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发表于 2003-9-4 07:59
LdT: A Highly Effective Treatment of HBV
By Brian Boyle, MD
Hepatitis B virus (HBV) infection causes high rates of morbidity and mortality around the world. Due to the limited treatment options that currently exist for HBV an intensive effort is underway to find new, highly-effective therapies. One such drug, LdT, is an L-nucleoside that preliminary data indicate has potent anti-HBV activity in vitro and a favorable preclinical safety profile.
In an ongoing dose escalation trial, 24 adults with chronic HBV were given varying doses of LdT. All doses tested (25, 50, 100 and 200 mg/day) were highly effective in reducing HBV DNA levels (>2-3 log10 copies/mL within 2-4 weeks), with no significant adverse events observed. In order to determine the optimal dose of LdT in this patient population, all of whom rapidly achieved a 2 log10 copies/mL reduction in HBV DNA levels and had variable baseline HBV DNA levels, quantitative HBV DNA levels for the four dosing cohorts were analyzed for first and second-phase HBV clearance and to a dose- and phase-related modeling of HBV dynamics.
The investigators found that with both analyses, second-phase HBV clearance was dose-proportional in the tested dosing range (25-200 mg/day). Further, this modeling predicted that higher doses (e.g., 600-800 mg/day) or longer treatment may result in HBV DNA reductions > 6-7 log10 copies/mL, a level of HBV suppression not previously achieved by a single therapeutic agent.
The authors conclude that "Novel analyses of HBV DNA reductions after week 1 and viral dynamics modeling of second-phase HBV clearance clarified the dose-proportionality of anti-HBV effects for LdT and supported testing of higher doses to maximize anti-HBV efficacy and minimize resistance with this agent." These are very encouraging data, and if future studies support increased efficacy and continued tolerability of LdT at the higher doses tested, and the resistance data are favorable, LdT has the potential to become a cornerstone of HBV therapy.
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