Threats to the effectiveness of insecticide-treated bednets for malaria control: thinking beyond insecticide resistance

From 2004 to 2019, insecticide-treated bednets (ITNs) have been the most effective tool for reducing malaria morbidity and mortality in sub-Saharan Africa. Recently, however, decline cases deaths has stalled. Some suggest that this inertia is due increasing resistance vectors pyrethroid insecticides used treating ITNs. However, there presently little evidence reach conclusion we therefore recommend a broader perspective evaluate ITN effectiveness terms of access nets, use bioefficacy, durability should be taken. We argue single focus on insecticide misses bigger picture. To improve effects ITNs, net coverage increase by funding programmes, adopting improved strategies uptake, enhancing longevity active ingredients physical integrity while simultaneously accelerating development evaluation novel vector control tools. major campaign based (ITNs), indoor residual spraying (IRS), prompt treatment with antimalarials, prevented an estimated 1·2 billion 7·1 million Africa.1WHOWorld Malaria Report 2020. WHO, Geneva2020https://www.who.int/publications/i/item/9789240015791Date accessed: June 9, 2021Google Scholar By far important contribution was responsible 68% averted.2Bhatt S Weiss DJ Cameron E et al.The effect Plasmodium falciparum Africa between 2000 2015.Nature. 2015; 526: 207-211Crossref PubMed Scopus (1332) Google The scale their deployment huge, 1·9 ITNs supplied region from 2019.1WHOWorld Despite massive roll-out, only 36% households owned at least one bednet every two persons, mere 1% 2000. Although still falling well short target providing protection against all who are risk, coordinated remarkable achievement. Unfortunately, since 2015, stalled, WHO's African failing meet 2020 Global Technical Strategy milestones 37% 25%.1WHOWorld A concern nets mosquitoes caused plateau. Consequently, WHO focused considerable efforts monitor presence populations around globe.3WHOGlobal plan management vectors. Geneva2012Google Further, threat shaped international policy, drives much investment research tools, eclipsing other factors also affect In Viewpoint, aim broaden discussion beyond stimulate consideration more comprehensive suite current contribute stalling progress towards eradication. article explained panel 1 how work 2.Panel 1Glossary termsDefinitions WHO•Bioefficacy: refers insecticidal activity measure knockdown, mortality, or inhibition blood feeding induced recorded test such as cone bioassay tunnel test.•Durability: considers combination survivorship, fabric integrity, (bioefficacy).•Effective coverage: fraction population bednets.•Entomological inoculation rate: number infective bites received per person given unit time human population.•Functional survival: proportion good acceptable condition (x) expressed percentage originally not away (x).•Insecticide resistance: property survive exposure standard dose insecticide; may result physiological behavioural adaptation.•Insecticidal (bioefficacy): degree susceptible mosquitoes, determined procedures criteria (ie, test). Insecticidal associated type content availability insecticide. g/kg mg/m2 method outlined specifications bednets. This information value interpreting data bioefficacy. can assessed function length use.•Knockdown: bioassays, knockdowned mosquito cannot stand (eg, legs), fly manner, lies its back, moving legs wings but unable take off briefly falls down immediately.•Mortality: it shows no sign life, immobile stand.•Physical (fabric) integrity: reflects number, location, size holes each net.•Survivorship: distributed available intended which they were after defined period 1, 2, 3 years).•Universal entire risk malaria.Panel 2How workBednets barrier reduce mosquito–human contact successful feeding. true whether treated not. Adding provides additional three ways. First, kill rapidly disorient it, potential keep searching potentially feed might inadvertently part body resting sleep. Second, death impairment reduces chances getting into net, if properly tucked under mattress, through hole when inevitably becomes damaged. Third, killing disorienting prevents them going bite people do times using nets. latter provide level community above personal protective long high enough. Other these primary (especially coverage), including reductions density adult changes age structure. Skewing structure younger marked transmission because typically takes 10–12 days parasites complete within initial infectious meal. Repeat over successive cycles live enough successfully incubate parasite, even overall remains relatively unchanged. Sublethal reduced propensity, host-searching capacity, delayed could accrue following exposure; contributing exhibit resistance. Definitions •Bioefficacy: malaria. Bednets Until last very years, pyrethroids, permethrin deltamethrin, highly lethal transient contact. Evolutionary theory, tells us sustained toxic substance fitness organism will probably select Over time, toxin pressure maintained, resistant individuals spread population. line expectation, first detected Anopheles gambiae, Africa's principal vector, Côte d'Ivoire 1993,4Elissa N Mouchet J Rivière F Meunier JY Yao K Resistance gambiae s.s. pyrethroids d'Ivoire.Ann Soc Belg Med Trop. 1993; 73: 291-294PubMed now widespread throughout region. There few, any countries, where remain fully susceptible.5Ranson H Lissenden Insecticide mosquitoes: worsening situation needs urgent action maintain control.Trends Parasitol. 2016; 32: 187-196Summary Full Text PDF (422) 20 years.6Hemingway Ranson insect disease.Annu Rev Entomol. 2000; 45: 371-391Crossref (979) Yet spite rapid predictable evolution response widescale failure mixed. Many laboratory semi-field studies show less instantaneous than populations.7N'Guessan R Corbel V Akogbéto M Rowland Reduced efficacy area, Benin.Emerg Infect Dis. 2007; 13: 199-206Crossref (391) Scholar, 8Toé KH Jones CM N'Fale Ismail HM Dabiré RK Increased decreased bed effectiveness, Burkina Faso.Emerg 2014; 20: 1691-1696Crossref (142) These entomological valuable insights performance tell what level. address limitation study9Churcher TS Griffin JT Worrall impact Africa.eLife. 5e16090Crossref (106) multiple small scale, short-term experiments parameterise mathematical model transmission. suggested levels would both clinical force infection. magnitude effect, sensitive net). further supported separate modelling study indicated moderate >50%), small.10Glunt KD Coetzee Huijben al.Empirical theoretical investigation impacts nets.Evol Appl. 2017; 11: 431-441Crossref (20) Therefore, although raise justifiable concern, plays out field clear. epidemiological Africa.11Lindblade KA Mwandama D Mzilahowa T al.A cohort prevent area resistance, Malawi.Malar J. 14: 31Crossref (59) 12Ochomo Chahilu Cook al.Insecticide-treated insecticide-resistant Western Kenya.Emerg 23: 758-764Crossref (24) 13Kleinschmidt I Bradley Knox TB al.Implications long-lasting nets: WHO-coordinated, prospective, international, observational study.Lancet 2018; 18: 640-649Summary (82) date, convincing examples rendering ineffective 2014, systematic review meta-analysis14Strode C Donegan Garner P Enayati AA Hemingway anopheline meta-analysis.PLoS Med. 11e1001619Crossref 36 24 found untreated irrespective similar analysis15Yang GG Kim Pham Paul CJ meta-regression analysis control: nets.Int Environ Res Public Health. 15: 546Crossref (17) published 2019 reported 60% reduction odds use.15Yang Malawi showed 30% incidence infection compared non-net use, despite vectors.11Lindblade Kenya, users protected 39% lower rates areas low 45% areas, users.12Ochomo largest study13Kleinschmidt date WHO-led multi-country done Benin, Cameroon, India, Sudan. Approximately 40 000 children followed up apart Sudan combined spraying. Children slept had 38% did non-users across range different intensities. association provided Again, continue benefits Two randomised controlled trials16Protopopoff Mosha JF Lukole al.Effectiveness piperonyl butoxide-treated spray interventions, separately together, transmitted pyrethroid-resistant cluster, controlled, two-by-two factorial design trial.Lancet. 391: 1577-1588Summary (147) 17Tiono AB Ouédraogo Ouattara al.Efficacy Olyset Duo, containing pyriproxyfen permethrin, versus permethrin-only rural Faso: cluster-randomised 392: 569-580Summary (50) vectors, next generation modes designed mitigate Tanzania, trial16Protopopoff plus butoxide, synergist disrupts capacity detoxify 63% infections Faso, trial17Tiono pyriproxyfen, growth regulator, enhanced conventional nets.17Tiono Taken face value, results resistance-breaking thereby An alternative, parsimonious explanation, simply alone similarly efficacious (or resistant) populations. For example, strain mosquito, Culex pipiens pallens, tested knockdown increased sharply addition butoxide.18Nishizawa Y Development new synthetic pyrethroids.Bull World Health Organ. 1971; 44: 325-336PubMed Moreover, trials19Skovmand O Comparing un-comparable: Plus Olyset, impact.Malar 17: 446Crossref (3) 20Ngufor N'guessan Fagbohoun al.Olyset Duo® (a mixture net): experimental hut trial quinquefasciatus Southern Benin.PLoS One. 9e93603Crossref bioavailability surface net. likely susceptible. taken together suggests having substantial control. Why case? intact undamaged.21Snow RW Rowan KM Lindsay SW Greenwood BM (mosquito nets) strategy Gambia, West Africa.Trans Trop Hyg. 1988; 82: 212-215Summary (80) sublethal irritancy netting, decreasing exposed mosquito's ability find host,10Glunt parasites.22Kristan Lines Nuwa Ntege Meek SR Abeku TA Exposure deltamethrin affects inside wild Uganda.Parasit Vectors. 9: 100Crossref (27) 23Alout Yameogo B Djogbénou LS al.Interplay mosquitoes.J 210: 1464-1470Crossref (32) competence absence survival susceptibles.24Alout al.Interactive cost gambiae.Sci Rep. 629755Crossref (39) 25Assogba BS Milesi ace-1 locus Is amplified consequences homogeneous heterogeneous duplications.PLoS Biol. 14e2000618Crossref (37) Fourth, fit ones,26Kliot Ghanim Fitness costs resistance.Pest Manag Sci. 2012; 68: 1431-1437Crossref (272) 27Collins Vaselli NM Sylla relationship prevalence s.l. Guinea.Sci 2019; 98846Crossref (23) survival, hence older mosquitoes. Overall, operate produce complex interactions dilute way commonly obscure demonstration link discriminating bioassay28World OrganisationTest monitoring Organisation, Geneva2013Google detect early stages populations, infer anything about implications assays expose 3–5-day-old, non-blood-fed tube lined paper twice concentration required 100% After 60 min removed then again h. characterised displays 90% real vary age, blood-feeding status frequency intensity previous Video studies29Parker JE Angarita-Jaimes Abe Towers CE McCall PJ Infrared video tracking reveals decisive brief localised contact.Sci 513392Crossref