Two Antivirals No Better Than One for Severe Flu

Adding baloxavir marboxil (Xofluza) to neuraminidase inhibitors (NAIs), like oseltamivir (Tamiflu), was no better for preventing severe outcomes among patients hospitalized for flu compared with NAIs alone, researchers found.

In a modified intention-to-treat analysis, there was no significant difference in time to clinical improvement among patients randomized to baloxavir plus NAIs (97.5 hours) compared with those randomized to placebo plus NAIs (100.2 hours; P=0.467), reported Nelson Lee, MD, of the University of Toronto in Canada, and colleagues, writing in Lancet Infectious Diseases.

While randomized trials were conducted on oseltamivir in outpatients or inpatients with influenza, Lee's group noted that most of the evidence on the agent's use in hospitalized and critically ill patients comes from observational studies, but "optimal treatment of [hospitalized] patients ... has not been established" from randomized trials, the authors added.

They also noted a similar lack of evidence in hospitalized patients with severe influenza for baloxavir, and noted that pre-clinical studies suggested that combining baloxavir and NAIs "can have synergistic effects on the inhibition of viral replication."

"Because [hospitalized] patients might have higher baseline viral loads and more prolonged viral replication, these patients could benefit from repeat dosing of baloxavir or combination therapy with baloxavir and oseltamivir," the researchers wrote.

The FLAGSTONE study was a randomized superiority trial across 25 countries, that included patients age 12 and up who were hospitalized with laboratory-confirmed influenza and had a National Early Warning Score (NEWS2) of 4 or more.

From January 8, 2019 to March 16, 2020, patients were randomized to receive either baloxavir plus NAIs or placebo plus NAIs. Baloxavir was administered enterally on day 1 and 4, and day 7 if there was no clinical improvement by day 5. NAIs were either oseltamivir, zanamivir (Relenza), or peramivir (Rapivab), based on local standard of care.

Primary outcome was time to clinical improvement.

The modified intention-to-treat population consisted of 208 patients in the intervention group and 114 in the control group. Patients were a mean age of 59-62, a little over half were male (52%-54%), and 73%-75% were white. About half (52%-53%) had pre-existing conditions. Thirty-seven percent of patients in the intervention group and 40% of those in the control group received oseltamivir within 48 hours of screening.

At day 1, 56% of patients were in a non-hospital ICU ward that required supplemental oxygen, but not invasive mechanical ventilation. Only 10%-13% were in the ICU at baseline.

Most patients in the intervention group (78%) received two doses of baloxavir, the authors noted.

While they added that there was no significant difference in the percentage of patients discharged up to day 14, the percentage was numerically higher for the intervention group versus controls (85% vs 77%, respectively). There were also no significant differences between groups in time to clinical response or time to hospital discharge.

Baloxavir was well tolerated, with the most common adverse events being pneumonia and constipation, the researchers said. There were slightly more serious adverse events occurring in the intervention group versus controls (15% vs 12%, respectively), and one case of orthostatic hypertension was considered to be related to the treatment. There were 11 deaths, but none were considered to be treatment-related.

'Particularly Relevant to Clinical Practice'

Despite the outcome, an accompanying editorial by Siddharth Sridhar, MBBS, and Kelvin Kai-Wang To, MD, of the University of Hong Kong, praised the study as "particularly relevant to clinical practice" for its study design.

They noted that the trial recruited patients with severe influenza, "for which current treatment protocols are inadequate," and examined time to clinical improvement, "a clinically relevant endpoint."

"Treatment was started at timepoints after symptom onset that closely reflect real-world situations," Sridhar and Wang To wrote.

The editorialists also addressed the issue of resistance, noting that giving multiple doses of baloxavir was "logical given the severity of infection and potentially higher viral loads predisposing to resistance after a single dose."

While adding baloxavir did not result in improved clinical outcomes, Sridhar and Wang To noted that combination antiviral therapy may lead to "a reduction in antiviral resistance." They cited the fact that antiviral resistance was lower for the baloxavir group (2.2%) compared with those receiving NAIs alone (4.2%).

"It is uncertain whether multiple doses, the neuraminidase inhibitor, or both, reduced emergence of resistance mutations in the polymerase acidic protein," the editorialists wrote.

Lee's group noted limitations to the data, including the heterogeneous population with multiple comorbidities, that enrollment cut-offs made it difficult to see if there were potential benefits of early versus late treatment and that it was not a true "treatment versus no treatment" trial, as it would be unethical to withhold treatment from this population.

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