Coronavirus continues to wreak havoc worldwide and no drug has been found or manufactured that can cope with it. Some people, such as US President Donald Trump, have been promoting the "possible" virtue of hydroxychloroquine, but another drug is attracting scientific attention – Favipiravir.

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What is Favipiravir? How Does It
Work for COVID-19?
Coronavirus continues to wreak havoc worldwide and no drug has been found
or manufactured that can cope with it. Some people, such as US President
Donald Trump, have been promoting the "possible" virtue of
hydroxychloroquine, but another drug is attracting scientific attention –
Favipiravir.
What is Favipiravir?
Favipiravir (CAS No.259793-96-9,
6-fluoro-3-hydroxy-2-pyrazinecarboxamide, T-705) is a new type of RNA
polymerase inhibitor, acting on viral genetic copying to prevent its
reproduction. As another weapon for anti-viral treatment of influenza A and B, it
was approved for marketing in Japan in March 2014. Studies have shown that,
in addition to influenza viruses, Favipiravir may also exhibit good antiviral
effects on a variety of RNA viruses, such as Ebola virus, sand virus, Bunia virus,
and rabies virus, etc. The COVID-19 is a coronavirus, a positive-stranded
single-stranded RNA virus with a coat, and from a mechanical perspective,
Favipiravir also has a potential antiviral effect on it.
Mechanisms of Action of Favipiravir
The mechanism by which favipiravir exerts a broad-spectrum antiviral activity
has not been fully elucidated, but the existing evidence supports that it can
selectively and potently inhibit RNA-dependent RNA polymerase (RdRp) of RNA
viruses. Favipiravir undergoes an intracellular phosphoribosylation to be an
active form, favipiravir-RTP (favipiravir ribofuranosyl-5′-triphosphate), which is
recognized as a substrate by RdRp, and inhibits the RNA polymerase activity.
The structure of favipiravir RTP is similar to that of purine, which can compete
with purine for viral RNA polymerase, causing it to be mistakenly recognized by
viral RNA polymerase, and inserted into the viral RNA chain or combined with
the viral RNA polymerase domain to induce fatal mutations, thus preventing
incorporation of nucleotides for viral RNA replication and transcription.

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Image source: https://www.ncbi.nlm.nih.gov/
Clinical Evidence
There are two published trials for favipiravir for the treatment of COVID-19:
· An open-label, non-randomised trial in Shenzhen (N=80)5 examined the
efficacy of favipiravir (n=35) versus lopinavir/ritonavir (n=45) for treating
COVID-19. Significantly shorter viral clearance time (primary endpoint) was
found for favipiravir versus lopinavir/ritonavir (median 4 days versus 11 days;
p<0.001). Patients receiving favipiravir also showed significant improvement in
chest imaging compared with those receiving lopinavir/ritonavir, with an
improvement rate of 91.43% versus 62.22% (p = 0.004). Fewer adverse
reactions were reported for favipiravir (11.43%) compared to
lopinavir/ritonavir (55.56%) (p><0.01).
· An open-label, randomised trial in Wuhan (N=240)6 examined the efficacy of
favipiravir (n=120) versus arbidol (n=120) for treating COVID-19. There was
no difference in the 7-day clinical recovery rate (primary endpoint) for
favipiravir versus arbidol in the overall population (61.21% versus 51.67%;
p=0.14). However, for a sub-population of non-critical patients without
hypertension or diabetes, the 7-day clinical recovery rate was significantly
better with favipiravir (71.43%; 70/98) versus arbidol (55.86%; 62/111) (p =
0.02).

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According to other news reports:
· A Japanese health ministry source suggested that favipiravir was not as
effective in patients with more severe symptoms, from their clinical studies of
70 to 80 participants.
· One medical center in South Korea started administration of favipiravir on 22
February and, while the drug has not been approved for treating COVID-19, the
Ministry of Food and Drug Safety (MFDS) in South Korea is considering a
fast-track approval to import favipiravir.
Recommendations from Professional Bodies
The US Food and Drug Administration (FDA) has not specifically approved any
drugs used to treat COVID-19. The World Health Organization (WHO), the
UK National Health Service (NHS) and the Australian health authorities have not
provided any advice on the use of favipiravir. It is also not included in the 7 th
edition of Chinese Guidelines for the Prevention, Diagnosis, and Treatment of
Novel Coronavirus-induced Pneumonia for tentative treatment of COVID-19.
Adverse Reactions
According to reports, no significant adverse reactions have been seen since the
listing of favipiravir. In the clinical study of COVID-19, no obvious adverse
reactions were found.
In the phase III clinical trial of favipiravir in Japan and internationally, a total of
501 patients participated in the evaluation, including 100 cases of adverse
reactions (19.96%). The main adverse reactions included 24 cases of increased
uric acid (4.79%) and 24 cases. Diarrhea (4.79%), 9 cases of neutropenia
(1.80%), 9 cases of aspartate aminotransferase increase (1.80%), 8 cases of
alanine aminotransferase increase (1.60%).
When applying piriravir clinically, attention should be paid to the interaction
with other drugs:
1. When combined with oseltamivir, the plasma concentrations of the two drugs
were not affected.
2. When combined with famciclovir and sulindac, favipiravir may reduce the
efficacy of these drugs.

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3. When combined with theophylline, the blood concentration of favipiravir
increases, and adverse drug reactions may occur.
4. When used in combination with repaglinide, the blood concentration of
repaglinide increases due to the inhibition of CYP2C8, which may cause side
effects.
5. When combined with pyrazinamide, it can promote the reabsorption of uric
acid by the renal tubules and increase uric acid.
6. When combined with acetaminophen, the risk of liver injury is low, but liver
function needs to be monitored.
7. When used in combination with a substrate for transport protein, favipiravir
has a weak inhibitory effect on P-glycoprotein (P-gp).
Conclusion
Given that favipiravir's public evidence is limited to two open-label trials, further
research is needed to determine its efficacy and safety in patients with
COVID-19. Three clinical trials are planned and the results may be reported in
the coming months. These findings will determine whether favipiravir should be
used more widely in this situation. At present, there is no international
professional body recommending the treatment of COVID-19 with favipiravir.
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