New approaches for quantitating the inhibition of HIV-1 replication by antiviral drugs in vitro and in vivo

Abstract

With highly active antiretroviral therapy, HIV-1 infection has become a manageable lifelong disease. Developing optimal treatment regimens requires understanding how to best measure anti-HIV activity in vitro and how drug dose-response curves generated in vitro correlate with in-vivo efficacy. Several recent studies have indicated that conventional multiround infectivity assays are inferior to single cycle assays at both low and high levels of inhibition. Multiround infectivity assays can fail to detect subtle but clinically significant anti-HIV activity. The discoveries of the anti-HIV activity of the hepatitis B drug entecavir and the herpes simplex drug acyclovir were facilitated by single-round infectivity assays. Recent studies using a single-round infectivity assay have shown that a previously neglected parameter, the dose-response curve slope, is an extremely important determinant of antiviral activity. Some antiretroviral drugs have steep slopes that result in extraordinary levels of antiviral activity. The instantaneous inhibitory potential, the log reduction in infectivity in a single-round assay at clinical drug concentrations, has been proposed as a novel index for comparing antiviral activity. Among in-vitro measures of antiviral activity, single-round infection assays have the advantage of measuring instantaneous inhibition by a drug. Re-evaluating the antiviral activity of approved HIV-1 drugs has shown that the slope parameter is an important factor in drug activity. Determining the instantaneous inhibitory potential by using a single-round infectivity assay may provide important insights that can predict the in-vivo efficacy of anti-HIV-1 drugs.