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A randomized open label trial of tenofovir monotherapy versus tenofovir plus telbivudine in spontaneous reactivation of hepatitis B.

ABSTRACT: Background/Aim:Acute-on-chronic liver failure (ACLF-B) in spontaneous reactivation of chronic hepatitis B (SR-CHB) has high mortality. Tenofovir disoproxil fumarate (TDF) improves survival by ~40% in ACLF-B but is potentially nephrotoxic. Combining telbivudine (LDT) with TDF may negate this risk and could boost rapid viral clearance and improve clinical outcomes. Patients and Methods:Seventy consecutive patients with SR-CHB were randomized to TDF (300 mg/day, n = 35) or TDF plus LDT (600 mg/day; n = 35). In all, 25 had ACLF-B and none had option for liver transplantation. Primary endpoint was survival at 3 months. Secondary endpoints were survival at 3 months in ACLF-B, serial reduction in hepatitis B virus (HBV) DNA, hepatitis B surface antigen (HBsAg) loss and liver-related complications. Results:Overall baseline clinical and laboratory parameters in the two groups were comparable. Reduction in HBV DNA at weeks 2, 4 and 12 was independent of treatment groups and presence of ACLF-B (P < 0.01). All six patients with HBsAg loss at 12 weeks had lower HBV DNA at baseline and none had ACLF-B. Patients with no ACLF-B had more rapid decline in bilirubin and alanine aminotraminase at week 2 compared with ACLF-B. Patients on TDF plus LDT showed significant improvement in AKI on follow-up (five of six patients) compared with TDF monotherapy (none of six patients) and had less reduction in estimated glomerular filtration rate at week 12. Eight of 10 patients with liver-related deaths received TDF monotherapy (P = 0.02). New-onset septic shock, TDF monotherapy, e-antibody positivity, and higher baseline model for end-stage liver disease score were predictors of mortality in ACLF-B. None had treatment-related severe adverse effects. Conclusion:Addition of LDT to tenofovir is safe and may be renoprotective in spontaneous reactivation of hepatitis B. Combination therapy improves survival in ACLF-B despite comparable HBV DNA suppression to tenofovir monotherapy.

SUBMITTER: Jindal A

PROVIDER: S-EPMC6784432 | biostudies-literature | 2019 Sep-Oct

REPOSITORIES: biostudies-literature

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A randomized open label trial of tenofovir monotherapy versus tenofovir plus telbivudine in spontaneous reactivation of hepatitis B.

Jindal Ankur A Vyas Ashish A Sharma Manoj M Kumar Guresh G Sarin Shiv K SK

Saudi journal of gastroenterology : official journal of the Saudi Gastroenterology Association 20190901 5

<h4>Background/aim</h4>Acute-on-chronic liver failure (ACLF-B) in spontaneous reactivation of chronic hepatitis B (SR-CHB) has high mortality. Tenofovir disoproxil fumarate (TDF) improves survival by ~40% in ACLF-B but is potentially nephrotoxic. Combining telbivudine (LDT) with TDF may negate this risk and could boost rapid viral clearance and improve clinical outcomes.<h4>Patients and methods</h4>Seventy consecutive patients with SR-CHB were randomized to TDF (300 mg/day, n = 35) or TDF plus L ...[more]

PMID: 31044748

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Project description:PurposeThis randomized phase 2 study sought to assess the treatment effect of a finite duration of apalutamide with and without androgen deprivation therapy (ADT) in biochemically recurrent prostate cancer (BCR PC). Materials and Methods. Patients with BCR PC after primary definitive therapy and prostate-specific antigen (PSA) doubling time ≤12 months were randomized to open-label apalutamide (240 mg/d) alone, apalutamide plus ADT, or ADT alone (1 : 1:1 ratio) for 12 months followed by a 12-month observation period (NCT01790126). Mean changes from baseline in Functional Assessment of Cancer Therapy-Prostate (FACT-P) at 12 months (primary endpoint) and other prespecified assessments of health-related quality of life (HRQoL), PSA nadir, time to PSA progression, time to testosterone recovery, recovered testosterone >150 ng/dL without PSA progression at 24 months, and molecular markers were evaluated.ResultsIn 90 enrolled patients (apalutamide plus ADT (n = 31), apalutamide (n = 29), ADT (n = 30)), FACT-P at 12 months was not significantly different between apalutamide, ADT and apalutamide, and ADT groups. Addition of apalutamide to ADT prolonged time to PSA progression but this change did not reach statistical significance (hazard ratio (HR): 0.56, 95% confidence interval (CI): 0.23-1.36, P=0.196); time to testosterone recovery was similar in the ADT-containing groups. In apalutamide plus ADT, apalutamide, and ADT groups, 37.9%, 37.0%, and 19.2% of patients, respectively, had testosterone >150 ng/dL at 24 months without confirmed PSA progression. Of the few biomarkers expressed in blood, EPHA3 was significantly associated with shorter time to PSA progression (P=0.02) in the overall population.ConclusionsHRQoL was similar in patients treated with apalutamide alone, ADT alone, or their combination, although apalutamide plus ADT did not demonstrate statistically significant noninferiority in change from baseline in overall HRQoL. The aggregated efficacy and safety outcomes support further evaluation of apalutamide plus ADT in BCR PC.

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.

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.

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A randomized open label trial of tenofovir monotherapy versus tenofovir plus telbivudine in spontaneous reactivation of hepatitis B.

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A randomized open label trial of tenofovir monotherapy versus tenofovir plus telbivudine in spontaneous reactivation of hepatitis B.

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