HIV/AIDS • CID 2007:44 (15 May) • 1361
H I V / A I D SM A J O R A R T I C L E
The Impact of Daily Cotrimoxazole Prophylaxis and
Antiretroviral Therapy on Mortality and Hospital
Admissions in HIV-Infected Zambian Children
A. Sarah Walker,1Veronica Mulenga,2Deborah Ford,1Desire Kabamba,2Frederick Sinyinza,2Chipepo Kankasa,2
Chifumbe Chintu,2Diana M. Gibb,1and the CHAP Team
1MRC Clinical Trials Unit, London, United Kingdom; and
2University Teaching Hospital, Lusaka, Zambia
(ART) in human immunodeficiency virus (HIV)–infected African children are few.
A total of 534 Zambian children with HIV infection were randomized to receive daily cotrimoxazole
prophylaxis or placebo in the Children with HIV Antibiotic Prophylaxis trial. Following trial closure, children who
receivedthe placebo initiatedcotrimoxazoleprophylaxis,andallchildrenwereobservedinaclosedcohort.Mortality
and hospital admission rates were compared, over calendar time, in 9-month periods: trial recruitment (March
2001 to April 2002, May 2002 to January 2003), trial follow-up to closure (February 2003 to October 2003), initial
follow-up posttrial (November 2003 to July 2004), and early and later ART availability (August 2004 to April
2005, and May 2005 to May 2006, respectively).
A total of 546 child-years of follow-up, 40 deaths, and 80 hospital admissions were observed between
the time of trial closure and June 2006. A total of 117 of 283 children who were alive at trial closure received
ART in the posttrial period (median child age at first use of ART, 8.8 years). Rates decreased in both groups during
the trial period, suggesting a survivorship effect. Mortality and hospital admission rates before trial closure were
14 (95% confidence interval [CI], 9–21) deaths per 100 child-years and 24 (95% CI, 15–39) hospital admissions
per 100 child-years, respectively, for children who were receiving cotrimoxazole, and were 23 (95% CI, 16–34)
deaths per 100 child-years and 35 (95% CI, 23–53) hospital admissions per 100 child-years, respectively, for
children who were receiving the placebo. After trial closure, rates remained stable in the cotrimoxazole group, but
decreased to 15 (95% CI, 8–26) deaths per 100 child-years and 19 (95% CI, 10–41) hospital admissions per 100
child-years, respectively, for the group of children who received placebo and then initiated cotrimoxazole pro-
phylaxis. In both groups combined, mortality rates decreased to 6 (95% CI, 3–11) deaths per 100 child-years and
then 2 (95% CI, 0.8–6) deaths per 100 child-years during periods of ART availability; hospital admission rates
decreased to 17 (95% CI, 11–27) hospital admissions per 100 child-years and 8 (95% CI, 4–15) hospital admissions
per 100 child-years, respectively.
The benefits of once-daily cotrimoxazole prophylaxis continued throughout the trial and after
trial closure. Mortality and hospital admissions decreased (by ∼6-fold and ∼3-fold, respectively) following ART
availability, similar to findings observed in resource-rich countries.
Data on the population effectiveness of cotrimoxazole prophylaxis and antiretroviral therapy
The past 5 years have seen a major shift in the man-
agement of HIV infection in resource-limitedcountries
with the introduction of cotrimoxazole prophylaxis
and, more recently, antiretroviral therapy (ART). Two
Received 2 November 2006; accepted 26 January 2007; electronically published
12 April 2007.
Reprints or correspondence: Dr. A. Sarah Walker, Medical Research Council
Clinical Trials Unit, 222 Euston Rd., London NW1 2DA, United Kingdom
Clinical Infectious Diseases2007;44:1361–7
? 2007 by the Infectious Diseases Society of America. All rights reserved.
questions exist: whether benefits observed at the pop-
ulation level are similar to those observed in resource-
rich countries and whether benefits observed in chil-
dreninresource-limited countries match those
observed in adults. Reductions in mortality of ∼5-fold
have been described following the introduction of 3-
or 4-drug ART regimens in HIV-infected children in
resource-rich countries, similar to observations made
in adults [1, 2]. However, even in resource-rich coun-
tries, ART was introduced later for children because of
difficulties developing appropriate formulations and
the lack of age-specific pharmacokinetic data to guide
pediatric dosing. In African countries, the issues of
by guest on February 2, 2016
HIV/AIDS • CID 2007:44 (15 May) • 1367
1. Gibb DM, Duong T, Tookey PA, et al. Decline in mortality, AIDS and
hospital admissions in perinatally HIV-1 infected children in the UK
and Ireland. BMJ 2003;327:1019–25. Available at: http://www
.chipscohort.ac.uk. Accessed 30 March 2007.
2. Gortmaker SL, Hughes M, Cervia J, et al. Effect ofcombinationtherapy
including protease inhibitors on mortality among children and ado-
lescents infected with HIV-1. N Engl J Med 2001;345:1522–8.
3. Ellis JC, L’homme RFA, Ewings FM, et al. Nevirapine concentrations
in HIV-infected children treated with divided fixed dose combination
antiretroviral tablets in Malawi and Zambia. Antivir Ther 2007;12:
4. Chintu C, Bhat GJ, Walker AS, et al. Cotrimoxazole as prophylaxis
against opportunistic infections in HIV-infected Zambian children
(CHAP): a double-blind randomized placebo-controlled trial. Lancet
5. World Health Organization. Antiretroviral therapy of HIV infection in
infants and children in resource-limited settings, towards universal
access: recommendations for a public health approach (2003revision).
Geneva: World Health Organization, 2003.
6. Cole TJ, Freeman JV, Preece MA. British 1990 growthreferencecentiles
for weight, height, body mass index and head circumference fitted by
maximum penalized likelihood. Stat Med 1998;17:407–29.
7. Mulenga V, Ford D, Walker AS, et al. Effect of cotrimoxazole on causes
of death, hospital admissions and antibiotic use in HIV-infected chil-
dren. AIDS 2007;21:77–84.
8. Newell ML, Coovadia H, Cortina-Borja M, et al. Mortality of infected
and uninfected infants born to HIV-infected mothers in Africa: a
pooled analysis. Lancet 2004;364:1236–43.
9. Walker AS, Mulenga V, Sinyinza F, et al. Determinants of survival
without antiretroviral therapy after infancy in HIV-1-infectedZambian
children in the CHAP trial. JAIDS 2006;42:637–45.
10. Mbewe M, Bolton C, Levy J, et al. Children enrolled in a public HIV
care and treatment program in Lusaka, Zambia: rapid scale-up and
first-year outcomes [oral abstract MOAB0201]. In: Program and ab-
stracts of the 16th International AIDS Conference (Toronto). Geneva:
International AIDS Society, 2006.
11. O’ Brien DP, Sauvageot D, Zachariah R, HumbletP.Inresource-limited
settings good early outcomes can be achieved in children using adult
fixed-dose combination antiretroviral therapy. Medecins Sans Fronti-
eres. AIDS 2006;20:1955–60.
12. Paediatric European Network for Treatment of AIDS (PENTA). Com-
parison of dualnucleoside-analoguereverse-transcriptaseinhibitorreg-
imens with and without nelfinavir in children with HIV-1 who have
not previously been treated: the PENTA 5 randomised trial. Lancet
13. Walker AS, Doerholt K, Sharland M, Gibb DM. Response to highly
active antiretroviral therapy varies with age: the UK and Ireland Col-
laborative HIV Paediatric Study. AIDS 2004;18:1915–24.
14. Resino S, Resino R, Micheloud D, et al. Long-term effects of highly
active antiretroviral therapy in pretreated, vertically HIV type 1–in-
fected children: 6 years of follow-up. Clin Infect Dis 2006;42:862–9.
15. Tarwater PM, Mellors J, Gore ME, et al. Methods to assess population
effectiveness of therapies in human immunodeficiency virus incident
and prevalent cohorts. Am J Epidemiol 2001;154:675–81.
16. Miettinen OS. The need for randomization in the study of intended
effects. Stat Med 1983;2:267–71.
17. World Health Organisation. Guidelines on co-trimoxazoleprophylaxis
for HIV-related infections among children, adolescents and adults:rec-
ommendations for a public health approach. Geneva: World
Health Organization, 2006. Available at: http://www.who.int/hiv/pub/
guidelines/ctx/en/index.html. Accessed 30 March 2007.
by guest on February 2, 2016