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

Abstract

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 (7%) of 44 [corrected] 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.

• Authors: T Mutabingwa, A Nzila, E Mberu, E Nduati, P Winstanley, E Hills, W Watkins
• Journal: Lancet (London, England) (Lancet) Vol. 358 Issue 9289 Pg. 1218-23 (Oct 13 2001) ISSN: 0140-6736 [Print] England
• PMID: 11675058 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimalarials
• Drug Combinations
• fanasil, pyrimethamine drug combination
• Sulfadoxine
• chlorproguanil
• Dapsone
• Proguanil
• Pyrimethamine

Topics

• Adolescent
• Adult
• Animals
• Antimalarials (therapeutic use)
• Child
• Child, Preschool
• Dapsone (therapeutic use)
• Drug Combinations
• Drug Resistance
• Genotype
• Humans
• Malaria, Falciparum (drug therapy)
• Middle Aged
• Plasmodium falciparum (drug effects, genetics)
• Point Mutation
• Proguanil (analogs & derivatives, therapeutic use)
• Pyrimethamine (therapeutic use)
• Sulfadoxine (therapeutic use)
• Tanzania