Middleman DARFT HPV.NASPAG.4.12.15 · 4/13/2015 5 Prevalence$of$HPV$6,$11,16,$18*in$CervicovaginalSwabs, by$Age$Group,$NHANES,$2003Z2006$and$2007Z2010,$U.S.$ 0 5 10 15 20 25 30 …

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1

HPV Types Differ in their Disease Associa5ons

Mucosal sites of infection

Cutaneous sites of infection

~ 80 Types

“Common” Hand and Foot

Warts

~40 Types

Genital Warts Laryngeal Papillomas

Low Grade Cervical Disease

Low risk (non-oncogenic) HPV 6, 11

High risk (oncogenic) HPV 16, 18

Cervical Cancer Anogenital Cancers

Oropharyngeal Cancer Cancer Precursors

Low Grade Cervical Disease

Numbers of Cancers and Genital Warts A@ributed to HPV Infec5ons, U.S.

CDC. Human papillomavirus (HPV)-‐associated cancers. Atlanta, GA: US Department of Health and Human Services, CDC; 2013. Available at hKp://www.cdc.gov/cancer/hpv/staNsNcs/cases.htm

Cancers A@ributed to HPV, U.S.

CDC, United States Cancer StaNsNcs (USCS), 2006-‐2010

Cancer site

Average number of cancers per year in sites where HPV

is oIen found Percentage of

cancers per year probably caused

by HPV

Average number of cancers per year probably caused

by HPV†

Male Female Both Sexes Male Female

Both Sexes

Anus 1,549 2,821 4,370 91% 1,400 2,600 4,000

Cervix 0 11,422 11,422 91% 0 10,400 10,400

Oropharynx 9,974 2,443 12,417 72% 7,200 1,800 9,000

Penis 1,048 0 1,048 63% 700 0 700

Vagina 0 735 735 75% 0 600 600

Vulva 0 3,168 3,168 69% 0 2,200 2,200

TOTAL 12,571 20,589 33,160 9,300 17,600 26,900

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Average Number of New Cancers Probably Caused by HPV, by Sex, United States 2006-‐2010

CDC, United States Cancer StaNsNcs (USCS), 2006-‐2010

Women (n = 17,600)

Oropharynx n=1,800 10%

Anus n=2,600 15%

Cervix n=10,400 59%

Vagina n=600 3%

Vulva n=2,200 13%

Men (n = 9,300)

Anus n=1,400 15%

Oropharynx n=7,200 77%

Penis n=700 8%

HPV-‐Associated Anal Cancer Rates by Race and Ethnicity, United States, 2004–2008

Watson et al. Human papillomavirus-‐associated cancers—United States, 2004-‐2008. MMWR 2012;61:258-‐261.

HPV-‐Associated Oropharyngeal Cancer Rates by Race and Ethnicity, United States, 2004–2008


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HPV-‐Associated Cervical Cancer Incidence Rates by State, United States, 2004-‐2008


HPV-‐Associated Cervical Cancer Rates by Race and Ethnicity, United States, 2004–2008


Without vaccina5on, annual burden of genital HPV-‐related disease in U.S. females:

American Cancer Society. 2008; Schiffman Arch Pathol Lab Med. 2003; Koshiol Sex Transm Dis. 2004; Insinga, Pharmacoeconomics, 2005

4,000 cervical cancer deaths 10,846 new cases of cervical cancer

330,000 new cases of HSIL: CIN2/3 (high grade cervical dysplasia)

1.4 million new cases of LSIL: CIN1 (low grade cervical dysplasia)

1 million new cases of genital warts

3 million cases and $7 billion

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HPV Prophylac5c Vaccines

HPV Virus-‐Like Par5cle

´ Recombinant L1 capsid proteins that form “virus-‐like” par5cles (VLP)

´ Non-‐infec5ous and non-‐oncogenic

´ Produce higher levels of neutralizing an5body than natural infec5on

Evolu5on of recommenda5ons for HPV vaccina5on in the United States

2006 2007 2008 2009 2010 2011 2012

11

Quadrivalent Rou5ne, females 11 or 12 yrs* and 13-‐26 yrs not previously vaccinated

Quadrivalent or Bivalent Rou5ne, females 11 or 12 yrs* and 13-‐26 yrs not previously vaccinated

Quadrivalent May be given, males 9-‐26 yrs*

Quadrivalent (HPV 6,11,16,18) vaccine; Bivalent (HPV 16,18) vaccine

Can be given starNng at 9 years of age; ** For MSM and immunocompromised males, quadrivalent HPV vaccine through 26 years of age

June

Quadrivalent Rou5ne, males 11 or 12 yrs* and 13-‐21 yrs not previously vaccinated May be given, 22-‐26 yrs**

October

HPV Vaccina5on Rates Lag Behind

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Prevalence of HPV 6, 11,16, 18* in Cervicovaginal Swabs, by Age Group, NHANES, 2003-‐2006 and 2007-‐2010, U.S.

0

5

10

15

20

25

30

14-‐19 20-‐24 25-‐29 30-‐39 40-‐49 50-‐59

Prevalen

ce (%

)

2003-‐2006 2007-‐2010

Age group (years)

*weighted prevalence

Markowitz, et al. ReducNon in HPV prevalence among young women following HPV vaccine introducNon in the United States, NHANES, 2003-‐2010. J Infect Dis 2103

56% decline

13

Rela5ve Contribu5on of HPV Types in 9vHPV Vaccine to Cervical Disease Worldwide

Type of Lesion 6/11/16/18 Contribu5on

31/33/45/52/58 Contribu5on

Overall 9V Contribu5on

Cervical cancer*

70% 20% 90%

CIN2/3** 50% 30% 80%

CIN1** 25% 25% 50%

* Among HPV-‐posiNve cervical cancers; based on de Sanjose et al, 2010, Serrano et al, 2012

** Based on several meta-‐analyses and results of analyses conducted among all lesions (HPV + and -‐) in placebo cohorts of several Gardasil trials.

9vHPV clinical trials

15

Study Design N Sex Age Objec5ves 9vHPV pivotal efficacy study

001 RCT 14215 F 16–26 years Efficacy, immunogenicity, safety

9vHPV immunobridging studies in adolescents

002 Obs 2999 F F, M

16–26 years 9–15 years

9vHPV adult-‐to-‐adolescent immunobridging, safety

009 RCT 600 F 9–15 years 4vHPV-‐to-‐9vHPV immunobridging, safety

9vHPV immunobridging studies in adult males

003 Obs 2520 F, M 16–26 years 9vHPV female-‐to-‐male immunobridging, safety

9vHPV concomitant use studies

005 Obs 1241 F, M 11–15 years Concomitant use: Menactra, Adacel

007 Obs 1054 F, M 11–15 years Concomitant use: Repevax

9vHPV in prior 4vHPV recipients

006 RCT 924 F 12–26 years 9vHPV in prior 4vHPV recipients RCT = randomized controlled trial; Obs = observaNonal study 9vHPV FDA Label: hKp://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM426457.pdf 9vHPV Clinical Trial: hKps://clinicaltrials.gov/ct2/show/NCT01651949?term=v503&rank=3

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Protocol 001: Immunogenicity in females aged 16–26 years 9vHPV compared with 4vHPV

9vHPV 4vHPV

Outcome n (%) GMT n (%) GMT

AnN-‐HPV 6 3993 (99.8) 893 3975 (99.8) 875

AnN-‐HPV 11 3995 (100) 666 3982 (99.9) 830

AnN-‐HPV 16 4032 (100) 3131 4062 (100) 3157

AnN-‐HPV 18 4539 (99.8) 805 4541 (99.7) 679

§  >99% seroconversion to HPV 6, 11, 16, 18 in both groups §  Non-‐inferiority criterion met for HPV 6, 11, 16, 18 (P<0.001)

Data from per protocol populaNon; AnNbody measured by cLIA at month 7

Protocol 001: Pivotal efficacy trial in females aged 16–26 years in per protocol popula5ona

HPV vaccine type Outcome

Incidence in 9vHPVb (n/N)

Incidence in 4vHPVb (n/N)

Vaccine efficacy % (95% CI)

31/33/45/ 52/58

≥CIN2 1/5948 27/5943 96.3 (79.5–99.8)

≥CIN2, VIN2/3, VaIN2/3 1/6016 30/6017 96.7 (80.9–99.8)

6-‐month persistent infecNon 26/5939 642/5953 96.2 (94.4–97.5)

6/11/16/18 ≥CIN2c 1/5715 0/5732 -‐-‐

Anogenital wartsd 4/4744 0/4805 -‐-‐

17

≥CIN = cervical intraepithelial neoplasia 2/3 or adenocarcinoma in situ; VIN = vulvar intraepithelial neoplasia; VaIN = vaginal intraepithelial neoplasia

aReceived all 3 vaccine doses within 1 year of enrollment, were PCR negaNve and seronegaNve to HPV 31, 33, 45, 52, 58 prior to dose 1, and remained PCR negaNve to the relevant HPV type(s) through one month post-‐dose 3. bIncidence over median 40 months of follow-‐up cHPV 16/18-‐related dHPV 6/11-‐related

9vHPV FDA Label: hKp://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM426457.pdf

9vHPV summary findings §  Efficacy

•  ~97% protec5on against HPV 31, 33, 45, 52, 58-‐related outcomes •  Similar protec5on against HPV 6, 11, 16, 18-‐related disease

§  Non-‐inferior immunogenicity •  For HPV 6, 11, 16, 18 compared with 4vHPV in 16–26 and 9–15 year

olds •  For all 9 HPV vaccine types in adolescent females and males compared

to adult females and in adult males compared to adult females

§  Concomitant use •  No impact on immunogenicity and safety when 9vHPV administered

concomitantly with meningococcal vaccine (Menactra), Tdap vaccine (Adacel), and Tdap-‐IPV vaccine (Repevax)

18

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9vHPV safety summary §  Generally well tolerated in >15,000 recipients

•  Adverse event profile similar to 4vHPV across age, gender, race, ethnicity

•  More injec5on site-‐related swelling and erythema in females who received 9vHPV (most mild/moderate in intensity)

•  Lower frequency of adverse events in males compared to females (similar to 4vHPV)

20

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8

9vHPV aIer 4vHPV §  Interval between vaccina5on series 12-‐36 months

§  An5-‐HPV 31,33,45,52,58 GMTs 25-‐63% of GMTs of those immunized with 9vHPV without prior 4vHPV

§  Clinical relevance unknown §  Efficacy preven5ng infec5on and disease not yet assessed

hKp://www.merck.com/product/usa/pi_circulars/g/gardasil_9/gardasil_9_pi.pdf

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Immunogenicity studies comparing 2 and 3 doses of HPV vaccine

Study Country Vaccine Design Age and doses

Schedules

Longest follow-‐up

Romanowski Hum Vaccin 2011 Hum Vaccin 2014

Canada/ Germany

HPV2 9-‐14 2 doses 9-‐14 3 doses 15-‐25 3 doses

0, 6 0, 1, 6 0, 1, 6

24 mos 48 mos

Puthanakit EUROGIN 2013 ESPID 2014

MulN-‐naNonal

HPV2 9-‐14 2 doses 9-‐14 2 doses 15-‐25 3 doses

0, 6 0, 12 0, 1, 6

~12 mos

Lazcano-‐Ponce Vaccine 2014

Mexico HPV2 9-‐10 2 doses 9-‐10 3 doses 18-‐24 3 doses

0, 6 0, 1, 6 0, 1, 6

21 mos

Dobson JAMA 2013

Canada HPV4 9-‐13 2 doses 9-‐13 3 doses 16-‐26 3 doses

0, 6 0, 2, 6 0, 2, 6

36 mos

Sankaranarayanan EUROGIN 2013

India HPV4 10-‐18 2 doses 10-‐18 3 doses

0, 6 0, 2, 6

18 mos

ACIP mtg, Atlanta, GA, 10/30/2014

Awaiting rigorous efficacy studies prior to change in the U.S.

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Summary: Data on 2-‐dose schedules §  Immunogenicity

§  GMTs non-‐inferior for two doses (0, 6 mos) in females ~9-‐14 yrs compared with 3 doses (0, 2, 6 mos) in females ~16-‐26 yrs

§  Efficacy §  Post-‐hoc analysis of 3-‐dose RTC (HPV2) found high efficacy for 2 doses

§  Effec5veness §  Post-‐licensure studies found lower effec5veness for 2 vs 3 doses (HPV prevalence, cervical precancers, genital warts)

§  Many limita5ons of post-‐licensure effec5veness evalua5ons (not 6 mo apart, differences between 2-‐ and 3-‐dose recipients)

From ACIP mtg, Atlanta, GA. 10/30/14

Regulatory Approval and Recommenda5ons for HPV Vaccine 2-‐dose Schedules

§ HPV2 and HPV4 have regulatory approval for use in 2-‐dose schedule in young adolescents from EMA and a variety of countries

§ WHO changed vaccina5on recommenda5ons in 2014: §  2-‐dose schedule 9-‐14 yr §  3-‐dose schedule if ini5ated >15 yr

§  Several countries recommended 2-‐dose schedules before WHO; more are changing

From ACIP mtg, Atlanta, GA. 10/30/14 EMA = European Medicines Agency

NIS-Teen Coverage Results

Vaccine 2008~ 2009# 2010* 2011` 2012

2013+

Tdap ater 10 years of age

40.8% 55.6% 68.7% 78.2% 84.6% 86.0%

≥3 doses HepB 87.9% 89.9% 91.6% 92.3% 92.8% 93.2% ≥2 doses MMR 89.3% 89.1% 90.5% 91.1% 91.4% 91.8% ≥2 dose of Varicella (no disease history)

34.1% 48.6% 58.1% 68.3%

74.9% 78.5%

MCV4 41.8% 53.6% 62.7% 70.5% 74.0% 77.8% HPV >1 dose Among Males

37.2% (17.9%)

44.3% (26.7%)

48.7% (32.0%) 1.4%

53.0% (34.8%) 8.3%

53.8% (33.4%) 20.8%

57.3% (37.6%) 34.6%

~based on 17,835 adolescents #based on 20,399 adolescents

*based on 19,257 adolescents `based on 23,564 adolescents ` based on 19,199 adolescents

+based on 18,264 adolescents

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HPV Vaccina5on Coverage (≥1 dose) among Girls 13-‐17 Years, by State, 2012 NIS-‐Teen, U.S.

0

10

20

30

40

50

60

70

80

Florida

Mississippi

Arkansas

Illinois

South Carolina

Kansas

Maryland

Utah

West V

irginia

Alabam

a Michigan

Indiana

Wisc

onsin

Virginia

South Da

kota

New

Mexico

Kentucky

Texas

Idaho

Missou

ri New

Ham

pshire

Georgia

North Carolina

Wyoming

Arizo

na

Tenn

essee

New

Jersey

Mon

tana

Oklahom

a New

York

Alaska

Ohio

Penn

sylvania

Iowa

Conn

ecNcut

Dist. of C

olum

bia

Oregon

Minne

sota

North Dakota

Colorado

Maine

Louisia

na

Nevada

Washington

Hawaii

California

Verm

ont

Delaware

Neb

raska

MassachuseK

s Rh

ode Island

Percen

t

State

ReducNon in prevalence of vaccine-‐type HPV by 56% in girls age 14-‐19 with vaccinaNon rate of just ~30%

HPV Vaccine is an An5-‐Cancer Vaccine

Markowitz et al. JID 2013;208:385-‐393. CDC unpublished model – H. Chesson et al -‐ for girls in US <13 at present, diff. betw 30% vs. 80% 3-‐dose coverage, lifeNme cerv. ca. risk

For every year we delay increasing vaccinaNon rates to this level, another 4,400 women will develop cervical cancer

Our low vaccinaNon rates will lead to 50,000 girls developing cervical cancer – that would be prevented if we reach 80% vaccinaNon rates

26 million: number of girls under 13 years of age in the United States

168,400: number who will develop cervical cancer if none are vaccinated

54,100: number will die from cervical cancer if none are vaccinated

For each year we stay at 30% coverage instead of achieving 80%

4,400: number of future cervical cancer cases we will not prevent

1,400: number of cervical cancer deaths we will not prevent

Adapted from Chesson HW et al, Vaccine 2011;29:8443-‐50

4/13/2015

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Trends in Total and Serious Female HPV4 Vaccine Reports to VAERS by Year, June 2006 – March 2013 (N=21,194)

MMWR 2013;62:591-‐595 34

Strength of HPV Vaccine Recommenda5on

for Female Pa5ents, Pediatricians and Family Physicians (N=609)

Allison et al. hKps://cdc.confex.com/cdc/nic2011/webprogram/Paper25181.html

Top 5 reasons for not vaccina5ng daughter, among parents with no inten5on to vaccinate

in the next 12 months, NIS-‐Teen 2012

* Not mutually exclusive. ** Did not know much about HPV or HPV vaccine.

NaNonal and State VaccinaNon Coverage Among Adolescents Aged 13–17 Years — United States, 2012 MMWR 2013; 62(34);685-‐693.

4/13/2015

13

Actual and Achievable Vaccina5on Coverage if Missed Opportuni5es Were Eliminated: Adolescents 13-‐17 Years, NIS-‐Teen 2012

54

93

0

20

40

60

80

100

HPV-1 (girls)

Perc

ent

Vacc

inat

ed

Vaccine

ActualAchievable

Missed opportunity: Healthcare encounter when some, but not all ACIP-‐recommended vaccines are given. HPV-‐1: Receipt of at least one dose of HPV.

Stokley S, CurNs R, Jeyarajah J. Human Papillomavirus VaccinaNon Coverage Among Adolescent Girls, 2007-‐2012, and Postlicensure Vaccine Safety Monitoring, 2006-‐2013 -‐ United States. MMWR. 62(29);591-‐595.

Among girls unvaccinated for HPV, 84% had a

missed opportunity

School Requirements Significantly Affect Coverage Rates – Recent Data

Adolescents 13-17 Years of Age

Vaccine Vaccina5on requirement

Educa5on Requirement

No Requirements

# of States (%) # of states (%) # of states (%)

>1 MCV4 3 (70.5) 10 (51.0) 38 (53.4) >1 Td/Tdap 32 (79.8) -‐-‐ -‐-‐ 19 (69.5) >1 HPV -‐-‐ -‐-‐ 6** (45.0) 45 (44.2)

Red font indicates significantly lower (p<0.05) coverage compared to states with vaccine requirements. *Status based on requirements for the 2008-2009 School Year **Because of small sample size, one state with a vaccine requirement is included with the states with education only requirements.

Bugenske et al. Pediatrics. 2012;129:1056-1063.

Potential Success with HPV Vaccine Mandate

´ Dynamic model developed of HPV vaccine uptake among adolescent, US females

´ Time to achieve 70% coverage =

Dempsey AF, Mendez D. JAH 2010;47:242-‐248.

With mandate 8 years

Without mandate 23 years

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14

Providers underes5mate the value parents place on HPV vaccine

9.4 9.5 9.5 9.3 9.3 9.2 9.2 9.2 9.3

7.0

5.2

7.8

0 1 2 3 4 5 6 7 8 9

10

Meningi5s Hepa55s Pertussis Influenza HPV Adolescent vaccines

Med

ian Va

lues

Parent Provider's es5mate

Adapted from Healy et al. Vaccine. 2014;32:579-‐584.

Impact of Reminder/Recall on Vaccina5on Rates among Adolescents

49.5*44.3*

26.5*

40.8

29.5

15.3

0

10

20

30

40

50

60

Tdap MCV4 HPV-1

InterventionControl

*p<0.05

Suh C et al. Pediatrics 2012;129:e1437-‐45

Vaccine

Perc

ent

Percentages of adolescents 11-‐18 years of age who received any vaccina5on at 4, 12, and 24 weeks: Text4Health-‐Adolescents, New York City, 2009

42 Stockwell et al. AJPH. 2012;102:e15-‐e21.

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Tdap MenACWY Varicella MMR Influenza HPV HBV

Houston, TX

41% 35% 39% 36% 57% 27% 37%

Aurora, CO

72% 71% 67% 53%

Differences by Vaccine ProporNon of parents willing to have child

vaccinated during school hours

Middleman AB, Tung JS. JAH 2010; 47:249-‐53. (Houston) Kelminson K et al. JAH 2012;51:190-‐6. (Aurora)

VANS – Vaccines Administered

Fall 2012 Spring 2013 N = unique parNcipants 522 189 Influenza vaccine (LAIV + IIV) 475 1 HPV vaccine (any dose in the series)

410 161

Tdap 328 100 MCV4 327 108 Other 82 156 TOTAL VACCINES 1622 526

Unpublished data, Middleman et al.

VANS -‐ % Par5cipants Receiving HPV

Fall 2012 79% Spring 2013 85% Total 80%

Unpublished data, Middleman et al.

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Source: Brewer NT, Chung JK, Baker HM, Rothholz MC, Smith JS. Pharmacist authority to provide HPV vaccine: novel partners in cervical cancer prevenNon. Gynecol Oncol. [Epub 2013 Dec 19].

Ra5onale for vaccina5ng early: Protec5on prior to exposure to HPV

Documents

Middleman DARFT HPV.NASPAG.4.12.15 · 4/13/2015 5 Prevalence$of$HPV$6,$11,16,$18*in$CervicovaginalSwabs, by$Age$Group,$NHANES,$2003Z2006$and$2007Z2010,$U.S.$ 0 5 10 15 20 25 30 …