Two Drugs Better Than One for Severe Influenza

Ricki Lewis, PhD

December 16, 2019

Taking two antivirals ― favipiravir and oseltamivir ― was more effective for treating severe influenza than taking oseltamivir alone, according to a comparison of results from two clinical trials published online December 11 in the Journal of Infectious Diseases.

Preclinical studies suggest synergy between favipiravir (Avigan, Toyama Chemical) and oseltamivir (Tamiflu, Genentech) as combination therapy to treat severe influenza, but the effectiveness of the drug combination has not been evaluated in controlled clinical trials.

Each year, approximately 300,000 to 650,000 people die from seasonal influenza. The only drug in widespread use, the neuraminidase inhibitor (NAI) oseltamivir, is of limited use, and its efficacy for severe cases has not been adequately studied. Adding an antiviral that works by a different mechanism might boost effectiveness, especially for the most compromised patients.

Favipiravir works differently from oseltamivir, targeting a viral RNA polymerase rather than the neuraminidase. In vitro studies have shown favipiravir to work synergistically with oseltamivir against influenza A viruses, and the combination has been shown to be effective late in the disease course for a strain of mice with lethal influenza A (H5N1) infection.

Yeming Wang, from the Chinese Academy of Medical Sciences in Beijing, and colleagues compared findings from two prospective studies involving patients hospitalized for influenza: the "combination study" used both drugs, and the "monotherapy study" used only oseltamivir for patients who had community-acquired pneumonia and influenza.

For both studies, outcomes included the rate of clinical improvement (a decrease of two categories on a seven-category scale) and detection of viral RNA over time. Risks were compared by calculating the subhazard ratio (sHR).

The combination study assessed 40 patients from February 2018 through 2019 at tertiary critical care centers in China. Participants had a positive rapid influenza A or B test result, were in respiratory failure (PaO2/FiO2 ≤ 300 mmHg or receiving mechanical ventilation) and had been ill for 10 or fewer days. They received oseltamivir 75 mg for 10 days and either of two regimens of favipiravir (1600 mg BID on day 1 and 600 mg BID on days 2 to 10, or 1800 mg BID on day 1 and 800 mg BID on days 2 to 10).

The 128 patients in the oseltamivir monotherapy group were part of a prospective multicenter observational study of community-acquired pneumonia and had laboratory-confirmed influenza. They were treated at a hospital in mainland China between October 2016 and February 2019.

To align the investigations, the researchers applied the three criteria of laboratory-confirmed diagnosis, respiratory failure, and symptoms for 10 or fewer days.

The primary clinical outcome was time to improvement after starting therapy, up to 28 days. That meant either hospital discharge or improvement on two of seven measures: not hospitalized with resumption of normal activities; not hospitalized but unable to resume normal activities; hospitalized but not requiring supplemental oxygen; hospitalized but requiring supplemental oxygen; hospitalized, with nasal high-flow oxygen therapy and/or noninvasive mechanical ventilation; hospitalized, with ECMO (extracorporeal membrane oxygenation) and/or invasive mechanical ventilation; and death.

The primary virologic endpoints were the proportion of patients whose nasopharyngeal swab test results were negative for influenza on days 2, 5, 7, and 10 after starting treatment.

On day 14, clinical improvement was greater among the patients who received both drugs (62.5% vs 42.2%; P = .0247), with adjusted sHR for combination therapy of 2.06. In addition, the proportion of patients with undetectable viral RNA at day 10 was higher in the combination group than in the monotherapy group (67.5% vs 21.9%; P < .01). Mortality did not differ.

"Our findings suggest that favipiravir and oseltamivir combination therapy may be associated with greater antiviral effects and faster clinical improvement in severe influenza" than monotherapy, the researchers conclude. They suggest that a double-blinded, randomized controlled clinical trial be conducted to confirm the finding.

The dual-drug approach could address "the relatively high frequency of emergence of oseltamivir-resistant [viral] variants in critically ill patients and their association with poor outcomes," the researchers write. In addition, results of the use of antibody-based therapies given with NAIs have been disappointing. Studies of other polymerase inhibitors (pimodivir and baloaxavir) given with NAIs to treat severe influenza in hospitalized patients are underway.

Study limitations include the retrospective design, small groups, and not analyzing coverage of influenza B strains.

The researchers have disclosed no relevant financial relationships.

J Inf Dis. Published online December 11, 2019. Abstract

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