Study to Improve Survival Among HIV-Exposed Infants in Botswana

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to find ways to improve infant health and survival among infants whose mothers are HIV-infected but who do not themselves have HIV.

Detailed Description
-----------------
As improved MTCT prevention interventions reduce the number of HIV-infected infants in the antepartum and peripartum periods, interventions to improve HIV-free survival among HIV-uninfected infants are needed. Morbidity and mortality are increased among HIV-uninfected infants born to HIV-infected mothers, and reduced infant survival among HIV-exposed infants may lead to as many deaths as HIV infection itself. In Botswana, the use of formula feeding or shorter breastfeeding may worsen the problem of early infant mortality among HIV-exposed infants. The study will enroll pregnant or postpartum HIV-1-infected women, and their HIV-uninfected infants in Botswana. At 2-4 weeks of age, live HIV-uninfected infants will be randomized to receive either double-blinded cotrimoxazole (CTX) or placebo from 2-4 weeks through 15 months. In addition, breastfeeding (BF) infants will be randomized to BF until either 6 or 12 months of age. Children will be followed prospectively until 18 months of age. The primary endpoint will be survival at 18 months comparing all infants in the CTX vs. placebo arms, and by randomized duration of BF among those BF at randomization. Secondary endpoints will evaluate survival and morbidity/mortality at 12 and 15 months; HIV-free survival to 18 months; and the safety of CTX prophylaxis. Secondary observational objectives include comparing MTCT and mortality by initial feeding method (formula feeding or any BF > 1 month), and an analysis of maternal characteristics as predictors for initial feeding choice and HIV-free survival. All women and infants will receive standard antenatal and peripartum prophylaxis from the Botswana government for MTCT prevention (PMTCT), and will choose a feeding method with counseling. Breastfeeding infants will receive infant nevirapine (NVP) prophylaxis or will be protected from MTCT by the use of maternal HAART.

Official Title
-----------------
A Randomized Study of Cotrimoxazole Prophylaxis and Longer Breastfeeding Duration to Improve Survival Among HIV-Exposed Infants in Botswana

Conditions
-----------------
HIV Infections, Neutropenia, Anemia

Intervention / Treatment
-----------------
* Drug: cotrimoxazole prophylaxis
* Drug: cotrimoxazole placebo
* Behavioral: exclusive breastfeeding until 6 months of age
* Behavioral: breastfeeding for 12 months


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: HIV-infected women, > 26 weeks gestation and < 34 days postpartum. Women must be ¬> 18 years of age and willing/able to sign informed consent. Women and infants must be able to follow up regularly at a study clinic through 18 months postpartum. For Feeding Randomization Only: Women must be willing to breastfeed for up to 12 months, and to stop at 6 months, depending upon their feeding assignment. Exclusion Criteria: Antepartum women: Known infant anomalies resulting in a high probability that the infant will not survive to 18 months. Postpartum women: Known HIV-infected infant, or infant medical condition making survival to 18 months unlikely.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: infant cotrimoxazole<br> | Drug: cotrimoxazole prophylaxis<br>* 100mg/20mg per day (or 2.5 mL of syrup from a 200mg/40mg per 5mL suspension) from 1-6 months, followed by 200mg/40mg per day (or 5 mL of syrup from a 200mg/40mg per 5 mL suspension) from 6 to 12 months<br>* Other names: Trimethoprim-Sulfamethoxazole Combination;|
| Placebo Comparator: infant placebo<br> | Drug: cotrimoxazole placebo<br>* 100mg/20mg per day (or 2.5 mL of syrup from a 200mg/40mg per 5mL suspension) from 1-6 months, followed by 200mg/40mg per day (or 5 mL of syrup from a 200mg/40mg per 5 mL suspension) from 6 to 12 months<br>|
| Active Comparator: exclusive breastfeeding for 6 months<br> | Behavioral: exclusive breastfeeding until 6 months of age<br>* Breastfeeding for 6 months, followed by formula feeding for 6 month. Breastfeeding infants will be prophylaxed with maternal highly active antiretroviral therapy (HAART) (if available) or with infant nevirapine.<br>|
| Active Comparator: exclusive breastfeeding for 12 months<br> | Behavioral: breastfeeding for 12 months<br>* Breastfeeding infants will be prophylaxed with maternal HAART (if available) or with infant nevirapine.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival | The primary outcome measure is survival at 18 months comparing all infants in the CTX vs. placebo arms, and by randomized duration of breastfeeding among those breastfeeding at randomization. | 18 months of age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HIV-free Survival | Secondary outcome measures will evaluate HIV-free survival between 4 weeks and 18 months among infants randomized to either 6 months or 12 months of breastfeeding. | 18 months of age | 
| Safety of CTX prophylaxis | Secondary outcome measures will evaluate the safety of CTX prophylaxis through 18 months | 18 months | 
| Morbidity and mortality | Secondary outcome measures will evaluate morbidity and mortality to 18 months. | 18 months of age | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HIV, Trimethoprim-Sulfamethoxazole Combination, Breast Feeding, Infant Mortality, Morbidity, Botswana, Africa, Infectious disease transmission, vertical, adverse drug event