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TENOFOVIR DF (TDF) SHOWED SUPERIOR ANTIVIRAL EFFICACY TO ADEFOVIR DIPIVOXIL IN TWO PIVOTAL, RANDOMIZED, DOUBLE-BLIND, STUDIES FOR THE TREATMENT OF HBEAG-NEGATIVE AND HBEAG-POSITIVE CHRONIC HEPATITIS B (CHB): STUDY 102 AND STUDY 103
J Heathcote1, P Marcellin2, K Kaita3, S Lee4, R Myers4, M Sherman5, J Sorbel6, J Anderson6, E Mondou6, F Rousseau6
1University of Toronto, Toronto, Ontario; 2Hospital Beaujon, Clichy, France; 3John Buhler Research Centre, University of Manitoba Health Science Center, Winnipeg, Manitoba; 4Heritage Medical Research Clinic, University of Calgary, Calgary, Alberta; 5Toronto General Hospital, Toronto, Ontario; 6Gilead Sciences, Durham NC
BACKGROUND: More than 6 years of clinical data and 1.3 million patient years of safety data have established a favorable safety and tolerability profile for tenofovir (TDF) in HIV patients.
AIM: The primary objective of these studies was to compare the safety and efficacy of 300 mg TDF versus 10 mg ADV at 48 weeks in subjects with HBeAg negative (–) and HBeAg positive (+) CHB.
METHODS: These studies were double-blind in mono-infected subjects with HBeAg+ or HBeAg- CHB randomized in a 2:1 ratio to TDF or ADV. Entry criteria included 18-69 years of age, compensated liver disease, a Knodell necroinflammatory score=>3, ALT >2×ULN (HBeAg+) or >ULN (HBeAg–), HBV DNA>106c/mL (HBeAg+) or > 105 c/mL (HBeAg–). Biopsies were performed pre-treatment and Week 48. HBV DNA was measured using the Roche COBAS TaqMan assay (LLQ=169c/mL).
RESULTS: HBeAg+: 266 nucleos(t)ide naïve subjects (176 TDF:90 ADV) were randomized and treated for 48 weeks; mean baseline HBV DNA was 8.72 log10c/mL and ALT was 147 IU/mL. HBeAg–: 375 subjects (250 TDF:125 ADV) both naïve and lamivudine experienced (18%) were randomized and treated for 48 weeks; mean baseline HBV DNA was 6.9 log10 c/mL and ALT was 140 IU/mL. More than 90% of the subjects completed primary endpoint assessments and overall 1% TDF-treated subjects discontinued due to an adverse event. Both drugs were well tolerated and had a comparable safety profile. Statistically significant greater response was observed for TDF-treated subjects: HBV DNA <400 c/mL (76% vs. 13% in HBeAg+ and 93% vs. 63% in HBeAg–; p<0.001), HBsAg loss (3.2% vs. 0%; p=0.018 in HBeAg+), ALT normal (69% vs. 54%; p=0.018 in HBeAg+). Similar proportions of TDF versus ADV-treated subjects experienced HBeAg seroconversion (21% vs. 18%) and histological improvement (72% vs. 69% in HBeAg- and 74% vs. 68% in HBeAg+). No subject developed mutations associated with tenofovir resistance.
CONCLUSION: TDF, at a dose of 300 mg QD, was well tolerated and demonstrated superior antiviral efficacy to ADV.
These studies were funded by Gilead Sciences.