Results of Favipiravir Combined Treatment in Intensive Care Patients With Covid-19


 Aim: Covid-19 (Coronavirus disease 2019) is a disease that has already taken place in human history. Although there is still no effective treatment and vaccine protocol, different treatment options are being tried. In this study, it was aimed to determine the basic characteristics and changes in laboratory findings of patients who were hospitalized with the diagnosis of Covid-19 in the intensive care unit and underwent treatment protocol containing favipiravir.Material and Method: It was carried out with the data of 179 inpatients in an intensive care unit between 01.06.2020 - 30.06.2020. The inclusion criterias of the study are to have a diagnosis of COVID-19 confirmed by PCR test, to be hospitalized in the intensive care unit, receiving therapy combined with favipravir and to have access to its data through the automation system. According to literature; the sociodemographic characteristics, some basic characteristics and some laboratory findings of the patients were evaluated. Statistical analyzes were performed using the Statistical Package for Social Sciences (SPSS) version 24.0 (IBM Corp .; Armonk, NY, USA).Findings: The average age of the study group is 60.9±16.4 years and 65.9% (n:118) of them are male. According to the clinical classification, more than half (50.8%, n: 91) are included in the "high" clinical classification. The most common chronic disease is "hypertension (HT)" (42.5%, n:76) and the most common symptom is "fever" (57.5%, n: 103). While 82.7% (n: 148) have widespread CT (Computed tomography) findings, CPR (C-Reactive protein) positivity rate is 65.4% (n: 117). Statistical significant difference was detected between three measurements of blood urea nitrogen (BUN), aspartat aminotransferase (AST), alanin aminotransfrase (ALT), CRP between the 1st and the 3rd day. Conclusion: Favipiravir demonstrates a proper safety profile. However, its side effects teratogenicity, hyperuricaemia and QTc (corrected QT interval) prolongation have not yet been adequately studied. It may be safe and tolerable in short-term use, but more evidence is needed to assess the longer-term effects of treatment.


Introduction
In the twentieth century, three new life-threatening diseases caused by coronavirus emerged. These are middle east respiratory syndrome (MERS), severe acute respiratory syndrome (SARS) and the new lung disease Covid-19 (1). All of them belong to the Coronaviridae family; kind of viruses that possess a positive-sense single-stranded RNA genome. Similar to other RNA viruses, this family is characterized by signi cant genetic variability and high recombination rate that enable them distributed easily among humans and animals worldwide (2). Covid-19 appeared in Wuhan, China in December 2019; it is a disease caused by the 2019 novel Coronavirus (2019-nCoV) that manifests itself with viral pneumonia in most patients (3). Due to its high infectivity and fatality rate; moreover, the absence of speci c medicine for 2019-nCoV, outbreak of the disease has brought heavy burden to the world. Symptoms in Covid-19; may range from mild illness to acute respiratory distress syndrome. The common characteristics of people with severe disease are; showing lymphocytopenia, being old and smoking (4).
In addition, in a meta-analysis consisting of 15 studies, it was stated that severe disease was associated with an underlying hypertension, diabetes, and a respiratory or cardiac pathology (5).
So far, there is no treatment protocol and vaccination for Covid-19 with proven safety and e cacy. Today, the main treatments are shaped according to our experiences with similar viruses such as SARS-Cov and MERS-Cov (3). In addition to symptomatic treatments; different treatment methods such as remdesivir, chloroquine and hydroxychloroquine, kaletra, favipiravir, tocilizumab, and stem cell therapy are used (6,7). As the virus causes endothelial dysfunction, procoagulant conditions and renin-angiotensinaldosterone system imbalance; use of low molecular weight heparin, low dose aspirin, angiotensin converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) in the early period is also recommended (8). Despite all this; there is currently no effective treatment available for coronavirus infections. Hard works have been made to develop vaccines and therapeutic drugs. Preclinical evidence has proven the potential of several countermeasures, yet large scale trials are still needed (2).
Favipiravir, one of the mentioned treatment methods; is a kind of RNA-dependent RNA polymerase (RdRp) inhibitor, blocking RNA virus replication. It is a potential antiviral agent used against SARS-CoV-2 (9).
Favipiravir is active against a variety of in uenza viruses including A (H1N1) pdm09, A (H5N1) and A (H7N9) avian in uenza viruses, and has a synergistic effect with oseltamivir (10). It is an approved treatment for in uenza. Besides; less studies has been published for favipiravir to treat SARS-CoV-2 compared to remdesivir. Indeed, favipiravir was approved by the National Medical Products Administration of China as the rst anti-COVID-19 drug in March 2020, as the clinical trial had demonstrated e cacy with minimal side effects (2). It accelerates clinical recovery by reducing respiratory problems (3). The effective dose of favipiravir used is 1600 mg twice daily ( rst day), 600 mg twice daily (days 2-5) and it not used more than 14 days. However, favipiravir is contraindicated in pregnant women because of teratogenicity and embryotoxicity in animals (10,11). Since the effectiveness and tolerability of hydroxychloroquine in treatment contain some question marks; recently, researchers have started to work mostly on remdesivir and favipiravir (8). In contrast to remdesivir, the studies on favipiravir in vitro and in vivo is limited. However, there are still three active clinical trials regarding favipiravir that have begun enrolling patients in China (12).
The Covid-19 pandemic stands as a serious health threat to humanity. The data obtained show that; the treatment approaches applied especially for patients who are being treated during the intensive care period, can make serious differences on prognosis. In this study, it was aimed to determine the basic characteristics and changes in laboratory ndings of patients who were hospitalized with the diagnosis of Covid-19 in the intensive care unit of a training and research hospital and underwent treatment protocol containing favipiravir.

Material And Method
The study was planned in a prospective, cross-sectional way. It was carried out with the data of inpatients at the Health Sciences University Istanbul Bağcılar Training and Research Hospital Adult Intensive Care Unit between 01.06.2020-30.06.2020. The inclusion criterias of the study are to have a diagnosis of COVID-19 con rmed by PCR test, to be hospitalized in the intensive care unit, receiving favipravir combined therapy and to have access to its data through the automation system. The study includes data from 179 patients who meet these criteria.
According to literature; the sociodemographic characteristics, some basic characteristics and some laboratory ndings of the patients were obtained from the hospital computer records.
Statistical analyzes were performed using the Statistical Package for Social Sciences version 24.0 (IBM Corp .; Armonk, NY, USA). Mean and standard deviation are given for the variables obtained by measurement, number and percentage distributions for the data obtained by counting. Friedman test in non-parametric conditions and ANOVA (Repeated Measure) test for repeated measurements in parametric conditions were used in comparison of admission, 1st day and 3rd day values of laboratory examination results. Statistical signi cance level was accepted as p < 0.05 considering the 95% con dence interval and 5% margin of error.
Shapiro-Wilk test was used to adapt to normal distribution in the evaluation of parametric conditions. It was observed that BUN and procalcitonin 3rd day values did not comply with the normal distribution (p < 0.05). Therefore, the Friedman test, which is a non-parametric test, was used in the analysis of these values. The ANOVA (Repeated Measure) test was used for repeated measurements, as the others conformed to the normal distribution. While evaluating the test results, Wilks'Lambda p value was taken into consideration when p < 0.05 according to Mauchly Sphericity test.

Findings:
One hundred seventy nine patients were included in the study. The average age of the study group is 60.9 ± 16.4 years and 65.9% (n:118) of them are male. According to the clinical classi cation, more than half (50.8%, n: 91) are included in the "high" clinical classi cation. The most common chronic disease is "hypertension (HT)" (42.5%, n:76) and the most common symptom is "fever" (57.5%, n: 103). While 82.7% (n: 148) have widespread CT ndings, PCR positivity rate is 65.4% (n: 117). The main characteristics of the patients are summarized in the table below (Table 1).
Laboratory measurements were carried out in intensive care hospitalization, on the 1st day and on the 3rd day. Some laboratory results, which were reported to have changed in the literature, were taken into consideration. Statistical signi cant difference was detected between three measurements of blood urea nitrogen (BUN), aspartat aminotransferase (AST), alanin aminotransfrase (ALT), C-reactive protein (CRP). In the pairwise comparisons, it was found that the hospitalization valueswere lower than the others. There was no signi cant difference between three measurements in terms of other values (Table 2).

Discussion
In Japan, favipiravir was approved as a stockpile against in uenza pandemics and was distributed as an option against for SARS-CoV-2 under government control. Still, the e cacies of antiviral therapies have not been clari ed clearly in the course of these patients. However, in the literatüre, there is a case report that emphasize recovery two days after favipiravir treatment. This case suggest that favipiravir may be contributed to the amelioration of the lung lesion in Covid-19 (13).
In a large scale study, among the 1,023 deaths, the majority were among patients of ≥ 60 years of age. The ≥ 80 age group was characterized by the highest fatality rate (20.3%) among all age groups (14).
Relatively fewer cases were reported among young children (0-9 years-old). While more males were affected by the disease, the male-to-female ratio varies between different populations. As the pathogen has been extraordinarily contagious, no deaths have occurred in mild or even severe cases; but the fatality rate reached 49% among patients that were classi ed as critical cases (14). These ndings are compatible with the presented study.
In a prospective, multicenter, open-label, randomized superiority trial examined the e cacy of favipiravir versus arbidol for treating COVID-19 (15). There was no difference in the 7-day clinical recovery rate for favipiravir versus arbidol in the overall population. However, this difference existed for a subgroup of noncritical patients without hypertension or diabetes (15). Three registered clinical trials are planned regarding the use of favipiravir against COVID-19 (16, 17,18). The presented study was performed in an intensive care unit and parallel to the mentioned studies; 42.5% of the patients (n:76) had hypertension and 29.1% (n:52) had diabetes mellitus.
There are some studies about the heart related disorders during medical treatment combined with favipravir. A study that reports prolonged QT interval due to favipiravir has been encountered (19). In another study; two patients who were followed-up in the Intensive Care Unit (ICU) with favipiravir combined treatment developed ventricular tachycardia; both had increased T peak to T end (Tp-e) interval and Tp-e/QTc ratio despite normal QTc intervals before treatment (21). In the presented study 23.5% (n:42) of the patients had heart disease during the hospitalization but no heart related problem was detected during follow-up.
In the presented study; no signi cant adverse ractions were noted related with favipravir combined treatment group. In another study, favipiravir had signi cantly fewer adverse effects than the lopinavir/ritonavir group (22). Similarly; in the trial conducted on patients with COVİD-19 indicated better results in patients treated with favipiravir than the group treated with lopinavir/ritonavir. Additionally, less side effects were noted in the treatment group (20).
Studies have reported that lymphocytopenia occurs in severe types of Covid-19 (23). Again; lymphocytopenia and hyponatremia were detected in a patient who recovered after treatment for Covid-19 pneumonia (24). In a Japanese clinical trial with 501 patients, the main adverse reactions were detected as rising uric acid (n:24, 4.79%), diarrhea (n:24, 4.79%), neutropenia (n:9, 1.80%), increased AST (n:9, 1.80%) and increased ALT (n:8, 1.60%) (25). In a trial of favipiravir with patients with COVID-19, the most common adverse events were liver enzyme abnormalities, psychiatric, gastrointestinal symptoms and serum uric acid elevations (26). The overall adverse reactions were mild symptoms, but pregnant woman should not be treated with favipiravir (25). In the presented study, serum uric acid levels were not evaluated but liver enzyme abnormalities were detected parallel to the literature.

Conclusion
Favipiravir demonstrates a proper safety pro le. However, its side effects teratogenicity, hyperuricaemia and QTc prolongation have not yet been adequately studied. It may be safe and tolerable in short-term use, but more evidence is needed to assess the longer-term effects of treatment. There is no nancial or non-nancial con ict of interest

*Funding
There is no any private funding used. Funding has been covered by authors.