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The impact of daily cotrimoxazole prophylaxis and antiretroviral therapy on mortality and hospital admissions in HIV-infected Zambian children.
Global Health Sciences Literature Digest
Published June 4, 2007
Journal Article

Walker AS, Mulenga V, Ford D, Kabamba D, Sinyinza F, Kankasa C, Chintu C, Gibb DM; CHAP Team.The impact of daily cotrimoxazole prophylaxis and antiretroviral therapy on mortality and hospital admissions in HIV-infected Zambian children. Clin Infect Dis 2007 May 15;44(10):1361-7.

Objective

To assess mortality and hospital admission rates among perinatally HIV-infected children following the introduction of daily cotrimoxazole prophylaxis and initiation of ART, in Lusaka, Zambia.

Study Design

Prospective three-year closed cohort study of children who had been enrolled and completed a randomized trial of daily cotrimoxazole versus placebo.

Setting

University Teaching Hospital, Lusaka, Zambia.

Study Design

Prospective three-year closed cohort study of children who had been enrolled and completed a randomized trial of daily cotrimoxazole versus placebo.

Setting

University Teaching Hospital, Lusaka, Zambia.

Participants

Five hundred thirty-four children, aged 1-14 years old, were recruited into the Children with HIV Antibiotic Prophylaxis (CHAP) trial from pediatric outpatient clinics at the University Teaching Hospital in Lusaka over a two-year period (2001-2003). The 283 children who were still alive when the CHAP trial ended in 2003 were followed for an additional three years. Follow-up data were available on 163 children in the original cotrimoxazole group and 120 children in the placebo group. The median age of children alive during the last trial period was 5.4 yrs in the cotrimoxazole group, and 5.9 years in the placebo group; during the last ART period, the median age was 7.9 years.

Intervention

In the original CHAP trial, children were randomized to receive either daily cotrimoxazole as prophylaxis (n=265) or placebo (n=269). Following trial closure in 2003, children who had previously received placebo were started on cotrimoxazole prophylaxis, and all children were then observed in a closed cohort. From August 2004-May 2005, ART was provided to the children with the most severe illness, after which ART was more widely available to those who met WHO criteria. A total of 117 of the 283 children alive at trial closure received ART in the post-trial period.

Primary Outcomes

Mortality and hospital admission rates were compared across randomized groups over time, censored upon death, loss to follow-up, or when the child stopped attending the clinic. Mortality and hospital admission rates were compared over nine-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 post-trial (November 2003 to July 2004), and early and later ART availability (August 2004 to April 2005, and May 2005 to May 2006, respectively).

Results

Original CHAP trial: Before trial closure, mortality rates were 14 per 100 child-years (p100py) (95% CI, 9 – 21), and 24 hospital admissions p100py (95% CI, 15-39) among those receiving cotrimoxazole, and 23 deaths p100py (95% CI 16-34) and 35 admissions p100py (95% CI, 23-53) in the placebo group.

Follow-up post-CHAP trial: After trial closure, mortality rates remained stable in children previously randomized to cotrimoxazole in CHAP. Among those who received placebo and then initiated cotrimoxazole, mortality decreased to 15 (95% CI, 8–26) deaths p100py and 19 (95% CI, 10–41) hospital admissions p100py. During periods of ART availability, mortality rates among both groups combined decreased to six (95% CI, 3–11) p100py (early ART) and then two (95% CI, 0.8–6) p100py (later ART). Hospital admission rates also decreased during ART to 17 (95% CI, 11–27) p100py and eight (95% CI, 4–15) p100py, respectively.

Conclusions

The authors state that the decrease in mortality over time in this cohort can largely be attributed to survivorship bias, meaning that the sickest children died earliest in the trial, leaving the healthier survivors available to take ART. Nevertheless, the benefits of once-daily cotrimoxazole prophylaxis continued throughout the trial and for the three years following trial closure. Mortality and hospital admissions decreased by six-fold and three-fold following ART, a result similar to findings in resource-rich countries.

Quality Rating

Based on the Newcastle-Ottawa rating system for observational cohorts, this study was of good quality. There were a few limitations. It was assumed that comparisons within the cohort could be made across different time periods, but it is possible that improvements in clinical care other than the introduction of cotrimoxazole prophylaxis and ART could be partly responsible for the observed decrease in mortality and hospital admissions.

In Context

Like many recent reports from Africa on results of ART initiation in children,(1, 2) this study found that when ART became available, most deaths occurred early after initiation of ART and among children with the most marked immunosuppression. In this study, introduction of ART was associated with decreases in mortality and hospital admission rates similar to decreases observed in resource-rich countries: a three-fold decrease in this study compared to a five-fold decrease reported in a pediatric cohort in the United Kingdom and Ireland. (3)In both these studies, reductions in hospital admissions rates occurred slightly later than reductions in mortality rates.

Programmatic Implications

This study provides information on the natural history of HIV infection in older children in southern Africa.(4 These data are relevant, as pediatric HIV infection may be first diagnosed when children present with symptoms to medical facilities. Cotrimoxazole prophylaxis is an important intervention to institute in eligible children, whether or not ART is available, and it may have longer term protective effects. Because many pediatric wards in African hospitals are overburdened with HIV-infected children, the reduction in hospital admissions among those taking cotrimoxazole may have important cost implications.

References

  1. 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]. Program and abstracts of the 16th International AIDS Conference (Toronto). Geneva: International AIDS Society, 2006. (No abstract available.)
  2. O'Brien DP, Sauvageot D, Zachariah R, Humblet P; Médecins Sans Frontières. In resource-limited settings good early outcomes can be achieved in children using adult fixed-dose combination antiretroviral therapy. AIDS 2006 Oct 3;20(15):1955-60.
  3. Gibb DM, Duong T, Tookey PA, Sharland M, Tudor-Williams G, Novelli V, et al. Decline in mortality, AIDS, and hospital admissions in perinatally HIV-1 infected children in the United Kingdom and Ireland. BMJ 2003 Nov 1;327(7422):1019.
  4. Walker AS, Mulenga V, Sinyinza F, Lishimpi K, Nunn A, Chintu C, et al. Determinants of survival without antiretroviral therapy after infancy in HIV-1-infected Zambian children in the CHAP Trial. J Acquir Immune Defic Syndr 2006 Aug 15;42(5):637-45.