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Clinical Use of HPV DNA Testing
Thomas C. Wright, Jr.College of Physicians and Surgeons of Columbia
University
Clinical Uses of HPV Testing
Spectrum of HPV associated disease
Clinical uses of HPV DNA testing
Topics to be covered:
Anogenital HPV Infections
Latent infection - no identifiable lesion
Exophytic condylomas
Low-grade and high-grade neoplasia
Invasive cancersCervix, vulva, anus, penis, head &
neck, esophagus, conjunctiva
Spectrum of clinical expression
Clinical Spectrum of Genital Infections
Latent Infection Genital Warts
Clinical Spectrum of Genital Infections
CIN 2,3 Invasive Cancer
Anogenital HPV Types
High-risk types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82
Possible high-risk 23, 53, 66
Low-risk types 6, 11, 40,, 42, 43, 44, 54, 61, 70, 72, 81
Munoz et al. (2003) NEJM
Wright and Schiffman (2003) NEJM
Natural History of HPV Infections
Clinical Uses of HPV Testing
Spectrum of HPV associated disease
Clinical uses of HPV DNA testing
Topics to be covered:
HPV DNA Testing
Management of ASC - US
Secondary follow-up - abnormal Pap
Follow-up post treatment
Primary screening
Potential clinical uses:
Atypical Squamous Cells -Undetermined Significance (ASC - US)
HPV Testing for Detecting CIN 2,3 in ASC
Wright* 144 0.78 54% 0.67 63%Manos* 995 0.89 40% 0.76 39%Bergeron 111 0.83 43% 0.67 32%Lin 74 1.00 53% -- -- Shlay 200 0.93 31% -- -- Solomon* 2324 0.96 56% 0.85 58%
HPV Testing Cytology Author No. Pts Sens Refer Sens. Refer
*from liquid cytology
2001 Consensus Guidelines
All three standard modalities are considered safe and effective (A I)
Because of costs, and patient convenience, "reflex" HPV testing is preferred if liquid-based cytology or co-collection available(A I)
Management of ASC-US:
Management of ASC-US
About 2.5 million ASC-US per year in U.S.
70% - 80% of these are liquid-based cytology specimens
70% - 80% of these get "reflex" HPV DNA testing and growing
Status as of January 2004:
HPV DNA Testing
Management of ASC - US
Secondary follow-up - abnormal Pap
Follow-up post treatment of CIN 2,3
Potential clinical uses:
HPV DNA Testing
Management of ASC - US
Secondary follow-up - abnormal Pap
Follow-up post treatment
Primary screening
Potential clinical uses:
HPV Testing for Screening
Who gets screened
Testing method and with or without Pap
Screening frequency
Management of screen positives and negatives
Questions to address:
Prevalence of HR HPV DNA
Netherlands^ 13% 10% 2% 2%Costa Rica^ 10% 6% 3% 3%Newfoundland* 17% 12% 5% 4%UK*^ 3% 3% 5%France* 21% 20% 13% 11%
% HPV (+) by AgeCountry < 25 25-34 35-44 45+
* all women, women without SIL, ^ by PCR, by HC II
HPV by PCR CIN3 +
0 %
5 %
10 %
15 %
20 %
25 %
18-19
20-24
25-29
30-34
25-29
20-24
18-19
35-50
30-34
35-50
Kulasingham SL et al JAMA 2002;288:1749-57.
Age-specific Prevalence of HPV and CIN 3 + in Planned Parenthood Study
HPV Testing for Screening
Women 30 years and older
FDA approval
ACOG Practice Bulletin
ACS Guidelines & NCI Workshop
May change with increased data
Age to initiate testing:
Primary Screening - Sensitivity: CIN 3+
Study No. Pap HPV Combo
Portland 10,031 52 71 81U.K. 9,761 90 94 98Mexico 6,115 58 95 97Costa Rica 6,176 82 94 97South Africa 2,925 84 90 93China 1,936 98 100 100Baltimore 1,040 50 100 100Germany 7,592 52 96 100
Primary Screening - Specificity: CIN 3+
Study No. Pap HPV Combo
Portland 10,031 98 92 91U.K. 9,761 97 97 96Mexico 6,115 99 94 93Costa Rica 6,176 94 94 90South Africa 2,925 86 80 76China 1,936 76 83 68Baltimore 1,040 98 96 96Germany 7,592 99 96 95
HPV Testing for Screening
Negativity for high-risk HPV identifies which women are at very low risk forhaving or developing CIN 2,3 over next 3 yrs
Allows targeted screening
Key advantage of using:
Predictive Value of HPV
20,817 women with adequate cytology at enrollment (1994-1996)
Tested frozen CVL samples with HC II
Follow-up was with cytology and "standard workup" of abnormals
NCI - Kaiser Portland, OR cohort:
Sherman (2003) JNCI
QuickTime™ and aGraphics decompressorare needed to see this picture.
0 0-9 9-21 21-33 33-45 45-122
0%
1%
2%
3%
4%
5%
6%
7%
8%
Length of Follow-up (mos)
Development of CIN 3 on Follow-up
HPV +
Pap & HPV Neg
HPV Testing for Screening
NCI, ASCCP, and ACS sponsored an experts' workshop to develop guidance for using HPV for screening.
Meeting held February 2003
Interim Guidance:
Wright et al. Obst. Gynecol. (2004)
NCI - ASCCP Interim GuidanceHPV DNA as an Adjunct to Cytology
HPV (-)ASC-US
BothNegative
Colposcopy
Pap> LSIL
Repeat Pap & HPV in 3 yrs in 12 mos
HPV (+)ASC-US
Results of HPV and Cytology
HPV Testing for Screening
Will definitely produce some level of anxiety in almost all patients
Concern was that clinicians would immediately perform colposcopy to rule out high-grade neoplasia
Very expensive - overload the system
Key issue is HPV (+) / Cytology (-)
LoSIL
HiSIL
Cancers
Deaths5,000
15,000
250,000
1,000,000
1,250,000 ASCUS1,250,000
1,875,000 (7.5% of 25 million) HPV (+)
Patient's comments when told about availability of HPV DNA
testing for screening
"Why the hell am I having a Pap smear every year if its not really finding out what we really need to find out? I would be really upset."
Anhang et al. (2004) Cancer
Screening is all about risk. So what's the
risk?
HPV (+) and Cytology (-)
Clavel - France: 4.2%
Cuzick - England: 2.8%
Wright - South Africa: 7.8%
Risk for CIN 2+ at 6 mos:
HPV (+) and Cytology (-)
Clavel - France:
10 of 10 CIN 2+
Cuzick - England:
9 of 9 CIN 2+
Wright - South Africa:
13 of 14 CIN 2+
Repeat HPV (+) @ 6 mos:
HPV (+) and Cytology (-)
Clavel - France: 40%
Cuzick - England: 55%
Wright - South Africa: 60%
Rates of HPV persistence - 6 mos:
Negative Cytology - HPV DNA Positive
Repeat both Pap & HPVIn 6 to 12 mos
HPV (-)ASC-US
High-risk HPV (+)
Colposcopy
BothNegative
Pap> LSIL
Repeat Pap & HPV in 12 mo. in 3 yrs
Clinical Uses of HPV Testing
Spectrum of HPV associated disease
Clinical uses of HPV DNA testing
Topics to be covered:
