mutation. All 4 patients responded to treatment with ADV, with a median change in HBV DNA levels of 4.0 log 10 copies/mL after 48 weeks of treatment. Phenotypic evaluation of clinical isolates and of a laboratory strain with the rtI233V mutation demonstrated their full susceptibility to adefovir in vitro, and HBV with the rtI233V mutation developed in none of the patients.Adefovir dipivoxil (ADV) is a nucleotide analogue that is used for the treatment of patients with chronic hepatitis B, including patients infected with HBeAg ϩ or HBeAg Ϫ types of hepatitis B virus (HBV), lamivudine-resistant HBV, liver transplant, and HIV coinfection [1]. On the basis of results on 0001ف patients enrolled in clinical studies of ADV, 2 mutations associated with resistance to adefovir were identified in the polymerase region of HBV: rtN236T and rtA181V [2]. These 2 mutations were demonstrated to have a strong correlation with clinical-treatment failure and to confer a statistically significant reduction of drug susceptibility in vitro [3]. The cumulative probability of mutations associated with resistance to adefovir is 0%, 3%, 11%, 18%, and 29% after 1, 2, 3, 4, and 5 years, respectively [4]. An isoleucine-to-valine change at position 233 (rtI233V) of HBV polymerase was recently reported to cause both primary resistance to ADV in 3 patients, as evidenced by a lack of suppression of HBV DNA levels on initiation of treatment with ADV, and a decrease in susceptibility to adefovir in vitro [1]. The aim of the present study was to evaluate the incidence of the rtI233V mutation and to evaluate its impact on treatment with ADV in a large cohort of patients enrolled in clinical studies of ADV. Patient and methods. Patients from 4 clinical studies of ADV were included in this evaluation: studies GS-98-437 and GS-98-438 were placebo-controlled phase 3 randomized trials designed to evaluate the efficacy of 10 mg of ADV over a 96-week period, in patients with HBeAg ϩ and HBeAg Ϫ chronic hepatitis B [5, 6], respectively; study GS-98-435 was an open-label phase 3 compassionate-use study designed to evaluate the safety and efficacy of 10 mg treatment with ADV in patients with lamivudineresistant chronic hepatitis B either before or after liver transplantation [7]; and study GS-98-412 (extension phase) was a phase 2 dose range-finding study of ADV. All studies were approved by local Investigational Review Boards, and all of the patients in these studies provided written informed consent. Levels of HBV DNA in the serum were determined by the Roche Amplicor polymerase chain reaction (PCR) assay, with 1000 copies/mL as the lower limit of quantitation. Genotypic analysis of the ...
Hepatitis B virus (HBV) pol/RT mutations that confer clinical resistance to tenofovir disoproxil fumarate (TDF) have not been detected to date. In vitro, the rtN236T adefovir dipivoxil (ADV)-associated resistance mutation confers low-level cross-resistance to tenofovir: 3- to 13-fold changes in EC(50) from wild type. This study evaluated the clinical response of rtN236T mutant viruses by comparing their early viral load decay kinetics to wild-type viruses in chronic HBV monoinfected patients harbouring rtN236T prior to initiating TDF or emtricitabine (FTC)/TDF therapy. Baseline samples (n = 105) from adefovir refractory patients were tested for the presence of rtN236T using a highly sensitive allele-specific PCR assay with an rtN236T detection cut-off of 0.5%. The rtN236T mutation was detected at baseline in 14.3% (14/98) of analysable patient samples (0.5-93.2%, rtN236T percentage range). The median change in total HBV DNA at week 24 was comparable for patients with rtN236T detected at baseline (-3.7 log(10) copies/mL, n = 14) as compared to patients with wild-type HBV (-3.2 log(10) copies/mL, n = 90). In patients with rtN236T, wild-type and rtN236T mutant virus showed similar rates of HBV DNA decline with no statistically significant difference observed at week 4. Moreover, the proportion of rtN236T remained unchanged in patients in either arm of the study during treatment. In conclusion, the rtN236T mutant virus showed similar HBV DNA decline kinetics to wild-type virus in adefovir refractory patients who switched to TDF or FTC/TDF. Despite low levels of cross-resistance in vitro, TDF similarly suppresses wild-type and rtN236T mutant viruses in vivo.
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