HPV€¦ · • HPV 16 (54%) and HPV 18 (21%) account for the majority of cervical cancers...

an evolving understanding of

an ancient and established virus

Audrey P Garrett, MD, MPH

PEACEHEALTH CME DINNER SERIESFEBRUARY 12, 2015

Disclosures‐1

• Merck– Speaker Panel for Gardasil

• Hologic– Speaker Panel for Cervista and Thin Prep

Disclosures‐2

Parent

Gynecologic Oncologist

VaccineEnthusiast

Objectives

• Epidemiology of HPV

• Role of HPV in oncogenesis

• Identify changes and controversies in cervical cancer screening recommendations

• Exciting future directions

EPIDEMIOLOGY

Could YOU have HPV?

YES… if you have…

• a cervix

• a vagina

• a penis

• tonsils

• a throat

• an anus

• ever had sex

HPV is Ubiquitous

• 85% have come in contact with it• The majority “clear it”• More common in smokers• More transmissible female to male• Resides in epithelial layer

– Basal layer required for replication

• Conserved in mammals– Across time and geography

JAMA 2007, 297 (8) 813‐819

• Over 100 types identified2

• 30−40 anogenital2,3

– 15−20 oncogenic2,3 types, including 16, 18, 31, 33, 35, 39, 45, 51, 52, 584

• HPV 16 (54%) and HPV 18 (21%) account for the majority of cervical cancers worldwide5

– Nononcogenic types include: 6, 11, 40, 42, 43, 44, 544

• HPV 6 and 11 account for 90% of external genital warts3

Human Papillomavirus (HPV) Is a Cause of Cervical Cancer

1. Howley PM. In: Fields BN, Knipe DM, Howley PM, eds. Philadelphia, Pa: Lippincott-Raven; 1996:2045–2076. 2. Schiffman M. Arch Pathol Lab Med. 2003;127:930–934.

3. Wiley DJ. Clin Infect Dis. 2002;35(suppl 2):S210–S224. 4. Muñoz N. N Engl J Med. 2003;348:518–527.

5. Smith J, et al. Int J Cancer. 2007;121:621-632.

Nonenveloped double-stranded DNA virus1

Smith J, et al. Int J Cancer. 2007;121:621-632.

16 alone

16 + 18

CumulativePrevalence

IncrementalPrevalence

> 75% of Squamous Cancers in the United States Are Caused by HPV 16/18

Proportion of Cancers Associated with HPV Types

Why Are HPV 16/18 Important?

HPV Facts: Most common STD in the U.S.

Approximately 20 million Americans are currently infected.1

•Estimated incidence of new cases 6 million per year1

•80% sexually active adults in U.S. infected w/ at least one HPV type by age 501

•Peak prevalence during adolescence and young adulthood

– Among sexually active 15‐24 year olds:• 74% new infections occur in this age group2• ~9.2 million currently infected2

1. Centers for Disease Control & Prevention, Rockville MD: CDC National Prevention Information Network; 20092. Weinstock H, et al. Perspect Sex Reprod Health. 2004;36:6-10.

US Cervical Cancer Statistics• Approximately 12,710 new cases/year1

• Approximately 4,290 deaths/year1

• Approximately 10 million cases of HPV infectionwithout cytologic abnormalities2

• Approximately 1 million cases CIN 12

• Approximately 300,000−700,000 cases of CIN2/3

• Direct cost of prevention and treatment of cervical cancer is $6 billion annually in the US

1. CA: A Cancer J for Clinicians 2011.2. Parkin et al. Int J Cancer. 1993;54:594-606.

33,000 cancer cases annually

CDC Info

HPV in Laryngeal Cancers

PLoS One 2014 Dec 29, 9(12)

Internationally

• 530,000 cases of cervical cancer– 230,000 deaths

• 30,000 cases of anal cancer– more female than male

• oropharyngeal cancer– new area of tabulation

• >600,000 cancer cases – >300,000 deaths

ONCOGENESIS

HPV in Cancer: History

• 1935 Francis Peyton Rous– caused skin cancer in rabbit

• 1972 Stefania Jablonska– identified HPV 5 in skin cancer

• 1976 Harald zur Hausen– hypothesized HPV cause of cervical cancer

• 1983 HPV 16• 1984 HPV 18• 2008 Nobel Prize in Medicine

How does HPV do it?

• interferes with the normal work of the cell– invades epithelium– evades “surveillance”– integrates into host genome

• E6– interrupts important work of p53

• E7– interrupts important work of RB

• Able to create immortal cell lines– HeLa cells: HPV 18

HPV enters the epithelium

• trauma of intercourse– micro‐abrasions

– coexisting infections

• “dry” intercourse

• anal intercourse

• areas of metaplasia/ transition

• oropharyngeal trauma

Papillomaviruses are absolutely species specific and tissue specific.

Stanley M A Clin. Microbiol. Rev. 2012;25:215-222

16 alone

16 + 18

SCREENING

Enter the Pap Smear

• Georgios Papanikolaou (1883‐1962)• 1920s describing the normal vagina• 1928 presented his findings• 1943 published his findings• 1965 ACS recommended screening• 1999 reflex HPV testing • 2009 co‐testing HPV and cytology• 2014 HPV primary testing

Limitations of Cytology

• Epidemiology– changing face of the disease

• Anatomy– screens ectocervix reliably but not endocervix

• Labor Intensive– limitations on cyto‐technologist work force

• Cost

2003 ACOG Guidelines2003 ACOG Guidelines

First screen three years after first

intercourse or by age 21

ACOG News Release July 31, 2003; ACOG Practice Bulletin Number 45, August 2003.

Annual pelvic exam AND

annual cytology

30 Years 30 Years21-29 Years21-29 Years< 21 Years< 21 Years HysterectomyHysterectomy

• If for benign reasons,

discontinue screening.

• If CIN2 or CIN3, discontinue

screening after 3 consecutive

negative vaginal cytology tests.

Screen every 2 to 3 years after

testing negative on 3 consecutive annual cervical

cytology tests, or screened every 3

years after cervical cytology

and an FDA-approved HPV DNA tests for high-risk HPV

strains are both negative.

2009 ACOG Guidelines2009 ACOG Guidelines

No routine speculum exam or cytology; STD

testing and counseling on safe sex and

contraception as needed

Annual pelvic exam AND cytologya

OR cytology plus HPV testing (if both are negative,

rescreen in 3 years)

aFrequency of screening can be decreased to 2-3 years after 3 normal test results if no history of CIN 2/3, no immuno-supression, HIV-negative, and no history of DES in utero.

bHistory of cervical cancer or DES in utero, HIV-positive, immunosuppression, or other risk factors for acquiring STDs.ACOG Practice Bulletin No. 109. Obstet Gynecol. 2009;114:1409-1420.

Annual pelvic exam AND biannual cytology

30-64 Years30-64 Years21-29 Years21-29 Years< 21 Years< 21 Years ≥ 65 Years≥ 65 Years

Annual pelvic exam AND consider

discontinuing cytology at 65 or 70 years of age if patient has had 3 or more normal test results in a

row, no abnormal test results in 10 years, and

lacks other risk factorsb

STD = Sexually transmitted disease

USPSTF and ACS/ASCCP/ASCPUSPSTF and ACS/ASCCP/ASCP

2012 Cervical Cancer Screening Guidelines2012 Cervical Cancer Screening Guidelines

• No routine speculum exam or

cytology regardless of age

of onset of intercourse or

other risk factors.

• STD testing and counseling on safe

sex and contraception as

needed.

• Annual pelvic exam AND

screening with

• Cytology and HPV testing (“co-testing”) every 5 years (preferred)

• Cytology alone every 3 years

(acceptable) is recommended.

Saslow D, Solomon D, Lawson HW et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. Am J Clin Pathol. 2012 Apr;137(4):516-42.

• Annual pelvic exam

• Screening with cytology alone every 3 years is recommended

30-65 Years30-65 Years21-29 Years21-29 Years< 21 Years< 21 Years > 65 Years> 65 Years

• Women with three

consecutive negative

cytology tests

• Two consecutive

negative co-tests within the last 10 years and with the most

recent test in the past 5 years

• No history of CIN2+ within the

last 20 years

Risk Stratification with HPV Types 16 and 18 in Women ≥ 30 Years of Age with Negative Cytology

HPV 16 positive

HPV 18 positive

Non‐HPV 16/18 positive

HPV‐negative

In women ≥ 30 years of age, 10‐year cumulative incidence of ≥ CIN 3 was 20% and 18% for HPV 16 and 18, respectively

Khan MJ, et al. J Natl Cancer Inst. 2005;87(14):1072-1079.

Follow‐up Time (Years)

Cumulative Incide

nce Ra

≥CIN 3 (%

0.4 1.25 2.25 3.25 4.25 5.25 6.25 7.25 8.25 9.25 9.95

Changing Epidemiology

CONTROVERSY

• April, 2014: Cobas HPV test approved for primary HPV screening

• January, 2015 SGO and ASCCP issue statements

• Common ground: Screening, by any modality, decreases cervical cancer

SCREENING

• Public Health mechanism

• For the asymptomatic patient

• Cost to patient and society

• Balance benefit versus harm

Hormuzd Katki, PhD

• Equal management of equal risks

• Don’t change risk thresholds for action

• Risk is a combination of immediate risk and future risk– 1000 women with LSIL pap

• 24 (2.4%) have CIN3+ at colpo

• 29 (2.9%) have CIN3+ over next 5 years

• cumulative risk 5.3%

What do we have at PeaceHealth?

• Thin Prep pap smear– liquid based cytology

• Cobas HPV test– HPV and genotyping

• Computer assisted cytology imaging– backed up by protocolized review

HPV 16 positive

HPV 18 positive

HPV‐negative

Cumulative Incide

nce Ra

≥CIN 3 (%

0.4 1.25 2.25 3.25 4.25 5.25 6.25 7.25 8.25 9.25 9.95

Cervical Cancer Prevention:Get with the times…

“This dial phone has always worked for me…”

“My patients would never be able to understand a more modern test…”

Papanicolau to zur Hausen

FUTURE DIRECTIONS

Vaccines

• Gardasil 4 (Merck) FDA approved 2006– 6,11,16,18

• Cervarix (GSK) approved 2009– 16,18

• Gardasil 9 (Merck) FDA approved 2014– 6,11,16,18,31,33,45,52,58

• Vaccines are controversial

Vaccine Efficacy

• 99‐100% immunogenicity

• 92‐99% efficacy

• Decrease CIN3 17‐33%

• Decrease colposcopy by 10%

• Decrease treatment by 25%

• Impeccable safety record

Vaccine Eligibility

• Gardasil 4 and Cervarix – Girls 9‐26

– Boys 9‐26

– Safety data exists for the “older woman”

• Gardasil 9– Girls 9‐26

HPV adjunctive testing

• Primary testing– controversial

• Cotesting– here to stay

• Enhanced HPV testing– Aptima test (Hologic) tests for mRNA

• Testing intervals– 3 lifetime screening tests?

Oropharyngeal Cancers

• 20‐40% are HPV positive

• HPV 16

• Better prognosis

• Decreased morbidity from scaled back treatment regimens

The Future

• Vaccines prevent cervical cancer

• Therapeutic “vaccines” eliminate any remaining HPV

• Cervical cancer goes the way of small pox– ? (and measles?)

The Future: Retirement??

Past . Present. Future.

Cervical Cancer Prevention:Get with the times…

“This dial phone has always worked for me…”

“My patients would never be able to understand a more modern test…”

Learning Objectives

At the conclusion of this presentation, you will be able to:•Describe the epidemiology and disease progression of cervical cancer

•Identify women at risk for cervical abnormalities and manage them in accordance with professional guidelines

•Understand the roles of cytology testing, high-risk HPV testing, and HPV genotyping in assessing risk of cervical disease, now and in the future

HPV = Human papillomavirus

Incidence of Cervical Cancer Epidemiology History of Screening

US Cervical Cancer Statistics

• Approximately 12,710 new cases/year1

• Approximately 4,290 deaths/year1

• Approximately 10 million cases of HPV infectionwithout cytologic abnormalities2

• Approximately 1 million cases CIN 12

• Approximately 300,000−700,000 cases of CIN2/32

1. CA: A Cancer J for Clinicians 2011.2. Parkin et al. Int J Cancer. 1993;54:594-606.

2006Gardasil®

HPV Vaccine

2006ThinPrep®

Receives Glandular Indication

2003ThinPrep®

Imaging System

1996ThinPrep®

Pap Test

1999Hybrid Capture® 2

HPV Test

2009Cervista® HPV HR Test and

Cervista® HPV 16/18 Genotyping Test

1941Pap Smear

1990s 2000s1940s

1999SurePath® Pap

2009Cervarix®

HPV Vaccine

1. zur Hausen H. Cancer Res. 1976;36:794.

1970sResearch by Harald zur Hausen linking

HPV to cervical cancer1

Major Advances in Cervical Cancer Screening

Screening Has Dramatically Reduced Cervical Cancer Incidence

http://www.cancer.gov/aboutnci/servingpeople/snapshots/cervical.pdf

US Cervical Cancer Incidence* US Cervical Cancer Mortality*

* Insufficient data available for time trend analysis for American Indians/Alaskan Natives. ** Incidence and mortality data not available before 1992.

WhitesHispanicsAfrican Americans**Asians/Pacific Islanders**

• Over 100 types identified2

• 30−40 anogenital2,3

– 15−20 oncogenic2,3 types, including 16, 18, 31, 33, 35, 39, 45, 51, 52, 584

– HPV 16 (54%) and HPV 18 (21%) account for the majority of cervical cancers worldwide5

– Nononcogenic types include: 6, 11, 40, 42, 43, 44, 544

– HPV 6 and 11 account for 90% of external genital warts3

Human Papillomavirus (HPV) Is a Cause of Cervical Cancer

1. Howley PM. In: Fields BN, Knipe DM, Howley PM, eds. Philadelphia, Pa: Lippincott-Raven; 1996:2045–2076. 2. Schiffman M. Arch Pathol Lab Med. 2003;127:930–934.

3. Wiley DJ. Clin Infect Dis. 2002;35(suppl 2):S210–S224. 4. Muñoz N. N Engl J Med. 2003;348:518–527.

5. Smith J, et al. Int J Cancer. 2007;121:621-632.

Nonenveloped double-stranded DNA virus1

HPV Facts: Most common STD in the U.S.

Approximately 20 million Americans are currently infected.1

•Estimated incidence of new cases 6 million per year1

•80% sexually active adults in U.S. infected w/ at least one HPV type by age 501

•Peak prevalence during adolescence and young adulthood

– Among sexually active 15-24 year olds:–74% new infections occur in this age group2

–~9.2 million currently infected2

1. Centers for Disease Control & Prevention, Rockville MD: CDC National Prevention Information Network; 20092. Weinstock H, et al. Perspect Sex Reprod Health. 2004;36:6-10.

Progression from HPV infection to Cervical Cancer

CDC. Epidemiology and Prevention of Vaccine-Preventable Diseases. 11th ed. 2009.

1-5 years

Progression to cervical cancer may take up to decades

Persistent Infection

HPV Clearance

Within 12 months

HR = High riskCIN = Cervical intraepithelial neoplasia

HR HPV InfectionHR HPV Infection

CIN 1/2CIN 1/2

CIN 2/3CIN 2/3

Cervical CancerCervical Cancer

Conventional Cervical Cytology (Papanicolaou Smear)

Dr. George N. Papanicolaou1883-1962

• First paper published in 1941

• Screening began in the 1950s

• Responsible for a >80% reduction in the incidence of invasive cervical cancer and mortality in the United States since 19501

1 Herrero R. Monogr NCI 1996; 21:1-6

Conventional Smear•Majority of cells discarded

•Nonrepresentative transfer of cells

•Clumping and overlapping of cells

•Obscuring material

ThinPrep Pap Test•Virtually all of sample is collected

•Randomized, representative transfer of cells

•Even distribution of cells

•Minimizes obscuring material

ThinPrep® Liquid-based Cytology: Mitigates Sampling Error and Improves Preservation

Source: Hutchinson ML, et al. Am J Clin Pathol. 1994;101:215-219.

FDA-ApprovedLiquid-based Cytology Technologies

1. ThinPrep 2000 System, Part No. 04141-001 Rev. D.00 [package insert]. Cytyc Corporation; 20072. AutoCyte/SurePath Package Insert: SurePath Collection Product Insert, Doc. No. 779-10001-03 Rev C [package insert]. Burlington:

TriPath Imaging, Inc.; 2008 3. http://www.accessdata.fda.gov/cdrh_docs/pdf9/K091724.pdf

PreservCyt ® Is Widely Used for Molecular Testing

The ThinPrep ® sample collection medium, PreservCyt, was used in many large-scale clinical trials:

Trial Methodology N

ARTISTIC (2009)1

Randomized trial of cytology vs cotesting over 3 years 24510

ALTS (2000)2 Monitoring of women with LSIL & ASC-US over 2 years 5060

NTCC (2010)3 Study of HPV testing in combination with LBC or alone 47369

FOCAL (2010)4 Randomized trial of HPV with cytology triage over 4 years 6150

ATHENA5 Multi-center study to assess HPV testing compared to LBC 47208

CERVISTA HPV HR6

Multi-center prospective study to evaluate performance for screening patients with ASC-US cytology results

CERVISTA HPV 16/187

Multi-center prospective study to evaluate performance for screening patients with ASC-US cytology results

1. Kitchener HC et al . Health Technol Assess 2009; 13:51 (ARTISTIC). 2. Solomon D, et al. J Natl Cancer Inst. 2001; 93:293-299 (ALTS).

3. Ronco et al . Lancet Oncol 2010; 11:249-257 (NTCC).4. Ogilvie et al. BMC Cancer 2010; 10:1-11 (FOCAL).

5. . Stoler H, Wright T, Sharma A, et al. Am J Clin Pathol. 2011; 135:468-475 (ATHENA).6. Cervista® HPV HR [package insert]. Madison, WI: Hologic, Inc.; 2009 (P/N 15-3100).

7. Cervista® HPV 16/18 [package insert]. Madison, WI: Hologic, Inc; 2009 (P/N 15-3101).

ACOG Practice Bulletin 109:

Cervical Cancer Screening

No routine speculum exam or

cytology; STD testing and

counseling on safe sex and

contraception as needed

Annual pelvic exam AND cytologya

OR cytology plus HPV testing (if both are negative,

rescreen in 3 years)

aFrequency of screening can be decreased to 2-3 years after 3 normal test results if no history of CIN 2/3, no immuno-supression, HIV-negative, and no history of DES in utero.

bHistory of cervical cancer or DES in utero, HIV-positive, immunosuppression, or other risk factors for acquiring STDs.ACOG Practice Bulletin No. 109. Obstet Gynecol. 2009;114:1409-1420.

Annual pelvic exam AND biannual

cytology

30-64 Years21-29 Years< 21 Years ≥ 65 Years

Annual pelvic exam AND consider discontinuing

cytology at 65 or 70 years of age if patient has had 3

or more normal test results in a row, no

abnormal test results in

10 years, and lacks other risk factorsb

STD = Sexually transmitted disease

Advantages of HPV Screening

• HPV testing is more sensitive than cytology • HPV testing has a high negative predictive

value • For women 30 and older, a negative Pap and

HPV test would allow for a patient to extend to a 3-year screening interval2

1. Bulkmans NWJ, Berkhof J, Rozendaal L, et al. Lancet 2007; 370:1764-72.2. J Clin Oncol May 2011 vol. 29 no. 15_suppl 1508

HPV DNA Testing Increases Sensitivity of Screening1

Screening Method

Detection of Histologically Proven High-grade Lesion

Sensitivity %1

(95% CI)Specificity %1

(95% CI)

Conventional cytology68.1

(55.4-79.2)95.3

(94.5-96.2)

Liquid-based cytologya 87.8(80.3-93.3)

93.1(92.4-93.8)

HPV DNA testb 100(96.4-100)

85.6(84.7-86.5)

1. Clavel C, et al. Br J Cancer. 2001;89:1616-1623.

a. Liquid-based cytology performed using the ThinPrep Pap Testb. HR HPV testing performed using hc2

FDA-Approved Indications for Use: HPV HR Screening

Indications for use:1-3

• To screen patients with ASC-US Pap results• To be used adjunctively with cervical

cytology to screen women 30 and older for the absence or presence of high-risk HPV types

1. Cervista® HPV HR [package insert]. Madison, WI: Hologic, Inc.; 2009 (P/N 15-3100).2. Roche Molecular Systems, Inc. Cobas® HPV Test for In Vitro Diagnostic Use Package Insert. Branchburg, NJ, 2011.3. Digene Corporation. Digene Hybrid Capture® 2 High-Risk HPV DNA Test® Package Insert. Gaithersburg, MD, 2007.

The ASC-US/LSIL Triage Study for Cervical Cancer (ALTS)

• Organized and funded by the National Cancer Institute

• Included more than 5000 women

• Began in November 1996 and concluded at the end of 2000

• Found that HPV testing identified 96% of the women with ASC-US who had a precancerous lesion

• The authors concluded that HPV testing is a viable and cost-effective option for the management of ASC-US

Solomon D, et al. J Natl Cancer Inst. 2001;93:293-299

ALTS Performance by Modality

*For detection of CIN 2+ Adapted from Table 5, Solomon D, et al. J Natl Cancer Inst. 2001;93:293-299.

Management Modality* Sensitivity % Referral % PPV % NPV %

Colposcopy 100 100 11 100

HPV 96 56 20 99

Cytology ASC-US+ 85 59 17 96

Cytology LSIL+ 59 26 26 94

Cytology HSIL+ 35 8 58 92

Management of Women With ASC-US

HPV DNA Testing*Preferred if liquid-based cytology or

co-collection availableRepeat Cytologyat 6 & 12 months

ColposcopyEndocervical sampling preferred in women with no lesions, and those with unsatisfactory colposcopy

Both Tests Negative

≥ASC(on either result)

Routine Screening

HPV Positive*(managed in same manner as

women with LSIL)

HPV Negative

Repeat Cytologyat 12 months

ASCCP. ASCCP Clinical Update. ASCCP: Hagerstown, MD; 2009.

*Test only for high-risk (oncogenic) types of HPVASC = atypical squamous cellsLSIL = low-grade squamous intraepithelial lesion

ASC-US

HPV 16 positive

HPV 18 positive

HPV‐negative

Cumulative Incide

nce Ra

≥CIN 3 (%

0.4 1.25 2.25 3.25 4.25 5.25 6.25 7.25 8.25 9.25 9.95

Rationale for Co-Testing

1 out of 6 women (15%) who are HPV positive and Pap negative will develop ASC-US+ within 5 years1

1. Castle, et al. CANCER. Nov 15, 2002:95(1).

Large Population-based Survey Demonstrates HPV Prevalence Varies with Age

NHANES, a survey of noninstitutionalized civilian women in the United States published in 2007, shows an overall HPV prevalence of 26.8%

Dunne EF, et al. JAMA. 2007;297:813-819.NHANES = National Health and Nutrition Examination SurveyData based on self-collected patient samples.

Why HPV Test Women 30 and Older?

1. Sellors et al. CMAJ. 2000;163:503.2. Ries et al. Surveillance, Epidemiology and End Results (SEER) Cancer Stats NCI, 1973-1997. 2000.

High-risk HPV types

Cancer

In 812,598 cotests from Kaiser in Northern California:1

• Overall HPV positive rate was lower than epidemiological studies have suggested

• Concerns about excessive numbers of positive HPV tests among women ≥30 years were not validated

Carcinogenic HPV testing has proven greater reproducibility and greater sensitivity for detection of CIN

3 and cancer than cytology alone1

Cotesting Increases Sensitivity of Screening

1. Castle PE, et al. Obstet Gynecol. 2009;113:595–600.

Co-Testing in Women 30 Years and Older

HPV (-) HPV (+)

Routine ScreeningNot before 3 years Repeat BOTH Tests

at 12 months

Manage per ASCCP Guideline

Both Negative Cytology Negative HPV (+)

Cytology Abnormal Any HPV Result

ColposcopyRoutine Screeningat 3 years

Cytology Negative

*Test only for high-risk (oncogenic) types of HPV

16 alone

16 + 18

HPV 16/18 Link to Cervical Adenocarcinoma

Castellsague X, et al. J Natl Cancer Inst. 2006;98:303-315.

HPV 16 HPV 18 Multiple Types

HPV DNA was detected in 93% of patients with cervical adenocarcinoma

≈ 75%

HPV 16 positive

HPV 18 positive

HPV‐negative

Cumulative Incide

nce Ra

≥CIN 3 (%

0.4 1.25 2.25 3.25 4.25 5.25 6.25 7.25 8.25 9.25 9.95

ASCCP Genotyping Algorithm

Use of HPV Genotyping to Manage HPV HRa Positive Cytology Negative Women 30 Years and Older

HPV 16/18 Positive HPV 16/18 Negative

Both Negative

Cytology Negative,HPV Positive

Cytology Abnormal,Any HPV Result

Repeat BOTH Tests at 12

MonthsColposcopy

Routine Screening at 3 Years Colposcopy Manage per

ASCCP Guidelines

HR HPV Positive,Cytology Negative

a Test that detects any of the 14 HR (oncogenic) types of HPV.

Utilization of 16/18 Genotyping Algorithm in Women 30 and Older

• The addition of 30+ co-testing and 16/18 genotyping allows selection of the patients most in need of management

• Limits colposcopy exams to those most at risk• Reduce the time to colposcopy exam by 1 year for women most at risk

Cervista® HPV HR :7% positive1

Cervista® HPV 16/18: 80% negative1

Cervista® HPV 16/18: 20% positive1

10,000 co-tested women > 30 with negative cytology

140Colposcopy

560Repeat testing in 1

Cervista® HPV 16/18 [package insert]. Madison, WI: Hologic, Inc; 2009 (P/N 15-3100).

What Is the Clinical Utility of HPV Genotyping?

Meijer CJ, et al. Gynecol Oncol. 2006;103:12-7.

“My patient is not at risk

• HPV is ubiquitous virus• Risk assessment does not work

– HIV– Hep B– HPV vaccination

“My patient is not at risk”

• Wife of Korean WHO Chief• 4J school teachers• Librarians, nurses• The girl next door• Anesthesiologists• Social workers

Product Overview

• Cervista ® HPV HR is an FDA-approved test that screens for the presence of 14 high-risk HPV types

• 100% detection of CIN3+1,2 and 99.1% NPV for CIN2+

• First FDA-approved HPV screening test with an internal control

• Reduces patient callbacks– Limits QNS (only 2-ml sample volume required)– <1% indeterminate rate– No equivocal zone for interpretation

• Minimizes the risk of unnecessary colposcopies due to cross-reactivity with common low-risk HPV types

1. 100% CIN3 Detection in ASC-US: 95% CI (85.1% - 100%).2. Cervista® HPV HR [package insert]. Madison, WI: Hologic, Inc.; 2009 (P/N 15-3100).

QNS=Quantity Not Sufficient

Invader® Chemistry

• Structure-specific recognition and cleavage with Cleavase® enzyme

• Signal amplification

• Isothermal reactions

• Fluorescence detection

ProbeRepeating Process

Amplifies SignalCleavase®

Enzyme

Cervista® HPV HR: The Benefits of an Internal Control

• Cervista HPV measures human histone 2 gene (HIST2H2BE) for each reaction

• An internal control is needed for several purposes:– Assess cellular adequacy– Detect interfering substances– Serve as a processing control

Johnson LR, et al. Am J Clin Pathol. 2008;130:401-408.

Reduced Patient Callbacks and Retesting: Cervista® HPV HR Compared with hc2®

• Low sample volume requirement (2 mL) increases likelihood of sample availability for further testing

• Provides clear results without an equivocal (gray) zone

• Low overall indeterminate rate (0.57%) reduces need for patient callbacks

1. Einstein MH, et al. Gynecol Oncol. 2010. doi: 10.1016/j.ygyno.2010.04.013.2. Cervista® HPV HR [package insert]. Madison, WI: Hologic, Inc.; 2009 (P/N 15-3100).

3. Solomon D, et al. J Natl Cancer Inst. 2001;93(4):293-299.

Cervista® Clinical Performance Summary ASC-US Cytology

Central Histology Result Cervista® HPV HR Test

≥ CIN 2

Sensitivity (95% CI) 92.8% (84.1-96.9)

Specificity (95% CI) 44.2% (41.5-46.9)

NPV (95% CI) 99.1% (98.1-99.6)

PPV (95% CI) 8.3% (7.6-8.9)

≥ CIN 3

Sensitivity (95% CI) 100% (85.1-100)

Specificity (95% CI) 43% (40.3-45.7)

NPV (95% CI) 100% (99.4-100)

PPV (95% CI) 2.9% (2.4-3.0)

Source: Table 2 in Einstein MH et al, Gynecologic Oncology, 2010

5% rate of CIN2+

ACOG Practice Bulletin 99:CIN3 is the Most Significant Clinical Target

• Although not all CIN3 lesions will progress to cancer, it is generally considered to be a cancer precursor– CIN3 prevalence peaks between ages 25 years

and 30 years– Progression to cancer usually takes at least a

decade or longer

• The significance of CIN2 is less clear– The risk of progression to CIN3 or cancer appears greater

for women with CIN2 than for women with CIN1– However, up to 40% of women with CIN2 will have

regression of their lesions without therapy

ACOG Practice Bulletin No. 99. Obstet Gynecol. 2008;112(6):1419-1444.CIN = Cervical Intraepithelial Neoplasia

CIN3+ Sensitivity and Negative Predictive Value of FDA-Approved HR HPV Tests

Test Sensitivity for CIN3+ NPV

Cervista® HPV HR 100% (85.1%-100%)1,4

100% (99.4%-100%)1,3

Roche cobas® 93.5% (82.5%-97.8%)5

99.7% (99.2%-99.9%)5

hc2 (ALTS trial)* 96%2 95%2

1. Cervista® HPV HR [package insert]. Madison, WI: Hologic, Inc.; 2009 (P/N 15-3100).2. Solomon D, Schiffman M, Tarone R, et al. J Natl Cancer Inst. 2001 Feb 21;93(4):293-9.

3. 100% ≥ CIN3 NPV in ASC-US: 95% CI (99.4% - 100%). 4. 100% CIN3 Detection in ASC-US: 95% CI (85.1% - 100%)

5. Stoler H, Wright T, Sharma A, et al. Am J Clin Pathol. 2011 135:468-475.*Data are percentages and involve 95% confidence intervals.

Technology

FDA-Approved HPV Tests

Cervista® HPV1 Hybrid Capture 2®2 cobas® 4800 HPV3

Approval 2009 1999 2011

Indications for use • ASC-US reflex • ≥ 30 adjunct testing

• ASC-US reflex • ≥ 30 adjunct testing

Approved specimen types

PreservCyt® Solution •PreservCyt® Solution•Sample Transfer Medium

PreservCyt® Solution

HPV types detected 14 high-risk types 13 high-risk types 14 high-risk types

Genotyping (IVD) 16/18 genotyping None (ASR only) 16/18 genotyping

Technology Signal amplification utilizing Invader®

Chemistry

In vitro nucleic acid hybridization assay with signal amplification and chemiluminescence

Multi-channel real-time PCR

1. Cervista® HPV HR [package insert]. Madison, WI: Hologic, Inc.; 2009 (P/N 15-3100).2. Digene Corporation. Digene Hybrid Capture® 2 High-Risk HPV DNA Test® Package Insert. Gaithersburg, MD, 2007.3. Roche Molecular Systems, Inc. Cobas® HPV Test for In Vitro Diagnostic Use Package Insert. Branchburg, NJ, 2011.

SHENCCAST II Study Overview

• First independent clinical study evaluating performance of Cervista® HPV HR and hc2® in the same patient population

• 8435 patients in final analysis– 3 sites in rural Guangdong Province as well as “inner-city” Shenzhen– 25-59 years of age, mean 38.8

• Physician obtains a direct cervical sample:– Cytology – Computer-assisted detection using the I2 Imager– hc2® assay– Cervista HPV assay– MALDI-TOF assay

• Patients positive for high-risk HPV and/or cytology ≥ ASC-US were recalled, underwent colposcopy and biopsy

Belinson JL. Am J Clin Pathol. 2011 May;135(5):790-5.

Does Cervical Screening Remain the Standard of Care in a Post-Vaccine World?

Vaccine does not protect against every HPV type.It only covers 4 types—6,11, (low risk) 16,18 (high risk)

Vaccination will prevent most future pre-invasive disease and cancer, but does not treat active pre-invasive disease

Routine screening continues to be recommended by societies such as ASCCP, ACOG, SGO, American Family Practice Association

What Is the future of cervical cancer screening?

• Cytology primary with: – HPV DNA co-test or triage?– Other biomarker triage (p16, Ki67, etc)?

• HPV primary with: – Cytology triage?– HPV genotyping triage?– Other biomarker triage? – Re-test at specified interval?

Conclusions

• The incidence and prevalence of cervical cancer has dramatically declined as a result of screening --although more than 4000 women in the United States will die from it each year.

• Today, advances in screening technologies have enabled clinicians to effectively and efficiently identify women at greatest risk for developing cervical cancer.

• Guidelines, including ACOG and ASCCP, have incorporated the use of cytology, HPV testing, and HPV genotyping to identify and treat those women most likely to develop cervical cancer.

Questions?

The Importance of FDA Approvals

Why should I use an FDA‐approved test?•Increased lab and healthcare provider confidence•Established technology supported by data•Adherence to professional guidelines

A Premarket Approval submission must provide valid scientificevidence collected from human clinical trials showing that the device is safe and effective for its intended use. Products that

receive Premarket Approval are “FDA approved.”1

Nygaard I. Obstet Gynecol. 2008;111(1):4-6.

CDC STD Testing Recommendations

CDC recommends testing at least 80% of women aged 15‐25 years for chlamydia

CDC Fact Sheet: Human Papillomavirus. April 2008.CDC Fact Sheet: Chlamydia. December 2007. CDC Fact Sheet: Gonorrhea. December 2007.

CDC = Centers for Disease ControlSTD = sexually transmitted disease

Two‐period, retrospective analysis of ≈ 2 million specimens showed with the ThinPrep Pap Test:•Improvement was statistically significanta

•Significant decrease in false-negative proportion

•233% improvement in the HSIL detection in high-risk cases

•Decrease in ASC-US to SIL ratio

Large, Retrospective Study Confirms Superiority of ThinPrep® Pap Test

aAfter authors’ correcting for selection bias.ASC-US = Abnormal squamous cells of undetermined significanceSIL = Squamous intraepithelial lesionsHSIL = High-grade squamous intraepithelial lesions

HSIL Detection–Period 2

233% Increase in Detection

SIL Detection–Period 1

162%Increase in Detection

Limaye A, et al. Arch Pathol La Med. 2003;127:200-204.

In Routine Use, ThinPrep® Pap TestConsistently Increases HSIL Detection

Published Peer‐reviewed Literature Direct‐to‐Vial

TPPT = ThinPrep Pap TestCP = Conventional Pap aBased on odds ratio

Author, Date Journal% Increase

from CP Smear# of TPPT Samples

Bolick et al, 1998 Acta Cytol 173% 10,694

Papillo et al, 1998 Acta Cytol 55% 8,574

Diaz-Rosario et al, 1999

Arch Pathol Lab Med 103% 56,339

Guidos et al, 1999 Diagn Cytopathol 233% 9,583

Yeoh et al, 1999 Hong Kong Med J 28% 16,541

Ferris et al, 2000 J Fam Pract 119% 992

Weintraub et al, 2000

Diagn Cytopathol 244%a 39,455

Limaye et al, 2003 Arch Pathol Lab Med 233% 166,619

Improved HSIL Detection with ThinPrep® Pap Test

HSIL DetectionMedian Laboratory

Reporting Ratep Value

Conventional 0.3

p = 0.05ThinPrep Pap Test 0.6

SurePath 0.3

Eversole GM, et al. Arch Pathol Lab Med. 2010; 134:331-335.

A recently published survey of 679 laboratories by the College of American Pathologists found a statistically significant

increase in HSIL detection with ThinPrep Pap Test

An increase in HSIL detection of this magnitude yields an additional 3 HSIL cases per 1,000 patients

Meta-analyses of SIL Detection

Improved Detection with ThinPrep® Pap Test vs. Conventional Smear

AnalysisEvaluation of All Available

LiteratureQuantitative Analysis of 24 Published Studies

Meta-analysis of 25 Published Studies

Scope 37,449 TP samples 35,172 patients 221,864 TP samples

Conclusions

ThinPrep has greater sensitivity for ASC-US, LSIL, and HSIL compared with conventional Pap and similar specificity

ThinPrep is superior to conventional Pap for evaluating LSIL and HSIL, and is more sensitive and more specific

ThinPrep led to improved sample adequacy and improved diagnosis if LSIL and HSIL

SourceKlinkhamer P, et al. Cancer Cytopath. 2003;99:263-271.

Abulafia O, et al. Gynecol Oncol. 2003;90:137-144.

Bernstein S, et al. Am J Obstet Gynecol. 2001;185:308-317.

TP = ThinPrep

Detecting Glandular Abnormalities

Combined adenocarcinoma = Cervical and endometrial adenocarcinomaAGUS = Atypical glandular cells of undetermined significance

p < 0.001

p < 0.001p < 0.002

Study Findings:• Increased sensitivity for all adenocarcinoma• Reduced false‐negative rate by 52%• Reduced AGUS

Schorge JO, et al. Cancer Cytopathol. 2002;96(6):338-343.

ThinPrep® Pap Test vs. Conventional Smear

Prevalence of HR HPV in Cervical Cancer Specimens

• Analysis of 932 specimens from women in 22 countries indicated 99.7% prevalence of HPV DNA in cervical cancers1

• Meta-analysis of worldwide publications has documented HR HPV DNA in 87.3% of 14,595 invasive cervical cancers and 84.9% of 7,094 high-grade cervical lesions2

Walboomers JM, et al. J Pathol. 1999;189:12-19. Clifford GM, et al. Br J Cancer. 2003;88:63-73.

Persistent HR HPV infection is a necessary precursor for the vast majority of cervical cancers

Prevalence• Age

• Race

• Sexual history

• Geography

• Screening sensitivity (clinic type)

• History of abnormal cytology

Specificity• Age (higher specificity is

found in women ≥ 30 years of age)

• Presence of disease (≥ CIN 2) in the tested population

• Cross-reactivity to untargeted HPV

Population Heterogeneity Influences HPV Prevalence

Emerging Data Demonstrate Prevalence Within Expected Range for Cervista® HPV HR

Study NILM ASC-US

Chehak, et al.CVS. 2010.7

12.8% (2,039/15,878)

47.5%(837/1,763)

Recently presented data support the prevalence found with Cervista HPV HR in NILM and ASC‐US populations and are in

line with previously published literature1‐6

1. Sherman M, et al. J Natl Cancer Inst. 2003;93(1):46-52.2. Schiffman M, et al. JAMA. 2000;283(1):87-93.

3. Wright T, et al. JAMA. 2000;283(1)81-86.4. Belinson J, et al. Gynecol Oncol. 2001;83:439-444.

5. Bory JP. Int J Cancer. 2002;102:519-525.6. Petry KU, et al. Br J Cancer. 2003;88:1570-1577.

7. Chehak L, et al. CVS. 2010.

Clinical Performance Summary forCervista® HPV HR

Einstein MH, et al. Gynecol Oncol.2010. doi: 10.1016/j.ygyno.2010.04.013.

Trial Endpoint ≥ CIN 2 95% CI ≥ CIN 3 95% CI

Sensitivity92.8%(64/69)

84.1-96.9100%

(22/22)85.1-100.0

Specificity44.2%

(558/1,263)41.5-46.9

43% (563/1,310)

40.3-45.7

NPV99.1%

(558/563)98.1-99.6

100% (563/563)

99.4-100.0

PPV = Positive predictive value NPV = Negative predictive value

Compared with Colposcopy/Central Histology Results

Phylogenetic Tree Basis of Cervista® HPV HR Test Design

Los Alamos National Laboratory. Human papillomaviruses: a compilation and analysis of nucleic acid and amino acid sequences. 1997. Available at: http://hpv-web.lanl.gov/.

HPV Group HPV Types

A5/A6 51, 56, 66

A718, 39, 45, 59,

A916, 31, 33, 35,

52, 58

Analytical Performance of Cervista®

HPV HR• Analytical sensitivity

– ≤ 5,000 copies per reaction

• Analytical specificity– No cross-reactivity to low-risk HPV types (1a, 6, 11, 42, 43, 44, 53) detected when

tested up to 1 x 107 copies/reaction– No cross-reactivity to 17 organisms that may be present in the cervical specimen

• Reproducibility– 16 samples were subjected to 15 measurements: 3 sites × 5 days × 1 run/day

– 208/210 (99%) for positive expected results – 30/30 (100%) for negative expected results

• Precision – At 5,000 copies/reaction, the plasmid DNA samples yielded 97.2% (1,143/1,176) of

expected positive results

• Interfering substance testing– No interference by substances that could be present in the sample with the

exception of high levels of antifungal cream and contraceptive jelly

Cervista® HPV HR [package insert]. Madison, WI: Hologic, Inc.; 2009 (P/N 15-3100).

Invader® HPV Reagents Show High Analytical Concordance

Analyte Specific Reagent (ASR). Analytical and performance characteristics are not established.Data based on independent assessments using laboratory-developed tests with ASRs. Analytical and performance characteristics are not established.aAn additional discordant sample (Invader-negative, HC2-positive) was positive for HPV 53 by PCR. While considered “probably high-risk” by IARC, it is not recommended for inclusion in HR assays.bSamples tested with both Invader and HC2 methods; 5,788 samples were part of the study.

Study Citation SamplesConcordant

SamplesDiscordant Samples

Discordance Resolution in

Agreement with Invader®

Discordance Resolution in

Agreement with HC2®

Resolution Method

North Shore-Long Island Jewish Health System Laboratories1

821 TP673/821 (81.97%)

148/821(18%)

60/84(71%)

24/84(29%)

Cedars-Sinai Medical Center2 133 SP

115/133 (86.6%)

12/133(9%)

8/12(67%)

4/12(33%)

Roche HPV Linear Array

CompuNet Clinical Laboratories3 87 TP

71/87 (81.6%)

16/87(18%)

11/11(100%)

(0%)PCR

Regional Medical Laboratory4 207 SPb 188/207

(90.8%)19/207

(9%)12/18(67%)

6/18(33%)

1. Ginocchio CC, et al. J Clin Microbiol. 2008;46(5):1641-1646.2. Wong AK, et al. J Clin Microbiol. 2008;46(3):869-875.

3. Schutzbank TE, et al. J Clin Microbiol. 2007;45(12):4067-4069. 4. Johnson LR, et al. Am J Clin Pathol. 2008;130:401-408.

ary Re

action

Second

ary Re

action

ultane

Signal amplification is typically ≈ 107

per molecule of target sequence

Summary of the Invader® Chemistry Reactions

Cervista® HPV Core Technology

Invader Chemistry Biplex Reaction

Invader®Oligo

Probe Probe

FRET Cassette 1 FRET Cassette 2

Released 5´ Flap

Cleavage Site

Human DNA‐specific Target HPV‐specific Targets

Cleavage Site

Invader®Oligo

Released 5´ Flap

CleavageSite

F1 Q F2 Q

ThinPrep® Pap Test Provides Specificity to the Co-testing Model

Belinson J, et al. Gynecol Oncol. 2001;83:439-444.Clavel C, et al. Br J Cancer. 2001;84(12):1616-1623.

NPV PPV

Belinson et al1

ThinPrep Pap Test cytology for ≥ HSIL 99.0% 61.0%

HPV direct test for ≥ HSIL 99.8% 23.0%

Clavel et al2

ThinPrep Pap Test cytology for HSIL in women > 30

99.8% 15.1%

HR HPV for HSIL in women > 30 100.0% 8.7%

Use of HPV Genotyping to Manage HPV HRa‐Positive, Cytology‐Negative Women 30 Years and Older

HPV 16/18 Positive HPV 16/18 Negative

Both NegativeCytology Negative,

HPV-PositiveCytology Abnormal,

Any HPV Result

HR HPV Positive,Cytology Negative

Repeat BOTH tests at 12 months

Colposcopy

Routine Screening at 3 Years

ColposcopyManage per ASCCP

Guidelines

ASCCP = American Society for Colposcopy and Cervical PathologyaTest that detects any of the 14 HR (oncogenic) types of HPV.

ASCCP Algorithm for HPV GenotypingFor Resolution of Discordant Results in Reflex Testing Women ≥ 30 Years

Cost-effectiveness and Clinical Utility of HPV Testing

• For women with ASC-US:– Triage based on a positive HR HPV test detected

more ≥ CIN 3 cases and was less costly than immediate colposcopy or conservative management1

– HPV testing was highly sensitive for detecting ≥ CIN 3 with dramatically fewer referrals for older women2

Kulasingam SL, et al. J Natl Cancer Inst. 2006;98(2):92-100.Sherman ME, et al. J Natl Cancer Inst. 2002;94(2):102-107.

Risk of ≥ CIN 2 with Different Cervista® HPV 16/18 Genotyping Outcomes

Among Women with Positive Cervista®

HPV HR and ASC‐US Cytology

Cervista HPV 16/18 Result Risk of ≥ CIN 2 95% CI

HPV 16 and/or 18 Positive17.1%

(44/257)13.0%-22.2%

HPV 16 and 18 Negative4.0%

(20/500)2.6%-6.1%

Prevalence of CIN 2 or greater: 5.3%Einstein MH, et al. Gynecol Oncol. 2010. doi: 10.1016/j.ygyno.2010.04.013.

Cervista® HPV 16/18 [package insert]. Madison, WI: Hologic, Inc; 2009 (P/N 15-3101).

Risk of ≥ CIN3 with Different Cervista® HPV 16/18 Outcomes

Einstein MH, et al. Gynecol Oncol. 2010. doi: 10.1016/j.ygyno.2010.04.013.Cervista® HPV 16/18 [package insert]. Madison, WI: Hologic, Inc.; 2009 (P/N 15-3100).Prevalence of CIN 3 or greater: 1.7%

Among Women with Positive Cervista®

HPV HR and ASC‐US Cytology

Cervista HPV 16/18 Result Risk of ≥ CIN 3 95% CI

HPV 16 and/or 18 Positive6.6%

(17/257)4.2%-10.3%

HPV 16 and 18 Negative1.0%

(5/500)0.4%-2.3%

Clinical Performance Summary of the Cervista® HPV 16/18 Genotyping Test

Trial Endpoint ≥ CIN 2 95% CI ≥ CIN 3 95% CI

Sensitivity68.8%

(44/64)56.6-78.8

77.3%(17/22)

56.6-89.9

Specificity69.3%

(480/693)65.7-72.6

67.3%(495/735)

63.9-70.6

NPV 96.0%93.9-97.4

99.0% 97.7-99.6

Compared with Colposcopy/Central Histology Results

Einstein MH, et al. Gynecol Oncol.2010. doi: 10.1016/j.ygyno.2010.04.013.

Cervista® HPV 16/18 Test Design

• Cervista HPV 16/18 Genotyping Test individually identifies and differentiates HR types 16 and 18 – Identifies the 2 most highly oncogenic and

persistent HR HPV types known to cause high-grade cervical neoplasia

– Uses the same technology as Cervista HPV HR, and the test may be run from the same 2-mL specimen

Cervista® HPV HR [package insert]. Madison, WI: Hologic, Inc.; 2009 (P/N 15-3100).

Cervista® HPV 16/18 Test Indications

Indications for usea:

• In women ≥ 30 years the Cervista HPV 16/18 test can be used adjunctively with the Cervista HPV HR test in combination with cervical cytology to assess the presence or absence of HR HPV types 16/18.

• To be used adjunctively with the Cervista HPV HR test in patients with ASC-US cervical cytology results to assess the presence or absence of HR HPV types 16/18. The results of this test are not intended to prevent women from proceeding to colposcopy.

aCervista HPV 16/18 Genotyping Test results should not be used as the sole basis for clinical assessment and treatment of patients. Cervista® HPV HR [package insert]. Madison, WI: Hologic, Inc.; 2009 (P/N 15-3100).

Society Statements on HPV Genotyping

SGO– “HPV typing for the most common types of the disease –

HPV 16 and HPV 18 is also now available for clinical use. SGO believes that HPV testing and typing should be viewed as important, additional diagnostic and screening tools.”

– SGO did note the following caveats:• These tests should not replace other cervical cancer screening

methods, including regular Pap tests and gynecologic examinations• HPV testing and HPV typing should not be used as a prescreening tool

for HPV vaccinationACOG

– DNA tests specific for HPV 16 and HPV 18 can be used as an adjunct in women with negative Pap test results, but who have tested positive for HR HPV by an assay testing for 13 or 14 HR types

SGO. Statement Regarding the Role of HPV Testing and HPV Typing inCervical Cancer Prevention and Detection. March 2009.

ACOG Committee Opinion No. 431. Obstet Gynecol. 2009;113(5):1190-1193.

Analytical Performance of Cervista® HPV 16/18 Genotyping

• Analytical Sensitivity– Approximately 1,250 copies per reaction

• Analytical Specificity– No cross-reactivity to low-risk HPV types (1, 6, 11, 42, 43, 44, 53) detected when

tested up to 1 x 107 copies/rxn– No cross-reactivity to HPV types 35, 39, 45, 51, 52, 58, 59, 66, 67, 68, 70 detected

when tested up to 1 x 107 copies/rxn– No cross-reactivity to HPV type 31 detected when tested up to 1 x 106 copies/rxn – No cross-reactivity to 17 organisms that may be present in the cervical specimen

• Reproducibility– 16 samples were subjected to 15 measurements: 3 sites × 5 days × 1 run/day– 100% agreement for positive and negative expected results

• Accuracy – 94.1% (177/188) positive agreement (95% CI: 89.8%-96.7%)– 85.7% (460/537) negative agreement (95% CI: 89.8%-96.7%)

• Interfering Substance Testing– No interference by substances that could be present in the sample with the

exception of high levels of antifungal cream and contraceptive jelly

Cervista® HPV 16/18 [package insert]. Madison, WI: Hologic, Inc.; 2009 (P/N 15-3101).MISC-00510-001 Rev 003

Adenocarcinoma Increasing, Invasive Squamous Cell Decreasing

Per 10

Invasive Squamous Cell Carcinoma

InvasiveAdenocarcinoma

Adapted from Wang SS, et al. Cancer. 2004;100(5):1035-1044.

Historical SEER Trends in North American Incidence of Cervical Adenocarcinoma

Black, USAWhite, USACanadaHispanic

Year of Birth

Cumulative Ra

te per

1930 1940 1950 1960

SEER = Surveillance, Epidemiology, and End Results Vizcaino AP, et al. Int J Cancer. 1998;75:536-545.

Independent Validation of Clinical Benefits of ThinPrep® Imaging System

• A study of TIS published in 2008 compared 54,565 manually screened ThinPrep® Pap Tests with 55,547 imaged ThinPrep Pap Tests – LSIL detection increased 29% (p < 0.001)– HSIL detection increased 24% (p = 0.051)– Biopsy confirmation rate increased from 75.0% to 86.1%

(p < 0.05)– Increased positive predictive value of HSIL diagnosis (p < 0.05)

Results of surgical correlation and HPV testing validated an increase in detection rates of

ASC-H, LSIL, and HSIL, as well as increased PPV of HSIL with the ThinPrep Imaging System.

Papillo JL, et al. Diagn Cytopathol. 2008;36(3):155-160.ASC-H = Atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion

• Abnormal cells commonly have large dark nuclei because of increased amount of DNA

• To the human eye, the ThinPrep® Stain looks like a routine Pap stain

• The ThinPrep® Stain allows the Image Processor to measure DNA content

The Imaging System Identifies Areas of Interest for the Cytotechnologist

Normal

Abnormal

ThinPrep® Imaging System Detects Glandular Lesions

• Prospective clinical study of 70 cases with AGC1: – TIS correctly identified 68 cases (97%) containing AGC in specimens

containing malignant glandular cells– Both cases not identified were “found to contain only rare

diagnostic tumor cells in the specimen”

• Retrospective analysis of 662 AGC cases with tissue follow-up2:– Verification bias-adjusted Pap screening sensitivity for “significant

neoplastic cervical disease” utilizing TIS was 93% – 86% of AGC-detected carcinomas were endometrial or ovarian in

origin

AGC = Atypical glandular cells1. Friedlander M, et al. Cancer. 2008;114:7-12.

2. Zhao C, et al. Gynecol Oncol. 2009;114(3):383-389.

1st Review• Imager scans every

cell and cell cluster on the slide, measuring DNA content

2nd Review• Cytotechnologist reviews 22 fields containing “objects of interest”– Full slide screened if any

cells judged abnormal

Clinical benefits over manually reviewed ThinPrep® Pap Test1:

•Increased sensitivity

•Increased specificity

•Reduced false‐negative fraction

ThinPrep® Imaging System with Dual Review™

Review Scope

Image Processor

1. ThinPrep Imaging System Operation Summary and Clinical Information. Cytyc Corporation; 2003.

Independent Study Demonstrates Improved Detection with ThinPrep® Imaging System

In a split-sample study of 55,164 women, ThinPrep Imaging System resulted in:

•Fewer unsatisfactory slides (1.8% with TIS vs. 3.1% with conventional cytology; p < 0.001)

•More slides classified as abnormal – Overall: 7.4% abnormal with TIS vs. 6.0% for conventional cytology– For ≥ CIN 1, 2.8% abnormal with TIS vs. 2.2% with conventional

cytology

•Significantly increased detection of histologic high-grade disease compared with conventional cytology

Davey E, et al. BMJ. 2007;335(7609):31.TIS = ThinPrep Imaging System

Imaging System Focuses Slide Review

120 Fields of View 22 Fields of View

•TIS more sensitive than manual screening for:–ASC‐US–Higher‐grade lesions with equivalent specificity for ASC‐US

– LSIL•Glandular malignancies not included in original studies, but data now support

ThinPrep® Imaging System Is Statistically More Sensitive Than Manual Screening

Cells Are Collected in Liquid for Laboratory Processing

Sample collected

• Representative sample

• Even distribution of cells

• Minimal obscuring material

Dispersion/Collection/Transfer

LaboratoryHealthcare Provider Office

Liquid-based Pap Technologies Have Substantially Different FDA Claims

ThinPrep® SurePath®

Year of Original FDA Approval 1996 1999

Replacement for Conventional Pap

Improved Specimen Quality

Improved HSIL Detection

Significantly More Effective Than Conventional Pap

Improved Glandular Disease Detection

Approved for Adjunctive HPV Testing (2 tests)

Approved for Adjunctive CT/NG Testing (3 tests) (1 test)

Cervista® HPV HR hc2®

Year of FDA Approval 2009 1999

Internal Control Yes1 No

HPV Types Detected14 High-Risk Types(genotypes covered by hc2

plus HPV 66)13 High-Risk Types

Sample Size Requirement 2 mL1 4 mL

Cross-Reactivity With Common Low-Risk Types

None1 Yes3,4

IVD Genotyping Test Yes; same 2mL sample1 No (ASR only)

CIN3 Sensitivity 100% (CI: 85.1%-100%) 1,5 96.3% (CI: 91.6%-98.8%)2

Cervista® HPV HR Compared with hc2®

1. Consult package insert (http://www.cervistahpv.com/laboratory/cervistahpvhr/index.html) for full clinical details. 2. Solomon D, Schiffman M, Tarone R, et al. J Natl Cancer Inst. 2001 Feb 21;93(4):293-9.

3. Castle PE, Solomon D, Wheeler CM, et al. J Clin Microbiol. 2008 Aug;46(8):2595-604. 4. Poljak M, Marin IJ, Seme K, Vince A. J Clin Virol. 2002 Dec;25:S89-97.

5. 100% CIN3 Detection in ASC-US: 95% CI (85.1% - 100%)MISC-00977-001 Rev 001

Cervista® HPV FDA Clinical Trial Results Compared with ALTS Data

Data are percentages and involve 95% confidence intervals.Consult package insert (http://www.cervistahpv.com/laboratory/cervistahpvhr/index.html) for full clinical details.

Solomon D, Schiffman M, Tarone R, et al. J Natl Cancer Inst. 2001 Feb 21;93(4):293-9. 100% ≥ CIN3 NPV in ASC-US: 95% CI (99.4% - 100%).

100% CIN3 Detection in ASC-US: 95% CI (85.1% - 100%)

≥CIN2 Detection

≥CIN3 Detection

≥CIN2 NPV

< 60% Colposcopy Referral Rate

Trial End‐PointCervista® HPVClinical Trial 1

93% (84.1‐96.9)

100%1,4 (85.1‐100.0)

99.1% (98.1‐99.6)

57% (All subjects)44% (Women >30)

hc2® ALTS Trial2

≥CIN3 NPV 100%1,3 (99.4‐100) 99.5%

MISC-00977-001 Rev 001

HPV€¦ · • HPV 16 (54%) and HPV 18 (21%) account for the majority of cervical cancers...

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