The perils of PCR: can we accurately 'correct' antimalarial trials?

Abstract

During follow-up in antimalarial drug trials, treated subjects can be newly infected. PCR correction is used to distinguish this re-infection from drug failure (recrudescence) and to adjust final drug efficacy estimates. The epidemiological, biological and technical limitations of PCR correction and how this can lead to misclassification in drug trial outcomes are underappreciated. This article considers these limitations and proposes a framework for reporting, interpreting and improving PCR correction of antimalarial trials.

Figure 1. Theoretical model for influence of misclassification on PCR correction

Misclassification in antimalarial trials will result in erroneous estimates of the clinical efficacy of a drug. Underestimation of efficacy occurs due to the re-infection of the patient with a common shared variant which appears to be a recrudescence. This will shift the efficacy rate to the left on the model. The inability to detect a minor variant at enrolment that later appears as a recrudescence leads to overestimation of the efficacy rate. These patients will be considered re-infections rather than ‘failures’ and the efficacy rate will shift to the right on the model.

Figure I for Box 2