Which Influenza Antivirals Are Actually Helping Patients?

Antivirals recommended by the Centers for Disease Control and Prevention (CDC) for treating influenza showed little benefit for nonsevere cases in a systematic review and meta-analysis published in JAMA Internal Medicine.

Oseltamivir (Tamiflu) and zanamivir (Relenza) had little to no effect on mortality, hospitalization rates, or symptom duration. Peramivir (Rapivab) had little to no impact on mortality rates and symptom duration and had no data available for its effect on hospitalization rates. However, one drug showed some promise.

Researchers used a grading method to assign each drug and its corresponding outcome a level of certainty based on consistency of results across studies and risk for bias, among other factors. “Low,” “medium,” and “high” were indicated to help clinicians in making treatment decisions.

Baloxavir (Xofluza) reduced hospitalization rates for high-risk patients but with a “low certainty” of evidence, and it reduced symptom duration by a day compared with standard care or a placebo with moderate certainty. The drug had no effect on mortality.

The analysis included 73 randomized controlled trials published between 1971 and 2023, consisting of 34,332 participants with nonsevere influenza, defined as those not requiring hospitalization in the initial 2-day onset of symptoms. The study looked at influenza antivirals available globally, four of which are approved by the US Food and Drug Administration.

Baloxavir did not increase adverse side effects such as gastrointestinal symptoms, neurologic symptoms, or respiratory symptoms. But the drug may have led to antiviral resistance in 10% of the patients, the researchers said.

“Our findings support the use of baloxavir for treatment of high-risk patients with nonsevere influenza,” wrote the study authors. They suggested monitoring resistance to the drug.

Regarding baloxavir, “prevention of hospitalization in and of itself is a worthy goal, even without evidence of decreased mortality,” said Laura Polito, MD, a family medicine physician and associate medical director of Urgent Care at the University of Washington Medicine in Seattle, who was not involved in the study. “For this point, the quality of evidence is not as good, but as baloxavir has fewer adverse events, the risk/benefit ratio is still good.”

Meanwhile, oseltamivir likely increased adverse side effects, the study showed.

Polito said she sparingly uses oseltamivir in her practice, even though it costs about $50 even without insurance.

And while baloxavir showed the best results in the analysis, she said not many pharmacies carry the drug, not many insurers cover it, and out-of-pocket costs can average $200 without insurance.

“When people come into urgent care, they feel terrible, and they’d like treatment,” Polito said. “We sit down with them and talk about the fact that there’s not good data for these medications. Oseltamivir has bad gastrointestinal effects, which nobody wants, and baloxavir is difficult to get, very expensive, and also doesn’t have much of a beneficial effect.”

“Moderate certainty” evidence indicated that zanamivir decreased symptoms by 0.68 days, and “high certainty” evidence indicated the drug had little to no effect on hospital admissions for high-risk patients and low-risk patients. A “high certainty” of evidence indicated that zanamivir had little to no impact on mortality rates for high- or low-risk patients.

The researchers found no data for peramivir’s impact on hospital admission rates. “Low certainty” evidence indicated peramivir reduced symptoms by less than a day. The drug had little impact on mortality rates for all patients with a high certainty.

Zanamivir and peramivir had little to no impact on adverse effects, both with a low certainty of evidence.

“I must admit that I am surprised by the findings because based on the recommendations from the WHO and CDC, I had trusted that antivirals would be effective against influenza,” said Maja Artandi, MD, professor of medicine in the Division of Primary Care and Population Health at Stanford University in Stanford, California.

“It seems as though for years, we have relied on medications that often fall short in effectiveness and, in some cases, may even come with undesirable side effects. It is frustrating that we don’t seem to have more effective medication to treat a potentially serious illness.”

Artandi said she uses oseltamivir exclusively in her practice. Based on the study, she said she will start prescribing baloxavir more frequently, but insurance coverage may be a barrier.

Arthi Balu, MD, associate clinical professor of medicine at the University of California, San Diego, questioned the study’s implications for oseltamivir.

“This meta-analysis seems to suggest that Tamiflu basically has no benefit whatsoever,” said Balu.

She said that while she is aware of Tamiflu’s limited efficacy in many patients, she sees value for high-risk patients such as the elderly or chronically ill.

“I’m not convinced by this meta-analysis to change my practice,” Balu said.

This study was supported by the World Health Organization (WHO). Gordon Guyatt was the method chair for the WHO guideline panel. No other disclosures reported.

Brittany Vargas is a medicine, mental health, and wellness journalist.