1. Clinical Uses of HPV DNA Testing
Shobhina G. Chheda MD MPH
February 1, 2006
No financial disclosures
Good morning. Before I start I would like to introduce two colleagues Lori Haack and Suzanne Baker from UWHC cytopathology lab who have been very interested in this area as well as Pap testing. Many of your clinic staff have had inservices done by Lori and Suzanne. They will tell you briefly about work they are doing and the focus of the inservices they have been providing to staff.

2. Objectives Review natural history of HPV
Discuss pros and cons of combined cytology and HPV DNA testing for primary screening
Outline management if combined testing done
Recognize utility of HPV DNA testing for abnormal cytology results
Review use of HPV DNA testing for colposcopy follow-up

3. Anogenital HPV types “Low risk” types “High risk” types (11)
6, 11 (Genital warts)
“High risk” types (11)
16, 18, 31, 33, 45, 56
More than a 100 types of HPV types have been described and greater than 40 types have been found to infect the human anogenital tract.
These HPV types are generally broken down into low and high risk types. Low risk types are mainly found in genital warts and high risk types are associates with invasive cervical cancer.
There are many Hpv types that are rare where no clear consensus has been reached in terms of categorizing them as high or low risk types.
For our purposes the most important thing to realize is that the types most often associated with genital warts 6 and 11 do not place individuals at direct increased risk of cervical cancer.
There are 11 high risk types that are consistently classified as placing women at risk of cervical cancer. Types 16,18,31,33 and 45 are the most common worldwide. With Type 16 accounting for 53% of worldwide cases of cervical cancer and 18 for 13% of cases in a study published by Monoz et al in 2203.
53%
13%
Munoz et al NEJM 2003

4. So what are the possibilities once a woman is infected with a high risk HPV type? It has been shown that between 60-75% of young women are infected with HPV .We know that the majority of women have only transient infection and do not go on to develop persistent infection. However, during the time of transient infection women may develop mild cytological abnormalities. It is felt to be only those with persistent infection that go on to develop precancerous lesions such as CIN 2 and 3 or invasive cervical cancer.
Wright et al NEJM 2003

5. Persistence of HPV infection in women without cervical cancer
% persistent at
Authors
No Pts
Mean age yrs
Type of Infection
6 mos
12 mos
24 mos
Woodman
1075 20
incident
24% 4%
< 1%
Moscicki
618
prevalent
50%
30%
10% Ho
608 _ 8%
Ahdieh
439 32
both
47%
36%
19%
Sun
231 34
35%
18%
Richardson
635 23
62%
Many studies have been done to determine rates of persistence. This slide summarizes results from various studies. The studies differ with respect to whether they enrolled women with new or prevalent infection. However you can see that at 24 months only up to 20% of women continued to show the same type of virus that they had initially. (Detecting the same type of HPV at subsequent visits)
Wright and Cox: Clinical Uses of HPV Testing

6. So what are the possibilities once a woman is infected with a high risk HPV type? It has been shown that between 60-75% of young women are infected with HPV .We know that the majority of women have only transient infection and do not go on to develop persistent infection. However, during the time of transient infection women may develop mild cytological abnormalities. It is felt to be only those with persistent infection that go on to develop precancerous lesions such as CIN 2 and 3 or invasive cervical cancer.
Wright et al NEJM 2003

7. “Clearance” ?? Possible explanations HPV DNA + to –
Immune system activated and completely eliminates
Immune system activated and decreases amount of virus shed to undetectable levels
Prolonged viral latency

8. Case of LR…
32 year old woman who has had “regular yearly Pap testing” (always normal) comes in for saying she recently saw some ads for a new test for HPV and she would like this done to screen for cervical cancer.
Should you do the HPV test along with her Pap?

11. Arguments for combined testing
Supported as option by ACS and ACOG
Age older than 30
Sensitivity for CIN 2, 3
HPV alone %
Single conventional Pap 50-90%
Single liquid- based Pap 70-90%
Extremely high negative predictive value
to 1.000
If both negative, extend interval to q3 years
For women over age 30…

12. Arguments against combined testing
Specificity CIN 2, 3
HPV alone 80-90%
Single conventional Pap 95%
Single liquid-based Pap 94%
In women > 30
5-15% HPV DNA +
0.5-1% CIN 2,3 or cervical cancer
Increased anxiety for no reason

13. Clavel et al Br. J Cancer 2001

14. Arguments against combined testing
In women > 30 with three negative consecutive Pap tests can space Pap only testing to q 2-3 years
Cost HPV test - $ 85 …..
Did we need another test?
Half of cases of cervical cancer (6,000 /yr) attributable to under screening

15. Bottom line on combined testing
Unlikely that changing from cytology alone to combined testing will significantly reduce risk of developing cervical cancer
May help space testing out for additional group of women
those >30 who have not yet had 3 consecutive normal Pap tests

16. Counseling of LR…. How will the test “help” her…
How could the test “harm” her…
Answering her questions about HPV…
Coming soon…..

17. Results obtained on cytology and HPV DNA testing
Wright et al. Obst Gynec 2004.

18. Use of HPV DNA test Management of ASCUS- “Reflex” HPV test
Run on same sample-liquid based test
Run on second sample collected initially
Management of LSIL
Usually do not* order HPV test on same sample
Adolescent- test at 12 months
Low- risk post-menopausal*- test at 12 months
If HPV + send for colposcopy

19. Use of HPV DNA test Colposcopy negative or CIN 1 follow-up
Single colposcopy can miss 1/3 of CIN 2,3
Test at 12 months if initial cytology
ASCUS
LSIL
ASC-H
If HPV + repeat colposcopy
Post-treatment CIN 2, 3 follow-up
Test at 6 months
Repeat cytology

20. Do not use: HPV DNA test STI screening Men
Women less than 30 for screening
Cannot use to space interval of screening in immunosuppressed women
Repeat cytology

21. Self-assessment answers

22. Objectives Review natural history of HPV
Discuss pros and cons of combined cytology and HPV DNA testing for primary screening
Review management if combined testing done
Highlight utility of HPV DNA testing for abnormal cytology results
Review use of HPV DNA testing for colposcopy follow-up