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Treatment and Prophylaxis of Influenza

Masoud Mardani M.D.Professor of Infectious Diseases

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Seasonasl Influenza

• Prophylaxis and Treatment

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Antiviral Therapies for Influenza

Neuraminidase (NA)

Matrix protein (M2 )

M2 Inhibitors• Amantadine• Rimantadine

NA Inhibitors• Oseltamivir• Zanamivir

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Antiviral Chemoprophylaxis of Influenza

Efficacy (vs placebo or no drug)

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 A et al. JAMA. 1999;282:31.2. Hayden F et al. N Engl J Med. 1999; 341:1336.3. Hayden F et al. N Engl J Med. 2000;343:12882.4. Gravenstein S et al. J Am Med Dir Assoc. 2005;6:359.5. Peters P et al. J Am Gerontol Soc. 2001;404:1025.

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Approved Antiviral Agents for Influenza Treatment and Prophylaxis

Amantadine* Rimantadine* Zanamivir Oseltamivir

Protein target

M2 M2 NA NA

Activity A only A only A and B A and B

TherapyAdults and children of1 year

Adults only

Adults andchildren of 5 years

Adults and children of 1 year

Prophylaxis Yes YesAdults andchildren of 7 years

Yes

Treanor J. Influenza Virus. In Mandell, Douglas, and Bennett's Principles and Practice of Infectious diseases. 6th ed. New York: Elsevier/Churchill Livingstone; 2005:2072.http://www.fda.gov/bbs/topics/NEWS/2006/NEW01341.html.

*CDC recommends that the previously approved M2 inhibitors amantadine (Symmetrel) and rimantadine (Flumadine) not be used for the treatment or chemoprophylaxis of influenza A infections in the United States for the remainder of the 2005-2006 season (CDC. MMWR Dispatch. January 17, 2006).

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Recommended Daily Dosage Treatment and Prophylaxis of Influenza A and B

http://www.cdc.gov/flu/professionals/antiviralback.htm#table1

Antiviral Agent Age Groups (years)

1-5 >5

Oseltamivir

Treatment By weight 75 mg BID

Prophylaxis By weight 75 mg QD

Zanamivir

Treatment* 10 mg (2 inhalations) QD 10 mg (2 inhalations) QD

Prophylaxis* 10 mg (2 inhalations) QD 10 mg (2 inhalations) QD

CDC recommends that the previously approved M2 inhibitors amantadine (Symmetrel) and rimantadine (Flumadine) not be used for the treatment or chemoprophylaxis of influenza A infections in the United States for the remainder of the 2005-2006 season (CDC. MMWR Dispatch. January 17, 2006).

*Zanamivir approved for treatment in children >7 years, for prophylaxis in children >5 years

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Oseltamivir: Resolution of All Flu SymptomsIntent to Treat and Laboratory Documented Influenza Groups

0

20

40

60

80

100

120

Influenza Infected Intent toTreat

Hou

rs

Placebo Oseltamivir 75 mg BID

Difference = 32 hours*

*P < .001†P = .004

Treanor J et al. JAMA. 2000;283:1016-1024.

Difference = 21 hours†

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Oseltamivir TreatmentCombined RCT Database, Confirmed Influenza

Placebo Oseltamivir % Reduction

Hospitalizations

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

High-risk + elderly 13/401 (3.2%) 6/368 (1.6%)

Total 18/1063 (1.7%) 9/1350 (0.7%) 59%*

Lower Respiratory Tract Complications Leading to Antibiotic Use

Healthy adults 35/662 (5.3%) 17/982 (1.7%)

High-risk + elderly 78/401 (18.5%) 45/368 (12.2%)

Total 109/1063 (10.3%) 62/1350 (4.6%) 55%†

Kaiser L et al. Arch Intern Med. 2003;163:1667.

*P = .02; †P < .001

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Oseltamivir ResistanceEmergence During Treatment

Setting Resistance Reported/Number Patients

Rate of Emergence

Adult trials 1/350 <<1%

US pediatric trial 5/147 4%

Japanese children 7/43 16%

Japanese children 9/50 18%

Kaiser L et al. Arch Intern Med. 2003;163:1667-1672.Whitley R et al. Pediatr Infect Dis J. 2001;20:127-133. Kiso M et al. Lancet. 2004;364:759-765.

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Oseltamivir: Time to Return to NormalImportant Quality of Life Assessments

Health Status Activity Level

0

12

8

6

4

2

Placebo(n = 129)

Oseltamivir75 mg BID(n = 124)

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Placebo(n = 129)

Oseltamivir75 mg BID(n = 124)

Da

ys

*P < .001†P = .02

Treanor J et al. JAMA. 2000;283:1016-1024.

Difference = 1.9 days* Difference = 2.8 days†

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Zanamivir Resistance

• Resistance not recorded in results from clinical trials1, 2, 3

• The only zanamivir-resistant mutant identified was in a virus from an immunocompromised child4

• Particular binding mechanisms may account for low levels of resistance to zanamivir5, 6

• Particular mutants are resistant to zanamivir in vitro7, 8

1. Monto A et al. Antimicrob Agents Chemother. 2006;50:2395-2402.2. Ambrozaitis A et al. J Am Med Dir Assoc. 2005;6:367-374. 3. Herlocher M et al. J Infect Dis. 2003;188:1355-1361.4. Gubareva L et al. J Infect Dis. 1998;178:1257-1262.5. Moscona A. N Engl J Med. 2005;353:2633-2636. 6. Gupta R and Nguyen-Van-Tam J. N Engl J Med. 2006;354:1423-1424.7. Yen H et al. Antimicrob Agents Chemother. 2005;49:4075-4084.8. Mishin V et al. Antimicrob Agents Chemother. 2005;49:4515-4520.

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Influenza in ChildrenOverview

• Flu symptoms in school-age children and adolescents are similar to those in adults

– Temperature of 101°F or above, cough, muscle ache, headache, sore throat, chills, fatigue, general malaise

– Public advised to contact physician for these symptoms

• Children tend to have higher temperatures than adults, ranging from 103°F to 105°F

• Flu in preschool children and infants is hard to pinpoint, since its symptoms are so similar to infections caused by other viruses

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Influenza in Immunocompromised Patients

• Immunocompromised patients suffer more complications and have higher morbidity and mortality from influenza infection

– High rate of hospitalization and ICU admissions

– Higher rate of pulmonary complications

• 50% of BMT and 13% renal transplant patients had lower respiratory tract infections

• 50% of BMT and 7% of renal transplant patients with influenza complicated by pneumonia

• 63% progressed to pneumonia

– 43% mortality

http://www.shea-online.org/Assets/files/W_-_Seasonal_and_Pandemic_Influenza_-_Children__Immunocompromised_Hosts__Pregnant_Women__and_Nursing_Home_Residents.ppt.

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Adjusted Incidence Rates of Acute CardiopulmonaryEvents per 10,000 Women-Months for High Risk Women

Neuzil K et al. Am J Epidemiol. 1998;148:1094-1102.

Influenza In Pregnant WomenE

ven

ts p

er 1

0,0

00

wo

me

n-m

on

ths

Pregnancy Status (Weeks) *November 1-April 30 period with no influenza activity

*

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Seasonal Influenza Prophylaxis and Treatment: Summary

• Efficacious and well-tolerated medications are available for prophylaxis and treatment of seasonal influenza

• Neuraminidase inhibitors are useful to limit durationand severity of influenza if taken early– Use of M2 inhibitors is limited by widespread resistance

• Influenza prevention and treatment remain challenging in special populations such as children, pregnant women, and immunocompromised individuals like transplant recipients

Pandemic Influenza

Avian Influenza in Humans

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Avian H5N1 Swelling of the head and face in an affected bird

http://www.aphis.usda.gov/vs/birdbiosecurity/photos.html

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Avian H5N1Purple discoloration of the comb in the affected bird

http://www.aphis.usda.gov/vs/birdbiosecurity/photos.html

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Nations with Confirmed Cases H5N1 Avian Influenza (May 19, 2006)

http://pandemicflu.gov/

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H5N1 Antiviral Treatment

• Most H5N1 viruses sensitive to oseltamivir and zanamivir: 3 H5N1 virus isolates reported resistant to oseltamivir

• Most clade 1 H5N1 viruses resistant to amantadine and rimantadine (most clade 2 viruses sensitive to amantadine and rimantadine)

• Neuraminidase inhibitor treatment recommended (oseltamivir)

http://www.who.int/csr/disease/avian_influenza/guidelines/protocolfinal30_05_06a.pdf.http://www.who.int/csr/disease/avian_influenza/guidelines/pharmamanagement/en/index.html.

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Pandemic InfluenzaPotential Antiviral Agents

Class/Agent Brand Name Route

M2 inhibitors

Amantadine Symmetrel PORimantadine Flumadine PO

NA inhibitors

Zanamivir (GG167) Relenza InhaledOseltamivir (GS4104) Tamiflu PO

Peramivir (BCX-1812)* PO/IV/IM

*Investigational in US

CDC recommends that the previously approved M2 inhibitors amantadine and rimantadine not be used for the treatment or chemoprophylaxis of influenza A infections in the United States for the remainder of the 2005-2006 season (CDC. MMWR Dispatch. January 17, 2006).

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Oseltamivir Therapy in H5N1 Thailand and Vietnam, 2004-2005

Oseltamivir Treatment Number Patients Number (%)

Survivors

Yes 25 6 (24%)

No 12 3 (25%)

Writing Committee. N Engl J Med. 2005;353:1374-1385.

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Oseltamivir Resistance N1 Neuraminidase

• Frequency of drug therapy in humans– H1N1: children 16% (7/43), adults 4% (2/50)

– H5N1: 2/8 (25%)

• Single nucleotide substitution (His274Tyr), leads to– ↓ oseltamivir susceptibility (400–fold)

• Reduced replication in cell culture (>2.0 log10), leads to

– ↓ infectivity in mouse (1000-fold) and ferret (>10-fold)

– Variable ↓ pathogenicity in ferret

• Transmissible in ferret model

Ives J et al. Antiviral Res. 2002;55:307-317. Herlocher M et al. J Infect Dis. 2004;190:1627-1630.

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Management

• Most hospitalized patients with avian influenza A (H5N1) have required ventilatory support within 48 hours after admission,

• Empirical treatment with broad-spectrum antibiotics, antiviral agents, alone or with corticosteroids, have been used in most patients

• Cultivable virus generally disappears within two or three days after the initiation of oseltamivir among survivors.

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Influenza A (H5N1) Pneumonia

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Case Detection and Management

• Hospitalization: in isolation whenever possible• Antiviral Agents • These viruses are susceptible in vitro to oseltamivir. • Early treatment will provide the greatest clinical benefit.

– oseltamivir • 75 mg twice daily for five days in adults weight-adjusted

twice-daily doses for five days in children older than one year of age — twice-daily doses of 30 mg for those weighing 15 kg or less, 45 mg for those weighing more than 15 to 23 kg, 60 mg for those weighing more than 23 to 40 kg, and 75 mg for those weighing more than 40 kg) are reasonable for treating early, mild cases of influenza A (H5N1)

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• Higher doses (150 mg twice daily in adults) and

treatment for 7 to 10 days are considerations in treating severe infections, but prospective studies are needed.

– long-acting topical neuraminidase inhibitors, ribavirin and possibly, interferon alfa.

• Immunomodulators– Corticosteroids have been used frequently in treating patients

with influenza A (H5N1), with uncertain effects.

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–QUESTIONS ?

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• Should oseltamivir, zanamivir, amantadine, and/or rimantadine be used for treatment or prophylaxis?

• Should ribavirin, corticosteroids, immunoglobulin, and/or interferon be used for treatment?

• Should broad-spectrum antibiotics be used for the prevention of secondary pneumonia?

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• To answer these questions, the guidelines include a table with the recommended dose and duration of treatment and chemoprophylaxis for management of human infection with avian influenza A (H5N1) virus in different age groups.

• Recommended agents include oseltamivir, zanamivir, amantadine, and rimantadine for treatment and prophylaxis.

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•

• Groups at moderate-risk exposure are defined as those with unprotected and very close direct exposure to sick or dead H5N1 infected animals or to poultry implicated directly in human cases,

• Those involved in handling sick animals or decontaminating known infected animals or environments without proper use of personal protective equipment,

• and healthcare personnel in close contact with strongly suspected or confirmed H5N1 patients or virus-containing samples

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• To determine who should receive chemoprophylaxis:

• We defined high-risk exposure groups as household or close family contacts of a strongly suspected or confirmed H5N1 patient

• Because of potential exposure to a common environmental or poultry source as well as exposure to the index case.

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• In a nonpandemic situation, recommendations for treatment of patients with confirmed or strongly suspected infection with avian influenza A (H5N1)

• are as follows:

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• Patients should receive oseltamivir treatment as soon as possible (strong recommendation).

• Clinicians might administer zanamivir (weak recommendation).

• If neuraminidase inhibitors are available, clinicians should not administer amantadine alone as a first-line treatment (strong recommendation).

• If neuraminidase inhibitors are not available and especially if the virus is known or likely to be susceptible, clinicians might administer amantadine as a first-line treatment (weak recommendation).

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• If neuraminidase inhibitors are available, clinicians should not administer rimantadine alone as a first-line treatment (strong recommendation).

• If neuraminidase inhibitors are not available and especially if the virus is known or likely to be susceptible, clinicians might administer rimantadine as a first-line treatment (weak recommendation).

• If neuraminidase inhibitors are available and especially if the virus is known or likely to be susceptible, clinicians might administer a combination of neuraminidase inhibitor and M2 inhibitor (weak recommendation). This should only be done in the context of prospective data collection.

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• High-risk exposure groups should receive oseltamivir as chemoprophylaxis continuing for 7 to 10 days after the last known exposure (strong recommendation).

• In moderate-risk exposure groups, oseltamivir may be administered as chemoprophylaxis, continuing for 7 to 10 days after the last known exposure (weak recommendation).

• Low-risk exposure groups should probably not receive oseltamivir for chemoprophylaxis (weak recommendation).

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Pandemic InfluenzaProphylaxis and Treatment Summary

• Combating an influenza pandemic includes seasonal influenza vaccination, social distancing techniques, possible ring chemoprophylaxis

• Current antiviral possibilities for both prophylaxis and treatment include NA inhibitors and M2 inhibitors

– NA inhibitors in limited supply and must be administered within 48 hours from symptom onset

– M2 inhibitors could be useful against pandemic influenza, but resistance to M2 inhibitors may develop rapidly

• Combinations of antivirals and of antivirals plus host immune response modifiers warrant study

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SeasonalInfluenza

Preparedness

Pandemic Influenza

Preparedness