Influenza Antivirals Perform Similarly Compared With Placebo

Tara Haelle

August 20, 2021

Although four different antiviral drugs for influenza successfully reduced the time it took to relieve symptoms, zanamivir outperformed the others by alleviating symptoms fastest, according to a meta-analysis published in the August issue of JAMA Open Network.

The study compared the four most commonly used drugs for influenza: three neuraminidase inhibitors and the endonuclease inhibitor baloxavir marboxil.

"The outcomes for all of the antiviral agents were similar for time to alleviation of influenza symptoms, except for 10 mg zanamivir compared with 40 mg or 80 mg baloxavir," report Jen-Wei Liu, PhD, from the Taipei Medical University School of Pharmacy in Taiwan, and his colleagues. "Based on moderate-quality evidence, 40 mg or 80 mg baloxavir was associated with fewer complications of influenza compared with placebo."

The study's conclusions, however, are limited by the few head-to-head comparisons between agents and the inclusion of studies with very different populations, pointed out Anthony Flores, MD, PhD, chief of pediatric infectious diseases at McGovern Medical School at UTHealth and a physician at Children's Memorial Hermann in Houston.

"It's important to note that in this study, versus placebo, all the studies examined showed significant decreases in time to alleviate symptoms in the agent tested," Flores, who was not involved in the study, told Medscape Medical News. The few studies that did compare agents with one another rarely found any significant differences, Flores added.

"Early treatment is key to alleviation of symptoms," Flores said. "Regardless of the agent used, the greatest benefits are seen when given within the first 48 hours of symptoms."

The researchers used Medline, Embase, and the Cochrane register of clinical trials to identify randomized controlled trials published before January 2020 that tested the efficacy of endonuclease or neuraminidase inhibitors against placebo or another drug in patients with influenza. The researchers included studies on baloxavir and on the neuraminidase inhibitors oseltamivir, peramivir, and zanamivir; they found no studies with efficacy data on laninamivir.

The researchers analyzed data from 26 randomized controlled trials that involved 11,897 patients with an average age of 32 years. Five trials involved only children and 12 involved only adults. They focused on three outcomes: time to alleviation of influenza symptoms, complications of influenza, and total adverse events related to the antiviral.

Among all the treatment tested against placebo, zanamivir 10 mg had the shortest time to alleviation of symptoms, with a 33% reduction in the relative risk for symptoms (hazard ratio [HR], 0.67). The other agents showed similar reductions but with statistically insignificant differences: peramivir 600 mg (HR, 0.69), oseltamivir 75 mg (HR, 0.74), oseltamivir 150 mg (HR, 0.75), peramivir 300 mg (HR, 0.75), and baloxavir 40 mg or 80 mg (HR, 0.79).

Baloxavir (40 mg or 80 mg) was associated with the lowest risk for flu-related complications, reducing relative risk by 49% (risk ratio, 0.51). Oseltamivir reduced the risk for flu-related complications by 39% at 75 mg and by 35% at 150 mg, and peramivir reduced the risk by 33% to 35%, depending on dosage. Zanamivir reduced the risk for flu-related complications by 18%.

Baloxavir also had the lowest risk for overall adverse events, compared with placebo, with a 16% lower likelihood of adverse events than placebo. However, "there were almost no differences among the multiple treatment comparisons," the authors noted. Peramivir 600 mg had the most adverse events.

The only antiviral with a statistically significant likelihood of causing nausea or vomiting was oseltamivir 75 mg, which increased the relative risk for nausea by 82% and for vomiting by 88%. Compared with oseltamivir, zanamivir was 70% less likely and baloxavir was 53% less likely to cause nausea.

Differences in Study Populations, Routes of Administration

The researchers note that their findings were limited by the various definitions of complications in the studies and a general dearth of studies on some of the antiviral agents. But Flores noted that the authors did not take into account the differences in study populations, including their degree of illness, which makes "direct comparisons outside of a clinical trial difficult."

"For example, in the CAPSTONE-2 trial referenced in the analysis, the majority of patients had underlying disease, such as diabetes, asthma, and obesity, or were over 65 years. Thus, this patient population may have benefited more no matter what agent was used," Flores told Medscape Medical News. "Further, in the comparison of baloxavir and oseltamivir in complications from influenza, there were no significant differences."

It is also important to consider the route of administration for different drugs, Flores said.

"Of the neuraminidase inhibitors, oseltamivir is the only oral agent; zanamivir is inhaled and peramivir is a single IV dose," he said. "Most providers prefer oseltamivir due to availability and more experience using it.” Baloxavir, meanwhile, is the newest agent, having only been approved in 2018, "and to date, only two clinical trials have been performed, showing no significant benefit over the use of oseltamivir," he said. "Baloxavir shows promise, but more time is needed to see if it's preferred over oseltamivir."

An outstanding issue not addressed by the meta-analysis, Flores said, is what benefits might result from combination therapy.

"Baloxavir has a novel mechanism of action, and there is a lot of interest to know if combination with oseltamivir in hospitalized or immunocompromised patients would show greater efficacy," he said.

Finally, Flores noted that choices are more limited for children. Oseltamivir is almost exclusively used, he said, and baloxavir is not approved for children younger than 12 years or weighing less than 40 kg (88 pounds). Zanamivir is only approved for children older than 5 years and is inhaled, so it be should be avoided in those with a history of asthma, he said.

The authors noted no source of funding. The authors and Flores reported no disclosures.

JAMA Netw Open. 2021;4(8):e2119151. Full text

Tara Haelle is a Dallas-based science and medical journalist.

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