Effectiveness and durability of insecticide mixtures for pyrethroid resistance in sub-Saharan Africa

Pyrethroid (PY) resistance is now rampant in most malaria-endemic countries, threatening to lower the effectiveness of standard long-lasting insecticide nets (LLINs) treated with PY only. Of the 88 countries that reported data on insecticide resistance monitoring to the WHO for the period 2010–2020, nearly all of them confirmed resistance to at least one insecticide in one malaria vector species.1WHOWorld malaria report 2022.https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2022Date: 2022Date accessed: July 9, 2023Google Scholar The next generation of LLINs that combine a PY with a synergist or another active ingredient promises to preserve the utility of LLINs in malaria prevention. There is evidence that these novel combinations are effective in reducing malaria incidence and achieving required entomological outcomes. Two recent landmark trials in Tanzania2Mosha JF Kulkarni MA Lukole E et al.Effectiveness and cost-effectiveness against malaria of three types of dual-active-ingredient long-lasting insecticidal nets (LLINs) compared with pyrethroid-only LLINs in Tanzania: a four-arm, cluster-randomised trial.Lancet. 2022; 399: 1227-1241Summary Full Text Full Text PDF PubMed Scopus (35) Google Scholar and Benin3Accrombessi M Cook J Dangbenon E et al.Efficacy of pyriproxyfen-pyrethroid long-lasting insecticidal nets (LLINs) and chlorfenapyr-pyrethroid LLINs compared with pyrethroid-only LLINs for malaria control in Benin: a cluster-randomised, superiority trial.Lancet. 2023; 401: 435-446Summary Full Text Full Text PDF PubMed Scopus (15) Google Scholar showed superiority of chlorfenapyr plus α cypermethrin compared with α cypermethrin either alone or in combination with other active ingredients. In the two studies, outcomes were reported at 24 months of follow-up. The long-term durability of this protection is critical, especially given that LLIN are intended to last a 3-year cycle in most national distribution cycles before they are replaced. In The Lancet Infectious Diseases, Jacklin F Mosha and colleagues4Mosha JF Matowo NS Kulkarni MA et al.Effectiveness of long-lasting insecticidal nets with pyriproxyfen–pyrethroid, chlorfenapyr–pyrethroid, or piperonyl butoxide–pyrethroid versus pyrethroid only against malaria in Tanzania: final-year results of a four-arm, single-blind, cluster-randomised trial.Lancet Infect Dis. 2023; (published online Sept 27.)https://doi.org/10.1016/S1473-3099(23)00420-6Google Scholar follow up participants to 36 months and provide the results of the final follow-up from their four-arm cluster trial in Tanzania. The four groups in this single-blind study were PY LLIN as the reference, pyripoxyfen-PY, synergist piperonyl butoxide (PBO)-PY mixture, and chlorfenapyr-PY. Study LLIN usage was low, at 1325 (30·7%) of 4310 at 30 months and 1023 (22·3%) of 4587 at 36 months. Malaria infection prevalence in children was lowest, at 261 (22·8%) of 1145 in the chlorfenapyr-PY arm compared to 407 (37·4%) of 1088 in the standard PY LLIN arm, 302 (28·8%) of 1050 in the pyripoxyfen-PY arm, and 338 (32·3%) of 1048 in the PBO-PY arm. Only in the chlorfenapyr-PY arm did the data show a significant protective effect (p=0·006) compared to the standard PY arm, and a sustained efficacy compared to the reference in the 3 years of follow-up. The results from this trial have significant policy implications. Even before the results of the 36-month follow-up became available, the WHO Vector Control Advisory Group used the results of the 24-month follow-up and those from the Benin trial3Accrombessi M Cook J Dangbenon E et al.Efficacy of pyriproxyfen-pyrethroid long-lasting insecticidal nets (LLINs) and chlorfenapyr-pyrethroid LLINs compared with pyrethroid-only LLINs for malaria control in Benin: a cluster-randomised, superiority trial.Lancet. 2023; 401: 435-446Summary Full Text Full Text PDF PubMed Scopus (15) Google Scholar to make positive recommendations about the field use of chlorfenapyr-PY in areas with PY resistance. The results at 36 months strengthen the recommendations of WHO in March, 2023 on the use of chlorfenapyr-PY versus PY-only LLINs in areas with PY resistance. However, WHO placed conditional recommendations on the use of pyripoxyfen-PY versus PY alone based on the poor cost-effectiveness of pyripoxyfen-PY, and on the use of chlorfenapyr-PY versus PBO-PY based on the side effects of PBO-PY. Chlorfenapyr acts through disruption of the oxidative phosphorylation in the mitochondria, rather than through the neural receptors, and also carries the advantage of no cross-resistance to PYs and other insecticides.5Raghavendra K Barik TK Sharma P et al.Chlorfenapyr: a new insecticide with novel mode of action can control pyrethroid resistant malaria vectors.Malar J. 2011; 10: 1-7Crossref PubMed Scopus (87) Google Scholar However, chlorfenapyr resistance has been detected in non-mosquito populations6Van Leeuwen T Stillatus V Tirry L Genetic analysis and cross-resistance spectrum of a laboratory-selected chlorfenapyr resistant strain of two-spotted spider mite (Acari: Tetranychidae).Exp Appl Acarol. 2004; 32: 249-261Crossref PubMed Scopus (136) Google Scholar and could spread widely. An important lesson from this trial, and others testing combined active ingredients for LLINs, is that more novel products need to be developed and tested. For instance, the LLINs with PBO-PY were protective up to 18 months only; however, in studies elsewhere, the protection lasted up to 2 or 3 years.7Chaplin M Choi L Ranson H Piperonyl butoxide (PBO) combined with pyrethroids in insecticide-treated nets to prevent malaria in Africa.Cochrane Database Syst Rev. 2021; 5CD012776Google Scholar, 8Protopopoff N Mosha JF Messenger LA et al.Effectiveness of three-year old piperonyl butoxide and pyrethroid-treated long-lasting insecticidal nets (LLINs) versus pyrethroid-only LLINs against malaria infection: results of a cluster randomised trial in Tanzania.medRxiv. 2022; (published online July 7.) (preprint).https://doi.org/10.1101/2022.07.06.22277292Google Scholar The decline and difference in protection elsewhere compared with the current trial has been attributed by the authors to many reasons, including differences in vector species, chemical specificity, and durability of the textile. The deployment of LLINs in malaria-endemic countries with PY resistance will be smoother if local programmes do not need to consider varying local factors, such as vector species, in order to make choices on the active ingredients in the LLINs to purchase. Another important lesson from this trial is that malaria control programmes may need to rethink the 3-year cycle for distribution of LLINs. First, the study LLIN usage was very low at 22·3% at 3 years. Use of non-study-related nets was high, probably because the study nets were torn and required replacement. Second, chemical analysis showed the partner active ingredients were very low, at 8% for chlorfenapyr and 7% for PBO. It is, therefore, likely that the overall impact at 36 months was underestimated. The above factors constitute some important weaknesses, which the authors have acknowledged. This trial has deservedly informed WHO recommendations on the use of active ingredients in LLINs for vector control in areas with PY resistance. However, more trials are needed to replicate and strengthen the basis of the current and future recommendations for malaria vector control. We declare no competing interests. Effectiveness of long-lasting insecticidal nets with pyriproxyfen–pyrethroid, chlorfenapyr–pyrethroid, or piperonyl butoxide–pyrethroid versus pyrethroid only against malaria in Tanzania: final-year results of a four-arm, single-blind, cluster-randomised trialDespite low coverage, the protective efficacy against malaria offered by chlorfenapyr–PY LLINs was superior to that provided by standard PY LLINs over a 3-year LLIN lifespan. Appropriate LLIN replacement strategies to maintain adequate usage of nets will be necessary to maximise the full potential of these nets. Full-Text PDF Open Access