Interactions Between HIV and Malaria in African Children (TCC)

Tracking Information
First Submitted Date ICMJE	September 10, 2007
First Posted Date ICMJE	September 11, 2007
Last Update Posted Date	October 11, 2013
Study Start Date ICMJE	August 2007
Actual Primary Completion Date	March 2013 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: February 17, 2009)	Incidence of clinical episodes of malaria [ Time Frame: 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 [ Time Frame: 28 days following each malaria treatment ]
Original Primary Outcome Measures ICMJE; (submitted: September 10, 2007)	Incidence of clinical episodes of malaria; 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.
Change History	Complete list of historical versions of study NCT00527800 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: February 17, 2009)	Prevalence of mutations known to confer resistance to antifolate drugs in pretreatment samples from patients diagnosed with malaria [ Time Frame: each time episode of malaria is diagnosed ]; Risk of adverse events [ Time Frame: 28 days following each malaria treatment ]
Original Secondary Outcome Measures ICMJE; (submitted: September 10, 2007)	Prevalence of mutations known to confer resistance to antifolate drugs in pretreatment samples from patients diagnosed with malaria; Risk of adverse events
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Interactions Between HIV and Malaria in African Children
Official Title ICMJE	Interactions Between HIV and Malaria in African Children
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.
Detailed Description	Not Provided
Study Type ICMJE	Interventional
Study Phase	Phase 3
Study Design ICMJE	Allocation: Randomized; Intervention Model: Factorial Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Malaria; HIV Infections
Intervention ICMJE	Drug: Dihydroartemisinin-piperaquine Once daily for 3 days, given in fixed dose tablets (40 mg dihydroartemisinin + 320 mg piperaquine) according to weight-based guidelines; 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; Drug: Trimethoprim-sulfamethoxazole Once daily dosing according to weight based guidelines
Study Arms	Experimental: 1 Treatment for episodes of uncomplicated malaria Intervention: Drug: Dihydroartemisinin-piperaquine; Active Comparator: 2 Treatment for uncomplicated malaria Intervention: Drug: Artemether-lumefantrine; Experimental: A Prevention of malaria in HIV uninfected, exposed children Intervention: Drug: Trimethoprim-sulfamethoxazole; No Intervention: B Prevention of malaria in HIV uninfected, exposed children
Publications *	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 malaria in Ugandan infants. J Infect Dis. 2013 Jun 1;207(11):1646-54. doi: 10.1093/infdis/jit078. Epub 2013 Feb 27.; 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 Med Hyg. 2013 Apr;88(4):736-43. doi: 10.4269/ajtmh.12-0654. Epub 2013 Feb 4.; 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. Malar J. 2012 Dec 28;11:435. doi: 10.1186/1475-2875-11-435.; 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 prospective study. Malar J. 2012 Mar 27;11:90. doi: 10.1186/1475-2875-11-90.; 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 trial. BMJ. 2011 Mar 31;342:d1617. doi: 10.1136/bmj.d1617.; 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 Chemother. 2011 Jun;55(6):2629-35. doi: 10.1128/AAC.01727-10. Epub 2011 Mar 7.; 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 uncomplicated malaria. Am J Trop Med Hyg. 2010 Oct;83(4):873-5. doi: 10.4269/ajtmh.2010.10-0158.; 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;55(2):253-61. doi: 10.1097/QAI.0b013e3181eb4fd7.; 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 uninfected children. Malar J. 2009 Nov 30;8:272. doi: 10.1186/1475-2875-8-272.; 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 young Ugandan children. Clin Infect Dis. 2009 Dec 1;49(11):1629-37. doi: 10.1086/647946.; Homsy J, Dorsey G, Arinaitwe E, Wanzira H, Kakuru A, Bigira V, Muhindo M, Kamya MR, Sandison TG, Tappero JW. Protective efficacy of prolonged co-trimoxazole prophylaxis in HIV-exposed children up to age 4 years for the prevention of malaria in Uganda: a randomised controlled open-label trial. Lancet Glob Health. 2014 Dec;2(12):e727-36. doi: 10.1016/S2214-109X(14)70329-8.; Wanzira H, Kakuru A, Arinaitwe E, Bigira V, Muhindo MK, Conrad M, Rosenthal PJ, Kamya MR, Tappero JW, Dorsey G. Longitudinal outcomes in a cohort of Ugandan children randomized to artemether-lumefantrine versus dihydroartemisinin-piperaquine for the treatment of malaria. Clin Infect Dis. 2014 Aug 15;59(4):509-16. doi: 10.1093/cid/ciu353. Epub 2014 May 13.; Conrad MD, LeClair N, Arinaitwe E, Wanzira H, Kakuru A, Bigira V, Muhindo M, Kamya MR, Tappero JW, Greenhouse B, Dorsey G, Rosenthal PJ. Comparative impacts over 5 years of artemisinin-based combination therapies on Plasmodium falciparum polymorphisms that modulate drug sensitivity in Ugandan children. J Infect Dis. 2014 Aug 1;210(3):344-53. doi: 10.1093/infdis/jiu141. Epub 2014 Mar 8.; Muhindo MK, Kakuru A, Jagannathan P, Talisuna A, Osilo E, Orukan F, Arinaitwe E, Tappero JW, Kaharuza F, Kamya MR, Dorsey G. Early parasite clearance following artemisinin-based combination therapy among Ugandan children with uncomplicated Plasmodium falciparum malaria. Malar J. 2014 Jan 28;13:32. doi: 10.1186/1475-2875-13-32.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: May 14, 2009)	351
Original Estimated Enrollment ICMJE; (submitted: September 10, 2007)	400
Actual Study Completion Date	March 2013
Actual Primary Completion Date	March 2013 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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
Sex/Gender	Sexes Eligible for Study: All
Ages	6 Weeks to 9 Months (Child)
Accepts Healthy Volunteers	Yes
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	Uganda
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT00527800
Other Study ID Numbers ICMJE	CDC- PEPFAR CoAg#U62P024421
Has Data Monitoring Committee	No
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	University of California, San Francisco
Study Sponsor ICMJE	University of California, San Francisco
Collaborators ICMJE	Centers for Disease Control and Prevention; Makerere University; The AIDS Support Organization
Investigators ICMJE	Principal Investigator: Grant Dorsey, MD, PhD University of California, San Francisco
PRS Account	University of California, San Francisco
Verification Date	October 2013
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP