The transmission blocking activity of artemisinin-combination, non-artemisinin, and 8-aminoquinoline antimalarial therapies: A pooled analysis of individual participant data

Background: Interrupting human-to-mosquito transmission is important for malaria elimination strategies as it can reduce infection burden in communities and slow the spread of drug resistance. Antimalarial medications differ in their efficacy in clearing the transmission stages of Plasmodium falciparum (gametocytes) and in preventing mosquito infection. Here, we present a retrospective combined analysis of six trials conducted at the same study site with highly consistent methodologies that allows for a direct comparison of the gametocytocidal and transmission-blocking activities of 15 different antimalarial regimens or dosing schedules. Methods and findings: Between January 2013 and January 2023, we conducted six clinical trials evaluating antimalarial treatments with transmission endpoints at the Clinical Research Centre of the Malaria Research and Training Centre of the University of Bamako in Mali. These trials tested Artemisinin-Combination Therapies (ACTs), non-ACT regimens and combinations with 8-aminoquinolines. Participants were males and non-pregnant females, between 5 and 50 years of age, who presented with P. falciparum mono-infection and gametocyte carriage by microscopy. We collected blood samples before and after treatment for thick film microscopy, infectivity assessments by mosquito feeding assays and molecular quantification of gametocytes. To combine direct and indirect effects of treatment groups across studies, we performed a network meta-analysis. This analysis quantified changes in mosquito infection rates and gametocyte densities within treatment groups over time and between treatments. In a pooled analysis of 422 participants, we observed substantial differences between antimalarials in gametocytocidal and transmission-blocking activities. Artemether-lumefantrine (AL) was significantly more potent at reducing mosquito infection rates within 48 h than dihydroartemisinin-piperaquine (p = 0.0164) and sulfadoxine-pyrimethamine plus amodiaquine (p = 0.0451), while this difference was near-significant for artesunate-amodiaquine (p = 0.0789) and pyronaridine-artesunate (p = 0.0519). The addition of single low-dose primaquine (SLD PQ) accelerated gametocyte clearance for any ACT and led to a substantially greater reduction in mosquito infection rate within 48 h of treatment for all ACTs except AL, while an SLD of the 8-aminoaquinoline tafenoquine showed a delayed activity, compared to SLD PQ, but was similarly effective. The main limitations of the study include the inclusion of highly infectious individuals, which may not reflect the broader malaria patient population with lower or undetectable gametocyte densities and the small sample sizes in some treatment groups, which resulted in wide confidence intervals and reduced the certainty of effect estimates. Conclusions: We found marked differences among ACTs and single low-dose 8-aminoquinoline drugs in their ability and speed to block transmission. The findings from this analysis can support treatment policy decisions for malaria elimination and be integrated into mathematical models to improve the accuracy of predictions regarding community transmission and the spread of drug resistance under varying treatment guidelines. Why was this study done?: What did the researchers do and find?: What do these findings mean?: Leen Vanheer and colleagues retrospectively analyzed individual participant data from six clinical trials of antimalarials to identify drug regimens that most effectively kill Plasmodium falciparum gametocytes in infected patients and rapidly block transmission of the parasite to mosquitoes. The study has potential implications for malaria control policies.