Combatting the second COVID 19 wave in India: Defining the role of Favipiravir

Published On 2021-05-12 07:15 GMT   |   Update On 2021-05-13 10:16 GMT

As India battles the second COVID-19 wave across all states, the healthcare system is overburdened with daily cases skyrocketing to more than 1.5 lac per day. There is a dire need for antiviral drugs that can reduce the severity and/or the duration of the illness in infected patients. Developing a new vaccine or a new antiviral drug takes a tremendous amount of resources and time. For instance, the first licensed COVID-19 vaccines were launched after almost a year from the documentation of index case in India. Developing a new antiviral drug may take even longer.

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Meanwhile, to circumvent the hurdles of drug clearance, repurposing drugs that have already been thoroughly investigated to treat other viral diseases can be an effective means of increasing the therapeutic options available. In this regard, Favipiravir, a drug already approved for treating Influenza and Ebola, was tested for its efficacy in COVID-19 and following encouraging results from initial studies, the drug was launched across many countries in the world including India in 2020. This article aims to recollect the available clinical evidence for favipiravir in managing coronavirus infection, as the utility of oral medicine that can manage the major chunk of mild to moderate infections on an outpatient basis cannot be over-emphasized in these pressing times.
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1. Favipiravir and Hit-early-Hit-hard principle
Favipiravir was discovered through the screening of a chemical library for antiviral activity against the influenza virus by the Toyama Chemical Co., Ltd. by chemical modification of a pyrazine analog in a pyrazine carboxamide derivative.1
Targeting the Achille's heel of COVID-19: Favipiravir (a prodrug) is a purine base analog that is converted to an active drug by intracellular phosphoribosylation. It is a selective and potent inhibitor of RNA-dependent RNA polymerase (RdRp) of RNA viruses. Favipiravir is incorporated into the nascent viral RNA by error-prone viral RdRp, which leads to chain termination and viral mutagenesis.2
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The RdRp existing in various types of RNA viruses enables a broader spectrum of antiviral activities of favipiravir.3 After RNA viral incorporation, favipiravir-RTP works as a mutagen, which is capable of fleeing coronavirus repair machinery. In total, along with the increased frequency of mutation, favipiravir-RTP has a positive effect on SARS-CoV-2 by a cytopathic effect, which is induced by the virus, reduction in the number of viral RNA, and infectious particles (Figure1). Hence, favipiravir targets the Achilles heel (RdRp complex) of SARS-CoV-2.
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Clinical studies have shown that antivirals previously tested for other coronaviruses like SARS-CoV and MERS-CoV shorten the course of the disease, reducing the viral load and viral shedding.4 This practice of hit–early–hit–hard can shorten the course of clinical illness and it can reduce the infectiousness to others by reducing viral shedding.
2. Current role of this antiviral as the nation fights the second wave :

Since the early half of March 2021, COVID-19 has been showing a consistent resurgence and from the starting of April, we have witnessed an unprecedented spread across the country. A notable observation is that still, almost three-fourths cases belong to the mild-to-moderate infection category and can be managed on an outpatient basis.
An antiviral drug that ameliorates the viral load and hastens the process of recovery will be beneficial in two ways: firstly, it will decrease the chances of developing a severe presentation (thus providing an individual benefit) and secondly, it will lower the spread of infection to high-risk groups by curtailing the infectivity period (thus providing a community benefit). Both these benefits can translate into easing the burden of healthcare facilities across the country.
3. Drug evidence and posology:
Favipiravir shows promising efficacy against SARS-CoV-2 in Vero E6 cells with an effective concentration (EC50) of 61.88 μM.5 In China, a control trial showed an excellent recovery rate (71.43%) of Covid-19 patients with less duration of fever and cough relief time, when treated with favipiravir as compared with umifenovir (55.86%).6 In Japan and China, there are about eight undergoing clinical trials of this drug to test its potential, efficiency, and efficacy against the Covid-19 disease.
Favipiravir has also shown a faster recovery rate of Covid-19 patients in clinical trials as compared with lopinavir/ritonavir. 7 A recent retrospective observational study from Thailand, which included hospitalized patients with COVID-19 who do not require oxygen supplementation demonstrated clinical improvement (92.6%) by day 7 with favipiravir.8
In India, the drug was approved for use in mild to moderate COVID-19 infected patients in June 2020.
The Indian perspective: A phase 3 randomized multicentre trial by Udwadia et al and published in November 2020 has shown significant improvement in time to clinical cure by favipiravir in mild-to-moderate COVID-19 infections. Moreover, there was a statistically significant difference in time to the first use of oxygen. In addition, when evaluated by COVID-19 severity, patients with moderate COVID-19 showed a statistically significant benefit with respect to time to clinical cure. 9
Dosing: The recommended dose is 1800mg twice daily on the first day of treatment, followed by 800mg twice daily up to a total treatment course of 14 days. For prophylaxis, 1600 mg orally twice daily on day 1 followed by 800 mg orally twice a day on days 2–25 has been suggested. 10
Safety profile: Favipiravir has an established and well-characterized safety profile.11 The common adverse events (AEs) include gastrointestinal, uric acid elevations, a decrease of neutrophil count, etc. The proportion of serious AEs is low (0.4%).
Contraindications, precautions, and warning: It is contraindicated in pregnant and lactating women, in patients with hypersensitivity, gout, severe hepatic impairment, and severe renal impairment. 12
4. Conclusion and future directions:
Favipiravir is the first oral antiviral drug approved for mild to moderate COVID-19. The literature supports its wide therapeutic efficacy and safety profile. Notably, studies exhibit the absence of resistance to favipiravir and broad-spectrum antiviral activity, which is a driving force to pursue clinical studies for distressing coronavirus infections. 13 The rapid viral clearance, higher clinical recovery rate, and availability as an oral drug with proven safety profile makes it the promising drug, repurposed to treat COVID-19.
Caring for COVID-19 patients post-discharge
An online initiative by Cipla is available for patients who suffered from mild to moderate COVID-19 infections. This website aims to assist the patients in rehabilitation post-recovery by providing health tips and information from credible sources like WHO with respect to physical well-being, mental well-being, diet and reshaping of the home environment. This information is available on the link below


References:
1. Furuta Y, Komeno T, Nakamura T. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc Jpn Acad Ser B Phys Biol Sci 2017;93:449–63
2. Baranovich T, Wong SS, Armstrong J, Marjuki H, Webby RJ, Webster RG, et al. T-705 (favipiravir) induces lethal mutagenesis in influenza A H1N1 viruses in vitro. J Virol 2013;87:3741–51.
3. Shannon A, Selisko B, Le N, Huchting J, Touret F, Piorkowski G, et al. Favipiravir strikes the SARS-CoV-2 at its Achilles heel, the RNA polymerase. bioRxiv 2020;, doi:http://dx.doi.org/10.1101/2020.05.15.098731 2020.05.15.098731; 2020.05.15.098731
4. Saber-Ayad M, Saleh MA, Abu-Gharbieh E. The rationale for potential pharmacotherapy of COVID-191. Pharmaceuticals (Basel) 2020;13:96
5. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30:269–71.
6. Chen C, Huang J, Cheng Z, Wu J, Chen S, Zhang Y, Chen B, Lu M, Luo Y, Zhang J, Yin P. Favipiravir versus arbidol for COVID-19: a randomized clinical trial. MedRxiv. 2020.
7. Cai Q, Yang M, Liu D, Chen J, Shu D, Xia J et al. Experimental treatment with favipiravir for COVID-19: an open-label control study. Engineering. Engineering (Beijing).2020.
8. Rattanaumpawan P, Jirajariyavej S, Lerdlamyong K, Palavutitotai N, Saiyarin J. Realworld experience with favipiravir for treatment of COVID-19 in Thailand: results from a multicenter observational study. medRxiv 2020
9. Udwadia ZF, Singh P, Barkate H, Patil S, Rangwala S, Pendse A, Kadam J, Wu W, Caracta CF, Tandon M. Efficacy and safety of favipiravir, an oral RNA-dependent RNA polymerase inhibitor, in mild-to-moderate COVID-19: A randomized, comparative, open-label, multicenter, phase 3 clinical trial. Int J Infect Dis. 2021 Feb;103:62-71.
10. Joshi S, Parkar J, Ansari A, Vora A, Talwar D, Tiwaskar M, Patil S, Barkate H. Role of favipiravir in the treatment of COVID-19. Int J Infect Dis. 2021 Jan;102:501-508.
11. Pilkington V, Pepperrell T, Hill A. A review of the safety of favipiravir — a potential treatment in the COVID-19 pandemic?. J Virus Erad 2020;6:45–51.
12. Fabiflu prescribing information. 2020.
13. Goldhill DH, Te Velthuis AJW, Fletcher RA, Langat P, Zambon M, Lackenby A, et al. The mechanism of resistance to favipiravir in influenza. Proc Natl Acad Sci U S A 2018;115:11613–8
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