Abstract
Background
Previous studies examining the association between male circumcision (MC) and human papillomavirus (HPV) infections have reported inconsistent results. We used data from the HPV Infection and Transmission Among Couples Through Heterosexual Activity (HITCH) cohort study to examine the association between MC and HPV infections in males and their female sexual partners.
Methods
We enrolled monogamous couples in a longitudinal study between 2005 and 2011 in Montreal, Canada. We used logistic and Poisson regression models with propensity score adjustment to estimate odds ratios (ORs) and rate ratios for the association between MC and the prevalence, transmission, and clearance of HPV infections.
Results
Four hundred thirteen couples were included in our study. The prevalence OR for the association between MC and baseline infections was 0.81 (95% confidence interval [CI], .56–1.16) in males and 1.05 (95% CI, .75–1.46) in females. The incidence rate ratio for infection transmission was 0.59 (95% CI, .16–2.20) for male-to-female transmission and 0.77 (95% CI, .37–1.60) for female-to-male transmission. The clearance rate ratio for clearance of infections was 0.81 (95% CI, .52–1.24).
Conclusions
We found little evidence of an association between MC and HPV infection prevalence, transmission, or clearance in males and females. Further longitudinal couple-based studies are required to investigate this association.
Keywords: circumcision, male circumcision, HPV, human papillomavirus, sexually transmitted infections
In this longitudinal study of 413 heterosexual monogamous couples, there was no strong evidence of a relationship between male circumcision and the prevalence, transmission, or clearance of human papillomavirus infections in males and females.
Human papillomavirus (HPV) is the most prevalent sexually transmitted viral infection [1]. Persistent oncogenic HPV infections may lead to anogenital and head and neck cancers whereas nononcogenic HPV types may cause anogenital warts [2]. Vaccination against HPV protects against up to 9 types (HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58) that are responsible for the greatest proportion of HPV-related morbidity and mortality [3]. Vaccination coverage is expanding globally but is still far from ideal [4]. Most mucosal HPV infections clear spontaneously [5]; however, there is no effective treatment available against persistent HPV infections. Screening for cervical cancer prevents significant HPV-related morbidity and mortality by providing an opportunity for early interventions [6]. Improved knowledge of the determinants of HPV infections may assist in developing effective interventions to prevent infections and HPV-related disease.
Several determinants of persistent HPV infections have been identified, including high-risk sexual behavior, infection with the human immunodeficiency virus, and lack of condom use [7–9]. Various studies have investigated the association between male circumcision (MC) and HPV infections and related disease in males and their female partners, with inconclusive results. In a multinational retrospective study of almost 2000 couples, penile HPV prevalence was significantly lower in circumcised males, and cervical cancer risk was reduced in females who had circumcised partners with multiple sexual partners as compared to a similar, uncircumcised population [10]. Similarly, in a randomized controlled trial conducted in Uganda, circumcised males had reduced penile HPV infections and lower viral loads [11, 12]. As well, penile HPV infections were decreased in circumcised males in a South African study [13], and MC resulted in a lower prevalence of HPV-related penile lesions in a Kenyan trial [14]. In contrast, multiple cohort and cross-sectional studies found no association between MC and the prevalence [15–18], incidence [19, 20], and clearance [19, 20] of HPV infections in males.
The results of some previous studies may have been confounded because of differences in baseline characteristics between uncircumcised and circumcised males and their female partners. For example, males who get circumcised for religious or cultural reasons may have different sexual behavior than uncircumcised males. Randomized controlled trials such as the previously mentioned Ugandan trial did not consider the altered sexual behavior that would result from circumcision of adult males [21]. Sexual behavior is likely to change after voluntary MC, not only due to pain and wound recovery directly after surgery, but also due to an individual’s beliefs, postoperative hygiene, and potential changes in sexual satisfaction [22–25]. Hence, the observed changes in HPV prevalence and transmission after MC could be due to indirect, often short-term consequences of the surgery.
Using data from the HPV Infection and Transmission Among Couples Through Heterosexual Activity (HITCH) cohort study, we evaluated the effect of MC on HPV prevalence, transmission, and clearance in young, recently formed heterosexual couples in Montreal, Canada. We hypothesized that MC would result in lower HPV concordance between couples, lower prevalence and transmission in males and females, and increased clearance in males.
METHODS
Study Design and Population
The HITCH cohort study protocol has been described previously [26]. In brief, the study was conducted between 2005 and 2011 in Montreal, Canada. Female students aged 18–24 years attending a postsecondary institution were enrolled in the study along with their male sexual partners aged ≥18 years. Couples were enrolled if they had initiated sexual contact within the previous 6 months. Females’ subsequent male partners could also enroll in the study.
Females had a baseline visit and 5 follow-up visits every 4–6 months over the course of 24 months, whereas males had a baseline visit and 1 follow-up visit approximately 4 months later. Participants filled out an online questionnaire and provided genital samples at each visit. Abstention from intercourse was requested for 24 hours prior to each visit to prevent contamination of genital samples by deposition. Ethical approval was obtained from the institutional review boards at McGill University, Concordia University, and Centre Hospitalier de l’Université de Montréal.
Data Collection
Information on sociodemographic factors, sexual history, and sexual behavior was collected using a self-administered questionnaire for both males and females. MC status was reported by the female partner and assessed by the research nurse during the male’s clinic visit. The nurse’s assessment was used in case of discordant reporting. Samples from the penis (ie, the glans up to and including the external opening of the meatus, coronal sulcus, penile shaft, and foreskin in uncircumcised males) and scrotum were collected separately. The penile skin swab specimens were collected using emery paper (3M 600A-grit Wetordry™ Tri-M-ite) exfoliation followed by gentle swabbing with a Dacron™ applicator. Vaginal specimens were self-collected by female participants using a Dacron™ swab.
HPV DNA Testing and Typing
Vaginal and penile samples were tested by polymerase chain reaction (PCR) using the Linear Array HPV genotyping assay (Roche Molecular Systems, Alameda, California), which detects the presence of 36 mucosal HPV genotypes (6, 11, 16, 18, 26, 31, 33, 34, 35, 39, 40, 42, 44, 45, 51, 52, 53, 54, 56, 58, 59, 61, 62, 66, 67, 68, 69, 70, 71, 72, 73, 81, 82, 83, 84, and 89) [27]. A β-globin DNA sequence was co-amplified to determine sample adequacy. Samples positive for HPV types 6, 11, 16, 18, 31, 42, and 51 were retested using real-time quantitative PCR with type-specific primers to measure viral load [28–30].
Statistical Analysis
We used data from couples (each female and her first enrolled male partner) who reported being in an ongoing and monogamous sexual relationship. Data from the baseline visit and first follow-up visit were analyzed, and valid baseline data were required from both individuals for them to be included.
We grouped HPV types into 3 subgenera based on phylogenetic homology, oncogenicity, and tissue tropism [31, 32]. Subgenus 1 includes low-risk HPV types 6, 11, 40, 42, 44 and 54; subgenus 2 includes high-risk HPV types 16, 18, 26, 31, 33, 34, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 67, 68, 69, 70, 73 and 82; and subgenus 3 includes commensal HPV types 61, 62, 71, 72, 81, 83, 84 and 89.
We calculated the proportion of couples in which at least 1 partner tested positive and in which both partners tested positive for a given HPV type. Partners who tested positive for the same HPV type were considered to have concordant infections. We calculated the expected frequency of concordant infections and computed the observed to expected (O:E) ratio of concordant infections for each HPV type.
We generated a propensity score for each couple using a logistic regression model [33]. The included independent variables were each male and female’s baseline report of their age, region born (Africa, Asia, Europe, Latin America, Middle East, North America), race (Asian, Black, White, other), highest educational attainment (high school or less, postsecondary), lifetime history of smoking 100 or more cigarettes (yes, no), lifetime history of having a same-sex sexual partner (yes, no), lifetime number of sexual partners (1–3, 4–6, 7–10, ≥11, unknown), lifetime number of vaginal sexual partners (1–2, 3–4, 5–9, ≥10, unknown), age at first vaginal sexual intercourse (≤15 years, 16–18 years, ≥19 years, unknown); each female’s history of being vaccinated against HPV (yes, no); and each couple’s baseline report of marital status (single, common-law, married), condom use (never, irregular, always), and weekly frequency of vaginal sex, as well as if either partner reported having a concurrent sexual partner at a future visit (yes, no). In analyses of prevalence and clearance, the regression model also included a term for if the individual’s partner was positive for a given HPV type at baseline (yes/no).
Our primary outcomes were the prevalence of HPV infections at baseline in males and females, clearance of baseline infections in males only, female-to-male transmission of infections, and male-to-female transmission of infections. Our secondary outcomes included the subgenus-specific analyses of prevalent baseline infections and transmission of infections. Prevalence at baseline was defined as being infected with any given HPV type at visit 1, whereas clearance of that infection was defined as being negative for that same type at visit 2. Transmission was defined as the acquisition of infection with a given HPV type at visit 2 if the partner was positive for the same type at visit 1.
For each outcome, we generated the propensity score in the eligible individuals and restricted our analytic sample to individuals in the region of common support to ensure that participants from both exposure groups were included along the propensity score continuum and thus prevent positivity violation [34].
We estimated the prevalence odds ratio (POR) for HPV infection prevalence at baseline, incidence rate ratio (IRR) for transmission of baseline HPV infections, and clearance rate ratio (CRR) for clearance of baseline HPV infections—along with their corresponding 95% confidence intervals (CIs)—using mixed-effects logistic and Poisson regression models. All regression models used robust variance estimation and had fixed effects at the level of the individual. We adjusted in all models for the propensity score modeled as a restricted cubic spline with 5 interior knots. As sensitivity analyses, we (1) used inverse probability of treatment weighting to estimate the average treatment effect in the study population [35] and (2) compared viral loads in HPV-infected circumcised and uncircumcised males using Wilcoxon rank-sum and Cochran–Mantel–Haenszel tests to ensure that HPV detectability was similar in both groups. All statistical analyses were performed using Stata version 17 software (StataCorp, College Station, Texas).
RESULTS
As shown in Figure 1, the HITCH cohort involved enrollment of 502 females and 548 males. Upon applying our inclusion criteria, 413 couples were eligible for analysis. Table 1 compares the baseline characteristics of male and female participants of these 413 couples. In general, covariates were balanced between uncircumcised males and circumcised males, females with an uncircumcised male partner and females with a circumcised male partner, and couples with an uncircumcised male and couples with a circumcised male. The mean time between visits was 165 days (standard deviation [SD], 68.9 days) among males and 161 days (SD, 63.0 days) among females.
Figure 1.
HITCH study participants and current analysis sample.
Table 1.
Baseline Characteristics of Human Papillomavirus Infection and Transmission Among Couples Through Heterosexual Activity (HITCH) Study Participants, by Male Circumcision Status
| Characteristic | Circumcision Status, No. (%) | |
|---|---|---|
| Males | Uncircumcised (n = 218) | Circumcised (n = 195) |
| Age, y, mean (SD) | 22.3 (3.5) | 22.3 (3.7) |
| Region born | ||
| Africa | 0 (0.0) | 10 (5.1) |
| Asia | 2 (0.9) | 4 (2.1) |
| Europe | 39 (17.9) | 13 (6.7) |
| Latin America | 16 (7.3) | 11 (5.6) |
| Middle East | 3 (1.4) | 20 (10.3) |
| North America | 158 (72.5) | 137 (70.3) |
| Race | ||
| Asian | 8 (3.7) | 6 (3.1) |
| Black | 6 (2.8) | 10 (5.1) |
| Other | 16 (7.3) | 16 (8.2) |
| White | 188 (86.2) | 163 (83.6) |
| Education | ||
| High school or less | 52 (23.9) | 47 (24.1) |
| Postsecondary | 166 (76.2) | 147 (75.4) |
| Smoker | 102 (46.8) | 93 (47.7) |
| No. of lifetime sexual partners, mean (SD) | 8.8 (10.4) | 9.9 (9.4) |
| No. of lifetime vaginal sexual partners, mean (SD) | 7.2 (8.3) | 8.1 (8.2) |
| Age at first vaginal sex, y, mean (SD) | 17.2 (2.2) | 17.2 (2.2) |
| Ever had a same-sex sexual partner | 20 (9.2) | 11 (5.6) |
| Had a concurrent sexual partner at future visit | 15 (6.9) | 21 (10.8) |
| Females | With Uncircumcised Partner (n = 218) | With Circumcised Partner (n = 195) |
| Age, y, mean (SD) | 20.6 (1.8) | 20.7 (1.8) |
| Region born | ||
| Africa | 3 (1.4) | 8 (4.1) |
| Asia | 6 (2.8) | 10 (5.1) |
| Europe or Oceania | 26 (11.9) | 15 (7.7) |
| Latin America | 8 (3.7) | 7 (3.6) |
| Middle East | 3 (1.4) | 10 (5.1) |
| North America | 172 (78.9) | 145 (74.4) |
| Race | ||
| Asian | 20 (9.2) | 10 (5.1) |
| Black | 6 (2.8) | 4 (2.1) |
| Other | 12 (5.5) | 19 (9.7) |
| White | 180 (82.6) | 162 (83.1) |
| Education | ||
| High school or less | 33 (15.1) | 26 (13.3) |
| Postsecondary | 184 (84.4) | 169 (86.7) |
| Smoker | 76 (34.9) | 64 (32.8) |
| No. of lifetime sexual partners, mean (SD) | 8.2 (14.7) | 9.0 (22.0) |
| No. of lifetime vaginal sexual partners, mean (SD) | 5.6 (5.1) | 5.8 (5.0) |
| Age at first vaginal sex, y, mean (SD) | 16.8 (2.0) | 17.2 (2.1) |
| Ever had a same-sex sexual partner | 25 (11.5) | 22 (11.3) |
| Had a concurrent sexual partner at future visit | 34 (15.6) | 25 (12.8) |
| Vaccinated against HPV at baseline | 41 (18.8) | 38 (19.5) |
| Couples | With Uncircumcised Male (n = 218) | With Circumcised Male (n = 195) |
| Marital status | ||
| Single | 139 (63.8) | 144 (73.9) |
| Common-law | 76 (34.9) | 48 (24.6) |
| Married | 3 (1.4) | 3 (1.5) |
| Condom use | ||
| Never | 35 (16.1) | 42 (21.5) |
| Irregularly | 119 (54.6) | 101 (51.8) |
| Always | 51 (23.4) | 43 (22.1) |
| Frequency of sexual acts per week, mean (SD) | 5.0 (3.1) | 5.5 (4.9) |
| Frequency of vaginal sex per week, mean (SD) | 4.3 (2.3) | 4.9 (4.6) |
| Male or female had a concurrent sexual partner at future visit | 45 (20.6) | 44 (22.6) |
| Days since beginning of sexual relationship, mean (SD) | 121.3 (69.1) | 118.7 (58.6) |
Data are presented as No. (%) unless otherwise indicated.
Abbreviations: HPV, human papillomavirus; SD, standard deviation.
Among circumcised and uncircumcised males, 56.8% and 52.6%, respectively, had at least 1 HPV infection present at baseline. A total of 287 HPV infections were detected at baseline in circumcised males and 291 in uncircumcised males, as shown in Table 2. The adjusted POR for the presence of all HPV infections at baseline was 0.81 (95% CI, .56–1.16) when comparing circumcised to uncircumcised males. The adjusted PORs were 0.90 (95% CI, .59–1.37) for subgenera 1 and 3 infections (combined) and 0.87 (95% CI, .59–1.27) for subgenus 2 infections.
Table 2.
Association Between Male Circumcision and Baseline Prevalence of Type-Specific Human Papillomavirus Infections in Males and Females
| Sex | HPV Infections | Uncircumcised (n = 218), No. of Infections (%)a | Circumcised (n = 195), No. of Infections (%)a | Crude POR (95% CI) | Adjusted POR (95% CI) |
|---|---|---|---|---|---|
| Males | Any | 291 (3.8) | 287 (4.5) | 1.21 (.88–1.66) | 0.81 (.56–1.16) |
| Subgenera 1 & 3 | 112 (3.8) | 111 (4.5) | 1.17 (.81–1.69) | 0.90 (.59–1.37) | |
| Subgenus 2 | 179 (3.9) | 176 (4.6) | 1.25 (.89–1.75) | 0.87 (.59–1.27) | |
| Females | Any | 277 (3.7) | 280 (4.4) | 1.24 (.92–1.68) | 1.05 (.75–1.46) |
| Subgenera 1 & 3 | 99 (3.4) | 107 (4.3) | 1.31 (.92–1.87) | 1.07 (.72–1.60) | |
| Subgenus 2 | 178 (3.8) | 173 (4.5) | 1.22 (.88–1.70) | 1.06 (.74–1.52) |
Types detected: HPVs 6, 11, 16, 18, 26, 31, 33, 34, 35, 39, 40, 42, 44, 45, 51, 52, 53, 54, 56, 58, 59, 61, 62, 66, 67, 68, 69, 70, 71, 72, 73, 81, 82, 83, 84, 89. Subgenera 1 and 3: HPVs 6, 11, 40, 42, 44, 54, 61, 62, 71, 72, 81, 83, 84, 89. Subgenus 2: HPVs 16, 18, 26, 31, 33, 34, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 67, 68, 69, 70, 73, 82.
Abbreviations: CI, confidence interval; HPV, human papillomavirus; POR, prevalence odds ratio.
Expressed as the percentage of potential infections, where each individual could have up to 36 infections.
Similarly, 56.3% of females with circumcised partners and 53.1% of females with uncircumcised partners were infected with at least 1 type of HPV at baseline. Females with circumcised partners had a total of 280 baseline infections whereas those with uncircumcised partners had 277. The adjusted PORs were 1.05 (95% CI, .75–1.46) for the presence of all baseline HPV infections, 1.07 (95% CI, .72–1.60) for subgenera 1 and 3 infections, and 1.06 (95% CI, .74–1.52) for subgenus 2 infections when comparing females with a circumcised partner to those without.
HPV-16 was the most prevalent type at baseline in couples with and without a circumcised male, with at least 1 partner being infected in 24.6% of couples with a circumcised male and 15.1% of couples with an uncircumcised male (Supplementary Table 1). We did not observe systematic differences in concordance of infections among couples with and without a circumcised male (Table 3).
Table 3.
Concordance of Type-Specific Human Papillomavirus Infections at Baseline in Couples by Male Circumcision Status
| Proportion of Couples With Concordant Infections | O:E Ratio of Concordant Infections | ||||
|---|---|---|---|---|---|
| HPV Typea | Subgenus | Uncircumcised, % | Circumcised, % | Uncircumcised | Circumcised |
| 6 | 1 | 4.1 | 2.1 | 16.8 | 10.8 |
| 11 | 1 | 0.0 | 1.0 | NA | 97.5 |
| 40 | 1 | 0.9 | 1.0 | 15.6 | 48.8 |
| 42 | 1 | 3.2 | 4.1 | 11.7 | 6.9 |
| 44 | 1 | 0.5 | 2.1 | 27.3 | 24.4 |
| 54 | 1 | 3.7 | 2.8 | 13.4 | 11.8 |
| 16 | 2 | 9.2 | 11.3 | 6.0 | 3.5 |
| 18 | 2 | 1.8 | 1.0 | 13.8 | 12.2 |
| 31 | 2 | 3.2 | 2.1 | 15.3 | 12.2 |
| 33 | 2 | 0.9 | 0.0 | 29.1 | NA |
| 34 | 2 | 0.0 | 0.0 | NA | NA |
| 35 | 2 | 0.9 | 0.5 | 72.7 | 97.5 |
| 39 | 2 | 3.2 | 3.1 | 9.9 | 7.5 |
| 45 | 2 | 0.0 | 1.0 | 0.0 | 24.4 |
| 51 | 2 | 5.0 | 6.2 | 6.3 | 5.4 |
| 52 | 2 | 4.6 | 3.1 | 12.1 | 10.0 |
| 53 | 2 | 2.8 | 6.2 | 11.9 | 7.3 |
| 56 | 2 | 3.2 | 1.5 | 10.7 | 10.4 |
| 58 | 2 | 1.8 | 1.5 | 36.3 | 10.8 |
| 59 | 2 | 4.6 | 4.1 | 9.1 | 13.3 |
| 66 | 2 | 5.0 | 2.6 | 8.8 | 8.7 |
| 67 | 2 | 0.9 | 2.6 | 6.9 | 10.2 |
| 68 | 2 | 1.8 | 1.5 | 36.3 | 19.5 |
| 70 | 2 | 0.5 | 0.0 | 109.0 | 0.0 |
| 73 | 2 | 2.8 | 3.1 | 15.6 | 14.4 |
| 82 | 2 | 0.9 | 3.1 | 29.1 | 18.3 |
| 61 | 3 | 0.5 | 2.6 | 24.2 | 13.5 |
| 62 | 3 | 3.7 | 5.1 | 7.1 | 7.3 |
| 71 | 3 | 0.0 | 0.0 | NA | NA |
| 72 | 3 | 0.0 | 0.0 | NA | 0.0 |
| 81 | 3 | 1.8 | 1.5 | 54.5 | 65.0 |
| 83 | 3 | 0.5 | 2.6 | 109.0 | 27.9 |
| 84 | 3 | 5.5 | 8.2 | 7.4 | 4.8 |
| 89 | 3 | 5.5 | 6.2 | 7.7 | 6.5 |
Abbreviations: HPV, human papillomavirus; NA, not applicable; O:E, observed to expected.
No participants tested positive for either HPV-26 or HPV-69.
There were 14 female-to-male transmission events among uncircumcised males over 15.9 person-years and 14 female-to-male transmission events among circumcised males over 18.1 person-years (Table 4), resulting in an adjusted IRR of 0.77 (95% CI, .37–1.60) for the transmission of any type-specific HPV infection comparing circumcised males to uncircumcised males. The adjusted IRRs were 0.72 (95% CI, .21–2.45) for combined subgenera 1 and 3 infections and 1.19 (95% CI, .44–3.23) for subgenus 2 infections.
Table 4.
Association of Male Circumcision With Transmission of Type-Specific Human Papillomavirus Infections
| Uncircumcised Males | Circumcised Males | ||||||
|---|---|---|---|---|---|---|---|
| Direction | HPV Infections | Events, No. (%)a | Time, PY | Events, No. (%)a | Time, PY | Crude IRR (95% CI) | Adjusted IRR (95% CI) |
| Female-to-male | Any | 14 (40.0) | 15.9 | 14 (29.2) | 18.1 | 0.88 (.43–1.81) | 0.77 (.37–1.60) |
| Subgenera 1 & 3 | 9 (64.3) | 6.2 | 3 (33.3) | 3.1 | 0.67 (.22–2.03) | 0.72 (.21–2.45) | |
| Subgenus 2 | 5 (23.8) | 9.7 | 11 (29.7) | 14.3 | 1.50 (.57–3.92) | 1.19 (.44–3.23) | |
| Male-to-female | Any | 8 (19.1) | 17.8 | 11 (17.7) | 26.2 | 0.94 (.45–1.95) | 0.59 (.16–2.20) |
| Subgenera 1 & 3 | 3 (20.0) | 6.4 | 2 (9.1) | 9.1 | 0.46 (.09–2.40) | 0.23 (.03–1.55) | |
| Subgenus 2 | 4 (16.7) | 10.6 | 2 (13.3) | 6.3 | 0.84 (.18–3.88) | 0.80 (.12–5.38) | |
Types detected: HPVs 6, 11, 16, 18, 26, 31, 33, 34, 35, 39, 40, 42, 44, 45, 51, 52, 53, 54, 56, 58, 59, 61, 62, 66, 67, 68, 69, 70, 71, 72, 73, 81, 82, 83, 84, 89. Subgenera 1 and 3: HPVs 6, 11, 40, 42, 44, 54, 61, 62, 71, 72, 81, 83, 84, 89. Subgenus 2: HPVs 16, 18, 26, 31, 33, 34, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 67, 68, 69, 70, 73, 82.
Abbreviations: CI, confidence interval; HPV, human papillomavirus; IRR, incidence rate ratio; PY, person-years.
Expressed as the percentage of possible transmission events.
Male-to-female transmission events were less common, with 8 events occurring over 17.8 person-years in females with an uncircumcised partner and 11 events occurring over 26.2 person-years in females with a circumcised partner. The adjusted IRR was 0.59 (95% CI, .16–2.20), comparing females with a circumcised partner to those with an uncircumcised partner. Subgenus-specific IRRs were 0.23 (95% CI, .03–1.55) for subgenera 1 and 3 infections and 0.80 (95% CI, .12–5.38) for subgenus 2 infections.
A total of 46 (28.4%) baseline infections were cleared over 76.8 person-years in uncircumcised males, compared to 50 (25.5%) over 83.8 person-years in circumcised males (Table 5). The adjusted CRR of baseline infections was 0.81 (95% CI, .52–1.24), comparing circumcised males to those uncircumcised.
Table 5.
Association of Male Circumcision With Clearance of Type-Specific Human Papillomavirus Infections
| Uncircumcised Males | Circumcised Males | |||||
|---|---|---|---|---|---|---|
| HPV Infections | Events, No. (%)a | Time, PY | Events, No. (%)a | Time, PY | Crude CRR (95% CI) | Adjusted CRR (95% CI) |
| Any | 46 (28.4) | 76.8 | 50 (25.5) | 83.8 | 1.00 (.67–1.49) | 0.81 (.52–1.24) |
Types detected: HPVs 6, 11, 16, 18, 26, 31, 33, 34, 35, 39, 40, 42, 44, 45, 51, 52, 53, 54, 56, 58, 59, 61, 62, 66, 67, 68, 69, 70, 71, 72, 73, 81, 82, 83, 84, 89. Subgenera 1 and 3: HPVs 6, 11, 40, 42, 44, 54, 61, 62, 71, 72, 81, 83, 84, 89. Subgenus 2: HPVs 16, 18, 26, 31, 33, 34, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 67, 68, 69, 70, 73, 82.
Abbreviations: CI, confidence interval; CRR, clearance rate ratio; HPV, human papillomavirus; PY, person-years.
Expressed as the percentage of possible clearance events.
Results from sensitivity analyses using inverse probability of treatment weighting were consistent with those obtained using propensity score adjustment. We observed a POR of 0.90 (95% CI, .60–1.33) for the presence of baseline infections in circumcised vs uncircumcised males, a POR of 1.19 (95% CI, .84–1.69) in females with a circumcised vs uncircumcised partner, an IRR of 0.54 (95% CI, .25–1.19) for female-to-male transmission in circumcised vs uncircumcised males, an IRR of 0.74 (95% CI, .24–2.32) for male-to-female transmission in females with a circumcised vs uncircumcised partner, and a CRR of 0.76 (95% CI, .44–1.31) for the clearance of baseline infections in circumcised vs uncircumcised males (Supplementary Table 2). There were no significant differences in viral load between circumcised and uncircumcised males (Supplementary Table 3).
DISCUSSION
In our study of young, recently formed heterosexual couples in Montreal, most of whom were unvaccinated against HPV, we found no statistical evidence of an association between MC and prevalent HPV infections in males or females nor an association with interpartner infection transmission or clearance.
Several analyses of >2000 males have failed to find a significant association between MC and prevalence of any HPV [15, 18] and high-risk HPVs [15]. Conversely, some studies reported that MC was negatively associated with the prevalence of low-risk HPV types [15, 36]. About half of the larger studies (1000 or more individuals) assessing incidence and clearance did not find a significant association with MC [12, 19, 20, 37], but these were not couple based and did not account for the sexual partner’s HPV status, which is an important factor to consider. Our study did not find a difference between possible, probable, and confirmed high-risk (subgenus 2) and low-risk (subgenera 1 and 3) HPV types.
It is unclear whether MC affects HPV prevalence in females [16, 21, 38]. Only 1 study has assessed the association between MC and female HPV acquisition and clearance [21]. The authors found that MC was associated with decreased incidence and increased clearance of oncogenic HPV infections in 1032 females, but was not associated with incidence of nononcogenic infections. However, as this study was not couple based, it could not adjust for the partner’s HPV positivity.
Anatomical site differences in HPV positivity pose another challenge for studies of HPV and MC. A 2008 study [8] of 379 males found a significant protective effect of MC on HPV prevalence at the glans, but not at the shaft or in a combined-site analysis. Similarly, a 2009 analysis [39] of 463 males found a stronger protective effect of MC toward HPV prevalence in the glans than in the shaft with no association in the scrotum. A 2011 study [40] of 477 males showed that of the males who acquired HPV infections, site-specific positivity varied by MC status; of circumcised HPV-positive males, about three-quarters were positive at the shaft and/or scrotum while just under half were positive at the glans, whereas of uncircumcised HPV-positive males, about two-thirds were positive at the shaft and/or scrotum and another two-thirds were positive at the glans. MC therefore may only confer a protective effect at the glans and distal end of the penis, and this effect would not have been detected in the many studies that combined several sites in their sample, including the HITCH study [9, 26].
Our study had several limitations. As previously mentioned, the HITCH study swabbed multiple sites of the penis and combined them in 1 sample, which limited our ability to assess the site-specific effect of MC. In addition, some HPV detections may have been a result of DNA deposition from sexual activity in the week prior to the visit. Male follow-up was short and female follow-up analysis was restricted to the first 2 visits to be able to adjust for the partner’s type-specific positivity. Hence, our ability to perform interval-censored analyses was limited by having data for 2 time points only. For this reason, we performed Poisson regression, which may have resulted in a dilution of the effect estimate. Furthermore, this limitation prevented us from evaluating the effect of MC on persistent HPV infections, which are of the greatest clinical significance.
Nevertheless, our study had some key strengths. By restricting our analysis to couples with similar propensity scores, our sample was better balanced, especially in important variables such as race, lifetime (vaginal) sexual partners, and same-sex partner history. Adjusting for propensity score minimized confounding bias while accounting for many covariates, thus providing more precision for the effect estimate. The results of our primary analyses were consistent with those using inverse probability of treatment weighting, which estimates the average treatment effect in the study population. Other strengths of our study lie in its couple-based approach; there have been few couple-based HPV studies, none of which assessed in detail the impact of MC on HPV infections in both males and females [16, 21]. HITCH intentionally recruited young couples in the early stages of their sexual relationships when HPV transmission is most likely to occur [7, 41]. Partner visits were at similar time points; this allowed us to adjust for each partner’s HPV positivity, which is the greatest predictor of an individual’s own HPV positivity [42].
More couple-based studies with a long follow-up period would be necessary to properly elucidate the effect of MC on HPV outcomes. MC is one of the most common surgeries performed worldwide [43] and may in time be shown to confer a protective effect as it does for various other sexually transmitted infections [44–46], but it is unlikely to prevent the acquisition of HPV infection on its own. Given that HPV-associated disease poses a significant burden worldwide, especially in low- and middle-income countries [47–50], the determinants of transmission and additional methods to prevent infections must be explored for disease and cancer control.
Supplementary Data
Supplementary materials are available at The Journal of Infectious Diseases online (http://jid.oxfordjournals.org/). Supplementary materials consist of data provided by the author that are published to benefit the reader. The posted materials are not copyedited. The contents of all supplementary data are the sole responsibility of the authors. Questions or messages regarding errors should be addressed to the author.
Supplementary Material
Contributor Information
Samantha B Shapiro, Division of Cancer Epidemiology, Department of Oncology, McGill University, Montréal, Quebec, Canada.
Michel D Wissing, Division of Cancer Epidemiology, Department of Oncology, McGill University, Montréal, Quebec, Canada.
Farzin Khosrow-Khavar, Division of Cancer Epidemiology, Department of Oncology, McGill University, Montréal, Quebec, Canada.
Mariam El-Zein, Division of Cancer Epidemiology, Department of Oncology, McGill University, Montréal, Quebec, Canada.
Ann N Burchell, Department of Family and Community Medicine and MAP Centre for Urban Health Solutions, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Unity Health Toronto, Toronto, Ontario, Canada.
Pierre Paul Tellier, Department of Family Medicine, McGill University, Montréal, Quebec, Canada.
François Coutlée, Division of Cancer Epidemiology, Department of Oncology, McGill University, Montréal, Quebec, Canada; Laboratoire de virologie moléculaire, Centre de recherche du Centre hospitalier de l’Université de Montréal, et Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec, Canada.
Eduardo L Franco, Division of Cancer Epidemiology, Department of Oncology, McGill University, Montréal, Quebec, Canada.
Notes
Acknowledgments. The authors thank the volunteering participants as well as Emilie Comète and Julie Guenoun for the processing and laboratory testing of samples. The authors thank the additional members of the HITCH Cohort Study group: Allita Rodrigues (study coordinator); Hélène Voyer and Véronique Legault (laboratory staff); Gail Kelsall, Suzanne Dumais, Natalia Morykon, and Amelia Rocamora (management of subject participation and specimen collection); Nathalie Slavtcheva (study management); Veronika Moravan (data management); Michel Roger (collaborator); and Vicky D’Anjou-Pomerleau, Jennifer Selinger, Elizabeth Montpetit-Dubrule, Jessica Sammut, Emilie Lapointe, Johanna Bleecker, and Shady Rahayel (study promotion). The authors also thank Melanie Drew (Student Health Services Clinic, Concordia University) and the staff of the Student Health Services Clinics at McGill and Concordia Universities, for their collaboration with HITCH research nurses.
Author contributions. E. L. F. and A. N. B. led the Human Papillomavirus HPV Infection and Transmission Among Couples Through Heterosexual Activity (HITCH) study. P.-P. T. and F. C. acted as co-investigators. F. C. was responsible for the laboratory analysis of biological specimens for HPV DNA testing. E. L. F. and M. D. W. conceptualized the current study. S. B. S., M. D. W., and F. K.-K. devised the analytical methodology. S. B. S. conducted the analyses. S. B. S. and M. D. W. drafted the manuscript. F. K.-K., A. N. B., M. Z., P.-P. T., F. C., and E. L. F. reviewed and edited the manuscript. E. L. F. and M. Z. provided supervision and guidance.
Data availability. The data underlying this article will be shared upon reasonable request to E. L. F.
Ethics approval. All subjects provided written informed consent. The study was conducted in accordance with the principles and articles stipulated by the Tri-Council Policy Statement Ethical Conduct for Research Involving Humans. Ethical approval was obtained from the institutional review boards at McGill University, Concordia University, and Centre Hospitalier de l’Université de Montréal. Ethics renewal approval is requested annually from McGill University (study number A09-M77-04A).
Financial support. This work was supported by the Canadian Institutes of Health Research (grant numbers MOP-68893 and CRN-83320 to E. L. F.) and the United States National Institutes of Health (grant number RO1AI073889 to E. L. F.). Supplementary and unconditional funding support was provided by Merck-Frosst Canada Ltd and Merck & Co Ltd. Validation of viral load assays was supported by the Réseau sida et maladies infectieuses du Fonds de recherche du Québec–Santé. S. B. S. was funded by the Carole Epstein Fellowship, awarded by McGill University. M. D. W. was funded by a fellowship from the Canadian Institutes of Health Research.
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