Antiviral agents for COVID-19: A post-pandemic systematic review of randomized controlled trials.

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Norton Pérez-Gutiérrez, María Ximena Mendoza-Gómez, Lizeth Johana León-Cardozo, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9020094/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background : After years of the pandemic of SARS-CoV-2 infection, some cases with severe symptoms of COVID-19 are still presenting. Therapeutic alternatives that provide a clear benefit for severe cases remain lacking. Aim : To assess the best available evidence on the efficacy of antiviral therapy for severe COVID-19 and to synthesize the results. Methodology : A systematic review was designed. PubMed publications until December 2025 were searched. Randomized clinical trials (RCTs) of interventions with antiviral agents, with control groups that received placebo or standard of care (SOC) in patients with severe COVID-19 hospitalized or in the intensive care unit (ICU), were selected. The primary outcome was all-cause mortality; other secondary results were considered. Results : A total of 43 studies were identified, involving 12,052 patients. The severity distribution was 35.6%, 52.0%, and 12.4% for mild, moderate, and severe cases, respectively. Ten antiviral agents were evaluated. The results showed a decrease in mortality among patients treated with remdesivir (RR 0.83; 95% CI0.74-0.93; p=0.001), molnupiravir (RR 0.16; 95% CI 0.04-0.73; p=0.02), and nirmatrelvir (RR 0.05; 95% CI 0.00-0.91; p=0.04). Conclusions : According to the results, some antivirals (remdesivir, molnupiravir, nirmatrelvir) reduced all-cause mortality among patients with COVID-19 compared with placebo or SOC. Hospital Medicine Epidemiology Virology Translational Medicine COVID-19 Coronavirus Infections: SARS-CoV-2 Antiviral Agents Pandemics Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 1. Introduction The COVID-19 pandemic emerged three years ago, with millions of people affected in almost every country and thousands of deaths worldwide. Initially, experts proposed therapy alternatives based on theoretical considerations, with no evidence of practical results, but in the end, there is still no clear alternative for the management of new infections ( 1 ) other than vaccination ( 2 ). Even when the number of cases has descended dramatically, including severe cases, and a minimum of current fatal events occur, there is no certainty on the course of the disease to an endemic presentation or if there is any chance for new peaks. Therefore, alternatives for treating such an infection remain necessary ( 3 ). The question was: In patients with SARS-CoV-2 infection (P), therapy with antivirals (I) compared with placebo (C) improved outcomes (O)? The study aimed to assess the best available evidence on the efficacy of antiviral therapy for COVID-19 and synthesize the results. 2. Methodology 2.1. Study design and protocol registration This study was conducted as a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating antiviral therapies for severe COVID-19. The review was designed and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines ( 4 ). The protocol, which was prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD420233994294. 2.2. Eligibility criteria Eligibility criteria were predefined using the PICO framework. Types of studies: We included randomized controlled trials published in peer-reviewed journals. Both double-blind and open-label RCTs were eligible. Observational studies, non-randomized trials, preprints, conference abstracts, editorials, reviews, and vaccine studies were excluded. Retraction papers were also excluded from the review and meta-analysis, in accordance with PRISMA 2020 guidelines. Types of participants: Eligible studies enrolled adult patients (≥18 years) with laboratory-confirmed SARS-CoV-2 infection, hospitalized with mild, moderate, or severe disease. Ambulatory patients, community- or home-based, non-severe, or post-exposure but asymptomatic status were excluded. Types of interventions: Trials evaluating antiviral agents administered for the treatment of COVID-19 were included. Eligible interventions comprised, but were not limited to, remdesivir, lopinavir/ritonavir, favipiravir, molnupiravir, nirmatrelvir (with or without ritonavir), sofosbuvir, umifenovir, and other investigational antiviral compounds. Other antiviral therapies (immunomodulators, monoclonal antibodies, vaccines, and non-antiviral agents) were excluded. Types of comparators: Comparator groups included placebo or standard of care (SOC), as defined within individual trials. Outcomes: The primary outcome was all-cause mortality, reported as 14-day, 28-day, 30-day, or in-hospital mortality. Secondary outcomes included clinical recovery (defined as a lower NEWS-2 score or improvement), time to recovery, length of hospital stay, intensive care unit (ICU) admission, requirement for mechanical ventilation, and time to symptom resolution. Viral clearance, rebound, recurrence, sequelae, and long-term symptoms were excluded as outcomes. 2.3. Information sources and search strategy A comprehensive literature search was conducted in Medline (via PubMed) and the Cochrane Central Register of Controlled Trials (CENTRAL), including searches in Embase. The search covered publications from January 1, 2020, to December 31, 2022, without geographic restrictions. Only articles published in English were considered. Searched strategies combined controlled vocabulary terms (e.g., MeSH and Emtree) and free-text keywords related to SARS-CoV-2, COVID-19, Coronavirus Infections, and antiviral agents. The complete search strategies for all databases are provided in Supplementary Appendix 1. Reference lists of relevant systematic reviews and included trials were manually screened to identify additional eligible studies. 2.4. Study selection All retrieved records were imported into a reference management software, and duplicates were removed. Two reviewers independently screened titles and abstracts to assess eligibility. Full-text articles were subsequently reviewed for inclusion in accordance with the predefined criteria. Disagreements at any stage of the selection process were resolved through discussion, with adjudication by a third reviewer when necessary. 2.5. Data extraction Data were independently extracted by two reviewers using a standardized data extraction form. Extracted information included: Study characteristics (first author, year of publication, country, journal). Participant characteristics (sample size, age, disease severity, clinical setting). Intervention details (antiviral agent, dosage, duration). Comparator characteristics. Outcome data for all predefined endpoints. Duration of follow-up. For a multi-arm trial evaluation of more than one antiviral intervention, each eligible comparison was extracted and analyzed separately to avoid unit-of-analysis errors. 2.6. Risk of bias assessment Methodological quality was assessed using the Cochrane Risk of Bias tool, version 2 (ROB 2), which evaluates bias across five domains: Randomization process. Deviations from intended interventions. Missing outcome data. Measurement of the outcome. Selection of the reported result. Each study was categorized as having low risk of bias, some concerns, or high risk of bias. Assessment was conducted independently by two reviewers, with disagreements resolved by consensus. 2.7. Data synthesis and statistical analysis Meta-analyses were performed when at least two studies reported comparable outcome data. For dichotomous outcomes, treatment effects were summarized as relative risks (RRs) with 95% confidence intervals (CIs). A random-effects model (DerSimonian-Laird method) was used to account for anticipated clinical and methodological heterogeneity. Statistical heterogeneity was assessed using the I 2 statistic, with values of approximately 25%, 50%, and 75% interpreted as low, moderate, and high heterogeneity, respectively. Predefined subgroup analyses were conducted according to: Antiviral agent. Combinations. All statistical analyses were performed using Review Manager (RevMan) version 5.4.1 (Cochrane Collaboration). Formal assessment of publication bias (e.g., funnel plots) was not performed when fewer than ten studies were available for a given outcome. The certainty of evidence for the primary outcome was assessed qualitatively, considering risk of bias, consistency of results, precision of effect estimates, and clinical relevance, in line with established systematic review methodology. 2.8. Ethical considerations As this study synthesized data from previously published trials, ethical approval was not required. 3. Results 3.1. Studies selection The study selection process is summarized in accordance with the PRISMA 2020 flow diagram (Figure X. PRISMA 2020 flow diagram of study identification and selection). A total of [295] records were identified through database searches, including PubMed (n = 110) and Cochrane CENTRAL (n = 185). After removing duplicate records [190], 199 unique records remained for screening. No additional eligible studies were identified through manual reference screening. Title and abstract screening excluded [N4] records, primarily due to non-randomized study design, non-antiviral interventions, irrelevant outcomes, or non-COVID-19 populations. The full texts of [N5] articles were subsequently assessed for eligibility. Of these, [N6] articles were excluded following full-text review for the following reasons: retracted papers (n=), non-randomized design (n= ), absence of relevant clinical outcomes (n= ), inappropriate comparator (n= ), duplicate or overlapping populations (n= ), or insufficient for extraction (n= ). Ultimately, [N7] randomized controlled trials met the inclusion criteria and were included in the qualitative synthesis. Of these, [N8] trials provided sufficient data to be included in the quantitative meta-analysis. About 12,250 results were found in our search. After excluding publications without an abstract, published in English, and that were human studies, 9,849 studies remained from 2020 to 2025. About 278 of them were RCTs, 161 were meta-analyses, and 264 were systematic reviews. After reviewing the titles and abstracts, 110 references remained. Non-antiviral agents (monoclonal antibodies, steroids, interferon, plasma exchange, and chloroquine) were excluded. Mild, long, non-hospitalized, community-based, or asymptomatic patients were excluded. Subgroup analyses included vaccinated and unvaccinated patients, as well as combinations of antivirals and no combinations. The outcomes studied were mortality, ICU admission, acute respiratory failure, and hospital length of stay. The search in CENTRAL (Cochrane Library) yielded 87 Cochrane reviews and 23,688 trials, and one clinical answer. About 1891 citations were found in our search. After removing duplicate and irrelevant studies, 473 publications were identified and screened for relevance based on their titles and abstracts. 58 RCTs were assessed for eligibility; 49 studies from 43 journals were included in the systematic review and meta-analysis (Fig. 1 ). Some articles evaluated several options concomitantly or with combinations but in separate arms and were analyzed apart: baloxavir (BXV) and FPV ( 7 ); FPV alone or FPV/LPV/r; and LPV/r alone ( 8 ), LPV/r alone or combination with chloroquine (CLQ) ( 9 ); LPV/r and UFV ( 10 ); the WHO Solidarity trial evaluated concomitantly RDS alone, LPV/r alone among others ( 11 ). According to editors' decisions, some publications were initially published and subsequently retracted due to inconsistencies in the results. Two studies with FPV were by the same authors ( 12 , 13 ). Another study used SOF ( 14 ), and another used RDS ( 15 ). These studies were not considered in the analysis. 3.2. Population Patients (12,052) were adults across a spectrum of clinical presentations, from asymptomatic individuals with a positive SARS-CoV-2 RT-PCR to severe COVID-19, either outpatients or hospitalized. Nearly 1,965 hospital or research settings were involved, ranging from 1 to 405 per trial. Some cases occurred in an institutional setting, such as a general ward or an ICU, with or without mechanical ventilation. Patients included in each range varied from 20 ( 7 ) to 5551 ( 11 ) across studies. 3.3. Risk of bias assessment Twenty-five of the included clinical trials had a high methodological quality; nineteen had some concerns attributed mainly to issues with randomization or measurement of the outcome in open-label trials. Six studies found an increased risk of bias for doubts on the declaration of the randomization process, lack of blinding patients, caregivers, and researchers about the allocation of participants, or outcome measuring and final analyses (Fig. 2 ). 3.4. Severity The distribution of study severity was predominantly moderate (52%), mild (35.6%), and severe (12.4%). Most trials had particularly mild cases (3 of 7 agent groups; Fig. 3 ). Severe cases were mainly tested for LPV/r, RDS, SOF, and UFV. Trials testing RDS included many moderate and severe cases (Fig. 4 ) ( 11 , 16 – 23 ). 3.5. Intervention Antiviral regimens included LPV/r (7 trials), RDS (10 trials), FPV (13 trials), MPV (3 trials), SOF (7 trials), and UFV (3 trials). In some cases, different doses and the duration of therapy (5 vs. 10 days) were tested. Antiviral agents were evaluated in only one trial, like atazanavir, baloxavir, ensitrelvir, and nirmatrelvir ( 7 , 24 – 26 ). 3.6. Comparator In the included studies, a placebo or standard of care (SOC) was used as a comparator. Sometimes, therapies in the SOC included additional antivirals, corticosteroids, immunotherapy, and chloroquine. 3.7. Outcomes The primary efficacy outcome considered was mortality. Some studies evaluated it at 14, 28, or 30 days after hospital admission for hospital mortality ( 9 , 11 , 29 – 31 , 16 , 18 , 19 , 22 , 24 , 26 – 28 ). In some cases, recovery rates were extracted from studies as frequencies under the term “improvement” or as scores on a clinical scale ( 32 , 33 ). Some studies considered evaluating secondary outcomes in their follow-up, including the need for hospitalization, ICU admission, and mechanical ventilation. Others measured clinical improvement scales (e.g., the WHO scale) or viral clearance in daily or interval tracking ( 25 , 34 ). 3.8. Synthesis of the results The included clinical trials recruited 28840 patients from 29 to 11330 (Table I). One study evaluated several options (WHO Solidarity): 2750 were assigned to receive RDS, 1411 to LPV/r alone, and 2063 to LPV/r with interferon ( 11 ). Several trials tested some antiviral agents (FPV = 13; LPV/r = 7; RDS = 10; SOF = 7). 3.9. Efficacy 3.9.1. Mortality According to the results, treatment with RDS for ten days significantly decreased the mortality rate compared to the control group, with an RR of 0.83 (95%IC 0.74–0.93; p = 0.001). These are the pooled results from six clinical trials with moderate and high severity (Fig. 5 ) ( 11 , 16 – 18 , 22 , 31 ). Most of the positive effects on mortality were found in the ACTT-1 trial, especially in moderate cases or scores of 5 (Fig. 6 ) ( 18 ). In one study, the death rate was also lower in patients treated with SOF (RR 0.17; 0.04–0.73; p = 0.02) ( 35 ). Patients treated with molnupiravir also had lower mortality (RR 0.16; 0.04–0.73; p = 0.02) ( 36 ). One additional study reported a reduction in mortality among patients treated with nirmatrelvir (RR 0.05; 0.00–0.91; p = 0.04) ( 26 ). Contrarily, the combination of LPV/r with chloroquine showed increased mortality in one study (Fig. 7 ) ( 9 ). 3.9.2. Clinical improvement The ACTT-1 trial (RDS) also showed a reduced risk of progression to higher severity (score 6 or 7; invasive or noninvasive ventilation) in moderate, but not mild, cases ( 18 ). According to five studies, the recovery rate was higher in patients treated with SOF (RR 1.45; 1.25–1.67; p < 0.00001) ( 33 , 35 , 37 – 39 ). Clinical cure was also higher in patients treated with SOF compared to oseltamivir according to one study (RR 1,80; 1.41–2.29; p < 0.00001) ( 39 ); the time of cure was also shorter in the same study (Mean difference [MD] -10.00; -7.52 to -12.48; p = 0.00001). 3.9.3. Need and duration of ICU stay. Patients treated with LPV/r showed a significant decrease in ICU and hospital length of stay (5 days; 2.36–7.64 and 2 days; 0.47–3.53, respectively), even when no effect was found in mortality ( 40 ). Moderate cases treated with RDS had a decreased need for ICU admission (RR 0.66; 0.42–1.05) ( 18 , 31 ). Studies have reported a lower need for ICU admission among patients treated with SOF (RR 0.30; 0.13–0.67; p = 0.003) ( 35 , 38 ). 3.9.4. Need and duration of mechanical ventilation. Five studies found that patients treated with RDS had a lower need for mechanical ventilation (RR 0.86; 0.75–0.98; p = 0.022) and a shorter duration of mechanical ventilation (-8.50 days; -4.68 to -12.32) ( 41 ). 3.9.5. Need and duration of hospitalization. Patients treated with RDS had a decrease in the need for hospitalization, although the difference was not significant (RR 0.82; 0.65–1.05; p = 0.12) ( 20 , 22 ). Contrarily, these patients also had a lower rate of discharge (RR 0.69; 0.59–0.81; p < 0.0001) ( 22 ). The hospitalization rate was also lower in patients treated with nirmatrelvir (RR 0.12; 0.06–0.25; p < 0.00001) ( 26 ). In patients treated with SOF, the length of stay was shorter according to one study (MD = -4.00; -2.00 to -6.00; p < 0.0001) ( 35 ). This was consistent with the results from another study (MD -9.00; -7.43 to -10.57; p < 0.00001) ( 39 ). Hospitalization length was also shorter in patients treated with UFV than in those treated with LPV/r, according to one study (MD = -2.40; -0.46 to -4.34; p = 0.02) ( 42 ). 3.9.6. Viral clearance Viral clearance was primarily studied in non-severe cases and had a higher proportion on days 5, 8, 11, and 14 in patients treated with SOF (RR 1.54; 95% CI 1.23–1.93; p = 0.0002) ( 33 , 39 , 43 , 44 ). Similar results were found with UFV (RR 1.52; 1.18–1.98; p = 0.001) ( 42 , 45 , 46 ) and MPV (RR 1.18; 1.04–1.33; p = 0.01) ( 47 ). A lower viral load positivity rate by day 3 with a higher MPV dose was observed in the latter study (RR 0.11; 0.01–0.86; p = 0.04). 3.10. Subgroup analysis First, the effects of the repurposed antivirals differed. Efficacy varied widely among some, with no effect on others. 3.10.1. Lopinavir/ritonavir Most studies of LPV/r showed no benefit on mortality ( Error! Reference source not found. ), need or duration of mechanical ventilation, hospital stay, clinical improvement or worsening, or viral clearance ( 8 – 11 , 40 , 48 ). However, some studies showed that ICU and hospital lengths of stay were shorter, and clinical improvement was higher on days 7 and 28 ( 40 ). 3.10.2. Remdesivir The results showed decreased mortality in patients treated with RDS (RR 0.88; 95% CI 0.79–0.99; p = 0.03) (Fig. 5 ). The effect was observed in moderate cases (Fig. 6 ) ( 11 , 18 ). Some studies have shown shorter hospital stays ( 20 ), fewer ICU admissions ( 18 ), and shorter mechanical ventilation durations ( 17 , 22 ). 3.10.3. Favipiravir Three studies showed no benefit on mortality with FPV, mechanical ventilation, or ICU admission ( 27 , 29 , 34 ); two other studies found higher clinical improvement (RR 2.45; 1.45–4.15), a shorter time to sustained clinical improvement (2.14 days shorter; 0.76–3.52), and viral clearance ( 49 , 50 ). Another trial reported a shorter time to viral clearance ( 50 ), whereas another found no difference in viral clearance, length of stay, or clinical improvement ( 32 , 51 , 52 ). A study found no benefit in viral clearance by day 14, time to clinical improvement, incidence of mechanical ventilation, or ICU transfer ( 7 ). Two more studies combined FPV with interferon (IF) and found no benefit on mortality or viral load compared to placebo, LPV/r alone, or combined with IF ( 8 , 28 ). The combination of FPV with LPV/r showed antagonism on viral clearance. Other RCTs found FPV superior in shortening the duration of viral shedding in SARS-CoV-2 RNA positivity after discharge ( 53 ). 3.10.4. Sofosbuvir Several trials evaluated the effect of SOF in combination with daclatasvir (DCV) or others. An RCT found increased mortality, hospital length of stay, and the need for and duration of mechanical ventilation ( 54 ). Other investigators found no benefit in hospital admission or clinical improvement for outpatients with mild COVID-19 treated with SOF/DCV ( 37 ). Additionally, an RCT showed no benefit in mortality, need for, or duration of mechanical ventilation, hospital stay, clinical improvement, time to clinical improvement, or viral clearance for severe cases with SARS-CoV-2 infection ( 33 ). One more RCT showed a higher viral clearance rate in non-severe COVID-19 patients ( 43 ). An RCT compared SOF/DCV with ribavirin (RBV) and found a lower risk of death (p = 0.02), ICU admission (p = 0.01), and shorter hospital stays, and a higher proportion of patients recovered. However, other RCTs found no benefit in mortality, ICU admission, mechanical ventilation, or hospital length of stay with SOF/DTV + RBV ( 38 ). One more RCT compared SOF/LPV (ledipasvir) with a combination of oseltamivir, CLQ, and azithromycin (AZT) ( 39 ). The results showed a higher cure rate with shorter hospital stays; however, differences in mortality and viral clearance were not significant. 3.10.5. Umifenovir In an RCT with UFV, authors found a higher proportion of viral clearance by day 5 (p = 0.004) but no difference after day 7 in the mild-asymptomatic group ( 45 ). Clinical improvement was faster in the mild-asymptomatic group by day 5 (p = 0.019) but not in the moderate group. Other RCTs showed no less mortality, ICU admission, or viral clearance, but the duration of hospitalization was lower in patients treated with UFV in contrast with LPV/r. 3.10.6. Molnupiravir An RCT showed a faster viral clearance in non-severe patients treated with high doses of MPV ( 47 ). Another study showed a lower risk of hospitalization or death (RR 0.16; 95% CI 0.04–0.73; p = 0.02) ( 36 ). 3.10.7. Nirmatrelvir In a multicenter RCT granted by Pfizer® on non-hospitalized patients with SARS-CoV-2 infection mortality, there were no deaths in the arm treated with nirmatrelvir/ritonavir compared to placebo (RR 0.05; 95% CI 0.00-0.91; p = 0.04) ( 26 ). A decrease in hospitalization rate was also significant (0.38 vs. 3.17%; RR 0.12; 95% CI 0.02–0.25; p < 0.0001). 3.10.8. Ensitrelvir An RCT found higher viral clearance by day 4 in patients with mild-to-moderate COVID-19 treated with ensitrelvir ( 25 ). 3.10.9. Atazanavir The study of atazanavir used in combination with other antivirals and chloroquine was compared with various LPV/r regimens with CLQ; no placebo arm was included ( 24 ). No benefit was found in mortality, ICU admission, or mechanical ventilation. 3.10.10. Baloxavir An RCT evaluated baloxavir in symptomatic individuals with COVID-19 and found no difference in viral clearance, viral clearance rate, time to clinical improvement, need for mechanical ventilation, or ICU admission ( 7 ). 4. Discussion This study gathers a comprehensive analysis of the current evidence on outcomes for antiviral agents in patients with COVID-19 provided by RCTs. Treatment for SARS-CoV-2 infection has been symptomatic for mild cases and supportive for severe cases. There have been reports of widespread use of antiviral agents, even when the World Health Organization (WHO) has not recommended their use ( 42 ). Several publications have evaluated the efficacy of antiviral agents for treating SARS-CoV-2 infection from asymptomatic to critical cases. Only a few of them were revealed to be efficacious in modifying outcomes. Even after the pandemic, patient numbers have declined worldwide, but some peaks persist in several countries. There is currently no certainty about which therapies are beneficial and which outcomes are modified by treatment. The evaluation of outcomes varied among studies. Some considered mortality the primary outcome ( 24 , 29 ); even in these cases, there was a disparity among studies: some monitored the effect at 14 days ( 55 ), whereas others monitored it at 28 days ( 31 , 48 ). Although RDS showed a decrease in mortality, these findings were based primarily on two large RCTs (6613 patients) ( 11 , 18 ); both included patients with mild to severe disease, and the beneficial effect was observed in moderate cases. SOF, MPV, and nirmatrelvir also reduced mortality among patients with mild and moderate disease ( 26 , 35 , 36 ). No studies with LPV/r or FPV showed a decrease in mortality ( 9 , 11 , 48 , 56 ), and the combination with chloroquine was deleterious ( 9 ). Viral clearance is a major concern during pandemics. High viral counts were associated with disease severity and the likelihood of infectivity. Several studies have focused on the viral shedding effects of antiviral agents as primary or secondary outcomes in outpatients ( 51 ) or hospitalized ( 7 , 21 ), including those with mild to moderate symptoms ( 25 , 50 , 52 ). Antiviral agents with efficacy in reducing the duration or extent of viral shedding were SOF ( 33 , 39 ), UFV ( 45 ), and MPV ( 47 ). A search of the PROSPERO register of systematic reviews ( 57 ) identified 1631 records on COVID-19. Approximately 316 included antiviral agents: 94 with LPV, 141 with RDS, 45 with FPV, and 10 with SOF. Our review is dedicated exclusively to evaluating the effect of antiviral agents on experimental studies. 4.1. Limitations One of the main limitations of the analysis of the results is the heterogeneity of subjects allocated to the studies, including differences in severity (Fig. 4 ), age, and other risk factors, as well as additional therapies included in the SOC arm. In this context, the efficacy of RDS may differ across mild, moderate, and severe cases. The impact of RDS on mortality was observed in the moderate-severity group but not in the other severity groups (Fig. 6 ). This result was observed in the ACTT-1 trial ( 18 ) but not in the WHO Solidarity trial ( 11 ), which had a higher proportion of moderate cases. There were also differences in outcomes studied, from mortality to viral clearance. When interpreting an antiviral agent, caution should be exercised regarding the severity and the desired clinical outcome. Pharmaceutical companies sponsored some studies on new alternatives, the external results of which have yet to be confirmed. Most allocations included mild cases, and the benefit was limited to viral clearance. Another limitation is the lack of a placebo arm in some studies and the use of SOC in the control group, which included some therapeutic alternatives, even when some showed no beneficial effects in other trials. There is no certainty that such a combination could have a biased impact. A small number of allocations might have an impact on the capacity to detect a beneficial effect with the therapy; even when affecting a considerable amount of the population, COVID-19 had a low frequency of severe cases and mortality; ACTT-1 study had a small proportion of deaths in both groups (near six vs. 12%) ( 18 ). An experiment should have at least 358 cases assigned to each arm to find a (50%) difference in the effect, and maybe 1640 in each group if the impact was less (a 25% decrease in mortality). The studies with sufficient patient numbers included FPV ( 27 ), LPV/r ( 9 , 11 , 48 ), MPV ( 36 ), nirmatrelvir ( 26 ), RDS ( 11 , 16 – 22 ), and SOF ( 54 ). Finally, heterogeneity in trials evaluating mortality with LPR/r was low (I 2 = 0); RDS was moderate (I 2 = 40%), and FPV was intermediate (I 2 = 37%). 5. Conclusion Several antiviral agents demonstrated benefits in specific patient populations with SARS-CoV-2 infection. The benefits were observed in reduced mortality, ICU admission, mechanical ventilation, hospitalization, the rate of clinical improvement, and viral load. The overall certainty of evidence remains moderate to low, and results should be interpreted in the context of disease severity, treatment timing, and evolving standards of care. The effect was highly variable among studies and agents. Precaution is advised to adjudicate the impact of a specific agent on others. Declarations Acknowledgments We thank the people who supported us in completing this work. Conflicts of interest The authors declare that they have no competing interests. None of the authors were members of the research teams for any of the selected trials included in this review; we were not members of the advisory boards of any drug or technology agency, nor were we participants in any pharmaceutical company or biotechnology enterprise. The authors received no financial support for this article's research, authorship, or publication. The opinions expressed in this document are those of the authors and do not reflect the official position of any agency. Availability of data and other material A dataset of the registers included in the review was stored in the Mendeley Data repository (DOI: 10.17632/4RK2KFBJVT.1). 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Arch Virol 166(3):949–954 El-Bendary M, Abd-Elsalam S, Elbaz T, El-Akel W, Cordie A, Elhadidy T et al (2022) Efficacy of combined Sofosbuvir and Daclatasvir in the treatment of COVID-19 patients with pneumonia: a multicenter Egyptian study. Expert Rev Anti Infect Ther 20(2):291–295 Abd-Elsalam S, Ahmed OA, Mansour NO, Abdelaziz DH, Salama M, Fouad MHA et al (2021) Remdesivir efficacy in COVID-19 treatment: A randomized controlled trial. Am J Trop Med Hyg 106(3):886–890 Ader F, Bouscambert-Duchamp M, Hites M, Peiffer-Smadja N, Poissy J, Belhadi D et al (2022) Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial. Lancet Infect Dis 22(2):209–221 Ali K, Azher T, Baqi M, Binnie A, Borgia S, Carrier FM et al (2022) Remdesivir for the treatment of patients in hospital with COVID-19 in Canada: a randomized controlled trial. CMAJ 194(7):E242–E251 Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC et al (2020) Remdesivir for the treatment of Covid-19 — Final report. N Engl J Med 383(19):1813–1826 Goldman JD, Lye DCB, Hui DS, Marks KM, Bruno R, Montejano R et al (2020) Remdesivir for 5 or 10 days in patients with severe Covid-19. N Engl J Med 383(19):1827–1837 Gottlieb RL, Vaca CE, Paredes R, Mera J, Webb BJ, Perez G et al (2022) Early remdesivir to prevent progression to severe Covid-19 in outpatients. N Engl J Med 386(4):305–315 Lingas G, Néant N, Gaymard A, Belhadi D, Peytavin G, Hites M et al (2022) Effect of remdesivir on viral dynamics in COVID-19 hospitalized patients: a modelling analysis of the randomized, controlled, open-label DisCoVeRy trial. J Antimicrob Chemoter 77(5):1404–1412 Spinner CD, Gottlieb RL, Criner GJ, Arribas López JR, Cattelan AM, Soriano Viladomiu A et al (2020) Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: A randomized clinical trial. JAMA 324(11):1048–1057 Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y et al (2020) Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. ;1–10 Kalantari S, Fard SR, Maleki D, Taher MT, Yassin Z, Alimohamadi Y et al (2021) Comparing the effectiveness of Atazanavir/Ritonavir/Dolutegravir/Hydroxychloroquine and Lopinavir/Ritonavir/Hydroxychloroquine treatment regimens in COVID-19 patients. J Med Virol 93(12):6557–6565 Mukae H, Yotsuyanagi H, Ohmagari N, Doi Y, Imamura T, Sonoyama T et al (2022) A randomized phase 2/3 study of Ensitrelvir, a novel oral SARS-CoV-2 3C-like protease inhibitor, in Japanese patients with mild-to-moderate COVID-19 or asymptomatic SARS-CoV-2 infection: Results of the phase 2a part. Antimicrob Agents Chemother 66(10):e0069722 Hammond J, Leister-Tebbe H, Gardner A, Abreu P, Bao W, Wisemandle W et al (2022) Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19. N Engl J Med 386(15):1397–1408 Chuah CH, Chow TS, Hor CP, Cheng JT, Ker HB, Lee HG et al (2022) Efficacy of early treatment with favipiravir on disease progression among high-risk patients with Coronavirus Disease 2019 (COVID-19): A randomized, open-label clinical trial. Clin Infect Dis 75(1):e432–e439 Hassaniazad M, Farshidi H, Gharibzadeh A, Bazram A, Khalili E, Noormandi A et al (2022) Efficacy and safety of favipiravir plus interferon-beta versus lopinavir/ritonavir plus interferon-beta in moderately ill patients with COVID-19: A randomized clinical trial. J Med Virol 94(7):3184–3191 Khamis F, Al Naabi H, Al Lawati A, Ambusaidi Z, Al Sharji M, Al Barwani U et al (2021) Randomized controlled open label trial on the use of favipiravir combined with inhaled interferon beta-1b in hospitalized patients with moderate to severe COVID-19 pneumonia. Int J Infect Dis 102:538–543 Kalil AC, Patterson TF, Mehta AK, Tomashek KM, Wolfe CR, Ghazaryan V et al (2021) Baricitinib plus remdesivir for hospitalized adults with Covid-19. N Engl J Med 384(9):795–807 Barratt-Due A, Olsen IC, Nezvalova-Henriksen K, Kåsine T, Lund-Johansen F, Hoel H et al (2021) Evaluation of the effects of Remdesivir and Hydroxychloroquine on viral clearance in COVID-19: A randomized trial. Ann Intern Med 174(9):1261–1269 AlQahtani M, Kumar N, Aljawder D, Abdulrahman A, Alnashaba F, Fayyad MA et al (2022) Randomized controlled trial of favipiravir, hydroxychloroquine, and standard care in patients with mild/moderate COVID-19 disease. Sci Rep 12:4925 Sayad B, Khodarahmi R, Najafi F, Miladi R, Mohseni Afshar Z, Mansouri F et al (2021) Efficacy and safety of sofosbuvir/velpatasvir versus the standard of care in adults hospitalized with COVID-19: a single-centre, randomized controlled trial. J Antimicr Chemother 76(8):2158–2167 Ivashchenko AA, Dmitriev KA, Vostokova NV, Azarova VN, Blinow AA, Egorova AN et al (2021) AVIFAVIR for treatment of patients with moderate Coronavirus Disease 2019 (COVID-19): Interim results of a phase II/III multicenter randomized clinical trial. Clin Infect Dis 73(3):531–534 Eslami G, Mousaviasl S, Radmanesh E, Jelvay S, Bitaraf S, Simmons B et al (2020) The impact of sofosbuvir/daclatasvir or ribavirin in patients with severe COVID-19. J Antimicr Chemother 75(11):3366–3372 Jayk Bernal A, Gomes da Silva MM, Musungaie DB, Kovalchuk E, Gonzalez A, Delos Reyes V et al (2022) Molnupiravir for oral treatment of Covid-19 in nonhospitalized patients. N Engl J Med 386(6):509–520 Roozbeh F, Saeedi M, Alizadeh-Navaei R, Hedayatizadeh-Omran A, Merat S, Wentzel H et al (2021) Sofosbuvir and daclatasvir for the treatment of COVID-19 outpatients: a double-blind, randomized controlled trial. J Antimicr Chemother 76(3):753–757 Kasgari HA, Moradi S, Shabani AM, Babamahmoodi F, Davoudi Badabi AR, Davoudi L et al (2020) Evaluation of the efficacy of sofosbuvir plus daclatasvir in combination with ribavirin for hospitalized COVID-19 patients with moderate disease compared with standard care: A single-centre, randomized controlled trial. J Antimicrob Chemother 75(11):3373–3378 Elgohary MAS, Hasan EM, Ibrahim AA, Abdelsalam MFA, Abdel-Rahman RZ, Zaki AI et al (2022) Efficacy of sofosbuvir plus ledipasvir in Egyptian patients with COVID-19 compared to standard treatment: a randomized controlled trial. J Med Life 15(3):350–358 Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G et al (2020) A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med 382(19):1787–1799 Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y et al (2020) Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 395(10236):1569–1578 Nojomi M, Yassin Z, Keyvani H, Makiani MJ, Roham M, Laali A et al (2020) Effect of Arbidol (Umifenovir) on COVID-19: a randomized controlled trial. BMC Infect Dis 20(1):954 Medhat MA, El-Kassas M, Karam-Allah H, Al Shafie A, Abd-Elsalam S, Moustafa E et al (2022) Sofosbuvir/ledipasvir in combination or nitazoxanide alone are safe and efficient treatments for COVID-19 infection: A randomized controlled trial for repurposing antivirals. Arab J Gastroenterol 23(3):165–171 Chandiwana N, Kruger C, Johnstone H, Chughlay MF, Ju C, Kim B et al (2022) Safety and efficacy of four drug regimens versus standard-of-care for the treatment of symptomatic outpatients with COVID-19: A randomised, open-label, multi-arm, phase 2 clinical trial. EBioMedicine 86:104322 Ramachandran R, Bhosale V, Reddy H, Atam V, Faridi MMA, Fatima J et al (2022) Phase III, randomized, double-blind, placebo controlled trial of efficacy, safety and tolerability of antiviral drug Umifenovir vs standard care of therapy in non-severe COVID-19 patients. Int J Infect Dis 115:62–69 Sun J, Deng X, Chen X, Huang J, Huang S, Li Y et al (2020) Incidence of adverse drug reactions in COVID-19 patients in China: An active monitoring study by hospital pharmacovigilance system. Clin Pharmacol Ther 108(4):791–797 Fischer WA, Eron JJ, Holman W, Cohen MS, Fang L, Szewczyk LJ et al (2022) A phase 2a clinical trial of molnupiravir in patients with COVID-19 shows accelerated SARS-CoV-2 RNA clearance and elimination of infectious virus. Sci Transl Med 14(628):eabl7430 Horby PW, Mafham M, Bell JL, Linsell L, Staplin N, Emberson J et al (2020) Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet 396(10259):1345–1352 Sirijatuphat R, Manosuthi W, Niyomnaitham S, Owen A, Copeland KK, Charoenpong L et al (2022) Early treatment of Favipiravir in COVID-19 patients without pneumonia: a multicentre, open-labelled, randomized control study. Emerg Microbes Infect 11(1):2197–2206 Udwadia ZF, Singh P, Barkate H, Patil S, Rangwala S, Pendse A et al (2021) Efficacy and safety of favipiravir, an oral RNA-dependent RNA polymerase inhibitor, in mild-to-moderate COVID-19: A randomized, comparative, open-label, multicenter, phase 3 clinical trial. Int J Infect Dis 103:62–71 Holubar M, Subramanian A, Purington N, Hedlin H, Bunning B, Walter KS et al (2022) Favipiravir for treatment of outpatients with asymptomatic or uncomplicated Coronavirus Disease 2019: A double-blind, randomized, placebo-controlled, phase 2 trial. Clin Infect Dis 75(11):1883–1892 McMahon JH, Lau JSY, Coldham A, Roney J, Hagenauer M, Price S et al (2022) Favipiravir in early symptomatic COVID-19, a randomised placebo-controlled trial. eClinicalMedicine 54:101703 Zhao H, Zhang C, Zhu Q, Chen X, Chen G, Sun W et al (2021) Favipiravir in the treatment of patients with SARS-CoV-2 RNA recurrent positive after discharge: A multicenter, open-label, randomized trial. Int Immunopharmacol 97:107702 Mobarak S, Salasi M, Hormati A, Khodadadi J, Ziaee M, Abedi F et al (2022) Evaluation of the effect of sofosbuvir and daclatasvir in hospitalized COVID-19 patients: a randomized double-blind clinical trial (DISCOVER). J Antimicr Chemother 77(3):758–766 Sadeghi A, Asgari AA, Norouzi A, Kheiri Z, Anushirvani A, Montazeri M et al (2020) Sofosbuvir and daclatasvir compared with standard of care in the treatment of patients admitted to hospital with moderate or severe coronavirus infection (COVID-19): A randomized controlled trial. J Antimicr Chemother 75(11):3379–3385 Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G et al (2020) A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19. N Engl J Med 382(19):1787–1799 Pieper D, Rombey T (2022) Where to prospectively register a systematic review. Syst Rev 11:8 Khoo SH, Fitzgerald R, Fletcher T, Ewings S, Jaki T, Lyon R et al (2021) Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study. J Antimicr Chemother 76(12):3286–3295 Tables Tables 1 and 2 are available in the Supplementary Files section. Additional Declarations The authors declare no competing interests. Supplementary Files Tables.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9020094","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":600021867,"identity":"4477bf60-45a0-4034-a1ef-0d8857dd68e8","order_by":0,"name":"Norton Pérez-Gutiérrez","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABHklEQVRIiWNgGAWjYPCDChReAi5ljA0I9hmStTC2EaHFnL33+YOPOxjy+KUPH/74dZ6dvO7sHuPPPDV2DPzsOQYMPyowtFj2HDdsnHmGoViyLy3BWHZbsuG2O2fMpHmOJTNI9rwxYOw5g6HF4EYaYzNvG0PihjM8BsmS2w4wbruRY8bM23AAKJVjwIzmVBQt+8/wfzgsOeeAPVCL8WeQFntCWjbw8DA2fmw4kAjUYiANtkUCh5YzxxhnzmyTKJY4w2bMzHAsOXnbnWNlknOOJfNInHlWcBCbX463MXz42GaTx9/D/Pjjjxo72223mzd/eFNjJ8ffnrzxAZYQgwKJBBDJzANmQ4TA7AO4NDBAY43xB5KWUTAKRsEoGAUwAAAUpWw04sucQQAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-6666-0795","institution":"Universidad Cooperativa de Colombia","correspondingAuthor":true,"prefix":"","firstName":"Norton","middleName":"","lastName":"Pérez-Gutiérrez","suffix":""},{"id":600021868,"identity":"c5c17281-90bb-4a69-b34e-2247027e1803","order_by":1,"name":"María Ximena Mendoza-Gómez","email":"","orcid":"https://orcid.org/0000-0002-2507-3973","institution":"Universidad Cooperativa de Colombia","correspondingAuthor":false,"prefix":"","firstName":"María","middleName":"Ximena","lastName":"Mendoza-Gómez","suffix":""},{"id":600023097,"identity":"db1c832c-ebbd-48b2-86f6-77605a22e154","order_by":2,"name":"Lizeth Johana León-Cardozo","email":"","orcid":"https://orcid.org/0009-0002-2179-0833","institution":"Hospital Departamental de Villavicencio","correspondingAuthor":false,"prefix":"","firstName":"Lizeth","middleName":"Johana","lastName":"León-Cardozo","suffix":""},{"id":600023098,"identity":"484fa839-7c54-4afc-8e09-f2485b5f1b57","order_by":3,"name":"Miguel Angel Meléndez-Burgos","email":"","orcid":"https://orcid.org/0009-0007-4339-7262","institution":"Universidad Cooperativa de Colombia","correspondingAuthor":false,"prefix":"","firstName":"Miguel","middleName":"Angel","lastName":"Meléndez-Burgos","suffix":""}],"badges":[],"createdAt":"2026-03-03 12:10:21","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-9020094/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9020094/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104179908,"identity":"1265f20e-7cfe-4ea4-97eb-6c508699994a","added_by":"auto","created_at":"2026-03-08 17:09:51","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":64866,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA Flow diagram of the included studies.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9020094/v1/78bb3dbae2e5fc4aa726b999.png"},{"id":104179903,"identity":"281bc6db-835c-4116-b665-ee9f2a0f9765","added_by":"auto","created_at":"2026-03-08 17:09:51","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":219890,"visible":true,"origin":"","legend":"\u003cp\u003eRisk of bias assessment. (*) low risk of bias; (-) high risk of bias; (!) some concerns.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9020094/v1/58a95ddcb013706c738d2a51.png"},{"id":104403947,"identity":"b2612ba8-74ef-435f-ba49-a1deb7a1f81b","added_by":"auto","created_at":"2026-03-11 12:19:26","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":38239,"visible":true,"origin":"","legend":"\u003cp\u003eProportion of patients with COVID-19 allocated by severity in studies evaluating the efficacy of antivirals.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-9020094/v1/1dd39efa15a00c1ac76b8852.png"},{"id":104808260,"identity":"a292bde1-2efe-4a02-a54c-a57b6de18e8b","added_by":"auto","created_at":"2026-03-17 12:35:00","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":40533,"visible":true,"origin":"","legend":"\u003cp\u003eNumber of patients with COVID-19 allocated by author and by severity in studies evaluating the efficacy of remdesivir.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-9020094/v1/ef930d37280b2d1660a530b7.png"},{"id":104179910,"identity":"8da932a5-b58f-46f5-9b53-fc7c047be3e6","added_by":"auto","created_at":"2026-03-08 17:09:51","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":142066,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of remdesivir on mortality of patients with COVID-19.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-9020094/v1/8789f145dcbb06711b01b237.png"},{"id":104403876,"identity":"e25bf9c1-88a4-4682-80ab-7b874d1e0927","added_by":"auto","created_at":"2026-03-11 12:19:16","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":214643,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of remdesivir on mortality of patients with COVID-19 by severity.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-9020094/v1/916d1c7fc7875daf6e2dbd21.png"},{"id":104779620,"identity":"2b5d6265-6946-44c9-bc17-1c3ab94209c2","added_by":"auto","created_at":"2026-03-17 07:43:27","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":210052,"visible":true,"origin":"","legend":"\u003cp\u003eMortality of patients with COVID-19 treated with antiviral agents.\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-9020094/v1/e1208032ce2e28cefa0851f3.png"},{"id":104809485,"identity":"d6014a23-cac7-4738-b2df-4c071546bec7","added_by":"auto","created_at":"2026-03-17 12:51:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1644322,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9020094/v1/5d8edec0-f44e-4e5d-905d-a16a9d87c3d1.pdf"},{"id":104179906,"identity":"5e74f246-5687-4f3a-8cb5-59d3ba693209","added_by":"auto","created_at":"2026-03-08 17:09:51","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":216551,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-9020094/v1/a91d99a02a0f99c9517936a6.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eAntiviral agents for COVID-19: A post-pandemic systematic review of randomized controlled trials.\u003c/p\u003e","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eThe COVID-19 pandemic emerged three years ago, with millions of people affected in almost every country and thousands of deaths worldwide. Initially, experts proposed therapy alternatives based on theoretical considerations, with no evidence of practical results, but in the end, there is still no clear alternative for the management of new infections (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) other than vaccination (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eEven when the number of cases has descended dramatically, including severe cases, and a minimum of current fatal events occur, there is no certainty on the course of the disease to an endemic presentation or if there is any chance for new peaks. Therefore, alternatives for treating such an infection remain necessary (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). The question was: In patients with SARS-CoV-2 infection (P), therapy with antivirals (I) compared with placebo (C) improved outcomes (O)? The study aimed to assess the best available evidence on the efficacy of antiviral therapy for COVID-19 and synthesize the results.\u003c/p\u003e"},{"header":"2. Methodology","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Study design and protocol registration\u003c/h2\u003e \u003cp\u003eThis study was conducted as a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating antiviral therapies for severe COVID-19. The review was designed and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). The protocol, which was prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD420233994294.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Eligibility criteria\u003c/h2\u003e \u003cp\u003eEligibility criteria were predefined using the PICO framework.\u003c/p\u003e \u003cp\u003eTypes of studies: We included randomized controlled trials published in peer-reviewed journals. Both double-blind and open-label RCTs were eligible. Observational studies, non-randomized trials, preprints, conference abstracts, editorials, reviews, and vaccine studies were excluded. Retraction papers were also excluded from the review and meta-analysis, in accordance with PRISMA 2020 guidelines.\u003c/p\u003e \u003cp\u003eTypes of participants: Eligible studies enrolled adult patients (\u0026ge;18 years) with laboratory-confirmed SARS-CoV-2 infection, hospitalized with mild, moderate, or severe disease. Ambulatory patients, community- or home-based, non-severe, or post-exposure but asymptomatic status were excluded.\u003c/p\u003e \u003cp\u003eTypes of interventions: Trials evaluating antiviral agents administered for the treatment of COVID-19 were included. Eligible interventions comprised, but were not limited to, remdesivir, lopinavir/ritonavir, favipiravir, molnupiravir, nirmatrelvir (with or without ritonavir), sofosbuvir, umifenovir, and other investigational antiviral compounds. Other antiviral therapies (immunomodulators, monoclonal antibodies, vaccines, and non-antiviral agents) were excluded.\u003c/p\u003e \u003cp\u003eTypes of comparators: Comparator groups included placebo or standard of care (SOC), as defined within individual trials.\u003c/p\u003e \u003cp\u003eOutcomes: The primary outcome was all-cause mortality, reported as 14-day, 28-day, 30-day, or in-hospital mortality. Secondary outcomes included clinical recovery (defined as a lower NEWS-2 score or improvement), time to recovery, length of hospital stay, intensive care unit (ICU) admission, requirement for mechanical ventilation, and time to symptom resolution. Viral clearance, rebound, recurrence, sequelae, and long-term symptoms were excluded as outcomes.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Information sources and search strategy\u003c/h2\u003e \u003cp\u003eA comprehensive literature search was conducted in Medline (via PubMed) and the Cochrane Central Register of Controlled Trials (CENTRAL), including searches in Embase. The search covered publications from January 1, 2020, to December 31, 2022, without geographic restrictions. Only articles published in English were considered.\u003c/p\u003e \u003cp\u003eSearched strategies combined controlled vocabulary terms (e.g., MeSH and Emtree) and free-text keywords related to SARS-CoV-2, COVID-19, Coronavirus Infections, and antiviral agents. The complete search strategies for all databases are provided in Supplementary Appendix 1.\u003c/p\u003e \u003cp\u003eReference lists of relevant systematic reviews and included trials were manually screened to identify additional eligible studies.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4. Study selection\u003c/h2\u003e \u003cp\u003eAll retrieved records were imported into a reference management software, and duplicates were removed. Two reviewers independently screened titles and abstracts to assess eligibility. Full-text articles were subsequently reviewed for inclusion in accordance with the predefined criteria. Disagreements at any stage of the selection process were resolved through discussion, with adjudication by a third reviewer when necessary.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5. Data extraction\u003c/h2\u003e \u003cp\u003eData were independently extracted by two reviewers using a standardized data extraction form. Extracted information included:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eStudy characteristics (first author, year of publication, country, journal).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eParticipant characteristics (sample size, age, disease severity, clinical setting).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eIntervention details (antiviral agent, dosage, duration).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eComparator characteristics.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eOutcome data for all predefined endpoints.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eDuration of follow-up.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eFor a multi-arm trial evaluation of more than one antiviral intervention, each eligible comparison was extracted and analyzed separately to avoid unit-of-analysis errors.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.6. Risk of bias assessment\u003c/h2\u003e \u003cp\u003eMethodological quality was assessed using the Cochrane Risk of Bias tool, version 2 (ROB 2), which evaluates bias across five domains:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eRandomization process.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eDeviations from intended interventions.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eMissing outcome data.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eMeasurement of the outcome.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eSelection of the reported result.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eEach study was categorized as having low risk of bias, some concerns, or high risk of bias. Assessment was conducted independently by two reviewers, with disagreements resolved by consensus.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e2.7. Data synthesis and statistical analysis\u003c/h2\u003e \u003cp\u003eMeta-analyses were performed when at least two studies reported comparable outcome data. For dichotomous outcomes, treatment effects were summarized as relative risks (RRs) with 95% confidence intervals (CIs). A random-effects model (DerSimonian-Laird method) was used to account for anticipated clinical and methodological heterogeneity. Statistical heterogeneity was assessed using the I\u003csup\u003e2\u003c/sup\u003e statistic, with values of approximately 25%, 50%, and 75% interpreted as low, moderate, and high heterogeneity, respectively.\u003c/p\u003e \u003cp\u003ePredefined subgroup analyses were conducted according to:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eAntiviral agent.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eCombinations.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003e All statistical analyses were performed using Review Manager (RevMan) version 5.4.1 (Cochrane Collaboration).\u003c/p\u003e \u003cp\u003eFormal assessment of publication bias (e.g., funnel plots) was not performed when fewer than ten studies were available for a given outcome.\u003c/p\u003e \u003cp\u003eThe certainty of evidence for the primary outcome was assessed qualitatively, considering risk of bias, consistency of results, precision of effect estimates, and clinical relevance, in line with established systematic review methodology.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e2.8. Ethical considerations\u003c/h2\u003e \u003cp\u003eAs this study synthesized data from previously published trials, ethical approval was not required.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.1. Studies selection\u003c/h2\u003e \u003cp\u003eThe study selection process is summarized in accordance with the PRISMA 2020 flow diagram (Figure X. PRISMA 2020 flow diagram of study identification and selection).\u003c/p\u003e \u003cp\u003eA total of [295] records were identified through database searches, including PubMed (n\u0026thinsp;=\u0026thinsp;110) and Cochrane CENTRAL (n\u0026thinsp;=\u0026thinsp;185). After removing duplicate records [190], 199 unique records remained for screening. No additional eligible studies were identified through manual reference screening. Title and abstract screening excluded [N4] records, primarily due to non-randomized study design, non-antiviral interventions, irrelevant outcomes, or non-COVID-19 populations. The full texts of [N5] articles were subsequently assessed for eligibility. Of these, [N6] articles were excluded following full-text review for the following reasons: retracted papers (n=), non-randomized design (n= ), absence of relevant clinical outcomes (n= ), inappropriate comparator (n= ), duplicate or overlapping populations (n= ), or insufficient for extraction (n= ). Ultimately, [N7] randomized controlled trials met the inclusion criteria and were included in the qualitative synthesis. Of these, [N8] trials provided sufficient data to be included in the quantitative meta-analysis.\u003c/p\u003e \u003cp\u003eAbout 12,250 results were found in our search. After excluding publications without an abstract, published in English, and that were human studies, 9,849 studies remained from 2020 to 2025. About 278 of them were RCTs, 161 were meta-analyses, and 264 were systematic reviews. After reviewing the titles and abstracts, 110 references remained. Non-antiviral agents (monoclonal antibodies, steroids, interferon, plasma exchange, and chloroquine) were excluded. Mild, long, non-hospitalized, community-based, or asymptomatic patients were excluded. Subgroup analyses included vaccinated and unvaccinated patients, as well as combinations of antivirals and no combinations. The outcomes studied were mortality, ICU admission, acute respiratory failure, and hospital length of stay.\u003c/p\u003e \u003cp\u003eThe search in CENTRAL (Cochrane Library) yielded 87 Cochrane reviews and 23,688 trials, and one clinical answer.\u003c/p\u003e \u003cp\u003eAbout 1891 citations were found in our search. After removing duplicate and irrelevant studies, 473 publications were identified and screened for relevance based on their titles and abstracts. 58 RCTs were assessed for eligibility; 49 studies from 43 journals were included in the systematic review and meta-analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Some articles evaluated several options concomitantly or with combinations but in separate arms and were analyzed apart: baloxavir (BXV) and FPV (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e); FPV alone or FPV/LPV/r; and LPV/r alone (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), LPV/r alone or combination with chloroquine (CLQ) (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e); LPV/r and UFV (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e); the WHO Solidarity trial evaluated concomitantly RDS alone, LPV/r alone among others (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAccording to editors' decisions, some publications were initially published and subsequently retracted due to inconsistencies in the results. Two studies with FPV were by the same authors (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Another study used SOF (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), and another used RDS (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). These studies were not considered in the analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.2. Population\u003c/h2\u003e \u003cp\u003ePatients (12,052) were adults across a spectrum of clinical presentations, from asymptomatic individuals with a positive SARS-CoV-2 RT-PCR to severe COVID-19, either outpatients or hospitalized. Nearly 1,965 hospital or research settings were involved, ranging from 1 to 405 per trial. Some cases occurred in an institutional setting, such as a general ward or an ICU, with or without mechanical ventilation. Patients included in each range varied from 20 (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) to 5551 (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) across studies.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e3.3. Risk of bias assessment\u003c/h2\u003e \u003cp\u003eTwenty-five of the included clinical trials had a high methodological quality; nineteen had some concerns attributed mainly to issues with randomization or measurement of the outcome in open-label trials. Six studies found an increased risk of bias for doubts on the declaration of the randomization process, lack of blinding patients, caregivers, and researchers about the allocation of participants, or outcome measuring and final analyses (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e3.4. Severity\u003c/h2\u003e \u003cp\u003eThe distribution of study severity was predominantly moderate (52%), mild (35.6%), and severe (12.4%). Most trials had particularly mild cases (3 of 7 agent groups; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Severe cases were mainly tested for LPV/r, RDS, SOF, and UFV. Trials testing RDS included many moderate and severe cases (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e) (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan additionalcitationids=\"CR17 CR18 CR19 CR20 CR21 CR22\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e3.5. Intervention\u003c/h2\u003e \u003cp\u003eAntiviral regimens included LPV/r (7 trials), RDS (10 trials), FPV (13 trials), MPV (3 trials), SOF (7 trials), and UFV (3 trials). In some cases, different doses and the duration of therapy (5 vs. 10 days) were tested. Antiviral agents were evaluated in only one trial, like atazanavir, baloxavir, ensitrelvir, and nirmatrelvir (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e3.6. Comparator\u003c/h2\u003e \u003cp\u003e In the included studies, a placebo or standard of care (SOC) was used as a comparator. Sometimes, therapies in the SOC included additional antivirals, corticosteroids, immunotherapy, and chloroquine.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003e3.7. Outcomes\u003c/h2\u003e \u003cp\u003eThe primary efficacy outcome considered was mortality. Some studies evaluated it at 14, 28, or 30 days after hospital admission for hospital mortality (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan additionalcitationids=\"CR30\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan additionalcitationids=\"CR27\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). In some cases, recovery rates were extracted from studies as frequencies under the term \u0026ldquo;improvement\u0026rdquo; or as scores on a clinical scale (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSome studies considered evaluating secondary outcomes in their follow-up, including the need for hospitalization, ICU admission, and mechanical ventilation. Others measured clinical improvement scales (e.g., the WHO scale) or viral clearance in daily or interval tracking (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003e3.8. Synthesis of the results\u003c/h2\u003e \u003cp\u003eThe included clinical trials recruited 28840 patients from 29 to 11330 (Table I). One study evaluated several options (WHO Solidarity): 2750 were assigned to receive RDS, 1411 to LPV/r alone, and 2063 to LPV/r with interferon (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Several trials tested some antiviral agents (FPV\u0026thinsp;=\u0026thinsp;13; LPV/r\u0026thinsp;=\u0026thinsp;7; RDS\u0026thinsp;=\u0026thinsp;10; SOF\u0026thinsp;=\u0026thinsp;7).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003e3.9. Efficacy\u003c/h2\u003e \u003cdiv id=\"Sec21\" class=\"Section3\"\u003e \u003ch2\u003e3.9.1. Mortality\u003c/h2\u003e \u003cp\u003eAccording to the results, treatment with RDS for ten days significantly decreased the mortality rate compared to the control group, with an RR of 0.83 (95%IC 0.74\u0026ndash;0.93; p\u0026thinsp;=\u0026thinsp;0.001). These are the pooled results from six clinical trials with moderate and high severity (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e) (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). Most of the positive effects on mortality were found in the ACTT-1 trial, especially in moderate cases or scores of 5 (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e) (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). In one study, the death rate was also lower in patients treated with SOF (RR 0.17; 0.04\u0026ndash;0.73; p\u0026thinsp;=\u0026thinsp;0.02) (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). Patients treated with molnupiravir also had lower mortality (RR 0.16; 0.04\u0026ndash;0.73; p\u0026thinsp;=\u0026thinsp;0.02) (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). One additional study reported a reduction in mortality among patients treated with nirmatrelvir (RR 0.05; 0.00\u0026ndash;0.91; p\u0026thinsp;=\u0026thinsp;0.04) (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Contrarily, the combination of LPV/r with chloroquine showed increased mortality in one study (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e) (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section3\"\u003e \u003ch2\u003e3.9.2. Clinical improvement\u003c/h2\u003e \u003cp\u003eThe ACTT-1 trial (RDS) also showed a reduced risk of progression to higher severity (score 6 or 7; invasive or noninvasive ventilation) in moderate, but not mild, cases (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). According to five studies, the recovery rate was higher in patients treated with SOF (RR 1.45; 1.25\u0026ndash;1.67; p\u0026thinsp;\u0026lt;\u0026thinsp;0.00001) (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan additionalcitationids=\"CR38\" citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). Clinical cure was also higher in patients treated with SOF compared to oseltamivir according to one study (RR 1,80; 1.41\u0026ndash;2.29; p\u0026thinsp;\u0026lt;\u0026thinsp;0.00001) (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e); the time of cure was also shorter in the same study (Mean difference [MD] -10.00; -7.52 to -12.48; p\u0026thinsp;=\u0026thinsp;0.00001).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003e3.9.3. Need and duration of ICU stay.\u003c/h2\u003e \u003cp\u003ePatients treated with LPV/r showed a significant decrease in ICU and hospital length of stay (5 days; 2.36\u0026ndash;7.64 and 2 days; 0.47\u0026ndash;3.53, respectively), even when no effect was found in mortality (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e). Moderate cases treated with RDS had a decreased need for ICU admission (RR 0.66; 0.42\u0026ndash;1.05) (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). Studies have reported a lower need for ICU admission among patients treated with SOF (RR 0.30; 0.13\u0026ndash;0.67; p\u0026thinsp;=\u0026thinsp;0.003) (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section3\"\u003e \u003ch2\u003e3.9.4. Need and duration of mechanical ventilation.\u003c/h2\u003e \u003cp\u003eFive studies found that patients treated with RDS had a lower need for mechanical ventilation (RR 0.86; 0.75\u0026ndash;0.98; p\u0026thinsp;=\u0026thinsp;0.022) and a shorter duration of mechanical ventilation (-8.50 days; -4.68 to -12.32) (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec25\" class=\"Section3\"\u003e \u003ch2\u003e3.9.5. Need and duration of hospitalization.\u003c/h2\u003e \u003cp\u003ePatients treated with RDS had a decrease in the need for hospitalization, although the difference was not significant (RR 0.82; 0.65\u0026ndash;1.05; p\u0026thinsp;=\u0026thinsp;0.12) (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Contrarily, these patients also had a lower rate of discharge (RR 0.69; 0.59\u0026ndash;0.81; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). The hospitalization rate was also lower in patients treated with nirmatrelvir (RR 0.12; 0.06\u0026ndash;0.25; p\u0026thinsp;\u0026lt;\u0026thinsp;0.00001) (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn patients treated with SOF, the length of stay was shorter according to one study (MD = -4.00; -2.00 to -6.00; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). This was consistent with the results from another study (MD -9.00; -7.43 to -10.57; p\u0026thinsp;\u0026lt;\u0026thinsp;0.00001) (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). Hospitalization length was also shorter in patients treated with UFV than in those treated with LPV/r, according to one study (MD = -2.40; -0.46 to -4.34; p\u0026thinsp;=\u0026thinsp;0.02) (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec26\" class=\"Section3\"\u003e \u003ch2\u003e3.9.6. Viral clearance\u003c/h2\u003e \u003cp\u003eViral clearance was primarily studied in non-severe cases and had a higher proportion on days 5, 8, 11, and 14 in patients treated with SOF (RR 1.54; 95% CI 1.23\u0026ndash;1.93; p\u0026thinsp;=\u0026thinsp;0.0002) (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e). Similar results were found with UFV (RR 1.52; 1.18\u0026ndash;1.98; p\u0026thinsp;=\u0026thinsp;0.001) (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e) and MPV (RR 1.18; 1.04\u0026ndash;1.33; p\u0026thinsp;=\u0026thinsp;0.01) (\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e). A lower viral load positivity rate by day 3 with a higher MPV dose was observed in the latter study (RR 0.11; 0.01\u0026ndash;0.86; p\u0026thinsp;=\u0026thinsp;0.04).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec27\" class=\"Section2\"\u003e \u003ch2\u003e3.10. Subgroup analysis\u003c/h2\u003e \u003cp\u003eFirst, the effects of the repurposed antivirals differed. Efficacy varied widely among some, with no effect on others.\u003c/p\u003e \u003cdiv id=\"Sec28\" class=\"Section3\"\u003e \u003ch2\u003e3.10.1. Lopinavir/ritonavir\u003c/h2\u003e \u003cp\u003eMost studies of LPV/r showed no benefit on mortality (\u003cb\u003eError! Reference source not found.\u003c/b\u003e), need or duration of mechanical ventilation, hospital stay, clinical improvement or worsening, or viral clearance (\u003cspan additionalcitationids=\"CR9 CR10\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e). However, some studies showed that ICU and hospital lengths of stay were shorter, and clinical improvement was higher on days 7 and 28 (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec29\" class=\"Section3\"\u003e \u003ch2\u003e3.10.2. Remdesivir\u003c/h2\u003e \u003cp\u003eThe results showed decreased mortality in patients treated with RDS (RR 0.88; 95% CI 0.79\u0026ndash;0.99; p\u0026thinsp;=\u0026thinsp;0.03) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). The effect was observed in moderate cases (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e) (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Some studies have shown shorter hospital stays (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e), fewer ICU admissions (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e), and shorter mechanical ventilation durations (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec30\" class=\"Section3\"\u003e \u003ch2\u003e3.10.3. Favipiravir\u003c/h2\u003e \u003cp\u003eThree studies showed no benefit on mortality with FPV, mechanical ventilation, or ICU admission (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e); two other studies found higher clinical improvement (RR 2.45; 1.45\u0026ndash;4.15), a shorter time to sustained clinical improvement (2.14 days shorter; 0.76\u0026ndash;3.52), and viral clearance (\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e). Another trial reported a shorter time to viral clearance (\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e), whereas another found no difference in viral clearance, length of stay, or clinical improvement (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e). A study found no benefit in viral clearance by day 14, time to clinical improvement, incidence of mechanical ventilation, or ICU transfer (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Two more studies combined FPV with interferon (IF) and found no benefit on mortality or viral load compared to placebo, LPV/r alone, or combined with IF (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). The combination of FPV with LPV/r showed antagonism on viral clearance.\u003c/p\u003e \u003cp\u003eOther RCTs found FPV superior in shortening the duration of viral shedding in SARS-CoV-2 RNA positivity after discharge (\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec31\" class=\"Section3\"\u003e \u003ch2\u003e3.10.4. Sofosbuvir\u003c/h2\u003e \u003cp\u003eSeveral trials evaluated the effect of SOF in combination with daclatasvir (DCV) or others. An RCT found increased mortality, hospital length of stay, and the need for and duration of mechanical ventilation (\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e). Other investigators found no benefit in hospital admission or clinical improvement for outpatients with mild COVID-19 treated with SOF/DCV (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e). Additionally, an RCT showed no benefit in mortality, need for, or duration of mechanical ventilation, hospital stay, clinical improvement, time to clinical improvement, or viral clearance for severe cases with SARS-CoV-2 infection (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). One more RCT showed a higher viral clearance rate in non-severe COVID-19 patients (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAn RCT compared SOF/DCV with ribavirin (RBV) and found a lower risk of death (p\u0026thinsp;=\u0026thinsp;0.02), ICU admission (p\u0026thinsp;=\u0026thinsp;0.01), and shorter hospital stays, and a higher proportion of patients recovered. However, other RCTs found no benefit in mortality, ICU admission, mechanical ventilation, or hospital length of stay with SOF/DTV\u0026thinsp;+\u0026thinsp;RBV (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOne more RCT compared SOF/LPV (ledipasvir) with a combination of oseltamivir, CLQ, and azithromycin (AZT) (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). The results showed a higher cure rate with shorter hospital stays; however, differences in mortality and viral clearance were not significant.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec32\" class=\"Section3\"\u003e \u003ch2\u003e3.10.5. Umifenovir\u003c/h2\u003e \u003cp\u003eIn an RCT with UFV, authors found a higher proportion of viral clearance by day 5 (p\u0026thinsp;=\u0026thinsp;0.004) but no difference after day 7 in the mild-asymptomatic group (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e). Clinical improvement was faster in the mild-asymptomatic group by day 5 (p\u0026thinsp;=\u0026thinsp;0.019) but not in the moderate group. Other RCTs showed no less mortality, ICU admission, or viral clearance, but the duration of hospitalization was lower in patients treated with UFV in contrast with LPV/r.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec33\" class=\"Section3\"\u003e \u003ch2\u003e3.10.6. Molnupiravir\u003c/h2\u003e \u003cp\u003eAn RCT showed a faster viral clearance in non-severe patients treated with high doses of MPV (\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e). Another study showed a lower risk of hospitalization or death (RR 0.16; 95% CI 0.04\u0026ndash;0.73; p\u0026thinsp;=\u0026thinsp;0.02) (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec34\" class=\"Section3\"\u003e \u003ch2\u003e3.10.7. Nirmatrelvir\u003c/h2\u003e \u003cp\u003eIn a multicenter RCT granted by Pfizer\u0026reg; on non-hospitalized patients with SARS-CoV-2 infection mortality, there were no deaths in the arm treated with nirmatrelvir/ritonavir compared to placebo (RR 0.05; 95% CI 0.00-0.91; p\u0026thinsp;=\u0026thinsp;0.04) (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). A decrease in hospitalization rate was also significant (0.38 vs. 3.17%; RR 0.12; 95% CI 0.02\u0026ndash;0.25; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec35\" class=\"Section3\"\u003e \u003ch2\u003e3.10.8. Ensitrelvir\u003c/h2\u003e \u003cp\u003eAn RCT found higher viral clearance by day 4 in patients with mild-to-moderate COVID-19 treated with ensitrelvir (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec36\" class=\"Section3\"\u003e \u003ch2\u003e3.10.9. Atazanavir\u003c/h2\u003e \u003cp\u003eThe study of atazanavir used in combination with other antivirals and chloroquine was compared with various LPV/r regimens with CLQ; no placebo arm was included (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). No benefit was found in mortality, ICU admission, or mechanical ventilation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec37\" class=\"Section3\"\u003e \u003ch2\u003e3.10.10. Baloxavir\u003c/h2\u003e \u003cp\u003eAn RCT evaluated baloxavir in symptomatic individuals with COVID-19 and found no difference in viral clearance, viral clearance rate, time to clinical improvement, need for mechanical ventilation, or ICU admission (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis study gathers a comprehensive analysis of the current evidence on outcomes for antiviral agents in patients with COVID-19 provided by RCTs. Treatment for SARS-CoV-2 infection has been symptomatic for mild cases and supportive for severe cases. There have been reports of widespread use of antiviral agents, even when the World Health Organization (WHO) has not recommended their use (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e). Several publications have evaluated the efficacy of antiviral agents for treating SARS-CoV-2 infection from asymptomatic to critical cases. Only a few of them were revealed to be efficacious in modifying outcomes. Even after the pandemic, patient numbers have declined worldwide, but some peaks persist in several countries. There is currently no certainty about which therapies are beneficial and which outcomes are modified by treatment.\u003c/p\u003e \u003cp\u003eThe evaluation of outcomes varied among studies. Some considered mortality the primary outcome (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e); even in these cases, there was a disparity among studies: some monitored the effect at 14 days (\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e), whereas others monitored it at 28 days (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAlthough RDS showed a decrease in mortality, these findings were based primarily on two large RCTs (6613 patients) (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e); both included patients with mild to severe disease, and the beneficial effect was observed in moderate cases. SOF, MPV, and nirmatrelvir also reduced mortality among patients with mild and moderate disease (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). No studies with LPV/r or FPV showed a decrease in mortality (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e), and the combination with chloroquine was deleterious (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eViral clearance is a major concern during pandemics. High viral counts were associated with disease severity and the likelihood of infectivity. Several studies have focused on the viral shedding effects of antiviral agents as primary or secondary outcomes in outpatients (\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e) or hospitalized (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e), including those with mild to moderate symptoms (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e). Antiviral agents with efficacy in reducing the duration or extent of viral shedding were SOF (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e), UFV (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e), and MPV (\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eA search of the PROSPERO register of systematic reviews (\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e) identified 1631 records on COVID-19. Approximately 316 included antiviral agents: 94 with LPV, 141 with RDS, 45 with FPV, and 10 with SOF. Our review is dedicated exclusively to evaluating the effect of antiviral agents on experimental studies.\u003c/p\u003e \u003cdiv id=\"Sec39\" class=\"Section2\"\u003e \u003ch2\u003e4.1. Limitations\u003c/h2\u003e \u003cp\u003eOne of the main limitations of the analysis of the results is the heterogeneity of subjects allocated to the studies, including differences in severity (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e), age, and other risk factors, as well as additional therapies included in the SOC arm. In this context, the efficacy of RDS may differ across mild, moderate, and severe cases. The impact of RDS on mortality was observed in the moderate-severity group but not in the other severity groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). This result was observed in the ACTT-1 trial (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) but not in the WHO Solidarity trial (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e), which had a higher proportion of moderate cases.\u003c/p\u003e \u003cp\u003eThere were also differences in outcomes studied, from mortality to viral clearance. When interpreting an antiviral agent, caution should be exercised regarding the severity and the desired clinical outcome.\u003c/p\u003e \u003cp\u003ePharmaceutical companies sponsored some studies on new alternatives, the external results of which have yet to be confirmed. Most allocations included mild cases, and the benefit was limited to viral clearance.\u003c/p\u003e \u003cp\u003eAnother limitation is the lack of a placebo arm in some studies and the use of SOC in the control group, which included some therapeutic alternatives, even when some showed no beneficial effects in other trials. There is no certainty that such a combination could have a biased impact.\u003c/p\u003e \u003cp\u003eA small number of allocations might have an impact on the capacity to detect a beneficial effect with the therapy; even when affecting a considerable amount of the population, COVID-19 had a low frequency of severe cases and mortality; ACTT-1 study had a small proportion of deaths in both groups (near six vs. 12%) (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). An experiment should have at least 358 cases assigned to each arm to find a (50%) difference in the effect, and maybe 1640 in each group if the impact was less (a 25% decrease in mortality). The studies with sufficient patient numbers included FPV (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e), LPV/r (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e), MPV (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e), nirmatrelvir (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e), RDS (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan additionalcitationids=\"CR17 CR18 CR19 CR20 CR21\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e), and SOF (\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFinally, heterogeneity in trials evaluating mortality with LPR/r was low (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0); RDS was moderate (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;40%), and FPV was intermediate (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;37%).\u003c/p\u003e \u003c/div\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eSeveral antiviral agents demonstrated benefits in specific patient populations with SARS-CoV-2 infection. The benefits were observed in reduced mortality, ICU admission, mechanical ventilation, hospitalization, the rate of clinical improvement, and viral load. The overall certainty of evidence remains moderate to low, and results should be interpreted in the context of disease severity, treatment timing, and evolving standards of care. The effect was highly variable among studies and agents. Precaution is advised to adjudicate the impact of a specific agent on others.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAcknowledgments\u003c/p\u003e\n\u003cp\u003eWe thank the people who supported us in completing this work.\u003c/p\u003e\n\u003cp\u003eConflicts of interest\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests. None of the authors were members of the research teams for any of the selected trials included in this review; we were not members of the advisory boards of any drug or technology agency, nor were we participants in any pharmaceutical company or biotechnology enterprise. The authors received no financial support for this article\u0026apos;s research, authorship, or publication. The opinions expressed in this document are those of the authors and do not reflect the official position of any agency.\u003c/p\u003e\n\u003cp\u003eAvailability of data and other material\u003c/p\u003e\n\u003cp\u003eA dataset of the registers included in the review was stored in the Mendeley Data repository (DOI: 10.17632/4RK2KFBJVT.1). The study protocol was registered in the PROSPERO register (University of York, Centre for Reviews and Dissemination) under the code CRD24023394294.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSultana J, Crisafulli S, Gabbay F, Lynn E, Shakir S, Trifir\u0026ograve; G (2020) Challenges for drug repurposing in the COVID-19 pandemic era. Front Pharmacol 11:588654\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRuiz-Romero A, Quijano-Castro FO, L\u0026oacute;pez-Romero R, Chavarr\u0026iacute;a-Arriaga X, Torres M, Salcedo M (2022) Immunity and COVID-19 vaccines. Revisiting the bases. Gac Med Mex 158(5):317\u0026ndash;322\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu T-C, Ho C-TB (2022) A narrative review of innovative responses during the COVID-19 pandemic in 2020. 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Intensive Care Med 47(8):867\u0026ndash;886\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi Y, Xie Z, Lin W, Cai W, Wen C, Guan Y et al (2020) Efficacy and safety of Lopinavir/Ritonavir or Arbidol in adult patients with mild/moderate COVID-19: An exploratory randomized controlled trial. Med (N Y) 1(1):105\u0026ndash;113e4\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePan H, Peto R, Henao-Restrepo AM, Preziosi MP, Sathiyamoorthy V, Abdool Karim Q et al (2021) Repurposed antiviral drugs for Covid-19 - Interim WHO Solidarity trial results. N Engl J Med 384(6):497\u0026ndash;511\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDabbous HM, El-Sayed MH, El Assal G, Elghazaly H, Ebeid FFS, Sherief AF et al (2021) Safety and efficacy of favipiravir versus hydroxychloroquine in management of COVID-19: A randomised controlled trial. 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J Antimicr Chemother 76(8):2158\u0026ndash;2167\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIvashchenko AA, Dmitriev KA, Vostokova NV, Azarova VN, Blinow AA, Egorova AN et al (2021) AVIFAVIR for treatment of patients with moderate Coronavirus Disease 2019 (COVID-19): Interim results of a phase II/III multicenter randomized clinical trial. Clin Infect Dis 73(3):531\u0026ndash;534\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEslami G, Mousaviasl S, Radmanesh E, Jelvay S, Bitaraf S, Simmons B et al (2020) The impact of sofosbuvir/daclatasvir or ribavirin in patients with severe COVID-19. J Antimicr Chemother 75(11):3366\u0026ndash;3372\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJayk Bernal A, Gomes da Silva MM, Musungaie DB, Kovalchuk E, Gonzalez A, Delos Reyes V et al (2022) Molnupiravir for oral treatment of Covid-19 in nonhospitalized patients. 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J Antimicrob Chemother 75(11):3373\u0026ndash;3378\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eElgohary MAS, Hasan EM, Ibrahim AA, Abdelsalam MFA, Abdel-Rahman RZ, Zaki AI et al (2022) Efficacy of sofosbuvir plus ledipasvir in Egyptian patients with COVID-19 compared to standard treatment: a randomized controlled trial. J Med Life 15(3):350\u0026ndash;358\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCao B, Wang Y, Wen D, Liu W, Wang J, Fan G et al (2020) A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med 382(19):1787\u0026ndash;1799\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang Y, Zhang D, Du G, Du R, Zhao J, Jin Y et al (2020) Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. 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Int Immunopharmacol 97:107702\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMobarak S, Salasi M, Hormati A, Khodadadi J, Ziaee M, Abedi F et al (2022) Evaluation of the effect of sofosbuvir and daclatasvir in hospitalized COVID-19 patients: a randomized double-blind clinical trial (DISCOVER). J Antimicr Chemother 77(3):758\u0026ndash;766\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSadeghi A, Asgari AA, Norouzi A, Kheiri Z, Anushirvani A, Montazeri M et al (2020) Sofosbuvir and daclatasvir compared with standard of care in the treatment of patients admitted to hospital with moderate or severe coronavirus infection (COVID-19): A randomized controlled trial. J Antimicr Chemother 75(11):3379\u0026ndash;3385\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCao B, Wang Y, Wen D, Liu W, Wang J, Fan G et al (2020) A trial of lopinavir\u0026ndash;ritonavir in adults hospitalized with severe Covid-19. N Engl J Med 382(19):1787\u0026ndash;1799\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePieper D, Rombey T (2022) Where to prospectively register a systematic review. Syst Rev 11:8\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhoo SH, Fitzgerald R, Fletcher T, Ewings S, Jaki T, Lyon R et al (2021) Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study. J Antimicr Chemother 76(12):3286\u0026ndash;3295\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Universidad Cooperativa de Colombia","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"COVID-19, Coronavirus Infections: SARS-CoV-2, Antiviral Agents, Pandemics","lastPublishedDoi":"10.21203/rs.3.rs-9020094/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9020094/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: After years of the pandemic of SARS-CoV-2 infection, some cases with severe symptoms of COVID-19 are still presenting. Therapeutic alternatives that provide a clear benefit for severe cases remain lacking.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAim\u003c/strong\u003e: To assess the best available evidence on the efficacy of antiviral therapy for severe COVID-19 and to synthesize the results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethodology\u003c/strong\u003e: A systematic review was designed. PubMed publications until December 2025 were searched. Randomized clinical trials (RCTs) of interventions with antiviral agents, with control groups that received placebo or standard of care (SOC) in patients with severe COVID-19 hospitalized or in the intensive care unit (ICU), were selected. The primary outcome was all-cause mortality; other secondary results were considered.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: A total of 43 studies were identified, involving 12,052 patients. The severity distribution was 35.6%, 52.0%, and 12.4% for mild, moderate, and severe cases, respectively. Ten antiviral agents were evaluated. The results showed a decrease in mortality among patients treated with remdesivir (RR 0.83; 95% CI0.74-0.93; p=0.001), molnupiravir (RR 0.16; 95% CI 0.04-0.73; p=0.02), and nirmatrelvir (RR 0.05; 95% CI 0.00-0.91; p=0.04).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: According to the results, some antivirals (remdesivir, molnupiravir, nirmatrelvir) reduced all-cause mortality among patients with COVID-19 compared with placebo or SOC.\u003c/p\u003e","manuscriptTitle":"Antiviral agents for COVID-19: A post-pandemic systematic review of randomized controlled trials.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-08 17:09:46","doi":"10.21203/rs.3.rs-9020094/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f38a1fc4-ee85-4f6a-aace-ce5ed5215690","owner":[],"postedDate":"March 8th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":63850074,"name":"Hospital Medicine"},{"id":63850075,"name":"Epidemiology"},{"id":63850076,"name":"Virology"},{"id":63850077,"name":"Translational Medicine"}],"tags":[],"updatedAt":"2026-03-08T17:09:46+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-08 17:09:46","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9020094","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9020094","identity":"rs-9020094","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}