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Abstract 597. SAFE AND POTENT SUPPRESSION OF HEPATITIS B VIRUS (HBV) WITH
L-DEOXYTHYMIDINE (LDT): RESULTS OF A DOSE-ESCALATION TRIAL
Reported by Jules Levin
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see NATAP website for more AASLD coverage www.natap.org
Ching-Lung Lai, Univ of Hong Kong, Pok Fu Lam Hong Kong; Maureen W Myers,
Deborah M Pow, Nathaniel A Brown, Novirio Pharmaceuticals, Inc, Cambridge,
MA; Yin-Mei Lee, National Univ Hosp, Singapore Singapore; Man-Fung Yuen, Univ
of Hong Kong, Pok Fu Lam Hong Kong; Seng Gee Lim, National Univ Hosp,
Singapore Singapore
Background: Therapy for chronic hepatitis B (CHB) is suboptimal due to
frequent non-response to interferon and resistance with lamivudine. LdT has
potent anti-HBV activity in vitro and in the woodchuck animal model and a
potentially attractive safety profile (Bryant et al., AAC Jan 2001).
Methods: The antiviral activity of LdT in adults with CHB is being
investigated in a dose-escalation trial, assessing 25, 50, 100, 200 and 400
mg once a day for 4 weeks with 12 weeks follow-up. Serum HBV DNA levels are
monitored weekly by a quantitative PCR method (COBAS Amplicor HBV Monitor
assay, Roche Molecular Systems).
Results: Four dosing cohorts (25, 50, 100, and 200 mg/day), comprising 24
total patients, have completed treatment to date, with the 400 mg/day cohort
presently ongoing. Over 4 weeks of treatment, mean (±SEM) total reductions in
HBV DNA levels have been 2.4±0.3 log10, 2.7±0.2 log10, 3.1±0.1 log10, and
2.9±0.2 log10 for the 25, 50, 100 and 200 mg/day cohorts, respectively. Thus
all LdT doses have been highly active, producing >99% reduction in serum
viral load within 4 weeks in most patients. In the ongoing 400 mg/day cohort,
HBV DNA reductions as high as 3.6 log10 have been observed by week 4.
Analysis of serum HBV DNA reductions after Week 1 indicates that second-phase
HBV clearance is dose-proportional, and post-treatment return of HBV DNA is
slower in the higher dose groups, consistent with a dose-related reduction of
HBV-infected hepatocytes. Pharmacokinetic data indicate that daily LdT AUC is
dose-proportional, so higher LdT doses will be tested to determine whether
even greater HBV suppression can be achieved early during LdT treatment.
Conclusions: LdT appears promising as a potent and safe new HBV therapeutic with marked anti-HBV activity within 4 weeks and a potential for profound HBV
suppression with higher and/or longer dosing. No significant or dose-related
toxicities have been identified to date.
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