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1.  Epidemiology and pathology of HPV disease in males 
Gynecologic oncology  2010;117(2 0):S15-S19.
It is currently recognized that besides the significant impact of human papillomavirus (HPV) infection in females, HPV causes substantial disease in men as well. Genital warts are a common manifestation of male infection with HPV. Genital warts are highly infectious and approximately 65% of people who have sex with an infected partner will develop warts themselves. More than 90% of genital warts are caused by non-oncogenic HPV types 6 and 11. In addition, recurrent respiratory papillomatosis is a rare disease most often associated with HPV types 6 and 11. Several cancers of the anogenital tract and upper aero-digestive tract, and their precursor lesions in men are now understood to be caused by infection with sexually transmitted HPV. For example, there is increasing incidence of anal cancer in western countries; however, there are limited data on its primary cause, anal canal HPV infection. Genital HPV infection is very common in men with an ongoing international study estimating a prevalence of 65.2% in asymptomatic males aged 18–70 years. Lifetime number of sexual partners was the most significant risk factor for the acquisition of HPV infection (P<0.05), and circumcision has been associated with reduced detection of HPV infection in men. HPV infections may be less likely to persist in men than in women. In men, the median time to clearance of any HPV infection was 5.9 months, with 75% of infections clearing within 12 months. More data are needed to better understand the natural history of HPV infection. Although the quadrivalent HPV vaccine has been shown to be effective and safe in men, low awareness of HPV in males may be a barrier to its use for the prevention of HPV infection.
doi:10.1016/j.ygyno.2010.01.026
PMCID: PMC4254924  PMID: 20138345
Male; HPV infection; Genital warts; Recurrent respiratory papillomatosis; Head and neck cancer; Penile cancer; Anal cancer; Transmission dynamics; Natural history
2.  Cutaneous human papillomavirus types detected on the surface of male external genital lesions: A case series within the HPV Infection in Men Study 
Background
Cutaneous human papillomaviruses (HPVs) may be associated with cutaneous epithelial lesions and non-melanoma skin cancers. No study has systematically evaluated the presence of genus beta [β]-HPV in male genital skin or external genital lesions (EGLs).
Objectives
To examine cutaneous β-HPV types detected on the surface of EGLs in men and describe their presence prior to EGL development.
Study design
A retrospective case series was conducted among 69 men with pathologically confirmed EGLs (n=72) who participated in the HPV Infection in Men Study. Archived exfoliated cells collected from the surface of each EGL and normal genital skin specimens 6–12 months preceding EGL development were tested for β-HPV DNA using a type-specific multiplex genotyping assay.
Results
β-HPV DNA was detected on 61.1% of all EGLs, with types 38 (16.7%), 5 (15.3%), and 12 (12.5%) most commonly identified. HPV prevalence differed across pathological diagnoses, with the largest number of β-HPV types detected on condylomas. Most β-HPV types were detected on normal genital skin prior to EGL development, though the prevalence was lower on EGLs compared to preceding normal genital skin.
Conclusions
EGLs and the normal genital skin of men harbor a large number of β-HPV types; however, it appears that β-HPVs are unrelated to EGL development in men. Despite evidence to support a causal role in skin carcinogenesis at UVR-exposed sites, cutaneous HPV appears unlikely to cause disease at the UVR-unexposed genitals.
doi:10.1016/j.jcv.2013.10.011
PMCID: PMC3866698  PMID: 24210970
3.  Consistent Condom Use Reduces the Genital Human Papillomavirus Burden Among High-Risk Men: The HPV Infection in Men Study 
The Journal of Infectious Diseases  2013;208(3):373-384.
Background. Data supporting the efficacy of condoms against human papillomavirus (HPV) infection in males are limited. Therefore, we examined the effect of consistent condom use on genital HPV acquisition and duration of infection.
Methods. A prospective analysis was conducted within the HPV Infection in Men Study, a multinational HPV cohort study. Men who were recently sexually active (n = 3323) were stratified on the basis of sexual risk behaviors and partnerships. Using Cox proportional hazards regression, type-specific incidence of HPV infection and clearance were modeled for each risk group to assess independent associations with condom use.
Results. The risk of HPV acquisition was 2-fold lower among men with no steady sex partner who always used condoms, compared with those who never used condoms (hazard ratio, 0.54), after adjustment for country, age, race, education duration, smoking, alcohol, and number of recent sex partners. The probability of clearing an oncogenic HPV infection was 30% higher among nonmonogamous men who always used condoms with nonsteady sex partners, compared with men who never used condoms (hazard ratio, 1.29), after adjustment for country, age, race, education duration, marital status, smoking, alcohol, and number of recent sex partners. No protective effects of condom use were observed among monogamous men.
Conclusions. Condoms should be promoted in combination with HPV vaccination to prevent HPV infection in men.
doi:10.1093/infdis/jit191
PMCID: PMC3699010  PMID: 23644283
condoms; human papillomavirus; males; cohort study; HIM Study
4.  Association of Chlamydia trachomatis infection and herpes simplex virus type 2 serostatus with genital human papillomavirus infection in men: the HIM Study 
Sexually transmitted diseases  2013;40(6):508-515.
Background
Studies in women indicate that some sexually transmitted infections promote human papillomavirus (HPV) persistence and carcinogenesis. Little is known about this association in men, therefore we assessed whether Chlamydia trachomatis (CT) infection and herpes simplex virus type 2 (HSV-2) serostatus are associated with genital HPV prevalence, an early event in HPV related pathogenesis.
Methods
Genital exfoliated cells, first-void urine and blood from 3,971 men recruited in the USA, Mexico, and Brazil, were tested for HPV, CT, and HSV-2 antibodies, respectively. Multivariable logistic regression was used to assess the association of CT infection and HSV-2 serostatus with four HPV outcomes (any, oncogenic, non-oncogenic only, and multiple infections).
Results
A total of 64 (1.6%) men were CT positive and 811 (20.4%) men were HSV-2 seropositive. After adjustment for potential confounders, CT was associated with any HPV (aOR 2.19, 95%CI: 1.13–4.24), oncogenic HPV (aOR 3.10, 95%CI: 1.53–6.28), and multiple HPV (aOR 3.43, 95%CI: 1.69-6.95) prevalence. HSV-2 serostatus was associated with any HPV (aOR 1.25, 95%CI: 1.02-1.52), non-oncogenic HPV only (aOR 1.38, 95%CI: 1.08-1.75), and multiple HPV (aOR 1.33, 95%CI: 1.06-1.68) prevalence. In analyses stratified by sexual behaviour, CT infection was significantly associated with HPV detection among men reporting ≥2 recent sexual partners, while HSV-2 serostatus was significantly associated with HPV detection in men reporting 0-5 lifetime sexual partners.
Conclusion
In this population, CT infection and HSV-2 serostatus were associated with prevalent genital HPV infection. Future prospective studies should investigate whether these infections influence HPV acquisition and/or persistence.
doi:10.1097/OLQ.0b013e318289c186
PMCID: PMC3904659  PMID: 23680908
Men; genital; sexually transmitted infection; Human papillomavirus; Chlamydia trachomatis; herpes simplex virus type 2
5.  Seroprevalence of Human Papillomavirus (HPV) Type 6 and 16 Vary by Anatomic Site of HPV Infection in Men 
Background
It is largely unknown if anti-HPV serum antibody responses vary by anatomic site of infection in men.
Methods
This study assessed type-specific anti-HPV serum antibody prevalence associated with corresponding HPV DNA detection in the external genitalia and the anal canal of 1587 heterosexual men and 199 men who have sex with men (MSM).
Results
We observed that HPV 6 and 16 seroprevalence was higher in the presence of same HPV type infection in the anal canal compared to the presence in the external genitalia only, and among MSM compared to heterosexual men. Seropositivity to HPV 6 was strongly associated with HPV 6 DNA detection in the anal canal but not in the external genitalia alone among both heterosexual men (Adjusted Prevalence Ratio (APR), anal+/genital+ vs. anal-/genital-: 4.2 [95% CI: 11.7-10.5]; anal+/genital- vs. anal-/genital-: 7.9 [95% CI: 3.7-17.0]) and MSM (APR, anal+/genital+ vs. anal-/genital-: 5.6 [95% CI: 2.7-11.9]; anal+/genital- vs. anal-/genital-: 3.2 [95% CI: 2.1-4.9]). Similar associations between seropositivity to HPV 16 and anal HPV 16 DNA detection were only observed in MSM (anal+/genital+ vs. anal-/genital-: 3.1 [95% CI: 2.0-5.0]; anal+/genital- vs. anal-/genital-: 2.2 [95% CI: 1.3-3.5]).
Conclusion
Our data demonstrated that seroprevalence varied by anatomic site of HPV infection, suggesting differences in epithelium type present at these anatomic sites may be relevant.
Impact
Our finding is instrumental in advancing our understanding of immune mechanism involved in anatomic site-specific antibody response.
doi:10.1158/1055-9965.EPI-12-0483
PMCID: PMC3466057  PMID: 22761306
Human Papillomavirus (HPV); heterosexual men; men who have sex with men (MSM); seroprevalence; external genitalia; anal canal
6.  Prevention of Invasive Cervical Cancer in the United States: Past, Present, and Future 
Over the past several decades, invasive cervical cancer (ICC) incidence in the United States has declined dramatically. Much of this decline has been attributed to widespread use of cytology screening followed by treatment of precancerous lesions. Despite available technologies to prevent ICC and screening programs targeting high-risk women, certain populations in the United States experience disproportionately high rates of ICC (e.g., racial/ethnic minorities and rural women). Limited access to and use of screening/follow-up services underlie this disparity. The licensure of the human papillomavirus (HPV) vaccine in 2006 introduced an additional method of ICC prevention. Unfortunately, dissemination of the vaccine to age-eligible females has been lower than expected (32% have received all 3 recommended doses). Decreasing the burden of HPV infection and HPV-related diseases in the United States will require greater dissemination of the HPV vaccine to adolescents and young adults, along with successful implementation of revised ICC screening guidelines that incorporate HPV and cytology cotesting. While a future without ICC is possible, we will need a comprehensive national health care program and innovative approaches to reduce ICC burden and disparities.
doi:10.1158/1055-9965.EPI-11-1158
PMCID: PMC3556792  PMID: 22556273
7.  Race and prevalence of human papillomavirus infection among men residing in Brazil, Mexico, and the United States 
HPV causes anal, penile and oropharyngeal cancers in men. Genital HPV prevalence in men appears to vary by world region with men residing in Asia having among the lowest prevalence. Unfortunately, there is little information on prevalence of HPV infection in men by race. The purpose of this study was to examine HPV prevalence by race across three countries. 3,909 men ages 18–70 years enrolled in an ongoing prospective cohort study of the natural history of HPV in men (The HIM Study) were included in the analysis. Participants completed risk factor questionnaires and samples were taken from the penile epithelium and scrotum for HPV detection. HPV testing of the combined DNA extract was conducted using PCR and genotyping. Asian/Pacific Islanders had the lowest HPV prevalence of 42.2% compared to Blacks (66.2%), and Whites (71.5%). The Asian/Pacific Islander race was strongly protective in univariate analysis (prevalence ratio(PR)= 0.59; 95% confidence interval(CI):0.48 – 0.74) and multivariate analysis for any HPV infection (PR= 0.65; 95% CI:0.52 – 0.8). Stratified analysis by lifetime number of female partners also showed strong inverse associations with the Asian/Pacific Islander race. We consistently observed the lowest prevalence of HPV infection among Asian/Pacific Islanders with moderate inverse associations even after various adjustments for potential confounding factors. Unmeasured behavioral factors, sexual mixing with low risk women, and/or race-specific differences in the frequency of germline variations among immune regulating genes may underlie these associations. Further studies among Asian populations that incorporate measures of immuno-genetics are needed to understand this phenomenon.
doi:10.1002/ijc.27397
PMCID: PMC3458422  PMID: 22161806
8.  Dietary Consumption of Antioxidant Nutrients and Risk of Incident Cervical Intraepithelial Neoplasia 
Gynecologic oncology  2010;118(3):289-294.
Objective
Women with human papillomavirus (HPV) infections are at risk for developing squamous intraepithelial lesions (SIL) of the cervix; however, other factors are required for infections to progress to SIL. We hypothesize that consumption of fruits and vegetables high in antioxidant nutrients may prevent, in part, the development of HPV-associated SIL.
Methods
This study is a nested case-control study of 265 HPV-positive women (93 SIL cases and 172 cytologically normal controls) in the Ludwig-McGill Cohort Study, Sao Paulo, Brazil. Diet was assessed by a self-administered food frequency questionnaire. The association between food and nutrient intake of antioxidants and incident SIL was determined by logistic regression and multinomial regression when comparing LSIL and HSILs.
Results
Higher reported consumption of papaya was inversely associated with risk of SIL (p trend=0.01) and strongest for ≥1 time/week (adjusted odds ratios (AORs)=0.19; 95%CI, 0.08-0.49). Risk of SIL was reduced among women reporting consumption of oranges ≥1 time/week (AOR=0.32; 95%CI, 0.12-0.87; p-trend = 0.02). Nutrient intakes of ß-cryptoxanthin and α-carotene were marginally protective against SIL.
Conclusions
Frequent consumption of fruits high in antioxidant nutrients appears to be associated with reduced risk of incident SIL among Brazilian women.
doi:10.1016/j.ygyno.2010.05.022
PMCID: PMC3691953  PMID: 20691333
cervical cancer; cervical intraepithelial neoplasia; human papillomavirus; diet; antioxidant nutrient
9.  Male Human Papillomavirus Prevalence and Association With Condom Use in Brazil, Mexico, and the United States 
The Journal of Infectious Diseases  2012;205(8):1287-1293.
Background. Reported associations of condom use and human papillomavirus (HPV) infection have been inconsistent. We investigated self-reported frequency of condom use and detection of genital HPV among men.
Methods. A cross-sectional analysis was conducted in men aged 18–70 years from Brazil, Mexico, and the United States. Men completed questionnaires on sexual history, condom use, and sociodemographic characteristics. Among 2621 men reporting recent vaginal sex, prevalence of any HPV, any oncogenic type, and nononcogenic types only was estimated by frequency of condom use (“always” or “not always”). Multivariable models were used to estimate prevalence ratios (PRs) for HPV according to frequency of condom use.
Results. The prevalence of any HPV was 70.5%; any oncogenic type, 34%, and nononcogenic types only, 22.2%. The adjusted PR for always vs not always using condoms was 0.87 (95% confidence interval [CI], .77–.97) for all countries combined. The association was stronger in the United States (PR, 0.70; CI, .55–.90) than in Brazil (PR, 0.84; CI, .71–1.01) or Mexico (PR, 1.05; CI, .89–1.25) (P for interaction = .025).
Conclusions. HPV prevalence was high even among those who reported always using condoms, and its associations with always using condoms varied among countries.
doi:10.1093/infdis/jis181
PMCID: PMC3308908  PMID: 22396601
10.  Prevalent Serum Antibody Is Not a Marker of Immune Protection against Acquisition of Oncogenic HPV16 in Men 
Cancer research  2011;72(3):676-685.
In women, naturally induced anti–human papilloma virus (HPV) serum antibodies are a likely marker of host immune protection against subsequent HPV acquisition and progression to precancerous lesions and cancers. However, it is unclear whether the same is the case in men. In this study, we assessed the risk of incident genital infection and 6-month persistent genital infection with HPV16 in relation to baseline serostatus in a cohort of 2,187 men over a 48-month period. Genital swabs were collected every 6 months and tested for HPV presence. Incidence proportions by serostatus were calculated at each study visit to examine whether potential immune protection attenuated over time. Overall, incidence proportions did not differ statistically between baseline seropositive and seronegative men at any study visit or over the follow-up period. The risk of incident and 6-month persistent infection was not associated with baseline serostatus or baseline serum antibody levels in the cohort. Our findings suggest that baseline HPV seropositivity in men is not associated with reduced risk of subsequent HPV16 acquisition. Thus, prevalent serum antibodies induced by prior infection may not be a suitable marker for subsequent immune protection against genital HPV16 acquisition in men.
doi:10.1158/0008-5472.CAN-11-0751
PMCID: PMC3474343  PMID: 22123925
11.  The Human Papillomavirus Infection in Men Study: Human Papillomavirus Prevalence and Type Distribution among Men Residing in Brazil, Mexico, and the United States 
Male sexual behavior influences the rates of cervical dysplasia and invasive cervical cancer, as well as male human papillomavirus (HPV) infection and disease. Unfortunately, little is known regarding male HPV type distribution by age and across countries. In samples combined from the coronal sulcus, glans penis, shaft, and scrotum of 1,160 men from Brazil, Mexico, and the United States, overall HPV prevalence was 65.2%, with 12.0% oncogenic types only, 20.7% nononcogenic types only, 17.8% both oncogenic and nononcogenic, and 14.7% unclassified infections. Multiple HPV types were detected in 25.7% of study participants. HPV prevalence was higher in Brazil (72.3%) than in the United States (61.3%) and Mexico (61.9%). HPV16 (6.5%), HPV51 (5.3%), and HPV59 (5.3%) were the most commonly detected oncogenic infections, and HPV84 (7.7%), HPV62 (7.3%), and HPV6 (6.6%) were the most commonly detected nononcogenic infections. Overall HPV prevalence was not associated with age. However, significant associations with age were observed when specific categories of HPV, nononcogenic, and unclassified HPV infections were considered. Studies of HPV type distribution among a broad age range of men from multiple countries is needed to fill the information gap internationally with respect to our knowledge of HPV infection in men.
doi:10.1158/1055-9965.EPI-08-0151
PMCID: PMC3471778  PMID: 18708396
12.  Associations between serum carotenoids and tocopherols and type-specific HPV persistence: The Ludwig-McGill cohort study 
Although oncogenic HPV infections have been established as the necessary cause of cervical cancer, most HPV infections are transient and rarely progress to cervical lesions. Current research is focused on identifying factors associated with viral persistence and clearance, such as nutritional status. We evaluated the association between serum antioxidant nutrients (retinol, 10 carotenoids and 3 tocopherols) and type-specific HPV persistence over 4 visits among 405 women participating in the Ludwig-McGill cohort study. We measured circulating carotenoids and tocopherol at 4 different clinical visits for each woman. We report the results from different analytic approaches (a case–control approach at both the woman and viral level, and a prospective approach based on persistent events) that examined the association between these micronutrients and type-specific oncogenic and nononcogenic HPV persistence. In the case–control analysis at the viral level, midcirculating levels of α-tocopherol were inversely associated with nononcogenic HPV persistent infection (adjusted odds ratio (AOR) = 0.28, 95% CI 0.14–0.57), while high levels were marginally associated (AOR = 0.59, 95% CI 0.28–1.19). Similarly, utilizing generalized estimating equation models, circulating levels of α- and δ-tocopherol in the middle or upper tertiles were inversely associated with type-specific nononcogenic HPV persistence (AOR = 0.44, 95% CI 0.19–0.97 and AOR = 0.46, 95% CI 0.19–1.11, respectively). Our study among Brazilian women suggests that serum levels of tocopherols may be protective against nononcogenic HPV persistence. However, we did not find a strong protective effect (as hypothesized) of other serum antioxidant nutrients and type-specific oncogenic HPV persistence measured over 4 clinical visits.
doi:10.1002/ijc.22346
PMCID: PMC3458424  PMID: 17096322
human papillomavirus; persistence; carotentoid; tocopherol
13.  Human Papillomavirus (HPV) 6, 11, 16, and 18 Seroprevalence Is Associated with Sexual Practice and Age: Results from the Multinational HPV Infection in Men Study (HIM Study) 
Background
Few human papillomavirus (HPV) serology studies have evaluated type-specific seroprevalence of vaccine HPV types in men. This study investigates seroprevalence of HPV 6, 11, 16, and 18, and associated risk factors in men residing in three countries (United States, Mexico, and Brazil).
Methods
Data from 1,477 men aged 18 to 70 enrolled in the HPV Infection in Men Study (HIM Study) were analyzed. Serum antibody testing was performed with virus-like particle-based ELISA. Potential risk factors were assessed for individual HPV types by the use of logistic regression.
Results
Overall, HPV-6, 11, 16, and 18 seroprevalence was 14.8%, 17.3%, 11.2%, and 5.8%, respectively. Thirty-four percent of men were seropositive to one or more HPV types. When examined by sexual practice, 31.2% of men who had sex with women, 65.6% of men who had sex with men (MSM), and 59.4% of men who had sex with both men and women (MSMW) were seropositive to one or more HPV types. Seroprevalence increased with age among young-to-middle-aged men with significant upward age trends observed for HPV 11, 16, and 18. Men with multiple lifetime male anal sex partners were 2 to 4 times more likely to be HPV 6 or 11 seropositive and 3 to 11 times more likely to be HPV 16 or 18 seropositive.
Conclusion
Our data indicate that exposures to vaccine HPV types were common in men and highly prevalent among MSM and MSMW.
Impact
Our study provides strong evidence that the practice of same-sex anal intercourse is an independent risk factor for seroprevalence of individual vaccine HPV types. Examination of antibody responses to HPV infections at various anatomic sites in future studies is needed to elaborate on the mechanism.
doi:10.1158/1055-9965.EPI-10-1160
PMCID: PMC3232028  PMID: 21378268
14.  Human Papillomavirus Vaccine Administration Among Medicaid Providers Who Consistently Recommended Vaccination 
Sexually transmitted diseases  2014;41(1):24-28.
We examined factors potentially related to providers’ self-reported human papillomavirus vaccine administration to female Medicaid enrollees among providers who consistently recommended vaccination. Some pronounced variability was observed in characteristics among providers who consistently administered vaccination, including provider age, race, and Vaccines for Children enrollment; patient/parent vaccine refusal; patient race/ethnicity; and patient volume.
doi:10.1097/OLQ.0000000000000064
PMCID: PMC3962075  PMID: 24335743
15.  Physicians’ Human Papillomavirus Vaccine Recommendations, 2009 and 2011 
Background
Physician recommendation is a key predictor of human papillomavirus (HPV) vaccine uptake. Understanding factors associated with recommendation is important for efforts to increase current suboptimal vaccine uptake.
Purpose
This study aimed to examine physician recommendations to vaccinate female patients aged 11–26 years, in 2009 and 2011, at 3 and 5 years postvaccine licensure, respectively. A second aim was to identify trends in factors associated with vaccine recommendation for ages 11 and 12 years.
Methods
Nationally representative samples of physicians practicing family medicine, pediatrics, and obstetrics and gynecology were randomly selected from the American Medical Association Physician Masterfile (n=1538 in 2009, n=1541 in 2011). A mailed survey asked physicians about patient and clinical practice characteristics; immunization support; and frequency of HPV vaccine recommendation (“always” = >75% of the time vs other). Analyses were conducted in 2012.
Results
Completed surveys were received from 1013 eligible physicians (68% response rate) in 2009 and 928 (63%) in 2011. The proportion of physicians who reported “always” recommending HPV vaccine increased significantly from 2009 to 2011 for patients aged 11 or 12 years (35% vs 40%, respectively; p=0.03), but not for patients aged 13–17 years (53% vs 55%; p= 0.28) or 18–26 years (50% vs 52%; p=0.52). Physician specialty, age, and perceived issues/barriers to vaccination were associated with vaccine recommendation for patients aged 11 or 12 in both years.
Conclusions
Results suggest a modest increase in recommendations for HPV vaccination of girls aged 11 or 12 years over a 2-year period; however, recommendations remain suboptimal for all age groups despite national recommendations for universal immunization.
doi:10.1016/j.amepre.2013.07.009
PMCID: PMC3895928  PMID: 24355675
16.  Quantification of secretory leukocyte protease inhibitor (SLPI) in oral gargle specimens collected using mouthwash 
Background
Secretory leukocyte protease inhibitor (SLPI) is an innate immunity-associated protein known to inhibit HIV transmission, and is thought to inhibit a variety of infectious agents, including human papillomaviruses (HPVs). We aimed to optimize an established ELISA-based SLPI quantification assay for use with oral gargle specimens collected using mouthwash, and to assess preliminary associations with age, smoking status, and alcohol intake.
Methods
Oral gargle supernatants from 50 individuals were used to optimize the Human SLPI Quantikine ELISA Kit. Sample suitability was assessed and quality control analyses were conducted.
Results
Salivary SLPI was successfully recovered from oral gargles with low intra-assay and high inter-individual variability. Initial measurements showed that salivary SLPI varied considerably across individuals, and that SLPI was inversely associated with age.
Conclusions
This optimized assay can be used to examine the role of SLPI in the acquisition of oral HPV and other infections.
doi:10.1016/j.jim.2013.10.005
PMCID: PMC3990009  PMID: 24140751
Secretory leukocyte protease inhibitor; SLPI; Innate immunity; Immune system protein; Oral disease; Oral gargle
17.  Incidence and clearance of genital human papillomavirus infection in men (HIM): a cohort study 
Lancet  2011;377(9769):932-940.
Summary
Background
Human papillomaviruses (HPVs) cause genital warts and cancers in men. The natural history of HPV infection in men is largely unknown, and that information is needed to inform prevention strategies. The goal in this study was to estimate incidence and clearance of type-specific genital HPV infection in men, and to assess the associated factors.
Methods
Men (aged 18–70 years), residing in Brazil, Mexico, and the USA, who were HIV negative and reported no history of cancer were recruited from the general population, universities, and organised health-care systems. They were assessed every 6 months for a median follow-up of 27·5 months (18·0–31·2). Specimens from the coronal sulcus, glans penis, shaft, and scrotum were obtained for the assessment of the status of HPV genotypes.
Findings
In 1159 men, the incidence of a new genital HPV infection was 38·4 per 1000 person months (95% CI 34·3–43·0). Oncogenic HPV infection was significantly associated with having a high number of lifetime female sexual partners (hazard ratio 2·40, 1·38–4·18, for at least 50 partners vs not more than one partner), and number of male anal-sexual partners (2·57, 1·46–4·49, for at least three male partners vs no recent partners). Median duration of HPV infection was 7·52 months (6·80–8·61) for any HPV and 12·19 months (7·16–18·17) for HPV 16. Clearance of oncogenic HPV infection decreased in men with a high number of lifetime female partners (0·49, 0·31–0·76, for at least 50 female partners vs not more than one partner), and in men in Brazil (0·71, 0·56–0·91) and Mexico (0·73, 0·57–0·94) compared with the USA. Clearance of oncogenic HPV was more rapid with increasing age (1·02, 1·01–1·03).
Interpretation
The data from this study are useful for the development of realistic cost-effectiveness models for male HPV vaccination internationally.
Funding
National Cancer Institute.
doi:10.1016/S0140-6736(10)62342-2
PMCID: PMC3231998  PMID: 21367446
18.  High genital prevalence of cutaneous human papillomavirus DNA on male genital skin: the HPV Infection in Men Study 
BMC Infectious Diseases  2014;14(1):677.
Background
The genital skin of males hosts a diversity of HPV genotypes and uncharacterized HPV genotypes. Previously we demonstrated that a specific viral genotype was not identified in 14% of all genital specimens (i.e., HPV unclassified specimens) using the Roche Linear Array method. Our goal was to identify and assess the prevalence of individual HPV types among genital HPV unclassified specimens collected in the HIM Study population, at enrollment, and examine associations with socio-demographic and behavioral characteristics.
Methods
Genital skin specimens of men that were considered unclassified (HPV PCR positive, no genotype specified) at enrollment were typed by sequencing amplified PGMY09/11 products or cloning of PGMY/GP+ nested amplicons followed by sequencing. PGMY/GP+ negative specimens were further analyzed using FAP primers. HPV type classification was conducted through comparisons with sequences in the GenBank database.
Results
Readable nucleotide sequences were generated for the majority of previously unclassified specimens (66%), including both characterized (77%) and yet uncharacterized (23%) HPV types. Of the characterized HPV types, most (73%) were Beta [β]-HPVs, primarily from β-1 and β-2 species, followed by Alpha [α]-HPVs (20%). Smokers (current and former) were significantly more likely to have an α-HPV infection, compared with any other genus; no other factors were associated with specific HPV genera or specific β-HPV species.
Conclusions
Male genital skin harbor a large number of β-HPV types. Knowledge concerning the prevalence of the diverse HPV types in the men genital is important to better understand the transmission of these viruses.
doi:10.1186/s12879-014-0677-y
PMCID: PMC4265346
Human papillomavirus; Cutaneous HPV; Males; HIM Study; Prevalence; Prospective study
19.  Men Who Purchase Sex, Who Are They? An Interurban Comparison 
Most research concerning clients of commercial sex workers (CSWs) relies upon CSW reports of client characteristics and behavior. We describe correlates of ever purchasing sex among 3,829 men from three cities: São Paulo, Brazil; Cuernavaca, Mexico; and Tampa, USA. A computer-assisted self-interview collected data on demographics and sexual behavior. There were significant site differences—26.5 % paid for sex in São Paulo, 10.4 % in Cuernavaca, and 4.9 % in Tampa. In all cities, men who had sex with men and women (versus sex with women only) were more likely to have ever paid for sex. In São Paulo and Cuernavaca, CSW clients were older, had higher educational attainment, and were less likely to be married. In Tampa, older age was associated with being a CSW client but not education and marital status. In São Paulo and Cuernavaca, CSW clients had more partners than men who had never paid for sex. In São Paulo, CSW clients initiated vaginal sex at an earlier age, while in Cuernavaca they were more likely to self-report a sexually transmitted infection. CSW clients varied with respect to demographics across the three cities while the association between paying for sex and risky sexual behavior seems to be somewhat conserved. These findings suggest that interventions among CSW clients should focus on condom use with commercial and non-commercial partners as these men may be at increased risk for transmitting and acquiring sexually transmitted infections to and from their sex partners. Better understanding of client characteristics is needed for targeting interventions and creating culturally appropriate content.
doi:10.1007/s11524-013-9809-8
PMCID: PMC3853174  PMID: 23719715
Commercial sex workers; Men; Clients; Brazil; Mexico; United States; Interurban
20.  TNFRSF10B polymorphisms and haplotypes associated with increased risk of death in non-small cell lung cancer 
Carcinogenesis  2013;34(11):2525-2530.
Presently, there are few validated biomarkers that can predict survival or treatment response for non-small cell lung cancer (NSCLC) and most are based on tumor markers. Biomarkers based on germ line DNA variations represent a valuable complementary strategy, which could have translational implications by subclassifying patients to tailored, patient-specific treatment. We analyzed single nucleotide polymorphisms (SNPs) in 53 inflammation-related genes among 651 NSCLC patients. Multivariable Cox proportional hazard models, adjusted for lung cancer prognostic factors, were used to assess the association of genotypes and haplotypes with overall survival. Four of the top 15 SNPs associated with survival were located in the TNF-receptor superfamily member 10b (TNFRSF10B) gene. The T-allele of the top ranked SNP (rs11785599) was associated with a 41% increased risk of death (95% confidence interval [CI] = 1.16–1.70) and the other three TNFRSF10B SNPs (rs1047275, rs4460370 and rs883429) exhibited a 35% (95% CI = 1.11–1.65), 29% (95% CI = 1.06–1.57) and 24% (95% CI = 0.99–1.54) increased risk of death, respectively. Haplotype analyses revealed that the most common risk haplotype (TCTT) was associated with a 78% (95% CI = 1.25–2.54) increased risk of death compared with the low-risk haplotype (CGCC). When the data were stratified by treatment, the risk haplotypes exhibited statistically significantly increased risk of death among patients who had surgery only and no statistically significant effects among patients who had surgery and adjuvant chemotherapy. These data suggest that possessing one or more risk alleles in TNFRSF10B is associated with an increased risk of death. Validated germ line biomarkers may have potential important clinical implications by optimizing patient-specific treatment.
doi:10.1093/carcin/bgt244
PMCID: PMC3810840  PMID: 23839018
21.  Racial differences in the incidence and clearance of human papillomavirus (HPV): The HPV in Men (HIM) Study 
Background
This analysis assessed the acquisition (incidence) and persistence (clearance) of HPV infection by self-reported race among men in The HPV in Men (HIM) Study, a multinational prospective study of the natural history of genital HPV infections.
Methods
Self-reported race was categorized as White, Black, Asian/Pacific Islander (PI), or multiple and mixed race. Genital samples were combined for HPV DNA testing and categorized by any-, oncogenic-, and non-oncogenic HPV infections.
Results
Asian/PI race had significantly the lowest incidence of any-, oncogenic-, and non-oncogenic HPV infection (P < 0.001). In multivariable analyses Asian/PI race was associated with a lower probability of acquiring any- (HR=0.63; 95% CI 0.42–0.95) and non-oncogenic HPV infection (HR=0.61; 95% CI 0.40–0.93) when compared to Whites. No significant associations were evident for Asian/PI race for clearance. Multiple and mixed race was significantly associated with lower probability of acquiring non-oncogenic HPV infection (HR=0.83; 95% CI 0.69–0.99) and borderline significant associations were observed for any HPV (HR=0.91) and oncogenic infections (HR=0.92). Multiple and mixed race was associated with a lower probability of clearing any- (HR=0.92; 95% CI 0.84–1.00) and oncogenic HPV infections (HR=0.85; 95% CI 0.75–0.95).
Conclusion
Asian/PI race had the lowest incidence of HPV and exhibited a lower probability of acquiring new HPV infections. Multiple and mixed race had the second lowest incidence of infection and was associated with a lower probability of acquiring and clearing a HPV infection.
Impact
Race-specific differences in HPV infection could be due to behavior, innate genetic differences, or circulating intratypic HPV variants.
doi:10.1158/1055-9965.EPI-13-0303
PMCID: PMC3795913  PMID: 23872745
22.  Associations between genetic variants in the TGF-β signaling pathway and breast cancer risk among Hispanic and non-Hispanic white women 
The TGF-β signaling pathway has a significant role in breast cancer initiation and promotion by regulating various cellular processes. We evaluated whether genetic variation in eight genes (TGF-β1, TGF-β2, TGF-βR1, TGF-βR2, TGF-βR3, RUNX1, RUNX2, and RUNX3) is associated with breast cancer risk in women from the Breast Cancer Health Disparities Study. A total of 3,524 cases (1,431 non-Hispanic whites (NHW); 2,093 Hispanics/Native Americans(NA)) and 4,209 population-based controls (1,599 NHWs; 2,610 Hispanics/NAs) were included in analyses. Genotypes for 47 single nucleotide polymorphisms (SNPs) were determined. Additionally, 104 ancestral informative markers estimated proportion of NA ancestry. Associations with breast cancer risk overall, by menopausal status, NA ancestry, and estrogen receptor (ER)/progesterone receptor tumor phenotype were evaluated. After adjustment for multiple comparisons, two SNPs were significantly associated with breast cancer risk: RUNX3 (rs906296 ORCG/GG = 1.15 95 % CI 1.04–1.26) and TGF-β1 (rs4803455 ORCA/AA = 0.89 95 % CI 0.81–0.98). RUNX3 (rs906296) and TGF-βR2 (rs3773644) were associated with risk in pre-menopausal women (padj = 0.002 and 0.02, respectively) and in those with intermediate to high NA ancestry (padj = 0.04 and 0.01, respectively). Self-reported race was strongly correlated with NA ancestry (r = 0.86). There was a significant interaction between NA ancestry and RUNX1 (rs7279383, padj = 0.04). Four RUNX SNPs were associated with increased risk of ER-tumors. Results provide evidence that genetic variation in TGF-β and RUNX genes are associated with breast cancer risk. This is the first report of significant associations between genetic variants in TGF-β and RUNX genes and breast cancer risk among women of NA ancestry.
doi:10.1007/s10549-013-2690-z
PMCID: PMC4088254  PMID: 24036662
reast cancer risk; Breast Cancer Health Disparities Study; TGF-β; signaling pathway; Native American ancestry; Hispanic; Non-Hispanic white
23.  Natural History of Cutaneous Human Papillomavirus (HPV) Infection in Men: The HIM Study 
PLoS ONE  2014;9(9):e104843.
Accumulating evidence suggests that cutaneous human papillomavirus (HPV) infection is associated with non-melanoma skin cancer (NMSC). Little is known about the natural history of cutaneous HPV. A sub-cohort of 209 men with no NMSC history, initially enrolled in the HPV infection in men (HIM) study, were followed for a median of 12.6 months. Epidemiological data were collected through self-administered questionnaires. Cutaneous HPV DNA was measured in normal skin swabs (SS) and eyebrow hairs (EB) for 25 and 16 HPV types in genera β and γ, respectively. Any β HPV infection was more prevalent in SS (67.3%) compared to EB (56.5%, p = 0.04). Incidence in SS was higher than 20 per 1,000 person-months for HPV types 4, 5, 23, 38 and 76. Median duration of persistence of β and γ HPV infection was 8.6 and 6.1 months in EB, respectively, and 11.3 months and 6.3 months, in SS, respectively. Older age (>44 years vs. 18-30 years) was significantly associated with prevalent (SS OR = 3.0, 95% CI = 1.2–7.0) and persistent β HPV infection (EB OR = 6.1, 95% CI = 2.6–14.1). History of blistering sunburn was associated with prevalent (OR = 2.8, 95% CI = 1.3–5.8) and persistent (OR = 2.3, 95% CI = 1.2–4.6) β HPV infection in SS. Cutaneous HPV is highly prevalent in men, with age and blistering sunburn being significant risk factors for cutaneous β HPV infection.
doi:10.1371/journal.pone.0104843
PMCID: PMC4157763  PMID: 25198694
24.  Incidence and clearance of oral human papillomavirus infection in men: the HIM cohort study 
Lancet  2013;382(9895):877-887.
Background
Oral human papillomavirus (HPV) infection causes a subset of oropharyngeal cancers. These cancers disproportionately affect men, are increasing in incidence, and have no proven prevention methods. We aimed to establish the natural history of oral HPV infection in men.
Methods
To estimate incidence and clearance of HPV infections, men residing in Brazil, Mexico, and the USA who were HIV negative and reported no history of anogenital cancer were recruited into the HPV Infection in Men (HIM) cohort study. A subset of the cohort who provided two or more oral rinse-and-gargle samples with valid HPV results and who completed a minimum of 2 weeks of follow-up were included in this analysis. Oral rinse-and-gargle samples and questionnaire data were obtained every 6 months for up to 4 years. Samples were analysed for the presence of oncogenic and non-oncogenic HPV infections by the linear array method.
Findings
1626 men aged 18–73 years and with a median follow-up of 12·7 months (IQR 12·1–14·7) were included in the analysis. During the first 12 months of follow-up, 4·4% (95% CI 3·5–5·6; n=115 incident infections) of men acquired an incident oral HPV infection, 1·7% (1·2–2·5; n=53 incident infections) an oral oncogenic HPV infection, and 0·6% (0·3–1·1; n=18 incident infections) an oral HPV 16 infection. Acquisition of oral oncogenic HPV was significantly associated with smoking and not being married or cohabiting, but was similar across countries, age groups, and reported sexual behaviours. Median duration of infection was 6·9 months (95 % CI 6·2–9·3; n=45 cleared infections) for any HPV, 6·3 months (6·0–9·9; n=18 cleared infections) for oncogenic HPV, and 7·3 months (6·0–not estimable; n=5 cleared infections) for HPV 16. Eight of the 18 incident oral HPV 16 infections persisted for two or more study visits.
Interpretation
Newly acquired oral oncogenic HPV infections in healthy men were rare and most were cleared within 1 year. Additional studies into the natural history of HPV are needed to inform development of infection-related prevention efforts.
doi:10.1016/S0140-6736(13)60809-0
PMCID: PMC3904652  PMID: 23827089
oral human papillomavirus; natural history; acquisition
25.  Concordance of human papillomavirus types detected on the surface and in the tissue of genital lesions in men 
Journal of medical virology  2013;85(9):10.1002/jmv.23635.
Summary
Swabbing the surface of a genital lesion to obtain a sample for HPV DNA testing is less invasive than a biopsy, but may not represent HPV types present in the lesion tissue. The objective of this study was to examine the concordance of HPV types detected in swab and biopsy samples from 165 genital lesions from men ages 18-70. Lesions included 90 condyloma, 10 penile intraepithelial neoplasia (PeIN), 23 non-condyloma with a known histology, and 42 lesions with an undetermined histology. All lesions were sampled by swabbing the surface of the lesion with a pre-wetted Dacron swab and taking a shave biopsy. HPV genotyping was performed using Linear Array for swab samples and INNO-LiPA for biopsy samples. The kappa and McNemar statistics were used to compare the concordance of detecting HPV types in swab and biopsy samples. Both sampling methods had high agreement for detection of HPV DNA in condyloma (87.8% agreement) and PeIN (100% agreement). There was also high concordance for detection of HPV16 (kappa = 1.00) and HPV18 (kappa = 1.00) in PeIN, however, agreement was low to moderate for detecting HPV6 (kappa = 0.31) and HPV11 (kappa = 0.56) in condyloma. Low to moderate agreement was also observed between sampling methods for detecting individual HPV types in the non-condyloma and lesions with an indefinite histology. The results suggest that obtaining a biopsy in addition to swabbing the surface of a lesion may provide additional information about specific HVP types associated with male genital lesions.
doi:10.1002/jmv.23635
PMCID: PMC3879682  PMID: 23852680
HPV; condyloma; penile intraepithelial neoplasia; kappa

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