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

Global advances in malaria control have led to increased international commitment to malaria elimination [1]. A major challenge in achieving elimination is the identification and targeting of sub-microscopic and asymptomatic malaria infections, which are important for continued malaria transmission in low transmission settings [2, 3]. Mass testing and treatment (MTAT) and mass drug administration (MDA) are two potential strategies for targeting such infections [4]. MTAT involves screening all individuals in a given geographical area and treating those found positive for malaria. MTAT has been evaluated for use in malaria elimination settings, including Zanzibar [4, 5], but has not proven to influence transmission possibly due to low sensitivity of available diagnostic tools such as microscopy and rapid diagnostic tests (RDTs) [4, 6]. MDA is defined as the empiric administration of a therapeutic course of an antimalarial regimen to a defined population at the same time without screening or diagnostic testing prior to administration [7]. MDA has been a historic component of many malaria control and elimination programmes, but was until recently not recommended by the World Health Organization (WHO) due to concerns about efficacy, logistical feasibility, sustainability, and the risk of accelerating drug resistance [4]. However, limitations of currently available diagnostic tools and the development of efficacious antimalarials with transmission-reducing effects, such as artemisinin-based combination therapies and primaquine, have renewed the interest for MDA [7‐9]. The WHO now supports MDA as an additional tool in low-endemic regions approaching interruption of transmission [4, 10].

Recent reviews have summarised the findings of MDA studies conducted in different settings in Asia, Africa, and the Americas [7, 8]. These studies employed a wide variety of MDA regimens incorporating different drugs, dosages, timings, and numbers of MDA rounds. In the first review in 2013, only two out of 32 included studies were conducted in areas of low endemicity (≤ 5% prevalence) [7, 11], and only two were designed as cluster randomised controlled trials (CRCTs) [11, 12]. Overall, the quality of evidence from areas of low endemicity was deemed to be very low [7]. In the more recent review, 48 out of 182 included studies had follow-up periods greater than 6 months. Only 12 of these 48 studies, conducted between 1961 and 2004, interrupted transmission for over 6 months post-MDA [8]. Only one of these 12 was conducted in sub-Saharan Africa. The consensus from both reviews is that MDA seems to have an immediate impact on malaria transmission, but only few studies have shown sustained impact beyond 6 months.

More recently, three pilot studies in Southeast Asia have shown over 90% reductions of the Plasmodium falciparum reservoir up to 12 months post-MDA [13‐15]. In highly endemic villages in Eastern Myanmar, an uncontrolled before-and-after study of monthly MDA with dihydroartemisinin-piperaquine (DP) and single low dose (SLD) of primaquine showed a sustained fivefold decrease in P. falciparum incidence [16]. A recent CRCT conducted in low transmission areas (< 10% prevalence) in southern Zambia reported a short-term impact 5 months after two rounds of community-wide MDA with DP (odds ratio (OR) 0.13; p = 0.04) [17]. Finally, modelling has predicted that high coverage of repeated mass treatment may result in sustained transmission reduction when combined with vector control in low-endemic areas [18‐20]. In conclusion, additional empirical evidence through high-quality CRCTs is clearly needed to determine the immediate and long-term impact of MDA, especially in low-endemic settings in sub-Saharan Africa where the goal is malaria elimination.

Zanzibar has, through high vector control coverage and good access to treatment, reached a state of malaria pre-elimination with low and seasonal transmission [21]. However, a persistent reservoir of sub-microscopic and asymptomatic infections remains an important obstacle in achieving elimination [22]. Zanzibar therefore represents an ideal situation to test MDA in the WHO recommended context of malaria elimination. A pilot MDA was conducted in response to a malaria outbreak in Zanzibar in 2013 [23]. Approximately 8800 inhabitants received a single round of MDA with DP. The MDA was well received by the community, with over 90% coverage and self-reported adherence. The impact of the intervention was, however, not monitored. In our present study, a CRCT was conducted to primarily assess the effectiveness and safety of two rounds of MDA with DP given together with SLD primaquine, for reducing seasonal malaria transmission towards its elimination in Zanzibar. Two rounds of MDA were chosen to maintain a balance between cost, feasibility, and impact. Importantly, this study adds to the limited evidence for the use of MDA in low transmission settings in sub-Saharan Africa, a primary goal for MDA [4].

Two rounds of MDA were implemented in a population of over 10,000 people in areas considered hotspots in Zanzibar. High intervention coverage and adherence (> 80%) was achieved in each treatment round, and MDA was well tolerated and accepted by the community. Despite successful implementation, no difference in malaria transmission was observed between the intervention and control arms in this pre-elimination setting.

Multiple rounds of MDA with high intervention coverage (i.e. over 80%) are deemed necessary when MDA is used to reduce transmission or eliminate malaria [8, 10]. Coverage is generally determined based on the amount of drugs dispensed and the number of persons targeted in each treatment round. This method may, however, overestimate treatment coverage if missing persons and mobile populations are not correctly accounted for [4]. In our study, population sizes were estimated from a census survey conducted in 2012 and IRS survey data from 2016. Similar numbers were obtained at the study baseline enumeration (data not shown), suggesting that the majority of the study population had been recorded. The coverage in each treatment round was 91.0% and 87.7%. High coverage is, however, only effective if an adequate number of people correctly complete the full course of antimalarial treatment [10]. Adherence is especially an issue when treatment is provided to individuals who are not sick. Adherence measurements mostly rely on self-reporting, but this may be subject to recall bias or over reporting. We therefore validated the self-reported adherence using day 7 piperaquine blood concentrations. This enabled an overall mean estimate regarding effective coverage (i.e. the proportion of the population completing the full treatment course) of 72.6% in each round.

The high coverage and compliance achieved in this study may partly be due to the familiarity of MDA as an intervention through its previous use in control and elimination of schistosomiasis and lymphatic filariasis [28, 29], as well as historic and more recent use in malaria control [23, 30]. Community engagement to build awareness of MDA for asymptomatic malaria and partnerships between researchers, local volunteers, and authorities are also factors noted to contribute to high intervention uptake [23, 30‐34]. These factors were considered in the community sensitisation that was conducted prior to the study start. In addition, over half of the head of households still recognise malaria as a health concern (Table 1) despite substantial reductions in malaria morbidity and mortality in Zanzibar, potentially adding to the high uptake of the intervention. Another important component for achieving adequate adherence is the safety and tolerability of the treatment regimen [10]. Pharmacovigilance in this study was planned to ensure training, detection, reporting, management, and follow-up of adverse events by both passive and active surveillance. In line with other studies [13, 14, 16, 34‐37], MDA with DP and SLD primaquine was deemed safe, with some transient adverse events and no reports of clinically serious adverse events. In addition, acceptability of the intervention was high with over 90% of survey respondents expressing willingness to participate in future MDAs.

Although high coverage and compliance were achieved, no significant impact on transmission was observed, although having received at least the first MDA was partly protective against asymptomatic infection 3 months post-MDA (aOR = 0.35; p = 0.02). Previous studies evaluating the impact of MDA have had varying results [7, 8, 13, 15‐17, 30]. Overall, MDA has mostly shown short-term impact on malaria transmission, and only a few studies have provided sustained results [14‐16, 38]. Recent studies have shown MDA to have an added effect in areas already experiencing a decline in the malaria burden, when deployed together with enhanced early diagnosis and treatment and supporting interventions that target malaria vectors [13‐17]. The study in Zambia is the only previous CRCT showing impact of MDA in a low-endemic area in sub-Saharan Africa [17]. This study reported a reduction in malaria prevalence 5 months after two rounds of MDA with DP, albeit with weak statistical significance (aOR 0.13, CI95% 0.02–0.92, p = 0.04).

The optimal transmission scenarios and drug intervention regimens for producing a sustained impact with MDA thus remain largely unknown, and it remains unclear when MDA may be of most benefit in the context of malaria elimination [39]. DP has been suggested as a suitable option for MDA, in view of its good efficacy, long post-treatment prophylaxis, and good tolerability [10]. The addition of SLD primaquine is recommended to further reduce the transmissibility of P. falciparum gametocytes in areas of low transmission [10, 40]. The number of treatment rounds required to obtain a sustained effect of MDA is however unclear. A single year of two rounds of MDA with an effective coverage of 70% is estimated to provide 14–35% reduction in P. falciparum prevalence 2 years after MDA [18]. Modelling suggests that increased number of rounds improves the effectiveness, with a greater sustained impact of MDA if continued over 2 years rather than one. The aim of successive rounds is total coverage, i.e. reaching people who were initially missed and people who were treated in the previous rounds but may have been re-infected after MDA [10, 18]. Adding a third treatment round with 70% effective coverage in models only improved effectiveness if additional people were reached who had not previously received treatment [18]. We estimated a mean effective coverage of 72.6% in each treatment round, with 60.6% of the population having received both rounds and 92.6% of the population having received at least one round. Whether or not this coverage is sufficient remains unclear. Perhaps, higher effective coverage of at least two consecutive rounds of MDA is required to provide a long enough prophylactic period to protect against reinfection from infected mosquitoes (i.e. covering a full man-mosquito-man cycle) in a population.

High coverage of consecutive MDA rounds may be especially important in low-endemic areas where imported malaria cases (which may not be affected by MDA) are expected to have a greater relative contribution to transmission [18]. In Zanzibar, the proportion of clinical malaria cases reporting travel has increased in recent years, clearly indicating imported malaria to be an important driver of remaining transmission (Björkman et al. submitted). In the present study, over a quarter of clinical malaria cases reported overnight stay outside of Zanzibar in the last month (Table 5) compared to less than 1% in the general population (Table 1). We therefore, suggest that two rounds of MDA in a single year may not be sufficient to have a sustained impact on transmission in a pre-elimination setting, especially when the impact of MDA is restricted by imported malaria.

Another possible explanation for the lack of impact on transmission could be the timing of the MDA. Modelling has predicted less influence on malaria transmission if MDA is conducted during peak transmission [18, 19]. It is therefore recommended in areas of seasonal transmission that MDA be deployed immediately before the start of the main transmission season [4, 9, 10, 14, 18]. The onset of this study was delayed due to political elections, and due to difficulties in importation and registration of the study drugs. The first round of MDA was conducted right at the beginning of the high transmission season and the second round during peak transmission (see Additional file 2: Figure S3). Having received the first round of treatment was indeed associated with reduced odds of PCR-detected malaria infection in the follow-up survey, whilst having only received the second round of treatment was not (see Additional file 3: Table S2b). These data suggest that there may have been a short and transient effect of MDA on local transmission, which had already been diluted when the follow-up survey was conducted 3 months post-MDA. In addition, the difference in the timing of the baseline surveys in the intervention and control shehias (see Additional file 2: Figure S3) may partly explain the difference in malaria prevalence at the study baseline (Table 1). This difference may however also be due to chance since the potential for imbalance across treatment groups despite randomisation is greater in a relatively small number of clusters.

Importantly, the ability to assess the true effectiveness of MDA in this study was affected by the overall decline in malaria transmission that occurred across Unguja island in 2016 (Fig. 4 and Additional file 2: Figure S2). The study was powered to detect a 50% drop in cumulative malaria incidence from 12/1000 to 6/1000 population in the intervention arm during the 6 months following MDA. However, the observed cumulative incidence (4.2/1000) in the control arm was lower than predicted (Table 3). Assessing the impact of interventions in low transmission settings is problematic, not only because it is difficult to achieve great enough power, but also because transmission may be geographically and temporally heterogeneous from year to year. Several other studies have also reported a decline in transmission across study arms [11, 13, 15, 17]. These studies, including the CRCT conducted in Zambia, have largely attributed these declines to the continuing effects of additional interventions such as high coverage with vector control and strong case management and surveillance. It has been argued that these additional interventions are a prerequisite for implementing MDA [17], but when all interventions are introduced simultaneously, the resulting large reductions in incidence may potentially mask the additional impact of MDA. In Zanzibar on the other hand, high vector control coverage, strong malaria case management, and malaria surveillance have been in place since 2008. Actellic®300CS has been in use since 2014 in the annual targeting of malaria hotspots with IRS, and continued high uptake of bed net usage has been reported in this study as well as elsewhere (Björkman et al., submitted). These additional interventions can therefore not explain the large decline in transmission observed across Zanzibar in 2016. Another more likely explanation for the reduction in transmission is the year-to-year fluctuations in climate [41]. Despite there not being any obvious difference in the total rainfall, the rains in 2016 were short and intense and stopped early with a very dry May compared to 2015 and 2017 (Additional file 2: Figure S2). Overall, these general declines in transmission across study arms highlight the importance of a cluster randomised study design when evaluating the impact of MDA on malaria transmission [17, 30, 39].

MDA was implemented with high coverage, adherence, and tolerability in Zanzibar. Despite this, no significant impact on malaria 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 impact of MDA 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.