Bed Nets and Decreased Plasmodium falciparum Resistance

Abstract & Commentary

Synopsis: A village in Tanzania has been found to have a decreased prevalence of P falciparum infections and an increased prevalence of wild type dihydrofolate reductase malaria parasites following the widespread use of permethrin-treated bed nets. The use of insecticide-treated bed nets is known to be an effective measure in the control of malaria; its possible role in reversing the trend toward increasing drug resistance is both encouraging and warrants further evaluation. Travel medicine providers should be aware of the ecological implications of their recommendations for malaria prevention.

Source: Alifrangis M, et al. Increasing prevalence of wild types in the dihydrofolate reductase gene of Plasmodium falciparum in an area with high levels of sulfadoxine/pyrimethamine resistance after introduction of treated bed nets. Am J Trop Med Hyg. 2003;69(3):238-243.

Two villages in northeastern tanzania with intense malaria transmission were monitored for resistance to sulfadoxine/pyrimethamine from 1998 to 2000. The 2 villages, Magoda and Mpapayu, are located 2 kilometers apart. Permethrin-treated bed nets were distributed to all households in Magoda village in 1998, while deltamethrin-treated bed nets were distributed to Mpapayu village during 2001. Study subjects were between 6 months and 5 years of age. Blood samples were collected during microscopic examination for malaria parasites, clonality assessment of P falciparum by PCR typing of merozoite surface protein 1 (msp1) and msp2 genes, and dihydrofolate/dihydropteroate synthetase (dhfr/dhps) genotyping.

The prevalence of P falciparum infections decreased significantly in both villages between 1998 and 1999, when assessed by microscopy; this was attributed to a decrease in rainfall in 1999. The P falciparum density (measured as parasites/mL) was lower in Magoda compared to Mpapayu in 1999 and 2000. The estimated mean number of clones per infection showed a greater decrease in Magoda from 1998 to 2000 when compared to Mpapayu.

In Magoda, the prevalence of wild dhfr genotypes at codons 51, 59, and 108 increased from 1998 to 2000, while in Mpapayu, the prevalence of wild genotypes remained constant. The prevalence of wild dhps genotypes at codon 540 increased more in Magoda than Mpapayu in 2000. However, such changes did not occur at codons 436 and 437. In fact, there was an increase in the prevalence of mutant type infections at codon 437 in Magoda in 2000.

Insecticide-treated bed nets appeared to favor wild dhfr genotype parasites as well as to reduce parasite density and the prevalence of P falciparum infections. Alifrangis and colleagues suggest that insecticide-treated bed nets lowered malaria transmission, reduced the prevalence of infections, and led to less frequent use of sulfadoxine/pyrimethamine. As a result, the sulfadoxine/pyrimethamine drug pressure decreased, which may have led to the selection of wild type parasites sensitive to sulfadoxine/pyrimethamine.

Comment by Lin H. Chen, MD

P falciparum drug resistance continues to spread. Tanzania has changed its first-line antimalarial therapy from chloroquine to sulfadoxine/pyrimethamine because of widespread chloroquine resistance. However, sulfadoxine-pyrimethamine resistance is well documented. Point mutations in the dhfr and dhps genes result in reduced drug-binding affinities for dihydrofolate reductase and dihydropteroate synthetase, respectively.1 As the authors have summarized, mutations in codons 51, 59, 108, and 164 in the dhfr gene lead to pyrimethamine resistance, and mutations in codons 436, 437, 540, 581, and 613 of the dhps gene lead to sulfadoxine resistance.

The study by Alifrangis et al is intriguing in showing the different trends of P falciparum infection prevalence, parasite density, clone multiplicity, and dhfr/dhps genotypes between the 2 villages that are only 2 kilometers apart. The use of insecticide-treated bed nets appears to have a positive effect in reducing the prevalence of infection and parasite density as well as selecting for wild dhfr genotype parasites. The results suggest that it may be possible to reverse the drug resistance in some areas by reducing antimalarial drug pressures.

Numerous studies have supported the efficacy of insecticide-treated bed nets in the control of malaria. In addition to reduced numbers of mosquito bites experienced by the individual net user, the use of insecticide-treated bed nets is associated with a reduction in mosquito bites outside of nets due to mass killing of mosquitoes.2,3 Therefore, in villages where nets are widely used, entire communities benefit from an overall reduction in malaria.2,3 The Alifrangis study illustrates the reduction in malaria prevalence. Moreover, the results support the selection for wild dhfr genotypes over mutant genotypes when insecticide-treated bed nets are used, possibly because of reduced drug pressure. The reversal of drug resistance trends may be an additional reason to promote the widespread use of insecticide-treated bed nets, but further studies are needed to confirm this finding.

It is also of concern that there is emerging resistance to insecticides. Pyrethroid resistance has been reported from Asia, Africa, and South America, although the resistance is more likely to arise from agricultural insecticide use than insecticide-treated nets.4 In Africa, pyrethroid resistance has been found among Anopheles gambiae sensu lato mosquitos in Côte d’Ivoire, Benin, and Burkina Faso, but not in Cameroon, Senegal, and Botswana.5 Some studies have indicated protection against malaria when untreated bed nets in good condition are used.6 It is possible that the physical barrier of nets, even untreated, may contribute to the reduction of infection with P falciparum and the increase in the wild type parasites in the Alifrangis study. This issue also needs further exploration.

Dr. Chen is Clinical Instructor, Harvard Medical School, Director, Travel Resource Center, Mt. Auburn Hospital, Cambridge, Mass. 

References

1. Wongsrichanalai C, et al. Epidemiology of drug-resistant malaria. Lancet Infect Dis. 2002;2:209-218.

2. Maxwell CA, et al. Effect of community-wide use of insecticide-treated nets for 3-4 years on malarial morbidity in Tanzania. Trop Med Int Health. 2002; 7(12):1003-1008.

3. Howard SC, et al. Evidence for a mass community effect of insecticide-treated bednets on the incidence of malaria on the Kenyan coast. Trans Royal Soc Trop Med Hyg. 2000;94:357-360.

4. Takken W. Do insecticide-treated bednets have an effect on malaria vectors? Trop Med Int Health. 2002;7(12):1022-1030.

5. Chandre F, et al. Status of pyrethroid resistance in Anopheles gambiae sensu lato. Bull World Health Organ. 1999;77(3):230-234.

6. Clarke SE, et al. Do untreated bednets protect against malaria? Trans Royal Soc Trop Med Hyg. 2001;95: 457-462.