key: cord-0769443-981wc6vw
authors: Tehrani Fateh, S.; Salehi, E.; Rezai, N.; Haririan, N.; Asgari, A.; Salehi-Najafabadi, A.
title: A single-center retrospective cohort study of Covid-19 medications: Remdesivir, Favipiravir, Methylprednisolone, Dexamethasone, and Interferon β1a and their combinations
date: 2021-03-08
journal: nan
DOI: 10.1101/2021.03.05.21251351
sha: 01f3ee42a3ad40e4d72cbfcf723291d7017f16ab
doc_id: 769443
cord_uid: 981wc6vw

Many drugs have been suggested to be used for Covid-19. A suitable and efficient choice of drug would make the course of Covid-19 easier. we have investigated the efficacy of different treatment regimen in reducing hospitalization period (HP) and mortality of 324 confirmed Covid-19 patients. Received drugs included single therapy or combinations of Methylprednisolone, Remdesivir, Favipiravir, Interferon {beta}1a, and Dexamethasone. HP and mortality were compared between different treatment groups to evaluate efficacy of each drug. HP and mortality were also calculated for patients in each treatment group based on their underlying diseases and age. we suggest that using IFN-{beta}1a, RDV and corticosteroids might not have a significant effect on the HP or mortality of the Covid-19 patients as it was thought before.

We compared the mean HP and mortality between different treatment groups to see if there is any significant difference between different drugs' performance in reducing the mean HP or mortality. To compare the mean HP of the two groups, we first compared the mean age and also the mean dose of drugs between the two groups to avoid any confounding variables. We also excluded patients who died during the study when comparing the mean HP between groups. We only compared groups that their treatment regimen differed only by one drug, including 1- We used the Anderson-Darling test to assess the normality of each variable in each group, and since almost none of them were normally distributed, we used the Mann-Whitney U test for continuous variables to assess the differences in means of two groups, whereas we used fisher's exact test for categorical variables. We did statistical analyses using R language (4.0.2 ed,2020) implemented in R studio (1.3.1093 ed,2020) 10, 11 and Microsoft Excel software. The significance for all statistical analyses was defined as p < 0.050.

A total of 324 patients was included in this study. The mean age, mean HP, and mortality for these patients were 61.37±16.76 and 7.22±4.23, and 27.47%, respectively. One hundred six of these patients had no underlying disease, and their mean age, mean HP, and mortality were 49.5±16.53, 7.25±4.74 and 16%, respectively. These indices were 67.14±13.54, 7.21±3.96, and 33.02%, respectively, for patients with underlying diseases of different kinds (n=218). There were 53 patients with hypertension, 41 with diabetes, 24 with hyperlipidemia and diabetes and hypertension, 20 with diabetes and hypertension, 19 with Heart disease, 16 with hyperlipidemia and hypertension, and patients with other diseases, which can be found in supplementary data.

The indices, as mentioned above for each disease and also age groups, can be found in supplementary data. 

Mean age, mean dose, and mean HP for the patients under MPS (n=77) were 63. 07± (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

Mean age, mean dose of RDV, mean dose of MPS, and mean HP for the patients under the combination of RDV and MPS (n=15) were 51.8±14.67, 4.8±1.78, 6.13±5.24, and 9.6±3.69 respectively, and the mortality for these patients was 40%. Among these patients, four patients All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

A total of 7 patients took the combination of RDV, DXM, MPS, and IFN-β1a during their course of treatment. The mean dose of RDV, DXM, MPS, IFN-β1a was 5±1.41, 10±6.78, 3.71±2.62, 1.71±1.11, respectively. Mean age, mean dose, and mortality for this group were 53.71±16.10, 7.28±3.72, and 57.14%, respectively. Four of these patients had underlying diseases while the other 3 had no underlying diseases, and the mean age, mean dose, mean HP, and mortality of these two sub-groups can be found in the supplementary data.

Thirty-two patients were taking the combination of RDV and DXM with the mean dose of 4.56±1.84 and 8.93±6.92. Mean age, mean HP, and mortality for these patients were 54.40±13.47, 6.62±3.32, and 28.12%, respectively. Sixteen patients with no underlying diseases were taking RDV and DXM with the mean dose of 4.62±1.96 and 8.93±8.11, and their mean age, mean HP, and mortality were 48.81±13.25, 6.43±3.53, and 25%, respectively. Other 16 patients with underlying diseases were taking RDV and DXM with the mean dose of 4.5±1.78 and 8.93±5.77, and their mean age, mean HP, and mortality were 60±11.52, 6.81±3.20, and 31.25%, respectively. The patients with underlying diseases were also further classified into different diseases, and the mean age, mean dose, mean HP, and mortality of each sub-group can be found in the supplementary data. These patients were also classified into three age groups, including <50 years old, 50-70 years old, and >70 years old. Patients in the <50years old age group (n=11) had the mean age, mean HP, and mortality of 39.72±7.90, 6.36±2.69, and 9.09%.

Patients in the 50-70years old age group (n=19) had mean age, mean HP, and mortality of 60.10±5.79, 6.63±3.83, and 42.10%. Patients in the >70years old age group (n=2) had mean age, mean HP, and mortality of 81±0.00, 8±1.41, and 0%. The mean dose of each drug of the current combination for all age sub-groups can be found in the supplementary data.

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(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. respectively. The patients with underlying diseases were also further classified into different diseases, and the mean age, mean dose, mean HP, and mortality of each sub-group can be found in the supplementary data. These patients were also classified into three age groups, including <50years old, 50-70years old, and >70 years old. Patients in the <50years old age group (n=12) had mean Age, mean HP, and mortality of 36.08±8.02, 11.25±7.80, and 25%. Patients in the 50-70years old age group (n=12) had mean Age, mean HP, and mortality of 60.16±5.00, 5.83±2.91, and 41.66%. Patients in the >70years old age group (n=5) had the mean Age, mean HP, and mortality of 73.8±4.08, 8±2.34, and 40%. The mean dose of each drug of the current combination for all age sub-groups can be found in the supplementary data.

A total of 8 patients with mean age, mean dose, mean HP of 69±14.92, 2.25±1.03, 4.37±1.50 was only on IFN-β1a during their course of the disease, and the mortality was 0% in this group.

Only one patient with no underlying diseases was in this group, while mean age, mean dose, mean HP, and mortality values for the patients with underlying diseases (n=7) were 70.85±15.09, 2.14±1.06, 4.57±1.51, and 0%.

Thirty-seven patients were taking the combination of IFN-β1a and DXM with the mean dose of 2.02±1.46 and 6.67±7.76, respectively. Mean age, mean HP, and mortality for these patients were 68.89±16.72, 5.43±3.79, and 16.21%, respectively. Mean age, mean HP, and mortality for the patients with no underlying diseases (n=4) were 51.25±6.60, 4±2.82, and 0%, respectively. All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. diseases were also further classified into different diseases, and the mean age, mean dose, mean HP, and mortality of each sub-group can be found in the supplementary data. These patients were also classified into three age groups, including <50 years old, 50-70 years old, and >70 years old. Patients in the <50 years old age group (n=4) had mean age, mean dose of FPV, mean HP, and mortality of 38.50±14.20, 23.50±7.68, 6.25±2.22, and 25%. Only two patients were in the 50-70 years old age group (n=2) with mean age, mean dose of FPV, mean HP, and mortality All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

A comparison between the mean dose of IFN-β1a and DXM and mean age of IFN-β1a/DXM medication group and IFN-β1a/DXM/MPS medication group revealed that there is no significant difference between the mean dose of DXM and mean age of both groups (p-value>0.05) while the mean dose of IFN-β1a is significantly different (p-value <0.05). Moreover, although there is a significant difference between the mean HP of both groups (P-value <0.05), the difference between the mortality of them is insignificant (P-value >0.1). By comparing the difference of mean age and mean dose of MPS in the MPS medication group and IFN-β1a /MPS medication group, it is revealed that both differences are insignificant (P-value >0.05). Moreover, the differences between the mean HP and mortality of these two groups are found to be insignificant (P-value >0.05). The same comparison was made between the MPS medication group and the RDV/MPS medication group, and the result indicated that there is no significant difference between mean age, mean dose, mean HP, and mortality of each group (P-value >0.05).

Comparison between RDV/DXM medication group and RDV/DXM/MPS medication group revealed that there is no statistically significant difference between the mean age, mean HP, mean dose of RDV, mean dose of DXM, and the mortality of both groups. In addition, there was no statistically significant difference between the RDV/MPS medication group and the RDV/DXM/MPS medication group in terms of mean age, mean HP, mean dose of RDV, and MPS and mortality (P-value >0.05). The difference between mean age, mean dose of FPV, mean HP, and mortality of FPV medication group and FPV/IFN-β1a medication group were calculated, and they found to be statistically insignificant; however, the calculated P-value related to the difference of mean HP of these two groups was 0.05054. All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

Since the outbreak of the coronavirus, many therapeutic agents have been suggested for the treatment of COVID-19. RDV, FPV, corticosteroids, and IFN are among the most used drugs in Iran. They inhibit viral activity by different mechanisms, including inhibiting the RNAdependent RNA polymerase, enhancing the immune system, and other unknown mechanisms.

RDV, which was initially developed as a treatment for Ebola infections, is a monophosphate prodrug, and its active metabolite interferes with the action of RNA-dependent RNA polymerase leading to an inhibition of viral RNA production 12 . RDV has been approved for COVID-19 emergency treatment by the FDA on October 22, 2020 13 . The approval of RDV was supported by data from three different randomized clinical trials that included patients hospitalized with mild to severe COVID-19; however, there are some controversial data from other studies [14] [15] [16] [17] . imaging. In addition, fewer adverse events were found in the FPV group than in the control group 7 . In another randomized clinical trial, patients who received FPV did not have significantly improved clinically recovery rate at day seven compared to patients who received Arbidol, but it led to significantly shorter latencies to relief for fever and cough 6 .In a study conducted by Yan et al., it was found that FPV antiviral activity is related to its concentration and its antiviral activity was not significant up to 100 μM in vitro, so they could not prove a benefit of the addition of FPV under the trial dosage to the existing standard treatment.

Insufficient concentration of this drug can be the reason for the lack of Antiviral effects and medical benefits 19 . In conclusion, the outcomes of studies on FPV are not consistent, and further studies are needed to demonstrate its efficacy for the treatment of COVID-19.

Interferons are shown to be effective on many human coronaviruses, including MERS and SARS; however, their performance against SARS-COV-2 is not clear 20 . Therefore, many studies are conducted in order to evaluate its efficacy in Covid-19 treatment. IFN-β 1a inhibits SARS-COV-2 activity in vitro when administered after virus infection. The antiviral activity of IFN-β 1a in vitro has been shown to effectively inhibit infectious virus particles and viral RNA on All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. taking group and control groups; however, 28-day overall mortality was significantly lower in the patients taking IFN than the control group, and also discharge rate was significantly higher in the IFN group 22 . Two other studies also demonstrated the benefit of adding IFN-β 1a to the antiviral treatment regimen in Covid-19 patients 23, 24 .

Corticosteroids are also evaluated for being effective in improving the clinical course of Covid-19; however, its usage in the treatment regimen of Covid-19 is still controversial, and different publications declare differently about their benefits. Although some randomized clinical trials and meta-analysis reports have concluded that corticosteroids may cause positive effects in the clinical course of Covid-19 8, [25] [26] [27] [28] [29] [30] , there exist some other reports, suggesting corticosteroids are inefficient or even cause adverse effects 9,31-35 . Interestingly, even late administration of MPS pulses during the second week of the disease is also suggested to improve patients' prognosis with Covid-19 pneumonia with features of inflammatory activity and respiratory deterioration 36 .

The beneficial effects of corticosteroids in improving the clinical course of Covid-19 may be due to their immunomodulatory effects as it is shown that administration of corticosteroids (e.g., MPS) either in low doses (≤ 2 mg/kg day) or high doses would inhibit IL-6 production without delaying virus clearance 37 .

Since our study lacks a control group, we were not able to determine the efficacy of each group of drugs(s); however, we could compare the groups of drugs with only one different drug in between. It is worth noting that we first checked whether both groups' properties except the mean HP and mortality are not significantly different. According to our data, IFN-β1a/DXM/MPS medication group had significantly higher mean HP than the IFN-β1a/DXM medication group, which may be due to the possibility that the patients in the latter group had more severe disease than the former group and hence they spend more time in the hospital in spite of the similar primary clinical status at the admission. Moreover, it can be suggested that using IFN-β1a does not present a significant improvement in a mean HP and mortality considering the fact that mean HP and mortality was not significantly different between IFN-β1a/MPS medication group and MPS medication group. Similarly, the same result can be probably concluded from comparing the FPV medication group and FPV/IFN-β1a medication group. A comparison between the MPS All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 8, 2021. ;  medication group and MPS/RDV medication group also revealed that there is no significant difference in mean HP and mortality, in addition to mean dose of MPS and mean age between these two groups in spite of the same severity of disease between patients, indicating that RDV might not have a significant effect on the clinical course of the diseases. In a similar way, by comparing other medication groups, differing in the presence of either MPS or DXM in the treatment regimen, it can be suggested that probably either MPS or DXM does not impose significant benefits on the clinical course of the disease.

After all, our study faces several limitations, including 1-Limited number of patients, 2-The existence of confounders that may not have been discovered, 3-The existence of a large variance between some parameters, 4-A slight difference in patients' conditions in terms of severity of the disease, 5-Not considering the clinical course of the disease and the fact that some patients progress to a need for mechanical ventilation and 6-Rarely in some cases some drugs were not started from the beginning of the hospitalization.

The mortality and hospitalization period for Covid-19 patients who were taking Remdesivir, Favipiravir, Methylprednisolone, Dexamethasone, and Interferon β1a or their combinations are considered and compared in this study. Many studies have been conducted on the efficacy of these drugs on clinical course and mortality of Covid-19 and no consensus has been achieved yet. This study suggests that using IFN-β1a, RDV and corticosteroids might not have a significant effect on the HP or mortality of the Covid-19 patients as it was thought before. More specific and accurate studies are needed for evaluating these drugs' efficacy.

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