The objective of this project is to understand how severe malnutrition affects the pharmacokinetics of highly active antiretroviral therapy (HAART) as well as antioxidant capacity and mitochondrial integrity in HIV infected children started on HAART and nutritional therapy. Pediatric dosing and kinetics for HAART drugs are based on data obtained in well nourished or only mildly malnourished children which may not be accurate for a severely malnourished child. Severely malnourished children have decreased lean body mass, decreased body fat and likely alterations in liver function, kidney function, and mitochondrial integrity that would affect drug metabolism and clearance. An observational study of a cohort of 117 HIV-infected children 6 to 24 months of age will be performed with 1/3 recovering from marasmus, 1/3 recovering from kwashiorkor and 1/3 a control group of well-nourished HIV-infected children all of whom are being started on HAART. Parameters to be studied at baseline and 2 and 8 weeks after starting HAART include lean body mass (calculated by deuterium oxide dilution method), mitochondrial integrity (measured by lactate and copy numbers of mitochondrial DNA/RNA in monocytes), antioxidant capacity (assessed by whole blood glutathione, red cell superoxide dismutase, glutathione peroxidase, and oxidized serum proteins), hepatic function and integrity (quantified by albumin, alanine transaminase and aspartate transaminase), renal function (measured by serum cystatin C) and immunologic function (characterized by lymphocyte subpopulations). Area under the curve pharmacokinetic measurements will be done for stavudine, lamivudine and nevirapine after 2 and 8 weeks of HAART. Primary outcomes will be the relationship between nutritional status and antioxidant capacity/mitochondrial toxicity and total drug dose and pharmacokinetics correlated with lean body mass. This project will help establish appropriate dosing for HAART in the severely malnourished child and decrease toxicity as well as minimize subtherapeutic dosing and the emergence of resistance. The project will also characterize mitochondrial damage and antioxidant stress which may lead to further therapies to decrease the toxicities of these therapies in these children.
This research proposal will study the appropriate dosing of HIV medications in severely malnourished HIV infected children in sub-Saharan Africa in order to decrease toxicities and minimize the emergence of drug resistant HIV infection in these children. We will also evaluate cellular damage in severely malnourished HIV infected children and the role of HIV medications in increasing this damage to hopefully lead to the discovery of ways to combat this toxicity.
