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Favipiravir Has Clinical Pluses vs
Standard Care for In-Hospital COVID-19
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CROI 2021, Conference on Retroviruses and Opportunistic Infections, March 6-10, 2021
Mark Mascolini
Favipiravir, a nucleoside antiviral originally developed for influenza, chalked up some clinical advantages over standard care in a nonrandomized multicenter Russian comparison of COVID-19 inpatients [1]. Three previous randomized trials found mixed results with favipiravir for COVID-19 [2-4].
With a mechanism of action similar to remdesivir [5], favipiravir is licensed to treat COVID-19 in Russia and some Latin American and Asian countries [1]. Favipiravir has one clear advantage over remdesivir—oral dosing. Russia first licensed favipiravir (brand name Avifavir) for inpatients then expanded the indication for outpatient use. But researchers reviewing favipiravir in India believe it is more appropriate for symptomatic people not sick enough to go to the hospital [5]. Across the world an estimated 1 million people took favipiravir from June 30 to December 31, 2020 [1].
The CROI study analyzed clinical outcomes in a retrospective comparison of favipiravir with standard care [1]. Researchers collected data from the Russian national healthcare database, selecting in-hospital patients who did or did not take favipiravir in May and June 2020. All participants were 18 or older and got admitted to the hospital within 10 days of confirmed SARS-CoV-2 infection.
The investigators did not say if they matched favipiravir and control patients, but the 470 people taking favipiravir and the 470 controls were similar in average age (54.9 and 55.5, P = 0.579), proportions of women (52.3% and 56.4%, P = 0.213), average time since symptom onset (4.9 and 4.7 days, P = 0.078), average oxygen saturation (94.5% and 94.3%, P = 0.731), and proportions with "satisfactory" disease severity (about 20%), moderately severe disease (60%), severe disease (18%), and extremely severe disease (1.3% and 1.9%) (P = 0.828 overall).
In the favipiravir group, people weighing less than 75 kg received 1600 mg orally twice daily on day 1 then 600 mg twice daily on days 2 through 10. People weighing more than 75 kg got 1800 mg orally twice daily on day 1 then 800 mg twice daily days 2 through 10. These people received favipiravir for a median of 10 days. The standard care group received antibiotics and medications for symptom relief but no COVID-19-specific therapy.
Median time to viral clearance was 6 days with favipiravir and 12 with standard care (P < 0.001). Respective median times to clinical improvement were 8 and 15 days (P < 0.001). The favipiravir group also had significantly higher proportions with clinical improvement (versus worsening or critical infection) on day 7 (about 23% vs 18%, P = 0.0248) and day 14 (about 45% vs 31%, P < 0.001). Median time to oxygen saturation at or above 95% was 2 days with favipiravir and 4 days with standard care (P = 0.001). During follow-up 27 people (5.7%) receiving favipiravir and 39 (8.3%) receiving standard care died.
The researchers used an unusual system to report treatment safety: No healthcare professionals and no patients reported serious or not serious adverse drug reactions in either the favipiravir group or the standard-care group, surprising results for a 940-person study. "Public healthcare authorities" reported 14 suspected serious adverse drug reactions with favipiravir and 2 unexpected adverse drug reactions. Numbers of suspected and unexpected "not serious" adverse drug reactions with favipiravir were 18 and 0.
A previous Russian trial involving 60 inpatients randomized to one of two favipiravir doses or to standard care found a significantly higher proportion in the favipiravir arms than the standard-care arm with viral clearance on day 5 (62.5% vs 30%, P = 0.018). Viral clearance rates on day 10 did not differ significantly between groups (92.5% vs 80%, P = 0.155).
In Japan an open-label trial randomized 89 in-hospital adults and adolescents with COVID-19 to early favipiravir (starting on hospital day 1) or late favipiravir (starting on hospital day 6) [4]. Everyone was asymptomatic or had mild disease. In 69 people evaluable for viral clearance, the early and late groups did not differ significantly. Time to normal temperature in 30 people with fever did not differ significantly between the early and late groups.
A Japanese study of 156 people admitted to the hospital with COVID-19 randomized them to high-dose favipiravir or placebo [5]. People randomized to favipiravir cleared virus faster than the placebo group (11.9 vs 14.7 days).
US researchers caution that more must be learned about the pharmacokinetics and pharmacodynamics of favipiravir "before we can begin optimizing dosing, particularly in patients with severe illness" [6]. Viriom Inc. in San Diego is developing favipiravir for US use.
References
1. Corritori S, Yakubova E, Ivashchenko A, et al. Multicenter, open-labeled efficacy study of Avifavir in patients with COVID-19. CROI 2021, Conference on Retroviruses and Opportunistic Infections, March 6-10, 2021. Abstract 390.
2. Ivashchenko AA, Dmitriev KA, Vostokova NV, et al. Avifavir for treatment of patients with moderate COVID-19: interim results of a phase II/III multicenter randomized clinical trial. Clin Infect Dis. 2020; doi: 10.1093/cid/ciaa1176. https://doi.org/10.1093/cid/ciaa1176
3. Doi Y, Hibino M, Hase R, et al. A prospective, randomized, open-label trial of early versus late favipiravir in hospitalized patients with COVID-19. Antimicrob Agents Chemother. 2020. DOI: 10.1128/AAC.01897-20
4. Favipiravir Observational Study Group FHU. Favipiravir observational study interim report 2. 2020. http://www.kansensho.or.jp/uploads/files/topics/2019ncov/covid19_favip_eng_0928.pdf
5. Agrawal U, Raju R, Udwadiac ZF. Favipiravir: A new and emerging antiviral option in COVID-19. Med J Armed Forces India. 2020;76:370-376. doi: 10.1016/j.mjafi.2020.08.004. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467067/
6. Ison MG, Scheetz MH. Understanding the pharmacokinetics of favipiravir: implications for treatment of influenza and COVID-19. EBioMedicine. 2021;63: 103204. DOI: https://doi.org/10.1016/j.ebiom.2020.103204
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