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

A Randomized, Double-Blind, Controlled Evaluation of Tenofovir DF Versus Adefovir Dipivoxil for the Treatment of Presumed Pre-Core Mutant Chronic Hepatitis B

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.

Study Overview

• Status: Completed
• Conditions: Chronic Hepatitis B
• Intervention / Treatment: Drug: TDF; Drug: ADV placebo; Drug: FTC/TDF; Drug: ADV; Drug: TDF placebo

• Study Type: Interventional
• Enrollment (Actual): 382
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
    • Concord, New South Wales, Australia, 2139
    • Westmead, New South Wales, Australia, 2145
  • Queensland
    • Woolloongabba, Queensland, Australia, 40102
  • Victoria
    • Clayton, Victoria, Australia, 3168
    • Fitzroy, Victoria, Australia, 3065
    • Heidelberg, Victoria, Australia, 3084
    • Prahan, Victoria, Australia, 3004
• Bulgaria
  • Sofia, Bulgaria, 1431
  • Sofia, Bulgaria, 1407
  • Varna, Bulgaria, 9010
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z6
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z1H2
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E3P4
  • Ontario
    • Toronto, Ontario, Canada, M5T 2S8
• Czech Republic
  • Brno, Czech Republic, 62500
  • Hradec Kralove, Czech Republic
  • Praha 4, Czech Republic, 14021
  • Praha 6 - Stresovice, Czech Republic, 169 02
• France
  • Clichy, France, 92110
  • Creteil, France, 94010
  • Lille, France, 59037
  • Lyon, France, 69317
  • Nancy, France, 54500
  • Paris, France, 75651
  • Strasbourg, France, 67901
  • Toulouse, France, 31059
• Germany
  • Duesseldorf, Germany, 40237
  • Frankfurt, Germany, 60590
  • Hamburg, Germany, 20099
  • Hannover, Germany, 30623
  • Herne, Germany, 44623
  • Homburg/Saar, Germany, 66421
  • Mainz, Germany, 55131
  • Munchen, Germany, 81377
  • Tubingen, Germany, 72076
• Greece
  • Athens, Greece, 11526
  • Larissa, Greece, 41110
  • Leipzig, Greece, 04103
  • Thessaloniki, Greece, 54636
  • Thessaloniki, Greece, 56429
  • Thessaloniki, Greece, 57010
• Italy
  • Bologna, Italy, 40138
  • Torino, Italy, 10134
• Netherlands
  • Rotterdam, Netherlands, 3015
• New Zealand
  • Auckland, New Zealand
  • Hamilton, New Zealand
  • Whakatane, New Zealand
• Poland
  • Bialystok, Poland, 15-540
  • Bydgoszcz, Poland, 85-030
  • Chorzow, Poland, 41-500
  • Krakow, Poland, 31-501
  • Warszawa, Poland, 01-201
  • Wroclaw, Poland, 50-136
• Spain
  • Barcelona, Spain, 08035
  • Valencia, Spain, 46009
  • Madrid
    • Majadahonda, Madrid, Spain, 28222
• Turkey
  • Bursa, Turkey
  • Istanbul, Turkey, 34098
  • Istanbul, Turkey, 34899
  • Izmir, Turkey
• United Kingdom
  • London, United Kingdom, NW1 2BU
  • London, United Kingdom, WC1E 6HX
• United States
  • California
    • La Jolla, California, United States, 92037
    • Pasadena, California, United States, 91105
    • San Diego, California, United States, 92123
    • San Diego, California, United States, 92105
    • San Francisco, California, United States, 94115
    • San Jose, California, United States, 95116
  • Georgia
    • Atlanta, Georgia, United States, 30308
  • Hawaii
    • Honolulu, Hawaii, United States, 96817
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
    • Detroit, Michigan, United States, 48202
  • Missouri
    • St. Louis, Missouri, United States, 63104
  • New York
    • Flushing, New York, United States, 11355
    • New York, New York, United States, 10029
    • New York, New York, United States, 10003
  • Virginia
    • Falls Church, Virginia, United States, 22042
    • Richmond, Virginia, United States, 23298

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 69 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Chronic hepatitis B virus (HBV) infection, defined as positive serum hepatitis B s-antigen (HBsAg) for at least 6 months.
• 18 through 69 years of age, inclusive.

• Active hepatitis B e-antigen (HBeAg) negative chronic HBV infection, with all of the following:

  • HBeAg negative and HBeAb positive at screening
  • Alanine aminotransferase (ALT) levels > the upper limit of the normal range (ULN) and ≤ 10 x ULN
  • Serum HBV DNA > 100,000 copies/mL at screening
  • Creatinine clearance ≥ 70 mL/min
  • Hemoglobin ≥ 8 g/dL
  • Neutrophils ≥ 1,000 /mL
• Knodell necroinflammatory score ≥ 3 and a Knodell fibrosis score < 4; however, up to 120 patients with cirrhosis, ie, a Knodell fibrosis score equal to 4, will be eligible for enrollment
• Negative serum β-human chorionic gonadotropin (hCG)
• Nucleotide naive, ie, no prior nucleotide (TDF or ADV) therapy for greater than 12 weeks
• Nucleoside naive, ie, no prior nucleoside (any nucleoside) therapy for greater than 12 weeks. However, up to 120 patients with > 12 weeks prior lamivudine experience will be eligible
• Willing and able to provide written informed consent
• Had a liver biopsy performed within 6 months of baseline and has readable biopsy slides or agrees to have a biopsy performed prior to baseline

Key Exclusion Criteria:

• Pregnant women, women who are breast feeding, or women who believe they may wish to become pregnant during the course of the study
• Males and females of reproductive potential who are unwilling to use an effective method of contraception during the study.
• Decompensated liver disease defined as conjugated bilirubin > 1.5 x ULN, prothrombin time (PT) > 1.5 x ULN, platelets < 75,000/mL, serum albumin < 3.0 g/dL, or prior history of clinical hepatic decompensation (eg, ascites, jaundice, encephalopathy, variceal hemorrhage)
• Received any nucleoside, nucleotide (TDF or ADV) or interferon (pegylated or not) therapy within 6 months prior to the pre treatment biopsy
• Evidence of hepatocellular carcinoma (HCC)
• Coinfection with hepatitis C virus (HCV), human immunodeficiency virus (HIV), or hepatitis D virus (HDV)
• Significant renal, cardiovascular, pulmonary, or neurological disease
• Received solid organ or bone marrow transplantation
• Is currently receiving therapy with immunomodulators (eg, corticosteroids, etc.), investigational agents, nephrotoxic agents, or agents susceptible of modifying renal excretion
• Has proximal tubulopathy

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TDF-TDF; TDF plus ADV placebo (double-blind period), followed by TDF (open-label period). Participants may add FTC (as part of emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) FDC tablet) to their treatment regimen in the open-label period.	Drug: TDF; 300 mg tablet administered orally once daily; Other Names: Viread®; Drug: ADV placebo; Tablet administered orally once daily; Drug: FTC/TDF; 200/300 mg fixed-dose combination (FDC) tablet administered orally once daily; Other Names: Truvada®
Active Comparator: ADV-TDF; ADV plus TDF placebo (double-blind period), followed by TDF (open-label period). Participants may add FTC (as part of FTC/TDF FDC tablet) to their treatment regimen in the open-label period.	Drug: TDF; 300 mg tablet administered orally once daily; Other Names: Viread®; Drug: FTC/TDF; 200/300 mg fixed-dose combination (FDC) tablet administered orally once daily; Other Names: Truvada®; Drug: ADV; 10 mg tablet administered orally once daily; Other Names: Hepsera®; Drug: TDF placebo; Tablet administered orally once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With HBV DNA < 400 Copies/mL and Histological Improvement (2-point Reduction in Knodell Necroinflammatory Score Without Worsening in Knodell Fibrosis Score) at Week 48	Complete response was a composite endpoint defined as histological response and HBV DNA < 400 copies/mL. Histological response was based on the Knodell numerical scoring of liver biopsy specimens and defined as at least a 2-point reduction in Knodell necroinflammatory score without worsening in Knodell fibrosis score. The Knodell necroinflammatory score is the combined necrosis and inflammation domain scores and ranges from 0 to 14; the Knodell fibrosis domain score ranges from 0 to 4. A participant was a nonresponder for the primary endpoint if either biopsy (baseline or end-of-treatment) was missing or if there was not an HBV DNA value available at or beyond Week 40.	Baseline; Week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With HBV DNA < 400 Copies/mL at Week 48		Week 48
Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 144, 192, 240, 288, 336, and 384		Weeks 144, 192, 240, 288, 336, and 384
Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 432 and 480		Weeks 432 and 480
Change From Baseline in HBV DNA at Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480		Baseline; Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480
Change From Week 48 in HBV DNA at Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480		Week 48; Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480
Percentage of Participants With Histological Response at Week 48	Histological response was based on the Knodell numerical scoring of liver biopsy specimens and defined as at least a 2-point reduction in Knodell necroinflammatory score without worsening in Knodell fibrosis score. The Knodell necroinflammatory score is the combined necrosis and inflammation domain scores and ranges from 0 to 14; the Knodell fibrosis domain score ranges from 0 to 4.	Baseline; Week 48
Percentage of Participants With Histological Response at Week 240	Histological response was based on the Knodell numerical scoring of liver biopsy specimens and defined as at least a 2-point reduction in Knodell necroinflammatory score without worsening in Knodell fibrosis score. The Knodell necroinflammatory score is the combined necrosis and inflammation domain scores and ranges from 0 to 14; the Knodell fibrosis domain score ranges from 0 to 4.	Baseline; Week 240
Change From Baseline in Knodell and Ishak Necroinflammatory Scores at Week 48	The Knodell necroinflammatory score is the combined score for necrosis and inflammation domains of the Knodell scoring system, and ranges from 0 (best) to 14 (worst). The Ishak score measures the degree of liver fibrosis (scarring) caused by chronic necroinflammation (inflammation leading to cell death) and ranges from 0 (best) to 6 (worst).	Baseline; Week 48
Change From Baseline in Knodell and Ishak Necroinflammatory Scores at Week 240	The Knodell necroinflammatory score is the combined score for necrosis and inflammation domains of the Knodell scoring system, and ranges from 0 (best) to 14 (worst). The Ishak score measures the degree of liver fibrosis (scarring) caused by chronic necroinflammation (inflammation leading to cell death) and ranges from 0 (best) to 6 (worst).	Baseline; Week 240
Ranked Assessment of Necroinflammation and Fibrosis at Week 48	Participants were ranked as having improvement, no change, worsening, or missing data (compared to Baseline) based on the Knodell scoring system, and results are presented as the percentage of participants in each category. The Knodell necroinflammatory score is the combined score for necrosis and inflammation domains of the Knodell scoring system, which ranges from 0 (best) to 14 (worst). The Knodell fibrosis domain score ranges from 0 (best) to 4 (worst). A decrease of 1 point or more indicated improvement, and an increase of 1 point or more indicated worsening.	Baseline; Week 48
Ranked Assessment of Necroinflammation and Fibrosis at Week 240	Participants were ranked as having improvement, no change, worsening, or missing data (compared to Baseline) based on the Knodell scoring system, and results are presented as the percentage of participants in each category. The Knodell necroinflammatory score is the combined score for necrosis and inflammation domains of the Knodell scoring system, which ranges from 0 (best) to 14 (worst). The Knodell fibrosis domain score ranges from 0 (best) to 4 (worst). A decrease of 1 point or more indicated improvement, and an increase of 1 point or more indicated worsening.	Baseline; Week 240
Percentage of Participants With ALT Normalization at Weeks 144, 192, 240, 288, 336, and 384	ALT normalization was defined as ALT > ULN at baseline and within the normal range at the subsequent time point. The ULN was 43 U/L for males and 34 U/L for females aged 18 to < 69, and 35 U/L for males and 32 U/L for females aged ≥ 69.	Baseline; Weeks 144, 192, 240, 288, 336, and 384
Percentage of Participants With ALT Normalization at Weeks 432 and 480	ALT normalization was defined as ALT > ULN at baseline and within the normal range at the subsequent time point. The ULN was 43 U/L for males and 34 U/L for females aged 18 to < 69, and 35 U/L for males and 32 U/L for females aged ≥ 69.	Baseline; Weeks 432 and 480
Change From Baseline in ALT at Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480		Baseline; Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480
Change From Week 48 in ALT at Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480		Week 48; Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480
Number of Participants With HBV Genotypic Changes From Baseline at Week 96 (Resistance Surveillance)	Of the total number analyzed, participants evaluated for resistance included those with HBV DNA ≥ 400 copies/mL at Week 96 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 48 with HBV DNA ≥ 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen and had HBV DNA ≥ 400 copies/mL at the time of the addition.	Baseline; Weeks 49 to 96
Number of Participants With HBV Genotypic Changes From Baseline at Week 144 (Resistance Surveillance)	Of the total number analyzed, participants evaluated for resistance included those with HBV DNA ≥ 400 copies/mL at Week 144 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 96 with HBV DNA ≥ 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen after Week 96 and had HBV DNA ≥ 400 copies/mL at the time of the addition.	Baseline; Weeks 97 to 144
Number of Participants With HBV Genotypic Changes From Baseline at Week 192 (Resistance Surveillance)	Of the total number analyzed, participants evaluated for resistance included those with HBV DNA ≥ 400 copies/mL at Week 192 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 144 with HBV DNA ≥ 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen after Week 144 and had HBV DNA ≥ 400 copies/mL at the time of the addition.	Baseline; Weeks 145 to 192
Number of Participants With HBV Genotypic Changes From Baseline at Week 240 (Resistance Surveillance)	Of the total number analyzed, participants evaluated for resistance included those with HBV DNA ≥ 400 copies/mL at Week 240 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 192 with HBV DNA ≥ 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen after Week 192 and had HBV DNA ≥ 400 copies/mL at the time of the addition.	Baseline; Weeks 193 to 240
Number of Participants With HBV Genotypic Changes From Baseline at Week 288 (Resistance Surveillance)	Of the total number analyzed, participants evaluated for resistance included those with HBV DNA ≥ 400 copies/mL at Week 288 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 240 with HBV DNA ≥ 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen after Week 240 and had HBV DNA ≥ 400 copies/mL at the time of the addition.	Baseline; Weeks 241 to 288
Number of Participants With HBV Genotypic Changes From Baseline at Week 336 (Resistance Surveillance)	Of the total number analyzed, participants evaluated for resistance included those with HBV DNA ≥ 400 copies/mL at Week 336 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 288 with HBV DNA ≥ 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen after Week 288 and had HBV DNA ≥ 400 copies/mL at the time of the addition.	Baseline; Weeks 289 to 336
Number of Participants With HBV Genotypic Changes From Baseline at Week 384 (Resistance Surveillance)	Of the total number analyzed, participants evaluated for resistance included those with HBV DNA ≥ 400 copies/mL at Week 384 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 336 with HBV DNA ≥ 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen after Week 336 and had HBV DNA ≥ 400 copies/mL at the time of the addition.	Baseline; Weeks 337 to 384
Number of Participants With HBV Genotypic Changes From Baseline at Week 432 (Resistance Surveillance)	Of the total number analyzed, participants evaluated for resistance included those with HBV DNA ≥ 400 copies/mL at Week 432 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 384 with HBV DNA ≥ 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen after Week 384 and had HBV DNA ≥ 400 copies/mL at the time of the addition.	Baseline; Weeks 385 to 432
Number of Participants With HBV Genotypic Changes From Baseline at Week 480 (Resistance Surveillance)	Of the total number analyzed, participants evaluated for resistance included those with HBV DNA ≥ 400 copies/mL at Week 480 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 432 with HBV DNA ≥ 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen after Week 432 and had HBV DNA ≥ 400 copies/mL at the time of the addition.	Baseline; Weeks 433 to 480
Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 96		Week 96
Percentage of Participants With ALT Normalization at Week 48	ALT normalization was defined as ALT > upper limit of normal (ULN) at baseline and within the normal range at the end of blinded treatment. The ULN was 43 U/L for males and 34 U/L for females aged 18 to < 69, and 35 U/L for males and 32 U/L for females aged ≥ 69.	Baseline; Week 48
Percentage of Participants With ALT Normalization at Weeks 96	ALT normalization was defined as ALT > ULN at baseline and within the normal range at Week 96. The ULN was 43 U/L for males and 34 U/L for females aged 18 to < 69, and 35 U/L for males and 32 U/L for females aged ≥ 69.	Baseline; Week 96
Percentage of Participants With Hepatitis B S-Antigen (HBsAg) Loss or Seroconversion Antibody to HBs (Anti-HBs) at Week 48	HBsAg loss was defined as HBsAg positive at baseline and HBsAg negative at Week 48. Seroconversion to anti-HBs was defined as change of detectable antibody to HBsAg from negative at baseline to positive at Week 48.	Baseline; Week 48
Percentage of Participants With HBsAg Loss and/or Seroconversion to Anti-HBs at Week 96	HBsAg loss was defined as HBsAg positive at baseline and HBsAg negative at Week 96. Seroconversion to anti-HBs was defined as change of detectable antibody to HBsAg from negative at baseline to positive at Week 96.	Baseline; Week 96
Percentage of Participants With HBsAg Loss and/or Seroconversion to Anti-HBs at Weeks 144, 192, 240, 288, 336, 384, 432, and 480	HBsAg loss was defined as HBsAg positive at baseline and HBsAg negative at the subsequent time point. Seroconversion to anti-HBs was defined as change of detectable antibody to HBsAg from negative at baseline to positive at the subsequent time point.	Baseline; Weeks 144, 192, 240, 288, 336, 384, 432, and 480
Number of Participants With HBV Genotypic Changes From Baseline at Week 48 (Resistance Surveillance)	Of the total number analyzed, participants evaluated for resistance included those with HBV DNA ≥ 400 copies/mL at Week 48, those with viral breakthrough, and those who discontinued after Week 24 with HBV DNA ≥ 400 copies/mL.	Baseline; Week 48

Collaborators and Investigators

• Sponsor: Gilead Sciences

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: February 1, 2005
• Primary Completion (Actual): April 1, 2007
• Study Completion (Actual): January 1, 2016

Study Registration Dates

• First Submitted: June 30, 2005
• First Submitted That Met QC Criteria: June 30, 2005
• First Posted (Estimate): July 8, 2005

Study Record Updates

• Last Update Posted (Actual): March 7, 2017
• Last Update Submitted That Met QC Criteria: January 16, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: tenofovir; hepatitis B virus; adefovir; HBeAg Negative
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Enterovirus Infections; Picornaviridae Infections; Hepatitis B; Hepatitis; Hepatitis A; Hepatitis B, Chronic; Hepatitis, Chronic; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Adefovir dipivoxil
• Other Study ID Numbers: GS-US-174-0102; 2004-005119-27 (EudraCT Number)