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 So. M 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, dermatomal rash • Pain pre rash in 74%: unilateral, first time ever, mod/severe • 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 • 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) • Recombinant Zoster Vaccine (RZV, Shingrix) • Zoster Eye Disease Study (ZEDS) NEI funded with CC at NYU is a randomized controlled clinical trial to evaluate prolonged suppressive antiviral treatment to reduce complications of HZO • Review of Herpetic Eye Disease study for HSV as background • Please refer your HZO patients to UBC Participating Clinical Center: Principal Investigator: Alfonso Iovieno Co-Investigator: Sonia Yeung Coordinator: Aleksandra Kuzmanovic

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 (~2 x), 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!

Incidence of Zoster • Increasing incidence of HZ 60 yrs • 1945 -60 v 1980 -2007 in MN • Incidence up >4 -fold in all ages • Inc pre/post varicella vaccination • Kawai Clin Infect Dis. 2016; 15: 63: 221 • Incidence HZ age 35+ 1993 -2014 • No acceleration of increase after varicella vaccine • Age 65+ plateau after 2007 • Continued increase age 35 -64 • Harpaz JID 2018: 218 (Suppl 2) S 57 • Incidence HZ 1991 -2016 • Increased 1991 -2012 all ages • Plateau 2013 -16, esp age 65+ • 1991 -95 inc 4 -6%/yr age 19 -64 vs 1996 -2016 inc 1 -5% • No inc in inc post varicella vax! • Wolfson Clin Infect Dis 2019 April 24 epub

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 However rise in zoster began before varicella vaccination, and rate of increase has not increased as predicted • Kawai Clin Infect Dis 2016; 63: 221 -6; Harpaz JID 2018: 218 (Suppl 2) S 57 -61. Wolfson Clin Infect Dis 2019 Apr 24; Harpaz Expert Rev Vaccines 2019 Jul 18 epub • Routine varicella vaccination not widespread in Europe (ex France, UK!) • Rates of HZ similar in these countries without varicella vaccination • Cause of increasing incidence of zoster is unknown!

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) • Misconception #2 • Herpes Zoster is only a disease of the elderly- it affects large number of people in their prime too!

Decreasing Age at Onset of HZO • Age of onset of HZO (Chen Cornea 2015; 34: 535) • 400 pts (58% women) HZO 1996 -2004 v. 2005 -2012 • Mean age • Less than age 60 yrs • Less than age 50 65 yrs 32% 16% • Age at presentation HZO • >900 acute HZO patient 2007 -2013 • Decrease in mean age 61 yrs 59 yrs 45% 30% P<0. 05 (Davies Br J Ophthalmol 2016; 100: 312) to 56 yrs P<0. 05 • Conclusions include: Recommend zoster vaccination adults age 50 years and older

Risk Factors for Development of Herpes Zoster • Well known: increasing age , immunocompromise, female sex • Recent additions to risk factors • Family history 3 x, depression 4 x, stress 3 x, history of zoster 80%, heart failure 2 x, traumatic brain injury 3 x, diabetes 45%, asthma 50%, acute kidney, autoimmune disease 70% • Marin Open Forum Infect Dis. 2016 Jun 13; 3; Kawai, Yawn Mayo Clin Proc 2017; 92: 1806 • Wu BMC Infect Dis 2015; 15: 17 • Tung PLo. SOne 2015 Jun 11; 10 • Suaya Open Forum Infectious Diseases 2014 Sep; Peng J Asthma 2016 Jul 13 [epub] • Yang Sci Rep 2015 Sep 3; 5: 13747; Kawai, Yawn Mayo Clin Proc 2017 Dec; 92: 1806 • Statin use • 13% inc risk: case control study in UK, high dose 27% inc risk • Matthews Br J Dermatol 2016; 175: 1183 -94 • 25% inc risk: population based prospective study in S Korea. • Age 70+ 39% inc risk (Kim MC PLo. S One. 2018 Jun 14) • Review 5 studies: in 2 inc risk HZ < 49 yrs old, vaccinate younger pts on statins? (Zuin Eur J Clin Microbiol Infect Dis 2019; 38: 93 -99) • Implications regarding importance of vaccination against zoster in patients with wide variety of medical conditions (EJC: Just do it!)

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 • Not to encourage smoking! • Personal comment: Study change in rates of smoking vs. HZ

Complications of HZ: Postherpetic Neuralgia (PHN) • Most common complication of zoster • Defined as pain/itch beyond 3 months after onset of zoster • Occurs in ~30% of HZO with eye involvement, mostly age 65+ • Borkar Ophthalmology 2103; 120: 451 -6 • 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 • 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 Nagel JID 2018: 218 (Suppl 2) S 107; Warren-Gash S 102 Zoster long known risk factor for • stroke • 55%-2 x inc stroke within 1 -3 mos, decreasing over 6 -12 mos • Yawn Mayo Clin Proc 2016; 91: 33 • 8 x risk stroke 1 mo age 18 -49 yrs • Patterson Mayo Clin Proc. 2019; 94: 763 • Should HZ pts have prophylactic antiviral treatment for 1 yr, esp if <50 years old? ? • Nagel Mayo Clin Proc 2019; 94: 742 -44 • 2 -4 x risk stroke after HZO vs HZ • Zoster reported as risk for heart disease, peripheral artery disease in people <50 • Breuer. Neurology 2014; 82: 1. Wu. J Med Virol 2014; 86: 772 -7. Lin Medicine 2016; 95: e 4480

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, giant cell pathology in 89% • GCA is VZV vasculopathy of TA • Antiviral treatment may benefit steroid treated GCA/TA patients • Should study in RCT • BUT: Only 3/25 GCA+ TAs + VZV antigen, 1 case GCA after HZO • Buckingham Am J Ophthalmol 2018; 187: 51 • Gilden >5000 slides vs. <1000/bx • Nagel JID 2018: 218(suppl 2)S 107 Courtesy of Don Gilden 15

Corneal Disease Classification of HZO • Recommend use same as HSV • White. 2014, Jul http: //one. aao. org/clinicalstatement/herpes-simplex-virus-keratitistreatment-guideline • Epithelial keratitis • Infectious dendriform • Stromal keratitis • Without ulceration • With ulceration (not microbial infection) • Endothelial keratitis • Uveitis • Neurotrophic keratopathy • With or without melting/perforation • With or without microbial superinfection Presentation Title Goes Here 16

Complications of HZO • Epidemiology HZO (N=67) • Recurrent disease (after quiet off meds 3 mos): • 8% at 1 yr 17% at 3 yrs 25% at 5 yrs 31% 6 yrs • Chronic (persistent active disease >90 days) in 23% • Tran Ophthalmology 2016; 123: 1469 -75 • Outcomes cataract surgery in HZO • Early improvement in VA, decreased by last fu due to retina (N=24) • He J Cataract Refract Surg. 2015; 41: 771 -7 • Recurrent keratitis/uveitis in 40%, esp if shorter time quiescent, inc # recurrences pre-op (N=57) (Lu LM J Cat Refract Surg 2019; 45: ) • Outcomes of PK for HZO (N=53, quiescent, 4 yr fu) • Complications: surface healing (23%), glaucoma (26%) • At 1, 2 -4, 5+ years 94%, 82%, 70% clear; improved VA at 1 yr only • Tanaka TS Br J Ophthalmol epub 14 Jan 2019; 45: 810 -815 • Increased risk wet AMD post HZO in retrospective cohort study • >1000 HZO, >5000 controls with 3 yr fu • HR >4. 5 x for HZO to develop wet AMD, due to vasculopathy? • Ho Acta Ophthalmol. 2019 Mar; 97(2): e 321 -e 322.

Vaccination to Prevent Zoster • Randomized clinical trial of Zoster Vaccine Live (ZVL) pts age 60+ • 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+ • Oxman NEJM 2005; 352: 2271 In 2006 ZVL, Zostavax (Merck) approved by FDA, recommended 2008 by CDC for adults age 60+ without immunocompromise 1 n 2011 FDA approved vaccine for age 50+ after shown to decrease incidence of HZ 70% in persons age 50 -59 MMWR June 6, 2008 / 57(05); 1 -30 Schmader Clinical Infectious Diseases 2012; 54(7): 922 -928. Since Sept, 2016, Ontario publicly funded only for age 65 -70

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 CD 4+ < or = 200 • Hx of stem cell transplant • Unspecified cellular immundeficiency • Immunosuppressive treatment • Prednisone 20 mg daily for 2+wks, wait 1 month after stop • Chemotherapy (more than low dose for inflammatory diseases), wait 3 mos • 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”)

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 • Vaccinate with caution in HZO • Khalifa, Jacoby, Margolis Arch Ophthalmol 2010; 128: 1079 • Sham Arch Opthalmol 2012; 130: 793 • Hwang Cornea 2013; 32: 508 -9 • Jastrzebski A Cornea 2017; 36: 740 • 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 6 -8 yrs • Yawn Mayo Clin Proc. 2011; 86: 88, Shiraki 2017; PMID: 28480280 • Acute retinal necrosis after HZ vaccine in 1 renal transplant and 1 CLL pt (contraindicated) and 1 end-stage renal disease pt • Charkoudian Arch Ophthalmol 2011; 129: 1495 • Menghini Retin Cases Brief rep 2018 july 25 • Betjes Immune cell dysfunction …in end-stage renal disease. Nat Rev Nephrol 2013; 9: 255 Zoster Vaccine Live contraindicated if impaired cellular immunity!! Presentation Title Goes Here 20

New Recombinant Zoster Vaccine (RZV) 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 vaccine (Glaxo. Smith. Kline) • Recombinant VZV glycoprotein E antigen, novel AS 01 B adjuvant • ZOE-50 RCT in immunocompetent adults age 50 years and older • 2 IM injections 2 months apart of vaccine or saline placebo • Results: ~97% efficacy for all age groups • Grade 3 severe acute symptoms interfering with activities in 17% • Vaccine efficacy pooled in 2 ZOE-70 , ZOE-50 trials • Results: efficacy : ~90% in vaccine recipients age 70 s and 80 s • Efficacy against HZ over time persisted: 85% yr 4 • Editorial: Local or systemic reactions raises concern about 2 nd dose • Neuzil N Engl J Med 2016; 1079 -80 • Post hoc evaluation efficacy by type of medical condition • 84% respiratory, 89% asthma, 91% DM, 97% CA • (Oostvogels Hum Vaccin Immunother. 2019 [epub] • FDA approved Recombinant Zoster Vaccine (RZV) Oct, 2017 age 50+ • CDC recommended Jan 26, 2018 MMWR for immunocompetent 50+ Presentation Title Goes Here 21

FDA Label for Shingrix • Recombinant Zoster Vaccine (RZV) 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 if given with a flu vaccine • VZV glycoprotein E antigen vial reconstituted with AS 01 B adjuvant • Before and after reconstituted: refrigerate, discard if frozen (vs ZVL) • Contraindications: anaphylaxis to component of vaccine or after a dose • Adverse reactions/events: • Local: pain 78%: General: myalgia 45%, fatigue 44% • Local and general reactions less age 70+ than age 50 -69 • Age 50 -59: pain 88%, myalgia 57%, fatigue 57%: grade 3: 8 -10%

Advisory Committee on Immunization Practices (ACIP), CDC Recombinant Zoster Vaccine (RZV, Shingrix) • Recombinant zoster vaccine (RZV, Shingrix) recommended for • Immunocompetent adults age 50 years and older • Adults previously received ZVL (Zostavax) • Persons with previous history of zoster • Shingrix is preferred over Zostavax • CDC published ACIP recommendations in MMWR Jan 2018 • Dooling, Guo, Pater, Lee, Moore, Belongia, Harpaz. MMWR Jan 26, 2018; 67: 103 -108 • CDC postlicensure safety surveillance via Vaccine Adverse Event Reporting System (VAERS, info@vaers. org) • >3 million doses in first 8 months, findings consistent with clinical trials • Systemic AEs more common age 50 -69 and local AEs age 70+ • Hesse EM MMWR Feb 1, 2019/68: 91 -94

Reactivation of HZO after RZV • 89 yo with HZO stable 1 yr on low dose topical steroids • 3 wks after first dose RZV developed recurrent stromal keratitis • Responsive to topical steroids • Lehmann, Matoba Ophthalmology 2018; 125: 1682 • My opinion re timing RZV in HZO • When stable • Monitor pre and post 2 shots • Not urgent: HZ stimulates VZV cellular immunity 1 yr+ • Should report complications to Vaccine Adverse Event Reporting System (VAERS, info@vaers. org)

We Can Do Better to Protect Our Patients Against Zoster! • Barriers to vaccination against zoster: high cost, insurance coverage, availability, and lack of strong recommendation by primary care MDs • 2016 survey shows primary care doctors more likely than in 2005, 2008 to think zoster is a serious disease and vaccination important, but more so for age 60 -79 (68%) than age 50 -59 (29%) • Guo Vaccine. 2019. 08. 002 • AAO Policy Statement updated 2018: ophthalmologists should recommend strongly persons age 50 years and older without contraindications get Shingrix • Ophthalmology 2018; 125: 1813 • Increase vaccination rate of doctors as evidence of importance • Bonanni Vaccine 2018; 36: 5358 -65 • An ounce of prevention can save a life! Presentation Title Goes Here 25

Recommended Treatment of Herpes Zoster • 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 -10 days • Reduces chronic eye disease from 50% to 30% • Does not reduce PHN!

Case • A healthy person in her 50’s, developed unilateral radicular thoracic pain and a rash 1 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! • Non PHN complications as common in younger patients

Possible New Treatment for 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 28

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 29

Herpes Simplex Virus Keratitis • Infectious dendritic epithelial keratitis • Stromal keratitis without ulceration • Endothelial keratitis • Iritis • Stromal keratitis with ulceration

Herpetic Eye Disease Study (HEDS) • Treatment studies • First: topical steroids with topical antivirals effective in stromal keratitis • Second: oral ACV 400 5 x 10 wks ineffective in treatment of steroid treated stromal keratitis

HEDS Treatment Studies (cont) • Third: oral acyclovir possible benefit in treatment of steroid treated iridocyclitis (dose 400 mg 5 x for 10 wks) • Low number of iritis study participants recruited • Trial not completed • Results did not reach statistical significance

HEDS Prevention Studies • First: oral acyclovir not effective in preventing stromal keratitis/iritis after viroptic treated dendrite • Stromal keratitis/iritis less common than expected, only~10% vs 20% expected • Past history of stromal keratitis was a risk factor for recurrent stromal keratitis/iritis

HEDS Acyclovir Prevention Trial • Patients with history of ocular HSV within 1 yr who were inactive 30 d off medications were randomized to acyclovir 400 mg bid for 1 yr and followed ever 3 months for 18 months • Acyclovir was effective in reducing recurrences • 32% vs. 19%, reduction of 45% • Without rebound after ACV stopped • Without persistient treatment effect either

HEDS Acyclovir Prevention Trial Results N Engl J Med 1998; 399: 300 -306

Oral Acyclovir (ACV) for HSV Keratitis • Herpetic Eye Disease Study (HEDS) summary of RCTs • ACV 400 mg 5 x per day not effective in treatment stromal keratitis • Does not facilitate tapering of topical steroids • Barron, B. A. , et al. Ophthalmology. 1994; 101(12): 1871 -82. • Possible benefit treatment with ACV 400 mg 5 x iridocyclitis (uveitis) • Arch Ophthalmol. 1996; 114: 1065072 • Not effective in decreasing stromal keratitis, iritis after dendrite • Arch Ophthalmol. 1997; 115: 703 -12. • Acylovir Prevention Trial (APT) • ACV 400 mg bid effective in prevention of recurrent HSV keratitis, oral/facial HSV, especially beneficial when hx of stromal keratitis • N Engl J Med 1998; 339: 300 -6 • This study changed the standard of care to include prolonged suppressive oral antiviral treatment in patients with recurrent HSV eye disease, and this treatment has improved outcomes

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 • Suppressive antiviral treatment is now standard of care for HSV keratitis, and has improved outcomes • 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 37

Thank you for referring all your HZO patients to an investigator or coordinator for the Zoster Eye Disease Study (ZEDS) whether or not you think they are currently eligible!

Professional Careers • Be optimistic • Be all in at each stage • Family and career can go together • Be open to shifts and changes • Be receptive to criticism, not defensive: it can help you! • Be persistent • Find your passion, what you do best • Give back and enjoy mentoring • Be optimistic