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Understanding Herpes Zoster and the Herpes Zoster Vaccine John W. Gnann, Jr. MD University of Alabama at Birmingham Birmingham, Alabama, USA Pre-Test Questions ? Outline – Herpes Zoster VZV Infections Epidemiology of Herpes Zoster Natural History Complications Medical Management of Herpes Zoster and Postherpetic Neuralgia Varicella-Zoster Virus alphaherpesvirus HHV-3 primary infection - varicella (chickenpox) 95% of U.S. adults are VZV-seropositive varicella is now preventable by vaccine (since 1995 in the US) – dramatically declining incidence Viral latency in cranial nerve and dorsal root ganglia reactivation of latent VZV results in dermatomal herpes zoster (shingles) VZV – Varicella and Herpes Zoster Viral Replication Results in Ganglionitis Skin or mucous membrane Pain perceived at skin or mucous membrane Descending noradrenergic and serotoninergic inhibitory fibers Ascending spinothalamic fibers Dorsal-root ganglion Modified from Kost R et al. N Engl J Med. 1996;335:32-42. 12 Herpes Zoster Lesions Reprinted with permission form Gnann JW, Whitley RJ. N Engl J Med. 2002;347:340-346. 13 Incidence of Herpes Zoster (Shingles) • Approximately 1 million cases of zoster in the United States annually1 • 3.2 to 3.7 cases of zoster per 1000 person-years across the population (all ages)2-5 • Risk of developing zoster is strongly age-dependent6 • Zoster incidence by decade4,5: – – – – 50-59 years of age 4.2-4.6 cases per 1000 person-years 60-69 years of age 6.0-6.9 cases per 1000 person-years 70-79 years of age 8.6-9.5 cases per 1000 person-years ≥80 years of age 10.7-10.9 cases per 1000 person-years 1. Oxman MN et al. N Engl J Med. 2005;352:2271-2284; 2. Jumaan AO et al. J Infect Dis. 2005;191:2002-2007; 3. Mullooly JP et al. Epidemiol Infect. 2005;133:245-253; 4. Yawn BP et al. Mayo Clin Proc. 2007;82:1341-1349; 5. Insinga RP et al. J Gen Intern Med. 2005;20:748-753; 6. Schmader K et al. J Infect Dis. 2008; 197(suppl 2):S207-S215. Incidence of Herpes Zoster Incidence rates of herpes zoster (HZ) among Olmsted County, MN, adults from 1996 to 2001, in 2-year increments Incidence rate of HZ per 1000 person-years 14 1996-1997 1998-1999 2000-2001 12 10 8 6 4 2 0 22-29 30-39 40-49 50-59 Age (years) Yawn BP et al. Mayo Clin Proc. 2007;82:1341-1349. 60-69 70-79 ≥80 Lifetime Risk of Herpes Zoster • Lifetime risk of herpes zoster is approximately 20% in the United States1 • 50% of individuals living until 85 years of age will ultimately develop herpes zoster2 • Risk of recurrent herpes zoster is low in the immunocompetent host— 1.7% to 5.2%3 1. Gnann JW Jr, Whitley RJ. N Engl J Med. 2002;347:340-346; 2. Katz J et al. Clin Infect Dis. 2004;39:342-348; 3. Ragozzino MW et al. Medicine (Baltimore). 1982;61:310-316. Risk Factors for Development of Herpes Zoster Advancing age (with declining VZV-specific CMI) Malignancy, esp. lymphoproliferative cancers (leukemia, lymphoma) Deficiencies in cell-mediated immunity, esp. HIV infection Medical / Iatrogenic: – Chemotherapy, radiation therapy – Corticosteroids (high dose, systemic) – Organ transplantation with anti-rejection therapy Acute Herpes Zoster – Evolution of the Cutaneous Eruption (prodromal pain) Evolution of the Rash Vesicles (3-7 days) Pustular lesions (4-6 days) Crusting of lesions (7-10 days) Resolution of rash (2-4 weeks) Pitfalls in Diagnosis of Herpes Zoster • 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 • Skin manifestations 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, IFA)2,3 – Occasional confusion with contact dermatitis HSV = herpes simplex virus; IFA = immunofluorescent 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. 19 Acute Herpes Zoster Pain: A Source of Significant Morbidity • Pain is the critical symptom of herpes zoster • Characteristics include burning, stabbing, stinging, and shooting pain1,2 • Patients report that acute zoster pain is “horrible” or “excruciating”3 • 45% of patients report that they experience pain every day3 • 23% of patients report that they experience pain the entire day3 1. Goh CL, Khoo L. Int J Dermatol. 1997;36:667-672. 2. Stankus SJ et al. Am Fam Physician. 2000;61:2437-2444. 3. Katz J et al. Clin Infect Dis. 2004;39:342-348. 20 Acute Herpes Zoster Pain Causes Significant Morbidity in Older Adults • Poorer physical, emotional, social, and role functioning • Interference with activities of daily living • Impaired physical and mental health • Lower vitality • Insomnia • Depression Schmader KE et al. Clin J Pain. 2007;23:490-496; 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. 21 Acute Herpes Zoster Pain Interferes With Activities of Daily Living Patients (%) Prospective, observational US study of 102 outpatients ≥60 years of age with herpes zoster, 7 days after rash onset 80 ZBPI ADLI ≥5 70 ZIQ ADLI ≥5 60 50 40 30 20 10 0 None (0) Mild (1-3) Moderate (4-7) Severe (8-10) (n=10) (n=25) (n=48) (n=19) Pain category ADLI=activities of daily living interference. Schmader KE et al. Clin J Pain. 2007;23:490-496. 22 Complications of Herpes Zoster Neurologic • Postherpetic neuralgia (PHN) • Motor neuropathy • Cranial palsy • Encephalitis • Transverse myelitis • Post-zoster stroke syndromes Cutaneous • Bacterial superinfection • Scarring Ophthalmic • Stromal keratitis • Iritis • Retinitis • Visual impairment • Episcleritis • Keratopathy Visceral • Pneumonitis • Hepatitis • Encephalitis Gnann JW Jr, Whitley RJ. N Engl J Med. 2002;347:340-346; Arvin AM. Clin Microbiol Rev. 1996;9:361-381. 23 Herpes Zoster Ophthalmicus • About 15% of zoster cases involve the ophthalmic division of the trigeminal nerve • Keratitis, conjunctivitis, scleritis, iritis, anterior uveitis, retinitis • Without antiviral therapy, 50%-70% of patients with HZO develop ocular complications • Can result in chronic ocular complications and reduced vision, even blindness • Refer patients with ocular involvement to an ophthalmologist immediately HZO=herpes zoster ophthalmicus. McPherson RE. J Am Optom Assoc. 1997;68:527-538. 25 Treatment of Acute Herpes Zoster Symptomatic Measures Treatment of skin: – Wet compresses – Non-occlusive dressings – Protection with bandages – Antibacterial drugs for superinfection Treatment of acute neuritis: – Pain – NSAIDs, opioid analgesics, nerve blocks – Itching – antihistamines (hydroxyzine, diphenhydramine) 1. Gnann JW, Whitley RJ. N Engl J Med. 2002;347:340–346. 2. Straus SE, Oxman MN. In: Freedberg IM, Eisen AZ, Wolff K, et al, eds. Fitzpatrick’s Dermatology in General Medicine. 5th ed. Vol 2. New York, NY: McGraw-Hill; 1999:2427–2450. Treatment of Acute Herpes Zoster • Antivirals - acyclovir, famciclovir, valacyclovir – Nucleoside analogues inhibit viral replication – Promote healing and reduce duration of pain of acute herpes zoster – Therapy must be initiated within 72 hours of onset of rash for maximal benefit • Corticosteroids – limited role – – – – Reduce inflammatory features of acute zoster Possibly prevent injury to affected neurons Used in combination with antivirals Do not alter the risk of PHN Kost R et al. N Engl J Med. 1996;355:32-42. 27 Antiviral Therapy for Herpes Zoster in Immunocompetent Patients Benefits of acyclovir, valacyclovir, or famciclovir therapy for herpes zoster proven in randomized, controlled clinical trials: • Shortened duration of new vesicle formation • Shortened duration of virus shedding • Accelerated lesion healing • Reduced duration of pain • For HZO, reduced risk of ocular complications HZO=herpes zoster ophthalmicus. Antiviral Therapy for Herpes Zoster Medication Typical Dosing Acyclovir (Zovirax®) 800 mg 5x/day, 7-10 days Famciclovir (Famvir®) 500 mg 3x/day, 7 days Valacyclovir (Valtrex®) 1000 mg 3x/day, 7 days Zovirax Package Insert, GlaxoSmithKline. Famvir Package Insert, Novartis Pharmaceuticals. Valtrex Package Insert, GlaxoSmithKline. 29 Circumstances That Favor the Use of Antiviral Therapy in Immunocompetent Patients With Herpes Zoster • Early zoster (lesions <72 hours) or ongoing new vesicle formation • Older patients1 – Primary goal: to reduce the duration of pain – However, this benefit is variable. Up to 20% of patients who have pain at 30 days still report pain at 6 months despite antiviral therapy • Extensive eruption or severe pain at presentation (predictors of chronic pain) • Herpes zoster ophthalmicus2 – Primary goal: to prevent ocular complications 1. Beutner K et al. Antimicrob Agents Chemother. 1995;39:1533-1546. 2. Gnann J et al. N Engl J Med. 2002;347:340-346. 30 Postherpetic Neuralgia – A Chronic and Disabling Neuropathic Pain Syndrome Chronic neuropathic pain that persists or develops after herpes zoster rash has healed1. Current definitions include pain persisting 90-120 days after rash onset1-3 Frequency is about 25% (range 10%-75%), depending upon age of the population and definition used. Both frequency and severity increase with advancing age4 Early antiviral therapy (within 72 hours of zoster lesion onset) is indicated to minimize duration of pain, but not reliably effective for preventing PHN PHN usually requires adjunctive pain-management interventions Dworkin and Schmader. CID 2003; 36:877-882; 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 Levin MJ et al. J Infect Dis. 2008;197:825-835. Incidence of Postherpetic Neuralgia Duration of herpes zoster-related pain among Olmsted County, MN, adults (≥22 years old), stratified by age Adults with HZ (%) 35 Pain ≥30 days Pain ≥60 days Pain ≥90 days 30 25 20 15 10 5 0 22-29 30-39 40-49 50-59 60-69 70-79 ≥80 Age (years) Yawn BP et al. Mayo Clin Proc. 2007;82:1341-1349. 32 Postherpetic Neuralgia Primary Characteristics: – Chronic pain – persistent or intermittent – Burning, itching, aching – Paroxysmal or lancinating pain – Abnormal skin sensations – paresthesia, hyperesthesia, allodynia Secondary Characteristics: – Sleep disturbance – Anorexia – Lassitude – Depression Factors Which Influence Pain Outcomes in Herpes Zoster Risk of Chronic Pain Increased if: Prodromal pain is present Age is >50 years old Initial acute pain is severe Involved skin surface area is extensive, with large numbers of lesions Whitley, R, et al. JID. 1998;178(S1): S71-S75. Whitley, R et al. JID. 1999; 179: 9-15. Severity of Acute Herpes Zoster Is a Major Risk Factor for Chronic Pain in Adults ≥50 Years of Age Patients reporting pain (%) 1.0 0.9 0.8 0.7 0.6 0.5 Severe or incapacitating pain and 47 lesions 0.4 No or mild acute pain and <47 lesions 0.3 0.2 0.2 0 0 15 30 45 60 75 90 105 120 135 150 165 180 Study day Modified from Whitley R et al. J Infec Dis. 1999;179:9-15; 35 Pharmacologic Management of PHN Interventions with benefits proven in controlled clinical trials: • Anticonvulsants (eg, gabapentin, pregabalin) – Better tolerated than other anticonvulsants; aid sleep – Easier dosing with pregabalin • Tricyclic antidepressants (eg, amitriptyline, nortriptyline) • Lidocaine patch – Safe, easy to use, rapid effect • Opioids (eg, methadone, morphine, oxycodone) • Topical capsaicin Problems include polypharmacy and adverse effects in elderly patients. Dubinsky RM et al. Neurology. 2004;63:959-965; Dworkin RH et al. Neurology. 2003;60:1274-1283; Stankus SJ et al. Am Fam Physician. 2000;61:2437-2444; Christo PJ et al. Drugs Aging. 2007;24:1-19; Wu CL, Raja SN. J Pain. 2008;9(suppl 1):S19-S30. Summary • Increased age and suppressed immune status are risk factors for reactivation of VZV • Zoster can be associated with numerous complications, including ocular injury, bacterial superinfection, and especially PHN • For maximal effectiveness, antivirals should be administered within 72 hours of rash onset • Strategies to prevent zoster occurrence may help reduce disease burden in susceptible populations 41 Outline – The Herpes Zoster Vaccine Rationale for the Vaccine The Shingles Prevention Study Vaccine Efficacy Vaccine Safety Recommendations for Use of the Herpes Zoster Vaccine Why Do We Need a Strategy to Prevent Shingles? • In immunocompetent persons, herpes zoster is a common condition (esp. among elderly patients) and is associated with substantial morbidity. • Once herpes zoster develops, the available treatments (including antiviral therapy) do not prevent PHN in all patients. • The treatments for PHN are complicated, associated with frequent adverse effects, and not always effective. • Prevention is preferable to treatment 43 Why Would We Expect a Zoster Vaccine to Work? • Fact: Herpes zoster incidence and severity increase with advancing age, primarily due to declining VZV-specific cell-mediated immunity (CMI) • Hypothesis: Boosting VZV-specific CMI with a vaccine before it reaches a critical level could suppress VZV reactivation and prevent or attenuate herpes zoster Oxman MN et al. N Engl J Med. 2005;352:2271-2284. 44 RCF (per 100,000 PBMC) CMI to VZV Decreases With Age 6 5 4 3 2 1 0 30 40 50 60 70 80 >85 Age (years) CMI=cell-mediated immunity; PBMC=peripheral blood mononuclear cell; RCF=responder cell frequency; VZV=varicella-zoster virus. Adapted from Levin MJ et al. Unpublished results. 45 Shingles Prevention Study • Efficacy trial to determine whether an attenuated livevirus “zoster vaccine” decreases the incidence and/or severity of herpes zoster and its complications • Placebo-controlled, randomized, double-blind study • 22 U.S. sites (VA and university medical centers) • Enrolled 38,456 adults >60 years • Single subQ injection of vaccine (live VZVOka) or placebo • Subjects followed for minimum of 3 years after enrollment • Monthly follow-up with automated telephone response system (ATRS) • Patients who developed zoster were offered appropriate antiviral therapy and standard-of-care pain medications Oxman M et al. N Engl J Med. 2005;352:2271-2284. 47 SPS - Inclusion and Exclusion Criteria • Inclusion – Adults >60 years old – Ambulatory – History of chickenpox (or >30 years residence in the continental US) • Exclusion – Prior episode of herpes zoster – Prior varicella vaccine – Immunosuppression resulting from: • Disease, malignancy • Corticosteroids • Other immunosuppressive/cytotoxic therapy – Expected survival <5 years Oxman M et al. N Engl J Med. 2005;352:2271-2284. 48 Shingles Prevention Study Endpoints • Primary Endpoint – Burden of illness of herpes zoster (a composite measure affected by zoster incidence plus the severity and duration of the associated pain and discomfort) • Secondary Endpoint – Incidence of PHN (pain persisting at severity >3/10 more than 90 days after rash onset) • Additional Endpoint – Incidence of herpes zoster Oxman MN et al. N Engl J Med. 2005;352:2271-2284 49 Primary Outcome Measure 1. Burden of illness (BOI) – defined as the sum of the areas under worst pain-vstime curves in all subjects who develop HZ in the vaccine vs the placebo group 2. Instrument: Zoster Brief Pain Inventory (ZBPI) – – Validated self-reported assessment of severity and impact of HZ-associated pain administered weekly to each HZ patient until pain was “≤3 out of 10” for two consecutive weeks 3. Measure the area-under-the-curve (AUC) of pain-vs-time. Sum the areas for all subjects (for patients without HZ, area = 0) Oxman M et al. N Engl J Med. 2005;352:2271-2284; Coplan et al. Journal of Pain 5:344-356, 2004 50 AUC of Worst Pain Scores Over Time 10 Worst pain score 9 8 7 6 5 4 3 2 1 0 0 10 20 30 40 50 60 70 Days since rash onset Oxman M et al. N Engl J Med. 2005;352:2271-2284. 51 SPS Randomization Subjects enrolled (n=38,546) Adverse events substudy (n=6616) Cell-mediated immunity substudy (n=1395) Age 60 to 69 years (n=20,747) VZV vaccine (n=10,378) Placebo (n=10,369) Oxman M et al. N Engl J Med. 2005;352:2271-2284. Age 70 years (n=17,799) VZV vaccine (n=8892) Placebo (n=8907) Disposition of SPS Subjects Enrolled 38,546 Zoster vaccine 19,270 Terminated before study end 793 (4.1%) Died 57 (0.3%) Withdrew 61 (0.3%) Lost to follow-up Completed study 18,359 (95.3%) Oxman M et al. N Engl J Med. 2005;352:2271-2284. Placebo 19,276 Terminated before study end 792 (4.1%) Died 75 (0.4%) Withdrew 52 (0.2%) Lost to follow-up Completed study 18,357 (95.2%) 53 Herpes Zoster Case Determination Suspected Cases of HZ N=1308 481 Zoster Vaccine 315 Evaluable Cases of HZ 294 (93.3%) VZV+ by PCR* 2 (0.6%) VZV+ by local culture 19 (6.0%) HZ by CEC only 827 Placebo 642 Evaluable Cases of HZ 600 (93.5%) VZV+ by PCR* 8 (1.2%) VZV+ by local culture 34 (5.3%) HZ by CEC only *VZV = varicella zoster virus. All VZV DNA was wild-type; no Oka detected. CEC = clinical evaluation committee; HZ = herpes zoster; PCR = polymerase chain reaction. Oxman M et al. N Engl J Med. 2005;352:2271-2284. 54 Vaccine Efficacy for Herpes Zoster Burden of Illness (BOI) 61.1% 65.5% 55.4% (95% CI) (51.1 – 69.1) (51.5 – 69.1) (39.9 – 66.9) HZ burden of illness Efficacy 9 8 7 6 5 4 3 2 1 0 5.68 7.78 Vaccine Placebo 4.33 3.47 2.21 1.50 All 60-69 yr 70 yr (P<0.001) Oxman M et al. N Engl J Med. 2005;352:2271-2284. 55 Vaccine Efficacy for Incidence of Herpes Zoster Efficacy 51.3% (95% CI) (44.2 - 57.6) Incidence of HZ (per 1000 person-years) 14 63.9% 37.6% Vaccine 12 11.12 10.79 11.50 Placebo 10 8 6 7.18 5.42 3.90 4 2 0 N= 315 642 All (P<0.001) Oxman M et al. N Engl J Med. 2005;352:2271-2284. 122 334 193 308 60-69 yr 70 yr (P<0.001) (P<0.001) 56 Cumulative incidence of HZ (%) Effects of Vaccine on Incidence of HZ over Time 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 Placebo P<.001 Zoster vaccine Placebo: n=19,247 Zoster vaccine: n=19,254 0 1 2 3 4 5 Years of follow-up Oxman M et al. N Engl J Med. 2005;352:2271-2284. 57 Vaccine Efficacy for Incidence of PHN Efficacy 66.5% 65.7% 66.8% (95% CI) (47.5 - 79.2) (20.4 - 86.7) (43.3 - 81.3) Incidence of PHN* 2.5 2.0 Placebo 1.38 1.5 1.0 0.5 0.0 2.13 Vaccine 0.74 0.71 0.46 0.26 N= 27 80 All Subjects 8 23 60-69 yr 19 57 70 yr (P<0.001) * Per 1000 person-years Oxman M et al. N Engl J Med. 2005;352:2271-2284. 58 Cumulative incidence of PHN (%) Effect of Zoster Vaccine on Postherpetic Neuralgia 1.0 0.9 0.8 P<.001 0.7 Placebo 0.6 0.5 0.4 Zoster vaccine 0.3 0.2 Placebo: n=19,247 Zoster vaccine: n=19,254 0.1 0.0 0 1 2 3 4 5 Years of follow-up Oxman M et al. N Engl J Med. 2005;352:2271-2284. 59 SPS - Adverse Events (Day of Vaccination to Day 42*) Event Vaccine No. (%) N=3,345 Placebo No. (%) N=3,271 Difference in Risk (95% CI) Erythema 1,188 (35.8) 227 (7.0) 31.7 (28.3 to 32.6) Pain or tenderness 1,147 (34.5) 278 (8.5) 28.8 (26.9 to 30.6) Death 14 (0.1) 16 (0.1) -0.01 (-0.1 to 0.1) One or more SAEs 255 (1.4) 254 (1.4) 0.01 (-0.2 to 0.3) 7 (<0.1) 24 (0.1) Confirmed case of HZ -0.09 (-0.16 to -0.03) * among AE substudy subjects who kept daily diaries Oxman M et al. N Engl J Med. 2005;352:2271-2284. 62 Herpes Zoster Vaccine Trials: Summary • Zoster vaccine efficacy1 – 61.1% reduction in the HZ burden of illness (BOI) – 66.5% reduction in the incidence of PHN – 51.3% reduction in the incidence of HZ • Zoster vaccine was safe and efficacious in preventing HZ and PHN in adults 60 years of age and over • Most common AE was tenderness and erythema at the injection site (36%) Oxman M et al. N Engl J Med. 2005;352:2271-2284. Hornberger J and Robertus K. Ann Int Med 2006; 145: 317-325. 63 Clinical Practice Recommendation • Practice Recommendation: Zoster vaccine is recommended for all adults age 60 and above. • Evidence-Based Source: National Guidelines Clearinghouse • Web Site of Supporting Evidence: http://www.guideline.gov/summary/summary.aspx?doc_id=120 93&nbr=006222&string=zoster+AND+vaccine • Strength of Evidence: Class A: Randomized, controlled trial; Class M: Meta-analysis, Systemic review, Decision analysis, Cost-effective analysis; Class R: Consensus statement, Consensus report, Narrative review 64 CDC Recommends Herpes Zoster Vaccination for Adults • October 2007 — CDC includes zoster vaccine in adult immunization schedule for adults ≥60 years of age • May 2008 — For the prevention of herpes zoster, the CDC recommends that the zoster vaccine be given to all people ≥60 years of age who have no contraindications, including1: – Patients who have had a previous episode of herpes zoster – Patients with chronic medical conditions 1. Centers for Disease Control and Prevention. MMWR. 2008;57:1-30. 65 Herpes Zoster Vaccine: Dosage and Administration • Zostavax® (Zoster Vaccine Live [Oka/Merck]) is a lyophilized preparation of the Oka/Merck strain of live, attenuated VZV. • For subcutaneous administration • Administered in a single dose of 0.65 mL • Stored frozen • Should be reconstituted immediately upon removal from freezer • Diluent should be stored separately • Discard reconstituted vaccine if not used within 30 minutes Zostavax [package insert]. Whitehouse Station, NJ: Merck & Co.; 2007. 67 Contraindications to Herpes Zoster Vaccine • History of anaphylactic/anaphylactoid reaction to neomycin (does not include contact dermatitis) • Serious current illness (or temperature ≥38.5°C) • History of immunodeficiency state, including – Leukemia, lymphomas, or other malignant neoplasms affecting bone marrow or lymphatic system – AIDS or other clinical manifestations of HIV infection • Immunosuppressive therapy, including high-dose corticosteroids • Active untreated tuberculosis • Known or suspected pregnancy Zostavax [package insert]. Whitehouse Station, NJ: Merck & Co.; 2007. 68 Herpes Zoster Vaccine Case #1 • A 52 y.o. woman comes to clinic for routine follow-up • Active problems - type 2 diabetes mellitus and hyperlipidemia, which are fairly well-controlled with medication. • Social history – successful corporate attorney, unmarried, no children • PMH – no prior zoster. Chickenpox history unknown • Two of her co-workers have had shingles in the last few months, both associated with severe pain and protracted absence from work. She requests the zoster vaccine. • What do you recommend to her? 69 ? Can Zoster Vaccine be Given to Patients <60 years of Age? • Current FDA approval only for age >60 years (the population studied in SPS) • In one recent study, 50-60 years was the decade with the highest absolute number of herpes zoster cases (incidence 4.2 cases/1000 person-yrs)1 • In studies with high-potency zoster vaccine in subjects 50-59 y.o., the vaccine was safe and immunogenic, but efficacy was not assessed2. Efficacy studies in this age group are ongoing. • Uncertainty regarding duration of protection when given to younger patients. Will they “outlive” vaccine efficacy? • In the absence of data, physicians and their patients <60 y.o. who desire vaccination will have to discuss the risk-benefit ratio. Unlikely to be covered by insurance. 1Yawn et al, Mayo Clin Proc 82:1341, 2007 et al, Vaccine 25:1877, 2007 2Tyring 72 Can Zoster Vaccine be Given to Patients with Unknown Chickenpox History? • VZV seropositivity rate among Americans >60 y.o. is >95%1. Most patients who do not recall a history of chickenpox are VZV seropositive. • Serologic testing was not requirement for SPS. • Limited data suggest no excess morbidity if VZV seronegative patients are given zoster vaccine2. • The efficacy of a single injection of zoster vaccine for protecting against chickenpox is unknown. • No recommendation that patients undergo VZV serologic testing before receiving zoster vaccine 1Kilgore, et al, J Med Virol 70 (suppl):S111, 2003 2Macalalad et al, Vaccine 25:2139, 2007. 73 Herpes Zoster Vaccine Case #2 • A 78 y.o. retired physician comes to clinic in December for a flu shot • Active problems – chronic bronchitis, ischemic heart disease, congestive heart failure, all adequately controlled with medication • Social history – previous heavy smoker, recently quit • PMH – MI 3 years ago. Herpes zoster (V-1 dermatome with ocular involvement and 18 months of PHN) 9 years ago. • Because of his prior severe case of shingles, he has read about the herpes zoster vaccine and wants to receive it today • What do you recommend to him? 74 ? Should Zoster Vaccine be Given to Patients With a Previous Episode of Herpes Zoster? • Use of zoster vaccine in those who have previously had herpes zoster. Considerations: – – – – – >15% of target population (>60 y.o.) has had prior HZ; Risk of a second case of HZ is small (2-5%); The diagnosis of remote herpes zoster is imperfect; No laboratory marker for prior herpes zoster or for zoster risk; No data on rate of decay in boost of VZV-CMI that occurs following naturally-occurring zoster. • Vaccine is likely to add protection when the initial HZ was in the “remote” past • Vaccinating patients who have already had HZ is unlikely to create safety concerns • ACIP recommends vaccination “whether or not they report a prior episode of herpes zoster.” 77 Clinical Practice Recommendation • Practice Recommendation: A history of prior shingles disease is not a contraindication to immunizing patients over age 60 against zoster/shingles. • Evidence-Based Source: Institute for Clinical Systems Improvement • Web Site of Supporting Evidence: http://www.icsi.org/immunizations/immunizations__guideline_. html • Strength of Evidence: Class A: Randomized, controlled trial; Class M: Meta-analysis, Systemic review, Decision analysis, Cost-effective analysis; Class R: Consensus statement, Consensus report, Narrative review 78 Can Zostavax be Co-Administered with Other Vaccines? • Concomitant use: – In general, live vaccine administration is acceptable any time before or after an inactivated vaccine1 – Few other live vaccines are routinely used in adults – Inactivated influenza and zoster vaccines can be given at the same time • Same immune response and safety when given concomitantly (N=382) or sequentially (N=380)2 – Pneumococcal PS – studies ongoing – Tdap – studies planned 1ACIP General Recommendations on Immunization—December 2006 2Kerzner et al, J Am Geriatr Soc 55:1499, 2007 79 Herpes Zoster Vaccine and Inactivated Influenza Vaccine Can Be Administered Concomitantly VZV antibody geometric mean titer (GMT) 1000 900 800 700 Estimated GMT ratio 0.9 (P<.001) Prevaccination GMFR Week 4 postvaccination (95% CI) 2.0 2.3 (1.8-2.2) (2.0-2.5) 600 500 400 300 200 100 0 Concomitant Nonconcomitant GMFR=geometric mean-fold rise; patients aged ≥60 years. Kerzner B et al. J Am Geriatr Soc. 2007;55:1499-1507. 80 Herpes Zoster Case #3 • A 61 y.o. woman comes to clinic for follow-up of breast cancer • Active problems – breast cancer, s/p lumpectomy and chemotherapy (completed 4 months ago); hypertension • PMH – hysterectomy for fibroids • PE – hair is growing back, breast well-healed, no adenopathy, no evidence of metastatic disease • Lab – HCT 29; WBC 7600 (65 PMN, 25 lymphs, 10 monos); PLT 180,000 • Both her mother and her father had severe cases of shingles in their 70s. She asks you if she should receive the zoster vaccine. • What do you recommend to her? 81 ? Can Zoster Vaccine be Given to Immunocompromised Patients? • Zoster vaccine contains replicating VZV. There is theoretical potential for vaccine virus to cause disease in immunocompromised patients. • Per package insert, zoster vaccine is contraindicated in immunocompromised patients • Patients with impaired cell-mediated immune responses likely to be at greatest risk include: – – – – HIV seropositive patients Organ transplant recipients on anti-rejection therapy Cancer patients actively receiving chemotherapy or radiation Patients receiving corticosteroids or other immunosuppressive therapy for autoimmune diseases However, many other “gray areas” remain where physicians must use clinical judgment 84 CDC Recommendations: Immunocompromised Patients • Corticosteroids: Patients ≥60 years of age receiving a dose equivalent to 20 mg/d prednisone for >2 weeks should not receive the zoster vaccine for at least 1 month after discontinuation of such therapy – Topical (e.g., skin, nasal, inhaled), intraarticular, bursal, or tendon injections are not considered sufficiently immunosuppressive to raise vaccine safety concerns • Immunosuppressive therapy not considered sufficiently immunosuppressive to raise vaccine safety concerns includes: • Methotrexate (≤0.4 mg/kg/week) • Azathioprine (≤3.0 mg/kg/d) • 6-Mercaptopurine (≤1.5 mg/kg/d) Centers for Disease Control and Prevention. MMWR . 2008;57:1-30. 85 CDC Recommendations: Immunocompromised Patients (cont’d) • Patients ≥60 years of age whose leukemia is in remission and who have not received chemotherapy or radiation therapy for at least 3 months can receive the zoster vaccine • Patients ≥60 years of age undergoing hematopoietic stem cell transplantation (HSCT) should be assessed on a case-by-case basis – Zoster vaccine should be given no sooner than 24 months after transplantation Centers for Disease Control and Prevention. MMWR. 2008;57:1-30. 86 CDC Recommendations: Immunocompromised Patients (cont’d) • Patients ≥60 years of age with impaired humoral immunity (e.g., dys- or hypogammaglobulinemia) can receive the zoster vaccine • Patients ≥60 years of age receiving recombinant human immune mediators or immune modulators should be assessed on a case-by-case basis – If it is not possible to administer zoster vaccine before the initiation of therapy, it should be deferred until at least 1 month after discontinuation of therapy Centers for Disease Control and Prevention. MMWR. 2008;57:1-30. 87 Herpes Zoster Vaccine Case #4 • An oncologist calls you to discuss a mutual patient, a 68 year old man with colon cancer • Active problems – Adenocarcinoma of the colon, s/p hemicolectomy 3 weeks ago. His post-op course was complicated by a COPD exacerbation that required a 10 day tapering course of prednisone (now completed). • PE – colostomy; abdominal wound healing well; lungs clear • The oncologist plans to initiate chemotherapy in about 3 weeks. She wants to know whether it might be a good idea to give the patient the zoster vaccine today. • What advice do you give her? 88 ? Can the Zoster Vaccine be Given in Advance of Immunosuppressive Therapy? • The concept of vaccination prior to planned immunosuppressive therapy is attractive, but unstudied • Potential situations: – Chemotherapy or radiation therapy planned for solid tumor malignancy (e.g., breast cancer) – TNF-alpha inhibitor therapy planned for autoimmune disease (e.g., rheumatoid arthritis) • What is a safe interval between vaccination and initiation of immunosuppressive therapy? • Safety and efficacy of this approach are unknown 91 CDC Recommendations: Special Groups and Circumstances • Patients ≥60 years old who are anticipating immunosuppression should receive zoster vaccine while immunity is intact—at least 14 days before initiating immunosuppressive therapy • Patients ≥60 years of age taking chronic acyclovir, famciclovir, or valacyclovir should not receive zoster vaccine until at least >24 hours after drug discontinuation • Zoster vaccine can be administered at any time before, concurrent with, or after receiving: – Blood – Antibody-containing blood products Centers for Disease Control and Prevention. MMWR. 2008;57:1-30. 92 Future of Herpes Zoster in the U.S. Incidence likely rising among adults (DOB before 1995) who had chickenpox. - aging population - more immunocompromised persons - reduced exposure to chickenpox - ? More zoster in the elderly will mean more PHN. Acceptance of vaccination of adults to prevent zoster? Impact of childhood varicella vaccination? - Dramatic decline in chickenpox. Will these vaccinated children be at higher or lower risk for shingles in 50 years? Reducing the Public Health Burden of Herpes Zoster and PHN Through Vaccination • Herpes zoster is a cause of major morbidity in older adults, significantly impacting their quality of life • Advancing age is the primary risk factor for herpes zoster and its major complication, PHN • Current treatment options for herpes zoster and PHN have limitations • Herpes zoster vaccine reduced the incidence and severity of herpes zoster and PHN in adults ≥60 years 94 Post-Test Questions ?