Transcript PowerPoint 簡報

Varicella Zoster Vaccine
in Preventing Zoster in
Elderly People
Dr David Dai
Prince of Wales Hospital
21st July, 2007
Today’s Talk
• Clinical features of Herpes
Zoster
• Post Herpetic Neuralgia (PHN)
• Treatment
• Prevention
Herpes Zoster (Shingles):
Etymology1
=
derived from Greek “herpein”
meaning “to creep”
zoster
=
a Greek word meaning
“girdle”
shingles
=
derived from Latin “cingere”
herpes
1. Dorland’s Illustrated Medical Dictionary. 28th ed. Philadelphia: WB Saunders Company, 1994:759.
Human Herpesviruses (HHV)
HHV family1
Alpha-HHV
HSV*
(HHV-1, -2)
VZV†
(HHV-3)
Primary infection:
varicella (chickenpox)2
Beta-HHV
Gamma-HHV
(HHV-6A, -6B)
(HHV-7)
EBV‡ (HHV-4)
CMV§ (HHV-5)
KSHV‫( ׀׀‬HHV-8)
Reactivation:
herpes zoster (shingles)2
*HSV
= herpes simplex virus
= varicella-zoster virus
‡EBV = Epstein-Barr virus
§CMV = cytomegalovirus
‫׀׀‬KSHV = Kaposi’s sarcoma-associated herpesvirus
†VZV
1. Roizman B et al. In: Fields Virology. 4th ed. Vol. 2. New York: Lippincott Williams & Wilkins, 2001:2381–2397. 2. Arvin AM. In: Fields
Virology. 4th ed. Vol. 2. New York: Lippincott Williams & Wilkins, 2001:2731–2767.
A typical case
(Clin Inf Disease 1999; 28: 736-9)
• 70 year old man
• Pain in RUQ, diagnosed as cholescystitis
• 4 days later, rash noted by nurse; diagnosis
reviewed as “Shingles”
• Rash persisted in next 3 weeks
• No relief of pain
• 5 yrs afterwards, still severe pain
•
•
•
•
•
Constant deep ache
Sharp pains
Involuntary muscle contractions
Extremely sensitive skin
Unable to wear clothes over the
area
Medications
•
•
•
•
•
•
•
Codeine, oxycodone, morphine
Amitriptyline, topical lidocaine
Capsaicin, mexilitine, phenytoin
Carbamazepine, NSAID
TENS
Epidural anaesthetic/steroid injection
Intercostal nerve blocks
All without relief
• Falls 2 years after onset and hip
fracture
• Forced retirement
Zoster: Clinical Features
• Usually limited to 1 or
2 adjacent, unilateral
dermatomes1,2
• “Grape-like” lesions
clustered on an
erythematous base1,2
• Lesions usually heal
within 4 weeks1
Courtesy of the American College of Physicians.
www.acponline.org/shell-cgi/printhappy.pl/bioterro/
smallpox_mimics.htm
1. Oxman MN. In: Varicella-Zoster Virus, Virology and Clinical Management. Cambridge: Cambridge University Press, 2000:246–275.
2. Lycka BAS et al. In: Herpes Zoster and Postherpetic Neuralgia, 2nd Revised and Enlarged Edition. Vol. 11. Amsterdam: Elsevier
Science B.V., 2001:97–106.
Zoster: Dermatomal Distribution
Image courtesy of Charles E. Crutchfield III, MD.
Zoster: Cranial
1
Involvement
I ophthalmic
II maxillary
III mandibular
Reproduced with permission.1
©Diepgen TL, Yihune G et al. Dermatology Online
Atlas (www.dermis.net) Reprinted with permission.
1. Stedman’s Medical Dictionary. 27th ed. Baltimore: Williams & Wilkens, 2000:1202.
Zoster Ophthalmicus
Image courtesy of
Dr. Dubin’s collection (www.skinatlas.com)
Image courtesy of
Charles E. Crutchfield III, MD.
KO Studios, Pacifica, CA.
©2002. Reprinted with permission.
Establishment of VZV Latency in Sensory-Nerve
Ganglia.
After a primary VZV infection (chickenpox), latent VZV
infection is established in the dorsal-root ganglia, and
zoster occurs with subsequent reactivation of the virus
N Engl J Med Vol 356(13) P1338-1343
Rate per 1000 per year
Incidence of Zoster and Postherpetic
Neuralgia (PHN) in the UK
11
10
9
8
7
6
5
4
3
2
1
0
Zoster cases/
1000/year
PHN/
1000/ year
0
10
20
30
40
50
Age (years)
1. Hope-Simpson RE. J R Coll Gen Pract 1975;25:571–575.
60
70
80+
Post Herpetic Neuralgia
( J Infect Dis 2002; 186(Suppl): 983-90)
Herpes Zoster pain
3 Phases:
1) Acute
2) Subacute: 4-5 weeks 28.4%
3) Chronic: > 3months 15%
> 12 months: 5-10%
Spontaneous remission: limited
Effects of PHN on Patients
Pain
•
•
•
•
•
Tender
Burning
Throbbing
Stabbing
Shooting/stabbing
• Allodynia
• Disturbance in physical and
psychological functioning
• Drug dependency
• Depression
• Suicide
Map of Sensory Disturbances of
PHN
• Allodynia
• Postherpetic scarring
• Reduced sensation to
pinprick, temperature
(cold), and touch
Reprinted from Herpes Zoster and Postherpetic Neuralgia, 2nd Revised and Enlarged Edition, Vol. 11, Watson CPN, Oaklander AL, Deck
JH, The neuropathology of herpes zoster with particular reference to postherpetic neuralgia and its pathogenesis, pp167–182, 2001, with
permission from Elsevier.
Map of Sensory Disturbances of PHN
Following Zoster Ophthalmicus
Reprinted from Herpes Zoster and Postherpetic Neuralgia, 2nd Revised and Enlarged Edition, Vol. 11, Watson CPN, Oaklander AL, Deck
JH, The neuropathology of herpes zoster with particular reference to postherpetic neuralgia and its pathogenesis, pp 219–222, 2001, with
permission from Elsevier.
Comparison of Pain Scores for
Various Conditions
More Pain
Acute Pain Conditions
50
Chronic Pain Conditions
40
Abdominal hysterectomy
30
Acute headache
Zoster
Labor pain
Postsurgical pain
Mucositis
Angioplasty sheath removal
Fibromyalgia
Postherpetic neuralgia
20
10
Atypical facial pain
Musculoskeletal pain
Arthritis
Osteoarthritis
Rheumatoid arthritis
0
Chronic cancer pain
Less Pain
Adapted from Surgical Clinics of North America, Vol 79, Katz J, Melzack R, Measurement of pain, pp 231–252.
Copyright® 1999, with permission from Elsevier.
Financial Impact
• UK(1994)
• Life unit cost for managing
PHN
• ₤ 770 per patient
Treatment
Antiviral therapy within 72
hours of rash:
• ↓duration (pain, rash healing)
• ↓eye complications
• ? Incidence of PHN
Table 1. Proportions (%) of patients (aged 50 years) with persisting pain in
controlled trials of antiviral therapies for herpes zoster [4 6, 36, 40].
Drugs compared
Acyclovir
(800 mg 5×/day,
7 10 days)
vs. placebo
Valacyclovir
(1000 mg
3×/day, 7 days)
vs. acyclovir
At 3
months
25 vs. 54a
31 vs. 38b
32 vs. 34c
34.9 vs. 49.2
At 6
months
15 vs. 35a
19.9 vs. 25.7d
19 vs. 19c
19.5 vs. 40.3a
PHN
pain
Valacyclovir
Famciclovir
(1000 mg 3×/day, 7 days) (500 mg 3×/day,
vs. famciclovir
7 days)
(500 mg 3×/day, 7 days)
vs. placebo
NOTE. PHN, postherpetic neuralgia.
a P < .05 from 95% confidence interval (CI) for the relative risk (RR) for the
difference between treatments.
b GlaxoSmithKine data on file.
c P = .84 from 95% CI for the RR for the difference between treatments.
d P = .08 from 95% CI for the RR for the difference between treatments
J Infectious Dis 2002;186(Suppl 1):S83-90
The problem
• Diagnosis in prodromal period
extremely difficult
• Majority of elderly patients with
localised, unilateral pain does not
develop herpes
Later therapy still has benefit
↓duration of illness
•
•
•
•
Immunocompromised
Older
Ophthalmic
New lesions after 72 hours
At Risk of PHN
•
•
•
•
•
•
•
Old age
Prodromal pain
Severe acute pain
Rash
? Female
Ophthalmic zoster
Preexisting neurological disorder
Figure 1. Annual Incidence of Herpes Zoster and Proportion of Patients with
Postherpetic Neuralgia.
Panel A shows the annual incidence of herpes zoster per 1000 persons in a general
medical practice.1 Panel B shows the percentage of patients with pain persisting
after the onset of the zoster-associated rash. Data are from the placebo group in
one large, double-blind treatment study.7 Panel C shows the proportion of patients
with postherpetic neuralgia according to age.16
N Eng J Med 335(1);32-42, 1996
Patients reporting pain (%)
Duration of Zoster-Associated Pain
According to Age1,2
100
>1 year
6–12 months
1–6 months
<1 month
80
60
40
20
0
(n)2
0–19
20–29
30–39
40–49
50–59
60–69
≥70
(24)
(53)
(69)
(136)
(204)
(270)
(160)
Age (years)
Adapted with permission from Kost RG et al.1 © 1996 Massachusetts Medical Society.
1. Kost RG et al. N Engl J Med 1996;335:33–42. 2. de Moragas JM et al. AMA Arch Derm 1957;75:193–196.
Treatment of established illness
•
•
•
•
Tricyclics
Anti-convulsants
Opiate analgesics
Surgery: sympathectomy, dorsal root entry
zone lesion, cordotomy, thalamotomy,
cingulumotomy, spinal cord and deep brain
stimulation
The Patient
Do anything to reduce the pain
Strategy
• Prevent or attenuate herpes
zoster
• Pain programme ( drug and
non-drug)
Prevention of PHN
• ? Antiviral therapy
• ? Oral steroids ( excessive side effects)
• Intervention to reduce acute inflammation
and tissue damage (attenuate peripheral
nocioceptive sensitisation and central
hyperexcitability)
Shingles Prevention Study
SPS
A vaccine to prevent Herpes
Zoster and Post Herpetic
Neuralgia in Older Patients
MN Oxman etal
NEJM 2005(352): 2271-84
The Question
In persons > 60 yrs, does a live
attenuated zoster virus( VZV)
vaccine decrease the burden of
illness caused by herpes zoster
and incidence of PHN?
ZOSTAVAX® [Zoster Vaccine Live
(Oka/Merck)] Product Profile
• Live, attenuated varicella-zoster virus
vaccine
• Minimum of 19,400 PFU* per dose
• No preservative
• Lyophilized product
• Same excipients as VARIVAX® [Varicella
Virus Vaccine Live (Oka/Merck)]
• Single subcutaneous dose
*PFU = plaque-forming units
Randomised placebo-controlled trial
•
•
•
•
Follow up period: 3.13 yrs (median)
Setting: 22 sites in US
Participants: 38,546 persons > 60yrs
Mean age: 69 yrs, 59% men, with a history
of varicella or had resided in US > 30yrs
• Immunocompromised persons excluded
Randomization of Subjects
Subjects Enrolled
38,546
Adverse Event (AE)
Substudy: 6616
CMI Substudy
1395
Age 60 to 69 years
20,747
Zoster vaccine
10,378
Placebo
10,369
1. Oxman MN et al. N Engl J Med 2005;352:2271–2284.
Age 70 years
17,799
Zoster vaccine
8892
Placebo
8907
Zoster and PHN
• Zoster cases were confirmed by
– Polymerase-chain-reaction (PCR) assay
– Viral culture
– Adjudication by a clinical evaluation committee
• PHN was defined as:
Zoster-associated pain rated as 3 or more on a 10point pain scale persisting or appearing at least 90
days after rash onset
Intervention
• Study group ( n= 19270): 1 subcut injection
of 0.5mL Oka/Merck VZV vaccine
• Placebo group (n= 19276)
• Vaccine has median potency of 24600
plaque-forming units
Outcomes
Vaccine efficacy:
• Relative reduction in burden-of- illness
sore(VEBOI): severity of and duration of
herpes zoster pain
• Incidence of PHN: pain rated as >3/10
Patient follow-up: 95%( modified
intention to- treat- analysis)
Definition and Measurement of
the BOI
Zoster BOI: Population
measure
Worst Pain
10
0
Days
Main Results
Vaccine Efficacy
Reduction of Cumulative
Incidence of Zoster
Percent of Subjects With Zoster
Cumulative Incidence Over Time*
6.0
5.5
5.0
4.5
4.0
3.5
Placebo
Zoster vaccine
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Logrank P-value = <0.001
0
1
2
3
Time Since the Start of Follow-Up
(in Years)
*A limited number of subjects were followed beyond Year 4.
1. Oxman MN et al. N Engl J Med 2005;352:2271–2284.
4
5
Reduction of Cumulative
Incidence of PHN
Cumulative Incidence Over Time*
0.8
Percent of Subjects With PHN
0.7
Placebo
Zoster vaccine
0.6
0.5
0.4
0.3
0.2
0.1
Logrank P-value = <0.001
0.0
0
1
2
3
Time Since the Start of Follow-Up
(in Years)
*A limited number of subjects were followed beyond Year 4.
1. Oxman MN et al. N Engl J Med 2005;352:2271–2284.
4
5
Overall Efficacy of the Zoster
Vaccine
25%=prespecified lower bound success criterion
Zoster
95% CI
51.3%
66.5%
PHN
61.1%
BOI
0
25
50
75
Vaccine Efficacy (%)
V211.VEsummary1c Sept. 30, 2005
1. Oxman MN et al. N Engl J Med 2005;352:2271–2284.
100
Efficacy of the Zoster Vaccine
by Age Stratum
Zoster
Ages 60 to 69
Ages 70
95% CI
PHN
BOI
0
20
40
60
80
100
Vaccine Efficacy (%)
v211ACM.Vbar1a Dec. 6, 2005
Shingles Prevention Study:
Summary of Efficacy
• The zoster vaccine was highly effective
in reducing the incidence and morbidity
from zoster and PHN
– Reduced the incidence of zoster by 51%
– Reduced the incidence of PHN by 67%
– Reduced the BOI associated with zoster
by 61%
1. Oxman MN et al. N Engl J Med 2005;352:2271–2284.
Vaccine Efficacy by Age Group
• The zoster vaccine benefited the 60- to 69-yearolds by reducing the incidence of zoster1:
– 60-to-69-year-old group: 63.9%
– 70-year-old group: 37.6%
• The zoster vaccine benefited the 70-year-olds by
decreasing disease severity1
– Efficacy for pain BOI was similar in both age groups
– Efficacy for PHN was similar in both age groups
1. Oxman MN et al. N Engl J Med 2005;352:2271–2284.
The AE Monitoring Substudy
AE
Injection Site
Erythema*
Pain / tenderness*
Swelling*
Hematoma
Pruritus
Warmth
Zoster
Vaccine
(N=3345)
%
Placebo
(N=3271)
%
35.8
34.5
26.2
1.6
7.1
1.7
7.0
8.5
4.5
1.4
1.0
0.3
*Designates a solicited adverse experience.
Injection-site adverse experiences solicited only from Days 0–4 postvaccination.
1. Oxman MN et al. N Engl J Med 2005;352:2271–2284.
Serious side effects
5 subjects:
1) asthma on D2
2) PMR on D3
3) Anaphylactoid reaction 90minures
4) PMR on D15
5) Goodpasture syndrome D52
Shingles Prevention Study:
Summary of Safety
• The zoster vaccine has demonstrated a favorable
safety profile.
• Transient injection-site reactions occurred in
approximately 50% of the vaccine recipients.
• There were clinically important differences between
the zoster vaccine and placebo with respect to
– SAEs (1.4% in each group)
– Systemic clinical AEs
• Following a dose of zoster vaccine, vaccineassociated rashes were uncommon (0.1%)
Conclusion
In persons >60 yrs, a live attenuated
varicella-zoster virus vaccine
decreased the burden of illness caused
herpes zoster and the incidence of PHN.
The incidence of herpes zoster was
also reduced to a greater extent in
vaccine recipients
Figure 3. Host Factors in Latent VZV Infection and Reactivation.
Varicella is the primary infection caused by VZV, and its resolution is associated
with the induction of VZV-specific memory T cells (blue line). Memory immunity to
VZV may be boosted periodically by exposure to varicella or silent reactivation
from latency (red peaks). VZV-specific memory T cells decline with age. The
decline below a threshold (dashed green line) correlates with an increased risk of
zoster. The occurrence of zoster, in turn, is associated with an increase in VZVspecific T cells. The administration of zoster vaccine to older persons may prevent
VZV-specific T cells from dropping below the threshold for the occurrence of zoster
(dashed blue line). (Reprinted from Arvin.19)
N Engl J Med Vol 356(13) P1338-1343
Unresolved Issues
(ACP Journal club 2005, 143(3): 61)
• Cost-effectiveness
• Optimal age at first
administration
• Duration of protection
Additional Comments
•
•
•
•
•
( MN Oxman , Human Vaccine 2007,3:2, 64-68)
Efficacy persist for at least 4 years
Young subjects: prevent HZ
Older subjects: attenuate HZ
No use in PHN treatment or HZ
Transmission of vaccine virus no
risk
• 86% of SPS subjects who develop HZ
received famcyclovir and analgesia, and 2/3
received anti-viral treatment within 72 hrs;
therefore, severity and duration of HZ pain
reduced and understimate efficacy of VZV
vaccine
Cost -effectiveness
• QOL and functional of older persons with
HZ comparable to CCF, MI, DM, major
depression
(Neurol; 45 Suppl 8: S52-3)
• PHN cause severe functional impairment,
fatigue, anorexia, weight loss, insomnia,
difficult concentration, depression, isolation,
loss of independence and death
Figure 2. Cost per quality-adjusted life-year (QALY) gained as a function of duration of vaccine efficacy
(from 3 to 30 years) and total vaccination costs (from $50 to $500).
Total vaccination costs include unit vaccine cost, a public awareness campaign, administration costs, patient travel
Ann Intern Med 2006;145:317-325
time and time receiving vaccine, and cost of treating adverse events.
• Cost of vaccine US$150 per dose, assuming
duration of efficacy 10 yrs:
• $ 2600 per HZ prevented
• $ 7500 per PHN prevented
• NNV to prevent a case of HZ: 18
• NNV to prevent a clinically significant case
of PHN: 1009
Improved Zoster vaccine
• Increased potency ( ↑quantity of infective
VZV and amount of VZV antigens)
• 5 times the current vaccine
• Likely to be well tolerated
• Effective inactivated zoster vaccine to
protect immunodeficient population
ZOSTAVAQX®
Stored frozen at an average
temperature of -15ºC or
colder until it is reconstituted
for injection.
Recommendations
The author has already been
vaccinated and has purchased
the vaccine and administrated to
his wife
Preventive Dermatology
(J Am Acad Derm 2007; 56:675-6)
Vaccination with live attenuated
VZV vaccine should be made
available to all immunocompetent
persons aged 60yrs and older
during routine office visits; and
before immunosuppresive atherapy
ACIP Provisional Recommendations
( October 25, 2006)
• A single dose of zoster vaccine is
recommended for adults 60 years of age
and older whether or not they report a
prior episode of herpes zoster. Persons
with chronic medical conditions may be
vaccinated unless a contraindication or
precaution exists for their condition.
•
Contraindications and precautions to use of zoster vaccine are
available at http://www.fda.gov/Cber/label/zosmer052506LB.htm
To give or not to give?
Give
Patient treatment experience
Storage
Cost