Addressing Unmet Needs in Herpes Zoster:

Sharing Strategies to Improve Care

Faculty
v Laura Hurley, MD v Charles Vega, MD
Associate Professor Professor, Family Medicine
Department of Medicine Director, UC Irvine Program in Medical Education
University of Colorado for the Latino Community (PRIME-LC), Family
Denver, CO Medicine
v Donald B. Middleton, M.D. School of Medicine Associate Dean for Diversity
Professor of Family Medicine and Inclusion
UPMC St. Margaret School of Medicine
Irvine, CA
University of Pittsburgh School of Medicine
Pittsburgh, PA

2
Disclosures
vDr. Hurley has no relevant financial conflicts of interest with any ACCME-defined
commercial interest.
vDr. Middleton has served as a Consultant for Pfizer and Sanofi Pasteur. Dr. Middleton
has reported that his relationship will not affect his ability to present an unbiased
presentation.
vDr. Vega has no relevant conflicts of interest with any ACCME-defined commercial
interest.

3
Learning Objectives
1. Assess the clinical impact of herpes zoster and postherpetic neuralgia
2. Evaluate the efficacy, safety, and tolerability of available vaccines to prevent herpes
zoster
3. Develop effective strategies to promote adherence to national vaccine guidelines

The Enemy:
Herpes Zoster

4
 Pre-test Questions

5
Pre-test Question 1
Pre-H1: Please rate your confidence in your ability to overcome barriers to herpes
zoster vaccination for appropriate patients:

1. Not at all confident

2. Slightly confident
3. Moderately confident
4. Pretty much confident
5. Very confident
Pre-test Question 2
Pre-H2: How often do you recommend herpes zoster vaccination for adult patients
>50 years of age who do not have a contraindication?

1. Never
2. Rarely
3. Sometimes
4. Often
5. Always

7
Pre-test Question 3
Pre-H3: Approximately what proportion of unvaccinated adults develop acute herpes
zoster by age 85 years?

1. 25%
2. 50%
3. 75%
4. >75%

8
Pre-test Question 4
Pre-H: Which of the following statements about postherpetic neuralgia (PHN) is most
accurate?

1. Approximately 40% of patients with herpes zoster develop PHN

2. PHN is defined by pain lasting one month after the onset of herpes zoster
3. Acyclovir is highly effective in the prevention of PHN when administered promptly
for herpes zoster
4. About one-third of patients with PHN have disability at 6 months after herpes
zoster

9
Pre-test Question 5
Pre-H5: Which of the following has the greatest influence on an adult’s decision to
get immunized?

1. Celebrities
2. Family member
3. Personal clinician
4. ACIP recommendations

10
Pre-test Question 6
Pre-H6: 64 y/o overweight woman with 15-year history of T2D. Family history of
herpes zoster and postherpetic neuralgia (PHN) in mother and sister.

Which of the following would be consistent with current evidence and ACIP
recommendations?
1. Recommend zoster vaccine live (ZVL)
2. Recommend acyclovir if acute herpes occurs
3. Recommend recombinant zoster vaccine (RZV)
4. Recommend herpes zoster vaccination by age 75 years

11
Pre-test Question 7
Pre-H7: A 75-y/o man presents for regular checkup. History of well-controlled
asthma, treated with an inhaled corticosteroid/long-acting beta agonist. You
recommend herpes zoster vaccine, but he says he’s heard they don’t work well or are
not safe.

Which message might be appropriate for this patient?

1. Efficacy of ZVL is durable for 10+ years
2. Efficacy of RZV is >90% for herpes zoster and >85% for PHN
3. Total side effect rates of zoster vaccines are similar to placebo
4. Most common adverse event with vaccines is acute herpes zoster

12
Why Zoster Matters

99.5% of adults
Herpes zoster
over 40 years of
affects
age exposed to
approximately
wild-type VZV
1 in 3 US adults
virus

US Centers for Disease Control and Prevention.

13 https://www.cdc.gov/shingles/hcp/clinical-overview.html
Herpes Zoster (HZ) Prevalence - tough to get old!

Annual prevalence HZ per 1000 persons

Approximately 1
12 million cases HZ
10
10 annually in the
8 US
6
4
4
½ of
2
unvaccinated
0
adults get HZ by
Overall Age > 60 age 85 years

US Centers for Disease Control and Prevention.

14 https://www.cdc.gov/shingles/hcp/clinical-overview.html
Other Risk Factors
Relative risk HZ in meta-analysis of 62 studies
4
3.59
3.5

2.5

2
1.67
1.5 1.31 1.25 1.3 0.54
1

0.5

Women Family hx RA DM Asthma Black race

15 Kawai K, Yawn BP. Mayo Clin Proc 2017; 92: 1806-21.

Clinical Presentation
vVariable
vUsually a prodrome
vHeadache, malaise > fever
vCan occur weeks before rash!
vPainful rash – aching, burning Don’t forget risk
vAlso…pruritus! of infection with
vRash X 7 to 10 days; resolution active lesions!
within 4 wks
vSuperinfection can complicate course

16 Harpaz R, et al. MMWR 2008; 57: 1-30.

Postherpetic Neuralgia (PHN)
vPain in affected area for at least 3 months after onset of rash
vApproximately 10% of patients with acute HZ
vMultiple symptoms
vConstant, deep burning or aching pain
vLancinating pain
vAllodynia
vPruritus
vSeverity & QOL ….

17 Hadley GR. Curr Pain Headache 2016; 20: 17

v261 pts with acute HZ
vFigure shows 24% of
patients who had PHN

18 Drolet M, et al. CMAJ 2010; 182: 1731-6.

PHN = Bad. Can Acute Treatment Help?
Antiviral therapy most effective if initiated within 72 hours of the
onset of symptoms
vRetrospective review of 278 ambulatory cases in New Zealand 2004 – 2009
vOne-third of cases presented in 3 days
vMen (24%) and low-income patients (25%) worse

19 Wallis KA, et al. J Prim Health Care 2014; 108-13

PHN = Bad. Can Acute Treatment Help?

4 trials with total 692 participants in meta-analysis

% with herpetic neuralgia at 1 month
P=0.01
60.0% 53.3%
50.0% 44.1%
40.0%
30.0%
20.0%
10.0%
0.0%

Acyclovir Placebo
20 Chen N, et al. Cochrane Database Syst Review 2014; CD006866
PHN = Bad. Can Acute Treatment Help?

Main analysis: 6 RCTs with 1211 participants

P>0.05
Acyclovir vs. placebo (risk ratio)
1.2
1.05
1
0.8 0.75
0.6
0.4
0.2
0

PHN after 4 mos PHN after 6 mos

21 Chen N, et al. Cochrane Database Syst Review 2014; CD006866
Prevention of HZ – Zoster Vaccine Live
vLong-Term Persistence Substudy of The Shingles Prevention Study (SPS)
vMean age 74.5 years
v97.8% white
v56.3% male

22 Morrison VA, et al. Clin Infect Dis 2015; 60: 900-9.

 Prevention of HZ – Zoster Vaccine Live

ZVL Efficacy
80
67.5
70 61.1 Vaccine efficacy against HZ
% Persistence 60 51.3
of Vaccine 50
37.3
greater than zero
35.4
only
Efficacy 40
30 through year 8! 21.1
20
10
0

Burden of illness PHN HZ

5 yr 11 yr

23 Morrison VA, et al. Clin Infect Dis 2015; 60: 900-9.

 Prevention of HZ – ZVL with significant reduction in efficacy after
1 and 2 years

ZVL Efficacy
90
79.2 83.4
80
69.8
70 62
% Persistence 60 54.9
of Vaccine 48.9
50
Efficacy
40
30
20
10
0

Burden of illness PHN HZ

1 yr 2 yr

Schmader KE, et al. Clin Infect Dis 2012; 55: 1320-8.

Zoster Vaccine Live - Safety
vReview of 10 years of post-marketing data
v23,556 adverse event reports to manufacturer
v93% non-serious
vInjection site reaction most common
v< 1% were severe
vHerpes zoster second most common
vMost within 2 wks of vaccine
vMost caused by wild-type virus
vBUT vaccine-type HZ was confirmed months after vaccine
vDisseminated HZ – 18 cases (<1%), 38% in immunocompromised

25 Willis ED, et al. Vaccine 2017; 35: 7231-9.

Recombinant Zoster Vaccine (RZV)
vVZV glycoprotein E
vEssential for replication, cell-to-cell spread
vTarget for VZV-specific immune response
vAS01B adjuvant system
vPromotes CD4+ T-cell & humoral immunity
vApproved October, 2017 by FDA
vMore than 7 million doses worldwide by Q3 2018
vDosing: 0.5 ml IM in 2 doses separated by 2 to 6
months

26
RZV - Efficacy
v15,411 adults at least 50 years of age in 18 countries
vExclusions:
vH/o HZ
vS/p ZVL
vImmunocompromised
vRandomized to 2 doses of RZV or placebo
vMain outcome: incident HZ
vTypical symptoms – eval encouraged within 48 hrs
v+ PCR test from lesions
vSecondary outcome: safety

27 Lal H, et al. N Engl J Med 2015; 372: 2087-96.

RZV – Efficacy Against Acute HZ
v51.2% from Europe
v61.2% female Annual Incidence HZ per 1000
vAverage age: 62.3 years person-years
10 9.1
vMean follow-up time: 3.2 years
8

Vaccine efficacy: 2 0.9

97.2% 0
RZV Placebo

28 Lal H, et al. N Engl J Med 2015; 372: 2087-96.

RZV – Efficacy Against Acute HZ by Age
100.0% 96.6% 97.4% 97.9%
90.0%
80.0%
70.0%
60.0%
50.0%
40.0%
30.0%
20.0%
10.0%
0.0%

50-59 60-69 70-79

29 Lal H, et al. N Engl J Med 2015; 372: 2087-96.
RZV – Efficacy – ZOE-70
v13,900 adults at least 70 Annual Incidence HZ per
years of age randomized to 10 1000 person-years 9.2
RZV or PBO
8
vMean age: 75.6 years 6

vMean follow up: 3.7 years 4

2 0.9
0

RZV Placebo

30 Cunningham AL, et al. N Engl J Med 2016; 375: 1019-32.

RZV – ZOE-70 - Efficacy by Age
100.0%
89.8% 90.0% 89.1%
90.0%
80.0%
70.0% 16,596 adults at least 70 yo in
60.0% ZOE-50 and ZOE-70:
50.0% RZV efficacy against HZ: 91.3%
40.0% RZV efficacy against PHN:
30.0% 88.8%
20.0%
10.0%
0.0%

Overall 70-79 80-89

31 Cunningham AL, et al. N Engl J Med 2016; 375: 1019-32.
Network Meta-analysis Vaccine Efficacy – ZVL vs RZV – acute HZ

100% 92% 91%

90%
80%
70%
60% 51%
50%
40% 37%
30%
20%
10%
0%

Age > 60 Age > 70

ZVL RZV

32 McGirr A , et al. Vaccine 2019; 37: 2896-909.

Network Meta-analysis Vaccine Efficacy – ZVL vs RZV – PHN

100%
89% 89%
90%
80%
70% 66% 67%
60%
50%
40%
30%
20%
10%
0%

Age > 60 Age > 70

ZVL RZV

33 McGirr A , et al. Vaccine 2019; 37: 2896-909.

RZV - Safety
v14,645 RZV recipients vs. 14,660 PBO recipients in ZOE-50 and ZOE-70

Adverse Events (%)

60.0%
50.5%
50.0%
40.0%
32%
30.0%
20.0%
10.0%
0.0%

RZV PBO

34 Lopez-Fauqued M, et al. Vaccine 2019; 37: 2482-93.

RZV - Safety
v14,645 RZV recipients vs. 14,660 PBO recipients in ZOE-50 and ZOE-70

Pain (%)
80.0%
70.0%
68.1%
60.0%
50.0%
40.0%
30.0%
20.0%
10.0% 6.9%
0.0%

RZV PBO

35 Lopez-Fauqued M, et al. Vaccine 2019; 37: 2482-93.

RZV - Safety
v14,645 RZV recipients vs. 14,660 PBO recipients in ZOE-50 and ZOE-70

Grade 3 Pain (%)

4.0% 3.8%
3.5%
3.0%
2.5%
2.0%
1.5%
1.0%
0.5% 0.2%
0.0%

RZV PBO

36 Lopez-Fauqued M, et al. Vaccine 2019; 37: 2482-93.

RZV - Safety
vMost common systemic symptoms (%) after RZV:
Median duration
100.0%
of local /
90.0%
80.0% systemic
70.0% symptoms 2 – 3
60.0% days
50.0%
40.0% 32.9% 32.2%
30.0%
20.0%
10.0%
0.0%

Myalgia Fatigue

37 Lopez-Fauqued M, et al. Vaccine 2019; 37: 2482-93.

RZV - Safety
v14,645 RZV recipients vs. 14,660 PBO recipients in ZOE-50 and ZOE-70
Serious Adverse Events (%)
100.0% 0.1% considered
90.0%
80.0%
related to
70.0% vaccine by
60.0% investigators
50.0%
40.0%
30.0%
20.0% 10.1% 10.4%
10.0%
0.0%

RZV PBO
38 Lopez-Fauqued M, et al. Vaccine 2019; 37: 2482-93.
RZV – safety over 4+ years
v14,645 RZV recipients vs. 14,660 PBO recipients in ZOE-50 and ZOE-70

Fatal Adverse Events (%)

10.0%

8.0%

6.0%
4.3% 4.6%
4.0%

2.0%

0.0%

RZV PBO
39 Lopez-Fauqued M, et al. Vaccine 2019; 37: 2482-93.
RZV – Safety Over 4+ Years
v14,645 RZV recipients vs. 14,660 PBO recipients in ZOE-50 and ZOE-70

Potential Immune-Mediated Diseases (%)

5.0%

4.0%

3.0%

2.0% 1.4%
1.2%
1.0%

0.0%

RZV PBO

40 Lopez-Fauqued M, et al. Vaccine 2019; 37: 2482-93.

RZV - Safety
vSubgroup analysis:

41 Lopez-Fauqued M, et al. Vaccine 2019; 37: 2482-93.

RZV – Post-marketing Surveillance
vCDC Vaccine Adverse Event Reporting System (VAERS)
v8 months / 3.2 million doses of RZV
v4381 adverse events. 3.0% serious
vCommon events
vFever (23.6% of total)
vPain at injection site (22.5%)
vErythema at injection site (20.1%)
v4 cases of Guillain-Barré syndrome
v2 cases prior to vaccination
v1 case w/ symptoms at vaccination
v1 case after vaccination

Hesse EM, et al. MMWR 2019; 68: 91-4.

42 Foster SL, Pharm Today 2019; 25: 16
 Discussion
What do YOU think about the data regarding
the herpes zoster vaccines?

43
 ACIP Recommendation re: HZ vaccine
vRZV more effective than ZVL for HZ
vRZV more effective than ZVL for PHN
vConfidence intervals overlap
vRZV preferred over ZVL for adults > 50 yo
vRZV – 2 doses separated by 2 to 6 months
vRZV indicated after ZVL – separate by at least 2 months
vSpecial populations:
vCan be given after HZ
vNo contraindication in chronic conditions such as CKD, DM, COPD
vAvoid in immunocompromised, including pts on equivalent of 20 mg/day prednisone or more
vDo not administer during acute HZ

44 Dooling KL, et al. MMWR 2018; 67; 103-8.

HZ Vaccination Gaps 2007 - 2013
vMarketScan database with over 13M adults Women, more
healthcare contact
HZ vaccine coverage (%) based on age associated with
30.0%
higher vaccine
23.9% HR = 0.54
25.0% rates
20.0%
14.5%
15.0%

10.0%

5.0%
1.7%
0.0%

50-59 60-64 >65

45 Zhang D, et al. Am J Prev Med 2017; 52: e17-23.
HZ Vaccination Gaps – Are Providers Part of the Problem?
vNearly 600 internists and family doctors answering survey
COST TO
Vaccine strongly recommended PTS/PRACTICE >>
100% 95% 96%
CONCERN THAN
80% EFFICACY/SAFETY
60%
41%
40%

20%

0%

HZ PCV Flu

46 Hurley LP, et al. Ann Intern Med 2010; 152: 555-60.

Vaccines Only Effective if they are Available…
vRZV approved 2017
vShortage apparent in 2018
v3M doses available 1st half of year; 5.3 M doses available 2nd half

vShipments now 2X per month

vNew production center in France
vWhat about pent-up demand? Pts may be missing 2nd dose due to shortage?

47 Umansky D. Consumer Reports 3/5/19. Accessed 7/17/19.

48
www.vaccinefinder.org
 Discussion
How do we increase rates of HZ vaccination?

49
Most Important People to Influence Adult Vaccination

80
69%
70
60
50
40
30
19%
20
10 7%
0
Personal clinician Family member Public figure /
celebrity physician

50 Brown MT, et al. Fam Pract Manag 2014; 21: 22-26.

Messaging on Vaccination – Best Practices
vMake it personal: “I recommend,” not “CDC (or other) recommends”
vOK to discuss what you recommend for yourself and your family

vAn ounce of prevention is worth a pound of cure

vAdults think that they will recover easily from illness, but HZV (or polio!) suggest
differently

vBe non-judgmental and express empathy

vKeep language simple

51 Brown MT, et al. Fam Pract Manag 2014; 21: 22-26.

What Works: Community Preventive Services Task Force

Recommended Insufficient Evidence

Home visits Clinic-based education alone

Patient incentives Community-based education alone

Patient reminder and recall systems Monetary sanction policies

Provider assessment and feedback Provider education when used alone

Standing orders, reducing out of pocket (OOP) costs also effective…

52 The Community Guide. https://www.thecommunityguide.org/content/task-force-findings-increasing-vaccination. Accessed 7/18/19.

EHR = BFF? Reminder Program for HBV Vaccine in Adults w DM

vIntervention and control sites over 12 months

Ratio of Rate Ratio

80 70.7
70
60
50
40
30
18.7
20
10
0

HBV initiation HBV 3rd dose

53 Hechter RC, et al. Vaccine 2019; 37: 195-201.
 The Buck Stops Here…

v6.3M adults at age 65 or more w Medicare OR vs. OOP < $801.9

2
vOutcome: “HZV vaccine abandonment” 1.8
1.6
vVariable: out of pocket cost 1.4
1.21
1.2
vOverall abandonment: 7.3%
1
0.8
0.6
0.4
0.2
0

$80-$90 > $90

54 Hechter RC, et al. Vaccine 2019; 37: 195-201.

The Finances of HZV Vaccination
vEstimated cost
vMedicare / Medicaid
vPrivate insurance

55
Clinical Highlights
vAcute herpes zoster is common - ~ 1 million cases annually in US
vHZ and PHN cause significant distress, most commonly pain
vPrevention for most can be accomplished through vaccination
vRecombinant zoster vaccine (RZV) >90% effective for HZ and >85% for
PHN across subgroups
vACIP recommends RZV over zoster vaccine live (ZVL) for adults >50 y/o
• 2 doses, separated by ≥ 2 months
vMost common side effects of RZV are pain, myalgia, and fatigue
• Serious adverse events similar to placebo (~10%)
vMost important person to recommend vaccination is personal clinician

56
 Post-test Questions

57
Post-test Question 1
Post-H1: After participating in this program, please rate your confidence now in your
ability to overcome barriers to herpes zoster vaccination for appropriate patients:

1. Not at all confident

2. Slightly confident
3. Moderately confident
4. Pretty much confident
5. Very confident

58
Post-test Question 2
Post-H2: After participating in this program, how often do you plan to recommend
herpes zoster vaccination for adult patients >50 years of age who do not have a
contraindication?

1. Never
2. Rarely
3. Sometimes
4. Often
5. Always

59
Post-test Question 3
Post-H3: Approximately what proportion of unvaccinated adults develop acute
herpes zoster by age 85 years?

1. 25%
2. 50%
3. 75%
4. >75%

60
Post-test Question 4
Post-H4: Which of the following statements about postherpetic neuralgia is most
accurate?

1. Approximately 40% of patients with herpes zoster develop PHN

2. PHN is defined by pain lasting one month after the onset of herpes zoster
3. Acyclovir is highly effective in the prevention of PHN when administered promptly
for herpes zoster
4. About one-third of patients with PHN have disability at 6 months after herpes
zoster

61
Post-test Question 5
Post-H5: Which of the following has the greatest influence on an adult’s decision to
get immunized?

1. Celebrities
2. Family member
3. Personal clinician
4. ACIP recommendations

62
Post-test Question 6
Post-H6: 64 y/o overweight woman with 15-year history of T2D. Family history of
herpes zoster and postherpetic neuralgia (PHN) in mother and sister

Which of the following would be consistent with current evidence and ACIP
recommendations?
1. Recommend zoster vaccine live (ZVL)
2. Recommend acyclovir if acute herpes occurs
3. Recommend recombinant zoster vaccine (RZV)
4. Recommend herpes zoster vaccination by age 75 years

63
Post-test Question 7
Post-H7: A 75-y/o man presents for regular checkup. History of well-controlled
asthma, treated with ICS/LABA. You recommend herpes zoster vaccine, but he says
he’s heard they don’t work well or are not safe

Which message might be appropriate for this patient?

1. Efficacy of ZVL is durable for 10+ years
2. Efficacy of RZV is >90% for herpes zoster and >85% for PHN
3. Total side effect rates of zoster vaccines are similar to placebo
4. Most common adverse event with vaccines is acute herpes zoster

64
 Q&A

65