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Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. An Addendum to this article was published on 01 February The novel coronavirus outbreak began in late December and rapidly spread worldwide, critically impacting public health systems.
A number of already approved and marketed drugs are being tested for repurposing, including Favipiravir. We aim to investigate the efficacy and safety of Favipiravir in treatment of COVID patients through a systematic review and meta-analysis.
All clinical trials which addressed the safety and efficacy of Favipiravir in comparison to other control groups for treatment of patients with confirmed infection with SARS-CoV2 were included. We assessed the risk of bias of the included studies using Cochrane Collaboration criteria. All analyses were performed using the Comprehensive Meta-Analysis software version 2, and the risk ratio index was calculated.
Egger and Begg test was used for assessing publication bias. Nine studies were included in our meta-analysis. Transferred to ICU and adverse events were not statistically different between two groups. 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 antiviral once the patient has symptoms is too late and this would explain their low efficacy in the clinical setting.
The novel coronavirus SARS-CoV-2 outbreak began in late December and rapidly spread worldwide, critically impacting public health systems 1. The clinical characteristics of Coronavirus disease COVID include respiratory symptoms, fever, cough, dyspnea, and pneumonia. In the absence of any established pharmacological agents, supportive care remains the cornerstone of clinical management for COVID 3.
An emergency use authorization EUA for convalescent plasma was announced on August 23, 6. An EUA was issued for baricitinib on November 19, for use, in combination with remdesivir 8 , and for casirivimab and imdevimab on November 21 9.
Due to the urgency of the situation, a number of already approved and marketed drugs are being tested for repurposing, including Favipiravir Favipiravir, also known as T, a purine nucleic acid analog, is one of the antiviral candidates considered in several clinical trials. It is a chemical used experimentally and was created by the Japanese company Toyama, a subsidiary of Fuji Film, as reported initially by Furuta in In , it was approved in Japan as a backup choice for resistant influenza infection and since then have been approved in several countries and is indicated for the treatment of patients with mild to moderate COVID disease As of the 12th October , there are 37 studies registered in the ClinicalTrials.
Even though multiple articles about Favipiravir are readily available for download online, including some systematic reviews and meta-analyses conducted on only two RCTs at this time 17 , 18 , 19 , 20 , 21 , the scientific community may find it challenging to get an overview regarding the safety and efficacy of this drug. Therefore, we aim to provide this systematic review and meta-analysis of Favipiravir.
To do so, we assess all available completed clinical trials till December 3. Also, we published this protocol in the BMJ Open journal 3. All clinical trials study design which addressed the safety and efficacy of Favipiravir intervention in comparison to other control groups comparison for treatment of patients with confirmed infection with SARS-CoV2 population were included.
There were no restrictions concerning gender, age, ethnicity, blinding, follow-up, or publication status. All publications in English and Farsi were included. It should be noted that some of the outcomes mentioned in the protocol were not analyzed due to the lack of sufficient data in the final included articles.
The data containing at least one Favipiravir-related outcome or side effects were considered sufficient. Articles with unavailable full text in English or Farsi languages or whose full text is not accessible were excluded from the study.
The studies with insufficient or incomplete data were not being incorporated. We also searched two preprint databases including MedRxiv and Research Square and, the reference lists of all included studies, reviews, and clinical trial registries, for an ongoing clinical trial. In addition, we created an alarm on Google Scholar and included new related articles. Once the records have been imported to EndNote X7 software and all duplicates have been removed, two reviewers SH and BA manually and independently screened titles, abstracts, and full-texts of included studies based on predefined eligibility criteria to identify studies concerning the safety and efficacy of Favipiravir among patients with COVID All potentials discrepancies were resolved upon consultation with a third reviewer MA-Z.
Two reviewers SH and BA independently extracted data from included studies, using a pre- piloted data extraction form. The data extraction form includes the following items; authors name, year of the publication, study design, study sample, country of origin, mean age of participants, gender, the severity of diseases, comorbidities, type of intervention and dose, control group, follow up, randomization, blinding, allocation concealment, primary and secondary outcomes, and adverse events 3 , All potentials discrepancies were resolved by consultation with a third reviewer RM.
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.
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