Key Updates to Influenza Management

Influenza is a common topic among pharmacists in the winter months. For many years, the focus of the conversation seemed to center on vaccines or the limited availability of treatment options. In recent years, new medications and new data have emerged that may change the way we approach this common, underappreciated, and burdensome virus. At the recent ASHP (American Society of Health-System Pharmacists) 54th Midyear Clinical Meeting & Exhibition in Las Vegas, Nevada, 3 speakers discussed new developments in influenza management.

One frequent topic of discussion on antivirals involves timing of initiation. All current influenza antivirals are recommended for initiation in outpatients with symptoms present for less than 48 hours. According to Tiffeny Smith, PharmD, BCIDP, early treatment not only reduces influenza symptoms by 1-2 days, it has been shown to reduce the risk of complications, hospitalizations, and death in high-risk patients.¹

Some studies indicate that high-risk patients can benefit from antiviral therapy even when treatment initiation does not occur until up to 5 days after symptom onset. The benefit of antiviral therapy initiation beyond 48 hours appears to extend to hospitalized patients as well. Hospitalized patients who were started on late antiviral therapy still had better clinical outcomes than those who did not receive antivirals, including a decreased hospital length of stay.²

The role of intravenous antivirals was further discussed by Janessa Smith, PharmD, BCPS-AQ ID.² Oseltamavir is the only option recommended for hospitalized patients, but interest in intravenous alternatives has been increasing due to the desire to have a nonoral option for patients unable to take medications by the oral or enteral route.

Currently peramivir, the only available IV antiviral, is FDA-approved for outpatient treatment. A 2014 phase 3 study of inpatients that were hospitalized within 72 hours of symptom onset showed no significant differences in time to clinical resolution or changes in virus titer within 48 hours of treatment initiation when compared to placebo. ²

A second phase 3 study compared intravenous zanamivir (not available in the United States) to oral oseltamivir in hospitalized patients that were within 24 hours of fever onset and within 6 days of other symptom presentation. There were no significant differences between the 2 treatments among time to clinical resolution, hospital length of stay, or ICU length of stay. ² Results remained similar in subgroups evaluating ICU patients and those who symptom onset was 4 or fewer days. ²

Edina Avidic, PharmD, MBA, BCPS-AQ ID completed the session by discussing the newest anti-influenza treatment—baloxavir marboxil—and emerging therapies under investigation.³ The 1-dose prodrug approved in October of 2018 is a first-in-class medication that works by inhibiting viral replication. Like the other recommended antivirals, it is active against both influenza A and B, and appears to have synergistic activity with neuraminidase inhibitors. Though originally approved for uncomplicated influenza in otherwise healthy patients aged 12-64 years, baloxavir received an FDA indication for high-risk patients, including those over the age of 65 years, in 2019. In clinical studies, baloxavir has shown a significantly shorter median time to symptom alleviation compared to placebo, and was similar to oseltamivir.

In the Capstone-2 study that evaluated high-risk patients, the median time to symptom improvement in patients with influenza B was 26 hours shorter with baloxavir compared to oseltamivir (p<0.05), and the median time to cessation of viral shedding in all patients was 48 hours shorter in baloxavir-treated patients than in those that received oseltamivir. The time to both symptom improvement and viral shedding cessation was similar between oseltamivir and placebo. Though more studies are needed to confirm this finding, it suggests that baloxavir may be more beneficial in patients with influenza B. Though not approved for prophylaxis, the impact on viral shedding may be an early indication of baloxavir’s potential for reducing influenza transmission. Faster clearance of the virus decreases the potential for transmission.

The unpublished phase 3 Blacksone study supports baloxavir’s role in influenza prophylaxis. In this randomized, placebo-controlled trial, household contacts who received a single dose of baloxavir were significantly less likely to develop influenza than those who received placebo (1.9% vs. 13.6%; p<0.0001). Baloxavir is not currently approved in the United States for those under age 12, but a 2019 study conducted in Japan of patients aged 1-11 years suggests that it may be safe and effective in younger children. Efficacy and safety outcomes were comparable to that seen in the studies evaluating older patients.

To date, all of the published data on baloxavir involves outpatients with influenza. An ongoing study of a 3-dose baloxavir regimen in combination with a neuraminidase inhibitor vs. neuraminidase monotherapy may define baloxavir’s role in complicated, severe influenza. Unfortunately, it unclear when the results of that study will be available; therefore at this time, oseltamivir continues to be the primary agent for those with severe enough illness to require hospitalization.

The session concluded with the discussion of 2 investigational antivirals. ³ Pimodivir inhibits the PB2 subunite of viral polymerase complex, while favipiravir inhibits the PB2 subunit of the same complex. Both antivirals are being evaluated in oral and parenteral formulations in 5-day regimens, but have key differences in their microbiology, pharmacokinetic, and safety profiles.

Pimodivir is only active against Influenza A, while favipiravir exhibits activity against both influenza A and B. Gastrointestinal upset appear to be the most common adverse effects with both agents, but the incidence appears to be notably higher with pimodivir in diarrhea (17% vs. 6.3%, nausea, 4% vs. 0.8%) and vomiting (3% vs. 0.5%). However, favipiravir may be impacted more by kidney dysfunction and is teratogenic, 2 characteristics that may limit its application in clinical practice. ³

The influx of new medications, and new data on old medications for influenza is welcome news on the common viral infection where treatment and prevention options appeared to be stagnant for many years. For the first time, an oral alternative to oseltamivir is available for most outpatients, and more alternatives and additional uses of current medications are under investigation. While more data and evaluation is still needed to make more complete roles in therapy determinations, the emerging research and attention on antivirals for influenza suggests that the approach to treatment and prevention of the virus may be remarkably different in not too distant future influenza seasons.

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REFERENCES

• Smith TT. (2019, December). Overview of influenza and treatment considerations. Presented at: ASHP (American Society of Health-System Pharmacists) Midyear Clinical Meeting & Exhibition; Las Vegas, Nevada. December 8-12, 2019.
• Smith JM. (2019, December). Oral vs. intravenous neuraminidase inhibitors: does it matter? Presented at: ASHP (American Society of Health-System Pharmacists) Midyear Clinical Meeting & Exhibition; Las Vegas, Nevada. December 8-12, 2019.
• Avdic E. (2019, December). New antiviral(s): game changer in influenza treatment. Presented at: ASHP (American Society of Health-System Pharmacists) Midyear Clinical Meeting & Exhibition; Las Vegas, Nevada. December 8-12, 2019.