Ten-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B virus infection.

BACKGROUND & AIMS: Tenofovir disoproxil fumarate (TDF) is a first-line treatment for chronic hepatitis B (CHB). We aimed to describe the efficacy and safety profiles of TDF treatment for up to 10 years in a well-described cohort of CHB patients. METHODS: Hepatitis B e antigen (HBeAg)-negative and HBeAg-positive patients from two randomised, double-blind trials (ClinicalTrials.gov: NCT00117676 and NCT00116805) completed 48 weeks of randomised treatment with TDF or adefovir dipivoxil. A subset of these patients was then eligible to receive open-label TDF treatment for up to 10 years. At Year 10, patients were assessed for virological suppression, alanine aminotransferase (ALT) normalisation, serological response, safety and tolerability. RESULTS: Of 641 randomised and treated patients, 585 (91%) entered the open-label extension phase with 203 (32%) patients completing Year 10 of the study. At Year 10, 118/118 (100%) of HBeAg-negative patients and 78/80 (98%) of HBeAg-positive patients with available data achieved hepatitis B virus (HBV) DNA < 69 IU/mL, while 88/106 (83%) and 60/77 (78%) patients achieved ALT normalisation, respectively. Of the 23 patients with HBeAg status available at Year 10, 12 (52%) and six (27%) experienced HBeAg loss and seroconversion, respectively. No resistance to TDF was documented up to Year 10. In the period between Year 8 and Year 10, the safety profile of TDF was similar to previous reports, with few patients experiencing renal- or bone-related adverse events. CONCLUSIONS: Over 10 years, TDF had a favourable safety profile, was well tolerated, and resulted in continued maintenance of virological suppression with no documented resistance.

Telbivudine vs tenofovir in hepatitis B e antigen-negative chronic hepatitis B patients: OPTIMA roadmap study.

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.

Kinetics of hepatitis B surface antigen loss in patients with HBeAg-positive chronic hepatitis B treated with tenofovir disoproxil fumarate.

BACKGROUND & AIMS: In a study of 266 chronic hepatitis B e antigen (HBeAg)-positive patients, 23 experienced hepatitis B surface antigen (HBsAg) loss with up to 5 years of tenofovir disoproxil fumarate (TDF) treatment. HBsAg kinetics in patients with and without HBsAg loss and predictors of HBsAg loss were evaluated. METHODS: HBsAg levels were quantified every 12 weeks. A multivariable regression analysis, involving prespecified baseline characteristics and on-treatment response parameters, was performed; a stepwise procedure identified independent predictors of HBsAg loss. RESULTS: Among patients with HBsAg loss, 14 (61%), 1 (4%), 0 and 7 (30%) were genotypes A through D, respectively; 1 (4%) was genotype F. HBsAg loss was preceded by viral suppression (HBV DNA <29 IU/ml; n=23) and HBeAg loss (n=19). Among treated patients the strongest independent predictors of HBsAg loss were Caucasian race with genotype A/D and ⩽4 years of infection (HR=14.3, 95% confidence interval [CI] 4.7-43.4; p<0.0001) and an HBsAg decline of ⩾1 log10 IU/ml at week 24 (HR=13.7, 95% CI 5.6-33.7; p<0.0001). Among TDF-treated patients, a reduction in HBsAg level of ⩾1-log10 by week 12 or 24 had a positive predictive value of 35%-45%, respectively, and a negative predictive value of 94%-97%, respectively. CONCLUSIONS: HBsAg loss in HBeAg-positive patients receiving TDF involves a chronology of virologic and serologic responses; patients with HBV genotypes A or D and a rapid early decline in HBsAg are more likely to lose HBsAg.

The prevention of an expected hepatic flare in HBe negative patients after lamivudine discontinuation.

The treatment with lamivudine leads to drug resistant mutations in 19 to 70% cases after 1- and 5-year therapy, respectively, associated with the risk of severe rebound of liver disease with alaninaminotransferase flare. In this situation, adefovir should be added, but this drug is not available in every country. We report three cases where we avoided the expected hepatic flare-ups by using IFN and isoprinosine. Based on this empirical experience, we suggest that the new drug has to be administered one month before discontinuation of lamivudine. Prospective trials are mandatory.