Quantifying the impact of nevirapine-based prophylaxis strategies to prevent mother-to-child transmission of HIV-1 using the population approach

Abstract

In 2011, a total of 330,000 (280,000–390,000) children acquired HIV infections predominantly during pregnancy, delivery, or breastfeeding in Africa,1UNAIDS. Report on the global aids epidemic. www.unaids.org/en/resources/publications/2012/name,76121,en.asp (2012).Google Scholar emphasizing the urgent need of effective strategies to prevent mother-to-child transmission of HIV-1 (PMTCT). Several medicines and dosing regimens have been suggested as PMTCT. Studies about these prevention strategies suffer from several constraints: due to resource limitations and to ethical reasons, intensive sampling is not feasible, typically resulting in a very sparse data situation. Hence, concepts capable of dealing with these situations seem very attractive: Pharmacometrics as an emerging science based on a transdisciplinary approach bridging ideas of biology, pharmacology, clinical pharmacy and pharmacology, medicine, mathematics, and statistics represents an attractive framework to understand drug–patient interactions for optimizing prevention or treatment strategies. In detail, pharmacokinetic/pharmacodynamic/biomarker/disease modeling by the population approach aims to elucidate the mechanism-based relationships between dose exposure/response while incorporating knowledge of the patients and their disease.2Barrett J.S. Fossler M.J. Cadieu K.D. Gastonguay M.R. J Clin Pharmacol. 2008; 48: 632-649Crossref PubMed Scopus (62) Google Scholar In the presentation, the population analysis approach, its benefits, and limitations will be explained and illustrated by an investigation of a PMTCT program containing nevirapine (NVP).3Frank M. von Kleist M. Kunz A. et al.Antimicrob Agents Chemother. 2011; 55: 5529-5540Crossref PubMed Scopus (14) Google Scholar For NVP: (1) the developed integrated pharmacokinetic model after oral administration to pregnant women and their newborns as well as derived stratified dosing strategies for different newborns will be demonstrated; and (2) how these concentration–time profiles of NVP were integrated into a stochastic model of HIV dynamics (including the viral cycle in host cells) and transmission. Based on the final model, HIV transmission rates were predicted for a 2-year period after birth which excellently agreed with data from 7 independent PMTCT trials. Moreover, new mechanistic insights into transplacental transmission as well as resistance were gained, both with respect to the underlying NVP concentration–time profiles in pregnant women/mothers and newborns. The framework developed contributes to improve and guide PMTCT strategies in NVP prophylaxis regimens and more importantly in antiretroviral combination regimens. None declared.