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Antiviral Treatment for COVID-19: A Systematic Review

Aim: In December 2019, there were reports of a new type of coronavirus that affects the different health systems of the world. We have carried out a systematic review of the possible antivirals studied that could be useful in this public health catastrophe. Data Sources: A search strategy with MESH terms was performed in PubMed, Web of Science, and Scopus. Also, RCTs published in clinicaltrials.gov were reviewed. The databases were searched between April and June 2020. Study Selection: We selected all Randomized Controlled Trials evaluating the effects of antivirals and 5 studies were included from a research database of 280 articles collected between. After removing duplicated articles, 43 were selected for review. Finally, 5 articles were eligible for full-text review and included in the article. Systematic Review Arias et al.; JPRI, 32(32): 39-51, 2020; Article no.JPRI.59476 40 Results: Current randomized controlled trial data showed no clinical improvement in terms of mortality, need for oxygen support or need for intubation in patients who used antivirals versus those who did not. No clinical improvement was demonstrated. It was observed that there is difficulty in calculating clinical improvement, this large difference makes the eligible studies difficult to compare. Conclusion: These predictors, however, need further work to validate reliability. More clinical trials involving antivirals are needed to observe a relationship between clinical improvement or mortality from SARS-CoV-19.

Results: Current randomized controlled trial data showed no clinical improvement in terms of mortality, need for oxygen support or need for intubation in patients who used antivirals versus those who did not. No clinical improvement was demonstrated. It was observed that there is difficulty in calculating clinical improvement, this large difference makes the eligible studies difficult to compare. Conclusion: These predictors, however, need further work to validate reliability. More clinical trials involving antivirals are needed to observe a relationship between clinical improvement or mortality from SARS-CoV-19.  [1].

Keywords
The fatal case index (CFR) is one of the important measures of impact during outbreaks, epidemics, or pandemics, it is defined as "the proportion of cases of a specified condition that are fatal within a specified time" [2]. What has been reported in studies of SARS-Cov 2 infection in China so far exhibit an approximate CFR of 4.0% [3,4]. In addition to the need for properly equipped intensive care units and their high contagion capacity, the search for an accurate and efficient treatment became a priority in the scientific community.
When the first patient arrived in the United States, experts recommended Remdesivir treatment, and its application was even approved by the Food and Drug Administration (FDA). 3 But the lack of information that will prove its efficacy and validity in the use of Covid-19 cases was quickly questioned [4,5].

Study Selection
We Selected all RCT's evaluating the effects of antivirals (Remdesivir, Oseltamivir, favipiravir, Lopinavir, ritonavir,) on mortality, rate of the need of mechanical ventilation, acute coronary syndrome, and harmful events in patients with a severe or moderate case of COVID. We included studies in any language or with any sample size. We excluded case reports, reviews, editorials, letters to editors, and retrospective studies. Abstracts from all engines were centrally collected in myendnoteweb.com, and duplicates were removed. The selection of abstracts was done independently by two investigators and any discrepancies were solved with a third investigator.

Data Extraction
Two investigators independently extracted the information from full texts of selected studies, and any discrepancies were solved by a third investigator. Extracted information included the year of publication, length of the study, place where the study was taken, trial phase, the population included, intervention drug, control, trial therapy, and time of follow-up. Also, data from the outcomes were extracted.

Outcomes
The main outcome considered in the study was mortality, while the secondary outcomes were clinical improvement as defined by the NEWS-2 score, severe respiratory failure (defined by the requirement of mechanical ventilation), the presence of Disseminated Intravascular Coagulation (defined by the increment of levels of D dimer and systemic organ failure) and Acute Heart Failure (defined by acute heart symptoms of fluid overload, acute pulmonary edema and/or left ventricular ejection fraction <40%). Finally, the most common side effects in studies are presented (ALT increase, Lymphopenia, Thrombocytopenia, Rash, Acute Kidney Injury, and Pneumothorax). All the definitions will be described in Table 2.

Risk of Bias Assessment
Two investigators evaluated the risk of bias of each eligible RCT using the Cochrane collaboration tool for assessing the risk of bias for randomized clinical trials [14]. Any discrepancies were solved by a third investigator. The following criteria were included in the evaluation: Randomness of Allocation sequence, Concealment of Allocation sequence, Blinding of the patient, the investigator and of the outcome, selective reporting, incomplete outcome, and any other biases. Each item was described for each study as Low, high or uncertain risk of bias.

Additional Analyses
A meta-analysis could not be performed due to the heterogeneity of the included studies. (Fig. 3)

Selection of trials
We identified a total of 280 articles in the search engines specified. After removing duplicates, 43 articles left. These were screened by title and abstract, where 36 articles were excluded. Finally, a full-text review was taken for eligibility in 7 articles, where 2 of them were excluded due to not including the outcomes searched in this study (Fig. 1). The characteristics of the 5 studies included in this review are shown in Table 1.

Description of trials
Overall baseline characteristics are presented in Table 1. The largest study population was presented by Beigel et al where a total of 1063 participants were considered in the analysis, while the smallest population included was by Hung et al with 127 patients [12,13]. Baseline characteristics show that the highest average age comes from the study by Wang et al. with a median age of 66 and an IQR: 57-73, while the predominant gender in almost all studies was male, the only exception being the arbidoltreated group in the trial developed by Chen et al. which showed 57.5% of the female population [7,11]

Risk of bias assessment
In selection bias, the generation of both random sequence and allocation concealment showed a low risk of bias in all 5 selected articles. showed an unclear risk of bias since this information was not specified [7,9,[11][12][13]. All articles presented a low risk of bias in reporting and attrition. Finally, only Beigel et al. showed a high risk of bias in the 'other' category because that study was sponsored by the pharmaceutical company producing Remdesivir [16] (Fig. 2).

Mortality
In the randomized clinical trials (RTC's) analyzed, it was evidenced that the drugs used did not associate improvement in mortality in patients with COVID -19 compared to standard care, the need for invasive ventilation, hospitalization without oxygen, hospitalization with oxygen or non-invasive ventilation, or treatment discontinuation [9,11]. Besides, the highest mortality of RCTs was from Beigel et al.
(54 %) in the control group compared to the rest of the trials, however, this also presented the largest study population (1063) from different nationalities, indicating that it included a larger and diverse population [13].

Clinical improvement
The studies that include the evaluation of clinical improvement as outcomes (Cao et al., Wang et al.) showed most patients that required hospitalization by day 14 were in the control subgroup, in comparison with the patients in the Lopinavir-Ritonavir subgroup [9,11]. Patients requiring Extracorporeal membrane oxygenation (ECMO) or mechanical ventilation were predominant in the control subgroup versus the patients receiving Remdesivir. There were no other major differences in the results reported. Remdesivir recently had proved better clinical outcomes in a phase 3 trial.

Severe Respiratory Failure, DIC, and AHF
One of the most outstanding results among secondary outcomes was the need for intubation due to severe respiratory failure, whose data were presented by Cao et al. and Wang et al. [9,11] They provide data on the number of days of intubation, and in addition to the IQR (Cao et al. 5 days, IQR: 3-9 and Wang et al. 8 days, IQR: 5-17); Regarding the trial developed by Wang et al, there was no significant difference between the different study groups, the following data being found in the group treated with remdesivir presented a median of 7 days with an IQR: 3-13.5; while the placebo group had a median of 16 days with an IQR: 8-21. [7,11] Regarding the presence of acute heart failure (ACI) Cao et al. it only showed 1% with this affection in the control group, Wang et al. presented 5% of cases of acute heart failure in the treatment group, and 9% of cases of acute heart failure in the placebo group. [9,11] Finally, disseminated intravascular coagulation (DIC) occurred only in the trial developed by Cao et al., Showing no significant difference between the analyzed groups [9].

Side effects of medications
In the set of side effects observed in the articles included in this systematic review, we considered 6 of them as the most relevant. Five of the six articles included presented these side effects. Beigel et al. does not present any side effects in their population [13]. The increase of ALT (Alanine aminotransferase) is the side effect more commonly presented. Hung et al. showed the highest prevalence of increased ALT in their population. Despite this information, it is known that patients without antiviral treatment raise ALT and AST levels [12,16]. The treatment group (Interferon beta-1b, lopinavir-ritonavir, and ribavirin group with 13%; and Lopinavir-ritonavir alone group with 17%). The lowest prevalence of increased ALT was presented by Wang et al. with 1% in the treatment group, and 0% in the placebo group [11]. The rash, acute kidney injury and thrombocytopenia were showed by Cao et al and Wang et al. [9,11]  Heidary et al. found that even though Ivermectin is an effective antiviral agent in vitro, its effect has not been reproduced in living mice models with a different virus. Also, the antiviral activity of this drug is being noted while using concentrations around 1ugram/ml, the doses used in humans is way lower in the range of 20-80ng/ml [24].
Additionally, Liu et al. found in their SR and metanalyses that there was insufficient evidence that suggests any benefit from the treatments included (Lopinavir/Ritonavir, Ribavirin, Chloroquine, hydroxychloroquine, arbidol, favipiravir) in the clinical outcomes of the patients. Also, they found an increase in the GI adverse events with the use of Lopinavir/ritonavir [18].
Di Lorenzo et al. and Yousefifard et al. concluded in their systematic reviews, that there is an urgent need for phase 3 RCT's to be completed and published, to find better associations between the clinical outcomes and the medications used [20,25].
Finally, it is well known that patients with SARS-CoV-2 with only supportive care presents some degree of liver damage, with a rise in AST and ALT levels, with no clinical manifestations [17].

What's new on our study
This study adds Clinical improvement as an outcome using the NEWS-2 Score, which was not included in previous systematic reviews. Also, this paper includes the evaluation of specific side effects of the antivirals; and besides, it includes the evaluation of some of the complications commonly associated with COVID-19. These outcomes were not included in most of the previously published systematic reviews. In this systematic review, the latest updates in clinical improvement of patients focused only on antivirals are studied.

LIMITATIONS
The main limitation of this study is that the data included was recollected from other studies. Furthermore, only a limited number of eligible published RCTs on the subject could be chosen, which did not have validation. Most of them also have a very small population included. Another limitation is the population from the studies are different from each other, and not all of them consider the same outcomes for their RCTs.

CONCLUSION
It is important to consider that the use of the antivirals mentioned in the study may cause certain adverse effects. Among them, the elevation of alanine aminotransferase was evident in all antivirals in this systematic review. The use of clinical improvement scales, as in the case of NEWS-2 Score, helps the follow-up of the patients included in the trials and allows us to have quick and understandable reading data. Some more serious side effects like CID and AHF are mentioned in 2 of these studies. Also, other adverse effects are mentioned in studies such as acute kidney damage, thrombocytopenia, among others. More clinical trials involving antivirals are needed to observe a relationship between clinical improvement or mortality from SARS-CoV-19.

DECLARATION
The Authors declare that they have taken extreme care with the handling of data and identity since it is a bibliometric study, no people have been surveyed or their data has been obtained, so we have not violated any normal ethics.

CONSENT
It is not applicable.