A Study to Compare Tenofovir Disoproxil Fumarate Versus Adefovir Dipivoxil for the Treatment of HBeAg-Negative Chronic Hepatitis B

Summary

This primary objectives of this study are to compare the efficacy, safety, and tolerability of tenofovir disoproxil fumarate (TDF) versus adefovir dipivoxil (ADV) for the treatment of pre-core mutant chronic hepatitis B. Participants will receive TDF or ADV for 48 weeks (double-blind). After 48 weeks, eligible participants switched to open-label TDF for up to 480 weeks.

Timeline

Start

2005-02

Primary completion

2007-04

Completion

2016-01

Outcome

Met primary endpoint

registry analysis (non-inferiority or equivalence test); TDF-TDF vs ADV-TDF; p <0.001; Difference in proportions 23.5 (95% CI 13.2 to 33.8) NCT00117676 ↗

paper At week 48, in both studies, a significantly higher proportion of patients receiving tenofovir DF than of those receiving adefovir dipivoxil had reached the primary end point PMID 19052126 ↗

release “achieved the primary endpoint compared to Hepsera-treated patients (71 percent versus 49 percent of patients in Study 102” gilead.com ↗

Publications

• Results Kitrinos KM, Corsa A, Liu Y, Flaherty J, Snow-Lampart A, Marcellin P, Borroto-Esoda K, Miller MD. No detectable resistance to tenofovir disoproxil fumarate after 6 years of therapy in patients with chronic hepatitis B. Hepatology. 2014 Feb;59(2):434-42. doi: 10.1002/hep.26686.
• Results Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, Washington MK, Germanidis G, Flaherty JF, Aguilar Schall R, Bornstein JD, Kitrinos KM, Subramanian GM, McHutchison JG, Heathcote EJ. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet. 2013 Feb 9;381(9865):468-75. doi: 10.1016/S0140-6736(12)61425-1. Epub 2012 Dec 10.
• Results Gordon SC, Krastev Z, Horban A, Petersen J, Sperl J, Dinh P, Martins EB, Yee LJ, Flaherty JF, Kitrinos KM, Rustgi VK, Marcellin P. Efficacy of tenofovir disoproxil fumarate at 240 weeks in patients with chronic hepatitis B with high baseline viral load. Hepatology. 2013 Aug;58(2):505-13. doi: 10.1002/hep.26277. Epub 2013 May 3.
• Results Tsai NC, Marcellin P, Buti M, Washington MK, Lee SS, Chan S, Trinh H, Flaherty JF, Kitrinos KM, Dinh P, Charuworn P, Subramanian GM, Gane E. Viral suppression and cirrhosis regression with tenofovir disoproxil fumarate in Asians with chronic hepatitis B. Dig Dis Sci. 2015 Jan;60(1):260-8. doi: 10.1007/s10620-014-3336-7. Epub 2014 Sep 2.
• Results Fung S, Gordon SC, Krastev Z, Horban A, Petersen J, Sperl J, Gane E, Jacobson IM, Yee LJ, Dinh P, Martins EB, Flaherty JF, Kitrinos KM, Dusheiko G, Trinh H, Flisiak R, Rustgi VK, Buti M, Marcellin P. Tenofovir disoproxil fumarate in Asian or Pacific Islander chronic hepatitis B patients with high viral load (>/= 9 log10 copies/ml). Liver Int. 2015 Feb;35(2):422-8. doi: 10.1111/liv.12694. Epub 2014 Oct 28.
• Results Buti M, Fung S, Gane E, Afdhal NH, Flisiak R, Gurel S, Flaherty JF, Martins EB, Yee LJ, Dinh P, Bornstein JD, Mani Subramanian G, Janssen HL, George J, Marcellin P. Long-term clinical outcomes in cirrhotic chronic hepatitis B patients treated with tenofovir disoproxil fumarate for up to 5 years. Hepatol Int. 2015 Apr;9(2):243-50. doi: 10.1007/s12072-015-9614-4. Epub 2015 Mar 13.
• Results Buti M, Tsai N, Petersen J, Flisiak R, Gurel S, Krastev Z, Aguilar Schall R, Flaherty JF, Martins EB, Charuworn P, Kitrinos KM, Subramanian GM, Gane E, Marcellin P. Seven-year efficacy and safety of treatment with tenofovir disoproxil fumarate for chronic hepatitis B virus infection. Dig Dis Sci. 2015 May;60(5):1457-64. doi: 10.1007/s10620-014-3486-7. Epub 2014 Dec 23.
• Results Corsa A, Liu Y, Flaherty JF, Marcellin P, Miller M, Kitrinos KM. No Detectable Resistance to Tenofovir Disoproxil Fumarate (TDF) in HBeAg+ and HBeAg- Patients With Chronic Hepatitis B (CHB) After Eight Years of Treatment [Abstract 1707]. The 65th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting (AASLD); 2014 08-10 November; Boston MA.
• Results Marcellin P, Gane EJ, Flisiak R, Trinh HN, Petersen J, Gurel S, et al. Long Term Treatment with Tenofovir Disoproxil Fumarate for Chronic Hepatitis B Infection is Safe and Well Tolerated and Associated with Durable Virologic Response with no Detectable Resistance: 8 Year Results from Two Phase 3 Trials [Abstract]. 55th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); 2014 November 7-11; Boston, MA.
• Results Gane EJ, Marcellin P, Sievert W, Trinh HN, Shiffman ML, Washington MK, et al. Five years of Treatment with Tenofovir DF for Chronic Hepatitis B Infection in Asian Patients is Associated with Sustained Viral Suppression and Significant Regression of Histological Fibrosis and Cirrhosis [Poster Number 1429]. 62nd Annual Meeting of the American Association for the Study of Liver Diseases; 2011 November 4-8; San Francisco, California.
• Results Liu Y, Corsa AC, Buti M, Cathcart AL, Flaherty JF, Miller MD, Kitrinos KM, Marcellin P, Gane EJ. No detectable resistance to tenofovir disoproxil fumarate in HBeAg+ and HBeAg- patients with chronic hepatitis B after 8 years of treatment. J Viral Hepat. 2017 Jan;24(1):68-74. doi: 10.1111/jvh.12613. Epub 2016 Sep 23.
• Marcellin P, Wong DK, Sievert W, Buggisch P, Petersen J, Flisiak R, Manns M, Kaita K, Krastev Z, Lee SS, Cathcart AL, Crans G, Op den Brouw M, Jump B, Gaggar A, Flaherty J, Buti M. Ten-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B virus infection. Liver Int. 2019 Oct;39(10):1868-1875. doi: 10.1111/liv.14155. Epub 2019 Jul 10.
• Buti M, Wong DK, Gane E, Flisiak R, Manns M, Kaita K, Janssen HLA, Op den Brouw M, Jump B, Kitrinos K, Crans G, Flaherty J, Gaggar A, Marcellin P. Safety and efficacy of stopping tenofovir disoproxil fumarate in patients with chronic hepatitis B following at least 8 years of therapy: a prespecified follow-up analysis of two randomised trials. Lancet Gastroenterol Hepatol. 2019 Apr;4(4):296-304. doi: 10.1016/S2468-1253(19)30015-9. Epub 2019 Feb 20.
• Jacobson IM, Washington MK, Buti M, Thompson A, Afdhal N, Flisiak R, Akarca US, Tchernev KG, Flaherty JF, Aguilar Schall R, Myers RP, Subramanian GM, McHutchison JG, Younossi Z, Marcellin P, Patel K. Factors Associated With Persistent Increase in Level of Alanine Aminotransferase in Patients With Chronic Hepatitis B Receiving Oral Antiviral Therapy. Clin Gastroenterol Hepatol. 2017 Jul;15(7):1087-1094.e2. doi: 10.1016/j.cgh.2017.01.032. Epub 2017 Feb 12.
• Pan CQ, Chan S, Trinh H, Yao A, Bae H, Lou L. Similar efficacy and safety of tenofovir in Asians and non-Asians with chronic hepatitis B. World J Gastroenterol. 2015 May 14;21(18):5524-31. doi: 10.3748/wjg.v21.i18.5524.
• Heathcote EJ, Marcellin P, Buti M, Gane E, De Man RA, Krastev Z, Germanidis G, Lee SS, Flisiak R, Kaita K, Manns M, Kotzev I, Tchernev K, Buggisch P, Weilert F, Kurdas OO, Shiffman ML, Trinh H, Gurel S, Snow-Lampart A, Borroto-Esoda K, Mondou E, Anderson J, Sorbel J, Rousseau F. Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology. 2011 Jan;140(1):132-43. doi: 10.1053/j.gastro.2010.10.011. Epub 2010 Oct 16.
• Marcellin P, Heathcote EJ, Buti M, Gane E, de Man RA, Krastev Z, Germanidis G, Lee SS, Flisiak R, Kaita K, Manns M, Kotzev I, Tchernev K, Buggisch P, Weilert F, Kurdas OO, Shiffman ML, Trinh H, Washington MK, Sorbel J, Anderson J, Snow-Lampart A, Mondou E, Quinn J, Rousseau F. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008 Dec 4;359(23):2442-55. doi: 10.1056/NEJMoa0802878.

Drugs

Evaluation	Drug	Modality	Dose	Route
Comparator	Adefovir dipivoxil	Small molecule	10 mg	Oral
Subject	Tenofovir disoproxil fumarate	Small molecule	300 mg	Oral
Subject	emtricitabine	Other / unclassified	200 mg	Oral

Indications