A systematic review and meta-analysis to demonstrate the treatment effects of favipiravir among patients with COVID-19.

Favipiravir showed a greater possibility for treating COVID-19, especially patients with mild-moderate illness, owing to its effective virus clearance rates. 

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first discovered in Wuhan, China, is the causative agent of the COVID-19 outbreak and has led to millions of deaths globally. Considering the wide array of clinical manifestations of coronavirus, ranging from the clinical symptoms of acute respiratory distress syndrome and serious pneumonia to asymptomatic disease course, the lungs, which have a very slow cell turnover, are the principal organs that the virus affects. At the initial stage of the pandemic, the pathophysiology and effective management ways were unknown, and there was unavailability of vaccine. Although the discovery of efficacious and safe management approaches was urgently needed, the discovery of novel antiviral agents against COVID-19 takes a long time.

SARS-CoV-2 (member of the coronaviridae family) is a positive strand RNA (+RNA) virus. This single-stranded RNA beta-coronavirus is responsible for encoding proteases and RNA-dependent RNA polymerase (RdRp). Both viral proteases and RdRp are believed to be pivotal targets for the promising therapeutic agents. Previously termed T-705, the antiviral drug favipiravir is prodrug of purine nucleotide favipiravir ribofuranosyl-5′-triphosphate. This active agent suppresses RNA polymerase, thus triggering suppression of viral replication. In the year 2014, favipiravir received approval from the Japan Pharmaceuticals and Medical Devices Agency to treat the re-emerging influenza infection.

Numerous studies reported its efficacy against other RNA viruses like Ebola virus, and other viruses like respiratory syncytial virus and rhinovirus. In the Vero E6 cells (in vitro), favipiravir showed 50% effective concentration (EC₅₀) of  61.88 μM/L against SARS-CoV-2. Therefore, favipiravir exhibits a great potential to manage individuals with coronavirus disease.

RATIONALE BEHIND RESEARCH

Research investigating favipiravir's efficacy and safety in people suffering from coronavirus disease is limited. Hence, this meta-analysis and systematic review was done.

OBJECTIVE

This study was carried out for systematically reviewing the application of favipiravir for coronavirus-infected people for identifying empirical evidence of its effectiveness. 

Literature search

Using key words, “novel coronavirus” OR “new coronavirus” OR “emerging coronavirus” OR “2019-nCoV” OR “COVID-19” OR “SARS-CoV-2” AND “favipiravir” OR “avigan” OR “T-705”, databases like Cochrane Library, MedRxiv, and PubMed, were explored (from inception to September 12, 2020) by two researchers for the appropriate studies.

The reference lists of all the incorporated studies, reviews, and clinical trial registries for the ongoing clinical trials examining favipiravir's efficacy or safety for coronavirus-infected people were explored. The investigators also reviewed the reference lists of eligible studies utilizing Google Scholar and carried out a manual search for ensuring that all the relevant studies were incorporated.

Inclusion criteria

Studies meeting the following selection criteria were incorporated in this systematic review:

• Study design and language: Observational studies, Randomized clinical trials (RCTs), and case series involving > 10 people, written in English language
• Population: People having lab-confirmed coronavirus infection who were hospitalized or received treatment in clinics
• Intervention: Favipiravir Administration
• Comparison intervention: Remdesivir, placebo, lopinavir/ritonavir, Standard of care (SOC),
• other available antivirals, hydroxychloroquine, different doses of favipiravir, combination treatment with favipiravir, or no comparator,
• Primary endpoint: Viral clearance and clinical improvement, including improvement in the chest computer tomography
• Secondary endpoint: Any outcome variable

Exclusion criteria

Studies were excluded if:

• there were ≤10 participants in case series
• there was no reporting of outcome variables
• the study did not have sufficient or complete data

Study selection and Data extraction

Data extraction was done by two investigators. The storage of the retrieved articles in the search was done in a citation manager. Following removal of redundant articles, the titles, abstracts, and then full-text articles were evaluated. Extraction of the following data was done: study site and design, inclusion/exclusion criteria of each study, and observational period.

The outcomes were extracted into the pre-designed data collection forms. Verification of the accuracy of data was done by assessing collection forms of each researcher. Any kind of discrepancies was solved via discussion among the researchers.

Data and Statistical Analysis

With the aid of a random-effects model (generic inverse variance method), estimation of the odds ratios (ORs) or the percentage of people for the primary endpoint with 95% confidence intervals (CIs) was done. For determining the percentage of outcome variables in people infected with SARS-CoV-2, the standard error was estimated utilizing Agresti-Coull methodology.

With the aid of the I² statistic, assessment of heterogeneity in the original studies was done. Utilizing funnel plot, publication bias was determined. For all the analyses, the significance levels were two-tailed, and p < 0.05 was statistically significant. All the statistical tests were done utilizing Review Manager.

Risk of Bias and Quality assessment

For the overall effect of the antiviral drug on clinical improvements and clearance of virus, determination of risk of bias (low risk, some concerns, or high risk) was done utilizing Cochrane Risk of Bias Assessment Tool.

The risk of bias evaluations was carried out independently by two researchers, with the disagreements resolved through discussion. The Grading of Recommendations Assessment and Evaluation approach was utilized for examining certainty of evidence that the antiviral drug favipiravir favored clinical improvement and decreased the time to viral clearance.

Study outcomes

• The major outcome was viral clearance and clinical improvement.

Outcomes

Study characteristics:

• Out of 163 references screened, 11 studies were found to be eligible. Out of 11 studies, 3 studies were RCTs, 6 studies were case series or observational studies, 1 study was a before and after non-randomized controlled study, and 1 study was a non-randomized controlled study.
• Out of 11 eligible studies, 5 studies incorporated a comparator group.
• For comparative studies, the comparators incorporated SOC, lopinavir/ritonavir, baloxavir marboxil, umifenovir, and hydroxychloroquine alone or in combination with azithromycin.
• Favipiravir's dosage usually matched the standard dose to treat influenza infection (twice daily 1600 mg on the 1^st day followed by twice daily 600 mg). However, in few eligible studies, the dosage was  twice daily 1800 mg on the 1^st  day that was followed by twice daily 800 mg.
• One study evaluated the loading dose. Among the 11 eligible studies, favipiravir's duration therapy was majorly 14 days.

Effect of intervention on the outcome:

• In comparison with the comparator group, the favipiravir-treated subjects displayed considerably better viral clearance on day 7 following initiation of therapy. No difference was found on day 14.
• Though there was a remarkable improvement in people treated with favipiravir on both days (7 and 14), the improvement was noted to be superior on day 14 when compared to on day 7.
• Estimated percentage of people with clinical improvement on days 7 and 14 in the favipiravir arm were 54.33% and 84.63%, respectively, in comparison with 34.4% and 65.77%, respectively, in the comparator arm.
• The estimated percentage of people with clearance of SARS-CoV-2 in the favipiravir-recipients were 65.42% on day 7 and and 88.9% on day 14 compared to 43.42% and 78.79% in the comparator arm, respectively. 

Utilizing the limited available evidence, this study demonstrated that favipiravir has excellent potential for the management of SARS-CoV-2 infection. In people having moderate COVID-19, favipiravir was found to accelerate clearance of the virus following seven days of therapy. Favipiravir also contribute to clinical improvement, particularly following 14 days of therapy. Drugs other than antiviral agents, like methylprednisolone or nafamostat, can be utilized in combination with favipiravir for people suffering from moderate or severe coronavirus infection. Favipiravir has shown effectiveness against numerous RNA viruses, suppresses RNA-dependent RNA polymerase, and it is one of the promising therapeutic agents that can be re purposed to manage coronavirus infection.

Although different comparators were utilized in the studies, it was found that favipiravir was linked with a considerably greater probability of SARS-CoV-2 clearance on day 7. Contrarily, the percentage of viral clearance was not considerably distinct by day 14. The SARS-CoV-2 load peaks around the onset of symptoms or a few days thereafter, and it becomes undetectable within about two weeks. Furthermore, among most of the included studies, duration of favipiravir treatment was 14 days. The paucity of a considerable difference in the percentage of SARS-CoV-2 clearance at day 14 between the therapies might reflect natural course of COVID-19 shedding. It was noted that median time to viral clearance in people given favipiravir on day 1 following COVID-19 onset was less than 12.8 days, when compared to 17.8 days for people who initiated therapy on day 6.

Since favipiravir is an oral drug, it can be easily administered to asymptomatic or mildly ill people with coronavirus infection. The drug led to substantial clinical improvement by 14 days, but not seven days, following initiation of therapy. On contrary, time to body temperature normalization was about two days. The studies demonstrated varied descriptions of clinical improvement. But, the variables that defined clinical improvement incorporated oxygen saturation, respiration rate, chest computed tomography improvement, and cough relief. These clinical symptoms and signs were influenced by pneumonia or lung injury.

In the current study, majority of the participants had mild-to-moderate coronavirus infection, and favipiravir therapy might have elicited lung recovery within 14 days from initiating therapy. A study of people having asymptomatic or mild coronavirus infection investigating early and late favipiravir initiation illustrated a considerable difference in duration of hospitalization. The outcomes showed the necessity of early favipiravir initiation even for people suffering from asymptomatic or mild coronavirus infection prior to development of pneumonia or worsening of lung damage. Furthermore, favipiravir's standard dose for influenza was twice daily 1600 mg on 1^st day. This was followed by 600 mg twice daily for five days.

The standard regimen was followed by most of the eligible studies. The duration of therapy was typically 14 days. But, few studies raised the dose to twice daily 1800 mg on 1^st day that was followed by twice daily 800 mg. Several dosing regimens have been suggested on the basis of type of infection. A loading dose of 2400–3000 mg every twelve hours (2 doses) has been thought to treat coronavirus infection, followed by the maintenance dose of 1200–1800 mg every twelve hours. Favipiravir's loading dose was assessed in a study by Rattanaumpawan et al., and it was found that for early clinical improvement, a low loading dose (≤45 mg/kg/day) of favipiravir was a poor prognosis factor. For optimal management of SARS-CoV-2, doses at higher end of the dosing range should be taken into consideration. In a review article, favipiravir exhibited a tolerable safety profile with regard to total and severe side effects in comparison with other therapeutic agents utilized for short-term therapy.

This showed compatibility with the present study, and hyperuricemia was witnessed in 84.1% of individuals having asymptomatic or mild coronavirus people in one study. Though there is limited clinical experience with favipiravir to combat SARS-CoV-2 infection, severe noxious events stimulated by favipiravir were not witnessed in the current study. Furthermore, favipiravir has only received conditional marketing approval for its production and clinical usage for the influenza virus infection due to the risk of embryo toxicity and teratogenicity.

The current study illustrated that favipiravir can stimulate viral clearance within seven days and clinical improvement within 14 days, particularly in individuals having mild-to-moderate coronavirus infection. The early commencement of favipiravir therapy may contribute to favorable outcomes for SARS-CoV-2 infection. In an effort to broaden the role of favipiravir to fight coronavirus disease,  this study revealed the high potentiality of favipiravir usage for people with asymptomatic and mild-to-moderate disease. The oral dosage of favipiravir provided added benefits for asymptomatic or mildly ill patients with COVID-19. But, there is an urgent requirement for additional well-designed studies, particularly trials investigating different duration and doses of therapy in people with distinct levels of disease severity.