Human Papillomavirus DNA Detection in Older Women—Implications for Cancer Screening and Prevention

The Journal of Infectious Diseases EDITORIAL COMMENTARY Human Papillomavirus DNA Detection in Older Women— Implications for Cancer Screening and Prevention Aaron C. Ermel1 and Kenneth H. Fife1,2,3 1 Department of Medicine, 2Department of Microbiology and Immunology, and 3Department of Pathology, Indiana University School of Medicine, Indianapolis (See the major article by Winer et al on pages 665–75.) Keywords. human papillomavirus; cancer screening; ageing Received and accepted 19 February 2016; published online 23 March 2016. Correspondence: K. H. Fife, Emerson Hall 421, 545 Barnhill Dr, Indianapolis, IN 46202 (). The Journal of Infectious Diseases® 2016;214:657–8 © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail . DOI: 10.1093/infdis/jiw075 one third of cases of incident HR-HPV DNA detection were not attributable to the acquisition of new sex partners raise certain questions that may influence our understanding of the natural history of HR-HPV infections, cervical cancer screening of mid-adult women, and how we use HPV vaccines. The pattern of detection of HR-HPV DNA and its significance has been investigated in longitudinal cohorts [2] or among mid-adult women [3]. The factors leading to persistent detection of HRHPV DNA are not clearly understood, and in some cases, HR-HPV redetection cannot always be attributed to the acquisition of a new partner [4, 5]. Attempts to properly elucidate whether type-specific HPV DNA detection represents a new infection or redetection have been hampered by a lack of long-term follow-up data, a lack of detailed behavioral data, biases (usually recall bias) associated with the collection of behavioral data, and the lack of a reliable serological marker of past infection to determine whether detection of a HR-HPV type represented new infection or redetection of previously acquired infection. The women included in the study by Winer et al were separated into 3 groups based on their sexual activity during the preceding 6 months. The investigators noted that nearly two thirds of the incident HR-HPV detection events were attributable to the acquisition of a new partner. However, a significant portion of these women who had newly detected HR-HPV DNA did not report a new partner, reinforcing the concept that episodic detection of HR-HPV may be responsible for this paradox. This is further supported by the increased risk attributed to lifetime number of sex partners prior to the study period (adjusted hazard ratio, 2.56; 95% confidence interval, 1.15–2.83), which remained an independent predictor even in the multivariate analysis. The behavioral data suggest that the majority of these infections are truly incident, but this cannot be determined with certainty. The significance of episodic detection of HR-HPV will become more relevant as the use of HPV DNA testing increases [6]. The results of the ATHENA trial [7] indicate a high negative predictive value (99.3%) for the presence of cervical intraepithelial neoplasia grade ≥2 (CIN2+), when testing specifically for HPV 16/18, and a relatively high positive predictive value for the presence of precancerous lesions, based on HPV 16/18 genotyping. This led to the recommendation that women with HPV 16/18–positive results undergo colposcopy without by cytologic testing. The study cohort in the ATHENA trial and participants in the National Health and Nutrition Examination Survey (NHANES) [8] had lower overall prevalence proportions of HR-HPV DNA detection (12.6% and 15.2%, respectively). These prevalence values are lower than that in the group studied by Winer et al, which had a cumulative incidence of HRHPV DNA detection of 25.4%. This could make findings of larger screening trials less generalizable for certain subgroups of the population who may be at higher risk for recent HR-HPV acquisition later EDITORIAL COMMENTARY • JID 2016:214 (1 September) • 657 In this era of declining marriage rates and increasing divorce rates, women are increasingly likely to acquire new sex partners at older ages. In this issue of The Journal of Infectious Diseases, Winer et al [1] present an interesting look at the incidence of high-risk human papillomavirus (HR-HPV) type DNA detection in a group of mid-adult women, defined as those aged 25–65 years, exhibiting “high-risk” sexual behaviors. The investigators collected behavioral data, including the lifetime number of male sex partners, age at first intercourse, smoking history, and, specifically, sex with ≥1 male partner within the preceding 6 months. They used these data in an attempt to characterize whether detection of HR-HPV DNA by type-specific polymerase chain reaction represented true incident infection or redetection of a previously acquired infection. This study provides insight into this subgroup of women who generally are well studied but do not constitute a large portion of the participants in trials of cervical cancer screening methods. The findings that the cumulative incidence of HR-HPV DNA detection was relatively high in a cohort of mid-adult women and that nearly new partner acquisition have influenced the seroprevalence of HR-HPV types [10]. The implication that waning natural immunity later in life could lead to increased HR-HPV DNA detection, whether it be related to true incident infection or redetection due to lack of immune control, is particularly important when considering the high-risk behaviors of the mid-adult women studied by Winer et al and their relatively high incidence of HR-HPV detection. The protection offered by natural immunity appears to be relatively insignificant, and the data regarding the protective effects of naturally acquired immunity are conflicting [11]. This and the increasing evidence of continued HR-HPV DNA detection in mid-adult women [12] may support vaccination of subgroups such as the one included in the current report. The implementation of cervical cytology screening, HPV DNA detection, and vaccines targeting HR-HPV types represent major advances in public health. We now face the challenge of adapting these to all segments of the population at risk. Indeed, longitudinal cohort studies, in particular those that provide longterm follow-up from near the age of acquisition to mid-adulthood, are necessary to fully understand the impact of changing behaviors on screening and prevention. Notes Financial support. This work was supported by the National Cancer Institute (grant U54 CA190151-01 to A. C. E.). Potential conflict of interest. Both authors: No reported conflicts. Both authors have submitted 658 • JID 2016:214 (1 September) • EDITORIAL COMMENTARY the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1. Winer RL, Hughes JP, Feng Q, Stern JE, Xi LF, Koutsky LA. 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