1. Latest update on Cervical Cancer Screening
guidelines and clinical published data
Michael D. Randell MD
Obstetrician and Gynecologist
Atlanta, Georgia

2. Objectives of Today’s Presentation
Burden of cervical cancer on women’s lives & U.S. prevention efforts
Latest guidelines for HPV DNA testing & interval extension
HPV test: Predictor of a woman’s risk for developing cervical disease
What do patients want to know about cervical cancer screening?
HPV vaccines - Will that make cervical screening obsolete?
Are the other HPV tests clinically better?
Cervical cancer is the easiest female cancer to prevent, with regular screening tests and follow-up. Two tests can help prevent cervical cancer or find it early:
The Pap test (or Pap smear) looks for precancers, cell changes on the cervix that might become cervical cancer if they are not treated appropriately.
The HPV test looks for the virus that can cause these cell changes.
We will review today the latest guidelines for Cx Ca screening and how to apply them to protect your patients and your practice.
We will review common questions about vaccines, counseling and other HPV tests

3. Cervical Cancer in U.S. Estimated Cancer New Cancer and Deaths in 2009
11,270 cases - invasive cervical cancer
4,070 deaths from cervical cancer
1 out of 50 cancer-related deaths
According to data from the American Cancer Society, in 2009 there were about 11,000 cases of invasive cervical cancer diagnosed in the US and 4,070 women died of this disease. This reflects the remarkable triumph of cytological screening for cervical cancer in the United States. Having said this, despite the fact that cervical cancer can be prevented by screening - each day 13 women die of this disease in the U.S.
Source: American Cancer Society - Facts and Figures 2009

4. Natural history of cervical cancer
Avg months
Avg. 10 years
HPV infection
CIN 1,2
CIN 2,3
Invasive Cervical Cancer
HPV disappearance
Avg months
Ho GY, et al. New England Journal of Medicine. 1998,338:
Bory JP, et al. Int J Cancer, 2002;102:
Nobbenhuis MAE, et al. Lancet. 1999;354:20-25.

5. Longitudinal Study of HPV persistence and CIN 2+
Critical role of age and duration of HPV infection
More than 90% of new infections with carcinogenic HPV types clear
Regardless of the woman’s age, newly detected infections were associated with very low absolute risks of persistence, CIN 2, or worse disease
Long duration of infection predicts
Risk of further persistence
Risk associated with CIN 2+
Cervical Cancer
At enrollment, of the 9466 participants eligible for pelvic examination, 9175 were screened for cervical neoplasia using multiple methods; those with CIN 2 or worse disease were censored and treated. Participants at low risk of CIN 2 or worse (n = 6029) were rescreened at 5 – 7 years (passively followed), whereas higher-risk participants (n =2115) and subsets of low-risk women (n = 540) and initially sexually inactive women (n = 410) were rescreened annually or semiannually (actively followed) for up to 7 years. HPV testing was done using a polymerase chain reaction – based method.
Rodriguez AC et al, J Natl Cancer Inst 2010;102:315–324

6. Clearance of carcinogenic HPV infections during 30 months of follow-up
Clearance of carcinogenic HPV infections during 30 months of follow-up. (n = 800 infections)
The x-axes represent months of follow-up, and the y-axes represent the percentage of infections that cleared ( unshaded ), persisted without evidence of cervical intraepithelial neoplasia grade 2 or worse (CIN2+; stippled ), or persisted with evidence of CIN2+ ( solid shading ).
Rodriguez , J Natl Cancer Inst 2008;100: 513 – 517

7. HPV Infection Persistence
How persistence is defined: Most studies of HPV persistence have defined persistence as the detection of the same HPV type at 2 and 3 consecutive visits, 2 to 24 months apart.
Risk factors for persistence:
HPV type
Weak immune system
Infection with multiple types
Age
Sycuro LA et al., J Infect Dis. 2008, 198:971=978

8. How good is cytology in Cervical Cancer Screening?
Cervical cancer screening and abnormal Pap management have been changing. Why?
How good is cytology in Cervical Cancer Screening?
Many studies free of verification bias found that: Sensitivity of Conventional Pap was 51% with a specificity of 98%
Liquid-based Pap tests may miss 15-35% according to the analysis published in the ACOG 61 bulletin.
Cytology Screening programs should compensate for the low sensitivity by requiring 2 to 3 annual Pap tests before screening can be performed less frequently
2 consecutive annual Pap tests: 51% + 51% of 49% = 76%
3 consecutive annual Pap tests: 76% + 51% of 24% = 88%
Pap would not be able to receive the FDA approval with such sensitivity today!
Nanda K. et al. Ann Intern Med, 2000; 132:
ACOG Practice Bulletin ;61:3
Evaluation of Cervical Cytology. Summary, Evidence Report/Technology Assessment: Number 5, January Agency for Health Care Policy and Research, Rockville, MD.

9. The following is based on good and consistent scientific evidence
“Because HPV DNA testing is more sensitive than cervical cytology in detecting CIN 2,3,… [ ] …..women with negative concurrent test results can be reassured that their risk of unidentified CIN 2,3 or cervical cancer is approximately 1 in 1,000.”
Slide 28:
The ACOG Practice Bulletin gave the following statement a Level A Recommendation based on good and consistent scientific evidence: “Because HPV DNA testing is more sensitive than cervical cytology in detecting CIN 2,3, women with negative concurrent test results can be reassured that their risk of unidentified CIN 2,3 or cervical cancer is approximately 1 in 1,000.”
ACOG Practice Bulletin. April 2005;61:9

10. but was insensitive in assessing future risk.”
Co-testing with the digene HPV Test plus any cytology achieves 100% clinical sensitivity
The digene HPV Test offers clinicians an objective measure of a woman's risk of developing cervical cancer. Used alone, a Pap may miss cervical disease up to 25 percent of the time. But any type of Pap in combination with the digene HPV Test detects the cause of high-grade cervical disease and cancer with sensitivity up to 100 percent – preventing false-negative results.
In a major U.S. study, the negative predictive value for the digene HPV Test/Pap combination was percent for CIN 3 and cancer.(Sherman ME, J Nat Cancer Inst, 2003). Women with persistent high-risk HPV infection are 300 times more likely to develop HSIL than those without.
“… the Pap test was useful in detecting lesions that were present at enrollment
but was insensitive in assessing future risk.”
Biscotti, C.V. et al. (2005) Am. J. Clin. Pathol
Clavel, C. et al. (2001) Br. J. Cancer
Cytyc Package Insert: ThinPrep® Imaging System, Table 2.
Mayrand, M.H. et al. (2007) N. Engl. J. Med
Ronco, G. et al. (2006) J. Natl. Cancer Inst

11. When to initiate co-testing with your patients
Why incorporate the digene HPV Test into your cervical cancer screening program for women 30 and older? Epidemiology data have shown that the prevalence of HPV in women generally decreases over time, while the incidence of cervical cancer increases. The point at which HPV prevalence meets cervical cancer incidence is around the age of 30, which supports the rationale for primary adjunctive screening (HPV + Pap) in women 30 and older. Identification of high-risk HPV DNA in this age group is more likely to signal persistent infection and increased risk of cervical disease. In fact, studies have shown that women older than 30 with normal cytology who are positive for high-risk HPV have a 116-fold greater risk of developing high-grade lesions compared with similar women who are HPV-negative (Melkert PW, et al. Int J Cancer 1993; 53).
HPV Prevalence and Cervical Cancer - Incidence by Age
Ries, L.A.G. et al. eds. SEER Cancer Statistics Review, , National Cancer Institute
Available at:

12. Why use HPV testing in cervical cancer screening?
More sensitive than cytology
Detects disease earlier therefore enables longer screening intervals
Can be automated, centralized and standardized among labs
Evidence that screening with HPV reduces cervical cancer incidence and mortality
Improves detection of glandular lesions & adenocarcinomas

13. Examples of randomized clinical trials that use HC2 HPV testing in screening
HART Trial: United Kingdom
POBASCAM Study: The Nederlands
Indian Trial: Osmanabad district
ARTISTIC Trial: United Kingdom
NTCC Study: Italy
SWEDESCAN: Sweden
CCCaST Study: Canada

15. HPV for Screening Italian Randomized Screening Trial
This study presents the first results from a randomized trial that compares conventional cytology and the combined use of HPV testing and liquid-based cytology (LBC)
33,364 women years of age recruited from 9 clinical centers:
Conventional cytology arm - colposcopy if ASCUS or greater
Experimental arm – LBC (ThinPrep) & HPV testing (HC2) colposcopy if >ASCUS or HPV (+)
Background: Although testing for HPV has higher sensitivity and lower specificity than cytology alone for detecting cervical intraepithelial neoplasia (CIN), studies comparing conventional and liquid-based cytology have had conflicting results.
Methods: In the first phase of a two-phase multicenter randomized controlled trial, women aged 35 – 60 years in the conventional arm ( n =16 658) were screened using conventional cytology, and women in the experimental arm ( n = ) had liquid based cytology and were tested for high-risk HPV types using the Hybrid Capture 2 assay.
Women in the conventional arm were referred to colposcopy with atypical cells of undetermined signifi cance (ASCUS) or higher and those in the experimental arm were referred with ASCUS or higher cytology or with a positive ( ≥ 1 pg/mL) HPV test.
Affi liations of authors: Unit of Cancer Epidemiology, Centro per la Prevenzione Oncologica, Turin, Italy (GR, NS);
Agency for Public Health, Lazio Region, Rome, Italy (PGR);
Centro per lo Studio e la Prevenzione Oncologica, Florence, Italy (MZ, FC, MC);
Unit of Pathology, Ospedale Maggiore, AUSL Bologna, Italy (GPC);
Unit of Pathology, Ospedale di Trento, Trento, Italy (PDP); Service
of Immunology and Cancer Molecular Diagnostics, Azienda Ospedaliera di Padova,Padua, Italy (ADM);
Unit of Pathology, Presidio Ospedaliero, AUSL Imola,Imola, Italy (SF);
Unit of Cancer Epidemiology and CPO, CERMS, University of Turin, Turin, Italy (AGT);
Preventive Gyneacological Oncology, Ospedale Civile Maggiore di Verona, Verona, Italy (GN);
Centro di riferimento screening — Assessorato alla Sanità — Regione Emilia-Romagna, Bologna, Italy (CN);
Centro Pre venzione Oncologica, AUSL Ravenna, Ravenna, Italy (PS);
Venetian Tumour Registry, Azienda Ospedaliera di Padova, Padua, Italy (MZ);
Queen Mary’s School of Medicine and Dentistry and Cancer Research UK, London, U.K. (JC).
Ronco et al. Journal of the National Cancer Institute, Vol. 98, No. 11, 2006

16. Italian Randomized Screening Trial - Comparison of Different Strategies Versus Regular Practice With Conventional Cytology
Using LBC with ASCUS+ as the only cutoff for referral to colposcopy, the sensitivity was similar to that obtained in the conventional arm with conventional cytology
Overall, 75 women with CIN2 + were identified in the experimental arm.
54 had ASCUS +
73 were HPV +
No high-grade lesion was found among 845 HPV negative women with ASCUS cytology.
Ronco et al. Journal of the National Cancer Institute, Vol. 98, No. 11, 2006

17. Italian Randomized Screening Trial - Results
Sensitivity & specificity of LBC & HPV testing in Experimental arm
(Table 4) HPV testing was more sensitive for CIN2+ than ASCUS+ LBC, with a similar specificity for both CIN2+ and CIN3+ histology endpoints.
Ronco et al. Journal of the National Cancer Institute, Vol. 98, No. 11, 2006

18. Italian Randomized Screening Trial - Conclusions
HPV testing alone was more sensitive than conventional cytology among women 35 – 60 years old.
HPV testing supplemented by LBC led to a substantial (47%) increase in sensitivity for CIN2+
Results:
The screening methods and referral criterion applied in the experimental arm had higher sensitivity than that in the conventional arm (relative sensitivity = 1.47; 95% confidence interval [CI] = 1.03 to 2.09) but a lower PPV (relative PPV = 0.40; 95% CI = 0.23 to 0.66).
With HPV testing alone at ≥1 pg/mL and at ≥2 pg/mL, the gain in sensitivity compared with the conventional arm remained similar (relative sensitivity = 1.43, 95% CI = 1.00 to 2.04 and relative sensitivity = 1.41, 95% CI = 0.98 to 2.01, respectively) but PPV progressively improved (relative PPV = 0.58, 95% CI =0.33 to 0.98 and relative PPV = 0.75, 95% CI = 0.45 and 1.27, respectively). Referral based on liquid-based cytology alone did not increase sensitivity compared with conventional cytology (relative sensitivity = 1.06; 95% CI = 0.72 to 1.55) but reduced PPV (relative PPV = 0.57; 95% CI = 0.39 to 0.82).
Conclusions: HPV testing alone was more sensitive than conventional cytology among women 35 – 60 years old. Adding liquid-based cytology improved sensitivity only marginally but increased false-positives. HPV testing using Hybrid Capture 2 with a 2 pg/mL cutoff may be more appropriate than a 1 pg/mL cutoff for primary cervical cancer screening. [J Natl Cancer Inst 2006;98:765 – 74]
Ronco et al. Journal of the National Cancer Institute, Vol. 98, No. 11, 2006

19. HPV used in screening randomized trial Canadian Cervical Cancer Screening Trial (CCCaST)
10,456 women yrs of age seeking screening in Montreal or St. Johns (Canada)
Women Had BOTH HC2 & conventional cytology. Women positive on either test had colposcopy
First large randomized trial where HPV testing has been compared directly as a stand alone test with Pap in North American population with access to quality care
Supported by a grant (MCT-54063) from the Canadian Institutes of Health Research and partially by an unrestricted grant from Merck Frosst Canada. Dr. Maynard was supported by a fellowship from the National Cancer Institute of Canada, Dr. Franco was the recipient of a Distinguished Scientist award from the Canadian Institutes of Health Research, and Dr. Coutlée was the recipient of a National Scholar award from the Fonds de la Recherche en Santé du Québec.
N Engl. J Med. 2007; 357(16):

20. CCCaST - Comparison of Pap and HPV testing
Cotesting achieved 100% sensitivity and resulted in a 7.9% referral rate. Performance was unaffected by the sequence of the tests.
The sensitivity of both tests used together was 100%, and specificity was 92.5%.
Triage procedures for Pap or HPV testing resulted in fewer referrals for colposcopy than did either test alone but were less sensitive.
Table 4. N Engl. J Med. 2007; 357(16):

21. CCCaST – Key Conclusions
Pap + DNA is the most sensitive method for cancer detection. Regardless of what type of Pap test you perform, you can only achieve 100% sensitivity by coupling it with the HPV DNA test.
The small decrease in specificity (2.7%) compared to Pap is off-set by the dramatic increase in cancer detection.
This study attracted international attention and domestic TV and newspaper coverage because it proposed “a shift from cellular to viral testing” (i.e. “HPV followed by Pap”) as a possible future strategy for improved cancer detection.
“As compared with Pap testing, HPV testing has greater sensitivity for the detection of cervical intraepithelial neoplasia.”
N Engl. J Med. 2007; 357(16):

22. Long term predictive values of cytology & HPV testing
in cervical cancer screening
Kaplan-Meier Plots of Cumulative Incidence Rate For CIN3+ for Women According to Baseline Test Results in the First 72 Months of Follow-up
Objective To obtain large scale and generalisable data on the long term predictive value of cytology and HPV testing for development of CIN 3 or cancer (CIN3+). Design Multinational cohort study (7 countries) with joint database analysis. Setting 7 primary HPV screening studies in 6 European countries. Participants 24,295 women attending cervical screening enrolled into HPV screening trials who had at least one cervical cytology or histopathology examination during follow-up. Main outcome measure Long term cumulative incidence of CIN3+.
Results The cumulative incidence rate of CIN3+ after six years was considerably lower among women negative for HPV at baseline than among women with negative results on cytology. By comparison, the cumulative incidence rate for women with negative cytology results at the most commonly recommended screening interval in Europe (three years) was 0.51% (0.23% to 0.77%). The cumulative incidence rate among women with negative cytology results who were positive for HPVincreased continuously over time, reaching 10%at six years, whereas the rate among women with positive cytology results who were negative for HPV remained below 3%.
Conclusions A consistently low six year cumulative incidence rate of CIN3+ among women negative for HPV suggests that cervical screening strategies in which women are screened for HPV every six years are safe and effective.
BMJ 2008;377:a1754
24,295 women enrolled into HPV screening trials & had at least 1 pap or histopathology examination follow-up their initial test.
Incidence rate of CIN3+ after six years was considerably lower among women HPV negative than among women with a negative cytology.
Dillner, J. et al. BMJ 2008;337:a1754

23. 2009 NEJM - Mortality Study (2000-2007)
131,746 women aged years
Married at time of trial or previously married
Randomly assigned to four groups
Screening by the digene HPV Test (34,126)
Pap (32,058)
visual inspection with acetic acid - VIA (34,074)
Control – only counseling (31,488)
Women who had positive results on screening underwent colposcopy and biopsy
Women with precancerous lesions or cancer received treatment
Methods
In this cluster-randomized trial conducted in 52 clusters of villages, 131,746 healthy women between the ages of 30 and 59 years were randomly assigned to four groups of 13 clusters each. The groups were randomly assigned to undergo screening by HPV testing (34,126 women), cytologic testing (32,058), or VIA (34,074) or to receive standard care (31,488, control group). Women who had positive results on screening underwent colposcopy and directed biopsies, and those with cervical precancerous lesions or cancer received appropriate treatment.
Results
In the HPV-testing group, cervical cancer was diagnosed in 127 subjects (of whom 39 had stage II or higher), as compared with 118 subjects (of whom 82 had advanced disease) in the control group (hazard ratio for the detection of advanced cancer in the HPV-testing group, 0.47; 95% confidence interval [CI], 0.32 to 0.69). There were 34 deaths from cancer in the HPV-testing group, as compared with 64 in the control group (hazard ratio, 0.52; 95% CI, 0.33 to 0.83). No significant reductions in the numbers of advanced cancers or deaths were observed in the cytologic-testing group or in the VIA group, as compared with the control group. Mild adverse events were reported in 0.1% of screened women.
Conclusions
In a low-resource setting, a single round of HPV testing was associated with a significant reduction in the numbers of advanced cervical cancers and deaths from cervical cancer.
Sankaranarayanan R, et al. N Engl J Med 2009;360:

24. 2009 NEJM Mortality Study
In addition to the lower incidence of cancer-related deaths amongst women diagnosed during this 8-year NEJM study, it also found that there were no cancer deaths among the HPV-negative women in the HPV testing group.
Screening with HPV DNA testing reduces mortality from invasive cervical cancer relative to other modalities. It is now proven that the digene HPV Test saves more lives from cervical cancer than VIA or Pap.
Sankaranarayanan R, et al. N Engl J Med 2009;360:

25. New England Journal of Medicine India Screening Study
“Our study found that a single round of HPV testing was associated with a significant decline in the rate of advanced cervical cancer and associated deaths...”
“We found that HPV testing was the most objective and reproducible of all cervical screening tests and was less demanding in terms of training and quality assurance.”
Sankaranarayanan R, et al. N Engl J Med 2009;360:

26. New screening guidelines: incorporates knowledge of the role of HPV

27. HPV Testing in cervical cancer screening
Age to initiate co-testing:
Women 30 years and older
FDA approval
ACOG Practice Bulletins
ASCCP Guidelines
SGO Recommendations on Genotyping
The age to initiate screening with HPV testing combined with cervical cytology recommended by ACOG and ACS is women age 30 and over, and is in agreement with the FDA approval for the use of HC2 . Combining HPV testing with cytology as a primary screen for women under the age of 30 is not recommended because the prevalence of high-risk HPV at this age is very high (15-46%) and most women testing positive have only transient infections. Additionally, cervical cancer is uncommon in women under the age of 30, although it does begin to rise between In contrast, the prevalence of high-risk HPV in women age 40 and over is approximately 5%. However, changes in age to initiate combined testing may occur with increasing data.

28. HPV DNA Testing for Screening Current state of science - 2010
Large number of cross-sectional studies demonstrating superiority of HPV DNA testing compared to cytology
Randomized screening trials are now being completed
Data is overwhelmingly in favor of any Pap plus HPV Test
offering women the best protection against cervical disease

29. HPV DNA Testing for Screening Current state of science – 2010
Two indications for HPV testing
Triage of ASC-US Pap tests to colposcopy women 21 & older
Co-testing women 30 & older
Two FDA approved tests (digene HPV Test , Cervista)
High risk types: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, (66), 68 (digene HPV Test , Cervista)
Genotyping: 16,18 (Cervista only)

30. ACOG Guidelines Recommend HPV co-testing since 2003
2009
2005
2008

31. ACOG Guidelines - Screening frequency
From onset of screening (> ): Paps biennially
Age > 30
Paps every 2 to 3 years if 3 consecutive normal Paps
Pap and HPV test no more often than every 3 years if done together and both normal (negative)

32. ACOG Practice Bulletin 109 upgraded recommendations for HPV co-testing
Women 30+ years with both (-) Pap test and (-) HR HPV test results are at extremely low risk of developing CIN 2+ during the next 4–6 years.
HPV co-testing for women 30 and older has now been upgraded to a Level A Recommendation
Seven studies were analyzed to compare HPV and Pap co-testing versus Pap alone in a total of 24,295 women.
The risk of CIN 3+ after 6 years of follow-up was 0.28% in women who tested (-) on co-testing at baseline. This rate for co-testing was considerably lower than for women with (-) Pap results at 0.97%.
ACOG Practice Bulletin, Number 109. Obstet Gynecol. 2009;114:

33. Screening environment is changing
Women between 21 and 29 years to receive screening every 2 years
 Potential for less Paps over time – how do you manage the impact of this?
HPV co-testing for women 30 and older has now been upgraded to a Level A recommendation
Women between 65 and 70 years who have 3 or more consecutive normal Paps can discontinue screening
Women treated in the past for CIN 2+ should continue to have annual screening for at least 20 years
There were no changes in the HPV co-testing guidance for women 30 and older – it is still recommended with the 3-year interval for double negative results
ACOG Practice Bulletin, Number 109. Obstet Gynecol. 2009;114:

34. 2007 ASCCP Consensus Guidelines American Society for Colposcopy & Cervical Pathology
146 experts from 29 organizations revised evidence-based guidelines for managing women with abnormal cervical cancer screening tests.
Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D. Am J Obstet Gynecol Oct;197(4):

35. ASCCP 2009 Guideline update on genotyping
The FDA has recently approved a DNA test specific for HPV-16 and HPV-18, which can be used as an adjunct in women with negative Pap test results, but who have tested positive for high-risk HPV by an assay testing for 13 or 14 high-risk types

36. SGO positioning on genotyping
Should not replace other cervical cancer screening methods
Should not be used as a prescreening tool for HPV vaccination.

37. HPV testing as predictor of a woman’s risk
for developing cervical disease & cost to society
Screening is all about risk.
So what is the risk?

38. HPV Testing for Screening A risk stratifier
A normal Pap and a negative HPV test give a % assurance that cervical cancer is not present and will not likely occur in the next few years.
Providing increased safety with less frequent screening
A positive HPV test and a normal Pap reflects increased risk for either missed disease or for the subsequent development of CIN 2/3 and cancer.
Requiring increased surveillance
HPV testing for screening is risk stratifier. Women having a normal Pap and a negative HPV test are given a % assurance that cervical cancer is not present and will not likely occur in the next few years, allowing less frequent screening. In contrast, a positive HPV test and a normal Pap reflect increased risk for either missed disease or for the subsequent development of CIN 2/3 and cancer. However, it must be remembered that even with this increased risk, most women with a positive test for high-risk HPV and a normal Pap do not have significant cervical neoplasia. Therefore, rather than immediately referring these women to colposcopy, such findings call only for increased surveillance.

39. Considering co-testing your patients?
Common questions
What is the rationale?
Will I be overloaded with counseling HPV (+) women?
HPV positive - Pap negative. How many are there?
HPV positive - Pap negative. Probability of HPV infection regressing
What does HPV positive / Pap negative mean?
The next question is how much of an impact combined screening with HC2 and a Pap test will have on clinic follow-up and colposcopy time. What will be the impact of adding to abnormal Pap follow-up women with normal cervical cytology testing who test HPV positive?

40. What is the rationale for combined screening?
“..persistent, high-risk HPV infection is necessary for the development of cervical cancer”
“..an obvious corollary is that the absence of HPV means that the risk of cervical cancer is negligible.”
Slide 25:
The rational for considering HPV testing in primary screening was nicely summed up in a 2003 NEJM commentary written by Wright and Schiffman. Because persistent high-risk HPV infection is necessary for the development of cervical cancer, (an obvious corollary is that the absence of HPV means that the risk of cervical cancer is negligible. Of course, no test or combination of tests, no matter how sensitive, will ever be perfect. Therefore, preventing all cases of cervical cancer is an unobtainable goal, even if all women accessed the best screening available. However, using the best screening available certainly holds the prospect of reducing the burden of cervical cancer as much as possible.
Wright TC, Schiffman MH NEJM 2003;348:489-90

41. Prevalence of Pap (-) / HPV (+) women: Impact of age in Kaiser study
Percentage of woman with normal Pap tests who tested positive for carcinogenic HPV by HC2 by age group
Castle et al, Obst & Gyn, Vol. 113, NO3, 03/2009

42. Probability of an HPV Infection regressing
39%
31%
% HPV (-) after 1st (+) test
81% resolved
In the study by Ho that was mentioned earlier
[Bullet 1] 31% of women who were newly HPV positive by PCR tested negative by this highly sensitive test within six months.
[Bullet 2] Another 39% tested negative by twelve months, and another
[Bullet 3] 11% by eighteen months.
Therefore, the total who became HPV negative over an 18 month period was 81%. As stated previously, it is impossible to prove whether this represents HPV that was suppressed below the levels of detection or whether it represents complete clearance.
11%
1 - 6 mo mo mo
Ho GYF et al. NEJM. 1998;328:

43. What does Pap (-)/HPV(+) result mean?
Acutely infected and likely to spontaneously regress.
Chronically infected and at increased risk for developing CIN and cancer.
Has CIN now and the Pap was falsely negative.
Wright TC, Cervical Disease. OBG Management 2007 Mar; 19 (3)

44. What do patients and providers want to know
about cervical cancer screening reimbursement?

45. Provider concerns with co-testing Extended screening intervals
Disconnect “the Pap” from the “annual exam”
The Pap is just one test done at intervals now more tailored to the individual’s needs
Women still need annual preventive health care
Contraception
Slide 21:
Breast and pelvic exam
Screening for STDs as needed
Cardiovascular, diabetes and other risk assessment
Bone density, peri- & postmenopausal concerns

46. Education about HPV at the screening visit
Destigmatize HPV
80% of the population is infected at one time or another
Testing positive can reflect exposure anytime from the onset of sexual activity
Slide 21:
The Pap has always been screening you for the effects of HPV, just most people didn’t explain it.

47. Coverage Environment for the digene HPV Test
Paid In Full
Patient Responsible for Co-pay
95% Claims Paid
First Submission
Deductible Not Met
95% Claims
No Screening Coverage
This is what the coverage looks like for the digene HPV Test: 95% of claims are covered. But not all those claims are paid in full. In some cases, the claim is subject to some form of cost sharing such as a deductible, or co-insurance where the patient is responsible for 10-20% of the cost. And in about 5% cases, the claim is denied. The most common reasons are the patient was under the age of 30, some kind of processing error, usually on the payer’s end which can be overturned if the claim is resubmitted for manual review. Or, the patient is on a low cost insurance plan which offers extremely limited preventative care.
Patient
Under
Age 30
5% Claims
Processing Error

48. “My patient received a bill. What happened?”
Paid In Full
95% Claims Paid
First Submission
Patient Responsible for Coinsurance
Deductible Not Met
Any cost-sharing viewed as a “denial”
The is what the coverage often looks like from a patient perspective. If the claim was paid in full, it was covered. But if the patient had a bill for any reason, the patient views that claim as denied. So that is something for you to be aware of as a clinician if the patient calls your office with a billing complaint for this test or any other test you ordered, it is likely that that bill was due to cost sharing, and not denied.
As you know, the digene HPV test is the only FDA-approved test on the market, From a reimbursement perspective, this is important because most payer coverage policies either require that an FDA-approved test be used, or specifically reference the digene HPV test as the appropriate technology. Some payers, like Aetna, state that PCR is considered investigational in accordance with the most recent ASCCP guidelines. Most labs offer the digene HPV test, but it is important to be aware of what your lab is offering, and request and FDA-approved test if they are offering a non-approved alternative.
Patient
Under
Age 30
No Screening Coverage
Processing Error

49. Patient counseling is reimbursable after a positive HPV result
CPT code
99212 Office visit, established patient, 10 minutes
99213 Office visit, established patient, 15 minutes
99214 Office visit, established patient, 25 minutes
ICD – 9 code
V65.45 Counseling on other sexually transmitted diseases
Cervical high-risk human papillomavirus (HPV) DNA positive
Most health plans cover a minute office visit to relay a positive HPV result, discuss the risk for cervical cancer, and reinforce the importance of follow-up testing in twelve months.
If you have patients with a positive HPV test result that want to spend some time discussing that result, you can have them come into the office for another visit to talk about it and the visit will be covered. Most payers will reimburse a minute office visit for this purpose. Appropriate ICD-9 codes would include V65.45 counseling on other sexually transmitted diseases and high risk HPV positive. If the primary reason for the visit is patient counseling, the CPT code is driven by the amount of time you spend with the patient.

50. Will that make cervical cancer screening obsolete?
HPV vaccines
Will that make cervical cancer screening obsolete?
Garnett GP, Kim JJ, French K, Goldie SJ. Vaccine 2006; 24 (suppl 3): S178–86

51. Current ACIP HPV Vaccine Recommendations
Age range (years)
11-12 yrs
13-18 yrs
19-26 yrs
Routine
Catch-up
ACIP = Advisory Committee on Immunization Practices
The ACIP recommendations differ from the indication for CERVARIX.
CERVARIX is approved for use in females 10 through 25 years of age
Current ACIP HPV Vaccine Recommendations
According to the Advisory Committee on Immunization Practices (ACIP), routine vaccination is recommended for females years of age.1,2 The ACIP also recommends catch-up vaccination for females years of age who have not been vaccinated previously or who have not completed the full vaccine series.1,2 Vaccinating girls prior to the onset of sexual activity is important, as prophylactic vaccines are likely to be most efficacious when administered to females who are naïve to infection with HPV types present in the vaccine.1 The ACIP recommendations differ from the indication for CERVARIX. CERVARIX is approved for use in females 10 through 25 years of age.3
References:
Markowitz L et al. MMWR. 2007;56(RR-2):1-24.
Advisory Committee on Immunization Practices Provisional Recommendations for HPV Vaccine. 2009;
Prescribing Information for CERVARIX.
Advisory Committee on Immunization Practices Provisional Recommendations for HPV Vaccine. 2009; Available at: 51

52. Composition of HPV Vaccines vaccine-like particles
1/Villa/p. 271/column 2/¶1; p.272/column1/¶3,4;p.275/column1/¶3
GARDASIL™1
Cervarix™2
HPV Types
Indication
CIN 1; CIN 2+; AIS;
VIN 2+; VAIN 2+; Cervical, vulvar, and vaginal cancer;
Genital warts;
CIN 1; CIN 2+; Cervical Cancer; AIS
Boys
Yes No
Cross Protection
Yes, Type 31 6 11 16 18
2/Harper/p. 1758/column 2/¶1
1. Villa LL, Costa RLR, Petta CA, et al. Lancet Oncol. 2005;6:671–678.
2. Harper DM, Franco EL, Wheeler C, et al. Lancet. 2004;364:1757–1765.

53. Impact of HPV Vaccines on Cervical Cancer incidence
Reductions in pre-invasive disease: Over the next several years, we will see dramatic reductions in:
Prevalence of Pap abnormalities
Number of colposcopy examinations
Diagnoses of CIN 2,3
Screening after vaccination: factors that influence vaccines' impact are:
Efficacy of screening
Vaccination coverage
Age of vaccination
Durability of vaccine response

54. Projected Number of Cancer Cases in Developed Countries, as a Function of % Immunized
“Vaccination is not a substitute for routine cervical cancer screening, and vaccinated females should have cervical cancer screening as recommended” : Recommendations of the Advisory Committee on Immunization Practices (ACIP) MMWR Recommendations Rep.2007
The vaccine does not protect women against approximately 30% of cervical cancer caused by HPV types other than HPV-16 and HPV-18.” ACOG Practice Bulletin No. 109
Plummer M, Franceschi S Vir Research 2002;89:285-93

55. Cervical cancer prevention through vaccination and screening
Schematic illustration of opportunities for cancer control interventions are provided by the illustrated stages of progression on the left and measurable outcomes on the right which apply to cervical cancer prevention via HPV vaccination (primary), screening with Pap cytology and HPV testing (secondary), and treatment (tertiary).
E.L. Franco et al. / Vaccine 24S3 (2006) S3/171–S3/177

56. Are other HPV tests clinically better?

57. CIN2 is the clinical threshold for patient treatment
co-testing allows to detect more women at risk.
1- ACOG Practice Bulletin, Number 99. Obstet Gynecol
2- Mayrand, M-H., Duarte-Franco, E., NEJM (2007)

58. Reliable and prompt diagnosis of CIN2+ is critical
Natural History of CIN lesions
% of lesions that:
LESION GRADE
REGRESS
PERSIST
PROGRESS *
CIN 1
57%
32%
11%
CIN 2
43%
35%
22%
CIN 3
56%
12%
* Progression to carcinoma in situ
CIN2 is threshold for patient management because 57% of CIN 2 persist or progress.
A test with lower CIN2+ sensitivity than the digene HPV Test
will not detect as many patients at risk of progression.
Castle et al. Ob. Gynecol. 2009;113:18-25
Image at:

59. CIN2+ detection (ASC-US data) HC2 is more sensitive than Cervista
CIN2+ is the clinical threshold for patient treatment because early detection improves clinical outcomes the need to catch it quickly is key.
The digene HPV Test ALTS
Cervista FDA
submitted data
Detection rate for CIN 2+ (sensitivity)
96%
93%
Arbyn JNCI 2004 and Cervista Clinical Package insert

60. NILM population, also known as Pap-normal or “within normal limits”
NILM (negative for intraepithelial lesions or malignancy) 30+ population from the Cervista Package Insert
NILM population, also known as Pap-normal or “within normal limits”
Be sure to be aware that NILM correlates to WNL – don’t assume that the MDs know, so explain to the doctors or correlate to WNL.
ASC-US Data

61. Negative for intraepithelial lesions or malignancy: Comparing Cervista data to HC2
Cervista had >4X positive HPV tests in NILM than HC2
Data published by Castle in 2009
Cervista : 18.5% , n= 1,9661
digene HPV Test : 3.99% , n= 798,0002
Cervista assay has a high false positive result in NILM group
Cervista Package Insert, page 18
2 Castle, PE, et al. Obstet Gynecol 2009;113:595–600.

62. Impact of increased Pap (-) / HPV (+) Cervista Assay
Significant increase in Pap (-) / HPV (+) rate will increase burden of patient counseling
NILM is most relevant for the Ob-Gyn or FP who currently co-tests
In addition to high false positives, the Cervista assay also has higher false negatives in the CIN 2+, ASC-US population
No co-testing data on 30+ yet available for Cervista

63. Non FDA approved tests using PCR technology
What are the benefits of PCR tests and limitations?

64. Best analytical sensitivity cut-off for clinically useful HPV DNA testing
Snijders et al J Pathol 201:1

65. Is PCR the right technology for HPV DNA screening?1
Detecting the lowest copy number does not necessary provide relevant clinical information.
Low number of published studies with low number of patients therefore clinical endpoints (CIN2/3) still in discussion.
HPV testing using PCR is not recommended by any major medical organizations and not approved by FDA
Too sensitive technology: irrelevant test results communicated to physicians & patients
Small changes in the viral DNA may give false negative results
Sensitivity 2
Publications 3
Endorsements
& FDA 4
False + 5
False -

66. Definition of an analytically and clinically validated HPV test for clinical implementation
The test should be capable of detecting at least the 13 high risk HPV types and should not include non-carcinogenic HPV types.
To meet currently achievable standards, the test should have a clinical sensitivity to detect at least 92% ± 3% of CIN 3+ such that the negative predictive value of the test is extremely high.

67. The digene HPV Test is the most extensively validated standardized HPV test
These studies, in total, found that the digene HPV HC2 DNA Test yielded results with a median of 94% clinical sensitivity.
In contrast, PCR procedures showed a clinical sensitivity of only 82%. The digene HPV HC2 DNA Test consistently provided superior sensitivity in detecting pre-cancerous stages — required for both primary screening and triage risk assessment.
Summary of HC2 vs. PCR clinical sensitivity. Numbers not boldfaced indicate highest and lowest sensitivities found in the studies
Source: Lorincz, A.T. and Smith, J.S. (2006) In: Lorincz, A.T., ed. Nucleic Acid Testing for Human Disease. Boca Raton: Taylor & Francis Group/CRC Press, p 243.

68. Thank you