This meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines20, 21. A quality check was conducted using the Critical Appraisal Skills Program checklist for randomized control trials (RCTs) and cohort studies22, 23.

Three authors independently searched the MEDLINE (PubMed) and Scopus databases for published articles. The search strategy was guided by the keywords "COVID-19," "remdesivir," and "favipiravir". A complete list of the keywords used for the search is presented in the appendix. Case-control, cohort, and RTCs were included in the searches. All of the articles were examined and there was no limitation according to study time or location. The population, intervention type, and study comparison criteria were adjusted to determine study inclusion and exclusion criteria.

The inclusion criteria were:

1) Studies using case-control, cohort, or RCT designs;

2) COVID-19 patients with positive laboratory tests;

3) Remdesivir and/or favipiravir having been administered to the treatment/intervention group;

4) Any medicines other than Remdesivir and Favipiravir in the control group; and

5) Disease and treatment-related outcomes were measured.

Case reports, reviews, animal research, in silico and in vitro studies, as well as articles with full texts that were unavailable (after contacting the authors), were excluded from the study.

Two authors independently extracted data from the selected articles using a checklist. First, the titles and abstracts of identified articles were examined, and articles that were unrelated to the meta-analysis were excluded. The full texts of the remaining articles were then reviewed and included in the analysis based on the inclusion criteria. Data on the first author, year of publication, location, type of study, blinding, randomization, disease severity, sample size, type and dose of the treatment drug, population type, other treatments used, duration of treatment, age, gender, length of the follow-up period, length of the hospitalization period, recovery ratio, recovery time, mortality rate, days to first improvement, mechanical ventilation, intensive care unit (ICU) admission, ICU length of stay, acute respiratory distress syndrome, intubation, and any adverse effects in treatment and control groups were collected.

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 I² 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 I² value is the ratio of real to observed heterogeneity. I² 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.

Table 1

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

Figure 1

Table 3

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

Table 4

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)

Figure 2

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Figure 9

The initial search uncovered 8,329 relevant records of which 3,561 duplicates were removed. After screening the titles and abstracts, 633 studies were considered eligible for further screening. Next, the full texts of the studies were assessed and 28 studies with a total of 10,871 adult participants were found to be eligible for inclusion in the meta-analysis (Figure 1).

As the included studies reported their outcomes differently, event counts rather than percentages and proportions were used. For mortality rates, some studies used counts while others used ORs. Therefore, an analysis was conducted for both indicators after converting the counts into ORs and 95% CIs. Hospitalization duration was also measured using the mean indicator and is presented as mean differences.