1. Treatment of Influenza in Adults Andrew T. Pavia M.D. George and Esther Gross Professor and Chief Pediatric Infectious Diseases University of Utah

2. Treatment of Influenza in Adults Andrew T. Pavia M.D. George and Esther Gross Professor and Chief Pediatric Infectious Diseases University of Utah

3. Outline Goals of treatment Antivirals for seasonal influenza –Prophylaxis –Treatment –Resistance Complications of influenza Gaps and priorities

4. Rates of Influenza Hospitalization by Age-Group, 1981-1983 Terebuh, Uyeki, Fukuda. PIDJ 2003;22:S231

5. *Thompson, et al. JAMA 2003 **Respiratory & Circulatory ** 0.6 0.40.5 7.5 98.3 0 20 40 60 80 100 120 < 1 Yrs1 - 4 Yrs5 - 49 Yrs50 - 64 Yrs65+ Yrs Age Group R&C Deaths Per 100,000 Person Years Influenza-Associated Deaths By Age Group*

6. M2 Channel Inhibitors (Adamantines)

7. Neuraminidase Inhibitors

8. Oseltamivir Bound to Neuraminidase and Location of Key Resistance Codons

9. 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)

10. Antiviral Chemoprophylaxis of Influenza StrategyAM/RMZNVOSEL Seasonal Non-immunized adults85-91%84% 1 84% Immunized NH elderly58-75%?92% Post-Contact/Post- exposure Households3-100%82% 3 67-89% 2 Nursing homesVariable61% 4 Yes 5 1 Monto JAMA 1999 282:31 2 Hayden NEJM 1999 341:1336 3 Hayden NEJM 2000 343:12882 4 Gravenstein J Am Med Dir Assoc 6:359 2005 5 Peters J Am Gerontol Soc 2001 404:1025

11. Antiviral Resistance to M2 Inhibitors in Community Isolates of A/H3N2, 1995-2005 Bright et al. Lancet 2005 Oct 1 366:1175

12. 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”

13. Oseltamivir Treatment: Antiviral Effect Treanor et al. JAMA 283:1016, 2000 Whitley et al. PIDJ 20:127, 2001 Adults Children

14. Effects of Oseltamivir on Time to Resolution of all Flu Symptoms 21 hours** 32 hours* *p<0.001 **p=0.004 Treanor et al. JAMA 283 ;2000

15. Effects of Oseltamivir on Return to Normal Activities *p<0.001 **p=0.02 Treanor et al. JAMA 283 ;2000 Time to return to normal health and activity (days) Health statusActivity * ** 1.9d 2.8d 0 12 8 6 4 2 Placebo (n=129) Oseltamivir 75mg bid (n=124) 10 Placebo (n=129) Oseltamivir 75mg bid (n=124)

16. Aoki et al. J Antimicrob Chemo 51:123, 2003 Oseltamivir: Effect of Time to Treatment

17. Oseltamivir Treatment Combined RCT Database: Effect on Hospitalizations Hospitalizations% Reduction PlaceboOseltamivir Healthy adults5/662 (0.8%)3/982 (0.3%)60% High-risk + elderly 13/401 (3.2%)6/368 (1.6%)50% Total18/1063 (1.7%)9/1350 (0.7%)59% (P=0.019) Kaiser et al. Arch Intern Med 163:1667, 2003

18. 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 < 0.01 Kaiser et al. Arch Intern Med 163:1667, 2003 Oseltamavir for Influenza Combined RTC data: Effect on Complications and Antibiotic Use

19. 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% 1% 0.4% Risk Reduction 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

20. Impact of Antiviral Therapy on Influenza Complications, Retrospective Analysis, Nursing Home Residents, Canada Percent Bowles et al. J Am Geriat Soc 2002

21. Oseltamivir Resistance Emergence During Treatment Setting Resistance reported/Patients Rate of emergence Adult trials1350<<1% US Pediatric Trial5/1474% Japanese Children7/4316% Japanese Children9/5018% Kaiser, Arch Int Med 2003 Whitley PIDJ 2003 Kiso Lancet 2004

22. 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

23. Adverse Effects of Antivirals for Influenza DrugFrequentSevere Amantadine Insomnia, irritability, anxiety, anorexia, nausea, strange dreams, confusion Seizures, psychosis, arrythmias Rimantadine Similar to amantadine but less common Rare: Seizures, ataxia, hallucinations ZanamavirCough, nausea (2%) Bronchospasm, allergic reaction Oseltamivir Nausea, vomiting, headache Exacerbation of DM

24. Summary Antiviral Resistance in Influenza M2 InhibitorOseltamivir Magnitude of resistanceHighHigh Primary resistance 1-90%No Frequency during therapyHigh Low Rapid developmentYesVariable Person-person transmissionYesNot-to- date PathogenicityYesReduced* Competition with wild-typeYes*Reduced* *Animal models

25. 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 mortality Rothberg. CID 2006;42:95

26. Influenza Complications 2003-2004: EIN Survey of Infectious Disease Physicians (Podewills L CID 2005:40:1693)

27. Necrotizing Pneumonia Due to PVL Positive MRSA After Influenza Francis JL. CID 2005; 40:100

28. 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

29. New Drugs, New Targets T-705; ribavirin, viramidine Peramavir; A-315675, R-118958 Cyanovirin N Amantadine Rimantadine

30. 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?