key: cord-0840759-ynv32z6o
authors: Alotaibi, Musim; Ali, Ahmed; Bakhshwin, Duaa; Alatawi, Yasser; Alotaibi, Sultan; Alhifany, Abdullah; Alharthi, Badr; Alharthi, Nasser; Alyazidi, Awatef; Alharthi, Yasmeen; Alrafiah, Aziza
title: Effectiveness and Safety of Favipiravir Compared to Hydroxychloroquine for Management of Covid-19: A Retrospective Study
date: 2021-09-14
journal: Int J Gen Med
DOI: 10.2147/ijgm.s329881
sha: 0aa19c156fdbd6d88b7ffe94df923e7397bd5186
doc_id: 840759
cord_uid: ynv32z6o

BACKGROUND: Coronavirus disease (COVID-19) is an infectious disease due to SARS-COV-2. Patients with risk factors are vulnerable to severe morbidity and mortality. Favipiravir (FPV) and hydroxychloroquine (HCQ) are considered possible COVID-19 treatments. OBJECTIVE: To investigate the effectiveness and safety of FPV compared to HCQ in patients with COVID-19 as the standard of care approved by the national protocol there. METHODS: This is a retrospective cohort study on patients with COVID-19 who were administered either FPV or HCQ at King Faisal Medical Complex, Taif, Saudi Arabia, from June 2020 to August 2020. RESULTS: In total, 508 patients were included in the analysis. Patients were categorized into three groups by medication. Patients enrolled in this study were 244 (55.8%) on FPV, 193 (44.2%) on HCQ and 71 (13.81%) on neither medication. Patients who received FPV had higher age and greater comorbidity. Most of the patients were discharged on day 14 (n = 303, 59.6%), 26 (36.6%) in neither med, 154 (63.1%) in FPV and 123 (63.7%) in HCQ groups with significant difference between groups (P < 0.0001). Mortality rate was 8.2% (n = 20) in FPV and 7.3% (n = 14) in HCQ groups with significant difference between groups (P = 0.048). Regarding drug safety, 19.7% of patients treated with FPV vs 7.8% HCQ have adverse effects with significant difference between groups (P < 0.0001). Most of the side effects were increase ALT and AST. Meanwhile, prolonged Q-T interval was reported only in the HCQ group (2.6%). From Cox regression modeling, only mechanical ventilation due to Covid 19 was predictive for mortality (HR: 16.598, 95% CI: 7.095–38.828, P < 0.0001). Meanwhile, there was no significant difference in the prediction of discharge of FPV (vs HCQ) (HR: 0.933, 95% CI: 0.729–1.195, P = 0.5843), predictors of mortality were HCQ (vs FPV) (HR: 2.3, 95% CI: 0.994–5.487, P = 0.0518). Kaplan–Meier survival curves showed improved survival time and discharged time among patients in the HCQ versus FPV group with an insignificant difference between them (P = 0.85, P = 0.06, respectively). CONCLUSION: The present study concluded that FPV and HCQ showed comparable efficacy in decrease mortality and oxygen requirements. FPV likely has a more favorable safety profile regarding cardiac toxicity. A randomized clinical trial with large patient numbers is recommended to confirm the effectiveness of these drugs in COVID-19 patients.

The World Health Organization approved coronavirus disease 2019 (COVID- 19) , a global pandemic on March 11th, 2019, resulting in millions of deaths. However, health authorities worldwide have officially authorized no therapy as a standard treatment agent for the virus. Therefore, health authorities around the world proposed several agents to be used in COVID-19 management. These agents include, for example, hydroxychloroquine (HCQ)/chloroquine, remdesivir, tocilizumab, prednisolone, and ivermectin. Unfortunately, many of these agents showed partial effectiveness but had many adverse effects. [1] [2] [3] Furthermore, several of these medications were found to be at unacceptable levels in COVID-19 patients, particularly those with diabetes, hypertension, cardiovascular disease, renal failure, liver cirrhosis, stroke, and other co-morbidities. 4 Furthermore, six additional Coronaviridae family members were known to produce infections in humans before discovering SARS-CoV-2, including the SARS-CoV infection, which was first reported in 2002, and the Middle East Respiratory Syndrome (MERS)-CoV infection, which was first reported in 2012. Because the genome sequence of SARS-CoV-2 shares about 75-80% similarity with SARS-CoV, and even more so with some bat coronaviruses, significant effort is being put into testing the efficacy of existing antiviral drugs for SARS-CoV -2 infection treatment, including those that are effective in other viral infections, such as ribavirin, lopinavir (ritonavir), and interferon. 5 Hence, it is crucial to find safe and effective treatment options for this disease.

The utilization of chloroquine in COVID-19 patients became standard treatment 6 after it was found to diminish infection in human cells 7 and pose a favorable action on viral clearance and clinical outcome in a clinical trial. Following these findings, a group of regulatory experts and governments proved that chloroquine had anti-COVID-19 concrete action. The drug was included in the National Health Commission of the People's Republic of China's Republic guidelines for preventing, diagnosing, and therapy COVID-19-related pneumonia. 8 One option to treat the novel COVID-19 virus is favipiravir (FPV), an RNA-dependent RNA polymerase (RdRp) inhibitor. It blocks the replication process by inhibiting the influenza virus's RdRp by adversely acting on genetic copying. It was approved by Japan Pharmaceuticals and Medical Devices Agency (PMDA) in 2014 as an antiviral for influenza. FPV has been included in COVID-19 treatment protocols after it showed promising results. 9,10 However, few studies have been reported supporting FPV use for COVID-19 therapy. The Saudi Ministry of Health protocol for patients with confirmed COVID-19 added FPV for COVID-19 management. 11 This study aimed to investigate the effectiveness and safety of FPV compared to hydroxychloroquine in patients with COVID-19 as the standard of care approved by the national protocol there.

The present retrospective cohort study was implemented at King Faisal Medical Complex in Taif, Saudi Arabia, from June 2020 to August 2020. King Faisal Medical Complex provided access authorization to the hospital electronic medical records through Taif Research and Ethics Committee (Approval # HAP-02-T-67) that was according to Declaration of Helsinki. Informed consent was waived as this was considered an exempt study. Health information was maintained in a confidential manner that prevents unauthorized use and disclosure to third parties. Included in this study were adult patients (≥18 years) with a verified PCR diagnosis of COVID-19. Excluded from this study were pregnant, breastfeeding females, or patients <18 years.

According to MOH protocols, 11 patients were classified into three groups: 1) FPV group: treated with FPV at a dose of 1800 mg/dose twice daily on the first day then 800 mg/dose two times daily for 7-10 days. 2) HCQ group: treated with HCQ at 400 mg/dose twice daily on the first day, then 200 mg/dose two times daily for 5-7 days. 3) and neither medications group.

Patients' information was gathered from medical records under the supervision of a competent medical professional. These data were demographic characteristics, comorbidities; vital signs; symptoms. As well as patient location (ward or intensive care unit [ICU]); type of respiratory support. The treatment impact on the outcomes was reported as mortality rate, discharge at day 14, the adverse event of treatments. 

In this study, 508 COVID-19 patients were enrolled. Of them, 244 patients received FPV, 193 patients received HCQ, 71 patients did not receive either med. There was a significant difference between the mean of the age in different treatment groups (P <0.0001, Table 1 ). The mean age was highest in the FPV group (54.80±14.87 years), then the HCQ group (49.59±12.63 years) and least in neither med group (41.67±16.61 years). In all the patients, age groups were mostly ≤ 65 years (n= 431, 84.8%) than > 65 years (n=77, 15.2%). There was a significant difference between age groups in different studied groups of patients (P <0.0001). In neither med, FPV and HCQ groups, the proportion of males (64.8%, 62.3% and 56.0%, respectively) were higher than females (35.2%, 37.7%, and 44.0%, respectively) with insignificant difference between groups (P =0.284). In this study, 55.5% (n= 282) of patients have a history of diseases (comorbidities). There was a significant difference between groups (P <0.0001) in terms of comorbidities. Comorbidities were highest in the FPV group (66.4%), followed by the HCQ group (50.3%), and least in the med group (32.4%). In neither med, FPV and HCQ groups, the percentage of patients with diabetes mellitus were (8.5%, 43.0% and 29.0%; P <0.0001), hypertension (18.3%, 28.3% and 18.1%; P =0.026), asthma (1.4%, 5.7% and 7.8%; P =0.149), hypothyroidism (2.8%, 7.0% and 4.1%; P =0.256). Meanwhile, patients in FPV and HCQ groups only had heart diseases (10.7% and 4.1%; P =0.001) and obesity (4.1% and 2.1%; P =0.136) ( Table 1) . Table 2 shows a comparison of clinical characteristics of patients between groups. In all groups, the manifestations of COVID-19 were mostly cough (83.7%), then fever (69.9%), low oxygen saturation (66.1%), shorting of breath (54.3%), headache (23.6%), running nose (4.3%), diarrhea (2.6%) and vomiting (1.7%). In neither med, FPV Regarding respiratory support, most patients were on oxygen only (72.8%), then on no oxygen (22.0%) and least was on mechanical ventilation (5.1%). The percentage of patients in neither med, FPV, and HCQ groups on no oxygen were (47.9%, 18.0%, and 17.6%, respectively). Those who received oxygen only (52.1%, 73.4%, and 79.8%, respectively) and those on mechanical ventilation were in FPV and HCQ groups only (9.5% and 2.8%, respectively) with significant differences between groups (P <0.0001). Most of the patients were in Ward (90.9%, n= 462), while only 9.1% (n=46) were admitted to ICU. The patients in Ward and ICU in neither med group were (98.6% and 1.4%), FPV treated group (86.5% and 13.5%), and in HCQ treated group (93.8% and 6.2%) with significant difference between groups (P =0.002), ( Table 2) .

According to Therapy Table 3 shows the outcomes of patients in different treatment groups. Most of the patients discharge at the end of treatment (n= 303, 59.6%), 26 (36.6%) in neither med, 154 (63.1%) in FPV and 123 (63.7%) in HCQ groups with significant differences between groups (P <0.0001). The number of patients transfer to ICU were 4 (5.8%) in neither med, 9 (4.3%) in FPV and 11 (6.0%) in HCQ groups with no significant difference between groups (P =0.715). There was a significant difference in mortality between groups (P =0.048). Mortality rate was 8.2% (n=20) in FPV and 7.3% (n=14) in HCQ groups. (Table 3 ).

In the multivariable Cox regression model 1 of mortality prediction utilizing the patient group-administered FPV as a reference, therapy with HCQ (vs FPV) (HR: 2.3,95% CI: 0.994-5.487, P =0.0518) not find statistical significance. Only mechanical ventilation due to Covid 19 was 

The drugs' adverse effects were significantly higher in FPV versus HCQ groups (19.7% versus 7.8%, P <0.0001). There was a significant increase in FPV versus HCQ groups in ALT level (13.9% and 2.6%, P <0.0001) and AST level (8.6% and 1.0%, P <0.0001). Meanwhile, there were no significant difference in FPV versus HCQ groups in vomiting (2.9% and 2.1%, P =0.418), nausea (1.6% and 1.6%, P =0.627), diarrhea 

Kaplan-Meier survival curves revealed improved survival between patients in HCQ therapy versus the FPV group ( Figure 1) . However, the mean survival time and standard error for the FPV group were 26.40±0.43 days, and for the HCQ group was 27.06±0.60 days with a non-significant difference between them (P =0.8554). Kaplan-Meier survival curves showed improved discharge time among patients in the HCQ versus FPV group ( Figure 2) . However, the mean discharge time and standard error for the FPV group was 16.64 ±0.63 days, and for the HCQ group was 14.051±0.63 days, with an insignificant difference between them (P =0.060).

The need for safe and efficient treatment options continues to be the main point of clinical research despite the advent of COVID-19 vaccines. Before the pandemic, scientists postulated that HCQ interacted with the virus, and in vitro evidence indicated an antiviral effect. 9, 12 FPV is an RNA-dependent RNA polymerase inhibitor promoted in China and Japan to treat influenza outbreaks. 13 Therefore, there was a considerable need for diverse research testing its efficacy and safety in such a setting, based on the limited published evidence about its usage in COVID-19 treatment. So that, the current retrospective cohort research aimed to study FPV's effectiveness and safety in managing COVID-19 cases in Saudi Arabia.

The first clinical study of FPV was non-randomized interventional research consisting of 80 cases with non-severe COVID-19 compared FPV to lopinavir/ritonavir and found that the FPV group improved viral clearance on day 7, indicating that FPV could be useful in the treatment of COVID-19. At day 14, FPV patients showed improved chest CT scans 32/ 35 (91.43%) versus lopinavir/ritonavir patients 28/45 (62.22%) (p=0.004). 10 Moreover, Rattanaumpawan et al 14 reported retrospective research included 274 COVID-19 cases admitted to 5 Thai hospitals, of whom 63 (23.0%) got FPV. About all cases were prescribed HCQ-based drug (98.4%) and a protease inhibitor (96.8%) within two days of starting FPV treatment; half of the cases were given azithromycin (49.2%). The research showed that FPV is successful in treating COVID-19 patients.

In demographic data, most of the patients were men in the FPV group (60.2%) and HCQ group (62.3%), with insignificant differences between groups. Above 60% of men also showed in another study. 15 FPV is mainly received by the middle-aged group, like in other studies. 15, 16 Comorbidities like hypertension, diabetes mellitus, and heart disease were manifested in both groups (FPV group and HCQ group). Researchers also found patients. 15, 17 In the current study, the main symptoms and signs reported in the two groups were cough, fever, low oxygen saturation, and shortness of breath. They were reported more frequently in the HCQ than the FPV group, and the difference was significant. Similarly, a study in the Third People's Hospital of Shenzhen examined clinical results in people with COVID-19 treated with FPV and those treated with LPV-RTV. They found that patients treated with FPV recovered faster, and the symptoms and signs of both groups showed more recovery in the FPV group than in the LPV-RTV group. 10 This study examined whether FPV improved COVID-19 patients' clinical outcomes in terms of time to discharge and mortality compared to HCQ treatment. In the current study, the mortality rate in the FPV group (8.2%) was higher versus patients in the HCQ group (7.3%). Also, hospital stays of more than 14 days were significantly highest in neither medication (63.4%) then FPV (36.9%) and lastly HCQ (36.3%) (P<0.0001). In France, Lagier et al 18 reported that therapy with HCQ and azithromycin decreased hospital stay duration, risk of ICU transfer, and deaths in COVID-19 cases. However, in the present study, ICU admission with FPV group (4.3%) compared to (6%) HCQ group with not statistically significant (p=0.715). Similarly, Guner et al compared the ICU admission rate of mild/moderate COVID-19 patients treated with HCQ, FPV, or HCQ plus FPV in the hospital setting study. They discovered no statistically significant difference in ICU admissions between the HCQ and HCQ plus FPV categories. 19 In the present study, the Kaplan-Meier survival curve showed better survival analysis with the enhanced survival persisting out to 30 days from admission and improved discharge time among patients in HCQ treated group, with an insignificant difference with the FPV treated group. In addition, Udwadia et al reported that Kaplan-Meier analyses of time to clinical cure exhibited significant improvement in time to clinical cure, suggests FPV may be beneficial in mild-to-moderate COVID-19. 20 In the present study, the Cox regression model for mortality prediction revealed that mechanical ventilation was predictive for mortality. Patients on mechanical ventilation had about 13 times more risk of death than others who did not receive mechanical ventilation. Numerous studies have been published in the literature that examine mortality as an outcome for patients undergoing mechanical ventilation. 21, 22 In the present study, the Cox regression model for discharge prediction showed that patients who prescribed neither medication had a significantly high risk of extended hospitalization after 30 days than those prescribed HCQ. In contrast, there was no significant difference between those who received FPV and those who received HCQ. Cox regression of the risk factors for discharge prediction revealed age >65 years and mechanical ventilation significantly high risk of extended hospitalization. According to a report conducted by Thai et al 23 the average length of stay in the hospital was 21 days. The multivariable Cox regression model demonstrates that prolonged hospital stays are significantly correlated with age, residency, and source of contamination.

In the current study, the most adverse effects of FPV were increasing ALT and AST, mild to moderate diarrhea, nausea, and vomiting, as reported by others. 24 In addition, the most often reported adverse events of FPV were gastrointestinal disturbances, uric acid elevations, neutrophil count decreased, ALT and AST elevations, psychological symptom reactions, and blood triglyceride elevations. 25 Also, Cai et al 10 reported a clinical trial in COVID-19 cases administered FPV. Adverse effects were observed in 11.4% of cases (4/35); two had diarrhea, one had liver disorders, and one had decreased appetite. Madelain et al 24 could explain that FPV is primarily metabolized in the liver by the aldehyde oxidase enzyme and metabolizes a small portion by xanthine oxidase.

Significant QT prolongation was observed in COVID19 patients treated with HCQ, a key finding in this study. However, this did not appear in patients who were given FPV. Only two small observational studies have reported associations between HCQ doses of 200-HCQ without collecting some baseline data, such as C-reactive protein (CRP), D-dimer, and lymphocyte count, that may have affected treatment allocation. Moreover, the current study has other limitations in that it only included hospitalized individuals in Taif province. Therefore results may not apply to different areas in the Kingdom. In addition, only one HCQ and FPV dosing regimen were investigated; multiple doses for safety evaluation are indicated.

The present study concluded that FPV and HCQ showed comparable efficacy in decrease mortality and oxygen requirements. Interestingly, FPV exhibited no prolonged Q-T interval, although there was a significant comorbidities association, especially heart disease, compared to the HCQ. A big RCT is required to validate or contradict our findings.

The study was conducted according to the guidelines of the bioethics and research committee of the King Faisal Medical Complex, Taif, Saudi Arabia, and approved by Taif Research and Ethics Committee (Approval # HAP-02-T-67) under the reference number of (Reference Approval # HAP-02-T-67).

Effect of hydroxychloroquine in hospitalized patients with COVID-19: preliminary results from a multi-center, randomized

Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial

Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial

Systematic review on repurposing use of Favipiravir against SARS-CoV-2

Genomic characterization and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding

Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Diagnosis and treatment protocol for novel coronavirus pneumonia (Trial version 8)

Favipiravir versus arbidol for COVID-19: a randomized clinical trial

Experimental treatment with favipiravir for COVID-19: an open-label control study

Saudi MoH protocol for patients suspected of/confirmed with COVID-19 supportive care and antiviral treatment of suspected or confirmed COVID-19 infection (version 1.4) AtS

A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19)

Report on the Deliberation Results. Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau. Ministry of Health. Labour and Welfare

Real-world experience with favipiravir for treatment of COVID-19 in Thailand: results from a multi-center observational study

Remdesivir and favipiravir changes hepato-renal profile in COVID-19 patients: a cross sectional observation in Bangladesh

Favipiravir use in COVID-19: analysis of suspected adverse drug events reported in the WHO database

Safety and efficacy of favipiravir versus hydroxychloroquine in management of COVID-19: a randomised controlled trial

Outcomes of 3737 COVID-19 patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: a retrospective analysis

Comparing ICU admission rates of mild/moderate COVID-19 patients treated with hydroxychloroquine, favipiravir, and hydroxychloroquine plus favipiravir

Efficacy and safety of favipiravir, an oral RNA-dependent RNA polymerase inhibitor, in mild-to-moderate COVID-19: a randomized, comparative, open-label, multi-center, Phase 3 clinical trial

Outcome of patients with severe asthma in the intensive care unit

Survival in patients receiving prolonged ventilation: factors that influence outcome

Factors associated with the duration of hospitalisation among COVID-19 patients in Vietnam: a survival analysis

Ebola virus infection: review of the pharmacokinetic and pharmacodynamic properties of drugs considered for testing in human efficacy trials

Role of favipiravir in the treatment of COVID-19

Chronic hydroxychloroquine use associated with QT prolongation and refractory ventricular arrhythmia

Long QT and hydroxychloroquine; A poorly recognised problem in rheumatology patients

The effect of favipiravir on QTc interval in patients hospitalized with coronavirus disease 2019

Lack of effect of favipiravir, a novel antiviral agent, on QT interval in healthy Japanese adults

This manuscript is a master's degree thesis that has been submitted to the Deanship of Graduate Studies, King Abdulaziz University.

The authors declare no conflicts of interest in this work.

The International Journal of General Medicine is an international, peer-reviewed open-access journal that focuses on general and internal medicine, pathogenesis, epidemiology, diagnosis, monitoring and treatment protocols. The journal is characterized by the rapid reporting of reviews, original research and clinical studies across all disease areas. The manuscript management system is completely online and includes a very quick and fair peer-review system, which is all easy to use. Visit http://www.dovepress.com/ testimonials.php to read real quotes from published authors.