key: cord-0908797-diiwq2lj
authors: Huang, Dong; Yu, He; Wang, Ting; Yang, Huan; Yao, Rong; Liang, Zongan
title: Efficacy and safety of umifenovir for coronavirus disease 2019 (COVID‐19): A systematic review and meta‐analysis
date: 2020-07-14
journal: J Med Virol
DOI: 10.1002/jmv.26256
sha: ebe1e3a29e20b3a2ebb311fbc662980a308ca936
doc_id: 908797
cord_uid: diiwq2lj

We conducted this systemic review and meta‐analysis in an attempt to evaluate the efficacy and safety of umifenovir in coronavirus disease 2019 (COVID‐19). We searched PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure, and medRxiv database. We included both retrospective and prospective studies. The mean difference (MD) and risk ratio (RR) with 95% confidence intervals (CI) were applied to assess the effectiveness of umifenovir for COVID‐19. A total of 12 studies with 1052 patients were included in our final studies. Compared with control group, umifenovir was associated with higher negative rate of PCR on day 14 (RR:1.27; 95% CI: 1.04 to 1.55). However, umifenovir is not related to nucleus acid negative conversion time (MD: 0.09; 95% CI: −1.48 to 1.65), negative rate on day 7 (RR:1.09; 95% CI: 0.91 to 1.31), incidence of composite endpoint (RR:1.20; 95% CI: 0.61 to 2.37), rate of fever alleviation on day 7 (RR:1.00; 95% CI: 0.91 to 1.10), rate of cough alleviation on day 7 (RR:1.00; 95% CI: 0.85 to 1.18), or hospital length of stay (MD: 1.34; 95% CI: ‐2.08 to 4.76). Additionally, umifenovir was safe in COVID‐19 patients (RR for incidence of adverse events: 1.29; 95% CI: 0.57 to 2.92). The results of sensitivity analysis and subgroup analysis were similar to pooled results. There is no evidence to support the use of umifenovir for improving patient‐important outcomes in patients with COVID‐19.

The fast worldwide spread and outbreak of coronavirus disease 2019 , which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has leaded to over 6.4 million infected cases and 370 000 deaths so far. 1 The epidemiologic situation is still severe around the world now due to lack of vaccine and specific antiviral drugs against this highly infectious virus. This has caused anxiety and stress in the general population. 2, 3 Based on previous treatments experience of severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS), some potential antiviral drugs have been approved and used urgently in COVID-19 patients, such as interferon, ribavirin, hydroxychloroquine, lopinavir and ritonavir, umifenovir, and so on. 4, 5 However, the specific effectiveness of these drugs for COVID-19 still remains unclear and controversial, especially considering that almost all recent multicenter, randomized, controlled trials (RCTs) failed to observed benefits of them. For instance, Cao et al 6 Recently more and more researchers start focusing on possible efficacy of umifenovir in COVID-19. Umifenovir is a broad-spectrum antiviral agent which could effectively inhibit the fusion of virus with host cells and is already licensed for prophylaxis and treatment of influenza. 9 Previous research has elucidated that umifenovir is an efficient inhibitor of SARS-CoV-2 in vitro. 10 

A systematic and comprehensive search was conducted in six databases: PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure, and medRxiv (https://www. medrxiv.org) from 1 December 2019 to 1 June 2020. Potentially relevant studies which reported the efficacy and safety of umifenovir in COVID-19 were identified. There was no limitation in the publication language. Both Medical Subject Headings terms and free text words were used to increase sensitivity for search strategy. The following search terms were used: "COVID-19" or "SARS-CoV-2" or "novel coronavirus pneumonia" or "novel coronavirus" and "arbidol" or "umifenovir" or "arbidol hydrochloride". The listed references of relevant studies were also manually evaluated to insure a complete search.

All searched results were evaluated according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. 13 At first the titles and abstracts were screened to identify related studies, and then full texts were evaluated carefully to determine included studies. The complete search and selection of related studies were performed by two independent researchers. Any disagreement was resolved through the third researcher and even team discussion until consensus was reached. The following exclusion criteria were used: (a) studies with insufficient data; (b) commentary, editorials, expert opinions, case reports, letters and reviews; (c) non-human studies.

The primary outcomes of our study included nucleus acid negative conversion time, negative rate of PCR on day 7, negative rate of PCR on day 14 and incidence of composite endpoint (admission to intensive care unit or mechanical ventilation or death). Nucleus acid Data were extracted by 2 investigators independently. Similarly, any disagreement was resolved through third investigator and team discussion until consensus was reached. Data were retrieved by using an Excel spreadsheet (Microsoft Corporation, Redmond, WA). The following information was extracted from each study: first author and publication year, study design, region, number of patients, specific therapies in umifenovir group and control group, key outcomes. The results were displayed in forest plots, and statistical significance was defined as P < .05. Based on the immunological study, the continuous variables were reported as mean and SD, 15, 16 whereas dichotomous variables were reported as frequency and proportion. 17 Statistical heterogeneity among included studies was evaluated via Cochran Q test and Higgins I 2 statistic. 18 Significant heterogeneity 2 | was rendered as P < .1 or I 2 > 50%. The random-effects model was used to calculate the pooled effects if significant heterogeneity was observed to generalize findings beyond the included studies by assuming that the selected studies are random samples from a larger population, 19 otherwise fixed-effects model was used. Mean difference (MD) and 95% confidence interval (CI) were calculated for continuous data, with risk ratio (RR) and 95% CI for dichotomous data.

To investigate the potential sources of heterogeneity for primary outcomes, we performed sensitivity analysis to further verify conclusions of meta-analysis by excluding some low-quality and dubious studies, and subgroup analysis in terms of different sample size, study design, and administrations of antiviral drugs in control group.

We used the Newcastle-Ottawa quality assessment scale (NOS) to assess quality of the included studies. 20 The NOS consists of three parameters of quality: selection, comparability, and outcome. A score of 0 to 9 was allocated to each study. Generally, studies which earned 6 or higher points were regarded as high-quality studies. Besides, the certainty of evidence at the outcome level was assessed using the GRADE approach. 21 Quality assessment was also conducted by two independent researchers.

A total of 290 records from all databases and other sources were identified. After duplicates removal, 137 records were screened for title and abstract. Then, 28 full-text studies were further assessed for eligibility, and eventually 12 studies were enrolled in our final analysis, including 10 retrospective studies 11,12,22-29 and 2 randomized controlled trials 30, 31 (Figure 1 ). 

A total of 7 studies 12,22-24,27,29,31 reported nucleus acid negative conversion time (Figure 2 Figure 6 ). Last but not the least, four studies 25, 26, 30, 31 reported the safety of umifenovir. The pooled results showed that use of umifenovir was safe in COVID-19 patients (RR for incidence of adverse events:1.29; 95% CI: 0.57 to 2.92; I 2 = 56%; Figure 7 ). According to the GRADE approach, these outcomes were all low certainty of evidence.

Among these included studies, the study of Wen et al 25 

Given that only under 10 studies were included in each outcome in our meta-analysis, the approaches to evaluate publication bias might have limited efficacy. Therefore, publication bias was not assessed.

It is acknowledged most of COVID-19 patients are now mainly receiving supportive and symptomatic therapies due to lack of clinical evidence for effective antiviral drugs against SARS-coV-2. Umifenovir has been recommended for the treatment of COVID-19 in some countries currently. However, the clinical evidence is still limited.

To our knowledge, this is the first systematic review and metaanalysis to assess exclusively efficacy and safety of umifenovir for COVID-19. Liu et al 32 Abbreviations: CI, confidence interval; MD, mean difference; NA, not acquired; RR, relative risk; RCT, randomized controlled trial.

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The authors declare that there are no conflict of interests.

DH, HY, TW, HY, RY, and ZL conceived the idea, designed, and supervised the study, drafted the manuscript, and had full access to all of the data and took responsibility for the integrity of the data. DH and HY collected data. DH and HY analyzed data and performed statistical analysis. All of the authors reviewed and approved the final version of the manuscript.

http://orcid.org/0000-0001-6598-0108