Tenofovir Versus Tenofovir + Telbivudine for Chronic Hepatitis B

Summary

Chronic Hepatitis B is the most common cause of chronic viral liver disease worldwide afflicting 350 million persons, leading to significant morbidity and mortality due to liver disease and HCC in 20-40% of infected persons. With the advent of nucleoside analogues, this rescued patients with significant risk of disease progression, but in most circumstances, therapy was needed long term as HBsAg seroclearance was an uncommon occurrence, and stopping therapy was associated with relapse of disease and hepatitis B flares. The use of pegylated interferons showed increased HBeAg seroconversion and HBsAg seroclearance rates compared to nucleoside analogues , however combination nucleos(t)ide analogue therapy has been quite disappointing. However a recent showed that the combination of telbivudine and tenofovir in a response guided therapy design, had a remarkable 6% HBsAg seroclearance at week 52 in patients. Such results require further confirmation. There is currently an unmet need for the large number of patients on long term nucleoside analogue therapy who have not achieved HBeAg seroconversion or HBsAg seroclearance. Such patients are seeking alternatives to long term therapy hence an exploration of other therapeutic strategies is attractive. An additional benefit of telbivudine has been the surprising improvement in renal function and this study seeks to examine whether this can improve the renal impairment that may be seen with tenofovir. Our study proposes to examine if the combination of tenofovir and telbivudine can improve endpoints. Patients fulfilling inclusion and exclusion criteria will be randomized to tenofovir or tenofovir and telbivudine (1:1 ratio). The primary endpoint will be a qHBsAg reduction of \>1log at week 96, which may predict future HBsAg seroclearance, which is also a secondary endpoint. An additional primary endpoint is increase in eGFR in the combination arm compared to the monotherapy arm. The study aims to enroll 146 patients randomized 1:1 ratio (73:73) patients. Multivariate analysis will be performed of baseline and on-treatment factors that predict the primary outcome.

Timeline

Start

2016-04

Primary completion

2020-07

Completion

2020-07

Publications

• Background European Association For The Study Of The Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol. 2012 Jul;57(1):167-85. doi: 10.1016/j.jhep.2012.02.010. Epub 2012 Mar 20. No abstract available.
• Background Piratvisuth T, Komolmit P, Tanwandee T, Sukeepaisarnjaroen W, Chan HL, Pessoa MG, Fassio E, Ono SK, Bessone F, Daruich J, Zeuzem S, Cheinquer H, Pathan R, Dong Y, Trylesinski A. 52-week efficacy and safety of telbivudine with conditional tenofovir intensification at week 24 in HBeAg-positive chronic hepatitis B. PLoS One. 2013;8(2):e54279. doi: 10.1371/journal.pone.0054279. Epub 2013 Feb 4.
• Background Liaw YF. Clinical utility of hepatitis B surface antigen quantitation in patients with chronic hepatitis B: a review. Hepatology. 2011 Aug;54(2):E1-9. doi: 10.1002/hep.24473.
• Background Chan HL, Thompson A, Martinot-Peignoux M, Piratvisuth T, Cornberg M, Brunetto MR, Tillmann HL, Kao JH, Jia JD, Wedemeyer H, Locarnini S, Janssen HL, Marcellin P. Hepatitis B surface antigen quantification: why and how to use it in 2011 - a core group report. J Hepatol. 2011 Nov;55(5):1121-31. doi: 10.1016/j.jhep.2011.06.006. Epub 2011 Jun 28.
• Background Wursthorn K, Jung M, Riva A, Goodman ZD, Lopez P, Bao W, Manns MP, Wedemeyer H, Naoumov NV. Kinetics of hepatitis B surface antigen decline during 3 years of telbivudine treatment in hepatitis B e antigen-positive patients. Hepatology. 2010 Nov;52(5):1611-20. doi: 10.1002/hep.23905.
• Background Gane EJ, Deray G, Liaw YF, Lim SG, Lai CL, Rasenack J, Wang Y, Papatheodoridis G, Di Bisceglie A, Buti M, Samuel D, Uddin A, Bosset S, Trylesinski A. Telbivudine improves renal function in patients with chronic hepatitis B. Gastroenterology. 2014 Jan;146(1):138-146.e5. doi: 10.1053/j.gastro.2013.09.031. Epub 2013 Sep 22.
• Background Gara N, Zhao X, Collins MT, Chong WH, Kleiner DE, Jake Liang T, Ghany MG, Hoofnagle JH. Renal tubular dysfunction during long-term adefovir or tenofovir therapy in chronic hepatitis B. Aliment Pharmacol Ther. 2012 Jun;35(11):1317-25. doi: 10.1111/j.1365-2036.2012.05093.x. Epub 2012 Apr 16.

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