Cuzick et al¹ reviewed data from North American and European studies including over 60,000 women. They reported that HPV testing was substantially more sensitive than cytology in detecting CIN2+ lesions (96.1% vs 53.0%), but only slightly less specific (90.7% vs 96.3%). Furthermore, the sensitivity of HPV testing varied less across populations and ages while the sensitivity of cytology was highly variable.

Arbyn et al² summarized recently published meta-analyses. They reported that when compared with cytology, primary screening with Hybrid Capture 2 (HC2) detects 23% more CIN2+ at an atypical squamous cells of uncertain significance (ASC-US) threshold, but is 6% less specific. Combining cytology and HC2 increases the sensitivity of screening by another 4%, but at the expense of a 7% loss in specificity compared to HC2 screening alone.

In a prospective randomized trial in Portland, OR, Sherman et al³ showed that in women over 30 years of age the 5-year cumulative risk of CIN3 was 4.4% for those who were HC2-positive at baseline (even if their Papanicolaou [Pap] test result was negative) compared with 0.24% for those who were HC2-negative (even if their Pap result was positive) and 0.16% if both HC2 and Pap results were negative. The cumulative 5-year risk of CIN3+ for a Pap-negative, HC2-negative woman is 0.9/1000 compared with 3/1000 in women with just a negative Pap result.

Based on this data, the FDA approved the use of HC2 as an adjunct (along with cytology) for triennial screening in women 30 years of age and older. According to the consensus guidelines of the American Society for Colposcopy and Cervical Pathology (ASCCP),⁴ women over 30 who test negative for both cervical cytology and HPV do not need rescreening for 3 years. Those also having abnormal cytology should be managed according to the guidelines for that cytologic abnormality. For women who have negative cytology but test positive for HPV, cytology and HPV tests should be repeated in one year and they should have colposcopy if their repeat cytology is reported as a low-grade squamous intraepithelial lesion (LSIL) or their HPV test is positive.

In 2005, Khan et al⁵ further analyzed the data from the Portland Cohort and showed that over the 10 years of the study the risk of CIN3+ was 17.2% for those women who were positive for HPV16 and 13.6% for HPV18 (HPV16-negative), compared with 3% for HC2-positive women negative for HPV16 or HPV18.

Based on this most recent data, the ASCCP expanded on their recommendation for cytology-negative, HPV-positive women.⁶ They added the option of doing a “reflex” test on these women to further characterize the nature of their HPV positivity. Those who have either HPV16 or HPV18 should undergo immediate colposcopy, whereas those who are positive for another (non-HPV16 or 18) high-risk HPV type can follow the previous guidelines and be retested in one year.

However, despite the advantages afforded by HPV testing and genotyping, it is important to note that HPV testing is not appropriate for everyone. Prevalence data indicate that up to 57% of sexually active female adolescents in the United States at any one point in time are infected with HPV.⁷ Natural history studies of adolescents with newly acquired HPV infection show that HPV usually becomes undetectable after an average of 8 months. In most adolescent patients with an intact immune system, most HPV infections will resolve within 24 months.⁷ This, combined with the rarity of cervical cancer in the adolescent population, forms the foundation for the recommendations of the American Cancer Society (ACS)⁸ and the American College of Obstetricians and Gynecologists (ACOG)⁹ to delay the first Pap test until approximately 3 years after the onset of vaginal intercourse or no later than age 21 years. ACOG¹⁰ additionally recommends against the use of HPV testing in this population under any circumstance, including triage of ASC-US and follow-up of LSIL. Rather than screening adolescents, ACOG recommends vaccination with an HPV vaccine for young women in this age group.¹¹ After age 21, the prevalence of HPV begins to decline so that reflex HPV testing becomes appropriate for ASC-US Pap tests, but remains inappropriate for screening until the age of 30.⁴

Finally, it is important to note that because the current HPV vaccines protect against only two of the high-risk HPV types, they do not provide primary protection against HPV types that cause 30% of cases of cervical cancer. Therefore, there should be no changes in screening or management of abnormal cervical cytology in vaccinated women.¹⁰

However, new data on the human papillomavirus (HPV) vaccines as well as data from European clinical trials of new HPV diagnostic tests clearly stood out. There were several entire sessions devoted to the HPV vaccines. One of the most interesting sessions looked at efforts being initiated around the world to monitor the impact of vaccination against HPV on rates of cytological abnormalities, cervical intraepithelial neoplasia (CIN), and invasive cervical cancer as well as cancers at other sites. Many of the Nordic countries have comprehensive vaccine and screening registries and will be able to carefully monitor the impact of vaccination both at the individual and population levels. Other important presentations included head-to-head immunogenicity trials of the bivalent and quadrivalent HPV vaccines, end-of-study results from the phase III bivalent HPV vaccine trial, and data on use of the quadrivalent vaccine in males and immunocompromised individuals.

Discussion of HPV DNA testing focused not only on European clinical trials of several new HPV molecular diagnostic tests but also on the new Care HPV Test which has been developed specifically as a robust and low cost alternative for HPV DNA testing in low resource settings. Now that a low cost HPV diagnostic test has become available, there was considerable interest in studies from developing countries that used HPV DNA testing in a novel "screen-and-treat" approach to cervical cancer prevention. This "screen-and-treat" approach tests women for high-risk types of HPV. After testing, all women found to be HPV DNA positive receive cryotherapy without the intervening steps of colposcopy and cervical biopsy. This approach eliminates many of the problems associated with more conventional cervical cancer strategies.

Management guidelines from both the American Society of Colposcopy and Cervical Pathology (ASCCP) and the American College of Obstetricians and Gynecologists (ACOG) recommend that when high-risk HPV DNA testing is utilized in conjunction with cervical cytology, women who are negative on both tests are not to be rescreened for 3 years.^1,2 The basis for this recommendation comes from both observational clinical trials and mathematical modeling studies. Older cross-sectional studies indicated that the risk of a missed CIN 2,3 lesion in a woman who is both high-risk HPV and cytology negative is only about 0.1%. More recent prospective follow-up studies indicate that even with longer term follow-up these women remain at quite low risk for being diagnosed with a CIN 3+ lesion. A recent analysis pooled data from 7 primary screening trials conducted in Europe that enrolled over 24,000 women who were screened using either cytology alone or a combination of cytology and HPV DNA testing and subsequently followed for up to 6 years.³ After 36 months of follow-up, the cumulative incidence of histologically-diagnosed CIN 3+ was approximately 50 cases per 10,000 women-years of follow-up among women who had a negative initial cervical cytology result. In contrast, the incidence of CIN 3+ was only 5 cases per 10,000 women-years of follow-up among women who were negative by both HPV DNA testing and cervical cytology. Even after 6 years of follow-up, the estimated incidence of CIN 3+ in women who were negative on both tests was only 20 cases per 10,000 women-years of follow-up. This observational data supports the conclusions of mathematical modeling studies which demonstrate that the risk for developing cervical cancer is essentially identical for women screened yearly with liquid-based cytology compared to those screened every 3 years using a combination of liquid-based cytology and HPV DNA testing.⁴

Based on this data you can counsel this patient that she does not need rescreening at this time, despite the fact that she has had new partners. You should emphasize to her that even if she did become infected with high-risk HPV, the most likely outcome is that the infection will spontaneously resolve without causing a lesion. Moreover, even if she has developed a CIN 2,3 lesion, many CIN 2,3 lesions also spontaneously resolve over a period of several years and almost none will progress to an invasive cervical cancer within a couple of years.

There are a number of estimates of the prevalence of high-risk HPV DNA positivity in women 30 years and older in the US. One recent prevalence survey conducted by the Centers for Disease Control and Prevention (CDC) found the overall prevalence of high-risk HPV DNA positivity to be 13% in women 30-39 years of age, 11% in women 40-49 years of age, and 6% in those 50-65 years of age.⁵ When restricted to women with normal cervical cytology, the overall prevalence observed in the CDC survey was similar: 9-11% in women in their 30s, 9-10% in women in their 40s, and 4-8% among women in their 50s. Potential problems with these estimates are that the number of women 30 years and older in this survey was rather limited and that the women were enrolled from sexually transmitted disease (STD) clinics and family planning clinics as well as primary care clinics. Therefore, women in this study may have been at higher risk for being infected with HPV than women in the general US population.

A better estimate of the prevalence of HPV DNA positive in women undergoing routine gynecological care in the US comes from a recent publication from Kaiser Northern California.⁶ This report analyzes the screening results over a 5-year period from almost 800,000 women 30 years and older who were screened using a combination of conventional cervical cytology and high-risk HPV DNA testing. Among women 30-39 years old, the prevalence of high-risk HPV DNA positivity was approximately 9.5%. This is somewhat higher than the prevalence of cytological abnormalities, 6.1%. However among women in their 40s, the prevalence of high-risk HPV DNA positivity was about 5.6% which is essentially identical to the prevalence of cytological abnormalities (5.7%). Among women in their 50s, high-risk HPV prevalence was 4.1% and that of cytological abnormalities was 4.3%. When restricted to women with normal cytology results, the prevalence of high-risk HPV DNA positivity was 5.9%, 3.4%, and 2.8% among women in their 30s, 40s, and 50s, respectively.

The objective of using high-risk HPV DNA testing when determining which women 21 years and older with atypical squamous cells of undetermined significance (ASCUS) require colposcopy is very different than the objective when using HPV DNA testing as an adjunct to cytological screening of women 30 years and older. In women with ASCUS, HPV DNA testing is used to identify those at highest risk for having a CIN 2,3 lesion who can then be referred to colposcopy. This strategy works because the risk that a woman with ASCUS will have a CIN 2,3 lesion is relatively high (5-17%).

Such a strategy does not work in women with a normal cervical cytology result because their risk of having a CIN 2,3 lesion is much lower (1-2%). Therefore, in the screening setting we utilize high-risk HPV DNA testing not to identify women who are infected with HPV, but instead to identify women with persistent high-risk HPV infections. This is why we wait and rescreen women who are initially HPV DNA positive and cytology negative 12 months later and only perform colposcopy if the woman is found at the 12 month repeat to be persistently high-risk HPV DNA positive or have a low-grade squamous intraepithelial lesion (LSIL) or greater cytology result. This strategy does not work in younger sexually active women. This is because the HPV DNA assays that we use when screening identify all of the 13-14 high-risk HPV types. Sexually active women in their 20s frequently develop sequential infections caused by different types of high-risk HPV and serial testing using our current screening tests cannot discriminate between a woman who has sequential infections with different high-risk types of HPV and a woman who has a persistent infection caused by a single high-risk HPV type. This is the reason the 2006 ASCCP Consensus Guidelines consider the use of high-risk HPV DNA testing as the preferred approach to managing women 21 years and older with ASCUS, but limit the use of HPV DNA testing in the screening setting to women 30 years and older.²

1. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin. Clinical Management Guidelines for Obstetrician-Gynecologists. Number 61, April 2005. Human papillomavirus. Obstet Gynecol. 2005;105(4):905-918.
2. Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D. 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol. 2007;197(4):346-355.
3. Dillner J, Rebolj M, Birembaut P, et al. Long term predictive values of cytology and human papillomavirus testing in cervical cancer screening: joint European cohort study. BMJ. 2008;337:a1754.
4. Goldie SJ, Kim JJ, Wright TC. Cost-effectiveness of human papillomavirus DNA testing for cervical cancer screening in women aged 30 years or more. Obstet Gynecol. 2004;103(4):619-631.
5. Datta SD, Koutsky LA, Ratelle S, et al. Human papillomavirus infection and cervical cytology in women screened for cervical cancer in the United States, 2003-2005. Ann Intern Med. 2008;148(7):493-500.
6. Castle PE, Fetterman B, Poitras N, Lorey T, Shaber R, Kinney W. Five-year experience of human papillomavirus DNA and Papanicolaou test cotesting. Obstet Gynecol. 2009;113(3):595-600.