Will a lack of fabric durability be their downfall? Impact of textile durability on the efficacy of three types of dual-active-ingredient long-lasting insecticidal nets: a secondary analysis on malaria prevalence and incidence from a cluster-randomized trial in north-west Tanzania.

BACKGROUND: The Dual-Active Ingredient long-lasting insecticidal nets (Dual-AI LLIN) have been developed to counteract the reduced efficacy of pyrethroid (PY)-only nets due to widespread pyrethroid insecticide resistance in malaria vector mosquitoes. They constitute half of the nets distributed in sub-Saharan Africa between 2022 and 2024. However, their effectiveness once they develop holes is unclear, particularly in pyrethroid-resistant settings. This study evaluates the textile integrity of three dual- AI LLINs compared to standard PY LLN, over 3 years of use in a community in Tanzania and the associated impact on malaria prevalence and incidence. METHODS: A secondary analysis of data from a randomized controlled trial (RCT) in North-western Tanzania was conducted to evaluate the effectiveness of α-cypermethrin only; pyriproxyfen and α-cypermethrin (PPF-PY); chlorfenapyr and α-cypermethrin (chlorfenapyr-PY); and the synergist piperonyl butoxide and permethrin (PBO-PY) LLINs on malaria infection prevalence and case incidence. The association between the net textile condition and 1/malaria prevalence over 3 years of use between 2019 and 2022, and 2/malaria case incidence in a cohort of children over 2 years of follow-up was assessed between 2019 and 2021. RESULTS: There was no significant association between damaged (OR 0.98, 95% CI 0.71-1.37, p-value = 0.655) and too-torn (OR 1.07, 95% CI 0.77-1.47, p-value = 0.694) compared to intact nets on malaria prevalence for all net types. However, there were reduced rates of malaria case incidence in children sleeping under a net in good condition compared to too-torn nets (incidence rate ratio (IRR) 0.76 [95% CI 0.63-0.92], p = 0.005). Malaria incidence was also consistently lower in too-torn PBO-PY LLIN (IRR = 0.37 [95% CI 0.19-0.72], p = 0.003) and chlorfenapyr-PY LLIN (IRR = 0.45 [95% CI 0.33-0.97], p = 0.053) compared to an intact PY-only LLIN during the first year of follow up. In year 2, the incidence was only significantly lower in intact chlorfenapyr-PY LLIN (IRR = 0.49 [95% CI 0.29-0.81], p = 0.006) compared to intact PY LLIN. CONCLUSION: The study confirmed that sleeping under a chlorfenapyr-PY LLIN or PBO-PY LLIN offered superior protection to pyrethroid-only nets even when torn. Preventing the development of holes is essential as they impact the level of protection offered against malaria infection. TRIAL REGISTRATION: ClinicalTrials.gov, number (NCT03554616).

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.

BACKGROUND: Long-lasting insecticidal nets (LLINs) have successfully reduced malaria in sub-Saharan Africa, but their effectiveness is now partly compromised by widespread resistance to insecticides among vectors. We evaluated new classes of LLINs with two active ingredients with differing modes of action against resistant malaria vectors. METHODS: We did a four-arm, cluster-randomised trial in Misungwi, Tanzania. Clusters were villages, or groups of hamlets, with at least 119 households containing children aged 6 months to 14 years living in the cluster's core area. Constrained randomisation was used to allocate clusters (1:1:1:1) to receive one of four types of LLIN treated with the following: α-cypermethrin only (pyrethroid-only [reference] group); pyriproxyfen and α-cypermethrin (pyriproxyfen group); chlorfenapyr and α-cypermethrin (chlorfenapyr group); or the synergist piperonyl butoxide and permethrin (piperonyl butoxide group). At least one LLIN was distributed for every two people. Community members and the field team were masked to group allocation. Malaria prevalence data were collected through cross-sectional surveys of randomly selected households from each cluster, in which children aged 6 months to 14 years were assessed for Plasmodium falciparum malaria infection by rapid diagnostic tests. The primary outcome was malaria infection prevalence at 24 months after LLIN distribution, comparing each of the dual-active-ingredient LLINs to the standard pyrethroid-only LLINs in the intention-to-treat population. The primary economic outcome was cost-effectiveness of dual-active-ingredient LLINs, based on incremental cost per disability-adjusted life-year (DALY) averted compared with pyrethroid-only LLINs, modelled over a 2-year period; we included costs of net procurement and malaria diagnosis and treatment, and estimated DALYs in all age groups. This study is registered with ClinicalTrials.gov (NCT03554616), and is ongoing but no longer recruiting. FINDINGS: 84 clusters comprising 39 307 households were included in the study between May 11 and July 2, 2018. 147 230 LLINs were distributed among households between Jan 26 and Jan 28, 2019. Use of study LLINs was reported in 3155 (72·1%) of 4378 participants surveyed at 3 months post-distribution and decreased to 8694 (40·9%) of 21 246 at 24 months, with varying rates of decline between groups. Malaria infection prevalence at 24 months was 549 (45·8%) of 1199 children in the pyrethroid-only reference group, 472 (37·5%) of 1258 in the pyriproxyfen group (adjusted odds ratio 0·79 [95% CI 0·54-1·17], p=0·2354), 512 (40·7%) of 1259 in the piperonyl butoxide group (0·99 [0·67-1·45], p=0·9607), and 326 [25·6%] of 1272 in the chlorfenapyr group (0·45 [0·30-0·67], p=0·0001). Skin irritation or paraesthesia was the most commonly reported side-effect in all groups. Chlorfenapyr LLINs were the most cost-effective LLINs, costing only US$19 (95% uncertainty interval 1-105) more to public providers or $28 (11-120) more to donors per DALY averted over a 2-year period compared with pyrethroid-only LLINs, and saving costs from societal and household perspectives. INTERPRETATION: After 2 years, chlorfenapyr LLINs provided significantly better protection than pyrethroid-only LLINs against malaria in an area with pyrethroid-resistant mosquitoes, and the additional cost of these nets would be considerably below plausible cost-effectiveness thresholds ($292-393 per DALY averted). Before scale-up of chlorfenapyr LLINs, resistance management strategies are needed to preserve their effectiveness. Poor textile and active ingredient durability in the piperonyl butoxide and pyriproxyfen LLINs might have contributed to their relative lack of effectiveness compared with standard LLINs. FUNDING: Joint Global Health Trials scheme (UK Foreign, Commonwealth and Development Office; UK Medical Research Council; Wellcome; UK Department of Health and Social Care), US Agency for International Development, President's Malaria Initiative.

Monitoring of Fabric Integrity and Attrition Rate of Dual-Active Ingredient Long-Lasting Insecticidal Nets in Tanzania: A Prospective Cohort Study Nested in a Cluster Randomized Controlled Trial.

Pyrethroid-treated long-lasting insecticidal nets (LLINs) have been the main contributor to the reduction in malaria in the past two decades in sub-Saharan Africa. The development of pyrethroid insecticide resistance threatens the future of LLINs, especially when nets become holed and pyrethroid decays. In this study, three new classes of dual-active ingredient (AI) LLINs were evaluated for their physical durability: (1) Royal Guard, combining pyriproxyfen, which disrupts female fertility, and a pyrethroid, alpha-cypermethrin; (2) Interceptor G2, which combines the pyrrole chlorfenapyr and a pyrethroid (alpha-cypermethrin); (3) Olyset Plus, which incorporates the pyrethroid permethrin and the synergist piperonyl butoxide, to enhance the pyrethroid potency; and Interceptor, a reference net that contains alpha-cypermethrin as the sole active ingredient. About 40,000 nets of each type were distributed in February 2019 to different villages in Misungwi. A total of 3072 LLINs were followed up every 6-12 months up to 36 months to assess survivorship and fabric integrity. The median functional survival was less than three years with Interceptor, Interceptor G2, and Royal Guard showing 1.9 years each and Olyset Plus showing 0.9 years. After 36 months, 90% of Olyset Plus and Royal Guard and 87% of Interceptor G2 were no longer in use (discarded) due to wear and tear, compared to 79% for Interceptor. All dual-AI LLINs exhibited poor textile durability, with Olyset Plus being the worst.

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.

BACKGROUND: New classes of long-lasting insecticidal nets (LLINs) containing two active ingredients have been recently recommended by WHO in areas where malaria vectors are resistant to pyrethroids. This policy was based on evidence generated by the first 2 years of our recently published trial in Tanzania. In this Article, we report the final third-year trial findings, which are necessary for assessing the long-term effectiveness of new classes of LLIN in the community and the replacement intervals required. METHODS: A third year of follow-up of a four-arm, single-blind, cluster-randomised controlled trial of dual active ingredient LLINs was conducted between July 14, 2021, and Feb 10, 2022, in Misungwi, Tanzania. Restricted randomisation was used to assign 84 clusters to the four LLIN groups (1:1:1:1) to receive either standard pyrethroid (PY) LLINs (reference), chlorfenapyr-PY LLINs, pyriproxyfen-PY LLINs, or piperonyl butoxide (PBO)-PY LLINs. All households received one LLIN for every two people. Data collection was done in consenting households in the cluster core area with at least one child between 6 months and 15 years of age who permanently resided in the selected household. Exclusion criteria were householders absent during the visit, living in the cluster buffer area, no adult caregiver capable of giving informed consent, or eligible children who were severely ill. Field staff and study participants were masked to allocation, and those analysing data were not. The primary 24-month endpoint was reported previously; here, we present the secondary outcome, malaria infection prevalence in children at 36 months post LLIN distribution, reported in the intention-to-treat analysis. The trial was registered with ClinicalTrials.gov (NCT03554616) and is now complete. FINDINGS: Overall usage of study nets was 1023 (22·3%) of 4587 people at 36 months post distribution. In the standard PY LLIN group, malaria infection was prevalent in 407 (37·4%) of 1088 participants, compared with 261 (22·8%) of 1145 in the chlorfenapyr-PY LLIN group (odds ratio 0·57, 95% CI 0·38-0·86; p=0·0069), 338 (32·2%) of 1048 in the PBO-PY LLIN group (0·95, 0·64-1·42; p=0·80), and 302 (28·8%) of 1050 in the pyriproxyfen-PY LLIN group (0·82, 0·55-1·23; p=0·34). None of the participants or caregivers reported side-effects. INTERPRETATION: Despite 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. FUNDING: Department for International Development, UK Medical Research Council, Wellcome Trust, Department of Health and Social Care, and Bill & Melinda Gates Foundation via the Innovative Vector Control Consortium.

Assessing risk factors for malaria and schistosomiasis among children in Misungwi, Tanzania, an area of co-endemicity: A mixed methods study.

Malaria and schistosomiasis are two major parasitic vector-borne diseases that are a particular threat to young children in Sub-Saharan Africa. In the present study, we investigated factors that are associated with malaria, schistosomiasis, and co-infection among school-aged children, using an explanatory sequential mixed-methods approach. A cross-sectional study was conducted in January 2022 in Misungwi, Tanzania, that sampled 1,122 children aged 5 to 14 years old for malaria and schistosomiasis infection. Mixed-effect logistic regression models were used to assess the association between infection prevalence or seroprevalence, and environmental determinants that create favorable conditions for vectors and parasites and social determinants that relate to disease exposure. Community mapping combined with direct field observations were conducted in August 2022 in three selected villages from the cross-sectional study to understand specific water use behaviors and to identify potential malaria mosquito larval breeding sites and freshwater snail habitat. The prevalence of malaria, seroprevalence of schistosomiasis, and co-infection in this study were 40.4%, 94.3%, and 38.1%, respectively. Individual-level factors emerged as the primary determinants driving the association with infection, with age (every one-year increase in age) and sex (boys vs girls) being statistically and positively associated with malaria, schistosomiasis, and co-infection (P<0.05 for all). Community maps identified many unimproved water sources in all three villages that were used by humans, cattle, or both. We found that children primarily fetched water, and that unprotected wells were dedicated for drinking water whereas ponds were dedicated for other domestic uses and cattle. Although not identified in the community maps, we found hand pumps in all three villages were not in use because of unpleasant taste and high cost. This study improves our understanding of individual, social and environmental factors that are associated with malaria, schistosomiasis, and co-infection, which can inform potential entry points for integrated disease prevention and control.