Treatment of Influenza in Adults

Andrew T. Pavia M.D.George and Esther Gross Professor and Chief

Pediatric Infectious DiseasesUniversity of Utah

Treatment of Influenza in Adults

Andrew T. Pavia M.D.

George and Esther Gross Professor and Chief

Pediatric Infectious Diseases

University of Utah

Outline

• Goals of treatment

• Antivirals for seasonal influenza– Prophylaxis

– Treatment

– Resistance

• Complications of influenza

• Gaps and priorities

Rates of Influenza Hospitalization by Age-Group, 1981-1983

0

50

100

150

200

250

300

<5 5 - 9 10 - 14 15 -19 20 - 24 25 - 34 35 - 44 45 - 54 55 - 64 >65

Age group

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Terebuh, Uyeki, Fukuda. PIDJ 2003;22:S231

*Thompson, et al. JAMA 2003**Respiratory & Circulatory

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Influenza-Associated Deaths By Age Group*

M2 Channel Inhibitors (Adamantines)

Neuraminidase Inhibitors

Oseltamivir Bound to Neuraminidase and Location of Key Resistance Codons

Monto, A. S. N Engl J Med 2005;352:323-325

Normal Budding and Release of Influenzavirus from an Infected Cell (Panel A) and Release

Restricted by a Neuraminidase Inhibitor (Panel B)

Antiviral Chemoprophylaxis of Influenza

Strategy AM/RM ZNV OSEL

Seasonal

Non-immunized adults 85-91% 84%1 84%

Immunized NH elderly 58-75% ? 92%

Post-Contact/Post-exposure

Households 3-100% 82%3 67-89%2

Nursing homes Variable 61%4 Yes5

1 Monto JAMA 1999 282:312 Hayden NEJM 1999 341:13363 Hayden NEJM 2000 343:128824 Gravenstein J Am Med Dir Assoc 6:359 20055 Peters J Am Gerontol Soc 2001 404:1025

Antiviral Resistance to M2 Inhibitors in Community Isolates of A/H3N2, 1995-2005

Bright et al. Lancet 2005 Oct 1 366:1175

• 109/120 (91%) of A H3N2 isolates in 2005-2006 have high level resistance to M2 ion channel inhibitors

• 3/3 (100%) of A H1N1 sensitive to M2 drugs

• 123/123 isolates sensitive to NI drugs

• “CDC recommends that neither amantadine nor rimantadine be used for the treatment or chemoprophylaxis of influenza A infections in the United States for the remainder of the 2005-2006 season”

Oseltamivir Treatment: Antiviral Effect

Treanor et al. JAMA 283:1016, 2000Whitley et al. PIDJ 20:127, 2001

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

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0 2 4 6 8 10

p<0.05

0.0

0.5

1.0

1.5

2.0

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3.5

4.0

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Day

Placebo

Oseltamivir 75 BID

Oseltamivir 150 BID

Adults Children

Effects of Oseltamivir on Time to Resolution of all Flu Symptoms

0

20

40

60

80

100

120

Influenza infected Intent to treat

Hou

rs

Placebo mg bid 75

21 hours**32 hours*

*p<0.001**p=0.004Treanor et al. JAMA 283 ;2000

Effects of Oseltamivir on Return to Normal Activities

*p<0.001**p=0.02Treanor et al. JAMA 283 ;2000

Time to return to normalhealth and activity (days)

Health status Activity

*

**

1.9d

2.8d

0

12

8

6

4

2

Placebo(n=129)

Oseltamivir75mg bid(n=124)

10

Placebo(n=129)

Oseltamivir75mg bid(n=124)

Aoki et al. J Antimicrob Chemo 51:123, 2003

Oseltamivir: Effect of Time to Treatment

Oseltamivir Treatment Combined RCT Database: Effect on Hospitalizations

Hospitalizations % Reduction

Placebo Oseltamivir

Healthy adults 5/662 (0.8%) 3/982 (0.3%) 60%

High-risk + elderly

13/401 (3.2%) 6/368 (1.6%) 50%

Total 18/1063 (1.7%) 9/1350 (0.7%) 59% (P=0.019)

Kaiser et al. Arch Intern Med 163:1667, 2003

Respiratory events

leading to antibiotics

All LRTI’s

Bronchitis

Pneumonia

Any Antibiotic use

Placebo

(n=1063)

10.3%

8.2%

1.8%

19.0%

Oseltamivir

(n=1350)

4.6%

3.9%

0.7%

14.0%

Risk

Reduction

55%*

52%**

61%

26%*

* P < 0.001**P < 0.01Kaiser et al. Arch Intern Med 163:1667, 2003

Oseltamavir for Influenza Combined RTC data: Effect on Complications and Antibiotic Use

Respiratory events leading to antibiotics

Any event

Upper respiratory

Lower respiratory

Acute bronchitis

Pneumonia

Hospitalizations

Placebo(n=765)

18%

8%

9%

7%

2%

0.4%

Zanamivir (n=807)

13%

7%

5%

5%

1%

0.4%

RiskReduction

28%*

10%

40%*

Kaiser et al. Arch Intern Med 160: 3234, 2000*p<0.05

Inhaled Zanamavir for Influenza Meta Analysis: Effect on Complications and Antibiotic Use

Impact of Antiviral Therapy on Influenza Complications, Retrospective Analysis,

Nursing Home Residents, Canada

0

10

20

30

40

50

60

Comp Hosp Death

No Rx (23)

Amantadine (19)

Osel <48 h (50)

Osel >48 h (23)

Pe

rce

nt

Bowles et al. J Am Geriat Soc 2002

Oseltamivir Resistance Emergence During Treatment

SettingResistance reported/Patients

Rate of emergence

Adult trials 1350 <<1%

US Pediatric Trial 5/147 4%

Japanese Children 7/43 16%

Japanese Children 9/50 18%

Kaiser, Arch Int Med 2003Whitley PIDJ 2003Kiso Lancet 2004

Summary of Ferret Transmission Experiments

• The R292K mutant did not transmit.

• The E119V and H274Y mutants DID transmit, although H274Y required a 100 fold higher dose for infection.

• The sequence of virus from recipient ferret revealed the NA mutation was still present.

• NA resistant virus appears to be less fit and transmission impaired

Herlocher JID 2004;190:167

Summary Antiviral Resistance in Influenza

M2 InhibitorOseltamivir

Magnitude of resistance High High

Primary resistance 1-90% No

Frequency during therapy High Low

Rapid development Yes Variable

Person-person transmission Yes Not-to-date

Pathogenicity Yes Reduced*

Competition with wild-type Yes* Reduced*

*Animal models

Beliefs and Use of Antivirals for Influenza

• Prescribed antivirals during 2003 2004 season– 76% Temple TX vs 48% Springfied MA

• Belief that antivirals– Shortened illness duration: 85-88%– Prevents complications: 25-31%– Decreases hospitalization: 42-44%

• Predictors of prescribing– Specialty: FP > ER > Peds > Int Med– Perform rapid test– Beliefs in effect on complications, hospitalization

and mortalityRothberg. CID 2006;42:95

Influenza Complications 2003-2004: EIN Survey of Infectious Disease Physicians

(Podewills L CID 2005:40:1693)

Necrotizing Pneumonia Due to PVL Positive MRSA After Influenza

Francis JL. CID 2005; 40:100

Questions About Managing Influenza Complications

• Are there predictors of bacterial complications?

• What is the current spectrum of bacterial complications?– Should empiric regimens be targeted at Ca-

MRSA?

– What is the role of influenza in the changing epidemiology of complicated pneumonia?

• Do antivirals influence early viral complications?– Encephalopathy, myositis, myocarditis, ARDS

New Drugs, New Targets

T-705; ribavirin, viramidine

Peramavir;A-315675,R-118958

Cyanovirin N

AmantadineRimantadine

Influenza Treatment - Questions

• Optimal use and deployment of current antivirals

• What are the contributors to NA resistance?– Will more fit variants emerge and persist?

• Can treatment decrease the R0 during outbreaks?

• Can new agents work if started later?

• Can we treat early viral complications?

• Can we manipulate immune response to influenza for treatment?