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

Abstract

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.

Conflict of interest statement

Declaration of interests We declare no competing interests.

Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1

Trial profile *See appendix (p 11) for a breakdown of reasons for exclusion. † From each household, up to two children were selected for rapid diagnostic testing. ‡Children did not attend clinical appointment and were not tested for malaria. §Malaria test results missing. ¶Exclusion criteria were the same as for cross-sectional prevalence surveys; however, as community health workers only recorded the consenting households, a breakdown of reasons for exclusion is unavailable. ||Some community health workers enrolled more than 35 or 40 households per cluster per year. **13 households per cluster were selected at each round of collections (four rounds in year 1 and five rounds in year 2); a fifth round of collections was added in year 2 to compensate for the suspension of collections between March and May, 2020, due to the SARS-CoV-2 pandemic. †† See appendix (p 18) for a breakdown of reasons for exclusion.

Figure 1

Trial profile *See appendix (p 11) for a breakdown of reasons for exclusion. † From each household, up to two children were selected for rapid diagnostic testing. ‡Children did not attend clinical appointment and were not tested for malaria. §Malaria test results missing. ¶Exclusion criteria were the same as for cross-sectional prevalence surveys; however, as community health workers only recorded the consenting households, a breakdown of reasons for exclusion is unavailable. ||Some community health workers enrolled more than 35 or 40 households per cluster per year. **13 households per cluster were selected at each round of collections (four rounds in year 1 and five rounds in year 2); a fifth round of collections was added in year 2 to compensate for the suspension of collections between March and May, 2020, due to the SARS-CoV-2 pandemic. †† See appendix (p 18) for a breakdown of reasons for exclusion.

Figure 1

Trial profile *See appendix (p 11) for a breakdown of reasons for exclusion. † From each household, up to two children were selected for rapid diagnostic testing. ‡Children did not attend clinical appointment and were not tested for malaria. §Malaria test results missing. ¶Exclusion criteria were the same as for cross-sectional prevalence surveys; however, as community health workers only recorded the consenting households, a breakdown of reasons for exclusion is unavailable. ||Some community health workers enrolled more than 35 or 40 households per cluster per year. **13 households per cluster were selected at each round of collections (four rounds in year 1 and five rounds in year 2); a fifth round of collections was added in year 2 to compensate for the suspension of collections between March and May, 2020, due to the SARS-CoV-2 pandemic. †† See appendix (p 18) for a breakdown of reasons for exclusion.

Figure 1

Trial profile *See appendix (p 11) for a breakdown of reasons for exclusion. † From each household, up to two children were selected for rapid diagnostic testing. ‡Children did not attend clinical appointment and were not tested for malaria. §Malaria test results missing. ¶Exclusion criteria were the same as for cross-sectional prevalence surveys; however, as community health workers only recorded the consenting households, a breakdown of reasons for exclusion is unavailable. ||Some community health workers enrolled more than 35 or 40 households per cluster per year. **13 households per cluster were selected at each round of collections (four rounds in year 1 and five rounds in year 2); a fifth round of collections was added in year 2 to compensate for the suspension of collections between March and May, 2020, due to the SARS-CoV-2 pandemic. †† See appendix (p 18) for a breakdown of reasons for exclusion.

Figure 2

Cost-effectiveness of dual-active-ingredient LLINs relative to pyrethroid-only LLINs over a 2-year period Cost-effectiveness planes are shown separately for societal, donor, public provider, and household perspectives. The public provider perspective combines costs borne by donors with costs borne by the public health service in providing LLINs and malaria diagnoses and treatments. Each data point reflects a single iteration in the Monte Carlo simulation; 1000 iterations were conducted. LLIN=long-lasting insecticidal net. DALYs=disability-adjusted life-years.