Table 1.

Summary of studies in HEU infants investigating the effect of CTX prophylaxis on general morbidity

Country (years)	Sample size and study population	Type of study	CTX outcomes
Uganda (2007–2008)33	185 HIV-exposed, uninfected infants who have received CTX prophylaxis while breastfeeding	Non-blinded RCT to evaluate the protective efficacy of CTX prophylaxis against malaria in HIV-exposed children. All children who remained HIV uninfected (n=185) after breastfeeding cessation were then randomised to stop CTX prophylaxis immediately or continue CTX until 2 years old.	CTX prophylaxis yielded a 39% reduction in malaria incidence, after adjustment for age at randomisation (incidence rate ratio 0.61 (95% CI 0.46 to 0.81), p=0.001). There were no significant differences in the incidence of complicated malaria, diarrhoea, pneumonia, hospitalisations or deaths between the two treatment arms.
Malawi (2004–2010)37	1522 Infants born to HIV-infected mothers as part of the BAN study	RCT evaluating the effect of a maternal nutritional supplement in addition to a three-group antiretroviral intervention (triple-drug antiretroviral regimen for the mother (maternal-regimen group), daily dose of NVP for the infant (infant-regimen group) or neither (control antiretroviral group)).	Secondary analysis: a significant decrease in malaria with CTX; no significant difference in diarrhoea, pneumonia or severe illness/death.
Malawi (2004–2010)38	2250 infants born to HIV-infected mothers as part of the BAN study	A later analysis of data from the BAN study above included more infants. All 2250 infants who had information on the outcomes of interest. Additionally, all outcomes were examined separately with all such events contributing through conditional gap time models—provided a more accurate analysis.	Secondary analysis: infant CTX significantly decreased morbidity, namely malaria (HR 0.33); diarrhoea (HR 0.64) and pneumonia (HR 0.8).
Malawi (2004–2009)34	1543 infants born to HIV-positive mothers	PEPI-Malawi study was a randomised clinical trial to assess efficacy of extended infant antiretroviral prophylaxis to reduce postnatal HIV transmission. All received CTX prophylaxis.	Secondary analysis: lower risk of illness and/or hospital admission with CTX (OR 0.56 at 6–9 months; OR 0.65 at 9–12 months and OR 0.77 at 12–15 months).
South Africa (2003–2010)31	480 breastfed infants who tested negative for HIV at 6 weeks of age.	Assessed the impact of CTX on diarrhoeal and respiratory morbidity in breastfed, HIV-exposed-negative infants in a community. CTX was received by 50.8% of infants for >60 days, whereas the remainder for 60 days or less, and the median duration of breastfeeding was 181 days.	Use of CTX for >60 days showed no consistent evidence of benefit for LRTI, although the incidence rate ration (IRR) was lower (0.71) and the CIs were wide in both directions (95% CI 0.39 to 1.26; p=0.241). Use of CTX for >60 days was associated with an increased risk of diarrhoea (IRR=1.38, 95% CI 0.98 to 1.94; p=0.065).
South Africa32	363 infants (HIV infected and uninfected) born to HIV-positive mothers	Prospective observational cohort study.	HIV-infected infants who received CTX had significantly lower incidence of LRTI (82%); but effect not seen in HEU infants. In HIV-infected and uninfected infants, there was a non-significant increased risk for diarrhoea in those who received CTX: in infected OR=1.58, p=0.45 and in uninfected infants OR=1.52, p=0.10.
Uganda (1997–2001) HIVNET012 (2004–2007) HIVIGLOB/NVP36	HIVNET012—623 HIV-exposed infants, breastfeeding for at least 6 months with no CTX prophylaxis HIVIGLOB/NVP—684 HIV-exposed infants breastfeeding for 3–6 months with abrupt weaning and receiving CTX prophylaxis	Two separate RCTs to assess the effect of NVP regimens on PMTCT.	Overall rates of serious gastroenteritis events were highest in the HIVIGLOB/NVP study with CTX at 8.0 events per 1000 child-months (95% CI 6.4 to 9.8), whereas in the HIVNET012 group with no CTX there were 3.1 events per 1000 child-months (95% CI 2.1 to 4.4) which was statistically significant (p<0.001).

BAN, Breastfeeding, Antiretrovirals and Nutrition; CTX, cotrimoxazole; HEU, HIV-exposed uninfected; LRTI, lower respiratory tract infections; NVP, Nevirapine; PMTCT, prevention of mother-to-child transmission; RCT, randomised control trial.