AIDS and Behavior

, Volume 13, Issue 1, pp 33–41 | Cite as

Adherence to Both Cotrimoxazole and Placebo is Associated with Improved Survival Among HIV-Infected Zambian Children

  • A. Sarah Walker
  • Deborah Ford
  • Veronica Mulenga
  • Margaret J. Thomason
  • Andrew Nunn
  • Chifumbe Chintu
  • Diana M. Gibb
  • David R. Bangsberg
Original Paper


In the CHAP randomized placebo-controlled trial of cotrimoxazole prophylaxis in HIV-infected Zambian children conducted between 2001 and 2003, cotrimoxazole was associated with significant mortality reductions. In a secondary analysis we used Cox regression models to estimate the association between adherence measured by bottle weights and caregiver report and subsequent mortality in children surviving >28 days (n = 496, 153 deaths). Adherence was high and similar in both cotrimoxazole and placebo groups; adherence from bottle weights was 100% at 71% of visits, while caregivers reported 100% adherence at 79% of visits. Every 10% lower adherence to cotrimoxazole or placebo measured by bottle weights was associated with a 10–11% increase in mortality risk. Effects remained after adjustment for baseline predictors of survival and for current and recent change in primary caregiver. Caregiver-reported adherence was not associated with survival. The association between bottle-weight adherence to placebo and survival is likely capturing unmeasured caregiver effects, whose identification will be essential for quantifying the impact of antiretroviral therapy (ART) adherence on clinical outcomes in children.


HIV Africa Adherence Cotrimoxazole 



We would like to thank the families and children enrolled in the CHAP trial. We also acknowledge Laura Farrelly, Nicola Kaganson and Patrick Phillips who organised adherence measurements in the trial and carried out initial exploratory analyses.

Sources of Support

The CHAP trial was funded by the Department for International Development, UK.

Cotrimoxazole and matching placebo suspension were provided by Interchem Ltd, Lusaka, and quality was tested at the Quality Control North West, Liverpool, UK.

The CHAP Trial Team

University Teaching Hospital, Lusaka, Zambia: Principal Investigators (Prof Chifumbe Chintu, Prof Ganapati Bhat), Project Management/Paediatricians (Dr Veronica Mulenga, Dr Kennedy Lishimpi, Dr Frederick Sinyinza, Dr Desire Kabamba), Microbiology (James Mwansa, Darlington Mwenya, Mr Mutela), Clinic Staff (Regina Chileshe, Catherine Kalengo, J Kaluwaji, Agness Simuchoba, Mrs Mutengo, Violet Bwalya, Mr Chitambala, Terence Chipoya, Betty Chanda), Data Management (Mwaka Choongo, Liffer Namakube, Paul Mutale), Virology (Gina Mulundu, Mrs Liwewe), Parasitology (Mr Mandanda), Pathology (Mr Mudenda).

Medical Research Council Clinical Trials Unit, London: Principal Investigators (Dr Di Gibb, Prof Andrew Nunn), Project/Data Management (Laura Farrelly, Nicola Kaganson, Dr Julia Abernethy, Dr Margaret Thomason, Alexander Ferrier), Statisticians (Prof Andrew Nunn, Dr Sarah Walker, Dr Deborah Ford).

Royal Free Hospital, London: Microbiology (Prof Stephen Gillespie, Sushma Patel, Claire Ling).

University College London: Principal Investigators (Prof Ali Zumla).


  1. Anglaret, X., Chene, G., Attia, A., Toure, S., Lafont, S., Combe, P., et al. (1999). Early chemoprophylaxis with trimethtoprim–sulphamethoxazole for HIV-1 infected adults in Abidjan, Cote d’Ivoire: A randomised trial. The Lancet, 353, 1463–1468.CrossRefGoogle Scholar
  2. Badri, M., Maartens, G., Wood, R., & Ehrlich, R. (1999). Co-trimoxazole in HIV-1 infection. The Lancet, 354, 334–335.CrossRefGoogle Scholar
  3. Bangsberg, D. R., Perry, S., Charlebois, E. D., Clark, R. A., Robertson, M., Zolopa, A. R., et al. (2001). Nonadherence to highly active antiretroviral therapy predicts progression to AIDS. AIDS, 15, 1181–1183.PubMedCrossRefGoogle Scholar
  4. Bikaako-Kajura, W., Luyirika, E., Purcell, D. W., Downing, J., Kaharuza, F., Mermin, J., et al. (2006). Disclosure of HIV status and adherence to daily drug regimens among HIV-infected children in Uganda. AIDS & Behavior, 10, S85–S93.CrossRefGoogle Scholar
  5. Chintu, C., Bhat, G. J., Walker, A. S., Mulenga, V., Sinyinza, F., Lishimpi, K., et al. (2004). Cotrimoxazole as prophylaxis against opportunistic infections in HIV-infected Zambian children (CHAP): A double-blind randomized placebo-controlled trial. The Lancet, 364, 1865–1871.CrossRefGoogle Scholar
  6. Eldred, L. J., Wu, A. W., Chaisson, R. E., & Moore, R. D. (1998). Adherence to antretroviral and pneumocystis prophylaxis in HIV disease. Journal of Acquired Immune Deficiency Syndromes & Human Retrovirology, 18, 117–125.Google Scholar
  7. El-Sadr, W. M., Luskin-Hawk, R., Yurik, T. M., Walker, J., Abrams, D., John, S. L., et al. (1999). A randomized trial of daily and thrice-weekly trimethoprim–sulfamethoxazole for the prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected persons. Clinical Infectious Diseases, 29, 775–783.PubMedCrossRefGoogle Scholar
  8. Freeman, J. V., Cole, T. J., Chinn, S, Jones, P. R. M., White, E. M., & Preece, M. A. (1995). Cross sectional stature and weight reference curves for the UK, 1990. Archives of Disease in Childhood, 73, 17–24.PubMedCrossRefGoogle Scholar
  9. Gibb, D. M., Goodall, R. L., Giacomet, V., McGee, L., Compagnucci, A., & Lyall, H., Paediatric European Network for Treatment of AIDS Steering Committee. (2003). Adherence to prescribed antiretroviral therapy in human immunodeficiency virus-infected children in the PENTA 5 trial. Pediatric Infectious Disease Journal, 22, 56–62.Google Scholar
  10. Grimwade, K., Sturm, A. W., Nunn, A. J., Mbatha, D., Zungu, D., & Gilks, C. F. (2005). Effectiveness of cotrimoxazole on mortality in adults with tuberculosis in rural South Africa. AIDS, 19, 163–168.PubMedCrossRefGoogle Scholar
  11. Hess, K. R. (1994). Assessing time-by-covariate interactions in proportional hazards regression models using cubic spline functions. Statistics in Medicine, 13, 1045–1062.PubMedCrossRefGoogle Scholar
  12. Jones, J. L., Hanson, D. L., Dworkin, M. S., Alderton, D. L., Fleming, P. L., Kaplan, J. E., et al. (1999). Surveillance for AIDS-defining opportunistic illnesses, 1992–1997. Morbidity & Mortality Weekly Report. Surveillance Summaries, 48, 1–22.Google Scholar
  13. Lee, J. Y., Kusek, J. W., Greene, P. G., Bernhard, S., Norris, K., Smith, D., et al. (1996). Assessing medication adherence by pill count and electronic monitoring in the African American Study of Kidney Disease and Hypertension (AASK) Pilot Study. American Journal of Hypertension, 9, 719–725.PubMedCrossRefGoogle Scholar
  14. Liu, H., Golin, C. E., Miller, L. G., Hays, R. D., Beck, C. K., Sanandaji, S., et al. (2001). A comparison study of multiple measures of adherence to HIV protease inhibitors. Annals of Internal Medicine, 134, 968–977. Erratum in: Annals of Internal Medicine, 136, 175, 2002.Google Scholar
  15. Mannheimer, S., Friedland, G., Matts, J., Child, C., & Chesney, M. (2002). The consistency of adherence to antiretroviral therapy predicts biologic outcomes for human immunodeficiency virus-infected persons in clinical trials. Clinical Infectious Diseases, 34, 1115–1121.PubMedCrossRefGoogle Scholar
  16. Martin, S., Elliott-DeSorbo, D. K., Wolters, P. L., Toledo-Tamula, M. A., Roby, G., Zeichner, S., et al. (2007). Patient, caregiver and regimen characteristics associated with adherence to highly active antiretroviral therapy among HIV-infected children and adolescents. Pediatric Infectious Disease Journal, 26, 61–67.PubMedCrossRefGoogle Scholar
  17. Matsui, D., Hermann, C., Klein, J., Berkovitch, M., Olivieri, N., & Koren, G. (1994). Critical comparison of novel and existing methods of compliance assessment during a clinical trial of an oral iron chelator. Journal of Clinical Pharmacology, 34, 944–949.PubMedGoogle Scholar
  18. McIntosh, N., Helms, P., & Smyth, R. (2003) Forfar and Arnneil’s textbook of paediatrics (6th ed., pp. 576–577). London: Churchill Livingstone.Google Scholar
  19. McNabb, J. J., Nicolau, D. P., Stoner, J. A., & Ross, J. (2003). Patterns of adherence to antiretroviral medications: the value of electronic monitoring. AIDS, 17, 1763–1767.PubMedCrossRefGoogle Scholar
  20. Mermin, J., Lule, J., Ekwaru, J. P., Malamba, S., Downing, R., Ransom, R., et al. (2004). Effect of cotrimoxazole prophylaxis on morbidity, mortality, CD4-cell count, and viral load in HIV infection in rural Uganda. The Lancet, 364, 1428–1434.CrossRefGoogle Scholar
  21. Mills, E. J., Nachega, J. B., Bangsberg, D. R., Singh, S., Rachlis, B., Wu, P., et al. (2006). Adherence to HAART; a systematic review of developed and developing nation patient-reported barriers and facilitators. PLoS Medicine, 3(11), e438.PubMedCrossRefGoogle Scholar
  22. Moss, A. R., Hahn, J. A., Perry, S., Charlebois, E. D., Guzman, D., Clark, R. A., et al. (2004). Adherence to highly active antiretroviral therapy in the homeless population in San Francisco: A prospective study. Clinical Infectious Diseases, 39, 1190–1198.PubMedCrossRefGoogle Scholar
  23. Simpson, S. H., Eurich, D. T., Majumdar, S. R., Padwal, R. S., Tsuyuki, R. T., Varney, J., et al. (2006). A meta-analysis of the association between adherence to drug therapy and mortality. British Medical Journal, 333(7557):15.PubMedCrossRefGoogle Scholar
  24. Walker, A. S., Mulenga, V., Sinyinza, F., Lishimpi, K., Nunn, A., Chintu, C., et al. (2006). Determinants of survival without antiretroviral therapy after infancy in HIV-1-infected Zambian children in the CHAP trial. Journal of Acquired Immune Deficiency Syndromes, 42, 637–645.PubMedCrossRefGoogle Scholar
  25. Waterhouse, D. M., Calzone, K. A., Mele, C., & Brenner, D. E. (1993). Adherence to oral tamoxifen: A comparison of patient self-report, pill counts and microelectronic monitoring. Journal of Clinical Oncology, 11, 1189–1197.PubMedGoogle Scholar
  26. Wiktor, S. Z., Sassan-Morroko, M., Grant, A. D., Abouya, L., Karon, J. M., Maurice, C., et al. (1999). Efficacy of trimethoprim–sulphamethoxazole prophylaxis to decrease morbidity and mortality in HIV-1 infected patients with tuberculosis in Abidjan, Cote d’Ivoire: A randomised controlled trial. The Lancet, 353, 1469–1475. Erratum in: The Lancet, 353, 2078, 1999.Google Scholar
  27. Wood, E., Hogg, R. S., Yip, B., Moore, D., Harrigan, P. R., & Montaner, J. S. (2006). Impact of baseline viral load and adherence on survival of HIV-infected adults with baseline CD4 cell counts > or =200 cells/microl. AIDS, 20, 1117–1123.PubMedCrossRefGoogle Scholar
  28. World Health Organization. (2006). Guidelines on co-trimoxazole prophylaxis for HIV-related infections among children, adolescents and adults in resource-limited settings: Recommendations for a public health approach. Retrieved from Accessed 31 Mar 2008.

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • A. Sarah Walker
    • 1
  • Deborah Ford
    • 1
  • Veronica Mulenga
    • 2
  • Margaret J. Thomason
    • 1
  • Andrew Nunn
    • 1
  • Chifumbe Chintu
    • 2
  • Diana M. Gibb
    • 1
  • David R. Bangsberg
    • 3
  1. 1.Medical Research Council Clinical Trials UnitLondonUK
  2. 2.University Teaching HospitalLusakaZambia
  3. 3.University of CaliforniaSan FranciscoUSA

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