Treating malaria in Africa

For many years the treatment of malaria in Africa has relied on chloroquine, sulfadoxine combined with pyrimethamine, and quinine, with the latter being used mainly to treat severe cases. Quinine remains efficacious, but chloroquine and sulfadoxine-pyrimethamine are failing, and this is leading to an increase in mortality from malaria especially in East Africa.¹,²

Although resistance to chloroquine was first detected on the east coast of Africa in 1977, the drug has provided effective treatment for malaria for much of Africa for over 20 years.³,⁴ Unfortunately this is unlikely to be the case for sulfadoxine-pyrimethamine, the combination adopted by several African countries as the first line treatment for malaria when chloroquine has failed. Systematic surveillance for resistance to malaria drugs and the results of trials of new drugs or drug combinations that could be used to replace chloroquine or sulfadoxine-pyrimethamine are showing a worryingly high level of resistance to sulfadoxine-pyrimethamine across eastern and southern parts of Africa.⁵,⁶ Resistance to sulfadoxine-pyrimethamine is particularly severe in north east Tanzania, where clinical failure rates of up to 50% have been described,⁷ but high levels of resistance have been recorded also in parts of Burundi, Kenya, Rwanda, and Uganda.⁸ Levels of resistance to sulfadoxine-pyrimethamine are generally lower in West Africa, but clinical failures are not infrequent, and parasites carrying mutations associated with resistance to sulfadoxine-pyrimethamine are distributed widely across West Africa. Genetic studies show that resistance to sulfadoxine-pyrimethamine may have arisen in southern and eastern Africa on only a few occasions, so these resistant strains have spread extensively and rapidly.⁹ Sulfadoxine-pyrimethamine seems to have little future as a first line antimalarial in Africa. However, the results of a recent study by Plowe et al (p 545) in Malawi raise the possibility that this conclusion may be too pessimistic.¹⁰

Malawi changed from chloroquine to sulfadoxine-pyrimethamine as first line treatment for malaria in 1993, the first country in Africa to do so. Plowe et al report clinical and parasitological responses of children with uncomplicated clinical episodes of malaria to treatment with sulfadoxine-pyrimethamine five to nine years later (in 1998 and 2002). In 1998, 86% of children showed an adequate clinical response 14 days after treatment; four years later the response rate was still 83%. Twenty eight days after treatment clinical response rates were 73% and 61%, respectively, a modest but statistically significant fall over time. Parasitological cure rates 14 days after treatment were 73% in 1998 and 60% in 2002 but were much worse 28 days after treatment—38% and 27%, respectively. Some of the apparent 28 day failures may have been reinfections, but even if this was the case it indicates a high level of resistance to sulfadoxine-pyrimethamine, as a single dose of sulfadoxine-pyrimethamine gives up to four weeks of prophylaxis against parasites that are sensitive to the combination.

How robust are these unexpected findings of a relatively stable level of resistance to sulfadoxine-pyrimethamine? The strengths of this study are that it was carried out by the same investigators at the same site using the same methods of analysis over the four year study period and that the numbers of children studied each year (82-425) were large enough to have detected a decline in efficacy. Dropout rates were quite high but were similar in each survey. A progressive fall in the clinical efficacy of sulfadoxine-pyrimethamine would have been detected had it occurred.

The results of this study from Malawi indicate that, in contrast to the situation in other countries such as Thailand and South Africa, a moderate level of resistance to sulfadoxine-pyrimethamine can be sustained over several years and that once resistance has emerged a rapid decline in sensitivity is not inevitable. Why this has happened in Malawi but not elsewhere is uncertain. The investigators think that this may be due to the high level of transmission of malaria in Malawi, which results in early acquisition of immunity and many asymptomatic infections. Because most asymptomatic infections are not treated, only a relatively small proportion of the parasites circulating in Malawi are exposed to an antimalarial at any one time. This contrasts with the situation in areas where transmission is low, such as Thailand, where nearly all infections cause symptoms and are treated, thus providing any resistant parasites with a strong survival advantage. Although considerations of this kind could explain why resistance seems to have developed more slowly in Malawi than in South East Asia, it does not account for the rapid spread of resistance to sulfadoxine-pyrimethamine in parts of East Africa where the level of transmission is as high as, or higher than, in Malawi.

Although the findings from this study are better than might have been expected, they should not induce complacency about the use of sulfadoxine-pyrimethamine for the treatment of malaria in Africa. Clinical and parasitological failure rates 28 days after treatment of 20% and 70% are not satisfactory, and many of the children with parasitaemia on day 28 will subsequently develop a clinical attack. If these findings are representative of the situation in other parts of Malawi a further change in treatment policy is needed. The results of this study should not be used to justify a switch to monotherapy with sulfadoxine-pyrimethamine by countries in Africa contemplating a change from chloroquine. Strong evidence now exists to support a change to combination therapy with two or more drugs, each of which is highly effective locally.¹¹ Malawi has been fortunate to obtain 10 years of effective use from sulfadoxine-pyrimethamine; other countries in Africa are unlikely to be as fortunate.