After being identified for the first time in December 2019 in Wuhan, China,    coronavirus disease 2019 (COVID-19) has spread over the world and become a pandemic.1 From its birthplace in Wuhan City, Hubei Province, China, the 2019 novel coronavirus (2019-nCoV), now known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is rapidly spreading around the globe.2 Patients infected with COVID-19 had elevated levels of plasma pro-inflammatory cytokines, increased leukocyte counts, and abnormal respiratory findings.3 Symptomatic or asymptomatic carriers of SARS-CoV-2 can spread the virus to others through respiratory droplets and fomites.40 Favipiravir is a pyrazincarboxamide derivative that acts as an inhibitor of  viral RNA-dependent RNA polymerase, causing chain termination and preventing RNA elongation. Favipiravir is a pro-drug that, after incorporated into infected human cells, has antiviral action.4 Upon entering infected cells, favipiravir is phosphoribosylated and   subsequently phosphorylated to become favipiravir ribofuranosyl-5-triphosphate (favipiravir-RTP), its active structure.5 Though several previous studies have been reported in literature evaluating the effects of Favipiravir in COVID-19 patients, their results are contradictory.6-8 Thus, this study was conducted to evaluate the effects of Favipiravir in patients diagnosed with mild to moderate Covid-19 in a tertiary care institute.

This retrospective investigation spanned one year within a tertiary care Hospital. Prior to the study's initiation, approval was obtained from the Institutional Review Board to ensure ethical compliance. Data pertaining to adult patients diagnosed with mild to moderate COVID-19, confirmed by reverse transcriptase-polymerase-chain reaction (RT-PCR), and admitted to the hospital till August 2022, was gathered from the medical records department. Study comprised of two groups: (i) Favipiravir group comprised 100 COVID-19 positive patients who were administered Favipiravir, and (ii) non-Favipiravir group consisted of 100 COVID-19 positive patients who did not receive Favipiravir. Within the Favipiravir group, patients were treated with Tablet Favipiravir in accordance with the treatment guidelines outlined by ICMR and the government of Gujarat: Tablet Favipiravir 1800 mg twice daily (9 tablets of 200 mg each) on day 1, followed by 800 mg twice daily (4 tablets of 200 mg each) for a total duration of 7 days. Patients were assessed with respect to time to clinical recovery, adverse events, and time to viral clearance.

The classification of severity was delineated as follows:

Mild: Characterized by patients exhibiting uncomplicated upper respiratory tract infections, often presenting with mild symptoms such as fever, cough, sore throat, nasal congestion, malaise, and headache. Notably, these patients do not display shortness of breath or hypoxia (normal saturation).

Moderate: Defined as pneumonia without indications of severe illness. Adults in this category may demonstrate features of dyspnea or hypoxia, accompanied by fever and cough, with SpO2 levels ranging from 90 to ≤93% on room air and a respiratory rate ≥24/min.

Severe: Describes cases of severe pneumonia. Adults with clinical signs of pneumonia in conjunction with one of the following: a respiratory rate exceeding 30/min, severe respiratory distress, or SpO2 levels below 90% on room air.

Statistical Analysis:

Categorical variables underwent analysis employing either the chi-square test or Fisher’s exact test. Mean comparisons were conducted using one-way ANOVA. Pearson correlation analysis was employed to establish correlations between two continuous variables. A significance level of p<0.05 was adopted to denote statistical significance.

The majority of COVID-19 patients in our study fell within the 41-50 age group (p>0.31). Males predominated over females in our study, indicating higher susceptibility to COVID-19 infection among males, although this difference was not statistically significant (p>0.064). The most frequently observed comorbidity was hypertension (HTN), and Diabetes Mellitus (DM). Common presenting signs and symptoms included fatigue (101), fever (69) and sore throat (67). Of 200 cases, 150 were diagnosed as mild and 50 were diagnosed as moderate in severity. (Table 1).

Table 1: Comparison of Parameters between Study group and Control group

Significant improvements in COVID-19 symptoms such as fever, fatigue, sore throat, shortness of breath, and headache were observed with early initiation of Favipiravir (p<0.05). (Table 2)

Table 2: Early initiation of favipiravir and symptomatic resolution

We found significantly higher incidence of adverse drugs events in Favipiravir group as compared to non-Favipiravir group patients (p<0.001). Altered liver function test and rise in uric acid level was significantly higher in patients who received Favipiravir (p<0.001). (Table 3)

Table 3: Comparison of adverse events between the two study groups

There was significant rise in the level of serum ALT and serum Uric Acid on Day 5 when compared to Day 1 in Favipiravir group (p=0.0001). (Table 4)

Table 4: Comparison of level of S. ALT (U/L) and S. Uric Acid (mg/dl) on Day 1 and 5 in Favipiravir group

The mean time to viral clearance was significantly lower in Favipiravir group as compared to patients in non-Favipiravir group        (p=0.0001). (Table 5)

Table 5: Comparison of time to viral clearance between the two study groups

The primary problem with COVID-19 is the absence of evidence for reliable   treatment alternatives, including medication and immunization that have been approved by the FDA.9 Favipiravir demonstrates broad-spectrum antiviral effectiveness against RNA viruses by selectively inhibiting the viral RNA polymerase enzyme. This mechanism prevents the replication and transcription of the viral genome.10 Recently, it has shown promise in treating emerging influenza viruses. Moreover, studies indicate its efficacy against RNA viruses responsible for viral hemorrhagic fevers such as Ebola.11 However, the primary endpoint of time to RT-PCR negative was not statistically significant in a randomized study with favipiravir in patients with mild to moderate     COVID-19.10 Due to conflicting data from therapeutic trials, we deemed it prudent to explore the potential utility of Favipiravir in treating COVID-19.

Both cohorts of COVID-19 patients exhibited a middle-aged demographic, with the median age ranging between 41 and 50 years (p>0.031). (Table 1) Certain studies suggested that advanced age represents a critical risk factor for the severity of COVID-19 illness, particularly beyond 50 years of age. Of the total number of participants in the study by Albanghali et al12, 19% were between the ages of 46 and 55. Patients older than 66 accounted for 14% of the total population of COVID-19 in another study.

Our study comprised 113 male participants and 87 female participants, with males constituting the clear majority (p>0.064). (Table 1) Similarly, one study documented 64.4% of COVID-19 patients were male and 35.6% were female.13 In contrast, another study reported 50.3% female and 49.7% male among COVID-19 infected patients.12 In our study, most commonly observed co-morbidities were HTN (31%) and DM (23%) (p>0.84). Another study involving COVID-19 patients showed that DM (31%) and HTN (24%) were the most common comorbidities.14

In our study, most commonly observed symptoms were fatigue, fever and sore throat. Similar observations were made in another single-center study done in Wuhan, wherein the most common symptoms of COVID-19 were fever, cough, and dyspnoea    (China).15 The majority of Indians, unlike most people in other countries, only experienced mild to moderate symptoms. Hospitalized patients were more likely to report cough and dyspnea in gathered epidemiological data. 16 Dry cough, fever, and exhaustion were the most common symptoms reported by COVID-19 patients, however, fever is the most prominent sign in other types of diseases as well.17 Hypogeusia, anosmia, headache, and diarrhoea were also observed, but at a lower frequency. The patients may also experience difficulties breathing, chest pain, and immobility. The most difficult problem is that many people who are infected with COVID-19 don't show any symptoms at all, making them a potential vector for the SARS-CoV-2 virus.18

Compared to patients who did not take Favipiravir, those who did had considerably more severe changes in liver function test and elevation in uric acid level (p<0.001). Similarly, Erdem et al9 observed that 13% of patients treated with Favipiravir experienced adverse events, including an increase in liver enzymes, total bilirubin, and uric acid, and some had gastrointestinal problems. Similar observations were made by Udwadia et al19 The five participants in this study all had an increase in liver enzymes ranging from mild to moderate, three had nausea, and one had neutropenia. There was no permanent damage, and the adverse effects went away on their own. In addition, no patients discontinued treatment with Favipiravir due to adverse effects, and there was no correlation between underlying disease and adverse events.9 In contrast to our findings, Hassanipour et al20 found that patients given Favipiravir had a significantly decreased risk of adverse events compared to those in the placebo group, consistent with the meta-analysis conducted by Shrestha et al21 Intervention with    Favipiravir, as reported by Khamis et al22, was associated with no hyperuricemia, abnormal liver enzymes, or QTc prolongation. Research conducted by Victoria Pilkington et al23 showed that Favipiravir was well tolerated by patients.

Time to viral clearance was substantially shorter in Favipiravir group (7.84+1.405 days) as compared to Non-Favipiravir group (9.78+1.77 days; p=0.0001) in our study. (Table 5) A systematic review and meta-analysis found that on day 7 following initiation of treatment, Favipiravir group had significantly greater viral clearance than the control group (odds ratio [OR] = 2.49, 95% confidence interval [CI] = 1.19-5.22), but on day 14, there was no difference between the two groups (OR = 2.19, 95% CI = 0.69-6.95).24 Another study reported that median time for viral clearance was 4 days in the Favipiravir group as compared to 11 days in the control group (p= 0.001).25 Due to a lack of defined methodology and a clear association with the clinical condition of the patient, viral clearance is not regarded  a predictive metric.26 Being a single centre retrospective study with smaller sample size, were few limitations of the study.

This study showed that patients with mild to moderate COVID-19 had significantly shorter times to clinical recovery, and viral clearance if Favipiravir was started during the early phase of treatment. Similar to past experience with favipiravir, the observed side effects were generally mild to moderate in severity and short-lived. No updated warning signs were present. Orally administered favipiravir looks to be a potential therapeutic option given the urgent clinical need for safe and effective therapies for mild to moderate COVID-19. However, future research, such as randomized, double-blind, placebo-controlled trials and those that   combine Favipiravir with other antiviral medications, will shed more light on the use of Favipiravir in the treatment of patients with COVID-19.

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