Comparative Effectiveness of Combined Favipiravir and Oseltamivir Therapy Versus Oseltamivir Monotherapy in Critically Ill Patients With Influenza Virus Infection

Abstract

Background A synergistic effect of combination therapy with favipiravir and oseltamivir has been reported in preclinical models of influenza. However, no data are available on the clinical effectiveness of combination therapy in severe influenza. Methods Data from 2 separate prospective studies of influenza adults were used to compare outcomes between combination and oseltamivir monotherapy. Outcomes included rate of clinical improvement (defined as a decrease of 2 categories on a 7-category ordinal scale) and viral RNA detectability over time. Subhazard ratios (sHRs) were estimated by the Fine and Gray model for competing risks. Results In total, 40 patients were treated with combination therapy and 128 with oseltamivir alone. Clinical improvement on day 14 in the combination group was higher than in the monotherapy group (62.5% vs 42.2%; P = .0247). The adjusted sHR for combination therapy was 2.06 (95% confidence interval, 1.30–3.26). The proportion of undetectable viral RNA at day 10 was higher in the combination group than the oseltamivir group (67.5% vs 21.9%; P < .01). No significant differences were observed in mortality or other outcomes. Conclusions Favipiravir and oseltamivir combination therapy may accelerate clinical recovery compared to oseltamivir monotherapy in severe influenza, and this strategy should be formally evaluated in a randomized controlled trial.

A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19

“…The primary end point was the time to clinical improvement, defined as the time from randomization to an improvement of two points (from the status at randomization) on a seven-category ordinal scale or live discharge from the hospital, whichever came first. The end point of clinical improvement was used in our previous influenza study 17 and was also recommended by the WHO R&D Blueprint expert group. 18 Ordinal scales have been used as end points in clinical trials in patients hospitalized with severe influenza.…”

“…18 Ordinal scales have been used as end points in clinical trials in patients hospitalized with severe influenza. [16][17][18][19] The seven-category ordinal scale consisted of the following categories: 1, not hospitalized with resumption of normal activities; 2, not hospitalized, but unable to resume normal activities; 3, hospitalized, not requiring supplemental oxygen; 4, hospitalized, requiring supplemental oxygen; 5, hospitalized, requiring nasal high-flow oxygen therapy, noninvasive mechanical ventilation, or both; 6, hospitalized, requiring ECMO, invasive mechanical ventilation, or both; and 7, death.…”

Favipiravir, an anti-influenza drug against life-threatening RNA virus infections

“…Favipiravir is significantly more effective in treating mice with severe influenza infections characterized by a high viral load than oseltamivir (Takahashi, et al, 2003), and a J o u r n a l P r e -p r o o f Journal Pre-proof favipiravir-resistant virus does not emerge during treatment. This outstanding feature of favipiravir as an anti-influenza drug has been exploited in treating patients with severe influenza in combination with oseltamivir in China (Cao, 2018;Wang et al, 2019).…”

“…Some treatments were used in emergencies, and some were used in the setting of a clinical trial. In addition, combination therapy of favipiravir with the other existing therapies is also an option and favipiravir and oseltamivir combination therapy showed accelerated clinical recovery J o u r n a l P r e -p r o o f compared to oseltamivir monotherapy in severe influenza in China (Cao, 2018;Wang et al, 2019).…”

“…Then, chain elongation stops at the site of favipiravir incorporation, and elongation does not proceed because favipiravir functions as a chain terminator. This RNA-favipiravir(-RdRp) J o u r n a l P r e -p r o o f (Bai, et al, 2016;Bixler, et al, 2018;Jacobs, et al, 2015;Oestereich, Ludtke, et al, 2014;Sissoko, et al, 2016;Smither, et al, 2014) Severe fever with thrombocytopenia syndrome (SFTS) caused by a virus infection 12-30% b (Gowen, Westover, Miao, et al, 2017a;Tani, et al, 2016;Yasukawa, 2016) Severe influenza (Cao, 2018;Wang et al, 2019) Lassa virus infection 1% a , severe cases 15% a (Gowen, Westover, Sefing, et al, 2017b;Mendenhall, et al, 2011;Oestereich, et al, 2016;Raabe, et al, 2017;Safronetz, et al, 2015) Rabies Approximately 100% a, b (Baker, 2017;Yamada, Noguchi, Komeno, Furuta, & Nishizono, 2015) Norovirus infection 50,000 deaths/year b (Arias, Thorne, & Goodfellow, 2014;Ruis, et al, 2018) Avian influenza A(H5N1) 52.8% (Sep 9, 2019) a Favipiravir is effective against influenza in animals and humans and has…”