Herpes Zoster and the Zoster Eye Disease Study (ZEDS) · antiviral treatment to reduce complications of Herpes Zoster Ophthalmicus . Herpes Zoster (HZ) / Shingles •Common disease

Herpes Zoster and the

Zoster Eye Disease

Study (ZEDS)

Elisabeth J Cohen, MD

Professor of Ophthalmology

New York University SoM

NYU Langone Health

Financial Disclosures

• I have no financial disclosures or conflicts of interest.

Presentations of Varicella Zoster Virus (VZV) Infection

•Herpes Zoster (HZ) caused by

reactivation of latent VZV in

persons who had chicken pox

•Typical painful, unilateral,

vesicular, dermatomal rash •Pain pre rash in 74%: unilateral,

first time, mod/severe, stabbing • Lee Clin Neurol Neurosurg 2017;152:90

•Herpes Zoster Sine Herpete:

radicular pain without rash • Lewis BMJ 1958

•Severe uveitis • Schwab Ophthalmology 97;104:1421

•Stroke due to HZ: 63% hx rash •Nagel Neurology 2008; 70:853-60

•HZ without rash dx missed!

What’s New in Herpes Zoster

• Increasing incidence of zoster

•Decreasing age of onset of zoster

•Risk factors before and after zoster

•Varicella Zoster Virus (VZV) trigger for temporal/giant cell arteritis

•Efficacy and safety of vaccines against zoster: need to increase use!

•Zoster Vaccine Live (ZVL, Zostavax)

•CDC recommended immunocompetent age 60+ since 2008

•FDA approved immunocompetent age 50+ since 2011

•Recombinant Zoster Vaccine (RZV, Shingrix)

•FDA approved Oct, 2017 for age 50+

•CDC recommended Jan, 2018 immunocompetent age 50+

•Zoster Eye Disease Study (ZEDS) NEI funded with CC at NYU

randomized controlled clinical trial to evaluate prolonged suppressive

antiviral treatment to reduce complications of Herpes Zoster

Ophthalmicus

Herpes Zoster (HZ) / Shingles

•Common disease

•1,200,000 new cases/yr in US • Suaya Open Forum Infect Dis 2014

•10-20% involve Vth nerve •>95% age 40+ in USA have had varicella, are at risk for HZ

•1 in 3 in US will have zoster • 1 in 2 age 85

•More common (~2x), severe in immunocompromised persons •> 90% of people with HZ are not immunocompromised

•Misconception #1 •Healthy people are not at risk for zoster and its potentially disabling sequelae- we are!

Increasing Incidence of Zoster Worldwide

• Increasing incidence of HZ over

60 yrs in population-based study

•1945-60 v 1980-2007 in MN

•59% women

• Incidence up >4-fold in all ages

• Increased steadily before and

after varicella vaccination • Kawai Clin Infect Dis. 2016;jul

15:63:221-6

•Significant increase in rate begins

age 40s, up sharply age 50s. •Rimland Clin Infect Dis. 2010;50:1000

Age-specific rate of unique zoster cases (national data, by year).

Rimland D , and Moanna A Clin Infect Dis. 2010;50:1000-1005

©2010 by Oxford University Press

Age at Onset of Zoster

•Rate goes up with age, but

number of cases highest in 50’s • Yawn Neurology 2013; 81:928 (Figure 1)

• Insinga J Gen Intern Med 2005;20:748-53 (2)

• Ghaznawi Ophthalmology 2011;118:2242 (3)

•CDC study mean age onset 52 yrs

• Hernandez J Clin Virol 2011; 52:344-8

•Taiwan population (35,000 HZ)

•Mean age 55 (Lin Medicine 2016;95)

•Misconception #2

•Herpes Zoster is only a

disease of the elderly- it

affects large number of

people in their prime too!

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43

Role of Varicella Vaccination in Zoster Increase

•Postponement of HZ by encounters with varicella “boosts” immunity

(Hope-Simpson Proc R soc Med. 1965;58: 9-20)

•Many think varicella/chicken pox vaccination cause of increase in zoster

and decrease in age at onset

•However rise in zoster began before varicella vaccination • Leung. Clin Infect Dis 2011; 52:332-40, Russell Vaccine 2014;32;6319-24

• Yawn. Mayo Clin Proc 2007; 82:1341, Kawai Clin Infect Dis 2016; 63:221-6

•Routine varicella vaccination not widespread in Europe!

•Rates of HZ similar in these countries (ex France vs US)

•Cause of increasing incidence of zoster is unknown!

Risk Factors for Development of Herpes Zoster

•Well known : increasing age , immunocompromise, female sex

•Recent additions to risk factors

•Family history 3x, depression 4x, stress 3x, history of zoster 80% • Marin Open Forum Infect Dis. 2016 Jun 13;3

• Kawai, Yawn Mayo Clin Proc 2017 Dec;92:1806

•Heart failure 2x • Wu BMC Infect Dis 2015; 15:17

•Traumatic brain injury 3x • Tung PLoSOne 2015 Jun 11;10

•Diabetes 45%, asthma 50%, acute kidney, autoimmune disease 70% • Suaya Open Forum Infectious Diseases 2014 Sep

• Peng J Asthma 2016 Jul 13 [epub]

• Yang Sci Rep 2015 Sep3;5:13747

• Kawai, Yawn Mayo Clin Proc 2017 Dec;92:1806

•Statin use 13% inc risk: case control study in UK, N=145,000 HZ

•Dose dependent: high dose 27% increase risk

•Decrease in risk with increased time since use of statin.

•Consistent with causal effect (Matthews Br J Dermatol 2016; 175:1183-94.)

• Implications regarding importance of vaccination against zoster in

patients with wide variety of medical conditions, and statin use

Smoking and Zoster

•Association of cigarette smoking with a past history and incidence of HZ • Ban J Epidemiol Infect. 2017 Jan 16:1-6 [epub ahead of print]

•Community-based prospective cohort study over 3 years in Japan

•Baseline survey: > 12,000 with information on smoking and history HZ

•Past history HZ: current vs never smokers: 0.67 odds ratio

• Incidence of HZ: current vs never smokers: 0.52 hazards ratio

•Conclusions

•Smoking inversely related to prevalence and incidence of HZ!

•Cellular immunity may be increased in light to moderate smokers

•Not to encourage smoking!

•Personal comment: Study change in rates of smoking vs. HZ

Postherpetic Neuralgia (PHN)

•Most common complication of zoster

•Defined as pain beyond 3 months after onset of zoster

•Occurs in 18% adults, 33% age 79+

•Occurs in ~30% of HZO with eye involvement, mostly age 65+ • Yawn Mayo Clin Proc 2007;82:1341, Borkar Ophthalmology 2103; 120:451

•Systematic reviews of risk factors for PHN

•Age, severity acute pain, rash, HZO • Forbes Pain. 2015 July 25 [epub], Kawai Int J Infect Dis. 2015; 34: 126-31

•Ongoing RCT on efficacy of acute high dose gabapentin to prevent PHN •Rullan M Trials 2017; 18:24

•Zoster risk factor for development major depression • Chen, M. H. Psychosom Med, 2014; 76:285-91.

•Zoster is most common cause of suicide due to pain in people age 70

years and older • Hess, TM. Minn Med. 1990; 73:37-40

Anecdote

•My mother worked full time to age 67…She then got very ill

with Shingles. Her optic nerve was involved and she was in

severe pain. You could not even touch her hair or face. She

suffered for many weeks…She was never the same….The

chronic pain caused her to sleep for most of the day.... The

pain never really went totally away… I received the vaccine

about 2 years ago, and pray I never get the disease.

Neither the polio (age 12), meningitis (age 41), or RA (age

67 treated with methotrexate) stopped my very active

mother, but the shingles destroyed her life.

•KC 2017

Zoster Risk for

Stroke, Heart,

Vascular Disease

Zoster long known risk factor for stroke

•30-90% inc stroke, especially younger pts

•2-4x risk stroke/TIA after HZO vs HZ • Zhang 2017; PMID 28501259

• Wang PLoS One 2016; 11:e0164019

• Kwon Clin Microbiol Infect 2016 Jun;22:542-8

• Yang J Stroke Cerebrovasc Dis 2016 [epub]

• Liu PLoS 2016 Oct, Marra BMC Infect Dis 2017 Mar

•Zoster reported as risk for heart disease

•HZ risk for MI < age 40 yrs

• Inc risk arrhythmia, CAD mean age 46 • Breuer. Neurology 2014;82:1

• Wu. J Med Virol 2014; 86:772-7

• Zhang 2017; PMID 28501259

•HZ risk for peripheral artery disease

•13% inc overall, 27% inc < 50 yrs old • Lin Medicine 2016;95:e4480

VZV as Trigger for Giant Cell (Temporal) Arteritis (GCA) Gilden, White, Khmeleva. Neurology.2015; 84:1948-55

•50 sections per temporal artery

(TA) biopsy (vs normal 3)

• Immunohistology for VZV antigen,

PCR for VZV DNA

•VZV antigen in 74% (61/82) GCA+

temporal arteries

• In sections adjacent to VZV ag,

giant cell pathology in 89%

•GCA is VZV vasculopathy of TA

•Antiviral treatment may benefit

steroid treated GCA/TA patients

•BUT: Buckingham Am J

Ophthalmol 2017 Dec 30[epub]

•Only 3/25 GCA+ TAs + for VZV

antigen, 1 case GCA after HZO

•False + calcifications, muscle

Courtesy of Don Gilden

14

Vaccine to Prevent Zoster

•Randomized clinical trial of HZ vaccine pts age 60+ (3 yr fu)

•61% reduced burden of illness (incidence, severity, duration)

•66% decrease in postherpetic neuralgia (secondary endpoint)

•51% decrease incidence zoster

•Efficacy against incidence zoster 64% age 60-69 v. 38% in 70+

•Effect on severity disease greater among persons age 70+ •Oxman NEJM 2005; 352:2271

In 2006 Zostavax (Merck) approved by FDA, in 2008 recommended by

CDC for adults age 60+ without immunocompromise

MMWR June 6, 2008 / 57(05); 1-30

1n 2011 FDA approved vaccine for age 50+ after shown to decrease

incidence of HZ 70% in persons age 50-59

Schmader Clinical Infectious Diseases 2012;54(7):922-928.

Contraindications

www.cdc.gov/vaccines

•Immunocompromise •Diseases affecting cell mediated immunity

•Leukemia, lymphoma, ca of bone marrow, lymphatics

•AIDS or clinical signs of HIV including CD4+ < or = 200

•Hx of stem cell transplant

•Unspecified cellular immundeficiency

• Immunosuppressive treatment •Prednisone 20 mg daily for 2+wks, wait 1month after stop

•Chemotherapy (more than low dose for inflammatory diseases), wait 3mos

•Recombinant immune mediators and immune modulation, especially

antitumor necrosis factor meds, wait 1 m after off these meds

•Anaphylactic allergy to gelatin, neomycin

•Pregnancy (“unlikely in target age group”)

CDC Recommendations and Safety Data

•Zoster vaccine live recommended for people with chronic medical

conditions, persons anticipating or recovered from immunocompromise

•Need to be off acyclovir, valacyclovir, famciclovir 1 day before and 2

weeks after Zoster Vaccine Live

•Safety and adverse events

•Mild local reactions in younger > older pts

• Age 50-59: 69% 60-69: 58% 70+: 41% •Oxman MN et al. N Eng J Med 2005;352:2271-84,

• Tyring SK et al. Vaccine 2007;25:1877-83

•Allergic reactions (N=190,000)

•Localized inflammation, no anaphylaxis

•Age 50s 10x; 60s 2.5x; 70s 1.5x; vs. age 80+ • Tseng J Intern Med 2012; 271:510-520

•10 year review of AEs reported to Merck

•34 millions doses, 24,000 AEs, 1700 SAEs

•14 cases caused by OKA strain, 5 immunosuppressed,1 fatal HZ •Willis ED Vaccine 2017 Dec 19;35:7231, Costa E BMJ Case Rep. 2016 May 4

Insurance Coverage of Zoster Vaccine

•USA complex coverage for age 60+, age 50-59 years in ~ 70% states

•Co-pays up to $100, none under affordable care act

•Co-pay over >$25 associated with canceled Medicare claims •Yan S Current Medical Research and Opinion DOI:

10.1080/03007995.20171416347

•Limited in other countries: UK, Fr, Australia, Israel, Can, Argentina, Italy

•Canada: Ontario covered age 65-70 beginning 2016!

•UK: age 70 with phased catch up age 78-79 since 2013

•Given with flu shots over 3 years

•High coverage: > 70% uptake age 70, ~ 60% catch up groups

•High effectiveness (reduction/coverage): 62% vs HZ •Amirthalingam G Lancet Public Health 2017 Dec 21 [epub]

Presentation Title Goes Here 18

Trends in Nationwide HZ Emergency D Utilization 2006-13 Dommasch ED JAMA Dermatol. 2017;153:874

•Methods: Nationwide (USA) ED Sample data examined

•HZ visits 2006-13 stratified by age

•< 20 years (varicella vaccine recommended)

•20-59 years (no vaccine CDC recommended)

•60 years+ (HZ vaccine recommended)

•Results: > 1,350,000 ED visits

•Mean age 54 years

•HZ % of all ED visits increased by 8%

•Due to increase in ED visits for HZ age 50-59 years by 23%

•Decreased age < 20 by 40%

•Decreased age 60+ years by 11%

•Conclusions: Vaccination against HZ may be associated with

reduction ED use for HZ

Under-Usage of Zoster Vaccine in USA

•Usage of Zoster Vaccine among immunocompetent age 60 years+

•2010 : 14% 2011: 16% 2012: 20% 2013: 24% 2014: 28%

•2015: 31% (MMWR Surveill Summ. 2017 May 5;66: 1) 2016: 33% (CDC)

•National and State-Specific Shingles Vaccination among age 60+

•Overall: 32%, variable: NY- 26%

•Age 50-59: 6% maybe due to lack of recommendation by CDC • Lu PJ Am J Prev Med 2017; 52:362-72

• Factors associated with vaccine uptake 2011-2014

•Wide inter-state variation of HZ vaccination from 21% to 43% age 60+

after adjusted for female sex, education, income which inc vaccination

•Local factors including attitudes, access, reimbursement, policies may

impact vaccination compliance • La Hum Vaccin Immunother. 2017:1-12. doi: 10.1080

Barriers to Use of the Zoster Vaccine

•Why is the vaccine against Zoster not used as recommended? •Cost •Expensive: ~ $200-250

•Reimbursement complex and partial •Medicare Part D Pharmacy for 65+, so difficult to provide in MD office

•Requires frozen storage in USA •Production problems in past (not since 2011) •MDs: lack of strong recommendation by physician

•Hurley Ann Intern Med 2010;152:555

•What can we do about this??

Interventions at NYU in 2011 to Increase Use of the Zoster

Vaccine According to Current Recommendations

•Education of physicians and patients

• Increased supply of vaccine at NYU Pharmacy

•Option at Pharmacy for pts with prescription to get HZ vaccine by nurse

•Available in NY at pharmacies with prescription since 2012, since

2015 without a prescription

•Epic EMR health maintenance reminders and alerts for zoster vaccine

with links to www.cdc.gov for more information

Study at NYU and Bellevue

Supported by MERCK Investigator Initiated Study Program

•Co Investigators in Departments of Ophthalmology, Medicine and

Biostatistics in a prospective IRB approved study

•Survey Division of General Internal Medicine MDs knowledge, attitudes,

practices pre and 1 yr post interventions •Elkin Z. Cornea. 2013; 32:976-81

•Elkin Z. Eye & Contact Lens. 2014; 40:225-31

•Obtained written consent to screen patients in Ophthalmology Clinic at

Bellevue for contraindications, have nurse give vaccine there to 100

eligible, willing patients at no cost to them •Jung J. Am J Ophthalmol 2013; 155:787-95

Bellevue Ophthalmology Clinic Results

•Do you have a regular doctor? Yes 94%

• If yes, how many visits last year? 2-6: 77%

•Would you consider getting the shingles vaccine if a doctor

recommended it? Yes 89%

•Most common reason patients who would follow a MD’s

recommendation declined vaccine (N=49) was they wanted to speak

with their primary care doctor

•Recommendations of primary care doctors regarding vaccination

are most important! • Kollipara Cutis 2015; 95:251; Valente BMJ Open 2016 Oct 18

Presentation Title Goes Here 24

Changes from Baseline to One Year Follow-up Surveys of

Primary Care Doctors

1. There are approx. 1,000,000

cases of shingles per yr in US

2. Importance of vaccines

•Herpes zoster vaccine

•Pneumonia and flu vaccines

Yellow: doses

Red: prescribers

Baseline Follow Up

30% 70% p<0.05

66% 69%

94-97% 94%

25

2017 Follow-up Survey of Primary Care MDs at NYULH Tsui, Gillespie, Perskin, Zabar, Wu, Cohen. Cornea 2018 accepted

•Similar internet survey re knowledge, attitudes and practices re zoster

vaccine 5 yrs after interventions to increase usage at NYULH

•Diverse practices settings different due to growth of faculty group

practice and addition of NYU Brooklyn

•Unable to do comparisons with 55 who responded to 2 prior surveys

•Results:

•26% (138/530) response rate

•Knowledge

•>80% knew vaccine recommended for 65 year old in good health or

on meds for DM, HTN, CAD or history of prostate ca, or past hx

zoster

•<80% knew approved for age 50 year old, 60 year without hx of

chicken pox, and CONTRAINDICATED for patient on infliximab

2017 Follow-up Survey of Primary Care MDs Results

•Rates (estimated) of Zoster Vaccination of immunocompetent

•Age 60+ : average: 43% (range 26% (Bellevue) - 55% voluntary

•Compared to FGP (43%), Bellevue lower (p=0.004)

•Age 50-59: average: 11%, range 5% (Bellevue) – 21% voluntary

•Compared to FGP (10%), Voluntary higher (p=0.026)

•Rates of pneumococcal vaccination age 65+: average:72%, similar

•Rates of annual flu vaccination: average 67%, range 50-72%, Bell low

•Attitudes re important clinical priority of vaccinations (p<0.001)

•Zoster: 76% agreed 35% strongly agreed

•Pneumococcal: 94% 68%

• Influenza 93% 74%

2017 Follow-up Survey of Primary Care MDs Results

•Attitudes re Age for Zoster Vaccination

•99% agree ACIP/CDC recommendations important determinants

•91% agreed with CDC recommendation to vaccinate at 60+

•63% strongly agreed, 64% recommend vaccine at age 60+

•72% agreed with FDA approval age 50+

•29% strongly agreed, 36% recommend vaccine at 50+

•Discussion

•Although higher than national average (33%), NY state (26%), rate of

zoster vaccination by NYU primary care docs (43%) remains

significantly lower than pneumonia (72%) and flu (68%)

•Lack of CDC rec for age 50+ (until Jan 2018 for Shingrix) reflected in

attitudes (above) and practices (11% vaccination rate 50-59)

•Stronger recommendation by primary doctors necessary!!!

• I URGE YOU TO STRONGLY RECOMMEND VACCINATION

AGAINST ZOSTER

•BE PART OF THE SOLUTION AND NOT THE PROBLEM!

Physician Attitudes toward Adult Vaccines…, US 2012 Hurley Public Health Rep. 2016 Mar-Apr; 131:320-30

•Survey of general internists and family physicians (N=850)

•Very important for 67 year healthy patient?

•Flu vaccine 89% Pneumococcal vaccine 80%

•Herpes zoster 47%

•MD attitudes likely influenced by

•Evidence for the vaccine

•Access due to insurance coverage and cost to provide in office

•Patient demand

•Experience treating disease

•Clarity of guidelines

•Whether or not service is tracked as a performance measure for the

practice

When Zoster Hits Close to Home

•Anecdote 2017: 58 year old friend

“Last year I was told by a doctor friend

to get a shingles shot. My thought was

that’s for old people- boy was I wrong!!

Six months later I had a pain in my

neck that kept me up at night and 2

days later I had a rash from the top of

my back around my neck to my chest. I

knew it was SHINGLES. I was so mad

at myself for not getting the vaccine. It’s

been 4 months and it is still painful and

it feels like it is going to stay with me

forever. I tell everyone I meet, please

go to your doctor and get the vaccine

as soon as you can. I have reached out

to friends around the world, and will

keep telling everyone this is nothing to

fool with!”

•Evidence

• Impact of personal zoster awareness

on zoster vaccine uptake in the US •Harpaz R Vaccine 2017;35:3457-60

•Vaccine uptake markedly increased

immediately after zoster in a spouse

•Relative incidence vaccination 7x

during month post vs 6 months pre

•Relative incidence 14x when

spouse severe zoster requiring

opiates

•No increase in pneumonia

vaccination during month post HZ

We Can Do Better to Protect Our Patients Against Zoster!

•How do we encourage MDs to strongly recommend the zoster

vaccine???

• Increase vaccination rate of doctors as evidence of importance • Bonanni Vaccine 2017 28807604

•American Academy of Ophthalmology Clinical Statement in 2016

recommends zoster vaccine age 50 years and older • http://www.aao.org/clinical-statement/recommendations-herpes-zoster-vaccine-

patients-50-

•American Academy of Dermatology became co-sponsor of this

statement in July, 2017

• Importance of a moral obligation to do the right thing to change

behavior (Arthur Caplan PhD)

Presentation Title Goes Here 31

Timing of Vaccination Against Zoster

•Since complications zoster increase with age, duration vaccine

protection uncertain, CDC recommendation for age 60+ same 2008-17. •Hales MMWR 2014; 63:729

•Duration zoster vaccine live (Zostavax) protection

•Short-term, Long-term Persistence Studies: efficacy wanes after 8 yrs

for incidence of zoster, 10 yrs for burden of disease, PHN in age 60+ • Schmader Clin Infect Dis. 2012; 55:1320, Morrison Clin Infect Dis. 2015; 60:900-9

•Effectiveness of zoster vaccine, case control study N=180,000

•Yr 1: 69% Yrs 3-6: 33% Yr 8: 4% • Tseng J Infect Dis 2016; Jun15;213:1872-5

•No data age 50-59, but may have longer protection due to greater

importance of age v. time since vaccine in age 60+ • Li Vaccine 2015 ;33:1499-505

Presentation Title Goes Here 32

Non Pain Complications of Zoster Yawn. Mayo Clin Proc. 2007; 82: 1341

•CDC evidence for non pain complications (eye, neuro) from one paper

•Results:

•10% have one or more non pain complication

• Increase with age of non pain complications not significant!

•Age 50-59: 314 cases Age 60-69: 284 cases

•Non pain: 26 (8%) 27 (10%)

•Difficult to understand as basis of CDC lack of recommendation for

zoster vaccine at age 50, unless only goal is to prevent

postherpetic neuralgia, and not zoster, pain less than 3 months,

and non pain complications! (personal opinion)

Cleveland Clinic Publications

•Cost-effectiveness HZ Vaccine Live for Persons Age 50 years

• Incremental Cost-Effectiveness Ratio (ICER) >$300,000 per QALY

•A number of questionable assumptions made

•Productivity loss due to absenteeism/presenteeism age 65+

similar to 60-64 and greater than age 50-59!!!

•Cost effectiveness of HZ/su vaccine (2 shot series) for 60+

•At $280 HZ/su more effective, less cost vs zoster vaccine live ($213)

• ICER/QALY~$30,000 age 60

•Assumed 19 year duration efficacy, waned 2x as fast if one dose!!

•Given at 60: 73% probability cost-effective at $50,000 cost/QALY

• Le P Ann Intern Med 2015; 163-489-497

• Le P Am J Prev Med 2017;53:829

• Le P JAMA Intern Med 2018 Jan 2 [epub]

New Vaccine Against Zoster Lal H et al. N Engl J Med 2015; 372:2087-96.

Cunningham N Engl J Med 2016; 375:1019-32

•Adjuvanted herpes zoster subunit (HZ/su) vaccine (GlaxoSmithKline)

•Recombinant contains VZV glycoprotein E antigen, AS01B adjuvant

•RCT in adults age 50 years and older without immunosuppression

•2 IM injections 2 months apart of vaccine or saline placebo

•Results: ~97% efficacy for all age groups

•Grade 3 severe acute symptoms in 17% vaccine

•Vaccine efficacy pooled in ZOE-70 , ZOE-50 trials in 2010-2011

•Results: efficacy : ~90% in vaccine recipients age 70s and 80s

•Efficacy against HZ over time: 85% yr 4

•Editorial: Local or systemic reactions preventing normal activity in 12%

vaccine raises concern about adherence to necessary 2 dose schedule. •Neuzil N Engl J Med 2016; 1079-80

•FDA approved Oct. 20, 2017 for age 50 and above

•CDC recommended Jan 26, 2018 MMWR for immunocompetent 50+

Presentation Title Goes Here 35

HZ/su (Shingrix) Papers

•2 doses compared to 1 resulted in >3x CMI response to gE VZV antigen

•CMI at 3yrs high more often after 2 (50%) v.1 dose (6%)

•2 doses over 6 yrs: CMI decreased but still ~4x higher than pre vaccine

• Chlibek Vaccine 2014; 32:1745; Chilibek Vaccine 2016; 34:863

• Immunogenic in adults 50+ with past history of zoster (antibodies)

•78/72% local/general AEs, 88% if HZ <= 4yrs ago, <70% if 5+ yrs ago •Godeaux Hum Vaccin Immunother. 2017; 13; 1051

•No interference antibody response if give with a llV4 flu vaccine • Schwarz TF J Infect Dis. 2017 Dec 12;216:1352

•But flu vaccines complex, variable Oxman J Infect Dis2017; 216:1329

•Strong immune response irrespective of prior ZVL, AEs comparable.

•Age 65+ with or without prior hx zoster vaccine live 5+ years ago •Grupping J Infect Dis. 2017 Sep 20 [epub ahead of print]

• Immune antibody response 0,6 months apart non inferior to 0,2 months • Lal H Vaccine 2018 Jan 2;36:148

FDA Label for Shingrix

•Name: Zoster vaccine recombinant, adjuvanted

•Vaccine indicated for prevention HZ in adults age 50 years and older

•Not just immunocompetent adults!

• Immunosuppressive treatment may reduce effectiveness

•Administer 2 doses IM at 0 and 2 to 6 months

•No evidence interference immune response when given with a

quadrivalent flu vaccine

•VZV glycoprotein E antigen vial reconstituted with vial of AS01B

adjuvant

•After reconstituted, use immediately or refrigerate up to 6 hours,

discard if frozen

•Storage before reconstituted: refrigerate, discard if frozen!

•Contraindications: anaphylaxis to component of vaccine or after a dose

FDA Label Shingrix

•Adverse reactions/events:

•Local: pain 78%, redness 38%, swelling 26%

•General: myalgia 45%, fatigue 44%, headache 38%, shivering 27%,

fever 20%, gi 17%

•Local and general reactions less age 70+ than age 50-69

•Age 50-59: pain 88%, grade 3: 10%; myalgia 57%, grade 3: 9%,

fatigue 57%, grade 3: 8%

•Median duration: 2-3 days

•Local reactions similar after dose 1 and 2

•Grade 3 general reactions more frequent after dose 2 than 1

(headache, shivering, myalgia, fatigue: 2.3-3.6% dose 2 vs 1.4-2.4%)

•Unsolicited AEs within 30 days

•Gout: 0.18% (n=27) vs 0.05% (n=8) placebo, insufficient information

to determine causal relationship

•Patient counseling information

• Importance of completing 2 dose series on schedule

• Inform re risks and benefits, including adverse reactions

Advisory Committee on Immunization Practices (ACIP)

Recommendations for HZ Subunit Vaccine (Shingrix)

October 25, 2017

•Herpes Zoster subunit (HZ/su) vaccine (Shingrix, GlaxoSmithKline)

recommended for immunocompetent adults age 50 years and older

(vote 14 to 1)

•No recommendation for immunocompromised because excluded from

studies

•Recommended for immunocompetent adults previously received Zoster

Vaccine Live (Zostavax, Merck) (vote 12 to 3)

•Shingrix is preferred over Zostavax (vote 8 to 7)

•CDC accepted ACIP recommendations

•MMWR Jan 26, 2018

CDC Recommendations of ACIP for Herpes Zoster Vaccines Dooling, Guo, Pater, Lee, Moore, Belongia, Harpaz. MMWR Jan 26, 2018; 67:103-108

•Recombinant Zoster Vaccine (RZV) and Zoster Vaccine Live (ZVL)

•Rationale for recommendations

•RZV use in immunocompetent age 50+

•Due to high efficacy and limited waning protection over 4 years.

•RZV in immunocompetent adults with previous ZVL

•Higher efficacy esp age 70+, ZVL efficacy wanes, RZV similar

immunogenicity regardless of prior ZVL

•Preferential use RZV

•Higher and more long lasting efficacy

•Post licensure to be determined possibility rare adverse events,

duration protection, adherence to 2 dose schedule, efficacy and

duration of one dose from real world data

CDC Recommendations (cont) MMWR Jan 26, 2018; 67:103-108

•Use RZV age 50+ irrespective past varicella or ZVL, without screening

for history of chicken pox.

•ZVL remains recommended vaccine immunocompetent 60+!!

•ZVL stored in freezer, give sub cu, RZV stored in refrigerator, give IM

•RZV 2 doses 2-6 months apart

• If second dose later, give it

• If second dose less than 4 wks after first, then repeat it

• If past history of zoster or ZVL, still need 2 doses RZV

•Timing of RZV after ZVL

•Consider age at ZVL and time since

•Only data for safety and immunogenicity 5+ yrs after ZVL at 60+

•Due to lower efficacy ZVL age 70+, consider shorter interval

•Should not give < 2 months after ZVL

•Co-administration with other recombinant and adjuvanted vaccines at

different anatomic locations

•Counsel re systemic and local reactions

•Encourage complete series after reactions to first dose

CDC Recommendations MMWR Jan 26, 2018; 67:103-108

•Special populations

•History of HZ: Should receive RZV at unspecified time afterwards

•Chronic medical conditions: should get RZV

• Immunocompromised persons (defined as contraindications for ZVL)

•Although FDA licensed for persons age 50+, no recommendations,

to be discussed as data available from ongoing studies

• If known VZV negative (screening not recommended): get varicella

vaccine

•Pregnancy: no recommendation

•Report vaccine adverse reactions to Vaccine Adverse Events Reporting

System (VAERS) 1-800-822-7967 and Vaccine Safety Datalink.

•Post-marketing safety monitoring by GSK reported to FDA

•Monitoring particularly important due to novel adjuvant with high

reactogenicity and immunogenicity

ACIP Recommended Immunization Schedule for Adults 2018

MMWR Feb, 6 2018; 67:1-3

•2 doses Recombinant Zoster Vaccine (RZV) 2-6 months apart to adults

age 50+ regardless of history of herpes zoster or Zoster Vaccine Live

(ZVL)

•2 doses RZV 2-6 months apart to adults who received ZVL at least 2

months after ZVL

•For adults age 60+ either RZV or ZVL (RZV preferred)

Anecdote

•A healthy neurosurgeon was planning to get the zoster vaccine. Two

days after his sixtieth birthday, he developed right sided headache and

ear pain, then a rash inside his ear 3-4 days later, followed by facial

weakness and hearing loss the next day. Intravenous acyclovir

treatment and oral corticosteroids were begun one day after the onset of

the rash, followed by a 2 week course of valacyclovir. The pain resolved

within one week, and the facial palsy resolved over 2 months. However,

one year later, the right ear has decreased hearing and tinnitus, but he

is back to work full time.

• If you are age 50+, just do it!!

Treatment of Herpes Zoster (HZ)

•Oral antivirals within 72 hours of rash are approved and recommended

•Valacyclovir 1000 mg three times daily for 7 days

•Famciclovir 500 mg three times daily for 7 days

•Acyclovir 800 mg five times daily for 7 days (not as effective)

•Reduces chronic eye disease from 50% to 30%, does not reduce PHN

•Herpes Zoster Vignette (Cohen JI N Eng J Med 2013;369:255-63)

•“Antiviral treatment most beneficial for persons who have

complications of HZ or who are at increased risk for complications,

such as older persons and immunocompromised persons…

•My opinion: Antiviral treatment should be given to all people with HZ as

soon as possible, since complications typically develop more than 72

hours after onset when treatment should be given, and can occur in

relatively young and healthy people!!!

Case

•A healthy person in her 50’s,

developed unilateral radicular

thoracic pain and a rash a wk

later. Treatment for HZ was

begun, next day had leg

numbness and weakness with

transverse myelitis due to HZ. At 1

year, still had PHN with constant

5/10 pain

•Lessons

•Recommend vaccine at age 50+

•Can’t predict who will have

serious complications of HZ!

Possible New Treatment for Herpes Zoster

Ophthalmicus (HZO)

•The Zoster Eye Disease Study (ZEDS) funded by NEI in

2016 to conduct a multicenter, Randomized, placebo

controlled Clinical Trial (RCT) to determine whether

prolonged, suppressive valacyclovir treatment reduces

complications of Herpes Zoster Ophthalmicus (HZO),

including eye disease and/or postherpetic neuralgia

Presentation Title Goes Here 47

ZEDS Study Structure

•60 Participating Clinical Centers (185 investigators in 29 states)

•Coordinating Center (CC) at NYU Langone Health

•Study Chair: Elisabeth Cohen, Co-Chair Bennie Jeng, U MD

•Multiple PIs: Judith Hochman, JD Goldberg CC NYUSoM, NYULH

•Executive Committee: Stephen McLeod, Todd Margolis, Christopher

Rapuano, James Chodosh, Anat Galor, Alice Matoba

•Medical monitors: Laura Balcer, Michael Perskin, Jennifer Lighter

•NYULH PCC: Ilyse Haberman, PI

•CC staff leader: Jacqueline Arciniega

•Clinical Event Review Committee: Kathryn Colby Chair

•Consultant: Deborah Langston

Presentation Title Goes Here 48

Participating Clinical Centers (PCC)

49

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• ~60 Participating Clinical Centers in 29 states in the US • New Centers in Virginia and Georgia being added • Community Based Centers = 32% • Academic Medical Centers = 68%

Background and Rationale of ZEDS

• Acute high dose oral antiviral treatment is recommended for Herpes

Zoster Ophthalmicus (HZO), but there is no standard approach to

antiviral treatment for ocular complications of HZO.

• Rationale of the Zoster Eye Disease Study (ZEDS)

• First:

• Relatively recent knowledge of infectious pathogenesis of

complications of Herpes Zoster and HZO

• Second:

• Significant benefit of suppressive antiviral treatment in

reducing recurrent Herpes Simplex Virus (HSV) eye disease

• HZO and HSV keratitis, caused by different herpes viruses,

are analogous in many ways

50

Rationale for Zoster Eye Disease Study (ZEDS)

51

• Evidence that Herpes Zoster is

associated with chronic active

infection with the varicella zoster

virus (VZV)

• Active infection contributes to

chronic eye disease

• Dendriform epithelial keratitis

PCR+ for VZV and responds to

topical ganciclovir

• Iritis: AC is PCR+ for VZV

Pavan Langston D. Arch Ophthalmol 1995;

111:1381

Hu AY, Am J Ophthalmol 2010; 149:214

Aggarwal S. Cornea. 2014; 33(2):109

Takase Jpn J Opthalmol 2014; 58:473

Rationale of Zoster Eye Disease Study

• Herpetic Eye Disease Study (HEDS) Acyclovir Prevention Trial (APT) • HEDS Study Group. N Eng J Med 1998; 339:300-306

• HEDS Study Group. Arch Ophthalmol 2000;118: 1030-36.

• Long-term suppressive treatment with oral acyclovir resulted in 45%

reduction in recurrent Herpes Simplex Virus disease at 1 yr

• Antiviral treatment was most beneficial in reducing stromal keratitis

• Although role of active viral infection unclear in stromal keratitis,

evidence is strong that antiviral suppression reduces it.

• ZEDS trial analogous to the HEDS APT study for ocular disease

caused by varicella zoster virus (VZV)

• Valacyclovir, prodrug of acyclovir, has higher plasma

concentration than acyclovir required for VZV

• Similar trial design: RCT of 1 yr of suppressive valacyclovir vs.

placebo with follow-up every 3 months for 18 months

52

Overview of Study Design

• Immunocompetent HZO patients, 18 years and older

• History of typical unilateral vesicular rash in V1 distribution

• Episode in medical record within the year prior to enrollment of

one of four specific eye disease manifestations

• Randomized 1:1 ratio to double masked valacyclovir 1000 mg or

placebo daily

• Randomized in 4 strata and by center

• Age of onset HZO: < 60 years vs 60 years or more

• Time since onset HZO < 6 months vs 6 months or more

• Timeline: NEI approval protocol (1/17), Central IRB approval (5/17),

activate 60 participating centers (~40 in 2017), first study participant

enrolled 10/17, (~50 in 2/18)

• Enroll 1050 study participants over 3 years, complete in 5 years

53

Primary Objective and Endpoint

• To evaluate whether or not

suppressive valacyclovir

treatment, compared with

placebo, will delay time to first

occurrence by 12 months of new

or worsening disease

manifestations similar to

eligibility criteria

• Dendriform epithelial

keratitis (DEK)

• Stromal keratitis without

ulceration(SK)

• Endothelial keratitis (EK)

• Iritis (IR)

• Stromal keratitis with

ulceration (SKU)

54

Secondary Study Objectives and Endpoints

• To evaluate whether or not the effect of treatment on primary

endpoint persists for 6 months after treatment by comparing rates of

new or worsening pre-specific eye manifestations by 18 months

follow-up in participants randomized to valacyclovir or placebo

• To test hypothesis that suppressive valacyclovir treatment reduces

the incidence, severity, duration of postherpetic neuralgia (PHN)

compared to placebo at 12 and 18 months

• If yes, then results likely to be generalizable to zoster in other

locations

55

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Please support the ZEDS study to try to improve

outcomes by referring your patients with

zoster/shingles of the eye to a study investigator

Thank you!

[email protected]

[email protected]

Herpes Zoster Vaccination

an ounce of

prevention can save a life!