key: cord-0683118-i9knav2a
authors: Boglione, Lucio; Dodaro, Valentina; Meli, Giulia; Rostagno, Roberto; Poletti, Federica; Moglia, Roberta; Bianchi, Bianca; Esposito, Maria; Borrè, Silvio
title: Remdesivir treatment in hospitalized patients affected by COVID‐19 pneumonia: A case‐control study
date: 2022-04-19
journal: J Med Virol
DOI: 10.1002/jmv.27768
sha: 816924f8fa6e688e9c8ab191922015d8341d916a
doc_id: 683118
cord_uid: i9knav2a

To date the optimal antiviral treatment against severe coronavirus disease 2019 (COVID‐19) has not been proven; remdesivir is a promising drug with in vitro activity against several viruses, but in COVID‐19 the clinical results are currently not definitive. In this retrospective observational study, we analyzed the clinical outcomes (survival analysis, efficacy, and safety) in a group of hospitalized patients with COVID‐19 treated with remdesivir in comparison with a control group of patients treated with other antiviral or supportive therapies. We included 163 patients treated with remdesivir and 403 subjects in the control group; the baseline characteristics were similar in the two groups; the mortality rate was higher in the control group (24.8% vs. 2.4%, p < 0.001), the risk of intensive care unit (ICU) admission was higher in the control group (17.8% vs. 9.8%, p = 0.008); hospitalization time was significantly lower in patients treated with remdesivir (9.5 vs. 12.5 days, p < 0.001). The safety of remdesivir was good and no significant adverse events were reported. In multivariate analysis, the remdesivir treatment was independently associated with a 34% lower mortality rate (odds ratio = 0.669; p = 0.014). In this analysis, the treatment with remdesivir was associated with lower mortality, lower rate of ICU admission, and shorter time of hospitalization. No adverse events were observed. This promising antiviral treatment should also be confirmed by other studies.

Due to the lack of a proven antiviral therapy, clinicians widely employed supportive treatment in advanced COVID-19 phases with oxygen, ventilatory support, corticosteroids (CS), and low-molecularweight heparin (LMWH). 3, 4 A specific antiviral treatment useful in the first phase of COVID- 19 , before the development of ARDS, has not yet been identified; despite the recent availability of oral antiviral molnupiravir and paxlovir is promising, other antivirals drugs with inhibition of viral protease or viral RNA synthetase have been repurposed for use against SARS-CoV-2 infection with conflicting results. 5, 6 Remdesivir (GS-5734; Gilead Sciences Inc.) is a nucleoside analog that inhibits RNA-dependent RNA polymerase that was previously proposed for the treatment of Ebola, the Middle-East respiratory syndrome coronavirus, and the SARS-CoV. [7] [8] [9] The effectiveness of remdesivir use in COVID-19 has not been definitively proven: in the first trial by Wang et al. 10 performed in Wuhan, remdesivir was not associated with a clinical or survival improvement; however, the small sample size of this study and the varying severity of the enrolled patients do not allow a definitive conclusion to be reached. In other recent studies, however, remdesivir treatment significantly improved survival and recovery both in early and in advanced disease, [11] [12] [13] but some studies reported a major impact on mortality and hospitalization when the remdesivir was administered in the early phase of viral infection, before the beginning of the "cytokine storm" (defined as hyperinflammation, dysregulation of cytokines, and immune response) or ARDS. 14, 15 For this reason, the Italian Medicines Agency (AIFA) approved the use of remdesivir (Veklury ® ) in Italy in patients with the onset of symptoms within 10 days. 16 2 | METHODS

This is a single-center, observational, "real-life," retrospective study considering all the consecutive patients admitted at our Infectious The use of corticosteroids was not different in the two groups:

we administered-according to national recommendations-a fixed dose of dexamethasone (20 mg/daily for the first 5 days, then 10 mg/ daily for 5 days) in all subjects with evidence of pulmonary disease, the need of oxygen support and hyperinflammation laboratory signs.

The study protocol was approved by the local Ethics Committee 

In descriptive statistics, continuous variables were summarized as median (interquartile range [IQR]: 25th-75th percentiles). Categorical variables were described as frequency and percentage. All data were assessed for normality using a Shapiro-Wilk test and categorical data were compared using the χ 2 -test or Fisher exact test. To investigate continuous data, a Spearman's rank correlation was utilized. Multivariate logistic regression analysis with stepwise forward selection was performed for mortality evaluation with p < 0.05 as the criteria for model inclusion. All p-values were two-tailed. p < 0.05 was considered statistically significant. Linear regression analysis was made to examine related factors with hospitalization time. Survival analysis was carried out comparing the two groups using the Kaplan-Meier plot and compared with the log rank (Mantel-Cox) test. Statistical analyses were conducted by using SPSS software package ver. 26.0.

In the study period, 696 patients with a confirmed diagnosis of SARS-CoV-2 infection were admitted to our center; 130 subjects were excluded according to the criteria reported above for the following reasons: 13 patients died within 24 h of hospital admission, 25 were directly admitted to the ICU, 71 required NIV or CPAP at admission, 18 had symptoms for more than 10 days, and 3 had no evidence of lung involvement. In the end, 566 subjects were enrolled in this analysis. Table 1 shows the baseline characteristics of the patients enrolled.

In the remdesivir group, we included 163 subjects, while there were 403 in the control group. No significant differences were observed in the baseline characteristics between the two groups according to age, sex, body mass index (BMI), days before the symptoms, MEWS score, or laboratory results. We reported a lower number of patients with chronic kidney disease in the remdesivir group (p = 0.027), and a lower number of subjects with the neoplastic disease in the control group (p = 0.020).

Observed comorbidities included: cardiovascular diseases, chronic obstructive pulmonary disease, diabetes, neurological, psychiatric, neoplastic, and kidney diseases.

In the remdesivir group, four patients died (2.4%), sepsis was observed in two subjects (1.2%); 54 (33.1%) required higher flow oxygen with CPAP or NIV, 16 (9.8%) were later admitted to the ICU; the median time on CPAP/NIV was 5 days, while the median hospitalization time was 9.5 days. In the control group, 100 patients died (24.8%), sepsis was observed in 60 (14.8%), 317 (78.6%) needed CPAP/NIV, and 72 (17.8%) needed ICU admission; the median time on CPAP/NIV was 9 days, and the median hospitalization time was 12.5 days. In the control group, treatment was given as follows: 3.3 | Univariate and multivariate analysis considering the mortality and hospitalization length in the study population

The following factors were considered in the univariate analysis: age >70 years, male sex, BMI > 25, MEWS score, presence of comorbidities, CPAP or NIV during the hospitalization, ICU admission, sepsis, corticosteroids, and remdesivir treatment ( Table 2 ). The following factors were statistically significant for mortality and were considered in the multivariate analysis: age >70 years, comorbidities, CPAP or NIV, ICU admission, sepsis, and remdesivir treatment. In the multivariate analysis, the following were significantly associated with mortality: age 

Survival analysis was carried out comparing the patients treated with remdesivir and the control group according to in-hospital mortality ( Figure 2 ) with a significant difference between the two groups (χ 2 = 15.185, p < 0.001). Figure 3 shows the probabilities of ICU admission and CPAP or NIV during hospitalization in the different groups; the probability of ICU admission was significantly higher in the control group (χ 2 = 9.159, p = 0.002) and the need of CPAP/NIV was more frequent in patients without remdesivir treatment (χ 2 = 14.766, p < 0.001).

This analysis was available for 462 subjects (81.6%); the PCR test was not repeated in deceased patients (n = 104). 

To conclude, remdesivir treatment was associated with encouraging and promising results in patients with early-stage SARS-CoV-2 infection with lung involvement without the need for ventilation.

In this context, the antiviral treatment seems to be the best choice, because monoclonal antibodies against SARS-CoV-2 should be used before pneumonia development, reserving the anti-cytokines drugs in the severe/critical patients with the hyperinflammatory syndrome. In our study lower mortality, shorter hospitalization time, and faster viral clearance were observed in patients treated with a 5-day course of remdesivir in comparison to the control group. Other studies and real-life data are urgently needed for the optimal use of remdesivir in SARS-CoV-2 infection.

All authors fulfill the criteria for authorship as defined by the ICMJE authorship criteria.

The authors would like to thank the study participants: authors shared their suffering, isolation, fear of death, lack of affection, and finally, the hope of going home. It was an unforgettable experience, for better or for worse. The authors are also indebted to all the nursing staff of the Infectious Diseases Unit of Saint Andrea Hospital (Vercelli, Italy), who took care of them day and night with invaluable dedication. Open access funding provided by universita degli studi del piemonte orientale amedeo avogadro within the CRUI-CARE Agreement.

The authors declare no conflicts of interest.

The reported data underlying this article will be shared upon reasonable request to the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

The study was approved by the Local Ethics Committee (August 4, 2020).

http://orcid.org/0000-0001-8326-4930 F I G U R E 4 Different times of viral clearance were measured by reverse transcriptase-polymerase chain reaction (PCR) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) according to received treatment.

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan

Acute respiratory failure in COVID-19: is it "typical

Dexamethasone in hospitalized patients with Covid-19

Adaptive randomized trial for therapy of corona virus disease 2019 at home with oral antivirals (ARCO-Home study)

SARS: systematic review of treatment effects

Treatment for COVID-19: an overview

Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys

Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease. mBio

Mechanism of inhibition of ebola virus RNA-dependent RNA polymerase by remdesivir

Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial

Remdesivir for severe COVID-19 versus a cohort receiving standard of care

Compassionate remdesivir treatment of severe Covid-19 pneumonia in intensive care unit (ICU) and non-ICU patients: clinical outcome and differences in posttreatment hospitalisation status

Delayed initiation of remdesivir in a COVID-19-positive patient

Remdesivir for the treatment of Covid-19-final report

Effectiveness of remdesivir for the treatment of hospitalized COVID-19 persons: a network metaanalysis

Farmaci utilizzabili per il trattamento della malattia COVID-19

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Efficacy and safety of remdesivir in hospitalized Covid-19 patients: systematic review and meta-analysis including network meta-analysis

Clinical efficacy and safety of remdesivir in patients with COVID-19: a systematic review and network meta-analysis of randomized controlled trials

Hepatic disorders with the use of remdesivir for coronavirus 2019

Remdesivir treatment in hospitalized patients affected by COVID-19 pneumonia: a case-control studyJ Med Virol