A Mathematical Modelling Framework to Assess the Impact of Nevirapine-based Prophylaxis on vertical HIV Transmission
M. von Kleist (1), M. Frank (2), A. Kunz (3), G. Harms (3), C. Schütte (1), C. Kloft (2,4)
(1) Department of Mathematics and Computer Science, Freie Universität Berlin, Berlin, Germany; (2) Department of Clinical Pharmacy, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany; (3) Institute of Tropical Medicine and International Health, Charité Universitätsmedizin Berlin, Berlin, Germany; (4) Department of Clinical Pharmacy, Freie Universität Berlin, Berlin, Germany
Objectives: Single dose nevirapine (NVP) prophylaxis, administered to HIV-positive mothers before birth and to their newborns shortly after birth, is a widely used intervention in resource-constrained settings to prevent vertical HIV transmission. The objective of this study was to develop a mathematical modelling framework to quantify the impact of different single and multiple dose NVP prophylaxis regimens on the risk of HIV transmission from mother-to-child and on drug resistance development.
Methods: We used a population pharmacokinetic (PK) approach to assess and describe the pharmacokinetics of NVP in Ugandan pregnant women and their newborns [1,2]. Subsequently, a stochastic model of HIV-1 dynamics, resistance development and vertical HIV transmission via intrapartum- and breastfeeding was developed. Individual NVP pharmacokinetics were then coupled to the HIV model to predict the cumulative two years postpartum HIV transmission risk after different single and multiple dose NVP prophylaxis regimens and to predict the risk of drug resistance development in the mothers and newborns.
Results: The risk of HIV transmission following three different short-course and extended NVP dosing regimens was well predicted. Our combined pharmacokinetic-pharmacodynamic investigation revealed that single dose maternal intrapartum NVP prevents newborn infection by providing protective NVP concentrations via placenta-transfer at delivery, while only insignificantly reducing the number of infectious viruses in the pregnant women coming into contact with the newborn during delivery. The predicted cumulative 2 years postpartum transmission risks, after 6-, 14-, 21-, 26-, 52-, 78- and 102 weeks of extended newborn NVP were 18.5% ± 2.1%, 16.1% ± 1.9%, 14.9% ± 1.9%, 14.3% ± 1.8%, 12.5% ± 1.6%, 8.6% ± 1.2% and 7.0% ± 0.9% respectively, when combined with perinatal NVP prophylaxis.
Conclusions: The developed mathematical modelling framework successfully combined in vitro and in vivo pharmacokinetic and pharmacodynamic data to estimate clinically relevant HIV transmission risks. These risks were very well predicted for all clinically investigated single and extended newborn NVP prophylaxis regimens. The presented modelling framework can be adapted to a priori assess the potential of other drugs/drug combinations in reducing HIV transmission and could therefore be used as a supportive tool for prospective studies to improve HIV prevention, maximize effectiveness and reduce the risk of resistance selection.
 Kunz, A., et al., Persistence of nevirapine in breast milk and plasma of mothers and their children after single-dose administration. J Antimicrob Chemother, 2009. 63(1): p. 170
 Frank, M., et al. Integrated Population Pharmacokinetic Model Development of Nevirapine for Mothers and Newborns including Healthy Male Volunteer Data. Submitted to PAGE (2011).
 von Kleist, M., et al., Drug-class specific impact of antivirals on the reproductive capacity of HIV. PLoS Comput Biol, 2010. 6(3): p. e1000720.