Chlorproguanil-dapsone for treatment of drug-resistant falciparum malaria in Tanzania

doi:10.1016/S0140-6736(01)06344-9

The Lancet

Volume 358, Issue 9289, 13 October 2001, Pages 1218-1223

https://doi.org/10.1016/S0140-6736(01)06344-9 Get rights and content

Summary

Background

Resistance to the affordable malaria treatments chloroquine and pyrimethamine-sulfadoxine is seriously impeding malaria control through treatment in east Africa. We did an open, alternate drug allocation study to assess the efficacy of chlorproguanil-dapsone in the treatment of falciparum malaria clinically resistant to pyrimethamine-sulfadoxine.

Methods

Children younger than 5 years with non-severe falciparum malaria, attending Muheza district hospital in Tanzania, were treated with the standard regimen of pyrimethamine-sulfadoxine. Patients whose clinical symptoms resolved but who remained parasitaemic 7 days after pyrimethamine-sulfadoxine were followed up for 1 month. Clinical malaria episodes were retreated with either single dose pyrimethamine-sulfadoxine or a 3-day regimen of chlorproguanil-dapsone. Those with parasitaemia after 7 days were treated with chlorproguanil-dapsone. Parasite DNA was collected on day 7 after first treatment with pyrimethamine-sulfadoxine and we looked for point mutations in the genes encoding dihydrofolate reductase (dhfr) and dyhydropteroate synthetase (dhps).

Findings

360 children were enrolled and treated with pyrimethamine-sulfadoxine. On day 7, 192 (55%) of 348 had cleared parasitaemia. Of the remaining 156 parasitaemic children, 140 (90%) were followed up to day 28, and 92 (66%) of 140 developed clinical malaria. These 92 patients were alternately retreated with either pyrimethamine-sulfadoxine (46) or chlorproguanil-dapsone (46). 28 (61%) of 46 children retreated with pyrimethamine-sulfadoxine were still parasitaemic at day 7, compared with three (15%) of 46 children retreated with chlorproguanil-dapsone. Resistance to pyrimethamine-sulfadoxine increased from 45% (156/348) at the first treatment to 61% (28/46) after retreatment. 83 of 85 parasite isolates collected after the first pyrimethamine-sulfadoxine treatment, and before and after the second treatments with pyrimethamine-sulfadoxine and chlorproguanil-dapsone showed triple-mutant dhfr alleles, associated with a variety of dhps mutations.

Interpretation

Most patients treated with pyrimethamine-sulfadoxine, who remain parasitaemic at day 7, develop new malaria symptoms within 1 month. Chlorproguanil-dapsone was a practicable therapy under these circumstances. Analysis of parasite dhfr and dhps before and after treatment supports the view that pyrimethamine-sulfadoxine resistance in this part of Africa is primarily due to parasites with three mutations in the dhfr domain.

Introduction

Chloroquine-resistant falciparum malaria is now widespread in Africa. The choice of a safe and efficacious replacement for chloroquine is dictated primarily by economic considerations, and pyrimethamine-sulfadoxine, a synergistic antifolate combination, is often the only practicable alternative. Pyrimethamine is an inhibitor of plasmodial dihydrofolate reductase (dhfr).¹ Sulfadoxine is an inhibitor of plasmodial dihydropteroate synthetase (dhps).2, 3 A single curative dose of pyrimethamine-sulfadoxine is now the first-line antimalarial treatment in Malawi, Botswana, South Africa, and Kenya, and may soon replace chloroquine in Tanzania and other countries of eastern Africa.

In areas of east Africa with documented parasitological resistance to pyrimethamine-sulfadoxine,4, 5 treatment commonly produces an adequate clinical response⁶ even though parasitaemia may not be completely cleared. Chlorproguanil-dapsone is a new antifolate combination that is more potent than pyrimethamine-sulfadoxine against African parasite strains with borderline responsiveness to pyrimethamine-sulfadoxine, and which could become a usable second-line drug. Thus the primary aim of our study was to find out the efficacy of chlorproguanil-dapsone, in comparison with pyrimethamine-sulfadoxine, in patients requiring retreatment after pyrimethamine-sulfadoxine failure. However, at the moment the only drug available to deal with pyrimethamine-sulfadoxine failure is further treatment with pyrimethamine-sulfadoxine. Therefore, we also aimed to find out the proportion of patients being treated with pyrimethamine-sulfadoxine who required retreatment, and the efficacy of pyrimethamine-sulfadoxine retreatment under these circumstances.

The WHO in-vivo test⁶ defines an adequate clinical response as either absence of parasitaemia on day 14 irrespective of axillary temperature, without previously meeting any of the criteria of early or late treatment failure; or axillary temperature of 37·5°C or more irrespective of the presence of parasitaemia, without previously meeting any of the criteria of early or late treatment failure. Although a useful test of short-term treatment efficacy, the WHO test does not assess the effect of parasitological failure, nor the development of further episodes of malaria, at times greater than 14 days after treatment. Since parasitological drug failure is commonly followed by the reappearance of illness within 1 month,⁷ we extended the follow-up period to 28 days.

Chlorproguanil-dapsone has a short elimination half-life, and a 3-day dosage regimen is necessary to maintain physiological drug concentrations which will eradicate parasite infections.⁸

We have also analysed point mutations in dhfr and in dhps of these antifolate resistant parasites so as to assess the relation between the dhfr and dhps genotype and antifolate resistance.

Section snippets

Study area

The study was done at Muheza Designated District Hospital in northeast Tanzania. The lowland parts of the district experience hyperendemic to holoendemic malaria.⁹ More than 95% of the malaria infections are caused by Plasmodium falciparum. In 1999, parasitological resistance to chloroquine was noted in 86% of 100 children younger than 5 years with uncomplicated falciparum malaria.¹⁰ Because of the high prevalence of chloroquine resistance, pyrimethamine-sulfadoxine has been the first-line drug

Clinicoepidemiological studies

360 children younger than 5 years were enrolled. At enrolment, 328 (91%) had a history of being treated at home for fever, either with aspirin or paracetamol (60%) or an antimalarial (31%), usually chloroquine. Responses to all treatments are shown in figure 1. First treatment with pyrimethamine-sulfadoxine was fully assessed in 348 (97%). 12 (3%) children exited the study because of progression to severe disease (two), otitis media (one), concomitant treatment with cotrimoxazole (one),

Discussion

In our study, first treatment with pyrimethaminesulfadoxine did not reduce parasitaemia below the patency level in 45% of the patients, although parasitaemia was reduced sufficiently to produce a temporary clinical improvement in all cases. Since the mid-1990s, there have been reports of parasite resistance to pyrimethamine-sulfadoxine in this district4, 5 and elsewhere in east Africa. In 1991 the drug was successfully used in the same district to clear parasites¹² before malaria control

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Prevalence of mutations in the antifolates resistance-associated genes (dhfr and dhps) in Plasmodium vivax parasites from Eastern and Central Sudan
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As a consequence, it is very important to be taken into account that SP treatment failure is more frequently associated with multiple mutations in pvdhfr and pvdhps (Peterson et al., 1988). Also, when parasite carries mutant alleles of both genes, clinical effectiveness is compromised (Plowe et al., 1997; Nzila et al., 2000; Mutabingwa et al., 2001; Kublin et al., 2002; Kyabayinze et al., 2003; Staedke et al., 2004; Nzila, 2006). Therefore, it can be concluded that there is slow evolution of pvdhfr/pvdhps in this region, where the double mutant allele (58R/117N) has widely spread, and there is no quintuple dhfr/dhps allele (57L/58R/61M/117N-383G/553G) after nine years of AS + SP use.
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Presence of 383G mutation along with double mutant of dhfr is very important to be taken into account, because treatment failure was more frequently associated with multiple mutations in pvdhfr and pvdhps (Peterson et al., 1988). Also, when the parasite carries mutant alleles of both genes, clinical effectiveness is compromised (Plowe et al., 1997; Nzila et al., 2000; Mutabingwa et al., 2001; Kublin et al., 2002; Kyabayinze et al., 2003; Staedke et al., 2004; Nzila, 2006). Therefore, increasing the prevalence of such mutations (L57R58/G383 and R58N117/G383) may further reduce the sensitivity to SP drugs in P. vivax population in this region.
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ArticlesChlorproguanil-dapsone for treatment of drug-resistant falciparum malaria in Tanzania

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Study area

Clinicoepidemiological studies

Discussion

Trans R Trop Soc Med Hyg

Acta Tropica

Trans R Soc Trop Med Hyg

Trans R Soc Trop Med Hyg

Acta Trop

Trans R Soc Trop Med Hyg

Trans R Soc Trop Med Hyg

Lancet

Pharm Ther

Parasitol Today

Trans R Soc Trop Med Hyg

Lancet

Molecular cloning and sequence analysis of the Plasmodium falciparum dihydrofolate reductase-thymidylate synthase gene

Proc Natl Acad Sci USA

Articles
Chlorproguanil-dapsone for treatment of drug-resistant falciparum malaria in Tanzania