Two classes of antivirals are approved for the prevention and treatment of influenza: adamantanes (amantadine and rimantadine) and neuraminidase inhibitors (oseltamivir, zanamivir, and peramivir). However, because of high resistance rates (>99%), adamantanes are no longer recommended for prophylaxis or treatment of influenza A.1
For the 2017-2018 season, although the majority of circulating viruses were susceptible to the neuraminidase inhibitors, approximately 1% of the H1N1pdm09 viruses were resistant to oseltamivir and peramivir, but susceptible to zanamivir.2
Baloxavir marboxil (baloxavir) is an investigational antiviral with a novel mechanism of action that targets the influenza polymerase complex. Baloxavir is a small-molecule prodrug of the selective polymerase acidic protein inhibitor S-033447 and has activity against influenzas A and B, including strains with neuraminidase inhibitor resistance. Results of a phase 2 dose-escalating study and a phase 3 placebo and active control trial were recently published.
In the phase 2 trial, 400 patients diagnosed with influenza were randomized to a single dose of 10-, 20-, or 40-mg baloxavir or placebo. Influenza A(H1N1)pdm09 accounted for the majority of infections in all groups. The median time to symptom alleviation was 77.7 hours in the placebo group. Baloxavir at all doses significantly shortened time to symptom alleviation compared with placebo: 10 mg, 54.2 hours (P
= .009); 20 mg, 51.0 hours (P
= .02); and 40 mg, 49.5 hours (P
= .005). Viral titer reductions were significantly lower on days 2 and 3 compared with placebo. Adverse effects were similar across all groups, with 29.0% of placebo patients and 23.0% to 27.0% of baloxavir patients reporting adverse reactions. The authors chose baloxavir 40 mg for the phase 3 trial.3
The phase 3 trial randomized 1436 patients aged 12 to 64 years with influenza to a single dose of baloxavir 40 mg, oseltamivir 75 mg twice daily for 5 days, or placebo. All patients received matching placebos for a duration of 5 days to maintain blindness. Patients were well matched at baseline with influenza A(H3N2) accounting for the majority of infections. For the primary outcome of time to symptom alleviation, baloxavir-treated patients had shorter times compared with placebo (53.7 vs 80.2 hours; P
<.001), but were no different from oseltamivir (53.5 vs 53.8 hours, respectively). There also was a faster time to symptom resolution if patients started therapy within 24 hours of symptom onset compared with a delayed start, for the baloxavir and placebo groups: 32.8 versus. 13.2 hours, respectively.3
A concerning finding was the emergence of polymerase acidic protein variants with I38T/M/F substitutions in 2.2% and 9.7% of baloxavir recipients in the phase 2 and phase 3 trials, respectively. A I38T/M/F substitution results in decreased baloxavir susceptibility.3
Baloxavir has been fast tracked by the US Food and Drug Administration, with a potential decision by the end of the year. The possibility of a new antiviral class administered as a single oral dose that is well tolerated will be a welcome addition to the treatment armamentarium for influenza. However, its use should be limited to carefully selected individuals. Similar to the neuraminidase inhibitors, baloxavir’s efficacy is greatly enhanced in patients with early disease: within 24 hours versus within 48 hours for neuraminidase inhibitors. Thus far, baloxavir has only been studied in uncomplicated influenza.
The fact that a less susceptible strain was isolated in almost 10% of patients following a single dose is concerning. If approved, rather than using this drug in the first line, clinicians should reserve it for oseltamivir- and peramivir-resistant infections, in patients unable or unwilling to use the inhaled zanamivir.
1. Influenza antiviral medications: summary for clinicians. CDC website. cdc.gov/flu/professionals/antivirals/summary-clinicians.htm
. Updated February 23, 2018. Accessed September 11, 2018.
2. Summary of the 2017-2018 influenza season. CDC website. cdc.gov/flu/about/season/flu-season-2017-2018.htm
. Updated August 31, 2018. Accessed September 11, 2018.
3. Hayden FG, Sugaya N, Hirotsu N, et al; Baloxavir Marboxil Investigators Group
. Baloxavir marboxil for uncomplicated influenza in adults and adolescents. N Engl J Med
2018;379(10):913-923. doi: 10.1056/NEJMoa1716197.
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