HPV (human papillomavirus) is a papovavirus that can cause effects ranging from genital warts to cancer.1 Due to the morbidity associated with cervical cancer in particular, proficient HPV testing is imperative.
Sexual contact is the primary mechanism of HPV transmission.2 This includes oral, anal or penetration sexual practices.2 When the epithelial tissue becomes aggravated, damaged or exposed, the virus is able to penetrate to the basal layer of cells within the epithelium.1 Once these basal cells are infected with the virus, the cells are altered and propagate.1
HPV genotypes are organized in correspondence to the tissue that is affected (cutaneous or mucosal).2 The 128 genotypes of HPV are subdivided into categories of high- and low-risk types.2 The highest risk HPV genotypes are types 16 and 18.2 These are the most common culprits in cervical cancer since they cause the primary precancerous dysplasia of cervical tissue.2 Precancerous changes of the cervix are termed cervical intraepithelial neoplasia CIN).1 The Bethesda system provides terminology for cervical cytology.3
Incidence and Prevalence
Mucosal HPV infections occur in 370 million people worldwide each year.2 Forty million people are infected with types that cause precancerous changes of the cervix.2 A half million of these women develop cervical cancer as a result.2
HPV is prevalent among sexually active women - so much so that about 75% are infected at some point in their lives.1 Given the more than 120 genotypes of HPV, men and women are likely to be contaminated if they are sexually active.1,2 Risk factors for the progressive development of cervical cancer include a weakened immune system or immunosuppression, smoking and multiple sexual partners.2
In March 2012, the American Cancer Society (ACS) updated its guidelines for cervical cancer screening based on the results of a joint panel.4 The ACS collaborated with the American Society of Clinical Pathology (ASCP) and the American Society for Colposcopy and Cervical Pathology (ASCCP) to issue the guideline update.4 The ACS guideline update was the result of a systematic review and incorporated the contributions and experience of other leading expert groups.4
The ACS now recommends that women 21 and older begin cervical cancer screening with a Pap test only.4 This should continue every 3 years until age 29.4 At age 30, women should undergo HPV testing in addition to the Pap test.4 HPV testing has typically been done as a co-test with cytology (Pap) in women 30 and older.5 Meta-analyses have shown that Pap tests have decreased sensitivity for CIN 2 and CIN 3 (high-grade squamous intraepithelial lesions; HG-SIL) compared to HPV tests.5 Pap tests have 6% increased specificity compared with HPV tests.5 The co-testing of HPV tests with cytology should continue every 5 years until age 65, according to the updated guidelines.4
In the case of a woman who has a negative Pap test and a positive HPV test, two options are recommended.4 The first is to wait 12 months and then re-screen with both tests.4 The second is to utilize an HPV test specific for genotype 16 or specific for both 16 and 18.4 If HPV 16 or 18 is detected at that time, the woman should be scheduled for colposcopy immediately.4 If option 1 is used and the patient tests positive on the Pap or HPV test 12 months after the initial screening, she should be referred for colposcopy immediately.4
Co-testing every 5 years is the main recommendation for women between the ages of 30 and 65.4 Women who have had a hysterectomy and have never been diagnosed with CIN 2 or greater should not be screened at all.4 Women 65 and older may discontinue screening measures if they tested negative 10 years prior.4 The guidelines also state that receiving the HPV vaccine should not alter the screening regimen.4
When a Pap test detects HPV, atypical squamous cells of undetermined significance (ASC-US) are identified.2 Pap smears, or liquid-based cytology testing, begin the triage of HPV diagnosis. An analysis published in 2010 concluded that Pap smears and liquid-based cytology tests are essentially equal.6 In addition, the positive and negative predictive values are comparative for the detection of CIN and cancer of the cervix.7
Although these first steps in screening are important in the triage of HPV, they do not confirm specific types of HPV. HPV DNA testing has a crucial role in the identification and further work-up of women with abnormal Pap smears.
Cobas HPV DNA Testing
The cobas HPV test is a recently approved HPV DNA test. This type of test is significant because of its high sensitivity and high negative predictive value.2 The cobas 4800 HPV has a real-time polymerase chain reaction method of detection.8 It detects 12 high-risk HPV genotypes, b-globin and most importantly, genotypes 16 and 18.2 This feature is the test's claim to excellence: It can detect the two highest-risk genotypes, which have a 70% chance of progressing to cervical cancer if not treated adequately.2,9
This partial HPV genotyping test is provided to clinicians in kits. It utilizes up to five channels, has a separate probe for HPV 16 and 18, and a separate probe for the remaining 12 high-risk HPV types (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68).8 These high-risk types are identified via nucleic acid hybridization.8
The cobas HPV test is indicated for use in women 30 or older and women 21 and older who have questionable cytology reports.8 It is not indicated for use as a primary screening tool or to replace routine cytology in women younger than 30.8 It also is not indicated to decide on treatment for women who do not have high-grade cervical dysplasia.8
A study called Addressing the Need for Advanced HPV Diagnostics (ATHENA) recently provided a supportive foundation for the cobas HPV test and its effectiveness in the early and sensitive detection of high-risk HPV genotypes.8 ATHENA was implemented to test the clinical utility of this new DNA test.10 It is also the primary study of the utility of HR-HPV testing, specifically for HPV types 16 and 18.8
The study compared the cobas HPV test with liquid-based cytology for cervical cancer screening.9 The study enrolled 47,208 women, and 40,901 of them met the eligibility criteria.9 Three control groups were created in this study. The first group was composed of women 21 and older with ASC-US who underwent cobas testing to triage them for colposcopy.9 The second group consisted of women 30 or older who had tested negative for intraepithelial lesion or malignancy (NLM). They were tested with both the cobas test and routine cytology.9 The third group of women was 25 and older with any cytology result. They underwent evaluation with the cobas test as the primary method of screening.9
The HPV DNA testing of these samples was completed using first- and second-generation assays: the Amplicor HPV test/Linear Array HPV genotyping test and the cobas HPV test.9 If a woman had ASC-US or worse cytology, or positive first-generation assay results, she underwent colposcopy and biopsy.9 Colposcopy and biopsies were also done on women with negative HPV and cytology results. The endpoint of the ATHENA study was the detection of CIN 3 or worse.9
Results showed that using the cobas HPV test along with cytology increased overall sensitivity for the detection of CIN 3 or worse.9 The study found that 10% of the participants had positive cobas HPV results and 6% had abnormal cytology, while 431 women actually tested positive for CIN 2 or worse.9 Finally, of the 40,901 women involved, 274 had CIN 3 or worse.9
This study also revealed that 1 of 10 women with normal Pap smear results tested positive for HPV 16 and HPV 18 with the cobas test.8 These select women (1 out of 10) actually had precancerous changes in the cervix that could have been overlooked without the specific cobas testing.8
ATHENA shows that although co-testing with cobas and cytology may assure practitioners who are not comfortable with using the HPV test alone, this is not necessary. HPV testing alone would be sufficient according to this study.9 Overall, compared with liquid-based cytology, the cobas HPV DNA test was more sensitive but less specific in detecting CIN 3 or worse.9 If the cobas HPV DNA test is combined with liquid-based cytology, sensitivity is increased by 5% in the detection of CIN 3 or worse.9
High-risk HPV types are detected with great sensitivity by molecular tests (DNA tests) and therefore are invaluable in the workup of abnormal cervical cytology results such as ASC-US.8 Results from a randomized, controlled trial also concluded that HPV DNA testing should be used in women 29 and older due to its increased effectiveness and earlier detection of CIN 2 or worse.10 Ordinarily, women 30 or older diagnosed with high-risk HPV are to repeat the high-risk HPV test and cytology in 1 year.4 However, women may not follow up at the suggested time and/or the abnormal cells could progress within that time frame.9 As a result, it has been suggested that instead of waiting a year for repeat testing when the Pap smear or cytology report comes back abnormal, an HPV DNA test such as cobas can be completed.9 This test would allow for the quick and simple diagnosis of high-risk HPV types, which can then be handled with more aggressive management. In addition, the woman would not have to wait and wonder for a year.
Reimbursement for the cobas HPV test depends on the patient's insurance provider.11 The CPT code for this HPV test is 87621.11
A study assessed the cost effectiveness of screening for HPV 16 and HPV 18 and found that with triage for HPV 16 and 18, the rates of death from cervical cancer decreased. The research concluded that HPV testing with liquid-based cytology is cost effective.12
In conclusion, the cobas HPV test could be used as a primary screening test for women 30 or older and relied upon due to its detection of the highest risk HPV genotypes. This test facilitates screening for CIN 3 or worse among women.9 Healthcare providers should be aware of the morbidity associated with high-risk types of HPV, the availability of new testing methods such as the cobas HPV DNA test, and remain mindful of the ways HPV management can be improved.
1. Latendresse G, et al. Alterations of the reproductive systems. In: McCance K, Huether S. Pathophysiology: The biologic basis for disease in adults and children. 6th ed. Maryland Heights, MO: Mosby; 2010: 841-941.
2. Kroupis C, Vourlidis N. Human papilloma virus (HPV) molecular diagnostics. Clin Chem Lab Med. 2011;49(11):1783-1799.
3. Solomon D, et al. The 2001 Bethesda system: Terminology for reporting results of cervical cytology. JAMA. 2002;287(16):2114-2119.
4. Saslow D, et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology Screening Guidelines for the Prevention and Early Detection of Cervical Cancer. Am J Clin Pathol. 2012;137(4):516-542.
5. Diagnosis of HPV-induced disease: Cervical intraepithelial neoplasia Grades 1,2,3 (CIN1, 2, and 3). American Society for Colposcopy and Cervical Pathology website. http://www.asccp.org/PracticeManagement/HPV/DiagnosisofHPVInducedDisease/tabid/5825/Default.aspx
6. Crawford-Faucher A. Conventional Pap smear vs. liquid-based cytology. Am Fam Physician. 2010; 81(4):542-549.
7. 2009 Algorithm: Use of HPV genotyping to manage HPV HR* positive/cytology Negative women 30 Years and Older. American Society for Colposcopy and Cervical Pathology website. http://www.asccp.org/Portals/9/docs/pdfs/Consensus%20Guidelines/hpv_genotyping_20090320.pdf
8. Wright TC, et al. Evaluation of HPV-16 and HPV-18 genotyping for the triage of women with high-risk HPV+ cytology-negative results. Am J Clin Pathol. 2011;136(4):578-586.
9. Castle PE, et al. Performance of carcinogenic human papillomavirus (HPV) testing and HPV 16 or HPV 18 genotyping for cervical cancer screening of women aged 25 years or older: a subanalysis of the ATHENA study. Lancet Oncol. 2011;12(9):880-890.
10. Rijkaart DC, et al. Human papillomavirus testing for the detection of high-grade cervical intraepithelial neoplasia and cancer: final results of the POBASCAM randomized controlled trial. Lancet Oncol. 2012;13(1):78-88.
11. Reimbursement. Cobas HPV (human papillomavirus) Test website. http://hpv16and18.com/hcp/know-her-risk/reimbursement.
12. Vijayaraghavan A, et al. Cost effectiveness of using human papillomavirus 16/18 genotype triage in cervical cancer screening. Gynecol Oncol. 2010;119(2):237-242.
Christi Burnett is a student in the primary care nurse practitioner program at the University of North Florida in Jacksonville. She has completed a disclosure statement and reports no relationships related to this article.