Radisson Hotel at Opryland

1
2008
Symposia Series 2

• Radisson Hotel at Opryland
• Nashville, Tennessee
• May 31, 2008

1
2
Strategies for Preventing Herpes Zoster and
Postherpetic Neuralgia Are Your Patients
Adequately Protected?

• Lawrence D. Gelb, MD
• Professor of Medicine
• Department of Internal Medicine
• Division of Infectious Diseases
• Washington University in St. Louis, School of
  Medicine
• St. Louis, Missouri

3
Faculty Disclosure

• Dr Gelb speakers bureau Merck Co., Inc.

4
Do you routinely recommend and administer the
herpes zoster vaccine to your patients who are
60 years of age?

1. Yes
2. No

Use your keypad to vote now!
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 gt65 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
Natural History of Herpes Zoster
VZV varicella-zoster virus Adapted from Kost
RG, Straus SE. N Engl J Med. 199635532-42
Hope-Simpson RE. Proc R Soc Med. 1965589-20.
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
What factors in this patients history may have
predisposed her to the development of herpes
zoster?

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

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.
2002347340-346 2Johnson RW, Whitton TL. Expert
Opin Pharmacother. 20045551-559 3Levin MJ et
al. J Infect Diseases. 2008197825-835
4Kawasaki H et al. J Pediatr. 1996128353-356
5Thomas SL, Hall JA. Lancet Infect Dis.
2004426-33.
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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.
19951551605-1609 Oxman MN et al. N Engl J Med.
20053522271-2284.
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Complications of Herpes Zoster
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
Gnann JW Jr, Whitley RJ. N Engl J Med.
2002347340-346 Arvin AM. Clin Microbiol Rev.
19969361-381Moriuchi K, Rodriguez W. Pediatr
Infect Dis J. 200019648-653.
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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. 20053522271-2284
2Wood MJ, Easterbrook P. Shingles, scourge of
the elderly. In Sacks SL et al, eds. Clinical
Management of Herpes Viruses. Amsterdam IOS
Press 1995193-209 3Jung BF. Neurology.
2004621545-1551 4 Kost RG, Straus SE. N Engl J
Med. 199635532-42.
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Impact of PHN on Quality of Lifein Older Adults
Physical Functional
Diminished energy Anorexia Weight loss Physical inactivity Impaired sleep Interference with basic activities of daily living including Dressing Bathing Eating Mobility
Psychological Social
Depression Anxiety Difficulty concentrating Decreased social gatherings Change in social role
Schmader KE. Clin J Pain. 200218350-354
Chidiac C et al. Clin Infect Dis. 20013362-69
Lydick E et al. Qual Life Res. 1995 441-45
Katz J et al. Clin Infect Dis. 200439342-348
Coplan PM et al. J Pain. 20045344-356.
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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 2000246-275.
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.
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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 2000246-275 2Rubben A et al. Br J
Dermatol. 1997137256-261 3Gershon AA et al.
Varicella-zoster virus. In Murray PR et al, eds.
Manual of Clinical Microbiology. 6th ed.
Washington, DC ASM Press 1995884-894.
24
Herpes Simplex Rash
Photo provided courtesy of Dr. Kenneth Schmader,
Associate Professor of MedicineGeriatrics, Duke
University School of Medicine.
25
Contact Dermatitis
Reprinted with permission from DermNet. Available
at http//dermnet.com. Accessed February 4, 2008.
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Treatment Strategies for Herpes Zoster and PHN
27
Case Study 1 (contd)

• 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

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

1. True
2. False
3. 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.
199633532-42 2Gnann JW Jr, Whitley RJ. N Engl
J Med. 2002347340-346 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.
2005721075-1080.
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Management StrategiesAcute Herpes Zoster
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.
198638363-365 Kalibala S et al. AIDS Action.
1990102-3.
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Case Study 1 (contd)

• The patients 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
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 reduction Adverse 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 56 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
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. 19982801837-1842
2Dworkin RH et al. Neurology. 2003601274-1283
3Pappagallo M, Haldey EJ. CNS Drugs. 2003
17771-780 4Watson CPN, Babul N. Neurology.
1998501837-1841 5Raja SN et al. Neurology.
2002591015-1021 6Davies PS, Galer BS. Drugs.
200464937-947.
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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

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.
199633532-42.
34
Case Vignette
35
Reducing the Incidence and Severity of Herpes
Zoster and PHN With Herpes Zoster Vaccination
36
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.
199635532-42 Hope-Simpson RE. Proc R Soc Med.
1965589-20.
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 (gt6.6 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. 20053522271-2284.
38
Herpes zoster vaccination reduces
the burden of illness associated
with zoster by

1. 30
2. 40
3. 50
4. 60
5. 70

Use your keypad to vote now!
39
Vaccine Efficacy for Herpes Zoster
Burden of Illness
Efficacy (95 CI) 61.1 (51.1-69.1) 65.5 (51.5-75.5) 55.4 (39.9-66.9)
9
Plt.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. 20053522271-2284.
Age (Years)
40
Herpes Zoster Vaccination Reduces Incidence of
Herpes Zoster and PHN
Oxman MN et al. N Engl J Med. 20053522271-2284.
41
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 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 (early release). 2008571-30.
42
Contraindications to Herpes Zoster Vaccine

• History of anaphylactic/anaphylactoid reaction to
  neomycin
• Serious current illness (or T 38.5C)
• 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

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.
200554S58-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 patients 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.
200325144-150.
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
Does this patient meet the criteria to
receive the herpes zoster vaccine,
and can it be given with
his flu shot?

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. No, he does not need the zoster vaccine because
   of his prior episode of herpes zoster.
5. Unsure

Use your keypad to vote now!
48
CDC Recommendations Immunocompromised Patients

• Corticosteroids Patients 60 years of age
  receiving a dose equivalent to 20 mg/d prednisone
  for gt2 weeks should not receive the zoster
  vaccine for at least 1 month after
  discontinuation of such therapy
• Topical (eg, 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
(early release). 2008571-30.
49
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). 2008571-30 2. Kerzner B
et al. J Am Geriatr Soc. 2007551499-1507.
50
Case Study
51
Case Study 3

• A 61-year-old woman, born and raised in
  Nashville, Tennessee, arrives at the clinic for
  routine followup
• Active problems hypertension, type 2 diabetes
• Social history investment banker, unmarried,
  no children
• Medical history no prior herpes zoster claims
  she has never had chickenpox

52
Which of the following is a true statement
concerning this patient?

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

Use your keypad to vote now!
53
Should the Herpes Zoster Vaccine Be Given to
Patients With Unknown Chickenpox History?

• VZV seropositivity rate among Americans 60 years
  of age is gt991
• 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. 200370(suppl
1)S111-S118. 2Macaladad N et al. Vaccine.
2007252139-2144.
54
Q A
55
PCE Takeaways
56
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
  health care burden of herpes zoster and its
  complications
• Continued

57
PCE Takeaways

• The CDC recommends vaccination of all people 60
  years of age with no contraindications, including
  those with previous history of herpes zoster or
  chronic medical conditions
• The CDC has included the herpes zoster vaccine
  in the 2007-2008 Recommended Adult Immunization
  Schedule

58
Do you now plan to routinely recommend and
administer the herpes zoster vaccine to your
patients who are 60 years of age?

1. Yes
2. No

Use your keypad to vote now!
59
Lunch

• Dont forget to complete your CME/CE evaluation
  form and return it to the registration desk at
  the end of our program

60
2008
Symposia Series 2

• Radisson Hotel at Opryland
• Nashville, Tennessee
• May 31, 2008