Abstract
Background
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.
Methods
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.
Results
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]).
Conclusions
Lifetime and recent number of FSPs, condom use, and smoking were modifiable risk factors associated with HPV infection in men.
Human papillomavirus (HPV) infection is the most common sexually transmitted infection and is the necessary cause of cervical cancer. An estimated 6.2 million people in the United States acquired a genital HPV infection in 2000 [1]. Approximately 60 HPV genotypes are known to infect the genital tract, 13 of which are considered to be high risk, or oncogenic [2, 3]. Although infection is most often asymptomatic and transient, oncogenic genotypes of HPV are strongly associated with cervical cancer and are associated to varying degrees with other anogenital cancers in both men and women [4]. Nononcogenic HPV genotypes can cause genital warts and other benign lesions; however, many HPV infections are clinically inapparent [5].
Factors associated with prevalent HPV infection in men include current and past sexual behavior, circumcision status, lack of condom use, history of other sexually transmitted infections, race and ethnicity, and education level [6–16]. The strength and significance of the reported associations vary across the populations under examination and depend on whether the outcome analyzed is all HPV types, oncogenic types, or nononcogenic types.
The most consistently reported risk factor for HPV infection in men is a greater lifetime number of female sex partners [8–11, 13, 15], with some studies reporting an association with the recent number of female sex partners [8, 13]. Most studies that have evaluated the association between circumcision and HPV prevalence found a lower prevalence in circumcised men [6, 7, 11–14, 16].
Two studies have found younger age (e.g., 18–24 years old vs. ≥35 years old) to be associated with both oncogenic and nononcogenic HPV infection [13, 14]. A younger age at first sexual intercourse was associated with HPV infection in 1 of 4 studies that examined the association [6, 8–11]. When condom use was evaluated in male HPV prevalence studies, 5 studies found no association with HPV detection [9–12, 15], and 3 found a lower odds of detection associated with condom use [6, 10, 14].
Two prospective studies of HPV in men have reported factors associated with HPV acquisition and persistence. Risk factors for acquisition included anal intercourse with men and having had at least 3 sex partners, whereas protective factors were high socioeconomic status and condom use [11, 17]. Both studies reported that infection with multiple HPV types at baseline was a risk factor for persistent infection, and Lajous et al. reported a protective effect of circumcision on HPV persistence [11, 17].
The present study was conducted to determine the behavioral and health factors associated with HPV detection in the entire anogenital area among asymptomatic men in the United States.
SUBJECTS, MATERIALS, AND METHODS
Study design, clinical sampling, and HPV testing have been described in detail elsewhere [18]. Briefly, a cross-sectional study of HPV infection in 463 men—359 in Tucson, Arizona, and 104 in Tampa, Florida—was completed from 2003 to 2006. Men were eligible if they (1) were between 18 and 40 years old, (2) had had sexual intercourse with a woman within the past year, (3) had no previous diagnosis of genital warts or of penile or anal cancer, (4) had no current penile discharge or pain during urination, and (5) had no current diagnosis of a sexually transmitted disease (STD).
All participants gave written informed consent, and all procedures were approved by the University of Arizona Human Subjects Protection Program, the Centers for Disease Control and Prevention Institutional Review Board, the US Department of Defense, and the University of South Florida Institutional Review Board.
Participants completed a self-administered, scannable questionnaire that included questions on demographic factors (race, ethnicity, age, income, occupation, education, country of origin, and length of US residency); alcohol and tobacco use; age at first sexual intercourse; lifetime number of female sex partners; frequency of sexual intercourse; ever having had sex with a man or having been diagnosed with an STD; and condom use during the past 3 months.
Men collected a semen sample by masturbation 12–36 h before the clinical visit. The study clinician examined each participant’s genital, abdominal, and anal areas and recorded the number and location of any lesions or warts. Lesions or warts were sampled by rubbing with a saline-wetted Dacron swab, and samples were stored separately. Because men were excluded if they had been given a diagnosis of genital warts or currently had a STD, very few lesions or warts were detected, and the HPV analysis of these samples is not included in this report. Acetowhitening was not done. The clinician also recorded the presence and location of any erythema, abrasions, rashes, inflammation, discharge, or piercings in the same regions and whether the participant was circumcised. The study clinician used a calcium alginate or Dacron urethral swab to sample the first 2 cm of the urethral epithelium. The clinician sampled other anogenital sites by rubbing separate saline-wetted Dacron swabs over the entire surface of the (1) glans penis/coronal sulcus, (2) penile shaft (including the prepuce, if present), (3) scrotum, and (4) perianal area. The anal canal up to the anal verge was sampled with another saline-wetted Dacron swab. The urethral sample was optional. The urethral and semen samples were eliminated in the third year of the study. Each specimen was evaluated separately for the presence of HPV DNA and human β-globin.
HPV DNA detection and genotyping
All samples were tested in a single laboratory at the H. Lee Moffitt Cancer Center and Research Institute. HPV testing of swabbed cellular material and semen was conducted by polymerase chain reaction (PCR) for amplification of a fragment of the L1 gene [19]. HPV genotyping was conducted using the reverse line blot method [20] on all samples, regardless of HPV PCR result. This detection method uses the HPV L1 consensus PCR products labeled with biotin to detect 37 HPV types. A trend toward increasing prevalence of HPV and increasing detection of β-globin was observed over the first half of the laboratory analysis period and is attributed to improvements in laboratory methods. Laboratory personnel were then cross-trained in a reference laboratory. This time trend was adjusted for by including a dichotomous variable—for before and after cross-training—in the statistical analyses. Between 83.7% and 99.7% of the samples, depending on the anatomic site or specimen sampled, were β-globin positive by PCR and/or genotyping [21].
Definition of HPV outcomes
The oncogenic HPV types associated with cervical dysplasia and cancer detected by the Roche line blot method include 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 66 [3]. The nononcogenic types detected by the Roche line blot method are 6, 11, 26, 40, 42, 53–55, 61, 62, 64, 67–73, 81–84, IS39, and CP6108. The presence of any HPV DNA was defined as a positive result by either PCR or genotyping. The absence of any HPV DNA was defined as a negative result by both PCR and genotyping in a sample positive for human β-globin. Samples without detection of β-globin or HPV were deemed to be inadequate for evaluation and were treated as missing. If the sample was positive for HPV by PCR but none of the 37 types was found in genotyping, the HPV type was classified as other or unknown.
A man was classified as having oncogenic infection if any of his samples contained 1 of the 13 oncogenic types, regardless of whether a nononcogenic type was also present. He was considered to have a nononcogenic infection if any of his samples were positive for 1 or more nononcogenic types only or for an unclassified type. The comparison group for all analyses was men who had no HPV detected at any site.
Statistical analysis
Frequencies and means of the responses to questionnaire items and the results from the clinical examination were calculated and compared between men who had no HPV infection at any site or specimen and those who had at least 1 positive HPV result. A t test was used to compare continuous measures and a χ2 test was used for categorical variables, with a P for trend calculated for those categories that were ordinal.
Logistic regression was used to model the associations between various reported or hypothesized risk factors and the outcomes (1) any HPV infection at any site, (2) an oncogenic HPV infection at any site (regardless of whether they also had a nononcogenic infection), and (3) nononcogenic HPV infection at any site (including men who had only nononcogenic infection and those who had unknown or other HPV types). Odds ratios (ORs) were first calculated using logistic regression for each potential risk factor, adjusting for date of laboratory analysis. Next, independent factors were determined by calculating adjusted ORs (AORs). Multivariate modeling used backward-selection logistic regression modeling, starting with the factors that had statistically significant (P < .10) ORs in the previous step.
To ensure that 2 or more variables were not included in a single multivariate model so as to cause multicollinearity [22], variance inflation factors (VIFs) were calculated for all variables in each of the 3 candidate multivariate models. A single VIF of 10 or more or a mean VIF of 6 or more for all variables in a model was the criterion used for multicollinearity [23]. No variables in the models presented here reached this criterion. Analyses were conducted using Intercooled Stata for Windows (version 9.1; StataCorp).
RESULTS
Results of recruitment and the demographic characteristics of the study population have been described elsewhere [18]. Three hundred three men (65.4%) were positive for any HPV type, 135 men (29.2%) were positive for at least 1 oncogenic HPV type, and 168 (36.3%) were positive for nononcogenic or unclassified types only. Of those positive for an oncogenic HPV type, 86 (63.7%) also had a nononcogenic HPV type detected. One hundred sixty men (34.6%) had no HPV detected at any site. HPV was more often detected in external genital sites (57.2%) than in anal sites (23.8%). Type-specific HPV prevalence by anatomic site for this study population has been reported elsewhere [18].
Factors associated with any HPV, oncogenic HPV, and nononcogenic HPV at any site in bivariate analyses are presented in tables 1–3. Notably, no sociodemographic characteristics were associated with HPV infection (table 1).
Table 1.
Association between sociodemographic characteristics and human papillomavirus (HPV) status of men in the HPV Detection in Men Study.
| Any HPV | Oncogenic HPV | Nononcogenic HPV | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Category, parameter | Subjects, total no. |
Positive, no. (%) |
ORa (95% CI) | P for trend (χ2) | Positive, no. |
ORa (95% CI) | P for trend (χ2) | Positive, no. |
ORa (95% CI) | P for trend (χ2) |
| Residence | ||||||||||
| Tucson, Arizona | 359 | 228 (63.5) | Reference | 101 | Reference | 127 | Reference | |||
| Tampa, Florida | 104 | 75 (72.1) | 1.2 (0.7–2.0) | 34 | 1.1 (0.6–2.0) | 41 | 1.3 (0.7–2.3) | |||
| Age | .879 | .529 | .759 | |||||||
| 18–19 years | 50 | 33 (66.0) | Reference | 11 | Reference | 22 | Reference | |||
| 20–24 years | 181 | 113 (62.4) | 0.8 (0.4–1.6) | 52 | 1.1 (0.5–2.7) | 61 | 0.7 (0.3–1.4) | |||
| 25–29 years | 90 | 64 (71.1) | 1.2 (0.6–2.6) | 28 | 1.6 (0.6–4.0) | 36 | 1.0 (0.5–2.3) | |||
| 30–34 years | 63 | 44 (69.8) | 1.2 (0.5–2.7) | 20 | 1.6 (0.6–4.4) | 24 | 1.0 (0.4–2.3) | |||
| 35–40 years | 79 | 49 (62.0) | 0.8 (0.4–1.7) | 24 | 1.2 (0.5–3.0) | 25 | 0.6 (0.3–1.4) | |||
| Race | ||||||||||
| White | 324 | 210 (64.8) | Reference | 89 | Reference | 121 | Reference | |||
| Black | 33 | 20 (60.6) | 0.8 (0.4–1.6) | 10 | 0.9 (0.4–2.1) | 10 | 0.7 (0.3–1.6) | |||
| Asian/Pacific Islander | 19 | 11 (57.9) | 0.7 (0.4–1.6) | 3 | 0.4 (0.1–1.6) | 8 | 0.9 (0.3–2.4) | |||
| American Indian/Alaska Native | 9 | 5 (55.6) | 0.7 (0.2–2.6) | 4 | 1.3 (0.3–5.6) | 1 | 0.2 (0.0–2.2) | |||
| Other/unknown | 78 | 57 (73.1) | 1.4 (0.8–2.5) | 29 | 1.7 (0.9–3.2) | 28 | 1.2 (0.7–2.3) | |||
| Ethnicity | ||||||||||
| Non-Hispanic | 384 | 240 (63.8) | Reference | 103 | Reference | 137 | Reference | |||
| Hispanic | 79 | 56 (70.9) | 1.3 (0.8–2.3) | 29 | 1.6 (0.9–3.0) | 27 | 1.1 (0.6–2.1) | |||
| Marital status | ||||||||||
| Single, never married | 327 | 220 (67.3) | Reference | 100 | Reference | 120 | Reference | |||
| Married | 59 | 36 (61.0) | 0.8 (0.4–1.4) | 12 | 0.6 (0.3–1.3) | 24 | 1.0 (0.5–1.8) | |||
| Cohabiting | 29 | 17 (58.6) | 0.8 (0.3–1.7) | 8 | 0.8 (0.3–2.1) | 9 | 0.7 (0.3–1.8) | |||
| Divorced/separated | 35 | 25 (71.4) | 1.4 (0.6–3.0) | 13 | 1.7 (0.7–4.0) | 12 | 1.2 (0.5–2.8) | |||
| Education | .255 | .607 | .750 | |||||||
| <12 years | 23 | 15 (65.2) | Reference | 6 | Reference | 9 | Reference | |||
| High school graduate | 94 | 63 (67.0) | 1.1 (0.4–2.9) | 27 | 1.2 (0.4–3.9) | 36 | 1.0 (0.3–3.0) | |||
| 13–16 years | 240 | 161 (67.1) | 1.1 (0.4–2.6) | 72 | 1.2 (0.4–3.6) | 89 | 1.0 (0.4–2.7) | |||
| ≥17 years | 101 | 59 (58.4) | 0.7 (0.3–1.9) | 27 | 0.9 (0.3–2.8) | 32 | 0.7 (0.2–1.9) | |||
NOTE. The no. of subjects varies because of missing data. CI, confidence interval; OR, odds ratio.
Adjusted for date of laboratory analysis.
Table 3.
Association between human papillomavirus (HPV) status and history of sexually transmitted infection in the HPV Detection in Men Study.
| Any HPV | Oncogenic HPV | Nononcogenic HPV | ||||||
|---|---|---|---|---|---|---|---|---|
| Category, parameter | Subjects, total no. |
Positive, no. (%) |
ORa (95% CI) | Positive, no. |
ORa (95% CI) | Positive, no. |
ORa (95% CI) | |
| Ever diagnosed with any STD | ||||||||
| No | 354 | 230 (65.0) | Reference | 101 | Reference | 129 | Reference | |
| Yes | 96 | 64 (66.7) | 1.1 (0.7–1.7) | 30 | 1.1 (0.6–2.0) | 34 | 1.0 (0.6–1.7) | |
| Genital wart(s) found during clinic visit | ||||||||
| No | 445 | 287 (64.5) | Reference | 125 | Reference | 162 | Reference | |
| Yes | 18 | 16 (88.9) | 4.5 (1.0–20.0) | 10 | 6.7 (1.4–31.3) | 6 | 3.0 (0.6–15.1) | |
| Ever had sex partner with genital warts | ||||||||
| No | 308 | 200 (64.9) | Reference | 84 | Reference | 116 | Reference | |
| Yes | 35 | 22 (62.9) | 0.9 (0.4–1.8) | 11 | 1.0 (0.4–2.4) | 11 | 0.8 (0.3–1.8) | |
| Don’t know | 119 | 81 (68.1) | 1.1 (0.7–1.7) | 40 | 1.3 (0.7–2.1) | 41 | 1.0 (0.6–1.6) | |
| Ever had sex partner with abnormal Pap smear results | ||||||||
| No | 153 | 100 (65.4) | Reference | 32 | Reference | 68 | Reference | |
| Yes | 107 | 75 (70.1) | 1.3 (0.7–2.1) | 41 | 2.2 (1.1–4.1) | 34 | 0.8 (0.5–1.5) | |
| Don’t know | 203 | 128 (63.1) | 0.9 (0.6–1.3) | 62 | 1.3 (0.7–2.3) | 66 | 0.7 (0.4–1.1) | |
NOTE. The no. of subjects varies because of missing data. CI, confidence interval; OR, odds ratio; STD, sexually transmitted disease.
Adjusted for date of laboratory analysis.
As shown in table 2, current smoking, compared with never smoking, was associated with the detection of any HPV (OR, 1.8 [95% confidence interval {CI}, 1.1–3.1]) and of oncogenic HPV (OR, 2.1 [95% CI, 1.2–3.9]). A similar magnitude of association was observed for detection of nononcogenic HPV (OR, 1.6 [95% CI, 0.9–2.8]), although the association was not statistically significant. A stronger association was observed between smoking 10 or more cigarettes per day (compared with smoking 0–9 cigarettes per day) and each of the 3 HPV outcomes: detection of any HPV (OR, 3.0 [95% CI, 1.4–6.4]), oncogenic HPV (OR, 3.7 [95% CI, 1.6–8.5]), and nononcogenic HPV (OR, 2.4 [95% CI, 1.1–5.6]) (table 2).
Table 2.
Association between human papillomavirus (HPV) status and sexual and health behaviors of men in the HPV Detection in Men Study.
| Any HPV | Oncogenic HPV | Nononcogenic HPV | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Category, parameter | Subjects, total no. |
Positive, no. (%) | ORa (95% CI) |
P for trend (χ2) | Positive, no. | ORa (95% CI) |
P for trend (χ2) | Positive, no. | ORa (95% CI) |
P for trend (χ2) |
| Cigarette smoker | ||||||||||
| Never | 263 | 164 (62.4) | Reference | 71 | Reference | 93 | Reference | |||
| Former | 87 | 55 (63.2) | 1.1 (0.6–1.8) | 23 | 1.1 (0.6–2.0) | 32 | 1.1 (0.6–1.9) | |||
| Current | 104 | 77 (74.0) | 1.8 (1.1–3.1) | 38 | 2.1 (1.2–3.9) | 39 | 1.6 (0.9–2.8) | |||
| No. of cigarettes currently smoked per day | ||||||||||
| 0–9 | 404 | 255 (63.1) | Reference | 111 | Reference | 144 | Reference | |||
| ≥10 | 51 | 42 (82.4) | 3.0 (1.4–6.4) | 22 | 3.7 (1.6–8.5) | 20 | 2.4 (1.1–5.6) | |||
| Monthly alcohol consumption | .187 | .041 | .617 | |||||||
| 0 drinks | 79 | 50 (63.3) | Reference | 21 | Reference | 29 | Reference | |||
| 1–30 drinks | 194 | 125 (64.4) | 1.1 (0.6–1.8) | 53 | 1.1 (0.5–2.1) | 72 | 1.1 (0.6–2.0) | |||
| 31–60 drinks | 66 | 42 (63.6) | 1.0 (0.5–2.0) | 16 | 0.9 (0.4–2.2) | 26 | 1.1 (0.5–2.4) | |||
| ≥61 drinks | 104 | 75 (72.1) | 1.5 (0.8–2.9) | 42 | 2.1 (1.0–4.4) | 33 | 1.2 (0.6–2.5) | |||
| Circumcised (clinician assessed) | ||||||||||
| No | 74 | 49 (66.2) | Reference | 23 | Reference | 26 | Reference | |||
| Yes | 389 | 254 (65.3) | 1.0 (0.6–1.7) | 112 | 0.9 (0.5–1.8) | 142 | 1.0 (0.6–1.9) | |||
| Age at first sexual intercourse | ||||||||||
| <18 years | 286 | 194 (67.8) | Reference | 91 | Reference | 103 | Reference | |||
| ≥18 years | 177 | 109 (61.6) | 0.8 (0.5–1.1) | 44 | 0.7 (0.4–1.1) | 65 | 0.9 (0.5–1.3) | |||
| Lifetime no. of female sex partners | <.001 | <.001 | .044 | |||||||
| 1–5 | 158 | 83 (52.5) | Reference | 26 | Reference | 57 | Reference | |||
| 6–10 | 92 | 63 (68.5) | 1.9 (1.1–3.2) | 27 | 2.5 (1.3–5.1) | 36 | 1.6 (0.9–2.9) | |||
| 11–20 | 105 | 76 (72.4) | 2.4 (1.4–4.2) | 35 | 3.7 (1.9–7.2) | 41 | 1.9 (1.1–3.5) | |||
| ≥21 | 87 | 66 (75.9) | 2.8 (1.5–4.9) | 40 | 5.3 (2.6–10.6) | 26 | 1.6 (0.8–3.1) | |||
| No. of female sex partners during the past 3 months | .005 | .007 | .025 | |||||||
| None | 61 | 33 (54.1) | Reference | 14 | Reference | 19 | Reference | |||
| 1 | 274 | 175 (63.9) | 1.5 (0.9–2.7) | 76 | 1.6 (0.8–3.3) | 99 | 1.5 (0.8–2.9) | |||
| ≥2 | 125 | 95 (74.2) | 2.5 (1.3–4.7) | 45 | 2.8 (1.1–4.7) | 50 | 2.3 (1.1–4.7) | |||
| New female sex partner during the past 3 months | ||||||||||
| No | 270 | 170 (63.0) | Reference | 76 | Reference | 94 | Reference | |||
| Yes | 193 | 133 (68.9) | 1.3 (0.9–1.9) | 59 | 1.2 (0.8–2.0) | 74 | 1.3 (0.8–2.0) | |||
| Frequency of sexual intercourse during the past month | .037 | .029 | .134 | |||||||
| None | 123 | 70 (56.9) | Reference | 31 | Reference | 39 | Reference | |||
| 1–10 times | 235 | 159 (67.7) | 1.6 (1.0–2.5) | 66 | 1.5 (0.9–2.6) | 93 | 1.7 (1.0–2.8) | |||
| ≥11 times | 105 | 74 (70.5) | 1.8 (1.0–3.1) | 38 | 2.0 (1.1–3.9) | 36 | 1.5 (0.8–2.9) | |||
| Frequency of sexual intercourse during the past 3 months | .023 | .005 | .200 | |||||||
| None | 53 | 29 (54.7) | Reference | 11 | Reference | 18 | Reference | |||
| 1–25 times | 277 | 180 (65.0) | 1.5 (0.8–2.8) | 76 | 1.7 (0.8–3.7) | 104 | 1.4 (0.7–2.8) | |||
| ≥26 times | 107 | 78 (72.9) | 2.2 (1.1–4.5) | 41 | 3.1 (1.3–7.3) | 37 | 1.7 (0.8–3.7) | |||
| Condom use with vaginal sex during the past 3 months | ||||||||||
| Less than half the time | 221 | 154 (69.7) | Reference | 84 | Reference | 43 | Reference | |||
| At least half the time | 187 | 119 (63.6) | 0.7 (0.5–1.1) | 39 | 0.4 (0.3–0.7) | 18 | 1.1 (0.7–1.8) | |||
NOTE. The no. of subjects varies because of missing data. CI, confidence interval; OR, odds ratio.
Adjusted for date of laboratory analysis.
Table 2 also shows that, in bivariate analyses, several sexual behavior variables were associated with HPV detection. Factors statistically significantly associated with any HPV infection were increasing lifetime number of female sex partners, number of female sex partners during the past 3 months, and increased frequency of intercourse during the past month and during the past 3 months.
Sexual behavior factors that were associated with oncogenic HPV in bivariate analyses were similar to those associated with any HPV but also included condom use during the past 3 months (table 2). Having oncogenic HPV detected was associated with a higher lifetime number of female sex partners, a greater number of female partners during the past 3 months, and a higher frequency of intercourse during the past month and during the past 3 months. Using condoms at least half the time was associated with a reduced odds of HPV detection (OR, 0.5 [95% CI, 0.3–0.7]).
Table 3 shows the association between HPV detection and STD history, current genital warts, and partners’ history of STD or abnormal Pap smear result. A history of STD infection was not associated with current HPV detection. Current presence of genital warts was, however, associated with any HPV (OR, 4.5 [95% CI, 1.0–20.0]) and oncogenic HPV (OR, 6.7 [95% CI, 1.4–31.3]). Also, having had a female sex partner with an abnormal Pap smear result was statistically significantly associated with having oncogenic HPV detected (OR 2.2 [95% CI, 1.1–4.1]).
Multivariate logistic regression modeling revealed that the set of variables that best explained the HPV outcome differed by the HPV category examined (table 4). Factors independently associated with any HPV were smoking 10 or more cigarettes per day (AOR vs. 0–9, 2.3 [95% CI, 1.0–5.3]; P = .046) and a greater lifetime number of female sex partners (AOR for ≥21 partners vs. 1–5 partners, 2.5 [95% CI, 1.3–4.6]). The factors independently associated with oncogenic HPV were lifetime number of female sex partners (AOR for ≥21 partners vs. 1–5 partners, 7.4 [95% CI, 3.4–16.3]) and using condoms during vaginal sex at least half the time during the past 3 months (AOR vs. using them less than half the time, 0.5 [95% CI, 0.3–0.8]). The factor independently associated with nononcogenic HPV was having 2 or more female sex partners during the past 3 months (AOR vs. none, 2.9 [95% CI, 1.4–6.3]).
Table 4.
Independent risk factors for human papillomavirus (HPV) infection among men in the HPV Detection in Men Study.
| OR (95% CI) | |||
|---|---|---|---|
| Category, parameter | Any HPV | Oncogenic HPV | Nononcogenic HPV |
| Smoke ≥10 cigarettes per daya | 2.3 (1.0–5.3) | 2.2 (0.8–5.8) | 2.0 (0.8–4.6) |
| Lifetime no. of female sex partners | |||
| 1–5 | Reference | Reference | Reference |
| 6–10 | 1.8 (1.0–3.1) | 3.0 (1.4–6.7) | 1.4 (0.7–2.6) |
| 11–20 | 2.3 (1.3–4.0) | 5.2 (2.4–11.4) | 1.6 (0.9–3.0) |
| ≥21 | 2.5 (1.3–4.6) | 7.4 (3.4–16.3) | 1.3 (0.7–2.7) |
| Condom use with vaginal sex during the past 3 months | |||
| Less than half the time | Reference | Reference | Reference |
| At least half the time | 0.8 (0.5–1.2) | 0.5 (0.3–0.8) | 1.0 (0.6–1.6) |
| No. of female sex partners during the past 3 months | |||
| None | Reference | Reference | Reference |
| 1 | 2.2 (0.6–7.8) | 1.6 (0.3–8.4) | 1.8 (0.9–3.6) |
| ≥2 | 2.8 (0.8–10.5) | 2.8 (0.5–15.5) | 2.9 (1.4–6.3) |
NOTE. The no. of subjects varies because of missing data. Odds ratios (ORs) and 95% confidence intervals (CIs) in boldface indicate the variables that were included in the final model for each HPV outcome. ORs for other variables are included for comparison among the 3 outcomes. All ORs are adjusted for date of laboratory analysis.
Reference category is <10 cigarettes per day.
DISCUSSION
Using complete anogenital sampling and HPV type detection, we found sexual history and tobacco use to be associated with HPV detection in asymptomatic men. Consistent condom use was associated with a lower prevalence of HPV.
Smoking was recently identified as a risk factor for HPV detection in men [14], and it has been reported to be associated with the persistence of HPV infection and with anal and penile cancer in men [24, 25]. Kjaer et al. [17] noted that current smoking along with having multiple HPV types or any highrisk HPV type at enrollment were the most important risk factors for HPV persistence in men. In 2 case-control studies, smoking was associated with penile cancer (OR, 4.5 [95% CI, 2.0–10.1]) [25] and anal cancer (OR, 3.9 [95% CI, 1.9–8.0]) [24]. In another case-control study, smoking 11 or more cigarettes per day (vs. not smoking) was associated with genital warts (OR, 1.9 [95% CI, 1.0–2.3]) [26]. Smoking among men has also been associated with their wives’ cervical cancer risk in a case-control study: after adjustment for the wife’s pack-years of smoking and other factors, the husband’s smoking was moderately associated with cervical cancer (AOR for ≥26.2 pack-years vs. none, 2.5 [95% CI, 1.4–4.4]) [27]. It is possible that, in the present study, smoking is associated with unmeasured sex partner characteristics. Further study of the impact of smoking on HPV infection in men, a factor that may be important in preventing HPV-related diseases in both men and women, is recommended.
We have previously reported an ~60% lower adjusted odds of any HPV type and 80% lower adjusted odds of oncogenic HPV detection with always versus never using condoms during the past 3 months [6]. Similarly, others have reported that a lower prevalence of HPV was found for those who always used condoms (20.7%), compared with those who never used condoms (26.1%) [10]. A recent study found significantly lower adjusted odds of HPV detection in men who used condoms with both regular sex partners and sex workers [14]. In the present study, men who had used condoms at least half the time during the past 3 months had significantly lower odds of oncogenic HPV detection (OR, 0.5) after adjustment for lifetime number of female sex partners; however, the association was not observed for nononcogenic HPV. We suggest that in studies in which only the glans penis/coronal sulcus, urethra, and/or penile shaft are sampled, an observed protective association with condom use might be stronger than in studies (such as the present one) in which the scrotum and anal sites are included.
We observed similarities in the magnitude of ORs across the 3 HPV outcomes for many of the health and behavioral factors measured. In bivariate analyses, associations with sexual factors— such as lifetime number of female sex partners and condom use during the past 3 months—were somewhat stronger for oncogenic HPV types than for the other 2 outcomes (table 3). These results might be explained by the inclusion of unclassified types, which may be false-positive result or HPV types not sexually transmitted, in the nononcogenic and any HPV type outcomes. Because we did not sequence unclassified types, we cannot determine the nature of the HPV DNA in the unclassified group. The consistency in the magnitude of ORs observed for the 3 multivariate models adds strength to the conclusion that smoking, lifetime and recent number of female sex partners, and condom use are associated with HPV detection in men (table 4).
Two other published multivariate models of risk factors for oncogenic, nononcogenic, and any HPV type infection in men reported somewhat different results [6, 13]. For example, Svare et al. [13] found that younger age (18–24 vs. ≥35 years) was associated with a greater odds of both oncogenic and nononcogenic HPV detection, whereas we and Baldwin et al. [6] found no association with age. Baldwin et al. [6] reported that lack of circumcision was a statistically significant independent risk factor for all 3 HPV outcomes, whereas Svare et al. [13] and we found no statistically significant association. Both previously published studies reported an association between nononcogenic HPV detection and genital warts. In the present study—perhaps because of our exclusion of men with such a history—the association was not statistically significant. Statistically significant factors the 3 studies had in common were lifetime and recent number of sex partners [6, 13].
It is of interest to determine whether risk factors differ by site. For example, although we did not observe a statistically significant association with circumcision at all sites combined, the effect of circumcision might be limited to certain penile sites. Similarly, condom use would logically be more strongly associated with HPV at the sites covered by condoms. These questions deserve further investigation.
The cross-sectional nature of the assessment of both exposures and HPV outcomes allowed us to detect associations between recent behaviors and current HPV detection. However, we are unable to assess causality or associations with infection duration. Analysis of sexual behaviors, including number of partners, smoking, and condom use, in a longitudinal cohort study of HPV in asymptomatic men is needed to provide evidence of factors that are related to viral acquisition and persistence.
Misclassification of potential risk behaviors is possible when participants fail to disclose accurate information about their sexual history or current practices. To limit this problem, we used a self-administered questionnaire. Prior research has shown the types of questions included in the present study should yield fairly reliable responses. One study of men found high reliability (≥90% agreement) between responses to questions on sexual activity reported for the previous 2 weeks and the previous 3 months but not between those shorter periods and the previous year [28]. In another study, test-retest agreement was also strong for age at first intercourse (86%) and lifetime number of sex partners (82%) [29]. Because most questions included in the present study asked men to reflect on lifetime questions or activities during the past 3 months, confidence is increased for reliability of responses. Although misclassification of HPV outcomes is also a possibility, we have observed high replicability of HPV detection among male anogenital samples across laboratories [30].
In summary, the present study has allowed the identification of associations between current HPV infection and current smoking as well as confirmation of previously identified associations between HPV and lifetime and recent number of sex partners. Future longitudinal studies of HPV in men and sex partners that use complete anogenital sampling, including of the penile shaft, and that include detailed assessments of smoking habits and condom use to determine their effects on incidence, persistence, and transmission are under way.
Acknowledgments
We thank the staff members of the University of Arizona Health Research Clinic (Tucson, Arizona); the Men’s Research Clinic at Lifetime Cancer Screening and Prevention Center, H. Lee Moffitt Cancer Center (Tampa, Florida); and the Pima County Theresa Lee Health Center (Tucson, Arizona). We also thank Danelle Smith, Steven McAnany, Shannon McCarthy, and Sireesha Banduvula for their work in the laboratory and Dr. Katherine Stone (Centers for Disease Control and Prevention, Atlanta, Georgia) for her assistance in the development of the ideas for the initial proposal. We are grateful to Digene Corporation (Gaithersburg, Maryland) for donating reagents and supplies.
Financial support: Centers for Disease Control and Prevention, through the Association of American Medical Colleges (AAMC) (cooperative agreement [grant U36/CCU319276; AAMC identification number MM-0579-03/03]); National Cancer Institute (R25 CA078447 to C.M.N.).
Publication and report contents are solely the responsibility of the authors and do not necessarily represent the official views of the Association of American Medical Colleges or the Centers for Disease Control and Prevention.
Footnotes
Potential conflicts of interest: A.R.G. is on the speakers’ bureau of Merck and has served as a consultant for the male human papillomavirus vaccine program at Merck. All other authors report no potential conflicts.
Presented in part: 23rd International Papillomavirus Conference and Clinical Workshop, Prague, 1–7 September 2006 (abstract P-490).
References
- 1.Weinstock H, Berman S, Cates W., Jr Sexually transmitted diseases among American youth: incidence and prevalence estimates, 2000. Perspect Sex Reprod Health. 2004;36:6–10. doi: 10.1363/psrh.36.6.04. [DOI] [PubMed] [Google Scholar]
- 2.de Villiers E-M, Fauquet C, Broker TR, Bernard H-U, zur Hausen H. Classification of papillomaviruses. Virology. 2004;324:17–27. doi: 10.1016/j.virol.2004.03.033. [DOI] [PubMed] [Google Scholar]
- 3.Cogliano V, Baan R, Straif K, et al. Carcinogenicity of human papillomaviruses. Lancet Oncol. 2005;6:204. doi: 10.1016/s1470-2045(05)70086-3. [DOI] [PubMed] [Google Scholar]
- 4.zur Hausen H. Papillomavirus infections—a major cause of human cancers. Biochim Biophys Acta. 1996;1288:F55–F58. doi: 10.1016/0304-419x(96)00020-0. [DOI] [PubMed] [Google Scholar]
- 5.Sanclemente G, Gill DK. Human papillomavirus molecular biology and pathogenesis. J Eur Acad Dermatol Venereol. 2002;16:231–240. doi: 10.1046/j.1473-2165.2002.00419.x. [DOI] [PubMed] [Google Scholar]
- 6.Baldwin SB, Wallace DR, Papenfuss MR, Abrahamsen M, Vaught LC, Giuliano AR. Condom use and other factors affecting penile human papillomavirus detection in men attending a sexually transmitted disease clinic. Sex Transm Dis. 2004;31:601–607. doi: 10.1097/01.olq.0000140012.02703.10. [DOI] [PubMed] [Google Scholar]
- 7.Castellsague X, Bosch FX, Munoz N, et al. Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners. N Engl J Med. 2002;346:1105–1112. doi: 10.1056/NEJMoa011688. [DOI] [PubMed] [Google Scholar]
- 8.Castellsague X, Ghaffari A, Daniel RW, Bosch FX, Munoz N, Shah KV. Prevalence of penile human papillomavirus DNA in husbands of women with and without cervical neoplasia: a study in Spain and Colombia. J Infect Dis. 1997;176:353–361. doi: 10.1086/514052. [DOI] [PubMed] [Google Scholar]
- 9.Franceschi S, Castellsague X, Dal Maso L, et al. Prevalence and determinants of human papillomavirus genital infection in men. Br J Cancer. 2002;86:705–711. doi: 10.1038/sj.bjc.6600194. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Hippelainen M, Syrjanen S, Hippelainen M, et al. Prevalence and risk factors of genital human papillomavirus (HPV) infections in healthy males: a study on Finnish conscripts. Sex Transm Dis. 1993;20:321–328. [PubMed] [Google Scholar]
- 11.Lajous M, Mueller N, Cruz-Valdez A, et al. Determinants of prevalence, acquisition, and persistence of human papillomavirus in healthy Mexican military men. Cancer Epidemiol Biomarkers Prev. 2005;14:1710–1716. doi: 10.1158/1055-9965.EPI-04-0926. [DOI] [PubMed] [Google Scholar]
- 12.Shin HR, Franceschi S, Vaccarella S, et al. Prevalence and determinants of genital infection with papillomavirus, in female and male university students in Busan, South Korea. J Infect Dis. 2004;190:468–476. doi: 10.1086/421279. [DOI] [PubMed] [Google Scholar]
- 13.Svare EI, Kjaer SK, Worm AM, Osterlind A, Meijer CJ, van den Brule AJ. Risk factors for genital HPV DNA in men resemble those found in women: a study of male attendees at a Danish STD clinic. Sex Transm Infect. 2002;78:215–218. doi: 10.1136/sti.78.3.215. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Vaccarella S, Lazcano-Ponce E, Castro-Garduno JA, et al. Prevalence and determinants of human papillomavirus infection in men attending vasectomy clinics in Mexico. Int J Cancer. 2006;119:1934–1939. doi: 10.1002/ijc.21992. [DOI] [PubMed] [Google Scholar]
- 15.van der Snoek EM, Niesters HG, Mulder PG, van Doornum GJ, Osterhaus AD, van der Meijden WI. Human papillomavirus infection in men who have sex with men participating in a Dutch gay-cohort study. Sex Transm Dis. 2003;30:639–644. doi: 10.1097/01.OLQ.0000079520.04451.59. [DOI] [PubMed] [Google Scholar]
- 16.Weaver BA, Feng Q, Holmes KK, et al. Evaluation of genital sites and sampling techniques for detection of human papillomavirus DNA in men. J Infect Dis. 2004;189:677–685. doi: 10.1086/381395. [DOI] [PubMed] [Google Scholar]
- 17.Kjaer SK, Munk C, Winther JF, Jorgensen HO, Meijer CJ, van den Brule AJ. Acquisition and persistence of human papillomavirus infection in younger men: a prospective follow-up study among Danish soldiers. Cancer Epidemiol Biomarkers Prev. 2005;14:1528–1533. doi: 10.1158/1055-9965.EPI-04-0754. [DOI] [PubMed] [Google Scholar]
- 18.Nielson CM, Flores R, Harris RB, et al. Human papillomavirus prevalence and type distribution in male anogenital sites and semen. Cancer Epidemiol Biomarkers Prev. 2007;16:1107–1114. doi: 10.1158/1055-9965.EPI-06-0997. [DOI] [PubMed] [Google Scholar]
- 19.Gravitt PE, Manos MM. Polymerase chain reaction-based methods for the detection of human papillomavirus DNA. IARC Sci Publ. 1992;119:121–133. [PubMed] [Google Scholar]
- 20.Gravitt PE, Peyton CL, Apple RJ, Wheeler CM. Genotyping of 27 human papillomavirus types by using L1 consensus PCR products by a single-hybridization, reverse line blot detection method. J Clin Microbiol. 1998;36:3020–3027. doi: 10.1128/jcm.36.10.3020-3027.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Giuliano AR, Nielson CM, Flores R, et al. The optimal anatomic sites for sampling heterosexual men for human papillomavirus (HPV) detection: the HPV Detection in Men Study. J Infect Dis. 2007;196:1146–1152. doi: 10.1086/521629. (in this issue). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Belsley DA, Kuh E, Welsch RE. Regression diagnostics: identifying influential data and sources of collinearity. Hoboken, NJ: John Wiley & Sons; 2004. [Google Scholar]
- 23.Chen X, Ender P, Mitchell M, Wells C. Regression with Stata. Los Angeles: University of California, Los Angeles; 2003. Available at: http://www.ats.ucla.edu/stat/stata/webbooks/reg/default.htm. [Google Scholar]
- 24.Daling JR, Madeleine MM, Johnson LG, et al. Human papillomavirus, smoking, and sexual practices in the etiology of anal cancer. Cancer. 2004;101:270–280. doi: 10.1002/cncr.20365. [DOI] [PubMed] [Google Scholar]
- 25.Daling JR, Madeleine MM, Johnson LG, et al. Penile cancer: importance of circumcision, human papillomavirus and smoking in in situ and invasive disease. Int J Cancer. 2005;116:606–616. doi: 10.1002/ijc.21009. [DOI] [PubMed] [Google Scholar]
- 26.Wen LM, Estcourt CS, Simpson JM, Mindel A. Risk factors for the acquisition of genital warts: are condoms protective? Sex Transm Infect. 1999;75:312–316. doi: 10.1136/sti.75.5.312. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Bosch FX, Castellsague X, Munoz N, et al. Male sexual behavior and human papillomavirus DNA: key risk factors for cervical cancer in Spain. J Natl Cancer Inst. 1996;88:1060–1067. doi: 10.1093/jnci/88.15.1060. [DOI] [PubMed] [Google Scholar]
- 28.Kauth MR, St Lawrence JS, Kelly JA. Reliability of retrospective assessments of sexual HIV risk behavior: a comparison of biweekly, three-month, and twelve-month self-reports. AIDS Educ Prev. 1991;3:207–214. [PubMed] [Google Scholar]
- 29.Van Duynhoven YT, Nagelkerke NJ, Van De Laar MJ. Reliability of self-reported sexual histories: test-retest and interpartner comparison in a sexually transmitted diseases clinic. Sex Transm Dis. 1999;26:33–42. doi: 10.1097/00007435-199901000-00006. [DOI] [PubMed] [Google Scholar]
- 30.Flores R, Papenfuss M, McAnany S, Kornegay J, Gravitt P, Giuliano A. Program and abstracts of the 23rd International Papillomavirus Conference and Clinical Workshop (Prague) International Papillomavirus Society; 2006. Inter-laboratory assessment of the linear array genotyping test for the study of HPV infection in men [abstract P-241] [Google Scholar]