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Go Back       Himalayan Journal of Medicine and Surgery | Volume:3 Issue:1 | Feb. 20, 2022
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DOI : 10.47310/Hjms.2022.v03i01.010       Download PDF       HTML       XML

Role of Favipiravir therapy in COVID 19 patients A Systematic Review and Meta Analysis

Shabarini Srikumar1, Aravind Muthiah1 and Shridharan Perumal3

1Medical Scholar, Tirunelveli Medical College, Tamil Nadu, India

2Associate Professor, Department of General Medicine, Government Pudukottai Medical College, Tamil Nadu India

*Corresponding Author

Shabarini Srikumar

Article History

Received: 27.01.2022

Accepted: 09.02.2022

Published: 20.02.2022

Abstract: The ongoing global problem of concern is the Coronavirus Disease 2019 (COVID-19) caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). With the sudden explosion of the disease, no drugs were experimentally proven in its management. This meta-analysis assessed the role of favipiravir in the management of COVID 19 disease, its efficacy and safety. A comprehensive search of databases including PubMed, Medline, Cochrane, Embase, Google scholar, Lancet, Elsevier and other modalities of search like website searching and citation tracking was made. Out of 687 articles identified, 8 articles were taken for the meta-analysis after several stages of exclusion. Out of the 8 studies selected, the results of 4 studies were in favour of favipiravir, while other 4 studies were against the efficacy of favipiravir. The result of our statistical analysis was that RR=0.9276 (95% CI; 0.6718 to 1.3944) for the effect of favipiravir on mortality reduction in COVID 19 patients. Favipiravir treatment in the early phase of infection (viral replication phase) have shown significant reduction in the viral load and good clinical recovery. It also prevents the progression of disease to critical stage by controlling the infection adequately in the early phase itself. But when the stage of viral replication has passed, there is no role of favipiravir in the management of the COVID 19 disease. Favipiravir has no significant effect on mortality reduction in COVID 19 patients.

Keywords: Antivirals, COVID 19, Favipiravir, Pharmacotherapy, Repurposing drugs, SARS CoV 2.


The ongoing global problem of concern is the Coronavirus Disease 2019 (COVID-19) caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). COVID-19 disease manifests grossly in 2 phases: The early phase of mild illness is caused by the virus followed by a late phase of severe and critical illness which is solely constituted by dysregulated inflammatory and immune responses (Srikumar, S., & Perumal, S. 2021). It is crucial to understand the course of the disease while aiming for treatment, as the treatment modality varies with the various stages. Early intervention, when possible, should predominantly target the viral multiplication that can largely limit the progression of the disease and the aftermath (Furuta, Y. et al., 2017).

With the compelling need to discover therapeutic options for COVID-19 disease, the idea of repurposing the existing drugs were thought (Lee, J. S. et al., 2019). Favipiravir, a purine nucleic acid analogue was initially developed by Toyama Chemical Co., Ltd. in Japan for the treatment of mild viral infections (FUJIFILM Toyama Chemical Co., Ltd.). It acts by inhibiting RNA dependent RNA polymerase enzyme (RdRp), thereby hindering the multiplication of RNA viruses (Manabe, T. et al., 2021). Ever since the COVID-19 disease was reported a pandemic, the role of favipiravir against SARS-CoV-2 was being evaluated. Various studies on favipiravir conducted during this crisis have shown mixed results: some regard it as a promising choice while others regard it as not of much significance. The intent of this meta-analysis is to assess the role of favipiravir, it’s safety and efficacy in the treatment of COVID-19.


This systematic review was performed in strict accordance with the Preferred Reporting Items of the Systematic review and Meta-Analysis (PRISMA) checklist. All steps were compliant with the Cochrane Handbook of Systematic Review and Meta-Analysis.

Search Strategy

We conducted a comprehensive literature review by searching the databases like PubMed, Medline, Cochrane, Embase, Google scholar, Lancet, Elsevier. The following search terms were used: ‘Favipiravir’ ‘Drug trials’ ‘Pharmacotherapy’ ‘randomized control trials’ ‘antivirals’. The search also included mining references from good quality articles, website searching and citation tracking.

Inclusion criteria

  • Studies on COVID-19 conducted between April 2020 and July 2021

  • Studies on pharmacotherapy for COVID-19 specially focussing favipiravir

  • Studies with sample size >100

  • Studies with good methodologies

  • Studies with properly outlined efficacy and safety endpoints of favipiravir

Exclusion criteria

  • Articles on COVID published before 2020

  • Studies showing in-vitro effects of favipiravir

  • Abstract-only papers, articles with full texts not available

  • Articles with only guidelines/protocol for management of COVID 19

  • Articles published in languages other than English

Data Extraction

The data was extracted independently from the eligible studies. The reliability of the data was cross-checked by reviewing the same article in multiple other systematic reviews of various authors. Generic inverse variance method (random-effects model) was used to estimate the odds ratios (OR) of patients for primary outcome variables with 95% confidence intervals (CI). Results after adjustments and propensity score matching were taken to eliminate ‘Selection bias’.

Statistical analysis

The odds ratios with 95% confidence intervals of the individual studies were compiled. The data were processed using the Statistical Package for the Social Sciences (SPSS) software version 20.0.


Study selection

A total of 687 articles were identified via database searches, website searching and reference chaining. After eliminating duplicate studies (143), articles that were inappropriate to the study topic (227) and articles that did not fit the eligibility criteria (303), 14 articles were eligible. After quality assessment, 8 articles were taken for the meta-analysis, of which 5 were Randomized control trials and 3 were Observational studies (Fig.1).

Figure Image is Available in PDF Format

Fig.1: Prisma flow chart showing study selection

Study characteristics

The studies were chosen based on the following details: date of publication, study design, country where the study was conducted, sample size, number of patients in the intervention group - treated with favipiravir, combination of drugs if given, number of deaths, number of ICU admissions, invasive mechanical ventilation, viral clearance time, length of hospital stay, comorbidities and number of patients in the control group who received standard care of treatment/placebo.

Synthesis of Results

In our meta-analysis, the following parameters were evaluated:

  1. Time taken for clinical recovery

  2. Length of hospital stay

  3. Changes in SpO2 levels during hospitalization

  4. Mortality

Data of 4304 patients collected from 8 studies conducted in different parts of the world are shown in Table 1.

Table 1: Summary of studies analysed in the meta-analysis

S. No

Study ID


Study design

Sample Size

Experimental group

Comparative group




Masoud et al.,



Multicentre observational study 


Patients treated with favipiravir (193)

Patients treated with lopinavir/ ritonavir (187)

HR=0.94 for clinical recovery in patients taking favipiravir vs lopinavir/ ritonavir.

Hospital stay and the time to clinical recovery of patients with favipiravir did not vary when compared to lopinavir and ritonavir. 


Yohei Doi et al., (2020) 


Observational study




Rates of symptomatic improvement were 87.8%, 84.5% and 60.3% at 14 days for mild, moderate and severe disease, respectively.  

Majority of patients who had taken favipiravir have had significant improvement and recovery of illness. 


Corritori et al., (2021)




Patients who took favipiravir (470)

Patients on standard care (470)

Median time of viral clearance in favipiravir group and standard care are 6 and 12 days, respectively. 

Favipiravir has a high clinical efficacy and tolerability in covid 19 patients.


Pinyo Rattanaumpawan et al., (2020)


Multicentre observational study 


Patients who received Favipiravir (63)

Patients who did not receive Favipiravir (184)

The clinical improvement rate on day 7 was 66.7% in all patients, 92.5% in patients who did not require O2-supplementation, and 47.2% in patients who required O2-supplementation.

Favipiravir shows promising effects in Covid-19. 


Chang Chen et al., (2020)


Prospective, open-label multicenter RCT


Patients who received Favipiravir (120)

Patients who received arbidol (120)

On day 7, the clinical recovery rate did not significantly vary between Favipiravir group (71/116) and Arbidol group (62/120).

Favipiravir did not significantly improve clinical recovery rate when compared with arbidol.


Zarir F. Udwadia et al., (2020)


Open-label, parallel-arm, multicenter RCT


Patients treated with favipiravir (75)

Patients not treated with favipiravir (75)

Median time to clinical improvement of symptoms was 3 days in the favipiravir group vs 5 days in the control group.

In mild to moderate COVID 19 patients, use of favipiravir showed significant clinical improvement in 3 days.


Faryal Khamis et al., (2020)


Open-label RCT


Patients who received Favipiravir + inhaled interferon beta-1b (44)

Patients who received HCQ (45)

The mortality rates were 11.4% and 13.3% in patients who received Favipiravir + inhaled interferon beta-1b and HCQ, respectively.

There was no significant reduction in mortality among hospitalised patients who received Favipiravir and inhaled interferon beta-1b combination therapy.


Hany M. Dabbous et al., (2021)




Patients treated with favipiravir (50)

Patients treated with HCQ + Oseltamivir (50)

PCR seronegative conversion on day 7 was 48% and 55.1% in the favipiravir and HCQ + oseltamivir groups, respectively.

In mild to moderate COVID 19 patients, treatment with favipiravir showed similar effects to that of HCQ and oseltamivir combination therapy.

Out of the 8 studies selected, the results of 4 studies were in favour of the use of favipiravir, while other 4 studies were against the efficacy of favipiravir. The result of our statistical analysis was that the relative risk (Fig.2) for mortality reduction of favipiravir in COVID 19 patients is 0.9276 (95% CI; 0.6718 to 1.3944).

Figure Image is Available in PDF Format

Fig.2: Relative risk of mortality reduction of favipiravir as per the analysed studies

Risk of bias assessment

We assessed the risk of bias (‘low risk’, ‘unclear’, or ‘high risk’) for the studies included in the meta-analysis using version 2 of the Cochrane Risk of Bias assessment tool for randomised control trials (Fig.3) and The New Castle Ottawa scale for non-randomised controlled trials (Table 2). Disagreements aroused during this process were resolved through discussion. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was utilised to assess the quality of the evidence obtained from various studies.

Figure Image is Available in PDF Format

Fig. 3: The Cochrane Risk of bias assessment for randomised control trial studies analysed

Table 2: The New Castle Ottawa scale for non-randomised controlled trial studies analysed

Table Image is Available in PDF Format


SARS CoV-2 is a single stranded positive sense RNA virus belonging to the corona viridae family. It is an enveloped virus with spike proteins on its surface (Zumla, A. et al., 2016). The virus encodes proteases and the enzyme RNA-dependent RNA polymerase (RdRp) (Vora, A., & Tiwaskar, M. 2020). Both RdRp and viral proteases were considered as prime targets for the development of potential therapeutic agents. Favipiravir is one such attempt.

Previously known as T-705, favipiravir (6-fluoro-3-hydroxypyrazine-2-carboxamid) is a pro-drug. Intracellularly, it undergoes ribosylation and phosphorylation to form favipiravir ribofuranosyl-5′-triphosphate (Favipiravir- RTP), the active metabolite. Favipiravir-RTP competes with purine nucleosides and hinders the viral replication. It integrates with the nascent viral RNA causing inhibition of viral RdRp which leads to termination of the chain and viral mutations (Shannon A, et al., 2020). Oral favipiravir is well absorbed with bioavailability of nearly 97.6%. Like most of the drugs, favipiravir is metabolized in liver, mostly by Aldehyde Oxidase enzyme and partly it is converted to a hydroxylated form by the enzyme Xanthine Oxidase. The hydroxylated form is then excreted by the kidneys (Du YX, et al., 2020; & AVIGAN 2017).

Time taken for clinical recovery

In an observational study of 380 patients conducted by Masoud et al., in Iran, treatment with favipiravir showed no difference in the time taken for clinical recovery when compared to the control group. The hazard ratio calculated using Cox proportional hazard modelling was 0.94 (95% CI: 0.75-1.17) (Solaymani-Dodaran, M. et al., 2021). The results were similar to that of the RCT conducted by Chang Chen et al., in China with 240 patients. The difference of recovery rate was 0.0954 (95% CI: 0.0305-0.2213) between the favipiravir group and the arbidol (control) group (Chen, C. et al., 2021). Further studies by Yohei Doi et al., in Japan involving 2158 patients (Doi, Y. et al., 2020) and by Pinyo Rattanaumpawan et al., in Thailand involving 247 patients (Rattanaumpawan, P. et al., 2020) also showed results that were consistent that time taken for clinical recovery in patients taking favipiravir and that of the control group was almost alike.

Length of stay in hospital

When observed the medically discharged patients as per physician’s advice in Masoud et al., study (Solaymani-Dodaran, M. et al., 2021), the median length of hospital stay was 7 days in the favipiravir group and 6 days in the control group (p=0.85). There was no significant variation between the results of the two groups. This is supported by the Randomised controlled trial conducted on 89 patients by Faryal Khamis et al., at Oman (Khamis, F. et al., 2021). The length of stay in hospital was similar in the favipiravir and the control group (p=0.948).

SpO2 change over-hospitalization

In the observational study by Masoud et al., (2021), out of 380 patients taken in the study, 193 patients were on favipiravir and 187 were on lopinavir/ ritonavir. Supplemental oxygen was paused for 5 minutes in un-intubated patients among the two groups to look for changes in the oxygen saturation (SpO2). The results were indistinguishable (OR=1.00, 95% CI: 0.71–1.42; p = 0.997).


In the Randomised controlled trial on 89 patients conducted by Faryal Khamis et al., in Oman (Khamis, F. et al., 2021), the mortality rates were 11.4% and 13.3% in the favipiravir and the non-favipiravir group (p=0.778). The results did not significantly differ among the two groups. It is in accordance to the results of Masoud et al., study (Masoud et al., 2021), where the number of deaths were 26 in the favipiravir group and 21 in the Lopinavir/Ritonavir group among the 47 deaths (p=0.49).

The possible explanation that could be regarded for the negative findings on the efficacy of Favipiravir against COVID 19 disease could be explained by the pathogenesis of this disease. The disease course includes 2 phases: The early phase of infection usually occurs in first 1 week from the day of acquiring the virus. Patients experience mild symptoms or are mostly asymptomatic (Catanzaro, M. et al., 2020; & Siddiqi, H. K., & Mehra, M. R. 2020). When infection not controlled in the early phase due to factors like immunosuppressed state, immunocompromised patients, patients with comorbidities like diabetes, coronary artery disease, the patients progress to the later stage of the disease, which is constituted by a surge of inflammatory reactions in response to the uncontrolled viral load. This gush of immune and inflammatory mediators is called the ‘cytokine shower’ and when it is massive, it is called the ‘cytokine storm (Wu, J. et al., 2020; Mason, R. J. 2020; & Giammaria, D., & Pajewski, A. 2020)’. Therefore, treatment in the early phase should aim the viral replication and in late phase should target the cytokine storm. If the patients included in the above studies had passed the viral replication phase, they are unlikely to benefit from the antiviral treatment.

Adverse events

Favipiravir is a drug with well-established safety profile and is usually tolerated well. The frequently reported adverse effects were diarrhoea, increased serum uric acid level, reduction of neutrophil count and abnormal liver function tests showing raised transaminases (AST, ALT) (Fabiflu® 2020). On further evaluation of patients who had increased serum uric acid level, it was found that they had developed Acute kidney injury (AKI). They were non-oliguric; urine analysis was unremarkable and ultrasound showed features of neither obstructive uropathy nor renal vasculature thrombosis. The AKI improved within 24-48 hours of discontinuation of favipiravir treatment, eliciting the association with the drug. The respiratory failure of the patients had resolved and inflammatory markers were lowered which eliminates the possibility of direct SARS-CoV-2 related AKI. This suggests that the AKI caused was ‘drug induced nephrotoxicity (Nasa, P. et al., 2014)’.

Favipiravir causing teratogenicity and early embryonic lethality have been observed in several animal models. Therefore, premenopausal women should be cautioned and pregnancy must be excluded before initiating favipiravir treatment. It is also essential that all patients and their sexual partners practice safe contraception during the treatment course and till 10 days after the end of favipiravir therapy.


Our study had two limitations. One, not all studies were Randomised controlled trials, which increases the risk of bias. Two, only 8 studies were taken for the review as no other studies were qualitatively and quantitatively eligible to take up. Many randomized controlled trials with ample sample size, reliable data collection and good quality results are necessary to arrive at more beneficial outcomes.


Favipiravir treatment in the early phase of infection (viral replication phase) have shown significant reduction in the viral load and good clinical recovery. It also prevents the progression of disease to critical stage by controlling the infection adequately in the early phase itself. But when the stage of viral replication has passed, there is no role of favipiravir in the management of the COVID 19 disease. Favipiravir has no significant effect on mortality reduction in COVID 19 patients.


We thank Ms.Sumithra. P, Department of Statistics from Manonmaniam Sundaranar University, Tirunelveli for helping us with the statistical analysis of our results. We also thank David Sam Selva Jeyam, medical scholar from Tirunelveli Medical College for helping us with the technical aspects of the write up.


  1. Srikumar, S., & Perumal, S. (2021). A systematic review of immune pathogenesis of SARS-COV-2 infection. Int J Adv Med 8, 978-83.

  2. Furuta, Y., Komeno, T., & Nakamura, T. (2017). Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proceedings of the Japan Academy, Series B, 93(7), 449-463.

  3. Lee, J. S., Adhikari, N. K., Kwon, H. Y., Teo, K., Siemieniuk, R., Lamontagne, F., ... & Fowler, R. A. (2019). Anti-Ebola therapy for patients with Ebola virus disease: a systematic review. BMC infectious diseases, 19(1), 1-11.

  4. FUJIFILM Toyama Chemical Co., Ltd. Drug Interview form. Avigan® Accessed 5 Apr 2020.

  5. Manabe, T., Kambayashi, D., Akatsu, H., & Kudo, K. (2021). Favipiravir for the treatment of patients with COVID-19: a systematic review and meta-analysis. BMC infectious diseases, 21(1), 1-13.

  6. Solaymani-Dodaran, M., Ghanei, M., Bagheri, M., Qazvini, A., Vahedi, E., Saadat, S. H., ... & Moazen, J. (2021). Safety and efficacy of Favipiravir in moderate to severe SARS-CoV-2 pneumonia. International immunopharmacology, 95, 107522.

  7. Doi, Y., Kondo, M., Matsuyama, A., Ando, M., & Kuwatsuka, Y. (2020). Takuma Ishihara. Preliminary report of the Favipiravir Observational Study in Japan. (2020/5/15) doi: May 26, 2020.

  8. Corritori, S,. Yakubova, E. Ivashchenko, A. Egorova, A. Merkulova, E. Blinow, A. Lomakin, N. Smolyarchuk, E. Papazova, N. Kravchenko, D. Baranovsky,S. Remeeva, J. Savchuk, N. & Ivachtchenko, A. Topics in Antiviral Medicine ; 29(1):138, 2021.

  9. Rattanaumpawan, P., Jirajariyavej, S., Lerdlamyong, K., Palavutitotai, N., & Saiyarin, J. (2020). Real-world experience with favipiravir for treatment of COVID-19 in Thailand: results from a multicenter observational study. MedRxiv.

  10. Chen, C., Zhang, Y., Huang, J., Yin, P., Cheng, Z., Wu, J., ... & Wang, X. (2021). Favipiravir versus arbidol for clinical recovery rate in moderate and severe adult COVID-19 patients: a prospective, multicenter, open-label, randomized controlled clinical trial. Frontiers in pharmacology, 2292.

  11. Udwadia, Z. F., Singh, P., Barkate, H., Patil, S., Rangwala, S., Pendse, A., ... & Tandon, M. (2021). 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. International Journal of Infectious Diseases, 103, 62-71.

  12. Khamis, F., Al Naabi, H., Al Lawati, A., Ambusaidi, Z., Al Sharji, M., Al Barwani, U., ... & Al-Zakwani, I. (2021). 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. International Journal of Infectious Diseases, 102, 538-543.

  13. Dabbous, H. M., El-Sayed, M. H., El Assal, G., Elghazaly, H., Ebeid, F. F., Sherief, A. F., ... & TagelDin, M. A. (2021). RETRACTED ARTICLE: Safety and efficacy of favipiravir versus hydroxychloroquine in management of COVID-19: A randomised controlled trial. Scientific reports, 11(1), 1-7.

  14. Zumla, A., Chan, J. F., Azhar, E. I., Hui, D. S., & Yuen, K. Y. (2016). Coronaviruses—drug discovery and therapeutic options. Nature reviews Drug discovery, 15(5), 327-347.

  15. Vora, A., & Tiwaskar, M. (2020). Favipiravir. Journal of the Association of Physicians of India, 91-92.

  16. Shannon A, et al., (2020). bioRxiv 2020 Jan 1.

  17. Du, Y. X., & Chen, X. P. (2020). Favipiravir: pharmacokinetics and concerns about clinical trials for 2019‐nCoV infection. Clinical Pharmacology & Therapeutics108(2), 242-247.

  18. AVIGAN [package insert]. Japan: Toyama Chemical Co. Ltd;2017.

  19. Catanzaro, M., Fagiani, F., Racchi, M., Corsini, E., Govoni, S., & Lanni, C. (2020). Immune response in COVID-19: addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2. Signal transduction and targeted therapy, 5(1), 1-10.

  20. Siddiqi, H. K., & Mehra, M. R. (2020). COVID-19 illness in native and immunosuppressed states: A clinical–therapeutic staging proposal. The journal of heart and lung transplantation, 39(5), 405-407.

  21. Wu, J., Li, W., Shi, X., Chen, Z., Jiang, B., Liu, J., ... & Li, L. (2020). Early antiviral treatment contributes to alleviate the severity and improve the prognosis of patients with novel coronavirus disease (COVID‐19). Journal of internal medicine, 288(1), 128-138.

  22. Mason, R. J. (2020). Pathogenesis of COVID-19 from a cell biology perspective. European Respiratory Journal, 55(4).

  23. Giammaria, D., & Pajewski, A. (2020). Can early treatment of patients with risk factors contribute to managing the COVID-19 pandemic?. Journal of global health, 10(1).

  24. Fabiflu® (2020). [package insert]. Mumbai. India: Glenmark Pharmaceuticals Ltd; 2020.

  25. Nasa, P., Shrivastava, P., Kulkarni, A., Vijayan, L., & Singh, A. (2014) Pharmaceuticals and Medical Devices Agency. Report on the Deliberation Results of Avigan Tablet 200 mg Published. Accessed.

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