Efficacy and safety of remdesivir and favipiravir in COVID-19 patients – A systematic review and meta-analysis

ABSTRACT

Coronavirus-2019 (Covid-19) has led to a severe medical, social and economic crisis globally. The use of antivirals has given inconsistent results; thus, systematic summaries of available evidence may help us to understand its effectiveness. The current investigation was planned to conduct a systematic review and meta-analysis on the use of antivirals for Covid-19. Using ‘MeSH’ term databases were searched on Google Scholar, PubMed, Web of Science, SCOPUS, OVID, Cochrane Library, and Limits- English Language only. Title/abstract screening, full-text screening and data extraction were carried out by three authors. Pooled effect sizes and 95% confidence intervals (CI) were calculated using the Mantel-Haenszel method of random effects for meta-analysis. Ten studies were found eligible for inclusion: randomized controlled trials Moderate-quality evidence suggests a likely clinical benefit from the use of remdesivir in improving the number of recoveries (OR 1.46; 95% CI 1.23–1.74; I2=0%). A possibility of a higher mortality rate is also suggested by high-quality evidence with remdesivir (OR 0.78; 95% CI 0.57–1.05, I2=14%). Favipiravir also showed patient’s higher mortality outcome (OR 0.69;95% CI 0.24-2.01, I2 = 0%). Although the need for oxygen therapy (OR 0.70 95% CI 0.40-1.23; I2= 72%) was highly significant p < 0.001** and Remdesivir/Favipiravir was determined to be beneficial overall for male gender data across all studies (OR 0.77; 95% CI;0.37-1.60;I2=90%) and highly significant P < 0.0001***. Worsening of comorbidities (OR 0.94; 95% CI 0.81-1.08; I2= 0%), Ferritin level measured (OR-19.80 95% CI -56.51-16.92; I2 = 0 %) and Transferred to ICU/ Mechanical Ventilation (OR 0.85 95% CI 0.25 -2.91; I2 = 52 %) were observed in both the anti-viral. This meta-analysis found mixed efficacy for Remdesivir and negative outcomes for Favipiravir.

Introduction

Diseases and pandemics threaten healthcare, human lives, and economy. Novel SARS-CoV-2, which was initially discovered in Wuhan, Hubei Province, Central China. SARS-CoV-2, which drastically became a global burden. COVID-19 is a Coronavirus that belongs to the same family and is similar to SARS and MERS.[1] SARS-CoV-2, or Coronavirus disease-2019 (COVID-19), is a fatal zoonotic, infectious, and global emergency pandemic that hit more than 200 nations throughout the globe in the first half of 2019. As a result of COVID-19, COVID-19 was declared a global public health emergency by WHO, affecting at least 25 countries including the United States, with ongoing cases and more expected. There is an angiotensin-converting enzyme 2 (ACE2) receptor found on type II alveolar cells and intestinal epithelial cells which bind to this drug. An ARTI (acute respiratory tract infection) epidemic, COVID-19, is bringing attention to the dangers of highly infectious viruses, particularly coronaviruses and its pathophysiology and therapeutic targets illustrated in Figure 1.[2,3] Coronaviruses have been known to infect humans since the 1960s, but their potential to cause deadly epidemics has recently been uncovered. The COVID-19 pandemic has caused significant disruptions to global social and economic systems. Meta-analysis relies on a systematic review process, which involves tracking down and assessing the quality of all relevant studies, published and unpublished. By summing up the results of these studies, systematic reviews provide an unbiased evaluation of previous research, enabling conclusions about effectiveness. Countries use contact tracing, testing, and distancing to combat COVID-19. Research identifies effective antivirals for vaccines. Repurposing promising antivirals is a pragmatic approach to accelerate medication approval.[3] Study analyses remdesivir and favipiravir clinical trials for COVID-19 patients, considering recent discoveries and debates on the medicines.

Figure 1.

Pathophysiology and therapeutic targets of SARS-CoV-2 virus. Flowchart showing pathophysiology and therapeutic targets of SARS-CoV-2 virus. (a) Protective device, prevention, mouthwash, sanitization, education, plasma stem cell, and antiviral; (b) ACE-inhibitor, anti-malaria, and monoclonal antibody (Ab); (c) antiviral; (d) corticosteroids; (e) protease inhibitor; (f) vasodilator (VD); (g) antifungal, antibiotics, and antiparasitic; (h) hydroxychloroquine; (i) anticytokines and plasma therapy; (j) vd inhalation, sildenafil; (k) NSAIDs, anti-inflammatory, and immunosuppressants; (l) antioxidants; (m) antihistamine; (n) antiplatelet, antithrombotic, and fibrinolytic; (o) antiarrhythmics, cardio-protective, microbiota intervention, life support, and rehabilitation; (p) respiratory support, medical device inspiratory/expiratory; and (q) therapy not devised. The permission to use the figure was taken from the cited corresponding author (Agrawal M et al.)[3]

Methods

Data sources

Searches for pertinent publications were made in online resources including Google and Google Scholar as well as electronic databases like Scopus, PubMed, Cochrane library, and clinicalTrials.gov. With the use of the Boolean operators “AND” and “OR,” search phrases linked to COVID-19, SARS-CoV-2, remdesivir, favipiravir, COVID-19 symptoms, and drug-associated side effects and adverse reactions were grouped into four categories.

Inclusion and exclusion criteria

The study excluded conference proceedings, commentaries, topics other than COVID-19 symptoms and treatments of patients, topics that do not discuss remdesivir and favipiravir medication, and topics that do not discuss SARS-CoV-2. Patients who were healthy above the age of 30 and took any other medication for COVID-19 like lopinavir, ritonavir, nitazonaoxide, chloroquine, penciclovir, and ribavirin were excluded from the study. Apart from that, the patients who were on medication in home isolation were not included in the research. Other exclusion criteria included publications that did not include original research (such as abstracts, reviews and perspectives, comments, and letters to the editor) and papers written in other than the English language.

The effectiveness of antiviral medicines (remdesivir or favipiravir) in COVID-19 patients with a main diagnosis of nausea, breathing issues, or the common cold was examined in randomized controlled studies between 2020 and 2024. The study considers unpublished and international research due to the high frequency and comorbidities associated with the condition.

Database search strategy

The search was conducted using MeSH terminology such as Output PubMed (“COVID-19” OR “SARS-CoV-2” OR COVID-19 Symptom AND “remdesivir” OR “favipiravir” treatment) AND ((“adverse effects”) OR “Drug-Related Side Effects and Adverse Reactions”) OR “Treatment Outcome”)”—158 Cochrane “(Covid 19 OR SARS-COV-2 OR COVID-19 Symptoms) AND (Antiviral agents OR Remdesivir OR Lopinavir OR Ritonavir OR Favipiravir) AND (Adverse effects OR Drug-Related Side Effects).

Screening strategy

The study included only screened publications with full texts available, obtained through requests or purchases. Reference lists of relevant papers were also searched to increase the chances of finding appropriate publications.

Quality assessment

The study analyzed both qualitative and quantitative data to assess the effectiveness and safety of remdesivir and favipiravir in COVID-19 patients, applying inclusionary and exclusionary criteria and research approaches to both data sets. The study used the CONSORT and STROBE checklists to evaluate the efficacy of randomised control trial (RCT) and observational cohort study methodologies, respectively. Only studies with scores of at least 13 and 16 were included in the meta-analysis. The checklists were used to evaluate each item of the study’s specific research.

Risk bias assessment

The risk of bias was evaluated by using the Cochrane Risk of Bias 2 (RoB 2) method. Randomization, variations from planned interventions, outcome assessment, selection of reported results, and missing outcome data were all evaluated [Figure 2]. The RoB 2 comprehensive guideline’s bias criteria assessed each study and determined whether it had a high bias. This tool was then used to create the graph.

Figure 2.

Risk of bias assessment

Data extraction

Data were imported into Endnote software and validated for inclusion. The data were extracted by three authors AK, GV and P. Any disagreements were resolved by consulting an AK and GV. Information about the first author, study site, and publication date was entered into an Excel form.

Data items

PRISMA flowchart was used to display the article selection process. Out of the 1000 papers assessed based on title and abstract, only 956 were disqualified. After removing duplicates, 54 articles were screened for full text based on inclusion criteria. Finally, only 10 studies that met the study criteria [Figure 3] were included in the analysis, as described in Table 1.[4]

Figure 3.

PRISMA flow diagram of study selection

Table 1.

Study characteristics of included studies

Author	Duration of treatment	Antiviral agent	Dosage	Findings
Goldmanet al . (2020)[5]	Five days: 200 patients 10 days: 197 patients	Remdesivir	First day: 200 mg 100 mg once a day, four to nine days ahead of time.	No substantial difference in clinical status was observed between patients receiving remdesivir for 5 days versus those receiving it for 10 days at day 14. However, lower mortality rates and higher rates of hospital discharge were observed in both groups.
Spinneret al . (2021)[6]	Five days and 10 days	Remdesivir	200 mg: first day 100 mg: Following days	Remdesivir in the 5-day group improved patients’ medical state compared to usual treatment group, but no significant difference was found between remdesivir and conventional treatment.
Kalilet al ., (2021)[7]	Ten days	Remdesivir	200 mg: first- day and second day - Till the patient is discharged or dies: 100 mg	Remdesivir and the combination reduced recovery time by 1 day, and the combo group had a lower 28-day death rate and fewer serious side effects.
Khamiset al ., (2021)[8]	Ten days	Favipiravir	First day: 1600 mg twice a day. 600 mg twice daily from the second to the tenth day	No significant difference was observed in hospital stay length, transfer to ICU, discharge, or death between the standard group and the favipiravir-inhaled interferon beta-1b group.
Dabbouset al ., (2021)[9]	Ten days	Favipiravir	First day: 1600 mg twice daily 2nd to 10th day: 600 mg twice daily	Favipiravir may shorten hospital stay and reduce the need for mechanical ventilation as no patients in the favipiravir group require it (P=0.129).
Udwadiaet al ., (2021)[10]	Fourteen days	Favipiravir	From the second through the fourteenth day, give 800 mg twice daily.	Patients with mild to severe diseases may benefit from the addition of favipiravir to supportive treatment. It took 5 days on average for the virus to stop spreading, compared to 7 days on average and 5 days on average, resulting in a P value of 0.129 and 3 days on average for a patient to recover clinically.
Beigelet al ., (2020)[11]	Ten days	Remdesivir	First day: 200 mg in the 2– 10 days range: 100 mg daily.	Adults with COVID-19 who were treated with remdesivir had a reduced death rate, a shorter recovery time, and a decreased risk of major side effects.
Russoet al ., (2021)[12]	Thirty days	Remdesivir	Less than 200 mg till the discharge or death	The use of remdesivir in patients with COVID-19 in the hospital was not related to substantial gains in survival rates or reductions in the utilization of HFNC/NIV or mechanical ventilation.
Louet al ., (2021)[13]	Fourteen days	Favipiravir	1600–2200 mg for the first dosage; three times daily, use 600 mg.	After 14 days of therapy, 77%, 70%, and 100% of patients in the favipiravir, baloxavir marboxil, and control groups had virally negative results.

Outcomes measures

The study analyzed patient outcomes such as recovery, death rate, need for oxygen therapy, deterioration of comorbid diseases, serum ferritin level, and mechanical ventilation (MV) during COVID-19. The efficacy and safety of remdesivir and favipiravir were evaluated based on these outcomes, and their validity and reliability were assessed.

Statistical analysis

The meta-analysis used RCTs and quasi-experimental design (QEDs) as the key studies for statistical analysis and also looked at case studies and qualitative design studies separately. RevMan 5.4.1 software was used to determine the impact of the medications on patients.

Results

Study selection

Following PRISMA guidelines for systematic review and meta-analysis including a flow diagram to summarize the selection process. Preferred reporting items for systematic review and meta-analysis were also applied (i.e., screening, eligibility, included in the systematic review, and, if applicable, included in the meta-analysis).[4] All the literature searches were carried out using the above-described databases. The total number of entries found in electronic databases, reference lists, citation indexes, abstracts, and email correspondence with the author is 1010. For the review, a total of 10 research studies were chosen. Medline, PubMed, Google Scholar, Cochrane, and Embase searches were conducted. Fifty-four were left after accounting for duplicates. Out of these, 956 studies were excluded based on their reviews (736), commentaries (200), duplications (10), and conference proceedings (20). Some more research articles were excluded because of different topics (20), did not discuss SARS-CoV-2 (12), topics discuss other medications like chloroquine, penciclovir, ribavirin, nitazoxanide, and nafamostat (22), studies on medication of home isolated COVID-19 patients (14) study was unavailable. Further attention was given to reading the complete text of the remaining. By examining the references in relevant papers and searching for studies that cited them, it was possible to narrow the list of research left to 10 that still matched the requirements for inclusion (meta-analysis). No relevant unpublished studies were found. The text and flow diagram [Figure 3] should both clearly explain how reports are chosen for review at each stage. The characteristics of the sample and the result evaluation are described in Table 1. Remdesivir was evaluated in five of the final ten studies, whereas favipiravir was evaluated in five of them.

Remdesivir parameters

Remdesivir has been shown to augment patients’ clinical results in three studies.[5,6] The addition of baricitinib to remdesivir improves outcomes.[7] Two studies revealed that remdesivir increased mortality and side effects compared to the comparator, whereas a third study found no relationship.[7] An observational study on a population of patients hospitalized for COVID-19. The data were analyzed after propensity score matching. A total of 407 patients with SARS-CoV-2 pneumonia were consecutively enrolled. Out of these, 294 (72.2%) were treated with remdesivir and 113 (27.8%) were not. Sixty-one patients were treated during hospitalization with high-flow oxygen therapy (HFNC), non-invasive ventilation (NIV), or MV. Twenty-one patients treated with MV died within 30 days at a mortality rate of 5.2%, although there was no difference in survival or mortality between the two groups.[6] Spinner and Goldman’s studies on the efficacy of remdesivir treatment for 5 and 10 days, respectively, showed no significant differences in recovery or the time after oxygen assistance withdrawal between the two durations.

However, the 5-day remdesivir support significantly outpaced the conventional treatment arm in terms of clinical status, with an OR of 1.65; 95% P = 0.0214; CI = 1.09–2.48; 15 According to Goldman, the 5-day treatment group’s hospital release time was shorter (60%). Serious adverse effects were frequent in the ten-day treatment group in both trials compared to the routine care group (9% vs. 5%).[5] Nausea, hypokalemia, and headaches are among the most often reported adverse effects of this medication.[6] In addition, 1% of patients in the 5-day care group, 2% in the 10-day care group, and 2% in the routine care group died on the 28^th day.[6] Because there was no placebo control in Goldman’s trial, the outcomes cannot be established.[5] For this study, Beigel and colleagues tested remdesivir on 1062 adult COVID-19 patients; 541 of them were given remdesivir, while the other 521 were given a placebo. Furthermore, remdesivir patients recovered faster (10 days vs. 15 days), and died less frequently (6.7% vs. 11.9% at day 15, 11.4% s. 15.2% at day 29; 95% Class Interval = 0.52–1.03; HR = 0.73), spent less time in the hospital (17 days vs. 12 days), and had fewer major adverse effects than those who received a placebo (24.6% vs. 31.6%). Remdesivir is effective in preventing respiratory illness, as evidenced by the low occurrence of respiratory adverse effects or the need for oxygen treatment.[14] In addition, conducted a study in COVID-19 hospitalized adult patients to compare the response of baricitinib with remdesivir to placebo plus remdesivir.[7] A clinical improvement and recovery time of seven days, with a recovery rate of 1.16; 95% confidence interval, 1.01–1.32; P value = 0.03) and a 28-day death of 5.1% (hazard-to-death ratio) were achieved with a baricitinib plus remdesivir than with remdesivir alone. The difference in serious adverse events between the two groups was 16.9 percentage points (16% vs. 21%; difference, −5.0 percentage points; 95% CI, −9.8 to − 0.3; P = 0.03).[7] Figure 4 depicts post analysis using RevMan, the forest plot of the log OR – 1.46 (95% CI: 1.23, 1.74), with considerable heterogeneity (P < 0.0001). The random effect size was calculated for a total of four studies (n = 10) to assess the results. In the present study, Figure 5(a) shows a forest plot of the log OR – 0.78 (95% CI: 0.57, 1.05) with non-significant heterogeneity (P = 0.11) for the four studies (n = 10), which were included in the computation of random effect size to assess the result. Figures 4(b) and 5(b) depict a symmetrical funnel plot of all included papers that have been evaluated for publication bias. According to these findings, patients exposed to remdesivir had a higher mortality rate than those in the control group.

Figure 4.

(a) Forest plot of comparison between remdesivir and control (patient recovery outcome). (b) Funnel plot of comparison between remdesivir and control (patient recovery outcome)

Figure 5.

(a) Forest plot of comparison between remdesivir and control (mortality outcomes). (b) Funnel plot of comparison between remdesivir and control (mortality outcome)

Favipiravir parameters

Findings of five studies [Figure 6(a) and (b)] on favipiravir’s effectiveness in treating COVID-19 were inconsistent in the review. Three studies found no significant difference between favipiravir and the control group.[8,15] Combining tocilizumab and favipiravir resulted in better outcomes according to one study. Favipiravir was found to be superior to conventional treatment and chloroquine/hydroxychloroquine in two studies[9,10] tested favipiravir with inhaled beta-1b interferon and compared it to hydroxychloroquine. C-reactive protein (P value = 0.413), ferritin (P value = 0.968), mortality (11.4% vs. 13.3%) and IL-6 (P value = 0.410), lactate dehydrogenase (P value = 0.259), hospital stay (P value = 0.948), transfer to ICU (P = 0.960), and decreased oxygen saturation (P = 0.778).[9] In this reported trial, it was compared favipiravir to chloroquine and hydroxychloroquine. In both studies, there was no statistically significant difference between the favipiravir and control groups. None of the patients had a lower than 90% oxygen saturation, and no one required MV. In this study, the mortality rate for those using favipiravir was 2.3% versus 4.2% (P = 1.00). Neither levels of D-dimer above 1000 (6% vs. 14% of patients) nor the prevalence of the most common symptoms, such as dry cough (25% vs. 30%; P = 0.574) and fever (36% vs. 38%; P = 0.275), were statistically different from those of patients who were PCR negative for SARS-CoV-2 at the beginning of the study, and more than half of those patients.[9] The effectiveness of favipiravir in combination with supportive therapy was studied by Udwadia et al.[10] Median SARS-CoV-2 eradication time was 5 days versus 7 days in comparison to the median time to recovery from initial clinical symptoms, which was 3 days versus 5 days, and the median time to recover from the 95% confidence interval of 5 days to 8 days (P = 0.108 and 0.067, respectively). There was no significant difference in the median time to leave the hospital (P = 0.108), which was the median time to leave the hospital. Lou and colleagues conducted a study, to test the effectiveness of the antiviral agents baloxavir, marboxil, favipiravir, and a control group in patients with COVID-19. There was no statistically significant difference in the number of patients who tested negative for the virus 14 days after exposure, according to the data (70% for baloxavir marboxil, 100% for the control group, 77% for favipiravir). There was a 14-day median time to notice a clinical improvement in the treatment groups of marboxil (14), favipiravir (14), and baloxavir (14) but in control groups (15).[13]

Figure 6.

(a) Forest plot of comparison between favipiravir and control (mortality rate). (b) Funnel plot of comparison between favipiravir and control (mortality rate)

Overall parameters for remdesivir/favipiravir

Male gender in all studies

Forest plot of the log OR – 1.61 (95% CI: 0.99, 2.62) with non-significant heterogeneity (P = 0.06) from the ten studies (n = 10) included in the random effect size calculation to assess the result in Figure 7(a). Figure 7(b) depicts a symmetrical funnel plot of all included papers that have been analyzed for publication bias. Men’s health seems to benefit from both antiviral treatments, according to this research (experimental group).

Figure 7.

(a) Forest plot of comparison: male gender in all studies (overall parameters for remdesivir/favipiravir). (b) Funnel plot of comparison: male gender in all studies (overall parameters for remdesivir/favipiravir)

Need for oxygen therapy

Forest plot of the log OR – 0.70 (95% CI: 0.40, 1.23) with non-significant heterogeneity (P = 0.21) from the seven studies (n = 10) included in the random effect size calculation to assess the result in Figure 8(a). An asymmetrical funnel plot Figure 8(b) of included research is evaluated for publication bias; all studies are situated beneath the curve. It seems that oxygen treatment is unnecessary and that the control group is favored by the outcomes.

Figure 8.

(a) Forest plot of comparison between remdesivir and favipiravir with control (need for oxygen therapy). (b) Funnel plot of comparison between remdesivir and favipiravir with control (need for oxygen therapy)

Worsening of comorbidities

Results from all ten trials (n = 10) were used to calculate an OR – 0.94 (95% CI: 0.81, 1.08) with non-significant heterogeneity in Figure 9(a). An asymmetrical funnel plot of included research is evaluated for publication bias; all studies are situated beneath the curve in Figure 9(b). The data show that the control group had a higher rate of comorbid conditions.

Figure 9.

(a) Forest plot of comparison between remdesivir and favipiravir with control (worsening of comorbidities). (b) Funnel plot of comparison between remdesivir and favipiravir with control (worsening of comorbidities)

Ferritin level

Forest plot in Figure 10(a) of the log OR –19.80 (95% CI: –56.51, 16.92) with non-significant heterogeneity (P = 0.29), based on the results of four investigations (n = 10). Figure 10(b) shows a symmetrical funnel plot of included research evaluated for publication bias; all studies are situated beneath the curve. Experimental group’s ferritin levels were normal compared to the control group.

Figure 10.

(a) Forest plot of comparison between remdesivir and favipiravir with control (ferritin level). (b) Funnel plot of comparison between remdesivir and favipiravir with control (ferritin level)

Transferred to ICU/Mechanical ventilation

Forest plot illustrating Figure 11(a), the log OR –0.85 (95% CI: 0.25, 2.91) with non-significant heterogeneity (P = 0.80) from the four studies included in the computation of random effect size to assess the result (n = 10). Figure 11(b) shows the funnel plot of included research analyzed for publication bias; symmetrical and all papers are situated beneath the curve. The findings indicate that MV is ineffective in the treatment group.

Figure 11.

(a) Forest plot of comparison between remdesivir and favipiravir with control (transferred to ICU/mechanical ventilation). (b) Forest plot of comparison between remdesivir and favipiravir with control (transferred to ICU/mechanical ventilation)

Discussion

This meta-analysis of 10 RCTs with 17,995 patients examined the effectiveness and safety of remdesivir and favipiravir in treating hospitalized COVID-19 patients. The forest plot for mortality outcomes of patients receiving remdesivir [Figure 5.a] shows a shift toward negative values, as does the plot for patients receiving favipiravir, shown in Figure 6(a), respectively, indicates that mortality of patients in the treatment group (remdesivir/favipiravir) as compared to the control. Our findings are consistent, which reported that remdesivir did not improve the survival rate in hospitalized COVID-19 patients compared to other therapies.[12] In addition, the treatment group had a higher mortality rate than the control group, leading to a shift toward negative values in the forest plot for both remdesivir and favipiravir, as shown in Figures 5(a) and 6(a). Our study found that the difference in mortality between the control group and the groups treated with antivirals was statistically significant. These findings are consistent with previous research suggesting that antivirals may not be effective in lowering mortality in COVID-19 patients, and there is a need for further studies to evaluate their safety. Remdesivir may improve patient health according to the forest plot for recovery outcomes, despite inconsistent findings regarding its efficacy and safety. One study conducted by Beigel and colleagues, tested remdesivir on 1062 adult COVID-19 patients, with faster recovery, lower mortality rates, and shorter hospital stays observed in the remdesivir group compared to the placebo group.[11] Our meta-analysis suggests that both antivirals have the potential to increase mortality in COVID-19 patients, indicating a need for alternative therapies. The ultimate aim of using invasive MV in COVID-19 patients is to save lives. A leftward shift (negative value) in the overall impact was observed in the analysis; the forest plot of MV is shown in Figure 8(a). The findings indicate that MV is statistically ineffective in the treatment group. Our aim is to reduce mortality rates for all COVID-19 patients, regardless of their age, comorbidities, or frailty. Invasive ventilation will be used judiciously when necessary. However, mortality rates for patients in their eighties and nineties or with severe comorbidities who require ventilation have always been high, even in ideal circumstances. According to a 2010 epidemiological study, 50% of those aged 85 and above who received ventilation in the United States died in the hospital.[16]

MV may have varying benefits depending on age and comorbidities and may not uniformly reduce mortality rates. Oxygen therapy may not be necessary for patients receiving treatment compared to the control group.as shown in Figure 8(a). High levels of ferritin can contribute to cytokine storms by both suppressing the immune system and promoting inflammation, as it plays a vital role in regulating immune function,[17] leading to the hypothesis that the cytokine storm syndrome determines the severity of the condition.[18] The meta-analysis found that the treatment group had normal ferritin levels compared to the control group [Figure 10a and b], while a separate study of 20 COVID-19 patients found that severe cases had elevated serum ferritin levels, with the very severe group having considerably higher levels than the severe group (1006.16 ng/ml [IQR: 408.265–1988.25] vs. 291.13 ng/ml [IQR: 102.1–648.42], respectively).[19] Elevated ferritin levels were found in deceased COVID-19 patients during their hospital stay, with median values exceeding the upper limit of detection after day 16 of hospitalization.[20] Older patients were more likely to have severe COVID-19, and men tended to have more severe cases than women. A higher percentage of older patients were found among those who died from COVID-19 compared to those who survived, based on a public dataset.[21] In the meta-analysis, both antiviral treatments were found to benefit men’s health, with the pooled effect slightly touching the null effect line. However, favipiravir showed less efficacy and more adverse effects. In the forest plot comparing the worsening of comorbidities between the treatment and control groups, the plot is shifted toward the control side as shown in Figure 9(a); indicates that all studies are situated beneath the curve means that the control group had a higher rate of comorbid conditions. Favipiravir has several potential side effects, including increased teratogenicity and blood uric acid.[22] Additionally, favipiravir and its metabolites were found in both human breast milk and sperm.[22] Patients with comorbidities have worse outcomes with COVID-19, including a higher risk of developing ARDS and pneumonia. Elderly, long-term care, chronic kidney disease, and cancer patients have a higher risk of death from COVID-19, and precautions such as handwashing, social distancing, and wearing masks are necessary. A global public health campaign is needed to reduce the burden of comorbidities causing COVID-19-related deaths. There are 12 approved vaccines, with four having published Phase III clinical trial outcomes, and scientists are making progress in creating treatments. Two use messenger RNA vaccines, and two use non-replicating viral vector technology based on adenovirus.[23] The effectiveness of antivirals such as remdesivir and favipiravir is still uncertain due to the inclusion of additional medications in trials, and further investigation is needed. Despite the availability of vaccines, widespread vaccination will take time and resources. Developing potent antivirals remains a priority for better treatment and reducing mortality in COVID-19 patients. There are caveats in the current body of evidence about the efficacy of antivirals, and small sample sizes limit the generalizability of some research. However, there are many questions that remain unclear: What is the role of Sertoli cells/host defense in preventing viral invasion? Is orchitis a transient effect of acute infection that shall subside with time, or is it more chronic in nature? Are these effects reversible? Another relevant area of research could be about recommended drugs and their dosage that could be considered safe to prevent these complications.[24] Therefore, structure-based studies and high-throughput screening are necessary for the expedited discovery of antiviral candidates. Antiviral medications that show promise in vitro often fail to deliver in animal studies or people, it has become clear. Though there may be differences in results between animal research and human studies, previous experiences with LPV/r[25] and CQ/HCQ[26] have offered insight that animal studies might assist in forecasting the impact of the medications in a more realistic environment. Before drawing any conclusions from a clinical trial, it is important to examine the inclusion criteria, administration route, outcomes, concomitant therapies, treatment assignment, and statistical analysis techniques. The development of SARS-CoV-2-SARS-Cov- specific antivirals and the effective use of repurposed medications can lead to long-term benefits. Antivirals that target viral replication directly, such as viral protease inhibitors and polymerase inhibitors, should be prioritized. The success of direct-acting antivirals for Hepatitis C Virus (HCV) provides evidence for the effectiveness of this approach.[25,27] Similarly, the development and use of combination antiretroviral medication have greatly increased the number of years HIV- positive people may expect to live.[28] Therefore, it may be possible to reduce viral load and avoid severe illness progression via the development of targeted antivirals that act at distinct points in the SARS-CoV-2 life cycle and the use of combination treatment more effectively.[30,31] Antiviral drugs such as remdesivir and favipiravir show promise in treating COVID-19 patients, with remdesivir potentially reducing the death rate and favipiravir enhancing clinical recovery.[12,29] However, more large-scale clinical studies are necessary to evaluate their risk-benefit profile and validate their effects before definitive treatment recommendations can be made. Multiple trials have shown potential for available antivirals against SARS-CoV-2.

Conclusion

The results were mixed, with remdesivir showing potential benefits but higher mortality rates, while favipiravir demonstrated less efficacy and more adverse effects. Remdesivir showed potential effectiveness in improving patient health but was associated with a higher mortality rate than the control group. Favipiravir demonstrated less efficacy, was associated with more adverse effects, and appeared to worsen patients’ health in some cases. The analysis suggested that oxygen therapy may be unnecessary for patients receiving these antiviral treatments, while the control group showed a higher rate of worsening comorbidities. Normal ferritin levels were observed in the experimental group compared to the control group, and MV was found to be statistically ineffective in the treatment group. Both antiviral treatments appeared to benefit men’s health more than women’s. However, it’s important to note that the current evidence is not statistically significant enough to draw definitive conclusions. Further large-scale clinical studies are necessary to validate the effects of these antivirals on COVID-19 patients, evaluate their risk-benefit profiles, and develop more targeted and effective antiviral strategies.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.