Impact of insecticide resistance in Anopheles arabiensis on malaria incidence and prevalence in Sudan and the costs of mitigation

Hmooda Toto Kafy, Bashir Adam Ismail, Abraham Peter Mnzava, Jonathan Lines, Mogahid Shiekh Eldin Abdin, Jihad Sulieman Eltaher, Anuar Osman Banaga, Philippa West, John Bradley, Jackie Cook, Brent Thomas, Krishanthi Subramaniam, Janet Hemingway, Tessa Bellamy Knox, Elfatih M Malik, Joshua O Yukich, Martin James Donnelly, Immo Kleinschmidt, Hmooda Toto Kafy, Bashir Adam Ismail, Abraham Peter Mnzava, Jonathan Lines, Mogahid Shiekh Eldin Abdin, Jihad Sulieman Eltaher, Anuar Osman Banaga, Philippa West, John Bradley, Jackie Cook, Brent Thomas, Krishanthi Subramaniam, Janet Hemingway, Tessa Bellamy Knox, Elfatih M Malik, Joshua O Yukich, Martin James Donnelly, Immo Kleinschmidt

Abstract

Insecticide-based interventions have contributed to ∼78% of the reduction in the malaria burden in sub-Saharan Africa since 2000. Insecticide resistance in malaria vectors could presage a catastrophic rebound in disease incidence and mortality. A major impediment to the implementation of insecticide resistance management strategies is that evidence of the impact of resistance on malaria disease burden is limited. A cluster randomized trial was conducted in Sudan with pyrethroid-resistant and carbamate-susceptible malaria vectors. Clusters were randomly allocated to receive either long-lasting insecticidal nets (LLINs) alone or LLINs in combination with indoor residual spraying (IRS) with a pyrethroid (deltamethrin) insecticide in the first year and a carbamate (bendiocarb) insecticide in the two subsequent years. Malaria incidence was monitored for 3 y through active case detection in cohorts of children aged 1 to <10 y. When deltamethrin was used for IRS, incidence rates in the LLIN + IRS arm and the LLIN-only arm were similar, with the IRS providing no additional protection [incidence rate ratio (IRR) = 1.0 (95% confidence interval [CI]: 0.36-3.0; P = 0.96)]. When bendiocarb was used for IRS, there was some evidence of additional protection [interaction IRR = 0.55 (95% CI: 0.40-0.76; P < 0.001)]. In conclusion, pyrethroid resistance may have had an impact on pyrethroid-based IRS. The study was not designed to assess whether resistance had an impact on LLINs. These data alone should not be used as the basis for any policy change in vector control interventions.

Trial registration: ClinicalTrials.gov NCT01713517.

Keywords: Anopheles; insecticide; malaria; pyrethroid; resistance.

Conflict of interest statement

The authors declare no conflict of interest.

Copyright © 2017 the Author(s). Published by PNAS.

Figures

Fig. 1.
Fig. 1.
Change in deltamethrin mortality (Upper) and Vgsc-1014F (Lower) across study years and between single (LLIN) and dual (LLIN + IRS) intervention arms. Box whisker plots show the median (bold line) and interquartile range (boxes). Phenotypic data were available from six LLIN and five LLIN + IRS clusters in 2012, six LLIN and six LLIN + IRS clusters in 2013, and 11 LLIN and 13 LLIN + IRS clusters in 2014. Genotypic data were available for all 26 clusters for all years. In 2014, there was significantly (P = 0.038) higher mortality (less resistance) in the LLIN + IRS arm (n = 13; mortality = 68%; 95% CI: 60.0–76.0) compared with the LLIN-only arm (n = 11; mortality = 56.1%; 95% CI: 47.1–64.9).
Fig. 2.
Fig. 2.
Cluster-specific malaria case incidence and cluster-specific malaria infection prevalence plotted against cluster-specific phenotypic resistance (bioassay mortality after standard exposure to deltamethrin) and against cluster-specific Vgsc-1014F allele frequency for 2012, 2013, and 2014 in Galabat, Sudan.
Fig. 3.
Fig. 3.
Map of the study area in Galabat, southeastern Sudan. Triangles denote clusters with LLIN only, and circles denote clusters with LLIN + IRS.

References

    1. World Health Organization . World Malaria Report 2015. WHO; Geneva: 2015.
    1. Bhatt S, et al. The effect of malaria control on Plasmodium falciparum in Africa between 2000 and 2015. Nature. 2015;526:207–211.
    1. Mitchell SN, et al. Identification and validation of a gene causing cross-resistance between insecticide classes in Anopheles gambiae from Ghana. Proc Natl Acad Sci USA. 2012;109:6147–6152.
    1. Mitchell SN, et al. Metabolic and target-site mechanisms combine to confer strong DDT resistance in Anopheles gambiae. PLoS One. 2014;9:e92662.
    1. Edi CVA, Koudou BG, Jones CM, Weetman D, Ranson H. Multiple-insecticide resistance in Anopheles gambiae mosquitoes, Southern Côte d’Ivoire. Emerg Infect Dis. 2012;18:1508–1511.
    1. World Health Organization-GMP . Global Plan for Insecticide Resistance Management in Malaria Vectors. WHO; Geneva: 2012.
    1. Ranson H, Lissenden N. Insecticide resistance in African Anopheles mosquitoes: A worsening situation that needs urgent action to maintain malaria control. Trends Parasitol. 2016;32:187–196.
    1. Kleinschmidt I, et al. Design of a study to determine the impact of insecticide resistance on malaria vector control: A multi-country investigation. Malar J. 2015;14:282.
    1. Noor AM, et al. Malaria risk mapping for control in the republic of Sudan. Am J Trop Med Hyg. 2012;87:1012–1021.
    1. Malik EM, et al. From chloroquine to artemisinin-based combination therapy: The Sudanese experience. Malar J. 2006;5:65.
    1. Petrarca V, et al. Cytogenetics of the Anopheles gambiae complex in Sudan, with special reference to An. arabiensis: Relationships with East and West African populations. Med Vet Entomol. 2000;14:149–164.
    1. Abdalla H, et al. Insecticide susceptibility and vector status of natural populations of Anopheles arabiensis from Sudan. Trans R Soc Trop Med Hyg. 2008;102:263–271.
    1. Himeidan YE, Chen H, Chandre F, Donnelly MJ, Yan G. Short report: Permethrin and DDT resistance in the malaria vector Anopheles arabiensis from eastern Sudan. Am J Trop Med Hyg. 2007;77:1066–1068.
    1. World Health Organization . Test Procedures for Insecticide Resistance Monitoring in Malaria Vector Mosquitoes. WHO; Geneva: 2012.
    1. World Health Organization . Making Choices in Health: WHO Guide to Cost-Effectiveness Analysis. WHO; Geneva: 2003.
    1. Bradley J, et al. A cluster randomized trial comparing deltamethrin and bendiocarb as insecticides for indoor residual spraying to control malaria on Bioko Island, Equatorial Guinea. Malar J. 2016;15:378.
    1. Ratovonjato J, et al. Entomological and parasitological impacts of indoor residual spraying with DDT, alphacypermethrin and deltamethrin in the western foothill area of Madagascar. Malar J. 2014;13:21.
    1. Hamainza B, et al. Incremental impact upon malaria transmission of supplementing pyrethroid-impregnated long-lasting insecticidal nets with indoor residual spraying using pyrethroids or the organophosphate, pirimiphos methyl. Malar J. 2016;15:100.
    1. Kleinschmidt I, et al. Reduction in infection with Plasmodium falciparum one year after the introduction of malaria control interventions on Bioko Island, Equatorial Guinea. Am J Trop Med Hyg. 2006;74:972–978.
    1. Kigozi R, et al. Indoor residual spraying of insecticide and malaria morbidity in a high transmission intensity area of Uganda. PLoS One. 2012;7:e42857.
    1. Maharaj R, Mthembu DJ, Sharp BL. Impact of DDT re-introduction on malaria transmission in KwaZulu-Natal. S Afr Med J. 2005;95:871–874.
    1. Hargreaves K, et al. Anopheles funestus resistant to pyrethroid insecticides in South Africa. Med Vet Entomol. 2000;14:181–189.
    1. Maharaj R, et al. Epidemiology of malaria in South Africa: From control to elimination. S Afr Med J. 2013;103:779–783.
    1. Kleinschmidt I, et al. Factors influencing the effectiveness of malaria control in Bioko Island, Equatorial Guinea. Am J Trop Med Hyg. 2007;76:1027–1032.
    1. Sharp BL, et al. Seven years of regional malaria control collaboration–Mozambique, South Africa, and Swaziland. Am J Trop Med Hyg. 2007;76:42–47.
    1. Strode C, Donegan S, Garner P, Enayati AA, Hemingway J. The impact of pyrethroid resistance on the efficacy of insecticide-treated bed nets against African anopheline mosquitoes: Systematic review and meta-analysis. PLoS Med. 2014;11:e1001619.
    1. Lindblade KA, et al. A cohort study of the effectiveness of insecticide-treated bed nets to prevent malaria in an area of moderate pyrethroid resistance, Malawi. Malar J. 2015;14:31.
    1. West PA, et al. Indoor residual spraying in combination with insecticide-treated nets compared to insecticide-treated nets alone for protection against malaria: A cluster randomised trial in Tanzania. PLoS Med. 2014;11:e1001630.
    1. Bagi J, et al. When a discriminating dose assay is not enough: Measuring the intensity of insecticide resistance in malaria vectors. Malar J. 2015;14:210.
    1. Clarkson CS, et al. Adaptive introgression between anopheles sibling species eliminates a major genomic island but not reproductive isolation. Nat Commun. 2014;5:4248.
    1. Mathias DK, et al. Spatial and temporal variation in the kdr allele L1014S in Anopheles gambiae s.s. and phenotypic variability in susceptibility to insecticides in Western Kenya. Malar J. 2011;10:10.
    1. Norris LC, et al. Adaptive introgression in an African malaria mosquito coincident with the increased usage of insecticide-treated bed nets. Proc Natl Acad Sci USA. 2015;112:815–820.
    1. Donnelly MJ, Isaacs AT, Weetman D. Identification, validation, and application of molecular diagnostics for insecticide resistance in malaria vectors. Trends Parasitol. 2016;32:197–206.
    1. Hamad AA, et al. A marked seasonality of malaria transmission in two rural sites in eastern Sudan. Acta Trop. 2002;83:71–82.
    1. Hayes RJ, Moulton LH. Cluster Randomised Trials, Interdisciplinary Statistics. Chapman and Hall/CRC; Boca Raton, FL: 2009. Introduction; p. 3.
    1. Sismanidis C, et al. Restricted randomization of ZAMSTAR: A 2 x 2 factorial cluster randomized trial. Clin Trials. 2008;5:316–327.
    1. World Health Organization 1998. Test procedures for insecticide resistance monitoring in malaria vectors, bio-efficacy and persistence of insecticides on treated surfaces (WHO, Geneva), Technical Report WHO/CDS/CPC/MAL/98.12.
    1. Scott JA, Brogdon WG, Collins FH. Identification of single specimens of the Anopheles gambiae complex by the polymerase chain reaction. Am J Trop Med Hyg. 1993;49:520–529.
    1. Bass C, et al. Detection of knockdown resistance (kdr) mutations in Anopheles gambiae: A comparison of two new high-throughput assays with existing methods. Malar J. 2007;6:111.
    1. Rao JN, Scott AJ. A simple method for the analysis of clustered binary data. Biometrics. 1992;48:577–585.
    1. Stata Corporation . Stata Survey Data Reference Manual: Release 14. Stata Press; College Station, TX: 2013.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir