Impact of TMP-SMX Prophylaxis on Malaria Infection and Immunity in Children in Uganda
Information source: National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Malaria
Phase: N/A
Status: Not yet recruiting
Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID) Official(s) and/or principal investigator(s): Steven J Reynolds, M.D., Principal Investigator, Affiliation: National Institute of Allergy and Infectious Diseases (NIAID)
Overall contact: Charlotte V Hobbs, M.D., Phone: (301) 402-4236, Email: hobbsc3@mail.nih.gov
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.
Clinical Details
Official title: Impact of Trimethoprim-sulfamethoxazole Prophylaxis on Malaria Infection and Immunity in Children in Uganda
Study design: Time Perspective: Prospective
Primary outcome: Malaria incidence rate (number of new malaria parasitemia episodes per time at risk) in HUE children on TMP-SMX prophylaxis compared to HUU children (not on TMP-SMX prophylaxis) between enrollment and study end. A malaria parasitemia episode is ...
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.
Eligibility
Minimum age: 2 Months.
Maximum age: 6 Months.
Gender(s): Both.
Criteria:
- INCLUSION CRITERIA:
1. Infant must be born during the period beginning May 1, 2014 and ending November
30, 2014.
2. Mothers of HUE subjects must be giving their child TMP-SMX prophylaxis at
screening (this does not apply to HUU subjects).
3. Mothers must be breastfeeding their child at screening.
4. Parent/legal guardian must be able and willing to provide signed informed
consent on behalf of the child subject, agree to bring the child to the study
site for visits, and seek medical care for intercurrent illness for the child
subject at the study site.
5. Parent/legal guardian of HUE subjects must agree to be compliant with
administering the daily prophylactic doses of TMP-SMX according to the standard
guidelines.
6. Mothers must consent to a review of their medical records and a monthly
assessment of breastfeeding status.
7. Mother/guardian must live within the Rakai District.
EXCLUSION CRITERIA:
1. Child has a diagnosis of HIV-infection or clinical or laboratory evidence of other
chronic infection or disease (including renal or hepatic insufficiency).
2. Clinical determination of conditions that would exclude the child
based on record review, history, and examination.
3. Participation in a malaria vaccine study or have a history of
involvement in such a study.
Locations and Contacts
Charlotte V Hobbs, M.D., Phone: (301) 402-4236, Email: hobbsc3@mail.nih.gov
Rakai Health Sciences Program Uganda Virus Research Institute, Kalisizo, Uganda; Not yet recruiting Charlotte Hobbs, M.D., Phone: (301) 402-4236, Email: hobbsc3@mail.nih.gov
Additional Information
Related publications: Mutanga JN, Raymond J, Towle MS, Mutembo S, Fubisha RC, Lule F, Muhe L. Institutionalizing provider-initiated HIV testing and counselling for children: an observational case study from Zambia. PLoS One. 2012;7(4):e29656. doi: 10.1371/journal.pone.0029656. Epub 2012 Apr 20. Erratum in: PLoS One. 2012;7(5): doi/10.1371/annotation/808bf191-73bc-4b7f-a0c3-7bbf18833a21. Flateau C, Le Loup G, Pialoux G. Consequences of HIV infection on malaria and therapeutic implications: a systematic review. Lancet Infect Dis. 2011 Jul;11(7):541-56. doi: 10.1016/S1473-3099(11)70031-7. Review. Hobbs CV, Voza T, Coppi A, Kirmse B, Marsh K, Borkowsky W, Sinnis P. HIV protease inhibitors inhibit the development of preerythrocytic-stage plasmodium parasites. J Infect Dis. 2009 Jan 1;199(1):134-41. doi: 10.1086/594369.
Starting date: March 2014
Last updated: July 25, 2015
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