Piperonyl butoxide (PBO) combined with pyrethroids in insecticide‐treated nets to prevent malaria in Africa

Abstract Background Pyrethroid long‐lasting insecticidal nets (LLINs) have been important in the large reductions in malaria cases in Africa, but insecticide resistance in Anopheles mosquitoes threatens their impact. Insecticide synergists may help control insecticide‐resistant populations. Piperonyl butoxide (PBO) is such a synergist; it has been incorporated into pyrethroid‐LLINs to form pyrethroid‐PBO nets, which are currently produced by five LLIN manufacturers and, following a recommendation from the World Health Organization (WHO) in 2017, are being included in distribution campaigns. This review examines epidemiological and entomological evidence on the addition of PBO to pyrethroid nets on their efficacy. Objectives To compare effects of pyrethroid‐PBO nets currently in commercial development or on the market with effects of their non‐PBO equivalent in relation to: 1. malaria parasite infection (prevalence or incidence); and 2. entomological outcomes. Search methods We 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 25 September 2020. We contacted organizations for unpublished data. We checked the reference lists of trials identified by these methods. Selection criteria We included experimental hut trials, village trials, and randomized controlled trials (RCTs) with mosquitoes from the Anopheles gambiae complex or the Anopheles funestus group. Data collection and analysis Two 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 data using Review Manager 5 and assessed the certainty of evidence using the GRADE approach. Main results Sixteen trials met the inclusion criteria: 10 experimental hut trials, four village trials, and two cluster‐RCTs (cRCTs). Three trials are awaiting classification, and four trials are ongoing. Two cRCTs examined the effects of pyrethroid‐PBO nets on parasite prevalence in people living in areas with highly pyrethroid‐resistant mosquitoes (< 30% mosquito mortality in discriminating dose assays). At 21 to 25 months post intervention, parasite prevalence was lower in the intervention arm (odds ratio (OR) 0.79, 95% confidence interval (CI) 0.67 to 0.95; 2 trials, 2 comparisons; moderate‐certainty evidence). In highly pyrethroid‐resistant areas, unwashed pyrethroid‐PBO nets led to higher mosquito mortality compared to unwashed standard‐LLINs (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 had 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 did 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 moderate (31% to 60% mosquito mortality), mosquito mortality was higher with unwashed pyrethroid‐PBO nets compared to unwashed standard‐LLINs (RR 1.68, 95% CI 1.33 to 2.11; 1007 mosquitoes, 2 trials, 3 comparisons; moderate‐certainty evidence), but there was little to no difference in effects on blood‐feeding success (RR 0.90, 95% CI 0.72 to 1.11; 1006 mosquitoes, 2 trials, 3 comparisons; moderate‐certainty evidence). For washed pyrethroid‐PBO nets compared to washed standard‐LLINs, we found little to no evidence for higher mosquito mortality or reduced blood feeding (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), studies reported little to no difference in the effects of unwashed pyrethroid‐PBO nets compared to unwashed standard‐LLINs on mosquito mortality (RR 1.25, 95% CI 0.99 to 1.57; 1580 mosquitoes, 2 trials, 3 comparisons; moderate‐certainty evidence), and we do not know if there was any effect on blood‐feeding success (RR 0.75, 95% CI 0.27 to 2.11; 1580 mosquitoes, 2 trials, 3 comparisons; very low‐certainty evidence). For washed pyrethroid‐PBO nets compared to washed standard‐LLINs, we do not know if there was any difference in mosquito mortality (RR 1.39, 95% CI 0.95 to 2.04; 1774 mosquitoes, 2 trials, 3 comparisons; very low‐certainty evidence) or on blood feeding (RR 1.07, 95% CI 0.49 to 2.33; 1774 mosquitoes, 2 trials, 3 comparisons; low‐certainty evidence). In areas where mosquito populations are susceptible to insecticides (> 90% mosquito mortality), there may be little to no difference in the effects 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 had any effect on the blood‐feeding success of susceptible mosquitoes (RR 0.52, 95% CI 0.12 to 2.22; 2791 mosquitoes, 2 trials, 2 comparisons; very low‐certainty evidence). The same applies to washed nets (RR 1.25, 95% CI 0.82 to 1.91; 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 comparisons) nor in mosquito parity (3 trials, 4 comparisons). Authors' conclusions In areas of high insecticide resistance, pyrethroid‐PBO nets have greater entomological and epidemiological efficacy compared to standard LLINs, with sustained reduction in parasite prevalence, higher mosquito mortality and reduction in mosquito blood feeding rates 21 to 25 months post intervention. Questions remain about the durability of PBO on nets, as the impact of pyrethroid‐PBO nets on mosquito mortality was not sustained over 20 washes in experimental hut trials, and epidemiological data on pyrethroid‐PBO nets for the full intended three‐year life span of the nets is not available. Little evidence is available to support greater entomological efficacy of pyrethroid‐PBO nets in areas where mosquitoes show lower levels of resistance to pyrethroids.