Prevention of Malaria and HIV Disease in Tororo, Uganda (PROMOTE)

Principal Investigators: Professor Moses Kamya, MU and Dr. Diane Havlir, UCSF
Co-Investigators: Jane Achan, MU; Veronica Ades, NYU; Edwin Charlebois, UCSF; Tamara Clark, UCSF; Deborah Cohan, UCSF; Grant Dorsey, UCSF; Maggie Feeney, UCSF; Bryan Greenhouse, UCSF; Lena Kim, UCSF; Pius Okong, Nsambya Hospital; Phil Rosenthal, UCSF; Ted Ruel, UCSF; Sera Young, Cornell University

Coordinators: Abel Kakuru, IDRC; Gloria Ikilezi, IDRC; Bridget Nzarubara, IDRC; Beth Osterbauer, UCSF; Barnabus Natamba, Cornell University; Julia Mwesigwa, IDRC; Paul Natureeba, IDRC; Flavia Luwedde, IDRC; Victor Birgira, IDRC; James Kapisi, IDRC; Steven Kinara, IDRC

Funded by: The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)/NIH

Location: Tororo, Uganda

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The PROMOTE program establishes new approaches to reduce HIV and malaria burdens in sub-Saharan Africa, and enhances the public health approach to both diseases. The PROMOTE program is funded by NIH and protease inhibitor (PI) drugs donated by Abbott Labs and consists of 5 projects. Three of the projects are interlinked hypothesis-based intervention cohort trials. The other 2 projects are linked to all of the clinical trials and utilize data and specimens from each of these trials to characterize nutrition and drug resistance. The PROMOTE program is being conducted in Tororo District, Uganda, a rural area with HIV seroprevalence of 8% and malaria transmission intensity of 562 infective bites per person year, and started accruing participants in October 2009. The five projects of this program are:

PROMOTE-Pediatrics:

A randomized open label trial of HIV protease inhibitors for the prevention of malaria in HIV-infected children. The study enrolled over 150 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.

PROMOTE-Pregnant Women and Infants (PIs):
A randomized open label trial of protease inhibitors to reduce malaria morbidity in HIV-infected pregnant women and infants. This study enrolled nearly 400 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.

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. This study enrolled 400 HIV-unexposed infants and 200 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 and an additional 12 months of follow up after study treatment for rebound malaria evaluation..

PROMOTE-Nutrition:

This project evaluates the nutritional status of PROMOTE program participants, identifying factors which increase the risk of nutritional deficiency and subsequent poor clinical outcomes, correlating levels of malnutrition and ART pharmacokinetic exposure and response, and pilots a nutritional supplementation strategy tailored to routine practice in resource limited settings.

PROMOTE-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.

Key Publications:

1. Achan J, Kakuru A, Ikilezi G, Ruel T, Clark TD, Nsanzabana C, Charlebois ED, Aweeka F, Dorsey G, Rosenthal PJ, Havlir DV, Kamya MR. Antiretroviral agents and prevention of malaria in HIV-infected Ugandan children.N Engl J Med. 2012 Nov 29;367(22):2110-8.PMID: 23190222

2. Gandhi M, Mwesigwa J, Aweeka F, Plenty A, Charlebois E, Huang Y, Clark TD, Ades V, Natureeba P, Luwedde F, Achan J, Kamya MR, Havlir DV, Cohan D. Hair and Plasma Data Show that Lopinavir, Ritonavir and Efavirenz All Transfer from Mother to Infant in Utero, but only Efavirenz Transfers via Breastfeeding.AIDS. In press.

3. Ikilezi G, Achan J, Kakuru A, Ruel T, Charlebois E, Clark TD, Rosenthal PJ, Havlir DV, Kamya MR, Dorsey G. Prevalence of asymptomatic parasitemia and gametocytemia among HIV-infected Ugandan children randomized to receive different antiretroviral therapies. Am J Trop Med Hyg. 2013 Jan 28. PMID: 23358639

4. Osterbauer B, Kapisi J, Bigira V, Mwangwa F, Kinara S, Kamya MR, Dorsey G. Factors associated with malaria parasitemia, malnutrition, and anemia among HIV-exposed and unexposed Ugandan infants. Malar J. 2012 Dec 27;11(1):432. PMID: 23270614

5. Young S, Murray K, Mwesigwa J, Natureeba P, Osterbauer B, Achan J, Arinaitwe E, Clark T, Ades V, Plenty A, Charlebois E, Ruel T, Kamya M, Havlir D, Cohan D. Maternal Nutritional Status Predicts Adverse Birth Outcomes among HIV-Infected Rural Ugandan Women Receiving Combination Antiretroviral Therapy. PLoS ONE 2012, 7:e41934. PMID: 22879899

6. Nsanzabana C, Rosenthal PJ. In vitro activity of antiretroviral drugs against Plasmodium falciparum. Antimicrob Agents Chemother. 2011 Nov;55(11):5073-7. Epub 2011 Aug 29. PMID: 21876053