Back to resultsA Study to Compare Tenofovir Disoproxil Fumarate Versus Adefovir Dipivoxil for the Treatment of HBeAg-Negative Chronic Hepatitis B
Primary Purpose
Chronic Hepatitis B
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
TDF
ADV
TDF placebo
ADV placebo
FTC/TDF
Sponsored by
About this trial
This is an interventional treatment trial for Chronic Hepatitis B focused on measuring tenofovir, adefovir, hepatitis B virus, HBeAg Negative
Eligibility Criteria
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.
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
TDF-TDF
ADV-TDF
Arm Description
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.
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.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
Percentage of Participants With HBV DNA < 400 Copies/mL at Week 48
Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 96
Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 144, 192, 240, 288, 336, and 384
Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 432 and 480
Change From Baseline in HBV DNA at 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
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.
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.
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).
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).
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.
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.
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.
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.
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.
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.
Change From Baseline in ALT at 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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00117676
Brief Title
A Study to Compare Tenofovir Disoproxil Fumarate Versus Adefovir Dipivoxil for the Treatment of HBeAg-Negative Chronic Hepatitis B
Official Title
A Randomized, Double-Blind, Controlled Evaluation of Tenofovir DF Versus Adefovir Dipivoxil for the Treatment of Presumed Pre-Core Mutant Chronic Hepatitis B
Study Type
Interventional
2. Study Status
Record Verification Date
January 2017
Overall Recruitment Status
Completed
Study Start Date
February 2005 (undefined)
Primary Completion Date
April 2007 (Actual)
Study Completion Date
January 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Gilead Sciences
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Hepatitis B
Keywords
tenofovir, adefovir, hepatitis B virus, HBeAg Negative
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
382 (Actual)
8. Arms, Groups, and Interventions
Arm Title
TDF-TDF
Arm Type
Experimental
Arm Description
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.
Arm Title
ADV-TDF
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
TDF
Other Intervention Name(s)
Viread®
Intervention Description
300 mg tablet administered orally once daily
Intervention Type
Drug
Intervention Name(s)
ADV
Other Intervention Name(s)
Hepsera®
Intervention Description
10 mg tablet administered orally once daily
Intervention Type
Drug
Intervention Name(s)
TDF placebo
Intervention Description
Tablet administered orally once daily
Intervention Type
Drug
Intervention Name(s)
ADV placebo
Intervention Description
Tablet administered orally once daily
Intervention Type
Drug
Intervention Name(s)
FTC/TDF
Other Intervention Name(s)
Truvada®
Intervention Description
200/300 mg fixed-dose combination (FDC) tablet administered orally once daily
Primary Outcome Measure Information:
Title
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
Description
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.
Time Frame
Baseline; Week 48
Secondary Outcome Measure Information:
Title
Percentage of Participants With HBV DNA < 400 Copies/mL at Week 48
Time Frame
Week 48
Title
Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 96
Time Frame
Week 96
Title
Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 144, 192, 240, 288, 336, and 384
Time Frame
Weeks 144, 192, 240, 288, 336, and 384
Title
Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 432 and 480
Time Frame
Weeks 432 and 480
Title
Change From Baseline in HBV DNA at Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480
Time Frame
Baseline; Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480
Title
Change From Week 48 in HBV DNA at Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480
Time Frame
Week 48; Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480
Title
Percentage of Participants With Histological Response at Week 48
Description
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.
Time Frame
Baseline; Week 48
Title
Percentage of Participants With Histological Response at Week 240
Description
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.
Time Frame
Baseline; Week 240
Title
Change From Baseline in Knodell and Ishak Necroinflammatory Scores at Week 48
Description
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).
Time Frame
Baseline; Week 48
Title
Change From Baseline in Knodell and Ishak Necroinflammatory Scores at Week 240
Description
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).
Time Frame
Baseline; Week 240
Title
Ranked Assessment of Necroinflammation and Fibrosis at Week 48
Description
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.
Time Frame
Baseline; Week 48
Title
Ranked Assessment of Necroinflammation and Fibrosis at Week 240
Description
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.
Time Frame
Baseline; Week 240
Title
Percentage of Participants With ALT Normalization at Week 48
Description
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.
Time Frame
Baseline; Week 48
Title
Percentage of Participants With ALT Normalization at Weeks 96
Description
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.
Time Frame
Baseline; Week 96
Title
Percentage of Participants With ALT Normalization at Weeks 144, 192, 240, 288, 336, and 384
Description
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.
Time Frame
Baseline; Weeks 144, 192, 240, 288, 336, and 384
Title
Percentage of Participants With ALT Normalization at Weeks 432 and 480
Description
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.
Time Frame
Baseline; Weeks 432 and 480
Title
Change From Baseline in ALT at Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480
Time Frame
Baseline; Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480
Title
Change From Week 48 in ALT at Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480
Time Frame
Week 48; Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480
Title
Percentage of Participants With Hepatitis B S-Antigen (HBsAg) Loss or Seroconversion Antibody to HBs (Anti-HBs) at Week 48
Description
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.
Time Frame
Baseline; Week 48
Title
Percentage of Participants With HBsAg Loss and/or Seroconversion to Anti-HBs at Week 96
Description
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.
Time Frame
Baseline; Week 96
Title
Percentage of Participants With HBsAg Loss and/or Seroconversion to Anti-HBs at Weeks 144, 192, 240, 288, 336, 384, 432, and 480
Description
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.
Time Frame
Baseline; Weeks 144, 192, 240, 288, 336, 384, 432, and 480
Title
Number of Participants With HBV Genotypic Changes From Baseline at Week 48 (Resistance Surveillance)
Description
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.
Time Frame
Baseline; Week 48
Title
Number of Participants With HBV Genotypic Changes From Baseline at Week 96 (Resistance Surveillance)
Description
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.
Time Frame
Baseline; Weeks 49 to 96
Title
Number of Participants With HBV Genotypic Changes From Baseline at Week 144 (Resistance Surveillance)
Description
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.
Time Frame
Baseline; Weeks 97 to 144
Title
Number of Participants With HBV Genotypic Changes From Baseline at Week 192 (Resistance Surveillance)
Description
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.
Time Frame
Baseline; Weeks 145 to 192
Title
Number of Participants With HBV Genotypic Changes From Baseline at Week 240 (Resistance Surveillance)
Description
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.
Time Frame
Baseline; Weeks 193 to 240
Title
Number of Participants With HBV Genotypic Changes From Baseline at Week 288 (Resistance Surveillance)
Description
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.
Time Frame
Baseline; Weeks 241 to 288
Title
Number of Participants With HBV Genotypic Changes From Baseline at Week 336 (Resistance Surveillance)
Description
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.
Time Frame
Baseline; Weeks 289 to 336
Title
Number of Participants With HBV Genotypic Changes From Baseline at Week 384 (Resistance Surveillance)
Description
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.
Time Frame
Baseline; Weeks 337 to 384
Title
Number of Participants With HBV Genotypic Changes From Baseline at Week 432 (Resistance Surveillance)
Description
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.
Time Frame
Baseline; Weeks 385 to 432
Title
Number of Participants With HBV Genotypic Changes From Baseline at Week 480 (Resistance Surveillance)
Description
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.
Time Frame
Baseline; Weeks 433 to 480
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
69 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gilead Study Director
Organizational Affiliation
Gilead Sciences
Official's Role
Study Director
Facility Information:
City
La Jolla
State/Province
California
ZIP/Postal Code
92037
Country
United States
City
Pasadena
State/Province
California
ZIP/Postal Code
91105
Country
United States
City
San Diego
State/Province
California
ZIP/Postal Code
92105
Country
United States
City
San Diego
State/Province
California
ZIP/Postal Code
92123
Country
United States
City
San Francisco
State/Province
California
ZIP/Postal Code
94115
Country
United States
City
San Jose
State/Province
California
ZIP/Postal Code
95116
Country
United States
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30308
Country
United States
City
Honolulu
State/Province
Hawaii
ZIP/Postal Code
96817
Country
United States
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48202
Country
United States
City
St. Louis
State/Province
Missouri
ZIP/Postal Code
63104
Country
United States
City
Flushing
State/Province
New York
ZIP/Postal Code
11355
Country
United States
City
New York
State/Province
New York
ZIP/Postal Code
10003
Country
United States
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
City
Falls Church
State/Province
Virginia
ZIP/Postal Code
22042
Country
United States
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23298
Country
United States
City
Camperdown
State/Province
New South Wales
ZIP/Postal Code
2050
Country
Australia
City
Concord
State/Province
New South Wales
ZIP/Postal Code
2139
Country
Australia
City
Westmead
State/Province
New South Wales
ZIP/Postal Code
2145
Country
Australia
City
Woolloongabba
State/Province
Queensland
ZIP/Postal Code
40102
Country
Australia
City
Clayton
State/Province
Victoria
ZIP/Postal Code
3168
Country
Australia
City
Fitzroy
State/Province
Victoria
ZIP/Postal Code
3065
Country
Australia
City
Heidelberg
State/Province
Victoria
ZIP/Postal Code
3084
Country
Australia
City
Prahan
State/Province
Victoria
ZIP/Postal Code
3004
Country
Australia
City
Sofia
ZIP/Postal Code
1407
Country
Bulgaria
City
Sofia
ZIP/Postal Code
1431
Country
Bulgaria
City
Varna
ZIP/Postal Code
9010
Country
Bulgaria
City
Calgary
State/Province
Alberta
ZIP/Postal Code
T2N 4Z6
Country
Canada
City
Vancouver
State/Province
British Columbia
ZIP/Postal Code
V5Z1H2
Country
Canada
City
Winnipeg
State/Province
Manitoba
ZIP/Postal Code
R3E3P4
Country
Canada
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5T 2S8
Country
Canada
City
Brno
ZIP/Postal Code
62500
Country
Czech Republic
City
Hradec Kralove
Country
Czech Republic
City
Praha 4
ZIP/Postal Code
14021
Country
Czech Republic
City
Praha 6 - Stresovice
ZIP/Postal Code
169 02
Country
Czech Republic
City
Clichy
ZIP/Postal Code
92110
Country
France
City
Creteil
ZIP/Postal Code
94010
Country
France
City
Lille
ZIP/Postal Code
59037
Country
France
City
Lyon
ZIP/Postal Code
69317
Country
France
City
Nancy
ZIP/Postal Code
54500
Country
France
City
Paris
ZIP/Postal Code
75651
Country
France
City
Strasbourg
ZIP/Postal Code
67901
Country
France
City
Toulouse
ZIP/Postal Code
31059
Country
France
City
Duesseldorf
ZIP/Postal Code
40237
Country
Germany
City
Frankfurt
ZIP/Postal Code
60590
Country
Germany
City
Hamburg
ZIP/Postal Code
20099
Country
Germany
City
Hannover
ZIP/Postal Code
30623
Country
Germany
City
Herne
ZIP/Postal Code
44623
Country
Germany
City
Homburg/Saar
ZIP/Postal Code
66421
Country
Germany
City
Mainz
ZIP/Postal Code
55131
Country
Germany
City
Munchen
ZIP/Postal Code
81377
Country
Germany
City
Tubingen
ZIP/Postal Code
72076
Country
Germany
City
Athens
ZIP/Postal Code
11526
Country
Greece
City
Larissa
ZIP/Postal Code
41110
Country
Greece
City
Leipzig
ZIP/Postal Code
04103
Country
Greece
City
Thessaloniki
ZIP/Postal Code
54636
Country
Greece
City
Thessaloniki
ZIP/Postal Code
56429
Country
Greece
City
Thessaloniki
ZIP/Postal Code
57010
Country
Greece
City
Bologna
ZIP/Postal Code
40138
Country
Italy
City
Torino
ZIP/Postal Code
10134
Country
Italy
City
Rotterdam
ZIP/Postal Code
3015
Country
Netherlands
City
Auckland
Country
New Zealand
City
Hamilton
Country
New Zealand
City
Whakatane
Country
New Zealand
City
Bialystok
ZIP/Postal Code
15-540
Country
Poland
City
Bydgoszcz
ZIP/Postal Code
85-030
Country
Poland
City
Chorzow
ZIP/Postal Code
41-500
Country
Poland
City
Krakow
ZIP/Postal Code
31-501
Country
Poland
City
Warszawa
ZIP/Postal Code
01-201
Country
Poland
City
Wroclaw
ZIP/Postal Code
50-136
Country
Poland
City
Majadahonda
State/Province
Madrid
ZIP/Postal Code
28222
Country
Spain
City
Barcelona
ZIP/Postal Code
08035
Country
Spain
City
Valencia
ZIP/Postal Code
46009
Country
Spain
City
Bursa
Country
Turkey
City
Istanbul
ZIP/Postal Code
34098
Country
Turkey
City
Istanbul
ZIP/Postal Code
34899
Country
Turkey
City
Izmir
Country
Turkey
City
London
ZIP/Postal Code
NW1 2BU
Country
United Kingdom
City
London
ZIP/Postal Code
WC1E 6HX
Country
United Kingdom
12. IPD Sharing Statement
Citations:
PubMed Identifier
23939953
Citation
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 Reference
result
PubMed Identifier
23234725
Citation
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 Reference
result
PubMed Identifier
23364953
Citation
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 Reference
result
PubMed Identifier
25179493
Citation
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 Reference
result
PubMed Identifier
25277773
Citation
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 Reference
result
PubMed Identifier
25788199
Citation
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 Reference
result
PubMed Identifier
25532501
Citation
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 Reference
result
Citation
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 Reference
result
Citation
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 Reference
result
Citation
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 Reference
result
PubMed Identifier
27658343
Citation
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.
Results Reference
result
PubMed Identifier
31136052
Citation
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.
Results Reference
derived
PubMed Identifier
30795958
Citation
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.
Results Reference
derived
PubMed Identifier
28215615
Citation
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.
Results Reference
derived
PubMed Identifier
25987775
Citation
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.
Results Reference
derived
PubMed Identifier
20955704
Citation
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.
Results Reference
derived
PubMed Identifier
19052126
Citation
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.
Results Reference
derived
Learn more about this trial
A Study to Compare Tenofovir Disoproxil Fumarate Versus Adefovir Dipivoxil for the Treatment of HBeAg-Negative Chronic Hepatitis B
We'll reach out to this number within 24 hrs