Prevention of Malaria and HIV Disease in Tororo (PROMOTE-II)
The purpose of the Prevention of Malaria and HIV Disease in Tororo (PROMOTE-II) program project is to evaluate promising interventions to reduce the burden of malaria and HIV among pregnant women and improve maternal child health through hypothesis based interventional studies. To achieve this overall goal, we are currently conducting 2 double blind randomized clinical trials (Birth Cohort 1 and 2) with and integrated immunology component to address the following 2 overarching questions:
- Can DP given to pregnant women and children up to 2 years of age reduce the burden of malaria compared to current standard malaria prevention (SMP) strategies?
- Will controlling malaria during pregnancy and the first years of life enhance antimalarial immunity?
Principal Investigators are Prof Moses Kamya of Makerere University/IDRC and Drs. Diane Havlir, Grant Dorsey and Maggie Feeney of UCSF.
i) Birth Cohort 1
This randomized, double-blinded, controlled trial of 300 HIV uninfected pregnant women and the children born to them, will be the first trial to evaluate the efficacy and safety of DP for the prevention of malaria in pregnant women. It will compare 2 dosing strategies of this novel intervention with the current standard of care of IPTp with SP in an area of high transmission intensity and widespread antifolate resistance. The study interventions will be divided into two phases. In the first phase, HIV uninfected women at 12-20 weeks gestation will be randomized in equal proportions to one of three IPTp treatment arms: 1) 3 doses of SP, 2) 3 doses of DP, or 3) monthly DP. Follow-up for the pregnant women will end approximately 6 weeks after giving birth. In the second phase of the study, all children born to mothers enrolled in the study will be followed from birth until they reach 36 months of age. Children born to mothers randomized to receive 3 doses of SP during pregnancy will receive DP every 3 months between 2-24 months of age. Children born to mothers randomized to receive 3 doses of DP or monthly DP during pregnancy will receive either DP every 3 months or monthly DP between 2-24 months of age. Children will then be followed an additional year between 24-36 months of age following the interventions. Pregnant women will undergo frequent sampling using a highly sensitive PCR assay to better define the timing and frequency of malaria infection during pregnancy and the primary outcome will be based on placental histopathology to maximize the detection of placental infection throughout pregnancy. We will test the hypothesis that IPT with DP will significantly reduce the burden of malaria in pregnancy and infancy and improve the development of naturally acquired antimalarial immunity.
ii) Birth Cohort 2
Strategic interventions such as monthly DP for HIV-infected pregnant women and their children to prevent malaria represent an opportunity to improve both maternal and child health outcomes. This is a double-blinded, randomized controlled trial of 200 HIV-infected pregnant women living in Tororo, Uganda, an area of high malaria transmission. 128 HIV-infected pregnant women between 12 and 28 weeks gestation will be randomized to receive enhanced malaria chemoprevention with monthly DP versus monthly DP placebo. Their HIV-exposed children will receive the same prevention regimen from 2 to 24 months of age to which the mothers were randomized. All women will receive daily TS throughout the study per Uganda MOH guidelines. Children will also receive daily TS from 6 weeks to 24 months of age. TS will be considered a study drug only in infants and children beginning 6 weeks after cessation of breastfeeding and upon exclusion of HIV infection. Women and their children will be followed for 36 months after delivery. This study tests the hypothesis that enhanced versus standard malaria chemoprevention in HIV-infected pregnant women and their children will reduce the incidence of malaria among children from 0 to 24 months of age.
This trial will also evaluate the pharmacokinetic exposure of concomitant DP and cART during pregnancy. DP and the first-line antiretroviral efavirenz (EFV) share metabolic pathways that could potentially lead to clinically relevant drug interactions. Pregnant women will undergo intensive PK evaluations for DP and EFV during the 3rd trimester. We will compare EFV PK in women receiving DP+TS vs. pl/TS and will compare DP PK between HIV-infected women receiving EFV-based cART and HIV-uninfected pregnant women receiving the identical regimen enrolled from Birth Cohort 1 not receiving ART.
iii) Immunology Project
The primary goals of this project are: 1. To determine whether exposure to malaria antigens in utero is associated with fetal tolerance, and whether limiting such exposure prevents the development of tolerance to malaria. We will determine whether in utero exposure is associated with tolerance, as evidenced by an expansion of functionally suppressive malaria-specific Tregs in cord blood. As a secondary analysis, we will assess whether chemoprevention during pregnancy prevents the development of tolerance. 2. To prospectively evaluate the impact of in utero antigen exposure on the natural acquisition of malaria-specific cellular immunity during early childhood. We will perform longitudinal assessments of malaria-specific T cells and immunoregulatory responses that develop following natural exposure to malaria, and relate these to in utero exposure and to the incidence of malaria during the first 3 years of life. 3. To determine whether the proportion of “tolerogenic” fetal T cells present at birth (TF:TA ratio) predicts neonatal immune tolerance to malaria antigens and the subsequent development of antimalarial immunity following postnatal exposure. We will measure the TF:TA ratio in cord blood and determine its association with regulatory and effector responses to malaria in cord blood, and with the incidence of malaria and the development of malaria-specific cellular immunity during childhood.
iv) Birth Cohort 3
Study period: 2016-2018.
Goal: To compare monthly sulfadoxine pyrimethamine commonly known as fansidar and monthly dihydroartemisinin-piperaquine commonly known as duocotexin for prevention of malaria in HIV-negative pregnant women, and to validate and adapt a gestational dating by metabolic profile at birth. Collaborators: University of California San Francisco, Makerere University, IDRC. Sponsored by: The National Institute of Child Health and Human Development, and the Bill and Melinda Gates Foundation