key: cord-1008706-ig7awd4f
authors: Vegivinti, Charan Thej Reddy; Evanson, Kirk W.; Lyons, Hannah; Akosman, Izzet; Barrett, Averi; Hardy, Nicole; Kane, Bernadette; Keesari, Praneeth Reddy; Pulakurthi, Yashwitha Sai; Sheffels, Erin; Balasubramanian, Prasanth; Chibbar, Richa; Chittajallu, Spandana; Cowie, Kathryn; Karon, J.; Siegel, Lauren; Tarchand, Ranita; Zinn, Caleb; Gupta, Nitin; Kallmes, Kevin M.; Saravu, Kavitha; Touchette, Jillienne
title: Efficacy of antiviral therapies for COVID-19: a systematic review of randomized controlled trials
date: 2022-01-31
journal: BMC Infect Dis
DOI: 10.1186/s12879-022-07068-0
sha: aa7c15d66ab1da3fe0bfc1e45d7905180fc49922
doc_id: 1008706
cord_uid: ig7awd4f

BACKGROUND: Coronavirus disease 2019 (COVID-19) continues to pose a significant threat to public health worldwide. The purpose of this study was to review current evidence obtained from randomized clinical trials on the efficacy of antivirals for COVID-19 treatment. METHODS: A systematic literature search was performed using PubMed to identify randomized controlled trials published up to September 4, 2021 that examined the efficacy of antivirals for COVID-19 treatment. Studies that were not randomized controlled trials or that did not include treatment of COVID-19 with approved antivirals were excluded. Risk of bias was assessed using the Scottish Intercollegiate Guidelines Network (SIGN) method. Due to study heterogeneity, inferential statistics were not performed and data were expressed as descriptive statistics. RESULTS: Of the 2,284 articles retrieved, 31 (12,440 patients) articles were included. Overall, antivirals were more effective when administered early in the disease course. No antiviral treatment demonstrated efficacy at reducing COVID-19 mortality. Sofosbuvir/daclatasvir results suggested clinical improvement, although statistical power was low. Remdesivir exhibited efficacy in reducing time to recovery, but results were inconsistent across trials. CONCLUSIONS: Although select antivirals have exhibited efficacy to improve clinical outcomes in COVID-19 patients, none demonstrated efficacy in reducing mortality. Larger RCTs are needed to conclusively establish efficacy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12879-022-07068-0.

demographical differences, patient/disease heterogeneity, differences in institutional practices and standards, and differences in healthcare infrastructure and financial support. As a result of the substantial heterogeneity across studies, a consensus on COVID-19 therapies has remained elusive.

Antiviral drugs, such as remdesivir, represent promising drug candidates to attenuate viral and disease progression. Although there have been comprehensive presentations of outcomes associated with antiviral treatments for COVID-19 obtained from randomized controlled design, the number of relevant randomized controlled trials were limited in these studies because they were either published early in the pandemic [4] or had search dates that ended during the middle of the pandemic [5] and many new trails have been published in the past year. Additionally, while a more recent review has been published, it did not include a description of how the study was carried out and was not PRISMA compliant [6] . Here, we conducted a systematic review of RCTs that examined antiviral efficacy for COVID-19 treatment.

A systematic literature search was conducted to identify RCTs that investigated antiviral treatments of COVID-19 using PubMed through Nested Knowledge, an AutoLit platform for living systematic reviews [7] . The search terms used are listed in Table 1 , and search filters or limits were not used. All fields were searched and the search was not limited to title/abstract. Databases used included Embase, PubMed, PubMed Central, and Web of Science. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [8] . A review protocol was created by the authors in order to establish the framework for this systematic review and can be viewed on the Nested Knowledge platform [9] . Concepts outlined in the protocol were then developed into a custom tagging hierarchy in order to tag each study, which reflected specific evidence underneath the categories we laid out. For example, under outcomes, there is a node for Clinical Improvement that reflects an outcome we intended to gather from each study. Tagging of full-text articles was completed in order to trace concepts and link qualitative synthesis. The review was not registered.

Studies published between November 1, 2019 and September 4, 2021 were considered. Prior to screening, all studies published before November 1, 2019 or not published in English were automatically excluded by Nested Knowledge. Additionally, during the screening process, a machine learning algorithm ordered studies based on what was most likely to be included, and the software automatically de-duplicated studies. No further automation was used, as each article was screened by one of nine contributors and inclusion was independently verified by one author (NH). All studies that used a randomized controlled design to examine clinical outcomes related to antiviral treatment of COVID-19 were included. Only drugs approved for use as antivirals were considered, including baloxavir marboxil [10], lopinavir/ ritonavir (LPV/r) [11] , atazanavir [12] , sofosbuvir [13] , daclatasvir [14] , remdesivir [15] , ribavirin [16] , favipiravir [17] , umifenovir (Arbidol) [18] , and azvudine [19] and novaferon [20] . The following article types were excluded: observational, editorial, opinion, in vitro or in vivo study, review, methods, case series or report, guidelines, and articles that were not published in English.

Data was manually extracted through the Nested Knowledge platform for living systematic reviews by one of 11 contributors and independently checked for accuracy by one author for each study. Tags from the custommade Nested Knowledge tagging hierarchy were preconfigured as data elements in order to keep variables organized. Variables in the platform were classified as continuous, categorical, or dichotomous, and manually extracting data from full-text articles facilitated statistical analysis and qualitative synthesis. When available, background characteristics were collected, including age, sex, time from symptom onset to the start of treatment, white blood cell count (WBC), and oxygen saturation (SpO 2 ). Intervention-related information, such as doses and regiment, follow-up period, and concomitant medications, were also collected. The outcomes collected included mortality, incidence of mechanical ventilation and intensive care unit (ICU) admission, number of patients with negative reverse transcription polymerase chain reaction (RT-PCR) tests, duration of hospitalization, incidence of clinical improvement, and improvement in SpO 2 .

Risk of bias was assessed using the Scottish Intercollegiate Guidelines Network (SIGN) checklist for randomized controlled trials [21] . Items that are considered in the SIGN checklist include an appropriate and clearly focused question, randomized assignment, adequate concealment, blinding, similar treatment and control groups at the start of the trial, the treatment is the only difference between groups, standard outcome measurement, percentage of subjects that dropped, intention to treat analysis, comparable results for all sites, and overall assessment of the study. The grading system includes levels of evidence rated from 1 + + high quality to 2-high risk of bias, as well as grades of recommendation, followed by grades of recommendation from grade A to D. Two independent reviewers assessed each study. Assessments were verified and disagreements were adjudicated by a third reviewer. Due to heterogeneity in treatments used and outcomes reported, inferential statistics were not performed, and data were expressed as descriptive statistics only. Continuous data were reported as mean ± standard deviation (SD) or median (interquartile range [IQR] ) unless otherwise noted.

A total of 2,284 articles were identified from the search terms, of which 31 studies that included 12,440 patients used randomized controlled designs to examine the efficacy of antiviral therapy on COVID-19 . A PRISMA diagram detailing the search strategy is shown in Fig. 1 . Of the articles identified, 30 were excluded after fulltext review . One study was originally included, but was later retracted due to concerns about data integrity, and thus was excluded [42] . Antiviral treatments compared in the included studies were umifenovir (Arbidol) [25, 29, 31, 47] , baloxavir marboxil [30] , enisamium [50] , OR Daclatasvir) AND (COVID-19 OR SARS-COV-2 OR "novel coronavirus") AND (RCT OR "randomized controlled trial" OR "randomised controlled trial" OR "randomized" OR "randomised")

Web of Science 12-01-2021 336 (Lopinavir OR Ritonavir OR Remdesivir OR Ribavirin OR Arbidol OR Favipiravir OR Sofosbuvir OR Daclatasvir) AND (COVID-19 OR SARS-COV-2 OR "novel coronavirus") AND (RCT OR "randomized controlled trial" OR "randomised controlled trial" OR "randomized" OR "randomised") Embase 12-01-2021 25

(Lopinavir OR Ritonavir OR Remdesivir OR Ribavirin OR Arbidol OR Favipiravir OR Sofosbuvir OR Daclatasvir) AND (COVID-19 OR SARS-COV-2 OR "novel coronavirus") AND (RCT OR "randomized controlled trial" OR "randomised controlled trial" OR "randomized" OR "randomised") SARs-CoV-2 OR SARs OR COVID-19 OR "coronavirus" OR covid AND ("antiviral drugs") AND (RCT OR "randomized controlled trial" OR "randomised controlled trial") PubMed 12-04-2021 14

("antiviral therapies" OR "antiviral drugs") AND (RCT OR "randomized controlled trial" OR "randomised controlled trial") AND (COVID-19 OR SAR-COV-2 OR coronavirus OR covid) favipiravir [25, 30, 35, 40-42, 44, 45, 48, 52] , lopinavir/ritonavir (LPV/r) [24, 26, 27, 29, 31, 37, 38, 44, 47] , remdesivir [23, 34, 36, 39, 51, 53] , ribavirin [22] , sofosbuvir/daclatasvir [22, 32, 33, 46, 49] , sofosbuvir/ledipasvir [28] , sofosbuvir/ravidasvir [46] , and sofosbuvir/velpatasvir [43] . The study characteristics and baseline patient characteristics are summarized in Table 2 . The outcomes of interest and study conclusions are summarized in Table 3 . Two studies were rated low quality on the risk of bias assessment, with bias favoring the test treatment [49, 51] . The remaining studies were rated either acceptable or high quality (Additional file 1).

Favipiravir is an antiviral used to treat influenza in Japan. It is a purine analog that inhibits viral RNA-dependent RNA polymerase, blocking viral genome replication and transcription [84] . We identified nine RCTs that examined the efficacy of favipiravir in treating COVID-19. Five trials found significant differences between the favipiravir treatment and comparator groups [35, 45, 48, 52, 85] and four did not find significant differences [30, 40, 41, 44] (Table 3) . Zhao et al. conducted a multicentric open-label trial that compared favipiravir with a control group [45] . Patients were randomly assigned to receive favipiravir or treatments other than favipiravir, chosen at the discretion of the treating physician. Patients treated with favipiravir had a significantly shorter median time to positive-to-negative RT-PCR SARS-CoV-2 test conversion (17 days) improvement of chest imaging findings (p = 0.029) and time to conversion to negative RT-PCR (p = 0.041) were significantly shorter in the favipiravir group compared to the placebo group, while temperature (p = 0.18) and SpO 2 (p = 0.51) showed no significant difference (Table 3) . Udwadia et al. conducted a multicentric, open-label trial to compare favipiravir to standard supportive care alone [35] . No significant difference was found in time to conversion to negative RT-PCR tests (p = 0.1290) or duration of hospital stay (p = 0.1079). However, the favipiravir group had a significantly shorter time to resolution of clinical symptoms (3 days [95% CI: 3-4 days]) compared to the control group (5 days [95% CI: 4-6 days], p = 0.030).

Doi et al. [48] conducted a multicentric, open-label trial to compare patients treated with favipiravir starting on either day 1 (early) or day 6 (late) after their hospital admission. Patients received favipiravir for up to 10 days. Treatment could be discontinued after 6 days if their symptoms had resolved and they had two consecutive negative RT-PCR tests, meeting the requirements to be discharged from the hospital. Favipiravir did not significantly affect viral clearance by day 6 (HR: 1.416 [95% CI 0.764-2.623]). However, early treatment did lead to a significantly higher chance of viral clearance at day 6 in patients who were enrolled in the study more than three days after their first positive RT-PCR test (HR: 2.829 [95% CI 1.198-6.683]), indicating that there may be a window after infection where initiating treatment is more effective.

Chen et al. compared favipiravir with umifenovir in COVID-19 patients [85] in a multicentric, open-label trial. Umifenovir is an antiviral drug that prevents cell attachment and viral entrance by trimerization of the SARS-CoV-2 spike glycoprotein. This blockade forms a naked or immature virus that less contagious [86] . Patients also received standard therapy, which consisted of antivirals, steroids, traditional Chinese herbal medicines, immunomodulatory drugs, steroids, antibiotics, psychotic drugs, nutritional supplements, and oxygen support. The primary outcome was rate of clinical recovery at day 7. Secondary outcomes were all-cause mortality, dyspnea, respiratory failure, auxiliary oxygen therapy or noninvasive mechanical ventilation (NMV), latency to pyrexia and cough relief, and need for intensive care. While no differences were found in clinical recovery (favipiravir 61.2% [71/116] ; umifenovir 51.7% [62/120]; P = 0.1396) or in most secondary outcomes between treatments, favipiravir did shorten the latency of pyrexia and cough relief.

Several trials did not find significant differences between treatment with favipiravir and their various comparator groups. Lou et al. conducted an open-label, single-center trial to evaluate the clinical outcomes and plasma concentrations of baloxavir acid and favipiravir in COVID-19 patients [30] . Patients were randomly assigned to one of three groups: a baloxavir marboxil group, a favipiravir group, and a control group, which included umifenovir. Median times from randomization to clinical improvement, viral negativity at day 7, and viral negativity at day 14 were similar between the three groups (Table 3) . One patient in the baloxavir marboxil group and two patients in the favipiravir group were transferred to the ICU within 7 days due to declines in oxygen index or progressive disease on computed tomography (CT). One patient in the baloxavir marboxil group required extracorporeal membrane oxygenation (ECMO) support after 10 days.

Dabbous et al. conducted a multicentric trial comparing favipiravir and chloroquine (CQ) in patients with confirmed cases of COVID-19 [41] . There were no significant differences between the groups in mortality (p = 1.00), duration of hospital stay (p = 0.060), mechanical ventilation (p = 0.118), or oxygen saturation (p = 0.129). Bosaeed et al. also compared favipiravir (10 days) and HCQ [40] . Nearly half of the favipiravir group discontinued therapy before the end of the trial due to pill burden or personal preference. This study found no significant difference in conversion to negative RT-PCR tests (p = 0. 73 

LPV/r is an HIV-1 protease inhibitor combination. Ritonavir is combined with lopinavir to increase the latter's plasma half-life by inhibiting cytochrome P450 [87] . LPV/r is approved by the FDA for treatment of HIV-1 infection in adult and pediatric patients [88] . LPV/r has also exhibited efficacy to treat influenza, severe acute respiratory syndrome (SARS), and Middle Eastern respiratory syndrome (MERS) infection [89] [90] [91] . Nine RCTs included LPV/r for COVID-19 therapy: two large trials (RECOVERY [26] and TOGETHER [27] ), and seven relatively smaller trials (n = 86-664) [24, 31, 37, 40, 44, 47] . The trial conducted by Solaymani-Dodaran et al. compared LPV/r to favipiravir and found no significant differences, as discussed in the Favipiravir section above [44] . Similarly, none of the other trials identified a significant positive effect of LPV/r on outcomes in COVID-19 patients.

The RECOVERY trial was an open-label, platform trial conducted between March 19, 2020 and June 29, 2020 among 176 hospitals in the United Kingdom (UK). Patients were randomized to either standard of care alone or standard of care plus oral LPV/r for 10 days or until discharge. The primary outcome was 28-day all-cause mortality, which did not significantly differ between the intervention and control groups (rate ratio [RR] 1.03, 95% CI 0.91-1.17; P = 0.60), and the results were consistent among all pre-specified subgroups. There was also no difference in the time until discharge alive or proportion of patients discharged alive within 28 days (RR 0.98, 95% CI 0.91-1.05; P = 0.53). Additionally, there was no difference in the proportion of patients who met the composite endpoint of invasive mechanical ventilation or death among patients who were not on invasive mechanical ventilation at baseline (RR 1.09, 95% CI 0.99-1.20; P = 0.092).

The TOGETHER trial was conducted between June 2, 2020 and September 20, 2020 in Brazil [27] . The trial compared LPV/r to HCQ or placebo. The trial was discontinued early after finding no significant difference between the groups in COVID-19-associated hospitalization (LPV/r: HR, 1. 16 16] ). Incidence of mortality was similar between the LPV/r and placebo groups. Ader et al. also compared LPV/r to HCQ and control, in addition to LPV/r with IFN-β-1a, and discontinued the LPV/r and HCQ arms early due to lack of significant difference in clinical status at day 15 compared to control [37] . Arabi et al. also conducted a randomized, multicentric trial comparing LPV/r, HCQ, or a combination to a control group with no antiviral therapy [40] . They found a 98.5% probability of harm compared to control for LPV/r alone based on inhospital mortality. Cao et al. conducted an open-label trial comparing LPV/r to standard of care in patients with SARS-CoV-2 infection and hypoxia [24] . There was no difference in time to clinical improvement (HR 1.24, 95% CI 0.90-1.72) or mortality at 28 days (19.2% vs. 25.0%; mean difference -5.8, 95% CI -17.3-5.7). The LPV/r group had a shorter median time to clinical improvement by one day compared to standard care alone on a modified intention-to-treat analysis (HR 1.39, 95% CI 1.00-1.91).

Three studies compared umifenovir to LPV/r [31, 47] . Li et al. conducted an exploratory trial to study the efficacy and safety of LPV/r versus umifenovir in patients with mild to moderate COVID-19 [31] . There were no differences in positive-to-negative conversion of SARS-CoV-2 RT-PCR tests on days 7 and 14. Also, there were no differences in mean time to test conversion (9.0, 9.1, and 9.3 days; P = 0.981) or in the conversion rate from moderate to severe/critical clinical status (23.5%, 8.6%, and 11.8%; P = 0.206) among LPV/r, umifenovir, and control groups, respectively.

Nojomi et al. investigated the efficacy of umifenovir compared to LPV/r in COVID-19 patients [31] . The patients were randomized to receive umifenovir or LPV/r for 7-14 days, based on disease severity, as well as HCQ on day 1. Patients that received umifenovir had a shorter duration of hospitalization (7.2 days) compared to patients that received LPV/r (9.6 days, P = 0.02). Moreover, 81% of patients in the umifenovir group had mild involvement on chest CT after 30 days of admission compared to 53% in the LPV/r group (P = 0.004).

Alavi Darazam et al. compared a combination of LPV/r, HCQ, and IFN-β1a with and without umifenovir in a single-center, open-label trial [47] . All patients received LPV/r, HCQ, and IFN-β1a. Half of the patients also received umifenovir. The groups did not have a significant difference in mortality (p = 0.62) or time to clinical improvement (p = 0.22), defined as improvement by two points on a seven-category ordinal scale. No significant difference in mortality was found between the groups when adjusted for time between symptom onset and trial enrollment either (presentation ≤ 7 days from symptom onset, p = 0.49; > 7 days, p = 1.00), indicating that starting treatment earlier is unlikely to affect the efficacy of combining umifenovir with LPV/r and other treatments.

Remdesivir is an RNA-dependent RNA polymerase inhibitor with in-vitro activity demonstrated against SARS-CoV-2 and MERS-CoV [34, 92] . It is FDAapproved for COVID-19 treatment in adult and pediatric patients (12 years or older and weighing at least 40 kg) requiring hospitalization [93] . We identified six trials used remdesivir to treat COVID-19. Three trials found significant differences between the remdesivir treatment and comparator groups [23, 34, 53] and three did not [36, 39, 51] .

The Adaptive Covid-19 Treatment Trial (ACTT-1) was a multicentric, double-blind, placebo-controlled trial of remdesivir in patients with severe COVID-19 pneumonia [23] . Median recovery times were lower in the remdesivir group, with a rate ratio for recovery of 1.29 (95% CI 1.12-1.49, P < 0.001). The patients who received remdesivir were more likely to have clinical improvement by day 15 when compared to placebo (OR 1.5, 95% CI 1.2-1.9, after adjustment for actual disease severity). The Kaplan-Meier estimates of mortality at days 15 and 29 were 6.7% and 11.4% in the remdesivir group and 11.9% and 15.2% in the control group, respectively. Spinner et al. compared remdesivir to standard of care in a multicentric, open-label trial of hospitalized patients with moderate COVID-19 pneumonia [34] . Patients were randomized to receive remdesivir for 5 or 10 days or standard care alone. On day 11, the odds for a better clinical status distribution were greater in the 5-day remdesivir group as compared to the standard care group (OR 1.65, 95% CI 1.09-2.48; P = 0.02) but was not significant between 10-day remdesivir and standard care groups (P = 0.18 by Wilcoxon Rank Sum test). Mortality at day 28 was 1%, 2%, and 2% in 5-day remdesivir, 10-day remdesivir, and standard care groups, respectively.

Goldman et al. also compared five-and ten-day courses of remdesivir [53] . Their open-label, phase 3 trial included patients with confirmed SARS-CoV-2 infection, SpO 2 of ≤ 94% on room air, and radiologic evidence of pneumonia. The patients randomized to the 10-day group had significantly worse clinical status than those in the 5-day group, as assessed on a seven-category ordinal scale (p = 0.02). Discharge rates were higher in patients whose symptoms started less than 10 days before receiving the first dose of remdesivir (62%) than in those whose symptoms started 10 or more days before their first dose (49%), indicating that regardless of drug regimen, there may be advantages to starting remdesivir earlier.

Several trials found no significant effect of remdesivir on patient outcomes. Wang et al. conducted a doubleblind, placebo-controlled, multicenter trial in COVID-19 patients with SpO 2 ≤ 94% in room air or PaO 2 /FiO 2 ratio ≤ 300 mmHg and radiological evidence of pneumonia [36] . Patients were assigned to remdesivir or placebo, along with standard of care. There was no difference in time to clinical improvement with remdesivir as compared to placebo (HR 1.23, 95% CI 0.87-1.75). Time to clinical improvement in a subgroup of patients with symptom duration ≤ 10 days was not significantly different with remdesivir compared to placebo (HR 1.52, 95% CI 0.95-2.43).

Mahajan et al. conducted a trial comparing remdesivir to standard of care in patients over 40 years old with moderate to severe COVID-19, but not on mechanical ventilation [51] . Clinical status was assessed with a sixpoint ordinal scale based on need for oxygen supplementation and ventilation, hospitalization and mortality status. The groups showed no significant difference in clinical status at day 24, including hospitalization and mortality (p = 0.749), despite the potential bias towards the remdesivir group found in the risk of bias assessment (Additional file 1). Discharge rates were higher for patients who received treatment less than 5 days after symptom onset regardless of treatment group. Barratt-Due et al. also conducted a RCT comparing remdesivir, HCQ, or standard of care alone and found no significant differences between the groups for in-hospital mortality (HR: 1.0 [95% CI 0.4-2.9]) and the groups had similar rates of viral clearance [39] .

Sofosbuvir and daclatasvir are antiviral agents that inhibit viral RNA replication via NS5A and NS5B polymerase inhibition, respectively [94, 95] . Sofosbuvir and daclatasvir are FDA-approved for treatment of chronic hepatitis C [51] . SARS-CoV-2 possesses similar mechanisms of RNA replication as observed in other RNA viruses; as such, sofosbuvir and daclatasvir combined may demonstrate efficacy to inhibit SARS-CoV-2 replication [22, 96, 97] . We identified seven RCTs that used sofosbuvir and daclatasvir or a combination of sofosbuvir and other drugs to treat COVID-19. Of the RCTs that used sofosbuvir/daclatasvir, all five reported significantly better results for the treatment group for at least one outcome, although the magnitude of the effect was often small [22, 32, 33, 46, 49] . Of the three RCTs that included sofosbuvir combined with drugs other than daclatasvir, none reported significant differences between the treatment and control groups [28, 43, 46] . Sadeghi et al. conducted a phase 3, multicenter trial to compare the effects of sofosbuvir/daclatasvir with standard of care versus standard of care alone (HCQ and LPV/r at physician discretion) in moderate to severe COVID-19 patients [33] . Sofosbuvir/daclatasvir was started later than treatment in the control arm due to delays in receiving RT-PCR reports. Clinical recovery within 14 days from enrollment was achieved in 88% (29/33) of patients in the sofosbuvir/daclatasvir arm and 67% (22/33) of patients in the control arm (P = 0.076). Patients in the sofosbuvir/daclatasvir group experienced shorter hospital stays than patients in the control group (6 [4-8] days vs. 8 [5] [6] [7] [8] [9] [10] [11] [12] [13] days, respectively; P = 0.029), and the sofosbuvir/daclatasvir group exhibited a higher cumulative incidence of hospital discharge as compared to the control group (Gray's P = 0.041). All-cause mortality was similar between groups.

Abbaspour Kasgari et al. conducted a single-center trial to evaluate the efficacy of sofosbuvir/daclatasvir in combination with ribavirin compared to standard of care (including other antivirals) for hospitalized patients with moderate COVID-19 [22] . Secondary outcomes included the frequency of ICU admission, duration of ICU admission, the frequency and time to recovery, mechanical ventilation, and invasive mechanical ventilation. There were no statistically significant differences in secondary outcomes between the two groups except for cumulative incidence of recovery (Gray's P = 0.033), which was higher in the sofosbuvir/daclatasvir arm.

Roozbeh et al. investigated the efficacy of sofosbuvir/ daclatasvir combined with HCQ for the treatment of COVID-19 outpatients compared to HCQ and standard of care using a double-blinded trial [32] . There was no difference between groups in the primary endpoint of symptom alleviation at day 7 follow-up or in the secondary endpoint of hospital admission (1 patient hospitalized in treatment group, 4 hospitalized in control group). Two patients in the sofosbuvir/daclatasvir arm reported fatigue at 1 month follow-up, while 16 patients reported fatigue in the control arm (P < 0.001). Dyspnea at 30-day follow-up was less common in the sofosbuvir/ daclatasvir arm (14.8% [4/27] ) than in the control arm (42.3% [11/26], P = 0.035).

El-Bendary et al. conducted a multi-centric trial comparing sofosbuvir/daclatasvir combined with HCQ to HCQ alone [49] . Patients treated with sofosbuvir/ daclatasvir had a significantly lower median duration of hospitalization (8 days vs. 10 days in control group, p < 0.01) and a higher incidence of negative RT-PCR tests at day 14, with 84% (81/96) negative compared to 47% (37/78) negative in the control group (p < 0.01). The groups showed no significant differences in mortality (p = 0.07), ICU admission (p = 0.10), and clinical improvement on a seven-category ordinal scale (p = 0.07). The risk of bias assessment identified potential bias in favor of the sofosbuvir/daclatasvir group, but the potential bias was not expected to fully account for the effect observed (Additional file 1).

Abbass et al. compared sofosbuvir/daclatasvir to standard of care, with all patients receiving additional therapies, such as HCQ, ivermectin, LPV/r, or remdesivir, at the treating physician's discretion [46] . Patients receiving sofosbuvir/daclatasvir showed significant clinical improvement compared to standard of care on both day 7 (p = 0.041) and day 10 (p = 0.040), as measured by the number of clinical symptoms experienced relative to day 3. The sofosbuvir/daclatasvir group also showed significant improvement in SpO 2 (91.3% ± 4.7%) compared to the standard of care group (87.4% ± 8.8%, p = 0.016) starting on day 4 and continuing until the data collection ended on day 10. The groups did not have significant differences in incidence of viral clearance (p = 0.581), ICU admission (p = 0.254), or mortality (p = 0.329).

Three RCTs combined sofosbuvir with other drugs. Abbass et al. included sofosbuvir/ravidasvir along with sofosbuvir/daclatasvir [46] . They found no significant difference between sofosbuvir/ravidasvir and standard of care in clinical improvement (p = 0.66969), oxygen saturation (p = 0.054), viral clearance (p = 0.893), ICU admission (p = 0.254), or mortality at day 10 (p = 0.329). Khalili et al. compared sofosbuvir/ledipasvir to standard of care alone [28] . They found that sofosbuvir/ledipasvir had a shorter time to clinical improvement (2 [1-3.75]) compared to control (4 [2-5, p = 0.02), but no significant differences in incidence of clinical improvement (p = 0.65), duration of hospital stay (p = 0.98), or 14-day mortality (p = 0.60) between the groups. Sayad et al. compared sofosbuvir/velpatasvir to standard of care alone [43] . They likewise found no difference in 28-day mortality (p = 0.38), time to clinical improvement (HR: 1.2 [95% CI 0.6-2.2], p = 0.30), or conversion to negative RT-PCR tests (p = 0.49).

One study evaluated the efficacy of enisamium, an antiviral drug whose metabolite is a viral RNA polymerase inhibitor [98] . Holubovska et al. conducted a doubleblind, placebo-controlled, phase 3 trial comparing enisamium to a placebo [50] . No differences in time to recovery was found overall or among patients who did not initially require oxygen. However, among patients who did require oxygen supplementation when enrolled, enisamium decreased the recovery time (11.1 days) compared to the placebo group (13.9 days, p = 0.0259). All patients in the enisamium group recovered by day 21, while not all patients in the placebo group recovered before data collection for interim analysis ended on day 29.

Here, we examined the results of RCTs that investigated the efficacy of antiviral drugs for the treatment of COVID-19. While clinical trials of new antiviral candidates are ongoing, current evidence suggests that the success of antiviral therapy for COVID-19 treatment is dependent on multiple factors, including time from symptom onset to treatment.

Of the antiviral therapies we reviewed, the antiviral combination of sofosbuvir/daclatasvir most consistently exhibited efficacy for COVID-19 treatment across some clinical outcomes, although study sizes were small, and results were often inconsistent [22, 32, 33, 46, 49] . Inclusion criteria for COVID-19 severity varied between studies, which may account for some of the inconsistency. In the largest sofosbuvir RCT, consisting of 174 patients, El-Bendary et al. reported that patients treated with sofosbuvir/daclatasvir had a lower duration of hospitalization and higher incidence of viral clearance [49] . Other studies reported positive effects of sofosbuvir/daclatasvir, but which outcomes were reported varied [22, 33, 46] . However, Roozbeh et al. did not observe a difference in symptoms between groups with mild COVID-19 after 7 days of treatment [32] , and there were no mortality benefits observed with sofosbuvir/daclatasvir treatment. Additionally, combinations of sofosbuvir with other drugs antiviral activity. Additionally, there are a number of drugs that possess little effect individually but can elevate the overall antiviral benefit when administered with other antivirals (eg, ribavirin). Thus, the magnitude of treatment effect for a given antiviral drug is uncertain. Studies were not screened based on severity of cases included, which likely accounts for some of the inconsistency in results. Also, 36 non-English articles were excluded, which may impact the conclusions. Finally, nine studies had group sizes of 40 subjects or less [20, 22, 30, 32, 33, 43, 45, 46, 51] , which may have resulted in insufficient statistical power and an increase in type II error (Additional file 2 and Additional file 3).

The design and implementation of RCTs is a time-consuming process that struggles to keep pace with the needs of clinicians during a pandemic. However, the high level of evidence obtained through sufficiently powered RCTs can provide confidence and/or clarification regarding results obtained from various observational studies. For antivirals that exhibit efficacy for COVID-19 treatment, early administration may be a critical factor in determining the quality of outcome. Larger studies are needed for antivirals that are less-described in COVID-19 treatment, such as sofosbuvir/daclatasvir, as these drugs may have equal or superior clinical outcomes compared to current therapies and may be more amenable for widespread use (ie, cheaper costs, oral availability).

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The authors acknowledge Karl Holub, Stephen Mead, Jeffrey Johnson, and Darian Lehmann-Plantenberg for their design and support of the Nested Knowledge meta-analytical software. The authors acknowledge Superior Medical Experts for their assistance in drafting and editing the manuscript. 

This work was sponsored by Nested Knowledge, Inc. Employees of Nested Knowledge, Inc. performed study design, data collection, analysis, and interpretation and assisted in writing the manuscript as part of their employee duties.

The datasets generated and/or analyzed during the current study are available in the Nested Knowledge website [9] .

Ethics approval and consent to participate Not applicable.

Not applicable.

JT is CEO and has ownership interest in Superior Medical Experts. ES and BK are employed by Superior Medical Experts. KE performed work on this project as an employee of Superior Medical Experts. KK is CEO of Nested Knowledge, Inc., has ownership interest in Nested Knowledge, Inc. and Superior Medical Experts, and consults for Medtronic. KC is employed by and has equity in Nested Knowledge. IZ, AB, CZ, NH, JK, HL, LS, and RT are employed by Nested Knowledge, Inc.

similar to daclatasvir did not lead to differences in outcomes compared to standard of care [28, 43, 46] . The fact that sofosbuvir/daclatasvir is available in pill form as opposed to IV (as is the case with remdesivir), its inexpensive price tag (14-day treatment is $4.42 USD) [99] , and its favorable safety profile noted in hepatitis C treatment [100, 101] make sofosbuvir/daclatasvir an appealing option, provided its efficacy can be established in larger RCTs.While remdesivir had shown early promise for effective treatment of COVID-19, the trials here demonstrated differing results. A previous meta-analysis found that remdesivir treatment of COVID-19 resulted in lower odds for mechanical ventilation or ECMO (OR 0.48, 95% CI 0.34, 0.69) and higher odds for hospital discharge at 28 days (OR 1.44, 95% CI 1.16, 1.79), while odds for mortality (OR 0.77, 95% CI 0.56, 1.06) were the same with or without remdesivir treatment [102] . Another meta-analysis found that remdesivir did not have a significant effect on the time to clinical improvement, or mortality but did have an effect on rate of recovered patients and hospital discharge [103] . Similarly, we found that four out of five studies comparing remdesivir to other treatments either failed to find significant differences in patient outcomes [36, 39, 51] or found unexpectedly opposing results between different remdesivir regimens and thus were inconclusive [34] . One placebo-controlled trial was stopped due to adverse events in patients treated with remdesivir [36] . Differences in findings may be due to different endpoints investigated or different levels of severity in patients, since the inclusion criteria varied between trials.LPV/r and umifenovir were initially recommended for treatment of COVID-19 in China [33, 94] . Early observational and randomized controlled studies of LPV/r failed to find a benefit with treatment [104] . A small systematic review that examined the efficacy and safety of lopinavir/ ritonavir in patients with COVID-19 found that lopinavir/ ritonavir did not significantly affect death, viral clearance, or "radiological improvement" when compared to other interventions [105] . Subsequent results obtained from two RCTs, RECOVERY [26] and DISCOVERY [37] , provided strong evidence against the use of LPV/r for COVID-19, and there were no benefits with early LPV/r treatment. Indeed, Arabi et al. reported that treatment with LPV/r led to worse outcomes compared to no antiviral treatment [40] . Thus, early administration of LPV/r or LPV/r use in patients with non-severe/non-critical forms of disease demonstrated little clinical value, and may be harmful.The efficacy of umifenovir is unclear due to conflicting results obtained from relatively small studies. Of the four studies that included umifenovir in the study design [31, 47, 85] , three studies failed to find a clinical benefit [31, 47, 85] . Moreover, early administration of umifenovir (median 6 days from symptom onset) did not influence the rate of positive-to-negative conversion of SARS-CoV-2 or rates of antipyresis, cough alleviation, or radiological findings of chest CT at days 7 or 14 after treatment [31] . In contrast, Nojomi et al. reported improvements in peripheral oxygen saturation, duration of hospitalization, need for ICU admission, white blood cell count, and erythrocyte sedimentation rate with umifenovir treatment as compared to LPV/r [31] . However, the time from symptom onset to treatment was not reported, and the group sizes were small (n = 50).Similar to our study, Okoli et al. found that antivirals did not have an effect on either viral clearance or (allcause mortality) but unlike our conclusions, they also found that antivirals did not significantly improve clinical progression [5] . Additionally, Lai, Chao, and Hsueh's systematic review conclusions parallel ours as they found that remdesivir may increase time to clinical improvement and may be an effective treatment for mild and moderate COVID-19 and that sofosbuvir/daclatasvir may positively affect COVID-19 survival and clinical recovery [6] . However, their study does not include their methodology.An important consideration when evaluating the efficacy of any drug, especially antivirals, is the state of disease course. Drugs that target viral replication, such as remdesivir, favipiravir, baloxavir marboxil, daclatasvir, and sofosbuvir, should be most effective if administered early in the viremic phase, as observed with other viruses (e.g. favipiravir treatment of Ebola) [106]. The SARS-CoV-2 viral load peaks within the first week of infection, which is earlier than that observed in SARS-CoV-1 (10-14 days) and MERS-CoV (7-10 days) [93] . Two of the trials we reviewed found that administering remdesivir within 10 days of symptom onset led to better patient recovery outcomes [23, 53] . Similarly, higher cumulative incidences of recovery were reported in moderate or severe COVID-19 patients treated with sofosbuvir/daclatasvir less than 8 days from symptom onset [22, 33] . In contrast, no differences in clinical outcomes were observed with baloxavir marboxil or favipiravir [30] or LPV/r when administered earlier relative to symptom onset. These data indicate that early administration of antiviral therapy may be critical to the efficacy of some COVID-19 treatments.

There were several limitations noted in the included studies. Standard of care varied across studies and included or could have included other antiviral therapies. In these cases, attributing a treatment effect to a specific drug can be difficult. Drugs that are not approved for use as antivirals may have unconfirmed 

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