The Significance of Remdesivir and Favipiravir Therapies to Survival of COVID-19 Patients

The coronavirus disease 2019 (COVID-19) pandemic and the infection escalation around the globe encourage the implementation of the global protocol for standard care patients aiming to cease the infection spread. Evaluating the potency of these therapy courses has drawn particular attention in health practice. This observational study aimed to assess the efficacy of Remdesivir and Favipiravir drugs compared to the standard care patients in COVID-19 confirmed patients. One hundred twenty-seven patients showed the disease at different stages, and one hundred and fifty patients received only standard care as a control group were included in this study. Patients under the Remdesivir therapy protocol were (62.20%); meanwhile, there (30.71%) were under Favipiravir therapy. From the total number of patients under both protocols, 75.6% of the total patients recovered, and 15.7% were deceased. The mortality rate was shown to be 14 out of 64 patients (22%) in critical COVID-19 patients in the Remdesivir group and 3 out of 37 patients (8%) in the Favipiravir group. Remdesivir drug lowered healing mean time to 6 days in mild-to-moderate. COVID-19 clinical manifestations are different among infected patients, and the therapy required to be carefully designed for critical cases in particular. Remdesivir and Favipiravir therapy tend to have a promising efficacy in reducing the mortality rate and time of recovery, especially among mild-to-moderate patients.

The emergence of a novel pandemic caused by COVID-19 poses a huge burden on humanity's health since the Spanish flu in 1918 exceeding 297 million nearly 7 million casualties by December 2021 worldwide.By first week of February, 2021, confirmed COVID-19 cases reached 106 million, mortality recorded over 2 and half millions worldwide 1 .Tremendous global efforts by health workers including clinicians and researchers in an attempt to come up with new drug options to seize the infection spread 2 .Many clinical trials have been conducted, but the clinical efficacy of any therapeutic agent for coronavirus disease has not been proven yet meanwhile, a few of them (Remdesivir, hINFa-2b, Ribavirin, Chloroquine, and Arbidol) are ongoing investigated under clinical trials for their efficacy against the disease 3 .
Remdesivir which is an adenosine triphosphate (ATP) structural analog inserted during RNA polymerase instead of the natural substrate into nascent viral RNA resultant in delayed replication due to termination of the chain leading to viral replication inhibition 4 .Remdesivir was suggested to treat SARS-CoV-2 confirmed infection through viral replication during the first week of the symptoms starts 5 .The purine nucleotide favipiravir ribofuranosyl-5'triphosphate, often known as favipiravir or T-705, is a prodrug whose active ingredient inhibits RNA polymerase, stopping viral replication 6,7 .The Japan Pharmaceuticals and Medical Devices Agency approved favipiravir for use in 2014 to treat novel and re-emerging influenza virus infection.In vitro study by Eloy et al., (2020)  stated that Favipiravir 50% effective concentration (EC50) against SARS-CoV-2 in Vero E6 cells was 61.88 µM/L 8 .Favipiravir, which focused on RNA-dependent RNA polymerase (RdRP) to treat influenza A, received approval in Japan with an IC50 range of (0.13 to 0.48 ug/ml) 6 .Influenza and SARS-CoV-2 are RNA genomes, they showed similar disease manifestations and organ tropism which they rely on (RdRp) for replication, their inhibitor Arbidol which they license for influenza treatment in Asia like Russia and China as an option of standard care for coronavirus disease 9,10 .Tocilizumab Actemra ® by Roche Pharma Company is attached to membrane-bound and soluble receptors of interleukin 6, so it is IgG1 mAb human recombinant.The signaling pathway inhibition leads to the reduction the proinflammator activity of the interleukin 6 11 .
There are currently significant efforts being made by researchers to carry out clinical trials and research studies to better understand the biology and clinical characteristics of COVID-19 12 .Information about the age and gender of patients 13,14 , as well as the effects of various treatment modalities on morbidity and death 15,16 .However, to the best of our knowledge, no studies from Iraq have been published to cover these pivotal aspects.Therefore, this observational study presenting the first study from Baghdad province to scrutinize the nature of the COVID-19 infection and to evaluate the impact of the proposed treatment protocols on the treated sample of COVID-19 patients seen in a single center from January to August 2020.The study includes the currently therapeutic regimen used such as Remdesivir, Actemra®, and Favipiravir and their effect on time of recovery and mortality rate.

Patients
In this prospective, open-label, singlecenter observational study, adult COVID-19 patients were included.The total number of the patients randomized in this study were 277 confirmed patients with COVID-19, 127 patients were enrolled under therapy protocols beside the supportive treatment and 150 patients were set as a control group received only standard care (Figure 1).The subjects were residents at Al-Forat General Hospital, Baghdad through January-August 2020.The single center patients were mostly inpatients and few were outpatients.They were classified according to the disease severity into mild-to-moderate patients in which were outpatients and all inpatients were severe and critical patients.The COVID-19 patients were evaluated clinically, radiological and confirmed by laboratory polymerase chain reaction (PCR) testing.According to World Health Organization (WHO) recommendations, the COVID-19 patient's condition was classified as mild, moderate, severe, or critical.The patients were considered recovered according to the symptoms vanishing, radiology of chest x-ray or Computerized tomography scan and PCR clearance.This study was authorized by the scientific committee of the college of science at the University of Baghdad.

CoVid-19 Patients therapy Protocols
If we put in mind that hospital stay was 14 days, and recovery rate from COVID-19 symptoms (fever, fatigue, or coughing) in the treatment groups.Senior medical staff at Al-Forat General Hospital in Baghdad implemented the treatment guidelines in accordance with those that the Iraqi Ministry of Health had approved.The therapies groups were as follows: Remdesivir therapy (d1 group) Remdesivir 200 mg (Intra venous injection) as a single dose on daily for 3 days, followed by 100 mg once within 7 days of symptom onset 17 .actemra ® therapy (d2 group) Actemra ® 80 mg/4 mL (Intra venous infusion bag) as a single dose once.One further Actemra® infusion may be given at least eight hours following the initial infusion if clinical signs or symptoms continue to deteriorate or do not improve after the first dose.Favipiravir therapy (D3 group) The Favipiravir dosage is the same as the recommended amount for treating influenza, which is 1600 mg given twice daily on day one and 600 mg given twice daily on day two.Favipiravir treatment lasted between 7 and 14 days. 18,19.

Control group
According to each patient's clinical status, the patients in this group only received standard care, which may have comprised all of the following or some of them.The standard of care for SARS-CoV-2 often included supportive therapies such oxygen therapy, antibiotic and antiinflammatory drugs, and symptomatic medicines, as well as some dietary support.According to the disease severity, patients were provided with COVID-19 standard care adopting the 4th edition of The Protocol for Diagnosis and Treatment of Novel Coronavirus Pneumonia (Table 1).

assessing study endpoints
The mortality rate and the recovery time were assessed in current study.For each of the three protocol therapies, the patients' survival, progression, and/or recovery were compared to those receiving only conventional treatment in the control group.

Recovery time
The time required to heal from the time of taking therapy.

Mortality Rate
The patients with mild-to-moderate, severe, or critical patients in therapy protocol group comparing to controls.

statistical analysis
The PSS software Version (SAS Institute, Cary, North Carolina) was used to perform the statistical analyses, two-sided, with p < 0.05 being considered statistically significant.Continuous variables were presented with mean ± standard deviation, and compared with independent t-test.Count (percentage) was used to summarize the categorical variables comparing with Chi-square tests.

Patients' clinical characteristics
About 127 COVID-19 patients were enrolled; their average age was 46.7 years, and they ranged in age from 23 to 87 years.Of these patients, 37% were men and 63% were women.The controls age and gender were matched, their mean age (50.3.2±9.5 year) with 48% male and 52% females (P > 0.05) (Figure 2) (Table 2).The status of COVID-19 patients through January to August 2020.The percentage of patients under the therapies protocol were shown in Figure 3.There were had high recovery rate with 75.6% and 15.7% of patients were deceased (Figure 4).

Recovery time
The recovery time was significantly reduced in the Remdesivir therapy (D1) comparing to controls, the mean time in group D1 was 6.23±2.1days,and the recovery mean time in control group, 3.22±2.1days(P<0.05).Hence, Remdesivir drug lowered healing mean time to 6 days in mild-to-moderate (Table 3).

Mortality rate
The mortality rate was 14/64 patients (22%) in critical COVID-19 patients in D1 group, 3 out of 37 patients (8%) in D2 group, and 3 out of 9 patients (33%) in group D3 (P=0.052).The infected patients taken Remdesivir drug were reduced regarding the death rate especially in COVID-19 critical cases, which in Iraq at the time of performing this observational study was might reach higher than above 50% according to on world data.disCussion SARS-CoV2 is novel virus which is require emergence of effective treatment methods, the vaccine was not an option during the first wave  of the epidemic.There was an urgently need to a new antiviral agent against SARS-CoV-2 to be applied.In this observational study, the aim was to screen the antiviral therapy protocol since January to end of August 2020 in a single health center (Tables 1 and 2).The COVID-19 treatment current recommendations as in Table 3.
Remdesivir has a high potential in many clinical trials to treat moderate to severe case, lowering required time to improve, and reducing mortality 20   It is important to note that this study concurs with a local study carried out by Darweesh et al. (2021) in the Kirkuk province, which highlighted the effectiveness of five different therapeutic protocols adopted by the healthcare system in Iraq in reference to WHO guidelines for management of COVID-19 infection and its relationship to mortality rate.This information may be useful for doctors and healthcare providers in choosing the most appropriate therapeutic regimens 24 .
However, this study disagrees with Goldman et al. (2020) study, which performed an open-label trial among 397 patients underwent randomization compared to standard care to evaluate the efficacy and safety of treatment with Remdesivir for 5 or 10 days in patients with severe COVID-19 patients.This study came to the conclusion that severe COVID-19 patients did not need the mechanical ventilation and that there were no significant differences for the both course duration of Remdesivir 25 .
A study by Chen and colleagues (2021), in China carried out open-label trail in multi-center to evaluate 2 therapy protocols for treating COVID-19 confirmed patients (Favipiravir Versus Arbidol), included 240 patients.Those under Favipiravir revealed tendency toward improvement in a week period, especially moderate case (71%) versus (56.%) respectively, as well as an earlier lowered in temperature and cough clearance 26 .Another openlabeled nonrandomized study by (Cai et al., 2020)  from China compared the effect of Favipiravir Versus lopinavir/ritonavir among mild-to-moderate COVID-19 cases.The study included 56 patients in which 35 patients were treated by Favipiravir.The authors concluded to safety of Favipiravir administration with no side effects.Favipiravir was used to treat 68% of patients' fevers, which resolved in 3 days as opposed to 6 days in the control group (standard of care). 27.
The systematic and meta-analysis review conducted by Manabe et al. in 2021 concluded that Favipiravir had a great promise for treating COVID-19 patients.Favipiravir enhanced viral clearance in patients with mild-to-moderate COVID-19 after 7 days of treatment, which is consistent with the results of this observational trial 28,29 .According to Brahmantya et al. (2021), oseltamivir or favipiravir, which is regarded as administering an antibiotic and has become routine therapy in Indonesia, is the antiviral that is advised in that country.Oseltamivir or favipiravir are still prescribed according to the Indonesian COVID-19 management guideline, despite the fact that the WHO does not advise doing so 30 .
A meta-analysis of observational studies investigating the effectiveness of tocilizumab on COVID-19 patient mortality was carried out by Malgie et al. in 2021.Ten studies including Tocilizumab therapy were included in the analysis, totaling 1358 patients.The findings showed that Tocilizumab group mortality was lower than control group mortality.Patients who took tocilizumab had a mortality rate that was (12%) lower than that of controls 31 .Ten randomized controlled trials examining Tocilizumab's effectiveness in COVID-19 patients were included in a review by Arthur et al. (2021).Standard care was provide to the control group.The primary findings were recorded mortality in the (28 to 30 day).A nearly 6500 were enrolled, around 3400 patients (52%) were treated by Tocilizumab.The therapy group was declined mortality (24 % versus 29%) 32 , meanwhile; Rosas et al (2021) study findings was not conclusive, mortality at day 28 was (20 %) under the Tocilizumab therapy and (19%) under the placebo 33 .Due to the few numbers of patients included in the current observational study who had been given Tocilizumab, we can roll out the efficacy effect of Tocilizumab.

study limitations
This study has a number of limitations, including the observational design, which may not account for all risk factors other than age, gender, and clinical classification, such as co-existing chronic conditions, which frequently necessitate the referral of patients to hospitals with a higher level of expertise.Second, it is exceedingly challenging to undertake a thorough study in the midst of such a public health catastrophe.Third, given the length of the patient's hospital stay, the follow-up period was quite brief.Four, access to such information is closely controlled by higher authorities and was at times prohibited in the initial few months of the pandemic.The data were gathered based on hospital registry data.

ConClusions
Health care providers are facing tremendous efforts in supplying pharmaceutical care.The symptomatology of COVID-19 are varied among patients, the therapy required to be designed towards certain symptoms as well as towards the progression of the infection among patients.Remdesivir and Favipiravir therapy tend to have a promising efficacy in reducing the mortality rate and time of recovery especially among mild-tomoderate patients.

aCknowledgMent
The author would like to thank all the medical staff in Al-Forat General Hospital, Baghdad for their cooperation, thanks are extended to all patients who agree to share their affliction through that difficult period.

Fig. 3 .
Fig. 3. Patients under the therapy protocols . A placebo-controlled experiment was done by Beigel et al. (2020) on 1062 individuals, 541 of whom were given Remdesivir and 521 received a placebo.The median recovery duration was 10 days (95% confidence interval [CI], 9 to 11 days) for Remdesivir recipients compared to 15 days (95% CI, 13 to 18) for placebo recipients.By day 15, the mortality rate was 6.7% in the Remdesivir group and 11.9% in the placebo group.The study found that Remdesivir reduced the amount of time adults hospitalized with COVID-19 needed to recover more quickly than a placebo 21 .Spinner et al. (2020) conducted a randomized, open-label trial of hospitalized patients in which Remdesivir-treated patients were compared with standard care included 596 patients (including 584 patients with moderate COVID-19), and the trial results showed that patients randomized to a 5-day course of Remdesivir had a statistically significant difference in clinical

table 2 .
Basic characteristics of the patients

table 3 .
Time of recovery of COVID-19 patients (Days) in protocol therapy