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CompletedNCT00117676Updated Mar 7, 2017Results posted

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

A Phase 3 interventional study of TDF and ADV in Chronic Hepatitis B, sponsored by Gilead Sciences. Completed at 80 sites in 15 countries. Open to participants aged 18 Years to 69 Years. Per ClinicalTrials.gov, last updated 2017-03-07.

Sponsored by Gilead Sciences · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
382
Allocation
Randomized
Ages
18 Years to 69 Years
Sex
All
01

Study 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.

02

Conditions studied

  • Chronic Hepatitis B

Keywords

  • tenofovir
  • adefovir
  • hepatitis B virus
  • HBeAg Negative
03

In context

Hepatitis A

2,709 studies on the registry are indexed under Hepatitis A; 142 are open to participants now.

This study's enrollment of 382 is above the median of 100 across 1,886 interventional studies indexed under Hepatitis A.

Browse Hepatitis A studies →

Lead sponsor

Gilead Sciences is the lead sponsor of 680 studies on the registry; 24 are open to participants now.

Of its 259 completed or terminated interventional studies of FDA-regulated products, 249 (96%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years to 69 Years
Sexes eligible
All
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.

05

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
382 participants (actual)

Study arms

  • 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 · Drug: ADV placebo · Drug: FTC/TDF

  • 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 · Drug: ADV · Drug: TDF placebo · Drug: FTC/TDF

Interventions

  • DrugTDF

    300 mg tablet administered orally once daily

    Also known as: Viread®

  • DrugADV

    10 mg tablet administered orally once daily

    Also known as: Hepsera®

  • DrugTDF placebo

    Tablet administered orally once daily

  • DrugADV placebo

    Tablet administered orally once daily

  • DrugFTC/TDF

    200/300 mg fixed-dose combination (FDC) tablet administered orally once daily

    Also known as: Truvada®

06

What researchers measure

Primary outcomes

  1. 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.

    Time frame: Baseline; Week 48

Secondary outcomes

  1. Percentage of Participants With HBV DNA < 400 Copies/mL at Week 48

    Time frame: Week 48

  2. Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 96

    Time frame: Week 96

  3. 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

  4. Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 432 and 480

    Time frame: Weeks 432 and 480

  5. 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

  6. 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

  7. 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.

    Time frame: Baseline; Week 48

  8. 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.

    Time frame: Baseline; Week 240

  9. 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).

    Time frame: Baseline; Week 48

  10. 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).

    Time frame: Baseline; Week 240

  11. 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.

    Time frame: Baseline; Week 48

  12. 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.

    Time frame: Baseline; Week 240

  13. 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.

    Time frame: Baseline; Week 48

  14. 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.

    Time frame: Baseline; Week 96

  15. 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.

    Time frame: Baseline; Weeks 144, 192, 240, 288, 336, and 384

  16. 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.

    Time frame: Baseline; Weeks 432 and 480

  17. 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

  18. 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

  19. 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.

    Time frame: Baseline; Week 48

  20. 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.

    Time frame: Baseline; Week 96

  21. 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.

    Time frame: Baseline; Weeks 144, 192, 240, 288, 336, 384, 432, and 480

  22. 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.

    Time frame: Baseline; Week 48

  23. 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.

    Time frame: Baseline; Weeks 49 to 96

  24. 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.

    Time frame: Baseline; Weeks 97 to 144

  25. 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.

    Time frame: Baseline; Weeks 145 to 192

  26. 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.

    Time frame: Baseline; Weeks 193 to 240

  27. 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.

    Time frame: Baseline; Weeks 241 to 288

  28. 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.

    Time frame: Baseline; Weeks 289 to 336

  29. 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.

    Time frame: Baseline; Weeks 337 to 384

  30. 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.

    Time frame: Baseline; Weeks 385 to 432

  31. 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.

    Time frame: Baseline; Weeks 433 to 480

07

Results

Posted May 19, 2010

Participant flow

Participants were enrolled at study sites in North America, Europe, and Australia/New Zealand. The first participant was screened on 07 June 2005. The last study visit occurred on 19 January 2016.

Double-blind Period Through Week 48
Participant flow — Double-blind Period Through Week 48
MilestoneTDF-TDFADV-TDF
Started254128
Completed244121
Not completed107
Withdrew: Randomized but not treated43
Withdrew: Lost to follow-up10
Withdrew: Protocol violation01
Withdrew: Safety, tolerability, or efficacy reason52
Withdrew: Withdrew consent01
Open-label Period: Weeks 49 - 96
Participant flow — Open-label Period: Weeks 49 - 96
MilestoneTDF-TDFADV-TDF
Started235112
Completed225110
Not completed102
Withdrew: Lost to follow-up20
Withdrew: Safety, tolerability, or efficacy reason31
Withdrew: Withdrew consent51
Open-label Period: Weeks 97 - 144
Participant flow — Open-label Period: Weeks 97 - 144
MilestoneTDF-TDFADV-TDF
Started225110
Completed219109
Not completed61
Withdrew: Lost to follow-up41
Withdrew: Safety, tolerability, or efficacy reason10
Withdrew: Withdrew consent10
Open-label Period: Weeks 145 - 192
Participant flow — Open-label Period: Weeks 145 - 192
MilestoneTDF-TDFADV-TDF
Started219109
Completed209106
Not completed103
Withdrew: Investigator's discretion20
Withdrew: Lost to follow-up31
Withdrew: Withdrew consent52
Open-label Period: Weeks 193 - 240
Participant flow — Open-label Period: Weeks 193 - 240
MilestoneTDF-TDFADV-TDF
Started209106
Completed202103
Not completed73
Withdrew: Investigator's discretion11
Withdrew: Lost to follow-up01
Withdrew: Safety, tolerability, or efficacy reason20
Withdrew: Withdrew consent41
Open-label Period: Weeks 241 - 288
Participant flow — Open-label Period: Weeks 241 - 288
MilestoneTDF-TDFADV-TDF
Started202103
Completed192100
Not completed103
Withdrew: Investigator's discretion01
Withdrew: Lost to follow-up21
Withdrew: Protocol violation20
Withdrew: Safety, tolerability, or efficacy reason10
Withdrew: Withdrew consent51
Open-label Period: Weeks 289 - 336
Participant flow — Open-label Period: Weeks 289 - 336
MilestoneTDF-TDFADV-TDF
Started192100
Completed18393
Not completed97
Withdrew: Investigator's discretion74
Withdrew: Lost to follow-up22
Withdrew: Withdrew consent01
Open-label Period: Weeks 337 - 384
Participant flow — Open-label Period: Weeks 337 - 384
MilestoneTDF-TDFADV-TDF
Started18393
Completed17690
Not completed73
Withdrew: Investigator's discretion11
Withdrew: Lost to follow-up31
Withdrew: Study site discontinued10
Withdrew: Withdrew consent21
Open-label Period: Weeks 385 - 432
Participant flow — Open-label Period: Weeks 385 - 432
MilestoneTDF-TDFADV-TDF
Started8246
Completed8244
Not completed02
Withdrew: Investigator's discretion01
Withdrew: Safety, tolerability, or efficacy reason01
Open-label Period: Weeks 433 - 480
Participant flow — Open-label Period: Weeks 433 - 480
MilestoneTDF-TDFADV-TDF
Started8243
Completed8041
Not completed22
Withdrew: Lost to follow-up10
Withdrew: Safety, tolerability, or efficacy reason11
Withdrew: Withdrew consent01

Outcome measures

PrimaryPercentage 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.

Time frame:
Baseline; Week 48
Reported as:
Number · percentage of participants
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
percentage of participantsTDF-TDFADV-TDF
Yes70.848.8
No29.251.2
Statistical analysis
  • TDF-TDF vs ADV-TDF · Z-test · p = <0.001 (P-value corresponds to a Z-test of the null hypothesis that the stratum-adjusted (baseline ALT ≥ 2 x ULN or \> 2 x ULN) difference is 0.) · Difference in proportions: 23.5 · 95% CI 13.2 to 33.8
SecondaryPercentage of Participants With HBV DNA < 400 Copies/mL at Week 48
Time frame:
Week 48
Reported as:
Number · percentage of participants
Percentage of Participants With HBV DNA < 400 Copies/mL at Week 48
percentage of participantsTDF-TDFADV-TDF
Percentage of Participants With HBV DNA < 400 Copies/mL at Week 4893.263.2
Statistical analysis
  • TDF-TDF vs ADV-TDF · Z-test · p = <0.001 (P-value corresponds to a Z-test of the null hypothesis that the stratum-adjusted difference is zero. Difference, standard error of the difference, and the CI are stratum adjusted based on baseline ALT category (≤ 2 x ULN or \> 2 x ULN).) · Difference in proportions: 30.3 · 95% CI 21.3 to 39.2
SecondaryPercentage of Participants With HBV DNA < 400 Copies/mL at Weeks 96
Time frame:
Week 96
Reported as:
Number · percentage of participants
Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 96
percentage of participantsTDF-TDFADV-TDF
Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 9690.689.3
Statistical analysis
  • TDF-TDF vs ADV-TDF · Z-test · p = 0.672 (P-value corresponds to a Z-test of the null hypothesis that the stratum-adjusted difference is zero. Two-sided 95% confidence intervals, stratified by baseline ALT (baseline ALT ≤ 2 x ULN, \> 2 x ULN), were used to evaluate treatment arm differences.) · Difference in proportions: 1.4 · 95% CI -5.2 to 8.0
SecondaryPercentage 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
Reported as:
Number · percentage of participants
Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 144, 192, 240, 288, 336, and 384
percentage of participantsTDF-TDFADV-TDF
Week 14486.788.4
Week 19284.086.8
Week 24082.883.9
Week 28880.582.9
Week 33677.078.0
Week 38474.376.3
SecondaryPercentage of Participants With HBV DNA < 400 Copies/mL at Weeks 432 and 480
Time frame:
Weeks 432 and 480
Reported as:
Number · percentage of participants
Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 432 and 480
percentage of participantsTDF-TDFADV-TDF
Week 43297.697.7
Week 480100.0100.0
SecondaryChange 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
Reported as:
Mean · log10 copies/mL
Change From Baseline in HBV DNA at Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480
log10 copies/mLTDF-TDFADV-TDF
Week 48-4.57 ± 1.347-4.07 ± 1.331
Week 96-4.54 ± 1.400-4.74 ± 1.260
Week 144-4.61 ± 1.285-4.77 ± 1.285
Week 192-4.56 ± 1.371-4.75 ± 1.271
Week 240-4.59 ± 1.288-4.77 ± 1.303
Week 288-4.61 ± 1.310-4.81 ± 1.310
Week 336-4.61 ± 1.329-4.81 ± 1.307
Week 384-4.56 ± 1.333-4.79 ± 1.314
Week 432-4.60 ± 1.376-4.69 ± 1.370
Week 480-4.57 ± 1.329-4.75 ± 1.349
SecondaryChange 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
Reported as:
Mean · log10 copies/mL
Change From Week 48 in HBV DNA at Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480
log10 copies/mLTDF-TDFADV-TDF
Week 960.02 ± 0.424-0.60 ± 1.138
Week 144-0.03 ± 0.378-0.63 ± 1.169
Week 1920.01 ± 0.610-0.61 ± 1.161
Week 240-0.04 ± 0.299-0.61 ± 1.195
Week 288-0.04 ± 0.353-0.64 ± 1.203
Week 336-0.05 ± 0.380-0.65 ± 1.230
Week 384-0.02 ± 0.241-0.66 ± 1.237
Week 432-0.04 ± 0.393-0.67 ± 1.378
Week 480-0.05 ± 0.366-0.72 ± 1.283
SecondaryPercentage 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.

Time frame:
Baseline; Week 48
Reported as:
Number · percentage of participants
Percentage of Participants With Histological Response at Week 48
percentage of participantsTDF-TDFADV-TDF
Yes72.468.8
No27.631.2
Statistical analysis
  • TDF-TDF vs ADV-TDF · Z-test · p = 0.293 (P-value corresponds to a Z-test of the null hypothesis that the stratum-adjusted difference is zero. Confidence interval stratum adjusted based on baseline ALT (≤ 2 x ULN, \> 2 x ULN).) · Difference in proportions: 5.2 · 95% CI -4.5 to 14.9
SecondaryPercentage 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.

Time frame:
Baseline; Week 240
Reported as:
Number · percentage of participants
Percentage of Participants With Histological Response at Week 240
percentage of participantsTDF-TDFADV-TDF
Yes87.385.1
No12.714.9
SecondaryChange 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).

Time frame:
Baseline; Week 48
Reported as:
Mean · units on a scale
Change From Baseline in Knodell and Ishak Necroinflammatory Scores at Week 48
units on a scaleTDF-TDFADV-TDF
Knodell Necroinflammatory Score-3.5 ± 2.50-3.4 ± 2.36
Ishak Necroinflammatory Score-2.6 ± 1.93-2.6 ± 1.90
SecondaryChange 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).

Time frame:
Baseline; Week 240
Reported as:
Mean · units on a scale
Change From Baseline in Knodell and Ishak Necroinflammatory Scores at Week 240
units on a scaleTDF-TDFADV-TDF
Knodell Score-4.6 ± 2.50-4.9 ± 2.53
Ishak Score-4.0 ± 2.16-4.2 ± 2.38
SecondaryRanked 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.

Time frame:
Baseline; Week 48
Reported as:
Number · percentage of participants
Ranked Assessment of Necroinflammation and Fibrosis at Week 48
percentage of participantsTDF-TDFADV-TDF
Improvement - Necroinflammation82.081.6
No Change - Necroinflammation6.88.0
Worsening - Necroinflammation4.80.8
Missing Data - Necroinflammation6.49.6
Improvement - Fibrosis22.025.6
No Change - Fibrosis63.254.4
Worsening - Fibrosis8.410.4
Missing Data - Fibrosis6.49.6
SecondaryRanked 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.

Time frame:
Baseline; Week 240
Reported as:
Number · percentage of participants
Ranked Assessment of Necroinflammation and Fibrosis at Week 240
percentage of participantsTDF-TDFADV-TDF
Improvement - Necroinflammation96.794.6
No Change - Necroinflammation2.71.4
Worsening - Necroinflammation0.74.1
Improvement - Fibrosis62.059.5
No Change - Fibrosis34.033.8
Worsening - Fibrosis4.06.8
SecondaryPercentage 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.

Time frame:
Baseline; Week 48
Reported as:
Number · percentage of participants
Percentage of Participants With ALT Normalization at Week 48
percentage of participantsTDF-TDFADV-TDF
Percentage of Participants With ALT Normalization at Week 4876.377.1
Statistical analysis
  • TDF-TDF vs ADV-TDF · Z-test · p = 0.859 (Statistical tests were not adjusted for baseline ALT stratum. Analysis set included only randomized and treated participants with baseline ALT \> ULN (biochemically evaluable analysis set).) · Difference in proportions: -0.8 · 95% CI -10.2 to 8.5P-value corresponds to a Z-test of the null hypothesis that the ALT stratum-adjusted difference is zero.
SecondaryPercentage 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.

Time frame:
Baseline; Week 96
Reported as:
Number · percentage of participants
Percentage of Participants With ALT Normalization at Weeks 96
percentage of participantsTDF-TDFADV-TDF
Percentage of Participants With ALT Normalization at Weeks 9672.468.5
Statistical analysis
  • TDF-TDF vs ADV-TDF · Z-test · p = 0.359 (P-value corresponds to a Z-test of the null hypothesis that the ALT stratum-adjusted difference is zero.) · Difference in proportions: 4.9 · 95% CI -5.5 to 15.3Difference, standard error of the difference, and confidence interval are stratum adjusted (baseline ALT ≤ 2 x ULN or \> 2 x ULN).
SecondaryPercentage 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.

Time frame:
Baseline; Weeks 144, 192, 240, 288, 336, and 384
Reported as:
Number · percentage of participants
Percentage of Participants With ALT Normalization at Weeks 144, 192, 240, 288, 336, and 384
percentage of participantsTDF-TDFADV-TDF
Week 14474.370.0
Week 19268.276.4
Week 24070.375.7
Week 28869.972.9
Week 33665.965.4
Week 38465.369.2
SecondaryPercentage 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.

Time frame:
Baseline; Weeks 432 and 480
Reported as:
Number · percentage of participants
Percentage of Participants With ALT Normalization at Weeks 432 and 480
percentage of participantsTDF-TDFADV-TDF
Week 43286.587.2
Week 48080.088.9
SecondaryChange 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
Reported as:
Mean · units per liter
Change From Baseline in ALT at Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480
units per literTDF-TDFADV-TDF
Week 48-95.0 ± 102.31-124.4 ± 137.23
Week 96-93.7 ± 106.66-138.5 ± 155.75
Week 144-99.1 ± 105.67-140.0 ± 155.43
Week 192-99.6 ± 109.46-140.3 ± 153.89
Week 240-97.7 ± 104.32-139.5 ± 156.90
Week 288-98.9 ± 104.66-134.7 ± 152.90
Week 336-98.9 ± 106.50-143.1 ± 160.15
Week 384-96.1 ± 105.43-132.6 ± 142.09
Week 432-97.0 ± 115.09-131.9 ± 136.65
Week 480-94.9 ± 117.60-129.2 ± 139.24
SecondaryChange 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
Reported as:
Mean · units per liter
Change From Week 48 in ALT at Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480
units per literTDF-TDFADV-TDF
Week 962.4 ± 22.01-0.6 ± 19.87
Week 144-0.6 ± 12.91-0.3 ± 22.48
Week 1920.7 ± 23.07-3.6 ± 22.77
Week 240-2.5 ± 14.64-3.9 ± 20.00
Week 288-3.9 ± 13.35-4.1 ± 22.30
Week 336-2.6 ± 15.69-2.0 ± 20.61
Week 384-2.9 ± 14.13-3.9 ± 21.00
Week 432-4.6 ± 15.65-8.9 ± 29.12
Week 480-2.8 ± 15.92-5.9 ± 24.12
SecondaryPercentage 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.

Time frame:
Baseline; Week 48
Reported as:
Number · percentage of participants
Percentage of Participants With Hepatitis B S-Antigen (HBsAg) Loss or Seroconversion Antibody to HBs (Anti-HBs) at Week 48
percentage of participantsTDF-TDFADV-TDF
HBsAg Loss00
Seroconversion to anti-HBs00
SecondaryPercentage 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.

Time frame:
Baseline; Week 96
Reported as:
Number · percentage of participants
Percentage of Participants With HBsAg Loss and/or Seroconversion to Anti-HBs at Week 96
percentage of participantsTDF-TDFADV-TDF
HBsAg Loss00
Anti-HBs Seroconversion00
SecondaryPercentage 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.

Time frame:
Baseline; Weeks 144, 192, 240, 288, 336, 384, 432, and 480
Reported as:
Number · percentage of participants
Percentage of Participants With HBsAg Loss and/or Seroconversion to Anti-HBs at Weeks 144, 192, 240, 288, 336, 384, 432, and 480
percentage of participantsTDF-TDFADV-TDF
HBsAg Loss - Week 14400
Anti-HBs Seroconversion - Week 14400
HBsAg Loss - Week 19200
Anti-HBs Seroconversion - Week 19200
HBsAg Loss - Week 24000.8
Anti-HBs Seroconversion - Week 24000
HBsAg Loss - Week 28800.8
Anti-HBs Seroconversion - Week 28800.8
HBsAg Loss - Week 33600.8
Anti-HBs Seroconversion - Week 33600.8
HBsAg Loss - Week 3840.80.8
Anti-HBs Seroconversion - Week 3840.40.8
HBsAg Loss - Week 4321.21.6
Anti-HBs Seroconversion - Week 4320.40.8
HBsAg Loss - Week 4801.22.4
Anti-HBs Seroconversion - Week 4800.80.8
SecondaryNumber 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.

Time frame:
Baseline; Week 48
Reported as:
Number · participants
Number of Participants With HBV Genotypic Changes From Baseline at Week 48 (Resistance Surveillance)
participantsTDF-TDFADV-TDF
Participants evaluated842
Changes at conserved sites in HBV polymerase07
Changes at polymorphic sites in HBV polymerase314
No genotypic changes (wild-type virus)420
Unable to be genotyped11
SecondaryNumber 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.

Time frame:
Baseline; Weeks 49 to 96
Reported as:
Number · participants
Number of Participants With HBV Genotypic Changes From Baseline at Week 96 (Resistance Surveillance)
participantsTDF-TDFTDF-TDF With Addition of FTCADV-TDFADV-TDF With Addition of FTC
Participants evaluated610—
Changes at conserved sites within HBV polymerase000—
Changes at polymorphic sites in HBV polymerase210—
No genotypic changes (wild-type virus)400—
Unable to be genotyped000—
SecondaryNumber 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.

Time frame:
Baseline; Weeks 97 to 144
Reported as:
Number · participants
Number of Participants With HBV Genotypic Changes From Baseline at Week 144 (Resistance Surveillance)
participantsTDF-TDFTDF-TDF With Addition of FTCADV-TDFADV-TDF With Addition of FTC
Participants evaluated400—
Changes at conserved sites within HBV polymerase000—
Changes at polymorphic sites in HBV polymerase100—
No genotypic changes (wild-type virus)200—
Unable to genotype100—
SecondaryNumber 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.

Time frame:
Baseline; Weeks 145 to 192
Reported as:
Number · participants
Number of Participants With HBV Genotypic Changes From Baseline at Week 192 (Resistance Surveillance)
participantsTDF-TDFTDF-TDF With Addition of FTCADV-TDFADV-TDF With Addition of FTC
Participants evaluated310—
Changes at conserved sites within HBV polymerase000—
Changes at polymorphic sites in HBV polymerase100—
No genotypic changes (wild-type virus)110—
Unable to genotype100—
SecondaryNumber 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.

Time frame:
Baseline; Weeks 193 to 240
Reported as:
Number · participants
Number of Participants With HBV Genotypic Changes From Baseline at Week 240 (Resistance Surveillance)
participantsTDF-TDFTDF-TDF With Addition of FTCADV-TDFADV-TDF With Addition of FTC
Participants evaluated122—
Changes at conserved sites within HBV polymerase100—
Changes at polymorphic sites in HBV polymerase020—
No genotypic changes (wild-type virus)000—
Unable to genotype002—
SecondaryNumber 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.

Time frame:
Baseline; Weeks 241 to 288
Reported as:
Number · participants
Number of Participants With HBV Genotypic Changes From Baseline at Week 288 (Resistance Surveillance)
participantsTDF-TDFTDF-TDF With Addition of FTCADV-TDFADV-TDF With Addition of FTC
Participants evaluated311—
Changes at conserved sites within HBV polymerase000—
Changes at polymorphic sites in HBV polymerase211—
No genotypic changes (wild-type virus)100—
Unable to genotype000—
SecondaryNumber 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.

Time frame:
Baseline; Weeks 289 to 336
Reported as:
Number · participants
Number of Participants With HBV Genotypic Changes From Baseline at Week 336 (Resistance Surveillance)
participantsTDF-TDFTDF-TDF With Addition of FTCADV-TDFADV-TDF With Addition of FTC
Participants evaluated011—
Changes at conserved sites within HBV polymerase000—
Changes at polymorphic sites in HBV polymerase000—
No genotypic changes (wild-type virus)010—
Unable to genotype001—
SecondaryNumber 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.

Time frame:
Baseline; Weeks 337 to 384
Reported as:
Number · participants
Number of Participants With HBV Genotypic Changes From Baseline at Week 384 (Resistance Surveillance)
participantsTDF-TDFTDF-TDF With Addition of FTCADV-TDFADV-TDF With Addition of FTC
Participants evaluated100—
Changes at conserved sites within HBV polymerase000—
Changes at polymorphic sites in HBV polymerase000—
No genotypic changes (wild-type virus)000—
Unable to genotype100—
SecondaryNumber 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.

Time frame:
Baseline; Weeks 385 to 432
Reported as:
Number · participants
Number of Participants With HBV Genotypic Changes From Baseline at Week 432 (Resistance Surveillance)
participantsTDF-TDFTDF-TDF With Addition of FTCADV-TDFADV-TDF With Addition of FTC
Participants evaluated201—
Changes at conserved sites within HBV polymerase000—
Changes at polymorphic sites in HBV polymerase001—
No genotypic changes (wild-type virus)200—
Unable to genotype000—
SecondaryNumber 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.

Time frame:
Baseline; Weeks 433 to 480
Reported as:
Number · participants
Number of Participants With HBV Genotypic Changes From Baseline at Week 480 (Resistance Surveillance)
participantsTDF-TDFTDF-TDF With Addition of FTCADV-TDFADV-TDF With Addition of FTC
Participants evaluated000—
Changes at conserved sites within HBV polymerase000—
Changes at polymorphic sites in HBV polymerase000—
No genotypic changes (wild-type virus)000—
Unable to genotype000—

Adverse events

Collected over Baseline to Week 480. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Double-Blind TDF—12/250 (4.8%)121/250 (48.4%)
Double-Blind ADV—7/125 (5.6%)61/125 (48.8%)
Open-Label TDF—90/347 (25.9%)256/347 (73.8%)
Most frequent serious events
Showing 10 of 141
Most frequent serious events
EventDouble-Blind TDFDouble-Blind ADVOpen-Label TDF
Hepatocellular carcinomaNeoplasms benign, malignant and unspecified (incl cysts and polyps)2/2500/1258/347
PneumoniaInfections and infestations0/2500/1255/347
Alanine aminotransferase increasedInvestigations3/2500/1252/347
Chest painGeneral disorders0/2500/1254/347
AppendicitisInfections and infestations0/2500/1253/347
Intervertebral disc protrusionMusculoskeletal and connective tissue disorders0/2500/1253/347
HepatitisHepatobiliary disorders0/2501/1251/347
Procedural hypotensionInjury, poisoning and procedural complications0/2501/1250/347
Diabetes mellitus inadequate controlMetabolism and nutrition disorders0/2501/1250/347
Myopathy toxicMusculoskeletal and connective tissue disorders0/2501/1250/347
Most frequent other events
Showing 10 of 22
Most frequent other events
EventDouble-Blind TDFDouble-Blind ADVOpen-Label TDF
NasopharyngitisInfections and infestations22/25012/12562/347
Back painMusculoskeletal and connective tissue disorders18/2507/12554/347
HypertensionVascular disorders9/2505/12553/347
HeadacheNervous system disorders26/25017/12549/347
InfluenzaInfections and infestations10/2503/12538/347
ArthralgiaMusculoskeletal and connective tissue disorders16/2500/12538/347
Abdominal pain upperGastrointestinal disorders22/25010/12536/347
DiarrhoeaGastrointestinal disorders16/2508/12531/347
Creatinine renal clearance decreasedInvestigations0/2501/12530/347
OsteopeniaMusculoskeletal and connective tissue disorders1/2500/12530/347

Baseline characteristics

Randomized and Treated Analysis Set: all participants who were randomized and received at least one dose of study medication

Age, Categorical
Age, Categorical(Participants)TDF-TDFADV-TDFTotal
<=18 years011
Between 18 and 65 years247123370
>=65 years314
Age, Continuous
Age, Continuous(years)TDF-TDFADV-TDFTotal
Mean44 ± 10.643 ± 10.044 ± 10.4
Gender
Gender(Participants)TDF-TDFADV-TDFTotal
Female572885
Male19397290
Race/Ethnicity, Customized
Race/Ethnicity, Customized(participants)TDF-TDFADV-TDFTotal
American Indian or Alaska Native000
Asian633093
Native Hawaiian or Other Pacific Islander729
Black or African American8412
White16181242
More than one race000
Unknown or Not Reported11819
Region of Enrollment
Region of Enrollment(participants)TDF-TDFADV-TDFTotal
United States251136
Greece19928
Spain15621
Turkey11314
Italy606
United Kingdom527
France13518
Czech Republic7512
Canada291847
Poland131124
Australia14822
Bulgaria492372
Germany191130
Netherlands112
New Zealand241236
Baseline Alanine Aminotransferase (ALT) Above the Upper Limit of the Normal (ULN) Range
Baseline Alanine Aminotransferase (ALT) Above the Upper Limit of the Normal (ULN) Range(participants)TDF-TDFADV-TDFTotal
Yes236118354
No14721
Prior Lamivudine or FTC Treatment
Prior Lamivudine or FTC Treatment(participants)TDF-TDFADV-TDFTotal
Yes432366
No207102309
Baseline Hepatitis B Virus Deoxyribonucleic Acid (HBV DNA)
Baseline Hepatitis B Virus Deoxyribonucleic Acid (HBV DNA)(log10 copies/mL)TDF-TDFADV-TDFTotal
Mean6.86 ± 1.3086.98 ± 1.2666.90 ± 1.294

1 further baseline measures are reported on the registry.

08

Study locations

80 sites
  • La Jolla, California 92037, United States
  • Pasadena, California 91105, United States
  • San Diego, California 92105, United States
  • San Diego, California 92123, United States
  • San Francisco, California 94115, United States
  • San Jose, California 95116, United States
  • Atlanta, Georgia 30308, United States
  • Honolulu, Hawaii 96817, United States
  • Boston, Massachusetts 02215, United States
  • Ann Arbor, Michigan 48109, United States
  • Detroit, Michigan 48202, United States
  • St. Louis, Missouri 63104, United States
  • Flushing, New York 11355, United States
  • New York, New York 10003, United States
  • New York, New York 10029, United States
  • Falls Church, Virginia 22042, United States
  • Richmond, Virginia 23298, United States
  • Camperdown, New South Wales 2050, Australia
  • Concord, New South Wales 2139, Australia
  • Westmead, New South Wales 2145, Australia
  • Woolloongabba, Queensland 40102, Australia
  • Clayton, Victoria 3168, Australia
  • Fitzroy, Victoria 3065, Australia
  • Heidelberg, Victoria 3084, Australia
  • Prahan, Victoria 3004, Australia
  • Sofia, 1407, Bulgaria
  • Sofia, 1431, Bulgaria
  • Varna, 9010, Bulgaria
  • Calgary, Alberta T2N 4Z6, Canada
  • Vancouver, British Columbia V5Z1H2, Canada
  • Winnipeg, Manitoba R3E3P4, Canada
  • Toronto, Ontario M5T 2S8, Canada
  • Brno, 62500, Czech Republic
  • Hradec Kralove, Czech Republic
  • Praha 4, 14021, Czech Republic
  • Praha 6 - Stresovice, 169 02, Czech Republic
  • Clichy, 92110, France
  • Creteil, 94010, France
  • Lille, 59037, France
  • Lyon, 69317, France
  • Nancy, 54500, France
  • Paris, 75651, France
  • Strasbourg, 67901, France
  • Toulouse, 31059, France
  • Duesseldorf, 40237, Germany
  • Frankfurt, 60590, Germany
  • Hamburg, 20099, Germany
  • Hannover, 30623, Germany
  • Herne, 44623, Germany
  • Homburg/Saar, 66421, Germany
  • Mainz, 55131, Germany
  • Munchen, 81377, Germany
  • Tubingen, 72076, Germany
  • Athens, 11526, Greece
  • Larissa, 41110, Greece
  • Leipzig, 04103, Greece
  • Thessaloniki, 54636, Greece
  • Thessaloniki, 56429, Greece
  • Thessaloniki, 57010, Greece
  • Bologna, 40138, Italy
  • Torino, 10134, Italy
  • Rotterdam, 3015, Netherlands
  • Auckland, New Zealand
  • Hamilton, New Zealand
  • Whakatane, New Zealand
  • Bialystok, 15-540, Poland
  • Bydgoszcz, 85-030, Poland
  • Chorzow, 41-500, Poland
  • Krakow, 31-501, Poland
  • Warszawa, 01-201, Poland
  • Wroclaw, 50-136, Poland
  • Majadahonda, Madrid 28222, Spain
  • Barcelona, 08035, Spain
  • Valencia, 46009, Spain
  • Bursa, Turkey
  • Istanbul, 34098, Turkey
  • Istanbul, 34899, Turkey
  • Izmir, Turkey
  • London, NW1 2BU, United Kingdom
  • London, WC1E 6HX, United Kingdom
09

References and documents

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. PubMed 23939953 ↗
  • 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. PubMed 23234725 ↗
  • 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. PubMed 23364953 ↗
  • 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. PubMed 25179493 ↗
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Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Mar 7, 2017, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT00117676
Lead sponsor
Gilead Sciences
Responsible party
Sponsor
First posted
Jul 8, 2005
Start date
Feb 2005
Primary completion
Apr 2007
Completion
Jan 2016
Results posted
May 19, 2010
Last update
Mar 7, 2017

Study contacts

Gilead Study Director
study director · Gilead Sciences

Oversight

Data monitoring committee
Yes
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