|The high rates of childhood and maternal morbidity and mortality in Africa are rooted in the overlapping and synergistic epidemics of HIV and malaria. UCSF investigators in collaboration with colleagues at Makerere University, Uganda, were funded by the National Institute of Allergy and Infectious Disease (NIAID) to evaluate interventions to reduce the burdens of malaria and HIV among pregnant women and children, the two most vulnerable populations. The PROMOTE Study builds upon studies previously carried out by these investigators, which revealed new opportunities to improve HIV and malaria outcomes among persons living in areas where these epidemics overlap. The studies will test the novel hypothesis that treatment with HIV protease inhibitors (PIs) will lower the incidence of malaria and consequent morbidity in HIV-infected children and pregnant women as compared to those treated with standard antiretroviral treatment (ART). This hypothesis is based on data from Dr. Rosenthal’s laboratory demonstrating that malaria parasites and HIV express biochemically similar proteases and that HIV PIs exert potent in vitro antimalarial activity. The project will also test the hypothesis that in HIV-uninfected children, continuous or intermittent antimalarial chemopreventive therapy, with more frequent dosing than recently studied intermittent preventive therapy regimens, will offer strong protection against malaria without increased risks of toxicity or increased malarial morbidity after discontinuation of the intervention. This study will enroll 1600 participants and be conducted by a multidisciplinary, multinational team, with close collaborations with the Ugandan Ministry of Health, Ugandan HIV care programs and the President’s Malaria Initiative. Our primary goal will be to build on current knowledge to improve standard care and limit the burden of HIV and malaria.||
The PROMOTE Study consists of 4 projects. Three of the projects are interlinked hypothesis-based intervention trials. The fourth project is linked to all of the clinical trials and utilizes specimens from each of these trials to characterize drug resistance. The projects will be conducted in Tororo District, Uganda (a rural area with HIV seroprevalence of 8% and malaria transmission intensity of 562 infective bites per person year), where we have established a research site and generated preliminary data for the proposed studies.
Project 1: PROMOTE-PEDIATRICS, A randomized open label trial of HIV protease inhibitors for the prevention of malaria in HIV-infected children will enroll 300 HIV-infected children with the aim of determining if the use of PI-based (LPV/r) ART versus NNRTI-based ART among HIV-infected children will reduce the incidence density of malaria in children.
Project 2: PROMOTE- PIs (Pregnant women and Infants), Protease inhibitors to reduce malaria morbidity in HIV-infected pregnant women will enroll 500 HIV-infected pregnant women with the primary objective of determining if the use of PI-based ART versus non-PI ART among HIV-infected pregnant women leads to reduced rates of placental malaria as measured by Giemsa-stained smear or polymerase chain reaction (PCR) of placental blood.
Project 3: PROMOTE- CHEMOPREVENTION, A randomized trial of monthly dihydroartemisinin-piperaquine versus monthly sulfadoxine-pyrimethamine versus daily trimethoprim-sulfamethoxazole versus no therapy for the prevention of malaria will enroll 400 HIV-unexposed infants and 400 HIV-exposed infants with the aim of comparing the incidence of malaria among these infants enrolled at 4-5 months of age and randomized to one of the four arms listed above until they reach the age of 24 months.
Project 4: Drug Resistance. This program project includes three randomized clinical trials to test whether long-term use of chemopreventive antimalarial therapies in children or of antiretroviral protease inhibitors in children or pregnant women will decrease the incidence of malaria and related malarial morbidity. These interventions offer the opportunity to significantly decrease the incidence and morbidity of malaria, the most important infectious disease in children and pregnant women in Africa. However, repeated or chronic therapy for infectious diseases routinely entails a risk of selection of drug-resistant parasites. This is a particular concern for malaria, as drug resistance already limits treatment options, and control efforts based of intermittent therapy have relied heavily on antifolates, against which resistance is increasing.
Thus, as our clinical trials test the preventive antimalarial efficacy of antiretroviral and antimalarial drugs, it is very important to characterize the impact of these interventions on the selection of drug-resistant malaria parasites. We hypothesize that intermittent or chronic use of antimalarial and antiretroviral therapies will decrease the incidence of malaria, but that these therapies will select for increasingly resistant parasites that may become refractory to control efforts. Further, we hypothesize that different drugs will offer different selective pressures. Therefore, an appreciation of the selective pressures for resistance of different drugs can, in addition to the results of our clinical trials, guide public policy for the management of HIV infection and malaria in Africa.
Project 4 will utilize parasitology and molecular techniques to test our hypotheses, benefiting from a clinical laboratory with focused expertise in Tororo, a central laboratory in Kampala with extensive molecular and parasitological capabilities, and a laboratory with 20 years of experience studying malaria parasites at UCSF. Our specific aims will be: 1) to characterize the selection of drug-resistant malaria parasites by antifolate chemopreventive regimens, 2) to characterize the selection of drug-resistant malaria parasites by chemoprevention with dihydroartemisinin/piperaquine, and 3) to characterize the selection of drug-resistant malaria parasites by antiretroviral protease inhibitors with antimalarial activity. These studies will complement our clinical trials to provide a balanced assessment of the costs and benefits of new chemopreventive measures to control malaria.
The PROMOTE Study establishes new approaches to reduce HIV and malaria burdens in sub-Saharan Africa, and enhances the public health approach to both diseases through answering the two main research questions below:
(1) Can the strategic use of HIV PIs improve outcomes of HIV-infected children and pregnant women who live in areas of high malaria transmission? Among children receiving PIs, compared to those receiving standard ART, will malaria incidence and complications of malaria be reduced? Among pregnant women, can PIs reduce the risk of placental malaria and lead to the measurable clinical benefit of a reduced risk of low birth weight, spontaneous abortions, or stillbirth? In both populations, are PIs tolerated as well as current ART regimens? Do PIs achieve levels of viral suppression and CD4 recovery as high as the current standard regimens for the treatment of HIV disease? Will PIs select for malaria parasites with decreasing sensitivity to these drugs?
(2) What is the optimal approach to malaria chemoprevention for children living in areas of high malaria transmission? Is daily prophylaxis with TS superior to IPT? Regarding IPT, does a new artemisinin-based treatment regimen offer benefit over the best-studied regimen, the antifolate sulfadoxine-pyrimethamine (SP)? Will monthly IPT offer a potent protective effect, as typically not seen with less frequent dosing? Do the benefits of chemopreventive strategies differ between children born to HIV-infected mothers compared to those born to HIV-uninfected mothers? What is the safety and tolerance of these regimens? How do children who break through IPT or daily TS respond to standard malaria treatment? Does IPT with SP and daily TS select for increasingly drug-resistant parasites and does the increasing problem of antifolate resistance limit the protective efficacies of these regimens? Is there any evidence of rebound in malaria, with heightened incidence of disease after discontinuation of chemopreventive strategies?