Gaylord National Resort & Convention Center National Harbor, Maryland April 12, 2008

1. Gaylord National Resort & Convention Center National Harbor, Maryland April 12, 2008 2008 Symposia Series 1 1 1

2. Strategies for Preventing Herpes Zoster and Postherpetic Neuralgia: Are Your Patients Adequately Protected? M. Susan Burke, MD Clinical Assistant Professor of Medicine Thomas Jefferson University Philadelphia, Pennsylvania Director, Internal Medical Clinical Care Center Lankenau Hospital Wynnewood, Pennsylvania

3. 0 Do you routinely recommend and administer the herpes zoster vaccine to your patients who are ≥60 years of age? • Yes • No Use your keypad to vote now!

4. Faculty Disclosure • Dr Burke:advisory board: Merck & Co., Inc.; speakers bureau: Merck & Co., Inc., Pfizer Inc

5. Learning Objectives • Discuss the natural history and public health burden of herpes zoster and postherpetic neuralgia (PHN) • Review the benefits and limitations of current treatment options for herpes zoster and PHN • Evaluate clinical trial data on the efficacy and safety of herpes zoster vaccination

6. Low Adult Immunization Rates • Only 2% of adults ≥60 years of age received herpes zoster vaccination in its first year of availability (2006) • Only 2% of adults aged 18 to 64 years reported receiving Tdap • 44% of adults >65 years of age reported receiving tetanus vaccination in the previous decade • Only 10% of women aged 18 to 26 years reported receiving at least 1 dose of the 3-dose human papillomavirus (HPV) vaccine course CDC and National Foundation for Infectious Diseases news conference, January 23, 2008. Anne Schuchat, MD, Assistant Surgeon General, United States Public Health Service; Director, National Center for Immunization and Respiratory Diseases, CDC. Michael N. Oxman, MD, Professor, University of California, San Francisco; Staff Physician, Infectious Disease Section, VA Medical Center, San Diego. Kristin Nichol, MD, MPH, Chief of Medicine, Minneapolis VA Medical Center; Professor of Medicine and Vice Chair, Department of Medicine, University of Minnesota.

7. Natural History, Epidemiology, and Health Burden of Herpes Zoster and PHN

8. Varicella Exposure Silent Reactivation? VZV T Cells Zoster Threshold Herpes Zoster Varicella Age Natural History of Herpes Zoster VZV = varicella-zoster virus Adapted from Kost RG, Straus SE. N Engl J Med. 1996;355:32-42; Hope-Simpson RE. Proc R Soc Med. 1965;58:9-20.

9. Case Study

10. Case Study 1 • A 61-year-old woman was recently diagnosed with cancer in her left breast and underwent port placement for chemotherapy. Several days later she developed burning, itching, and severe pain on her left chest (near the port site), arm, and back • A few days later, she developed a vesicular rash • She was unable to sleep because of excruciating discomfort • She cannot tolerate even contact with clothing to the affected area

11. Herpes Zoster Rash Photo provided courtesy of M. Susan Burke, MD, Director, Internal Medicine Clinical Care Center, Lankenau Hospital.

12. 0 What factors in this patient’s history may have predisposed her to the development of herpes zoster? • Impaired cell immunity due to advancing age, diseases, or immunosuppressive therapy • Psychological stress • Physical trauma • All of the above • None of the above Use your keypad to vote now!

13. Risk of Herpes Zoster Lifetime risk of herpes zoster is estimated to be 1 in 5 individuals1 50% of individuals living until 90 years of age will develop herpes zoster2 Risk factors for herpes zoster include Advancing age1-3 (reduced VZV-specific cell-mediated immunity [CMI]) Global reduction in CMI HIV/AIDS1,2 Hematologic and neoplastic malignancy1,2 Bone marrow and organ transplants1,4 Immunosuppressive therapy1,2 Psychological stress5 Physical trauma5 1Gnann JW Jr, Whitley RJ. N Engl J Med. 2002;347:340-346; 2Johnson RW, Whitton TL. Expert Opin Pharmacother. 2004;5:551-559;3LevinMJ et al. J Infect Diseases. 2008;197:825-835; 4Kawasaki H et al. J Pediatr. 1996;128:353-356; 5Thomas SL, Hall JA. Lancet Infect Dis. 2004;4:26-33. 13

14. Incidence of Herpes Zoster Increases With Age Estimated 1 million cases in the United States annually, which will likely increase as population ages 2000 Women 1629 Men 1500 1122 1118 Rate Per 100,000 Person-Years 1000 876 640 495 500 318 307 262 201 194 184 121 90 54 39 0 0-14 15-24 25-34 35-44 45-54 55-64 65-74 ≥75 Age (Years) Donahue JG et al. Arch Intern Med. 1995;155:1605-1609; Oxman MN et al. N Engl J Med. 2005;352:2271-2284.

15. Complications of Herpes Zoster Gnann JW Jr, Whitley RJ. N Engl J Med. 2002;347:340-346; Arvin AM. Clin Microbiol Rev. 1996;9:361-381;Moriuchi K, Rodriguez W. Pediatr Infect Dis J. 2000;19:648-653.

16. Postherpetic Neuralgia • Chronic neuropathic pain that persists or develops after herpes zoster rash has healed1 • Recent definitions include pain 90-120 days after rash onset1,3 • Clinical features of PHN include2 • Constant aching and burning, intermittent lancinating or stabbing pain, allodynia, hyperpathia • Risk factors include3 • Advancing age, severity of acute pain and rash, painful prodrome, and number of affected dermatomes • Incidence and duration increase with advancing age4 1Oxman MN et al. N Engl J Med. 2005;352:2271-2284; 2Wood MJ, Easterbrook P. Shingles, scourge of the elderly. In: Sacks SL et al, eds. Clinical Management of Herpes Viruses. Amsterdam: IOS Press; 1995:193-209; 3Jung BF. Neurology. 2004;62:1545-1551; 4 Kost RG, Straus SE. N Engl J Med. 1996;355:32-42.

17. Impact of PHN on Quality of Lifein Older Adults Schmader KE. Clin J Pain. 2002;18:350-354; Chidiac C et al. Clin Infect Dis. 2001;33:62-69; Lydick E et al. Qual Life Res. 1995; 4:41-45; Katz J et al. Clin Infect Dis. 2004;39:342-348; Coplan PM et al. J Pain. 2004;5:344-356.

18. Diagnosis of Herpes Zoster

19. Acute Herpes Zoster: Clinical Manifestations • Prodrome of dermatomal pain ≥2-5 days • Rash characteristics • Initially maculopapular, then vesicular with an erythematous base • Unilateral, although can slightly overlap midline • Usually involves 1 or 2 dermatomes • May be associated with pain or other abnormal sensations • Evolves over 7-10 days, healing over next 2-4 weeks • Reactivation may involve pain without rash (zoster sine herpete) Oxman MN. Clinical manifestations of herpes zoster. In: Arvin AM, Gershon AA, eds. Varicella-Zoster Virus: Virology and Clinical Management. Cambridge, UK: Cambridge University Press; 2000:246-275.

20. Acute Herpes Zoster Rash Order of rash progression Vesicles Pustular lesions Lesions crust over Resolution of rash Photo and slide courtesy of John W Gnann, Jr, MD.

21. Herpes Zoster Rash Photo provided courtesy of Dr. Kenneth Schmader, Associate Professor of Medicine – Geriatrics, Duke University School of Medicine.

22. Trigeminal Zoster Photo provided courtesy of M. Susan Burke, MD, Director, Internal Medicine Clinical Care Center, Lankenau Hospital.

23. Pitfalls in Diagnosis Prodrome of acute pain and paresthesias may be mistaken for other painful conditions1 Migraine, glaucoma, myocardial infarction, pleurisy, duodenal ulcer, cholecystitis, appendicitis, and biliary or renal colic Rash can appear similar to other rashes Zosteriform herpes simplex is the most frequent error in diagnosis2 Can be linear, but heals more rapidly, is likely to have less pain, and may recur in same area2 If indicated, only reliable way to distinguish between the two is with laboratory testing (PCR, culture, DFA)2,3 Occasional confusion with contact dermatitis HSV = herpes simplex virus; DFA = direct immunofluorescence assay; PCR = polymerase chain reaction. 1Oxman MN. Clinical manifestations of herpes zoster. In: Arvin AM, Gershon AA, eds. Varicella-Zoster Virus: Virology and Clinical Management. Cambridge, UK: Cambridge University Press; 2000:246-275; 2Rűbben A et al. Br J Dermatol. 1997;137:256-261; 3Gershon AA et al. Varicella-zoster virus. In: Murray PR et al, eds. Manual of Clinical Microbiology. 6th ed. Washington, DC: ASM Press; 1995:884-894. 23

24. Recurrent Herpes Simplex Photo provided courtesy of M. Susan Burke, MD, Director, Internal Medicine Clinical Care Center, Lankenau Hospital.

25. Contact Dermatitis Reprinted with permission from DermNet. Available at: http://dermnet.com. Accessed February 4, 2008.

26. Treatment Strategies for Herpes Zoster and PHN

27. Case Study 1 (cont’d) • The patient was started on • Valacyclovir 1000 mg 3 times per day for 7 days • Oxycodone 10 mg/acetaminophen 650 mg every 4-6 hours as needed • Gabapentin 300 mg, titrated up to 300 mg tid over the next 2 weeks • Silver sulfadiazine cream applied 1-2 times per day, and diphenhydramine 25 mg every 6 hours as needed for itching

28. 0 Antiviral therapy administered within 72 hours of rash onset can reliably prevent PHN. • True • False • Unsure Use your keypad to vote now!

29. Pharmacologic Management of Herpes Zoster: Antivirals • Most widely used treatment • Nucleoside analogs block viral replication1 and promote rash healing2 • 3 agents available • Acyclovir3: 800 mg 5x per day, 7-10 days • Famciclovir4: 500 mg q8h, 7 days • Valacyclovir5: 1000 mg 3x per day, 7 days • Shown to accelerate rash healing and resolution of acute pain (days 1-30)1 • Effective when administered within 72 hours of rash onset; efficacy beyond 72 hours is unknown1,6 • Do not reliably prevent PHN1,6 1Kost RG, Straus SE. N Engl J Med. 1996;335:32-42; 2Gnann JW Jr, Whitley RJ. N Engl J Med. 2002;347:340-346; 3Zovirax [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2004; 4Famvir [package insert]. East Hanover, NJ: Novartis Pharmaceuticals; 2002; 5Valtrex [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2005; 6Mounsey AL et al. Am Fam Physician. 2005;72:1075-1080.

30. Management Strategies:Acute Herpes Zoster CNS = central nervous system; NSAIDs = nonsteroidal anti-inflammatory drugs. Physicians’ Desk Reference. 62th ed. Montvale, NJ: Thomson PDR; 2008; Montes LF et al. Cutis. 1986;38:363-365; Kalibala S et al. AIDS Action. 1990;10:2-3.

31. Case Study 1 (cont’d) • The patient’s rash resolved about 1 month after initial onset, but she is still experiencing discomfort in the same area. She returns to the clinic several times over the course of the next 6 months, during which time gabapentin was titrated up slowly to 2400 mg per day in divided doses and opioid medication was discontinued, as she no longer required it • She presents again 7 months after rash onset because her pain has increased. She ran out of gabapentin 2 weeks ago

32. Treatments for PHN: Pain Response and Adverse Event Profiles Gabapentin, pregabalin, lidocaine patch 5%, and topical capsaicin are approved by the Food and Drug Administration (FDA) for the treatment of PHN. 1Rowbotham M et al. JAMA. 1998;280:1837-1842; 2Dworkin RH et al. Neurology. 2003;60:1274-1283; 3Pappagallo M, Haldey EJ. CNS Drugs. 2003; 17:771-780; 4Watson CPN, Babul N. Neurology. 1998;50:1837-1841; 5Raja SN et al. Neurology. 2002;59:1015-1021; 6Davies PS, Galer BS. Drugs. 2004;64:937-947.

33. Limitations of PHN Treatments • PHN is difficult to treat • Therapy does not work for every patient • Effect of therapy is often modest • Therapy must be individualized • Introduce and modify treatments sequentially to determine their efficacy and tolerability • Titrate dose so benefits exceed side effects • Introduce treatments separately Comorbid illness, the risk of drug interactions, and side effects must be considered when treating elderly patients with PHN Adapted from Kost RG, Straus SE. N Engl J Med. 1996;335;32-42.

34. Case Vignette

35. Reducing the Incidence and Severity of Herpes Zoster and PHN With Herpes Zoster Vaccination

36. Herpes Zoster Herpes Zoster Vaccination Varicella Exposure Silent Reactivation? ZosterVaccination VZV T cells Zoster Threshold Varicella Age Adapted from Kost RG, Straus SE. N Engl J Med. 1996;355:32-42; Hope-Simpson RE. Proc R Soc Med. 1965;58:9-20.

37. Shingles Prevention Study • A VA Cooperative Study to determine whether zoster vaccine decreased the incidence and/or severity of herpes zoster and PHN • Randomized, double-blind, placebo-controlled • 22 US sites (VA and university medical centers) • Enrolled 38,546 adults ≥60 years of age • 46% ≥70 years of age (>6.6% ≥80 years of age) • Study end points • Reduction in burden of illness (composite of incidence, severity, and duration of herpes zoster) • Incidence of herpes zoster and PHN VA = Department of Veterans Affairs. Oxman MN et al. N Engl J Med. 2005;352:2271-2284.

38. 0 Herpes zoster vaccination reduces the burden of illness associated with zoster by… • ~31% • ~41% • ~61% • 100% Use your keypad to vote now!

39. Vaccine Efficacy for Herpes Zoster Burden of Illness 9 P<.001 8 Vaccine 7 Placebo 6 Herpes Zoster Burden of Illness 5 4 3 2 1 0 All 60-69 70 CI = confidence interval Oxman MN et al. N Engl J Med. 2005;352:2271-2284. Age (Years)

40. Herpes Zoster PHN 6.0 1.0 5.5 Placebo 0.9 5.0 0.8 4.5 51% Placebo 0.7 4.0 P<.001 0.6 3.5 66.5% Cumulative Incidence (%) 3.0 0.5 Cumulative incidence (%) P<.001 2.5 0.4 2.0 0.3 Zoster Vaccine 1.5 0.2 Zoster Vaccine 1.0 0.1 0.5 0.0 0.0 0 1 2 3 4 5 0 1 2 3 4 5 Years of Follow-Up Years of Follow-Up Years of Follow-Up Years of Follow-Up Herpes Zoster Vaccination Reduces Incidence of Herpes Zoster and PHN Oxman MN et al. N Engl J Med. 2005;352:2271-2284. 40

41. CDC RecommendsHerpes Zoster Vaccination in Adults • October 25, 2006 — ACIP recommends that the zoster vaccine be given to all people ≥60 years of age, including those who have had a previous episode of herpes zoster1 • October 2007 — CDC includes zoster vaccine in adult immunization schedule for adults ≥60 years of age, including those who have had a previous episode of herpes zoster2 ACIP = Advisory Committee on Immunization Practices; CDC = Centers for Disease Control and Prevention. 1CDC’s Advisory Committee Recommends “Shingles” Vaccination [press release]. Atlanta, GA: CDC Press Office; October 26, 2006; 2Advisory Committee on Immunization Practices. Recommended adult immunization schedule: United States, October 2007–September 2008. Ann Intern Med. 2007;147.

42. Contraindications to Herpes Zoster Vaccine History of anaphylactic/anaphylactoid reaction to neomycin Serious current illness (or T ≥38.5°C) History of immunodeficiency states including Leukemia, lymphomas, or other malignant neoplasms affecting the bone marrow or lymphatic system AIDS or other clinical manifestations of infection with HIV Immunosuppressive therapy, including high-dose corticosteroids Active untreated tuberculosis Known or suspected pregnancy ZOSTAVAX [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2006.

43. Barriers to Vaccination • Patient-related issues • Lack of knowledge about immunizations • Fear of needles • Vaccine access • Vaccine coverage • Physician-related issues • Missed opportunities to vaccinate • Unfamiliar with vaccination guidelines • Lack of insight as to the importance of vaccination Adapted from Burns IT, Zimmerman RK. J Fam Pract. 2005;54:S58-S62.

44. Strategies to Improve Vaccination Rates • Communicate effectively with patients • Provide education and information about risks and benefits of vaccination • http://www.cdc.gov/vaccines/pubs/vis/vis-facts.htm • Develop office protocols • Assess each patient’s vaccination status • Administer and document vaccinations properly • Implement strategies to improve vaccination rates • eg, patient reminders • Facilitate patient access to recommended vaccinations • Identify and minimize office barriers • If needed, refer patients to other facilities offering vaccines • Health centers, travel clinics, infectious disease specialists Poland GA et al; and the National Vaccine Advisory Committee. Am J Prev Med. 2003;25:144-150.

45. Case Study

46. Case Study 2 • A 72-year-old man with a history of chronic obstructive pulmonary disease, coronary artery disease, and mild renal insufficiency arrives at the clinic for his yearly flu shot • Medical history includes a history of herpes zoster (V-1 dermatome with ocular involvement and 18 months of PHN) 9 years ago • Medications: inhaled corticosteroids, beta agonist, ASA, and ACE inhibitor • Because of his prior severe case of shingles, the patient has read about the herpes zoster vaccine and wants to receive it today ACE = angiotensin-converting enzyme; ASA = aspirin.

47. 0 Does this patient meet the criteria to receive the herpes zoster vaccine, and can it be given with his flu shot? • Yes, he should receive it, but should not get it at the same time as his flu shot • Yes, he should receive it, and can get the flu shot at the same time • No, he does not meet criteria to receive the zoster vaccine because his medications include inhaled corticosteroids • Unsure Use your keypad to vote now!

48. ACIP Guidance on What Constitutes Being “Immune Suppressed” • Corticosteroids — a dose equivalent to either >2 mg/kg of body weight or 20 mg/d of prednisone for >2 weeks raises concern about the safety of vaccination with live-virus vaccines • Individuals receiving chemotherapy or radiation for leukemia, other hematopoietic malignancies, or solid tumors • Live-attenuated vaccines should not be administered for at least 3 months after such immunosuppression or chemotherapy ACIP General Recommendations on Immunization—December 2006.

49. The Herpes Zoster Vaccine and Inactivated Influenza Vaccine Can Be Administered Concomitantly • Herpes zoster vaccine can be given with the influenza vaccine • Clinical data have shown both vaccines to demonstrate immunogenicity when administered concomitantly compared with individual administration Kerzner B et al. J Am Geriatr Soc. 2007;55:1499-1507.

50. Case Study