Survival and Biomarkers of COVID-19 Patients Treated with Remdesivir and Favipiravir in ICU during the Peak of Pandemic: A Single Center Study in Bangladesh

Since the first detection of a cluster of COVID-19 patients in China in late 2019, it becomes a global concern due to its transmissibility and ability to progress patients in severe respiratory failure and acute respiratory distress syndrome, which need intensive care unit support for a long time. We observed the repurposing use of remdesivir and favipiravir whether considered as a therapeutic option or not through survival rate and changes in biomarker during 10-day treatment stay in ICU. Original Research Article Nasir et al.; JPRI, 32(45): 14-22, 2020; Article no.JPRI.64130 15 The retrospective observational study in a tertiary care hospital dedicated to COVID-19 at Dhaka, Bangladesh was done at the peak of COVID-19 pandemic in Bangladesh. The mortality rate, length of ICU stays and eight prognostic biomarkers of patients treated with remdesivir and favipiravir was observed as one of the first ever reported experience in Bangladesh. Among the critically ill patients in ICU, 26 (44.8%) died and 32 (55.2%) were cured during the study period and highest mean duration of stay in ICU was observed (14.33 days and 18.13 days) in FPV-treated patients. Mean of means for all biomarkers CRP (26.0) and d-Dimer (2.64) was recorded higher in favipiravir treated patients in death cases, but NLR, d-NLR, platelet, PLR was much higher in remdesivir treated patient of both death and improved cases. Though overall outcome variables between death and improved cases were not statistically significant (p<0.39) The severity of disease progression in critically ill COVID-19 patients in ICU depends on comorbidities and hyper-responsive inflammatory or immunological biomarkers to predict. Though the emergency use authorization and repurposing use of different antivirals are still on trial, but remdesivir and favipiravir revealed not much hope in improving prognostic biomarkers, survival rate and disease progression at the peak of pandemic in Bangladesh.


INTRODUCTION
Since the cluster of novel respiratory viral infections first recognized in China in late December 2019, it was observed with growing apprehension as infections with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus-named Coronavirus Disease of 2019  have also spread to hospitals in Bangladesh. The progression and severity of COVID-19 have placed critical care physicians into attention. Its transmissibility caused the spread of the disease throughout a population quite rapidly and case counts might increase by hundreds or even thousands per day in densely populated metropolitan areas as no herd immunity exists to COVID-19. Unlike influenza virus infection, COVID-19 is manifested by a severe hypoxic respiratory failure requiring a long time intensive care with specialized support.
The common presenting complaints of COVID-19 patients are fever, cough, dyspnea, myalgia or weakness, sputum production, cerebral pain, hemoptysis, and loose motion. COVID-19 patients may present with solely neurological manifestations like loss of smell, loss of taste, stroke, vertigo, or respiratory failure even without having any respiratory symptoms. [1] The incubation period of this disease could be up to 14 days. The median time was found 4-5 days from the day of exposure to the virus. One study found that 97.5% of COVID-19 affected persons will develop the symptoms within 11.5 days [2]. A study comprises more than 44 thousand COVID-19 patients divided the symptoms into mild to moderate (81%), severe (14%), and critical (5%). Severe cases had dyspnea, hypoxia, or more than pulmonary involvement in imaging. Critical cases presented with multi-organ dysfunction, shock, or respiratory failure with an overall mortality rate of 49%. [3] In the intensive care unit (ICU), critically ill COVID-19 patients usually develop shortness of breathing within 5 to 8  Coagulopathy-related common laboratory abnormal findings are prolonged prothrombin time, increased D-dimer, increased fibrin degradation products, and mild to moderate thrombocytopenia. Increased D-dimer has been found strongly associated with a greater risk of death. [7] In Bangladesh, the treatment guideline initially included several medications for critically ill patients requiring ICU support. Besides oxygen therapy, high flow nasal cannula (HFNC), noninvasive ventilation (NIV), and invasive ventilation, different pharmacotherapy was tried under different protocols in search of a remedy. As the COVID-19 belongs to the same family as SARS and MERS and patients present with the same pneumonia-like symptoms, a variety of antiviral agents have been tried according to the clinical experience from SARS and MERS. The most commonly used broad-spectrum antiviral agent used against SARS and MERS was ribavirin, protease inhibitor lopinavir and ritonavir, oseltamivir, and immune up-regulator interferon. Similar agents are also being tried purposefully for COVID-19 patients [8]. Remdesivir and favipiravir are some of the proposed antiviral medicines which were attempted during the attack of EBOLA though the Food and Drug Administration (FDA) of USA rejected the drug due to lack of significant evidence in favor of it. This time also remdesivir was expected to be one of the promising options for treatment of COVID-19 based on some laboratory experiments and reports from some compassionate use and case reports [9]. Repurposing use of a lot of pharmacological compounds/drugs has been tried as a remedy. Favipiravir is one of the proposed antiviral medicine which was attempted during the attack of EBOLA. At first china and Japan, then many countries around the world started to use favipiravir against SARS-CoV-2, though the scarcity of published RCTs reflects a lack of significant evidence in favor of it [10]. The safety and efficacy of these drugs in COVID-19 require evidence-based, quality-designed, and sufficiently-powered clinical trials with a large sample size for defined decisions. Still, some clinical prognostic biomarkers of critically ill patients in ICU who were treated with remdesivir and/or favipiravir needed to be monitored and evaluated to add in search of effective pharmacotherapy. In this retrospective study, the overall treatment outcome was compared as improved or death cases along with different prognostic biomarkers of the critically ill patients treated with remdesivir and/or favipiravir in ICU of a tertiary care teaching hospital dedicated for COVID-19 during the peak of pandemic in the capital city of Bangladesh.

METHODOLOGY
The cross-sectional retrospective descriptive study was done on the critically ill patients admitted in Intensive Care Unit (ICU) of Holy Family Red Crescent Medical College Hospital, Dhaka, Bangladesh during the peak two months of pandemic in Bangladesh from 1 June 2020 to 31 July 2020. The study aimed to observe the survival outcome of COVID-19 patients in ICU treated with remdesivir and favipiravir in the tertiary care hospital of Bangladesh. The primary objective of this study was to observe the mortality and prognostic biomarkers of 10-day treatment outcome of different treatment groups among ICU admitted COVID-19 patients. The relationship between gender and age group, change and relationship of biomarkers with different groups of patients treated with remdesivir and favipiravir, along with convalescent plasma were also observed in the study.
Inclusion criteria: All COVID-19 patients (confirmed by rt-PCR) who were admitted in the ICU of Holy Family Red Crescent Medical College Hospital, Dhaka were included.
Exclusion criteria: COVIC-19 patients admitted anywhere other than ICU were not included, patients who did not receive Remdesivir (RDV) and/or Favipiravir (FPV), patients without documented predictor / outcome variables.
Data was collected from electronic medical information system database. Death and improved were set as primary outcome variable along with the duration of ICU stays. Eight biomarkers (d-dimer, ferritin, CRP, INR, NLR, d-NLR, platelet) were recorded as prognostic outcome variables during the 10-days of treatment with RDV and/or FPV. Convalescent plasma (CP) therapy was also observed as adjuvant with RDF and FPV. Data were transferred to SPSS IBM 23 spreadsheet. After the completion of enrollment data were calculated. Survival outcome among 5 treatment groups was calculated by one-way ANOVA and the t-test were done to evaluate the significance of variations of the biomarkers between RDV and FPV treated groups.

RESULTS
In total, 58 patients with confirmed COVID-19 were treated in ICU, of whom 45 (77.5%) were male and 13 ( Most of the improved patients (71.42%) were observed in the remdesivir, favipiravir and plasma (RDV+FPV+CP) treated group, whereas most of the dead patients (60.00%) were found in FPV group Fig. 1. The difference was found statistically significant (p< .05) with tvalue = 2.46789 and p-value = 0.019419 by ttest.
The mean duration of stay in ICU was observed highest (14.33 days and 18.13 days) in FPVtreated patients and lowest (11.22 days and 9.18 days) in RDV+Plasma treated patients in both the death and improved cases.
Comparing the mean of means for all available biomarkers of 10-day treatment, the CRP (26.0) and d-Dimer (2.64) was recorded higher in FPVtreated patients in death cases, but NLR, d-NLR, platelet, PLR was much higher in RDV-treated patient of both death and improved cases as shown in Table-II. Though overall outcome variables between death and improved cases were not statistically significant (p<0.39) between RDV and FPV treated groups Table 2.

DISCUSSION
The experimental antiviral drug remdesivir (manufactured by Gilead) was granted Emergency Use Authorization by the US-FDA in May 2020 for patients hospitalized with severe COVID-19 [11]. Besides the US and much of Europe, licensing agreement with manufacturers in Egypt, India, Pakistan, Philippines and Bangladesh that permit the sale of the generic version of the drug [12,13,14]. But at that time, only two randomized clinical trials (RCTs) were completed that compared a 10-day course of remdesivir with placebo. The National Institutes of Health-sponsored Adaptive COVID-19 Treatment Trial (ACTT-1) on 1063 patients found that those assigned a 10-day course of remdesivir had a shorter recovery time by 4 days (median, 11 vs 15 days) compared with placebo [8,9,15]. In this study, the mean duration of ICU stay was 11.78 days in RDV-treated patients whereas 18.13 days in FPV-treated patients who survived and improved. But among the death cases, this duration was 12.11 and 14.13 days respectively.  Among hematological parameters, lymphopenia is associated with disease severity; patients who have died from COVID-19 have had significantly lower lymphocyte counts than survivors. Repletion of lymphocytes may be an important factor for recovery [23].
Other blood cells including neutrophils, eosinophils, WBC, platelets, and CD8 cell counts were partial predictors in discriminating mild from severe COVID-19.
In the present study, the role of two commonly used antivirals (RDV and FPV) in the treatment of COVID-19 patients in ICU revealed not much hope in improving hematological biomarkers in limiting the disease progression. Some independent biomarkers like NLR (7.48 vs 3.31), d-NLR (5.10 vs 2.51), and d-Dimer (0.32 vs 1.10) showed significant variations (p < .00001) in improved cases between RDV and FPV treated patients for 10-day treatment in ICU.

CONCLUSION
The clinical status and coexisting comorbidities of COVID-19 patients largely determine admittance in ICU. Though the retrospective study was not inclusive of large or multi-center sampling, the preliminary observation revealed that the survival rate was significantly highest in FPV+RDV+plasma treated patients than the patients treated with RDV or FPV only. The change of biomarkers was not remarkable among the different treatment groups. Estimation of interleukins could be an important marker to observe the immunological responses, but the limitation of facilities was intense at the initial peak of the pandemic in the present study center in Bangladesh.

CONSENT
As per international standard or university standard, patient's consent has been collected and preserved by the authors.

ETHICAL APPROVAL
The study protocol was approved by the institutional ethics board of Holy Family Red Crescent Medical College Hospital (IERC/27/HF-Res/Jul/2020/18). Data were collected from electronic medical information system database.

ACKNOWLEDGEMENT
The authors acknowledge the contribution and dedication of all the healthcare workers of Holy Family Red Crescent Medical College Hospital for their services and participation to keep manual record of patients' information beside all limitations during pandemic.