Shrestha 

et al. Virol J (2020) 17:141

https://doi.org/10.1186/s12985-020-01412-z

RESEARCH Open Access

Favipiravir versus other antiviral or standard

of care for COVID‑19 treatment: a rapid
systematic review and meta‑analysis
Dhan Bahadur Shrestha1  , Pravash Budhathoki2  , Sitaram Khadka3*  , Prajwol Bikram Shah4  ,
Nisheem Pokharel5 and Prama Rashmi4

Abstract 
Background:  The COVID-19 causing coronavirus is an enveloped RNA virus that utilizes an enzyme RNA dependent
RNA polymerase for its replication. Favipiravir (FVP) triphosphate, a purine nucleoside analog, inhibits that enzyme.
We have conducted this systematic review and meta-analysis on efficacy and safety of the drug FVP as a treatment for
COVID-19.
Methods:  Databases like Pubmed, Pubmed Central, Scopus, Embase, Google Scholar, preprint sites, and clinicaltirals.
gov were searched. The studies with the standard of care (SOC) and FVP as a treatment drug were considered as the
treatment group and the SOC with other antivirals and supportive care as the control group. Quantitative synthesis
was done using RevMan 5.4. Clinical improvement, negative conversion of reverse transcription-polymerase chain
reaction (RT-PCR), adverse effects, and oxygen requirements were studied.
Results:  We identified a total of 1798 studies after searching the electronic databases. Nine in the qualitative studies
and four studies in the quantitative synthesis met the criteria. There was a significant clinical improvement in the FVP
group on the 14th day compared to the control group (RR 1.29, 1.08–1.54). Clinical deterioration rates were less likely
in the FVP group though statistically not significant (OR 0.59, 95% CI 0.30–1.14) at the endpoint of study (7–15 days).
The meta-analysis showed no significant differences between the two groups on viral clearance (day 14: RR 1.06, 95%
CI 0.84–1.33), non-invasive ventilation or oxygen requirement (OR 0.76, 95% CI 0.42–1.39), and adverse effects (OR
0.69, 0.13–3.57). There are 31 randomized controlled trials (RCTs) registered in different parts of the world focusing FVP
for COVID-19 treatment.
Conclusion:  There is a significant clinical and radiological improvement following treatment with FVP in comparison
to the standard of care with no significant differences on viral clearance, oxygen support requirement and side effect
profiles.
Keywords:  Antiviral agents, COVID-19, COVID-19 drug treatment, Favipiravir, Severe acute respiratory syndrome
coronavirus-2

Background
The outbreak of a novel coronavirus named severe acute
respiratory syndrome coronavirus-2 (SARS-CoV-2)
*Correspondence: sitaramkhadka5693@gmail.com; sitaram.khadka@naihs. started in Wuhan, China, in late December 2019. The
edu.np
3
COVID-19 caused by such a virus was declared a global
Shree Birendra Hospital, Nepalese Army Institute of Health Sciences,
Kathmandu, Nepal pandemic by WHO on 11th of March 2020 [1]. The num-
Full list of author information is available at the end of the article ber of cases and mortality that the virus has claimed

© The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and
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main/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Shrestha et al. Virol J (2020) 17:141 Page 2 of 15

around the globe is astronomical. As of 26 August 2020, with more than 5 patients, randomized controlled tri-
the number of confirmed cases and deaths reported has als, controlled clinical trials, prospective and retrospec-
reached 23,752,965 and 815,038 respectively [2]. This tive studies where FVP was used in the management of
virus is getting transmitted mainly via respiratory tracts COVID-19 patients in the qualitative analysis. Only the
through droplets or respiratory secretions. The disease is studies with both the treatment and the control groups
characterized by asymptomatic to flu-like mild respira- were included in quantitative synthesis.
tory symptoms including shortness of breath (SOB) lead-
ing to pneumonia, acute respiratory distress syndrome Types of participants
(ARDS), and even multiple organ dysfunction in severe The studies had patients with COVID-19 diagnosed
cases [3]. The coronavirus is an enveloped, non-seg- as per guidelines who were enrolled either in FVP and
mented positive-sense RNA virus that utilizes an enzyme SOC compared to standard of care alone in quantitative
RNA dependent RNA polymerase (RdRp) for its replica- analysis.
tion which could be a potential target for the treatment
development [4]. Types of interventions
The road to discovering the effective prophylaxis and FVP along with the SOC was taken in the treatment arm
treatment is still an ongoing process. Numerous trials of and SOC alone in the control arm. SOC included other
medications of different categories have been conducted antivirals, respiratory support, antibiotics, immunomod-
but none have succeeded to show promising results for ulators, and herbal medicines.
effective treatment [5, 6]. Some of the repurposed drugs
like remdesivir are being utilized along with supportive Types of outcome measures
care for the management of COVID-19 in different clini- Our outcomes of interest were clinical improvements fol-
cal settings. lowing the treatment with FVP in cases of COVID-19;
Favipiravir (FVP) triphosphate, a purine nucleoside negative seroconversion of RT-PCR; adverse effects that
analog, competitively inhibits the enzyme RdRp. It has were seen during the treatment; oxygen and mechanical
shown activity against influenza viruses, RNA viruses ventilation requirements.
associated with viral hemorrhagic fever, and even against
SARS-CoV-2 in vitro [7]. The evidence regarding FVP is Outcomes
relatively low as there have only been a handful of stud- The parameters for clinical improvements were sympto-
ies regarding its efficacy and safety among COVID-19 matic and radiological improvements (in CT scan), and
patients. We conducted this systematic review and meta- clinical deterioration at 7 and 14  days after treatment
analysis to evaluate the efficacy and safety of the drug between the treatment and control group. We also com-
FVP as a treatment for COVID-19. pared overall adverse effects that had occurred during the
treatment and respiratory support requirements between
Objective the treatment and control groups. We also compared the
To determine the clinical improvement following the time to negative RT-PCR and the percentage of negative
treatment with FVP in the cases of COVID-19, dura- RT-PCR at day 7 and 14 following treatment.
tion to attaining and percentage that attained negative
conversion of RT-PCR following the treatment, adverse Search methods for identification of studies
effects that were seen during the treatment, oxygen Studies were independently screened by two review-
and mechanical ventilation requirements following the ers (DBS and PB) using COVIDENCE and data were
treatment. extracted for both quantitative and qualitative synthesis.
The conflicts were resolved by taking the opinion of the
Methods third reviewer (NP). Assessment of biases and cross-
We used PRISMA for the systematic review of available checking of the selected studies were done by another
literature [8]. reviewer (SK).

Criteria for considering studies for this review Electronic searches

Types of studies We have included the electronic search strategy in Addi-
We included studies that were done to determine the tional file 1.
safety and efficacy of FVP along with the standard of
care (SOC) for COVID-19 diagnosed cases based on Data collection and analysis
guidelines in comparison to the control group receiving Databases like Pubmed, Pubmed central, Scopus,
standard of care alone. We only included the case series Embase, Google Scholar, bioRxiv, medRxiv, and
 Shrestha et al. Virol J (2020) 17:141 Page 3 of 15

clinicaltirals.gov were searched until 20th August, 2020.

We decided to include the preprints because the studies
on FVP are actively ongoing with very few papers pub-
lished in academic journals. We extracted data for quan-
titative synthesis and analyzed it using RevMan 5.4.

Selection of studies
We included RCTs, controlled clinical trials, prospective
and retrospective observational studies for all case series
with more than 5 patients for our qualitative analysis
in which FVP was used in the treatment of COVID-19
patients with sufficient details on outcomes. We included
studies with the treatment groups in which patients
received FVP and SOC in the treatment group and SOC
alone in the control group for quantitative analysis. Stud-
ies lacking control groups were excluded in the quanti-
tative analysis. We excluded studies where the outcomes
of the patients receiving favipiravir were not properly
defined. Case reports, reviews, protocols, in-vitro stud-
ies, and letters to editors were also excluded.

Data extraction and management

We evaluated the quality of the studies and included the
outcome of interest in the quantitative synthesis.
Fig. 1  Risk of bias assessment of trials

Assessment of risk of bias in included studies

We used the Cochrane risk of bias (ROB) tool to ana-
lyze the risk of bias shown in Fig.  1 [9]. We used the Data synthesis
NHLBI (National Heart, Lung, and Blood Institute) qual- We did a statistical analysis using RevMan 5.4 soft-
ity assessment tools (Additional file  2) to assess the risk ware. We used Risk Ratio (RR)/ Odds Ratio (OR) for
of bias in observational studies and case series (Table 1) outcome estimation whenever appropriate with 95%
[10]. We used the RevMan 5.4 for the creation of risk-of- Confidence Interval (CI). We used the fixed/random-
bias plots. effects model as per the heterogeneities. We assessed
the heterogeneity using the ­I2 test. We analyzed the
mean differences among the two groups for the dura-
Assessment of heterogeneity
tion of viral clearance using the median, sample size,
We assessed the heterogeneity using the I-squared (­I2)
and interquartile range whenever the means and
test. We used the Cochrane Handbook for Systematic
standard deviations were not provided in the study
Reviews of Interventions for interpretation of ­I2 test done
[17].
as follows based on “0–40%: might not be important;
30% to 60% may represent moderate heterogeneity; 50%
to 90%: may represent substantial heterogeneity; 75% to Subgroup analysis and investigation of heterogeneity
100%: considerable heterogeneity [16]. The importance of In the case of heterogeneity, we tried the inverse vari-
the observed value of ­I2 depends on (1) magnitude and ance, random-effect model. We then ran an analy-
direction of effects and (2) strength of evidence for het- sis excluding non-randomized study to evaluate their
erogeneity (e.g. P value from the chi-squared test, or a impact on the overall result wherever appropriate. We
confidence interval for I­ 2).” presented Forest plots to visualize the degree of varia-
tion between studies.

Assessment of reporting biases

We assessed the reporting biases through predetermined
outcome reporting documentation.
Shrestha et al. Virol J (2020) 17:141 Page 4 of 15

Table 1  NHLBI assessment of observational studies and case series

Study Study type Score Percentage Quality

Çalik BaŞaran et al. [11] Prospective observational study 10/14 71.4 Good
Doi et al. [12] Case series 6/9 66.66 Good
Irie et al. [13] Case series 6/9 66.66 Good
Rattanaumpawan et al. [14] Retrospective observational study 8/14 57.1 Fair
Yamamura et al. [15] Prospective single center study 10/14 71.4 Good
Good if they fulfilled 60–100% of the tool items, fair if 50–59% or Poor if 0–49%

Sensitivity analysis Results

For sensitivity analysis, we examined the effect of study Qualitative synthesis
based on their type (RCT and non-RCT) by excluding We identified a total of 1798 studies after searching the
non-RCT studies when appropriate and re-running the electronic databases. After the removal of 462 duplicates,
analysis to find any differences. the title and abstracts of 1336 studies were screened. We
Idenficaon

Records identified through Additional records identified through preprint

database searching (Total: 171 medRxiv = 87 and bioRxiv = 84 )
(n =1627 )

Records after duplicates removed

(n = 1336)
Screening

Records screened Records excluded

(n =1336) (n = 1284)

Full-text articles assessed

for eligibility 43 full-text articles excluded, with
(n = 52) reasons
Eligibility

• 16 Case reports
• 14 Reviews
Studies included in • 4 Poorly defined outcomes after
qualitative synthesis treatment
(n = 9) • 4 Letter to Editors
• 3 Protocol
• 2 Perspective
Included

Studies included in
quantitative synthesis
(n = 4)

Fig. 2  PRISMA flow chart

Table 2  Qualitative synthesis of selected studies
Study, Year Population Intervention Comparator Outcome

Cai et al. [18] 2020, Open label con- Total: 80 Treatment group Control group Median time of viral clearance
Shrestha et al. Virol J

trolled study, China T: 35 C: 45 FPV was 1600 mg twice daily on Day LPV/RTV was LPV 400 mg/RTV T: 4 d (IQR: 2.5–9); C: 11 d (IQR:8–13)
Sex: F = 45, M = men (35 of 80) 1 and 600 mg twice daily on days 100 mg twice daily D8: RT-PCR negative for viral clearance
History: Median age (IQR) 47 2–14 Medications were given till viral clear- T:26/35; C:17/45
(35.75–61) Medications were given till viral clear- ance was confirmed or 14 days had D16: RT-PCR negative for viral clearance
Inclusion criteria ance was confirmed or 14 days had passed T:33/35; C:33/45
Aged 16–75 years old; nasopharyn- passed Patients received IFN-a1b 60 mg CT improvement
geal swabs samples tested positive Patients received IFN-a1b 60 mg twice daily by aerosol inhalation D4: T:8/35; C:8/45
(2020) 17:141

for the novel coronavirus RNA twice daily by aerosol inhalation D9: T:18/35; C:16/45
Duration from disease onset to enrol- D14 T:32/35; C:28/45
ment was less than 7 d CT worse
Willing to take contraception during D14: T:1/35; C:9/45
the study and within 7 d after treat- Total number of adverse reactions
ment T:4/35; C:25/45
No difficulty in swallowing the pills
Exclusion
Severe clinical condition (meeting
one of the following criteria)
Resting respiratory rate greater than
30 per minute
Oxygen saturation below 93%, oxy-
genation index < 300 mm Hg
Respiratory failure, shock, and/or
combined failure of other organs
that required ICU monitoring and
treatment)
Chronic liver and kidney disease and
reaching end stages
Previous history of allergic reactions to
FPV or LPV/RTV
Pregnant or lactating women
Women of childbearing age with a
positive pregnancy test, breastfeed-
ing, miscarriage, or within 2 weeks
after delivery;
Participated in another clinical trial
against SARS-CoV-2 treatment cur-
rently or in the past 28 d
Page 5 of 15
Table 2  (continued)
Study, Year Population Intervention Comparator Outcome

Calik Basaran et al. [11] 2020, Prospec- Total: 174 32 patients received favipiravir, two patients received favipiravir monotherapy Median time to defervescence days
Shrestha et al. Virol J

tive observational study, Turkey M: 91, F: 83 while 30 received it to the initial regimen or with other antivirals HCQ: 1 (0–4); HCQ + AZT: 1 (0–11); FVP:
Mild: 35 23 patients received HCQ alone while 113 received HCQ + AZT in addition to 3 (0–8)
Moderate: 107 other supportive treatment Median time to clinical improvement
Severe: 32 on therapy
Inclusion criteria HCQ: 1 (1–6); HCQ + AZT: 1.5 (1–11);
Adult patients (More than or equal to FVP: 6 (1–10)
18 years) hospitalized in COVID ward Median duration LOS
(2020) 17:141

from March 20 to April 30, 2020 HCQ: 2 (1–21); HCQ + AZT: 4 (1–15);

Exclusion criteria FVP: 7.5 (2–24)
Critically ill patients with sepsis or Nausea/vomiting
ARDS requiring ICU at the time of HCQ: 1; HCQ + AZT: 5; FVP: 5
admission Elevation of transaminase
HCQ: 1; HCQ + AZT: 3; FVP: 10
Chen et al. [19] 2020, RCT, China Total: 236 Treatment group Control group D7 Clinical Recovery
T: 116 C: 120 Patients received FVP (1600 mg, twice Patients received Arbidol (200 mg, T: 71/116; C: 62/120
Inclusion the first day followed by 600 mg, three times daily) plus standard of Clinical deterioration (new dyspnea)
Age 18 years or older twice daily, for the following days care for 7 days T: 13/116; C: 15/120
Voluntarily provided informed plus standard care for 7 days Standard of care included traditional D7 NIMV OR Oxygen support
consent Chinese herbal medicine, antibiot- T: 21/116; C:27/120
Initial symptoms were within 12 days ics, additional antiviral treatment, Total number of adverse reactions
Diagnosed as COVID-19 pneumonia immunomodulatory drugs, steroids, T:37/116; C:28/120
Exclusion psychotic drugs, nutrition support, Respiratory failure
Allergic to FVP or Arbidol cardiovascular drugs, supportive T: 1/116; C: 4/120
Increased ALT/AST (> 6 × upper limit oxygen, noninvasive positive pres- No mortalities
of normal range) or with chronic sure ventilation (NPPV) or invasive
liver disease (cirrhosis at grade ventilation
Child–Pugh C)
Severe/critical patients whose
expected survival time were < 48 h
Pregnant female
HIV infected
Considered unsuitable by researchers
for patient’s interest
Doi et al. [12] 2020, Case series, Japan Total: 11 Treatment with nafamostat mesylate [0.2 mg per kg per hour by continuous Mortality: 1; 7 Patients weaned from
M: 10 F: 1 intravenous infusion, median treatment 14 days (IQR, 10 to 14 days)] and MV
Comorbidities FVP [3600 mg on day 1 and at 1600 mg per day on day 2 and subsequently Discharge from ICU: 9
HTN 4, DM 3, COPD 1 and Cancer 1 median treatment 14 days (IQR, 12 to 14 days) Discharge from hospital: 7
Age: 60–69 Adverse effect: 1 (Hyperkalemia)
All patients admitted to ICU
8 patients required MV and 3 required
VV-ECMO
Page 6 of 15
Table 2  (continued)
Study, Year Population Intervention Comparator Outcome

Lou et al. [20] 2020, Open-label RCT, Total: 29 Treatment group Control group Viral negative in Day 7
Shrestha et al. Virol J

China T = 9 and C = 10 Baloxavir marboxil or FVP to the cur- Patients received existing antiviral T(FVP group): 4/9; C: 5/10
T = FPV and C = Control rent standard antiviral treatment including lopinavir/ Viral negative in Day 14
Sex: F = 5, M = 14 treatment was randomly allocated ritonavir (400 mg/100 mg, twice a T(FVP group): 7/9; C: 10/10
History: (1:1:1) day orally) or 8 darunavir/cobicistat Clinical improvement
Median age (SD) T = 58.0 (8.1); FVP group FVP was used in combina- (800 mg/150 mg, four times a day Day 14
C = 46.6 (14.1) tion with the existing antiviral treat- orally) and arbidol (200 mg, thrice T(FVP group): 5/9; C: 5/10
Inclusion: ment. The first dose was 1600 mg or a day orally) along with interferon- Day 7
(2020) 17:141

All RT-PCR diagnosed 2200 mg orally, followed by 600 mg alpha inhalation T(FVP group): 2/9; C: 1/10
Exclusion: each time, three times a day, and D14 Discharge
Patients who dint complete the dos- the duration of administration was T(FVP group): 4/9; C: 4/10
age of the medication not more than 14 days Time to clinical improvement—median
Previous history of malignancy, COPD, Baloxavir group days (IQR)
renal insufficiency and hepatic The dose was 80 mg OD on Day 1 T(FVP group): 14 (6–38); C: 15 (6–24)
insufficiency and 4 and if patients are positive it Time to viral negative-median days
can be given on Day 7 but no more (IQR)
than 3 doses should be given T(FVP group): 9 (2–34; C: 9 (1–13)
Both groups received existing antiviral D14 NMV OR Oxygen support
treatment including lopinavir/ T: 3/9; C: 4/10
ritonavir (400 mg/100 mg, twice a
day orally) or 8 darunavir/cobicistat
(800 mg/150 mg, four times a day
orally) and arbidol (200 mg, thrice
a day orally) along with interferon-
alpha inhalation
Page 7 of 15
Table 2  (continued)
Study, Year Population Intervention Comparator Outcome

Ivaschenko et al. [21] 2020, Multi Total: 60 Treatment group Control group Viral clearance
Shrestha et al. Virol J

center, open label randomized Randomization in 1:1:1 in three One group received either AVIFAVIR Control group received standard of Day 5
Phase II/ III controlled trial, Russia groups comparable in demographic 1600 mg BID on Day 1 followed care according to national guideline TG(FVP group): 25/40; CG: 6/20
and baseline characteristics by 600 mg BID on Days 2–14 15 patients reveived HCQ or CQ Day 10
Intention to treat analysis was done (1600/600 mg) 1 patient received Lopinavir and TG: 37/40; CG: 16/20
Inclusion criteria Other group received AVIFAVIR ritonavir Median time to body temperature
Hospitalized men and non-pregnant 1800 mg BID on Day 1 followed 4 patients did not receive etiotropic normalization
women of 18 years or older who by 800 mg BID on Days 2–14 treatment TG: 2 days (IQR 1–3); CG: 4 days (IQR
(2020) 17:141

signed the informed consent form, (1800/800 mg) 1–8)

had moderate PCR-confirmed Patients receiving AVIFAVIR did not CT improvement at day 15
COVID-19 and were able to admin- receive other antivirals or antima- TG: 36/40; CG: 16/20
istrate the drug orally and willing to larial drugs Adverse effects
use adequate contraception during TG: 15/40; CG: 5/20
the study and 3 months after its Common side effects were diarrhea,
completion nausea, vomiting, chest pain and
increase in liver transaminase levels
Early drug discontinuation in 2 patients
out of 40 in treatment group
Mortality: 2 in TG
Discharge
AVIFAVIR 1600/600: 13/20
AVIFAVIR 1800/800: 17/20
CG: 17/20
Irie et al. [13] 2020, Case Series, Japan Total: 7 Patients were given 1600 mg FPV on day 1 and 600 mg from day 2–5 Clinical improvement: 3/7
M: 5 F: 2 At Day 7: 1/7
Comorbidities No requirement for mechanical ventila-
HTN: 3 tion: 1/7
DM: 2 At Day 14: 3/7
Hyperuricemia: 2 Weaned from mechanical ventilation:
Others included BPH, gout, and 3/7
fibroid No oxygenation support: 2/7
Inclusion: Adverse effect: 1/7 (Increase in
Critically ill patients admitted to ICU transaminase)
under mechanical ventilation
Page 8 of 15
 Shrestha et al. Virol J

Table 2  (continued)
Study, Year Population Intervention Comparator Outcome
(2020) 17:141

Rattanaumpawan et al. [14] 2020, Total: 247 Treatment group Outcomes of treatment groups have
Observational study, Thailand T: 63 C: 184 Patients received the median loading dose of FVP of 47.4 (29.1–71.1) MKD been only reported. N = 63
Inclusion: along with the standard of care, and one-third of 176 enrolled patients Clinical improvement
Patients aged at least 18 years who (33.3%) received a loading dose of ≤ 45 MKD D7: 42/63
had RT-PCR-confirmed SARS-CoV-2 The median maintenance 177 dose of FVP was 17.9 (10.9–26.7) MKD, and No requirement of oxygen supplemen-
based on a respiratory specimen 76.2% of the subjects received a 178 maintenance dose of ≤ 15 MKD tation: 25/63
(nasopharyngeal, oropharyngeal, The median duration of FVP therapy was 12 (2–17) days D14: 54/63
sputum, endotracheal aspirate, or Standard of care includes protease inhibitors, hydroxychloroquine, azithromy- No requirement of oxygen supplemen-
bronchoalveolar lavage sample) and cin, steroid, respiratory support, and tocilizumab tation: 27/63
received at least one dose of FVP Control group D28: 57/63
Exclusion: Patients received standard of care including protease inhibitors, hydroxychlo- No requirement of oxygen supplemen-
Patients who expired or were dis- roquine, azithromycin, steroid, tocilizumab, and respiratory support tation: 27/63
charged within 24 h of hospital stay Mortality
D14: 1
D28: 3
Adverse drug reaction
39/63
Most common diarrhea (34) and
hepatitis (4)
Yammamura et al. [15] 2020, Prospec- Total: 13 FPV (3600 mg on day 1, 1600 mg from day 2 to day 14), methylprednisolone Survival: 12
tive single center study, Japan M: 9 F: 4 (1000 mg for 3 days), and low molecular weight (2000 IU every 12 h) or Mortality: 1
Mean age: 63 unfractionated heparin (10,000–12,000 IU/day). Methylprednisolone admin- Improvement in IL-6 5 days after FPV
All patients were mechanically venti- istration was begun on the 5th day from initial FPV administration. Heparin therapy, PaO2/Fi02 in a week after
lated at the time of admission and dexmedetomidine were administered after intubation and mechanical FVP therapy
Comorbidities ventilation
HTN 8, DM 7, Bronchial asthma 1,
sleep apnea syndrome 3
ALT alanine transaminase, AST aspartate transaminase, BID twice a day, C control, COPD chronic obstructive pulmonary disease, CG control group, D day, DM diabetes mellitus, FPV favipiravir, F female, Fi02 fraction of
inspired oxygen, HIV human immunodeficiency virus, HTN hypertension, IU international unit, ICU intensive care unit, IQR interquartile range, M male, MKD mean dose per kg, MV mechanical ventilation, N total number
of patients, LPV Lopinavir, Pa02 partial pressure of oxygen, RNA ribonucleic acid, RT-PCR reverse transcription-polymerase chain reaction, RTV ritonavir, SARS severe acute respiratory syndrome, T treatment, TG treatment
group, VV-ECMO veno venous extra corporeal membrane oxygenation
Page 9 of 15
Shrestha et al. Virol J (2020) 17:141 Page 10 of 15

excluded 1284 studies after title and abstracts screening improvement on favipiravir arm but statistically not sig-
and 52 articles were assessed for full-text eligibility. A nificant (Additional file 3/Fig. 3).
total of 43 articles were excluded for definite reasons. We
included 9 studies in our qualitative study (Fig.  2). The FVP versus other antivirals: clinical/CT deterioration
summary of studies is discussed in Table 2. The meta-analysis on clinical deterioration rate at the end
of study duration showed clinical deteriorations is less
likely in the FVP treatment group than other antiviral
Quantitative analysis agents though statistically not significant (OR 0.59, 95%
Four studies meet the criteria and are included in the CI 0.30 to 1.14; participants = 376; studies =  3; ­I2 = 39%)
quantitative synthesis. In the present meta-analysis, (Fig. 5).
we have compared findings among randomized/non-
randomized controlled studies to extract outcome on
FVP group versus other antivirals or SOC group: Oxygen
viral clearances, improvements or deteriorations among
support or non‑invasive ventilation
FVP group in comparison to COVID-19 cases getting
Meta-analysis on the oxygen support requirements and
other antivirals or SOC, duration to viral clearance, the
non-invasive mechanical ventilation among included
requirement of non-invasive mechanical ventilation/
randomized studies showed decreased odds of oxygen
oxygen support and adverse effects.
support among FVP group but it is not statistically sig-
nificant (OR 0.76, 95% CI 0.42 to 1.39; participants = 255;
FVP versus other antivirals or SOC only; effectiveness studies =  2; ­I2 = 0%) (Fig. 6).
Among the treatment groups FVP in addition to SOC
versus  other antivirals or SOC we have compared the Adverse effects
duration of viral clearance (negative RT-PCR) and radio- Meta-analysis comparing adverse effects between the
logical/ clinical improvement. treatment and the control groups showed lesser odds
for adverse effect in the treatment arm but of no sta-
Viral clearance  The meta-analysis of risk ratios (RR) tistical significance (OR 0.69, 95% CI 0.13 to 3.57; par-
for FVP in addition to SOC effectiveness compared with ticipants = 376; studies =  3; ­I2 = 88%) (Fig.  7). Overall
other antivirals or SOC using random effect model among adverse effects among randomized controlled trials
randomized and non-randomized studies showed that after excluding non-randomized study by Cai et  al. [18]
there were no significant differences between two groups showed slight increase in adverse effects among favipira-
(Day 7: RR 1.13, 95% CI 0.55 to 2.33; Day 14: RR 1.06, 95% vir arm but statistically not significant. This may be due
CI 0.84 to 1.33). Also, there is no significant risk differ- to heterogeneity in treatments patients might be taking
ence (RD) for viral clearance between two groups FVP in other than favipiravir or other standard treatment (Addi-
addition to SOC versus other antivirals or SOC (Day 7: tional file 3/Fig. 4).
RD 0.06, 95% CI − 0.34 to 0.45; Day 14: RD 0.03, 95% CI
− 0.17 to 0.24) (Fig. 3). For heterogeneity, both subgroup Duration to convert negative RT‑PCR
assessments inverse variance method and excluding non- Our meta-analysis on negative conversion of RT-PCR
randomized study by Cai et al. [18] showed no significant demonstrated approximately 5 days (MD − 5.16, 95% CI
changes (Additional file 3/Figs. 1 and 2). − 6.95 to − 3.37; participants = 99; studies =  2; ­I2 = 45%)
earlier on treatment with FVP group (Fig. 8). Data being
Clinical/CT improvement  Among three studies, two subject to moderate heterogeneity sensitivity assessment
reported clinical and two reported CT improvement, using the random-effect model showed no significance
overall risk ratios (RR) for FVP in addition to SOC effec- (MD − 2.16, 95% CI − 13.28 to 8.97). This finding, thus
tiveness compared with other antivirals or SOC alone needs to be confirmed by further randomized studies
using fixed-effect model showed that there was a sig- (Additional file 3/Fig. 5).
nificant improvement on FVP groups on both ­7th and
­14th day of treatment (Day 7: RR 1.25, 95% CI 1.01 to 1.53; Clinical trials
Day 14: RR 1.29, 95% CI 1.08 to 1.54). Furthermore, there Focusing on the safety and efficacy of FVP for COVID-
are similar findings on risk difference (RD) between two 19 treatment along with different parameters, there
groups for improvement (Day 7: RD 0.11, 95% CI 0.01 to are 31 RCTs registered in different parts of the world
0.22; Day 14: RD 0.19, 95% CI 0.07 to 0.32) (Fig. 4). as of 25 August 2020 (Additional file  4) [22]. Five of
Clinical improvement on the 7th  and ­14th day among such trials have recently been completed from Egypt,
randomized controlled trials after excluding non- Iran, and Turkey. Among the registered RCTs, 14 trials
randomized study by Cai et  al. [18] showed slight are recruiting participants, 6 trials have not yet started
 Shrestha et al. Virol J (2020) 17:141 Page 11 of 15

Fig. 3  Forest plot for risk ratios and risk differences regarding FVP in addition to SOC effectiveness for viral clearance compared with other antivirals
or SOC

recruiting, and 4 trials are active but not recruiting any Discussion
participants. One of the trials has been withdrawn thus Our meta-analysis was focused on the assessment
not been included in this calculation. According to the of the clinical outcome and adverse effects following
location provided in 31 trials, a maximum number of therapy with FVP because it has emerged as one of the
trials are regulated by Turkey. treatments repurposed for COVID-19. Although some
Shrestha et al. Virol J (2020) 17:141 Page 12 of 15

Fig. 4  Forest plot for risk ratios and risk differences regarding FVP in addition to SOC effectiveness for clinical improvement compared with other
antivirals or SOC

promise has been shown by remdesivir and plasma ther- 1.01 to 1.53; Day 14: RR 1.29, 95% CI 1.08 to 1.54). The
apy, the lack of highly efficacious and safe treatment for clinical deterioration is less likely in the FVP treatment
COVID-19 remains one of the biggest conundrums of groups than other antiviral agents (OR 0.59, 95% CI 0.30
the twenty-first century. Our study found that patients to 1.14) following treatments though of no statistical sig-
had a significant improvement in FVP groups on both nificance. There were no significant differences between
the ­7th and 1
­ 4th day of treatment (Day 7: RR 1.25, 95% CI the two groups in terms of viral clearance (Day 7: RR
 Shrestha et al. Virol J (2020) 17:141 Page 13 of 15

Fig. 5  Forest plot for odds ratios regarding clinical deterioration among FVP group versus other antivirals

Fig. 6  Forest plot for odds ratios requiring oxygen support or non-invasive ventilation among FVP group versus other antivirals or SOC group

Fig. 7  Forest plot for odds ratios for adverse effects among FVP group versus other antivirals

Fig. 8  Forest plot of FVP in addition to standard of care or other anti-virals on duration for negative conversion of RT-PCR
Shrestha et al. Virol J (2020) 17:141 Page 14 of 15

1.13, 95% CI 0.55 to 2.33; Day 14: RR 1.06, 95% CI 0.84 results of ongoing clinical trials should be obtained to
to 1.33). There were lesser odds for adverse effect in the give any definite judgment on whether the treatment
treatment group but of no statistical significance (OR with FVP is the best option among antiviral treatments
0.69, 95% CI 0.13 to 3.57). In general, there were toler- for COVID-19 or not. Till then, our meta-analysis sup-
able minor side effects like nausea, vomiting, diarrhea ports judicial use of FVP in clinical settings.
and an increase in transaminases and no serious life-
threatening complications following the FVP treatment. Supplementary information
The possible side effects can however not be credited to Supplementary information accompanies this paper at https​://doi.
favipiravir alone because the patients in treatment groups org/10.1186/s1298​5-020-01412​-z.
were receiving other drugs in 3 trials except the one done
by Ivashchenko et al. [21]. As this is the first meta-anal- Additional File 1:  Search strategy
ysis comparing the clinical outcome and adverse effects Additional File 2:  NHLBI Bias of observational and case series
among patients receiving FVP compared to standard Additional File 3:  Synthesis and sensitivity assessment
of care, we could not compare our findings with other Additional File 4:  Clinical trials
meta-analyses. Additional File 5:  Prisma checklist
Although good promise has been shown by FVP, addi-
tional randomized double-blind clinical trials are needed Abbreviations
to give a definite opinion about the rationale of the drug. ALT: Alanine transaminase; ARDS: Acute respiratory distress syndrome; AST:
We could only include four studies for our quantitative Aspartate transaminase; C: Control; CI: Confidence interval; COPD: Chronic
obstructive pulmonary disease; COVID-19: Coronavirus disease-19; CT: Com-
analysis and one of the studies among them was non- puted Tomography; D: Day; DM: Diabetes mellitus; F: Female; FVP: Favipiravir;
randomized. The sample size was small in our studies HIV: Human immunodeficiency virus; HTN: Hypertension; I2: I-squared; ICU:
which could decrease the power of our study. The dura- Intensive care unit; IQR: Interquartile range; LPV: Lopinavir; M: Male; MKD:
Mean dose per kg; N: Total number of patients; NHLBI: National Heart, Lung,
tion of treatment and dosages were different among vari- and Blood Institute; OR: Odds ratio; PRISMA: Preferred reporting items for sys-
ous studies in qualitative analysis. Two of the RCTs that tematic reviews and meta-analyses; RCTs: Randomized controlled trials; RdRp:
were included for our analysis had a varied duration of RNA dependent RNA polymerase; ROB: Risk of bias; RR: Relative risk; RT-PCR:
Reverse transcription-polymerase chain reaction; RTV: Ritonavir; SARS-CoV-2:
treatment as well. Lack of randomization may have led to Severe acute respiratory syndrome coronavirus-2; SOB: Shortness of breath;
selection bias in the non-randomized studies. Blinding SOC: Standard of care; T: Treatment.
was not applied to source studies leading to biases. Selec-
Acknowledgements
tive reporting may have been a problem in Chen’s study Not applicable
[19] because of the limited observation time frame. It is
important to determine the appropriate dose and dura- Authors’ contributions
DBS, PB, and SK contributed in concept and design, analysis, and interpreta-
tion of treatment with FVP because low dose therapy is tion of data. PBS, NP, and PR contributed in literature search, data extraction,
found to be a bad prognostic factor for clinical improve- review and assisted in analysis. All authors were involved in drafting and revis-
ment and widespread variations in treatment duration ing the manuscript and approved the final version.
among studies and lack of effective plasma concentra- Funding
tions of drug in critically ill patients [13, 14]. Due to the This article did not receive any specific grant from funding agencies in the
early evidence of potential benefits shown by this drug public, commercial, or any other sectors.
in clinical improvement as well as imaging improve- Availability of data and materials
ment, it is necessary to conduct large-scale prospective, The datasets analyzed during the current study are available from the cor-
double-blind randomized controlled trials or wait for the responding author on reasonable request.
result of ongoing studies to come. This will embolden the Ethics approval and consent to participate
evidences led by our study and eliminate biases so that Not applicable.
definitive advice for treatment can be given in the coming
Consent for publication
days. Not applicable.

Competing interests
Conclusion The authors declare that they have no competing interests.
Our study concludes that patients had clinical and
radiological improvements following the treatment Author details
1
 Department of Emergency Medicine, Mangalbare Hospital, Morang, Nepal.
with FVP in comparison to that of the standard of care 2
 Dr Iwamura Memorial Hospital, Bhaktapur, Nepal. 3 Shree Birendra Hospital,
though no significant differences on viral clearance, Nepalese Army Institute of Health Sciences, Kathmandu, Nepal. 4 Nepal Medi-
oxygen support requirement and side effect profile. The cal College and Teaching Hospital, Kathmandu, Nepal. 5 KIST Medical College
and Teaching Hospital, Lalitpur, Kathmandu, Nepal.
 Shrestha et al. Virol J (2020) 17:141 Page 15 of 15

Received: 7 July 2020 Accepted: 16 September 2020 patients critically ill with Covid-19: a case series. Crit Care. 2020;24(1):392.
https​://doi.org/10.1186/s1305​4-020-03078​-z.
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