Human papillomavirus (HPV) infections Dorothy Wiley, MPH, PhD Associate Professor Translational Science Division University of California, Los Angeles School of Nursing Los Angeles, California

… were to build an HPV lesion... • You would need a few essential ingredients….

2

Basement membrane

Differentiating epithelium

3

4

I

Grade III: Must have mitosis in upper 2/3 of epithelium

III II

Estimated Annual Burden of HPVRelated Diagnoses in the United States >11,000-12,700 new cases of cervical cancer, 2007-20111 >4,000 new cases of vulvar cancer1.c >2,500 new cases of vaginal cancer 1.c >5,500 new anal cancer cases among men and women in 2011 1.c

Overall, ~1/3 of women dx’d will die from their Cervical Cancer

330,000 new cases of high-grade cervical dysplasia (CIN 2/3)2

CIN = cervical intraepithelial neoplasia.

1.4 million new cases of low-grade cervical dysplasia (CIN 1)2

1 million new cases of genital warts3

CIN = cervical intraepithelial neoplasia. 1. American Cancer Society. Cancer Facts and Figures 2007. Atlanta, Ga: American Cancer Society; 2006:4. American Cancer Society. Cancer Facts & Figures 2011. caner.org/acs/groups/content@epidemiologysurveillance/documents/document/acspc-029771.pdf . accessed 11/8/2011. 2. Schiffman M, Solomon D. Findings to date from the ASCUS-LSIL Triage Study (ALTS). Arch Pathol Lab Med. 2003;127:946–949. 3. Fleischer AB, Parrish CA, Glenn R, Feldman SR. Condylomata acuminata 10 (genital warts):Patient demographics and treating physicians. Sex Transm Dis. 2001;28:643–647.

Common HPV Types Associated With Benign and Malignant Genital Disease HPV Types Low-Risk

6, 11

Manifestations Benign low-grade cervical changes Condylomata acuminata (genital warts)

High-Risk

16, 18, 31, 33, 45

Low-grade cervical changes High-grade cervical changes Cervical cancer Anogenital and other cancers

Cox. Baillière’s Clin Obstet Gynaecol. 1995;9:1. Munoz et al. N Engl J Med. 2003;348:518.

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HPV Types 6, 11, 16, and 18 in Cervical Cancer, Cervical Dysplasia, and Genital Warts

Prevalence of HPV Type

HPV 16 and 18

HPV 6 and 11

100 90 80 70 60 50 40 30 20 10 0 CIN 1

1

CIN 2

CIN 3 and Cervical Cancer

Genital Warts 2

CIN = Cervical intraepithelial neoplasia 1. Clifford GM, Rana RK, Franceschi S, et al. Cancer Epidemiol Biomarkers Prev. 2005;14:1157-1164. 2. Gissmann L, Wolnik L, Ikenberg H, et al. Proc Natl Acad Sci USA. 1983;80:560–563.

Cancer Types, Other Than Cervical Cancer, Attributable to HPV Estimated percentage of cancer cases attributable to HPV 100

Estimated, %

80

70

60

50

50

50

40 20 20 0 Anal

Vulvar

Vaginal

Cancer Type

González Intxaurraga MA et al. Acta Dermatovenerol. 2002;11:1–8.

Penile

Oropharyngeal

Prevalence of HPV in Vulvar and Vaginal Precancers and Cancers VIN 2/3 (N=183)1

100 80 60 40 20 0

92% 76%

HPV Positive

VaIN 2/3 (N=11)1

100 80 60 40 20 0

Type 16 or 18 Positive

91% 64%

HPV Positive

Vulvar Cancer (N=48)1 100 80 60 40 20 0

Type 16 or 18 Positive

Vaginal Cancer (N=25)2 100 80 60

60%

HPV Positive

40

42%

Type 16 or 18 Positive

64%

20

58%

0 HPV Positive

Type 16 Positive

VIN = vulvar intraepithelial neoplasia; VaIN = vaginal intraepithelial neoplasia.

1. Hampl M et al. Obstet Gynecol. 2006;108:1361–1368. 2. Daling JR et al. Gynecol Oncol. 2002;84: 263–270.

HPV Infection in the United States 1% 4% 25%

10% Genital warts Detected by colposcopy HPV DNA positive: Colposcopy negative

~75% of population exposed to HPV

Presence of antibodies (negative HPV test) Not currently infected

60% Koutsky. Am J Med. 1997;102(5A):3.

15

HPV Infection in Young Women HPV positive (percent)

80

69

70 60

54

56

4-5

6-9

50 40 30 20

32 21

10 0

0-1

2-3

10+

Lifetime number of sex partners Ley et al. J Natl Cancer Inst. 1991;83:997.

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GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]

While the Cumulative Incidence of HPV Infection After Sexual Debut Is High Female College Students 1.0

Cumulative Incidence of HPV Infection

(n=296) 0.8

0.6

0.4

0.2

0.0 0

4

8 12 16 20 24 28 32 36 40 44 48 52 56

Months Since First Intercourse *Not all HPV-6/11 specimens were individually tested for HPV 6 and HPV 11 separately. †Types 31, 45, 51, 52, 55, 58, 56, 33, 35, 39, 40, 42, 53, 54. Adapted from Winer RL, Lee S-K, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Am J Epidemiol. 2003;157:218–226, by permission of Oxford University Press.

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GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]

… the Infection Rate for Any Specific Type Is Lower

Cumulative Incidence at 24 Months

45 40

Female College Students

35 30 25 20 15 10 5 0 16

18

6

11

6/11*

HPV Types

*Not all HPV-6/11 specimens were individually tested for HPV 6 and HPV 11 separately. †Types 31, 45, 51, 52, 55, 58, 56, 33, 35, 39, 40, 42, 53, 54. Adapted from Winer RL, Lee S-K, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Am J Epidemiol. 2003;157:218–226, by permission of Oxford University Press.

†

Other types

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Cervical Cancer 45

Rate per 100,000

40 35 30 25 20 15 10 5 0

Age at Diagnosis Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Databases: Incidence – SEER 11 Regs + AK Public-Use, Nov 2003 Sub for Expanded Races (1992-2001) and Incidence – SEER 11 Regs Public-Use, Nov 2003 Sub for Hispanics (1992-2001), National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2004, based on the November 2003 submission 19

Cervical Cancer Is Not an Equal Opportunity Disease

Rate per 100,000

45

White

40

Black

35

American Indian/Alaska Native

30

Asian or Pacific Islander

25

Hispanic

20 15 10 5 0

Age at Diagnosis Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Databases: Incidence – SEER 11 Regs + AK Public-Use, Nov 2003 Sub for Expanded Races (1992-2001) and Incidence – SEER 11 Regs Public-Use, Nov 2003 Sub for Hispanics (1992-2001), National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2004, based on the November 2003 submission 20

Healthcare Costs of Cervical HPV Cost per episode of care* ($)

3,000 2,349

2,500 2,000 1,275

1,500 1,000

1,509

732

500

57

299

0 Negative

ASC

Any abnormal

LSIL

AGC

HSIL

Visits (n)

1

2.6

3.5

4.5

5.1

6.9

Pap tests (n)

1

2.2

2.5

2.7

3.1

3.7

Duration (months)

−

7.4

9.6

10.9

13.7

17.4

*Average age adjusted to the 1998 US female population; all cost estimates were converted to 2002 dollars. ASC = atypical squamous cells; AGC = atypical glandular cells; LSIL = low-grade squamous intraepithelial lesion; HSIL = high-grade squamous intraepithelial lesion. Insinga et al. Am J Obstet Gynecol. 2004;191:114.

… for men, our original thoughts... …results from new studies changed ideas about infection….

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In males, unlike females, genital HPV infections appear to be common across the age span.

Nyitray, A. G., Carvalho da Silva, R. J., Baggio, M. L., Lu, B., Smith, D., Abrahamsen, M., . . . Giuliano, A. R. (2011). Age-specific prevalence of and risk factors for anal human papillomavirus (HPV) among men who have sex with women and men who have sex with men: the HPV in men (HIM) study. J Infect Dis, 203(1), 49-57. doi: 10.1093/infdis/jiq021[pii]

…genital HPV infections in men are differentially affected by HIV infection.

Group 1 HPVs

Low-Risk HPVs

Group 2 HPVs

Wiley, D. J., Li, X., Hsu, H., Seaberg, E. C., Cranston, R. D., Young, S., . . . Detels, R. (2013). Factors Affecting the Prevalence of Strongly and Weakly Carcinogenic and Lower-Risk Human Papillomaviruses in Anal Specimens in a Cohort of Men Who Have Sex with Men (MSM). PLoS One, 8(11), e79492. doi: 10.1371/journal.pone.0079492 PONE-D-13-22299 [pii]

…for 285 18-44 year old men, residing in Arizona, with >2 semi-annual visits…

Lu, B., Wu, Y., Nielson, C. M., Flores, R., Abrahamsen, M., Papenfuss, M., et al. (2009). Factors associated with acquisition and clearance of human papillomavirus infection in a cohort of us men: A prospective study. J Infect Dis, 199(3), 362-371.

…for 285 18-44 year old men, residing in Arizona, with >2 semi-annual visits…

Lu, B., Wu, Y., Nielson, C. M., Flores, R., Abrahamsen, M., Papenfuss, M., et al. (2009). Factors associated with acquisition and clearance of human papillomavirus infection in a cohort of us men: A prospective study. J Infect Dis, 199(3), 362-371.

With National Consensus: Strategies for Prevention • In females: – Vaccination to prevent cervical, vaginal, vulvar and anal high-grade squamous intraepithelial lesions (HSILs) and genital warts • Quadrivalent HPV vaccine (Gardasil, Merck & Co., Inc.) • Bivalent HPV vaccine (Cervarix, GlaxoSmithKline)

– Screening to detect cervical atypias – Treatment of HSILs to prevent cancers

• In males: – Vaccination to prevent genital warts and anal HSIL • Quadrivalent HPV vaccine (Gardasil, Merck & Co., Inc.)

– Digital anorectal exam, annually – Treatment for cancers

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HPV Vaccines are: 

Active Constituents: Laboratory produced proteins, adjuvant – –



Protein: Recombinant DNA strategies – –



The L1 proteins self-assemble into VLPs. Purified VLPs are adsorbed on aluminum-containing adjuvant. Gardasil® (HPV4): Saccharomyces cerevisiae; HPV6, 11, 16, 18 Cervarix® (HPV2) : Bacilovirus; HPV16, 18

Adjuvant: – –

Gardasil®: Amorphous aluminum hydroxyphosphate sulfate Cervarix®: aluminum hydroxide & monophosphoryl lipid A (MPL)

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Assembly of VLPs1–3

1. Berzofsky JA, et al. J Clin Invest. 2004;114:450–462. 2. Kirnbauer R, et al. Proc Natl Acad Sci USA. 1992;89:12180–12184. 3. Modis Y, et al. EMBO J. 2002;21:4754–4762.

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ACIP Recommendations: FEMALES • Routine vaccination of 11 &12 year old females with HPV4, in 3-doses – Vaccination as early as age 9 years – Vaccination recommended 13-26 year olds • not previously vaccinated • not completed the 3-dose series.

1. FDA licensure of bivalent human papillomavirus vaccine (HPV2, Cervarix) for use in females and updated HPV vaccination recommendations from the Advisory Committee on Immunization Practices (ACIP). (2010). MMWR Morb Mortal Wkly Rep, 59(20), 626629. doi: mm5920a4 [pii]

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ACIP Recommendations: MALES • Routine vaccination of 11 &12 year old males with HPV4, in 3-doses – Vaccination as early as age 9 years – Vaccination recommended 13-21 year olds • not previously vaccinated • not completed the 3-dose series.

• Permissive: 22-26 year olds may be vaccinated 1. Recommendations on the use of quadrivalent human papillomavirus vaccine in males--Advisory Committee on Immunization Practices (ACIP), 2011. (2011). MMWR Morb Mortal Wkly Rep, 60(50), 1705-1708. doi: mm6050a3 [pii]

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ACIP Recommendations: Timing • For Doses 1 and 2 – >4 weeks between dose 1 and 2 – 8 weeks, optimally

• For Doses 2 and 3: – >12 weeks between dose 2 and 3

• Overall, time between doses 1 and 3 – > 24 weeks. 1. FDA licensure of bivalent human papillomavirus vaccine (HPV2, Cervarix) for use in females and updated HPV vaccination recommendations from the Advisory Committee on Immunization Practices (ACIP). (2010). MMWR Morb Mortal Wkly Rep, 59(20), 626629. doi: mm5920a4 [pii]

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1. FDA licensure of bivalent human papillomavirus vaccine (HPV2, Cervarix) for use in females and updated HPV vaccination recommendations from the Advisory Committee on Immunization Practices (ACIP). (2010). MMWR Morb Mortal Wkly Rep, 59(20), 626629. doi: mm5920a4 [pii] 2. FDA licensure of quadrivalent human papillomavirus vaccine (HPV4, Gardasil) for use in males and guidance from the Advisory Committee on Immunization Practices (ACIP). (2010). MMWR Morb Mortal Wkly Rep, 59(20), 630-632. doi: mm5920a5 [pii]

Data published in 2010 show:

1. FDA licensure of bivalent human papillomavirus vaccine (HPV2, Cervarix) for use in females and updated HPV vaccination recommendations from the Advisory Committee on Immunization Practices (ACIP). (2010). MMWR Morb Mortal Wkly Rep, 59(20), 626629. doi: mm5920a4 [pii] 2. FDA licensure of quadrivalent human papillomavirus vaccine (HPV4, Gardasil) for use in males and guidance from the Advisory Committee on Immunization Practices (ACIP). (2010). MMWR Morb Mortal Wkly Rep, 59(20), 630-632. doi: mm5920a5 [pii]

Data published in 2011 show:

1. Recommendations on the use of quadrivalent human papillomavirus vaccine in males--Advisory Committee on Immunization Practices (ACIP), 2011. (2011). MMWR Morb Mortal Wkly Rep, 60(50), 1705-1708. doi: mm6050a3 [pii]

ACIP Recommendations: Coadministration of Vaccines • Live or killed vaccines may be coadministered with Gardasil (HPV4) or Cervarix (HPV2) – Before, together with or after HPV vaccines – Rationale: HPV vaccine is neither killed or live vaccine strategy – Not all vaccines have been tested for coadministration in trials – See CDC recommendations for coadministration of multiple vaccines 1. FDA licensure of bivalent human papillomavirus vaccine (HPV2, Cervarix) for use in females and updated HPV vaccination recommendations from the Advisory Committee on Immunization Practices (ACIP). (2010). MMWR Morb Mortal Wkly Rep, 59(20), 626629. doi: mm5920a4 [pii]

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GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]

Baseline HPV Status of Women Enrolled in Clinical Trials for GARDASIL Subjects Exposed to Any Vaccine HPV Type at Enrollment Efficacy Studies—Combined Population

Baseline HPV Status Naïve to all 4 types Positive to 1 type

73%

20%

Positive to 2 types

6% Positive to 3 types Positive to 4 types

1.2% 0.1%

• 73% of subjects were naïve to all 4 vaccine HPV types. • Among subjects who were positive to a vaccine HPV type, most were positive to only 1 type. • Inclusion criteria included 4 or fewer sexual partners. Data available on request from Merck & Co., Inc. Please specify information package 20651717(4)-GRD.

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Impacts • HPV vaccines are prophylactic vaccines! • Interesting results have been published since the first vaccine studies. These are not related to(FDA) on-label recommendation for vaccination: – Risk for high-grade cervical dysplasia in women vaccinated when asymptomatic but infected with HPV16/18 was lower than in placebo recipients.1 – One recently published small study shows longer time to recurrence for men who were HPV-vaccinated at the time high-grade anal dysplasia was treated.2

• More research is needed…. 1 who 2 Swedish,

K. A., Factor, S. H., & Goldstone, S. E. (2012). Prevention of recurrent high-grade anal neoplasia with quadrivalent human papillomavirus vaccination of men who have sex with men: a nonconcurrent cohort study. Clin Infect Dis, 54(7), 891-898. doi: 10.1093/cid/cir1036cir1036 [pii]

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Bridging the Efficacy of GARDASIL® From Young Adult Women to Adolescent Girls Adolescent Girls 9 to 15 years of age N = 1,121

Young Adult Women 16 to 26 years of age N = 4,229

6000

GMTs*

5000 4000 3000 2000 1000 0 Anti-HPV 6

Anti-HPV 11

*GMT = Geometric mean titer in mMU/mL (mMU = milli-Merck units).

Anti-HPV 16

Anti-HPV 18 40

Prevalence of HPV in Sexually Active Women 18 to 26 Years of Age in National Longitudinal Study of Adolescent Health 9%

91% PCRa negative to all 4 vaccine types (6, 11, 16, 18) PCR positive to at least 1 of the vaccine types (6, 11, 16, 18) n=3,276 women 18 to 26 years of age aPCR

= polymerase chain reaction. Dempsey AF et al. Vaccine. 2008;26(8):1111–1117. 41

Estimated Population-Level Impact of Not Vaccinating Women With >3 Lifetime Sex Partners 12% n=~300,000

n=~2,200,000

88%

% without current infection HPV 6, 11, 16, and/or 18 % with current infection HPV 6, 11, 16, and/or 18

Dempsey AF et al. Vaccine. 2008;26(8):1111–1117.

 Of the estimated 2.5 million women with >3 sex partners: – 12% would already be currently infected with 1 or more HPV vaccine types. – 88% would not be currently infected with 6, 11, 16, and/or 18.

 The population-level impact of not vaccinating women with >3 lifetime sex partners means an estimated 2.2 million women who could potentially benefit would not be vaccinated.

42

Risk-Based Vaccination Strategies: Study Conclusion  Vaccination based upon risk-factor analysis would cause HPV vaccines to be withheld from a large number of women without evidence of current infection. – Albeit that analyses for males have not been performed, no current evidence suggests risk-factor based vaccination is credible.

 The presence or absence of risk factors for infection seems a poor strategy for HPV catch-up vaccination of young adults.  The ACIP does not recommend a risk-based immunization strategy for HPV vaccination. Dempsey AF et al. Vaccine. 2008;26(8):1111–1117.

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