Ivermectin as a novel malaria control tool: Getting ahead of the resistance curse.

Reduction in malaria clinical cases is strongly dependent on the ability to prevent Anopheles infectious bites. Vector control strategies using long-lasting insecticidal nets and indoor residual spraying with insecticides have contributed to significantly reduce the incidence of malaria in many endemic countries, especially in the Sub-Saharan region. However, global progress in reducing malaria cases has plateaued since 2015 mostly due to the increased insecticide resistance and behavioral changes in Anopheles vectors. Additional control strategies are thus required to further reduce the burden of malaria and contain the spread of resistant and invasive Anopheles vectors. The use of endectocides such as ivermectin as an additional malaria control tool is now receiving increased attention, driven by its different mode of action compared to insecticides used so far and its excellent safety record for humans. In this opinion article, we discuss the advantages and disadvantages of using ivermectin for malaria control with a focus on the risk of selecting ivermectin resistance in malaria vectors. We also highlight the importance of understanding how ivermectin resistance could develop in mosquitoes and what its underlying mechanisms and associated molecular markers are, and propose a research agenda to manage this phenomenon.

Vector control for malaria prevention during humanitarian emergencies: a systematic review and meta-analysis.

BACKGROUND: Humanitarian emergencies can lead to population displacement, food insecurity, severe health system disruptions, and malaria epidemics among individuals who are immunologically naive. We aimed to assess the impact of different vector control interventions on malaria disease burden during humanitarian emergencies. METHODS: In this systematic review and meta-analysis, we searched ten electronic databases and two clinical trial registries from database inception to Oct 19, 2020, with no restrictions on language or study design. We also searched grey literature from 59 stakeholders. Studies were eligible if the population was affected by a humanitarian emergency in a malaria endemic region. We included studies assessing any vector control intervention and in which the primary outcome of interest was malaria infection risk. Reviewers (LAM, JF-A, KC, BP, and LP) independently extracted information from eligible studies, without masking of author or publication, into a database. We did random-effects meta-analyses to calculate pooled risk ratios (RRs) for randomised controlled trials, odds ratios (ORs) for dichotomous outcomes, and incidence rate ratios (IRR) for clinical malaria in non-randomised studies. Certainty of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. This study is registered with PROSPERO, CRD42020214961. FINDINGS: Of 12 475 studies screened, 22 studies were eligible for inclusion in our meta-analysis. All studies were conducted between Sept 1, 1989, and Dec 31, 2018, in chronic emergencies, with 616 611 participants from nine countries, evaluating seven different vector control interventions. Insecticide-treated nets significantly decreased Plasmodium falciparum incidence (RR 0·55 [95% CI 0·37-0·79]; high certainty) and Plasmodium vivax incidence (RR 0·69 [0·51-0·94]; high certainty). Evidence for an effect of indoor residual spraying on P falciparum (IRR 0·57 [95% CI 0·53-0·61]) and P vivax (IRR 0·51 [0·49-0·52]) incidence was of very low certainty. Topical repellents were associated with reductions in malaria infection (RR 0·58 [0·35-0·97]; moderate certainty). Moderate-to-high certainty evidence for an effect of insecticide-treated chaddars (equivalent to shawls or blankets) and insecticide-treated cattle on malaria outcomes was evident in some emergency settings. There was very low certainty evidence for the effect of insecticide-treated clothing. INTERPRETATION: Study findings strengthen and support WHO policy recommendations to deploy insecticide-treated nets during chronic humanitarian emergencies. There is an urgent need to evaluate and adopt novel interventions for malaria control in the acute phase of humanitarian emergencies. FUNDING: WHO Global Malaria Programme.

House modifications for preventing malaria.

BACKGROUND: Malaria remains an important public health problem. Research in 1900 suggested house modifications may reduce malaria transmission. A previous version of this review concluded that house screening may be effective in reducing malaria. This update includes data from five new studies. OBJECTIVES: To assess the effects of house modifications that aim to reduce exposure to mosquitoes on malaria disease and transmission. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE (PubMed); Embase (OVID); Centre for Agriculture and Bioscience International (CAB) Abstracts (Web of Science); and the Latin American and Caribbean Health Science Information database (LILACS) up to 25 May 2022. We also searched the World Health Organization International Clinical Trials Registry Platform, ClinicalTrials.gov, and the ISRCTN registry to identify ongoing trials up to 25 May 2022. SELECTION CRITERIA: Randomized controlled trials, including cluster-randomized controlled trials (cRCTs), cross-over studies, and stepped-wedge designs were eligible, as were quasi-experimental trials, including controlled before-and-after studies, controlled interrupted time series, and non-randomized cross-over studies. We sought studies investigating primary construction and house modifications to existing homes reporting epidemiological outcomes (malaria case incidence, malaria infection incidence or parasite prevalence). We extracted any entomological outcomes that were also reported in these studies. DATA COLLECTION AND ANALYSIS: Two review authors independently selected eligible studies, extracted data, and assessed the risk of bias. We used risk ratios (RR) to compare the effect of the intervention with the control for dichotomous data. For continuous data, we presented the mean difference; and for count and rate data, we used rate ratios. We presented all results with 95% confidence intervals (CIs). We assessed the certainty of evidence using the GRADE approach. MAIN RESULTS: One RCT and six cRCTs met our inclusion criteria, with an additional six ongoing RCTs. We did not identify any eligible non-randomized studies. All included trials were conducted in sub-Saharan Africa since 2009; two randomized by household and four at the block or village level. All trials assessed screening of windows, doors, eaves, ceilings, or any combination of these; this was either alone, or in combination with roof modification or eave tube installation (an insecticidal "lure and kill" device that reduces mosquito entry whilst maintaining some airflow). In one trial, the screening material was treated with 2% permethrin insecticide. In five trials, the researchers implemented the interventions. A community-based approach was adopted in the other trial. Overall, the implementation of house modifications probably reduced malaria parasite prevalence (RR 0.68, 95% CI 0.57 to 0.82; 5 trials, 5183 participants; moderate-certainty evidence), although an inconsistent effect was observed in a subpopulation of children in one study. House modifications reduced moderate to severe anaemia prevalence (RR 0.70, 95% CI 0.55 to 0.89; 3 trials, 3643 participants; high-certainty evidence). There was no consistent effect on clinical malaria incidence, with rate ratios ranging from 0.38 to 1.62 (3 trials, 3365 participants, 4126.6 person-years). House modifications may reduce indoor mosquito density (rate ratio 0.63, 95% CI 0.30 to 1.30; 4 trials, 9894 household-nights; low-certainty evidence), although two studies showed little effect on this parameter. AUTHORS' CONCLUSIONS: House modifications - largely screening, sometimes combined with insecticide and lure and kill devices - were associated with a reduction in malaria parasite prevalence and a reduction in people with anaemia. Findings on malaria incidence were mixed. Modifications were also associated with lower indoor adult mosquito density, but this effect was not present in some studies.

Vector control for malaria prevention during humanitarian emergencies: protocol for a systematic review and meta-analysis.

INTRODUCTION: Humanitarian emergencies, of either natural or anthropogenic origins, are equivalent to major disasters, which can lead to population displacement, food insecurity and health system disruptions. Almost two-thirds of people affected by humanitarian emergencies inhabit malaria endemic regions, particularly the WHO African Region, which currently accounts for 93% and 94% of malaria cases and deaths, respectively. As of late 2020, the United Nations Refugee Agency estimates that there are globally 79.5 million forcibly displaced people, including 45.7 million internally displaced people, 26 million refugees, 4.2 million asylum-seekers and 3.6 million Venezuelans displaced abroad. METHODS AND ANALYSES: A systematic review and meta-analysis will be conducted to evaluate the impact of different vector control interventions on malaria disease burden during humanitarian emergencies. Published and grey literatures will be systematically retrieved from 10 electronic databases and 3 clinical trials registries. A systematic approach to screening, reviewing and data extraction will be applied based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Two review authors will independently assess full-text copies of potentially relevant articles based on inclusion criteria. Included studies will be assessed for risk of bias according to Cochrane and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Eligible studies with reported or measurable risk ratios or ORs with 95% CIs will be included in a meta-analysis. Subgroup analyses, including per study design, emergency phase and primary mode of intervention, may be performed if substantial heterogeneity is encountered. ETHICS AND DISSEMINATION: Ethical approval is not required by the London School of Hygiene and Tropical Medicine to perform secondary analyses of existing anonymous data. Study findings will be disseminated via open-access publications in peer-reviewed journals, presentations to stakeholders and international policy makers, and will contribute to the latest WHO guidelines for malaria control during humanitarian emergencies. PROSPERO REGISTRATION NUMBER: CRD42020214961.

House modifications for preventing malaria.

BACKGROUND: Despite being preventable, malaria remains an important public health problem. The World Health Organization (WHO) reports that overall progress in malaria control has plateaued for the first time since the turn of the century. Researchers and policymakers are therefore exploring alternative and supplementary malaria vector control tools. Research in 1900 indicated that modification of houses may be effective in reducing malaria: this is now being revisited, with new research now examining blocking house mosquito entry points or modifying house construction materials to reduce exposure of inhabitants to infectious bites. OBJECTIVES: To assess the effects of house modifications on malaria disease and transmission. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE (PubMed); Embase (OVID); Centre for Agriculture and Bioscience International (CAB) Abstracts (Web of Science); and the Latin American and Caribbean Health Science Information database (LILACS), up to 1 November 2019. We also searched the WHO International Clinical Trials Registry Platform (www.who.int/ictrp/search/en/), ClinicalTrials.gov (www.clinicaltrials.gov), and the ISRCTN registry (www.isrctn.com/) to identify ongoing trials up to the same date. SELECTION CRITERIA: Randomized controlled trials, including cluster-randomized controlled trials (cRCTs), cross-over studies, and stepped-wedge designs were eligible, as were quasi-experimental trials, including controlled before-and-after studies, controlled interrupted time series, and non-randomized cross-over studies. We only considered studies reporting epidemiological outcomes (malaria case incidence, malaria infection incidence or parasite prevalence). We also summarised qualitative studies conducted alongside included studies. DATA COLLECTION AND ANALYSIS: Two review authors selected eligible studies, extracted data, and assessed the risk of bias. We used risk ratios (RR) to compare the effect of the intervention with the control for dichotomous data. For continuous data, we presented the mean difference; and for count and rate data, we used rate ratios. We presented all results with 95% confidence intervals (CIs). We assessed the certainty of evidence using the GRADE approach. MAIN RESULTS: Six cRCTs met our inclusion criteria, all conducted in sub-Saharan Africa; three randomized by household, two by village, and one at the community level. All trials assessed screening of windows, doors, eaves, ceilings or any combination of these; this was either alone, or in combination with eave closure, roof modification or eave tube installation (a "lure and kill" device that reduces mosquito entry whilst maintaining some airflow). In two trials, the interventions were insecticide-based. In five trials, the researchers implemented the interventions. The community implemented the interventions in the sixth trial. At the time of writing the review, two of the six trials had published results, both of which compared screened houses (without insecticide) to unscreened houses. One trial in Ethiopia assessed screening of windows and doors. Another trial in the Gambia assessed full screening (screening of eaves, doors and windows), as well as screening of ceilings only. Screening may reduce clinical malaria incidence caused by Plasmodium falciparum (rate ratio 0.38, 95% CI 0.18 to 0.82; 1 trial, 184 participants, 219.3 person-years; low-certainty evidence; Ethiopian study). For malaria parasite prevalence, the point estimate, derived from The Gambia study, was smaller (RR 0.84, 95% CI 0.60 to 1.17; 713 participants, 1 trial; low-certainty evidence), and showed an effect on anaemia (RR 0.61, 95% CI 0.42, 0.89; 705 participants; 1 trial, moderate-certainty evidence). Screening may reduce the entomological inoculation rate (EIR): both trials showed lower estimates in the intervention arm. In the Gambian trial, there was a mean difference in EIR between the control houses and treatment houses ranging from 0.45 to 1.50 (CIs ranged from -0.46 to 2.41; low-certainty evidence), depending on the study year and treatment arm. The Ethiopian trial reported a mean difference in EIR of 4.57, favouring screening (95% CI 3.81 to 5.33; low-certainty evidence). Pooled analysis of the trials showed that individuals living in fully screened houses were slightly less likely to sleep under a bed net (RR 0.84, 95% CI 0.65 to 1.09; 2 trials, 203 participants). In one trial, bed net usage was also lower in individuals living in houses with screened ceilings (RR 0.69, 95% CI 0.50 to 0.95; 1 trial, 135 participants). AUTHORS' CONCLUSIONS: Based on the two trials published to date, there is some evidence that screening may reduce malaria transmission and malaria infection in people living in the house. The four trials awaiting publication are likely to enrich the current evidence base, and we will add these to this review when they become available.

House modifications for preventing malaria.

BACKGROUND: Despite being preventable, malaria remains an important public health problem. The World Health Organization (WHO) reports that overall progress in malaria control has plateaued for the first time since the turn of the century. Researchers and policymakers are therefore exploring alternative and supplementary malaria vector control tools. Research in 1900 indicated that modification of houses may be effective in reducing malaria: this is now being revisited, with new research now examining blocking house mosquito entry points or modifying house construction materials to reduce exposure of inhabitants to infectious bites. OBJECTIVES: To assess the effects of house modifications on malaria disease and transmission. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE (PubMed); Embase (OVID); Centre for Agriculture and Bioscience International (CAB) Abstracts (Web of Science); and the Latin American and Caribbean Health Science Information database (LILACS), up to 1 November 2019. We also searched the WHO International Clinical Trials Registry Platform (www.who.int/ictrp/search/en/), ClinicalTrials.gov (www.clinicaltrials.gov), and the ISRCTN registry (www.isrctn.com/) to identify ongoing trials up to the same date. SELECTION CRITERIA: Randomized controlled trials, including cluster-randomized controlled trials (cRCTs), cross-over studies, and stepped-wedge designs were eligible, as were quasi-experimental trials, including controlled before-and-after studies, controlled interrupted time series, and non-randomized cross-over studies. We only considered studies reporting epidemiological outcomes (malaria case incidence, malaria infection incidence or parasite prevalence). We also summarised qualitative studies conducted alongside included studies. DATA COLLECTION AND ANALYSIS: Two review authors selected eligible studies, extracted data, and assessed the risk of bias. We used risk ratios (RR) to compare the effect of the intervention with the control for dichotomous data. For continuous data, we presented the mean difference; and for count and rate data, we used rate ratios. We presented all results with 95% confidence intervals (CIs). We assessed the certainty of evidence using the GRADE approach. MAIN RESULTS: Six cRCTs met our inclusion criteria, all conducted in sub-Saharan Africa; three randomized by household, two by village, and one at the community level. All trials assessed screening of windows, doors, eaves, ceilings or any combination of these; this was either alone, or in combination with eave closure, roof modification or eave tube installation (a "lure and kill" device that reduces mosquito entry whilst maintaining some airflow). In two trials, the interventions were insecticide-based. In five trials, the researchers implemented the interventions. The community implemented the interventions in the sixth trial. At the time of writing the review, two of the six trials had published results, both of which compared screened houses (without insecticide) to unscreened houses. One trial in Ethiopia assessed screening of windows and doors. Another trial in the Gambia assessed full screening (screening of eaves, doors and windows), as well as screening of ceilings only. Screening may reduce clinical malaria incidence caused by Plasmodium falciparum (rate ratio 0.38, 95% CI 0.18 to 0.82; 1 trial, 184 participants, 219.3 person-years; low-certainty evidence; Ethiopian study). For malaria parasite prevalence, the point estimate, derived from The Gambia study, was smaller (RR 0.84, 95% CI 0.60 to 1.17; 713 participants, 1 trial; moderate-certainty evidence), and showed an effect on anaemia (RR 0.61, 95% CI 0.42, 0.89; 705 participants; 1 trial, moderate-certainty evidence). Screening may reduce the entomological inoculation rate (EIR): both trials showed lower estimates in the intervention arm. In the Gambian trial, there was a mean difference in EIR between the control houses and treatment houses ranging from 0.45 to 1.50 (CIs ranged from -0.46 to 2.41; low-certainty evidence), depending on the study year and treatment arm. The Ethiopian trial reported a mean difference in EIR of 4.57, favouring screening (95% CI 3.81 to 5.33; low-certainty evidence). Pooled analysis of the trials showed that individuals living in fully screened houses were slightly less likely to sleep under a bed net (RR 0.84, 95% CI 0.65 to 1.09; 2 trials, 203 participants). In one trial, bed net usage was also lower in individuals living in houses with screened ceilings (RR 0.69, 95% CI 0.50 to 0.95; 1 trial, 135 participants). AUTHORS' CONCLUSIONS: Based on the two trials published to date, there is some evidence that screening may reduce malaria transmission and malaria infection in people living in the house. The four trials awaiting publication are likely to enrich the current evidence base, and we will add these to this review when they become available.

Indoor use of attractive toxic sugar bait in combination with long-lasting insecticidal net against pyrethroid-resistant Anopheles gambiae: an experimental hut trial in Mbé, central Côte d'Ivoire.

BACKGROUND: Indoor attractive toxic sugar bait (ATSB) has potential as a supplementary vector-control and resistance-management tool, offering an alternative mode of insecticide delivery to current core vector-control interventions, with potential to deliver novel insecticides. Given the high long-lasting insecticidal bed net (LLIN) coverage across Africa, it is crucial that the efficacy of indoor ATSB in combination with LLINs is established before it is considered for wider use in public health. METHODS: An experimental hut trial to evaluate the efficacy of indoor ATSB traps treated with 4% boric acid (BA ATSB) or 1% chlorfenapyr (CFP ATSB) in combination with untreated nets or LLINs (holed or intact), took place at the M'bé field station in central Côte d'Ivoire against pyrethroid resistant Anopheles gambiae sensu lato. RESULTS: The addition of ATSB to LLINs increased the mortality rates of wild pyrethroid-resistant An. gambiae from 19% with LLIN alone to 28% with added BA ATSB and to 39% with added CFP ATSB (p < 0.001). Anopheles gambiae mortality with combined ATSB and untreated net was similar to that of combined ATSB and LLIN regardless of which insecticide was used in the ATSB. The presence of holes in the LLIN did not significantly affect ATSB-induced An. gambiae mortality. Comparative tests against pyrethroid resistant and susceptible strains using oral application of ATSB treated with pyrethroid demonstrated 66% higher survival rate among pyrethroid-resistant mosquitoes. CONCLUSION: Indoor ATSB traps in combination with LLINs enhanced the control of pyrethroid-resistant An. gambiae. However, many host-seeking An. gambiae entering experimental huts with indoor ATSB exited into the verandah trap without sugar feeding when restricted from a host by a LLIN. Although ATSB has potential for making effective use of classes of insecticide otherwise unsuited to vector control, it does not exempt potential selection of resistance via this route.