Act Fast: Reducing the Impact of Influenza
Reductions in Viral Load and Viral Shedding Are Key to Decreasing Influenza Transmission
In influenza, viral load often correlates with the magnitude of a patient’s symptoms.1 While vaccination against influenza is the number one way to reduce viral load and transmission, antiviral agents are also an important tool for reducing the risk of post-exposure transmission. Unfortunately, antiviral agents against influenza are underutilized. Patients with suspected or confirmed influenza, particularly individuals who are at risk for influenza-associated complications, should be treated with anti-influenza drugs.2 Treatment not only reduces morbidity and mortality risk in patients, but also reduces the risk of transmission to family members and others.2
CDC-Preferred Antiviral Agents for the Treatment of Influenza
Multiple antiviral drugs are available for the treatment of influenza A and B with different indications and mechanisms of action (Table 1).3 Oseltamivir, zanamivir, and peramivir are neuraminidase inhibitors that have been available for over 20 years. Baloxavir marboxil (baloxavir) is a new single-dose antiviral agent that is a cap-dependent endonuclease inhibitor. It works earlier in the viral replication cycle than neuraminidase inhibitors and therefore results in greater reductions in viral load.4,5 All of these agents should be used within 48 hours of the onset of influenza illness. However, treatment after 48 hours of onset should be considered for individuals who have severe progressive illness or are at high risk of influenza-associated complications, such as patients with diabetes, heart failure, or who are 65 years of age or older.
Baloxavir Clinical Data
CAPSTONE-1 and CAPSTONE-2 randomized adolescents and adults with influenza with onset of symptoms ≤48 hours to one-dose baloxavir, a 5-day course of twice-daily oseltamivir, or matching placebos.4,5 CAPSTONE-1 involved 1,436 otherwise healthy patients with influenza while CAPSTONE-2 involved 2,184 patients who were at high risk for complications and was the largest clinical trial of this patient population to date. Baloxavir and oseltamivir outperformed placebo in both trials. In CAPSTONE-1, the median duration of infectious virus detection with baloxavir was 24.0 hours compared to 72.0 hours with oseltamivir (P < 0.001) and 96.0 hours with placebo (P < 0.001).4 In CAPSTONE-2, time to improvement of influenza symptoms (TTIIS) in the modified intention-to-treat population of patients with influenza A H3N2 virus infection was significantly shorter in the baloxavir group than in the placebo group (P = 0.014, Figure 1).5 In both trials, time to symptom improvement was significantly shorter with baloxavir than placebo in patients who initiated treatment within 24 hours after onset of symptoms.4,5 Specifically, the median difference in time to alleviation of symptoms in CAPSTONE-1 was 32.8 hours (P < 0.001) in patients who initiated baloxavir within 24 hours of symptom onset versus 13.2 hours (P = 0.008) in patients who initiated treatment after 24 hours.4
CAPSTONE-2 also showed that baloxavir and oseltamivir were associated with a lower risk of influenza-associated complications.5 Complications in the baloxavir groups were seen in 3% (n = 386) versus 10% (n = 386) of the placebo group (P < 0.001) while 5% (n = 389) of the oseltamivir group experienced complications (P = 0.26 compared with baloxavir). The difference between baloxavir and placebo was due to fewer patients in the baloxavir group having sinusitis or bronchitis or requiring antibiotics for suspected or proven secondary infections.5
MiniSTONE was a safety-based, phase 3, randomized, active controlled trial among children aged 1 to 12 years diagnosed with influenza.6 In total, 173 children with onset of symptoms ≤48 hours were randomized 2:1 to either baloxavir or oseltamivir. A placebo group was not included because it would not be ethical in children. Baloxavir and oseltamivir were similarly safe with an overall incidence of adverse effects of 46.1% (n = 115) with baloxavir and 52.4% (n = 58) with oseltamivir. Time to alleviation of signs and symptoms were also similar between the groups (Figure 2). The median time to cessation of viral shedding was shorter with baloxavir than oseltamivir (Table 2).6
Overall, infectious virus titers declined faster with baloxavir than with oseltamivir (Figure 3).4-6 Neuraminidase inhibitors, like oseltamivir, target the last stage of the viral life cycle and prevent replicated virus particles from spreading to nearby epithelial cells.7 Conversely, baloxavir inhibits the influenza-specific endonuclease required for viral replication and interferes prior to viral release.7 Baloxavir’s earlier targeting of the viral life cycle is the likely reason for faster reductions in virus titers.
When comparing the side effect profiles of baloxavir and oseltamivir, nausea and vomiting occurred more frequently with oseltamivir.4-6 This should be taken into consideration for patients with gastrointestinal disturbances, such as patients with diabetic gastroparesis or who have nausea and vomiting as part of their influenza symptomology.
Influenza Post-Exposure Prophylaxis
Post-exposure prophylaxis is an effective method of influenza management which should be used more often. Candidates for prophylaxis are individuals who have been exposed to the influenza virus within the past 48 hours. Candidates for prophylaxis include:
Individuals who have been vaccinated or are otherwise healthy are unlikely to benefit from prophylaxis. Baloxavir, oseltamivir, and zanamivir are all approved for use as post-exposure prophylaxis.8-10 Oseltamivir and zanamivir are each prescribed as a 7-day course of treatment. Baloxavir is a onetime treatment.
The BLOCKSTONE clinical trial was a double-blind, randomized, placebo-controlled study evaluating the efficacy of baloxavir versus placebo.11 Among 752 household contacts of 545 index patients with influenza, baloxavir was 86% effective in preventing transmission of influenza overall (P < 0.001; Figure 4). Side effects of treatment were low, and the safety profile was similar to placebo. These data demonstrate the efficacy of post-exposure prophylaxis in preventing transmission to household contacts. For patients who were already infected at baseline, treatment reduced the risk of severe symptoms and complications.11
Kate is a 42-year-old insurance agent who comes to your office with a likely influenza diagnosis. Upon probing, you discover that her husband, John, is a cross-country truck driver who is currently home before his next trip. John is 54 years old and has asthma. Kate and John’s 18-year-old son, Joseph, and Kate’s 64-year-old mother, Denise, currently reside with the family. Joseph is preparing to leave in 2 days for the winter college semester. Denise has type 2 diabetes with an A1c of 7.9 and high blood pressure (165/110 mm Hg) for which she takes daily medication.
Experts note that considering vaccination status is important to the post-exposure prophylaxis decision-making process. If patients have been vaccinated at least 2 weeks prior to exposure and do not have signs of severe immune compromise suggesting that vaccination would be less effective, then post-exposure prophylaxis does not need to be initiated. However, patients who are at high risk of complications should receive prophylaxis. Both John and Denise have high-risk conditions and quality for post-exposure prophylaxis. John has asthma, and although Denise does not qualify based on her age, she does qualify due to her diabetes. If John or Denise had not been recently vaccinated, then prophylaxis with either baloxavir or oseltamivir is warranted. For Denise, zanamivir is an alternative prophylaxis option, but this should not be given to John due to his asthma. Regarding the case of Joseph, he is young and otherwise healthy and therefore is at low risk of complications. At the same time, he is leaving for college in 2 days. As a public health measure, prophylaxis would protect him, his fellow travelers, his classmates, and particularly the students he will be living with in his dorm. Overall, everyone in this case should be vaccinated against influenza if they are not already. Vaccination will not protect them from this case of influenza, but it will protect them from future infections.
In the second half of this case, we consider the family of Kate’s brother, Alex, who live next door and who are also your patients. Kate has been in close contact with Alex within the past 24 hours since she works for his insurance agency, which is located on the ground floor of his house. Alex is 37 years old, and he indicates that he has a fever and feels achy. His wife, Janis, is 34 years old and pregnant with their second child. Also residing in the home is their 14-year-old daughter, Susan, and Alex’s 61-year-old father-in-law, Mitch. Mitch takes daily NSAIDs for arthritis in his neck but is otherwise healthy.
Experts recommend reaching out to Alex and his family since they are also your patients. Alex is symptomatic and given Kate’s probable influenza, he should be offered prophylaxis. Janis is pregnant, and she and her unborn child are at higher risks of complications, such as pneumonia and preterm delivery. If she had not been vaccinated as recommended by the Centers for Disease Control and Prevention (CDC), she should be offered post-exposure prophylaxis with oseltamivir. Janis would also be a candidate for post-exposure prophylaxis even if vaccinated. Oseltamivir has a well-established history and is the preferred agent for prophylaxis during pregnancy. In this case, a shared decision-making approach is important since Janis may have concerns about taking a medication during pregnancy. If she is resistant to prophylaxis, a delayed prescription for oseltamivir would be a reasonable management approach.
Using a delayed prescription approach would also be reasonable as prophylaxis for Susan and Mitch since both are otherwise healthy. Specifically in the case of Mitch, arthritis is not a high-risk condition. Also, he is younger than 65 years, which is the youngest age that the CDC recommends for prophylaxis in adults without influenza-associated complications.
In the urgent care and other settings, it is very important to educate patients and consider post-exposure prophylaxis. There is a short window of time when newly sick patients present, and the most important thing to ask about is the people they are living with.
There are several anti-influenza agents available now with different dosing regimens. Completing the full CDC-recommended 7-day course is important for reducing viral spread in high-risk settings, such as assisted living facilities and college campuses, yet many patients fail to do so. Prophylaxis with baloxavir is a onetime dose and is suitable for patients who have difficulty with adherence.
Additionally, there has been tremendous stress and tragedy with the COVID-19 pandemic, but do not forget about influenza. Plan to vaccinate all patients against influenza and watch the epidemiology of both influenza and COVID-19 during flu season. Symptomatic patients may require co-testing and treatment. Treatment for influenza should not be held back when it is circulating in the community.
- Hijano DR, Brazelton de Cardenas J, Maron G, et al. Clinical correlation of influenza and respiratory syncytial virus load measured by digital PCR. PLoS One. 2019;14(9):e0220908.
- Uyeki TM, Bernstein HH, Bradley JS, et al. Clinical practice guidelines by the Infectious Diseases Society of America: 2018 update on diagnosis, treatment, chemoprophylaxis, and institutional outbreak management of seasonal influenza. Clin Infect Dis. 2019;68(6):895-902.
- Centers for Disease Control and Prevention. Antiviral drugs for seasonal influenza: additional links and resources. Reviewed November 30, 2020. Accessed August 1, 2021. https://www.cdc.gov/flu/professionals/antivirals/links.htm
- Hayden FG, Sugaya N, Hirotsu N, et al. Baloxavir marboxil for uncomplicated influenza in adults and adolescents. N Engl J Med. 2018;379(10):913-923.
- Ison MG, Portsmouth S, Yoshida Y, et al. Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomised, placebo-controlled, phase 3 trial. Lancet Infect Dis. 2020;20(10):1204-1214.
- Baker J, Block SL, Matharu B, et al. Baloxavir marboxil single-dose treatment in influenza-infected children: a randomized, double-blind, active controlled phase 3 safety and efficacy trial (miniSTONE-2). Pediatr Infect Dis J. 2020;39(8):700-705.
- Bai Y, Jones JC, Wong SS, Zanin M. Antivirals targeting the surface glycoproteins of influenza virus: mechanisms of action and resistance. Viruses. 2021;13(4):624.
- XOFLUZA (baloxavir marboxil). Package insert. Genentech USA, Inc.; 2021.
- TAMIFLU (oseltamivir phosphate). Package insert. Genentech, Inc.; 2019.
- RELENZA (zanamivir inhalation powder). Package insert. GlaxoSmithKline; 2018.
- Ikematsu H, Hayden FG, Kawaguchi K, et al. Baloxavir marboxil for prophylaxis against influenza in household contacts. N Engl J Med. 2020;383(4):309-320.