Patient Safety and the Next Generation of HPV DNA Tests

Human papillomavirus (HPV) testing is more sensitive for the detection of cervical precancer and cancer than cervical cytology. The increased sensitivity of HPV testing and cytology combined (“cotesting”) compared to cytology alone permitted professional societies to recommend 3-year screening intervals among the cotest-negative results. However, there is an increasing recognition that both clinical sensitivity and specificity of cervical cancer screening are important to patient safety and must be considered in the context of using current and future HPV DNA tests. Exquisite analytic sensitivity for HPV does not increase clinical sensitivity of an HPV test but does result in excessive test positivity and decreased clinical specificity. A recent US Food and Drug Administration (FDA)approved HPV test, Cervista (Hologic, Bedford, MA), demonstrated excessive test positivity—2 to 4 times more positive than the other FDA-approved HPV test—from its premarketing approval trial. The poor specificity of Cervista raises questions about the safety and applicability of using this test in routine cervical cancer screening. These data provide a didactic example of the potential dangers of mistaking excellent analytic sensitivity and even clinical sensitivity for good clinical performance. Five years ago, there was a single US Food and Drug Administration (FDA)-approved human papillomavirus (HPV) test, Hybrid Capture 2 (HC2; Qiagen, Gaithersburg, MD). The cutting edge of physician education and guideline writing revolved around recognition of the differences in sensitivity for cervical intraepithelial neoplasia (CIN) grade 2 or more severe (CIN 2+) diagnoses between cytology and HPV testing or the combination of the 2 tests (“cotesting”). Practice recommendations were promulgated in which the “HPV test” was synonymous with HC2 because it was the only test commercially available with a sufficient body of clinical experience to assess performance. The recognition of the increased sensitivity of cotesting for CIN 2+ vs cytology alone permitted professional societies to recommend screening at 3-year intervals for women 30 years and older with cotest-negative results.1 The sensitivity of HPV tests was therefore perceived as the most important patient safety issue to permit screening interval extension without increasing cancer risk. Specificity was not considered a patient safety issue in the regulatory or the clinical practice setting because the consensus at that time was that the morbidity of excision treatments such as the loop electrosurgical excision procedure was minimal. Given the long time course and huge investment required for test development and approval, it is understandable that new tests have been planned and configured based on the consensus understanding of cervical cancer screening at the outset of their development. Yet, our understanding of cervical cancer screening and prevention has evolved. Specifically, clinical sensitivity and specificity of cervical cancer screening are important to patient safety and must be considered in the context of using current and future HPV DNA tests. Downloaded from https://academic.oup. com/ajcp/article-abstract/134/2/193/1760619 by guest on 28 July 2018 194 Am J Clin Pathol 2010;134:193-199 194 DOI: 10.1309/AJCPRI8XPQUEAA3K © American Society for Clinical Pathology Kinney et al / New HPV DNA Tests The guidelines governing the use of HPV DNA testing in the clinical management of cervical screening and treatment are totally dependent on the clinically validated performance of the HPV DNA test. The difficulty in hitting the mark in terms of balancing analytic detection with the clinical tradeoff of sensitivity and specificity for cervical precancer (CIN 3) and cancer (CIN 3+) has been amply documented by the numerous failures in the history of HPV DNA test development, most of which have mistaken high analytic sensitivity for good clinical performance. In contrast with other in vitro diagnostics such as HIV tests in which detection of all HIV is the goal, the objective of clinical HPV DNA detection is not the detection of all HPV; it is the detection of clinically relevant HPV, ie, HPV infections strongly associated with and accounting for the majority (>90%) of CIN 3+. Excessive analytic sensitivity for carcinogenic HPV results only in increasing the number of false-positive results (lowering clinical specificity) without the benefit of increasing clinical sensitivity. Expert opinions regarding what is or is not a good HPV DNA test in the United States have been published in an article accompanying the American Society for Colposcopy and Cervical Pathology Guideline revisions2 and similar criteria have been adopted by the European testing community3 as well. A recent regulatory approval of a new HPV DNA test provides an instructive lesson on the important distinction between good clinical and analytic performance for clinical HPV DNA testing, reminds us of the importance of clinical sensitivity and specificity in selecting an HPV test, and forces us to rethink the assumption that all HPV tests are and will be created equally, which is implicit in structure of the current guidelines for use of HPV testing in clinical practice. Cervista: Next Generation of HPV Tests? On March 12, 2009, the FDA approved 2 assays, Cervista HPV HR (high risk) and Cervista HPV 16/18 (Third Wave Technologies, Madison, WI; now owned by Hologic, Bedford, MA) for use in cervical cancer screening. Cervista HPV HR is a DNA test for 14 carcinogenic HPV genotypes. Cervista HPV HR was approved as a triage test for women with a cervical cytology interpretation of atypical squamous cells of undetermined significance, to determine who needs immediate colposcopy and as an adjunctive test with cervical cytology for routine screening in women 30 years or older. The indicated uses of Cervista HPV HR are in accordance with current national guidelines for use of HPV DNA tests1,4; other accepted applications of validated HPV DNA tests include postcolposcopic and posttreatment surveillance.4 Cervista HPV 16/18 was approved for the DNA detection of HPV-16 and HPV-18, the 2 most carci-