Estimating the overall effect of a mass drug administration strategy for malaria in Los Chiles, Costa Rica: One-year target trial emulation with synthetic controls

Background Mass drug administration (MDA) is a WHO-recommended strategy for the elimination of Plasmodium falciparum malaria in low-transmission settings close to elimination. After achieving zero autochthonous cases between 2013 and 2015, Costa Rica experienced a resurgence, primarily of P. falciparum, prompting an MDA intervention in 2023 in the Los Chiles focus. We evaluate its impact on the incidence of autochthonous malaria.

An MDA with two cycles of chloroquine (25 mg/kg per cycle, spaced seven weeks apart) was implemented between April—June 2023 in three localities (Medio Queso, Coquital, and San Gerardo) within the Los Chiles focus. We use a cluster-target trial emulation to estimate the overall average treatment effect on the treated (ATT) under an intention-to-treat approach. We use generalized synthetic control methods (GSCM) to construct a counterfactual for the intervened localities, using malaria surveillance data from January 2021 to April 2024. Our primary outcome was the autochthonous malaria case count at 1, 3, 6, and 12 months post-intervention.

We found that the MDA achieved 93.3% coverage across the two cycles (4,316/4,624 people received at least one dose). The first cycle had 77.3% coverage and the second 51.2%, achieving 68.1% adherence (full treatment in at least one cycle) and 20.4% in both cycles. Following the intervention, autochthonous malaria cases in the treated localities decreased to zero in the first month and remained at zero throughout the 12-month follow-up period. Overall, we estimated that in the absence of MDA, cases would have persisted (approximately 3-4 cases/month). The strategy was associated with a significant reduction in cases, with an overall post-intervention Rate Ratio (RR) of 0.23 (95% CI: 0.13, 0.49) and an average reduction of 3.72 cases per period (95% CI: −7.2, −0.94) compared to the synthetic control.

We found that the chloroquine-based MDA strategy implemented in the Los Chiles focus was highly effective in interrupting autochthonous malaria transmission in the short and medium term. Our results suggest that MDA, when well-planned and implemented in a low transmission setting with a strengthened health system, can be a powerful tool to accelerate malaria elimination. Competing Interest Statement The authors have declared no competing interest. Funding Statement Yes Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the National Health Research Council of Costa Rica (Consejo Nacional de Investigación en Salud, CONIS), under agreement 10/2024 (letter No. CONIS-448-2024). Our research involved secondary analysis of identifiable data, accessed with appropriate institutional authorization and in compliance with national data protection laws. Strict measures were taken to ensure data confidentiality and secure storage. All necessary ethical safeguards were implemented, and the use of identifiable information was justified and approved by the ethics committee. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability Limited anonymized datasets supporting the findings of this study are available via the Open Science Framework (OSF) at: https://osf.io/tk7s3/?view_only=25021eb260754252826a2bdb620b39c0. These datasets include aggregated and de-identified information derived from malaria surveillance and intervention monitoring. The full, individual-level datasets are owned by Costa Rica's Ministry of Health and are not publicly available due to data protection regulations. Interested researchers may request access to these data directly from Costa Rica's Ministry of Health, subject to institutional and ethical approvals.