Review 1: "The Transmission Blocking Activity of Artemisinin-Combination, Non-Artemisinin, and 8-Aminoquinoline Antimalarial Therapies: A Pooled Analysis of Individual Participant Data"

Leah Moriarty

doi:doi:10.1162/2e3983f5.0f219598

Reviewers raised concerns regarding the study's sample size, the need for clearer statistical measures, justification for their conclusions, and potential improvements in the organization and presentation of the results such as having supplementary results readily available.

by Leah Moriarty

Published onJan 04, 2025

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

by Leen N Vanheer, Jordache Ramjith, Almahamoudou Mahamar, Merel J Smit, Kjerstin Lanke, Michelle E Roh, Koualy Sanogo, Youssouf Sinaba, Sidi M. Niambele, Makonon Diallo, Seydina O Maguiraga, Sekouba Keita, Siaka Samake, Ahamadou Youssouf PharmD, Halimatou Diawara, Sekou F. Traore, Roly Gosling, Joelle M Brown, Chris Drakeley, Alassane Dicko, Will Stone, and Teun Bousema

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Published on Sep 29, 2024
www.medrxiv.org

Description

ABSTRACT 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 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 fifteen different antimalarial regimens or dosing schedules.Methods and findings Between January 2013 and January 2023, six clinical trials with transmission endpoints were conducted 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 5-50 years of age, who presented with P. falciparum mono-infection and gametocyte carriage by microscopy. Blood samples were taken before and after treatment for thick film microscopy, infectivity assessments by mosquito feeding assays and molecular quantification of gametocytes. Mixed-effects generalized linear models were fit with individual-specific random effects and fixed effects for time points, treatment groups and their interaction. Models quantified changes in mosquito infection rates and gametocyte densities within treatment arms over time and between treatments. In a pooled analysis of 422 participants, we observed substantial differences between ACTs in gametocytocidal and transmission-blocking activities, with artemether-lumefantrine (AL) being significantly more potent at reducing mosquito infection rates within 48 hours than dihydroartemisinin-piperaquine (DHA-PPQ), artesunate-amodiaquine (AS-AQ) and pyronaridine-artesunate (PY-AS) (p<0.0001). The addition of single low dose primaquine (SLD PQ) accelerated gametocyte clearance and led to a significantly greater reduction in mosquito infection rate within 48-hours of treatment for each ACT, while an SLD of the 8-aminoaquinoline tafenoquine (TQ) showed a delayed but effective response compared to SLD primaquine. Finally, our findings confirmed considerably higher post-treatment transmission after sulfadoxine-pyrimethamine plus amodiaquine (SP-AQ) compared to most ACTs, with a significantly lower relative reduction in mosquito infection rate at day 7 compared to DHA-PPQ, AS-AQ, and AL (p<0.0001). Therefore, adding an SLD PQ to SP-AQ may be beneficial to block malaria transmission in community treatment campaigns.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.

RR\ID Evidence Scale rating by reviewer:

Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review: Researchers examined data from 6 repeat studies to examine the transmission-blocking activities of several antimalarial medications in Mali. This is an important study in light of recent evidence of partial artemisinin resistance and low partner drug efficacy in Africa. National Malaria Programs should consider the transmission blocking effect on treatment regimens to slow the spread of resistant parasites in setting antimalarial drug policy. This well-written and described paper provides important evidence to inform these policies.

Methods:

There is no mention of sample size for this study- understanding this is a secondary analysis so the sample size wasn't likely powered for this study, but it is still important to contextualize the estimations being made.

Results

Line 263: Suggest to remove "depended strongly" and replace with a quantified measure
The results section could use some sub-headers. Authors may also consider re-arranging to organize the results by treatment instead of outcome. As it is currently written it is hard to follow.

Discussion

Line 440- not just artemisinin-resistant malaria infections but also infections less susceptible to lumefantrine, which is the case in several countries in Africa.
This reviewer recommends adding small sample size as a potential limitation- there is a lot of statistical inference here with a relatively small number of patients.

Review 1: "The Transmission Blocking Activity of Artemisinin-Combination, Non-Artemisinin, and 8-Aminoquinoline Antimalarial Therapies: A Pooled Analysis of Individual Participant Data"

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