Malaria and HIV infection are two of the most important health challenges of our time. Children under 5 years of age and pregnant women are particularly vulnerable to the complicating effects of malaria and HIV co- infection. Treatment options within Africa have improved, with increasing availability of artemisinin-based combination therapies (ACTs) for malaria and expanded access to antiretroviral therapy (ART) for HIV. ACTs are critical for treatment of malaria due to widespread resistance to older drugs. ACTs exhibit complex pharmacology, undergo activation and/or metabolism via cytochrome p450 pathways and are susceptible to physiological differences and drug-drug interactions with ARTs. However, treatment guidelines have largely stemmed from adult studies, and have ignored the impact of age or pregnancy on drug disposition. Mounting evidence, including studies from our group, indicates that ACTs may be underdosed in children or pregnant women, and are associated with significant drug interactions and heightened toxicities, in particular neutropenia, in the setting of HIV infection and concomitant ART. Proper dosing is critical to improve treatment efficacy and minimize risk of drug resistance and toxicity. NIH-funded trials comparing ART-based treatment strategies for reducing malaria morbidity in HIV-infected children and pregnant women (PROMOTE) are currently underway in Tororo, Uganda, a region with high rates of malaria transmission and HIV infection. This proposal will complement PROMOTE and investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of artemether-lumefantrine (AL), the most widely adopted ACT, in the context of ART, to optimize treatment for malaria and HIV.
The specific aims are 1) To evaluate the impact of ART and age on the pharmacokinetics and pharmacodynamics of artemether-lumefantrine (AL) in HIV-infected children;2) To evaluate the impact of ART and pregnancy on the PK and PD of artemether-lumefantrine in HIV-infected pregnant women;3) To determine if ART and AL exposure following standard dosing is predictive of neutropenia in children and pregnant women with HIV and malaria co-infection. HIV-infected children and pregnant women, treated with either protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART will be co- enrolled from PROMOTE, and undergo intensive PK evaluations for AL during treatment for malaria. PI-based regimens include lopinavir/ritonavir, and NNRTI-based regimens include either nevirapine or efavirenz. Results will be compared to intensive PK evaluations in HIV-uninfected children also residing in Tororo. To assess associations between drug exposure and clinical outcomes, longitudinal population PK/PD studies will determine if changes in AL exposure impact malaria treatment efficacy, and if AL and ART exposure correlates with high rates of neutropenia observed in HIV and malaria co-infected individuals. The proposed pharmacology studies will inform future dosing guidelines for the most widely adopted ACT and ART regimens in Africa.

Public Health Relevance

Children and pregnant women represent particularly vulnerable populations to the overlapping epidemics of malaria and HIV infection in sub-Saharan Africa.
We aim to characterize the pharmacokinetics of first-line antimalarial therapies in these groups, and correlate these parameters with treatment outcomes and adverse drug events. Findings should lead to specific artemether-lumefantrine dosing guidelines based on age, pregnancy, and use with concomitant antiretroviral therapy in HIV-infected populations.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD068174-02
Application #
8207927
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Mofenson, Lynne M
Project Start
2010-12-23
Project End
2015-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
2
Fiscal Year
2012
Total Cost
$535,652
Indirect Cost
$130,073
Name
University of California San Francisco
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Huang, Liusheng; Olson, Alexander; Gingrich, David et al. (2013) Determination of artemether and dihydroartemisinin in human plasma with a new hydrogen peroxide stabilization method. Bioanalysis 5:1501-6
Murphy, Sean C; Shott, Joseph P; Parikh, Sunil et al. (2013) Malaria diagnostics in clinical trials. Am J Trop Med Hyg 89:824-39