Infectious Disease

Flu treatment shift or drift? A focus on combination therapy

October 01, 2023

5 min read


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Ross reports no relevant financial disclosures.


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Influenza poses significant health and socioeconomic threats despite cases drastically dropping during the COVID-19 pandemic.

Jennifer Ross

Influenza vaccines, masking and other infection prevention methods are effective control measures. Still, threats of a severe influenza seasonal epidemic or pandemic persists because of antigenic mismatch between circulating viruses and vaccine strains, inadequate vaccine response among high-risk and immunocompromised patients, and the risk of zoonotic spillover to humans.


Antivirals have become a mainstay in influenza treatment to lessen viral replication and associated symptoms. Image: CDC

Antivirals have become a mainstay in influenza treatment to lessen viral replication and associated symptoms. Three classes of antiviral drugs — adamantanes, neuraminidase inhibitors and polymerase acidic endonuclease inhibitors — are approved for use in the United States. The efficacy of antiviral monotherapy — namely neuraminidase inhibitors such as oseltamivir, peramivir or zanamivir — in more severe infection and hospitalized patients is limited to observational studies.

The 2018 Infectious Diseases Society of America influenza guidelines recommend starting antiviral treatment with a single neuraminidase inhibitor as soon as possible in those who are hospitalized regardless of illness duration. The guidelines recommend against the use of combination therapy.

Combination antiviral therapy has improved clinical outcomes in other viral illnesses like HIV, hepatitis C and hepatitis B virus. Newer influenza agents with novel mechanisms of action expand the potential for combination therapy as a way to improve clinical outcomes, especially in severe disease.


Why combination therapy?

Seasonal influenza A or B infection have a wide range of manifestations, from asymptomatic infection to severe disease. As a single-stranded RNA virus, influenza’s lack of RNA polymerase proofreading during viral replication yields high mutation rates and a subsequent variation 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 can be infected with influenza multiple times over a lifetime and why influenza vaccine composition is reviewed annually. Antigenic shift causes an abrupt, major change resulting in new hemagglutinin and/or neuraminidase surface proteins. When antigenic shift happens, people often have little to no immunity. The constant evolution of the influenza virus continues to spark pursuit of combination antiviral therapy.

The paradigm of combination antivirals was explored in influenza as early as the 1970s. Several in vitro studies of dual antivirals have been published since, yet translation to improved efficacy and outcomes remains inconsistent. Combination therapy may reduce selection of antiviral resistance mechanisms. Resistant viral strains have been detected for all FDA-approved influenza antivirals. Adamantanes, which target the M2 proton channel of the influenza A viruses, now have limited clinical use because nearly all viruses have an M2 substitution that confers resistance. Combination antiviral therapy for HIV and HCV has been shown to decrease the selection of resistant viruses with optimal adherence. In addition, combination therapy may have the greatest benefit in high-risk groups, such as immunocompromised patients or severely ill patients, because extended antiviral durations may increase the probability of selecting for resistant viruses.

Other reasons driving interest in combination therapy include possible reduction in dosages that lower drug toxicity risks or adverse effects. However, combination therapy enhances the need for careful evaluation of drug-drug interactions. The possibility of reduced severe outcomes or complications of secondary infection with combination therapy is another possible advantage. Previous studies have shown shortened hospitalizations and reduced progression to severe disease with timely monotherapy; it will be important to compare these outcomes with combination therapy. An additional area of further examination is determining how in vitro antiviral combination synergistic effects (ie, viral load reduction) correlate to clinical outcomes and symptoms.



Kumar and colleagues performed a randomized, parallel-group, double-blind, placebo-controlled, superiority trial among hospitalized patients aged 12 years or older with severe influenza in 25 countries, called FLAGSTONE. They assigned patients to receive either 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 as a one-time dose, that was approved by the FDA in 2018 for the treatment of acute, uncomplicated influenza in patients aged 12 years or older who have been symptomatic for up to 48 hours.

The phase 3 CAPSTONE-1 and CAPSTONE-2 randomized controlled trials showed baloxavir led to faster symptom improvement and viral load reduction, as well as reduced complications among patients at high risk for influenza-associated complications, respectively, when compared with placebo. Additionally, the time to symptom improvement was similar between baloxavir and oseltamivir, with the greatest benefit occurring when the antivirals were given within 48 hours of symptoms.

In the FLAGSTONE trial, researchers administered baloxavir enterally on Day 1 for patients weighing between 40 kg and 80 kg, and on Days 1 and 4 for patients weighting greater than 80 kg. It was administered on Day 7 if no clinical improvement was seen at Day 5.

The study enrolled 366 patients up to 96 hours after symptom onset and randomly assigned them to either the baloxavir-oseltamivir group (n = 241) or the placebo-oseltamivir group (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), which all efficacy analyses were based on.

Of the 322 patents, 87% had an influenza A infection. Only 39% of patients in the baloxavir group received baloxavir within 48 hours of symptom onset. In all, 27 patients in the baloxavir cohort and 17 in the control group required ICU admission at baseline, with six and nine patients being mechanically ventilated, respectively.

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. Subanalyses, including time from symptom onset to study treatment and viral subtype, showed similar time to clinical improvement. The median time to cessation of viral shedding of culturable virus was significantly shorter in the baloxavir group (23.9 hours; 95% CI, 23.2-24.5) than the control group (63.7 hours; 95% CI, 46.4-68.1). Similar safety outcomes were seen between the two groups, with both being well-tolerated.

Combination therapy in the FLAGSTONE study did not result in improved clinical outcomes, even with the duration of viral shedding being longer in the control group. The timing of baloxavir administration — with most patients receiving it after 48 hours of symptom onset — may have impacted clinical outcomes.

Combination antiviral therapy aiming to rapidly inhibit viral replication may not be as efficacious in advanced, more severe disease. More investigation is needed to better understand the impact of combination therapy — especially baloxavir plus a neuraminidase inhibitor — among immunocompromised patients in whom prolonged viral shedding may be seen.

Although immunosuppression was not an exclusion criterion in the FLAGSTONE study, very few patients with this clinical characteristic were enrolled.

Combination antiviral therapy for influenza is not going to be the silver bullet, nor should it be administered per current guidelines until more robust, supportive data are published. As with other infections, a multipronged approach to optimally treating and managing influenza is needed. Development of new antivirals to combat the emergence of antiviral resistance is warranted.

Presently, influenza treatment drift is on the horizon, although a shift could take place with strategies that allow for earlier recognition, and subsequent treatment may not only improve antiviral efficacy, but also support key influenza infection prevention measures.


Jennifer Ross, PharmD, BCIDP, is an infectious diseases clinical pharmacist at M Health Fairview – University of Minnesota Medical Center. Ross can be reached at [email protected].


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