Human papillomavirus infections

Truth or consequences

Authors

  • Bradley J. Monk M.D.,

    Corresponding author
    1. Division of Gynecologic Oncology, University of California at Irvine, Irvine, California
    • Division of Gynecologic Oncology, University of California at Irvine Medical Center, 101 The City Drive, Orange, CA 92868
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    • Dr. Monk has received funding from Zycos (Lexington, MA), Trylon (Torrance, CA), and the National Cancer Institute for research in the area discussed in the current editorial. In addition, he has received grants from the National Institutes of Health, and the Chao Family Comprehensive Cancer Center (Irvine, CA). Dr. Monk has received speaker's honoraria from Digene (Gaithersburg, MD), Watson Pharmaceuticals (Corona, CA), Trylon (Torrance, CA), and Cytyc (Boxborough, MA).

    • Fax: (714) 456-6463

  • Dorothy J. Wiley Ph.D.

    1. School of Nursing, University of California at Los Angeles, Los Angeles, California
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  • See referenced original article on pages 308–14, this issue.

Abstract

In this issue of Cancer, Anhang et al. present a review of written and verbal media reports that concern human papillomavirus infection, cervical cancer screening, and sexually transmitted infection. Their findings suggest that it is little wonder that the public is informed so inadequately about the virus, the consequences of infection, and the natural history of cervical neoplasia.

See also pages 308–14.

The human papillomavirus (HPV) is etiologically associated with virtually all cases of preinvasive and invasive cervical neoplasia. Experts suggest that as many as 230 different HPV types may exist, based on data from partially sequenced virus fragments; however, 80 HPV types have been sequenced and typed officially, and more than 25 additional putative HPV types have been identified by laboratories and are reported by the Los Alamos National Laboratory at this time.1 Data suggest that about 30 specific HPV types infect the male and female genital tract and that about 20 types are classified as high risk due to their association with cervical malignancies.2 HPV types associated with genital warts have been designated as low risk (e.g., HPV type 6 [HPV-6] and HPV-11), because they seldom are associated with malignant disease. HPV infection is widely recognized as the most common sexually transmitted disease among sexually active men and women; however, the reason that so few malignancies result from such a common infection is not well understood.3 For example, approximately 500,000 incident invasive cervical cancers are diagnosed annually worldwide, and although the majority of affected women live in developing countries, invasive disease is rare.4 HPV-16 is associated with half of all cervical malignancies,2 and although invasive disease occurs domestically among ≈ 8 in 100,000 women annually, recent data suggest that 18% of females ages 12–49 years exhibit serologic (antibody) evidence of HPV-16 infection.5 The origin of this double-stranded, epitheliotropic DNA virus appears to be African, from prehuman primates, with subsequent worldwide spread to human races. The lack of transmission of papillomaviruses among species supports a gradual mode of molecular evolution, creating a symbiosis between pathogen and host.6

Using molecular tests, HPV testing in women is now both feasible and reimbursable by most third-party payers by either testing from the vial when a ThinPrep Papanicolaou (Pap) test (Cytyc Corporation, Boxborough, MA) is collected or by ‘cocollection’ with the Digene Cervical Sampler (Digene Corporation, Gaithersburg, MD). Currently, HPV testing for high-risk types has two clinical applications. The first application is triage of minimally abnormal Pap tests (atypical squamous cells of undetermined significance [ASC-US]). After a woman is diagnosed with ASC-US, HPV testing for high-risk types can determine whether colposcopy is necessary or, alternatively, if the HPV test is negative, whether to follow-up in 1 year.7 HPV testing is more sensitive than repeat Pap testing alone in finding high-grade dysplasia when ASC-US is detected and can reduce unnecessary colposcopies.8 Second, on April 1, 2003, Digene Corporation announced that the United States Food and Drug Administration (FDA) had approved Digene's Pre-Market Approval Supplement application for its Hybrid Capture 2 (hc2)/High-Risk HPV DNA Test for use with a Pap test to adjunctively screen women age ≥ 30 years to assess the presence or absence of high-risk HPV types. The FDA's decision allows Digene to market its HPV test in conjunction with the Pap test for screening.9 Consensus panels have endorsed these applications.10, 11 Some experts suggest that, after age 30 years, the predictive value of negative findings for both Pap and hc2 assays may justify the use of molecular typing every 3 years to improve the sensitivity of cervical cancer screening. In this circumstance, the costs of HPV testing may be offset; in fact, cost-effectiveness studies show that in low-resource settings, molecular HPV testing as a screening modality is superior to cytology alone.12 The American College of Obstetricians and Gynecologists recently stated in a Practice Bulletin that women age ≥ 30 years who receive negative results on cervical cytology screening and HPV DNA testing should be screened for cervical malignancy no more frequently than once every 3 years.10

Screening using Digene's Hybrid Capture 1 panel, which is less sensitive than hc2, has no clinical value. It also must be emphasized that testing for low-risk HPV types has no clinical application and may lead to confusion and excessive treatment and, thus, cannot be recommended.

In addition to new testing strategies, recent discoveries have shed new light on the prevention of cervical malignancies. Specifically, the natural history of HPV infections has been elucidated recently, and factors have been identified that may predict the spontaneous resolution of HPV infections and/or dysplasias. Previously, it was believed that HPV was a chronic infection, like the human immunodeficiency virus, and that spontaneous resolution was not possible. Now, untreated moderate and severe dysplasias can resolve as frequently as 58% and 47% of the time, respectively, after only a biopsy.13 In addition, recent advances show that preventive (HPV) vaccine strategies using virus-like particles hold great promise for preventing infection14 and that therapeutic vaccine strategies may promote the clearance of existing HPV infections and their associated lesions.15

Although new cervical cancer screening strategies that promote adjunctive molecular testing may prevent invasive cervical malignancy in a substantial proportion of affected women, it also will ensure that a large proportion of women who test positive for HPV will not be affected.16 The prevalence of HPV infection decreases with age, even in the absence of cervical cancer screening17; thus, when specificity is poor and the disease is rare, the numbers of unaffected women who are diagnosed as HPV positive will be greater than the numbers who truly are affected. For example, Guyot et al. recently reported that among women age ≥ 30 years who exhibited mild dyskaryosis and had a high relative light unit cutoff point, representing a positive hc2 test, the specificity of the assay was only 58%.16 Although the predictive power of a negative test is great, the numbers of false-positives still are expectedly high. For example, if hc2 performs accordingly, the proportion of women testing falsely positive when the prevalence ranges from 5% to 10% will range from 88% to 77%, respectively. Although the multiple responses elicited when women are told they are HPV positive cannot be anticipated completely, it is well recognized that many women experience the feelings of being frightened, angry, guilty, anxious, confused, dirty, regretful, and panicked. In addition, the receipt of a positive HPV test result often calls sexual fidelity into question. In a recent study, a greater negative emotion was associated with refusing HPV testing rather than taking the test.18 It is noteworthy that many reports have documented that the majority of women have little knowledge of HPV infections, and it has been hypothesized that many of the negative emotions associated with being informed of HPV positivity may be related to this lack of information.

In this issue, Anhang et al. present a review of written and verbal media reports that concern HPV infection, cervical cancer screening, and sexually transmitted infection. Their findings suggest that it is little wonder that the public is informed so inadequately about the virus, the consequences of infection, and the natural history of cervical neoplasia.19 Nonetheless, identifying a problem of such import obligates us to act to promote the public's health.

Thus, the first step in the dissemination of accurate and complete information about HPV is to outline the ‘truth’, thus avoiding the ‘consequences’ of misinformation and ignorance. During every physician-patient encounter and when any forum of public media discusses HPV, six points should be emphasized. First, HPV is a sexually transmitted disease. It is noteworthy that in the article by Anhang et al., only 79% of news media reports mentioned this fact. Second, HPV is very common and, in fact, is the most common sexually transmitted disease. Indeed, this was mentioned in only 50% of the media reports surveyed. Third, the overwhelming majority of women with HPV will not develop cervical malignancies. Indeed, cervical cancer is an extremely rare complication of a common infection. It is noteworthy that HPV increases the risk of cervical neoplasia, but only to a limited degree. Approximately 15% of women in annual screening programs who concurrently have a negative Pap test and a positive, high–risk HPV test will have a subsequent abnormal Pap test within 5 years.20 Fourth, the spontaneous resolution of HPV is common. Fifth, most women who test positive for high-risk HPV as part of a cervical cancer screening program will not be diagnosed with cervical malignancy or a precursor to malignancy upon further evaluation. Nevertheless, all women with high-risk HPV and an ASC-US pap need an initial, immediate colposcopy. The chance of having a high-grade lesion in this setting is 10–15%. Although HPV DNA testing can increase the sensitivity of cervical screening, it leads to many false-positive results. Indeed, the number of false-positive results associated with HPV testing as a primary screening modality has not been estimated completely. The incidence of CIN II–III after evaluation of a positive high-risk hc2 assay associated with a normal PAP is estimated to be approximately 4–5%. However, along with these false-positive results comes almost 100% sensitivity in detecting cervical malignancy or its precursors when combined with cervical cytology. Finally, the purpose of a Pap test is to detect HPV-related lesions, including cervical malignancies, and their precursors.

The first step in improving the public's health is clearly stating truths about HPV infection. Undoubtedly, the article by Anhang and colleagues has heightened our awareness of the miscommunication and misinformation that text and oral media may be conveying to our citizenry. However, it is likely that effective educational messages will require the collaboration of advocacy groups, of payers, and of providers with journalists to enhance their understanding and, subsequently, with the public to enhance decision making as it relates to (HPV-infection) prevention, screening, and treatment.

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