Asia Pacific Herpes Zoster Speakers’ Forum

A/Prof John Litt,Flinders University, Adelaide, Australia

Herpes Zoster: burden of

illness and prevention using the zoster vaccine

Overview • Adult immunisation in Australia

• Herpes zoster: – Epidemiology and burden of illness

- Clinical manifestations

- Complications including post herpetic neuralgia

• Shingles Prevention Study and related studies

• Strategies to maximise uptake – Implementation

• Frequently asked questions

Risk factors for Zoster1-4

• Increasing age • Female • Family history • People with compromised or suppressed immune systems who have an increased

risk for herpes zoster include those: – with cancer, especially leukemia and lymphoma, – with human immunodeficiency virus, – who have undergone bone marrow or solid organ (renal, cardiac, liver, and

lung) transplantation, or – who are taking immunosuppressive medications, including steroids,

chemotherapy, or transplant-related immunosuppressive medications.

1. Thomas & Hall Lancet Infect Dis 2004;4(1):26-33;

2. Liesegand et al Curr Opin Ophthalmol 2004;15:531-6:

3. Donohue et al Arch Int Med 1995;155(15):1605-9;

4. Gershon et al J Clin Virol 2010: 48: suppl2-7

Cunningham et al Med J Aust 2008; 188: 171–176

Varicella = Chickenpox Primary infection with VZV

shingles

Lifetime risk of zoster • More that 95% of adults have the Varicella-Zoster virus within their

dorsal root ganglion1

• Overall lifetime risk of zoster in the population is between 20% and 30% Lifetime risk (%) HZ (%)PHN – For a 60 year old2 40 9

– For an 85 year old3 50 21

• 120,000 cases of shingles per year in Australia4

• Less that 1 in 5 older adults believe they are likely or very likely to get

shingles5

Zoster in Australia

1. NNDSS Commun Dis Intell 2016;40:E48-E145.

*Excludes NSW Age of onset missing for 1 notification in 2009, 13 notifications in 2010, 18 notifications in 2011, 32 notifications in 2012, 59 notifications in 2013 and 59 notifications in 2014.

Notification rate for shingles, Australia,* 2009 to 2014, by year and selected age groups1

Adapted from NNDSS, 2016.1

VZV: LATENCY

• Viral latency is established during primary infection (varicella) – Transport of virus up sensory nerve from infected dermal sites – Dormant in dorsal root ganglion

Dorsal root ganglion

VZV establishes latency in the dorsal root ganglion

VZV moves along the sensory nerve to the dorsal root ganglion Varicella rash

Skin

Spinal cord

UNDERSTANDING LATENCY No electric field

Enough ‘charge’

Too much charge

VZV: REACTIVATION

Dorsal root ganglion

Spinal cord

VZV reactivates and moves along sensory nerve from dorsal root ganglion to skin

Skin

VZV emerges from sensory nerve endings in the skin to cause the unilateral rash of zoster

Inflammation and necrosis of nerve cells

DERMATOMAL DISTRIBUTION

Carpenter MB, Sutin J, eds. Human Neuroanatomy. 85th ed. Baltimore, MD: Williams & Wilkins; 1983. Reprinted with permission.

CLINICAL MANIFESTATION OF ZOSTER

Acute neuralgia, pain

Characteristic dermatomal rash

May or may not occur; most common is PHN

1. Oxman MN. In: Varicella-Zoster Virus: Virology and Clinical Management. Cambridge: Cambridge University Press, 2000:246–275.

Prodromal Phase

Acute Phase

Complications

Resolves

ZOSTER: CLINICAL FEATURES, RASH

• Vesicular, “grape-like” lesions clustered on an erythematous base

• Unilateral distribution in 1-2 adjacent sensory dermatomes – Thoracic dermatome (~50-

70%) – Cervical dermatome or

ophthalmic branch of trigeminal (each ~10-20%)

• Vesicles crust in 7-10 days; full healing may take up to 1 month

CDC. http://www.cdc.gov/shingles/about/photos.html

ZOSTER: CLINICAL FEATURES, PAIN

• Most common symptom of zoster is pain • Pain often precedes rash by days or weeks • Continuum: mild to severe

Throbbing, aching, stabbing, burning, tingling, itching - Allodynia: pain induced by minimal/non-painful stimuli – Paresthesias e.g., burning and tingling – Dysesthesia : altered or painful sensitivity to touch – Hyperesthesia: exaggerated or prolonged response to pain

• Pruritus is also commonly associated with herpes zoster. • May be confused with other pain syndromes

– Myocardial infarction, renal colic, cholecystitis, musculoskeletal pain • Skin sensitivity in a dermal distribution may exclude other

pain syndromes • Zoster sine herpete: nerve pain without rash

IMPACT OF HERPES ZOSTER IN PERSONS >50 YEARS OF AGE

PHN HZ

Drolet M, et al. CMAJ 2010;182:1731-36

EFFECT OF SHINGLES PAIN ON DAILY LIVING ACTIVITIES

0 10 20 30 40 50 60 70 80 90

100

0 1 2 3 4 5 6 7 8 9 10 Worst pain score

Patie

nts

repo

rtin

g in

terf

eren

ce (%

)

General activity Work Sleep Enjoyment of life

1. Adapted from Lydick E, Epstein RS, et al. Neurology; 1995;45 (suppl 8):S52

ZOSTER: COMPLICATIONS

• Cutaneous • Neurologic

• Ophthalmic • Disseminated

ZOSTER: CUTANEOUS COMPLICATIONS

• Scarring • Post-inflammatory pigmentation changes • Bacterial superinfection (~2% of cases)

– Commonly due to Staphylococci or group A Streptococci

– Impetigo, erysipelas, cellulitis can lead to bacteremia, toxic shock syndrome, and necrotizing fasciitis

ZOSTER: NEUROLOGIC COMPLICATIONS

• Postherpetic neuralgia (PHN) • Other neurologic complications

POSTHERPETIC NEURALGIA (PHN)1-3

• Most common and debilitating complication of zoster

• Chronic neuropathic pain in area of rash – Burning, throbbing, itching,

tender, stabbing, shooting, sharp, tingling

– May be triggered by even minor stimuli to the affected skin (allodynia) – in >90% of patients with PHN

1. Johnson et al NEJM 2014; 371(16)1526-33 2. Schmader CID 2001; 32(10) :1481-6 3. Chen May Clin Proc 2004: 79 (12):1533

INCIDENCE BY HERPES ZOSTER BY AGE AND FREQUENCY OF PHN

0

5

10

15

20

<44 45-54 55-64 65-74 75+Age

Herpes zoster incidence (per 1000 pt yr) Postherpetic neuralgia at 1 mo (%)

Opstelten W, et al. Fam Prac 2002;19:471-475

COMPARISON OF TOTAL PAIN RATING INDEX SCORES, McGILL PAIN QUESTIONNAIRE

Katz J, Melzack R. Surg Clin NA 1999;79:230

RISK FACTORS FOR PHN1-2

• Advancing age • Prodromal pain • Greater severity of acute pain • Greater rash severity • Greater degree of sensory impairment in the

affected dermatome • No clear evidence for gender, immune compromise, or

dermatome affected • No evidence of higher PHN with depression or cancer

1. Thomas and Hall Lancet Infect Dis. 2004 Jan;4(1):26-33. 2. Forbes et al. Pain 2015;·157 : 30–54

Kost R et al. N Engl J Med. 1996; 355:32-42.

Patie

nts

repo

rtin

g pa

in (%

)

Age (years)

0

100

80

60

40

20

0-19 20-29 30-39 40-49 50-59 60-69 ≥79

>1 yr

<1 mo

6 - 12 mo 1 - 6 mo

PREVALENCE OF SHINGLES-RELATED PAIN AND DURATION OF PAIN INCREASES WITH AGE

IMPACT OF SHINGLES AND POSTHERPETIC NEURALGIA (PHN) ON HEALTH

1. Johnson, R. The impact of herpes zoster and post- herpetic neuralgia on quality of life. BMC Medicine. 2010. 8:37. 2. Katz, J. Acute Pain in Herpes Zoster and Its Impact on Health-Related Quality of Life. Clinical Infectious Diseases. 2005. 39:342-8

Psychological • Depression • Anxiety • Emotional distress • Difficulty concentrating • Fear

Physical • Fatigue • Anorexia • Weight loss • Reduced mobility • Physical inactivity • Insomnia

Social • Withdrawal • Isolation • Attendance at fewer social

gatherings • Loss of independence • Change in social role

Functional • Dressing, bathing, eating,

mobility

• Travelling, cooking, housework, shopping

ZOSTER OPHTHALMICUS1 ©2002. Reprinted with permission. KO Studios, Pacifica, CA.

Image courtesy of

Dr. Dubin’s collection (www.skinatlas.com).

• 10-25% of all cases of herpes zoster • Most patients have the classic dermatomal rash, but a minority may have only

ophthalmic findings • Direct ocular involvement is NOT correlated with age, gender, or severity of

disease • Serious sequelae include chronic ocular inflammation, vision loss, and

disabling pain • Complications: keratitis/uveitis, secondary infection (Staph, Strep),

episcleritis/scleritis, corneal erosion, retinal necrosis, optic neuritis, and/or oculomotor palsies

1. Yawn et al Mayo Clin Proc 2013; 88(6):562-70

ZOSTER: GOALS OF THERAPY

• Control active disease

– Limit viral replication

– Limit inflammation

– Reduce pain

• Reduce complications (PHN)

ZOSTER: THERAPY

• Antiviral therapy1

– Reduces duration of viral shedding

– Reduces severity and duration of acute pain

– Accelerates rash healing – Limited impact on PHN *Ideally should begin within 72 hours of onset of symptoms and in all immunocompromised patients regardless of the duration of the rash

• Supportive care – Keep lesions clean and dry – Soaks/cool compresses

• Pain Control • Corticosteroids2

– May reduce intensity and duration of acute symptoms of HZ

– No effect on PHN

1. Li et al Cochrane Database Syst Rev 2009:2:CD006866 2. Wood et al N Engl J Med 1994 Mar 31;330(13):896-900. Whitley et al Ann Int Med 1996 Sep

1;125(5):376-83.

ZOSTER: MANAGING PAIN

• Paracetamol or NSAIDS • Opioids eg oxycodone (if more severe pain) • Additional agents

– Pregabalin/Gabapentin – Lignocaine patches (on intact skin) – Tricyclics (add to opioids)

28

Cohen NEJM 2013: 369:255-63

Prevention

ZOSTAVAX®1

• ZOSTAVAX® is a live-attenuated varicella-zoster virus vaccine1

• ZOSTAVAX® is indicated for the prevention of:1 • shingles in individuals 50 years of age and older • postherpetic neuralgia (PHN) and for reduction of acute

and chronic zoster-associated pain in individuals 60 years of age and older

• ZOSTAVAX ® will be provided free from 1st November on the National Immunisation Program for 70-79 year olds2

1. ZOSTAVAX® Approved Product Information. 2. Department of Health. Shingles NIP announcement. www.immunise.health.gov.au/internet/immunise/publishing.nsf/Content/news-20152307. Accessed September 2016

A Phase III Clinical Trial to Evaluate the Efficacy, Immunogenicity, Safety and

Tolerability of ZOSTAVAX™ in Adults 60 and Older

SHINGLE PREVENTION STUDY (SPS)

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

SHINGLES PREVENTION STUDY: SPS • Design1

– Randomized, multicenter, double-blind, placebo-controlled study • Randomization was stratified by age: 60–69 years, ≥70 years

– 38,546 varicella history-positive, HZ-negative adults aged ≥60 years – Objectives

Primary: • To determine if immunization with zoster vaccine will reduce the incidence and/or

severity of HZ and its complications, primarily PHN, in persons 60 years of age and older (as assessed by Burden of Illness (BOI))

• To determine if immunization with zoster vaccine will protect against PHN Secondary:

• To determine if immunization with zoster vaccine will reduce the incidence of HZ • To determine if immunization with zoster vaccine will reduce the duration of HZ pain • To determine if immunization with zoster vaccine will reduce Activities of Daily Living

Interference (ADLI). • Substudies

– Adverse Event Monitoring Substudy (AEMS)1,2

– Cell-mediated immunity substudy3

HZ=herpes zoster; PHN=postherpetic neuralgia.

1. Oxman MN et al. N Engl J Med. 2005;352:2271–2284. 2. Simberkoff MS et al. Ann Intern Med. 2010;152:545–554. 3. Levin MJ et al. J Infect Dis. 2008;197:825–835.

34

Summary: SPS Efficacy of the Zoster Vaccine by Age Stratum

63.9% 65.7% 65.5%

37.6%

66.8%

55.4%

0

20

40

60

80

100

Zoster PHN BOI

Vacc

ine

Effic

acy

(%)

Ages 60 to 69

Ages ≥70 Efficacy: 51.3%

(95%CI 44.2%–57.6%) Efficacy: 66.5%

(95%CI 47.5%–79.2% Efficacy: 61.1% (95%CI 51.1%–69.1%

Oxman MN, Levin MJ, Johnson GR, et al. N Engl J Med. 2005;352:2271–2284.

aPatients instructed to report adverse experiences on a VRC. bSolicited on the VRC.

Adverse Reaction

Solicitedb (%) Unsolicited (%)

Erythema Pain/ Tenderness Swelling Hematoma Pruritus Warmth

ZOSTAVAX (n=3,345) 35.8 34.5 26.2 1.6 7.1 1.7

Placebo (n=3,271) 7.0 8.5 4.5 1.4 1.0 0.3

Injection-site Reactions in ≥1% of Adults Who Received ZOSTAVAX or Placebo Within 42 Days Postvaccination From the AEMS of the SPS1,a

AEMS=Adverse Event Monitoring Substudy; SPS=Shingles Prevention Study; VRC=vaccination report card.

1. Oxman MN et al. N Engl J Med. 2005;352:2271–2284. 2. Simberkoff MS et al. Ann Intern Med. 2010;545–554.

Safety Profile for ZOSTAVAX in Adults Aged ≥60 Years: Injection-site Reactions

Most injection-site AE were reported as mild in intensity. 1,2

Most injection-site AE resolved within 3 to 4 days.2

36

ZOSTAVAX (NAEMS=3,345)

(NEntire study=19,270)

Placebo (NAEMS=3,271)

(NEntire study=19,276)

Serious Adverse Experience

Overall AEMS 1.9% 1.3%

Entire study 1.4% 1.4%

Cardiovascular AEMS 0.6% 0.4%

Entire study 0.4% 0.4%

Vaccine-relateda 2 3

Systemic Adverse Reaction

Headache AEMS 1.4% 0.9%

Safety Profile of ZOSTAVAX in Adults Aged ≥60 Years: Adverse Events

AEMS=Adverse Event Monitoring Substudy. 1. Oxman MN et al. N Engl J Med. 2005;352:2271–2284. 2. Simberkoff MS et al. Ann Intern Med. 2010;545–554.

Serious Adverse Experiences and Systemic Adverse Reactions Days 0–421,2

aFor entire study period

ZOSTAVAX® is generally well tolerated

• In clinical trials, ZOSTAVAX® has been evaluated for safety in more than 32,000 adults 50 years of age and older 1

• The most common adverse events (≥10%) reported in clinical trials were1

• Erythema, pain/tenderness, swelling and pruritus

• Over 33 million doses of ZOSTAVAX® have been distributed worldwide since 20062

• Results from “real world” post marketing safety studies support the safety profile seen in clinical trials3,4

1. ZOSTAVAX® Product Information. 2. Seqirus Data on file 3. Baxter et al Vaccine 2012; 30(47):6636-6641 4. Tseng et al Journal of Internal Medicine 2012;271(5):510-20

To report an adverse event contact CSL Medical Information: 1800 642 865 Email: MedicalInformation.Aust@csl.com.au

ZOSTAVAX® is contraindicated in patients with:1

• History of hypersensitivity to any component of the vaccine, including gelatin.

• History of anaphylactic/anaphylactoid reaction to neomycin • Primary and acquired immunodeficiency states e.g.

leukaemia, lymphoma, conditions affecting the bone marrow or lymphatic system, immunosuppression due to HIV/AIDS, cellular immune deficiencies

• Immunosuppressive therapy (including high-dose corticosteroids)

• Active untreated tuberculosis • Pregnancy

ZOSTAVAX® Approved Product Information.

ZOSTAVAX® dosage and administration1

• Individuals should receive a single dose (0.65mL) of the vaccine subcutaneously

• Reconstitute immediately after removal from the fridge

• Administer the vaccine immediately after reconstitution (discard if not used within 30 minutes)

Refer to product information for further information

ZOSTAVAX® Approved Product Information

COST EFFECTIVENESS • Systematic review of the cost effectiveness of herpes

zoster vaccination – literature search of the databases PubMed and

EMBASE →11 studies – All but one of the studies concluded that:

• most vaccination scenarios are cost effective • vaccination of specific subgroups such as the older age

group is most cost effective. – Model input parameters such as age at vaccination,

vaccine costs, HZ incidence, PHN length and duration of vaccine efficacy had a great impact on the estimated cost effectiveness of HZ vaccination.

Szucs and Pfeil Pharmacoeconomics 2013:32 (2)125-36