Efficacy of Favipiravir in Treatment of Mild & Moderate COVID-19 Infection in Nepal

COVID-19 stands for 2019 novel coronavirus or 2019-nCoV which is a new virus linked to the same family of viruses as Severe Acute Respiratory Syndrome (SARS), \& hence named as SARS-CoV-2. It has been revealed that SARS-CoV-2 has a genome sequence that is 75%-80% identical to that of SARS-CoV. Since its first discovery in Wuhan, China in late December, it has now become a pandemic disease claiming more than nine hundred forty-five thousand deaths world-wide so far. Majority of the patients are asymptomatic or mild symptomatic, \& recovery without any treatment. While there is disproportionately higher mortality among elderly \& people with co-morbidities like hypertension, diabetes, obesity, heart disease or any immunocompromised status. Recently, several regimens have been tried as antiviral medicine. Among these medicines, Favipiravir is considered a broad-spectrum antiviral with spectrum of activity noted against a wide range of RNA viruses namely Influenza, West Nile virus, Yellow fever virus, Food \& mouth virus, Flavivirus, Arenavirus, Bunyavirus \& Alpha virus. In the USA, Japan \& China, it has been approved for use in resistant Influenza. Regarding use of Favipiravir in COVID19, there have been some studies with limited data. The earlier Chinese study that compared between Favipiravir (35 patients) versus Lopinavir/Ritonavir (45 patients) among mild to moderate cases showed a trend towards earlier improvement in CT scan \& quicker viral clearance in Favipiravir arm with lesser side effects comparatively. Another randomized clinical trial in China conducted on patients with COVID19 pneumonia (moderate) failed to demonstrate a significant difference in clinical recovery rate at day 7 between Favipiravir (116 patients) versus Umifenovir (112 patients) however, Favipiravir was associated with earlier relief of pyrexia \& cough in comparison Another multicenter, open label, randomized phase II/III trial conducted in Russia on moderate COVID19 infection comparing Favipiravir against standard of care in total 60 patients randomized into three treatment groups with 20 patients each: Favipiravir 1600/600 mg, Favipiravir 1800/800 mg, or Standard of care (which included, hydroxychloroquine or chloroquine versus lopinavir/ritonavir versus no etiotropic treatment) concluded that Favipiravir enabled viral clearance in 62.5% patients within 4 days with good safety data, no matter which dosing was used. There has been an observational study on 2141 patients in Japan that showed good recovery among mild (not requiring oxygen), moderate case (requiring oxygen) or younger patients (59 years or younger) whereas poor prognosis in severe (requiring mechanical ventilation or ECMO) or older patients (60 years or older). The most common adverse events were hyperuricemia (335 patients; 15.52%) followed by liver injury or liver function test abnormalities (159 patients; 7.37%) in this study. Similarly, the open label randomized , multicenter clinical trial was conducted in 150 patients to evaluate the efficacy and safety of Favipiravir plus standard supportive care ( Favipiravir treatment arm, versus standard supportive care alone ( control arm ) across seven clinical sites in India.

It was evaluated among mild to moderate patients, randomized within a 48 hours window of testing RT-PCR positive for COVID-19 . The patients received Favipiravir tables of 3,600 mg (1,800 mg BID) (Day 1) + 1,600 mg (800 mg BID) (Day 2 or later) for up to maximum of 14 days , along with standard supportive care . The results from this Phase 3 trial conducted by Glenmark showed numerical improvement for the primary efficacy endpoint with 28.6% faster viral clearance in the overall population (Hazard Ratio 1.367 [95%CI 0.944,1.979]; p=0.129). Additionally , 69.8 % of patients in the Favipiravir treatment arm achieved clinical cure by Day 4, which was statistically significant compared to 44.9% observed in the control group (p=0.019). Likewise, Glenmark's Favipiravir was well tolerated with no serious adverse events or death in the Favipiravir treated arm but adverse events were reported in 26 patients in Favipiravir treatment arm. However, adverse events were mild to moderate and none led to drug discontinuation and dosing adjustments. This trial demonstrated statistically significant faster time to clinical improvement with Favipiravir treatment in Mild to moderate COVID-19 patients compared to the control group. Additionally, An open-label, nonrandomized, before-after controlled study was conducted in an isolation ward of the national clinical research center for infectious diseases at Shenzhen, China.35 patients was enrolled in the FPV arm and the 45 patients in the control arm, all baseline characteristics were comparable between the two arms. From 30 January to 14 February 2020, laboratory-confirmed patients with COVID-19 were consecutively screened, and eligible patients were included in the FPV arm of the study. Patients who had initially been treated with antiviral therapy with LPV/RTV from 24 January to 30 January 2020 were screened, and eligible patients were included in the control arm of the study. The dose was 1600 mg twice daily on Day 1 and 600 mg twice daily on Days 2-14. LPV/RTV (AbbVie Inc., 200 mg/50 mg per tablet) were given orally. The dose was LPV 400 mg/RTV 100 mg twice daily. Both FPV and LPV/RTV were continued until the viral clearance was confirmed or until 14 d had passed. For the 35 patients enrolled in the FPV arm and the 45 patients in the control arm, all baseline characteristics were comparable between the two arms. A shorter viral clearance time was found for the FPV arm versus the control arm (median (interquartile range, IQR), 4 (2.5-9) d versus 11 (8-13) d, P < 0.001). The FPV arm also showed significant improvement in chest imaging compared with the control arm, with an improvement rate of 91.43% versus 62.22% (P = 0.004). After adjustment for potential confounders, the FPV arm also showed a significantly higher improvement rate in chest imaging. Multivariable Cox regression showed that FPV was independently associated with faster viral clearance. In addition, fewer adverse events were found in the FPV arm than in the control arm.In this open-label before-after controlled study, FPV showed better therapeutic responses on COVID-19 in terms of disease progression and viral clearance.These preliminary clinical results provide useful information of treatments for SARS-CoV-2 infection. Doses of Favipiravir ranged widely across studies, from 400 mg up to 6000 mg loading doses, with the more common regimens being 1200 mg per day, split into twice or three times daily doses. 494 Studies were screened, 55 studies assessed for full text eligibility, 29 studies were included. Hyperuricemia was shown as the side effects.