TCC: Interactions Between HIV and Malaria in African Children

Sponsor

University of California, San Francisco (Other)

Overall Status

Completed

CT.gov ID

NCT00527800

Collaborator

Centers for Disease Control and Prevention (U.S. Fed), Makerere University (Other), The AIDS Support Organization (Other)

351

Enrollment

Location

Arms

Duration (Months)

5.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a prospective cohort study where HIV-infected and uninfected children will be enrolled between 6 weeks and 9 months of age and followed to the age of 21 months. All HIV-infected children will be given trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis as of 6 weeks of age. HIV-uninfected children born to HIV-infected mothers will be given TMP/SMX prophylaxis for the duration of breastfeeding and then randomized to the continuation of TMP/SMX or discontinuation of TMP/SMX prophylaxis. HIV-uninfected children born to HIV-uninfected mothers will not be given TMP/SMX prophylaxis. Study participants will be followed for all of their health care needs in a designated study clinic. All mother-child pairs will receive a basic care package including insecticide-treated bednets (ITNs) at enrollment. All HIV-infected mothers and children will receive antiretroviral therapy if eligible according to standardized World Health Organization (WHO) criteria. Study participants 4 months of age or older and at least 5 kg will be randomized to treatment with artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP) at the time of their first diagnosis of uncomplicated malaria. Study participants will receive the same antimalarial treatment regimen for all future episodes of uncomplicated malaria. Study participants less than 4 months of age or less than 5 kg diagnosed with malaria and all episodes of complicated malaria will be treated with quinine in accordance with local guidelines.

The investigators will test the hypotheses that:

TMP/SMX prophylaxis is highly effective in preventing malaria in both HIV-infected and HIV-uninfected children
The use of TMP/SMX prophylaxis is associated with an increased risk of infection with malaria parasites containing antifolate resistance-conferring mutations.
The use of antiretroviral (ARV) drugs is associated with a decreased incidence of malaria.
The efficacy, safety, and tolerability of AL and DP for the treatment of uncomplicated malaria differ.

In 2008, we received approval and funding to extend the trial until 2012. We are now following all children through 5 years of age. First randomization to continue or discontinue TMP/SMX prophylaxis in our HIV-exposed population occurs 6-8 weeks after cessation of breastfeeding when HIV status can be confirmed as negative by DNA PCR. A second randomization occurs at 2 years of age in our HIV-exposed participants. At that point all HIV-exposed children who were originally randomized to continue TMP/SMX prophylaxis are again randomized to either immediately discontinue TMP/SMX prophylaxis or continue prophylaxis until age 4 years. All children will be off TMP/SMX between 4 and 5 years of age.

We have also added an additional hypothesis to test during the study extension:

Prolonged TMP/SMX prophylaxis will result in an increased incidence of malaria in children in the year immediately following cessation of prophylaxis compared to children who have not used prophylaxis for over a year and those who have never been on prophylaxis.

Condition or Disease	Intervention/Treatment	Phase
Malaria HIV Infections	Drug: Dihydroartemisinin-piperaquine Drug: Artemether-lumefantrine Drug: Trimethoprim-sulfamethoxazole	Phase 3

Study Design

Study Type:

Interventional

Actual Enrollment :

351 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Interactions Between HIV and Malaria in African Children

Study Start Date :

Aug 1, 2007

Actual Primary Completion Date :

Mar 1, 2013

Actual Study Completion Date :

Mar 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Treatment for episodes of uncomplicated malaria	Drug: Dihydroartemisinin-piperaquine Once daily for 3 days, given in fixed dose tablets (40 mg dihydroartemisinin + 320 mg piperaquine) according to weight-based guidelines
Active Comparator: 2 Treatment for uncomplicated malaria	Drug: Artemether-lumefantrine Dosed twice daily for 3 days, given in fixed dose tablets (20 mg artemether + 120 mg lumefantrine) according to weight-based guidelines
Experimental: A Prevention of malaria in HIV uninfected, exposed children	Drug: Trimethoprim-sulfamethoxazole Once daily dosing according to weight based guidelines
No Intervention: B Prevention of malaria in HIV uninfected, exposed children

Outcome Measures

Primary Outcome Measures

Incidence of clinical episodes of malaria [over entire course of follow-up]
Risk of treatment failure at Day 28 defined as any early treatment failure or late clinical/parasitological failure adjusted and unadjusted by genotyping to distinguish recrudescence (treatment failure due to drug resistance) and new infections [28 days following each malaria treatment]

Secondary Outcome Measures

Prevalence of mutations known to confer resistance to antifolate drugs in pretreatment samples from patients diagnosed with malaria [each time episode of malaria is diagnosed]
Risk of adverse events [28 days following each malaria treatment]

Eligibility Criteria

Criteria

Ages Eligible for Study:

6 Weeks to 9 Months

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Age 6 weeks to 9 months
Documented HIV-1 status of mother and child
Agreement to come to the study clinic for any febrile episode or other illness
Agreement to avoid medications administered outside the study protocol
Guardian age 18 years or older (no age limit for parents)
Parent or guardian willing to provide informed consent
Residence within a 30 km radius of the study clinic

Exclusion Criteria:

HIV-exposed infants who have already stopped receiving TMP/SMX as a result of having stopped breastfeeding and having been tested HIV-negative before screening
Intention to move more than 30 km from the study clinic during the follow-up period
History of allergy or sensitivity to AL or DP or TMP/SMX
Active medical problem requiring in-patient evaluation at the time of screening