Articles
Combination of malaria vector control interventions in pyrethroid resistance area in Benin: a cluster randomised controlled trial

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Summary

Background

Malaria control efforts and elimination in Africa are being challenged by the development of resistance of parasites to antimalarial drugs and vectors to insecticides. We investigated whether the combination of long-lasting insecticidal mosquito nets (LLINs) with indoor residual spraying (IRS) or carbamate-treated plastic sheeting (CTPS) conferred enhanced protection against malaria and better management of pyrethroid-resistance in vectors than did LLINs alone.

Methods

We did a cluster randomised controlled trial in 28 villages in southern Benin, west Africa. Inclusion criteria of the villages were moderate level of pyrethroid resistance in malaria vectors and minimum distance between villages of 2 km. We assessed four malaria vector control interventions: LLIN targeted coverage to pregnant women and children younger than 6 years (TLLIN, reference group), LLIN universal coverage of all sleeping units (ULLIN), TLLIN plus full coverage of carbamate-IRS applied every 8 months (TLLIN+IRS), and ULLIN plus full coverage of CTPS lined up to the upper part of the household walls (ULLIN+CTPS). The interventions were allocated to villages by a block randomisation on the basis of preliminary surveys and children of each village were randomly selected to participate with computer-generated numbers. The primary endpoint was the incidence density rate of Plasmodium falciparum clinical malaria in children younger than 6 years as was analysed by Poisson regression taking into account the effect of age and the sampling design with a generalised estimating equation approach. Clinical and parasitological information were obtained by active case detection of malaria episodes during 12 periods of 6 consecutive days scheduled at six weekly intervals and by cross-sectional surveys of asymptomatic plasmodial infections. Children or study investigators were not masked to study group. This study is registered with Current Controlled Trials, number ISRCTN07404145.

Findings

Of 58 villages assessed, 28 were randomly assigned to intervention groups. 413–429 children were followed up in each intervention group for 18 months. The clinical incidence density of malaria was not reduced in the children from the ULLIN group (incidence density rate 0·95, 95% CI 0·67–1·36, p=0·79), nor in those from the TLLIN+IRS group (1·32, 0·90–1·93, p=0·15) or from the ULLIN+CTPS group (1·05, 0·75–1·48, p=0·77) compared with the reference group (TLLIN). The same trend was observed with the prevalence and parasite density of asymptomatic infections (non significant regression coefficients).

Interpretation

No significant benefit for reducing malaria morbidity, infection, and transmission was reported when combining LLIN+IRS or LLIN+CTPS compared with a background of LLIN coverage. These findings are important for national malaria control programmes and should help the design of more cost-effective strategies for malaria control and elimination.

Funding

Ministère Français des Affaires Etrangères et Européennes (FSP project 2006-22), Institut de Recherche pour le Développement, President's Malaria Initiative (PMI) of US Governement.

Introduction

Despite substantial efforts and increasing international funding dedicated throughout the world to control and eliminate malaria,1 the disease is still a major public health issue with nearly 216 million cases a year and about 655 000 deaths, 86% of whom are children younger than 5 years.2 Recommendations of the World Health Organization (WHO Global Malaria Programme-Roll Back Malaria [RBM] Partnership) to combat malaria include artemisinin-based combination therapy and long-lasting insecticidal nets (LLIN), supported by indoor residual spraying of insecticide (IRS) and intermittent preventive treatment during pregnancy. Between 2008 and 2010, nearly 289 million insecticide-treated mosquito nets were delivered to sub-Saharan Africa, enough to protect 578 million people. Additionally, about 81 million people, representing 11% of the population at risk, were also protected by IRS.2 Deployment of such strategies has shown important reduction in malaria-associated morbidity and mortality in settings with moderate-to-high transmission levels in sub-Saharan Africa,3, 4 but a recent increase of malaria cases was reported in some African countries, hence underlining the fragility of malaria prevention and control in this part of the world.2, 5

The overarching goal of malaria vector control is to decrease the vectorial capacity of local vector populations below the critical threshold needed to achieve a malaria reproduction number (R0, the expected number of human cases that arise from each human case in a population) of less than one. Unfortunately, current methods (LLIN and IRS) are highly dependent on a single class of insecticides, the pyrethroids, for which malaria vectors have developed various resistance mechanisms.6 To ensure the success of vector control efforts and malaria elimination in Africa, the WHO-RBM and Malaria Eradication Research Agenda (malERA) consultative vector control group emphasised the need to search for innovative strategies. These strategies should aim at more effective control of pyrethroid-resistant malaria vectors to strongly decrease and interrupt disease transmission in endemic areas.7, 8

In some countries where more resources have become available, malaria control programmes have recently deployed both IRS and LLIN in the same malaria risk areas.2 The aims of this combined approach are to reduce transmission—and hence the malaria burden—more rapidly than might be feasible with one method alone and to delay the emergence of insecticide resistance by use of different classes of insecticide for IRS and LLINs. So far, a small number of studies9, 10 and mathematical modelling exercises11, 12 suggest that such combination has an added benefit for reduction of the risk of infection because the people not protected by one of the interventions are protected by the other. However, all the available studies were observational (ie, non experimental, without randomised allocation of the interventions), and in none of them could confounding factors be entirely excluded. Despite the great interest in combining methods for malaria control and elimination, no evidence exists for an epidemiological effect of LLIN and IRS, which we define here as the implementation of both interventions at the same time, in the same community, and against the same vector population.

The aim of this study was to investigate whether the use of both interventions in combination (ie, LLIN plus IRS or LLIN plus carbamate-treated plastic sheeting [CTPS]) afforded enhanced protection against clinical malaria at community level and a better management of pyrethroid-resistance in malaria vectors than did a selective coverage of LLIN in children younger than 6 years (reference group according to recommendations by the National Malaria Control Programme [NMCP]). The rationale behind the use of CTPS came from results of preliminary experimental hut studies in west Africa that showed good insecticidal activity of CTPS against pyrethroid-resistant malaria vectors.13, 14 The trial also aimed at determining whether universal coverage of LLIN could afford better protection against malaria than would selective coverage by achieving a mass killing effect.15 The assumption is that much more reduction of transmission is expected with universal coverage of all sleeping units with LLIN (ULLIN) because of a reduction of the infection rate of vectors by poor access to the largest part of the human population that is infected (oldest children and adults) and the shortening of the life expectancy of the vectors.

Section snippets

Study design

We did a cluster randomised controlled trial in the health district of Ouidah-Kpomassè-Tori Bossito (OKT), southern Benin, between June 23, 2008, and Dec 24, 2009. The inclusion criteria for villages were moderate level of pyrethroid resistance in malaria vectors (kdr allelic frequency <40%), minimum distance of 2 km between villages, population size of 250–500 inhabitants with non-isolated habitations, and absence of a local health centre. Inclusion criteria for children were age (0–71 months)

Results

Of the 58 villages screened, 28 were enrolled and randomly assigned to vector control intervention (TLLIN, ULLIN, TLLIN+IRS, and ULLIN+CTPS; figure 1). Between 651 and 920 children were assessed for eligibility in every group and 40–60% of them were randomised (figure 2). A total of 16 327 blood thick films were analysed (about 4000 in each group). In every group, about 20% of the recordings were not taken into account because of loss to follow-up (17%), death of children (1·5%), and refusal

Discussion

We investigated the efficacy of new vector control strategies for malaria control and whether the use of combined interventions (ie, LLIN+IRS or LLIN+CTPS) would reduce malaria morbidity and transmission and allow better management of pyrethroid-resistance in malaria vectors relative to a background of LLIN coverage. Overall, however, neither clinical malaria nor the prevalence of infection and parasite density of asymptomatic infection in children younger than 6 years were reduced in southern

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