key: cord-0711552-0i77t3o4
authors: Hung, Dang The; Ghula, Suhaib; Aziz, Jeza Muhamad Abdul; Makram, Abdelrahman M.; Tawfik, Gehad Mohamed; Abozaid, Ali Ahmed-Fouad; Pancharatnam, Rohan Andrew; Ibrahim, Amr Mohamed; Shabouk, Muhammad Besher; Turnage, Morgan; Nakhare, Saloni; Karmally, Zahra; Kouz, Basel; Le, Tran Nhat; Alhijazeen, Suleiman; Phuong, Nguyen Quoc; Ads, Alaa Mohamed; Abdelaal, Ali Hussein; Nam, Nguyen Hai; Iiyama, Tatsuo; Kita, Kyoshi; Hirayama, Kenji; Huy, Nguyen Tien
title: The efficacy and adverse effects of favipiravir on COVID-19 patients: a systematic review and meta-analysis of published clinical trials and observational studies
date: 2022-04-22
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2022.04.035
sha: 0fe8df809feded8fc3501752f9a694a7d5eea3c8
doc_id: 711552
cord_uid: 0i77t3o4

Objectives This study aimed to evaluate the efficacy and adverse events of favipiravir in COVID-19 patients. Methods Our protocol was registered on PROSPERO (CRD42020206305). Fourteen databases were searched until February 8th, 2021. An update search for new RCTs was done on March 2nd, 2022. Meta-analysis was done for randomized controlled trials (RCTs) and non-RCTs. Results Overall, 157 studies (24 RCTs, one non-RCT, 21 observational studies, two case series, and 106 case reports) were included. On hospitalized patients, in comparison to standard of care, favipiravir showed a higher rate of viral clearance at day 5 (RR=1•60, p=0•02), defervescence at day 3-4 (RR=1•99, p<0•01), chest radiological improvement (RR=1•33, p<0•01), hospital discharge at day 10-11 (RR=1•19, p<0•01), and shorter clinical improvement time (MD=-1.18, p=0.05). Regarding adverse events, favipiravir groups had higher rates of hyperuricemia (RR=9•42, p<0•01), increased alanine aminotransferase (RR=1•35, p<0.01), but lower rates of nausea (RR=0•42, p<0•01) and vomiting (RR=0•19, p=0•02). There were no differences regarding mortality (RR=1•19, p=0.32), and increased aspartate aminotransferase (RR=1•11, p=0•25). On non-hospitalized patients, no significant differences were reported. Conclusion Adding favipiravir to the standard of care provides better outcomes for hospitalized COVID-19 patients. Pregnant, lactating women, and patients with a history of hyperuricemia should avoid using favipiravir.

COVID-19 was declared a worldwide pandemic by the World Health Organization (WHO) on March 11, 2020, because of its widespread prevalence and life-altering consequences (WHO, 2020) . The disease is caused by the SARS-CoV-2 virus, an enveloped positive-sense RNA virus that relies primarily on RNA-dependent-RNApolymerase (RdRp) for viral gene transcription and replication (Zhu et al., 2020) . It is well recognized for its unprecedented speed of transmission in asymptomatic and presymptomatic carriers (Gandhi et al., 2020) . Until April 10, 2022, nearly 500,000,000 cases of SARS-CoV-2 infection have been confirmed and over 6,000,000 people have died globally as a result (Johns Hopkins, 2020) . This had stretched intensive care units to their maximum capacity and beyond. Consequently, there is an urgent need for efficient and safe drugs to combat this pandemic.

Currently, the recommended treatments for COVID-19 are limited. Favipiravir is a promising antiviral medication (Agrawal et al., 2020) , which was initially used as an anti-influenza agent in Japan in 2014, and was also used to treat Ebola and other viral diseases (Guedj et al., 2018, Shiraki and Daikoku, 2020) . As a nucleoside analog, it inhibits the RdRp complex of SARS-CoV-2 through binding to its catalytic domain and preventing the inclusion of nucleotides for viral RNA replication, leading to an increased mutation frequency, and perhaps lethal mutagenesis (Shannon et al., 2020) . RdRp has been shown to have an exceptionally high polymerization rate in combination with low fidelity and is highly error-prone in SARS-CoV-2 which makes it the target of choice with polymerase inhibitors like favipiravir (Shannon et al., 2020) . Additionally, favipiravir does not affect the human DNA or proteins because RdRp has no host cell homolog (Zhu et al., 2020) .

There have been many trials and observational studies that report the efficacy and adverse events of favipiravir in the management of COVID-19 patients , Kocayigit et al., 2021 , Pushkar, 2020 , Udwadia et al., 2021 . Early similar metaanalyses were done to summarize this evidence (Hassanipour et al., 2021 , Manabe et al., 2021 , Prakash et al., 2020 , Shrestha et al., 2020 . However, as the number of new papers increased day by day, we conducted this systematic review and meta-analysis to provide more clinical evidence for the efficacy and adverse effects of favipiravir in COVID-19 patients.

Our systematic review and meta-analysis followed a previously published method (Tawfik et al.) and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist (Page et al., 2021) Table 1 

Fourteen electronic databases were searched on February 8 th of 2021. The detailed databases and search terms could be found in Supplemental Table 2 . An additional manual search on March 20 th was done. All search results were imported into EndNote X9 to remove duplicated entries.

The titles and abstracts were screened first, then the full texts of eligible studies were downloaded and checked for final inclusion. Any primary studies in which favipiravir was used on COVID-19 patients would be eligible. Non-peer-reviewed articles and data from trial registries were included. We excluded non-human studies, duplicated articles, and studies with unextractable data or missing full texts.

Data were extracted into an excel form. For randomized controlled trials (RCTs) and non-RCTs, we extracted age, gender, follow-up day and any quantity data relating to favipiravir efficacy and side effects. Regarding category data, sample size, number of concerned events, and timepoints were extracted to calculate the risk ratio (RR) and their 95% confidence interval (95% CI). For continuous data, mean, standard deviation (SD), and sample size were extracted or estimated from median and range/interquartile range (Wan et al., 2014) to calculate the mean difference (MD) and 95% CI. Outcomes regarding favipiravir efficacy and side effects from observational studies and case reports were reported in quality review.

The RCTs and non-RCTs were assessed by the Cochrane Collaboration's second version of the risk of bias tool for randomized trials (RoB 2) (Higgins et al., 2011) and the risk of bias in non-randomized studies of interventions (ROBIN-I) (Sterne et al., 2016) . Observational, cross-sectional studies and case series were assessed using the National Institutes of Health (NIH) quality assessment tool (National Heart). Case reports were assessed as recommended by the Clinical Guidelines Network Cancer Council Australia (CCA) handbook (Sydney: Cancer Council Australia, 2014). For important outcomes in the meta-analyses, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to assess the certainties of evidence (Atkins et al., 2004) .

The study selection, data extraction, and quality assessment were done by at least two independent authors who engaged in a formal discussion later to resolve any disagreements. A difficult decision would be consulted with a senior member to resolve.

Meta-analysis using inverse variance method was conducted by the meta package in R 4·0·4 (Deeks JJ, 2021) . The heterogeneity was assessed using I 2 and Cochrane Q test.

If I 2 was higher than 50% or the p-value less than 0·10, heterogeneity would be considered statistically significant, random-effect model and Hartung-Knapp-Sidik-Jonkman method would be used. Otherwise, a fixed-effect model would be applied. For each outcome, all trials comparing favipiravir to the standard of care (SOC) were pooled. Sensitivity analysis was conducted by removing studies using another antiviral drug as comparison. The pooled results were considered statistically significant if the p-value was below 0·05. A multivariate time series meta-analysis using Musekiwa et al.'s method with the metafor package (Musekiwa et al., 2016) was performed on viral clearance rate at multiple timepoints, all described models were tried and one bestfitting model with the least Akaike Information Criterion (AIC) was visualized using Microsoft Excel. If ten or more studies were found for any outcomes, we would use Egger's regression test to assess for publication bias and visualize with Begg's funnel plot. A p-value less than 0·10 would be considered significant, and Duvall and Tweedie's method of trim and fill would be performed.

On February 8 th , 2021, database search identified 6707 papers. A manual search on March 2 nd of 2022 for RCTs found additionally 14 papers. Using Endnote, 3637 duplications were removed. Later, 2764 records were removed after title and abstract screening. After full-text assessment, a total of 157 publications (24 RCTs, one non-RCT, 21 observational studies, two case series, and 106 case reports) entered the extraction and analysis stage. The detailed progress is presented in the PRISMA flow diagram in Figure 1 .

We performed meta-analysis for 16 RCTs (Balykova et al., 2020a , Balykova et al., 2020b , Balykova et al., 2020c , Bosaeed et al., 2021 , Chen et al., 2020a , Chuah et al., 2021 , Doi et al., 2020 , Finberg et al., 2021 , Ivashchenko et al., 2021 , Pushkar, 2020 , Ruzhentsova et al., 2021 , Shenoy et al., 2021 , Shinkai et al., 2021 , Solaymani-Dodaran et al., 2021 , Tabarsi et al., 2021 , Udwadia et al., 2021 and 1 non-RCTs (Cai et al., 2020) , which studied the effect of favipiravir on hospitalized patients. The baseline characteristics of the controlled trials could be found in Supplemental Table 3 .

Using data from 8 studies, we plotted RR for the number of patients having the viral clearance from day 3 to day 16, using Musekiwa et al.'s univariate and multivariate model (Musekiwa et al., 2016) . Multivariate model 5 had the least AIC and was used for the analysis. In multivariate model, although all RR values were greater than one, significant better outcomes were found only at day 5 (RR=1·60, 95% CI [1·07, 2·36], p=0·02) ( Figure 2 ). In the sensitivity analysis, multivariate model 2 fitted better (smallest AIC), however, significant results were still found on day 5 (Supplemental Figure 1 ).

Detailed forest plots for univariate analysis at day 5 and 10 were given in the same figures, detailed numbers could be found in Supplemental Table 4 .

Despite insignificance, mean viral clearance time was shorter in patients received favipiravir (MD=-2·62, 95% CI [-7·28, 2·03], p=0·21, I 2 =74%) (Supplemental Figure 3a ). Sensitivity analysis made heterogeneity plummeted (I 2 =25%), with a smaller MD and 95% CI (MD=-1·08, 95% CI [-2·25, -0·08], p=0·07) (Supplemental Figure 3b ).

The pooled RR for clinical improvement rate from eight RCTs was higher but not statistically significant (RR=1·27, 95% CI [0·88, 1·85], p=0·17) with high heterogeneity (I 2 =73%) (Figure 3a ). On the other hand, the pooled RR from five papers for defervescence at day 3-4 was significantly better in the favipiravir group (RR=1·99, 95% CI [1·63, 2·43], p<0·01, I 2 =6%) (Figure 3b ). Favipiravir group also showed better chest radiological improvement rate (RR=1·33, 95% CI [1·17, 1·51], p<0·01, I 2 =0%) from six papers ( Figure 3c ). Sensitive analysis showed the same patterns for these three outcomes (Supplemental Figure 2a, The definitions for these outcomes differed between studies and are given in Supplemental Table 5 .

Regarding the discharge rate, significant pooled results from five studies were found for favipiravir at day 10-11 (RR=1·19, 95% CI [1·06, 1·33], p<0·01, I 2 =43%) but no difference was found at day 14-15 (RR=1·00, 95% CI [0·93, 1·09], p=0·92, I 2 =0%). Also, the difference was insignificant in length of hospitalization (MD=-0·19, 95% CI [-0·67, 0·29], p=0·44, I 2 =0%) as well as in the sensitivity analysis (Supplemental Figure 4a-d).

No differences were found for mortality when pooling twelve studies with RR=1·19, 95% CI [0·85, 1·66], p=0·32, I 2 =0%. Also, sensitivity analysis did not change the outcome (Supplemental Figure 5a and b).

A summary of baseline characteristics and outcomes from observational studies and case series is given in Supplemental Table 6 .

Administrating favipiravir early (at the time of diagnosis) and late (few days later) were compared in some studies. While an RCT showed insignificant differences (Doi et al., 2020) , a case-control study showed better outcomes on viral negativity (p<0·001) and disease progression (p<0·05) (Uçan et al., 2021) , and another retrospective cohort showed a lower mortality rate in early favipiravir treatment group (p=0·002) (Karatas et al., 2021) .

A higher favipiravir dosage was suggested to be more effective in two investigations. A retrospective study reported that a low loading dose of favipiravir (≤45 mg/kg/day) was a poor predictive factor for clinical improvement on day 7 (p=0·006) (Rattanaumpawan et al., 2020) . In a non-controlled study, most of 49 blood samples from 13 patients, who received 1600 mg twice on the first day followed by 600 mg twice from day 2, had favipiravir concentration less than the lower limit of quantification (1 μg/mL) and lower than the in-vitro half-maximal effective concentration (Irie et al.) . In a RCT on mild to moderate patients, ivermectin plus doxycycline show better results than favipiravir group even though they were not significant.

On non-hospitalized patients, favipiravir did not affect the outcomes in two doubleblinded controlled RCTs (Holubar et al., 2021 , Lowe et al., 2022 . Regarding hospitalized patients, a non-RCT reported favipiravir to be superior to lopinavir/ritonavir regarding viral clearance and chest imaging (p<0·01) (Cai et al., 2020) . Favipiravir could also shorten the time having pyrexia and cough compared to umifenovir in a RCT (p<0·01) (Chen et al., 2020b) . In a cross-sectional survey, favipiravir group had a considerably decreased death rate in the comparison with remdesivir (p<0·01) (Ara Perveen et al., 2021) . No significant data was found when compared favipiravir to baloxavir marboxil (Lou et al., 2021) . In combination with tocilizumab, favipiravir showed a better lung lesion remissions when compared to favipiravir alone in an RCT (p<0·05) (Zhao et al., 2021b) . In patients with recurrent positive, the favipiravir group achieved negative PCR in a significantly shorter period than standard of care (p=0.038) (Zhao et al., 2021a) .

By pooling 14 RCTs and 1 non-RCTs, 17 adverse events ranging in severity were metaanalyzed. Because no significant heterogeneity was found, fixed-effect model was applied to all adverse events (Supplemental Figure 6) . The adverse events that had higher risks following favipiravir usage compared to the control groups was respectively, while the latter reported that most patients' uric acid levels normalized at day 28 (Balykova et al., 2020c , Ruzhentsova et al., 2020 . Additionally, a case with acute gouty arthritis triggered by the hyperuricemia effect of favipiravir was described . Finally, when combined with tocilizumab, a significant increase in uric acid level was detected when compared to favipiravir or tocilizumab alone (Zhao et al., 2021b) .

There were no significant differences in the RR for increased aspartate aminotransferase (RR=1·11, 95% CI [0·93, 1·32], p=0·25, I 2 =11%) (Figure 4c ). On the other hand, favipiravir reduced risk for nausea (RR=0·42, 95% CI [0·25, 0·70], p<0·01, Various observational studies had addressed safety profiles of favipiravir. In comparison to pre-treatment values, while the drug seemed not to affect the QT interval on electrocardiogram (Çap et al., 2020) , it was reported to be associated with increased liver enzymes (Yilmaz et al., 2020) , increased platelet and lymphocyte count, decreased neutrophil and red blood cell count (Yaylaci et al., 2020) . Significant retinol depletions were also reported (Sarohan et al., 2021) . A summary table for these outcomes is presented in Supplemental Table 7 .

A total of 106 studies with 142 cases were found (Supplemental Table 8 ). The mean age was 52·70±17·13 (range: 1-85) with a male-female ratio of 101:41. After favipiravir administration, the clinical status improved in 74 cases, worsened in 48 cases (with 21 deaths) and was unclear in 20 cases. The reported side effects were hyperuricemia , Hosoba et al., 2020 , Ono et al., Takoi et al., 2020 , fever (Koba et al., 2020 , Takoi et al., 2020 , lymphocytosis (Dauby et al., 2021) , eosinophilia (Takoi et al., 2020) , lymphocytopenia (Atallah et al., 2020) , hepatotoxicity (Hosoba et al., 2020 , Takumida et al., 2021 , Yamazaki et al., 2021 , nephrotoxicity (Nasa et al., 2021) , acute pancreatitis (Khan et al., 2021) , wood's lamp fluorescence on nails and hair and nausea (Aslan Kayiran et al., 2021) .

Regarding the overall risk of bias judgment, all RCTs were of some concerns except three papers that had low risk of bias due to proper blinding. One non-RCT study had moderate overall risk-of-bias. Among twenty-one observation studies, seven papers had a good rating, the other fourteen had a fair rating. Two case series were given a 'fair' rating and all fifty-three case reports had a high overall risk of bias. The detailed results of the quality assessment were provided in Supplementary Tables S9-S13.

Using GRADE, there was a high certainty that patients received favipiravir had faster recovery from fever and higher rate of hyperuricemia, moderate certainties for better virological, clinical, radiological responses and lower nausea rate (Table 1) . No differences in mortality rate were found with a moderate certainty.

In hospitalized patients, favipiravir showed a superior trend compared to standard of care. In our multivariate time series meta-analysis analysis, the differences in viral clearance rate peaked on day 5 then decreased in the follow-up days. This could be explained by the fact that most of the patients in the included trials recovered at the end of the studies and therefore shrunk the differences between the two groups as time passed. It was consistent with the fact that there was a significant difference in the number of patients being discharged on days 10-11 but no difference on day 14-15 as well as no difference in the pooled RR for mortality at the end of the trials. Overall, it seemed that favipiravir could induce a better virological response in COVID-19 patients as well as reduce the need for medical care, but more evidence would be needed.

Chest radiological imaging, which had slower recovery rate (Rong et al., 2021) , still showed fibrotic-like changes on more than one-third of severe COVID-19 patients after six months (Han et al., 2021) , and therefore, in our analysis, this outcome was found to be significantly better after 10 days on chest X-ray and 14-15 days on computerized tomography imaging. This suggested a favorable outcome in the long term for favipiravir groups. Accordingly, future RCTs for moderate to severe patients should consider it as a main outcome and also monitor long-term differences on imaging as it is a potential indicator for the effectiveness.

Regarding clinical improvement, the pooled RR showed that clinical improvement rate at day 10 was higher in favipiravir groups (despite being insignificant with p value of 0·17). The mean clinical improvement time was significant shorter in favipiravir group in both the main and the sensitive analysis. Significant differences that favored favipiravir were also found in defervescence rate at day 3-4 and mean defervescence time in both the main and sensitive analysis. Taking everything into account, favipiravir could induce a better clinical improvement, however, more data would be needed for a concrete conclusion.

The similarity in the mortality rates between those taking favipiravir and not taking the drug can lead to the assumption that favipiravir, when used, can decrease the time till clinical, laboratory, or radiologic recovery, but not an overall reduction in the morbidity or mortality. However, it is important to highlight that most of the included studies reported near-zero mortality rate and therefore it was still too soon to make this conclusion.

In nearly all the included RCTs, favipiravir was use early (at day 1 of diagnosis). The benefit of early usage of favipiravir was reported in some observational studies (Karatas et al., 2021 , Uçan et al., 2021 , the viral clearance was also reported to be directly related to the early initiation of antiviral therapy and before the peak of viremia, leading some practitioners to start antiviral medications in the pre-symptomatic phase of COVID-19 (Goyal et al., 2020) . Accordingly, even though no strong evidence was found, early usage of favipiravir could provide better outcomes for COVID-19 patients.

On non-hospitalized mild patients, two double-blinded controlled RCTs showed that favipiravir had no effect compared to standard of care on (Holubar et al., 2021 , Lowe et al., 2022 . This suggest that favipiravir should not be used on mild cased with low risk and focus on moderate and severe cases.

A wide variety of adverse events have also been linked to favipiravir intake. Our metaanalysis strongly concluded that favipiravir usage significantly increases the risk of hyperuricemia when compared to control, which is consistent with other reports , Koseki et al., 2022 . Increased levels of liver enzymes had been associated with COVID-19 (Kaneko et al., 2020) as well as many antiviral drugs (Vitiello et al., 2021) , including favipiravir. Our analysis detected a significant increase in alanine aminotransferase but not aspartate aminotransferase. However, these were not the main outcomes of the RCTs as well as the effect sizes were small. The pooled RR were greatly contributed by one paper due to its high number of events. Moreover, on studies that focus on increase liver enzymes, no significant differences were found (Bayram et al., 2021) . Therefore, more studies should be conducted before concluding the effect of favipiravir on liver enzymes. Nausea and vomiting turned out to be lower in favipiravir group. However, the pooled RR were mainly contributed by two papers comparing favipiravir versus lopinavir/ritonavir, which was known for the nausea and vomiting adverse events (Hurst and Faulds, 2000) . Therefore, this conclusion should not be concrete. Having potential teratogenic effects in some animal studies, favipiravir was contraindicated during pregnancy and lactation as well as in men seeking conception (Agrawal et al., 2020) . High attention should be paid in these situations.

Two dosage regimens with a dissimilar duration (varying from two to fourteen days) were found in most of the included studies. They all started with a loading dose of 1600 or 1800 mg doses twice a day on the first day and continues by 600 or 800 mg twice daily. However, two included observational studies suggested that higher doses than these could improve the efficacy of favipiravir (Irie et al., Uçan et al., 2021) . In Ebola virus disease, the doses were amplified to 6000 mg loading dose and 2400 mg maintenance dose daily, however, it had not been associated with a major enhancement in the outcomes but might yield higher rates of side effects (Nguyen et al., 2017) . Overall, we believed that more trials are needed to investigate how much can we increase the dose to maximize the efficacy without causing extra harm to our patients.

Remdesivir, an antiviral drug also targets the RdRp complex (Aleem A, 2021) , received approval from the Japanese government for using in severe COVID-19 cases on May 7 th , 2020 (Lamb, 2020). It was also the first FDA-approved treatment on October 22 nd , 2020 (Rubin et al., 2020) . Previous studies found better results for remdesivir on clinical improvement and discharge rate compared to SOC (Enoki et al., 2021 , Jiang et al., 2021 , Piscoya et al., 2020 , Yokoyama et al., 2020 . Despite being marginal, similar conclusion were also found in favipiravir. Moreover, favipiravir also proved to be better than SOC regarding viral clearance, defervescence, and chest radiological improvement, which, in our opinions, were lacking in evidence for remdesivir. Although some low level of evidence suggested that favipiravir is better than remdesivir (Ara Perveen et al., 2021) , more RCTs comparing the two drugs would be required before making any conclusions.

Earlier systematic reviews and meta-analyses detected better viral clearance and clinical improvement in favipiravir group compared to SOC, which is consistent with our conclusion (Hassanipour et al., 2021 , Manabe et al., 2021 , Prakash et al., 2020 , Shrestha et al., 2020 . Compared to these studies, our search was conducted later which resulted in more papers included for the meta-analysis. We all applied a similar approach: pooling all trials that compared favipiravir versus SOC or any antiviral drugs used in these SOC. However, as we had a wider selection, we also performed a sensitivity analysis by removing any trials comparing favipiravir versus single antiviral drugs. Additionally, we provided meta-analyses for defervescence, chest radiological improvement, and hospital discharge outcomes. Our analyses for adverse events were also more thorough and revealed the differences in the risk of hyperuricemia, vomiting, and nausea. New meta-analyses in near future should be performed for higher-quality insights about favipiravir as the number of RCTs keeps increasing.

Due to the small number of the published studies, some outcomes were borderline as well as the data compared favipiravir versus other drugs was limited. Subgroup metaanalyses were not possible for different severities, different doses, and non-hospitalized patients. All papers entered the meta-analysis were open-label except one singleblinded RCT and one double-blinded RCT, therefore future RCTs with appropriate blinding are needed. In our meta-analysis, because of ethical issues, the control groups in most RCTs were the national SOC, which differed a lot from one trial to another (Supplemental Table 3 ), yet favipiravir was found to be more effective regardless of the treatment plan. Another issue with the included papers was that the definition of chest radiological imaging and clinical improvement statuses differ according to the protocol each country followed. These caused higher heterogeneity and therefore increased the 95% CI in some analyses. The fact that even RCTs comparing favipiravir versus other antiviral drugs were pooled in the main meta-analyses could make us underestimate the effect size.

In conclusion, adding favipiravir to the standard of care provides faster viral clearance and clinical improvement, and better radiological imaging improvement for hospitalized patients. Non-hospitalized patients might not receive the benefit from favipiravir.

Hyperuricemia should be noted when using favipiravir for prompt cessation of drug intake. Contrastingly, elevated hepatic enzymes might not be side effects for using favipiravir in COVID-19 considering other published studies. Further cautions should be applied when administrating it to pregnant or lactating women due to its probable teratogenic effects. Larger RCTs with proper blinding are required to detect the best dosage and administration time of favipiravir as well as to fortify the borderline results. 

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Efficacy and Safety of Favipiravir in Moderate COVID-19 Pneumonia Patients without Oxygen Therapy: A Randomized, Phase III Clinical Trial

Favipiravir, an anti-influenza drug against life-threatening RNA virus infections

Favipiravir versus other antiviral or standard of care for COVID-19 treatment: a rapid systematic review and metaanalysis

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

Sydney: Cancer Council Australia. Clinical Guidelines Network Cancer Council Australia. Development of Clinical Practice Guidelines Using Cancer Council Australia's Cancer Guidelines Wiki. Handbook for section authors and the guideline working party

Favipiravir Effects on the Control of Clinical Symptoms of Hospitalized COVID-19 Cases: An Experience with Iranian Formulated Dosage Form

Favipiravir-induced fever in coronavirus disease 2019: A report of two cases

Sustained coronavirus disease 2019-related organizing pneumonia successfully treated with corticosteroid

A step by step guide for conducting a systematic review and meta-analysis with simulation data

Benefits of Treatment With Favipiravir in Hospitalized Patients for COVID-19: a Retrospective Observational Case-control Study

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

The risks of liver injury in COVID-19 patients and pharmacological management to reduce or prevent the damage induced

Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range

Director-General's opening remarks at the mission briefing on COVID-19

Suspected cholestatic liver injury induced by favipiravir in a patient with COVID-19

The effects of favipiravir on hematological parameters of covid-19 patients

Results of Favipiravir Combined Treatment in Intensive Care Patients With Covid-19

Effect of remdesivir on patients with COVID-19: A network meta-analysis of randomized control trials

Favipiravir in the treatment of patients with SARS-CoV-2 RNA recurrent positive after discharge: A multicenter, open-label, randomized trial

Tocilizumab combined with favipiravir in the treatment of COVID-19: A multicenter trial in a small sample size

RNA-Dependent RNA Polymerase as a Target for COVID-19 Drug Discovery

Ethical Approval: This study is exempt from ethical approval.

We declare no competing interests.

 Figure 1 . PRISMA flow diagram of the literature search and screening for eligibility steps.Records identified from: Pubmed (n=329) Google Scholar (n=252) Scopus (n=929) Embase (n=978) Clinicaltrial.gov (n=49)Cochrane (n=108) Eurompc.org (n=1669) ISI (n=280) COVID-evidence (n=56) VHL (n=352) iSearch COVID-19 (n=1310) mRCT ( Studies included (n = 157) Studies included in meta-analysis (n = 17) 7 (1339) High* We grade down the quality by one because the data were sparse and imprecise due to low prevalence of the event. However, the RR was high therefore the evidence was upgrade by one.

*One non-RCTs entered these meta-analyses, however, no differences were found in the baseline characteristics in this study, removing the paper from the meta-analysis also did not significantly alter the results, therefore we still decided to still start the GRADE with high.