key: cord-0815183-shf69a6g
authors: Yu, Miao; Wang, Deng‐Chao; Li, Sheng; Lei, Yue‐Hua; Wei, Jian; Huang, Li‐Yan
title: Meta‐analysis of arbidol versus lopinavir/ritonavir in the treatment of coronavirus disease 2019
date: 2021-12-06
journal: J Med Virol
DOI: 10.1002/jmv.27481
sha: b659fc48e9b289f3e49a89ea8a4e71a47726fda8
doc_id: 815183
cord_uid: shf69a6g

OBJECTIVES: To systematically evaluate the efficacy and safety of arbidol and lopinavir/ritonavir (LPV/r) in the treatment of coronavirus disease 2019 (COVID‐19) using a meta‐analysis method. METHODS: The China Knowledge Network, VIP database, WanFang database PubMed database, Embase database, and Cochrane Library were searched for a collection of comparative studies on arbidol and lopinavir/ritonavir in the treatment of COVID‐19. Meta‐analysis was used to evaluate the efficacy and safety of Arbidol and lopinavir/ritonavir in the treatment of COVID‐19. RESULTS: The results of the systematic review indicated that Arbidol had a higher positive‐to‐negative conversion rate of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) nucleic acid on Day 7 (p = 0.03), a higher positive‐to‐negative conversion rate of SARS‐CoV‐2 nucleic acid on Day 14 (p = 0.006), a higher improvement rate of chest computed tomography on Day 14 (p = 0.02), a lower incidence of adverse reactions (p = 0.002) and lower rate of mortality (p = 0.007). There was no difference in the rate of cough disappearance on Day 14 (p = 0.24) or the rate of severe/critical illness (p = 0.07) between the two groups. CONCLUSIONS: Arbidol may be superior to lopinavir/ritonavir in the treatment of COVID‐19. However, due to the small number of included studies and the number of patients, high‐quality multicenter large‐sample randomized double‐blind controlled trials are still needed for verification.

experience with the treatment of SARS and MERS and related clinical and basic research, it is speculated that lopinavir/ritonavir may have a certain effect on the treatment of COVID-19.

Lopinavir/Ritonavir is an aspartic protease inhibitor used to treat human immunodeficiency virus (HIV) infection and is currently a second-line antiretroviral therapy drug. 9 The results of animal experiments show that lopinavir/ritonavir can inhibit the activity of β-coronaviruses to a certain extent. 10 Arbidol, a drug for the prevention and treatment of influenza, is a synthetic broad-spectrum antiviral compound mainly used to prevent and treat human influenza A and B (flu) and other acute respiratory viral infections. 11, 12 In addition to having antiviral and antiinflammatory activities against various types of influenza viruses (especially H1N1), arbidol has broad-spectrum antiviral activity in vitro and in vivo. 13 It is also recommended for COVID-19.

However, whether arbidol is an effective antiviral treatment for COVID-19 compared with other antiviral treatments remains controversial. 14 Therefore, timely and systematic evaluation of the therapeutic effects of the above two drugs on COVID-19 is of great significance. In this study, a systematic evaluation method was used to retrieve controlled clinical trials of Arbidol and lopinavir/ritonavir for COVID-19 and to further evaluate the efficacy of arbidol and lopinavir/ritonavir for COVID-19 patients to provide evidence-based medical evidence for clinical treatment.

Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, 15 OR "novel coronavirus-infected pneumonia" OR "2019-nCoV" OR "COVID-19"; #2: "Arbidol" OR "lopinavir" OR "lopinavir/ritonavir"; #3: #1 AND #2. The search references were combined in the literature retrieved, and as many relevant studies were obtained as possible.

Two researchers strictly followed the inclusion and exclusion criteria to independently screen the literature. If there was a disagreement, the full text of the literature was read, and then the two parties discussed the article; when necessary, a third researcher decided whether the study was included. Preliminary elimination was performed by reading the title and abstract, obtaining the full text of the preliminarily screened literature, and then screening further by reading the full text, extracting the information of the literature, including the first author, study type, study period, number of patients, sex, age, treatment time, case classification, drug usage, and outcome indicators.

The literature quality evaluation was performed independently by two researchers, and a third party participated in the discussion and facilitated an agreement when they disagreed. The randomized trial used the modified Jadad et al. 16 scoring scale to evaluate the quality of the included studies from the following four aspects: (1) whether the random method was used (appropriate 2 points, unclear 1 point, inappropriate 0 points);

(2) whether there was allocation hiding (2 points for proper, 1 point for unclear, 0 points for inappropriate or unused);

(3) whether a blinding method was used (2 points for appropriate, 1 point for unclear, 0 points for inappropriate); and (4) whether there was loss to follow-up or withdrawal (1 point if described, 0 points if not described). The total possible score is 7 points; scores from 1 to 3 are considered low-quality research, and scores from 4 to 7 are categorized as high-quality research. Four were case-control studies, so the Newcastle-Ottawa Scale (NOS) 17 was used for quality evaluation. According to the NOS scoring system, the selection (4 points), comparability (2 points) and outcome/exposure (3 points) of each study was determined.

Studies with a score of >7 were considered to have a low risk of bias, studies with a score of 5-7 had a moderate risk of bias, and studies with a score of <5 had a high risk of bias. Articles with a high risk of bias were excluded. For randomized controlled trial (RCTs), in addition to using the modified Jadad scoring scale, we also used the Cochrane Collaboration tool to assess the risk of bias. 18 Day 14, rate of becoming severely/critically ill, rate of mortality and incidence of adverse reactions were binary variables, and the odds ratio (OR) and 95% confidence interval (CI) were used to demonstrate an effect. For continuous variables, mean difference and its 95% CI were used as the effect value. If there was no significant difference by the Q test (p > 0.10, I 2 ≤ 50%), the fixedeffects model was used for the meta-analysis. 19 If there was a significant difference (p ≤ 0.10 and I 2 > 50%), If there was a significant difference (p ≤ 0.10 and I 2 > 50%), sensitivity analysis or subgroup analysis was conducted to determine the source of heterogeneity, and the source of heterogeneity was eliminated to check whether the results were the same. If the heterogeneity test could not be carried out and the source of heterogeneity could not be eliminated, then the statistical heterogeneity between studies was considered too large for a comparative analysis, and only a descriptive analysis was performed. When p < 0.05, there was a significant difference. If the number of studies was greater than 10, publication bias was evaluated by funnel plots. 20 3 | RESULTS

Initially, 143 studies were retrieved through databases. By reading the titles and abstracts, 41 duplicate studies, 19 studies that were irrelevant to the research purpose, 62 reviews, 8 experience summaries, and 3 cases were excluded. The remaining 10 studies were rescreened after reading the full text, and 1 study without a control group and 2 studies with combination medication were excluded. After the above step-by-step screening process, 7 studies 21-27 were ultimately included. The screening process is shown in Figure 1 . The basic information of the literature is shown in Table 1 .

Three studies 21, 23, 27 were RCTs and were scored by modified Jadad et al. 16 

Since the number of studies was less than 10, a funnel plot to demonstrate publication bias was not applied in this metaanalysis.

The global situation of COVID-19 is becoming increasingly severe, affecting hundreds of countries around the world. It is listed by the World Health Organization as a "public health emergency of international concern," which seriously threatens the lives of people around the world and arouses global attention. 28, 29 Since 2019, COVID-19 has exhibited a high infection rate and high mortality rate; in addition to a lack of targeted antiviral drugs, 30 the number of confirmed cases and deaths is still increasing.

Therefore, finding effective antiviral drugs is extremely important for the clinic.

LPV/r is mainly used to treat HIV and can also be used to patient's viral load decreased, and clinical symptoms were alleviated. 34 Arbidol is a broad-spectrum antiviral over-the-counter drug developed in Russia with low toxicity. As an anti-influenza drug, it has been used clinically in several countries for decades and has good efficacy and safety. 35 38 induce interferon, 39 and improve bodily immunity. 40 

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None.

This work was not funded.

The authors declare that there are no conflict of interests. 

All data relevant to this study are included in this article.

http://orcid.org/0000-0003-1120-4319