key: cord-0806381-8xq7vy45
authors: Cummins, Nathan W
title: Remdesivir: An antiviral still seeking a raison d'être
date: 2021-03-22
journal: Clin Infect Dis
DOI: 10.1093/cid/ciab220
sha: bcca3f190cf28abda156bad556c2f2c44c633d66
doc_id: 806381
cord_uid: 8xq7vy45

nan

colleagues' report on the PREVAIL IV trial in this issue of Clinical Infectious Diseases is a suitable reminder that there have been and will continue to be infectious diseases other than COVID-19, and that we are all still trying to figure out the best ways to use this novel antiviral agent.

The PREVAIL (Partnership for Research on Ebola Vaccines in Liberia) group has previously published remarkable trials investigating novel Ebola virus vaccines (3, 4) and therapeutics (5) in relation to the 2014-2016 Ebola outbreak in West Africa. The PREVAIL IV trial was designed to address a potentially important complication of Ebola virus disease (EVD)persistent viral shedding in semen in EVD survivors that may contribute to epidemic or endemic spread through sexual transmission. Thirty-eight male EVD survivors from the West Africa Ebola epidemic, who had Ebola virus RNA detectable in the semen a median of 2 years after onset of clinical disease, were enrolled and randomized to receive 5 days of intravenous remdesivir or placebo control. Repeated semen samples were collected during two phases, a 28-day "treatment phase" and a 5-month "follow up phase" and assessed for presence of Ebola virus RNA by RT-PCR. The pre-specified primary outcome was the difference in mean "assay negativity rate" (ANR), or the average frequency of negative samples out of all the samples tested during the two phases.

Enrollment of the trial was terminated early due to decreasing probability of enrollment with increasing time from the end of the epidemic and therefore limited the power A c c e p t e d M a n u s c r i p t 3 of the study. This limitation is well discussed by the investigators, and an anticipated possibility when conducting clinical trials in an epidemic setting, including for COVID-19.

Despite this notable limitation, remdesivir treatment was associated with an increased ANR compared to placebo during the follow-up phase of sampling (p=0.041), but not during the treatment phase. The authors rightfully conclude that a larger follow up study is necessary to confirm whether remdesivir treatment reduces Ebola virus persistence in semen. One could argue that a more important outcome, though, would be prevention of sexual transmission of EVD, but such a study would be formidable to design and conduct in optimal settings, and probably impossible to conduct during an ongoing EVD epidemic.

On the other hand, there are several aspects about this study that are worth reviewing in detail, as they may be informative in a broader sense about the clinical utility of remdesivir, and antiviral therapy strategies in general. First, the participants were enrolled a median of 2 years after onset of the initial EVD, which is typically considered an acute viral infection, albeit with potential long-term sequelae. Second, the participants were considered to have Ebola virus "persistence" in the semen because of this time lapse from overt clinical disease. However, viral RNA was measured by nucleic acid testing, the presence of which does not de facto prove infectious virus persistence, in the truest meaning of that term, but could instead represent shedding of non-viable virus or virus particles. Furthermore, a semi- (8, 9) , whereas two did not show any benefit with remdesivir (10, 11). More trials, "living" meta-analyses and systematic reviews will try to tease out the hint of a possibility of small therapeutic benefits of remdesivir for COVID-19. It is safe to say that if remdesivir truly had a clinically meaningful impact, with a reasonable It is likely that any viral replication that would be biologically important to inhibit therapeutically, in the context of an acute viral infection, such as EVD or COVID-19, occurs prior to: 1) the recognition of the viral infection (based on symptom or diagnostic testing), 2) initiation of treatment, and 3) accumulation of sufficient active drug in the relevant cellular and tissue compartments that would be needed to inhibit said replication. The battle is over, and the enemy has moved on before the first defensive maneuver is even begun. Anything after that results only in loud noises and wasted bullets to no effect. It seems then, that attempting to treat most acute viral infections with current antivirals is probably a losing strategy using tools still searching for a useful function. Dr. Higgs et al suppose that treating EVD survivors closer to the time of the acute infection with remdesivir may improve the therapeutic effectiveness in clearing persistent Ebola virus from the semen, and propose this strategy for the next, bigger study. Based on the above, it is unclear if that will increase the apparent therapeutic benefit of remdesivir for this indication.

There is another way, and hope yet for remdesivir, and antivirals for acute viral infections in general. Although Benjamin Franklin's adage of "An ounce of prevention is worth a pound of cure" is nearly three centuries old, "Prevention is Treatment" is a recent prophylaxis for adults exposed to SARS-CoV-2 (NCT04364022). It may be hard to justify a same-day ring prophylaxis trial of intravenous remdesivir for COVID-19 post-exposure prophylaxis, due to the imbalance in drug and administration cost versus absolute risk of severe complications, except in the highest risk individuals. However, the individual risk for morbidity and mortality in EVD are so much greater than COVID-19. Perhaps the use of remdesivir as ring prophylaxis for EVD, with or without concomitant monoclonal antibody therapy, would better prevent Ebola virus persistence in semen of male survivors of EVD and ongoing sexual transmission, than its use during or shortly after acute EVD. It might also prevent EVD, which would indeed be worth a pound of cure, and provide a raison d'être. A c c e p t e d M a n u s c r i p t

GS-5734 and its parent nucleoside analog inhibit Filo

FDA Approval of Remdesivir -A Step in the Right Direction

Phase 2 Placebo-Controlled Trial of Two Vaccines to Prevent Ebola in Liberia

PREVAIL I Cluster Vaccination Study With rVSVDeltaG-ZEBOV-GP as Part of a Public Health Response in Liberia

A Randomized, Controlled Trial of ZMapp for Ebola Virus Infection

Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys

A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics

Investigators G-U-. 2020. Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial

Remdesivir for the Treatment of Covid-19 -Final Report

Repurposed Antiviral Drugs for Covid-19 -Interim WHO Solidarity Trial Results

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