key: cord-0703042-jh4amjwa
authors: Tillotson, Glenn S
title: A new dawn for the management of influenza?
date: 2020-06-08
journal: Lancet Infect Dis
DOI: 10.1016/s1473-3099(20)30459-x
sha: cc7e2aafee00f0bd7a2babfcf7423c5e4e055985
doc_id: 703042
cord_uid: jh4amjwa

nan

At the time of writing, coronavirus disease 2019 (COVID-19) is the world's focus with a global incidence of more than 4 million cases and more than 300 000 deaths. The USA is the epicentre of the pandemic with more than 1·2 million cases and over 80 000 deaths. These numbers are probably underestimates. However, despite these very troubling times, putting these numbers into some context via a comparison with influenza might be useful. Influenza first gained global notoriety in 1918 when it was described as causing "havoc, death and desolation of a society fighting a war against nature". 1 Descriptions of the 1918 influenza pandemic are reminiscent of the pneumonic plague or even poison gas because of the extremely severe illness it caused. 1 Even today, some influenza infections remain serious. The burden of influenza worldwide is staggering, with pneumonia and influenza the leading causes of death from infectious diseases in the USA. Recent estimates regarding influenza in the USA are remarkable and thoughtprovoking in an era of vaccines. In 2017-18, the number of reported infections was 45 million, and although this number decreased in 2018-19, more than 35 million cases were recorded in that year. The number of hospital admissions associated with influenza was 810 000 in 2017-18 and 490 000 in 2018-19, with 61 099 deaths in 2017-18 and 34 200 deaths in 2018-19. 2 In addition to this health burden, influenza is responsible for substantial economic burden: in 2003, influenza-related costs in the USA were estimated to be US$100 billion in direct medical costs, with an overall economic burden amounting to $87·1 billion, calculated on the basis of projected earnings. 3 Influenza can be grouped into subgroups A H1N1, A H3, A not subgrouped, and B. These subtypes have distinct geographical and seasonal distributions. Data collected by WHO for 2020 show subtype A to be responsible for about 55% of infections and type B for about 40% in the USA, whereas subtype A is seen in more than 65% of infections in Europe. These differences could have therapeutic implications (eg, oseltamivir is less effective against type B). 4 Influenza, like COVID-19, infects the most vulnerable individuals, including people older than 70 years and those with cardiovascular diseases, metabolic conditions, obesity, asthma, and chronic lung disease. 4 Thus, treatments for influenza must account for the age of the patient, potential comorbidities, and potential subgroups of the virus. Antiviral agents such as amantadine and rimantadine were early therapeutic efforts. However, these drugs were administered via inhalation, thus influencing adherence, which can select for resistance. 5 In an effort to improve adherence, the neuraminidase inhibitors were developed. Zanamavir was shown to be effective against subgroups A and B, most notably in highrisk patients, 6 and along with another neuraminidase inhibitor, peramivir, was administered intravenously. 7 However, neither of these drugs were of an optimal formulation for patient satisfaction or compliance. Oseltamivir is recommended by the US Centers for Disease Control and Prevention and administered as a tablet or suspension twice a day for 5 days. 8 In a meta-analysis of nine trials, Dobson and colleagues 9 showed that oseltamivir alleviates symptoms in a shorter time than do other drugs when compared with placebo.

A novel antiviral class shown to be at least as safe and efficacious as oseltamivir but given via a single dose would be an important progression in the treatment of influenza. In The Lancet Infectious Diseases, Michael G Ison and colleagues 10 report the findings of their doubleblind, placebo-controlled and oseltamivir-controlled, randomised, phase 3 trial on baloxavir marboxil, a small molecule prodrug of baloxavir acid that is active against influenza A and B. Baloxavir is a selective inhibitor of influenza cap-dependent endonuclease. In adolescent and adult outpatients with uncomplicated influenza who were at high risk of influenza-associated complications, Ison and colleagues compared the safety and efficacy of a single oral dose (40 mg or 80 mg, depending on bodyweight) of baloxavir with that of oseltamivir (75 mg twice daily) given for 5 days or matched placebo. The modified intentionto-treat population of 1163 patients comprised 557 (48%) patients with influenza A H3N2, 484 (42%) with influenza B, 80 (7%) with influenza A H1N1, 14 with mixed infection, and 28 with infections caused by non-typeable viruses. 319 (27%) of 1163 patients were considered to be at high risk of influenza-related complications because they were aged 65 years or older, and most of the participants were adults. Ison and colleagues found that single-dose baloxavir was superior to placebo and similar to oseltamivir in reducing the duration of illness with influenza. The median time to improvement of influenza symptoms (the primary endpoint) was 73·2 h (95% CI 67·2-85·1) in the baloxavir group, 81·0 h (69·4-91·5) in the oseltamivir group, and 102·3 h (92·7-113·1) in the placebo group. The study also showed that baloxavir was superior to placebo in both influenza A and influenza B cases and to oseltamivir in influenza B cases. Importantly, the study was not powered to compare baloxavir with oseltamivir or for comparisons by influenza subtype. A quicker time to reduction of symptoms, more rapid cessation of viral shedding, and fewer adverse events, including sinusitis, bronchitis, and nausea, were reported with baloxavir than with placebo. Most of these improved outcomes were seen in those who received their therapy within 0-36 h of symptoms being reported (rather than at timepoints after 36 h).

Despite the sound design and thorough conduct of the study, it has some limitations, such as the absence of immunosuppressed patients, pregnant women, and those with liver dysfunction. Additionally, there were few cases of influenza A H1N1 subgroup infections. However, the results of this study hold considerable promise for an efficacious, well-tolerated single-dose oral therapy for influenza, including in those at high risk of influenza complications. I report being a paid consultant to various companies not involved in the production of antivirals (Melinta, Summit, Ferring).

The Great Influenza

estimated influenza illnesses, medical visits, hospitalizations, and deaths and estimated influenza illnesses, medical visits, hospitalizations, and deaths averted by vaccination in the United States

The annual impact of seasonal influenza in the US: measuring disease burden and costs

Emergence and transmission of influenza A viruses resistant to amantadine and rimantadine

Zanamivir for the treatment of influenza A and B infection in high-risk patients

Centers for Disease Control and Prevention. What you should know about flu antiviral drugs

Oseltamivir treatment for influenza in adults: a meta-analysis of randomized controlled trials

Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomised, placebo-controlled, phase 3 trial