How radical is radical cure? Site-specific biases in clinical trials underestimate the effect of radical cure on Plasmodium vivax hypnozoites

Malaria Journal

Cristian Koepfli¹  T. Alex Perkins¹  Guido España¹  John H. Huber¹  Narimane Nekkab²  Michael T. White² 

[1] Department of Biological Sciences and Eck Institute for Global Health, University of Notre Dame, Notre Dame, IN, USA;Unité Malaria: Parasites et Hôtes, Département Parasites et Insectes Vecteur, Institut Pasteur, Paris, France;

关键词: Plasmodium vivax;    Radical cure;    Clinical trials;    Bias;   

DOI  :  10.1186/s12936-021-04017-1

来源: Springer

【 摘 要 】

BackgroundPlasmodium vivax blood-stage relapses originating from re-activating hypnozoites are a major barrier for control and elimination of this disease. Radical cure is a form of therapy capable of addressing this problem. Recent clinical trials of radical cure have yielded efficacy estimates ranging from 65 to 94%, with substantial variation across trial sites.MethodsAn analysis of simulated trial data using a transmission model was performed to demonstrate that variation in efficacy estimates across trial sites can arise from differences in the conditions under which trials are conducted.ResultsThe analysis revealed that differences in transmission intensity, heterogeneous exposure and relapse rate can yield efficacy estimates ranging as widely as 12–78%, despite simulating trial data under the uniform assumption that treatment had a 75% chance of clearing hypnozoites. A longer duration of prophylaxis leads to a greater measured efficacy, particularly at higher transmission intensities, making the comparison between the protection of different radical cure treatment regimens against relapse more challenging. Simulations show that vector control and parasite genotyping offer two potential means to yield more standardized efficacy estimates that better reflect prevention of relapse.ConclusionsSite-specific biases are likely to contribute to variation in efficacy estimates both within and across clinical trials. Future clinical trials can reduce site-specific biases by conducting trials in low-transmission settings where re-infections from mosquito bite are less common, by preventing re-infections using vector control measures, or by identifying and excluding likely re-infections that occur during follow-up, by using parasite genotyping methods.

【 授权许可】

CC BY