A biomarker of unprotected receptive anal intercourse (RAI) could improve validity of sexual behavior measurement. We quantified prostate-specific antigen (PSA) from rectal swabs from men who have sex with men (MSM). One swab was PSA-positive. Using current methods, PSA is an inadequate biomarker of recent unprotected RAI in MSM

Davis, John A.

Ervin, Melissa

Fields, Karen S.

Gallo, Maria F.

Hobbs, Marcia M.

Lynch, Courtney D.

Norris, Alison H.

Rice, Cara E.

Turner, Abigail Norris

PubMed

Carolina Digital Repository

Prostate-specific antigen is unlikely to be a suitable biomarker of semen exposure from recent unprotected receptive anal intercourse in men who have sex with menCara E. Rice, MPH1, Maria F. Gallo, PhD1, Marcia M. Hobbs, PhD3, Courtney D. Lynch, PhD4, Alison H. Norris, MD, PhD1,2, John A. Davis, MD, PhD2, Karen S. Fields, RN, BSN5, Melissa Ervin5, and Abigail Norris Turner, PhD2,11Division of Epidemiology, College of Public Health, The Ohio State University, Columbus, OH, USA2Division of Infectious Diseases, College of Medicine, The Ohio State University, Columbus, OH, USA3Division of Infectious Diseases, School of Medicine, University of North Carolina, Chapel Hill, NC, USA4Department of Obstetrics and Gynecology, College of Medicine, The Ohio State University, Columbus, OH, USA5Sexual Health Clinic, Columbus Public Health, Columbus, OH, USAAbstractA biomarker of unprotected receptive anal intercourse (RAI) could improve validity of sexual behavior measurement. We quantified prostate-specific antigen (PSA) from rectal swabs from men who have sex with men (MSM). One swab was PSA-positive. Using current methods, PSA is an inadequate biomarker of recent unprotected RAI in MSM.KeywordsMSM; Receptive anal intercourse; Prostate specific antigen (PSA); Measurement; Validity; biomarkerMen who have sex with men (MSM) in the United States are particularly vulnerable to and disproportionately affected by HIV.The estimated probability of HIV transmission per act of unprotected receptive anal intercourse (RAI) ranges from 0.27% (1) to 3.38% (2). Valid measurement of sexual Corresponding Author: Cara E. Rice, 1144 N Doan Hall, OSU, 410 West 10th Ave, Columbus, OH 43210, Phone: (678) 429-0159, FAX: (614) 293-4556. Conflicts of Interest:No conflicts of interest were declared.The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Advancing Translational Sciences or the National Institutes of Health.NIH Public AccessAuthor ManuscriptSex Transm Dis. Author manuscript; available in PMC 2014 October 22.Published in final edited form as:Sex Transm Dis. 2014 June ; 41(6): 377–379. doi:10.1097/OLQ.0000000000000129.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscriptbehaviors, including RAI, is critical for HIV prevention interventions. Yet, to date, nearly all sexual health research has relied on self-reported data, despite questionable validity (3, 4). Individuals may not accurately report whether, when, and how often they engage in risky behaviors, and research findings based on self-reported information may be biased. Because no other measures have been available, despite the recognized limitations of self-reported sexual behavior data, all large-scale HIV prevention clinical trials among MSM rely on self-reported information (5, 6). A biomarker that replaces self-reported sexual behavior data would be a meaningful methodological advancement.Prostate-specific antigen (PSA) is a protein produced in the prostate and secreted into the urethra during ejaculation. The detection of PSA in vaginal fluid has been used in forensic medicine, and more recently in research, as a biomarker of recent exposure to semen (7, 8, 9). PSA is highly specific in confirming exposure to ≥1mL of semen in women, with excellent detection immediately after exposure and almost complete clearance by 48 hours after exposure (7, 10). PSA has been used in many studies to assess the reliability of self-reported sexual behavior and as a proxy measure of condom efficacy (7, 8, 11).We evaluated PSA as a biomarker of recent unprotected RAI among MSM. We hypothesized that rectal specimens would be PSA-positive only following recent unprotected RAI or RAI marked by condom misuse or malfunction.This investigation was part of a larger study of MSM recruited from a public sexual health clinic in the Midwestern United States. Participants were 18 or older, spoke and read English, and reported anal intercourse (receptive or insertive) with another man within the past year. The subset of men who reported receptive anal intercourse within the past two weeks was included in this analysis.Per clinic protocol, any man reporting RAI in the past year had a rectal swab collected for assessment of gonococcal and chlamydial infection via nucleic acid amplification tests. Swabs were inserted 2–4 centimeters into the rectum and gently rotated clockwise for 2–3 seconds to ensure adequate specimen collection. To measure PSA, an additional rectal swab was collected from each participant and frozen at −80°C until testing.Following their physical examination, participants completed a comprehensive behavioral questionnaire. Exposure to semen was assessed through questions about sexual practices in three time periods: the last 24 hours, 24 to 48 hours ago, and 48 to 72 hours ago. For each time period, participants were asked whether: they had RAI; a condom was used; any issues occurred with condom usage; the partner ejaculated; the partner withdrew prior to ejaculation; and lubricant was used. Men were also asked to provide the date and time of their last bowel movement and last anal douching. Men were compensated $10.PSA was measured using methods previously developed for vaginal swab specimens (7, 9, 12). Swabs were hydrated for 10 minutes in 1 mL of phosphate-buffered saline and vortexed vigorously to elute the contents into the buffer. Eluates were then centrifuged for 10 minutes at 10,000 RPM in a microcentrifuge to remove particulate matter; 300μL of the resulting supernatant was tested with the Abbott Architect Total PSA assay (Abbott Diagnostics, Abbott Park, IL, USA). The PSA assay has excellent sensitivity (detectable range: 0.01–100 Rice et al. Page 2Sex Transm Dis. Author manuscript; available in PMC 2014 October 22.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscriptng/mL) and specificity. In accordance with prior studies using vaginal swab specimens, a positive PSA result was defined as ≥1 ng PSA/mL rectal swab eluate.Statistical analyses were conducted using SAS (Version 9.3, Cary NC). Using a Kruskal-Wallis test, we compared PSA concentrations by self-reported sexual behavior within the past 48 hours: no RAI, protected RAI only, and at least one unprotected RAI act. Among those who reported any RAI within 72 hours, we used Spearman’s rank correlation coefficient to quantify the association between PSA concentration and hours since last reported RAI (13).Fifty-four men met eligibility criteria, provided informed consent, and enrolled. Participants were 18–56 years of age (median: 26 years). Two-thirds had completed at least some college (n=36). Eighty-one percent (n=44) identified as gay. When asked about position preference, nine men (17%) classified themselves as “mostly top”, 23 (43%) as “half top and half bottom”, 20 (37%) as “mostly bottom”, and two men (4%) as “exclusively bottom”.Of 54 participants, 41 reported no RAI in the past 48 hours, 3 reported only protected (condom) RAI in the past 48 hours, and 10 reported unprotected RAI in the past 48 hours (Table 1). PSA concentrations for the 54 specimens ranged from 0.000 ng/mL to 1.512 ng/mL, with a median of 0.017 ng/mL (IQR: 0.003 to 0.040). One specimen with 1.512 ng/mL tested positive for PSA according to the 1 ng/mL threshold for positivity (Table 1). The single positive specimen was collected from a man who reported protected RAI 14 hours prior to swab collection, and no unprotected RAI in the 72 hours preceding swab collection.PSA concentrations for men who reported no RAI in the past 48 hours (median, 0.017 ng/mL); protected RAI only (median, 0.051 ng/mL); or at least one unprotected act (median, 0.018 ng/mL) did not differ significantly (Kruskal-Wallis test, p=0.49) (Table 1). Among those who reported any RAI in the last 72 hours (n=21), PSA concentration was not significantly correlated with hours since last RAI (p=0.41). Figure 1 depicts the relationship among MSM who report RAI in the previous 72 hours between PSA concentration and hours since last RAI by self-report of RAI behavior (unprotected, protected, or none) in the previous 48 hours (Figure 1).HIV/STI prevention research in women has been meaningfully strengthened by the availability of biomarkers of recent unprotected sex, including PSA. The validation of a biological marker of unprotected RAI would help to assess exposure to HIV or STIs and substantially improve the validity and reliability of prevention research in MSM.Of 54 men, five reported RAI in the previous 24 hours (3 unprotected), 13 in the previous 48 hours (10 unprotected), and 21 in the previous 72 hours (14 unprotected). Given these self-reports, we detected PSA in substantially fewer men than expected, especially compared to similar work in women (3). Low PSA levels prevented us from performing more sophisticated analyses of discordance (positive PSA despite report of no unprotected sex). The low number of men reporting recent RAI may be related to our STD clinic sample. Men often present at an STD clinic because of symptoms or suspicion of infection, which may limit their sexual activity in the days immediately preceding the visit. However, Anderson et Rice et al. Page 3Sex Transm Dis. Author manuscript; available in PMC 2014 October 22.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscriptal, recently detected PSA in 8% of symptomatic women presenting to an STD clinic, which provides support for our study design (14).In women, PSA sensitivity is highest immediately after exposure (96%) and decreases over time, with 65% sensitivity six hours after sex, 21–29% after 24 hours, and 3–7% after 48 hours (7,10). Specificity ranges from 91–97% (7). Given the high specificity of the PSA assay in women, a positive test for PSA is unlikely to occur without exposure to semen. However, whether PSA persists similarly in the rectum and in men is unknown. The only previous study on PSA testing on rectal swabs from men was completed on cadavers, and found PSA in 64% of male rectal swabs (15). Sexual orientation of men in that study was unknown (15), and whether PSA migrated to the rectum post-mortem is unclear. Notably, the single individual in whom PSA was detected in our study reported protected RAI 14 hours prior to collection of the rectal swab, highlighting the potential weaknesses of self-report.PSA concentration was not significantly correlated with time since last RAI among men who reported RAI in the past 72 hours. While Figure 1 suggests a correlation between PSA and time since last RAI among men with the most recent sexual encounters, with one exception, detected PSA levels in this small study were all below the accepted threshold for positivity and orders of magnitude below levels reported in post-coitus vaginal samples (3). Even if the positive result detected in this analysis represents a true positive, a biomarker with such limited range would be of limited utility, as it would be difficult to separate true positives from background noise. In contrast, PSA used for identifying vaginal exposures results in much higher concentrations. Gallo et al found PSA levels of 100 ng/mL or higher in more than 20% of women (8), while median PSA levels in our study were well below 1 ng/mL, even after stratification by timing of last RAI (Table 1).We hypothesized that PSA clearance from the rectum could be affected by anal douching, bowel movements, or lubricant use (16). However, of the 13 men reporting sex in the last 48 hours, only one did not report having a bowel movement in the time between last RAI and his examination. Similarly, 12 of 13 reported lubricant use at last RAI. Thus, we could not assess the effect of these behaviors on PSA detection because of lack of variability in participant reports. Similarly, PSA detection may be affected by whether ejaculation occurred. Nine of the 13 men reporting RAI in the last 48 hours report ejaculation as part of the sex act.Our data suggest that PSA is not a suitable biomarker of recent unprotected RAI in MSM recruited from a STD clinic. However, our data do not rule out a use for PSA in a highly controlled setting. Future studies may assess whether PSA can be reliably measured immediately after a known rectal exposure – in the absence of lubricant use, anal hygiene, or bowel movements – in order to use the biomarker in future studies to evaluate the effectiveness of barrier methods for RAI (17).To our knowledge, the lack of association between PSA and recent RAI presented here is the first evidence that PSA, as currently measured, is not a suitable biomarker of unprotected RAI among MSM. The need for a biomarker in this population remains high.Rice et al. Page 4Sex Transm Dis. Author manuscript; available in PMC 2014 October 22.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptAcknowledgmentsSource of Funding:This project was supported by the Ohio State University Center for Clinical and Translational Science (OSU CCTS). The OSU CCTS is supported by the National Center for Research Resources, Grant UL1RR025755, and is now at the National Center for Advancing Translational Sciences, Grant 8UL1TR000090-05, the Alumni Grant for Graduate Research and Scholarship, and The Ohio State University Presidential Fellowship. Laboratory activities for the study were supported in part by the Southeastern Sexually Transmitted Infections Cooperative Research Center funded by the National Institute of Allergy and Infectious Diseases grant U19-AI031496.The authors thank Mysheika Williams Roberts, Jose Bazan, Maurizio Macaluso, Abigail Shoben, and the Division of Infectious Diseases at The Wexner Medical Center at Ohio State University for their support of this project. The authors thank the clinicians from Columbus Public Health SHC and study volunteers (Alexandra Medoro, Aliza Spaeth-Cook, Angela Palmer-Wackerly, Chelsea Muyskens, Courtney Maierhofer, Julie Anderson, Laura Drew, Samantha Lahey, and Tiffany Wang) for their assistance with data collection, and thank Dana Lapple for PSA testing.References1. Vittinghoff E, Douglas J, Judson F, et al. Per-contact risk of human immunodeficiency virus transmission between male sexual partners. American Journal of Epidemiology. 1999; 150(3):306–311. [PubMed: 10430236] 2. Powers KA, Poole C, Pettifor AE, et al. Rethinking the heterosexual infectivity of HIV-1: a systematic review and meta-analysis. Lancet Infect Dis. 2008; 8:553–563. [PubMed: 18684670] 3. Gallo MF, Steiner MJ, Hobbs MM, et al. Biological markers of sexual activity: tools for improving measurement in HIV/STI prevention research. Sex Transm Dis. 2013; 40:447–52. [PubMed: 23677018] 4. Zenilman JM, Weisman CS, Rompalo Am, et al. 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Gallo MF, Behets Frieda M, Steiner M, et al. Prostate-specific antigen to ascertain reliability of self-reported coital exposure to semen. Sexually Transmitted Diseases. 2006; 33(8):476–479. [PubMed: 16865047] 9. Macaluso M, Blackwell R, Jamieson DJ, et al. Efficacy of the male latex condom and of the female polyurethane condom as barriers to semen during intercourse: A Randomized Clinical Trial. American Journal of Epidemiology. 2007; 166(1):88–96. [PubMed: 17420182] 10. Jamshidi R, Penman-Aguilar A, Wiener J, Gallo MF, Zenilman JM, Melendez JH, Snead M, Black CM, Jamieson DJ, Macaluso M. Detection of two biological markers of intercourse: prostate-specific antigen and Y-chromosomal DNA. Contraception. 2013 Aug 14. Epub ahead of print. 11. Aho J, Koushik A, Diakité SL, et al. Biological validation of self-reported condom use among sex workers in Guinea. AIDS Behav. 2010; 14(6):1287–93. [PubMed: 19680799] 12. Lawson ML, Maculuso M, Bloom A, et al. Objective markers of condom failure. Sexually Transmitted Diseases. 1998; 25(8):427–432. [PubMed: 9773437] 13. Fowler R. Power and robustness in product-moment correlation. Applied Psychological Measurement. 1987; 11(4):419–428.Rice et al. Page 5Sex Transm Dis. Author manuscript; available in PMC 2014 October 22.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript14. Anderson C, Gallo MF, Hylton-Kong T, et al. Randomized controlled trial on the effectiveness of counseling messages for avoiding unprotected sexual intercourse during sexually transmitted infection and reproductive tract infection treatment among female sexually transmitted infection clinic patients. Sex Transm Dis. 2013 Feb; 40(2):105–10. [PubMed: 23321990] 15. Lunetta P, Sippel H. Positive prostate-specific antigen (PSA) reaction in post-mortem rectal swabs: A cautionary note. Journal of Forensic and Legal Medicine. 2009; 16:397–399. [PubMed: 19733329] 16. Snead MC, Kourtis AP, Black CM, et al. Effect of topical vaginal products on the detection of prostate-specific antigen, a biomarker of semen exposure, using ABA cards. Contraception. 2013; 88(3):382–6. [PubMed: 23218862] 17. Macaluso M, Lawson ML, Hortin G, et al. Efficacy of the female condom as a barrier to semen during intercourse. Am J Epidemiol. 2003; 157:289–97. [PubMed: 12578798] Rice et al. Page 6Sex Transm Dis. Author manuscript; available in PMC 2014 October 22.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptSHORT SUMMARYProstate-specific antigen (PSA), collected via rectal swab, is an inadequate biomarker of recent unprotected receptive anal intercourse among men who have sex with men (MSM).Rice et al. Page 7Sex Transm Dis. Author manuscript; available in PMC 2014 October 22.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptFigure 1. Among those who reported RAI in the previous 72 hours (n=21), PSA concentration (ng/mL) by hours since last RAIRice et al. Page 8Sex Transm Dis. Author manuscript; available in PMC 2014 October 22.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptRice et al. Page 9Table 1PSA Level by Self-reported Sexual Behavior (n=54)Self-ReportsMedian (ng PSA/mL)IQR (ng PSA/mL)PSA PositivePSA NegativeN(%)N(%)Past 24 hours >=1 Unprotected RAI0.1270.000–0.9660(0)3(6) Protected RAI only0.7580.003–1.5121(2)1(2) No RAI0.0170.003–0.0340(0)49(91)Past 48 hours >=1 Unprotected RAI0.0180.000–0.0200(0)10(19) Protected RAI only0.0510.003–1.5121(2)2(4) No RAI0.0170.002–0.0370(0)41(76)Sex Transm Dis. Author manuscript; available in PMC 2014 October 22.

Prostate-Specific Antigen is Unlikely to Be a Suitable Biomarker of Semen Exposure From Recent Unprotected Receptive Anal Intercourse in Men Who Have Sex With Men

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Prostate-Specific Antigen is Unlikely to Be a Suitable Biomarker of Semen Exposure From Recent Unprotected Receptive Anal Intercourse in Men Who Have Sex With Men

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