Epidemiology and Social: Editorial Comments
Cotrimoxazole prophylaxis for African HIV-infected children: no more delays, no more misinterpretations!
Msellati, Philippea; Moatti, Jean-Paulb,c
From the aIRD (French Research Institute for Development), Unit 145 (HIV/AIDS and Comorbidities), Montpellier, Aix en Provence, France
bUniversity of the Mediterranean & Director of INSERM research Unit 379 (Social Sciences Applied to Medical Innovations), Marseilles, France
cINSERM Research Unit 379 (Social Sciences Applied to Medical Innovations), Marseilles, France.
Correspondence to Jean Paul Moatti, INSERM Research Unit 379, 23 rue Stanislas Torrents,13006 Marseille, France. E-mail: firstname.lastname@example.org
The provision of cotrimoxazole as primary or secondary prophylaxis for the prevention of Pneumocystis jiroveci pneumonia and toxoplasmosis has been part of the standard care in the management of HIV-infected individuals in developed countries since the early 1990s. In spite of the differences in aetiology and the burden of common opportunistic infections between developed and resource-poor countries, clear evidence that cotrimoxazole prophylaxis is also effective for decreasing morbidity and mortality among HIV-infected adults who live in sub-Saharan Africa, including those treated for tuberculosis, has been available since the end of the 1990s [1,2]. WHO/UNAIDS guidelines recommending that this prophylaxis should be included in the routine care of HIV-infected adults have been in place since 2000 . Although cotrimoxazole is widely available in both syrup and solid formulations at low unit cost in most places, including resource-limited settings, most African countries have not yet implemented this intervention widely among adults.
Evidence in favour of the extension of cotrimoxazole prophylaxis to HIV-infected children is more recent. The main source of evidence comes from the CHAP (Children with HIV Antibiotic Prophylaxis) trial carried out in Zambia . Results of this trial were first published in 2004 and showed a significant 43% reduction in mortality in HIV-infected children benefiting from cotrimoxazole prophylaxis when compared with placebo. It is important to note that the trial also showed that this prophylaxis is effective even when the in-vitro bacterial analysis presents a low efficacy and a high level of resistances. It took two years for the WHO guidelines to be modified accordingly as a result of these results and to recommend the systematic use of this prophylaxis for children . To date, this recommendation is far from having become a reality: It is estimated that 4 million children who could benefit from cotrimoxazole are currently not receiving it in developing countries, and that fewer than 5% of all infants born to HIV-positive mothers received cotrimoxazole in 2005 .
One major barrier for access is that cotrimoxazole is not available in many settings because public health authorities and health professionals are still not convinced of the efficacy of its prophylactic use and do not consider it as a rationale choice for allocating limited resources. In this issue of AIDS, Ryan et al.  clearly demonstrate that such views are mistaken. These authors present the results of an economic analysis that was carried out alongside the CHAP trial and that satisfies the best methodological standards for economic evaluation . In line with previous results of cost-effectiveness studies carried out among adults , their results bring an additional argument in favour of the feasibility of generalizing cotrimoxazole prophylaxis as part of the routine care of HIV-infected children. They calculate the incremental cost per life-year saved by cotrimoxazole prophylaxis in this population in the order of magnitude of US$70–90. Whereas interventions that cost less than one times the gross domestic product (GDP) per capita are usually considered as ‘very cost-effective’ , these estimations are more than 10 times lower than the Zambian GDP per capita and would be lower than a GDP per capita threshold in any other sub-Saharan country.
The article by Ryan et al.  confirms to African decision-makers and health professionals that there are no longer any reasons to delay the inclusion of cotrimoxazole prophylaxis in national guidelines for the management and care of HIV-infected children and for its large-scale implementation in clinical practice all over Africa.
Unfortunately, inadequate policy guidance is not the only barrier to be removed for access to cotrimoxazole prophylaxis by HIV-infected children . Most affected children in sub-Saharan Africa are not diagnosed with their HIV infection because their family environment does not recognize their HIV-related symptoms or does not seek care for them because of a lack of financial resources or fear of stigma. Even when HIV-infected children consult for care, they often have no access to HIV testing and diagnosis, and care givers may sometimes pay no attention to the possibility that HIV may be the underlying cause for the observed morbidity. Moreover, without appropriate care, HIV-infected children suffer from a very high and early mortality. Most families remain unaware that these children can survive a lot longer than the 2 or 3 first years of life if they are given treatment, and paediatric care givers may often have other priorities. These attitudes from both families and health professionals are deeply rooted in a complex interplay of cultural practices, structural inequality, and power differentials that tend to produce stigma and neglect towards children living with HIV/AIDS .
In such a context, readers of the article by Ryan et al.  should be careful to avoid misinterpretations. The legitimate claims, based on the data presented by these authors, that cotrimoxazole prophylaxis is very ‘cost-effective’ and should be implemented in routine care for HIV-infected children, should not be used as an argument to delay or dismiss access to other components of HIV paediatric care on the grounds that they are likely to be ‘less cost-effective’.
For some years, a number of experts have been arguing that antiretroviral treatment (ART) was not a rational investment in Africa because it was not ‘cost-effective’ compared with alternative uses of resources for HIV prevention and care that would consequently ‘save more lives’ [12–15]. These views were based on the misleading and mechanistic concept that the allocation of resources between health interventions should be based on a strict increasing hierarchy of marginal cost per life-year saved. It ignores the methodological problems raised by the comparative use of cost-effectiveness ratios generated by different studies with different aims and the additional problems related to the fact that the ratio of each intervention may vary with its scope and scale [16,17]. The more pragmatic approach proposed by the Commission on Macroeconomics and Health, which labelled interventions that have cost-effectiveness ratios of less than three times the GDP per capita as ‘cost-effective’ and those that cost less than one times the GDP per capita as ‘very cost-effective’, is a lot more appropriate to select interventions. It should remain a matter of debate at country level which interventions satisfying these thresholds should be given priority in budget allocation.
According to this pragmatic approach, cotrimoxazole prophylaxis has now been proved to be cost-effective for affected children in Africa, but paediatric ART is also likely to be cost-effective if it is appropriately administered. There is already undisputable evidence that ART can be made just as virologically, immunologically and clinically effective in HIV-infected children of developing countries as it has been in developed countries [18,19]. The example of the cost-effectiveness study carried out alongside the CHAP trial urgently needs to be extended to trials and cohorts dealing with paediatric ART in Africa. Because both cotrimoxazole prophylaxis and ART are complementary tools for the adequate management of HIV-infected children in low-resource settings, economic analysis should not be used as a pretext to oppose one over the other but rather to help determine their best combinations in guidelines and care practices.
1. Anglaret X, Chêne G, Attia A, Toure S, Lafont S, Combe P, et al
. Early chemoprophylaxis with trimethoprim–sulphamethoxazole for HIV-infected adults in Abidjan, Côte d'Ivoire: a randomised trial. Lancet 1999; 353:1463–1468.
2. Wiktor SZ, Sassan-Morokro M, Grant AD, Abouya L, Karon JM, Maurice C, et al
. Efficacy of trimethoprim-sulphamethoxazole prophylaxis to decrease morbidity and mortality in HIV infected patients with tuberculosis in Abidjan, Côte d'Ivoire: a randomized controlled trial. Lancet 1999; 353:1469–1475.
3. Joint United Nations Programme on HIV/AIDS. Provisional WHO/UNAIDS secretariat recommendations on the use of cotrimoxazole prophylaxis in adults and children living in HIV/AIDS in Africa.
Geneva: UNAIDS; 2000.
4. Chintu C, Bhat GJ, Walker AS, Mulenga V, Sinyinza F, Lishimpi K, et al
. Co-trimoxazole as prophylaxis against opportunistic infections in HIV-infected Zambian children (CHAP): a double-blind randomized placebo-controlled trial. Lancet 2004; 364:1865–1871.
5. World Health Organization. Expert consultation on cotrimoxazole prophylaxis in HIV infection. WHO technical report series HIV/01.
2006. Geneva: WHO; 2006.
6. Luo C, Akwara C, Ngongo N, Doughty P, Gass R, Ekpini R, et al
. Global progress in PMTCT and paediatric HIV care and treatment in low- and middle-income countries in 2004–2005. Reprod Health Matters 2007; 15:179–189.
7. Ryan M, Griffin S, Chitah B, Walker AS, Mulenga V, Kalolo D, et al
. The cost-effectiveness of cotrimoxazole prophylaxis in HIV-infected children in Zambia. AIDS 2008; 22:749–757.
8. Goldie S, Yazdanpanah Y, Losina E, Weinstein M, Anglaret X, Walensky R, et al
. Cost-effectiveness of HIV treatment in resource-poor settings – the case of Côte d'Ivoire. N Engl J Med 2006; 355:1141–1153.
9. Hutubessy RCW, Baltussen RMPM, Tan-Torres-Edjerer T, Evans DB, WHO-CHOICE Working Group. WHO-CHOICE:CHOosing interventions that are cost-effective. In: Murray CJL, Evans DB, editors. Health systems performance assessment: debates, methods and empiricism. Geneva: WHO Editions; 2003. pp. 823–835.
10. Zachariah R, Harries AD, Luo C, Bachman G, Graham SM. Scaling-up co-trimoxazole prophylaxis in HIV-exposed and HIV-infected children in high HIV-prevalence countries. Lancet Infect Dis 2007; 7:686–693.
11. Castro A, Farmer P. Understanding and addressing AIDS-related stigma: from anthropological theory to clinical practice in Haiti. Am J Pub Health 2005; 95:53–59.
12. Ainsworth M, Teokul W. Breaking the silence: setting realistic priorities for AIDS control in less developed countries. Lancet 2000; 356:55–60.
13. Creese A, Floyd K, Alban A, Guinness L. Cost-effectiveness of HIV/AIDS interventions in Africa: a systematic review of the evidence. Lancet 2002; 359:1635–1642.
14. Marseille E, Hofmann PB, Kahn KG. HIV prevention before HAART in sub-Saharan Africa. Lancet 2002; 359:1851–1856.
15. Canning D. The economics of HIV/AIDS in low-income countries: the case for prevention. J Eco Perspect 2006; 3:121–142.
16. Garber AM. Advances in cost-effectiveness analysis of health interventions.
In: Culyer AJ, Newhouse JP, editors. Handbook of health economics 2000
, 1st Ed, Vol 1. Amsterdam: Elsevier Science BV; 2000. pp 181–221.
17. Moatti JP, N'Doye I, Hammer SM, Hale P, Kazatchkine M. Antiretroviral treatment for HIV infection in developing countries: an attainable new paradigm. Nat Med 2003; 9:1449–1452.
18. Puthanakit T, Oberdorfer A, Akarathum N, Kanjanavanit S, Wannarit P, Sirisanthana T, et al
. Efficacy of highly active antiretroviral therapy in HIV-infected children participating in Thailand's national access to antiretroviral program. Clin Infect Dis 2005; 41:100–107.
19. Rouet F, Fassinou P, Inwoley A, Anaky MF, Kouakoussui A, Rouzioux C, et al
. Long-term survival and immuno-virologic response of African HIV-1-infected children to highly active antiretroviral therapy regimens containing a protease or a nonnucleoside reverse transcriptase inhibitor. AIDS 2006; 20:2315–2319.
© 2008 Lippincott Williams & Wilkins, Inc.