Interactions Between HIV and Malaria in African Children

NCT00527800 | Completed Phase 3

• 1 other identifier: CDC- PEPFAR CoAg#U62P024421
• Study Type: interventional
• Target: 351
• Locations: 1 country
• Sites: 1

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:

1. 1.TMP/SMX prophylaxis is highly effective in preventing malaria in both HIV-infected and HIV-uninfected children
2. 2.The use of TMP/SMX prophylaxis is associated with an increased risk of infection with malaria parasites containing antifolate resistance-conferring mutations.
3. 3.The use of antiretroviral (ARV) drugs is associated with a decreased incidence of malaria.
4. 4.The efficacy, safety, and tolerability of AL and DP for the treatment of uncomplicated malaria differ.
5. 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.

Conditions

Malaria; HIV Infections

Keywords

Malaria; HIV; Trimethoprim-sulfamethoxazole; Artemether-lumefantrine; Dihydroartemisinin-piperaquine; Acute Infection

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (2)

• 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

Study Arms (4)

1

EXPERIMENTAL

Treatment for episodes of uncomplicated malaria

Drug: Dihydroartemisinin-piperaquine

2

ACTIVE COMPARATOR

Treatment for uncomplicated malaria

Drug: Artemether-lumefantrine

A

EXPERIMENTAL

Prevention of malaria in HIV uninfected, exposed children

Drug: Trimethoprim-sulfamethoxazole

B

NO INTERVENTION

Prevention of malaria in HIV uninfected, exposed children

Interventions

Dihydroartemisinin-piperaquine DRUG

Once daily for 3 days, given in fixed dose tablets (40 mg dihydroartemisinin + 320 mg piperaquine) according to weight-based guidelines

1

Artemether-lumefantrine DRUG

Dosed twice daily for 3 days, given in fixed dose tablets (20 mg artemether + 120 mg lumefantrine) according to weight-based guidelines

2

Trimethoprim-sulfamethoxazole DRUG

Once daily dosing according to weight based guidelines

A

Eligibility Criteria

• Age: 6 Weeks - 9 Months
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of California, San Francisco: lead
• Centers for Disease Control and Prevention: collaborator
• Makerere University: collaborator
• The AIDS Support Organization: collaborator

Study Sites (1)

Tororo District Hospital

Tororo, Uganda

Location

Related Publications (14)

• 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.

  PMID: 23447696 RESULT

• 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.

  PMID: 23382157 RESULT

• 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.

  PMID: 23273022 RESULT

• 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.

  PMID: 22453048 RESULT

• 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.

  PMID: 21454456 RESULT

• 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.

  PMID: 21383095 RESULT

• 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.

  PMID: 20889882 RESULT

• 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.

  PMID: 20683193 RESULT

• 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.

  PMID: 19948038 RESULT

• 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.

  PMID: 19877969 RESULT

• 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.

  PMID: 25433628 DERIVED

• 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.

  PMID: 24825870 DERIVED

• 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.

  PMID: 24610872 DERIVED

• 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.

  PMID: 24468007 DERIVED

Related Links

• MU-UCSF Research Collaboration website

MeSH Terms

Conditions

Malaria; HIV Infections

Interventions

Artemether, Lumefantrine Drug Combination; Trimethoprim, Sulfamethoxazole Drug Combination

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Artemether; Artemisinins; Reactive Oxygen Species; Free Radicals; Inorganic Chemicals; Organic Chemicals; Lumefantrine; Fluorenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sesquiterpenes; Terpenes; Polycyclic Compounds; Drug Combinations; Pharmaceutical Preparations; Sulfamethoxazole; Benzenesulfonamides; Sulfonamides; Amides; Sulfanilamides; Aniline Compounds; Amines; Benzene Derivatives; Sulfones; Sulfur Compounds; Trimethoprim; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Grant Dorsey, MD, PhD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 10, 2007
• First Posted: September 11, 2007
• Study Start: August 1, 2007
• Primary Completion: March 1, 2013
• Study Completion: March 1, 2013
• Last Updated: October 11, 2013

Record last verified: 2013-10

Locations

UG (1)