Treating malaria in Africa
--------------------------
Sulfadoxine-pyrimethamine may still have a future despite re-
ports of resistance
BMJ 2004;328:534-535 (6 March):
http://bmj.bmjjournals.com/cgi/content/full/328/7439/534
For many years the treatment of malaria in Africa has relied on
chloroquine, sulfadoxine combined with pyrimethamine, and qui-
nine, 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 coun-
tries 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 combina-
tions 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 par-
ticularly severe in north east Tanzania, where clinical failure
rates of up to 50% have been described,7 but high levels of re-
sistance 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 dis-
tributed 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 Sul-
fadoxine-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%, re-
spectively, 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 investiga-
tors 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 effi-
cacy 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 in-
evitable. 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 infec-
tions. 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 Af-
rica. 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.
Brian Greenwood, professor of clinical tropical medicine
Department of Infectious and Tropical Diseases
London School of Hygiene and Tropical Medicine
London WC1E 7HT, UK
mailto:brian.greenwood@lshtm.ac.uk
References
1. Trape J-F, Pison G, Preziosi M-P, Enel C, Desgrées du Loû A,
Delaunay V, et al. Impact of chloroquine resistance on malaria
mortality. C R Acad Sci Paris 1998;321: 689-97.[Medline]
2. Korenromp EL, Williams BG, Gouws E, Dye C, Snow RW. Measure-
ment of trends in childhood malaria mortality in Africa: an as-
sessment of progress towards targets based on verbal autopsy.
Lancet Infect Dis 2003;3: 349-58.[CrossRef][ISI][Medline]
3. Fogh S, Jepsen S, Efferson P. Chloroquine-resistant Plasmo-
dium falciparum in Kenya. Trans R Soc Trop Med Hyg 1979;73: 228-
9.[ISI][Medline]
4. Kean BH. Chloroquine-resistant falciparum malaria from Af-
rica. JAMA 1979;241: 395.[CrossRef][ISI][Medline]
5. East Africa Network for Monitoring Antimalarial Treatment
(EANMAT). Monitoring antimalarial drug resistance within na-
tional malaria control programmes: the EANMAT experience. Trop
Med Int Health 2001;6: 891-8.[CrossRef][ISI][Medline]
6. Wongsrichanalai C, Pickard AL, Wernsdorfer WH, Meshnick SR.
Epidemiology of drug-resistant malaria. Lancet Infect Dis
2002;2: 209-18.[CrossRef][ISI][Medline]
7. Mutabingwa T, Nzila A, Mberu E, Nduati E, Winstanley P, Hills
E, et al. Chlorproguanil-dapsone for treatment of drug-resistant
falciparum malaria in Tanzania. Lancet 2001;358: 1218-
23.[CrossRef][ISI][Medline]
8. East African Network for Monitoring Antimalarial Treatment
(EAN MAT). The efficacy of antimalarial monotherapies, sul-
phadoxine-pyrimethamine and amodiaquine in East Africa: implica-
tions for sub-regional policy. Trop Med Int Health 2003;8: 860-
7.[ISI][Medline]
9. Roper C, Pearce R, Bredenkamp B, Gumede J, Drakeley C, Mosha
F, et al. Antifolate antimalarial resistance in southeast Af-
rica: a population-based analysis. Lancet 2003;361: 1174-
81.[CrossRef][ISI][Medline]
10. Plowe CV, Kublin JG, Dzinjalamala FK, Kamwendo DS, Mukadam
RAG, Chimpeni P, et al. Sustained efficacy sulfadoxine-
pyrimethamine for uncomplicated falciparum malaria in Malawi af-
ter 10 years as first line treatment: five year perpspective
study. BMJ 2004:328: 545-8.
11. Nosten F, Brasseur P. Combination therapy for malaria. The
way forward. Drugs 2002;62: 1315-29.[ISI][Medline]
Other related articles in BMJ:
Papers
Sustained clinical efficacy of sulfadoxine-pyrimethamine for un-
complicated falciparum malaria in Malawi after 10 years as first
line treatment: five year prospective study.
Christopher V Plowe, James G Kublin, Fraction K Dzinjalamala,
Deborah S Kamwendo, Rabia A G Mukadam, Phillips Chimpeni, Mal-
colm E Molyneux, and Terrie E Taylor
BMJ 2004 328: 545-0. [Abstract] [Abridged text] [Full text]