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Two reviewers MF and FH independently assessed the risk of bias among the included studies. We assessed the risk of bias of the included studies using Cochrane Collaboration criteria, including seven items of selection bias random sequence generation and allocation concealment , performance bias, detection bias, attrition bias, reporting bias, and other forms of bias 3 , Any discrepancies were resolved upon consultation with a third reviewer MA-Z.

CMA software has the ability to combine different indices and to combine the effect of sample size and the difference of the index being compared We used the I 2 statistics and Cochran test with significantly less than 0. In cases where there was heterogeneity, we performed the random-effect model. We also used a subgroup analysis based on follow up days for clinical improvement and viral clearance. One-leave-out sensitivity analysis were conducted for all outcomes based on Cochrane recommendation.

We identified a total of records after searching the databases. After the removal of duplicate records, the title and abstracts of records were screened. Eight hundred eighty-five records were excluded after title and abstracts screening, and 24 records were assessed for full-text screening. A total of 15 records were excluded based on eligibility criteria. Finally, nine studies were included in our meta-analysis 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 Fig.

Nine studies encompassing patients were included. According to the geographical area, four studies were conducted in China Only one study was nonrandomized. The minimum follow-up time was 10 days, and the maximum was 30 days.

The doses of Favipiravir and control drugs in each study were different. All studies registered in clinical trial registries. The summary characteristics of the included studies have been summarized in Table 1. Eight Six studies None of the studies reported acceptable blinding for participants and personnel. Only one study The risk of bias summary and risk of bias graph is reported in Supplementary file 2 and 3. Among the included studies, six studies assessed clinical improvement during 14 days after hospitalization, and five studies were assessed during seven days after hospitalization.

The meta-analysis of clinical improvement of Favipiravir on COVID patients black circle: individual studies; orange diamond: overall of subgroups; red diamond: overall of all included studies. The meta-analysis of viral clearance of Favipiravir on COVID patients orange diamond: summery of sub groups; red diamond: summery of total.

The meta-analysis of requiring supplemental oxygen therapy of Favipiravir on COVID patients red diamond: summery of total. Almost all adverse events of Favipiravir were mild to moderate and in an equal or lower rate compared to the control groups. The most prevalent adverse events included nausea, vomiting, diarrhea, chest pain as well as increase in serum liver transaminase and uric acid levels.

The results of sensitivity analysis did not show any difference in all outcomes and confirmed the previous results. The number of infected cases, as well as the mortality rate associated with the virus, has astronomically raised around the world. The main challenge of COVID is the lack of approved pharmacotherapy and vaccination, as well as the absence of evidence for reliable treatment options Although various agents are undergoing clinical trials, the urgency of the situation has made scientists repurpose the antiviral agents.

Favipiravir, as a ribonucleotide analog and selective inhibitor of the viral RNA polymerase enzyme, can cause widespread antiviral activity against RNA-carrying viruses, thereby preventing replication and transcription of the viral genome It has been approved for the treatment of new influenza viruses in Japan and China. It has also been shown to be effective against Ebola and RNA viruses caused by viral hemorrhagic fever Moreover, this drug revealed controversial results in different clinical trials conducted on COVID Our meta-analysis was carried out on nine eligible studies with patients.

The obtained results demonstrated the clinical improvement after seven and 14 days of hospitalization was more remarkable in patients taking Favipiravir than those receiving other drugs. Another meta-analysis conducted by Shrestha et al. Udwadia et al. The viral clearance after 14 days of hospitalization among patients taking Favipiravir was more than those taking other drugs.

However, this difference was not statistically significant after seven and ten days, which could be related to inappropriate dose and duration of treatment with Favipiravir In another meta-analysis by Shrestha et al. This difference between the results of our analysis and the mentioned meta-analysis might be due to an insufficient number of studies and a small sample size in the Shrestha et al.

Our study showed requiring supplemental oxygen therapy among patients taking Favipiravir was less than those taking control drugs. Dhan Bahadur Shrestha et al. The results of the present study showed that the groups treated with Favipiravir had a lower chance of side effects compared to the control groups.

This finding is consistent with the meta-analysis carried out by Shrestha et al. Khamis et al. Erdem et al. The most common side effects were elevation of liver enzymes, total bilirubin, and uric acid, as well as gastrointestinal disorders. This trial consists of five patients, and All five experienced mild to moderate rise in liver enzymes, three of them nausea, and one of them neutropenia.

All side effects were self-limited. There was no association between underlying disease and serious side effects, and no patients stopped Favipiravir due to side effects Victoria Pilkington et al. However, an increase in serum uric acid remains a concern, and the analysis of studies showed some evidence of a dose-dependent increase in this biochemical parameter. Other complications, including teratogenic potential and QTc prolongation, have not been sufficiently studied Denis Malvy et al.

However, more evidence is necessary to conclude long-term safety On the other hand, gastrointestinal disorders were minimal Totally, intervention with Favipiravir exerted minor tolerable side effects, including nausea, vomiting, diarrhea, and elevated serum transaminases. There were no serious life-threatening side effects after treatments with Favipiravir. Possible side effects could not be attributed to the only consumption of Favipiravir. Patients in the Favipiravir groups received other drugs in all three trials Our analysis showed the need for admission in ICU is not statistically significant between the Favipiravir groups and control groups.

Additionally, Yan Lou et al. Based on the results of the analysis, there has been a decrease in all-cause mortality in patients who took Favipiravir compared to those who took control of drugs. In a study carried out by Dabbous, one patient in the hydroxychloroquine group expired.

However, no death was reported in the Favipiravir group Despite the limitation, the present study provided the information needed for treating COVID, suggesting that Favipiravir is associated with significant clinical and laboratory improvement in most patients and it is a safe drug with no serious side effects There is some evidence to support the safety and tolerability of Favipiravir in short-term administration. However, more evidence is necessary to evaluate the exact long-term effects of this intervention.

Due to limited evidence and other specific safety concerns, caution should be considered in the widespread use of Favipiravir against the COVI D epidemic There are some limitations to the included studies. First, the sample size is low in each study. Second, due to multiple drug pharmacotherapy of patients with COVID in the most included study, there was, therefore, a risk of influencing the efficacy and also the safety of intervention with Favipiravir.

Third, the dosage and duration of intervention with Favipiravir are different among the included studies. Fourth, it is difficult to determine the clinical improvement found in patients treated with Favipiravir from different disease severity, ages, and medical conditions in the different studies. Overall, Favipiravir possibly exerted no significant beneficial effect in the term of mortality in the general group of patients with mild to moderate COVID We should consider that perhaps the use of antivirals once the patient has symptoms is too late and this would explain their low efficacy in the clinical setting.

There upon, more clinical trials with a larger sample size are necessary to evaluate the exact efficacy and safety of this intervention. Arab-Zozani, M. Favipiravir for treating patients with novel coronavirus COVID : Protocol for a systematic review and meta-analysis of randomised clinical trials. Article PubMed Google Scholar. Food, U. Rubin, D. FDA approval of remdesivir—a step in the right direction.

New Engl. This is complete offline installer and standalone setup for EndNote X9. This would be compatible with both 32 bit and 64 bit windows. Get Into PC. Follow Us. Some databases e. The user can then import the citations into the EndNote software. It is also possible to search library catalogs and free databases, such as PubMed, from within the EndNote software program itself.

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