Reducing the Risk: Advanced Influenza Treatment Options for the 2020-2021 Season
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Reducing the Risk: Advanced Influenza Treatment Options for the 2020-2021 Season
Learning Objectives
• 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
2Epidemiology and Burden of Seasonal Influenza in the US
Annual Estimates by the CDC From 10 Influenza • Rates of serious illness and death
Seasons (2010-2011 through 2019-2020)* from seasonal influenza are
highest in persons >65 years, in
9.3 to 45 million illnesses childrenPneumonia, Influenza, and COVID-19 Mortality: 2017-2020
28 Number of influenza coded deaths 18,000
26
Number of COVID-19 coded deaths 16,000
24
% of All Deaths Due to PIC
% of deaths due to PIC
22 14,000
Number of Deaths
Seasonal baseline
20
Epidemic threshold 12,000
18
16 10,000
14
12 Epidemic Threshold 8000
10
6000
8
6 4000
4
2000
2 Seasonal baseline
0 0
40 50 10 20 30 40 50 10 20 30 40 50 10 20 30 40 50 10 20 30 40
2017 2018 2019 2020
MMWR Week
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. 4Pandemics: Influenza and COVID-19 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) *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. 5
Influenza Virus
• The family Orthomyxoviridae has 3 genera, or types, Hemagglutinin
Hemagglutinin NANA
that infect humans: influenza viruses A, B, and C
NSNS2
2
• Influenza A virus subtypes are based on specific HA
and NA glycoproteins that they express
− 18 HAs (H1-H18)
Lipid
Lipid
− 11 NAs (N1-N11) bilayer
bilayer
− Potential for 144 HA and NA combinations (some
HAs and NAs cannot work together)
Ion Ion
• Birds are reservoir for 16 HA and 9 NA subtypes channel
channel
Matrix
Matrix
protein
protein
Negative-sense
HA = hemagglutinin; NA = neuraminidase; NS = nonstructural protein; RNA = ribonucleic acid; ss = single stranded. ssRNA
Clancy S. Nature Education. 2008;1:83; Vemula SV, et al. Viruses. 2016;8:96. 6Case Study: Victor, a 55-Year-Old Male of Hispanic and
Native-American Descent
• Victor visits your primary care practice in November for an annual checkup
• Height: 5 ft 8 in
• Weight: 265 lb (BMI = 40.3 kg/m 2)
• 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
7
7Focus on Patients at Higher Risk for Influenza Complications Demographic factors Chronic Medical Conditions • Adults aged ≥65 years • Asthma • Children
Influenza Vaccines: 2020-2021 Influenza Season
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 Egg based† ≥65 years IM Prefilled syringe
MF59 adjuvant
IIV3 standard dose with Egg based† ≥65 years IM Prefilled syringe
MF59 adjuvant
RIV4 Recombinant HA ≥18 years IM Prefilled syringe
LAIV4‡ Egg based† 2 to 49 years Intranasal Single-use intranasal spray
*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. 9Vaccine Composition: 2020-2021 Influenza Season Egg-based influenza vaccines (ie, vaccines Cell culture-based inactivated (ccIIV4) and other than ccIIV4 and RIV4) will contain HA recombinant (RIV4) influenza vaccines will derived from: contain HA derived from: Influenza A/Guangdong-Maonan/SWL1536/2019 Influenza A/Hawaii/70/2019 (H1N1)pdm09-like (H1N1)pdm09-like virus virus Influenza A/Hong Kong/2671/2019 (H3N2)-like Influenza A/Hong Kong/45/2019 (H3N2)-like virus virus Influenza B/Washington/02/2019 (Victoria Influenza B/Washington/02/2019 (Victoria lineage)-like virus lineage)-like virus Influenza B/Phuket/3073/2013 (Yamagata Influenza B/Phuket/3073/2013 (Yamagata lineage)-like virus (for quadrivalent vaccines only) lineage)-like virus ACIP = Advisory Committee on Immunization Practices. Grohskopf LA, et al. MMWR Recomm Rep. 2020;69:1-24. 10
Case Study (cont’d): Victor
• 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
11
11Influenza Symptoms and Clinical Course
• Classic flu • Complications
– Abrupt onset of fever, chills, myalgia, – Sinusitis, otitis media
headache, fatigue, nonproductive cough, – Pneumonia—primary viral or secondary bacterial
sore throat, rhinitis
– Coinfections with other bacterial/viral pathogens
– Some people may have GI symptoms
– Exacerbation of underlying medical conditions
(eg, nausea, diarrhea)
(eg, COPD, asthma, cystic fibrosis, diabetes)
– Typically resolves within 3 to 7 days
– Associations with cardiovascular events (eg, MI,
– Cough, malaise can persist for >2 weeks stroke), parotitis
• Mild illness without fever may also occur
• Atypical presentations may occur in elderly,
immunocompromised hosts, infants
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. 12Differential Diagnosis of URIs, Influenza, and COVID-19 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 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. 13
Influenza vs COVID-19: Differentiation Considerations
Influenza COVID-19
Transmission: Respiratory droplet, contaminated Transmission: Respiratory droplet, contaminated
surfaces 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
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. 14Respiratory Syncytial Virus Infection (RSV) • 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 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. 15
Multiplex PCR: A New Testing Option • 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 US Food and Drug Administration. Press Release. 2020. https://www.fda.gov/media/142438/download 16
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
Interpreting Influenza Testing Results
• Use information on local influenza activity (eg, from health
Cannot rule out flu, department), patient history and travel, clinical signs/symptoms,
Negative especially if test does and physical examination to decide if treatment is indicated
result not have high sensitivity • Initiate antiviral treatment if flu is suspected and patient is at high
or if specimen was risk for complications or is being admitted to the hospital
collected >4 days after • Consider additional diagnostic testing for other pathogens
illness onset
• Initiate antiviral treatment if indicated
Positive result Influenza virus
• Implement infection prevention and control measures
(A or B) infection likely
• Consider additional influenza testing if subtype info is desired
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. 18When to Treat Influenza: Complicated vs Uncomplicated 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 without known risk factors for severe illness if treatment can be initiated within 48 hours of onset Uyeki TM, et al. Clin Infect Dis. 2019;68:895-902. 19
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. 20
Influenza Antivirals: Mechanisms of Action
Adsorption Packaging and budding Release
Receptor
containing
sialic acid
M2 inhibition
Antibodies (adamantanes)
Endocytosis mRNA NA inhibitors
Cap snatching (oseltamivir,
and fusion Uncoating (baloxavir, peramivir,
RNA (+/-) zanamivir)
pimodivir)
RNA polymerase
inhibition
(favipiravir)
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. 21FDA-approved Antiviral Agents for Influenza Treatment • 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 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. 22
Antivirals for Influenza: Dosing Considerations
Age Route of
Antiviral Dosage Indication Administration Precautions
Baloxavir Single oral dose ≥12 years Tablets Do not take with:
• 40 mg for patients 40 to 80 kg • Dairy products or calcium-fortified
• 80 mg for patients ≥80 kg beverages
• Polyvalent cation-containing
laxatives
Oseltamivir Twice daily for 5 days ≥2 weeks Capsule or oral
• 75 mg (≥13 years) suspension —
• Weight based (1-12 years)
• 3 mg/kg (2 weeks-1 year)
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
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. 23Antivirals for Influenza: Adverse Events (AEs)
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*
*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
24 [prescribing information], BioCryst Pharmaceuticals; 2018; Relenza [prescribing information]. GlaxoSmithKline; 2018; Tamiflu [prescribing
information]. Genentech; 2019; Xofluza [prescribing information]. Genentech; 2019. 24CAPSTONE-1: Time to Alleviation of Symptoms
With Baloxavir vs Placebo
100 ++ • Phase 3 study
+
+
+ + ‒ 1436 otherwise healthy patients
Patients Who Did Not Have
Symptom Alleviation (%)
80 +
+ Placebo
‒ 12 to 64 years of age
60
‒ Symptomatic uncomplicated flu
40
Baloxavir + • Time to alleviation of symptoms
+
20
++
+ +
‒ Baloxavir group: 53.7 hours
++ + + + +++++++ ‒ Placebo group: 80.2 hours (PCAPSTONE-2: Baloxavir vs Placebo or Oseltamivir
in Patients at High Risk for Influenza Complications
• 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
P Value P Value
Measure* Baloxavir Placebo Oseltamivir
(Baloxavir vs Placebo) (Baloxavir vs Oseltamivir)
Overall TTIIS 73.2 h 102.3 hCase Conclusion
• 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
27Case 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/m 2); 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
28Case 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
29Case 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
30MINISTONE-2: Baloxavir vs Oseltamivir in Pediatric Patients With Influenza-like Symptoms • Phase 3 multicenter study in patients 1 to
BLOCKSTONE: Baloxavir Prophylaxis vs Placebo in Subjects
Living With Someone With Confirmed Influenza
• Phase 3 randomized study assessing Percentage of household contacts infected
post-exposure prophylaxis in after treatment with baloxavir or placebo
unvaccinated household contacts of
30
influenza-infected patients (influenza
PConsiderations Regarding Baloxavir
• 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
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. 33PCE 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
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