Download pdf - Herpes Zoster and the Zoster Eye Disease Study …...Herpes Zoster and the Zoster Eye Disease Study (ZEDS) Elisabeth J Cohen, MD Professor of Ophthalmology New York University SoM

Herpes Zoster and the

Zoster Eye Disease

Study (ZEDS)

Elisabeth J Cohen, MD

Professor of Ophthalmology

New York University SoM

NYU Langone Medical Center

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 have had varicella

•Typical painful, unilateral,

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

first time ever, moderate to

severe, stabbing pain • Lee Clin Neurol Neurosurg

2017;152:90-94

•Herpes Zoster Sine Herpete:

radicular pain without rash • Lewis BMJ 1958

•Severe uveitis •Schwab Ophthalmology

97;104:1421

•Stroke due to HZ: only 63% hx

zoster rash •Nagel Neurology 2008; 70:853-60

•HZ without rash not very rare!

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

•Ongoing debate regarding timing of vaccination at age 50 or 60

•I will make the case for age 50 years and above

•Zoster Eye Disease Study (ZEDS) randomized controlled clinical trial

to evaluate prolonged suppressive antiviral treatment to reduce

complications of Herpes Zoster Ophthalmicus, NEI funded fall, 2016

begins enrollment in spring, 2017

Herpes Zoster (HZ) / Shingles

•Common disease

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

2014;1(2)

•10-20% involve Vth nerve •~99% 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, 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

• Increase in Australia

•2000-2006 v. 2006-2013, pre-

and post- universal varicella

vaccination •MacIntrye PLoS One. 2015 Apr

30;10(4)

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!

0

5

10

15

20

25

30

Num

ber o

f p

atients

0-9

10--19

20-29

30-39

40-49

50-59

60-69

70-79

80-89

90-99

431. Insinga RP et al. J Gen Intern Med. 2005;20:748–753.

Zoster Incidence by Age Group1

0

200

400

600

800

1,000

1,200

1,400

1,600

1,800

2,000

0-14 15-29 30-39 40-49 50-59 60-69 70-79 80+

0

2

4

6

8

10

12Number of Cases

Rate per person-years

Age

Ra

te p

er

1,0

00

Pe

rso

n-Y

ea

rs

Nu

mb

er

of

Cas

es

of

Zo

ste

r (n

= 9

,15

2)

43

Decreasing Age at Onset of Zoster

•Age of onset of HZO (Chen Cornea 2015; 34:535)

•400 pts (58% women) HZO onset 1996-2004 v. 2005-2012

•Mean age 65 yrs 59 yrs P<0.05

•Less than age 60 yrs 32% 45% P<0.05

•Less than age 50 16% 30% P<0.05

•Age at presentation HZO (Davies Br J Ophthalmol 2016; 100:312)

•>900 acute HZO patient 2007-2013

•Decrease in mean age 61 yrs to 56 yrs (P<0.05)

•Conclusion: Recommend zoster vaccination immunocompetent adults

age 50 years and older

Role of Varicella Vaccination in Zoster Increase

•Postponement of HZ: 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!

• Increase in rates of HZ reported similar in these countries

•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

•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 disease 70% • Suava Open Forum Infectious Diseases 2014 Sep; 1(2)

• Peng J Asthma 2016 Jul 13 [epub]

• Yang Sci Rep 2015 Sep3;5:13747

•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

•3 years active surveillance for incidence 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 ~30% of HZO with eye involvement, mostly age 65+

•Systematic reviews of risk factors for PHN

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

•Efficacy of (acute high dose) gabapentin to prevent PHN RCT

•Prevent central nervous system sensitization •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, she resigned as a deacon of the church as

she could no longer attend services or meetings due to the pain. 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

•90% inc stroke, especially in younger pts

•~2x risk neuro complications after HZO

than HZ elsewhere age 45-64 • Wang PLoS One 2016; 11:e0164019

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

•Meta-analyses of relative risk (RR):

•45% inc after HZ, 4.4 x inc after HZO

•78% inc in first month, 2x after HZO • 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

•HZ risk for peripheral artery disease

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

•HZ risk for Parkinson’s age 65+ •17% inc overall, 3x during first 3 months

• Lai SW Medicine 2017;96:e6075

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

•Present in artery adventitia >

media >intima

• In sections adjacent to VZV,

giant cell pathology in 89%

•GCA is VZV vasculopathy of TA

•Antiviral treatment may benefit

steroid treated GCA/TA patients

•Antiviral treatment should be

studied in RCT

Courtesy of Don Gilden 15

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

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.

• In my opinion, it is better to get the vaccine in

your 50’s and 60’s, but it is never too late!

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

•Zoster vaccine live recommended for people with chronic medical

conditions, persons likely to become immunocompromised!

•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

Case Reports of Complications in Ophthalmic Literature

•Episodes of zoster keratitis, uveitis 2-5 wks after zoster vaccination

•Recommend monitor HZO patients 4-6 wks after zoster vaccine

•Vaccination with caution in HZO •Khalifa, Jacoby, Margolis Arch Ophthalmol 2010; 128:1079

•Sham Arch Opthalmol 2012; 130:793

•Hwang Cornea 2013;32:508-9 (pt had hx of lymphoma contraindication)

•My opinion: despite some risk of recurrent inflammation, recommend

vaccine 1-3 yrs post HZO, when stable, and monitor patients

•6% risk second episode in 8 yrs (Yawn Mayo Clin Proc. 2011; 86:88)

•Acute retinal necrosis after HZ vaccine in renal transplant pt

(contraindicated) and end-stage renal disease pt •Charkoudian Arch Ophthalmol 2011;129:1495

•Betjes Immune cell dysfunction …in end-stage renal disease. Nat Rev

Nephrol 2013; 9:255

Zoster Vaccine Live contraindicated if impaired cellular immunity!!

Inactive zoster vaccine under study in stem cell transplant pts (4 shots)

Presentation Title Goes Here 19

Insurance Coverage of Zoster Vaccine

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

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

•Other countries

•UK: partial coverage age 70s

•France: covered age 65-74

•Australia: covered age 70s

• Israel: partial coverage (~50% of price) age 50+

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

•Argentina: covered by a few HMOs

• Italy age 50+ (Merck personal communication)

•Due to underuse, zoster vaccine has not yet affected global

epidemiology •Yawn Neurology 2013; 81:928


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% (MMWR Surveill Summ. 2016 Feb 5;65:1-68)

•Higher coverage for whites (32% vs 12% blacks, 15% Hispanics),

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

•2014 data telephone survey (vs in person survey above)

•Overall: 32%, variable: CA-36%. NH-39%, NY- 26%

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

•Given that half of patients with zoster are less than age 60, ~15% of

people at risk have had the zoster vaccine in USA

Why is the vaccine against Zoster not used as

recommended? What can we do about it??

Barriers to Use of the Zoster Vaccine

•Cost

•Expensive: ~ $190

•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

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

http://www.cdc.gov/

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

•5 year follow-up survey underway winter, 2017 (Tsui)

•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, but ophthalmologists and other doctors

should recommend vaccination against zoster too, and will be

more effective if have a strong relationship with patients! • Kollipara Cutis 2015; 95:251.


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%

26

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

•Advice of general practitioners highly significant (p<0.0001) in decision

by patients to get zoster vaccine (Valente BMJ Open 2016 Oct 18)

We Can Do Better to Protect Our Patients Against Zoster!

•How do we encourage MDs to strongly recommend the zoster

vaccine???

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

behavior (Arthur Caplan PhD)

•American Academy of Ophthalmology Clinical Statement recommends

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

patients-50-


Timing of Vaccination Against Zoster

•Update on recommendations for use of HZ vaccine •Hales MMWR 2014; 63:729

•Since complications of zoster increase with age, duration of vaccine

protection is uncertain, CDC recommendation for age 60+ unchanged.

•Duration vaccine 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


Booster for Zoster Vaccine?

•CDC: Booster dose at 10 years compared to first dose had comparable

immunogenicity outcomes, but this does not adequately predict

protection to recommend second dose. (ACIP Summary Report June, 2015)

•CMI VZV correlated with protection against HZ (Levin J Infect Dis 2008;197:825)

• Immune response to second dose zoster vaccine after 10+ years

•Cellular mediated immunity (CMI) after booster at age 70+ yrs

compared to first dose at age 50-59, 60-69, 70+ years

•Effect of vaccine on VZV CMI in age 70+ persisted for 10 yrs, and

increased by booster

•Age 50-59 highest CMI to VZV (baseline and post vaccine)

•Supports investigation vaccination sooner vs later and of booster,

duration of protection age 50-59 may be longer • Levin J Infect Dis 2016;213: 14-22

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 and non pain

complications! (personal opinion)

Cost-Effective Analyses of Zoster Vaccine

•CDC Advisory Committee on Immunization Practices (ACIP) 2013

•Much higher Incremental Cost Effectiveness Ratio (ICER), dollars per

unit of health gained

•Vaccinate at age 50 ($287,000) compared to 60 ($86,000)

•United Kingdom data showed cost-effective to vaccinate age 50+ •Moore Cost Eff Resour Alloc. 2010; 8:7

• ICER per Quality Adjusted Life Year (QALY) gained <~$45,000

•Age 50-59: medical ICER: ~$19,000

•Age 60-69: medical ICER: ~$16,000

• If duration efficacy 10 years, and 50% get booster, ICER ~$37,000

•Aged 50 and over in Germany (Preaud Hum Vaccin Immunother 2015; 11:884-96)

•Vaccinating 60+ vs age 50+ similar ICER/QALY insurance

•Age 60+ 39,000 EU vs age 50+ 40,000 EU


Cleveland Clinic Publications

•Cost-effectiveness HZ Vaccine for Persons Age 50 years

•Determining optimal vaccination schedule for HZ • Le Ann Intern Med 2015; 163-489-497

• Le J Gen Intern Med. 2016 oct 14 [epub ahead of print]

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

•Assumptions made

•Incidence would plateau by 2010-2015 (F)

•Efficacy wanes at same rate age 50-59 vs 60+( unlikely)

•Very limited data on non PHN complications

•Serious vaccine reactions : 3 days hospital (F)

•Productivity loss due to absenteeism/presenteeism age 65+

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

•Vaccination at 70 plus one booster after 10 yrs: ICER/QALY $37,000

•Vaccination at 60, 2 boosters most effective, ICER/QALY $154,000

• ICER/QALY < $100,000 compliance with booster >67%, if vaccine

cost <$156, initial efficacy >69%, serious reaction <0.3%

Promising 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 placebo

•Results: 97% efficacy for all age groups

•Grade 3 severe acute symptoms in 17% vaccine, 3% placebo

•Editorial comment: adjuvant not licensed (Cohen N Engl J Med 2015; 372:2149)

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

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

•Efficacy HZ over time: 98% yr 1, 88% yr 4

•Acute injection site and systemic reactions in 79% v. 30% placebo

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

vaccine v 2% placebo raises concern about adherence to necessary 2

dose schedule. (Neuzil N Engl J Med 2016; 1079-80)


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 1000 mg tid. 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+ and are eligible for the zoster vaccine, 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!

Corneal Disease

Classification of HZO

•Recommend use same as HSV •White.2014, Jul

http://one.aao.org/clinical-

statement/herpes-simplex-virus-keratitis-

treatment-guideline

•Epithelial keratitis • Infectious dendriform

•Stromal keratitis •Without ulceration

•With ulceration

•Endothelial keratitis

•Uveitis

•Neurotrophic keratopathy •With or without melting/perforation

•With or without microbial superinfection


http://one.aao.org/clinical-statement/herpes-simplex-virus-keratitis-treatment-guideline













Complications of HZO

•Outcomes cataract surgery in chronic HZO (N=24)

•Early improvement in VA, decreased by last fu due to retina •He J Cataract Refract Surg. 2015; 41:771-7

•Personal experience: after stable 4yrs on steroids, retina issues

•Well treated HZO may be associated with posterior segment problems

more often than expected

•Epidemiology HZO in VA hospitals in S Florida (N=67)

•Recurrent disease (after quiet off meds 3 mos):

•8% at 1 yr 17% at 3yrs 25% at 5 yrs 31% 6 yrs

•Chronic (persistent active disease >90 days) in 23%

•Uveitis, increased IOP, chronic disease are risk factors for recurrent

and/or chronic disease • Tran Ophthalmology 2016;123:1469-75

Possible New Treatment for HZO

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

9/30/2016 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


ZEDS Study Structure

•60 Participating Clinical Centers (>150 investigators in 28 states),

including 18 centers that treated > 100 HZO patients in a year

•Coordinating Center (CC) including data management at NYU Langone

Medical Center

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

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

•Executive Committee: Stephen McLeod, Todd Margolis, Christopher

Rapuano, James Chodosh, Anat Galor, Alice Matoba

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

•CC staff leaders: Jacqueline Arciniega, Meelee Tom

•Clinical Event Review Committee: Kathryn Colby

•Consultants: Roy Beck, Deborah Langston


Participating Clinical Centers (PCC)

• ~60 Participating Clinical Centers in 28 states in the US.

• Academic medical centers and community based clinics.

42

Principal Investigators (State)

Abazari (NY), Agrawal (AZ), Amescua (FL), Ansari (IL),

Asbell (NY), Baratz (MN), Beretsky (MN), Bokosky (CA),

Chamberlain (OR), Chodosh (MA), Chow (CT), Ciralsky

(NY), Daluvoy (NC), Ewald (TN), Fowler (AL), Geggel (WA),

Gonzales (CA), Green (MD) Greiner (MA), Gupta (OH),

Haberman (NY), Hammersmith (PA), Heidemann (MI),

Hindman (NY), Holland (CA), Honig (MD), Huang (MO), Katz

(KY), Kenyon (MA), Kieval (MA), Lee H (MA), Lopatynsky

(NJ), Macsai (IL), Matoba (TX), McCulley (TX), Mian (MI),

Miller (NH), Munir (MD), Nehls (WI), Nettune (TZ), Oboh-

Weilke (DC), Orlin (PA), Park (IL), Raber (PA), Reeves

(MN), Reilly (TX), Ritterband (NY), Rosenfeld (FL), Shatz

(MA), Sherman (CA), Siatkowski (OK),Sikder (MD),

Soukiasian (MA), Steiner (NY), Straiko (OR), Sugar (IL),

Tran (TN),Tuli (FL), Weiss (LA), Wise (CO)

Co-Investigators

Akpek (MD), Aldave (CA), Al-Mohtaseb (TX), Ayres (PA), Barato (NJ), Barney

(WI), Bartley (TX), Beebe (TX), Bleiman (MA), Boehlke (NC), Bowman B (TX),

Bowman W (TX), Bunya (PA), Cavanagh (TX), Chan (MA), Chou (NY), Corrent

(FL), Cykiert (NY), Davidson (CO), Delmonte (NC), Deng (CA), Dunn (MI),

Edginton (OR), Ehlen (MN), Etter (MD), Fernandez (NY), Flynn (TX), Flynn-

Thompson (MA), Gadaria (NY), Gelender (TX), Gire (MD), Goldstein (MA), Gray

(FL), Gregory (CO), Gupta (NC), Hardten (MN), Herz (IL), Hood (MI), Huang

(OR), Hubbe (MA), Iyer (TX), Jafri (CA), Keenan (CA), Kelleher (MD), Kombo

(CT), Koplin (NY), (CA), Kruger (MA), Kubal (FL), Lai (NY), Lass (OH), Levinson

(CA), Levinson (MD), Lobo (IL), Loushin (MN), Lubniewski (MO), Lustbader (DC),

Maguire (MN), Margolis (MO), Massaro (PA), McCall (TX), McLoed (CA),

Mondino (CA), Mootha (TX), Nagra (PA), Negahban (MA), Patel (MN), Raizman

(MA), Rao (MA), Ramsey (MN), Ransome (CA), Rapoza (MA), Rapuano (PA),

Rashid (TX), Read (AL), Rice (TX), Rosenblatt (NY), Sarkar (NJ), Sayegh (OH),

Schiff (AZ), Schrack (PA), Schrier (NY), Seedor (NY), Shah (IL), Shield (MA),

Shih (NY). Shtein (MI), Sinclair (MN), Sippel (NY), Snyder (MD), Solomon (NY),

Soong (MI), Sood (NY), Sperber (NY), Srikumaran (MD), Starr (NY), Stein (MI),

Sugar (MI), Sulewski (PA), Taravella (CO), Terry (OR), Thorne (TX), Tu (IL),

Udell (NY), Van Meter (KY), Verity (TX), Weikert (TX), Williamson (TN), Winnick

(FL), Woodward (MI), Wu (MA), Wu (NY), Zegans (NH)

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

45

Rationale for Zoster Eye Disease Study (ZEDS)

46

• 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, more effective against VZV than acyclovir

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

placebo with follow-up every 3 months for 18 months

47

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

• Dendriform epithelial keratitis (DEK)

• Stromal keratitis (SK)

• Endothelial keratitis (EK) (disciform keratitis)

• Iritis (IR)

• Randomized 1:1 ratio to valacyclovir 1000 mg daily or placebo

• 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: 6 months start-up: NEI approval protocol, NYU IRB

approval in Jan, 2017, activation process of participating centers:

begin enrollment spring, 2017, enroll 1050 study participants over 3

years, complete in 5 years

48

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

• Dendriform epithelial keratitis (DEK)

• Stromal keratitis (SK)

• Endothelial keratitis (EK) (disciform keratitis)

• Iritis (IR)

• In HZO patients who have a history of one of these disease

manifestations within year prior to enrollment

• SK, EK, IR requiring substantial increase in treatment (at least 2x

increase in frequency, or change from loteprednol 0.5% to pred1%

• Not occurring within 3 months of substantial decrease of treatment

for same disease manifestation (50% decrease, or change to

weaker steroid)

49

Study Medication: Valacyclovir

• FDA approved since 1995 for:

• Acute treatment for Zoster:

• 1000 mg tid for 7 days within 72 hours of onset of rash

• Suppressive treatment for HSV genital infections:

• 1000 mg daily for one year

• FDA IND obtained for this study as approved dose is being used for

a different patient population.

• Applied for IND exemption due to long and excellent safety record of

this drug, protocol designed to minimize risk, belief that HZO

patients not at significantly greater risk than HSV patients for

complications due to suppressive treatment with valacyclovir, turned

down.

50

Eligibility/Inclusion Criteria

51

• Age 18 years or older

• History characteristic unilateral

cranial nerve V1 rash

• Medical record documentation

• Dendriform epithelial keratitis

• Stromal keratitis

• Endothelial keratitis

• Iritis

• If HZO onset 6 or more months

prior to enrollment: on stable

topical steroids and off antivirals

30+ days, or enrollment delayed

Exclusion Criteria

• Immunocompromise by CDC criteria for impaired cellular immunity

due to disease or treatment (making ineligible for zoster vaccine)

• History of lymphoma, bone marrow malignancy, hematopoietic

stem cell transplant, or leukemia, unless leukemia in remission

off chemo 3 months

• AIDS or HIV with CD4 count less than or equal to 200

• Immunosuppressive therapy including

• Prednisone 20mg daily within 1 month

• Chemotherapy for cancer within 3 months

• Immune modulators, especially anti-tumor necrosis agents,

within 1 month

• Medical history of disease making likely to become ineligible during

18 month study

• History of corneal transplant or refractive surgery in HZO eye

• Incarceration, unable to give informed consent, comply with

protocol, or complete 18 months of follow-up

52

Other Exclusion Criteria Due to Study Medication

• Renal insufficiency with estimated Glomerular Filtration Rate (eGFR)

< 45 (normal 60+)

• Allergy, adverse reaction to valacyclovir or acyclovir

• Study med and placebo do not contain lactose

• Vaccination against zoster within 1 month

• On systemic antivirals valacyclovir, acyclovir, or famciclovir within 1

month for any reason except treatment of acute HZO

• History of another condition that requires, or may require, treatment

with these 3 antivirals, such as genital, ocular or oral facial HSV

• Pregnant, nursing, or sexually active women in reproductive years

who do not agree to use contraception for one year of study med

53

Concomitant Medications and Treatments

• Topical steroid use during study strongly recommended to be

prednisolone acetate1% and loteprednol 0.5% with frequency at

discretion of study investigator

• Primary endpoint of dendriform epithelial keratitis will be

recommended to be treated with topical ganciclovir 5x daily until

healed, then 2x daily for 2 wks, and study medication will be

continued while on topical ganciclovir

• Use of open-label antiviral treatment for HZO allowed only after

primary endpoint has been reached

• No contraindications for use of other medications with valacyclovir

per FDA label

54

Definitions of Stromal Keratitis With or Without Ulceration,

Endothelial Keratitis, Iritis and Dendriform Epithelial Keratitis

•Stromal Keratitis without ulceration: Localized or diffuse stromal infiltrates

with or without keratic precipitates, corneal edema, or corneal

neovascularization, and is without an epithelial defect by fluorescein staining.

•Endothelial Keratitis: Disciform (localized) or diffuse corneal stromal, and

usually epithelial edema, with keratic precipitates out of proportion to anterior

chamber reaction (none or trace: 5 cells or less per field).

• Iritis: Anterior chamber reaction graded ≥1+ (6 or more cells/field using 1x1mm

slit beam) in the absence of suspected or proven microbial keratitis.

•Stromal Keratitis with ulceration: Stromal infiltrates with an overlying epithelial

defect by fluorescein staining due to active stromal keratitis and not neurotrophic

keratopathy or suspected or proven microbial superinfection. Microbial

superinfection should be ruled out by negative corneal smears and cultures

and/or lack of response to intensive antibiotic treatment every hour.

•Dendriform Epithelial Keratitis: Linear or elongated, often branching lesion(s)

on the corneal surface that stain at least minimally with fluorescein. They are

usually elevated, non-ulcerated, and without terminal bulbs.

55

56

57

* Full Strength and Weaker Steroids for Endpoint Definition:

•Full strength steroids:

• Prednisolone Acetate 1% (strongly recommended)

• Comparable for endpoint definition:

• Difluprednate 0.05%,

• Dexamethasone 0.1%,

• Prednisolone phosphate 1%

• Weaker Steroids:

• Loteprednol 0.5% (strongly recommended)

• Comparable for endpoint definition:

• Rimexolone 1%

• Prednisolone acetate 0.12%

• Fluoromethalone 0.1% or 0.25%

• Loteprednol 0.2%

58

59

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 DEK, SK, EK, IR 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

• PHN measured by worst pain in last 24 hours on scale of 1-10

• Severity of PHN by potency and dosage of medications used

60

Other Secondary Endpoints

• Development of specific disease manifestations of HZO

• Primary endpoints: DEK, SK, EK, I

• Neurotrophic keratopathy with and without melting, perforation,

presumed or proven microbial superinfection

• Episcleritis, Scleritis

• Effect of past history of specific manifestations on their

recurrence

• Glaucoma: by IOP and treatment required

• Outcomes when valacyclovir adjusted to 500 mg 2x daily or 1x daily

61

Participant Recruitment and Screening

• Recruitment materials provided by NYU Coordinating Center and

approved by Participating Clinical Center local or central IRB

• Retrospective review of records in past year with HZO diagnostic

codes (IRB approved)

• Potential study participants can be contacted at an office visit, by

letter, phone, email, electronic health record (EHR) patient portal,

advertising, referrals by doctors, all using IRB approved scripts

• Pre-screening for information pre consent in 2 IRB approved ways:

• First screening log for participating center use only containing

Protected Health Information (PHI) to identify and contact

potential participants

• Second screening log system submitted to NYU CC without

PHI

62

Study Procedures

• Source Documents and Case Report Forms (CRFs) at each visit

• Source documents

• Routine office record, including drawings/images

• Information on electronic CRFs not contained in routine office

record, so electronic submission can be checked for accuracy

• Case Report Forms for Electronic Data Capture (EDC)

• The primary data collection instrument for the study

• Schedule of forms for each visit, some required, some prn

• At office visits between study visits, CRFs will also need to be

completed, the number depending on whether or not a primary

endpoint may have occurred

63

Study Visits and Treatment

•Screening visit, after review of medical record determines appears

eligible and discussion with patient has determined interest

•Consent obtained, then eGFR and pregnancy tests ordered

•Enrollment/randomization visit within 30 days of tests

•Study medication consisting of 3 mos supply of masked valacyclovir

and placebo pills dispensed, to be taken 2 pills once daily

•Valacyclovir 500 mg used because 1000 mg too big for

encapsulation (and option for bid and daily dosing if side effects)

•Follow up visits every 3 months for 18 months

•12 month study visit: study medication discontinued


Please support the ZEDS study to try to improve

outcomes in HZO by participating, or referring your

patients to a study investigator

Thank you!

[email protected]

[email protected]

Herpes Zoster Vaccine

an ounce of

prevention can save a life!