Impact of TMP-SMX Prophylaxis on Malaria Infection and Immunity in Children in Uganda
Condition: Malaria
MeSH terms: Malaria
Study type: Observational

Summary: 
      Background:

      - Malaria is a disease that affects many children and adults in Uganda and Africa. If it is
      not treated, it can make some people severely ill. TMP-SMX (Trade names Bactrim, Septrin) is
      a drug that is given to children born to HIV-positive mothers to help prevent infection.
      Studies have shown that TMP-SMX also may kill malaria infection in the very early stages of
      infection in the body, which may positively impact the way the body can fight malaria
      infection. Researchers want to know if giving TMP-SMX for 6 months longer than usual helps
      children fight malaria better in this way.

      Objective:

      - To find out if taking TMP-SMX for longer than usual helps fight off malaria in infants.

      Eligibility:

      - Infants 0-6 weeks of age who are HIV negative.

      Design:

        -  Infants will be screened with a medical history and physical exam. A small amount of
           blood will be taken. The mothers medical records will be reviewed. Mothers will be asked
           about when they breastfeed.

        -  Participants will take TMP-SMX according to their doctor s orders. In Uganda, mothers
           will get a mosquito net with insecticide on it as per standard of care.

        -  Participants will come to the clinic once a month, every month, until the study ends in
           2 3 years. Each visit will repeat the screening visit.

        -  Participants will also visit the clinic every month for a medical history, physical
           exam, and different blood tests.

        -  Six weeks after breastfeeding is stopped, children taking TMP-SMX will come into the
           clinic and will either be taken off the drug or will continue taking the drug for 6 more
           months.

        -  If a child becomes sick, it is important that the mother bring him or her to the RHSP
           clinic in Rakai.
    

Detailed description: 
      Malaria remains one of the most significant causes of morbidity and mortality throughout the
      world. Recent studies indicate that drugs used in HIV management can have antimalarial
      properties. In animal models, prophylactic doses of trimethoprim-sulfamethoxazole (TMPSMX),
      an antibiotic commonly used as prophylaxis against opportunistic infections in HIVexposed and
      HIV-infected patients, have been shown to arrest liver stage development of malaria
      parasites. Indeed, the liver stage of malaria parasites may be important to target since it
      is during this stage that clinical symptoms are absent and fewer parasites are present.
      TMP-SMX, used in HIV-exposed and HIV-infected subjects for opportunistic infection
      prophylaxis, significantly reduces clinical malaria, even in areas of moderate to high
      transmission intensity and high antifolate drug resistance. It is possible that reduction in
      liver stage parasite burden contributes to this unexpected effect. Nonetheless, the
      contribution of this liver-stage parasite killing to the reduction in clinical malaria
      observed in patients receiving TMP-SMX remains undescribed. Our primary objective aims to
      answer whether TMP-SMX reduces liver stage malaria infection.

      For our exploratory objectives, we are interested in TMP-SMX effects on the development of
      anti-infection malaria immunity and effects on transmission. In mice, TMP-SMX prophylaxis
      during repeated malaria exposures has been shown to induce protective, anti-infection
      immunity against malaria (Charlotte Hobbs, unpublished data), which is distinct from
      naturally acquired immunity in which, after multiple infections, patients have less severe
      disease. TMP-SMX impact on the development of malaria-specific immunity, however, requires
      further investigation. Also, TMP-SMX has been shown to have sporonticidal (mosquito-oocyst
      killing) activity at levels achieved in patients on TMP-SMX prophylaxis in susceptible
      strains of P. falciparum, but the effects of TMP-SMX on transmission in the field remain
      undescribed.

      This randomized study plans to enroll 164-220 HIV-uninfected, HIV-exposed (HUE) and 60
      HIV-uninfected, HIV-unexposed (HUU) children in Kalisizo Hospital Health Center, Labor and
      Delivery Unit, Kalisizo, located within Rakai District, Uganda. HUE children will be
      randomized 1:1 into 2 arms. In the first arm (Standard of Care [SOC] arm), 82-110 children
      will receive TMP-SMX until 6 weeks after cessation of breast-feeding (age 12-18 months). In
      the second arm (Extended Prophylaxis [EP] arm), 82-110 children will receive SOC and remain
      on TMP-SMX for an additional 6 months after the cessation of breast-feeding. The 60 HUU
      children will serve as controls to establish baseline infection parameters in the community.
      Blood will be drawn from all subjects monthly via heel/finger stick to analyze malaria
      parasitemia. Additionally, venous blood will be drawn every 6 months to analyze cellular and
      humoral immunity. The duration of this study participation will be a minimum of 2 and up to 3
      years.

      Assessment of TMP-SMX impact on liver stage malaria infection and the development of
      protective anti-infection immunity in children will help guide decisions regarding TMP-SMX
      prophylaxis duration for HIV-exposed children in malaria endemic areas.
    

Observational model: Case-Control
Time perspective: Prospective
Keywords: Parasitemia; HIV-Exposed; HIV-Unexposed; Liver Stage; Randomized