Danelle Smith

Incidence and clearance of genital human papillomavirus infection in men (HIM): a cohort study

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.

The Optimal Anatomic Sites for Sampling Heterosexual Men for Human Papillomavirus (HPV) Detection: The HPV Detection in Men Study

Background. 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.Methods. 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.Results. 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.Conclusions. 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.

The Epidemiology of Oral HPV Infection among a Multinational Sample of Healthy Men

Background: Oral human papillomavirus type-16 (HPV16) infection is a risk factor for oropharyngeal cancer. We examined oral HPV infection among healthy men. Methods: Oral rinse/gargle specimens and questionnaire data were collected from 1,688 healthy men aged 18 to 74 (median = 31 years), from the United States, Mexico, and Brazil. HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59, and noncarcinogenic HPV types were detected using Roche Linear Array. Results: Oral HPV DNA was detected in 67 of 1,680 (4.0%, 95% CI = 3.1%–5.0%) β-globin–positive specimens; carcinogenic HPVs were detected in 1.3% (95% CI = 0.8%–2.0%; n = 22) and HPV16 was the most commonly detected carcinogenic HPV type (0.6%, 95% CI = 0.2%–1.1%; n = 10). The prevalence of oral HPV infection was similar by country except for HPV55, which had notably higher prevalence in Mexico (3.0%) than Brazil (0%) or the United States (0.2%). Oral HPV prevalence nonsignificantly increased over increasing age categories (Ptrend = 0.096). The strongest predictor of oral HPV was current tobacco use, which increased the odds 2.5-fold (95% CI = 1.4–4.4). Oral sexual behaviors were not associated with oral HPV infection. Conclusions: Oral HPV16 infection was rare in healthy men, especially at younger ages, and was positively associated with current tobacco use. Impact: Oral HPV appears to be about 10-fold less prevalent than infection at genital sites in men (4% vs. ∼40%, respectively). It remains unclear whether this reflects reduced exposure or if the oral region is more resistant to HPV infection compared with anogenital sites. Cancer Epidemiol Biomarkers Prev; 20(1); 172–82. ©2011 AACR.

Age-specific prevalence of and risk factors for anal human papillomavirus (HPV) among men who have sex with women and men who have sex with men: the HPV in men (HIM) study.

BACKGROUND An increasing incidence of anal cancer among men suggests a need to better understand anal canal human papillomavirus (HPV) infection among human immunodeficiency virus-negative men. METHODS Genotyping for HPV was conducted on cells from the anal canal among men who have sex with women (MSW) and men who have sex with men (MSM), aged 18-70 years, from Brazil, Mexico, and the United States. Factors associated with anal HPV infection were assessed using multivariable logistic regression. RESULTS The prevalence of any HPV type and oncogenic HPV types did not differ by city. Anal canal HPV prevalence was 12.2% among 1305 MSW and 47.2% among 176 MSM. Among MSW, reporting a lifetime number of ≥ 10 female sex partners, a primary sexual relationship <1 year in duration, and a prior hepatitis B diagnosis were independently associated with detection of any anal HPV in multivariable analysis. Among MSM, a younger age, reporting ≥ 2 male anal sex partners in the past 3 months, and never using a condom for anal sex in the past 6 months were independently associated with detection of any anal HPV in multivariable analysis. CONCLUSIONS Number of sex partners was associated with anal HPV infection in both MSW and MSM. Anal HPV infection in men may be mediated by age, duration of sexual relationship, and condom use.

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. Cancer Epidemiol Biomarkers Prev; 20(5); 990–1002. ©2011 AACR.

Prevalent Serum Antibody Is Not a Marker of Immune Protection against Acquisition of Oncogenic HPV16 in Men

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.

Seroprevalence of human papillomavirus (HPV) type 6 and 16 vary by anatomic site of HPV infection in men.

Background: It is largely unknown if antihuman papillomavirus (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 1,587 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 with same HPV-type infection in the external genitalia only, and among MSM compared with the 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% confidence interval (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 showed 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. Cancer Epidemiol Biomarkers Prev; 21(9); 1542–6. ©2012 AACR.

Clustering of Human Papillomavirus (HPV) Types in the Male Genital Tract: The HPV in Men (HIM) Study

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 assays 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.

Race and prevalence of human papillomavirus infection among men residing in Brazil, Mexico and the United States.

Human papillomavirus (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.

Male circumcision and prevalence of genital human papillomavirus infection in men: a multinational study

BackgroundAccumulated evidence from epidemiological studies and more recently from randomized controlled trials suggests that male circumcision (MC) may substantially protect against genital HPV infection in men. The purpose of this study was to assess the association between MC and genital HPV infection in men in a large multinational study.MethodsA total of 4072 healthy men ages 18–70 years were enrolled in a study conducted in Brazil, Mexico, and the United States. Enrollment samples combining exfoliated cells from the coronal sulcus, glans penis, shaft, and scrotum were analyzed for the presence and genotyping of HPV DNA by PCR and linear array methods. Prevalence ratios (PR) were used to estimate associations between MC and HPV detection adjusting for potential confounders.ResultsMC was not associated with overall prevalence of any HPV, oncogenic HPV types or unclassified HPV types. However, MC was negatively associated with non-oncogenic HPV infections (PR 0.85, 95% confident interval: 0.76-0.95), in particular for HPV types 11, 40, 61, 71, and 81. HPV 16, 51, 62, and 84 were the most frequently identified genotypes regardless of MC status.ConclusionsThis study shows no overall association between MC and genital HPV infections in men, except for certain non-oncogenic HPV types for which a weak association was found. However, the lack of association with MC might be due to the lack of anatomic site specific HPV data, for example the glans penis, the area expected to be most likely protected by MC.