Kinetics of the viral cycle influence pharmacodynamics of antiretroviral therapy
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Background: More and more antiretroviral therapies are being developed for treatment of HIV infection. The in-vivo efficacy of these drugs is commonly predicted based on in-vitro measures of antiviral effect. One primary in-vitro measure is the IC50, the amount of drug required for 50% inhibition of viral replication. We have previously shown that HIV life-cycle kinetics impact clinically observed HIV viral dynamics. Here we present a mathematical model of how they affect the pharmacodynamics of antiretroviral drugs. Results: We find that experimentally measured antiretroviral IC50s are determined by three factors: (i) intrinsic drug properties (e.g. drug-target binding), (ii) kinetics of the HIV life cycle, and (iii) kinetics of drug-inhibited infected cells. Our model predicts that the IC50 is a declining function of the duration of the drug-susceptible stage in the host cell. We combine our model with known viral life-cycle kinetics to derive a measure of intrinsic properties, reflecting drug action, for known antiretroviral drugs from previously measured IC50s. We show that this measure of intrinsic drug property correlates very well with in vitro-measured antiviral activity, whereas experimentally measured IC50 does not. Conclusions: Our results have implications for understanding pharmacodynamics of and improving activity of antiretroviral drugs. Our findings predict that drug activity can be improved through co-administration of synergistic drugs that delay the viral life cycle but are not inhibitory by themselves. Moreover, our results may easily extend to treatment of other pathogens. This article was reviewed by Dr. Ruy Ribeiro, Dr. Ha Youn Lee, Dr. Alan Perelson and Dr. Christoph Adami.
Ahmad R. Sedaghat is with the Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA -- Claus O. Wilke is with the Section of Integrative Biology, Center for Computational Biology and Bioinformatics, and Institute for Cell and Molecular Biology, The University of Texas at Austin, Austin, TX 78712, USA