Using Natural Historyof HPV to GuideCervical Cancer Prevention Strategies

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Using Natural History of HPV to Guide Cervical
Cancer Prevention Strategies

• Philip Castle, PhD, MPH
• HREB/DCEG/NCI/NIH/DHHS
• August 4, 2008

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Disclaimers, Disclosures, Conflict of Interest

• I work with a number of companies and groups on
  the research, development, and the validation of
  new biomarkers, assays, and vaccines. Under a
  fair broker policy, I work collaboratively with
  them and serve as a unpaid technical advisor. I
  have no CDA with them. I do not accept research
  dollars and I do not receive any personal
  compensation.
• My aim in these interactions is to encourage the
  development of clinical tests with excellent and
  reliable performance

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Re-Insert Cervical Cancer Here (Please!)
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Todays Talk

• U.S. and Global Perspective of Cervical Cancer
• Natural History of HPV Rational Basis for
  Cervical Cancer Prevention
• New Tools HPV Vaccines and Testing
• U.S. How do we make it more efficient?
• Global How do we make it available?

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George Papanicolaou (1883-1962)
Inventor of the Pap smear
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Incidence of Cervical Cancer Worldwide
Cases/100K
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Todays Talk

• U.S. and Global Perspective of Cervical Cancer
• Natural History of HPV Rational Basis for
  Cervical Cancer Prevention
• New Tools HPV Vaccines and Testing
• U.S. How do we make more efficient?
• Global How do we make it available?

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Cervical Cancer Continuum
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Molecular Pathology Model of Cervical Cancer
Wright and Schiffman, NEJM, 2003
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Viral Replication Capsid Proteins
Genomic Chaos with Centrosomal Aberrations and
Aneuploidy
Viral Genome Structure
Integration into Host Cell Genome
episomal
Viral Oncogene E6 / E7 Expression
Replication
HPV Infection Koilocytosis
CIN1
CIN2
CIN3
Carcinoma
Normal Epithelium
100
50
lt 10
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Cervical Cancer Continuum
Precancer
HPV
CIN3
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CUMULATIVE INCIDECE OF HPV INFECTION AFTER
INITIATION OF SEXUAL ACTIVITY IN THE UNITED STATES
1 0.9 0.8
0.7 0.6 0.5
0.4 0.3 0.2
0.1 0
CUMULATIVE INCIDENCE OF HPV INFECTION
0 4 8
12 16 20 24
28 32 36 40
44 48 52
56 60
NO. OF MONTHS SINCE FIRST INTERCOURSE
Winer et al., AJE, 2003
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Baseline, Age-Specific Prevalence of HPV in
Women Participating in CVT
Unpublished Data
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Short-Term HPV Persistence
Plummer et al., JID, 2007
ALTS
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Persistence vs. Acquisition
60.0
Oncogenic
Non-Oncogenic
50.0
40.0
Infections at Follow-up Due to Persistence
30.0
20.0
10.0
0.0
lt25
25-34
35-44
45-54
55-64
65
Age Group (Years Old)
Guanacaste
Castle et al. , JID, 2005
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Persistence of prevalent and incident
carcinogenic HPV infections 1, 2 and 3 years
after detection by age group
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Natural History Profile of HPV
Schiffman et al., Lancet, 2007
Guanacaste
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Risk of Invasion (Median Age late 30s)
Mccredie et al., Lancet Onc., 2008
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EIGHT MOST COMMON HPV TYPES IN MORE THAN 14,500
CERVICAL CANCER CASES BY REGION
Smith et al., IJC, 2007
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Todays Talk

• U.S. and Global Perspective of Cervical Cancer
• Natural History of HPV Rational Basis for
  Cervical Cancer Prevention
• New Tools HPV Vaccines and Testing
• U.S. How do we make it more efficient?
• Global How do we make it available?

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Think Not Efficacy But Attributable Benefit
100 vs. 0 Efficacy 100
10 vs. 0 Efficacy 100
1 vs. 0 Efficacy 100
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Prophylactic Vaccine Efficacy Merck GSK
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HPV-16/18 Clearance by Trial Arm
N HPV16 181(V)/232(P) HPV18 81(V)/81(C)
Hildesheim et al., JAMA, 2007
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FUTURE I and II
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Cytology Positive CIN2
Cuzick et al., IJC, 2006 Mayrand et al., NEJM,
2007
CIN 2
HART
Tuebingen
Hannover
Jena
French Public
French Private
Seattle
Canada
Combined
0
10
30
50
70
90
100
Cytology Positivity
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HPV Positive CIN2
Cuzick et al., IJC, 2006 Mayrand et al., NEJM,
2007
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Cytology and HPV Positive No CIN
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HPV Positivity in the U.S. 5-Year, 800,000
Co-testing Experience
Castle et al., submitted
KPNC
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Todays Talk

• U.S. and Global Perspective of Cervical Cancer
• Natural History of HPV Rational Basis for
  Cervical Cancer Prevention
• New Tools HPV Vaccines and Testing
• U.S. How do we make it more efficient?
• Global How do we make it available?

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Age of CIN2/3 in the U.S.
Castle et al., in preparation
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Age of CIN2/3 in the U.S. (conti.)
Castle et al., in preparation
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Influence of Age of Vaccination on Prevention of
HPV16-associated Cervical Cancer Finland
100
sexually Active Fn vs. US
Age at vaccination
80
- 12
lt1 ND


- 15
11 26
60
of cases prevented
40
- 18
65 70
20
gt99 81
- 21
Vaccine

0

2000
2010
2020
2030
2040
2050
2060
year
70 of females in each age group are immunized
in 2008
.
Adapted from French et al., Brit. J. Cancer
96514-8, 2007
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Pap smear screening without vaccination would

prevent more cervical cancer deaths than
HPV16/18 vaccination without Pap screening
100
8
0
Prevention
6
0
of cervical
cancer
deaths
4
0
2
0
0
Vaccine
Current Pap

Vaccine Pap

alone
screening in

screening
USA
Assumptions 1) Current Pap screening protects
against 80 of cancer deaths.

2) HPV16 18 vaccination will be 90
effective.
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Vaccination at different ages
Goldhaber-Fiebert et al., JNCI, 2008
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100
CIN3 Biopsy
HSIL HPV H-G Colpo
CIN2 Biopsy
HSIL
40
HPV/ASC-US
LSIL
HPV
10
Increasing Risk of Precancer (CIN3)
ltCIN2 Biopsy
ASC-US
HPV/Cyto-
2
HPV/Cyto-
HPV-
HPV-/ASC-US
All ?
Cyto-
HPV-/Cyto-
0
Cytology
HPV Testing
Post- Colpo
Colposcopy
Biopsy
Screening
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Risk Stratification Impact of Vaccination on
Screening Tests (It is all about Risk!!!)
Khan et al., JNCI, 2005
Portland
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One-Year Persistence
Castle et al., submitted
Guanacaste
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Sensitivity of colposcopically-guided biopsy
result of CIN2 to detect 2-year cumulative
diagnosis of CIN3
Total sensitivity includes 26 cases of
cumulative CIN3 disease where no biopsies were
taken at colpo exam
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Normal Biopsies and HPV Tests in 2-Years of
Follow-up
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CIN 3 Histology
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Todays Talk

• U.S. and Global Perspective of Cervical Cancer
• Natural History of HPV Rational Basis for
  Cervical Cancer Prevention
• New Tools HPV Vaccines and Testing
• U.S. How do we make it more efficient?
• Global How do we make it available?

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The Discovery-Delivery Disconnect
Discovery
Development
Delivery
Critical Disconnect
This discovery to delivery disconnect is a key
determinant of the unequal burden of cancer.
Voices of a Broken System Real People, Real
Problems Presidents Cancer Panel, Harold
Freeman, March 2002
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The Promise of Global Cervical-Cancer Prevention
Schiffman and Castle, NEJM, 2005
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Screen-and-Treat HPV vs. VIA
7.0
HPV
VIA
6.0
None
5.0
4.0
Cumulative Incidence of CIN2
3.0
2.0
1.0
0.0
6-Month
12-Month
Follow-Up Time
Denny et al., JAMA, 2005
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fastHPV for Developing Countries
Assay will be based on hc2 platform.

• Main goals
• Decrease assay time to 2hrs.
• Keep 1 pg/ml sensitivity.
• More-flexible capture approaches
• paramagnetic beads instead of plates.
• Alternative detection strategies simpler
  instrumentation, battery operated.
• Stabilized reagents.

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fastHPV
Dry swab in empty tube
45 min, 65C
Add RNA and magnetic beads via dropper
bottles hyb and capture 30 min at 65C
Combination heat block, shaker, magnetic capture
Combined SCM DNR
45C
DR-1, 15 min
Wash, 10 min
DR-2 and expose to instant film 10 min
Combination heat block, shaker, magnetic capture
New luminometer readout of plate
or
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fastHPV vs. hc2
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Visual Inspection with Acetic Acid
Sankaranarayanan et al., Lancet, 2007
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The Menu of Options
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Efficacy x Adoption Effectiveness

• Adoption is function of cost, competing needs,
  cultural and sexual norms, technology transfer,
  local infrastructure, etc.
• If Adoption is a total failure, 100 Efficacy
  will achieve 0 Effectiveness!
• We need to get into the trenches to realize the
  potential---who is going to lead the way?

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there is a difference between knowing the path
and walking the path. -Morpheus From the Matrix
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