Interactions Between HIV and Malaria in African Children
Condition: Malaria; HIV Infections
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 3

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.
    


Intervention name(s): Dihydroartemisinin-piperaquine; Artemether-lumefantrine; Trimethoprim-sulfamethoxazole
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Once daily for 3 days, given in fixed dose tablets (40 mg dihydroartemisinin + 320 mg piperaquine) according to weight-based guidelines; Dosed twice daily for 3 days, given in fixed dose tablets (20 mg artemether + 120 mg lumefantrine) according to weight-based guidelines; Once daily dosing according to weight based guidelines
Intervention MeSH terms: Lumefantrine; Artemether; Piperaquine; Trimethoprim; Artemether, Lumefantrine Drug Combination; Artenimol; Trimethoprim, Sulfamethoxazole Drug Combination; Sulfamethoxazole
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Malaria; HIV; Trimethoprim-sulfamethoxazole; Artemether-lumefantrine; Dihydroartemisinin-piperaquine; Acute Infection