Combination Therapy for Malaria in Africa: Hype or Hope?

By Bloland, Peter B.; Ettling, Mary et al. | Bulletin of the World Health Organization, December 2000 | Go to article overview

Combination Therapy for Malaria in Africa: Hype or Hope?


Bloland, Peter B., Ettling, Mary, Meek, Sylvia, Bulletin of the World Health Organization


Bulletin of the World Health Organization, 2000, 78: 1378-1388.

Voir page 1385 le resume en francais. En la pagina 1386 figura un resumen en espanol.

Introduction

The African Region has the largest number of people exposed to stable malaria transmission and the greatest burden of malaria morbidity and mortality in the world (1, 2). The problems associated with malaria treatment in Africa can be expected to increase the rates of severe illness and death substantially. This may already have occurred in Senegal (3). These problems can also be expected to contribute to epidemics and to the expansion of the disease into previously malaria-free areas (1, 4, 5). Several countries have already abandoned chloroquine (CQ) in favour of sulfadoxine/pyrimethamine (SP) because of worsening CQ resistance, and more are considering the revision of treatment guidelines. This process has improved malaria treatment and in some settings has resulted in noticeable declines in rates of severe illness and malaria-related mortality (P. Kazembe, personal communication). However, the resistance of the malaria parasite to SP is growing and there is no obvious affordable alternative (6).

There is an urgent need to make efficacious and affordable therapy available in regimens that encourage compliance by patients and providers. Decisions made now about antimalarial therapy in Africa will affect future options. The inappropriate use of the limited and shrinking pharmacopoeia of affordable and effective antimalarial drugs should not be allowed to continue. New therapeutic strategies, a better understanding of the mechanisms of resistance, improved drug utilization, and new partnerships to tackle cost barriers should all be brought into play.

The situation is exacerbated by generally poor access to health care, chronic underfunding of public health services, and deficient training of health workers, who are inadequately motivated, equipped and supported (7). The newer antimalarials tend to be more expensive than African economies can bear (8). These factors add up to a malaria disaster (9).

Recent observations in South-East Asia, especially on Thailand's borders with Cambodia and Myanmar, suggest that a highly efficacious combination therapy, including the use of an artemisinin derivative, has halted a rapid decline in the efficacy of mefloquine (MQ) and may have reduced overall malaria transmission (10-12). These observations have led to a plea for rapid deployment of this strategy in other malarious areas, especially sub-Saharan Africa. There is even an implication that the use of single agents is unethical (13).

The experience in South-East Asia offers much hope for Africa. However, the extrapolation of observations from a specific epidemiological context to an entire continent with very different malaria epidemiology is problematic and may offer false prospects. Several current studies impinge on outstanding issues and questions concerning the applicability of combination therapy strategies in Africa (P. Olliaro, personal communication; 14). When the results become available it will be important to maintain a clear understanding of these issues and their implications for the ultimate success of combination therapy in Africa. We describe these issues, review the current state of knowledge about them, consider the potential limitations of combination therapy, and identify, some of the problems that must be overcome if the continent is to benefit from it.

The logic of combination therapy

The basic tenet of combination therapy is that the probability of resistance developing simultaneously to two chemotherapeutic agents with independent mechanisms of action is extremely low, of the order of once in [10.sup.12] treatments. This frequency is the product of the probabilities of the acquisition of a resistant mutation to each drug multiplied by the number of parasites in a typical infection (12). …

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