1. Will Pap Smears become a thing of the past? J. L. Ellis, M.D.
The Role of Human Papillomavirus (HPV) Infection in Abnormalities of the Cervix
Will Pap Smears become a thing of the past?
J. L. Ellis, M.D.

2. Learning Objectives
To understand the role of HPV in causing abnormalities in the Cervix as well as abnormal pap smears
To understand the strengths and weakness of current pap testing as well as HPV testing
To become familiar with the current status of HPV vaccine development and the role this may play in the future

3. Cervical Cancer Facts
At the beginning of the 1900’s the single most common cause of cancer death among women was cervical cancer
By the year 2000 it was the 11th most common cause of cancer death in women
This is almost entirely a result of the pap smear

4. Cervical Cancer Facts
In the developing world where pap testing is not available cervical cancer is the number one cause of cancer death in women

6. Human Papillomavirus (HPV)
It is no longer a mystery as to what causes cervical cancer
It is the lowly wart virus
It is very rare to have a virus known to cause cancer!
There are > 200 known HPV types

7. Human Papillomavirus (HPV)
HPV is a double stranded DNA virus
The different types are tissue specific
HPV-1 causes plantar warts
HPV-2 and 4 cause common skin warts
HPV 6 and 11 cause genital warts
HPV 16 and 18 cause anogenital cancers

8. Human Papillomavirus (HPV)
About 40 types infect the anogenital tract
About 66% of these are types 6, 11, 16 and 18
About 20 HPV types can cause cancer
80% of cancers are due to types: 16, 18, 31 and 45
HPV cause >99% of cervical cancers

9. Human Papillomavirus (HPV)
HPV type 16 and 18 were first isolated from cervical cancer in 1984
The relationship between HPV and cervical cancer is VERY strong
It is times stronger than the relationship of cigarette smoking to lung cancer

10. Human Papillomavirus (HPV)
It is the single most common venereal disease but it is rare to detect clinically since most are asymptomatic
> 5 million Americans-infected yearly
20-50 million Americans are currently infected
Between 50-90% of American Women will become infected at some point in their life

11. Human Papillomavirus (HPV)
Condoms do not effectively prevent HPV infection but may decrease cancer risk
It may be possible to spread the virus via exfoliated HPV infected cells such as on shared underwear
Believe it or not toilet seats can indeed be contaminated with HPV infected cells

12. Human Papillomavirus (HPV)
For two uninfected individuals who have never had any sexual partners except each other the risk of HPV infection is essentially zero
Vaccination against HPV 16 and 18 prior to the onset of sexual activity has the potential to be highly effective at preventing cervical cancer

13. Human Papillomavirus (HPV)
The incidence of infection falls with age
35-50% of women in their 20’s are infected
Less than 20% of women in their 30’s
5-10% of women after age 50 are infected
Adolescents may be biologically more susceptible to HPV infection due to a difference in the anatomy of their cervix

14. Human Papillomavirus (HPV)
Most HPV infections are transient and usually last about 1 year
About 50% of women in their 20’s will clear an HPV infection on there own in 18 months without treatment
By age more than 90% of women have cleared HPV and test negative for it
A few remain HPV + (persistent inf.)

15. Human Papillomavirus (HPV)
Persistent HPV infection is a major risk factor for developing cervical cancer
Persistent infection is defined as having the same specific TYPE of HPV (16, 18 etc.) detected at least twice over 1-2 years
Persistent infection is more common with the high risk types of HPV

16. How is HPV transmitted? Permissive vs. nonpermissive infections
“Permissive” permits full virus replication into a particle that can infect other people
“Nonpermissive” refers to the virus integrating into the host DNA and not being capable of infecting other people

21. How good is the pap “smear” for identifying HPV infections?
The pap smear is the single most effective cancer reduction program ever devised
It is NOT PERFECT!
It requires a number of steps to be in place
Patient-Probably the most important
Health Care Provider
Cytotechnologist
Pathologist

22. Why is the patient the most important link in the chain?
Univ of Chicago study of Cervical Cancer patients showed:
Almost 400 had never had a pap or had not had one in the last 10 years
Of 50 that had a pap test in the previous 5 years that had been abnormal:
42 had not returned for therapy

23. How good is the pap “smear” for identifying HPV infections?
The pap smear probably picks up 50% of abnormalities of the cervix
As such it is crucial to obtain routine pap tests to increase the pick up rate
The pap test doesnt show the virus but shows changes in the cells caused by it

25. How good is the pap “smear” for identifying HPV infections?

26. How good is the pap “smear” for identifying HPV infections?
Since koilocytes are not always shed from the surface of the cervix they are consequently only seen in about 20-33% of women with HPV infection
These koilocytes are indicative of a “permissive” infection
They are usually absent in “nonpermissive” infections where the virus has integrated into the host DNA

27. Are there other methods for testing for HPV infection?
Hybrid Capture-is the method most commonly used to detect HPV infection

28. What is the HPV DNA hybrid capture test?
A complementary RNA probe for either high risk types or low risk types of HPV can be used
The probe for high risk types includes HPV types 16, 18, 31, 33, 35, 39, 45 and others
It will not tell you what type is there it will only tell you that a high risk type is present

29. What is the HPV DNA hybrid capture test?
The target HPV DNA is combined with the RNA probe to form a DNA-RNA “hybrid”
This “hybrid” is then “captured” with an antibody to DNA-RNA hybrids
This will detect down to about 5000 virons per milliliter of sample

30. Is there a test even more sensitive for HPV detection?
Polymerase chain reaction is a method in which the HPV DNA is multiplied millions of times in a test tube and then probed
In theory this should detect a single virus particle in 1 million cells
This sensitivity is so high that it often picks up things that are not there
Some HPV genotypes are patented!!!!
What was patent office thinking?

31. Combined Pap and HPV testing
The combination is felt to have a sensitivity approaching 95%
The negative predictive value is high
If both are negative then the patient can be followed with a combination of both every 3 years and NOT yearly
Cost is a real issue! Hybrid Capture HPV testing is over $200

32. Low risk and High Risk HPV types
All anogenital HPV’s can induce low grade lesions because these are the productive types of infections that allow spread from person to person
High risk viral types (type 16, 18 etc) are more likely to integrate into the hosts DNA and produce high grade lesions and cervical cancers

33. Low risk and High Risk HPV types
HPV can only integrate in the actively dividing basal cells while the permissive infections are occurring above this level

34. How does the integrated HPV cause cancer?
The HPV DNA “hijacks” the host cell
Two host genes are responsible for controlling cell division and repairing damage DNA (Rb gene and p53 gene)
The HPV DNA cause the cell to produce proteins that block these two genes resulting in loss of control of the cell division and inability to repair itself

39. How does the integrated HPV cause cancer?

40. Since this cancer is caused by a virus could a vaccine be used?
Two companies (Merck and Glaxo) and the NIH are looking into this
The Lancet Oncology, May looked at 552 women age who had never had an abnormal pap smear
They received 3 total injections of HPV vaccine against types 6,11,16 and 18 and then followed for 30 months after the last shot

41. Since this cancer is caused by a virus could a vaccine be used?
The study showed a 90% reduction in infection in the 30 month period than the placebo group for those 4 types of HPV

42. What is the status of the vaccine
Merck quadrivalent vaccine 6,11,16,18 should be approved by July
The use will be in preadolescent girls ages with catch up in women up to 25 y/o
It is given in doses: 0, 2 and 6 months
Estimated cost is $300-$500

43. What is the status of the vaccine
It is probably not a lifetime protection
FDA will likely make it recommended but not mandatory
There is no reason to make vaccination a requirement for public school attendance
Making vaccinations mandatory would require action by individual states

44. Summary HPV causes >99% of cervical cancer
80% of cervical cancers are caused by 1 of 4 types of HPV: 16, 18, 31 and 45
Pap test are good screen but not perfect!
Patient is the most important link in chain

45. Summary
Combined Pap/HPV testing improves the sensitivity over either test alone
HPV vaccine is almost here and may help in lowering the risk of HPV associated abnormalities of the cervix
The vaccine is expensive and it is unknown whether it will be accepted

46. Special Thanks
Robert Sloss, M.D.
Diane Davey, M.D.

47. Will Pap Smears become a thing of the past? J. L. Ellis, M.D.
The Role of Human Papillomavirus (HPV) Infection in Abnormalities of the Cervix
Will Pap Smears become a thing of the past?
J. L. Ellis, M.D.