Promising Drugs Require Proper Testing

I commend Ben Ghezala et al. [1] for their autopsic analysis of pharmacological aspects in drug repurposing for COVID-19, which highlights important lessons for translating preclinical findings into clinical research. They concluded: “All clinical trials that aimed to repurpose existing drugs for Covid-19 were unsuccessful.” However, I think their analysis of tenofovir disoproxil fumarate plus emtricitabine (TDF/FTC) is not entirely fair. Surprisingly, they cited our AR0-CORONA phase two randomized controlled trial comparing 7-day TDF/FTC (loading dose at Day 1) to standard of care, which enrolled symptomatic outpatients with recent COVID-19 [2]. Although the authors noted that studies “lacked clinically relevant endpoints,” demonstrating an effect of TDF/FTC on viral clearance [2] supports rather than refutes a potential clinical benefit [3-5]. The two other trials testing TDF/FTC included mainly hospitalized patients [1]. It is possible that the timing of administration in these two trials was not sufficiently early independently of the TDF/FTC clinical pharmacology, but this is not discussed. Antiviral drugs active against COVID-19 must be administered early in the course of infection because their efficacy depends on inhibiting viral replication before the disease progresses to the inflammatory phase. In my opinion, the absence of evidence supporting a clinical benefit of TDF/FTC does not reflect a failure of pharmacology, as the authors suggest. Rather, the failure was not conducting the study that could reveal its clinical benefit, if any. I would like to thank the Scientific Expert Committee of ANRS-MIE/REACTing for reviewing Phases 2 and 3 of the AR0-CORONA protocol for potential funding. The phase 2 of AR0-CORONA was sponsored by Caen University Hospital. J.-J.P. reports personal fees and grant support from Gilead Sciences, Merck Sharp & Dohme and ViiV Healthcare.