Detection of Incident Anal High-Risk Human Papillomavirus DNA in Men Who Have Sex With Men: Incidence or Reactivation?

The Journal of Infectious Diseases MAJOR ARTICLE Detection of Incident Anal High-Risk Human Papillomavirus DNA in Men Who Have Sex With Men: Incidence or Reactivation? Denise E. Twisk,1 Marianne A. B. van der Sande,2,3,4 Arne van Eeden,5 Daniëlle A. M. Heideman,6 Fiona R. M. van der Klis,2 Henry J. C. de Vries,1,2,7 and Maarten F. Schim van der Loeff1,8 1Department of Infectious Diseases, Public Health Service Amsterdam, 2Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, and 3Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, The Netherlands; 4Department Public Health, Institute of Tropical Medicine, Antwerp, Belgium; 5Department of Internal Medicine, DC Klinieken Oud Zuid, Amsterdam, 6Department of Pathology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, and 7Department of Dermatology, and 8Amsterdam Infection and Immunity Institute (AIII), Academic Medical Center, The Netherlands. Background. We aimed to assess whether sexual exposure may explain all incident anal human papillomavirus (HPV) detections among men who have sex with men (MSM). Methods. A longitudinal study among MSM was conducted between 2010 and 2013 with visits every 6 months and up to 24 months of follow-up. Risk-factor questionnaires, blood samples, and anal and penile self-swabs were collected at each visit. Selfswabs were used for detection and genotyping of HPV by the broad spectrum L1 based SPF10 PCR DNA/enzyme immunoassay LiPA25 system. Serum samples were tested for high-risk HPV (hrHPV) antibodies. Incident anal HPV detection rates among sexually non-, low, and highly exposed MSM were compared. Factors associated with incident anal hrHPV detection were assessed using multivariable Cox regression. Results. Seven hundred fourteen men (median age, 40 years; 39% human immunodeficiency virus [HIV] infected) were included in the analysis. Incident anal detections of all hrHPV types were observed among both sexually nonexposed and exposed MSM. In multivariable analyses, being highly sexually exposed, being HIV infected, and having a penile HPV infection were positively associated with incident anal HPV detection; those reporting more sex partners had a nonsignificantly increased risk of HPV detection. Conclusions. Incident anal hrHPV detection is common among recently nonexposed MSM, suggesting that a reactivated latent HPV infection instead of an incident infection may underlie incident HPV detection. Keywords. HPV; HIV; incidence rate; men who have sex with men; latency. Human papillomavirus (HPV) infections are very common among sexually active people [1]. Persistent high-risk HPV (hrHPV) infections of the cervix and anus are associated with high-grade dysplasia and cancer [2, 3]. Only a small proportion of all HPV infections persist. Up to 90% of all high- or low-risk HPV infections become undetectable after acquisition within about 2 years [4–6]. It is generally assumed that undetectable infections are cleared, but latency may provide another explanation [7–10]. Typically, individuals with a positive HPV DNA test are considered to be HPV infected, whereas a negative HPV DNA test represents HPV-uninfected individuals [7]. To avoid false-negative test results, some studies require at least 2 consecutive negative tests to declare clearance. However, ≥2 negative test results Received 22 December 2017; editorial decision 2 April 2018; accepted 8 May 2018; published online May 16, 2018. Correspondence: M. F. Schim van der Loeff, MD, PhD, Department of Infectious Diseases, Public Health Service Amsterdam, PO Box 2200, 1000 CE, Amsterdam, The Netherlands (). The Journal of Infectious Diseases®  2018;218:1018–26 © The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: . DOI: 10.1093/infdis/jiy276 1018 • JID 2018:218 (1 October) • Twisk et al do not rule out an HPV infection as HPV might persist in tissues below the limit of detection, displaying viral latency [7]. The current analysis aims to increase understanding of the meaning of incident anal hrHPV detection among men who have sex with men (MSM) by using data of the longitudinal HPV in HIV-Negative and HIV-Positive Infected MSM (H2M) study. We assessed the incidence of anal hrHPV infections in MSM in relation to the level of sexual exposure. METHODS The current study is based on data from the H2M study, a longitudinal cohort study with a follow-up time of 24 months. The overall aim of the H2M study was to assess the epidemiology of HPV in human immunodeficiency virus (HIV)–negative and HIV-infected MSM. Details on enrollment, data collection, HPV DNA detection and genotyping, and HPV serology were previously described [11– 13]. Upon cohort entry, all men reported having had sex with men. Study Participants Between July 2010 and July 2011, 317 HIV-infected and 461 HIV-negative men aged ≥18 years were enrolled in the H2M (See the Editorial Commentary by Burchell, on pages 1015–7.) study [11]. All participants provided written informed consent prior to participation. The Medical Ethics Committee of the Academic Medical Center Amsterdam approved the H2M study. Data Collection HPV DNA Detection and HPV Serology Anal and penile swabs were tested and typed using the highly sensitive broad spectrum L1 based SPF10 PCR DNA/enzyme immunoassay LiPA25 system (version 1, Labo Biomedical Products, Rijswijk, the Netherlands), which is able to recognize at least 68 HPV genotypes [15]. Serum samples of 7 hrHPV types (16, 18, 31, 33, 45, 52, and 58) were tested for HPV antibodies to the major HPV capsid protein L1 by a virus-like particle–based multiplex immunoassay [16–18]. Statistical Methods For analyses we focused on 7 hrHPV types: 16, 18, 31, 33, 45, 52, and 58. Detection of type-specific incident anal HPV DNA (hereafter referred to as incident anal HPV detection) was defined as an HPV-positive visit preceded by at least 2 consecutive HPV-negative visits for this specific HPV type. We assumed that incidence occurred at the midpoint between the date of the last negative sample and the date of the positive sample. For type-specific HPV detection rates, only participants at risk for type-specific incident anal HPV detection were included. Men were considered at risk if they completed at least 3 visits and were negative for this specific HPV type on their first 2 study visits. Time at risk for an HPV type ended when that specific HPV type was detected using the midpoint date, or at the date of the last collected sample. Type-specific anal HPV incident detection rates were calculated by dividing the number of incident detections by the number of person-years (PY) at risk, and expressed as events per 100 PY with 95% confidence intervals (95% CI). The same method was used to calculate incident detection rates of type-specific penile HPV. To account fo (...truncated)