scholarly journals Escalation of Pyrethroid Resistance in the Malaria Vector Anopheles funestus Induces a Loss of Efficacy of Piperonyl Butoxide–Based Insecticide-Treated Nets in Mozambique

2019 ◽  
Vol 220 (3) ◽  
pp. 467-475 ◽  
Author(s):  
Jacob M Riveron ◽  
Silvie Huijben ◽  
Williams Tchapga ◽  
Magellan Tchouakui ◽  
Murielle J Wondji ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Pyrethroid Resistance ◽  
Anopheles Funestus ◽  
Resistance Mechanisms ◽  
Piperonyl Butoxide ◽  
Insecticide Treated Nets ◽  
Molecular Analyses ◽  
Cytochrome P450 Genes ◽  
High Degree ◽  
Long Lasting Insecticidal Nets

Abstract Background Insecticide resistance poses a serious threat to insecticide-based interventions in Africa. There is a fear that resistance escalation could jeopardize malaria control efforts. Monitoring of cases of aggravation of resistance intensity and its impact on the efficacy of control tools is crucial to predict consequences of resistance. Methods The resistance levels of an Anopheles funestus population from Palmeira, southern Mozambique, were characterized and their impact on the efficacy of various insecticide-treated nets established. Results A dramatic loss of efficacy of all long-lasting insecticidal nets (LLINs), including piperonyl butoxide (PBO)–based nets (Olyset Plus), was observed. This An. funestus population consistently (2016, 2017, and 2018) exhibited a high degree of pyrethroid resistance. Molecular analyses revealed that this resistance escalation was associated with a massive overexpression of the duplicated cytochrome P450 genes CYP6P9a and CYP6P9b, and also the fixation of the resistance CYP6P9a_R allele in this population in 2016 (100%) in contrast to 2002 (5%). However, the low recovery of susceptibility after PBO synergist assay suggests that other resistance mechanisms could be involved. Conclusions The loss of efficacy of pyrethroid-based LLINs with and without PBO is a concern for the effectiveness of insecticide-based interventions, and action should be taken to prevent the spread of such super-resistance.

scholarly journals Pyrethroid Resistance Aggravation in Ugandan Malaria Vectors Is Reducing Bednet Efficacy

Pathogens ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 415
Author(s):  
Magellan Tchouakui ◽  
Leon M. J. Mugenzi ◽  
Benjamin D. Menze ◽  
Jude N. T. Khaukha ◽  
Williams Tchapga ◽  
...  
Keyword(s):  
High Intensity ◽  
Pyrethroid Resistance ◽  
Anopheles Funestus ◽  
Resistance Mechanisms ◽  
Malaria Vectors ◽  
Insecticide Treated Nets ◽  
Over Expression ◽  
Cytochrome P450 Genes ◽  
Long Lasting Insecticidal Nets ◽  
Urgent Action

Monitoring cases of insecticide resistance aggravation and the effect on the efficacy of control tools is crucial for successful malaria control. In this study, the resistance intensity of major malaria vectors from Uganda was characterised and its impact on the performance of various insecticide-treated nets elucidated. High intensity of resistance to the discriminating concentration (DC), 5× DC, and 10× DC of pyrethroids was observed in both Anopheles funestus and Anopheles gambiae in Mayuge and Busia leading to significant reduced performance of long-lasting insecticidal nets (LLINs) including the piperonyl butoxide (PBO)-based nets (Olyset Plus). Molecular analysis revealed significant over-expression of cytochrome P450 genes (CYP9K1 and CYP6P9a/b). However, the expression of these genes was not associated with resistance escalation as no difference was observed in the level of expression in mosquitoes resistant to 5× DC and 10× DC compared to 1× DC suggesting that other resistance mechanisms are involved. Such high intensity of pyrethroid resistance in Uganda could have terrible consequences on the effectiveness of insecticide-based interventions and urgent action should be taken to prevent the spread of super-resistance in malaria vectors.

scholarly journals Evaluating insecticide resistance across African districts to aid malaria control decisions

2020 ◽  
Vol 117 (36) ◽  
pp. 22042-22050 ◽  
Author(s):  
Catherine L. Moyes ◽  
Duncan K. Athinya ◽  
Tara Seethaler ◽  
Katherine E. Battle ◽  
Marianne Sinka ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Pyrethroid Resistance ◽  
Resistance Mechanisms ◽  
World Health ◽  
Malaria Vector Control ◽  
Ensemble Model ◽  
Metabolic Resistance ◽  
The World ◽  
Susceptibility Tests ◽  
Health Organization

Malaria vector control may be compromised by resistance to insecticides in vector populations. Actions to mitigate against resistance rely on surveillance using standard susceptibility tests, but there are large gaps in the monitoring data across Africa. Using a published geostatistical ensemble model, we have generated maps that bridge these gaps and consider the likelihood that resistance exceeds recommended thresholds. Our results show that this model provides more accurate next-year predictions than two simpler approaches. We have used the model to generate district-level maps for the probability that pyrethroid resistance inAnopheles gambiaes.l. exceeds the World Health Organization thresholds for susceptibility and confirmed resistance. In addition, we have mapped the three criteria for the deployment of piperonyl butoxide-treated nets that mitigate against the effects of metabolic resistance to pyrethroids. This includes a critical review of the evidence for presence of cytochrome P450-mediated metabolic resistance mechanisms across Africa. The maps for pyrethroid resistance are available on the IR Mapper website, where they can be viewed alongside the latest survey data.

scholarly journals Evaluating the Evidence from Molecular Structure and Population Studies for Cross-Resistance to the Pyrethroids Used in Malaria Vector Control

2020 ◽  
Author(s):  
Catherine L. Moyes ◽  
Rosemary S. Lees ◽  
Cristina Yunta ◽  
Kyle J. Walker ◽  
Kay Hemmings ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Malaria Vector ◽  
Pyrethroid Resistance ◽  
Anopheles Funestus ◽  
Malaria Vectors ◽  
Cross Resistance ◽  
Malaria Vector Control ◽  
Insecticide Treated Nets ◽  
The Common ◽  
The Impact

Abstract The primary malaria control intervention in high burden countries is the deployment of long-lasting insecticide-treated nets (LLINs) treated with pyrethroids, alone or in combination with a second active ingredient or synergist. It is essential to understand whether the impact of pyrethroid resistance can be mitigated by switching between different pyrethroids or whether cross-resistance precludes this. Structural diversity within the pyrethroids could mean some compounds are better able to counteract the resistance mechanisms that have evolved in malaria vectors. Here we consider variation in vulnerability to the P450 enzymes that confer metabolic pyrethroid resistance in Anopheles gambiae s.l. and Anopheles funestus. We assess the relationships among pyrethroids in terms of their binding affinity to key P450s and the percent dep­letion by these P450s, in order to identify which pyrethroids diverge from the others. We then investigate whether these same pyrethroids also diverge from the others in terms of resistance in vector populations. We found that etofenprox, which lacks the common structural moiety of other pyrethroids, potentially diverges from the commonly deployed pyrethroids in terms of P450 binding affinity and resistance in malaria vector populations, but not depletion by the P450s tested. These results are supplemented by an analysis of resistance to the same pyrethroids in Aedes aegypti populations, which also found etofenprox diverges from the other pyrethroids in terms of resistance in wild populations. In addition, we found that bifenthrin, which also lacks the common structural moiety of most pyrethroids, diverges from the commonly deployed pyrethroids in terms of P450 binding affinity and depletion by P450s. However, resistance to bifenthrin in vector populations is largely untested. The prevalence of resistance to the pyrethroids α-cypermethrin, cyfluthrin, deltamethrin, λ-cyhalothrin, and permethrin was correlated across malaria vector populations and switching between these compounds as a tool to mitigate against pyrethroid resistance is not advised without strong evidence supporting a true difference in resistance.

scholarly journals A quasi-experimental study estimating the impact of long-lasting insecticidal nets with and without piperonyl butoxide on pregnancy outcomes

2022 ◽  
Vol 21 (1) ◽  
Author(s):  
Michelle E. Roh ◽  
Brenda Oundo ◽  
Grant Dorsey ◽  
Stephen Shiboski ◽  
Roly Gosling ◽  
...  
Keyword(s):  
Pregnancy Outcomes ◽  
Low Birthweight ◽  
Pyrethroid Resistance ◽  
Controlled Trial ◽  
Piperonyl Butoxide ◽  
Difference In Differences ◽  
Quasi Experimental ◽  
The Impact ◽  
Long Lasting Insecticidal Nets ◽  
In Pregnancy

Abstract Background Long-lasting insecticidal nets (LLINs) are the main vector control tool for pregnant women, but their efficacy may be compromised, in part, due to pyrethroid resistance. In 2017, the Ugandan Ministry of Health embedded a cluster randomized controlled trial into the national LLIN campaign, where a random subset of health subdistricts (HSDs) received LLINs treated with piperonyl butoxide (PBO), a chemical synergist known to partially restore pyrethroid sensitivity. Using data from a small, non-randomly selected subset of HSDs, this secondary analysis used quasi-experimental methods to quantify the overall impact of the LLIN campaign on pregnancy outcomes. In an exploratory analysis, differences between PBO and conventional (non-PBO) LLINs on pregnancy outcomes were assessed. Methods Birth registry data (n = 39,085) were retrospectively collected from 21 health facilities across 12 HSDs, 29 months before and 9 months after the LLIN campaign (from 2015 to 2018). Of the 12 HSDs, six received conventional LLINs, five received PBO LLINs, and one received a mix of conventional and PBO LLINs. Interrupted time-series analyses (ITSAs) were used to estimate changes in monthly incidence of stillbirth and low birthweight (LBW; <2500 g) before-and-after the campaign. Poisson regression with robust standard errors modeled campaign effects, adjusting for health facility-level differences, seasonal variation, and time-varying maternal characteristics. Comparisons between PBO and conventional LLINs were estimated using difference-in-differences estimators. Results ITSAs estimated the campaign was associated with a 26% [95% CI: 7–41] reduction in stillbirth incidence (incidence rate ratio (IRR) = 0.74 [0.59–0.93]) and a 15% [-7, 33] reduction in LBW incidence (IRR=0.85 [0.67–1.07]) over a 9-month period. The effect on stillbirth incidence was greatest for women delivering 7–9 months after the campaign (IRR=0.60 [0.41–0.87]) for whom the LLINs would have covered most of their pregnancy. The IRRs estimated from difference-in-differences analyses comparing PBO to conventional LLINs was 0.78 [95% CI: 0.52, 1.16] for stillbirth incidence and 1.15 [95% CI: 0.87, 1.52] for LBW incidence. Conclusions In this region of Uganda, where pyrethroid resistance is high, this study found that a mass LLIN campaign was associated with reduced stillbirth incidence. Effects of the campaign were greatest for women who would have received LLINs early in pregnancy, suggesting malaria protection early in pregnancy can have important benefits that are not necessarily realized through antenatal malaria services. Results from the exploratory analyses comparing PBO and conventional LLINs on pregnancy outcomes were inconclusive, largely due to the wide confidence intervals that crossed the null. Thus, future studies with larger sample sizes are needed.

scholarly journals Evidence supporting deployment of next generation insecticide treated nets in Burkina Faso: bioassays with either chlorfenapyr or piperonyl butoxide increase mortality of pyrethroid-resistant Anopheles gambiae s.l.

2021 ◽  
Author(s):  
Sawdetuo Aristide HIEN ◽  
Dieudonné D. Soma ◽  
Dramane Coulibaly ◽  
Abdoulaye Diabaté ◽  
Allison Belemvire ◽  
...  
Keyword(s):  
Burkina Faso ◽  
Anopheles Gambiae ◽  
High Intensity ◽  
Large Scale ◽  
Pyrethroid Resistance ◽  
Piperonyl Butoxide ◽  
Sub Saharan Africa ◽  
Insecticide Treated Nets ◽  
Bobo Dioulasso ◽  
Sub Saharan

Abstract Background Pyrethroid resistance poses a major threat to the efficacy of insecticide treated nets (ITNs) in Burkina Faso and throughout sub-Saharan Africa, particularly when resistance is present at high intensity. For such areas there are alternative ITNs available, including the synergist piperonyl butoxide (PBO)-based ITNs and dual active ingredient ITNs such as Interceptor G2 (treated with chlorfenapyr and alpha-cypermethrin). Before deploying alternative ITNs on a large scale it is crucial to characterize the resistance profiles of primary malaria vector species for evidence-based decision making Methods Larvae from the predominant vector, Anopheles gambiae s.l., were collected from 15 sites located throughout Burkina Faso and reared to adults for bioassays to assess insecticide resistance status. Resistance intensity assays were conducted using WHO tube tests to determine the level of resistance to pyrethroids commonly used on ITNs at 1x, 5x and 10x times the diagnostic dose. WHO tube tests were also used for PBO synergist bioassays with deltamethrin and permethrin. Bottle bioassays were conducted to determine susceptibility to chlorfenapyr at a dose of 100µg/bottle. Results WHO tube tests revealed high intensity resistance in An. gambiae s.l. to deltamethrin and alpha-cypermethrin in all sites tested. Resistance intensity to permethrin was either moderate or high in 13 sites. PBO pre-exposure followed by deltamethrin restored full susceptibility in 1 site but partially restored susceptibility in all but one of the remaining sites (often reaching mortality greater than 80%). PBO pre-exposure followed by permethrin partially restored susceptibility in 12 sites. There was no significant increase in permethrin mortality after PBO pre-exposure in Kampti, Karangasso-Vigué or Mangodara; while in Seguenega, Orodara and Bobo-Dioulasso there was a significant increase in mortality, but rates remained below 50%. Susceptibility to chlorfenapyr was confirmed in 14 sites. Conclusion High pyrethroid resistance intensity in An. gambiae s.l. is widespread across Burkina Faso and may be a predictor of reduced pyrethroid ITN effectiveness. PBO + deltamethrin ITNs would likely provide greater control than pyrethroid nets. However, since susceptibility in bioassays was not restored in most sites following pre-exposure to PBO, Interceptor G2 may be a better long-term solution as susceptibility was recorded to chlorfenapyr in nearly all sites. This study provides evidence supporting the introduction of both Interceptor G2 nets and PBO nets, which were distributed in Burkina Faso in 2019 as part of a mass campaign.

scholarly journals Evidence supporting deployment of next generation insecticide treated nets in Burkina Faso: bioassays with either chlorfenapyr or piperonyl butoxide increase mortality of pyrethroid-resistant Anopheles gambiae

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Aristide S. Hien ◽  
Dieudonné D. Soma ◽  
Samina Maiga ◽  
Dramane Coulibaly ◽  
Abdoulaye Diabaté ◽  
...  
Keyword(s):  
Burkina Faso ◽  
Anopheles Gambiae ◽  
High Intensity ◽  
Large Scale ◽  
Pyrethroid Resistance ◽  
Piperonyl Butoxide ◽  
Sub Saharan Africa ◽  
Insecticide Treated Nets ◽  
Bobo Dioulasso ◽  
Sub Saharan

Abstract Background Pyrethroid resistance poses a major threat to the efficacy of insecticide-treated nets (ITNs) in Burkina Faso and throughout sub-Saharan Africa, particularly where resistance is present at high intensity. For such areas, there are alternative ITNs available, including the synergist piperonyl butoxide (PBO)-based ITNs and dual active ingredient ITNs such as Interceptor G2 (treated with chlorfenapyr and alpha-cypermethrin). Before deploying alternative ITNs on a large scale it is crucial to characterize the resistance profiles of primary malaria vector species for evidence-based decision making. Methods Larvae from the predominant vector, Anopheles gambiae sensu lato (s.l.) were collected from 15 sites located throughout Burkina Faso and reared to adults for bioassays to assess insecticide resistance status. Resistance intensity assays were conducted using WHO tube tests to determine the level of resistance to pyrethroids commonly used on ITNs at 1×, 5 × and 10 × times the diagnostic dose. WHO tube tests were also used for PBO synergist bioassays with deltamethrin and permethrin. Bottle bioassays were conducted to determine susceptibility to chlorfenapyr at a dose of 100 µg/bottle. Results WHO tube tests revealed high intensity resistance in An. gambiae s.l. to deltamethrin and alpha-cypermethrin in all sites tested. Resistance intensity to permethrin was either moderate or high in 13 sites. PBO pre-exposure followed by deltamethrin restored full susceptibility in one site and partially restored susceptibility in all but one of the remaining sites (often reaching mortality greater than 80%). PBO pre-exposure followed by permethrin partially restored susceptibility in 12 sites. There was no significant increase in permethrin mortality after PBO pre-exposure in Kampti, Karangasso-Vigué or Mangodara; while in Seguenega, Orodara and Bobo-Dioulasso there was a significant increase in mortality, but rates remained below 50%. Susceptibility to chlorfenapyr was confirmed in 14 sites. Conclusion High pyrethroid resistance intensity in An. gambiae s.l. is widespread across Burkina Faso and may be a predictor of reduced pyrethroid ITN effectiveness. PBO + deltamethrin ITNs would likely provide greater control than pyrethroid nets. However, since susceptibility in bioassays was not restored in most sites following pre-exposure to PBO, Interceptor G2 may be a better long-term solution as susceptibility was recorded to chlorfenapyr in nearly all sites. This study provides evidence supporting the introduction of both Interceptor G2 nets and PBO nets, which were distributed in Burkina Faso in 2019 as part of a mass campaign.

scholarly journals Cis-regulatory CYP6P9b P450 variants associated with loss of insecticide-treated bed net efficacy against Anopheles funestus

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Leon M. J. Mugenzi ◽  
Benjamin D. Menze ◽  
Magellan Tchouakui ◽  
Murielle J. Wondji ◽  
Helen Irving ◽  
...  
Keyword(s):  
Pyrethroid Resistance ◽  
Resistance Management ◽  
Anopheles Funestus ◽  
Central Africa ◽  
Malaria Vectors ◽  
Insecticide Treated Nets ◽  
Metabolic Resistance ◽  
P450 Gene ◽  
Regulatory Variants ◽  
The Impact

Abstract Elucidating the genetic basis of metabolic resistance to insecticides in malaria vectors is crucial to prolonging the effectiveness of insecticide-based control tools including long lasting insecticidal nets (LLINs). Here, we show that cis-regulatory variants of the cytochrome P450 gene, CYP6P9b, are associated with pyrethroid resistance in the African malaria vector Anopheles funestus. A DNA-based assay is designed to track this resistance that occurs near fixation in southern Africa but not in West/Central Africa. Applying this assay we demonstrate, using semi-field experimental huts, that CYP6P9b-mediated resistance associates with reduced effectiveness of LLINs. Furthermore, we establish that CYP6P9b combines with another P450, CYP6P9a, to additively exacerbate the reduced efficacy of insecticide-treated nets. Double homozygote resistant mosquitoes (RR/RR) significantly survive exposure to insecticide-treated nets and successfully blood feed more than other genotypes. This study provides tools to track and assess the impact of multi-gene driven metabolic resistance to pyrethroids, helping improve resistance management.

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