Skip to main content
Download PDF

Efficacy of antiviral therapies for COVID-19: a systematic review of randomized controlled trials

BMC Infectious Diseases volume 22, Article number: 107 (2022) Cite this article

Abstract

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.

Peer Review reports

Background

Coronavirus disease 2019 (COVID-19) continues to present a significant challenge to healthcare systems worldwide, with approximately 269 million confirmed cases of the disease that have led to 5.3 million deaths as of December 12, 2021 [1]. COVID-19 develops from a viral infection, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which can elicit exaggerated immune and inflammatory responses if the infection progresses [2]. As such, there are a wide variety of therapeutic strategies that have been used to treat the disease at various stages, including antiviral, antiretroviral, antimalarial, anti-inflammatory, corticosteroid, immunomodulatory, and immunoglobulin therapies [3].

Research on drug therapies for COVID-19 has relied heavily on results obtained from observational studies, many of which contain biases resulting from 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.

Methods

Literature search

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.

Table 1 Search terms
Full size table

Study selection and quality assessment

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 collection

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 custom-made Nested Knowledge tagging hierarchy were pre-configured 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 (SpO2). 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 SpO2.

Risk of bias and statistical analysis

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.

Results

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 [22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53]. A PRISMA diagram detailing the search strategy is shown in Fig. 1. Of the articles identified, 30 were excluded after full-text review [54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83]. 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], favipiravir [25, 30, 35, 40,41,42, 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).

Fig. 1
figure 1

PRISMA flowchart for study inclusion

Full size image
Table 2 Study and patient characteristics
Full size table
Table 3 Patient Outcomes
Full size table

Favipiravir

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) compared to the control group (26 days; hazard ratio [HR]: 2.1 [95% confidence interval [CI] 1.1–4.0], p = 0.038). The trial ended after 30 days, at which time the favipiravir group had a significantly higher incidence of conversion to negative RT-PCR tests (80.6% [29/36]) compared to the control group (52.6% [10/19], p = 0.030). Mortality did not occur in either group within the 30-day study period.

Shinkai et al. investigated the efficacy of favipiravir in COVID-19 patients without oxygen therapy in a single-blind, placebo-controlled trial [52]. Patients received favipiravir or a placebo on the same schedule. They defined clinical improvement by four clinical parameters: temperature, oxygen saturation, chest imaging findings, and viral clearance assessed with RT-PCR. Patients treated with favipiravir met the criteria for clinical improvement significantly earlier (11.9 days [95% CI: 10.0–13.1 days]) than patients in the placebo group (14.7 days [95% CI: 10.5–17.9 days], p = 0.014). The difference in time to improvement was also significant in the covariate-adjusted Cox proportional hazards model (HR: 1.59 [95% CI 1.02–2.48]). Within the individual parameters, time to 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 SpO2 (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), time to clinical improvement (p = 0.29), duration of hospital stay (p = 0.42), 28-day mortality (p = 0.45), and 90-day mortality (p = 0.91). Solaymani-Dodaran et al. conducted a multicentric, open-label trial to compare favipiravir (in addition to HCQ) to LPV/r [44]. They found no significant differences between the groups for mortality (p = 0.52), transfer to the ICU (p = 0.47), time to clinical recovery (p = 0.54), incidence of clinical recovery (HR: 0.94 [95% CI 0.75–1.17]), or change in oxygen saturation (p = 0.46).

Lopinavir/Ritonavir

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 [95% CI, 0.53–2.56]) or viral clearance at day 14 (LPV/r: odds ratio [OR], 1.04 [95% CI, 0.94–1.16]). 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 in-hospital 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

Remdesivir is an RNA-dependent RNA polymerase inhibitor with in-vitro activity demonstrated against SARS-CoV-2 and MERS-CoV [34, 92]. It is FDA-approved 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, SpO2 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 double-blind, placebo-controlled, multicenter trial in COVID-19 patients with SpO2 ≤ 94% in room air or PaO2/FiO2 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 six-point 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/Daclatasvir

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 [5–13] 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 SpO2 (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).

Enisamium

One study evaluated the efficacy of enisamium, an antiviral drug whose metabolite is a viral RNA polymerase inhibitor [98]. Holubovska et al. conducted a double-blind, 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.

Discussion

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 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 (all-cause 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.

Limitations

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 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).

Conclusions

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).

Availability of data and materials

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

Abbreviations

ACTT-1:

Adaptive Covid-19 Treatment Trial

CI:

Confidence interval

COVID-19:

Coronavirus disease 2019

CQ:

Chloroquine

CT:

Computed tomography

ECMO:

Extracorporeal membrane oxygenation

GI:

Gastrointestinal

HCQ:

Hydroxychloroquine

HR:

Hazard ratio

ICU:

Intensive care unit

IFN:

Interferon

IQR:

Interquartile range

LPV/r:

Lopinavir/ritonavir

MERS:

Middle Eastern respiratory syndrome

NMV:

Noninvasive mechanical ventilation

OR:

Odds ratio

PRISMA:

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

RCTs:

Randomized control trials

RR:

Rate ratio

RT-PCR:

Reverse transcription polymerase chain reaction tests

SaO2 :

Oxygen saturation

SARS:

Severe acute respiratory syndrome

SARS-CoV-2:

Severe acute respiratory syndrome coronavirus 2

SD:

Standard deviation

SIGN:

Scottish Intercollegiate Guidelines Network method

SpO2 :

Oxygen saturation

UK:

United Kingdom

WBC:

White blood cell count

References

  1. Weekly epidemiological update on COVID-19 - 14 December 2021. World Health Organization. https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---14-december-2021. Accessed 16 Dec 2021.

  2. García LF. Immune response, inflammation, and the clinical spectrum of COVID-19. Front Immunol. 2020;11:1441.

    PubMed  PubMed Central  Google Scholar 

  3. Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review. JAMA. 2020;323(18):1824–36.

    CAS  PubMed  Google Scholar 

  4. Liu W, Zhou P, Chen K, Ye Z, Liu F, Li X, He N, Wu Z, Zhang Q, Gong X, et al. Efficacy and safety of antiviral treatment for COVID-19 from evidence in studies of SARS-CoV-2 and other acute viral infections: a systematic review and meta-analysis. CMAJ. 2020;192(27):E734–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Okoli GN, Rabbani R, Al-Juboori A, Copstein L, Askin N, Abou-Setta AM. Antiviral drugs for coronavirus disease 2019 (COVID-19): a systematic review with network meta-analysis. Expert Rev Anti Infect Ther. 2021. https://doi.org/10.1080/14787210.2021.1961579.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Lai CC, Chao CM, Hsueh PR. Clinical efficacy of antiviral agents against coronavirus disease 2019: A systematic review of randomized controlled trials. J Microbiol Immunol Infect. 2021;54(5):767–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Nested Knowledge. https://nested-knowledge.com/. Accessed 31 Dec 2021.

  8. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. PLOS Med. 2021;18(3):e1003583.

    PubMed  PubMed Central  Google Scholar 

  9. COVID-19 RCTs - Phase I. Nested Knowledge, Inc. https://nested-knowledge.com/nest/qualitative/212. Accessed 14 Sep 2021.

  10. Baloxavir Marboxil. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed 20 Dec 2021.

  11. Lopinavir/Ritonavir. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed 20 Dec 2021.

  12. Atazanavir. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed 20 Dec 2021.

  13. Sofosbuvir. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed 20 Dec 2021.

  14. Daclatasvir. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed 20 Dec 2021.

  15. Remdesivir. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed 20 Dec 2021.

  16. Ribavirin. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed 20 Dec 2021.

  17. Shiraki K, Daikoku T. Favipiravir, an anti-influenza drug against life-threatening RNA virus infections. Pharmacol Ther. 2020;209:107512.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Leneva IA, Russell RJ, Boriskin YS, Hay AJ. Characteristics of arbidol-resistant mutants of influenza virus: implications for the mechanism of anti-influenza action of arbidol. Antiviral Res. 2009;81(2):132–40.

    CAS  PubMed  Google Scholar 

  19. A Drug Safety and Dose-exploratory Clinical Study of Azvudine Tablets in Patients Who Have Not Received Anti-HIV Treatment. https://ClinicalTrials.gov/show/NCT04109183. Accessed 20 Dec 2021.

  20. Zheng F, Zhou Y, Zhou Z, Ye F, Huang B, Huang Y, Ma J, Zuo Q, Tan X, Xie J, et al. SARS-CoV-2 clearance in COVID-19 patients with Novaferon treatment: a randomized, open-label, parallel-group trial. Int J Infect Dis. 2020;99:84–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Methodology checklist 2: randomised controlled trials. https://www.sign.ac.uk/what-we-do/methodology/checklists/. Accessed 14 Sep 2021.

  22. Abbaspour Kasgari H, Moradi S, Shabani AM, Babamahmoodi F, Davoudi Badabi AR, Davoudi L, Alikhani A, Hedayatizadeh Omran A, Saeedi M, Merat S, et al. 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. 2020;75(11):3373–8.

    PubMed  Google Scholar 

  23. Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, Hohmann E, Chu HY, Luetkemeyer A, Kline S, et al. Remdesivir for the treatment of Covid-19—final report. N Engl J Med. 2020;383(19):1813–26.

    CAS  PubMed  Google Scholar 

  24. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med. 2020;382(19):1787–99.

    PubMed  Google Scholar 

  25. Chen C, Zhang Y, Huang J, Yin P, Cheng Z, Wu J, Chen S, Zhang Y, Chen B, Lu M, et al. Favipiravir versus Arbidol for COVID-19: a randomized clinical trial. MedRxiv. 2020. https://doi.org/10.1101/2020.03.17.20037432.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Group RC. Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2020;396(10259):1345–52.

    Google Scholar 

  27. Reis G, Moreira Silva E, Medeiros Silva DC, Thabane L, Singh G, Park JJH, Forrest JI, Harari O, Quirino Dos Santos CV, Guimarães de Almeida APF et al. Effect of early treatment with hydroxychloroquine or Lopinavir and Ritonavir on risk of hospitalization among patients with COVID-19: The TOGETHER Randomized Clinical Trial. JAMA Netw Open. 2021;4(4):e216468.

  28. Khalili H, Nourian A, Ahmadinejad Z, Emadi Kouchak H, Jafari S, Dehghan Manshadi SA, Rasolinejad M, Kebriaeezadeh A. Efficacy and safety of sofosbuvir/ledipasvir in treatment of patients with COVID-19; a randomized clinical trial. Acta Biomed. 2020;91(4):e2020102.

    PubMed  PubMed Central  Google Scholar 

  29. Li Y, Xie Z, Lin W, Cai W, Wen C, Guan Y, Mo X, Wang J, Wang Y, Peng P, et al. Efficacy and safety of lopinavir/ritonavir or arbidol in adult patients with mild/moderate COVID-19: an exploratory randomized controlled trial. Med (N Y). 2020;1(1):105-113.e104.

    Google Scholar 

  30. Lou Y, Liu L, Yao H, Hu X, Su J, Xu K, Luo R, Yang X, He L, Lu X, et al. Clinical outcomes and plasma concentrations of baloxavir marboxil and favipiravir in COVID-19 Patients: an exploratory randomized. Controlled Trial Eur J Pharm Sci. 2021;157:105631.

    CAS  PubMed  Google Scholar 

  31. Nojomi M, Yassin Z, Keyvani H, Makiani MJ, Roham M, Laali A, Dehghan N, Navaei M, Ranjbar M. Effect of Arbidol (Umifenovir) on COVID-19: a randomized controlled trial. BMC Infect Dis. 2020;20(1):954.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Roozbeh F, Saeedi M, Alizadeh-Navaei R, Hedayatizadeh-Omran A, Merat S, Wentzel H, Levi J, Hill A, Shamshirian A. Sofosbuvir and daclatasvir for the treatment of COVID-19 outpatients: a double-blind, randomized controlled trial. J Antimicrob Chemother. 2021;76(3):753–7.

    CAS  PubMed  Google Scholar 

  33. Sadeghi A, Ali Asgari A, Norouzi A, Kheiri Z, Anushirvani A, Montazeri M, Hosamirudsai H, Afhami S, Akbarpour E, Aliannejad R, et al. 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 Antimicrob Chemother. 2020;75(11):3379–85.

    CAS  PubMed  Google Scholar 

  34. Spinner CD, Gottlieb RL, Criner GJ, Arribas López JR, Cattelan AM, Soriano Viladomiu A, Ogbuagu O, Malhotra P, Mullane KM, Castagna A, et al. Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial. JAMA. 2020;324(11):1048–57.

    CAS  PubMed  Google Scholar 

  35. Udwadia ZF, Singh P, Barkate H, Patil S, Rangwala S, Pendse A, Kadam J, Wu W, Caracta CF, Tandon M. 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. 2021;103:62–71.

    CAS  PubMed  Google Scholar 

  36. Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, Fu S, Gao L, Cheng Z, Lu Q, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020;395(10236):1569–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Ader F, Peiffer-Smadja N, Poissy J, Bouscambert-Duchamp M, Belhadi D, Diallo A, Delmas C, Saillard J, Dechanet A, Mercier N, et al. An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-β-1a and hydroxychloroquine in hospitalized patients with COVID-19. Clin Microbiol Infect. 2021. https://doi.org/10.1016/j.cmi.2021.05.020.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Arabi YM, Gordon AC, Derde LPG, Nichol AD, Murthy S, Beidh FA, Annane D, Swaidan LA, Beane A, Beasley R, et al. Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial. Intensive Care Med. 2021;47(8):867–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Barratt-Due A, Olsen IC, Nezvalova-Henriksen K, Kåsine T, Lund-Johansen F, Hoel H, Holten AR, Tveita A, Mathiessen A, Haugli M, et al. Evaluation of the effects of remdesivir and hydroxychloroquine on viral clearance in COVID-19: a randomized trial. Ann Intern Med. 2021. https://doi.org/10.7326/m21-0653.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Bosaeed M, Mahmoud E, Alharbi A, Altayib H, Albayat H, Alharbi F, Ghalilah K, Al Arfaj A, AlJishi J, Alarfaj A, et al. Favipiravir and hydroxychloroquine combination therapy in patients with moderate to severe COVID-19 (FACCT Trial): an open-label, multicenter, randomized. Controlled Trial Infect Dis Ther. 2021. https://doi.org/10.2139/ssrn.3829663.

    Article  PubMed  Google Scholar 

  41. Dabbous HM, Abd-Elsalam S, El-Sayed MH, Sherief AF, Ebeid FFS, El Ghafar MSA, Soliman S, Elbahnasawy M, Badawi R, Tageldin MA. Efficacy of favipiravir in COVID-19 treatment: a multi-center randomized study. Arch Virol. 2021;166(3):949–54.

    CAS  PubMed  Google Scholar 

  42. Dabbous HM, El-Sayed MH, El Assal G, Elghazaly H, Ebeid FFS, Sherief AF, Elgaafary M, Fawzy E, Hassany SM, Riad AR, et al. Safety and efficacy of favipiravir versus hydroxychloroquine in management of COVID-19: a randomised controlled trial. Sci Rep. 2021;11(1):7282.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Sayad B, Khodarahmi R, Najafi F, Miladi R, Mohseni Afshar Z, Mansouri F, Rahimi Z, Shirvani M, Salimi M, Vaziri S, et al. Efficacy and safety of sofosbuvir/velpatasvir versus the standard of care in adults hospitalized with COVID-19: a single-centre, randomized controlled trial. J Antimicrob Chemother. 2021;76(8):2158–67.

    CAS  PubMed  Google Scholar 

  44. Solaymani-Dodaran M, Ghanei M, Bagheri M, Qazvini A, Vahedi E, Hassan Saadat S, Amin Setarehdan S, Ansarifar A, Biganeh H, Mohazzab A, et al. Safety and efficacy of Favipiravir in moderate to severe SARS-CoV-2 pneumonia. Int Immunopharmacol. 2021;95:107522.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Zhao H, Zhang C, Zhu Q, Chen X, Chen G, Sun W, Xiao Z, Du W, Yao J, Li G, et al. Favipiravir in the treatment of patients with SARS-CoV-2 RNA recurrent positive after discharge: a multicenter, open-label, randomized trial. Int Immunopharmacol. 2021;97:107702.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Abbass S, Kamal E, Salama M, Salman T, Sabry A, Abdel-Razek W, Helmy S, Abdelgwad A, Sakr N, Elgazzar M, et al. Efficacy and safety of sofosbuvir plus daclatasvir or ravidasvir in patients with COVID-19: A randomized controlled trial. J Med Virol. 2021. https://doi.org/10.1002/jmv.27264.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Alavi Darazam I, Shokouhi S, Mardani M, Pourhoseingholi MA, Rabiei MM, Hatami F, Shabani M, Moradi O, Gharehbagh FJ, Irvani SSN, et al. Umifenovir in hospitalized moderate to severe COVID-19 patients: A randomized clinical trial. Int Immunopharmacol. 2021;99:107969.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Doi Y, Hibino M, Hase R, Yamamoto M, Kasamatsu Y, Hirose M, Mutoh Y, Homma Y, Terada M, Ogawa T, et al. A prospective, randomized, open-label trial of early versus late favipiravir therapy in hospitalized patients with COVID-19. Antimicrob Agents Chemother. 2020. https://doi.org/10.1128/AAC.01897-20.

    Article  PubMed  PubMed Central  Google Scholar 

  49. El-Bendary M, Abd-Elsalam S, Elbaz T, El-Akel W, Cordie A, Elhadidy T, Elalfy H, Farid K, Elegezy M, El-Badrawy A, et al. Efficacy of combined Sofosbuvir and Daclatasvir in the treatment of COVID-19 patients with pneumonia: a multicenter Egyptian study. Expert Rev Anti-infect Ther. 2021. https://doi.org/10.1080/14787210.2021.1950532.

    Article  PubMed  Google Scholar 

  50. Holubovska O, Bojkova D, Elli S, Bechtel M, Boltz D, Muzzio M, Peng X, Sala F, Cosentino C, Mironenko A, et al. Enisamium is an inhibitor of the SARS-CoV-2 RNA polymerase and shows improvement of recovery in COVID-19 patients in an interim analysis of a clinical trial. MedRxiv. 2021. https://doi.org/10.1101/2021.01.05.21249237.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Mahajan L, Singh AP, Gifty. Clinical outcomes of using remdesivir in patients with moderate to severe COVID-19: a prospective randomised study. Indian J Anaesth. 2021;65(Suppl 1):S41-S46.

  52. Shinkai M, Tsushima K, Tanaka S, Hagiwara E, Tarumoto N, Kawada I, Hirai Y, Fujiwara S, Komase Y, Saraya T, et al. Efficacy and safety of favipiravir in moderate COVID-19 pneumonia patients without oxygen therapy: a randomized, phase III clinical trial. Infect Dis Ther. 2021. https://doi.org/10.1007/s40121-021-00517-41.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Goldman JD, Lye DCB, Hui DS, Marks KM, Bruno R, Montejano R, Spinner CD, Galli M, Ahn M-Y, Nahass RG, et al. Remdesivir for 5 or 10 Days in Patients with Severe Covid-19. N Engl J Med. 2020;383(19):1827–37.

    CAS  PubMed  Google Scholar 

  54. Sekhavati E, Jafari F, SeyedAlinaghi S, Jamalimoghadamsiahkali S, Sadr S, Tabarestani M, Pirhayati M, Zendehdel A, Manafi N, Hajiabdolbaghi M, et al. Safety and effectiveness of azithromycin in patients with COVID-19: an open-label randomised trial. Int J Antimicrob Agents. 2020;56(4):106143.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Hung IF, Lung KC, Tso EY, Liu R, Chung TW, Chu MY, Ng YY, Lo J, Chan J, Tam AR, et al. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet. 2020;395(10238):1695–704.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Zhao H, Zhu Q, Zhang C, Li J, Wei M, Qin Y, Chen G, Wang K, Yu J, Wu Z, et al. Tocilizumab combined with favipiravir in the treatment of COVID-19: a multicenter trial in a small sample size. Biomed Pharmacother. 2021;133:110825.

    CAS  PubMed  Google Scholar 

  57. Zheng F, Zhou Y, Zhou Z, Ye F, Huang B, Huang Y, Ma J, Zuo Q, Tan X, Xie J, et al. A novel protein drug, novaferon, as the potential antiviral drug for COVID-19. MedRxiv. 2020;395:565.

    Google Scholar 

  58. Khamis F, Al Naabi H, Al Lawati A, Ambusaidi Z, Al Sharji M, Al Barwani U, Pandak N, Al Balushi Z, Al Bahrani M, Al Salmi I, et al. 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. 2021;102:538–43.

    CAS  PubMed  Google Scholar 

  59. Okumuş N, Demirtürk N, Çetinkaya RA, Güner R, Avcı İY, Orhan S, Konya P, Şaylan B, Karalezli A, Yamanel L, et al. Evaluation of the effectiveness and safety of adding ivermectin to treatment in severe COVID-19 patients. BMC Infect Dis. 2021;21(1):411.

    PubMed  PubMed Central  Google Scholar 

  60. Mahmud R, Rahman MM, Alam I, Ahmed KGU, Kabir A, Sayeed S, Rassel MA, Monayem FB, Islam MS, Islam MM, et al. Ivermectin in combination with doxycycline for treating COVID-19 symptoms: a randomized trial. J Int Med Res. 2021;49(5):3000605211013550.

    CAS  PubMed  Google Scholar 

  61. Group PTC. Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. Lancet. 2021;397(10279):1063–74.

    Google Scholar 

  62. López-Medina E, López P, Hurtado IC, Dávalos DM, Ramirez O, Martínez E, Díazgranados JA, Oñate JM, Chavarriaga H, Herrera S, et al. Effect of ivermectin on time to resolution of symptoms among adults with mild COVID-19: a randomized clinical trial. JAMA. 2021;325(14):1426–35.

    PubMed  PubMed Central  Google Scholar 

  63. Group RC. Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021;397(10274):605–12.

    Google Scholar 

  64. Ahmed S, Karim MM, Ross AG, Hossain MS, Clemens JD, Sumiya MK, Phru CS, Rahman M, Zaman K, Somani J, et al. A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness. Int J Infect Dis. 2021;103:214–6.

    CAS  PubMed  Google Scholar 

  65. Omrani AS, Pathan SA, Thomas SA, Harris TRE, Coyle PV, Thomas CE, Qureshi I, Bhutta ZA, Mawlawi NA, Kahlout RA, et al. Randomized double-blinded placebo-controlled trial of hydroxychloroquine with or without azithromycin for virologic cure of non-severe Covid-19. EClinicalMedicine. 2020;29:100645.

    PubMed  Google Scholar 

  66. Furtado RHM, Berwanger O, Fonseca HA, Corrêa TD, Ferraz LR, Lapa MG, Zampieri FG, Veiga VC, Azevedo LCP, Rosa RG, et al. Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial. Lancet. 2020;396(10256):959–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Brown SM, Peltan I, Kumar N, Leither L, Webb BJ, Starr N, Grissom CK, Buckel WR, Srivastava R, Butler AM, et al. Hydroxychloroquine vs. azithromycin for hospitalized patients with COVID-19 (HAHPS): results of a randomized, active comparator trial. Ann Am Thorac Soc. 2020;18(4):590–7.

    Google Scholar 

  68. Purwati, Budiono, Rachman BE, Yulistiani, Miatmoko A, Nasronudin, Lardo S, Purnama YI, Laely M, Rochmad I, et al. A randomized, double-blind, multicenter clinical study comparing the efficacy and safety of a drug combination of lopinavir/ritonavir-azithromycin, lopinavir/ritonavir-doxycycline, and azithromycin-hydroxychloroquine for patients diagnosed with mild to moderate COVID-19 infections. Biochem Res Int. 2021;2021:6685921.

  69. Gupta S, Dixit PK, Ghana P, Abhisheka K, Khurana H, Jha VK, Mahapatra D, Goel J, Ahmed S, Varadaraj G. Open-label randomized control trial of hydroxychloroquine in patients with moderate to severe coronavirus disease 2019 infection. Med J Armed Forces India. 2021;77(Suppl 2):S305-s311.

    PubMed  PubMed Central  Google Scholar 

  70. Rahmani H, Davoudi-Monfared E, Nourian A, Khalili H, Hajizadeh N, Jalalabadi NZ, Fazeli MR, Ghazaeian M, Yekaninejad MS. Interferon β-1b in treatment of severe COVID-19: a randomized clinical trial. Int Immunopharmacol. 2020;88:106903.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Vlaar APJ, de Bruin S, Busch M, Timmermans S, van Zeggeren IE, Koning R, Ter Horst L, Bulle EB, van Baarle F, van de Poll MCG, et al. Anti-C5a antibody IFX-1 (vilobelimab) treatment versus best supportive care for patients with severe COVID-19 (PANAMO): an exploratory, open-label, phase 2 randomised controlled trial. Lancet Rheumatol. 2020;2(12):e764–73.

    PubMed  PubMed Central  Google Scholar 

  72. Wu X, Yu K, Wang Y, Xu W, Ma H, Hou Y, Li Y, Cai B, Zhu L, Zhang M, et al. Efficacy and safety of triazavirin therapy for coronavirus disease 2019: a pilot randomized controlled trial. Engineering (Beijing). 2020;6(10):1185–91.

    CAS  Google Scholar 

  73. Horby P, Mafham M, Linsell L, Bell JL, Staplin N, Emberson JR, Wiselka M, Ustianowski A, Elmahi E, Prudon B, et al. Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med. 2020;383(21):2030–40.

    PubMed  Google Scholar 

  74. Abella BS, Jolkovsky EL, Biney BT, Uspal JE, Hyman MC, Frank I, Hensley SE, Gill S, Vogl DT, Maillard I, et al. Efficacy and safety of hydroxychloroquine vs placebo for pre-exposure SARS-CoV-2 prophylaxis among health care workers: a randomized clinical trial. JAMA Intern Med. 2021;181(2):195–202.

    CAS  PubMed  Google Scholar 

  75. Alavi Darazam I, Shokouhi S, Pourhoseingholi MA, Naghibi Irvani SS, Mokhtari M, Shabani M, Amirdosara M, Torabinavid P, Golmohammadi M, Hashemi S, et al. Role of interferon therapy in severe COVID-19: the COVIFERON randomized controlled trial. Sci Rep. 2021;11(1):8059.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Li C, Luo F, Liu C, Xiong N, Xu Z, Zhang W, Yang M, Wang Y, Liu D, Yu C, et al. Effect of a genetically engineered interferon-alpha versus traditional interferon-alpha in the treatment of moderate-to-severe COVID-19: a randomised clinical trial. Ann Med. 2021;53(1):391–401.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Kalil AC, Patterson TF, Mehta AK, Tomashek KM, Wolfe CR, Ghazaryan V, Marconi VC, Ruiz-Palacios GM, Hsieh L, Kline S, et al. Baricitinib plus remdesivir for hospitalized adults with Covid-19. N Engl J Med. 2021;384(9):795–807.

    CAS  PubMed  Google Scholar 

  78. Johnston C, Brown ER, Stewart J, Karita HCS, Kissinger PJ, Dwyer J, Hosek S, Oyedele T, Paasche-Orlow MK, Paolino K, et al. Hydroxychloroquine with or without azithromycin for treatment of early SARS-CoV-2 infection among high-risk outpatient adults: a randomized clinical trial. EClinicalMedicine. 2021;33:100773.

    PubMed  PubMed Central  Google Scholar 

  79. Seet RCS, Quek AML, Ooi DSQ, Sengupta S, Lakshminarasappa SR, Koo CY, So JBY, Goh BC, Loh KS, Fisher D, et al. Positive impact of oral hydroxychloroquine and povidone-iodine throat spray for COVID-19 prophylaxis: an open-label randomized trial. Int J Infect Dis. 2021;106:314–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Kestelyn E, Dung NTP, Lam Minh Y, Hung LM, Quan NM, Dung NT, Minh NNQ, Xuan TC, Phong NT, Ninh Thi Thanh V, et al. A multi centre randomized open label trial of chloroquine for the treatment of adults with SARS-CoV-2 infection in Vietnam. Wellcome Open Res. 2020;5:141.

    PubMed  PubMed Central  Google Scholar 

  81. Les Bujanda I, Loureiro-Amigo J, Bastons FC, Guerra IE, Sánchez JA, Murgadella-Sancho A, Rey RG, López JL, Álvarez JS. Treatment of COVID-19 pneumonia with glucocorticoids (CORTIVID): a structured summary of a study protocol for a randomised controlled trial. Trials. 2021;22(1):43.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Duška F, Waldauf P, Halačová M, Zvoníček V, Bala J, Balík M, Beneš J, Klementová O, Kozáková I, Kubricht V, et al. Azithromycin added to hydroxychloroquine for patients admitted to intensive care due to coronavirus disease 2019 (COVID-19)-protocol of randomised controlled trial AZIQUINE-ICU. Trials. 2020;21(1):631.

    PubMed  PubMed Central  Google Scholar 

  83. Bosaeed M, Alharbi A, Hussein M, Abalkhail M, Sultana K, Musattat A, Alqahtani H, Alshamrani M, Mahmoud E, Alothman A, et al. Multicentre randomised double-blinded placebo-controlled trial of favipiravir in adults with mild COVID-19. BMJ Open. 2021;11(4):e047495.

    PubMed  Google Scholar 

  84. Furuta Y, Komeno T, Nakamura T. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc Jpn Acad Ser B Phys Biol Sci. 2017;93(7):449–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Wang S, Dong K, Chen W. Development of a hemoptysis risk prediction model for patients following CT-guided transthoracic lung biopsy. BMC Pulm Med. 2020;20(1):247.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Vankadari N. Arbidol: A potential antiviral drug for the treatment of SARS-CoV-2 by blocking trimerization of the spike glycoprotein. Int J Antimicrob Agents. 2020;56(2):105998.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Mangum EM, Graham KK. Lopinavir-Ritonavir: a new protease inhibitor. Pharmacotherapy. 2001;21(11):1352–63.

    CAS  PubMed  Google Scholar 

  88. Tanabe Y, Sakamoto N, Enomoto N, Kurosaki M, Ueda E, Maekawa S, Yamashiro T, Nakagawa M, Chen CH, Kanazawa N, et al. Synergistic inhibition of intracellular hepatitis C virus replication by combination of ribavirin and interferon- alpha. J Infect Dis. 2004;189(7):1129–39.

    CAS  PubMed  Google Scholar 

  89. Chu CM, Cheng VC, Hung IF, Wong MM, Chan KH, Chan KS, Kao RY, Poon LL, Wong CL, Guan Y, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004;59(3):252–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Kiselev OI, Maleev VV, Deeva EG, Leneva IA, Selkova EP, Osipova EA, Obukhov AA, Nadorov SA, Kulikova EV. Clinical efficacy of arbidol (umifenovir) in the therapy of influenza in adults: preliminary results of the multicenter double-blind randomized placebo-controlled study ARBITR. Ter Arkh. 2015;87(1):88–96.

    CAS  PubMed  Google Scholar 

  91. Spanakis N, Tsiodras S, Haagmans BL, Raj VS, Pontikis K, Koutsoukou A, Koulouris NG, Osterhaus AD, Koopmans MP, Tsakris A. Virological and serological analysis of a recent Middle East respiratory syndrome coronavirus infection case on a triple combination antiviral regimen. Int J Antimicrob Agents. 2014;44(6):528–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Sheahan TP, Sims AC, Leist SR, Schäfer A, Won J, Brown AJ, Montgomery SA, Hogg A, Babusis D, Clarke MO, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun. 2020;11(1):222.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Cevik M, Tate M, Lloyd O, Maraolo AE, Schafers J, Ho A. SARS-CoV-2, SARS-CoV, and MERS-CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and meta-analysis. Lancet Microbe. 2021;2(1):e13–22.

    CAS  PubMed  Google Scholar 

  94. Diagnosis and treatment of pneumonia caused by new coronavirus (trial version 6). Medical Administration and Hospital Authority. www.nhc.gov.cn/yzygj/s7653p/202002/8334a8326dd94d329df351d7da8aefc2.shtml. Accessed 28 Apr 2021.

  95. Bhatia HK, Singh H, Grewal N, Natt NK. Sofosbuvir: A novel treatment option for chronic hepatitis C infection. J Pharmacol Pharmacother. 2014;5(4):278–84.

    PubMed  PubMed Central  Google Scholar 

  96. Chien M, Anderson TK, Jockusch S, Tao C, Li X, Kumar S, Russo JJ, Kirchdoerfer RN, Ju J. Nucleotide analogues as inhibitors of SARS-CoV-2 polymerase, a key drug target for COVID-19. J Proteome Res. 2020;19(11):4690–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Elfiky AA. Ribavirin, remdesivir, sofosbuvir, galidesivir, and tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): a molecular docking study. Life Sci. 2020;253:117592.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Walker AP, Fan H, Keown JR, Margitich V, Grimes JM, Fodor E, Te Velthuis AJW. Enisamium is a small molecule inhibitor of the influenza A virus and SARS-CoV-2 RNA polymerases. BioRxiv. 2020. https://doi.org/10.1101/2020.04.21.053017.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Hill A, Wang J, Levi J, Heath K, Fortunak J. Minimum costs to manufacture new treatments for COVID-19. J Virus Erad. 2020;6(2):61–9.

    PubMed  PubMed Central  Google Scholar 

  100. Merat S. SD1000: high sustained viral response rate in 1361 patients with hepatitis C genotypes 1, 2, 3, and 4 using a low-cost, fixed-dose combination tablet of generic sofosbuvir and daclatasvir: a multicenter, phase III clinical trial. Clin Infect Dis. 2020;70(10):2206–12.

    CAS  PubMed  Google Scholar 

  101. Poustchi H, Majd Jabbari S, Merat S, Sharifi AH, Shayesteh AA, Shayesteh E, Minakari M, Fattahi MR, Moini M, Roozbeh F, et al. The combination of sofosbuvir and daclatasvir is effective and safe in treating patients with hepatitis C and severe renal impairment. J Gastroenterol Hepatol. 2020;35(9):1590–4.

    CAS  PubMed  Google Scholar 

  102. Reddy Vegivinti CT, Pederson JM, Saravu K, Gupta N, Barrett A, Davis AR, Kallmes KM, Evanson KW. Remdesivir therapy in patients with COVID-19: A systematic review and meta-analysis of randomized controlled trials. Ann Med Surg (Lond). 2021;62:43–8.

    Google Scholar 

  103. Al-Abdouh A, Bizanti A, Barbarawi M, Jabri A, Kumar A, Fashanu OE, Khan SU, Zhao D, Antar AAR, Michos ED. Remdesivir for the treatment of COVID-19: a systematic review and meta-analysis of randomized controlled trials. Contemp Clin Trials. 2021;101:106272.

    PubMed  PubMed Central  Google Scholar 

  104. Joseph BA, Dibas M, Evanson KW, Paranjape G, Vegivinti CTR, Selvan PT, Saravu K, Gupta N, Pulakurthi YS, Keesari PR, et al. Efficacy and safety of lopinavir/ritonavir in the treatment of COVID-19: a systematic review. Expert Rev Anti Infect Ther. 2021;19(6):679–87.

    CAS  PubMed  Google Scholar 

  105. Patel TK, Patel PB, Barvaliya M, Saurabh MK, Bhalla HL, Khosla P. Efficacy and safety of lopinavir-ritonavir in COVID-19: a systematic review of randomized controlled trials. J Infect Public Health. 2021;14(6):740–8.

    PubMed  PubMed Central  Google Scholar 

  106. Madelain V, Oestereich L, Graw F, Nguyen TH, de Lamballerie X, Mentré F, Günther S, Guedj J. Ebola virus dynamics in mice treated with favipiravir. Antiviral Res. 2015;123:70–7.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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.

Funding

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.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Jacobi Medical Center, Albert Einstein College of Medicine, 1400 Pelham Pkwy S, Bronx, NY, USA

    Charan Thej Reddy Vegivinti & Prasanth Balasubramanian

  2. Superior Medical Experts, 1425 Minnehaha Ave E, P.O. Box 6000545, St Paul, MN, 55106, USA

    Kirk W. Evanson, Bernadette Kane, Erin Sheffels & Jillienne Touchette

  3. Nested Knowledge, 1430 Avon Street N, Saint Paul, MN, 55117, USA

    Hannah Lyons, Izzet Akosman, Averi Barrett, Nicole Hardy, Kathryn Cowie, J. Karon, Lauren Siegel, Ranita Tarchand, Caleb Zinn & Kevin M. Kallmes

  4. Ohio University Heritage College of Osteopathic Medicine, 6775 Bobcat Way, Dublin, OH, 43016, USA

    Hannah Lyons

  5. Kamineni Academy of Medical Sciences and Research Center, Hyderabad, Telangana, 500068, India

    Praneeth Reddy Keesari & Yashwitha Sai Pulakurthi

  6. Department of Medicine, Lakeridge Health, 1 Hospital Crt, Oshawa, ON, L1G 2B9, Canada

    Richa Chibbar

  7. Reading Hospital, 420 South 5th Avenue, West Reading, PA, 19611, USA

    Spandana Chittajallu

  8. Department of Infectious Disease, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India

    Nitin Gupta & Kavitha Saravu

  9. Manipal Center for Infectious Diseases, Prasanna School of Public Health, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India

    Nitin Gupta & Kavitha Saravu

  10. Weill Cornell Medical College, 1300 York Ave, New York, NY, 10065, USA

    Izzet Akosman

Authors
  1. Charan Thej Reddy Vegivinti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kirk W. Evanson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hannah Lyons
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Izzet Akosman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Averi Barrett
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nicole Hardy
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bernadette Kane
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Praneeth Reddy Keesari
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yashwitha Sai Pulakurthi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Erin Sheffels
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Prasanth Balasubramanian
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Richa Chibbar
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Spandana Chittajallu
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Kathryn Cowie
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. J. Karon
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Lauren Siegel
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Ranita Tarchand
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Caleb Zinn
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Nitin Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Kevin M. Kallmes
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Kavitha Saravu
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Jillienne Touchette
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

CTRV: Conceptualization, Writing—Original Draft, Supervision. KE: Conceptualization, Writing—Original Draft, Visualization. H: Formal Analysis, Investigation, Data Curation, Visualization. IA: Formal Analysis, Investigation, Data Curation. AB: Formal Analysis, Investigation, Data Curation. NH: Conceptualization, Investigation, Data Curation, Writing—Review & Editing, Supervision, Project Administration. BK: Writing—Original Draft, Writing—Review & Editing, Visualization. PRK: Conceptualization, Methodology, Investigation, Writing—Original Draft. YSP: Writing—Original Draft, Visualization. ES: Conceptualization, Writing—Original Draft, Writing—Review & Editing, Supervision, Project Administration. PB: Writing—Original Draft. RC: Conceptualization, Writing—Review & Editing. SC: Writing—Original Draft, Visualization. KC: Data Curation, Supervision, Writing—Review & Editing, Project Administration. JK: Formal Analysis, Investigation, Data Curation. LS: Formal Analysis, Investigation, Data Curation, Visualization. RT: Formal Analysis, Investigation, Data Curation, Visualization. CZ: Formal Analysis, Investigation, Data Curation. NG: Conceptualization, Methodology, Writing—Review & Editing. KMK: Conceptualization, Resources, Supervision. KS: Conceptualization, Writing—Review & Editing, Supervision. JT: Writing—Review & Editing, Supervision. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Erin Sheffels.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

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.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Additional file 1: Table S1.

Summary of risk of bias assessed with the Scottish Intercollegiate Guidelines Network (SIGN) randomized controlled trials checklist. Risk of bias assessment

Additional file 2.

PRISMA checklist.

Additional file 3.

PRISMA abstract checklist.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vegivinti, C.T.R., Evanson, K.W., Lyons, H. et al. Efficacy of antiviral therapies for COVID-19: a systematic review of randomized controlled trials. BMC Infect Dis 22, 107 (2022). https://doi.org/10.1186/s12879-022-07068-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12879-022-07068-0

Keywords

BMC Infectious Diseases

ISSN: 1471-2334

Contact us