Advanced Influenza Treatment Options for the 2020-2021 Season - - PowerPoint PPT Presentation

Reducing the Risk: Advanced Influenza Treatment Options for the 2020-2021 Season

2

• Identify patients at high risk for complications of influenza
• Select influenza treatment for adult patients at high risk of complications

based on current recommendations and evidence

• Individualize influenza treatment in pediatric patients based on current

recommendations

Learning Objectives

3

• Rates of serious illness and death

from seasonal influenza are highest in persons >65 years, in children <2 years, and in anyone with medical conditions at increased risk for complications

• During the 2017-2018 flu season,

influenza is estimated to have killed 61,000 people in the United States, more than any other year since 2010

Epidemiology and Burden of Seasonal Influenza in the US

*Data for 2017-2018, 2018-2019, 2019-2020 are preliminary estimates. Centers for Disease Control and Prevention. cdc.gov/flu/about/burden/index.html. Accessed Nov 2, 2020; Centers for Disease Control and Prevention. gis.cdc.gov/GRASP/Fluview/FluHospRates.html. Accessed Nov 2, 2020; Rolfes MA, et al. Influenza Other Respir Viruses. 2018;12:132-137.

Annual Estimates by the CDC From 10 Influenza Seasons (2010-2011 through 2019-2020)* 9.3 to 45 million illnesses 140,000 to 810,000 hospitalizations 12,000 to 61,000 deaths 14.2 to 21 million outpatient medical visits

4

Pneumonia, Influenza, and COVID-19 Mortality: 2017-2020

COVID-19 = Coronavirus disease 2019; PIC = pneumonia, influenza, or COVID-19. Centers for Disease Control and Prevention. www.cdc.gov/flu/weekly/overview.htm#anchor_1539281356004. Accessed Nov 2, 2020.

% of All Deaths Due to PIC Number of Deaths MMWR Week

40 50 10 20 30 40 50 10 20 30 40 50 10 20 30 40 50 10 20 30 40 18,000 16,000 14,000 12,000 10,000 8000 6000 4000 2000 28 26 24 22 20 18 16 14 12 10 8 6 4 2

Number of influenza coded deaths Number of COVID-19 coded deaths % of deaths due to PIC Seasonal baseline Epidemic threshold

Epidemic Threshold Seasonal baseline 2017 2018 2019 2020

5

Pandemics: Influenza and COVID-19

*Projected as of Oct 2, 2020. Dawood FS, et al. Lancet Infect Dis. 2012;12:687-695; Johns Hopkins University & Medicine. coronavirus.jhu.edu/map.html. Accessed Nov 2, 2020; Johnson NP, et al. Bull Hist Med. 2002;76:105-115; Saunders-Hastings PR, et al. Pathogens. 2016;5:66; Simonsen L, et al. PLoS Med. 2013;10:e1001558; Taubenberger JK, et al. Emerg Infect Dis. 2006;12:15-22; University of Washington Institute for Health Metrics and Evaluations. covid19.healthdata.org/global?view=total-deaths&tab=trend. Accessed Nov 2, 2020.

Common Name Year Virus Estimated No. of Deaths Spanish flu 1918 H1N1 50 million-100 million Asian flu 1958 H2N2 1 million-2 million Hong Kong flu 1968 H3N2 500,000-2 million H1N1 pandemic 2009 H1N1 151,700-575,400 COVID-19 2020 SARS-CoV-2 2,342,648* (by Jan 1, 2021)

6

• The family Orthomyxoviridae has 3 genera, or types,

that infect humans: influenza viruses A, B, and C

• Influenza A virus subtypes are based on specific HA

and NA glycoproteins that they express − 18 HAs (H1-H18) − 11 NAs (N1-N11) − Potential for 144 HA and NA combinations (some HAs and NAs cannot work together)

• Birds are reservoir for 16 HA and 9 NA subtypes

Influenza Virus

HA = hemagglutinin; NA = neuraminidase; NS = nonstructural protein; RNA = ribonucleic acid; ss = single stranded. Clancy S. Nature Education. 2008;1:83; Vemula SV, et al. Viruses. 2016;8:96.

Hemagglutinin NA NS 2 Lipid bilayer Ion channel Matrix protein Hemagglutinin NA NS2 Lipid bilayer Ion channel Matrix protein Negative-sense ssRNA

7

• Victor visits your primary care practice in November for an annual checkup
• Height: 5 ft 8 in
• Weight: 265 lb (BMI = 40.3 kg/m2)
• Blood pressure: 132/79 mm Hg (controlled with medication)
• Unvaccinated against influenza and skeptical about the vaccine

⎻ He received the vaccine last year and “got the flu” the day after

• You recommend influenza vaccination, but he refuses

Case Study: Victor, a 55-Year-Old Male of Hispanic and Native-American Descent

7

8

Chronic Medical Conditions

• Asthma
• Neurologic and neurodevelopmental conditions
• Blood disorders (eg, sickle cell disease)
• Certain types of cancer (lymphoma and leukemia) and cancer

survivors

• Chronic lung disease (eg, COPD, cystic fibrosis)
• Diabetes
• Kidney disorders
• Liver disorders
• Morbid obesity (BMI ≥40 kg/m2)
• <19 years of age and on long-term aspirin- or salicylate-containing

medications

• Compromised immune system or on immunosuppressive therapies

Focus on Patients at Higher Risk for Influenza Complications

Demographic factors

• Adults aged ≥65 years
• Children <5 years (highest risk in children

<2 years, especially if <6 months)

• Pregnant women and women up to 2

weeks postpartum

• American Indians/Alaska Natives
• Residents of nursing homes and other

long-term care facilities

Centers for Disease Control and Prevention. cdc.gov/flu/highrisk/index.htm. Accessed Nov 2, 2020.

9

Manufacturing Process Age Indication Route Formulations IIV4 standard dose Egg based† ≥6 months IM Prefilled syringe, MDV* IIV4 standard dose Cell culture based ≥4 years IM Prefilled syringe, MDV* IIV4 high dose Egg based† ≥65 years IM Prefilled syringe IIV4 standard dose with MF59 adjuvant Egg based† ≥65 years IM Prefilled syringe IIV3 standard dose with MF59 adjuvant Egg based† ≥65 years IM Prefilled syringe RIV4 Recombinant HA ≥18 years IM Prefilled syringe LAIV4‡ Egg based† 2 to 49 years Intranasal Single-use intranasal spray

Influenza Vaccines: 2020-2021 Influenza Season

*MDV = multidose vials containing ≤25 ug/0.5 mL thimerosal; †Contraindicated only if history of severe allergic reaction (eg, anaphylaxis) to egg;

‡Precautions in individuals with asthma or underlying medical conditions that may predispose to complications after wild-type influenza infection.

IIV3 = inactivated influenza vaccine, trivalent; IIV4 = inactivated influenza vaccine, quadrivalent; IM = intramuscular; LAIV4 = Live attenuated influenza vaccine; RIV4 = recombinant influenza vaccine, quadrivalent. Grohskopf LA, et al. MMWR Recomm Rep. 2020;69:1-24.

10

Egg-based influenza vaccines (ie, vaccines

• ther than ccIIV4 and RIV4) will contain HA

derived from: Cell culture-based inactivated (ccIIV4) and recombinant (RIV4) influenza vaccines will contain HA derived from: Influenza A/Guangdong-Maonan/SWL1536/2019 (H1N1)pdm09-like virus Influenza A/Hawaii/70/2019 (H1N1)pdm09-like virus Influenza A/Hong Kong/2671/2019 (H3N2)-like virus Influenza A/Hong Kong/45/2019 (H3N2)-like virus Influenza B/Washington/02/2019 (Victoria lineage)-like virus Influenza B/Washington/02/2019 (Victoria lineage)-like virus Influenza B/Phuket/3073/2013 (Yamagata lineage)-like virus (for quadrivalent vaccines only) Influenza B/Phuket/3073/2013 (Yamagata lineage)-like virus

Vaccine Composition: 2020-2021 Influenza Season

ACIP = Advisory Committee on Immunization Practices. Grohskopf LA, et al. MMWR Recomm Rep. 2020;69:1-24.

11 11

• Returns to your office in early December after sudden onset of symptoms the

previous morning ⎻ Fever (101.8°F), chills, body aches, intense headache, extreme fatigue, cough

• Missed work today and yesterday
• Several coworkers have been sick with flu-like illness
• Influenza and COVID-19 are highly prevalent in the community
• 3 days earlier, Victor babysat his 4-year-old grandson who was having some head

congestion and coughing

• Wife, aged 57 years, has not been vaccinated

Case Study (cont’d): Victor

11

12

• Classic flu

– Abrupt onset of fever, chills, myalgia, headache, fatigue, nonproductive cough, sore throat, rhinitis – Some people may have GI symptoms (eg, nausea, diarrhea) – Typically resolves within 3 to 7 days – Cough, malaise can persist for >2 weeks

• Mild illness without fever may also occur
• Atypical presentations may occur in elderly,

immunocompromised hosts, infants

Influenza Symptoms and Clinical Course

MI = myocardial infarction. Centers for Disease Control and Prevention. cdc.gov/flu/symptoms/symptoms.htm. Accessed Nov 2, 2020; Kwong JC, et al. N Engl J Med. 2018;378:345-353; Rolfes MA, et al. Clin Infect Dis. 2018;67:485-492; Uyeki TM, et al. Clin Infect Dis. 2019;68:895-902.

• Complications

– Sinusitis, otitis media – Pneumonia—primary viral or secondary bacterial – Coinfections with other bacterial/viral pathogens – Exacerbation of underlying medical conditions (eg, COPD, asthma, cystic fibrosis, diabetes) – Associations with cardiovascular events (eg, MI, stroke), parotitis

13

Differential Diagnosis of URIs, Influenza, and COVID-19

URI = upper respiratory tract infection. Centers for Disease Control and Prevention. www.cdc.gov/flu/index.htm. Accessed Nov 2, 2020; Centers for Disease Control and Prevention. www.cdc.gov/flu/symptoms/flu-vs-covid19.htm. Accessed Nov 2, 2020; National Institutes of Health. newsinhealth.nih.gov/2014/10/cold-flu-or-allergy. Accessed Nov 2, 2020.

Symptom Acute URI (common cold) Influenza COVID-19 Itchy, watery eyes Uncommon Uncommon Uncommon Nasal discharge Very common Common Common Nasal congestion Very common Common Common Sore throat Very common Sometimes Common Cough Common Common Common Headache Sometimes Common Common Fever/chills Rare (adults) possible (children) Common Common Fatigue, weakness Sometimes Very common Common Shortness of breath Rare Common Common Myalgia Rare Very common Uncommon Loss of taste or smell Uncommon Uncommon Common Symptom start, duration 3 to 14 days 3 to 10 days; several weeks cough, fatigue 5 to 14 days

14

Influenza vs COVID-19: Differentiation Considerations

Auwaerter PG. www.hopkinsguides.com/hopkins/view/Johns_Hopkins_ABX_Guide/540747/all/Coronavirus_COVID_19__SARS_CoV_2_. Accessed Nov 2, 2020; Centers for Disease Control and Prevention. www.cdc.gov/flu/about/disease/spread.htm. Accessed Nov 2, 2020; Johns Hopkins University & Medicine. coronavirus.jhu.edu/map.html. Accessed Nov 2, 2020; Verity R, et al. Lancet Infect Dis. 2020;20:669-677.

Influenza COVID-19

Transmission: Respiratory droplet, contaminated surfaces Transmission: Respiratory droplet, contaminated surfaces, and contributions of aerosolization Incubation: 2 days (mean), range 1-4 days Incubation: 6.4 days (mean), range 2-12 days Age range for high risk of illness: ≤5 and ≥ 65 Age range for high risk of illness: >50 (risk increases with advancing age) Hospitalization rate: 2% Hospitalization rate: Age 20-29 = 1.1%; age 80+ = 18.4% Fatality rate: approximately 0.1% Estimated fatality rate: Approximately 6- to 12-fold greater than influenza; preliminary data range = 0.66% to >4%, with an increasing age gradient

15

• Common cause of childhood illness but causes annual outbreaks of respiratory illness

in all age groups

• Clinical symptoms nonspecific; can overlap with other viral respiratory infections
• Symptoms include:

‒ Nasal congestion or rhinorrhea ‒ Dry cough ‒ Low-grade fever ‒ Sore throat ‒ Mild headache

• May cause severe disease in infants and young children, as well as older adults
• In severe cases, RSV infection can cause pneumonia or bronchiolitis

Respiratory Syncytial Virus Infection (RSV)

Centers for Disease Control and Prevention. www.cdc.gov/rsv/clinical/index.html. Accessed Nov 2, 2020; Mayo Clinic. www.mayoclinic.org/diseases-conditions/respiratory-syncytial-virus/symptoms-causes/syc-20353098 Accessed Nov 2, 2020.

16

Multiplex PCR: A New Testing Option

US Food and Drug Administration. Press Release. 2020. https://www.fda.gov/media/142438/download

• A number of molecular multiplex panels are approved or seeking approval to include

the novel coronavirus

• For example, Cepheid received Emergency Use Authorization (EUA) from the FDA for

its GeneXpert combination test for: ‒ SARS-CoV-2 ‒ Influenza A ‒ Influenza B ‒ RSV

• Provides rapid detection of COVID-19 within 30 minutes
• Provides results for all four pathogens within 45 minutes

17

Laboratory Diagnostic Methods to Confirm Influenza A and B

Test Method Test Time Sensitivity Specificity Rapid molecular assay Nucleic acid amplification 15 to 30 minutes High High RIDT Antigen detection <30 minutes Low/Moderate* High Immunofluorescence assay Antigen detection 1 to 4 hours Moderate High Molecular assays, including RT-PCR Nucleic acid amplification 1 to 8 hours High High Multiplex molecular assays Nucleic acid amplification 1 to 2 hours High High Rapid cell culture (shell vials, cell mixtures) Virus isolation 1 to 3 days High High Viral cell culture Virus isolation 3 to 10 days High High

*Higher sensitivity with analyzer reader device. FDA now requires RIDTs to achieve 80% sensitivity. RT-PCR = reverse transcription polymerase chain reaction. Centers for Disease Control and Prevention. cdc.gov/flu/professionals/diagnosis/overview-testing-methods.htm. Accessed Nov 2, 2020; Uyeki TM, et al. Clin Infect Dis. 2019;68:895-902.

18

Interpreting Influenza Testing Results

Centers for Disease Control and Prevention. cdc.gov/flu/professionals/diagnosis/algorithm-results-circulating.htm. Accessed Nov 2, 2020; Centers for Disease Control and Prevention. cdc.gov/flu/professionals/diagnosis/overview-testing-methods.htm. Accessed Nov 2, 2020.

• Initiate antiviral treatment if indicated
• Implement infection prevention and control measures
• Consider additional influenza testing if subtype info is desired
• Use information on local influenza activity (eg, from health

department), patient history and travel, clinical signs/symptoms, and physical examination to decide if treatment is indicated

• Initiate antiviral treatment if flu is suspected and patient is at high

risk for complications or is being admitted to the hospital

• Consider additional diagnostic testing for other pathogens

Cannot rule out flu, especially if test does not have high sensitivity

• r if specimen was

collected >4 days after illness onset

Negative result

Influenza virus infection likely Positive result (A or B)

19

Confirmed or suspected influenza

• Initiate antiviral treatment as soon as possible for patients who:

⎻ Have severe, complicated, or progressive illness ⎻ Require hospitalization ⎻ Are at higher risk for complications due to age or underlying conditions

• Do not wait for test results in patients who have a serious illness or are
• therwise at high risk
• Consider antiviral treatment for outpatients without known risk factors for severe

illness if treatment can be initiated within 48 hours of onset

When to Treat Influenza: Complicated vs Uncomplicated

Uyeki TM, et al. Clin Infect Dis. 2019;68:895-902.

20

Why Is It Important to Treat Early?

• RCTs show that antiviral treatment within 2 days of illness onset can

lessen symptoms, shorten disease course, and reduce complications and hospitalization risk

• Observational studies indicate that timely antiviral treatment can reduce

complications and hospitalization risk, and decrease mortality in hospitalized patients (up to 4-5 days after symptom onset)

RCT = randomized controlled trial. Dobson J, et al. Lancet. 2015;385:1729-1737; Jain S, et al. N Engl J Med. 2009;361:1935-1944; McGeer A, et al. Clin Infect Dis. 2007;45:1568- 1575; Muthuri SG, et al. Lancet Respir Med. 2014;2:395-404; Venkatesan S, et al. Clin Infect Dis. 2017;64:1328-1334.

21

Influenza Antivirals: Mechanisms of Action

Finberg RW, et al. J Infect Dis. 2019;219:1026-1034; Li TC, et al. Viruses. 2015;7:4929-4944; Noshi T, et al. Antiviral Res. 2018;160:109-117.

Adsorption Packaging and budding Release

Cap snatching (baloxavir, pimodivir)

mRNA RNA (+/-)

Endocytosis and fusion Uncoating Receptor containing sialic acid

NA inhibitors (oseltamivir, peramivir, zanamivir)

M2 inhibition (adamantanes) Antibodies

RNA polymerase inhibition (favipiravir)

22

FDA-approved Antiviral Agents for Influenza Treatment

Centers for Disease Control and Prevention. cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. Accessed Nov 2, 2020; Grohskopf LA, et

• al. MMWR Recomm Rep. 2019;68:1-21; Wester A, et al. Infect Drug Resist. 2016;9:201-214.
• NAs: oseltamivir, peramivir, zanamivir

– Activity against both influenza A and B viruses – Oseltamivir, zanamivir also used as prophylaxis

• Baloxavir

– Activity against both influenza A and B viruses – Inhibits endonuclease, enzyme required for viral gene transcription

• Adamantanes: amantadine, rimantadine

– Activity against influenza A only – Widespread resistance, not recommended

23

Antivirals for Influenza: Dosing Considerations

Centers for Disease Control and Prevention. cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. Accessed Nov 2, 2020; Rapivab [prescribing information]. BioCryst Pharmaceuticals; 2018; Relenza [prescribing information]. GlaxoSmithKline; 2018; Tamiflu [prescribing information]. Genentech; 2019; Xofluza [prescribing information]. Genentech; 2019.

Antiviral Dosage Age Indication Route of Administration Precautions Baloxavir Single oral dose

• 40 mg for patients 40 to 80 kg
• 80 mg for patients ≥80 kg

≥12 years Tablets Do not take with:

• Dairy products or calcium-fortified

beverages

• Polyvalent cation-containing

laxatives Oseltamivir Twice daily for 5 days

• 75 mg (≥13 years)
• Weight based (1-12 years)
• 3 mg/kg (2 weeks-1 year)

≥2 weeks Capsule or oral suspension — Peramivir Single dose of 600 mg over 15 min ≥2 years Intravenous — Zanamivir 10 mg twice daily for 5 days ≥7 years Oral inhalation Do not use in patients with:

• Underlying respiratory disease
• History of milk protein allergy

24

Antiviral AEs Baloxavir Diarrhea, bronchitis, nausea, sinusitis, headache Postmarketing reports: Swelling of the face, eyelids or tongue; dysphonia; angioedema; anaphylactic reactions, anaphylactic shock, anaphylactoid reactions; rash, urticaria, erythema multiforme; vomiting, bloody diarrhea, melena, colitis; delirium, abnormal behavior, hallucinations Oseltamivir Nausea, vomiting, headache Postmarketing reports: serious skin reactions; sporadic, transient neuropsychiatric events* Peramivir Diarrhea Postmarketing reports: serious skin reactions; sporadic, transient neuropsychiatric events* Zanamivir Oropharyngeal or facial edema; skin rash; bronchospasm, especially in the setting of underlying airways disease; sinusitis; dizziness; ear, nose, and throat infections Postmarketing reports: sporadic, transient neuropsychiatric events*

Antivirals for Influenza: Adverse Events (AEs)

*Self-injury or delirium; mainly reported among Japanese adolescents and adults; may be due to viral infection itself. Centers for Disease Control and Prevention. cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. Accessed Nov 2, 2020; Rapivab [prescribing information], BioCryst Pharmaceuticals; 2018; Relenza [prescribing information]. GlaxoSmithKline; 2018; Tamiflu [prescribing information]. Genentech; 2019; Xofluza [prescribing information]. Genentech; 2019.

24

25

100 80 60 40 20

• Phase 3 study

‒ 1436 otherwise healthy patients ‒ 12 to 64 years of age ‒ Symptomatic uncomplicated flu

• Time to alleviation of symptoms

‒ Baloxavir group: 53.7 hours ‒ Placebo group: 80.2 hours (P <.001)

• Baloxavir generally well tolerated

‒ Diarrhea most common AE, but less frequent than with placebo

CAPSTONE-1: Time to Alleviation of Symptoms With Baloxavir vs Placebo

Hayden FG, et al. N Engl J Med. 2018;379:913-923.

Patients Who Did Not Have Symptom Alleviation (%) Hours From Start of Trial Regimen

0 30 60 90 120 150 180 210 240 270 300 330 Baloxavir Placebo + + + + + + + + + + + + + + ++ + + + + + + + + + + +

26

• Phase 3 study in patients ≥12 years (N = 2184) presenting ≤48 hours of symptom onset and at high

risk of influenza complications (eg, asthma or chronic lung disease, age ≥65 years)

• Primary endpoint: Time to improvement of influenza symptoms in baloxavir vs placebo groups
• Adverse events were similar among groups

CAPSTONE-2: Baloxavir vs Placebo or Oseltamivir in Patients at High Risk for Influenza Complications

*All reported values are medians; **As determined by virus titer. NS = not significant; TTIIS = Median time to improvement of influenza symptoms. ClinicalTrials.gov. clinicaltrials.gov/ct2/show/results/NCT02949011. Accessed Nov 2, 2020; Ison MG, et al. Lancet Infect Dis. 2020;20:1204-1214.

Measure* Baloxavir Placebo P Value (Baloxavir vs Placebo) Oseltamivir P Value (Baloxavir vs Oseltamivir) Overall TTIIS 73.2 h 102.3 h <.0001 81.0 h .8347 Influenza A/H3N2 TTIIS 75.4 h 100.4 h .014 68.2 NS Influenza B TTIIS 74.6 h 100.6 h .014 101.6 h .025 Time to cessation of viral shedding** 48 h 96 h <.0001 96 h <.0001

27 27

• Swab test for COVID-19 was negative
• You prescribe baloxavir for Victor, advising him not to take it with:

⎻ Dairy products, calcium-fortified beverages, polyvalent cation-containing laxatives, antacids, or oral supplements (eg, calcium, iron, magnesium, selenium, or zinc)

• He feels better within a few days; 12 days later he feels almost completely better,

except for a slight lingering cough

• He has urged his wife and family to get vaccinated and is committed to getting

vaccinated himself early in the season each year

Case Conclusion

28

Case Study: Allie, an 11-Year-Old Student

• Has mild, intermittent asthma, which is treated with albuterol PRN
• Sudden onset of headache, pharyngitis, fever, chills, nasal congestion yesterday;

symptoms worse today and now include dry cough, fatigue, weakness

• OTC meds providing limited relief
• Flu prevalent at school and in community
• Height: 5 ft, 4 in; weight: 105 lb (BMI: 18 kg/m2); blood pressure: 118/73 mm Hg
• Temperature: 103.5°F; heart rate: 95 beats/min; respiration rate: 14 breaths/min;

SpO2: 98% on room air

• Lungs: slight wheezing
• Rapid strep test: negative
• Oral salivary test for COVID-19 sent out for laboratory analysis

29

Case Study (cont’d): Allie

• Given Allie’s symptoms and underlying asthma, which puts her at high risk

for influenza complications, as well as the fact that flu is currently circulating in the community, your clinical judgment is that a flu test is: ‒ Not necessary for diagnosis ‒ Would not change your approach to management

• You discuss antiviral treatment options with Allie and her mother

30

Case Conclusion

• You prescribe Allie oseltamivir, 75 mg twice daily for 5 days, because it is

approved for children of Allie’s age and has more than 20 years of clinical use

• Her symptoms start to resolve over the next few days and by the weekend she

is feeling much better

• You recommend she get vaccinated early in the next flu season

31

• Phase 3 multicenter study in patients 1 to <12 years of age with confirmed influenza
• Primary endpoint: Proportion of patients exhibiting AEs or severe AEs for up to day 29
• Patients randomized to baloxavir (single dose; N = 115) or oseltamivir (twice daily for 5 days; N = 58)
• No serious AEs, deaths, AEs of special interest, or new safety signals observed

MINISTONE-2: Baloxavir vs Oseltamivir in Pediatric Patients With Influenza-like Symptoms

CI = confidence interval. *Determined via virus titer. Baker J, et al. Pediatr Infect Dis J. 2020;39:700-705.

Measure Baloxavir Oseltamivir Patients with at least 1 AE 46.1% 53.4% Median time to cessation of viral shedding* (95% CI) 24.2 h (23.5 to 24.6) 75.8 h (68.9 to 97.8) Median time to alleviation of influenza signs and symptoms (95% CI) 138.1 h (116.6 to 163.2) 150.0 h (115.0 to 165.7)

32

1.9 13.6 5 10 15 20 25 30 Category 1

Influenza Positive (%)*

Baloxavir Placebo

• Phase 3 randomized study assessing

post-exposure prophylaxis in unvaccinated household contacts of influenza-infected patients (influenza confirmed by RIDT)

• Household contacts randomized to

single-dose baloxavir vs placebo

• Primary endpoint: Proportion of

participants testing positive for influenza (RT-PCR positive, with fever and ≥1 symptom[s]) during 10-day assessment period

• Serious AEs not observed

BLOCKSTONE: Baloxavir Prophylaxis vs Placebo in Subjects Living With Someone With Confirmed Influenza

Ikematsu H, et al. N Engl J Med. 2020;383:309-320.

Percentage of household contacts infected after treatment with baloxavir or placebo

P <0.001

Baloxavir Placebo

*Influenza positive = baloxavir 7 of 374 [1.9%] vs placebo 51

• f 375 [13.6%]; adjusted risk ratio, 0.14; 95% CI, 0.06 to 0.30.

33

• Current FDA-approved indication

⎻ Treatment of acute uncomplicated influenza in patients ≥12 years who have been symptomatic for ≤48 hours and who are otherwise healthy, or at high risk for influenza-related complications

• Convenience of single oral dose
• Offers another option if/when viruses become resistant to NA inhibitors
• Resistance to baloxavir occurs in 9.7% to 23.4% of recipients
• Quicker reduction of influenza B symptoms than oseltamivir
• Faster clearance of virus than oseltamivir
• CDC does not recommend use of baloxavir in pregnant women, breastfeeding mothers, outpatients

with complicated or progressive illness, severely immunosuppressed people, or hospitalized patients because of lack of data in these groups

Considerations Regarding Baloxavir

Centers for Disease Control and Prevention. www.cdc.gov/flu/treatment/baloxavir-marboxil.htm. Accessed Nov 2, 2020; ClinicalTrials.gov. clinicaltrials.gov/ct2/show/NCT02949011. Accessed Nov 2, 2020; Hayden FG, et al. N Engl J Med. 2018;379:913-923; Ison MG, et al. IDSA Week.

• 2018. Abstract LB16; Xofluza [prescribing information]. Genentech; 2019; Hayden FG, et al. N Engl J Med. 2018;379:913; Hirotsu N, et al. Clin

Infect Dis. 2020;71:971.

34

PCE Action Plan

✓ Be aware of the potential for influenza complications, especially in higher risk patients ✓ Confirm influenza using rapid molecular assay if available; RIDT 2nd choice ✓ Despite COVID-19, consider a clinical influenza diagnosis without diagnostic lab testing for stable outpatients with signs and symptoms consistent with flu, especially during periods of influenza activity in the community ✓ Initiate antiviral treatment as early as possible and preferably within 2 days to ensure best treatment outcomes ✓ Treat influenza A and B with an NA inhibitor or baloxavir PCE Promotes Practice Change