aDepartment Paediatrics and Child Health
bProgramme of Biostatistics, Research Ethics and Medical Law, School of Family and Public Health, University of KwaZulu-Natal, Durban, South Africa.
Correspondence to Professor Anna Coutsoudis, PhD, Department Paediatrics and Child Health, University of KwaZulu-Natal, Durban, South Africa. Tel: +27 31 2604489; e-mail: firstname.lastname@example.org
Received 24 June, 2011
Accepted 12 July, 2011
WHO guidelines recommend cotrimoxazole prophylaxis (CTXP) in all HIV-exposed negative infants who are still breastfeeding. This is based on the evidence of efficacy in HIV-infected infants, but there is no evidence of benefit in HIV-negative, breast-fed infants. We assessed the impact of CTXP on diarrhoeal and respiratory morbidity in breast-fed, HIV-exposed negative infants in a community programme. CTXP for more than 60 days showed no consistent evidence of benefit for incidence of lower respiratory tract infection [incidence rate ratio (IRR) 0.71, 95% confidence interval (CI) 0.39–1.26; P = 0.241] but an increased incidence of diarrhoea (IRR = 1.38, 95% CI 0.98–1.94; P = 0.065). The guidelines should be reconsidered by conducting a randomized control trial.
Although evidence exists from a randomized controlled trial (RCT) conducted in Zambia  that cotrimoxazole (CTX) prophylaxis (CTXP) provided to HIV-infected children (1–14 years of age) significantly reduces mortality, there is only limited evidence of any benefit to HIV-exposed, but HIV-negative infants. CTXP was effective in reducing incidence of malaria in HIV-negative children (5–15 years of age) in Mali  and Ugandan HIV-exposed, HIV-negative infants, after breastfeeding cessation. Only the Ugandan study  also examined the impact of CTXP on non-malaria morbidity; they reported no impact on bacterial infections.
Furthermore, despite no study showing efficacy of CTXP in HIV-exposed, breast-fed infants, the WHO guidelines  continue to be followed. Human breast milk has important protective benefits against diarrhoea and pneumonia due to the immune protection provided by breast milk. Furthermore, breast-fed infants have a well developed gastrointestinal barrier and repeated use of antibiotics destroys the normal gut flora allowing colonization with pathogenic bacteria .
As suggested in a recent commentary published in the Bulletin of the WHO , CTXP may not be necessary in HIV-exposed, HIV-negative infants who are already being provided with cover against infection through breast milk. In the light of the above finding and in view of the expected impact on the new 2010 WHO prevention of mother-to-child transmission of HIV guidelines, the authors of this commentary called for a re-examination of the guidelines for CTXP of HIV-exposed, HIV-negative infants. To provide further information for this debate, we interrogated data from our cohort of breast-fed, HIV-exposed, but HIV-negative infants. As not all infants in our programme received CTX for the optimal period, we were able to examine the impact of optimum vs. minimal CTXP to test whether the putated benefit of CTXP does indeed exist for HIV-exposed, but HIV-negative, breast-fed infants.
The mother-to-child transmission (MTCT) Plus programme operated within a municipal clinic in a disadvantaged community in Durban, South Africa. Pregnant mothers attended the general clinic for antenatal care services and those who tested positive were referred to the MTCT Plus programme. The goal of the programme was not only to reduce MTCT, but also to improve child health. Ethical approval for monitoring and evaluation of this programme was obtained from the Biomedical Ethics Research Committee of the University of KwaZulu-Natal (E121/02). We evaluated the impact of CTXP on morbidity in breast-fed infants who were HIV negative at 6 weeks of age.
HIV-exposed infants had PCR testing at 6 weeks of age and were prescribed CTXP according to the WHO guidelines. At each visit (6, 10, and 14, weeks and 6, 9, and 12 months), growth and morbidity data were collected as well as information on whether CTX or any other medication was taken since the last visit. Due to a variety of reasons (which were not documented for each child) such as drug out of stock and failure on the part of the caregiver to collect drug supplies from pharmacy, not all children received CTX optimally. We therefore report morbidity data according to duration of CTXP during the first 12 months of life.
Data were analysed using SPSS, version 15.0 (SPSS Inc., Chicago, Illinois, USA) and Stata version 11 (StataCorp., College Station, Texas, USA). A P-value of less than 0.05 was considered statistically significant. Poisson regression models were used to estimate incidence rate ratios (IRRs) for CTX exposure on diarrhoeal and lower respiratory tract infection (LRTI) morbidity while adjusting for confounding socio-demographic factors in this observational study.
During the period from March 2003 to April 2010, there were 480 breast-fed infants who tested negative for HIV at 6 weeks of age. Of these 480 infants, 244 (50.8%) received CTX for more than 60 days, whereas the remainder for 60 days or less, and the median duration of breastfeeding was 181 days (range 1–365 days).
Controlling for maternal socio-economic factors such as electricity, water, employment, education and CD4 cell count, we determined the IRR for diarrhoeal and LRTI episodes in the first year of life in the infants who received CTX for more than 60 days compared with those who received it for 60 days or less.
Use of CTXP for more than 60 days showed no consistent evidence of benefit for LRTI, although the IRR was lower (0.71) and the confidence intervals (CIs) were wide in both directions (95% CI 0.39–1.26; P = 0.241). Of importance was that use of CTX for more than 60 days was associated with an increased risk of diarrhoea (IRR = 1.38, 95% CI 0.98–1.94; P = 0.065).
This analysis showed no evidence of a consistent benefit on incidence of LRTI and there was a trend for increased risk of diarrhoea. Similar findings were found in retrospective analysis of an earlier South African study . The Ugandan study  in HIV-negative infants of similar ages, but who were not breast-fed, found that although children randomized to receive CTXP had significantly reduced incidence of malaria, there were no differences in terms of diarrhoeal and respiratory infections. Also of note is that, although not powered to detect effect on mortality and hospitalizations, the CTX group experienced higher rates of mortality and hospitalization than the control group (10.2% vs. 5.7%, difference not significant).
Although we realize the limitation of these findings, because this is not a RCT, we believe our findings are important because they highlight the importance of more fully examining whether CTXP to HIV-exposed, breast-fed infants does indeed provide protection against bacterial infections which overshadows the well documented protection provided by breastfeeding. Our findings also suggest that there is a need to determine whether the potential negative factors such as side-effects, health system costs and drug costs  justify the benefit which is now being called into question. We believe the time is right to settle these controversies in a RCT to ensure that we are not using CTXP inappropriately. Such a study is vital in cognisance of the recent WHO World Health Day Call  for renewed attention to appropriate use of antibiotics in order to contain antimicrobial resistance.
We would like to thank the mothers and infants for their participation in the monitoring and evaluation of the MTCT Plus Programme. We would also like to thank the MTCT Plus Programme staff, as well as the staff of Umkhumbane clinic.
A.C. and G.K. devised the study and wrote the manuscript. T.E. did the statistical analysis for the study. All authors read and approved the final manuscript.
Conflicts of interest
The programme and its monitoring and evaluation was funded by grants from the MTCT Plus Initiative (MTCTPCU516760) and the HHS Centres for Disease Control and Prevention (CDC), National Centre for HIV, STD, and TB Prevention (NCHSTP), Global AIDS Program (GAP) Cooperative Agreement [U62/CCU223540-04]. The contents of this research letter are solely the responsibility of the authors and do not necessarily represent the official views of CDC.
There are no conflicts of interest.
1. Chintu C, Bhat GJ, Walker AS, Mulenga V, Sinyinza F, Lishimpi K, et al. for the CHAP trial teamCo-trimoxazole as prophylaxis against opportunistic infections in HIV-infected Zambian children (CHAP): a double-blind randomized placebo-controlled trial. Lancet 2004; 364:1865–1871.
2. Thera MA, Sehdev PS, Coulibaly D, Traore K, Garba MN, Cissoko Y, et al. Impact of trimethoprim-sulfamethoxazole prophylaxis on falciparum malaria infection and disease. J Infect Dis 2005; 192:1823–1829.
3. Sandison TG, Homsy J, Arinaitwe E, Wanzira H, Kakuru A, Bigira V, et al. Protective efficacy of co-trimoxazole prophylaxis against malaria in HIV exposed children in rural Uganda: a randomized clinical trial. BMJ 2011; 342:d1617.
4. WHO/UNAIDS/UNICEF. Joint statement on use of cotrimoxazole as prophylaxis in HIV exposed and HIV infected children. Press statement, WHO, Geneva, 22 November 2004.
5. Walker A. Breast milk as the gold standard for protective nutrients. J Pediatr 2010; 156:S3–S7.
6. Coutsoudis A, Coovadia HM, Kindra G. Time for new recommendations on cotrimoxazole prophylaxis for HIV-exposed infants in developing countries?. Bull World Health Organ 2010; 88:949–950.
7. Coutsoudis A, Pillay K, Spooner E, Coovadia HM, Pembrey L, Newell M-L. Routinely available cotrimoxazole prophylaxis and occurrence of respiratory and diarrhoeal morbidity in infants born to HIV infected mothers in South Africa. S Afr Med J 2005; 95:339–345.
8. Weerasuriya K, Stelling J, O’Brien TF. Containing antimicrobial resistance: a renewed effort. Bull World Health Organ 2010; 88:878doi: 10:2471/BLT.10.084236.
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