TORORO CHILDREN COHORT

Interactions Between HIV and Malaria in African Children

ClinicalTrials.gov Identifier: NCT00527800

Principal Investigators: Professor Moses Kamya, Makerere University and Dr. Frank Kaharuza, CDC-Uganda

Co-Investigators: Grant Dorsey, UCSF; Anne Gasasira, MU; Phil Rosenthal, UCSF; Jordan Tappero, CDC; Jaco Homsy, UCSF; Sunil Parikh, UCSCF; David Serukka, PREFA; Emmanuel Arinaitwe, IDRC; Maggie Feeney, UCSF; Bryan Greenhouse, UCSF; Ted Ruel, UCSF

Coordinator: Mary Muhindo, IDRC

Funded by: CDC

Location: Tororo, Uganda

HIV-infected and HIV-uninfected children were enrolled in a prospective cohort study between the ages of 6 weeks and 12 months and followed at the Tororo Research Clinic for all of their health care needs. HIV-infected children who meet and who do not yet meet standardized criteria to initiate antiretroviral therapy (ART) were included in the study. All HIV-exposed children (i.e. born to HIV-infected mothers) receive trimethoprim-sulfamethoxazole (TMP/SMX) prophylaxis as of 6 weeks of age. Once weaned, children who prove to be HIV-uninfected are randomized to continuation of TMP/SMX vs. discontinuation of TMP/SMX through 24 months of age. At 24 months of age, the 100 HIV-exposed children initially randomized to continue TMP-SMX will again be randomized in a 1:1 ratio to either discontinue TMP/SMX or to continue TMP/SMX through 4 years of age. HIV-uninfected children born to HIV-uninfected mothers do not receive TMP/SMX prophylaxis. Study participants 4 months of age or older are randomized to treatment with artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP) at the time of their first diagnosis of uncomplicated malaria and will continue to receive the same antimalarial treatment regimen for all future episodes of uncomplicated malaria. All mother-child pairs enrolled in the study were offered support counseling and a basic care package including 2 insecticide-treated bednets (ITNs), a safe water vessel, multivitamins and condoms. The study objectives are:

1. To compare the incidence of malaria in a cohort of children stratified by HIV status, mother’s HIV status, and use of TMP/SMX prophylaxis in an area where malaria is highly endemic

WHO recommends that all babies born to HIV-infected mothers receive TMP/SMX prophylaxis as of 4-6 weeks of age until the complete cessation of breastfeeding and the exclusion of HIV infection. There is strong evidence that TMP/SMX reduces morbidity and mortality in adults and children infected with HIV. However, there are no recommendations for the use of TMP/SMX prophylaxis among HIV-uninfected children beyond exposure and among HIV-unexposed children.

We will follow a cohort of 350 children divided into 4 exposure groups according to the child’s HIV status, the mother’s HIV status, and the use of TMP/SMX prophylaxis:

1) 50 HIV-infected children born to HIV-infected mothers given TMP/SMX prophylaxis
2) Approximately 100 HIV-uninfected children born to HIV-infected mothers given TMP/SMX following completion of breast feeding
3) Approximately 100 HIV-uninfected children born to HIV-infected mothers not given TMP/SMX following completion of breast feeding, and
4) 100 HIV-uninfected children born to HIV-uninfected mothers not given TMP/SMX.

At the end of the initial follow-up to 24 months of age, the 100 HIV-uninfected children born to HIV-infected mothers who were randomized to continue TMP/SMX will again be randomized in 1:1 ratio so that approximately 50 children will continue to receive TMP/SMX prophylaxis through 4 years of age and the other 50 children will discontinue TMP/SMX prophylaxis at the time of this second randomization.

The primary observation period of interest will be the period following completion of breastfeeding until the age of 4 years. Standardized methods will be used to diagnose malaria. The primary outcome of interest will be the incidence of malaria among the various exposure groups. Additionally we will compare the following outcomes:

1) Prevalence of asymptomatic parasitemia
2) Incidence of complicated malaria
3) Incidence of diarrheal illnesses (using standardized definition)
4) Incidence of respiratory tract infections (using standardized definition)

2. To assess the effect of TMP/SMX prophylaxis on the selection of malaria parasites containing mutations conferring resistance to antifolate drugs

We will test the hypothesis that TMP/SMX prophylaxis is associated with an increased risk of infection with malaria parasites containing antifolate resistance-conferring mutations by comparing the prevalence of infecting parasites containing these mutations between children taking TMP/SMX prophylaxis and children not receiving TMP/SMX. Furthermore, we will also test the in vitro susceptibility of parasites cultured from the blood of our participants to antifolate drugs and correlate these levels of resistance with known and new markers of antifolate resistance. This will allow a more complete characterization of the effect of TMP/SMX on the development of antifolate resistance-conferring genotypes and the corresponding antifolate resistance phenotypes.

3. To assess the effect of ARV use on malaria incidence among HIV-infected children

We will test the hypothesis that use of antiretroviral (ARV) therapy in HIV-infected children will decrease the incidence of malaria. Preliminary data from our group have shown that certain ARV drugs have direct antimalarial effects in vitro, but it is unknown whether these drugs also provide clinical protection against malaria. We will test the hypothesis that the use of ARV drugs is associated with a decreased incidence of malaria.

4. To compare the efficacy, safety, and tolerability of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) for the treatment of uncomplicated falciparum malaria among HIV-infected and uninfected children

We will test the hypothesis that there are significant differences in the efficacy, safety, and tolerability between AL and DP for the treatment of uncomplicated malaria. Both HIV-infected and -uninfected children age 4 months or greater will be randomized to open-label AL or DP following the diagnosis of their first episode of uncomplicated malaria. Study participants will be treated with the same allocated treatment regimen for all subsequent episodes of uncomplicated malaria diagnosed over the course of the study. We will compare the treatment efficacy and safety/tolerability of the two regimens using standardized outcomes. We will also test the hypothesis that efficacy and safety/tolerability of each regimen differs according to HIV status.

To allow for complete characterization of the consequences of frequent, repeated antimalarial therapy with our study drugs, we also intend to culture parasites as part of our surveillance for the emergence of resistance to AL and DP. Unlike antifolate resistance in malaria, the development of resistance to artemisinins and the partner drugs lumefantrine and piperaquine is not well characterized. Therefore, we must find resistant parasites through in vitro sensitivity testing of cultured parasite lines and then test for an association with single nucleotide polymorphsims (SNPs) within the P. falciparum genome. Though novel SNPs will initially be seen only rarely, once they enter the circulating population of parasites in a community they may increase in prevalence and impact the therapeutic efficacy of the antimalarial drugs. Identification of SNPs associated with emerging resistance to these two artemisinin-combination therapies (ACTs) would be of worldwide public health importance.

5. To assess the effect of TMP-SMX prophylaxis on the incidence of malaria following cessation of prophylaxis

Immunity to malaria is acquired slowly and cumulatively from repeated infections. There is concern that chemoprophylaxis of children will prevent acquisition of malaria-specific immunity, resulting in an increased or rebound incidence of malaria following cessation of chemoprophylaxis. We will test the hypothesis that prolonged TMP/SMX prophylaxis will result in an increased incidence of malaria in those children in the year immediately following cessation of prophylaxis compared to those who have not used prophylaxis for over a year and those who have never been on prophylaxis. Initially, we will compare those HIV-exposed children randomized to stop TMP/SMX prophylaxis at 24 months with HIV-exposed children randomized to stop TMP/SMX prophylaxis following cessation of breastfeeding (at approximately 9 months of age). We will measure the incidence of malaria for an additional year following cessation of prophylaxis at 24 months. Then we will compare the HIV-exposed children randomized to continue TMP/SMX through 4 years of age with HIV-exposed children randomized to discontinue TMP/SMX prophylaxis at breastfeeding and at 24 months of age. We will measure the incidence of malaria for these groups from 4 years through 5 years of age. During this time we will also measure the incidence of malaria in HIV-uninfected children in Tororo to provide a baseline with which to compare the other measurements.