Clinical Relevance of HPV Genotyping. A New Dimension In Human Papillomavirus Testing. w w w. a u t o g e n o m i c s. c o m

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1 Clinical Relevance of HPV Genotyping A New Dimension In Human Papillomavirus Testing

2 Human Papillomavirus: Incidence HPV prevalence was 26.8% for women in US aged yrs 1 20 million Americans are currently infected million become newly infected each year 3 By 50 years of age, 80% of women have had a HPV infection % of cervical cancers caused by chronic HPV infections 1. E.F. Dunne, et al., Prevalence of HPV Infection Among Females in the United States, JAMA, Feb.28, 2007, Vol.297, No. 8, pp J.L.Gergerding Report to Congress, Prevention of Genital Human Papillomavirus Infection, Center for Disease Control and Prevention, Dept. of Health and Human Services, Jan

3 Testing Guidelines ACOG Cervical Cancer Screening guidelines (July 31, 2003 press release) (partial list of guidelines shown) First screen -- Screening of cervical cytology (cervical cells) start 3 years after first sexual intercourse or by age 21, whichever comes first. Women up to age Annual cervical cytology screening. Women under age 30 have a higher likelihood than older women of acquiring high-risk types of HPV that cause pre-malignant cervical disease, which should be ruled out before extending the testing intervals. Women age 30 and older -- two acceptable screening options Testing using cervical cytology alone. Negative results on three consecutive annual cervical cytology tests Re-screened with cervical cytology alone every 2-3 years. Cervical cytology test and an FDA-approved test for high-risk types of HPV Negative on both tests they should be re-screened every 3 years. If only one of the tests is negative, however, more frequent screening will be necessary. The combined testing is not appropriate for women under age 30, since they frequently test positive for HPV that will clear up on its own.

4 HPV DNA Testing Changes Impending Changes: Screen primarily with HPV DNA assay Follow-up positive results with liquid cytology 1 1. Dr. Ronco American Society of Clinical Oncology, Web site posting of a Lancet Oncology excerpt: June 28 th, 2006 (

5 Why HPV Genotyping Is Key Together, women with ASCUS or LSILs who were HPV16-positive had the highest 2-year risk for CIN3 compared with women who were HPV-negative 1 1. P.E. Castle, et al., Human Papillomavirus Type 16 Infection and 2-Year Absolute Risk of Cervical Precancer in Women With Equivocal or Mild Cytologic Abnormalities, JNCI, Vol. 97, No. 14, July 20, 2005, P

6 Risk Associated With HPV Types ALTS ASCUS LSIL Triage Study HPV Risk Category Risk % CIN3 ASCUS w/hpv ASCUS w/ Oncogenic HPV LSIL w/hpv All ASCUS 8.8 P.E. Castle, et al., Human Papillomavirus Type 16 Infection and 2-Year Absolute Risk of Cervical Precancer in Women With Equivocal or Mild Cytologic Abnormalities, JNCI, Vol. 97, No. 14, July 20, 2005, P

7 Risk Associated With HPV Types Risk of Squamous-Cell Cervical Cancer HPV Type Odds Ratio (95%CI) 1 Type Type Type Type Type Type HPV neg 1.0 N.Munoz, et al., Epideminologic Classification of Human Papillomavirus Types Associated With Cervical Cancer, NEJM Vol.348, No.6, Feb.6, 2003, P

8 Risk Associated With HPV Types 19.9% of HPV Type-16 Diagnosed with CIN3/cancer at enrollment or within the 5 year follow-up Schiffman, M., et al., Carcinogenicity of Human Papillomavirus Types Reflects Viral Evolution, Virology, Jun 20, Vol. 337, No.1, 2005, P

9 Risk Associated With HPV Types Our data ( Table 1 ) suggest that HPV DNA screening of the general population of women aged 30 years and older, with separate typing of HPV16 and HPV18, might be a more powerful predictor of future CIN3 and cancer than ASC or even LSIL cytology. (1) 1. M.J.Khan, etal. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice, JNCI, Vol.97, No.14, p , July 20, 2005.

10 Risk Associated With HPV Types Based on our data, we suggest that separating HPV16 and HPV18, the two most risky oncogenic HPV types, from the other oncogenic HPV types would help to identify, among HPV positive women, the majority destined to progress to CIN3, justifying immediate colposcopy of this subset of infected women and providing reassurance regarding the safety of a 12-month interval without colposcopy if other oncogenic HPV types are detected. 1 HPV persistence is more likely with HPV16 1. M.J.Khan, etal. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice, JNCI, Vol.97, No.14, p , July 20, 2005.

11 Risk Associated With HPV Types Women with non-hpv16/18 oncogenic HPV infections will still need to be followed more carefully than women without oncogenic HPV infections, but perhaps more conservatively than women with HPV16 and HPV18 infections. This new screening strategy could help to reduce the number of women who are referred to colposcopy for a positive HPV test (1) 1. M.J.Khan, etal. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice, JNCI, Vol.97, No.14, p , July 20, 2005.

12 SEER Incidence Rates Incidence of cervical cancer begins between ages years old Age-Specific (Crude) SEER Incidence Rates by 'Expanded' Race For Cervix Uteri Cancer, Females SEER 17 Registries for nce&site=cervix+uteri+cancer&x=17&y=16

13 Multiple Type HPV Infections 8.1% (141 patients / 1739 total HPV positives) presented with multiple HPV types Risk of squamous-cell cervical cancer with Type16 plus any other high risk type: Odds Ratio Type 16 alone Odds Ratio N. Munoz, et al., Epideminologic Classification of Human Papillomavirus Types Associated With Cervical Cancer, NEJM Vol.348, No.6, Feb.6, 2003, P

14 Digene HPV DNA Test The Digene HPV DNA Test determines the presence of high risk types The assay does not determine the presence of individual or multiple types

15 INFINITI HPV Genotyping* *Research Use Only (RUO) Identified 26 HPV Types simultaneously BioFilmChip microarray

16 INFINITI HPV Genotyping*: Specifications HPV Genotypes: High Risk 16,18,31,33,34,35,39,45,53,58,59,66,68 High Intermediate Risk 26,51,52,56,67,69,73,82 Low Risk 6,11,30,70,85 Sample: Sample Preparation: Method of identification: Method of Hybridization: Liquid Cytology Specimens SurePath ThinPrep Single Tube Multiplex PCR PCR / Detection Primer Extension Zipcode / Anti-Zipcode * Research Use Only

17 INFINITI Analyzer Load: Reagents, Amplified Samples & Go RESULTS Amplified Sample

18 INFINITI HPV Genotyping*: Detection Example HPV genotype reports from the INFINITI Analyzer * Research Use Only

19 Conclusion Managing costs associated with increased detection of positive HPV patients is needed Risk varies with HPV types High risk HPV types can be identified HPV genotyping will help manage HPV positives