COMMENT|ONLINE FIRST
Severe influenza: is there a role for antiviral combinations?
Siddharth Sridhar, Kelvin Kai-Wang To
Lancet Infect Dis Published:January 24, 2022
DOI:https://doi.org/10.1016/S1473-3099(21)00484-9
Neuraminidase inhibitors have been approved for over 20 years and are currently the standard of care for the treatment of influenza. However, meta-analyses have shown only modest benefit of neuraminidase inhibitors for influenza.1, 2 New treatment strategies for severe influenza are urgently required. A novel antiviral, baloxavir marboxil (baloxavir hereafter), was first approved in Japan in 2018, and subsequently in other countries. Baloxavir belongs to a new class of antivirals that inhibit the endonuclease function of the polymerase acidic protein.3 In a 2018 clinical trial,4 a single dose of baloxavir produced greater reductions in influenza viral load than did oseltamivir, with equivalent time to symptom alleviation.The combination of antivirals with different targets is an attractive strategy for improving treatment effectiveness in severe influenza. A previous study of combination therapy for influenza has yielded some success.5 The combination of baloxavir and neuraminidase inhibitors showed synergism in vitro.6 The FLAGSTONE study,7reported by Deepali Kumar and colleagues in The Lancet Infectious Diseases, investigated whether baloxavir and standard-of-care neuraminidase inhibitor combination therapy improves outcomes of severe influenza compared with neuraminidase inhibitors alone. Overall, the study found that the baloxavir–neuraminidase inhibitor combination was not superior to neuraminidase inhibitors alone in terms of reduction of median time to clinical improvement (97·5 h [95% CI 75·9–117·2] in the baloxavir–neuraminidase inhibitor group vs 100·2 h [95% CI 75·9–144·4] in the neuraminidase inhibitor group; median difference −2·7 h [95% CI −53·4 to 25·9], p=0·467). This observation held for a variety of subgroups based on age, time-to-treatment initiation, clinical severity, and influenza subtype (although most patients were infected with influenza A). However, patients treated with baloxavir–neuraminidase inhibitor generally cleared infectious virus from the upper respiratory tract sooner than did patients treated with neuraminidase inhibitor alone (23·9 h [95% CI 23·2–24·5] vs 63·7 h [95% CI 46·4–68·1]; p<0·0001). This finding is consistent with a previous study.4Kumar and colleagues' study is particularly relevant to clinical practice for several reasons. First, the trial recruited patients with severe influenza, a group for which current treatment protocols are inadequate. Second, the primary outcome of this study—time to clinical improvement—is a clinically relevant objective endpoint. Third, treatment was started at timepoints after symptom onset that closely reflect real-world situations. Fourth, the investigators opted for multiple doses of baloxavir, which is logical given the severity of infection and potentially higher viral loads predisposing to resistance after a single dose. Lastly, virological outcomes, emergence of resistance during treatment, safety, and drug pharmacokinetics were rigorously investigated.The disconnect between viral load reduction and clinical outcomes observed in Kumar and colleagues' study is probably explained by immunopathology and secondary bacterial infections driving poor influenza outcomes despite rapid virological clearance. Despite the non-superior clinical improvement in the baloxavir–neuraminidase inhibitor combination group, a rapid reduction in viral load is important for infection control. Lower viral load is associated with reduced transmissibility.8 The lower viral load in the baloxavir–neuraminidase inhibitor combination group might suggest that this combination therapy is potentially useful in outbreak situations, such as those in long-term care facilities. However, it is uncertain whether this treatment combination reduces viral loads more effectively than baloxavir alone.Another potential benefit of combination therapy is reduction in antiviral resistance, which is hinted at by Kumar and colleagues' study. A previous trial suggested that the clarithromycin–naproxen–oseltamivir combination therapy resulted in a lower rate of neuraminidase inhibitor-resistant influenza A H3N2 virus quasispecies than oseltamivir alone.5 In Kumar and colleagues' study,7 the rate of antiviral resistance was also lower for the baloxavir–neuraminidase inhibitor combination group (2·2%) versus the neuraminidase inhibitor group (4·2%). Baloxavir resistance after a single dose is well documented.4 It is uncertain whether multiple doses, the neuraminidase inhibitor, or both, reduced emergence of resistance mutations in the polymerase acidic protein.The results from Kumar and colleagues' trial echo those for another polymerase acidic protein inhibitor, pimodivir. A phase 3 trial comparing pimodivir plus standard-of-care neuraminidase inhibitor and standard-of-care neuraminidase inhibitor alone was halted due to lack of benefit.9 Kumar and colleagues' trial suggests the importance of careful clinical evaluation of antiviral combinations.Treatment success for severe influenza probably relies on both prompt viral load reduction and immunomodulation. The baloxavir–neuraminidase inhibitor combination therapy in the trial by Kumar and colleagues achieved viral load reduction effectively, but the journey to better clinical outcomes in severe influenza is clearly incomplete. Future investigational regimens would do well to borrow from experience gained from immunomodulation for severe COVID-19.10SS received speaker's honoraria from Abbott Laboratories. KK-WT has participated in trials involving baloxavir and neuraminidase inhibitors.
