Effectiveness, Safety, and Acceptability of Primaquine Mass Drug Administration in Low-Endemicity Areas in Southern Thailand: Proof-of-Concept Study

Background: A challenge in achieving the malaria-elimination target in the Greater Mekong Subregion, including Thailand,is the predominance of Plasmodium vivaxmalaria, which has shown extreme resilience to control measures. Objective: This proof-of-concept study aimed to provide evidence for implementing primaquine mass drug administration(pMDA) as a strategy for P. vivaxelimination in low-endemicity settings. Methods: The study employed a mixed-methods trial to thoroughly evaluate the effectiveness, safety, acceptability, andcommunity engagement of pMDA. The quantitative part was designed as a 2-period cluster-crossover randomized controlledtrial. The intervention was pMDA augmented to the national prevention and control standards with directly observed treatment(DOT) by village health volunteers. The qualitative part employed in-depth interviews and brainstorming discussions. The studyinvolved 7 clusters in 2 districts of 2 southern provinces in Thailand with persistently low P. vivaxtransmission. In the quantitativepart, 5 cross-sectional blood surveys were conducted in both the pMDA and control groups before and 3 months after pMDA.The effectiveness of pMDA was determined by comparing the proportions of P. vivaxinfections per 1000 population betweenthe 2 groups, with a multilevel zero-inflated negative binomial model adjusted for cluster and time as covariates and the interaction.The safety data comprised adverse events after drug administration. Thematic content analysis was used to assess the acceptabilityand engagement of stakeholders. Results: In the pre-pMDA period, the proportions of P. vivaxinfections in the pMDA (n=1536) and control (n=1577) groupswere 13.0 (95% CI 8.2-20.4) and 12.0 (95% CI 7.5-19.1), respectively. At month 3 post-pMDA, these proportions in the pMDA(n=1430) and control (n=1420) groups were 8.4 (95% CI 4.6-15.1) and 5.6 (95% CI 2.6-11.5), respectively. No statistically significant differences were found between the groups. The number of malaria cases reduced in all clusters in both groups, andthus, the impact of pMDA was inconclusive. There were no major safety concerns. Acceptance among the study participants andpublic health care providers at local and national levels was high, and they believed that pMDA had boosted awareness in thecommunity. Conclusions: pMDA was associated with high adherence, safety, and tolerability, but it may not significantly impact P. vivaxtransmission. As this was a proof-of-concept study, we decided not to scale up the intervention with larger clusters and samples.An alternative approach involving a targeted primaquine treatment strategy with primaquine and DOT is currently beingimplemented. We experienced success regarding effective health care workforces at point-of-care centers, effective collaborationsin the community, and commitment from authorities at local and national levels. Our efforts boosted the acceptability of themalaria-elimination initiative. Community engagement is recommended to achieve elimination targets. Trial Registration: Thai Clinical Trials Registry TCTR20190806004; https://www.thaiclinicaltrials.org/show/TCTR20190806004