A cluster randomised controlled trial of two rounds of mass drug administration in Zanzibar, a malaria pre-elimination setting-high coverage and safety, but no significant impact on transmission

Abstract

Background: Mass drug administration (MDA) has the potential to interrupt malaria transmission and has been suggested as a tool for malaria elimination in low-endemic settings. This study aimed to determine the effectiveness and safety of two rounds of MDA in Zanzibar, a pre-elimination setting.

Methods: A cluster randomised controlled trial was conducted in 16 areas considered as malaria hotspots, with an annual parasite index of > 0.8%. The areas were randomised to eight intervention and eight control clusters. The intervention included two rounds of MDA with dihydroartemisinin-piperaquine and single low-dose primaquine 4 weeks apart in May-June 2016. Primary and secondary outcomes were cumulative confirmed malaria case incidences 6 months post-MDA and parasite prevalences determined by PCR 3 months post-MDA. Additional outcomes included intervention coverage, treatment adherence, occurrence of adverse events, and cumulative incidences 3, 12, and 16 months post-MDA.

Results: Intervention coverage was 91.0% (9959/10944) and 87.7% (9355/10666) in the first and second rounds, respectively; self-reported adherence was 82.0% (881/1136) and 93.7% (985/1196). Adverse events were reported in 11.6% (147/1268) and 3.2% (37/1143) of post-MDA survey respondents after both rounds respectively. No serious adverse event was reported. No difference in cumulative malaria case incidence was observed between the control and intervention arms 6 months post-MDA (4.2 and 3.9 per 1000 population; p = 0.94). Neither was there a difference in PCR-determined parasite prevalences 3 months post-MDA (1.4% and 1.7%; OR = 1.0, p = 0.94), although having received at least the first MDA was associated with reduced odds of malaria infection (aOR = 0.35; p = 0.02). Among confirmed malaria cases at health facilities, 26.0% and 26.3% reported recent travel outside Zanzibar in the intervention and control shehias (aOR ≥ 85; p ≤ 0.001).

Conclusions: MDA was implemented with high coverage, adherence, and tolerability. Despite this, no significant impact on transmission was observed. The findings suggest that two rounds of MDA in a single year may not be sufficient for a sustained impact on transmission in a pre-elimination setting, especially when the MDA impact is restricted by imported malaria. Importantly, this study adds to the limited evidence for the use of MDA in low transmission settings in sub-Saharan Africa.

Trial registration: ClinicalTrials.gov, NCT02721186 (registration date: March 29, 2016).

Keywords: Adherence; Coverage; Dihydroartemisinin-piperaquine; Effectiveness; Elimination; Low transmission; Malaria; Mass drug administration; Safety; Single low-dose primaquine.

Conflict of interest statement

Ethics approval and consent to participate

Ethical approval was obtained from the Zanzibar Medical Research and Ethics Committee [ZAMREC/0001/January/2016] and the Zanzibar Food and Drugs Board [No.ZFDB/M.M:B:L:Z/16]. Verbal consent to conduct the study was sought from district authorities and from village leaders prior to the study onset. Written informed consent to participate in the study was sought from the head of household and household members over the age of 16 on the day of the first survey; it was made clear that individual participation in the study was voluntary. Ethical approval for molecular work at Karolinska Institutet was granted by the Regional Ethics Committee in Stockholm, Sweden [2013/836-32].

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1

Unguja Island, Zanzibar. The map highlights the 16 shehias included in the study. Shehias randomised to the control arm are shaded in red, and shehias randomised to the intervention arm are shaded in green

Fig. 2

Flow chart of participation in the first and second rounds of MDA. HH household, MDA mass drug administration, DP dihydroartemisinin-piperaquine, DOT directly observed treatment, SLD PQ single low-dose primaquine

Fig. 3

Flow chart of self-reported adherence after the first and second rounds of MDA

Fig. 4

Confirmed malaria case incidence rates as reported in MCN before and after MDA. Error bars represent the range in monthly incidence rates in the control (red) and intervention (green) shehias. Horizontal bars represent the monthly rainfall on Unguja according to the Tanzanian Meteorological Agency Zanzibar Office. The blue bars under the x-axes represent the timing of IRS with Actellic®300CS, which is conducted annually in Feb–March in hotspot shehias. The yellow bars represent the two phases of the universal LLIN distribution in April 2015 and June–July 2016. The green bars indicate the timing of the two rounds of MDA (30 April–7 May and 28 May–4 June, respectively). The orange bar indicates the timing of the follow-up survey (30 Aug–9 Sept), and the primary endpoint of the study (30 Nov) is marked out with a black arrowhead