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A Randomized, Double-Blind, Comparison of Tenofovir DF (TDF) versus Adefovir Dipivoxil (ADV) for the Treatment of HBeAg-Negative Chronic Hepatitis B (CHB): Study GS-US-174-0102
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Reported by Jules Levin
AASLD, Nov 2-6, 2007, Boston, MA
P Marcellin1, M Buti2, Z Krastev3, G Germanidis4, K Kaita5, I Kotzev6, P Buggisch7, F Weilert8, H Trinh9, J Sorbel10, J Anderson10, E Mondou10, F Rousseau10
1Hospital Beaujon, Clichy France; 2Hebron Hospital, Barcelona Spain; 3University Hospital "St Ivan Rilsky", Sofia, Bulgaria; 4General Hospital of Thessaloniki, Thessaloniki, Greece; 5John Buhler Research Centre, University of Manitoba, Winnipeg MB Canada; 6University Hospital "Sveta Marina", Varna Bulgaria; 7Medizinische Universitatsklinik Eppendorf, Hamburg Germany; 8Waikato Hospital, Hamilton, New Zealand; 9San Jose Gastroenterology, San Jose, CA; 10Gilead Sciences, Durham NC.
AUTHOR CONCLUSIONS
TDF demonstrated superior efficacy to ADV: 93% HBV DNA < 400 copies/mL
No subject developed mutations associated with TDF resistance
TDF was well tolerated
TENOFOVIR SAFETY
Grade 2-4 AEs: No significant differences between treatment groups
AEs leading to discontinuation:
- TDF: bladder neoplasm, cervix carcinoma, feeling hot, anorexia, fatigue
- ADV: myopathy, liposarcoma
No TDF subject had a confirmed 0.5 mg increase in serum creatinine or creatinine clearance < 50 ml/min
The incidence of ALT flare (>10 x ULN and 2 x baseline) was low and similar in the two treatment groups (1.2% vs. 0.8%)
RESISTANCE
Evaluated all TDF-treated subjects with HBV DNA ≥ 400 c/mL at Week 48 (8 subjects)
No subject developed mutations associated with TDF resistance
Tenofovir DF (TDF) is Superior to Adefovir Dipivoxil (ADV) in
HBeAg Positive Chronic Hepatitis B: Study 103
TDF demonstrated superior efficacy to ADV:
- 76% HBV DNA < 400 copies/mL
- 3.2% HBsAg Loss
- No resistance associated with tenofovir
J Heathcote et. al. Late Breaker Poster #6
INTRODUCTION
Tenofovir DF (TDF) is a nucleotide analogue
-- Inhibits HIV-1 RNA transcriptase and HBV DNA polymerase
-- Obligate chain terminator
TDF shown to have activity in patients mono-infected with HBV and co-infected with HIV/HBV
TDF is approved for the treatment of HIV-1 infection
-- 1.3 million patient years safety exposure in HIV and 6 years clinical safety data
STUDY DESIGN
Patients were randomized 2:1 to tenofovir 300mg (n=250) or adefovir 10mg (n=125) for 48 weeks; liver biopsy performed pre-treatment and at week 48. Thereafter is an open-label tenofovir study for a total of 5 years, and week 240 liver biopsy performed.
Study Endpoints (Week 48)
Primary Endpoint:
Complete response: HBV DNA <400 c/mL and histologic improvement (at least a 2-point reduction in the Knodell necroinflammatory score without worsening in fibrosis)
Secondary Endpoints:
-HBV DNA < 400 c/mL
-Normal ALT
-Histological Improvement
-Resistance surveillance
METHODS
Key eligibility criteria
- HBeAg- subjects
- age 18-69 years
- compensated liver disease
- lamivudine experienced or naive
- HBV DNA > 105 c/mL
- ALT ≥ ULN and <10xULN
- Knodell Necroinflammatory score ≥ 3
- HIV, HDV, HCV negative
Assessments
- A liver biopsy was obtained pre-treatment and between Weeks 44 and 48
- Laboratory analyses (HBV DNA, serum chemistry, hematology, and urinalysis) were evaluated every 4 weeks
- HBsAg was tested every 12 weeks
- HBV DNA was measured using the Roche COBAS TaqMan assay (LLOQ=169 c/mL)
- Resistance surveillance performed at Week 48 for all viremic subjects (≥ 400 c/mL)
RESULTS
Patient disposition
375 patients randomized and treated: 250 to tenofovir and 125 to adefovir.
Discontinued prior to week 48 or no evaluable biopsy: TDF=16, ADV=12.
234 on TDF completed week 48 with biopsy, 113 completed ADV week 48 with biopsy.
Baseline Disease and Demographic Characteristics
Average age=44 yrs. 65% white. Mean HBV DNA 6.86 log in TDF group and 6.98 log in ADV group. Mean ALT 128 in TDF group and 164 in ADV group. Mean Knodell Necroinflammatory Score 7.8 in TDF group and ADV group. Mean Knodell Fibrosis Score 2.3 in TDF group and 2.4 if ADV group. Knodell Fibrosis Score =4 (cirrhosis) 19% in TDF group, 20% in ADV group.
Primary and Secondary Endpoints
71% in TDF group and 49% in ADV group achieved primary endpoint (p<0.001). 72% in TDF and 69% in ADV group had histological improvement (p>0.05). HBV DNA < 400 c/ml: 93% on TDF and 63% on ADV (p<0.001).
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