icon_folder.gif   Conference Reports for NATAP  
  AASLD ( American Association for the Study of Liver Diseases)
November 9-13, 2001, Dallas
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Reported by Jules Levin
  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.