Most Antiviral Drugs Showed Limited or No Effects Against Flu

Antiviral drugs commonly used to treat non-severe influenza appeared to have little or no effect on key clinical outcomes, except for baloxavir (Xofluza), according to a systematic review and meta-analysis of 73 randomized trials.

Compared with standard care or placebo, all antiviral drugs had little or no effect on mortality for low- and high-risk patients (all high certainty), but baloxavir likely reduced risk of hospital admission in high-risk patients (risk difference [RD] -1.6%, 95% CI -2.0 to 0.4; low certainty) and probably reduced symptom duration (mean difference -1.02 days, 95% CI -1.41 to -0.63; moderate certainty), reported Qiukui Hao, MD, of McMaster University in Hamilton, Ontario, and colleagues.

However, baloxavir may have resulted in treatment resistance in approximately 10% of those treated, the authors noted in JAMA Internal Medicine, which means that monitoring for drug resistance may be needed.

Also of note, oseltamivir (Tamiflu) had little or no effect on risk for hospital admission in high-risk patients (RD -0.4%, 95% CI -1.0 to 0.4; high certainty), and all the other antivirals included in the study had little effect or an uncertain effect. Oseltamivir also likely had no important effect on symptom duration (mean difference -0.75 days, 95% CI -0.93 to -0.57; moderate certainty).

For adverse events related to treatment, baloxavir (RD -3.2%, 95% CI -5.2 to -0.6; high certainty) had few or no adverse events, and oseltamivir (RD 2.8%, 95% CI 1.2-4.8; moderate certainty) likely increased adverse events.

Antiviral drugs such as neuraminidase inhibitors (oseltamivir) and selective cap-dependent endonuclease inhibitors (baloxavir) “may play a role in reducing illness duration, preventing serious complications, and lowering morbidity and mortality, particularly in high-risk populations,” Hao and team wrote, adding that the World Health Organization (WHO) released guidelines for the clinical management of severe illness caused by influenza in 2022, which conditionally recommended the use of oseltamivir.

In an accompanying editor’s note, Deborah Grady, MD, MPH, of the University of California San Francisco, and colleagues noted that they “found it surprising that antivirals seem to make little difference for individuals with influenza in outpatient settings, even in the optimized setting of randomized clinical trials,” given that guidance from the CDC and other organizations encourages treatment with antivirals for influenza.

“For outpatients with risk factors, as well as their household contacts, antiviral therapy is recommended on the basis that it might help,” they wrote. “For outpatients without risk factors, antiviral therapy may nonetheless be prescribed based on clinical judgment. In either case, pressure to start treatment as early as possible means that antivirals are often prescribed without diagnostic testing for influenza or thoughtful consideration of their benefits and risks.”

A factor that should be considered when prescribing antivirals is the out-of-pocket costs for patients, Grady and colleagues added. Oseltamivir may be covered by insurance, but there may be a substantial copay. No generic is available for baloxavir.

For this systematic review and meta-analysis, Hao and colleagues searched several databases for randomized trials up to September 2023 that compared direct-acting influenza antiviral drugs to placebo, standard care, or another antiviral drug for treating people with nonsevere influenza. Overall, 73 trials with 34,332 participants were eligible.

In addition to baloxavir and oseltamivir, the researchers included several other drugs in their analysis, including zanamivir, amantadine (Symmetrel), rimantadine (Flumadine), and laninamivir (never approved in the U.S.).

They noted that event rates were often very low for some patient outcomes, including mortality and hospitalization, which was a limitation to their study. In addition, many of the included studies may have lacked the power to detect these outcomes, and even pooled analyses may have insufficient statistical power to accurately evaluate antiviral effects, they said.