Mulenga V, Ford D, Walker AS, Mwenya D, Mwansa J, Sinyinza F, Lishimpi K, Nunn A, Gillespie S, Zumla A, Chintu C, Gibb DM; CHAP Trial Team. Effect of Cotrimoxazole on Causes of Death, Hospital Admissions and Antibiotic Use in HIV-Infected Children. AIDS. 2007 Jan 2;21(1):77-84.
To compare the causes of mortality, hospital admissions, and antibiotic use among HIV-infected children randomized to either cotrimoxazole prophylaxis or placebo.
This study was a randomized placebo-controlled single-center trial; randomization occurred between March 2001 and January 2003. The trial was stopped in October 2003 after a median follow-up of 19 months due to substantial and statistically significant reduction in mortality in the cotrimoxazole group. This article reports on the causes of death, hospital admissions not ending in death, and antibiotic use among HIV-infected children participating in the CHAP trial. Details of the design and main results of the CHAP trial have been published elsewhere.(1)
An urban teaching hospital in Lusaka, Zambia.
A total of 534 HIV-infected children were randomized to receive cotrimoxazole prophylaxis or matching placebo. The median age of the children included in this study was 4.4 years, with 36% under 2 years, 28% 2-5 years, 21% 6-9 years and 15% 10 years or older. Underlying malnutrition was prevalent in this group of children. At baseline, median CD4 cell counts, as expressed as percentage of total lymphocyte counts, were similar between the cotrimoxazole and placebo groups (11% vs. 10%).(1)
CHAP compared cotrimoxazole prophylaxis with placebo in HIV-infected children in Zambia, where background bacterial resistance to cotrimoxazole is high. Most children (84%) were treated with short-term antibiotics for infections at some time during the trial. Fourteen children (5%) on cotrimoxazole and 11 (4%) on placebo received antiretroviral therapy at some stage during the trial.(1)
The primary outcomes investigated in this analysis included incidence of death, causes of death, days in hospital, frequency of hospital admissions not ending in death, diagnosis at hospital admission, and antibiotic use. Where a child died in the hospital, causes of death were assigned by the treating pediatrician, or if the child died before seeing a pediatrician, by trial clinical officers, based on information from hospital notes and nursing staff. Subsequently, all hospital deaths were reviewed and a primary cause of death assigned by two pediatricians, blind to assignment to cotrimoxazole or placebo, who had access to case report forms, death certificates, hospital notes, post-mortem findings and laboratory data.
Overall, 74 (28%) children died in the cotrimoxazole group and 112 (42%) died in the placebo group [hazard ratio (HR) 0.57; 95% confidence interval (CI) 0.43-0.7]. As reported previously, mortality was reduced across all ages (heterogeneity p=0.82) and across levels of baseline CD4 cell percentage (p=0.36).(1) Ninety-one children died in the hospital, 92 at home, two on the way to hospital, and one in a local clinic. Children receiving cotrimoxazole had similar reductions in the instantaneous risk of hospital death [cause-specific hazard ratio (CHR) 0.55; 95% CI, 0.36–0.84] and non-hospital death (CHR 0.60; 95% CI, 0.40–0.90) compared with the placebo group. There were 368 hospital admissions in total, of which 91 were admissions prior to death in hospital. Of the remaining 277 admissions in 166 children, 135 admissions were among 76 children on cotrimoxazole and 142 were among 90 children on placebo. The rate of hospital admissions not ending in death was 41 per 100 child-years at risk in the cotrimoxazole group and 53 in the placebo group [incidence rate ratio (IRR) 0.78; 95% CI, 0.55–1.10; p=0.16]. The number of days spent in-hospital was higher in the placebo group (1043 days) than in the cotrimoxazole group (881 days; p=0.03), but individual lengths of hospital stay were similar. Serious bacterial infections--predominantly pneumonia--were the leading designated cause of death (45/91), followed by diarrhea (12/91) and malnutrition (7/91). The largest difference in causes of hospital death between randomized groups was pneumonia or emphysema (mostly diagnosed presumptively), accounting for 10 (29%) of 35 hospital deaths in children on cotrimoxazole compared with 22 (39%) of 56 hospital deaths on placebo (p=0.37). By two years, the cumulative probability of dying in hospital from a serious bacterial infection was 7% in the cotrimoxazole group and 12% in the placebo group (p=0.08, adjusted for competing risks due to other causes of death). Corresponding probabilities for hospital death due to other primary causes were 8 and 13% (p=0.12); and 18 and 26% for death outside the hospital (p=0.04). By two years, the cumulative probability of first admission to or death in hospital with serious bacterial infections was 15% in the cotrimoxazole group and 25% in the placebo group (p=0.05). There was no evidence that mortality reductions in the cotrimoxazole group varied by cause (serious bacterial infections versus other) or place of death. Despite less total follow-up due to higher mortality, more antibiotics, particularly penicillin, were prescribed in the placebo group in year one [6083 compared to 4972 days in the cotrimoxazole groups (p=0.05)].
The authors concluded that cotrimoxazole prophylaxis appears to mainly reduce death and hospital admissions from respiratory infections, supported by lower rates of antibiotic prescribing. The authors further concluded that, as such infections occur at high CD4 cell counts and are common in Africa, the role of continuing cotrimoxazole prophylaxis after starting antiretroviral therapy requires further investigation.
Using the Jadad criteria for rating randomized controlled trials, this study received a quality rating of 5 out of a possible 5 points. One point was received for describing the randomization, one for adequate randomization, one for double-blinding, one for appropriate blinding, and one for description of loss to follow-up.
Overall, results from this analysis confirm the authors' original conclusion that cotrimoxazole appears to primarily reduce death and hospitalization from lower respiratory tract infections.(1) Further evidence of the protective effect of cotrimoxazole prophylaxis against bacterial disease was observed in this study, in that antibiotic use, particularly penicillin, was reduced in children receiving cotrimoxazole despite their longer survival. The results of this analysis are supported by three studies that reported the efficacy of cotrimoxazole in adults (in Malawi, Côte d'Ivoire and Uganda) despite high background levels of resistance.(2,3,4)
Findings of this analysis suggest that there is a significant role for continuing cotrimoxazole prophylaxis alongside antiretroviral therapy as recommended for children under five years of age in the recently updated WHO guidelines.(5)
- Chintu C, Bhat GJ, Walker AS, et al. Cotrimoxazole as prophylaxis against opportunistic infections in HIV-infected Zambian children (CHAP); a double blinded randomized placebo-controlled trial. Lancet 2004 Nov 20-26;364(9448):1865-71.
- Anglaret X, et al. Pattern of bacteria resistance in a cohort of HIV-1-infected adults receiving cotrimoxazole prophylaxis in Abidjan, Côte d'Ivoire. AIDS 2003;17:575-84.
- van Oosterhout JJ, Laufer MK, Graham SM, et al. A community based study of the incidence of trimethoprim-sulfamethoxazole-preventable infections in Malawian adults living with HIV. J Acquir Immune Defic Syndr 2005 Aug 15;39(5):626-31.
- Mermin J, Lule J, Ekwaru JP, et al. Effect of co-trimoxazole prophylaxis on morbidity, mortality, CD4-cell count, and viral load in HIV infection in rural Uganda. Lancet 2004; 364:1428-34.
- World Health Organization. Guidelines on co-trimoxazole prophylaxis for HIV-related infections among children, adolescents and adults in resource-limited settings. WHO, 2006. [PDF, 1.1MB]