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      The Impact of Pyrethroid Resistance on the Efficacy of Insecticide-Treated Bed Nets against African Anopheline Mosquitoes: Systematic Review and Meta-Analysis

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          Abstract

          In a systematic review and meta-analysis, Clare Strode and colleagues assess whether insecticide resistance in African Anopheline mosquitoes affects the efficacy of insecticide-treated bed nets.

          Please see later in the article for the Editors' Summary

          Abstract

          Background

          Pyrethroid insecticide-treated bed nets (ITNs) help contribute to reducing malaria deaths in Africa, but their efficacy is threatened by insecticide resistance in some malaria mosquito vectors. We therefore assessed the evidence that resistance is attenuating the effect of ITNs on entomological outcomes.

          Methods and Findings

          We included laboratory and field studies of African malaria vectors that measured resistance at the time of the study and used World Health Organization–recommended impregnation regimens. We reported mosquito mortality, blood feeding, induced exophily (premature exit of mosquitoes from the hut), deterrence, time to 50% or 95% knock-down, and percentage knock-down at 60 min. Publications were searched from 1 January 1980 to 31 December 2013 using MEDLINE, Cochrane Central Register of Controlled Trials, Science Citation Index Expanded, Social Sciences Citation Index, African Index Medicus, and CAB Abstracts. We stratified studies into three levels of insecticide resistance, and ITNs were compared with untreated bed nets (UTNs) using the risk difference (RD). Heterogeneity was explored visually and statistically. Included were 36 laboratory and 24 field studies, reported in 25 records. Studies tested and reported resistance inconsistently. Based on the meta-analytic results, the difference in mosquito mortality risk for ITNs compared to UTNs was lower in higher resistance categories. However, mortality risk was significantly higher for ITNs compared to UTNs regardless of resistance. For cone tests: low resistance, risk difference (RD) 0.86 (95% CI 0.72 to 1.01); moderate resistance, RD 0.71 (95% CI 0.53 to 0.88); high resistance, RD 0.56 (95% CI 0.17 to 0.95). For tunnel tests: low resistance, RD 0.74 (95% CI 0.61 to 0.87); moderate resistance, RD 0.50 (95% CI 0.40 to 0.60); high resistance, RD 0.39 (95% CI 0.24 to 0.54). For hut studies: low resistance, RD 0.56 (95% CI 0.43 to 0.68); moderate resistance, RD 0.39 (95% CI 0.16 to 0.61); high resistance, RD 0.35 (95% CI 0.27 to 0.43). However, with the exception of the moderate resistance category for tunnel tests, there was extremely high heterogeneity across studies in each resistance category (chi-squared test, p<0.00001, I 2 varied from 95% to 100%).

          Conclusions

          This meta-analysis found that ITNs are more effective than UTNs regardless of resistance. There appears to be a relationship between resistance and the RD for mosquito mortality in laboratory and field studies. However, the substantive heterogeneity in the studies' results and design may mask the true relationship between resistance and the RD, and the results need to be interpreted with caution. Our analysis suggests the potential for cumulative meta-analysis in entomological trials, but further field research in this area will require specialists in the field to work together to improve the quality of trials, and to standardise designs, assessment, and reporting of both resistance and entomological outcomes.

          Please see later in the article for the Editors' Summary

          Editors' Summary

          Background

          Every year more than 200 million cases of malaria occur worldwide, and more than 600,000 people, mostly children living in sub-Saharan Africa, die from this parasitic infection. Malaria is transmitted to people through the bites of night-flying mosquitoes. Soon after entering the human body, the parasite begins to replicate in red blood cells, bursting out every 2–3 days and infecting more red blood cells. The presence of the parasite in the bloodstream causes malaria's recurring flu-like symptoms, which need to be treated promptly with antimalarial drugs to prevent anemia (a reduction in red blood cell numbers) and life-threatening organ damage. Malaria can be prevented by using insecticides to control the mosquitoes (vectors) that spread the parasite and by sleeping under insecticide-treated bed nets (ITNs) to avoid mosquito bites. High levels of ITN use reduce malaria-related deaths among children by about 20%. Consequently, the widespread provision of ITNs is a mainstay of global efforts to control malaria.

          Why Was This Study Done?

          About 50% of African households now possess an ITN. However, the emergence of resistance to pyrethroid insecticides—the insecticide class recommended by the World Health Organization for use in ITNs—in some mosquitoes potentially threatens the efficacy of ITNs. Pyrethroids kill Anopheles mosquitoes (the main malaria vectors in sub-Saharan Africa) but also prevent mosquitoes entering houses (deterrence), disrupt feeding, and encourage mosquitoes to leave homes prematurely (“induced exophily”; Anopheles mosquitoes usually rest inside for a while after feeding). Worryingly, 27 countries in sub-Saharan Africa have already reported resistance to pyrethroids in Anopheles mosquitoes. In this systematic review and meta-analysis, the researchers assess the impact of pyrethroid resistance on the efficacy of ITNs against African anopheline mosquitoes in terms of entomological outcomes. A systematic review identifies all the research on a given topic using predefined criteria, meta-analysis uses statistical methods to combine the results of several studies, and entomological outcomes are measures of mosquito behavior and survival.

          What Did the Researchers Do and Find?

          The researchers identified 25 reports of laboratory and field studies of the impact of ITNs on African malaria vectors that measured the mosquitoes' resistance to pyrethroid insecticides at the time of the study. The laboratory studies used two assays to measure entomological outcomes. The cone test measured mosquito mortality (death), percent of mosquitoes knocked down (immobilized) after 60 minutes, and the time to knock down 50% or 95% of the mosquitoes after brief exposure to an ITN or untreated bed net (UTN). In the tunnel test, mosquitoes had to pass through a holed ITN or UTN to reach animal baits; counts of live and dead mosquitoes, and fed and unfed mosquitoes on both sides of the net measured deterrence, blood feeding, and mosquito mortality. In the field studies, volunteers slept under an ITN or UTN in an experimental hut. Subsequent counts of live and dead mosquitoes and fed and unfed mosquitoes inside the huts and in exit traps measured deterrence, blood feeding, mosquito mortality, and induced exophily. The researchers report that the measurement of insecticide resistance was inconsistent across the identified studies. Nevertheless, their analysis found that ITNs are more effective than UTNs in relation to mosquito mortality, regardless of resistance. There was a relationship between resistance and the risk difference for mosquito mortality in laboratory and field studies, but the substantive variation between studies means that the findings should be interpreted with caution.

          What Do These Findings Mean?

          These findings show that pyrethroid resistance clearly affects entomological outcomes in laboratory studies, and suggests that this pattern may also be observed in field trials. However, ITNs remained at least somewhat effective despite insecticide resistance in terms of personal protection. The researchers note that there was considerable variability (heterogeneity) among the results obtained in the field trials and suggest that poorly standardized methods and reporting might have masked the true relationship between insecticide resistance and ITN efficacy in these studies. Thus, although ITNs continue to have a substantive effect in many laboratory studies in the face of insecticide resistance, whether ITNs are likely to remain effective against insecticide-resistant mosquitoes in the real world cannot be definitively concluded. Malaria experts and vector biologists need to work together to improve the quality of field trials and to standardize the measurement of insecticide resistance and entomological outcomes, suggest the researchers. Such collaborations, they conclude, are essential to provide the data that policy makers need to plan malaria control strategies.

          Additional Information

          Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001619.

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          Most cited references 49

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          Pyrethroid resistance in African anopheline mosquitoes: what are the implications for malaria control?

          The use of pyrethroid insecticides in malaria vector control has increased dramatically in the past decade through the scale up of insecticide treated net distribution programmes and indoor residual spraying campaigns. Inevitably, the major malaria vectors have developed resistance to these insecticides and the resistance alleles are spreading at an exceptionally rapid rate throughout Africa. Although substantial progress has been made on understanding the causes of pyrethroid resistance, remarkably few studies have focused on the epidemiological impact of resistance on current malaria control activities. As we move into the malaria eradication era, it is vital that the implications of insecticide resistance are understood and strategies to mitigate these effects are implemented. Copyright © 2010 Elsevier Ltd. All rights reserved.
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            Insecticide-treated bed nets and curtains for preventing malaria.

             C Lengeler (2003)
            Malaria is an important cause of illness and death in many parts of the world, especially in sub-Saharan Africa. There has been a renewed emphasis on preventive measures at community and individual levels. Insecticide-treated nets (ITNs) are the most prominent malaria preventive measure for large-scale deployment in highly endemic areas. To assess the impact of insecticide-treated bed nets or curtains on mortality, malarial illness (life-threatening and mild), malaria parasitaemia, anaemia, and spleen rates. I searched the Cochrane Infectious Diseases Group trials register (January 2003), CENTRAL (The Cochrane Library, Issue 1, 2003), MEDLINE (1966 to October 2003), EMBASE (1974 to November 2002), LILACS (1982 to January 2003), and reference lists of reviews, books, and trials. I handsearched journals, contacted researchers, funding agencies, and net and insecticide manufacturers. Individual and cluster randomized controlled trials of insecticide-treated bed nets or curtains compared to nets without insecticide or no nets. Trials including only pregnant women were excluded. The reviewer and two independent assessors reviewed trials for inclusion. The reviewer assessed trial methodological quality and extracted and analysed data. Fourteen cluster randomized and eight individually randomized controlled trials met the inclusion criteria. Five trials measured child mortality: ITNs provided 17% protective efficacy (PE) compared to no nets (relative rate 0.83, 95% confidence interval (CI) 0.76 to 0.90), and 23% PE compared to untreated nets (relative rate 0.77, 95% CI 0.63 to 0.95). About 5.5 lives (95% CI 3.39 to 7.67) can be saved each year for every 1000 children protected with ITNs. In areas with stable malaria, ITNs reduced the incidence of uncomplicated malarial episodes in areas of stable malaria by 50% compared to no nets, and 39% compared to untreated nets; and in areas of unstable malaria: by 62% for compared to no nets and 43% compared to untreated nets for Plasmodium falciparum episodes, and by 52% compared to no nets and 11% compared to untreated nets for P. vivax episodes. When compared to no nets and in areas of stable malaria, ITNs also had an impact on severe malaria (45% PE, 95% CI 20 to 63), parasite prevalence (13% PE), high parasitaemia (29% PE), splenomegaly (30% PE), and their use improved the average haemoglobin level in children by 1.7% packed cell volume. ITNs are highly effective in reducing childhood mortality and morbidity from malaria. Widespread access to ITNs is currently being advocated by Roll Back Malaria, but universal deployment will require major financial, technical, and operational inputs.
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              • Record: found
              • Abstract: found
              • Article: not found

              The molecular basis of insecticide resistance in mosquitoes.

              Insecticide resistance is an inherited characteristic involving changes in one or more insect gene. The molecular basis of these changes are only now being fully determined, aided by the availability of the Drosophila melanogaster and Anopheles gambiae genome sequences. This paper reviews what is currently known about insecticide resistance conferred by metabolic or target site changes in mosquitoes.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS Med
                PLoS Med
                PLoS
                plosmed
                PLoS Medicine
                Public Library of Science (San Francisco, USA )
                1549-1277
                1549-1676
                March 2014
                18 March 2014
                : 11
                : 3
                Affiliations
                [1 ]Liverpool School of Tropical Medicine, Liverpool, United Kingdom
                [2 ]Edge Hill University, Ormskirk, United Kingdom
                [3 ]School of Public Health and Health Sciences Research Center, Mazandaran University of Medical Science, Sari, Iran
                Kenya Medical Research Institute - Wellcome Trust Research Programme, Kenya
                Author notes

                JH is Director of the Liverpool School of Tropical Medicine and until August 2013 was CEO of the Innovative Vector Control Consortium (IVCC). The IVCC is a Product Development Partnership funded by the Bill & Melinda Gates Foundation, DFID, and USAID. It operates as a virtual organisation working with industry to stimulate the discovery, development, and production of new products for malaria and dengue vector control. IVCC holds no Intellectual Property and receives no revenue stream or financial benefit from the new products that are produced. This study was supported by a small grant from Roll Back Malaria to JH for the specific purpose of undertaking this systematic review.

                Conceived and designed the experiments: CS AE JH. Performed the experiments: CS AE. Analyzed the data: CS SD PG. Contributed reagents/materials/analysis tools: CS SD PG. Wrote the first draft of the manuscript: CS SD PG. Contributed to the writing of the manuscript: CS SD PG JH. ICMJE criteria for authorship read and met: CS SD PG AE JH. Agree with manuscript results and conclusions: CS SD PG AE JH.

                Article
                PMEDICINE-D-13-00318
                10.1371/journal.pmed.1001619
                3958359
                24642791

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 32
                Funding
                CS and AE were funded by Roll Back Malaria via the Vector Control Working Group (VCWG). SD and PG are funded by the UK Department for International Development (DFID) for the benefit of developing countries. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Zoology
                Entomology
                Medicine and Health Sciences
                Infectious Diseases
                Parasitic Diseases
                Malaria

                Medicine

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