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Tenofovir monotherapy versus tenofovir plus lamivudine or telbivudine combination therapy in treatment of lamivudine-resistant chronic hepatitis B.

ABSTRACT: Tenofovir disoproxil fumarate (TDF) monotherapy is a therapeutic option for chronic hepatitis B (CHB) patients infected with hepatitis B virus (HBV) variants resistant to lamivudine (LAM). We evaluated the antiviral efficacy and safety of TDF alone compared to those of TDF plus LAM or telbivudine (LdT) combination in patients harboring HBV variants with genotypic resistance to LAM. This multicenter retrospective study included consecutive patients who had LAM-resistant HBV variants and were treated with TDF alone (monotherapy group) or TDF combined with LAM or LdT (combination therapy group) for at least 6 months. Inverse probability of treatment weighting (IPTW) for the entire cohort was applied to control for treatment selection bias. Overall, 153 patients (33 in the monotherapy group and 120 in the combination therapy group) were analyzed. The overall probability of achieving complete virologic suppression at month 12 was 91.6%: 88.6% in the monotherapy group and 92.6% in the combination therapy group. Combination therapy was not superior to monotherapy in viral suppression before and after IPTW (P=0.562 and P=0.194, respectively). Hepatitis B e antigen (HBeAg) loss, biochemical response, and virologic breakthrough did not differ between treatment groups. The probabilities of complete virologic suppression were comparable between treatment groups in the subsets according to HBeAg status and HBV DNA levels at baseline. No patient experienced any significant renal dysfunction during the treatment period. In conclusion, TDF monotherapy has antiviral efficacy comparable to that of TDF plus LAM or LdT combination therapy, with a favorable safety profile in CHB patients with LAM-resistant HBV variants.

SUBMITTER: Lee YB

PROVIDER: S-EPMC4335865 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Tenofovir monotherapy versus tenofovir plus lamivudine or telbivudine combination therapy in treatment of lamivudine-resistant chronic hepatitis B.

Lee Yun Bin YB Jung Eun Uk EU Kim Bo Hyun BH Lee Jeong-Hoon JH Cho Hyeki H Ahn Hongkeun H Choi Won-Mook WM Cho Young Youn YY Lee Minjong M Yoo Jeong-Ju JJ Cho Yuri Y Lee Dong Hyeon DH Cho Eun Ju EJ Yu Su Jong SJ Park Sung Jae SJ Kim Yoon Jun YJ Park Joong-Won JW Lee Youn Jae YJ Kim Chang-Min CM Yoon Jung-Hwan JH Kim Chung Yong CY Lee Hyo-Suk HS

Antimicrobial agents and chemotherapy 20141124 2

Tenofovir disoproxil fumarate (TDF) monotherapy is a therapeutic option for chronic hepatitis B (CHB) patients infected with hepatitis B virus (HBV) variants resistant to lamivudine (LAM). We evaluated the antiviral efficacy and safety of TDF alone compared to those of TDF plus LAM or telbivudine (LdT) combination in patients harboring HBV variants with genotypic resistance to LAM. This multicenter retrospective study included consecutive patients who had LAM-resistant HBV variants and were trea ...[more]

PMID: 25421484

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Project description:BackgroundThe efficacy of switching to tenofovir disoproxil fumarate (TDF) monotherapy from lamivudine (LAM) plus adefovir dipivoxil (ADV) combination therapy (stable switching) in patients with LAM-resistant chronic hepatitis B (CHB) and undetectable hepatitis B virus (HBV) DNA is not clear.MethodsIn this non-inferiority trial, patients with LAM-resistant CHB and undetectable serum HBV DNA (<20 IU/mL) for >6 months after initiating LAM+ADV combination therapy were randomized (1:2) either to continue the combination therapy (LAM+ADV group, n = 58) or switched to TDF monotherapy (TDF group, n = 111). They were followed-up with serum biochemistry tests and HBV DNA measurement at 12-week intervals for 96 weeks. The primary endpoint of this study was the proportion of patients with viral reactivation at week 96.ResultsPatients with CHB enrolled in this study (n = 169) included 74 patients with compensated liver cirrhosis. In total, 9 patients (4 in the LAM+ADV group and 5 in the TDF group) dropped-out from the study. After a mean follow-up period of 96 weeks, the proportion of HBV reactivation observed was 6.8% (4/58) in the LAM+ADV group and 4.5% (5/111) in the TDF group by using intention-to-treat analysis (difference, -2.3%; 95% CI, -9.84-5.24%). None of the subjects in either group experienced viral reactivation based on per protocol analysis. No serious adverse reactions were observed. In the subgroup analysis for estimated glomerular filtration rate (eGFR) before and after treatment, decreased eGFR was observed only in the TDF group with cirrhosis (85.22 vs. 79.83 mL/min/1.73 m2, p = 0.000).ConclusionsStable switching to TDF monotherapy yielded non-inferior results at 96 weeks compared to the results obtained with LAM+ADV combination therapy in patients with LAM-resistant CHB and undetectable HBV DNA. However, TDF monotherapy in patients with cirrhosis requires close attention with respect to renal function.Trial registrationClinicalTrials.gov NCT01732367.

Project description:IntroductionViral kinetics has proved useful in understanding antiviral potency, determining antiviral profiles and optimizing treatment strategy.MethodsThis was a randomized, open-label study comparing the viral kinetics in 46 hepatitis B e antigen-positive patients during 12-week treatment with telbivudine monotherapy, tenofovir monotherapy or the combination of telbivudine plus tenofovir. A standard biphasic mathematical model was used to compare hepatitis B virus (HBV) DNA decay parameters.ResultsForty-six patients received telbivudine (n = 16), tenofovir (n = 14) or telbivudine plus tenofovir (n = 16). From baseline to Week 12, the mean (SD) reduction in HBV DNA levels was not significantly different between treatment groups: -3.9 (0.9) log10 copies/mL in telbivudine group, -4.2 (0.7) log10 copies/mL in tenofovir group, and -4.4 (1.0) log10 copies/mL in combination group. No significant difference was observed among the three groups for viral clearance rate per day (0.97, 1.02, and 0.88, respectively) or for infected cell loss rate per day (0.04, 0.05, and 0.05, respectively). Antiviral efficiency in blocking viral production was similar in the monotherapy groups (median; 99.7% in telbivudine group and 99.4% in tenofovir group), but was slightly better and more homogeneous in the combination treatment group than in the monotherapy groups: mean (SD), 99.1% (0.8%) and 98.8% (1.6%), respectively (Wald-Wolfowitz test; P = 0.038). All treatments were well tolerated and no serious adverse event was reported during the study. Of the 46 patients in the safety population, 23 experienced adverse events. Most of the adverse events were not suspected to be related to the study drug by the investigators.ConclusionMonotherapy with telbivudine or tenofovir showed similar antiviral effectiveness in HBV DNA reduction and viral kinetics of HBV DNA decay. Efficiency in blocking viral production was slightly improved in the combination treatment group compared to the monotherapy groups.

Project description:AIM:To make efficacy and safety comparison of telbivudine-raodmap and tenofovir-roadmap in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients. METHODS:This was the first prospective, randomised, two-arm, open-label, non-inferiority study in HBeAg-negative CHB patients that compared telbivudine and tenofovir administered as per roadmap concept. Patients were treated up to 24 wk and, depending on virologic response, continued the same therapy or received add-on therapy up to 104 wk. Eligible patients received an additional 52 wk of treatment in the extension period (i.e., up to 156 wk). Patients who developed virologic breakthrough (VB) while on monotherapy also received add-on therapy. The primary efficacy endpoint was the rate of patients achieving hepatitis B virus (HBV) DNA < 300 copies/mL at week 52. Secondary efficacy endpoints included the rates of HBV DNA < 300 and < 169 copies/mL, HBV DNA change from baseline, alanine aminotransferase normalisation, hepatitis B surface antigen (HBsAg) loss, HBsAg seroconversion, VB, and emergence of resistance at various timepoints throughout the study. Safety and estimated glomerular filtration rate (eGFR) were also analysed. RESULTS:A total of 241 patients were randomised. Non-inferiority of telbivudine arm to tenofovir arm was demonstrated at week 52 (± 7 d window), with over 91% of patients in each treatment arm achieving HBV DNA level < 300 copies/mL. Both arms were similar in terms of key secondary efficacy variables at weeks 104 and 156. The percentage of patients achieving HBV DNA < 300 copies/mL remained high and was similar in the telbivudine and tenofovir arms at both weeks 104 and 156. Over 82% of patients in both arms achieved alanine aminotransferase normalisation at week 52, and this percentage remained high at weeks 104 and 156. Telbivudine treatment progressively reduced serum HBsAg levels from baseline while no change was reported in quantitative HBsAg during therapy with tenofovir. Both treaments showed acceptable safety profiles. The telbivudine arm showed eGFR improvement unlike the tenofovir arm. CONCLUSION:Efficacy was shown for both telbivudine-roadmap and tenofovir-roadmap regimens in HBeAg-negative CHB patients over 156 wk. Telbivudine arm was associated with renal improvement.

Dataset Information

Tenofovir monotherapy versus tenofovir plus lamivudine or telbivudine combination therapy in treatment of lamivudine-resistant chronic hepatitis B.

Publications

Tenofovir monotherapy versus tenofovir plus lamivudine or telbivudine combination therapy in treatment of lamivudine-resistant chronic hepatitis B.

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