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Table 2 Qualitative synthesis of selected studies

From: Favipiravir versus other antiviral or standard of care for COVID-19 treatment: a rapid systematic review and meta-analysis

Study, Year Population Intervention Comparator Outcome
Cai et al. [18] 2020, Open label controlled study, China Total: 80
T: 35 C: 45
Sex: F = 45, M = men (35 of 80)
History: Median age (IQR) 47 (35.75–61)
Inclusion criteria
Aged 16–75 years old; nasopharyngeal swabs samples tested positive for the novel coronavirus RNA
Duration from disease onset to enrolment was less than 7 d
Willing to take contraception during the study and within 7 d after treatment
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%, oxygenation 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, breastfeeding, miscarriage, or within 2 weeks after delivery;
Participated in another clinical trial against SARS-CoV-2 treatment currently or in the past 28 d
Treatment group
FPV was 1600 mg twice daily on Day 1 and 600 mg twice daily on days 2–14
Medications were given till viral clearance was confirmed or 14 days had passed
Patients received IFN-a1b 60 mg twice daily by aerosol inhalation
Control group
LPV/RTV was LPV 400 mg/RTV 100 mg twice daily
Medications were given till viral clearance was confirmed or 14 days had passed
Patients received IFN-a1b 60 mg twice daily by aerosol inhalation
Median time of viral clearance
T: 4 d (IQR: 2.5–9); C: 11 d (IQR:8–13)
D8: RT-PCR negative for viral clearance
T:26/35; C:17/45
D16: RT-PCR negative for viral clearance
T:33/35; C:33/45
CT improvement
D4: T:8/35; C:8/45
D9: T:18/35; C:16/45
D14 T:32/35; C:28/45
CT worse
D14: T:1/35; C:9/45
Total number of adverse reactions
T:4/35; C:25/45
Calik Basaran et al. [11] 2020, Prospective observational study, Turkey Total: 174
M: 91, F: 83
Mild: 35
Moderate: 107
Severe: 32
Inclusion criteria
Adult patients (More than or equal to 18 years) hospitalized in COVID ward from March 20 to April 30, 2020
Exclusion criteria
Critically ill patients with sepsis or ARDS requiring ICU at the time of admission
32 patients received favipiravir, two patients received favipiravir monotherapy while 30 received it to the initial regimen or with other antivirals
23 patients received HCQ alone while 113 received HCQ + AZT in addition to other supportive treatment
Median time to defervescence days
HCQ: 1 (0–4); HCQ + AZT: 1 (0–11); FVP: 3 (0–8)
Median time to clinical improvement on therapy
HCQ: 1 (1–6); HCQ + AZT: 1.5 (1–11);
FVP: 6 (1–10)
Median duration LOS
HCQ: 2 (1–21); HCQ + AZT: 4 (1–15); FVP: 7.5 (2–24)
Nausea/vomiting
HCQ: 1; HCQ + AZT: 5; FVP: 5
Elevation of transaminase
HCQ: 1; HCQ + AZT: 3; FVP: 10
Chen et al. [19] 2020, RCT, China Total: 236
T: 116 C: 120
Inclusion
Age 18 years or older
Voluntarily provided informed consent
Initial symptoms were within 12 days
Diagnosed as COVID-19 pneumonia
Exclusion
Allergic to FVP or Arbidol
Increased ALT/AST (> 6 × upper limit of normal range) or with chronic liver disease (cirrhosis at grade 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
Treatment group
Patients received FVP (1600 mg, twice the first day followed by 600 mg, twice daily, for the following days plus standard care for 7 days
Control group
Patients received Arbidol (200 mg, three times daily) plus standard of care for 7 days
Standard of care included traditional Chinese herbal medicine, antibiotics, additional antiviral treatment, immunomodulatory drugs, steroids, psychotic drugs, nutrition support, cardiovascular drugs, supportive oxygen, noninvasive positive pressure ventilation (NPPV) or invasive ventilation
D7 Clinical Recovery
T: 71/116; C: 62/120
Clinical deterioration (new dyspnea)
T: 13/116; C: 15/120
D7 NIMV OR Oxygen support
T: 21/116; C:27/120
Total number of adverse reactions
T:37/116; C:28/120
Respiratory failure
T: 1/116; C: 4/120
No mortalities
Doi et al. [12] 2020, Case series, Japan Total: 11
M: 10 F: 1
Comorbidities
HTN 4, DM 3, COPD 1 and Cancer 1
Age: 60–69
All patients admitted to ICU
8 patients required MV and 3 required VV-ECMO
Treatment with nafamostat mesylate [0.2 mg per kg per hour by continuous intravenous infusion, median treatment 14 days (IQR, 10 to 14 days)] and FVP [3600 mg on day 1 and at 1600 mg per day on day 2 and subsequently median treatment 14 days (IQR, 12 to 14 days) Mortality: 1; 7 Patients weaned from MV
Discharge from ICU: 9
Discharge from hospital: 7
Adverse effect: 1 (Hyperkalemia)
Lou et al. [20] 2020, Open-label RCT, China Total: 29
T = 9 and C = 10
T = FPV and C = Control
Sex: F = 5, M = 14
History:
Median age (SD) T = 58.0 (8.1); C = 46.6 (14.1)
Inclusion:
All RT-PCR diagnosed
Exclusion:
Patients who dint complete the dosage of the medication
Previous history of malignancy, COPD, renal insufficiency and hepatic insufficiency
Treatment group
Baloxavir marboxil or FVP to the current standard antiviral
treatment was randomly allocated (1:1:1)
FVP group FVP was used in combination with the existing antiviral treatment. The first dose was 1600 mg or 2200 mg orally, followed by 600 mg each time, three times a day, and the duration of administration was not more than 14 days
Baloxavir group
The dose was 80 mg OD on Day 1 and 4 and if patients are positive it can be given on Day 7 but no more than 3 doses should be given
Both groups received existing antiviral treatment including lopinavir/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
Control group
Patients received existing antiviral treatment including lopinavir/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
Viral negative in Day 7
T(FVP group): 4/9; C: 5/10
Viral negative in Day 14
T(FVP group): 7/9; C: 10/10
Clinical improvement
Day 14
T(FVP group): 5/9; C: 5/10
Day 7
T(FVP group): 2/9; C: 1/10
D14 Discharge
T(FVP group): 4/9; C: 4/10
Time to clinical improvement—median days (IQR)
T(FVP group): 14 (6–38); C: 15 (6–24)
Time to viral negative-median days (IQR)
T(FVP group): 9 (2–34; C: 9 (1–13)
D14 NMV OR Oxygen support
T: 3/9; C: 4/10
Ivaschenko et al. [21] 2020, Multi center, open label randomized Phase II/ III controlled trial, Russia Total: 60
Randomization in 1:1:1 in three groups comparable in demographic and baseline characteristics
Intention to treat analysis was done
Inclusion criteria
Hospitalized men and non-pregnant women of 18 years or older who signed the informed consent form, had moderate PCR-confirmed COVID-19 and were able to administrate the drug orally and willing to use adequate contraception during the study and 3 months after its completion
Treatment group
One group received either AVIFAVIR 1600 mg BID on Day 1 followed by 600 mg BID on Days 2–14 (1600/600 mg)
Other group received AVIFAVIR 1800 mg BID on Day 1 followed by 800 mg BID on Days 2–14 (1800/800 mg)
Patients receiving AVIFAVIR did not receive other antivirals or antimalarial drugs
Control group
Control group received standard of care according to national guideline
15 patients reveived HCQ or CQ
1 patient received Lopinavir and ritonavir
4 patients did not receive etiotropic treatment
Viral clearance
Day 5
TG(FVP group): 25/40; CG: 6/20
Day 10
TG: 37/40; CG: 16/20
Median time to body temperature normalization
TG: 2 days (IQR 1–3); CG: 4 days (IQR 1–8)
CT improvement at day 15
TG: 36/40; CG: 16/20
Adverse effects
TG: 15/40; CG: 5/20
Common side effects were diarrhea, 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
M: 5 F: 2
Comorbidities
HTN: 3
DM: 2
Hyperuricemia: 2
Others included BPH, gout, and fibroid
Inclusion:
Critically ill patients admitted to ICU under mechanical ventilation
Patients were given 1600 mg FPV on day 1 and 600 mg from day 2–5 Clinical improvement: 3/7
At Day 7: 1/7
No requirement for mechanical ventilation: 1/7
At Day 14: 3/7
Weaned from mechanical ventilation: 3/7
No oxygenation support: 2/7
Adverse effect: 1/7 (Increase in transaminase)
Rattanaumpawan et al. [14] 2020, Observational study, Thailand Total: 247
T: 63 C: 184
Inclusion:
Patients aged at least 18 years who had RT-PCR-confirmed SARS-CoV-2 based on a respiratory specimen (nasopharyngeal, oropharyngeal, sputum, endotracheal aspirate, or bronchoalveolar lavage sample) and received at least one dose of FVP
Exclusion:
Patients who expired or were discharged within 24 h of hospital stay
Treatment group
Patients received the median loading dose of FVP of 47.4 (29.1–71.1) MKD along with the standard of care, and one-third of 176 enrolled patients (33.3%) received a loading dose of ≤ 45 MKD
The median maintenance 177 dose of FVP was 17.9 (10.9–26.7) MKD, and 76.2% of the subjects received a 178 maintenance dose of ≤ 15 MKD
The median duration of FVP therapy was 12 (2–17) days
Standard of care includes protease inhibitors, hydroxychloroquine, azithromycin, steroid, respiratory support, and tocilizumab
Control group
Patients received standard of care including protease inhibitors, hydroxychloroquine, azithromycin, steroid, tocilizumab, and respiratory support
Outcomes of treatment groups have been only reported. N = 63
Clinical improvement
D7: 42/63
No requirement of oxygen supplementation: 25/63
D14: 54/63
No requirement of oxygen supplementation: 27/63
D28: 57/63
No requirement of oxygen supplementation: 27/63
Mortality
D14: 1
D28: 3
Adverse drug reaction
39/63
Most common diarrhea (34) and hepatitis (4)
Yammamura et al. [15] 2020, Prospective single center study, Japan Total: 13
M: 9 F: 4
Mean age: 63
All patients were mechanically ventilated at the time of admission
Comorbidities
HTN 8, DM 7, Bronchial asthma 1, sleep apnea syndrome 3
FPV (3600 mg on day 1, 1600 mg from day 2 to day 14), methylprednisolone (1000 mg for 3 days), and low molecular weight (2000 IU every 12 h) or unfractionated heparin (10,000–12,000 IU/day). Methylprednisolone administration was begun on the 5th day from initial FPV administration. Heparin and dexmedetomidine were administered after intubation and mechanical ventilation Survival: 12
Mortality: 1
Improvement in IL-6 5 days after FPV therapy, PaO2/Fi02 in a week after FVP therapy
  1. 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
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