1. Varicella Zoster Vaccine in Preventing Zoster in Elderly People Dr David Dai Prince of Wales Hospital 21 st July, 2007

2. Today’s Talk Clinical features of Herpes Zoster Post Herpetic Neuralgia (PHN) Treatment Prevention

3. Herpes Zoster (Shingles): Etymology 1herpes = derived from Greek “ herpein ” meaning “ to creep ” zoster = a Greek word meaning “ girdle ” shingles = derived from Latin “ cingere ” 1. Dorland’s Illustrated Medical Dictionary. 28th ed. Philadelphia: WB Saunders Company, 1994:759.

4. Human Herpesviruses (HHV) HHV family 1 Alpha-HHV Beta-HHV Gamma-HHV VZV † (HHV-3) HSV * (HHV-1, -2) EBV ‡ (HHV-4) CMV § (HHV-5) KSHV ׀ ׀ (HHV-8) 1. Roizman B et al. In: Fields Virology. 4th ed. Vol. 2. New York: Lippincott Williams & Wilkins, 2001:2381–2397. 2. Arvin AM. In: Fields Virology. 4th ed. Vol. 2. New York: Lippincott Williams & Wilkins, 2001:2731–2767. Reactivation: herpes zoster (shingles) 2 Primary infection: varicella (chickenpox) 2 (HHV-6A, -6B) (HHV-7) * HSV = herpes simplex virus † VZV = varicella-zoster virus ‡ EBV = Epstein-Barr virus § CMV = cytomegalovirus ׀׀ KSHV = Kaposi’s sarcoma-associated herpesvirus

5. A typical case (Clin Inf Disease 1999; 28: 736-9) 70 year old man Pain in RUQ, diagnosed as cholescystitis 4 days later, rash noted by nurse; diagnosis reviewed as “Shingles” Rash persisted in next 3 weeks No relief of pain 5 yrs afterwards, still severe pain

6. Constant deep ache Sharp pains Involuntary muscle contractions Extremely sensitive skin Unable to wear clothes over the area

7. Medications Codeine, oxycodone, morphine Amitriptyline, topical lidocaine Capsaicin, mexilitine, phenytoin Carbamazepine, NSAID TENS Epidural anaesthetic/steroid injection Intercostal nerve blocks All without relief

8. Falls 2 years after onset and hip fracture Forced retirement

9. Zoster: Clinical Features Usually limited to 1 or 2 adjacent, unilateral dermatomes 1,2 “ Grape-like ” lesions clustered on an erythematous base 1,2 Lesions usually heal within 4 weeks 1 Courtesy of the American College of Physicians. www.acponline.org/shell-cgi/printhappy.pl/bioterro/ smallpox_mimics.htm 1. Oxman MN. In: Varicella-Zoster Virus, Virology and Clinical Management. Cambridge: Cambridge University Press, 2000:246–275. 2. Lycka BAS et al. In: Herpes Zoster and Postherpetic Neuralgia, 2nd Revised and Enlarged Edition. Vol. 11. Amsterdam: Elsevier Science B.V., 2001:97–106.

10. Zoster: Dermatomal Distribution Image courtesy of Charles E. Crutchfield III, MD.

11. Zoster: Cranial Involvement 1 Reproduced with permission. 1 ©Diepgen TL, Yihune G et al. Dermatology Online Atlas (www.dermis.net) Reprinted with permission. I ophthalmic II maxillary III mandibular 1. Stedman’s Medical Dictionary. 27th ed. Baltimore: Williams & Wilkens, 2000:1202.

12. Zoster Ophthalmicus Image courtesy of Charles E. Crutchfield III, MD. KO Studios, Pacifica, CA. ©2002. Reprinted with permission. Image courtesy of Dr. Dubin’s collection (www.skinatlas.com)

13. Establishment of VZV Latency in Sensory-Nerve Ganglia. After a primary VZV infection (chickenpox), latent VZV infection is established in the dorsal-root ganglia, and zoster occurs with subsequent reactivation of the virus N Engl J Med Vol 356(13) P1338-1343

14. Incidence of Zoster and Postherpetic Neuralgia (PHN) in the UK Rate per 1000 per year 01020304050607080+ 11 10 9 8 7 6 5 4 3 2 1 0 Zoster cases/ 1000/year PHN/ 1000/ year Age (years) 1. Hope-Simpson RE. J R Coll Gen Pract 1975;25:571–575.

15. Post Herpetic Neuralgia ( J Infect Dis 2002; 186(Suppl): 983-90) Herpes Zoster pain 3 Phases: 1)Acute 2)Subacute: 4-5 weeks 28.4% 3)Chronic: > 3months 15% > 12 months: 5-10% Spontaneous remission: limited

16. Effects of PHN on Patients Pain Tender Burning Throbbing Stabbing Shooting/stabbing

17. Allodynia Disturbance in physical and psychological functioning Drug dependency Depression Suicide

18. Map of Sensory Disturbances of PHN Allodynia Postherpetic scarring Reduced sensation to pinprick, temperature (cold), and touch Reprinted from Herpes Zoster and Postherpetic Neuralgia, 2nd Revised and Enlarged Edition, Vol. 11, Watson CPN, Oaklander AL, Deck JH, The neuropathology of herpes zoster with particular reference to postherpetic neuralgia and its pathogenesis, pp167–182, 2001, with permission from Elsevier.

19. Map of Sensory Disturbances of PHN Following Zoster Ophthalmicus Reprinted from Herpes Zoster and Postherpetic Neuralgia, 2nd Revised and Enlarged Edition, Vol. 11, Watson CPN, Oaklander AL, Deck JH, The neuropathology of herpes zoster with particular reference to postherpetic neuralgia and its pathogenesis, pp 219–222, 2001, with permission from Elsevier.

20. Comparison of Pain Scores for Various Conditions Acute Pain Conditions Chronic Pain Conditions Less Pain More Pain 0 10 20 30 40 50 Abdominal hysterectomy Acute headache Zoster Labor pain Postsurgical pain Mucositis Angioplasty sheath removal Postherpetic neuralgia Chronic cancer pain Fibromyalgia Rheumatoid arthritis Osteoarthritis Arthritis Musculoskeletal pain Atypical facial pain Adapted from Surgical Clinics of North America, Vol 79, Katz J, Melzack R, Measurement of pain, pp 231–252. Copyright ® 1999, with permission from Elsevier.

21. Financial Impact UK(1994) Life unit cost for managing PHN ₤ 770 per patient

22. Treatment Antiviral therapy within 72 hours of rash: ↓ duration (pain, rash healing) ↓ eye complications ? Incidence of PHN

23. Table 1. Proportions (%) of patients (aged 50 years) with persisting pain in controlled trials of antiviral therapies for herpes zoster [4 6, 36, 40].4 63640 PHN pain Drugs compared Acyclovir (800 mg 5×/day, 7 10 days) vs. placebo Valacyclovir (1000 mg 3×/day, 7 days) vs. acyclovir Valacyclovir (1000 mg 3×/day, 7 days) vs. famciclovir (500 mg 3×/day, 7 days) Famciclovir (500 mg 3×/day, 7 days) vs. placebo At 3 months 25 vs. 54 a a 31 vs. 38 b b 32 vs. 34 c c 34.9 vs. 49.2 At 6 months 15 vs. 35 a a 19.9 vs. 25.7 d d 19 vs. 19 c c 19.5 vs. 40.3 a a NOTE. PHN, postherpetic neuralgia. a P <.05 from 95% confidence interval (CI) for the relative risk (RR) for the difference between treatments. b GlaxoSmithKine data on file. c P =.84 from 95% CI for the RR for the difference between treatments. d P =.08 from 95% CI for the RR for the difference between treatments a b c d J Infectious Dis 2002;186(Suppl 1):S83-90

24. The problem Diagnosis in prodromal period extremely difficult Majority of elderly patients with localised, unilateral pain does not develop herpes

25. Later therapy still has benefit ↓ duration of illness Immunocompromised Older Ophthalmic New lesions after 72 hours

26. At Risk of PHN Old age Prodromal pain Severe acute pain Rash ? Female Ophthalmic zoster Preexisting neurological disorder

27. Figure 1. Annual Incidence of Herpes Zoster and Proportion of Patients with Postherpetic Neuralgia. Panel A shows the annual incidence of herpes zoster per 1000 persons in a general medical practice.1 Panel B shows the percentage of patients with pain persisting after the onset of the zoster-associated rash. Data are from the placebo group in one large, double-blind treatment study.7 Panel C shows the proportion of patients with postherpetic neuralgia according to age.16 N Eng J Med 335(1);32-42, 1996

28. Duration of Zoster-Associated Pain According to Age 1,2 (n) 2 (24)(53)(69)(136)(204)(270)(160) Adapted with permission from Kost RG et al. 1 © 1996 Massachusetts Medical Society. 1. Kost RG et al. N Engl J Med 1996;335:33–42. 2. de Moragas JM et al. AMA Arch Derm 1957;75:193–196.

29. Treatment of established illness Tricyclics Anti-convulsants Opiate analgesics Surgery: sympathectomy, dorsal root entry zone lesion, cordotomy, thalamotomy, cingulumotomy, spinal cord and deep brain stimulation

30. The Patient Do anything to reduce the pain

31. Strategy Prevent or attenuate herpes zoster Pain programme ( drug and non-drug)

32. Prevention of PHN ? Antiviral therapy ? Oral steroids ( excessive side effects) Intervention to reduce acute inflammation and tissue damage (attenuate peripheral nocioceptive sensitisation and central hyperexcitability)

33. Shingles Prevention Study SPS A vaccine to prevent Herpes Zoster and Post Herpetic Neuralgia in Older Patients MN Oxman etal NEJM 2005(352): 2271-84

34. The Question In persons > 60 yrs, does a live attenuated zoster virus( VZV) vaccine decrease the burden of illness caused by herpes zoster and incidence of PHN?

35. ZOSTAVAX ® [Zoster Vaccine Live (Oka/Merck)] Product Profile Live, attenuated varicella-zoster virus vaccine Minimum of 19,400 PFU* per dose No preservative Lyophilized product Same excipients as VARIVAX ® [Varicella Virus Vaccine Live (Oka/Merck)] Single subcutaneous dose *PFU = plaque-forming units

36. Randomised placebo-controlled trial Follow up period: 3.13 yrs (median) Setting: 22 sites in US Participants: 38,546 persons > 60yrs Mean age: 69 yrs, 59% men, with a history of varicella or had resided in US > 30yrs Immunocompromised persons excluded

37. Randomization of Subjects Subjects Enrolled 38,546 Age 60 to 69 years 20,747 Placebo 10,369 Zoster vaccine 10,378 Adverse Event (AE) Substudy: 6616 CMI Substudy 1395 Age  70 years 17,799 Placebo 8907 Zoster vaccine 8892 1. Oxman MN et al. N Engl J Med 2005;352:2271–2284.

38. Zoster and PHN Zoster cases were confirmed by – Polymerase-chain-reaction (PCR) assay – Viral culture – Adjudication by a clinical evaluation committee PHN was defined as: Zoster-associated pain rated as 3 or more on a 10- point pain scale persisting or appearing at least 90 days after rash onset

39. Intervention Study group ( n= 19270): 1 subcut injection of 0.5mL Oka/Merck VZV vaccine Placebo group (n= 19276) Vaccine has median potency of 24600 plaque-forming units

40. Outcomes Vaccine efficacy: Relative reduction in burden-of- illness sore(VEBOI): severity of and duration of herpes zoster pain Incidence of PHN: pain rated as >3/10 Patient follow-up: 95%( modified intention to- treat- analysis)

41. Definition and Measurement of the BOI Zoster BOI: Population measure Worst Pain Days 0 10

42. Main Results Vaccine Efficacy

43. Reduction of Cumulative Incidence of Zoster Cumulative Incidence Over Time* Percent of Subjects With Zoster Time Since the Start of Follow-Up (in Years) Placebo Zoster vaccine Logrank P-value = <0.001 *A limited number of subjects were followed beyond Year 4. 1. Oxman MN et al. N Engl J Med 2005;352:2271–2284.

44. Reduction of Cumulative Incidence of PHN Placebo Zoster vaccine Logrank P-value = <0.001 Time Since the Start of Follow-Up (in Years) Percent of Subjects With PHN Cumulative Incidence Over Time* *A limited number of subjects were followed beyond Year 4. 1. Oxman MN et al. N Engl J Med 2005;352:2271–2284.

45. Overall Efficacy of the Zoster Vaccine 51.3% 66.5% 61.1% 25%=prespecified lower bound success criterion 0255075100 Vaccine Efficacy (%) V211.VEsummary1c Sept. 30, 2005 BOI PHN Zoster 95% CI 1. Oxman MN et al. N Engl J Med 2005;352:2271–2284.

46. Efficacy of the Zoster Vaccine by Age Stratum v211ACM.Vbar1a Dec. 6, 2005 020406080100 Vaccine Efficacy (%) BOI PHN Zoster Ages 60 to 69 Ages  70 95% CI

47. Shingles Prevention Study: Summary of Efficacy The zoster vaccine was highly effective in reducing the incidence and morbidity from zoster and PHN –Reduced the incidence of zoster by 51% –Reduced the incidence of PHN by 67% –Reduced the BOI associated with zoster by 61% 1. Oxman MN et al. N Engl J Med 2005;352:2271–2284.

48. Vaccine Efficacy by Age Group The zoster vaccine benefited the 60- to 69-year- olds by reducing the incidence of zoster 1 : –60-to-69-year-old group: 63.9% –  70-year-old group: 37.6% The zoster vaccine benefited the  70-year-olds by decreasing disease severity 1 –Efficacy for pain BOI was similar in both age groups –Efficacy for PHN was similar in both age groups 1. Oxman MN et al. N Engl J Med 2005;352:2271–2284.

49. The AE Monitoring Substudy AE Zoster Vaccine (N=3345) % Placebo (N=3271) % Injection Site Erythema* Pain / tenderness* Swelling* Hematoma Pruritus Warmth 35.8 34.5 26.2 1.6 7.1 1.7 7.0 8.5 4.5 1.4 1.0 0.3 *Designates a solicited adverse experience. Injection-site adverse experiences solicited only from Days 0–4 postvaccination. 1. Oxman MN et al. N Engl J Med 2005;352:2271–2284.

50. Serious side effects 5 subjects: 1) asthma on D2 2) PMR on D3 3) Anaphylactoid reaction 90minures 4) PMR on D15 5) Goodpasture syndrome D52

51. Shingles Prevention Study: Summary of Safety The zoster vaccine has demonstrated a favorable safety profile. Transient injection-site reactions occurred in approximately 50% of the vaccine recipients. There were clinically important differences between the zoster vaccine and placebo with respect to –SAEs (1.4% in each group) –Systemic clinical AEs Following a dose of zoster vaccine, vaccine- associated rashes were uncommon (0.1%)

52. Conclusion In persons >60 yrs, a live attenuated varicella-zoster virus vaccine decreased the burden of illness caused herpes zoster and the incidence of PHN. The incidence of herpes zoster was also reduced to a greater extent in vaccine recipients

53. Figure 3. Host Factors in Latent VZV Infection and Reactivation. Varicella is the primary infection caused by VZV, and its resolution is associated with the induction of VZV-specific memory T cells (blue line). Memory immunity to VZV may be boosted periodically by exposure to varicella or silent reactivation from latency (red peaks). VZV-specific memory T cells decline with age. The decline below a threshold (dashed green line) correlates with an increased risk of zoster. The occurrence of zoster, in turn, is associated with an increase in VZV- specific T cells. The administration of zoster vaccine to older persons may prevent VZV-specific T cells from dropping below the threshold for the occurrence of zoster (dashed blue line). (Reprinted from Arvin.19) N Engl J Med Vol 356(13) P1338-1343

54. Unresolved Issues (ACP Journal club 2005, 143(3): 61) Cost-effectiveness Optimal age at first administration Duration of protection

55. Additional Comments ( MN Oxman, Human Vaccine 2007,3:2, 64-68) Efficacy persist for at least 4 years Young subjects: prevent HZ Older subjects: attenuate HZ No use in PHN treatment or HZ Transmission of vaccine virus no risk

56. 86% of SPS subjects who develop HZ received famcyclovir and analgesia, and 2/3 received anti-viral treatment within 72 hrs; therefore, severity and duration of HZ pain reduced and understimate efficacy of VZV vaccine

57. Cost -effectiveness QOL and functional of older persons with HZ comparable to CCF, MI, DM, major depression (Neurol; 45 Suppl 8: S52-3) PHN cause severe functional impairment, fatigue, anorexia, weight loss, insomnia, difficult concentration, depression, isolation, loss of independence and death

58. Figure 2. Cost per quality-adjusted life-year (QALY) gained as a function of duration of vaccine efficacy (from 3 to 30 years) and total vaccination costs (from $50 to $500). Total vaccination costs include unit vaccine cost, a public awareness campaign, administration costs, patient travel time and time receiving vaccine, and cost of treating adverse events. Ann Intern Med 2006;145:317-325

59. Cost of vaccine US$150 per dose, assuming duration of efficacy 10 yrs: $ 2600 per HZ prevented $ 7500 per PHN prevented NNV to prevent a case of HZ: 18 NNV to prevent a clinically significant case of PHN: 1009

60. Improved Zoster vaccine Increased potency ( ↑quantity of infective VZV and amount of VZV antigens) 5 times the current vaccine Likely to be well tolerated Effective inactivated zoster vaccine to protect immunodeficient population

61. ZOSTAVAQX® Stored frozen at an average temperature of -15ºC or colder until it is reconstituted for injection.

62. Recommendations The author has already been vaccinated and has purchased the vaccine and administrated to his wife

63. Preventive Dermatology (J Am Acad Derm 2007; 56:675-6) Vaccination with live attenuated VZV vaccine should be made available to all immunocompetent persons aged 60yrs and older during routine office visits; and before immunosuppresive atherapy

64. ACIP Provisional Recommendations ( October 25, 2006) A single dose of zoster vaccine is recommended for adults 60 years of age and older whether or not they report a prior episode of herpes zoster. Persons with chronic medical conditions may be vaccinated unless a contraindication or precaution exists for their condition. Contraindications and precautions to use of zoster vaccine are available at http://www.fda.gov/Cber/label/zosmer052506LB.htm

65. To give or not to give? Give Patient treatment experience Storage Cost