How radical is radical cure? Site-specific biases in phase-III clinical trials underestimate the effect of radical cure against Plasmodium vivax hypnozoites
Authors: Huber John H. , Koepfli Cristian , España Guido , Nekkab Narimane , White Michael T. , Perkins T. Alex 
Published: January 2021

Plasmodium vivax relapses caused by reactivating hypnozoites are a major barrier for elimination and control of this form of malaria. 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. We performed an analysis of simulated trial data using a transmission model to demonstrate that variation in efficacy estimates across trial sites can arise from differences in the conditions under which trials are conducted. Our analysis revealed that differences in transmission intensity, heterogeneous exposure, and relapse rate can yield efficacy estimates ranging as wide 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 of the protection of different radical cure treatment regimens against relapse more challenging. We show that vector control and parasite genotyping offer two potential means to yield more standardized efficacy estimates that better reflect protection against relapse. We predict that site-specific biases are likely to contribute to variation in efficacy estimates both within and across phase-III clinical trials. Future clinical trials can reduce site-specific biases by conducting trials in low-transmission settings where reinfections from mosquito biting are less common, by preventing reinfections using vector control measures, or by identifying and excluding likely reinfections that occur during follow-up using parasite genotyping methods.

AUTHOR SUMMARY

Radical cure holds promise as a strategy for Plasmodium vivax malaria control by clearing the parasites known as hypnozoites that latently infect the liver and cause relapsing infections. The efficacy of radical cure treatment regimens is evaluated in phase-III clinical trials. Recent trial results have noted substantial variation in efficacy estimates across trial sites, complicating the interpretation of the benefit of radical cure. However, P. vivax infections identified during the course of the clinical trial could include reinfections from mosquito biting that do not directly reflect the effect of the therapeutic being trialed, potentially biasing efficacy estimates. In this study, we simulated clinical trials to identify the causes and solutions of these site-specific biases. We found that features of both the trial location, such as the transmission intensity, and the trial design, such as the duration of follow-up, lead to an underestimate of the effect of radical cure against hypnozoites. We then demonstrated that vector control and parasite genotyping are two possible strategies to reduce these biases. These insights can be leveraged to aid in the interpretation of past trial results and to help design future clinical trials that minimize site-specific biases.