Medications and the Elderly - GRECC Audio Conferences

Medications and the Elderly - GRECC Audio Conferences

Where Do We Stand with the Zoster (Shingles) Vaccine?: Clinical Implications of the CDCs Advisory Committee on Immunization Practices (ACIP) Recent Recommendations Kenneth Schmader, MD Director, GRECC ACOS Geriatrics and Extended Care Durham VA Medical Center Durham, NC Objectives Understand the burden of illness due to herpes zoster Discuss the benefits and risks of

zoster vaccination in older adults Understand the practice implications of ACIP recommendations Learn the latest information on immunogenicity and durability of vaccine response CDC MMWR 2008;57(05):1-30 Patient Letter Dr. Schmader, I sure hope you can help me with this shingles pain, it is so bad it has changed my whole life. I am unable to do any of the things I used to do. I am willing to start all over if you think you can help me Pain is the Cardinal Problem in Herpes Zoster Acute and Chronic Pain Incidence of Herpes

Zoster About 1 million cases in the US annually 11.8 cases per 1000 person-years in adults 60 years of age and older Gnann J et al. N Engl J Med. 2002;347:340-346; Thomas SL et al. Lancet Infect Dis 2004;4:26-33; Oxman et al. NEJM. 2005;352:2271-84; Schmader KE et al. J Infect Dis 2008;197:207-15 Electron Micrograph of Varicella Zoster Virus Grose&Padilla. Varicella-Zoster Virus 2001, Arvin & Gershon, eds. VZV Latency and Reactivation Straus. JAMA. 1989;262:3455-3458.

Age and Incidence of Herpes Zoster Rate Per Thousand 12 10 8 6 4 2 0 10 Hope-Simpson RE. Proc R Soc Med 1965;58:9-20 20 30 40

50 60 70 80 Age Groups Age- specific Incidence of Zoster 90 Patients reporting pain (%) Prevalence and Duration of Zoster Associated Pain Increases with Age >1 yr 100 6 - 12 mo

1 - 6 mo 80 <1 mo 60 40 20 0 0-19 20-29 30-39 40-49 50-59 60-69 79 Age (years) Kost R et al. N Engl J Med. 1996;355:32-42. Acute Pain in Herpes Zoster and Postherpetic Neuralgia Interferes with Functional Status and Quality of Life in Older Adults

Poorer physical, emotional, social, and role functioning Interference with basic and instrumental activities of daily living Impaired vitality, sleep and mental health Schmader KE et al. Clin J Pain. 2007;23:490-496; Chidiac C et al. Clin Infect Dis. 2001;33:6269; 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; Scott et al, Vaccine 2006;24:1308-16; Schmader KE. Clin Infect Dis 2001;32(10):1481-6 Rationale for Developing and Using A Zoster Vaccine for Older Adults Herpes zoster (HZ) is common and adversely affects quality of life among older adults Antiviral therapy does not prevent postherpetic neuralgia (PHN), and once

established, PHN is difficult to treat Cell-mediated immunity (CMI) to varicellazoster virus (VZV) declines with aging Highly correlated with the increase in the incidence and severity of HZ and PHN in older persons Kost R et al. N Engl J Med 1996;355:32-42. A VA COOPERATIVE STUDY CARRIED OUT WITH THE COLLABORATION OF THE NIAID AND MERCK & COMPANY Volume 352:2271-2284 June 2, 2005 Number 22 A Vaccine to Prevent Herpes Zoster and Postherpetic Neuralgia in Older Adults M.N. Oxman, M.D., M.J. Levin, M.D., G.R. Johnson, M.S., K.E. Schmader, M.D.,

S.E. Straus, M.D., L.D. Gelb, M.D., R.D. Arbeit, M.D., M.S. Simberkoff, M.D., A.A. Gershon, M.D., L.E. Davis, M.D., A. Weinberg, M.D., K.D. Boardman, R.Ph., H.M. Williams, R.N., M.S.N., J. Hongyuan Zhang, Ph.D., P.N. Peduzzi, Ph.D., C.E. Beisel, Ph.D., V.A. Morrison, M.D., J.C. Guatelli, M.D., P.A. Brooks, M.D., C.A. Kauffman, M.D., C.T. Pachucki, M.D., K.M. Neuzil, M.D., M.P.H., R.F. Betts, M.D., P.F. Wright, M.D., M.R. Griffin, M.D., M.P.H., P. Brunell, M.D., N.E. Soto, M.D., A.R. Marques, M.D., S.K. Keay, M.D., Ph.D., R.P. Goodman, M.D., D.J. Cotton, M.D., M.P.H., J.W. Gnann, Jr., M.D., J. Loutit, M.D., M. Holodniy, M.D., W.A. Keitel, M.D., G.E. Crawford, M.D., S.-S. Yeh, M.D., Ph.D., Z. Lobo, M.D., J.F. Toney, M.D., R.N. Greenberg, M.D., P.M. Keller, Ph.D., R. Harbecke, Ph.D., A.R. Hayward, M.D., Ph.D., M.R. Irwin, M.D., T.C. Kyriakides, Ph.D., C.Y. Chan, M.D., I.S.F. Chan, Ph.D., W.W.B. Wang, Ph.D., P.W. Annunziato, M.D., J.L. Silber, M.D., for the Shingles Prevention Study Group Zoster Vaccine (Oka/Merck) Live, attenuated, cell-free preparation of Oka/Merck strain

VZV Attenuated by 31 passages in tissue culture (human embryonic lung fibroblasts, guinea pig embryonic cells, human diploid cells) Contains whole live virus, viral antigen and Neomycin, sucrose, gelatin, glutamate, inorganic salts Formulated to contain substantially

more live virus and viral antigen than are contained in the varicella vaccine Shingles Prevention Study Design: Randomized, double-blind, placebo-controlled, stratified by age, 60-69 and 70 Setting: 22 US sites (16 VA and 6 university medical centers) Participants: 38,546 immunocompetent adults 60 years old 19,270 zoster vaccine 19,276 placebo Oxman M et al. N Engl J Med. 2005;352:2271-2284.

Shingles Prevention Study Outcomes Burden of illness (pain severity by duration) Incidence of PHN Incidence of herpes zoster Oxman MN et al. N Engl J Med. 2005;352:2271-2284 Shingles Prevention Study Results All Ages Outcome Vaccine Efficacy (95% CI) (%) Burden of Illness (BOI)* 61.1 (51.1-69.1) PHN Incidence

66.5 (47.5-79.2) Herpes Zoster Incidence 51.3 (44.2-57.6) *BOI = pain severity by duration Oxman MN et al. N Engl J Med. 2005;352:2271-2284 Adverse Events Injection Site 60-69 Years of Age 70 Years of Age Injection Site Adverse Events Vaccine Placebo Vaccine Placebo (n=1732 (n=1727 (n=1613) (n=154 )

) 4) % One or more 56 19 39 14 % Pain/Tenderness 43 10 25 7

% Erythema 42 8 29 6 % Swelling 32 5 19 4 % Itching 9

1 4 1 Oxman MN et al. N Engl J Med. 2005;352:2271-2284; Simberkoff et al. Abst G-406 IDSA Annual Meeting 2008 Number of Subjects with 1 Serious Adverse Experience (0-42 Days Postvaccination) in Overall Study Cohort Vaccine n/N % Placebo n/N % Relative Risk (95% CI) All Ages

255/18671 1.4% 254/18717 1.4% 1.01 (0.85, 1.20) 60-69 yrs. 113/10100 1.1% 101/10095 1.0% 1.12 (0.86, 1.46) 70-79

yrs. 115/7351 1.6% 27/1220 2.2% 132/7333 1.8% 21/1289 1.6% 0.87 (0.68, 1.11) 1.36 (0.78, 2.37) Age 80 yrs. http://www.fda.gov/cber/label/zosmer052506LB.pdf

Effect of Zoster Vaccination on Functional Status in Older Adults The zoster vaccine reduced HZ related interference with ADL by ~ 66% in older adults Most of this reduction was due to vaccine efficacy at preventing HZ HZ interference with ADL was reduced by ~ 30% in vaccine recipients who developed HZ Schmader KE et al. Abstract #859 IDSA Annual Meeting, 2006 R C F V alu e 12

Vaccine Placebo VZVSpecific Immune Response s by Time Since Vaccinatio n 9 6 3 0 E L IS P O T C o u n t 120

90 60 N =V/P 691/704 30 0 (n = 704) g p E L IS A T ite r 500 400 300 200 100 0 Day 0

N =V/P 691/704 6 Weeks 686/702 1 Year 2 Years 669/682 659/665 635/632 Time Since Randomization 3 Years Levin et al J Infect Dis 2008;197:82535 FDA Label Zoster Vaccine INDICATIONS AND USAGE Indicated for prevention of herpes

zoster (shingles) in individuals 60 years of age and older http://www.fda.gov/cber/label/zosmer052506LB.pdf FDA Label Zoster Vaccine CONTRAINDICATIONS History of anaphylactic/anaphylactoid reaction to gelatin, neomycin, or any other component of the vaccine History of primary or acquired immunodeficiency states including leukemia; lymphomas of any type, or other malignant neoplasms affecting the bone marrow or lymphatic system; or AIDS or other clinical manifestations of infection with human

immunodeficiency viruses On immunosuppressive therapy, including highdose corticosteroids. Active untreated tuberculosis. http://www.fda.gov/cber/label/zosmer052506LB.pdf Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control (CDC) ACIP recommends routine vaccination of all persons aged 60 years with one dose of zoster vaccine. CDC MMWR 2008;57(05):1-30 The zoster vaccine is on the VA National Formulary VHA health care providers can prescribe the vaccine

www.pbm.va.gov /Clinical Guidance/Criteria For Use/Zoster Vaccine Criteria for Use (Rev 20080714).doc Top Five Clinical Issues and Implications Age issues Screening for varicella and herpes zoster Disease considerations Transmission of vaccine virus Storage and administration Age Considerations

What about use of the vaccine in the old-old persons 80 years old? What about the use of the vaccine in persons <60 years old? Zoster Vaccine Efficacy vs. Age 100% 90% Vaccine Efficacy 80% 70% 60% 50% 40% 30% 20% 10% 0%

60 - 64 65 - 69 70 - 74 75 - 79 >79 Age at Randomization (Years) HZ Burden of Illness (BOI) Incidence of PHN Incidence of HZ Vaccine Efficacy for Incidence of PHN in Patients with Herpes Zoster % of Zoster Cases with Postherpetic Neuralgia

50 Efficacy Placebo (95% CI) 40 26% 30 20 10 Zoster Vaccine 55% 39% (7%, 59%)

(18%, 76%) 5% (69%, 68%) 25.5 18.9 17.2 (107%, 56%) 12.5 8.6 6.9 7.7 6.6 0 All Subjects

No. PHN Cases No. HZ Cases 80 27 642 315 Age 6069 23 8 334 122 http://www.fda.gov/cber/label/zosmer052506LB.pdf; Oxman MN et al. N Engl J Med. 2005;352:2271-2284 7079 45

80 12 12 7 261 156 47 37 Use in Persons 80 Years Old or Frail Older People The Issue . . .

The number of individuals over age 80 years in the trial was insufficient to determine vaccine efficacy in this age group alone. The study was never intended to be powered for outcomes in this age group Furthermore, few frail elderly individuals were enrolled in the trial. Use in Persons 80 Years Old or Frail Older People Skepticism . . . Unknown adequacy of the immune response to the vaccine in this population

Efficacy against herpes zoster declined with increasing age Safety data are limited Utility in malnourished individuals or in those with limited life expectancy Use in Persons 80 Years Old or Frail Older People However . . . Efficacy in reducing pain relatively preserved with increasing age, including severe PHN Zoster vaccine was effective at reducing interference with activities of daily living Incidence of zoster and PHN are highest in this age group, this population may derive significant benefit reserve to withstand pain and adverse effects of

potent analgesics is lower than younger individuals on average . . .Neither FDA nor ACIP specifies an upper age limit on the use of the vaccine CDC MMWR 2008;57(05):1-30 Use in persons < 60 years old Middle-aged individuals may seek the zoster vaccine ACIP does not recommend the routine vaccination of persons < 60 years of age Off-label prescribing in the US

Ongoing international randomized controlled trial of the zoster vaccine in persons 50-59 years old CDC MMWR 2008;57(05):1-30 Ask About History of Varicella (Chickenpox) Before Vaccination? Not necessary to take a varicella history or do serologic testing for varicella immunity before administration of zoster vaccine Nearly all older adults in the US are VZV seropositive and latently infected regardless of the history they give regarding varicella If known that patient is VZV seronegative, then the patient should receive a two dose

regimen of the varicella vaccine CDC MMWR 2008;57(05):1-30 Ask About History of Herpes Zoster Before Vaccination? ACIP recommends the zoster vaccine for eligible persons whether or not they report a prior episode of zoster, not necessary to screen for past herpes zoster Many older adults have past history of herpes zoster and specifically ask for the vaccine Self-report of herpes zoster and physician diagnosis sometimes in error Recurrent zoster occurs in 1-5% of cases No reason that it would be unsafe CDC MMWR 2008;57(05):1-30

Disease Considerations Herpes Zoster and PHN Older adults who are experiencing herpes zoster or PHN may ask for the vaccine Zoster vaccination is not indicated to treat acute zoster or to treat PHN CDC MMWR 2008;57(05):1-30 Disease Considerations HIV Infection Not specifically contraindicated for use in persons with less-advanced HIV infection CD4+ T-lymphocyte values >200 per mm3 and/or >15% of total lymphocytes

In HIV-infected children without prior varicella and CD4+ counts as low as 15% the varicella vaccine was immunogenic and safe (Levin, 2006) If zoster vaccination planned in an HIV infected individual with less advanced disease, check serum VZV IgG before giving the vaccine Seronegative individuals should receive the varicella vaccine Seropositive individuals should receive the zoster vaccine CDC MMWR 2008;57(05):1-30 What About Transmission of Vaccine Virus After Zoster Vaccination? Shingles Prevention Study Potential transmission requires a vesicular rash containing vaccine virus afte

vaccination; if there is no vesicular rash, there is no chance for transmission Rash Vaccine (n=19270) Placebo p (n=19276 ) Varicella-like at 20 (0.11) inoculation site* Varicella-like not 18 (0.10 at inoculation site* 7 (0.04) 0.012 14 (0.07)

0.476 Herpes Zoster 24 (0. 13) 0.002 7 (0.04) *Neither vaccine virus nor wild type virus were detected by DNA PCR testing What About Transmission of Vaccine Virus After Zoster Vaccination? No documented episodes of transmission of vaccine virus from vaccine recipients to contacts

Persons receiving zoster vaccine that have susceptible, pregnant or immune compromised contacts need not take any precautions following vaccination except in the rare situation that a rash develops, in which case standard contact precautions are adequate CDC MMWR 2008;57(05):1-30 Key Points on Administration and Storage Stored frozen at an average temperature 5F (-15C) Reconstitute with diluent, give subcu. (0.65 mL) in the upper arm within 30 minutes of reconstitution Each 0.65-mL dose contains at least 19,400 PFU of vaccine virus 14 times the dose of varicella vaccine

Zoster vaccine can be co-administered with the inactivated influenza, tetanus-diptheria, or pneumococcal polysaccharide vaccines at different body sites Should not be given same time as another live attenuated vaccine (e.g, varicella, BCG, polio, measles, mumps, yellow fever, rubella) Administer at least 4 weeks before or after another live vaccine Durability of Vaccine Response Shingles Prevention Study Oxman MN, et al. N Engl J Med. 2005;352:2271-84 Durability of Vaccine Response SPS Persistence Substudy 3.5-7.0 years post vaccination Outcome Burden of Illness (BOI)*

Vaccine Efficacy (95% CI) (%) 50.1 (14.1, 71.0) PHN Incidence 60.1 (-9.8, 86.7) Herpes Zoster Incidence 39.6 (18.2, 55.5) *BOI = pain severity by duration Schmader KE et al. Abstract G-409 IDSA Annual Meeting, 2008 Summary Herpes zoster is a common disease in older veterans that substantially lowers quality of life from acute and chronic pain The zoster vaccine is immunogenic and effective in reducing the incidence of zoster and pain in older adults and is safe and well tolerated

The durability of vaccine response appears to be at least 7 years based on recent analyses Gnann J et al. N Engl J Med 2002;347:340-6; Schmader KE et al. J Infect Dis 2008;197:207-15; Levin et al J Infect Dis 2008;197:825-35 Oxman MN et al. N Engl J Med 2005;352:2271-84; Schmader KE et al. Abst G-409 IDSA Annual Meeting, 2008 Summary Key Practice Points Indicated for eligible persons 60 years old with no upper age limit No need to screen for a history of varicella or herpes zoster before vaccination

Not for treatment of herpes zoster or PHN Transmission of zoster vaccine virus very unlikely No precautions for susceptible, pregnant or immune compromised contacts except in the rare situation that a rash develops, in which case standard contact precautions are adequate Must be given within 30 minutes of reconstitution CDC MMWR 2008;57(05):1-30; Oxman MN et al. N Engl J Med. 2005;352:2271-2284 Contact Information For information about this specific presentation please contact Ken Schmader, MD, at [email protected]

For any questions about the monthly GRECC Audio Conference Series please contact Tim Foley at [email protected] or call (734) 222-4328 For the link to the evaluation form for this conference that will confer CE credit please go to http://vaww.sites.lrn.va.gov/vacatalog/cu_ detail.asp?id=25148 and click the Handout: Registration and Evaluation link

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