Transcript Shingles Prevention Study

Division of Viral Diseases
Herpes Zoster Vaccine:
Implementation Issues
Rafael Harpaz, MD MPH
Medical Epidemiologist
National Center for Immunizations and Respiratory Diseases
Centers for Disease Control and Prevention
Atlanta, GA
Outline
• Background
 Clinical manifestations of herpes zoster (HZ)
 Epidemiology of HZ
 The pivotal HZ vaccine (HZV) study
• Recommendations & implementation of HZV
Clinical Manifestations
of HZ
Definition:
HZ (zoster, shingles): reactivation of varicella zoster virus (VZV)
leading to crop of blisters in a dermatomal pattern (an area of
skin supplied by sensory nerves from 1 nerve root)
• After initial infection (chickenpox), VZV establishes a latent
infection in nerve cell bodies along the central nervous system
• Years or decades later VZV reactivates
• VZV virions reappear & spread to skin via peripheral nerves
Manifestations of HZ: Rash
• Unilateral; 1-3 adjacent dermatomes
• Typically resolves over ~5-25 d
• Occasional complications: bacterial infections, scarring
• VZV from rash can spread to susceptible persons and
cause varicella (HZ is ~20% as contagious as varicella)
Classic HZ Rashes:
Thoracic, Lumbar Distribution
T1-T2
T7-T8
L3-L4
Classic HZ Rashes:
Cranial (Trigeminal) Distribution
Trigeminal:
Mandibular
Trigeminal:
Ophthalmic
Manifestation of HZ: Pain
• Often precedes rash by days or weeks
• Can be excruciating (e.g., like renal colic, childbirth)
• Described as aching, burning, stabbing, shock-like
• Continuous or paroxysmal
• Often associated with:
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Altered or painful sensitivity to touch
Provoked by trivial stimuli like bed sheets
Unbearable itching
Complications of HZ:
Post Herpetic Neuralgia (PHN)
• Prolonged, often severe, pain after resolution of the rash
Variable definitions of “prolonged”
May persist months or years; some experience recurrence
No consistently effective ways to prevent or treat PHN
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Complications of HZ: PHN
Impact on Quality of Life
• Comparable to congestive heart failure, diabetes & depression
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PHYSICAL
Chronic fatigue
Anorexia & weight loss
Physical inactivity
Insomnia
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PSYCHOLOGICAL
Anxiety
Difficulty concentrating
Depression, suicidal
ideation
SOCIAL
FUNCTIONAL
• Fewer social gatherings • Interferes with activities
of daily living: dressing,
• Change in social role
bathing, eating, travel,
cooking, shopping
Schmader KE. Clin Infect Dis2001;32(10):1481-6
Complications of HZ: Herpes
Zoster Ophthalmicus
• Involvement of
ophthalmic
division of
trigeminal nerve
• ~15% of HZ cases
• Can lead to
chronic ocular
complications,
reduced vision,
even blindness
Courtesy of MN Oxman UCSD/San Diego VAMC
Uncommon HZ Complications
• Neurologic:
 Encephalitis, myelitis, optic neuritis, palsies
 Hearing impairment, vertigo, loss of taste
 Neurologic dysfunction of diaphragm, bladder,
colon
• Oral (destruction of alveolar bone with loss of teeth)
• Immunocompromised:
 Above complications can be much more agressive
 Dissemination: generalized rash +/- visceral involvement
(pneumonia, encephalitis, hepatitis)
• Mortality: mostly in immunocompromised persons
Epidemiology of HZ
Zoster linguae
Epidemiology of HZ in U.S.
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Annual rate 3-4 per 1000 population per year
~1 million cases in the U.S. annually
Age-adjusted rates appear to be increasing
Lifetime risk of developing HZ: ~30%
Risk Factors for HZ
• Age (detailed in next slide)
 Dominant
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factor influencing incidence in population
Immunosuppression
 Less common but influential due to magnitude of risk:
– Following bone marrow transplant: 17-52%
– Patients with hematological malignancies: 5-14%
– HIV: risk  12-17 fold, recurrences common
Rate of HZ per 1000 per year
Risk Factors for HZ: Age
Hope-Simpson, UK (1975)
11
10
9
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5
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3
2
1
0
N=321
0
10
20
30
40
50
Age (years)
60
70
80+
Risk Factors for HZ:
Unconfirmed or lower magnitude
• Gender: most studies show risk  in females
• Race: risk in blacks <1/2 that in whites (U.K., U.S.)
• Local trauma: 30-day risk in affected area  12-fold
• Stress: risk  ~40% following stressful life events
• Certain illnesses: diabetes, Crohn’s, rheumatoid arthritis
• Varicella exposure (“external boosting”): risk 
 However, we don’t know why some immunocompetent
persons get HZ and others do not!!
Epidemiology of PHN in U.S.
• Proportion of HZ patients that develop PHN:
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10% of HZ patients will have ≥90 days of pain
18% of HZ patients will have ≥30 days of pain
• 100 to 200 thousand new PHN cases per year
Risk Factors for PHN
• Of those with HZ, age is key risk factor for developing PHN
• Risk of progression to PHN (≥90 days) in HZ patients:
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Persons 22-49 years of age:
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Persons at least 80 years of age: 20%
Since risk of HZ itself increases with age, PHN is ~20X
more likely to occur in persons >80 y.o. vs. <40 y.o.
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6%
The Shingles Prevention Study
Mandibular
Shingles Prevention Study:
Methods
• Double-blind, placebo-controlled, multicenter trial
• Enrolled 38,546 healthy subjects 60 years old
• Randomized: HZV vs. placebo
Attenuated VZV; titer ≥14X higher than varicella vaccine
Follow up: median of ~3.1 years
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Shingles Prevention Study:
Vaccine Efficacy for HZ & PHN (≥90
days)
Vaccine Efficacy (%)
100%
90%
80%
70%
PHN
HZ
67%
51%
60%
50%
40%
30%
20%
10%
0%
ALL
60 - 64
65 - 69
70 - 74
75 - 79
Age at Randomization (Years)
>79
Shingles Prevention Study:
Vaccine Efficacy for PHN of Varying Duration
PHN Defined by
Varying Duration
(days)
Vaccine Efficacy
VEPHN (95% CI)
30
60
90
120
180
59% (47, 69)
60% (44, 73)
67% (48, 79)
69% (45, 83)
73% (42, 89)
Shingles Prevention Study:
Adverse events: appears to be safe
• No pattern suggesting causal link to serious adverse events
• Vaccine rashes did not occur in the trial
• Excess of local injection site reactions
 Vaccinees:
48%
 Placebo recipients: 17%
Durability of protection:
• Vaccine efficacy against HZ & PHN declined during the 1st
year of observation but remained stable at above 50% for
the remaining 3 years of observation
Recommendations and
Implementation: HZV
ACIP (Oct. 2006)
ACIP recommends a dose of HZV for
all adults ≥60 years of age unless
they have contraindications
Implementation
HZV should be offered at the patient’s first
available clinical encounter
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• The average adult ≥60 y.o. has 5-8 clinical encounters a year;
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HZV can be offered at the first available opportunity
It can also be given along w/ influenza vaccine (see next slide)
Residents of chronic care facilities should be included in
vaccination activities if no contraindications exist
Implementation
HZV can be administered with other vaccines
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• Simultaneous administration with live or inactivated vaccines
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is acceptable, as is non-simultaneous administration with
inactivated vaccines
The only issue arises with non-simultaneous administration
with other live vaccines
 Not acceptable unless separated by >28 days
 Persons ≥ 60 y.o. only rarely require other live vaccine
(e.g., yellow fever) but this might occur if the patient was
accidentally given varicella vaccine
Implementation
HZV is recommended whether or not the patient
reports a prior episode of HZ
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• Patients (and less commonly, doctors) misdiagnose HZ, and
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there are no tools to confirm or rule-out a history of prior HZ
Validating an HZ history can thus be a real challenge for
providers & introduce a major barrier to vaccination
Having >1 episode of HZ is not uncommon; the rate of HZ after
a prior episode may be similar to the rate of a first episode
Following an episode of HZ, there is no specific minimal time
interval before one can receive HZV
Implementation
It is not necessary to check varicella history or
titers before administering HZV
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• Virtually all persons ≥60 years of age have serologic evidence
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of prior varicella, even if they do not recall having the illness
There is no evidence that HZV inadvertently given to persons
without prior varicella raises safety concerns
Determining varicella history would introduce a major and
unnecessary barrier to vaccination
Implementation
HZV should be offered to eligible persons including
those >80 y.o., frail, or with chronic illnesses
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• While HZV is less effective at preventing HZ in persons >80 yrs
of age, its effectiveness at preventing PHN is better
• The oldest and frailest population
 Experiences the largest burden of HZ and PHN, so even
less effectiveness translates to more prevention
 Least able to seek medical attention and access care
 Least able to tolerate powerful meds used to control pain
 Has least physical, social, psych reserve to handle HZ or PHN
Implementation
HZV must be kept ≤5°F until reconstitution
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• Any freezer with separate sealed freezer door that can reliably
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maintain average temp of <5°F (-15°C) is acceptable (dormstyle units are not)
Caution: for some combined fridge/freezer models, setting the
freezer to low temps for HZV can reduce fridge temps below
freezing and ruin refrigerated vaccines
Unused HZV must be discarded 30 min after reconstitution
Implementation
Immunosuppression (high-dose steroids, biological
response modifiers, chemotherapy, AIDS) is a
contraindication for HZV
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• BUT there is neither contraindication nor recommendation to
offer HZV to HIV infected persons without AIDS
 Expert opinion: HZV is likely to be safe for HIV+ persons
with less immunosuppression (as is varicella vaccine)
 …but no safety & efficacy data for this population
 Studies of HZV safety & efficacy among HIV+ persons
are being initiated and will guide future recommendations
Implementation
Persons ≥60 y.o. anticipating immunodeficiency
due to initiation of treatments or progression of
illness should be offered HZV
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• Increasing numbers of diseases are now being treated with
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various immunosuppressive medications (rheumatoid
arthritis, lupus, inflammatory bowel disease, psoriasis)
Patients should be screened for eligibility to get HZV before
starting such treatments
Implementation
HZV is not recommended for persons ≥60 y.o.
who have received the varicella vaccine
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• HZ risk in varicella vaccine recipients is not yet well known but
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appears much lower than for persons who had chickenpox
Very few persons who have received varicella vaccine are
eligible for HZV (≥60 y.o.); this will be so for over a decade
As data on risk & severity of HZ following varicella vaccination
accumulate we will re-evaluate this guidance
Implementation
Monitoring & reporting of adverse events
following administration of HZV is emphasized
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• HZV is the 1st live attenuated vaccine targeted to the elderly & it
presents special safety monitoring challenges in this population:
 High level of “background noise”; i.e., incident medical
events (heart attacks, Alzheimer’s diagnosis, falls, strokes)
 Prevalent chronic disease may pose unexpected risks
 Frequent use of multiple meds may pose unexpected risks
 Adverse medical events may coincidently follow HZV but
they may be caused by HZV
 Significant adverse events should be reported to VAERS
Thank You!!!
…Questions??
Key remaining questions,
activities & challenges
Key Remaining Questions
• What is the duration of protection from HZ vaccine?
• Is there a role for HZ vaccine among immunosuppressed
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persons (e.g. corticosteroids, chemotherapy, biological
response modifiers, AIDS with CD4+ counts ≤200)?
What is appropriate vaccination policy for those with early
HIV or treated AIDS (and CD4+ counts >200)?
What about vaccinating persons <60 yrs of age, especially
if they anticipate becoming immunocompromised due to
progression of illness or immunosuppressive treatment?
Why do HZ rates appear to be increasing in many settings?
Key activities and challenges
• Disease surveillance: how to monitor impact of HZ vaccine
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No disease reporting
No capacity to distinguish wild-type & vaccine strain HZ
(i.e., vaccine failure from vaccine adverse events)
 Key impact pain (how to track pain intensity/duration?)
 How can we track vaccine impact given the changing
baseline rates of HZ in absence of vaccine?
 Medicare data as a key surveillance tool?
Assuring access and financing for those desiring vaccine
 Medicare part D: depending on setting, beneficiaries may
have to pay many hundreds of dollars up-front
 Must be stored frozen: most adult providers not used to
or equipped to handle such requirements
Key activities and challenges
• How to monitor vaccine coverage and disparities
• How to monitor adverse events?
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This it the first live vaccine just for the elderly
– The elderly have high rates of medical events (“noise”)
– But the elderly also may be frail, have co-morbidities,
and take multiple meds so unexpected adverse events
can be plausible