Introduction

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) was first reported in late December 2019 in Wuhan, China, and has since spread globally1. By October 2021, more than 237 million people had been infected by the virus that causes Covid-19 and approximately 4.5 million people had died from their infections2. The Covid-19 pandemic is an ongoing global health crisis that requires immediate attention to quickly find an appropriate treatment to reduce global mortality and morbidity associated with the disease. Currently, drugs including arbidol3, ribavirin4, chloroquine or hydroxychloroquine, lopinavir/ritonavir, remdesivir, and favipiravir are among those used to treat the infection experimentally. There is no known cure for SARS-CoV-2 infection5, although there are some effective treatments. Specifically, convalescent plasma6, interleukin (IL)-1 or IL-6 inhibitors7, and interferons3 have been used as supportive therapy. Medications given to COVID-19 patients include antimalarial drugs such as chloroquine and hydroxychloroquine, which are also used to treat autoimmune diseases8, while lopinavir/ritonavir is an FDA-approved HIV treatment drug9. Gilead Science collaborated with the US Centers for Disease Control and Prevention (CDC) and the US Army Medical Research Institute of Infectious Diseases to develop remdesivir, an intravenous adenosine nucleotide analog prodrug with activity against several RNA viruses10, 11. Similarly, favipiravir is an antiviral that works against viruses containing RNA. Toyama Chemical Company was the first to approve this drug, which was used to treat influenza in Japan and China3, 12, 13, 14, 15.

The Solidarity World Health Organization International Trial was a collaborative effort to find potential treatments for Covid-19 that involved 52 countries. Drugs that were investigated included remdesivir, hydroxychloroquine, lopinavir, and interferon, of which remdesivir, hydroxychloroquine, lopinavir, and interferon were found to be ineffective or have little effect for the treatment of Covid-19 hospitalized patients16. In contrast, according to the findings of another review study, there was a higher rate of improvement in patients who received remdesivir than in those who received a placebo; however, there was no difference in the 14-day mortality rate17. Another review found that remdesivir significantly reduced recovery time and the occurrence of side effects, but was ineffective in treating the disease if used alone. Hence, there was improved performance when remdesivir was combined with other antiviral drugs18. Favipiravir was found to be effective in treating patients with mild to moderate disease only19.

Covid-19 is treated with antiviral drugs and supportive therapies, and numerous studies and clinical trials have been carried out to confirm the effectiveness of the drugs in combating infection. Therefore, this study aims to support the development and implementation of effective treatments for Covid-19 and analyze the results of published studies investigating the use of either remdesivir or favipiravir in COVID-19 patients to clarify their efficacy in relation to different patient outcomes.

Methods

Statistical Analysis

We used a proposed estimation model24 to justify the scale and outcome indicators (median, interquartile range (IQR), mean and standard deviation (SD)). We anticipated significant heterogeneity among the studies and, therefore, used a random effects model. To examine the heterogeneity of the effect-size estimates among the studies, the Q-statistic, its p-value, a forest plot, and I were used. The Q-statistic was used to compare the observed and expected effect size dispersions across the studies, and the p-values for statistical significance are provided. The I value is the ratio of real to observed heterogeneity. I values between 0% and 50% were considered to be acceptable heterogeneity, while values greater than 50% were considered to indicate significant heterogeneity25. Subgroup analysis and meta-regression were used to determine the sources of heterogeneity when it was significant26. A funnel plot and Egger's regression test were used to evaluate publication bias (given the low power of the test, a = 0.1 was used)27. Stata Statistical Software Version 15.1. (StataCorp LP., College Station, TX, USA) was used for all analyses.

No	First author	Country	Study Design	Blinding type	Randomization	Covid status	Sample Size	Population type	Treatment protocol (days and dose)	Mean Age	Follow-up Duration (days)	Control group	Outcomes
1	Alessandro Russo28	Italy	Observentional-Cohort	No data	No data	Hospitalization	294	Normal	Remidisivir	63.20	30	Non	-Hospitalization Days -Mortality
2	Andreas Barratt-Due29	Norway	Interventional	Triple	Yes	Hospitalization	42	Normal	Remidisivir 100 mg per day	59.70	90	Routine cares	-Mortality
3	Anıl Uc30	Turkey	Observentional-Cohort	No data	Yes	Hospitalization	48	Normal	Favipiravir + Hydro 1200 mg per day	58.50	14	Hydrox	-Mortality -ICU admition
4	Areej A Malhani31	Saudi Arabia	Observentional-Cohort	No	No	Hospitalization	154	Normal	Favipiravir 1600 mg per day	55	28	IFN	-Hospitalization Days -Mortality -ICU admition
5	Carlos K H Wong32	Hong Kong	Observentional-Cohort	No	No	Hospitalization	466	Normal	Remid+Dexametasone	64.80	11	Dexa	-Mortality
6	Christoph D. Spinner 33	United States, Europe, and Asia	Interventional	No	Yes	Hospitalization	193	Normal	Remidisivir 100 mg per day	55.66	11	Routine cares	-Mortality -Adverse effect
7	Eun-Jeong Joo34	S. Korea	Observentional-Cohort	No	No	Hospitalization	48	Normal	Remidisivir 100 mg per day	69.02	30	Routine cares	-Hospitalization Days -Time to recovery -Mortality
8	Faryal Khamis35	Oman	Interventional	No	Yes	Hospitalization	44	Normal	Favipiravir 1600 mg per day	54	14	Routine cares	-Hospitalization Days -Mortality -ICU admition
9	George A Diaz 36	USA	Observentional-Cohort	No	No	Hospitalization	286	Normal	Remidisivir 100 mg per day	61.40	30	Routine cares	-Mortality
10	Halit ÇINARKA37	Turkey	Observentional-Cohort	No data	No data	Hospitalization	131	Normal	Favipiravir	55.97	14	Iopinavir	-Hospitalization Days -Mortality -ICU admition
11	Hany M Dabbous38	Egypt	Interventional	No data	Yes	Hospitalization	44	Normal	Favipiravir 1200 mg per day	34.86	10	Chloroquine	-Hospitalization Days -Mortality
12	Havva Kocayiğit39	Turkey	Observentional-Cohort	No	No data	ICU	65	Normal	Favipiravir	69.80	70	lopinavir	-Mortality -ICU stay
13	J.H. Beigel 40	United States (45 sites), Denmark (8), the United Kingdom (5), Greece (4), Germany (3), Korea (2), Mexico (2), Spain (2), Japan (1), and Singapore (1)	Interventional	Double	Yes	Hospitalization	541	Normal	Remidisivir 100 mg per day	58.60	10	Placebo	-Time to recovery -Mortality -Adverse effect
14	Lakshmi Mahajan41	India	Interventional	No	Yes	Hospitalization	34	Normal	Remidisivir 100 mg per day	58.08	12	Routine cares	-Mortality
15	Markos Kalligeros42	USA	Observentional-Cohort	No	No	Hospitalization	99	Normal	Remidisivir 100 mg per day	58.66	28	Routine cares	-Mortality
16	Masaharu Shinkai 43	Japan	Interventional	Single	Yes	No data	107	Normal	Favipiravir 1600 mg per day	43.80	28	Placebo	-Mortality -Adverse effect
17	Masoud Solaymani-Dodaran 44	Iran	Interventional	Single	Yes	Hospitalization	190	Normal	Favipiravir 1800 mg per day	58.60	10	lopinavir	-Mortality -ICU admition
18	Michael E Ohl 45	USA	Observentional-Cohort	No data	No data	Hospitalization	1172	Normal	Remidisivir	66.60	30	Routine cares	-Mortality -ICU admition
19	Nouf K Almaghlouth46	USA	Observentional-Cohort	No	No	Hospitalization	33	Normal	Remid+Tocilizumab 100 mg per day		7	Tocli	-Mortality
20	Regine Padilla 47	USA	Observentional-Cohort	No	No	Hospitalization	11	Normal	Remidisivir 100 mg per day		7	Convalescent plasma	-Mortality
21	Robert Flisiak48	Poland	Observentional-Cohort	No	No	Hospitalization	122	Normal	Remidisivir 100 mg per day	58.70	28	lopinavir	-Hospitalization Days -Mortality -Adverse effect
22	Susan A Olender 49	USA	Observentional-Cohort	No	No	Hospitalization	298	Normal	Remidisivir 100 mg per day		14	Routine cares	-Time to recovery -Mortality
23	Toshiki Kuno 50	Japan, USA	Observentional-Cohort	No	No	Hospitalization	1336	Normal	Remidisivir 100 mg per day	65.70	14	Steroids	-Mortality -ICU admition
24	Vishal Gupta51	India	Observentional-Cohort	No data	No	Hospitalization	414	Normal	Remidisivir	57	14	Tocli	-Hospitalization Days -Mortality
25	WHO Solidarity Trial Consortium; Hongchao Pan52	WHO	Interventional	Double	Yes	Hospitalization	2743	Normal	Remidisivir 100 mg per day		30	Placebo	-Mortality
26	Yeming Wang53	Italy	Interventional	Double	Yes	Hospitalization	158	Normal	Remidisivir 200 mg per day	64	28	Placebo	-Hospitalization Days -Time to recovery -Mortality
27	Zainab Almoosa54	Saudi Arabia	Observentional-Cohort	No data	No data	Hospitalization	110	Normal	Favipiravir 1400 mg per day	56.80	14	Routine cares	-Time to recovery -Mortality -ICU admition
28	Zeno Pasquini55	Italy	Observentional-Cohort	No data	No data	ICU	25	Normal	Remidisivir 100 mg per day	64	10	Ventilation	-Mortality

Outcome	N studies	OR (95% CI)	Heterogeneity %I2 (p-value)	Egger’s test p-value
Mortality1
Remdesivir	17	0.893 (0.676-1.180)	78.47 (0.003)	0.654
Favipiravir	8	0.984 (0.540-1.793)	54.65 (0.038)
ICU admission
Remdesivir	3	0.74 (0.26-1.86)	97.09 (0.001)	0.772
Favipiravir	4	0.49 (0.11-2.09)	91.44 (0.001)
Any adverse effects
Remdesivir	4	0.86 (0.46-1.58)	90.06 (0.002)	0.583
Outcome	N studies	Mean difference p-value	Heterogeneity %I2 (p-value)	Egger’s test p-value
Hospitalization Duration, days
Remdesivir	3	0.000	96.15 (0.000)	0.017
Favipiravir	3	0.019	77.54 (0.030)

Outcome	Remdesivir effect p-value/%I2	Favipiravir effect p-value/%I2	N studies
Mortality/Study design
Interventional	0.418 / 18.90	0.632 / 0.00	11
Observational	0.325 / 28.24	0.125 / 79.20	14
Treatment Duration
<7	0.652 / 0.00	0.238 / 28.15	10
>7	0.896 / 0.00	0.623 / 0.00	10
Mean Age
<59	0.119 / 62.82	0.156 / 42.12	13
>59	0.965 / 64.23	0.178 / 44.27	10

Outcome	Remdesivir p-value (%I2)	Favipiravir p-value (%I2)
Mortality
Study design	0.835 (63.5)	0.089 (19.2)
Hospitalization section	0.864 (64.24)	-
Treatment Duration	0.049 (0.00)	0.010 (0.00)
Mean Age	0.510 (62.82)	0.473 (41.17)
Country (continent)	0.711 (63.11)	0.654 (33.12)

Results

Discussion

This study aimed to evaluate the effectiveness of two well-known drugs, remdesivir and favipiravir, for treating Covid-19 infection. Remdesivir was introduced as an effective drug for the treatment of Covid-19 after obtaining its first emergency use authorization in May 2020 in the United States and then later in Japan. However, its use has had many critics56. Unfortunately, despite both the passage of time and an increase in the number of observational studies and RCTs, questions regarding the efficacy of these drugs remain unanswered primarily because the results have been controversial and heterogeneous between the various investigations. One way to address this issue is to conduct systematic reviews and meta-analysis studies.

As a ribonucleotide analog and selective inhibitor of the viral RNA polymerase enzyme, favipiravir performs a wide range of antiviral activities against RNA-carrying viruses, which includes blocking viral genome replication and transcription. In Japan and China, favipiravir is licensed for the treatment of novel influenza viruses. It is also effective against Ebola and other RNA-based viruses that cause hemorrhagic fevers35. However, according to the findings of the current meta-analysis, favipiravir had no significant effect on reducing the mortality rate or ICU admissions in Covid-19 patients. Other meta-analyses have also found that the drug does not decrease many of the indicators associated with Covid-19, including death, hospitalization duration, transfer to the ICU, .57, 58. However, in this study, favipiravir was found to reduce hospitalization duration by 0.06 days. Although this reduction was statistically significant, it is clinically equivalent to approximately 86 minutes, which would not be considered important from a patient perspective. We also found that favipiravir administration did not induce more side effects compared with controls. This result is consistent with those from another meta-analysis59. However, few interventional and secondary studies using favipiravir have been conducted, and finding high-quality interventional studies with large sample sizes is challenging. Furthermore, the high heterogeneity in the results suggests substantial variation in the target parameters of these studies.

Remdesivir is an adenosine nucleotide analogue prodrug that inhibits viral replication by inducing chain termination in the RNA-dependent RNA polymerase enzyme of SARS-CoV-260. However, there are debates concerning the effectiveness of remdesivir, and studies, including meta-analyses, have not yet reached a consensus regarding its efficacy. According to some of the articles used in the current study, the use of remdesivir did not effect the mortality or ICU admission rates in Covid-19 patients. In contrast, others have found that the use of the drug reduced the mortality rate by 34% (OR: 0.66). These inconsistent results have been found in other meta-analyses as well61, 62, 63. We also found that taking remdesivir increased treatment duration by 0.1 days (144 minutes). While this finding is not consistent with other, similar studies that have found remdesivir neither changes hospitalization duration61 nor reduces it62, 63, it should be noted that there was both high heterogeneity and publication bias, both of which could have affected our findings. The effect of the treatment duration variable in heterogeneity should be also taken into account. Specifically, if only this variable is considered, it is possible to assume that treatment duration changes remdesivir’s efficacy.

One limitation of this study (and similar meta-analyses) is the severe lack of high-quality, interventional studies with appropriate sample sizes, sufficient follow-up periods, and similar treatment protocols needed to reduce heterogeneity. One of the strengths of this study was the simultaneous review of observational and interventional studies as well as sub-group analyses of different outcome variables.

Conclusion

Based on the results of this meta-analysis, both remdesivir and favipiravir have very slight or no effect on mortality rates, ICU admissions, or hospitalization duration in Covid-19 patients. However, more vigorous interventional studies are needed before coming to firm conclusions about the effects of these drugs on covid-19 patient outcomes.

Abbreviations

FDA: United States of America Food and Drug Administration; PRISMA: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis; ICUs: Intensive care units; ARDS: Acute respiratory distress syndrome; IQR: Interquartile range; SD: Standard Deviation

Acknowledgments

None.

Author’s contributions

Y.KH: Contribution to study concept and design, acquisition, analysis and interpretation of data, drafting of the manuscript. M.M: Contribution to study concept and design, drafting of the manuscript. R.K: Contribution to study concept and design, drafting of the manuscript SS. HN: Contribution to study concept and design, acquisition, analysis and interpretation of data, drafting of the manuscript. All authors read and approved the final manuscript.

Funding

None.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

All methods were carried out in accordance with relevant guidelines and regulations.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.