Shift or drift in flu treatment?Focus on combination therapy

October 1, 2023

5 min read


Disclosure: Ross did not report related financial disclosures.

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Despite a significant decline in cases during the COVID-19 pandemic, influenza still poses a significant health and socioeconomic threat.

Jennifer Ross

Infection prevention methods such as influenza vaccines and masks are effective control measures. Nonetheless, the threat of severe seasonal or pandemic influenza remains due to antigenic mismatches between circulating viruses and vaccine strains, inadequate vaccine responses in high-risk and immunocompromised patients, and the risk of zoonotic spread to humans. .

Antiviral drugs have become the mainstay of influenza treatment, reducing viral replication and associated symptoms. Image: Centers for Disease Control and Prevention

Antiviral drugs have become the mainstay of influenza treatment, reducing viral replication and associated symptoms. Three classes of antiviral drugs—adamantane, neuraminidase inhibitors, and polymerase acid endonuclease inhibitors—are approved for use in the United States. The efficacy of antiviral monotherapy (ie, neuraminidase inhibitors such as oseltamivir, peramivir, or zanamivir) in more severe infections and hospitalized patients is limited to observational studies.

The 2018 Infectious Disease Society of America influenza guidelines recommend that antiviral therapy with a single neuraminidase inhibitor should be initiated as soon as possible in hospitalized patients regardless of illness duration. The guidelines recommend against the use of combination therapy.

Combination antiviral therapy improves clinical outcomes in other viral diseases such as HIV, hepatitis C, and hepatitis B virus. New influenza drugs with novel mechanisms of action expand the potential of combination therapies as a way to improve clinical outcomes, particularly in severe disease.

Why combine treatment?

Seasonal influenza A or B infection can manifest in many forms, from asymptomatic infection to severe illness. As a single-stranded RNA virus, influenza lacks RNA polymerase proofreading during viral replication, resulting in high mutation rates and subsequent changes in disease severity. Antigenic drift results in single point mutations that lead to changes in surface proteins called hemagglutinin and neuraminidase. Antigenic drift is an important reason why people get the flu multiple times throughout their lives and why flu vaccine ingredients are reviewed annually. Antigenic shift results in sudden major changes resulting in the generation of new hemagglutinin and/or neuraminidase surface proteins. When antigenic shift occurs, people often have little immunity. The ongoing evolution of influenza viruses continues to inspire the pursuit of combination antiviral therapies.

The paradigm of combination antiviral drugs was explored for influenza as early as the 1970s. Several in vitro studies of dual antiviral agents have since been published, but translation of improved efficacy and outcomes remains inconsistent. Combination therapy may reduce the selection of antiviral resistance mechanisms. Drug-resistant strains of the virus have been detected in all FDA-approved influenza antivirals. Adamantane drugs target the M2 proton channel of influenza A virus and currently have limited clinical application because almost all viruses have M2 substitutions, leading to drug resistance. Combination antiviral therapy for HIV and HCV has been shown to reduce the selection of drug-resistant viruses and have optimal compliance. Furthermore, combination therapy may have the greatest benefit in high-risk groups (e.g., immunocompromised patients or critically ill patients), as prolonged antiviral duration may increase the likelihood of selection of drug-resistant viruses.

Other reasons for interest in combination therapy include the possibility of dose reduction to reduce the risk of drug toxicity or adverse effects. However, combination therapy increases the need for careful evaluation of drug-drug interactions. Combination therapy may reduce the serious consequences or complications of secondary infection, which is another possible advantage. Previous studies have shown that prompt monotherapy shortens hospital stay and reduces disease progression; it will be important to compare these results with combination therapy. Another area for further examination is determining how the synergistic effects (i.e., viral load reduction) of in vitro antiviral combinations relate to clinical outcomes and symptoms.

slate study

Kumar and colleagues conducted a randomized, parallel-group, double-blind, placebo-controlled superiority trial, called FLAGSTONE, in hospitalized patients aged 12 years or older with severe influenza in 25 countries. They had patients receive baloxavir plus a neuraminidase inhibitor or placebo plus a neuraminidase inhibitor between January 2019 and March 2020.

Baloxavir marboxil is a cap-dependent endonuclease inhibitor administered in a single dose and was approved by the FDA in 2018 for the treatment of acute, uncomplicated influenza.

The Phase 3 CAPSTONE-1 and CAPSTONE-2 randomized controlled trials showed that compared with placebo, baloxavir improved symptoms more quickly, reduced viral load, and reduced complications in patients at high risk for influenza-related complications, respectively. In addition, the time to symptom improvement was similar for baloxavir and oseltamivir, with the greatest benefit when antiviral drugs were taken within 48 hours of symptom onset.

In the FLAGSTONE trial, investigators administered baloxavir enterally on day 1 to patients weighing 40 kg to 80 kg and on days 1 and 4 to patients weighing >80 kg. Loxavir. If no clinical improvement is seen on day 5, dose on day 7.

The study enrolled 366 patients within 96 hours of symptom onset and randomly assigned them to baloxavir-oseltamivir (n = 241) or placebo-oseltamivir (n = 125) . Of these, 322 patients were included in the modified intention-to-treat population (208 in the baloxavir group and 114 in the control group), on which all efficacy analyzes were based.

Of the 322 patients, 87% had been infected with influenza A. Only 39% of patients in the baloxavir group received baloxavir within 48 hours of symptom onset. Overall, 27 patients in the baloxavir cohort and 17 patients in the control group required ICU admission at baseline, with 6 and 9 patients, respectively, receiving mechanical ventilation.

The median time to clinical improvement was 97.5 hours (95% CI, 75.9-117.2) in the baloxavir group and 100.2 hours (95% CI, 75.9-144.4) in the control group. Subgroup analyses, including time from symptom onset to study treatment and viral subtype, showed similar times to clinical improvement. The median time to cessation of shedding of culturable virus was significantly shorter in the baloxavir group (23.9 hours; 95% CI, 23.2-24.5) than in the control group (63.7 hours; 95% CI, 46.4-68.1). Safety results were similar between the two groups and well tolerated.

Combination therapy in the FLAGSTONE study did not improve clinical outcomes, even though viral shedding lasted longer in the control group. The timing of baloxavir administration (most patients received it 48 hours after the onset of symptoms) may affect clinical outcomes.

Combination antiviral treatments designed to rapidly suppress viral replication may not be as effective in advanced, more severe disease. Additional studies are needed to better understand the impact of combination therapy, particularly baloxavir plus neuraminidase inhibitors, in immunocompromised patients who may experience prolonged viral shedding.

Although immunosuppression was not an exclusion criterion in the FLAGSTONE study, patients with this clinical profile were rarely included.

Combination antiviral therapy for influenza will not be a panacea and should not be treated in accordance with current guidelines until more reliable supporting data are released. As with other infections, a multi-pronged approach is needed to optimize treatment and management of influenza. There is a need to develop new antiviral drugs to combat the emergence of antiviral resistance.

Currently, a drift in influenza treatment is imminent, although this can be shifted through strategies that allow for early identification and subsequent treatment to not only improve antiviral efficacy but also support critical influenza infection prevention measures.

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Jennifer Ross, PharmD, BCIDP, is an infectious disease clinical pharmacist at M Health Fairview, University of Minnesota Medical Center. Ross can be reached at

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