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Background: Understanding the natural history of human papillomavirus (HPV) infections is essential to cervical cancer prevention planning. We estimated HPV type-specific infection detection and clearance in young women., Methods: The HPV Infection and Transmission among Couples through Heterosexual activity (HITCH) study is a prospective cohort of 502 college-age women who recently initiated a heterosexual relationship. We tested vaginal samples collected at 6 clinical visits over 24 months for 36 HPV types. Using rates and Kaplan-Meier analysis, we estimated time-to-event statistics with 95% confidence intervals (CIs) for detection of incident infections and clearance of incident and present-at-baseline infections (separately). We conducted analyses at the woman- and HPV-levels, with HPV types grouped by phylogenetic relatedness., Results: By 24 months, we detected incident infections in 40.4% (CI, 33.4%-48.4%) of women. Incident subgenus 1 (43.4; CI, 33.6-56.4), 2 (47.1; CI, 39.9-55.5), and 3 (46.6; CI, 37.7-57.7) infections cleared at similar rates per 1000 infection-months. We observed similar homogeny in HPV-level clearance rates among present-at-baseline infections., Conclusions: Our analyses provide type-specific infection natural history estimates for cervical cancer prevention planning. HPV-level analyses did not clearly indicate that high oncogenic risk subgenus 2 infections persist longer than their low oncogenic risk subgenera 1 and 3 counterparts., Competing Interests: Potential conflicts of interest. M. Z. and E. L. F. hold a patent related to the discovery “DNA methylation markers for early detection of cervical cancer,” registered at the Office of Innovation and Partnerships, McGill University, Montréal, Québec, Canada, October 2018. A provisional utility patent application before the United States Patent and Trademark Office was also filed (November 2018) and a patent cooperation treaty application (PCT/IB2020/050885), filed in February 2020, has been published (No. WO 2020/115728; June 2020). E. L. F. reports grants and personal fees from Merck outside of the submitted work. F. C. reports grants from Réseau FRQS-SIDA during the conduct of the study, and grants to his institution for HPV-related work from Merck Sharp and Dome, Roche Diagnostics, and Becton Dickinson outside of the submitted work. All other authors report no potential conflicts. All authors have submitted 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., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Humoral immune responses may be critical for preventing, controlling, and/or eliminating human papillomavirus (HPV) infection. We analyzed humoral response to natural HPV infection considering phylogenetic relatedness among unvaccinated women., Methods: We included 399 young women attending university/college in Montreal, Canada who were participants of the HITCH cohort. Participants provided blood samples at baseline and 5 follow-up visits. Antibody response to bacterially expressed L1 and E6 glutathione S-transferase (GST) fusion proteins, and virus-like particles (VLP-L1) of Alphapapillomavirus types were measured using multiplex serology. We assessed correlations and associations between HPV types at baseline using Pearson correlation coefficients (r) and univariable linear regressions., Results: At baseline, > 40% were seropositive for GST-L1 antibodies of at least 1 HPV type. Strong correlations between GST-L1 were observed for α9 HPV types: 58-52 (r = 0.86), 58-33 (r = 0.75), 33-52 (r = 0.72), and between GST-E6: 52-11 (r = 0.84), 52-18 (r = 0.79), 58-33 (r = 0.78), 35-11 (r = 0.76). HPV16 VLP-L1 moderately explained variability in HPV16 GST-L1 (regression coefficient [b] = 0.38, R2 = 43.1%), and HPV45 GST-L1 in HPV18 GST-L1 (b = 0.68, R2 = 42.8%). GST-E6 antibodies accounted for a low to moderate proportion of variability in HPV16 and HPV18 GST-E6 (R2 = 6.4%-62.2%)., Conclusions: Associations between naturally induced HPV-specific antibodies depend on phylogenetic relatedness., Competing Interests: Potential conflicts of interest . E. L. F. has served as an occasional advisor to companies involved with human papillomavirus (HPV) diagnostics (Roche, BD, Qiagen, Gen-Probe) and HPV vaccines (Merck, GSK); and his institution has received unconditional grants from Merck in aid of investigator-initiated studies. M. Z. and E. L. F. hold a patent related to the discovery “DNA methylation markers for early detection of cervical cancer”, registered at the Office of Innovation and Partnerships, McGill University, Montreal, Quebec, Canada (October 2018). F. C. has received grants or free reagents through his institution from Merck Sharp and Dohme, Becton Dickinson, and Roche; and honoraria from Merck and Roche for lectures on HPV. T. W. serves on advisory boards for MSD (Merck) Sharp & Dohme. M. D. W. is currently a senior medical writer at Certara Synchrogenix consulting services. None of the work presented in this manuscript was paid for or influenced by Certara Synchrogenix. All other authors report no potential conflicts of interest. All authors have submitted 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., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Preclinical studies have demonstrated carrageenan's anti-human papillomavirus (HPV) activity. We assessed efficacy of a carrageenan-based gel compared to a placebo gel in increasing the clearance of anal HPV infections among gay, bisexual, and other men who have sex with men (gbMSM). Of 255 enrolled gbMSM, 134 were HPV positive at baseline and had valid HPV results for ≥2 visits. Carrageenan did not differ from placebo in clearing all baseline infections (hazard ratio, 0.84 [95% confidence interval, .31-2.27]), based on having 2 consecutive HPV-negative visits following at least 1 HPV-positive visit. There were no remarkable differences for analyses at the HPV type level or by human immunodeficiency virus status., Clinical Trials Registration: NCT02354144., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Previous studies examining the association between male circumcision (MC) and human papillomavirus (HPV) infections have reported inconsistent results. We used data from the HPV Infection and Transmission Among Couples Through Heterosexual Activity (HITCH) cohort study to examine the association between MC and HPV infections in males and their female sexual partners., Methods: We enrolled monogamous couples in a longitudinal study between 2005 and 2011 in Montreal, Canada. We used logistic and Poisson regression models with propensity score adjustment to estimate odds ratios (ORs) and rate ratios for the association between MC and the prevalence, transmission, and clearance of HPV infections., Results: Four hundred thirteen couples were included in our study. The prevalence OR for the association between MC and baseline infections was 0.81 (95% confidence interval [CI], .56-1.16) in males and 1.05 (95% CI, .75-1.46) in females. The incidence rate ratio for infection transmission was 0.59 (95% CI, .16-2.20) for male-to-female transmission and 0.77 (95% CI, .37-1.60) for female-to-male transmission. The clearance rate ratio for clearance of infections was 0.81 (95% CI, .52-1.24)., Conclusions: We found little evidence of an association between MC and HPV infection prevalence, transmission, or clearance in males and females. Further longitudinal couple-based studies are required to investigate this association., Competing Interests: Potential conflicts of interest. E. L. F. and M. Z. hold a patent related to the discovery “DNA methylation markers for early detection of cervical cancer,” registered at the Office of Innovation and Partnerships, McGill University, Montreal, Quebec, Canada (October 2018). F. C. has received grants through his institution from Merck, Becton Dickinson, and Roche, as well as honoraria from Merck and Roche for lectures on HPV. All other authors report no potential conflicts of interest.. All authors have submitted 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., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Human leukocyte antigen (HLA) polymorphism influences innate and adaptive immune responses. Among heterosexual couples in the HPV Infection and Transmission Among Couples Through Heterosexual Activity (HITCH) cohort study, we examined whether allele sharing in a couple predicted the partners' infections with the same human papillomavirus (HPV) type., Methods: We tested genital samples from 271 couples for 36 HPV genotypes by polymerase chain reaction. We used direct DNA sequencing to type HLA-B07, -DRB1, -DQB1 and -G. Generalized estimating equations were used to examine the associations between the extent of allele sharing and HPV type concordance in which at least 1 of the partners was HPV positive., Results: We identified 106 different HLA alleles. The most common HLA alleles among couples were G*01:01:01 (95.6%), G*01:01:02 (60.1%), DQB1*03:01 (57.2%), and DRB1*07:01 (46.9%). Allele sharing was as follows: 19.6% shared none, 43.2% shared 1 only, 25.1% shared 2, and 12.5% shared 3-5. Irrespective of HLA class, grouped or in combination, the extent of allele sharing was not a significant predictor of type-specific HPV concordance in a couple (odds ratio, 1.1 [95% confidence interval, .5-2.1], for 3-5 vs none)., Conclusions: We found no evidence that the extent of HLA allele concordance influences the likelihood of HPV transmission in newly formed heterosexual couples., Competing Interests: Potential conflicts of interest. E. L. F. has served as an occasional advisor to companies involved with HPV diagnostics (Roche, BD, Abbott) and HPV vaccines (Merck, GSK), and his institution has received unconditional grants from Merck in aid of investigator-initiated studies. F. C. has received grants through his institution from Merck and Roche, as well as honoraria from Merck and Roche for lectures on HPV. All other authors report no potential conflicts of interest. All authors have submitted 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. Presented in part: 30th International Papillomavirus Society Conference, Lisbon, Portugal, 17–21 September 2015., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: We assessed the association between serum 25-hydroxyvitamin D levels and genital human papillomavirus (HPV) prevalence, incidence, and clearance among female participants in the HPV Infection and Transmission among Couples through Heterosexual activity (HITCH) Cohort Study., Methods: We genotyped HPV DNA in vaginal samples and quantified baseline serum 25-hydroxyvitamin D levels using Roche's Linear Array and Total vitamin D assay, respectively. We used logistic and Cox proportional hazards models, respectively, to estimate adjusted odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs)., Results: There was no association between vitamin D levels (every 10-ng/mL increase) at baseline and HPV prevalence (OR, 0.88; 95% CI, .73-1.03) or incidence (HR, 0.88; 95% CI, .73-1.06), but we observed a modest negative association with HPV clearance (HR, 0.76; 95% CI, .60-.96). Vitamin D levels <30 ng/mL, compared with those ≥30 ng/mL, were not associated with HPV prevalence (OR, 0.98; 95% CI, .57-1.69) or incidence (HR, .87; 95% CI, .50-1.43), but they were associated with a marginally significant increased clearance (OR, 2.14; 95% CI, .99-4.64). We observed consistent results with restricted cubic spline modeling of vitamin D levels and clinically defined categories. HPV type-specific analyses accounting for multiple HPV infections per participant showed no association between vitamin D levels and all study outcomes., Conclusions: This study provided no evidence of an association between low vitamin D levels and increased HPV prevalence, acquisition, or clearance., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: We studied the association between human papillomavirus (HPV) viral load (VL) and HPV concordance., Methods: The HITCH cohort study included young, heterosexual, recently formed, sexually active couples. Questionnaires and genital samples were collected at 0 and 4 months. Samples were tested for HPV DNA by polymerase chain reaction (PCR; Linear Array). VLs of HPV6/11/16/18/31/42/51 were quantified using type-specific real-time PCR. Correlations between VL and type-specific HPV prevalence and incidence were evaluated using multilevel, mixed-effects linear/logistic regression models., Results: We included 492 couples. VLs were higher in penile than vaginal samples. VL at subsequent visits correlated significantly within men (r, 0.373), within women (r, 0.193), and within couples (r range: 0.303-0.328). Men with high VL had more type-specific persistent HPV infections (odds ratio [OR], 4.6 [95% confidence interval {CI}, 2.0-10.5]). High VL in men was associated with prevalent (OR, 5.3 [95% CI, 2.5-11.2]) and incident (OR, 6.7 [95% CI, 1.5-30.7]) type-specific HPV infections in their partner. Women's VL was associated with type-specific HPV prevalence in their partner at the same (OR, 5.9) and subsequent (OR, 4.7) visit., Conclusions: Persistent HPV infections have limited VL fluctuations. VL between sex partners are correlated and seem predictive of transmission episodes., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Detection of human papillomavirus (HPV) DNA in genital samples may not always represent true infections but may be depositions from infected sexual partners. We examined whether sexual risk factors and a biomarker (Y chromosome DNA) were associated with genital HPV partner concordance and estimated the fraction of HPV detections potentially attributable to partner deposition., Methods: The HITCH study enrolled young women attending a university or college in Montréal, Canada, and their male partners, from 2005 to 2010. We tested baseline genital samples for Y chromosome DNA and HPV DNA using polymerase chain reaction., Results: Type-specific HPV concordance was 42.4% in partnerships where at least one partner was HPV DNA positive. Y chromosome DNA predicted type-specific HPV concordance in univariate analyses, but in multivariable models the independent predictors of concordance were days since last vaginal sex (26.5% higher concordance 0-1 vs 8-14 days after last vaginal sex) and condom use (22.6% higher concordance in never vs always users). We estimated that 14.1% (95% confidence interval [CI], 6.3-21.9%) of HPV DNA detections in genital samples were attributable to vaginal sex in the past week., Conclusions: A substantial proportion of HPV DNA detections may be depositions due to recent unprotected vaginal sex., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: We studied features that predict the presence of human papillomavirus (HPV) in a new sexual partnership., Methods: We analyzed data from the "HPV Infection and Transmission Among Couples Through Heterosexual Activity" (HITCH) Cohort Study of recently formed partnerships ("dyads"). Women aged 18-24 and their male partners were recruited during 2005-2010 in Montreal, Canada. We tested genital swabs for detection of 36 HPV types. We defined HPV in a partnership as the presence of 1 or more HPV types in either or both partners. Using baseline data from 482 dyads, we calculated prevalence ratios to evaluate candidate risk factors., Results: Most women (88%) were unvaccinated. Sixty-seven percent of dyads harbored HPV. For 49% of dyads, both partners were HPV+. HPV was least prevalent in dyads who were in their first vaginal sex relationship (17%) and was virtually ubiquitous in dyads for which both partners had concurrent partners (96%). Dyads that always used condoms with previous partner(s) were 27% (95% confidence interval, 9%-42%) less likely to have HPV., Conclusions: The finding that condom use limited onward spread to future partners is in support of condom promotion to prevent sexually transmitted infections. Ongoing monitoring of HPV in sexual networks is needed, particularly in populations with suboptimal vaccine coverage., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

We estimated human papillomavirus (HPV) transmission rates among persons with documented sexual exposure to an infected partner. Recently formed couples enrolled in the HITCH Study (HPV Infection and Transmission among Couples through Heterosexual activity) in Montreal, Canada, and provided genital specimens for DNA testing of 36 HPV genotypes. At enrollment, 179 couples were discordant for ≥1 HPV types; transmission was observed at follow-up in 73 partnerships. There was little difference between the male-to-female (3.5 per 100 person-months, 95% confidence interval [CI], 2.7-4.5) and female-to-male (4.0 per 100 person-months, 95% CI, 3.0-5.5) transmission rates. Rates did not vary with the lifetime number of partners reported by the initially uninfected partner, providing no evidence of reduced susceptibility for those with extensive sexual histories. Transmission was also relatively homogeneous across HPV genotypes and alpha species and oncogenic risk categories. The findings contribute to a small but growing evidence base regarding the natural history of HPV transmission.

Background: Only a minority of women with human papillomavirus (HPV) infection eventually develop cervical cancer, which suggests that host immune mechanisms play a role in the disease. HLA polymorphisms have been linked to the risk of cervical cancer, but very little is known about the role that they play in the acquisition and persistence of HPV infection., Methods: A cohort study of cervical HPV infections was used to examine the role that 5 HLA alleles (B*07, DQB1*03, DQB1*0602, DRB1*13, and DRB1*1501) play in determining the risk of HPV positivity and persistence in 524 female university students in Montreal. HPV positivity was determined by use of the MY09/11 polymerase-chain-reaction protocol. HLA alleles from purified DNA from cervical specimens were typed by use of a polymerase-chain-reaction technique using sequence-specific primers., Results: HLA DRB1*13 was associated with cumulative risk of HPV infections (odds ratio [OR], 1.7 [95% confidence interval {CI}, 1.0-2.8]), for oncogenic HPV (OR, 1.6 [95% CI, 0.9-2.8]), and for HPV-16 (OR, 2.0 [95% CI, 0.9-4.4]). DQB1*03 was consistently associated with a lower cumulative risk of HPV infections, but this association was not statistically significant. None of the alleles affected the risk of HPV persistence., Conclusions: The results of this study support the hypothesis that certain HLA class II polymorphisms mediate genetic susceptibility to the acquisition of HPV infection.