Improving maternal child health among HIV-infected pregnant women and their children in Africa requires strategies that effectively address HIV and co-morbidities. Success of antiretroviral therapy is resulting in a growing population of HIV -exposed uninfected (HEU) children, still suffering poor outcomes. A high malaria burden among pregnant women and children, despite insecticide treated nets and trimethoprim- sulfamethoxazole (TS), contribute to these poor outcomes. Dihydroartemisinin-piperaquine (DP), an artemisinin combination therapy (ACT) with a long post treatment prophylactic effect, is highly effective and safe for malaria treatment in pregnant women and children but has not been evaluated for malaria prevention. We propose to test the hypothesis that enhanced malaria chemoprevention (DP +TS) vs. TS in pregnant women and their children during the first 2 years of life will reduce the incidence of malaria during the first 2 years of life. This hypothesis is based on observations that maternal and placental malaria increase the risk of infant malaria and that DP chemoprevention of HEU reduces malaria incidence. Additionally, we will evaluate the safety and pharmacokinetics of DP including interactions with efavirenz and examine malaria incidencein HEU after malaria chemoprevention discontinuation at 2 years of age. We plan to test our hypotheses in a double-blind, placebo-controlled, randomized tnal of HIV-infected pregnant women in Tororo, Uganda, an area of high malaria transmission. The primary study endpoint is malaria incidence in children from birth to 24 months. Our 3 aims are: 1) To determine if enhanced (DP+TS) versus standard malana chemoprevention (TS) during both pregnancy and infancy reduces malaria during the first 24 months of life. W e will randomize 200 HIV-infected pregnant women to monthly DP+daily TS vs monthly placebo+daily TS during pregnancy. Infants will receive the same prevention regimen as their mother for 24 months. 2) To evaluate safety of monthly DP given for malaria prevention during pregnancy and early childhood. We will compare grade 3 and 4 toxicity and birth outcomes between the arms 3) To evaluate the pharmacokinetic exposure of concomitant DP and efavirenz during pregnancy. We will perform intensive PK for DP and EFV during the 3""""""""^ trimester and compare DP between HIV infected and uninfected pregnant women.

Public Health Relevance

This study seeks to advance the current public health framework of maternal child health from reduction of perinatal HIV transmission to elimination of perinatalHIV transmission and malaria at the most vulnerable time period-the first 2 years of life.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
2P01HD059454-06A1
Application #
8614265
Study Section
Special Emphasis Panel (ZRG1-AARR-D (42))
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-06-30
Support Year
6
Fiscal Year
2013
Total Cost
$350,403
Indirect Cost
$72,624
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Wallender, Erika; Vucicevic, Katarina; Jagannathan, Prasanna et al. (2018) Predicting Optimal Dihydroartemisinin-Piperaquine Regimens to Prevent Malaria During Pregnancy for Human Immunodeficiency Virus-Infected Women Receiving Efavirenz. J Infect Dis 217:964-972
Odorizzi, Pamela M; Jagannathan, Prasanna; McIntyre, Tara I et al. (2018) In utero priming of highly functional effector T cell responses to human malaria. Sci Transl Med 10:
Savic, Rada M; Jagannathan, Prasanna; Kajubi, Richard et al. (2018) Intermittent Preventive Treatment for Malaria in Pregnancy: Optimization of Target Concentrations of Dihydroartemisinin-Piperaquine. Clin Infect Dis 67:1079-1088
Jagannathan, Prasanna; Kakuru, Abel; Okiring, Jaffer et al. (2018) Dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria during pregnancy and risk of malaria in early childhood: A randomized controlled trial. PLoS Med 15:e1002606
Jagannathan, Prasanna; Kajubi, Richard; Aweeka, Francesca T (2018) Response to ""Antiretroviral Therapy With Efavirenz in HIV-Infected Pregnant Women: Understanding the Possible Mechanisms for Drug-Drug Interaction"". Clin Pharmacol Ther 103:571
Roh, Michelle E; Shiboski, Stephen; Natureeba, Paul et al. (2017) Protective Effect of Indoor Residual Spraying of Insecticide on Preterm Birth Among Pregnant Women With HIV Infection in Uganda: A Secondary Data Analysis. J Infect Dis 216:1541-1549
Koss, Catherine A; Natureeba, Paul; Kwarisiima, Dalsone et al. (2017) Viral Suppression and Retention in Care up to 5 Years After Initiation of Lifelong ART During Pregnancy (Option B+) in Rural Uganda. J Acquir Immune Defic Syndr 74:279-284
Conroy, Andrea L; McDonald, Chloe R; Gamble, Joel L et al. (2017) Altered angiogenesis as a common mechanism underlying preterm birth, small for gestational age, and stillbirth in women living with HIV. Am J Obstet Gynecol 217:684.e1-684.e17
Kapisi, James; Kakuru, Abel; Jagannathan, Prasanna et al. (2017) Relationships between infection with Plasmodium falciparum during pregnancy, measures of placental malaria, and adverse birth outcomes. Malar J 16:400
Prahl, Mary; Jagannathan, Prasanna; McIntyre, Tara I et al. (2017) Sex Disparity in Cord Blood FoxP3+ CD4 T Regulatory Cells in Infants Exposed to Malaria In Utero. Open Forum Infect Dis 4:ofx022

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