drug-class specific impact of antivirals on the reproductive capacity of hiv药品类特定的hiv病毒的抗病毒药物对生殖能力的影响.pdfVIP

Drug-Class Specific Impact of Antivirals on the Reproductive Capacity of HIV 1,2 2 1 Max von Kleist *, Stephan Menz , Wilhelm Huisinga 1 Hamilton Institute, Computational Physiology Group, National University of Ireland Maynooth, Kildare, Ireland, 2 Department of Mathematics and Computer Science, ¨ Freie Universitat Berlin, Berlin, Germany Abstract Predictive markers linking drug efficacy to clinical outcome are a key component in the drug discovery and development process. In HIV infection, two different measures, viral load decay and phenotypic assays, are used to assess drug efficacy in vivo and in vitro. For the newly introduced class of integrase inhibitors, a huge discrepancy between these two measures of efficacy was observed. Hence, a thorough understanding of the relation between these two measures of drug efficacy is imperative for guiding future drug discovery and development activities in HIV. In this article, we developed a novel viral dynamics model, which allows for a mechanistic integration of the mode of action of all approved drugs and drugs in late clinical trials. Subsequently, we established a link between in vivo and in vitro measures of drug efficacy, and extract important determinants of drug efficacy in vivo. The analysis is based on a new quantity—the reproductive capacity—that represents in mathematical terms the in vivo analog of the read-out of a phenotypic assay. Our results suggest a drug-class specific impact of antivirals on the total amount of viral replication. Moreover, we showed that the (drug-)target half life, dominated by immune-system related clearance processes, is a key characteristic that affects both the emergence of resistance as well as the in vitro–in vivo correlation of effic