2020 Symposia Series 1

Weighing the Options: Prevention and

Management of Influenza in Patients at

High Risk for Complications

3

Learning Objectives

• Identify available and emerging options for prevention 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

4

• 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

• In the 2017-2018 flu season, influenza killed

and hospitalized more people in the US than

any other year since 2010

Epidemiology and Burden of Seasonal Influenza in the US

*Data for 2017-2018 and 2018-2019 are preliminary estimates.

Centers for Disease Control and Prevention. cdc.gov/flu/about/burden/index.html. Accessed Apr 5, 2020; Centers for Disease Control and Prevention.

gis.cdc.gov/GRASP/Fluview/FluHospRates.html. Accessed Apr 5, 2020; Rolfes MA, et al. Influenza Other Respir Viruses. 2018;12:132-137.

Burden of Influenza: Annual Estimates by the CDC From 9 Influenza Seasons (2010-2011 through 2018-2019)*

9.3 to 45 million illnesses caused

140,000 to 810,000 hospitalizations

12,000 to 61,000 deaths

14.2 to 21 million outpatient medical visits

5

Influenza-Positive Tests Reported to CDC: National Summary, 2019-2020 Season

Centers for Disease Control and Prevention. cdc.gov/flu/weekly/index.htm. Accessed Apr 5, 2020.

0

500

1000

1500

2000

2500

3000

3500

4000

2019-40 2019-42 2019-44 2019-46 2019-48 2019-50 2019-52 2020-02 2020-04 2020-06 2020-08 2020-10 2020-12 2020-14 2020-16 2020-18 2020-20

Num

ber

of P

ositiv

e S

pe

cim

en

s

Week

B (Yamagata Lineage) B (Victoria Lineage) B (lineage not performed) A (H3N2) A (H1N1)pmd09 A (subtyping not performed)

6

Number of Specimens Tested and Percent Positive for SARS-CoV-2

SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.

Centers for Disease Control and Prevention. cdc.gov/coronavirus/2019-ncov/covid-data/covidview/index.html. Accessed Apr 5, 2020.

0

1000

2000

3000

4000

2019-40 2019-42 2019-44 2019-46 2019-48 2019-50 2019-52 2020-02 2020-04 2020-06 2020-08 2020-10 2020-12 2020-14 2020-16 2020-18 2020-20

B (Yamagata Lineage) B (Victoria Lineage)

B (lineage not performed) A (H3N2)

A (H1N1)pmd09 A (subtyping not performed)

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

13000

14000

15000

16000

SARS-CoV-2

7

Outpatient Visits for Influenza-like Illness Reported to CDC: National Summary, 2009-2020

ILI = influenza-like Illness.

Centers for Disease Control and Prevention. cdc.gov/flu/weekly/index.htm. Accessed Apr 5, 2020.

0

1

2

3

4

5

6

7

8

9

40 42 44 46 48 50 52 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38

% o

f V

isito

rs fo

r IL

I

Week

2018-19 season

2017-18 season

2015-16 season

2014-15 season

2011-12 season

2009-10 season

2019-20 National Baseline

2019-20 season

8

Influenza Pandemics

*As of May 11, 2020; COVID-19 = Coronavirus disease 2019.

Dawood FS, et al. Lancet Infect Dis. 2012;12:687-695; Johnson NP, et al. Bull Hist Med. 2002;76:105-115; Saunders-Hastings PR, et al. Pathogens.

2016;5:e66; Simonsen L, et al. PLoS Med. 2013;10:e1001558; Taubenberger JK, et al. Emerg Infect Dis. 2006;12:15-22; COVID-19 Dashboard by

the Center for Systems Science and Engineering at Johns Hopkins University. coronavirus.jhu.edu/map.html. Accessed May 11, 2020; University of

Washington Institute for Health Metrics and Evaluations. www.covid19.healthdata.org Accessed May 11, 2020.

Common Name Year Virus Estimated No. of Deaths (range)

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-2 137,184* (by Aug 4, 2020)

9

• 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; ss = single stranded.

Clancy S. Nature Education. 2008;1:83; Vemula SV, et al. Viruses. 2016;8:96.

Hemagglutinin NA

NS2

Lipid

bilayer

Ion

channel

Matrix

protein

Negative-sense

ssRNA

10

Case Study: Joanne, a 52-year-old female

• Joanne visits your primary care practice in November for an annual checkup

• She is under the care of a rheumatologist for psoriatic arthritis and well managed with methotrexate and etanercept

• No other chronic medical problems

⎻ 5 ft 6 in; 249 lb; BMI: 40.2 kg/m2; blood pressure: 128/78 mm Hg

• Unvaccinated against influenza and skeptical about the vaccine

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

• You recommend influenza vaccination, but she refuses

10

11

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 Apr 5, 2020.

Chronic Medical Conditions

• Asthma

• Neurologic and neurodevelopmental conditions

• Blood disorders (eg, sickle cell disease)

• Chronic lung disease (eg, COPD, cystic fibrosis)

• Diabetes

• Kidney disorders

• Liver disorders

• Morbid obesity (BMI ≥40 kg/m2)

• <19 years and on long-term aspirin- or salicylate-

containing medications

• Compromised immune system or on

immunosuppressive therapies

12

Influenza Vaccination: Effective but Underutilized

• Most effective means of preventing seasonal influenza virus infection

– Recommended in all persons ≥6 months in the United States

• 38% to 61% of population gets vaccinated*

• Because of changes in circulating influenza strains, vaccine reformulated every year

• Vaccination can prevent serious illness

⎻ CDC estimates that during the 2018-2019 season, flu vaccine prevented an estimated:

• 4.4 million illnesses

• 2.3 million medical visits; 58,000 hospitalizations

• 35,000 deaths

*Estimated from percentage of patients with acute respiratory illness who were vaccinated for the 2019-2020 flu season.

Dawood FS, et al. MMWR Morb Mortal Wkly Rep. 2020;69:177-182.

13

• Vaccination does not guarantee protection

• Interim data for vaccine effectiveness during 2019-2020 flu season (adjusted):

– 55% against influenza B/Victoria

– 37% against influenza A(H1N1)pdm09

– 45% overall effectiveness against influenza A and B combined

• Despite overall vaccine effectiveness of 38% in 2017-2018 season, flu vaccine prevented:

‒ 7.1 million illnesses, 3.7 million medical visits

‒ 109,000 hospitalizations, 8000 deaths

Interim Data for Influenza Vaccine Effectiveness During the 2019-2020 Season

Dawood FS, et al. MMWR Morb Mortal Wkly Rep 2020;69:177-182; Grohskopf LA, et al. MMWR Recomm Rep. 2019;68:1-21.13

14

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*

IIV3 high dose 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: 2019-2020 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. 2019;68:1-21.

15

• Vaccine composition:

‒ A/Brisbane/02/2018 (H1N1) pdm09-like virus

‒ A/Kansas/14/2017 (H3N2)-like virus

‒ B/Colorado/06/2017-like virus (B/Victoria/2/87 lineage)

‒ B/Phuket/3073/2013-like virus (B/Yamagata/16/88 lineage) [quadrivalent only]

• Clinicians may administer any licensed, age-appropriate influenza vaccine to all patients

‒ Includes those with egg allergy, except for history suggestive of anaphylaxis

ACIP Guideline Update for 2019-2020 Influenza Season

ACIP = Advisory Committee on Immunization Practices.

Grohskopf LA, et al. MMWR Recomm Rep. 2019;68:1-21.

16

Influenza Vaccination in Children Aged 6 Months Through 8 Years

Grohskopf LA, et al. MMWR Recomm Rep. 2019;68:1-21.

Has the child received ≥2 doses of influenza vaccine previously

(excluding the current influenza season)?

2 doses of 2019-2020

influenza vaccine

(≥4 weeks apart)

1 dose of 2019-2020

influenza vaccine

Yes No or don’t know

17

High-dose and MF59-adjuvanted Seasonal Influenza Vaccines in Patients ≥65 Years

RCT = randomized controlled trial.

Centers for Disease Control and Prevention. cdc.gov/flu/professionals/acip/2019-2020/acip-table.htm. Accessed Apr 5, 2020; ClinicalTrials.gov.

clinicaltrials.gov/ct2/show/NCT03183908. Accessed Apr 5, 2020; Czaja CA, et al. Open Forum Infec Dis. 2019;6:ofz225; DiazGranados CA, et al.

N Engl J Med. 2014;371:635-645; Gravenstein S, et al. Lancet Respir Med. 2017;5:738-746; Grohskopf LA, et al. MMWR Recomm Rep.

2019;68:1-21; Izurieta HS, et al. Lancet Infect Dis. 2015;15:293-300; Lapi F, et al. Expert Rev Vaccines. 2019;18:663-670; Reed C, et al. PLoS

One. 2015;10:e0118369; Shay DK, et al. J Infect Dis. 2017;215:510-517; Van Buyunder PG, et al. Vaccine. 2013;31:6122-6128.

• Population accounts for up to 90% of seasonal flu-related deaths and 50% to 70% of hospitalizations

• High-dose vs standard-dose vaccine (RCTs and observational studies)

⎻ Higher immunogenic responses

⎻ Improved protection against influenza and related complications

• MF59-adjuvanted vaccine vs nonadjuvanted inactivated influenza vaccine (observational studies)

⎻ Greater vaccine efficacy for lab-confirmed influenza and influenza-related hospitalizations

⎻ Results of RCT comparing immunogenicity of MF59-adjuvanted to high-dose vaccines pending

(NCT03183908)

• ACIP recommends no preference for particular vaccine types

⎻ Vaccination should not be delayed if a specific product is not available

18

• 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

CF = cystic fibrosis; CV = cardiovascular; MI = myocardial infarction.

Centers for Disease Control and Prevention. cdc.gov/flu/symptoms/symptoms.htm. Accessed Apr 5, 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, CF, diabetes)

– Associations with CV events (eg, MI, stroke),

parotitis

19

Case Study (cont’d): Joanne

• Joanne returns to your office in early December after sudden onset of symptoms the previous morning

⎻ Symptoms include fever (101.8°F), chills, body aches, intense headache, extreme fatigue, and cough

• Has missed work yesterday; unable to perform household chores

• Several coworkers have been sick with flu-like illness, and Joanne is concerned that she may have the flu

• Adult daughter and a grandchild (newborn) will be visiting soon, and she wants to avoid spreading her illness

• Husband, aged 60 years, has not been vaccinated

19

20

Differential Diagnosis of Allergies, URIs, and Influenza in a Typical Influenza Season

Centers for Disease Control and Prevention. www.cdc.gov/flu.htm. Accessed Apr 5, 2020; National Institutes of Health. newsinhealth.nih.gov/2014/10/cold-flu-or-

allergy. Accessed Apr 5, 2020.

Symptom Allergy Acute URI (common cold) Influenza

Itchy, watery eyes Common Rare; conjunctivitis may occur with

adenovirus

Soreness behind eyes, sometimes

conjunctivitis

Nasal discharge Common Very common Common

Nasal congestion Common Very common Sometimes

Sneezing Very common Very common Uncommon

Sore throat Sometimes Very common Sometimes

Cough Sometimes Common Very common

Headache Sometimes Sometimes Common

Fever Never Rare in adults, possible in children Very common

Malaise Sometimes Sometimes Very common

Fatigue, weakness Sometimes Sometimes Very common

Myalgia Never Rare Very common

Duration of symptoms Weeks 3 to 14 days 3 to 10 days; several weeks of cough, fatigue

21

Laboratory Diagnostic Methods to Detect 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.

Centers for Disease Control and Prevention. cdc.gov/flu/professionals/diagnosis/overview-testing-methods.htm. Accessed Apr 5, 2020; Uyeki TM, et

al. Clin Infect Dis. 2019;68:895-902.

22

RT-PCR RIDT

Diagnostic accuracy ✓ Higher sensitivity → fewer false

negatives

Specific → Limited false positives

Lower sensitivity → more false

negatives (newer tests have improved)

Specific → Limited false positives

Discriminate influenza

A subtypes ✓ Yes, if subtype primers used No

Time to results ≤30 minutes to several hours ✓ 10 to 15 minutes

Availability in office

setting More expensive and less available ✓ More likely to be available

RT-PCR Versus RIDT: Preferred Tests

✓ = preferred.

Centers for Disease Control and Prevention. cdc.gov/flu/professionals/diagnosis/overview-testing-methods.htm. Accessed Apr 20, 2020; Merckx J,

et al. Ann Intern Med. 2017;167:394-409; Uyeki TM, et al. Clin Infect Dis. 2019;68:895-902.

23

Interpreting Influenza Testing Results

Centers for Disease Control and Prevention. cdc.gov/flu/professionals/diagnosis/algorithm-results-circulating.htm. Accessed Apr 5, 2020; Centers

for Disease Control and Prevention. cdc.gov/flu/professionals/diagnosis/overview-testing-methods.htm. Accessed Apr 5, 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

or if specimen was

collected >4 days after

illness onset

Negative

result

Influenza virus

infection likelyPositive result

(A or B)

24

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 otherwise at high risk

• Consider antiviral treatment for outpatients if treatment can be initiated within 48 hours of onset without known risk factors for severe illness

When to Treat Influenza: Complicated vs Uncomplicated

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

25

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)

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 Infec 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.

26

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)

27

FDA-approved Antiviral Agents for Influenza

Centers for Disease Control and Prevention. cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. Accessed Apr 28, 2020; Grohskopf LA, et

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

• Neuraminidase inhibitors: 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

28

Antivirals for Influenza: Age Indications and Dosage

Centers for Disease Control and Prevention. cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. Accessed Apr 20, 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

29

Drugs 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, and 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 Apr 20, 2020; Tamiflu

[prescribing information]. Genentech; 2019; Xofluza [prescribing information]. Genentech; 2019; Rapivab [prescribing information], BioCryst

Pharmaceuticals; 2018; Relenza [prescribing information]. GlaxoSmithKline; 2018.29

30

100

80

60

40

20

0

• 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 h

‒ Placebo group: 80.2 h (P <.001)

• Baloxavir generally well tolerated

‒ Diarrhea most common adverse event, but less frequent than with placebo

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

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

Pa

tie

nts

Wh

o D

id N

ot H

ave

Sym

pto

m A

llevia

tio

n (

%)

Hours From Start of Trial Regimen

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

Baloxavir

Placebo

+ +++

+++

+

+

+++

++

++

+

+

+ ++++++++

31

• 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.

NA = not available; TTIIS = Median time to improvement of influenza symptoms.

Ison MG, et al. Abstract LB16, IDSA Week, Oct 6, 2018; Xofluza [prescribing information]. Genentech; 2019; Xofluza [approval letter], October 16,

2019. www.accessdata.fda.gov/drugsatfda_docs/nda/2019/210854Orig1s001.pdf. Accessed Apr 13, 2020; ClinicalTrials.gov.

clinicaltrials.gov/ct2/show/NCT02949011. Accessed Apr 5, 2020.

Measure* Baloxavir PlaceboP 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 .0141 NA NA

Influenza B TTIIS 74.6 h 100.6 h .0138 101.6 h .0251

Time to cessation of viral

shedding**

48 h 96 h <.0001 96 h <.0001

32

Joanne: Case Conclusion

• You prescribe baloxavir for Joanne, advising her 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)

• She feels better within a few days; 12 days later she feels almost completely better, except for a slight lingering cough

• She’s looking forward to spending time with her daughter and new grandchild during their upcoming visit

• She has urged her husband and her college-aged children to get vaccinated and is committed to getting vaccinated herself early in the season each year

33

Case Study: Sarah, an 11-year-old Student

• Usually in excellent health

• Sudden onset of headache, pharyngitis, fever, chills, nasal congestion yesterday;

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

• Mother reports OTC meds providing limited relief

• Flu prevalent at her school and 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: clear to auscultation

• Rapid strep test: negative

34

Case Study: Sarah

• Given Sarah’s symptoms and 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 Sarah and her mother

35

Case Conclusion: Sarah

• You prescribe Sarah oseltamivir, 75 mg twice daily for 5 days, because

it is approved for children of Sarah’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 well enough to travel for her quiz bowl event

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

36

• Phase 3 multicenter in patients 1 to <12 years of age and influenza confirmed by RIDT

• 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 AE, deaths, adverse events of special interest, or new safety signals observed

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

*Determined via virus titer.

Baker J, et al. OPTIONS X 2019. Abstract 11756; ClinicalTrials.gov. clinicaltrials.gov/ct2/show/NCT03629184. Accessed Apr 5, 2020; Roche.

www.roche.com/investors/updates/inv-update-2019-07-03.htm. Accessed Apr 5, 2020.

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)

37

• 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. OPTIONS X 2019. Abstract 11718; Roche. www.roche.com/media/releases/med-cor-2019-09-02b.htm. Accessed Apr 5, 2020.

Measure Baloxavir (n = 374) Placebo (n = 375) P Value

Subjects developing flu 1.9% 13.6% <.0001

Subjects at high risk of flu-associated

complications developing flu

2.2% 15.4% .0435

Children <12 years of age 4.2% 15.5% .0339

Influenza A (H1N1) 1.1% 10.6% .0023

Influenza A (H3N2) 2.8% 17.5% <.0001

Incidence of AEs 22.2% 20.5% —

38

• 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

• Quicker reduction of influenza B symptoms than oseltamivir

• Faster clearance of virus than oseltamivir

• CDC does not recommend use of baloxavir in pregnant or breastfeeding women, outpatients with complicated or progressive illness, 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 Apr 5, 2020; ClinicalTrials.gov.

clinicaltrials.gov/ct2/show/NCT02949011. Accessed Apr 5, 2020; Hayden FG, et al. N Engl J Med. 2018;379:913-923; Ison MG, et al. IDSA Week,

Oct 6, 2018. Abstract LB16; Xofluza [prescribing information]. Genentech; 2019.

39

Tell Your Patients to Be Proactive…Get Flu Vaccination, Not the Flu

Oct Nov Dec Jan Feb

Month

Ca

se

s

Optimal time for

vaccination

Height of flu

season

40

PCE Action Plan

✓ Beware of potential for influenza complications, especially in higher risk patients

✓ Strongly recommend influenza vaccination for all patients older than 6 months and GET

YOURSELF VACCINATED

✓ Confirm influenza using rapid molecular assay if available; RIDT 2nd choice

✓ Consider clinical diagnosis without diagnostic lab testing for patients 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

2020 Symposia Series 1