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Gonahasa, Samuel, Namuganga, Jane Frances, Nassali, Martha J., Maiteki‑Sebuguzi, Catherine, Nabende, Isaiah, Epstein, Adrienne, Snyman, Katherine, Nankabirwa, Joaniter I., Opigo, Jimmy, Donnelly, Martin 
ORCID: https://orcid.org/0000-0001-5218-1497, Dorsey, Grant, Kamya, Moses R. and Staedke, Sarah
(2025)
'LLIN Evaluation in Uganda Project (LLINEUP2) – Effect of long-lasting insecticidal nets (LLINs) treated with pyrethroid plus pyriproxyfen vs LLINs treated with pyrethroid plus piperonyl butoxide in Uganda: A cluster-randomised trial'. PLOS Global Public Health, Vol 5, Issue 2, e0003558.
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Abstract
Between 2000 and 2015, intensified efforts to control malaria substantially reduced malaria case incidence and parasite prevalence across Africa, with the majority of cases averted attributed to the distribution of long-lasting insecticidal nets (LLINs) [1]. More recently, however, progress on malaria control has stalled. Globally, malaria cases increased from 230 million in 2015 to 249 million in 2022, with 95% of cases reported from Africa [2]. Four African countries, including Uganda, accounted for nearly half of all cases worldwide in 2022. In 2022, Uganda reported the third highest number of malaria cases, representing 5% of the global burden of malaria [2]. In Uganda, implementation of malaria control interventions including repeated national LLIN distribution campaigns, indoor residual spraying (IRS) of insecticides in selected high-transmission districts, case management with effective artemisinin-based combination therapy, and intermittent preventive treatment in pregnancy (IPTp) reduced the malaria burden, with parasite prevalence by microscopy in children under-five decreasing from 45% in 2009 to 9% in 2018-2019 [3]. Progress in malaria control in Uganda has been difficult to sustain, however, despite ongoing implementation of effective control interventions [4,5].
In Uganda, and across Africa, LLINs are the most widely-used malaria prevention tool [6]. As recommended by the World Health Organization (WHO), the Ugandan Ministry of Health distributes LLINs through mass campaigns approximately every three years, aiming for universal coverage [7]. Currently, LLINs rely on pyrethroid insecticides, but resistance to pyrethroids has spread rapidly in malaria vectors, threatening the effectiveness of LLINs [8, 9]. The causal mechanisms of pyrethroid resistance are complex, but point mutations in the voltage-gated sodium channel where pyrethroids bind (‘knock down resistance’), and alterations in enzymes that metabolize pyrethroids, commonly cytochrome P450s, are key features [10, 11]. Pyrethroid resistance is widespread in Uganda [12, 13].
To combat emerging resistance, next generation LLINs that incorporate a second chemical in addition to pyrethroids have been developed. One such net includes piperonyl butoxide (PBO), a synergist which inhibits P450 enzymes, overcoming metabolic resistance mechanisms in mosquitoes, and partially restoring susceptibility to pyrethroids [13, 14]. Supported by evidence from trials conducted in Tanzania and Uganda [15–17], demonstrating the superiority of pyrethroid-PBO LLINs over pyrethroid-only LLINs, the WHO endorsed deployment of pyrethroid-PBO LLINs in areas where malaria vectors exhibit pyrethroid resistance. The WHO’s recommendation was conditional due to uncertainty about the cost-effectiveness and durability of pyrethroid-PBO LLINs [18, 19]. Another new type of LLIN combines pyrethroids with pyriproxyfen, an insect growth regulator which acts as a sterilising agent, reducing the vector population density and lifespan of adult mosquitoes. Pyrethroid-pyriproxyfen LLINs are promising, but trials comparing these nets to pyrethroid-only LLINs in Burkina Faso and Tanzania have produced mixed results [20, 21]. Additional studies evaluating the effectiveness of nets incorporating pyriproxyfen are needed.
Uganda has embraced next-generation LLINs to combat pyrethroid resistance. While only pyrethroid-only LLINs were available for distribution in 2013-2014, pyrethroid-PBO LLINs were distributed to selected areas in 2016-2017 and were found to be superior to pyrethroid-only LLINs in a large-scale cluster-randomised trial [16,17]. In 2020-2021, pyrethroid-PBO LLINs and pyrethroid-pyriproxyfen LLINs were distributed across Uganda, providing an opportunity to evaluate the effectiveness of these LLINs in a ‘real-world’ setting. With support from the Ministry of Health, donors, and partners, a large cluster-randomised trial (LLINEUP2) was embedded within this national distribution campaign, allowing us to rigorously compare the impact of these LLINs on epidemiological indicators. Leveraging mass campaigns is an innovative, pragmatic approach to evaluate the ‘real-world’ effectiveness of novel malaria control interventions, which has been applied successfully in Uganda [16,17]. We aimed to test the hypothesis that malaria incidence would be lower in intervention clusters (randomised to receive pyrethroid-pyriproxyfen LLINs) than in control clusters (randomised to receive pyrethroid-PBO LLINs). Malaria surveillance data at health facilities were collected between 17 October 2020 and 31 March 2023, and cross-sectional community survey data between 24 November 2021 to 1 April 2022 (12-months) and 23 November 2022 to 21 March 2023 (24-months) post-LLIN distribution.
| Item Type: | Article |
|---|---|
| Subjects: | QX Parasitology > Insects. Other Parasites > QX 510 Mosquitoes QX Parasitology > Insects. Other Parasites > QX 600 Insect control. Tick control WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria |
| Faculty: Department: | Biological Sciences > Vector Biology Department |
| Digital Object Identifer (DOI): | https://doi.org/10.1371/journal.pgph.0003558 |
| SWORD Depositor: | JISC Pubrouter |
| Depositing User: | JISC Pubrouter |
| Date Deposited: | 24 Mar 2025 09:10 |
| Last Modified: | 24 Mar 2025 09:10 |
| URI: | https://archive.lstmed.ac.uk/id/eprint/26249 |
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