Impact of TMP-SMX Prophylaxis on Malaria Infection and Immunity in Children in Uganda
| Status: | Recruiting |
|---|---|
| Conditions: | Infectious Disease |
| Therapuetic Areas: | Immunology / Infectious Diseases |
| Healthy: | No |
| Age Range: | Any |
| Updated: | 5/5/2014 |
| Start Date: | March 2014 |
| End Date: | March 2019 |
| Contact: | Charlotte V Hobbs, M.D. |
| Email: | hobbsc3@mail.nih.gov |
| Phone: | (301) 402-4236 |
Impact of Trimethoprim-sulfamethoxazole Prophylaxis on Malaria Infection and Immunity in Children in Uganda
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.
- 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.
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.
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.
- INCLUSION CRITERIA:
1. Infant must be 0-6 weeks of age.
2. 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.
3. Parent/legal guardian of HUE subjects must agree to be compliant with
administering the daily prophylactic doses of TMP- SMX according to the schedule
provided by the study team.
4. Mothers must consent to a review of their medical records and a monthly
assessment of breast-feeding status.
5. Mother/guardian must live within 15 km of the Kaliziso District Hospital.
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. Other condition that in the opinion of the investigator would jeopardize the safety
or rights of a subject participating in the study or would render the subject unable
to comply with the protocol.
3. Other than the study described above in Subject Recruitment and Enrollment (Study
#13-I-N074), study subjects should not participate in a malaria vaccine study or have
a history of involvement in such a study.
4. Contraindication to TMP-SMX (HUE subjects only) that in the judgment of the
investigator contraindicates participation in this study including:
1. Documented megaloblastic anemia due to folate deficiency.
2. Hyperbilirubinemia
3. Marked hepatic damage
4. Renal insufficiency
We found this trial at
1
site
Bethesda, Maryland 20892
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