A systematic review and meta‑analysis of Arbidol therapy for acute respiratory viral infections: A potential treatment for COVID‑19
- Authors:
- Published online on: October 31, 2022 https://doi.org/10.3892/etm.2022.11672
- Article Number: 736
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Copyright: © Feng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Acute respiratory tract infections are the third leading factor of morbidity and mortality worldwide, and constitute an enormous economic burden and public health threat worldwide (1). There are numerous and diverse viruses, which cause co-infections with other causative agents, such as fungus, atypical pathogens and other bacteria (2). Respiratory viruses are detected more frequently compared with bacteria in adults with pneumonia (3). Multiple viruses have been linked to acute respiratory viral infections (ARVI), such as influenza virus, parainfluenza viruses, respiratory syncytial virus, rhinovirus and coronaviruses (4). Influenza virus has caused several pandemics worldwide, and has become one of the most widely recognized viral infections. More recently, 2019 novel coronavirus (SARS-CoV-2) has crossed the species barrier and become a global pandemic. According to the World Health Organization report, Corona Virus Disease 2019 (COVID-19) has infected >514 million patients and resulted in >6 million deaths worldwide (as of May 6, 2022). SARS-CoV-2 can affect multiple organs, which can lead to severe disease in patients with underlying comorbidities (5). Given the rapid emergence and global spread, reducing SARS-CoV-2 infection and increasing recovery rate are critical.
Arbidol (ARB) was developed in Russia and has been used for >10 years in China for prophylaxis and treatment of influenza (6). Due to its high consumption for the prevention and treatment of COVID-19 and some other viral infections (7), it is important to reappraise the effect in reducing the risk of COVID-19(8). As the only available antiviral drug that targets hemagglutinin (HA) (9), ARB has shown broad-spectrum antiviral activity to inhibit the replication of multiple viruses (10), and has been reported to have preventive and therapeutic effects against influenza, COVID-19 or other ARVI (6).
ARB is recommended by Chinese guidelines (11) as a potential medication against COVID-19. ARB monotherapy or in combination with other antiviral drugs are suggested as potential strategies to combat SARS-CoV-2 (12,13). However, the effectiveness of ARB remains controversial. To the best of our knowledge, systematic reviews evaluating outcomes of clinical ARB application on ARVI are lacking. Therefore, it is important to analyze the available data on the efficacy of ARB and its therapeutic potential in COVID-19. Herein, the present study conducted a systematic review and meta-analysis of published studies and clinical trials to assess the efficacy of ARB on ARVI in order to provide guidance for the treatment of COVID-19.
Materials and methods
Search strategies
The present systematic review was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses principles. The PubMed (www.ncbi.nlm.nih.gov/pubmed), MedLine, EmBase (www.embase.com), Web of Science (www.webofknowledge.com), Foreign Medical Literature Retrieval Service (FMRS) (fmrs.metstr.com) and mdRxiv (www.medrxiv.org) databases were systematically searched for relevant studies published up to May 6, 2022. Search terms used were as follows: Arbidol/umifenovir, respiratory viral infection, novel coronavirus, COVID-19, influenza, SARS (severe acute respiratory syndrome), Middle East respiratory syndrome and related words. The references of selected articles were reviewed for additional studies not retrieved by the initial search.
Inclusion and exclusion criteria
Studies conducted in humans describing the impact of ARB treatment against RVI were included. In vitro and animal studies, articles written in languages other than English, review articles and studies focused on the mechanism of action of drugs were excluded. Two investigators (JY and HD) independently screened and extracted the relevant data from the included studies.
Data extraction
Information from selected studies was extracted and tabulated. The extracted data included the first author, year of publication, country, study type, characteristics of patients, treatment plan and outcomes. The primary outcomes included PCR negative rate on day 7 and 14, PCR negative conversion time, rate of clinical improvement, time of clinical improvement, rate of chest computed tomography (CT) absorption and duration of chest CT absorption. The secondary outcomes included hospital length of stay, duration of fever, rate of disease progression, adverse events and mortality.
Risk of bias assessment
Two investigators (YS and XZ) independently assessed the risks of bias in each included study. For observational studies the Newcastle-Ottawa scale (NOS) (14) was used, which consists of three domains: Selection, comparability and outcome. NOS scores of 1-4, 5-7 and 8-9 indicated low, moderate and high quality. Generally, studies which earned ≥five points were included in the final analysis. For randomized controlled trials (RCTs), the Cochrane risk of bias (RoB) tool (15) was used, which consists of five domains: Selection bias, performance bias, attrition bias, reporting bias and other biases. The potential bias was graded as low, unclear or high.
Statistical analysis
The analysis was conducted using the Review Manager software (version 5.4; Cochrane) (https://training.cochrane.org/online-learning/core-software/revman). Mean difference (MD) was used for continuous outcomes, and risk ratio (RR) was used for dichotomous variables. A 95% confidence interval (CI) was calculated for each study. Statistical heterogeneity was evaluated using the I-square and χ2 tests, where I-square >50% or P<0.10 were considered to indicate a statistically significant difference. The random-effects model was used for studies with significant heterogeneity. Otherwise, the fixed-effect model was used. Sensitivity analyses was performed manually by single study elimination method in Review Manager 5.4 software to verify conclusions of meta-analysis and explore the possible reasons of heterogeneity. Publication bias was evaluated using funnel plots. Review Manager software (version 5.3; Cochrane) was used to statistically analyze all of the data.
Results
Search results
A total of 1,529 articles were retrieved from the initial search of databases. Of those, 1,500 articles were excluded due to the following reasons: Duplicates (n=873), review articles (n=176), in vitro and animal studies (n=214), pharmacology (n=197), unrelated to ARB (n=32) and were not written in the English language (n=9) or describe the treatment (n=8). Therefore, only 20 articles (16-36) eventually met the inclusion and exclusion criteria, and were included in the final analysis (Fig. 1). Overall, one study reported therapeutic effect among patients with influenza during epidemic period, while 19 studies reported on the therapeutic and prophylaxis effect among patients with COVID-19. Characteristics of the 20 studies included in the present review are summarized in Table I. Assessment of quality of the results of RoB and NOS were presented in Table I and Fig. 2. More than half of the observational studies (n=10) were moderate quality, the main reasons were being the lack of ascertainment of exposure and adequacy of follow up of cohorts. The other six studies were high quality (n=6). All of the included four RCTs had a low risk of bias for random sequence generation. With regard to other risk of bias, in the study by Chang et al (20), the staff knew the patient grouping and did not acquire complete outcome data; therefore, the high risk of bias was due to allocation concealment, insufficient blinding, incomplete outcome and selective reporting.
Efficacy of ARB in influenza
According to the inclusion and exclusion criteria, there was only one article among patients with influenza or acute respiratory tract infection that was included in the final study. In the retrospective study performed on 442 patients with influenza (16), the patients treated with oseltamivir or ARB had significantly lower chances (0 and 0.3%, respectively) of developing pneumonia compared with patients who did not receive antiviral therapy (23.7%; P<0.001).
Therapeutic effects of ARB in COVID-19
Numerous studies have been conducted on ARB effect against COVID-19. The 17 available (17-34) articles were mostly from China. A total of four RCTs and 13 observational studies reported clinical outcome data of therapeutic effects on ARB treatment. Overall, sixteen studies were from China and one study was from Iran.
The PCR negative conversion
There were 4 and 6 studies that reported PCR negative rate on days 7 and 14, respectively. As depicted in Fig. 3, ARB was not significantly associated with higher negative rate of PCR on day 7 (RR, 1.1; 95% CI, 0.87-1.40; Fig. 3A) and day 14 (RR, 1.24; 95% CI, 0.92-1.67; Fig. 3B). A total of seven studies reported PCR negative conversion time. No significant difference was observed for PCR negative conversion time (MD, -0.26; 95% CI, -1.41-0.90; Fig. 3C).
Main symptom improvement
There were three studies that reported the rate and time of clinical improvement, respectively. ARB demonstrated significant difference in the rate of clinical improvement (RR, 0.81; 95% CI, 0.67-0.97; Fig. 4A), but this difference was not significant in the time of clinical improvement (MD, 1.11; 95% CI, 0.01-2.22; Fig. 4B). A total of seven studies reported the duration of fever that is the most representative main symptom of COVID-19. ARB was associated with shorter duration of fever (MD, -0.38; 95% CI, -0.74- -0.02; Fig. 4C). In addition, five studies reported the hospital length of stay. ARB showed no significant difference in terms of hospital stay (MD, 0.16; 95% CI, -1.62-1.93; Fig. 4D).
Chest CT absorption
There were four and two studies that reported the rate and duration of chest CT absorption, respectively. No significant difference was observed between ARB and non-ARB group in rate of improvement on chest CT (RR, 1.19; 95% CI, 0.74-1.91; Fig. 5A) and duration of CT absorption (MD, -1.43; 95% CI, -10.28-7.42; Fig. 5B).
Preventive effects of ARB
In addition to therapeutic effect, clinical studies recommended ARB for prophylaxis. The two studies (35,36) reported prophylaxis effects on ARB treatment. The retrospective study, conducted on 66 family members and 126 healthcare workers who were exposed to confirmed patients with COVID-19, revealed that ARB post-exposure prophylaxis was a protective factor against the development of COVID-19 (P<0.01) (35). Another study (36) reported that the cumulative uninfected rate of healthcare professionals in the ARB group was significantly higher compared with that of individuals in the non-ARB group; and the hospitalization rate was significantly associated with age and oral ARB administration.
Safety of ARB
There were eight and five studies that reported the rate of disease progression and mortality, respectively. As shown in Fig. 6, no significant difference was observed in terms of disease progression (RR, 1.05; 95% CI, 0.64-1.71; Fig. 6A) and mortality (RR, 0.68; 95% CI, 0.42-1.11; Fig. 6B). A total of four studies reported the adverse events. ARB showed significant difference in terms of adverse events (RR, 0.65; 95% CI, 0.45-0.94; Fig. 6C).
Publication bias and sensitivity analysis
Given that only a few studies (n<10) were included in each outcome, funnel plots to evaluate publication bias might have limited. Thus, publication bias was not analyzed further. For outcomes with high heterogeneity, sensitivity analysis was performed to verify conclusions of meta-analysis. After excluding each single study, sensitivity analysis had similar results (I2 67-91%; P>0.05) which did not change the significance in outcomes. Generally, the conclusion of the present study was relatively stable.
Discussion
The present study described and summarized the available published literature on the outcomes of ARB on ARVI. Although ARB has shown inhibitory activity against various viruses, evidence for clinical beneficial effects on ARVI mainly focused on patients suffering from influenza or COVID-19(6). The present study reviewed current clinical studies on ARB and discussed whether patients would benefit from this antiviral drug.
Since the emergence of the COVID-19 pandemic, the antiviral treatments remain limited. Some FDA-approved drugs (even originally non-antiviral) could have a potential benefit against SARS-CoV-2. Jeon et al (37) and Weston et al (38) reported >20 potential antiviral drug candidates inhibit SARS-CoV-2 in vitro. An RCT (39) that enrolled 379 patients with severe COVID-19 revealed that hydrocortisone has a 80-93% probability of superiority compared with no hydrocortisone. Some other drugs (Favipiravir, Remedsivir) have also been recommended, although there is insufficient evidence to support their effectiveness (40). Repurposing and reappraising existing antiviral drugs is the most appropriate recommendation, which deserves further consideration. ARB has improved efficacy and advantages over other commonly used antiviral drugs. M2 ion channel blockers (amantadine and rimantadine) may lead to significant adverse events, and are not recommended for treating influenza due to drug resistance (41). Neuraminidase inhibitors (NA) (zanamivir and oseltamivir) are more expensive compared with ARB (42) and ineffective in inhibiting SARS-CoV-2(41). Given the shortcomings of these currently approved compounds and the potential risk of antiviral resistance, there is an urgent need for developing new antiviral drugs (43). Leneva et al (16) reported that both ARB and oseltamivir are efficient at reducing the duration of overall illness and main influenza symptoms. Another study performed on patients diagnosed with COVID-19(17) suggested that ARB monotherapy may be superior to lopinavir/ritonavir (LPV/r). Therefore, ARB could be a suitable candidate to combat COVID-19 and other respiratory viral infections.
The majority of studies have revealed that ARB possesses a dual pharmacological action, specific antiviral effect and anti-inflammatory efficacy (6,44,45). ARB has been regarded as the pioneer of HA-targeted drugs. By inhibiting HA located on the surface of influenza virus, ARB can specifically inhibit virus attachment to host cells, and block viral fusion and viral replication. A recent study (10) demonstrated sequence and structural similarities between influenza virus (H3N2) HA protein and SARS-CoV-2 spike glycoprotein, which indicates how the influenza virus drug ARB can be a potential drug for SARS-CoV-2 infections. Another study (41) also revealed that ARB interferes with SARS-CoV-2 binding and intracellular vesicle trafficking. In addition, ARB inhibits the release of several pro-inflammatory cytokines (IL-6, IL-8, IL-10 and TNF-a) in serum induced by influenza (46). The inhibitory effect of ARB on sudden cytokine storm in patients with COVID-19 has also been suggested (47). Furthermore, ARB can influence non-specific defense factors, induce interferon and specifically activate phagocytes (48). A study based on the dual pharmacological action, ARB could therefore constitute an alternative drug for the prophylaxis and treatment of influenza, COVID-19 and other respiratory viruses.
In the present study, available clinical data on the use of ARB against SARS-CoV-2 were collected from limited studies. The majority of studies reported that ARB treatment shows a tendency to minimize the duration of symptoms, diminish SARS-CoV-2 replication, decrease the mortality rate and improve the discharge rate (21,23,27). Seasonal and post-exposure prophylaxis with ARB can reduce the infection risk of SARS-CoV-2 and significantly prevent transmission (35). Yang et al (36) also concluded that prophylactic oral ARB is associated with a lower incidence of SARS-CoV-2 infection but not hospitalization rate among healthcare professionals. Although the treatment of ARB alone may be beneficial for numerous viral infections, combination therapy with other drugs with different antiviral mechanisms and resistance profiles may be able to produce the desired results in the fight against COVID-19(49). The most commonly used combination is ARB and LPV/r. Two studies (23,27) have demonstrated that patients with COVID-19 show significant improvement in pneumonia-associated symptoms and apparent favorable clinical response with ARB+LPV/r. Another study (28) infers that ARB+IFN-2b therapy can be used as an effective method to improve COVID-19 pneumonia of mild patients, although it could not accelerate viral clearance. Hence, ARB may show an improved efficacy if combined with other antiviral drugs. However, ARB effect on COVID-19 remains controversial. Several studies (30,32) infer that ARB presents little benefit for improving the symptoms of patients or reducing the negative conversion time of SARS-CoV-2 nucleic acid. Furthermore, a timely initiation of antiviral treatment is likely an important factor that may be able to influence the prognosis of ARVI (50). Early antiviral treatment within 48 h of symptom onset shows a shorter overall illness compared with delayed antiviral treatment (16). Another study also found that early prescription of ARB in the acute stage of influenza can majorly reduce the duration, severity of all symptoms and minimize the risk of development of complications (35).
ARB is well tolerated and safe in the treatment of influenza, COVID-19 and other ARVI (51). Most studies did not find apparent side effects in the ARB treatment group (30,31). The adverse events reported were gastrointestinal symptoms, increased transaminase, moderate thirst and less sleep (23). Xu et al (28) reported that 18.8% of patients treated with ARB demonstrate mild nausea and stomachache, but all patients can tolerate this without giving up treatment. However, not all studies have arrived at a consistent conclusion on ARB safety. Deng et al (27) observed that 68.7% of patients demonstrate elevated levels of bilirubin and 43.7% patients demonstrate digestive issues, such as mild diarrhea and nausea (P>0.05), but no premature discontinuation secondary to adverse effects was observed. Jiang et al (52) demonstrated that LPV/r can significantly inhibit the metabolism of ARB, hence the combination treatment of LPV/r and ARB was an independent risk factor for liver injury. Another study (28) revealed that adverse reactions occur more frequently in groups receiving LPV/r or ARB compared with the control group (P<0.05). Therefore, the adverse reactions of the antiviral medication should be carefully monitored.
The present review aimed to summarize all relevant published clinical data updated until May 6, 2022. The results suggested significant potential for using ARB in the prophylaxis and treatment of influenza and the target of future COVID-19 studies. However, available clinical data on the ARB treatment for COVID-19 comes from limited studies. The designs of the observational studies were inconclusive; the RCT data was lacking, and the quality evidence of the case series reports was very low. These studies were heterogeneous and thus a definitive conclusion that ARB was beneficial against COVID-19 could not be established. Many of the patients underwent multiple concurrent and comprehensive treatments; so it is not known whether the clinical benefit was from ARB or other treatments.
In summary, the HA inhibitor ARB has been extensively used to combat influenza. Potential associations were investigated, and the majority of studies reported ARB efficacy. Based on the experience from influenza therapy, ARB could be a potential treatment for SARS-CoV-2. However, there is no consensus on the ARB therapy in ARVI caused by coronaviruses. It is still uncertain whether ARB improves clinical outcomes of COVID-19. Hence, repurposing existing antiviral drugs against COVID-19 deserves further evaluation and clinical verification. High quality evidence is needed to assess the benefits of ARB in treating COVID-19 to improve clinical and programmatic decisions.
Acknowledgements
Not applicable.
Funding
Funding: This study was supported by Science and Technology Planning Project of Sichuan Province (grant no. 2019YFS0309) and Cadre Health Care Project of Sichuan Province (grant no. 2018-224).
Availability of data and materials
All data generated and/or analyzed during this study are included in this published article.
Authors' contributions
TF, JG and RT were involved in the design, analysis and manuscript writing. YS and XZ performed statistical analysis and assessed the quality of the study. JY and HD extracted and analyzed the data. TF and RT confirm the authenticity of all the raw data. All authors have read and approved the manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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