Favipiravir and the Need for Early Ambulatory Treatment of SARS-CoV-2 Infection (COVID-19).

It is becoming increasingly clear that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), like most human viral infections, will require multiple drugs in combination to treat COVID-19 illness. In this issue of the Journal, Doi and colleagues describe successful treatment of patients with early COVID-19 with favipiravir, an oral polymerase inhibitor, to rapidly and substantially clear SARS-CoV-2 from nasal secretions irrespective if it was started relatively early or later within the first week of infection. These data support the concept that favipiravir could be paired with at least one more off-target antiviral agent (doxycycline, azithromycin, or ivermectin) followed by corticosteroids and antithrombotics to prevent COVID-19 hospitalization and death in those over age 50 and/or those with one or more comorbidities. Clinical trials and advanced practice should immediately pivot to combination/sequential drug therapy for ambulatory COVID-19 illness.

TEXT

The unprecedented global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and symptomatic patients with COVID-19 has driven new thinking on the evaluation of medical evidence for drug efficacy. As in all areas of medicine, the large randomized, placebo-controlled, parallel-group clinical trial in appropriate patients at risk with meaningful outcomes is the theoretical gold standard for recommending therapy. Many guidelines espouse at least two completed and concordant trials to recommend treatment (1). These standards are not sufficiently rapid or responsive to the COVID-19 pandemic. A full cycle of trial design, funding, site initiation, treatment allocation, monitoring, follow-up, analysis, and publication may take 2 or more years. One could argue that the results of definitive trials were needed at the outset of the pandemic and certainly are needed now, with over 30 million cases and 950,000 deaths worldwide (https://www.worldometers.info/coronavirus/). Because COVID-19 is highly communicable, many ambulatory clinics do not care for patients in face-to-face visits and these patients are commonly declined by pharmacies, laboratories, and imaging centers.

It has become clear that the immediate release and use of early ambulatory therapy for COVID-19 should be based on pathophysiologic rationale and supportive data while larger conclusive randomized trials are under way. In this issue of the Journal, Doi and colleagues present a prospective, randomized open-label trial of early (day 1) versus late (day 6) treatment with oral favipiravir; both groups of patients demonstrated what should be considered rapid and substantial viral clearance by 6 days (2). Given the known variability of the asymptomatic phase of SARS-CoV-2 and the rigor with which daily nasal testing was performed, one could conclude that if favipiravir could have been started within the first few hours of symptoms, by and large COVID-19 could be a self-limited infection lasting a week or less. Recently there has been published guidance from an international collaboration that recommends favipiravir as one of several antiviral medications to be used immediately at the onset of symptoms at home in persons over age 50 or with one or more medical comorbidities (3). This is to be followed by corticosteroids at day 5 or the onset of pulmonary symptoms. Lastly, if at risk for thromboembolism or with difficulty breathing or desaturation, the addition of oral antithrombotics is recommended (4). With this approach, one can see how favipiravir, a viral RNA-dependent RNA polymerase, would be an ideal front line medication to be used in conjunction with the sequential therapy as shown in Fig. 1.

FIG 1

Treatment algorithm for COVID-19-like and confirmed COVID-19 illness in ambulatory patients at home in self-quarantine. Yr, year; BMI, body mass index; Dz, disease; DM, diabetes mellitus; CVD, cardiovascular disease; CKD, chronic kidney disease; HCQ, hydroxychloroquine; Mgt, management; Ox, oximetry. Reproduced from reference 3.

Given the long delays for randomized trials to be completed, analyzed, and reported, the data presented by Doi and colleagues are valuable support for the early ambulatory use of medications to reduce viral replication in SARS-CoV-2 infection. It is unlikely that any single drug alone will reduce hospitalization or death; however, drugs used in sequenced combination are likely to turn the tide against this deadly pandemic.