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
Written by on January 25, 2023
Summary
Background
New classes of long-lasting insecticidal nets (LLINs) combining mixtures of insecticides with different modes of action could put malaria control back on track after rebounds in transmission across sub-Saharan Africa. We evaluated the relative efficacy of pyriproxyfen-pyrethroid LLINs and chlorfenapyr-pyrethroid LLINs compared with standard LLINs against malaria transmission in an area of high pyrethroid resistance in Benin.
Methods
Findings
Between May 23 and June 24, 2019, 53 854 households and 216 289 inhabitants were accounted for in the initial census and included in the study. Between March 19 and 22, 2020, 115 323 LLINs were distributed to 54 030 households in an updated census. A cross-sectional survey showed that study LLIN usage was highest at 9 months after distribution (5532 [76·8%] of 7206 participants), but decreased by 24 months (4032 [60·6%] of 6654). Mean malaria incidence over 2 years after LLIN distribution was 1·03 cases per child-year (95% CI 0·96–1·09) in the pyrethroid-only LLIN reference group, 0·84 cases per child-year (0·78–0·90) in the pyriproxyfen-pyrethroid LLIN group (hazard ratio [HR] 0·86, 95% CI 0·65–1·14; p=0·28), and 0·56 cases per child-year (0·51–0·61) in the chlorfenapyr-pyrethroid LLIN group (HR 0·54, 95% CI 0·42–0·70; p<0·0001).
Interpretation
Over 2 years, chlorfenapyr-pyrethroid LLINs provided greater protection from malaria than pyrethroid-only LLINs in an area with pyrethroid-resistant mosquitoes. Pyriproxyfen-pyrethroid LLINs conferred protection similar to pyrethroid-only LLINs. These findings provide crucial second-trial evidence to enable WHO to make policy recommendations on these new LLIN classes. This study confirms the importance of chlorfenapyr as an LLIN treatment to control malaria in areas with pyrethroid-resistant vectors. However, an arsenal of new active ingredients is required for successful long-term resistance management, and additional innovations, including pyriproxyfen, need to be further investigated for effective vector control strategies.
Funding
UNITAID, The Global Fund.
Introduction
World malaria report 2021.
This rebound is likely to be a consequence of the continued spread of resistance to pyrethroid insecticides in malaria-transmitting mosquitoes, coinciding with a plateau in malaria control investment, leading to suboptimal coverage of interventions. Urgent actions are needed to prevent malaria resurgences, which were previously observed in sub-Saharan Africa in the 1980s after malaria control measures were scaled down.
- Cohen JM
- Smith DL
- Cotter C
- et al.
Evidence before this study
There is a paucity of evidence concerning the efficacy of new classes of insecticidal-treated nets against malaria, especially in west Africa, where vectors usually have high insecticide resistance. On March 31, 2022, we searched PubMed, with no language or date restrictions, using the terms “randomised controlled trial” AND “malaria” AND “insecticide-treated net” OR “long-lasting insecticidal net”, combined with either “pyriproxyfen” OR “chlorfenapyr” OR “piperonyl butoxide”. The search yielded four studies, of which two were directly relevant to our study. The effectiveness of pyriproxyfen-pyrethroid long-lasting insecticidal nets (LLINs) was assessed in Burkina Faso and Tanzania, and chlorfenapyr-pyrethroid nets were evaluated in Tanzania. The trial in Burkina Faso used a step-wedge design to compare the pyriproxyfen-pyrethroid LLINs to standard pyrethroid-only LLINs over 18 months, whereas the Tanzanian study was a four-arm superiority trial comparing chlorfenapyr-pyrethroid LLINs, pyriproxyfen-pyrethroid LLINs, and piperonyl-butoxide (PBO)-pyrethroid LLINs versus standard pyrethroid-only LLINs over 2 years. In the Burkina Faso trial, the authors showed a 12% reduction in malaria case incidence in children receiving pyriproxyfen-pyrethroid LLINs compared with those who received standard pyrethroid-only LLINs, and observed no effect of the pyriproxyfen-pyrethroid LLINs on malaria prevalence. In the Tanzania trial, there was no evidence of superior effect of the pyriproxyfen-pyrethroid LLINs on any malaria outcomes over 2 years; children had 55% lower odds of malaria infection and 44% lower risk of malaria incidence over 2 years in villages that received chlorfenapyr-pyrethroid LLINs compared with villages that received pyrethroid-only LLINs. PBO-pyrethroid LLINs were consistently found to be more effective than pyrethroid-only LLINs; however, the duration of the superior effect varied from 12 months to 21 months according to the different trials.
Added value of this study
To our knowledge, this is the second study aiming to compare the efficacy of the next generation of LLINs combining pyriproxyfen or chlorfenapyr and pyrethroid versus standard pyrethroid-only LLINs, and the first of its kind to be conducted in west Africa. This trial confirmed the superior efficacy of chlorfenapyr-pyrethroid LLINs, in terms of malaria case incidence, prevalence, and transmission in children, over 2 years of use in the community, in an area of moderate malaria transmission and with high insecticide resistance intensity in malaria vectors, in Benin. However, pyriproxyfen-pyrethroid LLINs did not offer additional protection against malaria outcomes compared with pyrethroid-only LLINs.
Implications of all the available evidence
Given the positive findings, both in Benin and Tanzania, for chlorfenapyr-pyrethroid LLINs, they are likely to become the first WHO-recommended LLINs impregnated with an insecticide class other than pyrethroids. The absence of superior efficacy of pyriproxyfen-pyrethroid LLINs compared with standard pyrethroid-only LLINs is consistent with the results of the previous Tanzania study and calls into question the role of the current pyriproxyfen-pyrethroid LLINs in future malaria vector strategies.
Report of the 15th WHOPES Working Group meeting.
,
Report of the twentieth WHOPES Working Group meeting, WHO/HQ, Geneva, 20–24 March 2017: review of Interceptor G2LN, DawaPlus 3.0 LN, DawaPlus 4.0 LN, SumiLarv 2 MR, Chlorfenapyr 240 SC.
The first net combined a pyrethroid insecticide and the synergist piperonyl butoxide (PBO) and, following a randomised controlled trial,
- Protopopoff N
- Mosha JF
- Lukole E
- et al.
received a WHO policy recommendation in 2017. Other next-generation LLINs have shown encouraging results against resistant vectors in laboratory and small-scale entomological studies.
Report of the twentieth WHOPES Working Group meeting, WHO/HQ, Geneva, 20–24 March 2017: review of Interceptor G2LN, DawaPlus 3.0 LN, DawaPlus 4.0 LN, SumiLarv 2 MR, Chlorfenapyr 240 SC.
,
- Ngufor C
- Agbevo A
- Fagbohoun J
- Fongnikin A
- Rowland M
,
- N’Guessan R
- Boko P
- Odjo A
- Knols B
- Akogbeto M
- Rowland M
One of these nets is a dual active-ingredient LLIN combining a pyrethroid and a pyrrole (chlorfenapyr). Both insecticides lead to mosquito mortality, with chlorfenapyr disrupting the production of cellular energy rather than targeting the nervous system, as pyrethroids do. Another dual active-ingredient LLIN combines a pyrethroid with an insect growth regulator (pyriproxyfen), which leads to sterility in exposed adult mosquitoes.
- Harris C
- Lwetoijera DW
- Dongus S
- et al.
- Mosha JF
- Kulkarni MA
- Lukole E
- et al.
Using a pyriproxyfen-pyrethroid LLIN reduced the odds of malaria infection prevalence by 41% during the first year of use but the effect was not sustained during the second year, and no significant effect was seen on malaria cases in either year. Another trial conducted in Burkina Faso with a different brand of pyriproxyfen-pyrethroid LLIN showed a 12% reduction in malaria case incidence compared with the standard pyrethroid-only LLIN group, with no effect on malaria infection prevalence.
- Tiono AB
- Ouédraogo A
- Ouattara D
- et al.
The evaluation process for vector control products.
We assessed the relative efficacy of pyriproxyfen-pyrethroid LLINs and chlorfenapyr-pyrethroid LLINs compared with standard pyrethroid-only LLINs against malaria case incidence, infection prevalence, and transmission, in an area of pyrethroid resistance in Benin.
Methods
Study design and participants
- Yovogan B
- Sovi A
- Padonou GG
- et al.
- Accrombessi M
- Cook J
- Ngufor C
- et al.
Ethics approval was obtained from the Benin Ministry of Health ethics committee (6/30/MS/DC/SGM/DRFMT/CNERS/SA), the London School of Hygiene & Tropical Medicine ethics committee (16237), and the WHO Research Ethics Review Committee (ERC.0003153). The trial was independently monitored by a data safety monitoring board and a trial steering committee.
Epidemiological effect was estimated through measuring malaria case incidence in the 2 years after net distribution by active case detection in a cohort of children. A cohort of approximately 30 children aged 6 months–9 years randomly selected (by simple random sampling using a random number generator) from each cluster (1800 in total) was enrolled in July, 2020. Children were eligible for inclusion if they were permanent residents in the cluster, had no serious illnesses, and written informed consent was obtained from their guardians.
Malaria infection prevalence (in all ages) was measured by cross-sectional surveys at 6 months and 18 months after net distribution. 72 individuals residing in the core of each cluster were randomly selected (using a random number generator) from the census for each cross-sectional survey. Each prevalence survey collected data on malaria infection, measured using malaria rapid diagnostic tests (CareStart malaria HRP2/pLDH [pf/pan] combo, DiaSys, UK), net ownership and use, sex, and household assets (as a proxy for socioeconomic status).
Entomological effects were measured using human landing catches in four randomly selected houses every 3 months in each cluster. Insecticide resistance intensity was measured in two clusters per group (six clusters total) at baseline and in each follow-up year.
Written informed consent was obtained from all participants, or from guardians for participants younger than 18 years. Assent was sought for children aged between 10 and 18 years. Written consent was also obtained from volunteer mosquito collectors who were all aged 18 years or older and who were vaccinated against yellow fever. All participation was voluntary, and participants could withdraw at any time. Study investigators sought consent in French or local languages.
Randomisation and masking
We used restricted randomisation to randomly assign 60 clusters to one of three LLIN groups (1:1:1), to receive nets containing either pyriproxyfen and alpha-cypermethrin (pyrethroid), chlorfenapyr and alpha-cypermethrin, or alpha-cypermethrin only (reference). Restricted randomisation was used to ensure balanced cluster allocation between study groups with respect to population size, malaria infection prevalence (measured in the baseline survey), district (n=3), and socioeconomic status.
To mask the net types from the participants and the field workers, the nets were designed to look as similar as possible. Each net was rectangular, was requested to be the same size (1·8 m length, 1·9 m width, and 1·8 m height), and blue. To differentiate the nets in the field, a colour-coded loop was attached to the net. All data analyses were performed masked.
Procedures
The nets tested in the trial were: Royal Guard (Disease Control Technologies, Greer, SC, USA), polyethylene netting (120 deniers incorporating 220 mg/m2 pyriproxyfen and 220 mg/m2 alpha-cypermethrin); Interceptor G2 (BASF SE, Ludwigshafen, Germany), polyester netting (100 deniers coated with 200 mg/m2 chlorfenapyr and 100 mg/m2 alpha-cypermethrin); and the reference net, Interceptor (BASF SE, Ludwigshafen, Germany), polyester netting (100 deniers coated with 200 mg/m2 of alpha-cypermethrin). Nets were distributed in collaboration with the Benin National Malaria Control Program. Households were asked to collect their nets from a central point and received one net per every two residents in their household, rounded up for odd numbers. Nets already in houses were not removed but householders were encouraged to use the new study nets. Additionally, net hang-up campaigns to encourage net use took place at 1 month and 7 months after distribution. Net coverage surveys to assess net ownership and usage were done at 1, 9, and 24 months after distribution. Throughout the follow-up period, children enrolled in the analysis cohort and participants enrolled in the cross-sectional surveys were also asked about their net use.
Insecticide content at baseline was assessed on 30 randomly selected new nets per LLIN brand, by gas chromatography with Flame Ionisation Detection, at the Centre Wallon de Recherches Agronomiques, Gembloux, Belgium. The insecticidal and physical durability of the study nets is being assessed in a separate study.
Due to the COVID-19 pandemic, there was a 3-month gap between the distribution of the nets and the enrolment of children in the cohort. At enrolment and at 1 year after distribution (April, 2021), children were treated with antimalarial drugs (artemether–lumefantrine) to clear any underlying infection. The cohort was monitored from August, 2020, to April, 2022, a 21-month period, which encompassed the first 2 years after net distribution. Study nurses visited children every 2 weeks during the transmission season (April–October) and every 1 month in the dry season (November–March). At each visit, children were clinically examined and if they were febrile or had a history of fever in the past 48 h, they were tested for malaria using a malaria rapid diagnostic test. If the test was positive, the child was treated with artemether–lumefantrine, according to national guidelines.
During cross-sectional surveys, all participants were tested for malaria using a malaria rapid diagnostic test and received treatment if the test was positive, and children younger than 5 years were tested for anaemia. Information regarding net ownership and usage, and other household-level indicators were collected at the same time.
- Santolamazza F
- Mancini E
- Simard F
- Qi Y
- Tu Z
- della Torre A
A random sample of Anopheles spp (up to 30% from each nightly catch in each cluster) were tested for sporozoites using the ELISA circumsporozoite protein technique.
- Wirtz RA
- Zavala F
- Charoenvit Y
- et al.
Outcomes
The primary outcome was malaria case incidence (infrared frontal temperature ≥37·5°C or reported fever in the previous 48 h, and positive malaria rapid diagnostic test) in children enrolled in the active case detection cohort in the 2 years after net distribution. Visits of children in the cohort at health facilities were monitored and the results of malaria rapid diagnostic tests and any treatment given were recorded. However, it was difficult to assess with certainty if malaria rapid diagnostic tests were used only if the child was symptomatic (as our protocol specified); therefore, the passive data was not included in the primary analyses.
Secondary clinical outcomes were malaria infection prevalence in all age groups and anaemia (defined as haemoglobin concentration <10 g/dL) prevalence in children aged 5 years or younger at 6 months and 18 months after net distribution.
Type and duration of adverse events related to usage of nets were recorded using a prespecified questionnaire at each cohort visit and during net usage and cross-sectional surveys. Data on hospitalisation and death in children in the cohort were collected by interviewing the child’s guardian and reviewing the hospital record, following receipt of consent.
Test procedures for insecticide resistance monitoring in malaria vector mosquitoes.
Mortality was recorded at 30 min for all four doses of alpha-cypermethrin (insecticide resistance intensity measurement), and at 24, 48, and 72 h after exposure for chlorfenapyr. The reduction in fecundity rate induced by pyriproxyfen relative to unexposed mosquitoes was assessed by ovarian dissection, 3 days after pyriproxyfen exposure. Other outcomes included in the protocol (parity, resting behaviour, survivorship, and other resistance measures) are still to be analysed and will be published elsewhere.
Statistical analysis
The study was designed to detect a 30% difference in malaria case incidence, assuming a control group incidence of 1 malaria case per child-year and a coefficient of variation of 0·3 between clusters. This design required 20 clusters per group and 25 (20 + 5 allowing for loss to follow-up) children per cluster followed up for 2 years to give 80% power. Due to the delay in enrolment, which resulted in a shorter follow-up time, the number of children per cluster was increased to 30 (1800 children total). This sample size calculation includes adjustment for multiple testing (allowing for the three groups) using a Bonferroni-corrected two-sided α of 2·5%.
For malaria infection prevalence, it was assumed that the prevalence in the reference group was 40%, with a coefficient of variation between clusters of 0·3. With 72 individuals per cluster, the study had 80% power to detect a 30% lower prevalence in the intervention groups compared with the reference group, using a Bonferroni-corrected α for multiple comparisons.
The primary intention-to-treat analysis was a comparison of incidence of clinical malaria episodes between each dual active-ingredient LLIN group and the reference group (pyrethroid-only LLIN). A child was not considered at risk for 2 weeks after treatment and malaria cases detected within 2 weeks of a previous malaria case were not counted, to allow for circulating histidine-rich protein after parasite clearance. We performed sensitivity analyses increasing the censoring period after treatment to 4 weeks or requiring at least one negative visit after a positive diagnosis before follow-up time was uncensored. Survival analysis was used to compare the risk of having a malaria case in each group, using a Cox proportional hazards model allowing for multiple events per child and using cluster-robust estimates of variance by adjusting the SEs. The effect of intervention nets on malaria infection prevalence and anaemia was estimated using mixed-effects logistic models in intention-to-treat analyses with cluster included as a random effect. In per-protocol analyses, only participants who reported using the appropriate study nets in each group were included. Missing data was assessed and found to be missing at random (data not shown), so no imputation was performed.
Indoor and outdoor malaria vector density was calculated for each household visit. A pooled entomological inoculation rate was calculated for each cluster at each visit (eight visits per cluster, 480 visits total). Nightly entomological inoculation rate was calculated as the mean number of mosquitoes per household multiplied by the proportion of sporozoite-positive mosquitoes. Mixed-effect generalised linear models with a negative binomial distribution were used to analyse entomological inoculation rate and mosquito density and a mixed-effect logistic regression for sporozoite rate. Vector density and sporozoite rate were calculated at the household level, with collection timepoint and cluster as random effects. Entomological inoculation rate was calculated at the cluster level for each timepoint, with cluster included as a random effect in the models.
Post-hoc sensitivity analyses for malaria incidence and prevalence included adjusting for baseline cluster-level variables used in restricted randomisation and for entomological outcomes, adjusting for their respective value in the baseline survey. Time-by-study group interactions were examined for each model. Stata (version 16) was used to analyse epidemiological and entomological data.
Role of the funding source
The funders of the study had no role in study design, data collection, data analysis, data interpretation, writing of the report, or in the decision to submit for publication.
Results
Table 1Baseline characteristics
Data are n or %; n/N unless otherwise stated. EIR=entomological inoculation rate. LLIN=long-lasting insecticidal net.
Table 2Malaria case incidence in children aged 6 months–10 years per year of follow-up and overall (including active visits only)
Each intervention was compared with the pyrethroid-only LLIN group for the same timepoint. LLIN=long-lasting insecticidal net.
Table 3Malaria infection and anaemia prevalence in the study population at 6 months and 18 months after net distribution (intention-to-treat analysis)
Anaemia was defined as a haemogloblin concentration of <10 g/dL. LLIN=long-lasting insecticidal net. OR=odds ratio.
Table 4Indoor entomological outcomes per year of collection and overall (year 1 and 2 combined).
Each intervention group was compared with the pyrethroid-only LLIN group for the same timepoint. Entomological inoculation rate was calculated as the product of human biting density multiplied by sporozoite rate at cluster level. LLIN=long-lasting insecticidal net.
Discussion
- Mosha JF
- Kulkarni MA
- Lukole E
- et al.
and this is likely to be associated with the high concentration of alpha-cypermethrin in those nets compared with the chlorfenapyr-pyrethroid LLINs.
- N’Guessan R
- Ngufor C
- Kudom AA
- et al.
,
- Camara S
- Ahoua Alou LP
- Koffi AA
- et al.
,
- Bayili K
- N’do S
- Namountougou M
- et al.
,
- Tungu PK
- Michael E
- Sudi W
- Kisinza WW
- Rowland M
The previous trial in Tanzania reported a malaria case incidence reduction of 44%, a 55% decrease in odds of malaria prevalence, and 85% reduction in entomological inoculation rate compared with the pyrethroid-only group, consistent with these results, despite the differing malaria vector populations and intensity of pyrethroid resistance in the mosquitoes.
- Mosha JF
- Kulkarni MA
- Lukole E
- et al.
In both trials, per-protocol analyses suggested that individuals living in the chlorfenapyr-pyrethroid clusters benefited regardless of whether they were using a study net, suggesting a community effect of the net, which was likely to be obtained by the overall reduction of mosquito density, which remained considerably lower than in the pyrethroid-only group in both years of this trial after net distribution. Community effect is also indicated by the reduction in both indoor and outdoor entomological indices in the chlorfenapyr-pyrethroid group in the present study.
- Mosha JF
- Kulkarni MA
- Lukole E
- et al.
the pyriproxyfen-pyrethroid LLINs we tested did not provide additional protection against malaria infection or disease compared with pyrethroid-only LLINs. However, there was evidence of an effect on indoor transmission, with the strongest effect seen in the first year after net distribution. Tiono and colleagues
- Tiono AB
- Ouédraogo A
- Ouattara D
- et al.
have previously reported a 12% reduction in malaria incidence and 49% reduction in entomological inoculation rate with a pyriproxyfen-pyrethroid LLIN compared with pyrethroid-only LLINs over 18 months in a stepped-wedge randomised trial in Burkina Faso. The different study design, length of follow-up, and brand of net might explain the differences seen between the two studies. In Benin, laboratory and semi-field experimental hut studies have shown the superior efficacy of pyriproxyfen-pyrethroid nets on entomological indicators compared with standard pyrethroid-only LLINs,
- Ngufor C
- Agbevo A
- Fagbohoun J
- Fongnikin A
- Rowland M
,
- Djènontin A
- Ahoua Alou LP
- Koffi A
- et al.
,
- Ngufor C
- N’Guessan R
- Fagbohoun J
- et al.
and are consistent with the decrease in indoor vector density observed in our trial. However, the decrease in indoor vector density did not translate into significant disease reduction, suggesting that a larger effect on malaria transmission (entomological inoculation rate) is crucial to provide community protection. Although lower net usage in the pyriproxyfen-pyrethroid LLIN group could have partially contributed to the lack of effect, we are also assessing textile durability, sterilisation effects, and chemical content of pyriproxyfen-pyrethroid LLINs to fully understand these results.
Vector control products pipeline. Prequalification of medical products (IVDs, medicines, vaccines and immunization devices, vector control).
as well as the development of chlorfenapyr product formulations for indoor residual spraying.
- Ngufor C
- Fongnikin A
- Hobbs N
- et al.
Although chlorfenapyr-pyrethroid nets offer a superior alternative to pyrethroid-only nets in areas of pyrethroid resistance, to preserve their effectiveness optimal resistance-management strategies should be used. There was no evidence of the development of resistance to chlorfenapyr during the 2 years of this trial; however, the wide-scale deployment of one type of insecticide risks the rapid development of resistance, which could result in a similar situation to the current widespread resistance to pyrethroids. The nets should be deployed ideally alongside other insecticides as part of a strategy aimed to reduce selection pressure for development of resistance in mosquito vectors. Given the significant effect of the pyriproxyfen-pyrethroid LLINs on malaria transmission during the first year after net distribution, additional studies are necessary to evaluate the potential value of active ingredients such as pyriproxyfen, which are not primarily intended to kill resistant adult mosquitoes but rather to sterilise them. There might still be a role for these hormone growth-regulator insecticides in combination with other active ingredients for net treatment in long-term resistance management.
Data requirements and protocol for determining non-inferiority of insecticide-treated net and indoor residual spraying products within an established WHO intervention class.
might be a useful alternative for second-in-class chlorfenapyr-pyrethroid LLINs. Further work to investigate the capacity of such entomological studies to predict the performance of the trial nets against clinical malaria is ongoing.
- Sherrard-Smith E
- Ngufor C
- Sanou A
- et al.
- Mosha JF
- Kulkarni MA
- Lukole E
- et al.
showed that dual active-ingredient LLINs can be highly cost-effective and even cost-saving compared with pyrethroid-only LLINs when providing sufficient protection.
Norms, standards and processes underpinning development of WHO recommendations on vector control.
Currently, the only class of next-generation LLIN to receive a WHO recommendation are the PBO synergist nets. However, previous publications have shown concerns about the durability of these nets.
- Lukole E
- Cook J
- Mosha JF
- et al.
This trial provides the second key evidence for the effectiveness of chlorfenapyr-pyrethroid nets in an area with pyrethroid-resistant vectors and will therefore support a WHO policy recommendation. However, the effect of the nets was reduced in the second year of the trial, and there is no evidence for the efficacy of the nets in their third year of use. Many studies report that the durability of nets is much less than the 3 years required to be designated as long lasting.
- Briet O
- Koenker H
- Norris L
- et al.
,
- Lorenz LM
- Bradley J
- Yukich J
- et al.
The next-generation LLINs might face the same problems of fabric integrity and durability of insecticidal content unless standards of manufacture are improved. Different channels of distribution (eg, school-based, antenatal care visits, or expanded programme immunisation visits) could play a key role in maintaining high levels of net use in communities.
- Stuck L
- Chacky F
- Festo C
- et al.
Although generating this evidence to support a WHO recommendation for another class of bednet is a key turning point in malaria control, without new insecticides and new ways to deploy them, we risk repeating the mistakes of the past. Now is the time for more innovation and less complacency.
Contributors
NP, JC, and CN conceived and designed the study, with contributions from MR, IK, LAM, and MCA. JC and MA led the development of the analysis plan, with input from BA, ASo, and NP. MA, CN, JC, NP, FT, and MCA coordinated the trial implementation with local and national authorities, RA, and AO-H. MA, BY, HA, ASo, and LA led the data collection in the field with CA and GGP, and oversight from MCA, JC, and NP. ASo, BY, ASi, and RA led the molecular laboratory work, supervised by MCA and supported by LAM and NP. MA, JC, and NP wrote the data management plan and, with ED, developed collection tools and managed the data. MA, ED, LA, BA, ASo, and JC did the statistical analysis of the epidemiological and entomological outcomes with input from MCA and NP. MA, JC, and NP wrote the first draft of the manuscript with input from ASo, CN, MR, IK, and MCA. MA and JC accessed and verified the data. MA, JC, and NP had full access to all the data and had final responsibility for the decision to submit for publication. All authors reviewed, read, and approved the final version of the manuscript.
Data sharing
Data collected for the study, including deidentified participant data and data dictionaries, might be made available at the end of the third year of trial follow-up upon reasonable request to the corresponding author.
Declaration of interests
We declare no competing interests.
Acknowledgments
This trial was funded by a grant to the London School of Hygiene & Tropical Medicine from UNITAID and The Global Fund via the Innovative Vector Control Consortium. This trial is part of a larger project, The New Nets project. We thank the communities from the three study districts (Covè, Zagnanado, Ouinhi), particularly the participants, children and their parents, community health workers, staff in health clinics, and the regional study team. We thank colleagues and staff at the Centre de Recherche Entomologique de Cotonou and those at the National Malaria Control Program. We also thank the trial steering committee, the data safety monitoring board, and Charles Thickstun (School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada) for supporting the mapping and cluster delineation.
Supplementary Material
References
- 1.
World malaria report 2021.
World Health Organization,
Geneva2021 - 2.
Malaria resurgence: a systematic review and assessment of its causes.
Malar J. 2012; 11: 122
- 3.
Report of the 15th WHOPES Working Group meeting.
World Health Organization,
Geneva2012 - 4.
Report of the twentieth WHOPES Working Group meeting, WHO/HQ, Geneva, 20–24 March 2017: review of Interceptor G2LN, DawaPlus 3.0 LN, DawaPlus 4.0 LN, SumiLarv 2 MR, Chlorfenapyr 240 SC.
World Health Organization,
Geneva2017 - 5.
Effectiveness of a long-lasting piperonyl butoxide-treated insecticidal net and indoor residual spray interventions, separately and together, against malaria transmitted by pyrethroid-resistant mosquitoes: a cluster, randomised controlled, two-by-two factorial design trial.
Lancet. 2018; 391: 1577-1588
- 6.
Efficacy of Royal Guard, a new alpha-cypermethrin and pyriproxyfen treated mosquito net, against pyrethroid-resistant malaria vectors.
Sci Rep. 2020; 1012227
- 7.
Control of pyrethroid-resistant Anopheles gambiae and Culex quinquefasciatus mosquitoes with chlorfenapyr in Benin.
Trop Med Int Health. 2009; 14: 389-395
- 8.
Sterilising effects of pyriproxyfen on Anopheles arabiensis and its potential use in malaria control.
Parasit Vectors. 2013; 6: 144
- 9.
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: 1227-1241
- 10.
Efficacy of Olyset Duo, a bednet containing pyriproxyfen and permethrin, versus a permethrin-only net against clinical malaria in an area with highly pyrethroid-resistant vectors in rural Burkina Faso: a cluster-randomised controlled trial.
Lancet. 2018; 392: 569-580
- 11.
The evaluation process for vector control products.
World Health Organization,
Geneva2017 - 12.
Pre-intervention characteristics of the mosquito species in Benin in preparation for a randomized controlled trial assessing the efficacy of dual active-ingredient long-lasting insecticidal nets for controlling insecticide-resistant malaria vectors.
PLoS One. 2021; 16e0251742
- 13.
Assessing the efficacy of two dual-active ingredients long-lasting insecticidal nets for the control of malaria transmitted by pyrethroid-resistant vectors in Benin: study protocol for a three-arm, single-blinded, parallel, cluster-randomized controlled trial.
BMC Infect Dis. 2021; 21: 194
- 14.
Insertion polymorphisms of SINE200 retrotransposons within speciation islands of Anopheles gambiae molecular forms.
Malar J. 2008; 7: 163
- 15.
Comparative testing of monoclonal antibodies against Plasmodium falciparum sporozoites for ELISA development.
Bull World Health Organ. 1987; 65: 39-45
- 16.
Test procedures for insecticide resistance monitoring in malaria vector mosquitoes.
2nd edn. World Health Organization,
Geneva2016 - 17.
Cluster randomised trials.
2nd edn. Chapman and Hall,
London2017 - 18.
Mosquito nets treated with a mixture of chlorfenapyr and alphacypermethrin control pyrethroid resistant Anopheles gambiae and Culex quinquefasciatus mosquitoes in west Africa.
PLoS One. 2014; 9e87710
- 19.
Efficacy of Interceptor G2, a new long-lasting insecticidal net against wild pyrethroid-resistant Anopheles gambiae s.s. from Côte d’Ivoire: a semi-field trial.
Parasite. 2018; 25: 42
- 20.
Evaluation of efficacy of Interceptor G2, a long-lasting insecticide net coated with a mixture of chlorfenapyr and alpha-cypermethrin, against pyrethroid resistant Anopheles gambiae s.l. in Burkina Faso.
Malar J. 2017; 16: 190
- 21.
Efficacy of interceptor G2, a long-lasting insecticide mixture net treated with chlorfenapyr and alpha-cypermethrin against Anopheles funestus: experimental hut trials in north-eastern Tanzania.
Malar J. 2021; 20: 180
- 22.
Insecticidal and sterilizing effect of Olyset Duo, a permethrin and pyriproxyfen mixture net against pyrethroid-susceptible and -resistant strains of Anopheles gambiae s.s.: a release-recapture assay in experimental huts.
Parasite. 2015; 22: 27
- 23.
Efficacy of the Olyset Duo net against insecticide-resistant mosquito vectors of malaria.
Sci Transl Med. 2016; 8356ra121
- 24.
Vector control products pipeline. Prequalification of medical products (IVDs, medicines, vaccines and immunization devices, vector control).
- 25.
Indoor spraying with chlorfenapyr (a pyrrole insecticide) provides residual control of pyrethroid-resistant malaria vectors in southern Benin.
Malar J. 2020; 19: 249
- 26.
Data requirements and protocol for determining non-inferiority of insecticide-treated net and indoor residual spraying products within an established WHO intervention class.
World Health Organization,
Geneva2019 - 27.
Inferring the epidemiological benefit of indoor vector control interventions against malaria from mosquito data.
Nat Commun. 2022; 133862
- 28.
Norms, standards and processes underpinning development of WHO recommendations on vector control.
World Health Organization,
Geneva2020 - 29.
Protective efficacy of holed and aging PBO-pyrethroid synergist-treated nets on malaria infection prevalence in north-western Tanzania.
PLoS Glob Public Health. 2022; 2e0000453
- 30.
Attrition, physical integrity and insecticidal activity of long-lasting insecticidal nets in sub-Saharan Africa and modelling of their impact on vectorial capacity.
Malar J. 2020; 19: 310
- 31.
Comparative functional survival and equivalent annual cost of 3 long-lasting insecticidal net (LLIN) products in Tanzania: a randomised trial with 3-year follow up.
PLoS Med. 2020; 17e1003248
- 32.
Evaluation of long-lasting insecticidal net distribution through schools in Southern Tanzania.
Health Policy Plan. 2022; 37: 243-254
Article info
Publication history
Published: January 24, 2023
Identification
DOI: https://doi.org/10.1016/S0140-6736(22)02319-4
Copyright
© 2022 The Author(s). Published by Elsevier Ltd.
User license
Creative Commons Attribution (CC BY 4.0) |
ScienceDirect
Access this article on ScienceDirect
Linked Articles
- Getting ahead of insecticide-resistant malaria vector mosquitoes
-
In The Lancet, Manfred Accrombessi and colleagues1 report the results of a rigorous cluster-randomised, controlled, superiority trial in Benin, encompassing 54 030 households and 216 289 people, which confirms that the addition of the pyrrole insecticide chlorfenapyr to long-lasting insecticidal nets (LLINs), as a second active ingredient to back up the pyrethroids we have relied upon so heavily for so long, can have invaluable effects on malaria transmission and disease burden. A total of 115 323 LLINs were distributed to 54 030 households and the primary outcome of mean malaria case incidence 24 months after LLIN distribution in a cohort of children aged 6 months to 10 years showed 1·03 cases per child-year (95% CI 0·96–1·09) in the pyrethroid-only LLIN reference group, 0·56 cases per child-year (0·51–0·61) in the chlorfenapyr-pyrethroid LLIN group (hazard ratio [HR] 0·54, 95% CI 0·42–0·70; p<0·0001), and 0·84 cases per child-year (0·78–0·90) in the pyriproxyfen-pyrethroid LLIN group (HR 0·86, 95% CI 0·65–1·14; p=0·28).
- Full-Text
-
watch avatar the way of water full movie
watch avatar the way of water full movie
watch avatar the way of water full movie
