key: cord-0797621-wtprcurv
authors: Siang Kow, Chia; Sangarran Ramachandram, Dinesh; Shahzad Hasan, Syed
title: Future of antivirals in COVID-19: the case of favipiravir
date: 2021-12-13
journal: Int Immunopharmacol
DOI: 10.1016/j.intimp.2021.108455
sha: 93f719ce40afc05fd4f92f67f843e2422ea4bb2b
doc_id: 797621
cord_uid: wtprcurv

nan

We appreciate the publication of the randomized controlled trial by Solaymani-Dodaran et al. [1] , which aimed to determine the effect of favipiravir on the clinical outcomes among patients with moderate-tosevere course of COVID-19. It was reported from the randomized trial that patients who were randomized to favipiravir, which is an antiviral agent that selectively and potently inhibits the RNA-dependent RNA polymerase of RNA viruses, had no significant difference in terms of mortality rate, compared to their counterparts who were randomized to lopinavir/ritonavir (favipiravir group: 13.7% versus lopinavir/ritonavir group: 11.5%). The trial [1] might be underpowered to detect mortality differences; since there have been few trials that reported the association between the use of favipiravir and the risk of mortality in patients with COVID-19, we summarized the overall evidence in the form of meta-analysis from all the randomized trials which reported mortality outcomes with the use of favipiravir in patients with COVID-19.

We performed a systematic literature search in electronic databases, including PubMed, Google Scholar, Cochrane Central Register of Controlled Trials, and preprint servers to identify eligible studies published up to November 25, 2021. Studies eligible for inclusion were randomized controlled trials that reported the risk of mortality using favipiravir in patients with COVID-19 relative to non-use of favipiravir. Metaanalysis with the random-effects model was used to estimate the pooled odds ratio of mortality using favipiravir relative to non-use of favipiravir, at 95% confidence intervals (CIs). In addition, we examined the heterogeneity between studies using the I 2 statistics and the χ 2 test, with significant heterogeneity being considered at 50% and P<0.10, respectively. All analyses were performed using Meta XL, version 5.3 (EpiGear International, Queensland, Australia).

Our systematic literature search retrieved 1493 hits, of which 613 were unique. After screening, we included six randomized controlled trials ( Table 1 ) [1] [2] [3] [4] [5] [6] , with a total of 1,669 patients with COVID-19. The meta-analysis of the included trials [1] [2] [3] [4] [5] [6] revealed no significant difference in the odds of mortality with the use of favipiravir among patients with COVID-19, relative to non-use of favipiravir; the estimated effect though indicated increased mortality (Figure 1 ; pooled odds ratio = 1.09; 95% confidence interval 0.76 to 1.56) but is without adequate evidence against the null hypothesis of 'no significant difference,' at the current sample size.

The absence of mortality benefits with favipiravir in patients with COVID-19 might be attributed to the low plasma concentrations achieved since favipiravir has a complex pharmacokinetic profile. Recently, it has been reported that combined treatment of favipiravir and molnupiravir results in a potentiation of antiviral efficacy in a SARS-CoV-2 hamster infection model [7] . Therefore, we believe that future trials should aim to determine the clinical efficacy of such combination instead of favipiravir alone; apart from potentially increased efficacy, such combination could also result in lower doses of both agents to be administered, which can be cost-saving since molnupiravir is relatively expensive. Besides, with lower doses of molnupiravir being administered, the safety profile may be more favorable, especially when there have been some safety concerns with the use of molnupiravir. 

Safety and efficacy of Favipiravir in moderate to severe SARS-CoV-2 pneumonia

Favipiravir and Hydroxychloroquine Combination Therapy in Patients with Moderate to Severe COVID-19 (FACCT Trial): An Open-Label, Multicenter, Randomized, Controlled Trial

Efficacy of early treatment with favipiravir on disease progression among high risk COVID-19 patients: a randomized, open-label clinical trial

Randomized controlled open label trial on the use of favipiravir combined with inhaled interferon beta-1b in hospitalized patients with moderate to severe COVID-19 pneumonia

Various Combinations of Favipiravir, Lopinavir-Ritonavir, Darunavir-Ritonavir, High-Dose Oseltamivir, and Hydroxychloroquine for the Treatment of COVID-19: A Randomized Controlled Trial (FIGHT-COVID-19 Study)

Favipiravir In Adults with Moderate to Severe COVID-19: A Phase 3 Multicentre, Randomized, Double-Blinded, Placebo-Controlled Trial

The combined treatment of Molnupiravir and Favipiravir results in a potentiation of antiviral efficacy in a SARS-CoV-2 hamster infection model