Archives of Academic Emergency Medicine. 2022; 10(1): e46 OR I G I N A L RE S E A RC H Effect of Sofosbuvir on Length of Hospital Stay in Moder- ate COVID-19 Cases; a Randomized Controlled Trial Rama Bozorgmehr1, Farbod Amiri2∗, Mohammad Hosein Zadeh3, Fariba Ghorbani4, Arash Khameneh Bagheri5, Esmat Yazdi3, Sayyed Mojtaba Nekooghadam3, Guitti Pourdowlat6, Alireza Fatemi2 1. Clinical Research Development Unit, Shohada-e Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 2. Men’s Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 3. Department of internal medicine, Shohada-e Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 4. Tracheal Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 5. Department of Radiology, Shohada-e Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 6. Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Disease (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. Received: April 2022; Accepted: May 2022; Published online: 9 June 2022 Abstract: Introduction: Efforts to control the COVID-19 pandemic are still on. This study aimed to evaluate the effect of sofosbuvir on length of hospital stay and complications in COVID-19 cases with moderate severity. Methods: This randomized clinical trial was done on moderate COVID-19 cases, who were admitted to Shohadaye Tajrish Hospital, Tehran, Iran, from 4/2021 to 9/2021. Eligible patients were randomly allocated into two groups of intervention (sofosbuvir) and control, and their outcomes were compared regarding the length of hospital stay and complications. Results: 100 COVID-19 cases were randomly divided into two groups of 50 patients, as the intervention and control groups. The mean age of patients was 50.56 ± 12.23 and 57.1±14.1 years in the intervention and control groups, respectively (p = 0.02). The two groups were similar regarding distribution of gender (p = 0.15), underlying diseases (p = 0.08), the severity of COVID-19 (p = 0.80) at the time of admission, signs and symptoms (p > 0.05), and essential laboratory profile (p > 0.05). The length of hospital stay in the control and intervention groups was 7.7 ± 4.09 days and 4.7±1.6 days, respectively (p = 0.02). None of our patients needed ICU or mechanical ventilation. Conclusion: Sofosbuvir may decrease the length of hospital stay of COVID-19 cases with moderate severity, without a significant effect on the rate of intensive care unit (ICU) need and mortality. Keywords: SARS-CoV-2; Treatment Outcome; Sofosbuvir; Duration of Therapy Cite this article as: Bozorgmehr R, Amiri F, Hosein Zadeh M, Ghorbani F, Khameneh Bagheri A, Yazdi E, Nekooghadam SM, Pourdowlat G, Fatemi A. Effect of Sofosbuvir on Length of Hospital Stay in Moderate COVID-19 Cases; a Randomized Controlled Trial. Arch Acad Emerg Med. 2022; 10(1): e46. https://doi.org/10.22037/aaem.v10i1.1621. 1. Introduction Since the influenza pandemic in 1819, COVID-19 has been one of the deadliest diseases we have ever faced. It has af- fected so many different aspects of human life, including health, economy, social life, schooling, travel, etc. (1). In- ∗Corresponding Author: Farbod Amiri; Men’s Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran, postal code:1989930002, Email: Farbod.amiri1996@gmail.com, ORCID: http://orcid.org/0000-0002-8596-1948. troduction of the first vaccines against it in 2020 with their high efficacy, promised a near COVID-19-free world (2). New variants, like delta and omicron, the different level of access to vaccine among different countries (3), and a variable ac- quired immunity among different individuals (4), especially immunocompromised patients (5), showed us that although vaccines are very effective, we are still far from an end to the pandemic. So, the need for a therapeutic alternative is still on. This need is more evident in times of COVID-19 peaks, which put healthcare systems in danger of crash (6). One cheaper This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem R. Bozorgmehr et al. 2 and more scalable approach is repurposing the already avail- able drugs (7). Hepatitis C virus (HCV ) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are both categorized as positive-sense Ribonucleic acid (RNA) viruses and have similar replication mechanisms. Sovodac (FDA ap- proved) is standardly used to treat chronic HCV infection (8) and it functions by targeting the dependent RNA polymerase enzyme (9). It is one of the antiviral drugs considered for treatment of COVID-19and has been studied in different clin- ical trials (10). According to a study, which evaluated in vitro effecst of this medication on SARS-COV-2, sofosbuvir could prevent RNA synthesis via chain termination, and daclatasvir targets the folding process of secondary RNA units in SARS- CoV-2 (11). Moreover, clinical trials (10) showed an associa- tion between lower mortality rates and the need for ICU in COVID-19 patients treated with sofosbuvir/daclatasvir (12). Another aspect to consider is the financial burden of produc- ing these drugs, in a nutshell, active ingredients for sofosbu- vir and daclatasvir cost a reasonable amount of 700$/kg and 600$/kg, respectively. Some studies suggest that sofosbuvir shows more affinity to mRNA of the virus compared to da- clatasvir, so the efficacy of each drug in treating COVID-19 patients may be different (13-15). In terms of safety, in a ran- domized clinical trial (RCT) with Sofosbuvir/Ledivaspir, no side effect leading to withdrawal from the study was reported (16). Similarly, in another RCT with Sofosbuvir/Daclatasvir, no severe side effects were reported (17). Given sofosbuvir’s availability in Iran, as well as it cost, effi- cacy, and safety background, we aimed to evaluate the effects of sofosbuvir alone (not in combination with any other drug) only in patients with moderate COVID-19. 2. Methods 2.1. Study design and setting This randomized clinical trial was aimed to evaluate the safety and efficacy of sofosbuvir in management of moder- ate COVID-19 cases, who were admitted to the COVID-19 ward of Shohadaye Tajrish Hospital, a tertiary teaching hos- pital in Tehran, Iran, from 4/2021 to 9/2021. Eligible patients were randomly allocated to either the intervention or con- trol group and their outcomes were compared regarding the length of hospital stay and complications. The Ethics Committee of Shahid Beheshti University of Medical Sciences approved the study protocol (Ethics code: IR.SBMU.RETECH.REC.1399.1322). This trial was regis- tered on the Iranian Registry of Clinical Trials (IRCT: IRCT20180302038915N1). All the patients were required to fill out the consent form to enter the trial. Researchers ad- hered to ethical considerations of Helsinki Declaration and confidentiality of patients’ information. 2.2. Participants Confirmed COVID-19 cases with ages ranging from 18 to 80 years, who were admitted to the hospital with at least one of the symptoms of: Fever (Oral temperature ≥ 38 °C), Res- piratory rate >24/minutes, 90% 0.05), and es- sential laboratory profile (p > 0.05). 3.2. Outcomes The length of hospital stay in the control and intervention groups was 7.7 ± 4.09 days and 4.7±1.6 days, respectively (p = 0.02). None of our patients needed ICU or mechanical ven- tilation or expired during our study. Two patients from our control group required re-admission 14 days after discharge. One patient in the sofosbuvir group experienced nausea, so the medication was discontinued. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 5 Archives of Academic Emergency Medicine. 2022; 10(1): e46 4. Discussion We intended to evaluate the safety and efficacy of sofosbuvir in cases with moderate COVID-19. We concluded that sofos- buvir may decrease the length of hospital stay (LOHS) but has no significant effect on the rate of Intensive care unit (ICU) need and mortality. Eslami et al. study revealed that sofos- buvir/daclatasvir could decrease LOHS, ICU admission rate, and mortality in patients with severe acute respiratory syn- drome coronavirus 2 (SARS-CoV-2) (20). On the other hand, Abbaspour Kasgari et al. did not report any reduction in LOHS with sofosbuvir/daclatasvir/ribavirin administration. Limitations of their study include a small sample size (48 pa- tients) (21). Moreover, Sayad et al. reported that sofosbuvir/velpatasvir did not improve mortality, ICU admission, and LOHS. The limitation of their study is lining up moderate and severe pa- tients in one arm. They revealed that the severity can dra- matically change the response to treatments (22). Sofosbuvir in mild COVID-19 could improve neither hospital admission rate nor lead to symptom alleviation (17). Our study demonstrated that sofosbuvir could significantly reduce LOHS, but it has no significant effect on ICU admis- sion and mortality rate. We suggest initiating treatment with sofosbuvir in moderate COVID-19 to prevent exacerbation to severe infection. In this study, we answered if sofosbu- vir alone is effective for COVID-19 by focusing on moderate cases. More studies are required to determine the ideal time for starting this drug to achieve the most in terms of reaching clinical recovery sooner. 5. Limitations This study has some limitations. We missed the opportu- nity to compare laboratory findings, especially inflammatory markers, before and after administering sofosbuvir due to the lack of consistency in available data. Besides, we missed the opportunity of strengthening our methodology by using placebos and blinding; ethical issues and concern for pa- tients’ survival were the most important barriers. 6. Conclusion It seems that, Sofosbuvir can decrease the length of hospital stay in cases with moderate COVID-19 without having a sig- nificant effect on the rate of ICU need and mortality. 7. Declarations 7.1. Acknowledgments We would like to thank Dr. Laya Ohadi who helped us during this study and also the medical staff of the hospital’s COVID- 19 ward who facilitated the interventions of the study. 7.2. Data availability The data used in this study is available from the first author on reasonable request. 7.3. Authors’ contributions All authors met the four criteria for authorship contribution based on recommendations of the International Committee of Medical Journal Editors. Writing the first draft: RM Revise: FA, MH Data collection: AK, EZ, SN Data analysis: FG, AF Data interpretation: FG, GP Design: FA 7.4. Funding and supports No additional funding for the execution of the present study was received 7.5. Conflict of interest The authors declare they have no conflict of interests References 1. Baud D, Qi X, Nielsen-Saines K, Musso D, Pomar L, Favre G. Real estimates of mortality following COVID-19 infec- tion. The Lancet infectious diseases. 2020;20(7):773. 2. Luchsinger LL, Hillyer CD. Vaccine efficacy probable against COVID-19 variants. Science. 2021;371(6534):1116-. 3. Acharya KP, Ghimire TR, Subramanya SH. Access to and equitable distribution of COVID-19 vaccine in low- income countries. npj Vaccines. 2021;6(1):1-3. 4. Kwok KO, McNeil EB, Tsoi MTF, Wei VWI, Wong SYS, Tang JWT. 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Downloaded from: http://journals.sbmu.ac.ir/aaem Introduction Methods Results Discussion Limitations Conclusion Declarations References