Quantifying the Impact of Nevirapine-Based Prophylaxis Strategies To Prevent Mother-to-Child Transmission of HIV-1: a Combined Pharmacokinetic, Pharmacodynamic, and Viral Dynamic Analysis To Predict Clinical Outcomes

• Published in: Antimicrobial Agents and Chemotherapy Vol. 55; no. 12; pp. 5529 - 5540
• Main Authors: Frank, M, von Kleist, M, Kunz, A, Harms, G, Schütte, C, Kloft, C
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for Microbiology 01.12.2011
• Subjects: Adolescent; Adult; Anti-HIV Agents; Anti-HIV Agents - pharmacokinetics; Anti-HIV Agents - pharmacology; Anti-HIV Agents - therapeutic use; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral Agents; Biological and medical sciences; breast feeding; Chemoprevention; combination drug therapy; cost effectiveness; disease control; drug resistance; drugs; Female; HIV Infections; HIV Infections - drug therapy; HIV Infections - transmission; HIV-1; HIV-1 - drug effects; HIV-1 - physiology; Human immunodeficiency virus 1; Human viral diseases; Humans; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Infant, Newborn; Infectious Disease Transmission, Vertical; Infectious Disease Transmission, Vertical - prevention & control; Infectious diseases; mathematical models; Medical sciences; Models, Biological; mothers; neonates; Nevirapine; Nevirapine - pharmacokinetics; Nevirapine - pharmacology; Nevirapine - therapeutic use; pharmacokinetics; Pharmacology. Drug treatments; Predictive Value of Tests; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Complications, Infectious - drug therapy; Pregnancy Complications, Infectious - virology; Reverse Transcriptase Inhibitors; Reverse Transcriptase Inhibitors - pharmacokinetics; Reverse Transcriptase Inhibitors - pharmacology; Reverse Transcriptase Inhibitors - therapeutic use; risk; transplacental transmission; Treatment Outcome; Uganda - epidemiology; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; viral load; Viral Load - drug effects; viruses; women; Young Adult; Uganda; Pharmacokinetic pharmacodynamic relationship; Antiretroviral agent; RNA-directed DNA polymerase; Prognosis; Nevirapine; HIV-1 virus; Non nucleoside compound; Prevention; Dynamics; Reverse transcriptase inhibitor; Antiviral; Quantitative analysis; Immunopathology; Enzyme; Transferases; Enzyme inhibitor; Retroviridae; AIDS; Immune deficiency; Lentivirus; Infection; Virus; Nucleotidyltransferases; Viral disease; Strategy; Vertical transmission; Human immunodeficiency virus; Predictive factor
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.00741-11

Single-dose nevirapine (sd-NVP) and extended NVP prophylaxis are widely used in resource-constrained settings to prevent vertical HIV-1 transmission. We assessed the pharmacokinetics of sd-NVP in 62 HIV-1-positive pregnant Ugandan woman and their newborns who were receiving sd-NVP prophylaxis to prevent mother-to-child HIV-1 transmission. Based on these data, we developed a mathematical model system to quantify the impact of different sd-NVP regimens at delivery and of extended infant NVP prophylaxis (6, 14, 21, 26, 52, 78, and 102 weeks) on the 2-year risk of HIV-1 transmission and development of drug resistance in mothers and their breast-fed infants. Pharmacokinetic parameter estimates and model-predicted HIV-1 transmission rates were very consistent with other studies. Predicted 2-year HIV-1 transmission risks were 35.8% without prophylaxis, 31.6% for newborn sd-NVP, 19.1% for maternal sd-NVP, and 19.7% for maternal/newborn sd-NVP. Maternal sd-NVP reduced newborn infection predominately by transplacental exchange, providing protective NVP concentrations to the newborn at delivery, rather than by maternal viral load reduction. Drug resistance was frequently selected in HIV-1-positive mothers after maternal sd-NVP. Extended newborn NVP prophylaxis further decreased HIV-1 transmission risks, but an overall decline in cost-effectiveness for increasing durations of newborn prophylaxis was indicated. The total number of infections with resistant virus in newborns was not increased by extended newborn NVP prophylaxis. The developed mathematical modeling framework successfully predicted the risk of HIV-1 transmission and resistance development and can be adapted to other drugs/drug combinations to a priori assess their potential in reducing vertical HIV-1 transmission and resistance spread.