key: cord-0948618-2xlnimka
authors: Lai, Chih-Cheng; Chao, Chien-Ming; Hsueh, Po-Ren
title: Clinical efficacy of antiviral agents against coronavirus disease 2019: A systematic review of randomized controlled trials
date: 2021-06-26
journal: J Microbiol Immunol Infect
DOI: 10.1016/j.jmii.2021.05.011
sha: 4506ee87324bf6c7061c6df8116dd0e8b726de54
doc_id: 948618
cord_uid: 2xlnimka

Despite aggressive efforts on containment measures for the coronavirus disease 2019 (COVID-19) pandemic around the world, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is continuously spreading. Therefore, there is an urgent need for an effective antiviral agent. To date, considerable research has been conducted to develop different approaches to COVID-19 therapy. In addition to early observational studies, which could be limited by study design, small sample size, non-randomized design, or different timings of treatment, an increasing number of randomized controlled trials (RCTs) investigating the clinical efficacy and safety of antiviral agents are being carried out. This study reviews the updated findings of RCTs regarding the clinical efficacy of eight antiviral agents against COVID-19, including remdesivir, lopinavir/ritonavir, favipiravir, sofosbuvir/daclatasvir, sofosbuvir/ledipasvir, baloxavir, umifenovir, darunavir/cobicistat, and their combinations. Treatment with remdesivir could accelerate clinical improvement; however, it lacked additional survival benefits. Moreover, 5-day regimen of remdesivir might show adequate effectiveness in patients with mild to moderate COVID-19. Favipiravir was only marginally effective regarding clinical improvement and virological assessment based on the results of small RCTs. The present evidence suggests that sofosbuvir/daclatasvir may improve survival and clinical outcomes in patients with COVID-19. However, the sample sizes for analysis were relatively small, and all studies were exclusively conducted in Iran. Further larger RCTs in other countries are warranted to support these findings. In contrast, the present findings of limited RCTs did not indicate the use of lopinavir/ritonavir, sofosbuvir/ledipasvir, baloxavir, umifenovir, and darunavir/cobicistat in the treatment of patients hospitalized for COVID-19.

Since the end of 2019, when coronavirus disease 2019 (COVID-19) was first identified, more than 123 million people have been infected by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). [1] [2] [3] Moreover, more than 2.7 million deaths have been caused by the COVID-19 pandemic. 3 Despite aggressive efforts on containment measures for the COVID-19 pandemic around the world, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is continuously spreading. [4] [5] [6] [7] [8] [9] Therefore, there is an urgent need for effective antiviral agents. 10 To date, many studies have been performed to develop different approaches to COVID-19 therapy. In addition to early observational studies, which could be limited by study design, small sample size, non-randomized design, or different treatment timings, an increasing number of randomized controlled trials (RCTs) investigating the clinical efficacy (541 patients under treatment for 10 days) and placebo (521 patients) groups for evaluation. 12 The remdesivir group had a shorter median recovery time (10 days vs. 15 days; ratio for recovery rate, 1.29; 95% CI, 1.12-1.49; p < 0.001, using a log-rank test) than the placebo group; nevertheless, no significant difference was observed between the remdesivir and placebo groups with respect to mortality on day 15 (6.7% vs. 11.9%) and day 29 (11.4% vs. 15 .2%) (hazard ratio, 0.73; 95% CI, 0.52-1.03). 12 16 In this study, a total of 596 patients were randomized in a 1:1:1 ratio to receive a 10-day course of remdesivir (n = 197), a 5-day course of J o u r n a l P r e -p r o o f remdesivir (n = 199), and standard care (n = 200), respectively. On day 11, the 5-day remdesivir group had statistically significantly higher odds of a better clinical status distribution than the group receiving standard care (odds ratio, 1.65; 95% CI, 1.09-2.48), but the clinical status distribution on day 11 between the 10-day remdesivir and standard care groups was not significantly different (p = 0.18). Moreover, all-cause mortality on day 28 was 1% for the 5-day remdesivir group (log-rank test, p = 0.43 vs. standard care), 2% for the 10-day remdesivir group (p = 0.72 vs. standard care), and 2% for the standard care group. 16 Fifth, according to the interim report of the World Health Organization Solidarity trial, in which 11,330 adults underwent randomization and 2,750 were assigned to receive remdesivir, no significant difference was observed between remdesivir and control groups regarding risk of in-hospital mortality (mortality rate ratio, 0.95; 95% CI, 0.81-1.11). 15 Finally, Kalil et al. further investigated the effect of remdesivir plus baricitinib on hospitalized adults with COVID-19 in a randomized, double-blind, placebo-controlled trial including a total of 1,033 patients; 515 patients were assigned to combination treatment and 518 to control. 14 The combination group had a shorter recovery time (rate ratio, 1.16; 95% CI, 1.11-1.32) and higher odds of clinical improvement (odds ratio, 1.3; 95% CI, 1.0-1.6) than the control group. In contrast, no significant J o u r n a l P r e -p r o o f difference was observed between the combination and control groups with respect to 28-day mortality (5.1% vs. 7.8%, hazard ratio, 0.65; 95% CI, 0.39-1.09). 14 In summary, treatment with remdesivir accelerated clinical improvement but lacked additional survival benefit. However, further subgroup analysis is warranted to identify the specific group that has benefited from remdesivir treatment.

Lopinavir acts as an inhibitor of human immunodeficiency virus type 1 aspartate protease and exhibits in vitro inhibitory activity against SARS-CoV. 18, 19 Moreover, ritonavir can extend the plasma half-life of lopinavir by inhibiting cytochrome P450. Several RCTs have been conducted to investigate the efficacy and safety of oral lopinavir/ritonavir against SARS-CoV-2 infection. 15, [20] [21] [22] The first single-center RCT was conducted in Hubei, China, which included a total of 199 adult patients with severe COVID-19 randomly assigned in a 1:1 ratio to receive either lopinavir/ritonavir (400 mg/100 mg, orally) twice daily for 14 days along with standard care or standard care alone. 20 No difference was observed between the treatment group and standard care group with respect to the time to clinical improvement J o u r n a l P r e -p r o o f 9 (hazard ratio, 1.31; 95% CI, 0.95-1.80) and mortality on day 28 (19.2% vs. 25 .0%; 95% CI, −17.3-5.7). 20 Another single-center study in China enrolled patients with mild/moderate COVID who were randomly assigned to receive lopinavir/ritonavir (n = 34) and a control group that was not administered any antiviral medication (n = 17); no significant difference was observed between the intervention and control groups in terms of virological eradication rate on day 7 (35.3% vs. 41.2%) and day 14 (85.3% vs. 76.5%). 21 A multicenter trial was conducted in UK, in which 1,616 patients were randomly allocated to receive lopinavir/ritonavir and 3,424 patients to receive standard care, and showed similar findings in both the groups; lopinavir/ritonavir group was not associated with significant reduction in 28-day mortality (23% vs. 22%, p = 0.60), duration of hospital stay (median 11 days [interquartile range (IQR) 5 to >28] in both groups), or risk of progress to invasive mechanical ventilation or death (risk ratio 1·09, 95% CI 0·99-1·20) compared with the standard care group. 22 To summarize all these findings and the interim report of the World Health Organization Solidarity trial, 15 the use of lopinavir/ritonavir for the treatment of hospitalized patients COVID-19 is not supported.

Favipiravir is an RNA-dependent RNA polymerase inhibitor that behaves as a purine analog that inhibits viral DNA replication. 23 It is a prodrug that can be ribosylated and phosphorylated to convert it into its active metabolite, favipiravir ibofuranosyl-5'-triphosphate. The report of the interim results of a phase II/III multicenter RCT conducted in Russia revealed that the viral clearance rate on day 5 in patients treated with favipiravir was significantly higher than that under standard care (62.5% [25/40] 24 Udwadia et al. conducted a phase 3, open-label, multicenter trial, which included 150 patients with confirmed mild/moderate COVID-19, who were randomized to favipiravir (n = 75) and control (n = 75) groups. 25 They observed shorter median time to the cessation of viral shedding in the favipiravir group than that in the control group (5 days vs. 7 days, p = 0.129), but the difference was not statistically significant. However, they found that the median time to 26 However, there were no significant differences in the levels of inflammatory biomarkers at hospital discharge between the study and control groups indicated by p > 0.05 for C-reactive protein, ferritin, lactate dehydrogenase, and interleukin-6; moreover, there were no significant differences between the two groups with regard to the overall length of hospital stay (7 days vs. 7 days; p = 0.948), transfer to the intensive care unit (ICU) (18.2% vs. 17.8%; p = 0.960), discharge rate (65.9% vs. 68.9%; p = 0.764), and overall mortality (11.4% vs. 13.3%; p = 0.778). 26 An exploratory RCT conducted in China included 30 hospitalized patients with COVID-19 who were randomly assigned in a 1:1:1 ratio to baloxavir marboxil, favipiravir, and control groups, respectively. 27 This study showed no significant difference in the percentage of patients who turned virus-negative after a 14-day treatment (77% vs. 100%) and the time to clinical improvement days vs. 15.9  4.8 days, p = 0.06). In addition, two patients (mortality rate, 4.2%) in the chloroquine group and one (2.3%) in the favipiravir group was deceased (p = 1.00). 28 The effect of early vs. late treatment initiation of favipiravir was assessed in a prospective, randomized, open-label trial for adolescent and adult patients hospitalized for asymptomatic/mild COVID-19. 29 There was no significant difference in viral clearance after 6 days of treatment between the two groups to evaluate the clinical efficacy and safety of sofosbuvir/daclatasvir (400/60 mg) for the treatment of patients with COVID-19. First, a single-center trial was conducted to assess the efficacy of sofosbuvir/daclatasvir plus ribavirin for treating hospitalized patients with moderate COVID-19. 35 Although the sofosbuvir/daclatasvir plus ribavirin group had a significantly shorter recovery time (6 [5-7] days vs. 6 [5] [6] [7] [8] days, p = 0.033) than control group, no significant difference was observed between the sofosbuvir/daclatasvir plus ribavirin group (n = 24) and the standard care group (n = 24) regarding duration of hospital stay (6 days vs. 6 days, p = 0.398), mortality rate (0% vs. 3%, p = 0.234), and ICU admission (0% vs. 17%, p = 0.109). Moreover, there were two major limitations of this study, including a very small sample size and an imbalance in the baseline characteristics between the arms. 35 36 Fourth, the effect of sofosbuvir/daclatasvir on COVID-19 outpatients was evaluated in a double-blind RCT including 55 patients, and no significant difference was observed in symptoms, including fever, cough, sore throat, headache, myalgia, xerostomia, and olfactory loss on day 7 between the treatment (n = 27) and control (n = 28) groups. 38 39 These findings suggest the potential of sofosbuvir/daclatasvir-based treatment for patients with COVID-19. However, all these studies [35] [36] [37] [38] were conducted in Iran; the results might not be generalizable, and therefore, a large multinational study is warranted to uphold this conclusion.

Another RCT was conducted in Iran for assessing the efficacy and safety of another combination, sofosbuvir/ledipasvir, against mild to moderate COVID-19. 40 In this open-label clinical trial, 82 patients were randomly assigned to receive either sofosbuvir/ledipasvir (400/100 mg daily) along with standard care (n = 42) or standard care alone (n = 40) for 10 days. Although the clinical response rates, duration of hospital and ICU stay, and 14-day mortality were comparable between the groups, the clinical recovery time was significantly shorter in the sofosbuvir/ledipasvir group than in the control group (2 days vs. 4 days, p = 0.02). 40 Nonetheless, the sample size was small, and therefore, RCTs with large sample sizes are necessary to further investigate the efficacy of sofosbuvir/ledipasvir.

Umifenovir is a hemagglutinin inhibitor that can effectively block the fusion of influenza virus with its host cell and is effective against all strains of influenza viruses (A, B, and C), especially influenza A viruses (H1N1, H2N2, and H3N3) , and has few side effects. 41 Recently, two RCTs 21,42 were conducted to assess its efficacy for the treatment of COVID-19. In the ELACOI trial, 21 patients with mild/moderate COVID were randomly assigned to receive umifenovir (n = 35) and no antiviral medication (control group, n = 17); no significant difference was observed between the intervention and control groups regarding virological eradication rate on day 7 (37.1% vs. 41.2%) and day 14 (91.4% vs. 76.5%), the duration from positive-to-negative conversion of SARS-CoV-2 nucleic acid (9.1 days vs. 9.3 days), and the rate of clinical deterioration from moderate to severe/critical status (8.6% vs. 11.8%) (all p > 0.05). In addition, no significant difference was observed in other secondary outcomes, including the rate of antipyresis, cough resolution, and improvement of chest computed tomography score on day 7 and day 14 (all p > 0.05). Another study recruited 100 hospitalized patients with COVID-19 who were randomly assigned to two groups of hydroxychloroquine followed by lopinavir/ritonavir and hydroxychloroquine followed by umifenovir. 42 They found that the umifenovir group was associated with a shorter duration of hospital stay (7.2 days vs. 9.6 J o u r n a l P r e -p r o o f days, p = 0.02) and higher peripheral oxygen saturation level on day 7 (94% vs. 92%, p = 0.02) than the lopinavir/ritonavir group. In contrast, no significant difference was observed with respect to the time to defervescence (2.7 days vs. 3.1 days, p = 0.2) and the risk of intubation (6% vs. 4%, p = 0.6) and mortality (2% vs. 4%, p = 0.5). 42 However, both these studies have small sample sizes to draw any conclusion, and further study on the effectiveness of umifenovir against COVID-19 using a larger sample size and multicenter design is warranted.

Baloxavir marboxil is a prodrug that is metabolized to its active form, baloxavir acid, and the first cap-dependent endonuclease enzyme inhibitor that can block influenza virus replication. 43 Most clinical studies have focused on its efficacy in influenza, [44] [45] [46] [47] and only one RCT was conducted to assess its effect on SARS-CoV-2 infection. 27 The study demonstrated that baloxavir was not associated with higher rates of virological eradication and clinical improvement than standard care (virological eradication after 14-day treatment: 70% vs. 100%; the time to clinical improvement: 14 days vs. 15 days). 27 A similar trend was found in the secondary outcomes, including rates of incidence of J o u r n a l P r e -p r o o f mechanical ventilation (10% vs. 0%) and ICU admission (10% vs. 0%). The lack of efficacy of baloxavir in this study might be attributable to delay in randomization and treatment with baloxavir after onset of symptoms (12.7  3.5 days). In addition, the study number was limited (baloxavir group, n = 10; control group, n = 10); therefore, larger studies are warranted in future.

Darunavir is a human immunodeficiency virus-1 protease inhibitor that has a mechanism of action similar to that of lopinavir. A single-center RCT was conducted in China to investigate the efficacy and safety of darunavir/cobicistat in treating pneumonia caused by SARS-CoV-2. 48 

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