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Embassy Suites Raleigh-Durham/Research TriangleCary, North Carolina

June 21, 2008

Symposia Series 22008

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Strategies for Preventing Herpes Zoster and Postherpetic Neuralgia: Are Your Patients Adequately Protected?

Kevin P. High, MD, MSc

Chief, Section on Infectious Diseases

Professor of Medicine

Sections on Infectious Diseases, Hematology/Oncology,

and Molecular Medicine

Co-Director, Molecular Medicine Graduate Program

Wake Forest University School of Medicine

Winston-Salem, North Carolina

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Faculty Disclosure

Dr High: advisory board/speakers bureau: Merck & Co., Inc.; research grants: ViroPharma Inc.

Do you routinely recommend and administer the herpes zoster vaccine to your patients who are ≥60 years of age?

Use your keypad to vote now!Use your keypad to vote now!

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KEY QUESTION?

1 2

0%

100%1. Yes

2. No

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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

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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.

Natural History, Epidemiology, and Health Burden

of Herpes Zoster and PHN

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Natural History of Herpes Zoster

VZV = varicella-zoster virusAdapted from Kost RG, Straus SE. N Engl J Med. 1996;355:32-42; Hope-Simpson RE. Proc R Soc Med. 1965;58:9-20.

Age

VZ

V T

Cel

ls

Varicella Herpes Zoster

Zoster Threshold

VaricellaExposure

SilentReactivation?

Case Study

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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

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

Herpes Zoster Rash

What factors in this patient’s history may have predisposed her to the development of herpes zoster?


?DECISION POINT

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1 2 3 4 5

100%

0% 0%0%0%

1. Impaired cell immunity due to advancing age, diseases, or immunosuppressive therapy

2. Psychological stress

3. Physical trauma

4. All of the above

5. None of the above

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; 3Levin MJ 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.

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Incidence of Herpes Zoster Increases With Age

Donahue JG et al. Arch Intern Med. 1995;155:1605-1609; Oxman MN et al. N Engl J Med. 2005;352:2271-2284.

Estimated 1 million cases in the United States annually, which will likely increase as population ages

Rat

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ears

Age (Years)

1629

876

640

318194184

9054 39121

11181122

495

307262201

0

500

1000

1500

2000

0-14 15-24 25-34 35-44 45-54 55-64 65-74 ≥75

WomenMen

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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.

Neurologic Ophthalmic PHN Motor neuropathy Cranial palsy Encephalitis Transverse myelitis Postzoster stroke syndromes

Stromal keratitis Iritis Retinitis Visual impairment Episcleritis Keratopathy

Cutaneous Visceral Bacterial superinfection Scarring Disfigurement

Pneumonitis Hepatitis Encephalitis

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

Frequency and severity 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; 4Levin MJ et al. J Infect Dis. 2008;197:825-835.

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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.

Physical FunctionalDiminished energyAnorexiaWeight lossPhysical inactivity Impaired sleep

Interference with basic activities of daily living including

– Dressing– Bathing– Eating– Mobility

Psychological SocialDepressionAnxietyDifficulty concentrating

Decreased social gatheringsChange in social role

Diagnosis of Herpes Zoster

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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.

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Acute Herpes Zoster RashOrder of rash progression

Vesicles

Pustular lesions

Lesions crust over

Resolution of rashPhoto and slide courtesy of John W Gnann, Jr, MD.

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Herpes Zoster Rash

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

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Trigeminal Zoster


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

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.

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Recurrent Herpes Simplex


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Contact Dermatitis

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

Treatment Strategies for Herpes Zoster and PHN

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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

Antiviral therapy administered within 72 hours of rash onset can reliably prevent PHN


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?DECISION POINT

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1 2 3

100%

0%0%

1. True

2. False

3. Unsure

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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.

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Treatment Whom to Treat Limitations

Oral antivirals Patients with zoster rash Use within 72 hours of rash onset

IV acyclovir Selective use in immunosuppressed patients or those with CNS disease

May use after 72 hours in immunosuppressed patients

Oral corticosteroids

Adjunctive therapy for patients with moderate to severe pain (controversial)

Side effects: use with caution in patients with underlying illnesses

Aspirin, NSAIDs, antihistamines, calamine, silver sulfadiazine

Patients with minor pain or itching May not provide adequate pain relief

Opioids, opioid-like drugs

Patients with moderate to severe pain

Significant side effects, potential for addiction

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.

Management Strategies:Acute Herpes Zoster

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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

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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.

Medication Pain Response and Adverse Event Profile

Gabapentin, pregabalin1,2 33% reduction in pain with gabapentin; 63% of patients receiving pregabalin experience clinically significant pain reductionAdverse events include somnolence, dizziness, and peripheral edema

Tricyclic antidepressants3 47% to 67% of patients report at least moderate pain relief Adverse events include sedation, confusion, urinary retention, dry mouth, postural hypotension, and arrhythmia

Opioid analgesics4,5 38% to 58% of patients report pain relief Adverse events include constipation, nausea, loss of appetite, dizziness, and drowsiness

Lidocaine patch 5%6 60% efficacy (ie, at least moderate pain relief)No systemic adverse events, but local reactions include erythema and skin rash

Capsaicin cream Moderate pain relief but often with intolerable burning

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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

Adapted from Kost RG, Straus SE. N Engl J Med. 1996;335;32-42.

Comorbid illness, the risk of drug interactions, and side effects must be considered when treating elderly patients with PHN

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Case Vignette

Reducing the Incidence and Severity of Herpes Zoster and PHN

With Herpes Zoster Vaccination

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Age

VZ

V T

cel

ls

Varicella

Zoster Threshold

VaricellaExposure

SilentReactivation?

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Herpes Zoster Vaccination

ZosterVaccination

Herpes Zoster

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.

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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.

Herpes zoster vaccination reduces the burden of illness associated with zoster by…


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KEY QUESTION?

38

1 2 3 4

100%

0%0%0%

1. ~31%

2. ~41%

3. ~61%

4. 100%

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Vaccine Efficacy for Herpes Zoster

Efficacy(95% CI)

61.1% (51.1-69.1)

65.5% (51.5-75.5)

55.4% (39.9-66.9)

CI = confidence intervalOxman MN et al. N Engl J Med. 2005;352:2271-2284.

0

1

2

3

4

5

6

7

8

9

All 60-69 70

Her

pes

Zo

ster

B

urd

en o

f Il

lnes

s

Vaccine

Placebo

P<.001

Age (Years)

Burden of Illness

Herpes Zoster Vaccination Reduces Incidence of Herpes Zoster and PHN

Oxman MN et al. N Engl J Med. 2005;352:2271-2284.

6.0

Herpes Zoster

Years of Follow-Up Years of Follow-Up

1.0

PHN

Years of Follow-Up Years of Follow-Up

5

0.7

Placebo

Zoster Vaccine

Cu

mu

lati

ve In

cid

ence

(%

)

0 1 2 3 4

5.55.04.54.03.53.0

0.5

1.51.0

0.0

2.52.0

P<.001Placebo

Cu

mu

lati

ve in

cid

ence

(%

)

0 1 2 3 4 5

0.9

0.8

0.6

0.5

0.4

0.3

0.2

0.1

0.0

P<.001

51%

66.5%

Zoster Vaccine

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CDC RecommendsHerpes Zoster Vaccination in Adults

October 2007 — CDC includes zoster vaccine in adult immunization schedule for adults ≥60 years of age

May 15, 2008 — For the prevention of herpes zoster, the CDC recommends that the zoster vaccine be given to all persons ≥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 (early release). 2008;57:1-30.

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Contraindications to Herpes Zoster Vaccine

ZOSTAVAX [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2006.

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 Please see full CDC recommendations at:

http://www.cdc.gov/mmwr/pdf/rr/rr57e0515.pdf

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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.

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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.

Case Study

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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.

Does this patient meet the criteria to receive the herpes zoster vaccine, and can it be given with his flu shot?


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?DECISION POINT

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1 2 3 4

100%

0%0%0%

1. Yes, he should receive it, but should not get it at the same time as his flu shot

2. Yes, he should receive it, and can get the flu shot at the same time

3. No, he does not meet criteria to receive the zoster vaccine because his medications include inhaled corticosteroids

4. Unsure

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 (eg, skin, nasal, inhaled), intra-articular, 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 (early release). 2008;57:1-30.

CDC Recommendations: Immunocompromised Patients

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CDC Recommendations: Herpes Zoster Vaccine and Inactivated Vaccines Can Be Administered Concomitantly

Immunogenicity of zoster and influenza vaccines is not compromised when the 2 are administered simultaneously1

Zoster and influenza vaccines given concomitantly are generally well tolerated in older adults2

Simultaneous administration of inactivated vaccines should not result in an impaired immune response or an increased rate of adverse events1

– Therefore, the zoster vaccine can be administered with other indicated vaccines within the same visit (eg, Td, Tdap, PPV)

1. Centers for Disease Control and Prevention. MMWR (early release). 2008;57:1-30; 2. Kerzner B et al. J Am Geriatr Soc. 2007;55:1499-1507.

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Case Study

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Case Study 3

A 61-year-old woman, born and raised in Cary, North Carolina, arrives at the clinic for routine follow up

Active problems: hypertension, type 2 diabetesSocial history: investment banker, unmarried,

no childrenMedical history: no prior herpes zoster; claims

she has never had chickenpox

Which of the following is a true statement concerning this patient?


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?DECISION POINT

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1 2 3 4

100%

0%0%0%

1. She should not receive the herpes zoster vaccine

2. She should not receive the herpes zoster vaccine until she receives 2 doses of the varicella vaccine

3. She should have varicella titers taken first and, if positive, may receive the herpes zoster vaccine

4. She may receive the herpes zoster vaccine today

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Should the Herpes Zoster Vaccine Be Given to Patients With Unknown Chickenpox History?

VZV seropositivity rate among Americans ≥60 years of age is >99%1

– Most patients who do not recall history of chickenpox are VZV seropositive

– Serologic testing was not an entry requirement for the Shingles Prevention Study

Data have shown herpes zoster vaccination to be safe in VZV-seronegative patients2

VZV serologic testing is not recommended prior to receiving herpes zoster vaccine

1Kilgore PE et al. J Med Virol. 2003;70(suppl 1):S111-S118. 2Macaladad N et al. Vaccine. 2007;25:2139-2144.

Q & A

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PCE Takeaways

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PCE Takeaways

Incidence and severity of herpes zoster increase with advancing age to produce substantial negative effects on quality of life

Antiviral therapy may reduce the incidence and severity of acute herpes zoster, but does not reliably prevent PHN

Herpes zoster vaccination offers a safe and highly effective method of reducing the public healthcare burden of herpes zoster and its complications

continued5656

PCE Takeaways

The CDC recommends vaccination of all persons ≥60 years of age with no contraindications, including those with a history of herpes zoster or chronic medical conditions

The CDC has included the herpes zoster vaccine in the 2007-2008 Recommended Adult Immunization Schedule

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Do you now plan to routinely recommend and administer the herpes zoster vaccine to your patients who are ≥60 years of age?


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KEY QUESTION?

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1. Yes

2. No

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LunchDon’t forget to complete your CME/CE

evaluation form and return it to the registration desk at the end of

our program

Embassy Suites Raleigh-Durham/Research TriangleCary, North Carolina

June 21, 2008

Symposia Series 22008

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