A cluster-randomized trial of targeted control to eliminate malaria in Central Senegal.

The purpose of this trial was to evaluate the extent to which a targeted malaria control strategy combining vector control with indoor residual spraying (IRS) and chemotherapy, delivered by district health staff to hotspot villages, can substantially reduce the overall incidence of malaria. We also sought to determine if transmission reduction contributes to this impact, by evaluating the effect of targeted control in non-target villages. The trial was also designed to determine whether the chemotherapy should be delivered to all members of targeted communities (MDA, Mass Drug Administration) or only those who have been tested and are known to be infected (MSAT, Mass Screening and Treatment). 40 clusters were randomized. Each cluster was a health post and the population it serves. In 30 clusters, all households in hotspot villages were targeted to receive IRS with Actellic 300CS (the organophosphate insecticide pirimiphos-methyl, formulated in capsules to provide a long-lasting effect) in July each year. In 15 of these 30 clusters, IRS was followed by MDA with dihydroartemisinin-piperaquine (DHA-PQ) administered to all persons in the household, except pregnant women and children under 3 months of age, at the end of August and again in October. In the other 15 clusters, instead of MDA, all persons in the household were screened using a malaria Rapid Diagnostic Test (RDT, First Response) and those who tested positive treated with DHA-PQ. 10 clusters served as controls. In all three arms, health promotion activities encouraged care seeking for fever, and free long-lasting insecticide-treated bednet was provided to each patient treated for malaria at health facilities in order to top-up coverage. The intervention strategy was delivered over two years (2013 and 2014), and the primary outcomes were the incidence of malaria, and the prevalence of parasitaemia just after the main peak period of transmission, in year 2. In MDA and MSAT arms, the first dose of the 3-day regimen was supervised and adherence to the remaining doses, and adverse events, were assessed in a sample of recipients 4 days after the round. Adverse events were also monitored through passive surveillance at heath facilities. Acceptability was investigated using in-depth interviews and quantitative surveys, and the financial and economic costs of the interventions to the provider were assessed. In 2013, 228 out of 716 villages (32%) were categorized as hotspots. Villages which were hotspots in 2013, were less likely to be hotspots in 2014 in the IRS+MDA arm than was the case in the control arm (relative odds ratio 0.29, 95%CI 0.14,0.59, P=0.001), and than in the IRS+MSAT arm (relative odds ratio 0.41, 95%CI 0.20,0.83, P=0.013). Households in target villages received IRS with Actellic 300-CS at the start of each rainy season. In 2013, only 23% of households were treated due to a shortage of insecticide. In 2014, 75% households were treated. In 2013, about 80,000 persons were treated in MDA round 1 and 69,000 in round 2, and 63,000 persons were screened in MSAT round 1 and 53,000 in round 2. In 2014, 70,000 received MDA in round 1 and 77,000 in round 2, and 70,000 were screened in MSAT round 1 and 71,000 in round 2. In both arms about 25% of the population declared to be resident were not available at the household to be included at the time of MDA and MSAT rounds. Of those present, average refusal rates were 1.1% (MDA) and 12% (MSAT). In MSAT clusters, the overall percentage who tested positive in 2013 was 1.0% in round 1 and 1.3% in round 2, and 1.1% in each of the two rounds in 2014. The percentage testing positive in each MSAT cluster ranged from 0.03% to 5.2%. Adherence appeared excellent, with 1.7% in the MDA arm having leftover medication, and 2% of those treated in the MSAT arm having leftover medication, on day 4. When persons who had been treated were asked on day 4 about their symptoms, mild headache, dizziness, diarrhoea, fever and abdominal pain were the most commonly reported. About 25% of persons surveyed in the MDA group reported symptoms. However this did not seem to adversely affect adherence to daily doses or compliance with subsequent rounds. 364 persons attended outpatient clinics with suspected side effects. Headache, nausea and vomitting were the most common symptoms. One individual, a boy aged 28 months in the MDA arm of the trial, died shortly after administration of DHA-PQ. The incidence of malaria (RDT-confirmed cases at health facilities) was 11 per 1000 in the year before intervention (2012) and the prevalence of parasitaemia by microscopy in a cross-sectional survey in November 2012 was 1.9%. The effectiveness of IRS+MDA in hotspot communities (the % reduction in number of cases during the same calendar year, relative to the hotspot communities in the control arm) was 49% (95%CI 43%,55%) in 2013 and 46% (38%,52%) in 2014. The corresponding estimates for the IRS+MSAT arm were 38% (31%,44%) in 2013 and 52% (47%,58%) in 2014. An improvement in effectiveness in 2014, when IRS coverage and quality of spraying was greater, was thus noticeable in the MSAT arm but not in the MDA arm. In non-target communities, there was no evidence of an intervention impact in 2013. In 2014, there was reduced incidence in non-target communities near to treated hotspots, with an efficacy of IRS+MDA of 69% (49%,82%) <1km, 41% (20%,57%) <2km, and -4.0% (-31%,18%) <3km from a treated hotspot, and in the IRS+MSAT arm, 57% (25%,75%) <1km, 24% (-2.0%,44%) <2km and -2.1% (-30%,20%) <3km from a treated hotspot. The overall efficacy (including target and non-target villages) for the IRS+MDA arm was 37% (31%,43%) in 2013 and 37% (31%,44%) in 2014, and for the MSAT arm, 31% (25%,37%) in 2013 and 44% (38%,49%) in 2014. In areas where scaling-up of existing policies has reduced transmission to low levels but additional measures are needed for elimination, targeted control with IRS and MDA or MSAT could be used to reduce malaria transmission, but MDA was cheaper and somewhat more effective than MSAT.