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1.  Differences between Hispanic and non-Hispanic White Women with Breast Cancer for Clinical Characteristics and their Correlates 
Annals of epidemiology  2013;23(4):227-232.
Body size and ethnicity may influence breast cancer tumor characteristics at diagnosis. We compared Hispanic and non-Hispanic white cases for stage of disease, estrogen receptor status, tumor size, and lymph node status, and the associations of these with body size in the 4-Corners Breast Cancer Study (4-CBCS).
1,527 Non-Hispanic white and 798 Hispanic primary incident breast cancer cases diagnosed between October 1999 and May 2004 were included. Odds ratios (OR) and 95% Confidence Intervals (CI) were calculated by multiple logistic regression.
Hispanic women were more likely to have larger (>1cm), ER- tumors, and >4 positive lymph nodes (p < 0.003). Lymph node status was not associated with body size. However, among non-Hispanic white women, obesity (BMI >30) and increased waist circumference (> 38.5 inches) were significantly, positively associated with ER- tumor status; ORs = 1.87, 95% CI 1.24–2.81 and 2.59, 95% CI 1.58–4.22, respectively. In contrast, among Hispanic women, obesity and waist circumference had inverse associations with ER- status (OR = 0.49, 95% CI 0.29–0.84) and (0.56, 95% CI 0.30–1.05), respectively.
Hispanic ethnicity may modify the association of body size and composition with ER- breast cancer. This finding could have relevance to clinical treatment and prognosis.
PMCID: PMC3605206  PMID: 23369848
Breast Neoplasms; Hispanic Americans; Obesity
2.  Cognitive and Emotional Responses to Human Papillomavirus Test Results in Men 
HPV infection has been associated with a wide range of psychosocial responses among women; however, few studies have examined emotional responses among men.
To examine psychosocial differences among self-reported HPV-positive and HPV-negative Florida men who were tested for HPV.
Men (n=536) in a natural history study of HPV completed a cross-sectional psychosocial survey between 2007 and 2010.
Most participants were White, non-Hispanic, unmarried and had some college education. HPV knowledge was high, with no statistically significant differences between groups. Significantly higher negative emotional responses and perceived threat scores were found among HPV-positive men (p<0.05). The majority of men (91%) reported they were very likely or likely to get the HPV vaccine if it became available for men, but identified barriers as factors to consider. HPV-negative men were significantly more likely to tell a sex partner their test results than HPV-positive men.
Men experienced a range of negative emotions after receiving HPV test results, but most disclosed their test result to their sexual partner and reported high intentions to receive the HPV vaccine in the future. Findings should be considered when implementing health-related interventions among men to assist in decreasing psychosocial sequalae associated with HPV.
PMCID: PMC3904642  PMID: 23026036
3.  The Optimal Anatomic Sites for Sampling Heterosexual Men for Human Papillomavirus (HPV) Detection: The HPV Detection in Men Study 
The Journal of infectious diseases  2007;196(8):1146-1152.
Human papillomavirus (HPV) infection in men contributes to infection and cervical disease in women as well as to disease in men. This study aimed to determine the optimal anatomic site(s) for HPV detection in heterosexual men.
A cross-sectional study of HPV infection was conducted in 463 men from 2003 to 2006. Urethral, glans penis/coronal sulcus, penile shaft/prepuce, scrotal, perianal, anal canal, semen, and urine samples were obtained. Samples were analyzed for sample adequacy and HPV DNA by polymerase chain reaction and genotyping. To determine the optimal sites for estimating HPV prevalence, site-specific prevalences were calculated and compared with the overall prevalence. Sites and combinations of sites were excluded until a recalculated prevalence was reduced by <5% from the overall prevalence.
The overall prevalence of HPV was 65.4%. HPV detection was highest at the penile shaft (49.9% for the full cohort and 47.9% for the subcohort of men with complete sampling), followed by the glans penis/coronal sulcus (35.8% and 32.8%) and scrotum (34.2% and 32.8%). Detection was lowest in urethra (10.1% and 10.2%) and semen (5.3% and 4.8%) samples. Exclusion of urethra, semen, and either perianal, scrotal, or anal samples resulted in a <5% reduction in prevalence.
At a minimum, the penile shaft and the glans penis/coronal sulcus should be sampled in heterosexual men. A scrotal, perianal, or anal sample should also be included for optimal HPV detection.
PMCID: PMC3904649  PMID: 17955432
4.  Risk Factors for Anogenital Human Papillomavirus Infection in Men 
The Journal of infectious diseases  2007;196(8):10.1086/521632.
Human papillomavirus (HPV) is strongly associated with cervical and other anogenital cancers. Identification of risk factors for HPV infection in men may improve our understanding of HPV transmission and prevention.
HPV testing for 37 types was conducted in 463 men 18–40 years old recruited from 2 US cities. The entire anogenital region and semen were sampled. A self-administered questionnaire was completed. Multivariate logistic regression aided the identification of independent risk factors for any HPV type, oncogenic HPV types, and nononcogenic HPV types.
Prevalence was 65.4% for any HPV, 29.2% for oncogenic HPV, and 36.3% for nononcogenic HPV. Factors significantly associated with any HPV were smoking ≥10 cigarettes per day (odds ratio [OR], 2.3 [95% confidence interval {CI}, 1.0–5.3]) and lifetime number of female sex partners (FSPs) (OR for ≥21, 2.5 [95% CI, 1.3–4.6]), and factors significantly associated with oncogenic HPV were lifetime number of FSPs (OR for ≥21, 7.4 [95% CI, 3.4–16.3]) and condom use during the past 3 months (OR for more than half the time, 0.5 [95% CI, 0.3–0.8]). For nononcogenic HPV, a significant association was found for number of FSPs during the past 3 months (OR for ≥2, 2.9 [95% CI, 1.4–6.3]).
Lifetime and recent number of FSPs, condom use, and smoking were modifiable risk factors associated with HPV infection in men.
PMCID: PMC3877918  PMID: 17955431
5.  Epidermal growth factor receptor (EGFR) polymorphisms and breast cancer among Hispanic and non-Hispanic white women: the Breast Cancer Health Disparities Study 
The epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases, functions in cellular processes essential to the development of cancer. Overexpression of EGFR in primary breast tumors has been linked with poor prognosis. We investigated the associations between 34 EGFR tagging SNPs and breast cancer risk and breast cancer-specific mortality in 4,703 Hispanic and 3,030 non-Hispanic white women from the Breast Cancer Health Disparities Study. We evaluated associations with risk of breast cancer defined by estrogen/progesterone receptor (ER/PR) tumor phenotype. Only one association remained statistically significant after adjusting for multiple comparisons. Rs2075112GA/AA was associated with reduced risk for ER-/PR+ tumor phenotype (odds ratio (OR), 0.34; 95% confidence interval (CI) 0.18-0.63, p adj=0.01). All additional results were significant prior to adjustment for multiple comparisons. Two of the EGFR polymorphisms were associated with breast cancer risk in the overall study population (rs11770531TT: OR, 0.56, 95% CI 0.37-0.84; and rs2293348AA: OR, 1.20, 95% CI 1.04-1.38) and two polymorphisms were associated with risk among Hispanics: rs6954351AA: OR, 2.50, 95% CI 1.32-4.76; and rs845558GA/AA: OR, 1.15, 95% CI 1.01-1.30. With regard to breast cancer-specific mortality, we found positive associations with rs6978771TT hazard ratio (HR), 1.68; 95% CI 1.11-2.56; rs9642391CC HR, 1.64; 95% CI 1.04-2.58; rs4947979AG/GG HR, 1.36; 95% CI 1.03-1.79; and rs845552GG HR, 1.62; 95% CI 1.05-2.49. Our findings provide additional insight for the role of EGFR in breast cancer development and prognosis. Further research is needed to elucidate EGFR’s contribution to ethnic disparities in breast cancer.
PMCID: PMC3852643  PMID: 24319539
Breast cancer; Hispanic; epidermal growth factor receptor; polymorphisms; tumor phenotype
6.  SEPP1 Influences Breast Cancer Risk among Women with Greater Native American Ancestry: The Breast Cancer Health Disparities Study 
PLoS ONE  2013;8(11):e80554.
Selenoproteins are a class of proteins containing a selenocysteine residue, many of which have been shown to have redox functions, acting as antioxidants to decrease oxidative stress. Selenoproteins have previously been associated with risk of various cancers and redox-related diseases. In this study we evaluated possible associations between breast cancer risk and survival and single nucleotide polymorphisms (SNPs) in the selenoprotein genes GPX1, GPX2, GPX3, GPX4, SELS, SEP15, SEPN1, SEPP1, SEPW1, TXNRD1, and TXNRD2 among Hispanic/Native American (2111 cases, 2597 controls) and non-Hispanic white (NHW) (1481 cases, 1586 controls) women in the Breast Cancer Health Disparities Study. Adaptive Rank Truncated Product (ARTP) analysis was used to determine both gene and pathway significance with these genes. The overall selenoprotein pathway PARTP was not significantly associated with breast cancer risk (PARTP = 0.69), and only one gene, GPX3, was of borderline significance for the overall population (PARTP =0.09) and marginally significant among women with 0-28% Native American (NA) ancestry (PARTP=0.06). The SEPP1 gene was statistically significantly associated with breast cancer risk among women with higher NA ancestry (PARTP=0.002) and contributed to a significant pathway among those women (PARTP=0.04). GPX1, GPX3, and SELS were associated with Estrogen Receptor-/Progesterone Receptor+ status (PARTP = 0.002, 0.05, and 0.01, respectively). Four SNPs (GPX3 rs2070593, rsGPX4 rs2074451, SELS rs9874, and TXNRD1 rs17202060) significantly interacted with dietary oxidative balance score after adjustment for multiple comparisons to alter breast cancer risk. GPX4 was significantly associated with breast cancer survival among those with the highest NA ancestry (PARTP = 0.05) only. Our data suggest that SEPP1 alters breast cancer risk among women with higher levels of NA ancestry.
PMCID: PMC3835321  PMID: 24278290
7.  Provider Factors Associated with Disparities in HPV Vaccination among Low-Income 9–17-Year-Old Girls 
Cancer  2012;119(3):621-628.
Many women who develop cervical cancer are eligible for or are participants of Medicaid. Providing human papillomavirus (HPV) vaccination to girls enrolled in Medicaid may reduce cervical cancer disparities in low-income and minority women. This study evaluated provider characteristics associated with HPV vaccination among 9–17-year-old female Medicaid enrollees.
A random sample of 800 providers from the Florida Medicaid Master Provider File was mailed a survey in October 2009 that evaluated demographic and practice characteristics, HPV information and knowledge, barriers to HPV vaccination, vaccine practices, and vaccine recommendation practices. To measure HPV vaccination, Medicaid claims data were used to calculate the proportion of eligible patients who received at least one dose of the vaccine from participating providers within the study period. Provider factors associated with vaccination at the bivariate level were evaluated in a multiple linear regression model.
The response rate was 68.3% (N = 485). After excluding ineligible respondents, the current analysis included 433 providers. HPV vaccination prevalence ranged from 0% to 61.9% (M = 20.4, SD = 14.5). HPV vaccination rates were higher among providers who: were Pediatricians, had a private practice, practiced in a single specialty setting, were VFC providers, saw primarily non-Hispanic White patients, used ≥2 strategies for vaccine series completion, and did not refer out for HPV vaccination.
Despite financial coverage for Medicaid-eligible girls, HPV vaccination rates are low. Study findings can be used to target health services interventions to providers least likely to administer HPV vaccine to female Medicaid enrollees.
PMCID: PMC3800018  PMID: 23341308
human papillomavirus; HPV vaccine; cancer vaccine; cervix cancer; low-income population; Medicaid; physician
8.  Do Florida Medicaid Providers’ Barriers to HPV Vaccination Vary Based on VFC Program Participation? 
Maternal and child health journal  2013;17(4):609-615.
This study aimed to determine if physicians’ perceived barriers to HPV vaccination were associated with participation in the federal Vaccines for Children (VFC) program.
A sample of 800 Florida Medicaid providers was randomly selected from the Florida Medicaid Master Provider File. A cross-sectional study was conducted using a 27-item survey that included 13 potential barriers to immunizing Medicaid patients against HPV, including concerns about vaccine safety and efficacy, discussing sexuality, vaccinated teens practicing riskier sexual behaviors, cost and reimbursement, ensuring 3-dose series completion, and school attendance requirements associated with HPV vaccination. Pearson Chi-square tests were conducted to investigate differences between each barrier and VFC program participation. Data were analyzed for 449 physicians.
Compared to non-VFC providers, VFC providers were significantly less likely to somewhat or strongly agree that the following were barriers to vaccination: the cost of stocking the HPV vaccine (p = 0.0011), lack of adequate reimbursement for HPV vaccination (p < 0.0001), and lack of timely reimbursement for HPV vaccination (p < 0.0001). After adjusting for provider specialty and number of years since completion of residency training, VFC status remained significantly associated with the barrier regarding lack of adequate reimbursement for vaccination such that non-VFC providers had a 2.6-fold (95% confidence interval, 1.1–5.8) greater odds of somewhat or strongly agreeing that this barrier applied to them.
Increasing participation in the VFC program may decrease physicians’ cost-related barriers, which may increase the number of children vaccinated on time according to the recommended schedule.
PMCID: PMC3795412  PMID: 22569945
9.  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.
PMCID: PMC3556792  PMID: 22556273
10.  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.
PMCID: PMC3458422  PMID: 22161806
11.  Genital Human Papillomavirus (HPV) Concordance in Heterosexual Couples 
The Journal of Infectious Diseases  2012;206(2):202-211.
Background. Few studies have assessed genital human papillomavirus (HPV) concordance and factors associated with concordance among asymptomatic heterosexual couples.
Methods. Genotyping for HPV was conducted with male and female sex partners aged 18–70 years from Tampa, Florida. Eligibility included no history of HPV-associated disease. Type-specific positive concordance (partners with ≥1 genotype in common) and negative concordance (neither partner had HPV) were assessed for 88 couples. Factors associated with concordance were assessed with Fisher exact tests and tests for trend.
Results. Couples reported engaging in sexual intercourse for a median of 1.7 years (range, 0.1–49 years), and 75% reported being in the same monogamous relationship for the past 6 months. Almost 1 in 4 couples had type-specific positive concordance, and 35% had negative concordance for all types tested, for a total concordance of 59%. Concordance was not associated with monogamy. Type-specific positive concordance was associated with an increasing difference in partners’ lifetime number of sex partners and inversely associated with an increasing difference in age. Negative concordance was inversely associated with both the couple's sum of lifetime number of sex partners and the difference in the partners’ lifetime number of sex partners.
Conclusions. Genital HPV concordance was common. Viral infectiousness and number of sex partners may help explain concordance among heterosexual partners.
PMCID: PMC3490693  PMID: 22539815
12.  Circulating Biomarkers of Iron Storage and Clearance of Incident Human Papillomavirus Infection 
Iron is an essential mineral for both cellular and pathogen survival and is essential for viral replication. In turn, iron metabolism has been shown to be altered by several viral infections. However, little is known regarding the association between iron status and HPV natural history. We hypothesize iron to be an HPV-cofactor that is associated with longer duration of infection.
Ferritin and soluble transferrin receptor (sTfR) were measured in baseline serum samples from 327 women enrolled in the Ludwig-McGill Cohort. Incident HPV clearance rates (any-type, oncogenic HPV, non-oncogenic HPV, and HPV-16) over 36 months were estimated from Cox-proportional hazard models accounting for correlations between multiple infections.
Women with ferritin levels above the median were less likely to clear an incident oncogenic HPV (AHR=0.73; 95%CI 0.55–0.96) and HPV-16 infections (AHR=0.29; 95%CI 0.11–0.73). Using physiological cut-points, women with enriched iron stores (≥120ug/L) were less likely to clear incident oncogenic HPV infections compared to those with low-levels of iron (<20ug/L)(AHR=0.34; 95%CI 0.15–0.81).
This study observed that women with the highest ferritin levels were less likely to clear incident oncogenic and HPV-16 infections compared to women with low ferritin. Rising iron stores may decrease probability of clearing new HPV infection, possibly by promoting viral activity and contributing to oxidative DNA damage.
This novel study suggests that elevated iron stores may put women at risk for persistent HPV infection, an early event in cervical carcinogenesis. Further examination of the association between iron status and HPV natural history is warranted.
PMCID: PMC3709556  PMID: 22426142
Human Papillomavirus; clearance; Ferritin; Iron; Transferrin
13.  Biomarkers of oxidant load and type-specific clearance of prevalent oncogenic human papillomavirus infection: Markers of immune response? 
Human papillomavirus (HPV) infection is the cause of cervical cancer. Increased production of reactive oxygen species (ROS) maybe the common mechanism through which HPV-cofactors (i.e. smoking and inflammation) influence duration of infections. Biomarkers of total oxidant load may serve as cumulative measures of ROS exposure due to these cofactors. Therefore, we conducted a study evaluating the association between biomarkers of oxidant load and duration of HPV infections, early HPV natural history events. Serum samples were obtained from 444 HPV-positive women in the Ludwig-McGill Cohort Study. Anti-5-hydroxymethyl-2’-deoxyuridine autoantibody (anti-HMdU aAb) and malondialdehyde (MDA) were measured at baseline. Cox-proportional hazard models were used to estimate the probability of clearing any HPV, oncogenic HPV, non-oncogenic HPV, and HPV-16 infections. Women with elevated MDA were significantly more likely to clear prevalent oncogenic HPV infections compared to those with lower MDA levels (Adjusted Hazard Ratio (AHR)=2.7; 95%CI=1.4–5.1). There did not appear to be an association between elevated MDA and clearance of incident oncogenic HPV infections. Similarly, women with elevated anti-HMdU aAb levels had higher rates of prevalent oncogenic HPV infection clearance (Quartile 3:AHR=2.2; 95%CI=1.2–4.4; Quartile 4:AHR=2.4; 95%CI=1.2–4.9). Higher levels of oxidant load biomarkers were associated with increased clearance of prevalent HPV infections. However, oxidant load biomarkers measured prior to incident infections were not associated, suggesting that the elevation of MDA and anti-HMdU aAb may reflect an ongoing effective immune response, such as increased innate immunity. More research focused on the immune responses to HPV and elevated markers of oxidant load is needed.
PMCID: PMC3319468  PMID: 21858808
Human Papillomavirus; clearance; cervical cancer; oxidative stress; reactive oxygen species
14.  Dietary Consumption of Antioxidant Nutrients and Risk of Incident Cervical Intraepithelial Neoplasia 
Gynecologic oncology  2010;118(3):289-294.
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.
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.
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.
Frequent consumption of fruits high in antioxidant nutrients appears to be associated with reduced risk of incident SIL among Brazilian women.
PMCID: PMC3691953  PMID: 20691333
cervical cancer; cervical intraepithelial neoplasia; human papillomavirus; diet; antioxidant nutrient
15.  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.
PMCID: PMC3308908  PMID: 22396601
16.  HPV-related information sharing and factors associated with US men's disclosure of an HPV test result to their female sexual partners 
Sexually transmitted infections  2012;88(3):171-176.
Prevalence of human papillomavirus (HPV) is high in both men and women, yet men have seldom been involved in HPV education/prevention programmes, and their disclosure of known HPV infection has rarely been studied. This analysis sought to determine factors associated with men's HPV test result disclosure and HPV-related information sharing with partners.
From 2007 to 2010, men enrolled in a psychosocial study of responses to HP testing who reported having a female main sexual partner (N=251) completed surveys including questions about HPV test results, disclosure of HPV test results to partner(s), relationship characteristics and stigma (for those who reported HPV-positive results) approximately 3 weeks after receiving an HPV test result. Logistic regression was conducted to determine factors associated with disclosure of HPV test results in cross-sectional analysis.
Most men disclosed their test results to a main partner (82%). Self-reported HPV-negative test result, a high school education and a higher commitment to a sexual partner were significantly associated with increased disclosure in multivariable analysis. Men who disclosed (vs those who did not) were significantly more likely to provide their partners with HPV-related information. Among men who disclosed to their main partner, nearly half reported that partner asked them questions about HPV.
Results from this study highlight the critical role that men who are symptomatic for, who are tested for or who are vaccinated against HPV can play in educating their sexual partners, independent of whether they actually disclose their test results.
PMCID: PMC3471785  PMID: 22215695
17.  Human papillomavirus infection in head and neck cancer: The role of the secretory leukocyte protease inhibitor 
Oncology Reports  2013;29(5):1962-1968.
We previously showed that secretory leukocyte protease inhibitor (SLPI) gene and protein expression is significantly lower in metastatic versus non-metastatic head and neck squamous cell carcinoma (HNSCC). However, we did not assess the human papillomavirus (HPV) status of these cases. Since SLPI plays a role in HIV and herpes simplex virus (HSV) infections, we hypothesized that SLPI may be involved in HPV-infected HNSCC. In HNSCC tissue (n=54), HPV DNA was determined and correlated with SLPI expression. Additionally, to investigate a possible role of smoking on SLPI expression in clinically normal mucosa, 19 patients treated for non-malignant diseases (non-HNSCC) were analyzed for SLPI expression and correlated with smoking habits. In HNSCC patients, SLPI expression showed a significant inverse correlation with HPV status. In patients with moderate/strong SLPI expression (n=19), 10.5% were HPV-positive. By contrast, patients with absent/weak SLPI expression (n=35), 45.7% were HPV-positive. Low SLPI expression was correlated with metastasis (P=0.003) independent of HPV status. HPV-positivity was clearly associated with lymph node status (81.3% N1-3 cases). In smoking non-HNSCC patients (n=7), 42.9% showed absent/weak and 57.1% moderate/strong SLPI staining. In non-smoking non-HNSCC patients (n=10) 83.3% showed absent/weak and 16.7% moderate/strong SLPI expression. For the first time, a correlation between SLPI downregulation and HPV infection was demonstrated, suggesting that high levels of SLPI, possibly induced by environmental factors such as tobacco smoking, correlate with protective effects against HPV infection. SLPI may be a potential biomarker identifying head and neck cancer patients not at risk of developing metastases (SLPI-positive), and those at risk to be infected by HPV (SLPI-negative) and likely to develop metastases.
PMCID: PMC3658815  PMID: 23467841
head and neck squamous cell carcinoma; human papillo- mavirus; secretory leukocyte protease inhibitor; p16
18.  Risk Factors for Incident Condyloma in a Multinational Cohort of Men: The HIM Study 
The Journal of Infectious Diseases  2012;205(5):789-793.
Identifying factors associated with condyloma are necessary for prevention efforts. Risk factors for incident condyloma were examined in a cohort of 2487 men from the United States, Brazil, and Mexico and were followed up every 6 months (median, 17.9 months). Factors strongly associated with condyloma were incident infection with human papillomavirus (HPV) types 6 and 11 (hazard ratio [HR], 12.42 [95% confidence interval {CI}, 3.78–40.77]), age (HR, 0.43 [95% CI, .26–.77]; 45–70 vs 18–30 years), high lifetime number of female partners (HR, 5.69 [95% CI, 1.80–17.97]; ≥21 vs 0 partners), and number of male partners (HR, 4.53 [95% CI, 1.68–12.20]; ≥3 vs 0 partners). The results suggest that HPV types 6 and 11 and recent sexual behavior are strongly associated with incident condyloma.
PMCID: PMC3274369  PMID: 22238467
19.  Evolutionary Ecology of Human Papillomavirus: Trade-offs, Coexistence, and Origins of High-Risk and Low-Risk Types 
The Journal of Infectious Diseases  2011;205(2):272-279.
Background. We address the ecological and evolutionary dynamics of human papillomavirus (HPV) that lead to the dichotomy between high-risk (HR) and low-risk (LR) types. We hypothesize that HPV faces an evolutionary tradeoff between persistence and per-contact transmission probability. High virion production enhances transmissibility but also provokes an immune response leading to clearance and limited persistence. Alternatively, low virion production increases persistence at the cost of diminished transmission probability per sexual contact. We propose that LR HPV types use the former strategy and that HR types use the latter. Sexual behaviors in a host population determine the success of each strategy.
Methods. We develop an evolutionary model of HPV epidemiology, which includes host sexual behavior, and we find evolutionarily stable strategies of HPV.
Results. A slow turnover of sexual partners favors HR HPV, whereas high frequency of partner turnover selects for LR. When both sexual behaviors exist as subcultures in a population, disruptive selection can result in the coevolution and ecological coexistence of both HR and LR HPV types.
Conclusions. Our results indicate that the elimination of HR HPV through vaccines may alter the evolutionary trajectory of the remaining types and promote evolution of new HR HPV types.
PMCID: PMC3244363  PMID: 22090448
20.  Smoking and Human Papillomavirus (HPV) Infection in the HPV in Men (HIM) Study 
The influence of smoking on the natural history of HPV infection in men is not well-understood. Smoking could influence the incidence and persistence of HPV infections by suppressing local immune function, increase cellular proliferation, up-regulate pro-inflammatory factors, or cause host DNA damage resulting in increased susceptible to infection. The purpose of this analysis is to assess prevalent HPV infections by smoking status in men, and to determine baseline risk of HPV infection associated with smoking.
The HPV in Men (HIM) study is a multinational prospective study of the natural history of HPV infections in men. Samples from the coronal sulcus, glans penis, shaft, and scrotum were combined for HPV DNA testing. Multivariable logistic regression was used to assess the association between smoking and any-, oncogenic-, and non-oncogenic HPV infections.
Our analyses revealed that current smoking was associated with an increased risk of any HPV infection (OR = 1.19; 95% CI 1.01 – 1.41) and oncogenic HPV infection (OR = 1.24; 95% CI 1.05 – 1.47). However, the association between smoking and any HPV infection (OR = 1.35; 95% CI 1.05 – 1.73) and oncogenic HPV infection (OR = 1.46; 95% CI 1.11 – 1.92) was only evident among men reporting fewer lifetime sexual partners.
These results suggest that current smokers with the fewest number of sexual partners are associated with an increased risk for oncogenic HPV infection.
The relationship between smoking and HPV infection remains understudied in men; these data sheds new light on the interplay between smoking, sexual activity, and risk of HPV infection.
PMCID: PMC3253903  PMID: 22016473
Smoking; HPV; Men; Genital Infection; Oncogenic HPV
22.  Incidence and Human Papillomavirus (HPV) Type Distribution of Genital Warts in a Multinational Cohort of Men: The HPV in Men Study 
The Journal of Infectious Diseases  2011;204(12):1886-1892.
Background. Data on the natural history of human papillomavirus (HPV)–related genital warts (GWs) in men are sparse. We described the distribution of HPV types in incident GWs and estimated GW incidence and time from type-specific incident HPV infections to GW detection in a multinational cohort of men aged 18–70 years.
Methods. Participants included 2487 men examined for GWs and tested for HPV every 6 months and followed up for a median of 17.9 months. Samples were taken from 112 men with incident GWs to test for HPV DNA by polymerase chain reaction.
Results. Incidence of GWs was 2.35 cases per 1000 person-years, with highest incidence among men aged 18–30 years (3.43 cases per 1000 person-years). HPV 6 (43.8%), HPV 11 (10.7%), and HPV 16 (9.8%) were the genotypes most commonly detected in GWs. The 24-month cumulative incidence of GWs among men with incident HPV 6/11 infections was 14.6% (95% confidence interval [CI], 7.5%–21.1%). Median time to GW detection was 17.1 months (95% CI, 12.4–19.3 months), with shortest time to detection among men with incident infections with HPV 6/11 only (6.2 months; 95% CI, 5.6–24.2 months).
Conclusions. HPV 6/11 plays an important role in GW development, with the highest incidence and shortest time to detection among men with incident HPV 6/11 infection.
PMCID: PMC3209812  PMID: 22013227
23.  Six-Month Incidence, Persistence, and Factors Associated With Persistence of Anal Human Papillomavirus in Men: The HPV in Men Study 
The Journal of Infectious Diseases  2011;204(11):1711-1722.
Background. Although there are limited numbers of incidence and persistence estimates for anal human papillomavirus (HPV) in women and in men who have sex with men (MSM), there are no such reports for men who have sex with women (MSW).
Methods. Genotyping was performed on anal samples from men, aged 18–70, from São Paulo, Brazil; Cuernavaca, Mexico; and Tampa, Florida, who provided specimens at enrollment and the 6-month visit of a 4-year prospective study. Eligibility included no history of genital warts or human immunodeficiency virus. A total of 954 MSW and 156 MSM provided evaluable specimens at both visits. Persistence was defined as type-specific infection at each visit.
Results. Incident anal infection was common among both MSM and MSW but generally higher for MSM for HPV groups and specific genotypes. A total of 5.1% of MSM and 0.0% of MSW had a persistent HPV-16 infection at the 6-month visit. Cigarette smoking among MSM and age among MSW were associated with persistent infection with any HPV genotype.
Conclusions. Although anal HPV infection is commonly acquired by both MSW and MSM, incident events and persistence occurred more often among MSM. Cigarette smoking is a modifiable risk factor that may contribute to HPV persistence among MSM.
PMCID: PMC3203231  PMID: 21964400
24.  Clustering of Human Papillomavirus (HPV) Types in the Male Genital Tract: The HPV in Men (HIM) Study 
The Journal of Infectious Diseases  2011;204(10):1500-1504.
Objective. To evaluate clustering patterns of prevalent infection with multiple human papillomavirus (HPV) types in 3677 men from the HPV in Men (HIM) study.
Methods. HPV testing was performed in samples combined from the glans penis/coronal sulcus, the shaft, and the scrotum by Linear Array methodology. Linear Array uses a mixed probe to assess HPV52 positivity, which limits the assay’s ability to determine HPV52 status in the presence of HPV33, 35, or 58. Logistic regression was used to model type-specific HPV positivity, adjusted for age, study area, lifetime number of sexual partners, and specific HPV type prevalence. Participant-level random effects were added to represent unobservable risk factors common to all HPV types.
Results. The observed-to-expected ratio for infections with ≥ 3 types was 1.09 (95% credible interval, 1.04–1.14). For the majority of 2-type combinations, no evidence was found of a significant departure of the observed from the expected number. An apparent clustering of HPV52 with HPV35 or 58 was observed, because of limitation in the ability of Linear Array to define HPV52 positivity.
Conclusions. Our study showed that, despite obvious anatomical differences, HPV coinfections do seem to occur at random in the male external genitalia as in the female cervix.
PMCID: PMC3222106  PMID: 21908729
25.  Efficacy of Quadrivalent HPV Vaccine against HPV Infection and Disease in Males 
The New England journal of medicine  2011;364(5):401-411.
Infection with human papillomavirus (HPV) and diseases caused by HPV are common in boys and men. We report on the safety of a quadrivalent vaccine (active against HPV types 6, 11, 16, and 18) and on its efficacy in preventing the development of external genital lesions and anogenital HPV infection in boys and men.
We enrolled 4065 healthy boys and men 16 to 26 years of age, from 18 countries in a randomized, placebo-controlled, double-blind trial. The primary efficacy objective was to show that the quadrivalent HPV vaccine reduced the incidence of external genital lesions related to HPV-6, 11, 16, or 18. Efficacy analyses were conducted in a per-protocol population, in which subjects received all three vaccinations and were negative for relevant HPV types at enrollment, and in an intention-to-treat population, in which subjects received vaccine or placebo, regardless of baseline HPV status.
In the intention-to-treat population, 36 external genital lesions were seen in the vaccine group as compared with 89 in the placebo group, for an observed efficacy of 60.2% (95% confidence interval [CI], 40.8 to 73.8); the efficacy was 65.5% (95% CI, 45.8 to 78.6) for lesions related to HPV-6, 11, 16, or 18. In the per-protocol population, efficacy against lesions related to HPV-6, 11, 16, or 18 was 90.4% (95% CI, 69.2 to 98.1). Efficacy with respect to persistent infection with HPV-6, 11, 16, or 18 and detection of related DNA at any time was 47.8% (95% CI, 36.0 to 57.6) and 27.1% (95% CI, 16.6 to 36.3), respectively, in the intention-to-treat population and 85.6% (97.5% CI, 73.4 to 92.9) and 44.7% (95% CI, 31.5 to 55.6) in the per-protocol population. Injection-site pain was significantly more frequent among subjects receiving quadrivalent HPV vaccine than among those receiving placebo (57% vs. 51%, P<0.001).
Quadrivalent HPV vaccine prevents infection with HPV-6, 11, 16, and 18 and the development of related external genital lesions in males 16 to 26 years of age. (Funded by Merck and others; number, NCT00090285.)
PMCID: PMC3495065  PMID: 21288094

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