A trial of proguanil-dapsone in comparison with sulfadoxine-pyrimethamine for the clearance of Plasmodium falciparum infections in Tanzania.

Considerable levels of resistance to sulfadoxine-pyrimethamine (SP) have been reported in Plasmodium falciparum in north-eastern Tanzania, and the identification of a suitable antimalarial to replace SP is now a high priority. We conducted a trial in July 2000 to determine the efficacy of proguanil (PG) plus dapsone (DS), compared with that of SP, for the treatment of asymptomatic falciparum infection. A total of 220 children with parasitaemia > or = 2000 per microL completed the study; 112 had received a single dose of SP (dosage calculated for pyrimethamine 1.25 mg/kg and sulfadoxine 25 mg/kg) and 108 had taken PG 10 mg/kg with DS 2.5 mg/kg each day for 3 days. Clearance of asexual parasites at day 7 was 14.3% with SP, but 93.5% with PG-DS. The remarkably high failure rate with SP was not associated with occurrence of leucine substitution at position 164 of the dhfr gene. Both treatment regimens were well tolerated. Compared with available data on another antifolate combination, chlorproguanil-dapsone ('Lapdap'), PG-DS was slightly but significantly inferior in achieving parasite clearance (99.5% versus 93.5%). The estimated cost of a 3-day course of PG-DS treatment for a child weighing 18 kg is US $0.15. With the rising incidence of SP-resistant P. falciparum infection, PG-DS could provide an effective, affordable and already available therapeutic alternative for malaria in East Africa at least until chlorproguanil-dapsone is registered.

Trial of pyrethroid impregnated bednets in an area of Tanzania holoendemic for malaria. Part 4. Effects on incidence of malaria infection.

Groups of about 30 children in each of five villages were given pyrimethamine-sulfadoxine to clear their malaria parasitaemia, and they were followed up with fortnightly blood slides. Parasitaemia returned rapidly in the absence of vector control, but more slowly when pyrethroid impregnated nets were in use or the houses had been sprayed with DDT. Variation between the incidence of malaria infection in these cases seemed to depend more on ecological or social factors than on the particular form of vector control adopted.

The effects of house spraying with DDT or lambda-cyhalothrin against Anopheles arabiensis on measures of malarial morbidity in children in Tanzania.

The effects of house spraying of DDT and lambda-cyhalothrin against populations of Anopheles arabiensis were assessed in children aged between 1 and 10 years with regard to fever episodes and parasite prevalences. DDT and lambda-cyhalothrin treatment did not reduce the prevalence of malaria episodes as defined by fever (temperatures > or = 37.4 degrees C and/or fever reported) combined with high parasitaemia (> or = 100 parasites/200 leucocytes). However, the prevalence of malaria parasitaemia, of the episodes of fever with any level of malaria parasitaemia and of high parasitaemia alone were significantly reduced. Furthermore, the reduction in mean parasite densities was greater in children of the 1-2 years age group for both insecticides and also for children of 3-5 years age group with lambda-cyhalothrin. Measured and/or reported fever and high parasitaemia were correlated and the data indicated that most of the fevers in these children could be attributed to malaria. Using this criterion it is concluded that the population of An. arabiensis responded to both DDT and lambda-cyhalothrin house spraying which in turn also reduced malaria-related morbidity.

Trial of pyrethroid impregnated bednets in an area of Tanzania holoendemic for malaria. Part 3. Effects on the prevalence of malaria parasitaemia and fever.

Children aged 1-10 in five villages were contacted fortnightly. Their axillary temperatures, reports of fevers and blood slides were taken. Following the introduction of permethrin impregnated nets into two estate villages the slide positivity for falciparum malaria declined markedly. In traditional villages the introduction of impregnated nets had less convincing effects than in the estate villages and DDT spraying had no perceptible effect on malaria. Over all villages there was a clear relationship between axillary temperature greater than 37.4 degrees C, reports of fever and high parasitaemia. We defined malaria fever in this way, and found in some cases significant reductions in occurrence of such fever following some time after introduction of permethrin impregnated nets. No such effects were found with lambdacyhalothrin nets or with DDT spraying.

Mutations in dhfr in Plasmodium falciparum infections selected by chlorproguanil-dapsone treatment.

Treatment with the novel antifolate drug combination chlorproguanil-dapsone effectively cleared asymptomatic Plasmodium falciparum infections in 246 (93.5%) of 263 children in the Usambara Mountains of Tanzania during the course of a 2-week follow-up. Samples from 71 recurrent infections, collected over a 9-week follow-up, showed selection for parasites with the triple mutant Ile(51)-Arg(59)-Asn(108) in dihydrofolate reductase. There was no selection for mutations in dihydropteroate synthetase, the target enzyme of dapsone. Search for complete identity in the highly polymorphic genes coding for merozoite surface proteins 1 and 2 in parasite samples collected before and after treatment indicated that the majority of recurrent parasitemias were new infections. These observations on selection in Tanzania and the lack of selection reported from a less endemic area suggest that the active metabolite of chlorproguanil, which has a short half-life in the blood, may persist in the liver, where it exerts selective pressure on growing preerythrocytic stages.