• Katherine Gleave, Natalie Lissenden, Marty Richardson, Leslie Choi, and Hilary Ranson.
• Department of Vector Biology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, UK, L3 5QA.
• Cochrane Db Syst Rev. 2018 Nov 29; 11 (11): CD012776CD012776.

BackgroundPublic health strategies that target mosquito vectors, particularly pyrethroid long-lasting insecticidal nets (LLINs), have been largely responsible for the substantial reduction in the number of people in Africa developing malaria. The spread of insecticide resistance in Anopheles mosquitoes threatens these impacts. One way to control insecticide-resistant populations is by using insecticide synergists. Piperonyl butoxide (PBO) is a synergist that inhibits specific metabolic enzymes within mosquitoes and has been incorporated into pyrethroid-LLINs to form pyrethroid-PBO nets. Pyrethroid-PBO nets are currently produced by four LLIN manufacturers and, following a recommendation from the World Health Organization (WHO) in 2017, are being included in distribution campaigns in countries. This review examines epidemiological and entomological evidence on whether the addition of PBO to LLINs improves their efficacy.Objectives1. Evaluate whether adding PBO to pyrethroid LLINs increases the epidemiological and entomological effectiveness of the nets.2. Compare the effects of pyrethroid-PBO nets currently in commercial development or on the market with their non-PBO equivalent in relation to:a. malaria infection (prevalence or incidence);b. entomological outcomes.Search MethodsWe searched the Cochrane Infectious Diseases Group (CIDG) Specialized Register; CENTRAL, MEDLINE, Embase, Web of Science, CAB Abstracts, and two clinical trial registers (ClinicalTrials.gov and WHO International Clinical Trials Registry Platform) up to 24 August 2018. We contacted organizations for unpublished data. We checked the reference lists of trials identified by the above methods.Selection CriteriaWe included laboratory trials, experimental hut trials, village trials, and randomized clinical trials with mosquitoes from the Anopheles gambiae complex or Anopheles funestus group.Data Collection And AnalysisTwo review authors assessed each trial for eligibility, extracted data, and determined the risk of bias for included trials. We resolved disagreements through discussion with a third review author. We analysed the data using Review Manager 5 and assessed the certainty of the evidence using the GRADE approach.Main ResultsFifteen trials met the inclusion criteria: two laboratory trials, eight experimental hut trials, and five cluster-randomized controlled village trials.One village trial examined the effect of pyrethroid-PBO nets on malaria infection prevalence in an area with highly pyrethroid-resistant mosquitoes. The latest endpoint at 21 months post-intervention showed that malaria prevalence probably decreased in the intervention arm (OR 0.40, 95% CI 0.20 to 0.80; 1 trial, 1 comparison, moderate-certainty evidence).In highly pyrethroid-resistant areas (< 30% mosquito mortality), in comparisons of unwashed pyrethroid-PBO nets to unwashed standard-LLINs, PBO nets resulted in higher mosquito mortality (risk ratio (RR) 1.84, 95% CI 1.60 to 2.11; 14,620 mosquitoes, 5 trials, 9 comparisons, high-certainty evidence) and lower blood feeding success (RR 0.60, 95% CI 0.50 to 0.71; 14,000 mosquitoes, 4 trials, 8 comparisons, high-certainty evidence). However, in comparisons of washed pyrethroid-PBO nets to washed LLINs we do not know if PBO nets have a greater effect on mosquito mortality (RR 1.20, 95% CI 0.88 to 1.63; 10,268 mosquitoes, 4 trials, 5 comparisons, very low-certainty evidence), although the washed pyrethroid-PBO nets do decrease blood feeding success compared to standard-LLINs (RR 0.81, 95% CI 0.72 to 0.92; 9674 mosquitoes, 3 trials, 4 comparisons, high-certainty evidence).In areas where pyrethroid resistance is considered moderate (31% to 60% mosquito mortality), there may be little or no difference in effects of unwashed pyrethroid-PBO nets compared to unwashed standard-LLINs on mosquito mortality (RR 1.16, 95% CI 0.88 to 1.54; 242 mosquitoes, 1 trial, 1 comparison, low-certainty evidence), and there may be little or no difference in the effects on blood feeding success (RR 0.87, 95% CI 0.67 to 1.13; 242 mosquitoes, 1 trial, 1 comparison, low-certainty evidence). The same pattern is apparent for washed pyrethroid-PBO nets compared to washed standard-LLINs (mortality: RR 1.07, 95% CI 0.74 to 1.54; 329 mosquitoes, 1 trial, 1 comparison, low-certainty evidence; blood feeding success: RR 0.91, 95% CI 0.74 to 1.13; 329 mosquitoes, 1 trial, 1 comparison, low-certainty evidence).In areas where pyrethroid resistance is low (61% to 90% mosquito mortality), there is probably little or no difference in the effect of unwashed pyrethroid-PBO nets compared to unwashed standard-LLINs on mosquito mortality (RR 1.10, 95% CI 1.05 to 1.16; 708 mosquitoes, 1 trial, 2 comparisons, moderate-certainty evidence), but there is no evidence for an effect on blood feeding success (RR 0.67, 95% CI 0.06 to 7.37; 708 mosquitoes, 1 trial, 2 comparisons, very low-certainty evidence). For washed pyrethroid-PBO nets compared to washed standard-LLINs we do not know if there is any difference in mosquito mortality (RR 1.16, 96% CI 0.83 to 1.63; 878 mosquitoes, 1 trial, 2 comparisons, very low-certainty evidence), but blood feeding may decrease (RR 1.50, 95% CI 0.89 to 2.54; 878 mosquitoes, 1 trial, 2 comparisons, low-certainty evidence).In areas were mosquito populations are susceptible to insecticides (> 90% mosquito mortality), there may be little or no difference in the effect of unwashed pyrethroid-PBO nets compared to unwashed standard-LLINs on mosquito mortality (RR 1.20, 95% CI 0.64 to 2.26; 2791 mosquitoes, 2 trials, 2 comparisons, low-certainty evidence). This is similar for washed nets (RR 1.07, 95% CI 0.92 to 1.25; 2644 mosquitoes, 2 trials, 2 comparisons, low-certainty evidence). We do not know if unwashed pyrethroid-PBO nets have any effect on blood feeding success of susceptible mosquitoes (RR 0.50, 95% CI 0.11 to 2.32; 2791 mosquitoes, 2 trials, 2 comparisons, very low-certainty evidence). The same applies to washed nets (RR 1.28, 95% CI 0.81 to 2.04; 2644 mosquitoes, 2 trials, 2 comparisons, low-certainty evidence).In village trials comparing pyrethroid-PBO nets to LLINs, there was no difference in sporozoite rate (4 trials, 5 comparison) and mosquito parity (3 trials, 4 comparisons).Authors' ConclusionsIn areas of high insecticide resistance, pyrethroid-PBO nets reduce mosquito mortality and blood feeding rates, and results from a single clinical trial demonstrate that this leads to lower malaria prevalence. Questions remain about the durability of PBO on nets, as the impact of pyrethroid-PBO LLINs on mosquito mortality was not sustained over 20 washes in experimental hut trials. There is little evidence to support higher entomological efficacy of pyrethroid-PBO nets in areas where the mosquitoes show lower levels of resistance to pyrethroids.

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