key: cord-0819630-rh9fpr0w
authors: Zhong, Han; Wang, Yan; Zhang, Zai-Li; Liu, Yang-Xi; Le, Ke-Jia; Cui, Min; Yu, Yue-Tian; Gu, Zhi-Chun; Gao, Yuan; Lin, Hou-Wen
title: Efficacy and safety of current therapeutic options for COVID-19 - lessons to be learnt from SARS and MERS epidemic: A systematic review and meta-analysis
date: 2020-04-30
journal: Pharmacol Res
DOI: 10.1016/j.phrs.2020.104872
sha: b0cfa8eb6ed4b972ec0283b05822bf3155055d7b
doc_id: 819630
cord_uid: rh9fpr0w

Abstract The rapidly progressing of coronavirus disease 2019 (COVID-19) pandemic has become a global concern. This meta-analysis aimed at evaluating the efficacy and safety of current option of therapies for severe acute respiratory syndrome (SARS), Middle Eastern respiratory syndrome (MERS) besides COVID-19, in an attempt to identify promising therapy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected patients. We searched PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), and WANFANG DATA for randomized controlled trials (RCTs), prospective cohort, and retrospective cohort studies that evaluated therapies (hydroxychloroquine, lopinavir/ritonavir-based therapy, and ribavirin-based therapy, etc.) for SARS, MERS, and COVID-19. The primary outcomes were mortality, virological eradication and clinical improvement, and secondary outcomes were improvement of symptoms and chest radiography results, incidence of acute respiratory disease syndrome (ARDS), utilization of mechanical ventilation, and adverse events (AEs). Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated using random-effects models, and the quality of evidence was appraised using GRADEpro. Eighteen articles (5 RCTs, 2 prospective cohort studies, and 11 retrospective cohort studies) involving 4,941 patients were included. Compared with control treatment, anti-coronary virus interventions significantly reduced mortality (RR 0.65, 95% CI 0.44-0.96; I 2 = 81.3%), remarkably ameliorate clinical improvement (RR 1.52, 95% CI 1.05-2.19) and radiographical improvement (RR 1.62, 95% CI 1.11-2.36, I 2 = 11.0 %), without manifesting clear effect on virological eradication, incidence of ARDS, intubation, and AEs. Subgroup analyses demonstrated that the combination of ribavirin and corticosteroids remarkably decreased mortality (RR 0.43, 95% CI 0.27-0.68). The lopinavir/ritonavir-based combination showed superior virological eradication and radiographical improvement with reduced rate of ARDS. Likewise, hydroxychloroquine improved radiographical result. For safety, ribavirin could induce more bradycardia, anemia and transaminitis. Meanwhile, hydroxychloroquine could increase AEs rate especially diarrhea. Overall, the quality of evidence on most outcomes were very low. In conclusion, although we could not draw a clear conclusion for the recommendation of potential therapies for COVID-19 considering the very low quality of evidence and wide heterogeneity of interventions and indications, our results may help clinicians to comprehensively understand the advantages and drawbacks of each anti-coronavirus agents on efficacy and safety profiles. Lopinavir/ritonavir combinations might observe better virological eradication capability than other anti-coronavirus agents. Conversely, ribavirin might cause more safety concerns especially bradycardia. Thus, large RCTs objectively assessing the efficacy of antiviral therapies for SARS-CoV-2 infections should be conducted with high priority.

Coronavirus disease 2019 (COVID-19) is a novel viral respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1, 2] . The first report took place in china in 2019 and subsequently spread across the globe rapidly.

As of 14 April 2020, a total of 1,844,863 confirmed infections have been reported with 117,021 deaths [3] . Upon the emerging COVID-19, there is no known approved, specific, effective antiviral treatment to treat this fatal disease [4] . Therefore, it is of utmost urgency to identify potential therapies for SARS-CoV-2 infected patients [5] .

As the COVID-19 resemble severe acute respiratory syndrome (SARS) and

Middle Eastern respiratory syndrome (MERS) phylogenetically and symptomatically, a variety of agents have been tried according to the clinical experience from SARS and MERS [6, 7] . The broad-spectrum antiviral agent ribavirin [8] , protease inhibitor lopinavir and ritonavir [9, 10] and immune up-regulator interferon [11, 12] were most commonly used. In addition, in vitro or in vivo studies have suggested that chloroquine and hydroxychloroquine [13, 14] , remdesivir [15] and arbidol [16] are effective in inhibiting viral replication in SARS-associated coronavirus (CoV), MERS-CoV and SARS-CoV-2 infections [17] . However, the efficacy and safety of these treatments for COVID-19 remains unclear [4] .

Few systematic reviews have previously summarized clinical trials of potential therapeutic agents for SARS, MERS or COVID-19, resulting inconclusive outcomes [4, [18] [19] [20] [21] . Herein, we conduct this review to identify the efficacy and safety of current option of therapies for SARS, MERS besides COVID-19, in an attempt to identify promising therapy for SARS-CoV-2 infected patients.

The present study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and previously published protocol (PROSPERO: CRD42020168639).

A comprehensive searching of PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), and WANFANG DATA was performed from inception to April 14th, 2020 without language restriction. Unpublished trials were also identified from clinical trial registry platforms (http://clinicaltrials.gov/ and http://www.chictr.org.cn/). Preprint articles were also retrieved from the websites MedRxiv (https://www.medrxiv.org) and BioRxiv (https://www.biorxiv.org). Manual search was conducted by screening the reference lists of inclusive studies. The search strategy consisting of patient relevant terms (COVID-19, Middle East respiratory syndrome, severe acute respiratory syndrome, etc.) and intervention relevant terms (lopinavir, ritonavir, chloroquine, hydroxychloroquine, interferon, ribavirin, remdesivir, arbidol, etc.) was applied both in Medical Subject Headings (MeSH) and free text. The comprehensive search syntax was available in Supplemental Table 1 .

Two authors (Z. Z. and H.Z.) independently screened the titles, abstracts and full-text of retrieved articles to identify their eligibility ( Figure 1 ). The studies were considered for inclusion if they were randomized controlled trials (RCTs), prospective cohort, or retrospective cohort studies; performed among adult patients with COVID-19 or MERS or SARS; evaluated the efficacy and safety of anti-coronavirus agents.

Furthermore, the studies were considered to be excluded if they lacked a control group or target quantitative outcomes; were in vitro or in vivo studies. Disagreements will be resolved by discussions with the corresponding author (Z. G.). The primary outcomes of this study included mortality, virological eradication, and clinical improvement. The secondary outcomes included improvement of symptoms, time to J o u r n a l P r e -p r o o f become afebrile, improvement of chest radiography results, utilization of mechanical ventilation, intensive care unit admission, and adverse events (AEs).

Data extraction was independently conducted by two authors (H. Z. and Z. Z.) using a standardized data collection form, which included study characteristics (author, year of publication, region, study design, sample size), population characteristics (age, gender, indication), intervention characteristics (anti-coronavirus agents, dosage, duration, concomitant therapy), and outcomes (mortality, viral eradication, clinical outcomes, and AEs). The risk of bias of inclusive RCTs were assessed in accordance with the Cochrane Collaboration Risk of Bias Tool [22] . The methodological quality assessment of prospective cohort and retrospective cohort studies were performed using the New-castle Ottawa Scale (NOS) [23] . The risk of bias of individual study was rated as low, moderate, or high. The quality of evidence was assessed with the GRADEpro software and were graded as high, moderate, low, and very low [24] .

Dichotomous data was shown as relative risks (RR) with 95% confidence intervals (CIs) and continuous variables were calculated as weight mean difference (WMD) with associated 95% CIs using random-effects model, with a I 2 >50% representing notable heterogeneity [25] . Subgroup analysis for treatments including hydroxychloroquine, lopinavir/ritonavir alone or combination, ribavirin alone or combination, arbidol and interferon were performed. To detect the robustness of the results, sensitivity analysis was conducted by sequential elimination of each study from the pool. Potential publication bias was assessed using visual inspection of funnel plots when the number of included studies was more than ten. Statistics were performed using STATA software (version13, Statacorp, College Station, Texas, USA), with P<0.05 indicating a statistically significant difference.

The present searches totally identified 5,192 citations and excluded 5,105 publications after cautious screening of titles and abstracts. Of the 87 potential studies, full-text were assessed for eligibility, 69 were excluded because they were reviews, did not contain eligible comparators, did not report outcomes of interest, were case series or others ( Figure 1 ). Finally, 18 articles [10, 12, [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] with 4,941 patients met the inclusion criteria and were retrieved for quantitative synthesis ( Table 1) .

There were 5 RCTs [28, 37, 38, 40, 41] and 2 prospective studies [12, 32] , whilst the remaining 11 trials were retrospective studies [10, 26, 27, 29-31, 33-36, 39] . Thirteen studies were conducted in China [10, 27, 28, 30, 31, 33-38, 40, 41] , 3 in Canada [12, 26, 31] , 2 in Saudi Arabia [29, 39] , and 1 in France [32] . There were 7 studies involving patients with COVID-19 [27, 28, 32, [36] [37] [38] 40] , 9 studies involving patients with SARS [10, 12, 26, 30, 31, [33] [34] [35] 41] , and 2 studies involving patients with MERS [29, 39] . The interventions included arbidol (1 study) [36] , arbidol and lopinavir/ritonavir (1 study) [37] , hydroxychloroquine (4 studies) [28, 32, 37, 40] , interferon and corticosteroid (2 studies) [12, 30] , lopinavir/ritonavir (2 studies) [36, 38] , lopinavir/ritonavir plus ribavirin and corticosteroids (2 studies) [10, 35] , ribavirin (4 studies) [26, 31, 33, 41] , ribavirin and interferon (3 studies) [29, 34, 39] , ribavirin and corticosteroids (1 study) [31] ( Table 1 ).

The primary outcomes were mortality reported in 10 studies (4,282 patients) [10, 12, 26, 29, 31, 34, 35, 38, 39, 41] , virological clearance reported in 7 studies (663 patients) [27, 32, [35] [36] [37] [38] 40] , clinical improvement reported in 1 study (199 patients) [38] . The secondary outcomes were radiographical improvement reported in 2 studies (95 patients) [27, 28] , acute respiratory disease syndrome (ARDS) reported in 2 studies (346 patients) [35, 38] , intubation reported in 5 studies (1,494 patients) [10, 12, 26, 29, 41] , and adverse events (AEs) reported in 4 studies (436 patients) [28, 37, 38, 40] , leukopenia reported in 2 studies (281 patients) [30, 38] , anemia reported in 4 studies (723 patients) [26, 34, 37, 38] , thrombocytopenia reported in 2 studies (387 patients) [34, 38] , transaminitis reported in 4 studies (633 patients) [26, 34, 37, 38] , J o u r n a l P r e -p r o o f elevated total bilirubin reported in 3 studies (330 patients) [27, 34, 38] , elevated creatinine reported in 3 studies (324 patients) [36] [37] [38] , bradycardia reported in 2 studies (487 patients) [26, 33] , and diarrhea reported in 5 studies (708 patients) [35] [36] [37] [38] 40 ].

Considering RCTs, the information of randomization was unclear in 2 studies [37, 41] , while the concealing of allocation was absent or unclear in 3 studies [37, 40, 41] .

Moreover, blinding of participants and the outcome assessors were absent or unclear in 4 studies [37, 38, 40, 41] (Supplementary Table S2 ). Therefore, we decided to identify these 4 studies with risk of bias. In terms of observational studies, the NOS scores were 6-9, indicating most of the studies were of low risk of bias (Supplementary Table S3 ).

We performed a meta-analysis of the 10 studies (4,282 patients) demonstrating data on mortality when the indication was not considered [10, 12, 26, 29, 31, 34, 35, 38, 39, 41] . Compared with comparators, interventions could notably reduce mortality 

Seven studies (663 patients) documented data on virological eradication when the indication was not taken into consideration [27, 32, [35] [36] [37] [38] 40] . The pooled result J o u r n a l P r e -p r o o f showed that the virological eradication ability of interventions were equal to that of comparator group (RR 1.33, 95% CI 0.97-1.81, I 2 = 89.8%). In subgroup analysis, the combination of lopinavir/ritonavir and arbidol, and the combination of lopinavir/ritonavir, ribavirin and corticosteroids appeared to show a superior ability in virological eradication, generating RR of 1.77 (95% CI 1.11-2.82), RR of 2.93 (95% CI 2.24-3.82), respectively. Additionally, the value of P for interaction was less than 0.01, indicating a significant difference across treatments ( There were 4 studies (313 patients) demonstrated time to become afebrile. The present of data were diversity, showing as mean±SD or medium (range), thus we could not generate a meta-analysis of this outcome. In addition, the results were controversial. On one hand, one study reported hydroxychloroquine treatment significantly shortened fever recovery time than control group 2.2±0.4 vs 3.2±1.3 [28] . On the other hand, Chen et al showed hydroxychloroquine treatment observed no difference in time course to become afebrile, which is 1(0-2) vs 1(0-3) [37] .

Another 2 studies also documented that the lopinavir/ritonavir, arbidol, and the combination of interferon and corticosteroids therapies had no effects on time course of defervescence compared to control therapy [30, 36] .

As for radiographical improvement, the meta-analysis of 2 studies generated a RR of 1.62 (95% CI 1.11-2.36, I 2 = 11.0 %), indicating a superior ability of interventions for radiographical improvement. In subgroup analysis, the combination of lopinavir/ritonavir and arbidol, and hydroxychloroquine both showed notable 

Because of inadequate inclusive studies, we did not perform a sensitivity analysis to assess the influence of each included study. We did not generate funnel plot to evaluate publication bias either with the same reason.

The quality of evidence is outlined in Table 2 . The quality of findings relevant to mortality, virological clearance, radiographical improvement, prevalence of ARDS, intubation and mechanical ventilation were very low. In addition, the total AEs, leukopenia, anemia, thrombocytopenia, diarrhea, transaminitis, increased total bilirubin had very low quality of evidence as well. However, the outcome quality of clinical improvement and increased creatinine were low, while the bradycardia had a moderate quality of evidence.

Upon the emergency of SARS-CoV-2, we conducted this systematic review and metaanalysis to identify the potential therapeutic options for COVID-19 based on previous studies of therapies for SARS or MERS. In the present review, we included 18 articles involving 4,941 patients. Compared with control treatment, anti-coronavirus interventions significantly reduced mortality, notably augmented clinical improvement and radiographical improvement, without significant effect on symptoms alleviation, time to become afebrile, virologic eradication, incidence of ARDS, intubation, and AEs.

Hydroxychloroquine had earned a reputation for potential promising role in COVID-19 [42] . Increasing number of studies had been conducted and published [28, 32, 37, 40] . Recently, chloroquine and hydroxychloroquine were demonstrated to inhibit SARS-CoV-2 in vitro (EC50=5.47%µM, EC50=0.72%µM, respectively) [32, 43] . The underlying mechanisms were inferred as follows: (1) as weakly alkaline, chloroquine could increase endosomal pH therefore block virus infection [42, 44] ; (2) as spike (S) protein angiotensin-converting enzyme 2 (ACE2) blocker, chloroquine and hydroxychloroquine interfered with the glycosylation of cellular SARS-CoV receptor thus inhibit virus attacking [4] ; (3) as immunomodulant, chloroquine and hydroxychloroquine could counteract pro-inflammatory cytokine storm in critically ill patients with COVID-19 [28, 45] . Unfortunately, the outcomes of hydroxychloroquine [37, 40] . Additionally, the hydroxychloroquine therapy improved more radiographical benefit [28] , despite accompanied with more AEs especially diarrhea [40] . Up to date, we could not recommend hydroxychloroquine superior to the standard care of SARS-CoV-2 infection, and we need to wait for larger randomized trials with target population and sensitive endpoints to valid the value of hydroxychloroquine for COVID-19.

As an inhibitor of human immunodeficiency virus (HIV) protease, lopinavir/ritonavir was a major focus as it was recommended for patients with MERS [27] or COVID-19 [46] . It was reported lopinavir could inhibit SARS-CoV and MERS-CoV replication in vitro with EC50 at 17.1 μM and 8 μM respectively [47] . Lopinavir was also found to demonstrated antiviral effect against SARS-CoV-2 in Vero E6 cells with EC50 at 26.1 μM [48] . Ritonavir had no effect against coronavirus but prolonged bioavailability of J o u r n a l P r e -p r o o f lopinavir by inhibiting host's cytochrome P450 3A4 enzyme [49] . Five studies had reported the effectiveness and safety of lopinavir/ritonavir alone or combination therapy. Lopinavir/ritonavir alone or in combination with ribavirin and corticosteroids did not show any mortality benefit. However, lopinavir/ritonavir-based treatments had observed inconsistent results of virological clearance with RR of between 0.97-2.93.

Lopinavir/ritonavir alone was revealed ineffective in lowering virus load of SARS-CoV-2 [36, 38] , while the lopinavir/ritonavir accompanying with arbidol or ribavirin augmented the eradication of SARS-CoV-2 [27, 35, [47] [48] [49] . It was speculated that lopinavir/ritonavir (400 mg/100 mg) twice daily may reach the minimal lopinavir serum concentration at 9.4 μM (7.2-12.1 μM), which was inadequate for inhibition of SARS-CoV-2 [50] . Nevertheless, lopinavir/ritonavir accompanied with the other agents showing effects against SARS-CoV-2 might decrease the inhibitory concentration of lopinavir and produce synergy [48] . Furthermore, lopinavir/ritonavirbased therapies documented notably better clinical and radiographical improvement and reduced incidence of ARDS or intubation. Take adverse reactions into consideration, most of the AEs rate were comparable between groups. Conversely, lopinavir/ritonavir alone showed tendency of more diarrhea events, while the combination of lopinavir/ritonavir, ribavirin and corticosteroids reduced incidence of diarrhea significantly. It was suspected that lopinavir/ritonavir alone did not show demonstrably beneficial effects for COVID-19, but the lopinavir/ritonavir combinations might play roles in the eradication of SARS-CoV-2 [21] .

The most extensively used therapies were ribavirin and ribavirin-based combinations.

Ribavirin was reported to tightly bind to SARS-CoV-2 RNA dependent RNA Polymerase (RdRp) with binding energy of -7.8 kcal/mol, and thus may be used to against COVID-19 [51] . There were 9 studies reporting SARS and MERS patients treated with ribavirin or combinations with ribavirin. The meta-analysis yielded inconsistent results for mortality with RR of between 0.38 and 0.82, while the combination of ribavirin and corticosteroids showed remarkable lower mortality J o u r n a l P r e -p r o o f compared with control group. In addition, patients treated with ribavirin-based therapies showed comparable rates of intubation and mechanical ventilation with control group. Of note, the major problem of ribavirin was significantly higher incidence of adverse events especially bradycardia, anemia and transaminitis compared with control group. Intriguingly, the combination of ribavirin and interferon did not observe these problems. Summarily, as the inconsistent benefit, considerable safety concerns, and very low quality of evidence, it was hard to make a clear recommendation for the use of ribavirin and ribavirin-based combinations for COVID-19.

It was revealed that arbidol had in vitro antiviral activity in early replication stage of SARS-CoV [52] . However, the arbidol alone generated equivalent outcome in patients with COVID-19 compared with control group, while the addition of lopinavir/ritonavir showed better efficacy [27] . Furthermore, interferon had been widely used through SARS and MERS epidemic [18] , and there were 5 studies reported combinations with interferon. Unfortunately, no difference was noted between treatment and control group in terms of mortality, intubation rate, and adverse reactions. The recommendation of these treatments was uncertain because of the small sample size of study and other risk of low quality [12, 27, 36] .

Firstly, to best of our knowledge, this is the first systematic review and meta-analysis capability than other anti-coronavirus agents. Conversely, ribavirin might cause more safety concern especially bradycardia.

Currently, growing trials related to anti-coronavirus agents were ongoing, including The lopinavir/ritonavir as initial therapy was associated with lower mortality compared with matched cohorts. The Lopinavir/ritonavir as rescue therapy observed no difference in mortality, compared with matched cohorts.

The Lopinavir/ritonavir as initial therapy was associated with lower rate of incubation and use of corticosteroids at a reduced dose compared with matched cohorts. The lopinavir/ritonavir as rescue therapy observed no difference in rates of intubation and oxygen desaturation compared with matched cohorts.

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A field trial for evaluating the safety of recombinant human interferon alpha-2b for nasal spray], Zhonghua shi yan he lin chuang bing du xue za zhi = Zhonghua shiyan he linchuang bingduxue zazhi =

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Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies

Broadspectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses

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*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).CI: Confidence interval; RR: Risk ratio;

High quality: Further research is very unlikely to change our confidence in the estimate of effect.Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

We are very uncertain about the estimate. 1 Patients, caregivers, those recording outcomes, and data analysts are lack of blinding. Therefore, we decided to downgrade the quality of evidence as risk of bias.2 There is serious heterogeneity among the studies included in the analysis of mortality (I 2 = 81.3%). Overall, we decided to downgrade by one level when considering these issues along with inconsistency.3 95% confidence interval around the pooled effect includes both 1) no effect and 2) appreciable benefit. Overall, we decided to downgrade the quality of evidence because of imprecision.J o u r n a l P r e -p r o o f 4 There is serious heterogeneity among the studies included in the analysis of virological clearance (I 2 = 89.8%). Overall, we decided to downgrade by one level when considering these issues along with inconsistency. 5 Total number of events is less than 300. Overall, we decided to downgrade the quality of evidence because of imprecision. 6 Random sequence generation and allocation concealment are unclear. The blinding of patients, caregivers, and data analysts are unclear as well. Therefore, we decided to downgrade the quality of evidence as risk of bias. 7 There is serious heterogeneity among the studies included in the analysis of intubation and mechanical ventilation (I 2 = 67.8%). Overall, we decided to downgrade by one level when considering these issues along with inconsistency. 8 There is serious heterogeneity among the studies included in the analysis of AEs (I 2 = 71.0%). Overall, we decided to downgrade by one level when considering these issues along with inconsistency. 9 There is serious heterogeneity among the studies included in the analysis of anemia (I 2 = 53.3%). Overall, we decided to downgrade by one level when considering these issues along with inconsistency. 10 There is serious heterogeneity among the studies included in the analysis of diarrhea (I 2 = 73.2%). Overall, we decided to downgrade by one level when considering these issues along with inconsistency. 11 The effect was large (RR >2) in analysis of bradycardia. Therefore, we decided to upgrade the quality of evidence as large magnitude of effect.