Interactions Between HIV and Malaria in African Children

HIV Infections Clinical Trial

— TCC  

Official title:

Interactions Between HIV and Malaria in African Children

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00527800
• Other study ID #: CDC- PEPFAR CoAg#U62P024421
• Status: Completed
• Phase: Phase 3
• First received: September 10, 2007
• Last updated: October 9, 2013
• Start date: August 2007
• Est. completion date: March 2013

Study information

• Verified date: October 2013
• Source: University of California, San Francisco
• Contact: n/a
• Is FDA regulated: No
• Health authority: Uganda: National Council for Science and TechnologyUganda: Research Ethics CommitteeUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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:

1. TMP/SMX prophylaxis is highly effective in preventing malaria in both HIV-infected and HIV-uninfected children

2. The use of TMP/SMX prophylaxis is associated with an increased risk of infection with malaria parasites containing antifolate resistance-conferring mutations.

3. The use of antiretroviral (ARV) drugs is associated with a decreased incidence of malaria.

4. 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:

5. 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 351
• Est. completion date: March 2013
• Est. primary completion date: March 2013
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 6 Weeks to 9 Months

Eligibility

Inclusion Criteria:

1. Age 6 weeks to 9 months

2. Documented HIV-1 status of mother and child

3. Agreement to come to the study clinic for any febrile episode or other illness

4. Agreement to avoid medications administered outside the study protocol

5. Guardian age 18 years or older (no age limit for parents)

6. Parent or guardian willing to provide informed consent

7. Residence within a 30 km radius of the study clinic

Exclusion Criteria:

1. 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

2. Intention to move more than 30 km from the study clinic during the follow-up period

3. History of allergy or sensitivity to AL or DP or TMP/SMX

4. Active medical problem requiring in-patient evaluation at the time of screening

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Factorial Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• HIV Infections
• Malaria

Intervention

Drug:
• Dihydroartemisinin-piperaquine
Once daily for 3 days, given in fixed dose tablets (40 mg dihydroartemisinin + 320 mg piperaquine) according to weight-based guidelines
• Artemether-lumefantrine
Dosed twice daily for 3 days, given in fixed dose tablets (20 mg artemether + 120 mg lumefantrine) according to weight-based guidelines
• Trimethoprim-sulfamethoxazole
Once daily dosing according to weight based guidelines

Locations

Country	Name	City	State
Uganda	Tororo District Hospital	Tororo

Sponsors (4)

Lead Sponsor	Collaborator
University of California, San Francisco	Centers for Disease Control and Prevention, Makerere University, The AIDS Support Organization

Country where clinical trial is conducted

Uganda, 

References & Publications (10)

Arinaitwe E, Gasasira A, Verret W, Homsy J, Wanzira H, Kakuru A, Sandison TG, Young S, Tappero JW, Kamya MR, Dorsey G. The association between malnutrition and the incidence of malaria among young HIV-infected and -uninfected Ugandan children: a prospecti — View Citation

Arinaitwe E, Sandison TG, Wanzira H, Kakuru A, Homsy J, Kalamya J, Kamya MR, Vora N, Greenhouse B, Rosenthal PJ, Tappero J, Dorsey G. Artemether-lumefantrine versus dihydroartemisinin-piperaquine for falciparum malaria: a longitudinal, randomized trial in — View Citation

Creek D, Bigira V, Arinaitwe E, Wanzira H, Kakuru A, Tappero J, Kamya MR, Dorsey G, Sandison TG. Increased risk of early vomiting among infants and young children treated with dihydroartemisinin-piperaquine compared with artemether-lumefantrine for uncomp — View Citation

Creek DJ, Bigira V, McCormack S, Arinaitwe E, Wanzira H, Kakuru A, Tappero JW, Sandison TG, Lindegardh N, Nosten F, Aweeka FT, Parikh S. Pharmacokinetic predictors for recurrent malaria after dihydroartemisinin-piperaquine treatment of uncomplicated malar — View Citation

Jagannathan P, Muhindo MK, Kakuru A, Arinaitwe E, Greenhouse B, Tappero J, Rosenthal PJ, Kaharuza F, Kamya MR, Dorsey G. Increasing incidence of malaria in children despite insecticide-treated bed nets and prompt anti-malarial therapy in Tororo, Uganda. M — View Citation

Kakuru A, Jagannathan P, Arinaitwe E, Wanzira H, Muhindo M, Bigira V, Osilo E, Homsy J, Kamya MR, Tappero JW, Dorsey G. The effects of ACT treatment and TS prophylaxis on Plasmodium falciparum gametocytemia in a cohort of young Ugandan children. Am J Trop — View Citation

Katrak S, Gasasira A, Arinaitwe E, Kakuru A, Wanzira H, Bigira V, Sandison TG, Homsy J, Tappero JW, Kamya MR, Dorsey G. Safety and tolerability of artemether-lumefantrine versus dihydroartemisinin-piperaquine for malaria in young HIV-infected and uninfect — View Citation

Sandison TG, Homsy J, Arinaitwe E, Wanzira H, Kakuru A, Bigira V, Kalamya J, Vora N, Kublin J, Kamya MR, Dorsey G, Tappero JW. Protective efficacy of co-trimoxazole prophylaxis against malaria in HIV exposed children in rural Uganda: a randomised clinical — View Citation

Verret WJ, Arinaitwe E, Wanzira H, Bigira V, Kakuru A, Kamya M, Tappero JW, Sandison T, Dorsey G. Effect of nutritional status on response to treatment with artemisinin-based combination therapy in young Ugandan children with malaria. Antimicrob Agents Ch — View Citation

Vora N, Homsy J, Kakuru A, Arinaitwe E, Wanzira H, Sandison TG, Bigira V, Kamya MR, Tappero JW, Dorsey G. Breastfeeding and the risk of malaria in children born to HIV-infected and uninfected mothers in rural Uganda. J Acquir Immune Defic Syndr. 2010 Oct; — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of clinical episodes of malaria		over entire course of follow-up	No
Primary	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	No
Secondary	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	No
Secondary	Risk of adverse events		28 days following each malaria treatment	Yes

External Links

•   MU-UCSF Research Collaboration website