Abstract
Background:
This study investigated the prevalence of and risk factors for oral human papillomavirus (HPV) infection with multiple genotypes in the United States.
Methods:
Data were from the nationally representative 2009–2012 National Health and Nutrition Examination Survey. This analysis comprised 9257 participants for whom data on oral HPV (37 genotypes) and associated risk factors were available.
Results:
The weighted prevalence of multitype (2–6 types) oral HPV infection was 1.5% (2.5% for men, 0.4% for women) in the whole sample and 19.7% (22.0% for men, 12.1% for women) in those who had any type of oral HPV positivity. Most multitype oral HPV cases (83.8%) harbored one or more oncogenic types. In the adjusted multinominal logistic regression model, being male (relative risk ratio [RRR] = 3.69; 95% confidence interval [CI], 1.57–8.65), being a current cigarette smoker (RRR = 2.57; 95% CI, 1.23–5.36), and having a new sex partner in the past year (RRR = 2.10; 95% CI, 1.03–4.28) were associated with an increased risk of multitype oral HPV infection over single-type HPV infection.
Conclusions:
Men, smokers, and those who had new sexual partners were at a significantly higher risk for multitype oral HPV infection.
Oral human papillomavirus (HPV) infection with oncogenic (ie, high-risk) types is an etiological risk factor for a subset of head and neck cancers.1 In the United States, the HPV-related oropharyngeal cancer incidence has tripled in the past 3 decades (from 0.8 per 100,000 to 2.6 per 100,000).2 In the general US population, the prevalence of HPV infection of any type (henceforth referred to as any-type HPV infection) was 10.1% for men and 3.7% for women, and high-risk HPV-16 was the most common type (1.0%).3 Risk factors for oral HPV infection that have been commonly suggested in literature include cigarette smoking and sexual behaviors, such as having oral sex or a higher number of lifetime sex partners.3–5
Very little is known about oral concurrent HPV infection with multiple genotypes (referred to as multitype oral HPV infection), particularly among generally healthy populations. At the cervical site, concurrent infection with multiple HPV types is relatively common worldwide, with the prevalence ranging from 0.3% to 12.0%.6–8 Natural seroconversion induced by infection with 1 HPV type cannot prevent infection with another HPV type9; in contrast, infection with 1 HPV type increases the likelihood of infection with another type.10,11 In the oral cavity, a cohort study of 324 Finnish pregnant women reported that the prevalence of multitype oral HPV infection varied from 1.7% to 5.6% for different follow-up periods.12 Factors correlated with multitype oral HPV infections were not identified or reported in previous oral HPV studies.
Assessing multitype HPV infection, particularly with high risk types, is important because of its potential unfavorable out comes. At the genital sites, some studies have revealed that people who had multitype genital HPV infection had a lower likelihood of HPV clearance13 and a longer duration of HPV persistence,8 both of which are essential to oncogenesis. Other studies revealed an association between multitype genital HPV infection and an increased risk of high-grade precancerous lesions.6,8 People with multitype HPV infection were also fivefold more likely to have low treatment responses than those with single-type HPV infection.14 In the past 2 decades, the prevalence of multitype HPV infection found in invasive cervical cancers has increased almost fourfold (from 4.0% to 15.7%).15 Although this increase may be due to advances in HPV testing that can detect multiple genotypes, it signifies that multitype HPV infection contributes to the development of cancers. No similar investigations have been done for oral sites yet; however, the evidence from analyses of genital sites suggests multitype oral HPV infection plays a potential role in an increased risk of the development and progression of a subset of head and neck cancer. Despite this potential risk, to our knowledge, no study has reported the prevalence of multitype oral HPV infection in the general population and its associated factors. In this study, we sought to estimate the prevalence of and identify the determinants of multitype oral HPV infection in the US general population.
MATERIALS AND METHODS
Study Design and Population
This study used the US nationally representative 2009–2012 National Health and Nutrition Examination Survey (NHANES) data.16 Complex, multistage, and probability sampling methods were used to recruit participants who were noninstitutionalized US citizens. The NHANES 2011–2012 oversampled the Asian population in addition to oversampling Hispanics, non-Hispanic Blacks, older adults (≥60 years), and low-income people as did the NHANES 2009–2010. Further details regarding study design and population are described on the NHANES website.16 Respectively, 10,537 and 9756 people were selected for in-home interviews in the 2009–2010 and 2011–2012 cohorts. Of those, 10,253 and 9338, respectively, completed health examinations at specially designed and equipped mobile centers; thus, the 2 cohorts comprised a total of 19,591 participants. Our analysis was restricted to 9257 participants in the 2 cohorts who were randomly selected to a laboratory subsample and thus had available oral HPV results.
Oral Specimens and HPV Genotyping
Oral rinse specimens were collected by dental examiners at the mobile centers. Participants were asked to swish a 10-mL sample of Scope mouthwash or a sterile saline solution (if preferred by participants) in their mouth and then expectorate the sample into a sterile collection cup. The samples were then processed, stored, and transferred to The Ohio State University’s Gillison laboratory for HPV DNA testing. This test could detect 37 HPV types, including 16 low risk (6, 11, 40, 42, 54, 55, 61, 62, 64, 71, 72, 81, 82 sub type IS39, 83, 84, and 89 [cp6108]), and 21 high risk (16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 67, 68, 69, 70, 73, and 82, which belong to group 1, 2A, and 2B in the classification of International Agency for Research on Cancer).17,18 Samples that were negative for β-globin (2 cases) were considered of inadequate quality for HPV results and were recoded as missing values.
Outcome: Multitype Oral HPV Infection
Unless otherwise specified, multitype oral HPV infection in this analysis is defined as infection with 2 or more HPV types using the aforementioned HPV genotyping test.
Sociodemographic and Behavioral Characteristics
Data about sociodemographic characteristics used in this analysis were obtained from a household interviewer-administered interview. These included age, gender, race/ethnicity, education, income-to-poverty ratio, and marital status. Data about behavior characteristics were obtained from an audio-computer–assisted self interview at the mobile examination centers. These characteristics were cigarette smoking status, average number of alcoholic drinks consumed in the past year, former and current use of marijuana, sexual orientation, oral sexual behaviors, and vaginal sexual behaviors. In this analysis, the number of lifetime any-sex partners was the sum of all reported numbers of different partners for oral sex, vaginal sex, and anal sex. Other characteristics examined were the current use of birth control or female hormones, overall oral health, number of teeth lost, history of genital herpes or genital warts, and HPV vaccination status.
Statistical Analysis
To take into account differential selection probabilities and geographic clustering, all analyses followed design-based analysis procedures, using Stata 11 (StataCorp LP, College Station, TX). Combining the NHANES 2009–2010 and 2011–2012 to form a 4-year data set affords greater precision (ie, smaller sampling errors) in estimates. According to the NHANES instructions,16 the weight for the 2 survey cycles used in this analysis was the 2-year medical examination sample weight divided by 2.
Frequency distributions were used to examine the weighted prevalence of oral HPV infection with any type, a single type, and multiple types. We also preliminarily assessed the independence of infection with an additional HPV type by estimating the observed-to-expected ratios. If independent, the observed numbers of cases having an additional HPV type would mirror a Poisson distribution; thus, the observed-to-expected ratios would not be different from one. We concurrently evaluated and compared sociodemographic or behavioral characteristics associated with multitype, single-type, and no oral HPV infection using multinominal logistic regression models. The multinominal logistic model has been shown to have smaller standard errors than multiple separate binomial logistic regression models that compare each category with a reference. We were mainly interested in factors that potentially elevated or reduced the risk for multitype oral HPV infection over single-type infection (ie, when single-type infection was the comparison group); thus, this is the main focus of our report. The selection of variables for adjustment in multivariable models was based on a priori knowledge of risk factors for oral HPV infection previously reported in the literature. To prevent multicollinearity, we examined each sexual behavioral variable in a separate multivariable model. Unadjusted and adjusted associations with oral HPV infection were assessed using the survey design-adjusted Wald F test. Relative risk ratios (RRRs) and 95% confidence intervals (CIs) were reported. We also examined interaction terms between cohorts or sex and other independent variables in the multivariable models.
RESULTS
Prevalence of Multitype Oral HPV Infection
The overall prevalence of multitype (≥2 types) oral HPV infection was 1.5% (95% CI, 1.2%–1.8%) in the whole sample and 19.7% (95% CI, 16.4%–23.6%) in those who had any-type oral HPV infection (Table 1). Men had a significantly higher prevalence of oral multitype HPV infection (2.5%; 95% CI, 2.1%–3.1%) than women (0.4%; 95% CI, 0.2%–0.8%; P < .001). Most multitype oral HPV cases (83.8%) harbored 1 or more oncogenic types, and 22.1% of multitype oral HPV cases included HPV 16. The most common 2-type HPV concurrences were pair 56 and 66 (14/154; 10.3%; 95% CI, 5.1%–19.7%) and pair 62 and 72 (8/154; 6.0%; 95% CI, 2.5%–13.3%). The 56 and 66 pair was also pre-dominantly present in cases concurrently infected with 3 or more HPV types (5/33; 7.9%; 95% CI, 2.5%–22.1%). Among those who had HPV 16 infection (n = 217), 3.4% were infected with type 16 only (ie, single-type infection), 14.7% were infected with an additional type, and 51.8% were infected with 2 or more additional types. The observed-to-expected ratios by numbers of HPV types infected did not have a clear and significant trend (Table 2); thus, we did not examine this issue further.
TABLE 1.
Weighted Oral HPV Prevalence, NHANES 2009–2012
| Unweighted Counts | Prevalence in Total Cohorts, % (95% CI) | Prevalence Among HPV-Positive With Any Type, % (95% CI) | Prevalence Among Multitype HPV Infection (≥2 Types), % (95% CI) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| HPV Infection With | Total | Male | Female | Total (9257) | Male (4601) | Female (4656) | Total (747) | Male (561) | Female (186) | Total (154) | Male (132) | Female (22) |
| Any type | 747 | 561 | 186 | 7.4 (6.5–8.4) | 11.4 (9.9–13.2) | 3.4 (2.8–4.2) | — — | — — | — — | — — | — — | — — |
| Any single type | 593 | 429 | 164 | 6.0 (5.1–6.9) | 8.9 (7.5–10.5) | 3.0 (2.4–3.7) | 80.3 (76.4–83.7) | 78.0(73.7–81.7) | 87.9 (78.7–93.5) | — — | — — | — — |
| ≥2 types | 154 | 132 | 22 | 1.5 (1.2–1.8) | 2.5 (2.1–3.1) | 0.4 (0.2–0.8) | 19.7(16.4–23.6) | 22.0(18.3–26.3) | 12.1 (6.5–21.4) | — — | — — | — — |
| Any 2 types | 121 | 102 | 19 | 1.1 (0.9–1.4) | 1.9 (1.5–2.3) | 0.4 (0.2–0.7) | 15.1 (12.2–18.6) | 16.3(13.1–20.2) | 11.0 (5.9–19.5) | 76.5 (67.0–84.0) | 74.2 (63.6–82.5) | 90.9 (76.4–96.8) |
| Any 3 types | 23 | 20 | 3 | 0.2 (0.1–0.4) | 0.4 (0.2–0.7) | <0.1 (<0.1–0.1) | 2.7 (1.4–5.2) | 3.2 (1.6–6.3) | 1.1 (0.3–3.5) | 13.8 (7.3–24.6) | 14.5 (7.3–27.0) | 9.1 (3.2–23.6) |
| Any 4–6 types | 10 | 10 | 0 | 0.1 (<0.1–0.3) | 0.3 (0.1–0.7) | 0.0 | 1.9 (0.8–.4) | 2.5 (1.1–5.6) | 0.0 | 9.7 (4.2–20.9) | 11.3 (4.9–23.8) | 0.0 |
| ≥2 types, with at least one high-risk type | 126 | 108 | 18 | 1.2 (1.0–1.5) | 2.1 (1.7–2.7) | 0.3 (0.2–0.7) | 16.5 (13.4–20.2) | 18.6 (14.9–22.8) | 9.8 (4.7–19.2) | 83.8 (75.1–89.9) | 84.3 (74.3–90.9) | 81.1 (50.7–94.7) |
| ≥2 types, with HPV 16 | 26 | 25 | 1 | 0.3 (0.2–0.6) | 0.6 (0.3–1.1) | <0.1 (<0.1–0.5) | 4.4 (2.4–7.9) | 5.1 (2.7–9.4) | 2.0 (0.3–13.7) | 22.1 (12.1–37.1) | 23.0 (12.4–38.9) | 16.6 (2.1–65.0) |
TABLE 2.
Observed-to-Expected Ratios of Multitype Oral HPV Infection, NHANES 2009–2012, Total Unweighted n = 9257
| No. HPV Types | Observed Number (O) | Poisson Expected Number (E) | O/E (95% CI) |
|---|---|---|---|
| 0 | 747 | 794.2 | 0.94 (0.87–1.01) |
| 1 | 593 | 501.8 | 1.18(1.09–1.28) |
| 2 | 121 | 158.5 | 0.76(0.63–0.91) |
| 3 | 23 | 33.4 | 0.69 (0.44–1.00) |
| 4–6 | 10 | 5.3 | 1.89 (0.90–3.24) |
Factors Associated With Multitype Oral HPV Infection in Univariate Multinominal Logistic Regression Models
Table 3 displays bivariate unadjusted associations between multitype oral HPV infection and sociodemographic and behavioral factors, using single-type oral HPV infection as a reference category (for multitype infection versus no infection and single-type infection versus no infection, please see Supplementary Table 1, http://links.lww.com/OLQ/A145). There was no significant difference in the prevalence of multitype oral HPV infection by age or between the 2 NHANES cohorts of interest. Behavioral and health factors associated with a higher prevalence of multitype over single-type oral HPV infection included current cigarette smoking (RRR, 2.52; 95% CI, 1.39–4.57), having a new any-sex partner in the past year (RRR, 1.82; 95% CI, 1.01–3.29), current use of birth control or female hormones (RRR, 5.65; 95% CI, 1.15–27.62), poorer self-rated overall oral health (RRR, 1.70; 95% CI, 1.12–2.61), and a higher number of teeth lost (P trend = 0.003). Sexual behavior factors, including ever performing oral sex, the number of lifetime oral sex partners, and the number of lifetime any-sex partners, were significantly associated with multitype oral HPV infection when compared with no oral HPV infection (Supplementary Table 1); however, these associations were not statistically significant when compared with single-type oral HPV infection. Alcohol use in the past year, marijuana use, and the completion of three doses of HPV vaccines were not associated with multitype HPVoral infection.
TABLE 3.
Unadjusted Associations Between Multitype* Oral HPV Infection (Compared to Single-Type HPV Infection) and Sociodemographic and Behavioral Characteristics, NHANES 2009–2012
| Multitype Oral HPV Infection | |||||
|---|---|---|---|---|---|
| Characteristics | Unweighted Counts† (Weighted % in Total Cohorts) | Unweighted Counts | Weighted % Among HPV-Positive With Any Type (95% CI) | Unadjusted Relative Risk Ratios, Multitype vs Single-Type (95% CI) | P (for Trend) |
| Total | 9257 | 154 | 19.7 (16.4–23.6) | ||
| Cohort | |||||
| 2009–2010 | 4847 (49.1) | 76 | 8.1 (6.3–10.5) | 1 | |
| 2011–2012 | 4410 (50.9) | 78 | 11.6 (8.9–15.0) | 1.45 (0.92–2.27) | 0.104 |
| Age | (0.224) | ||||
| 18–29 | 2415 (24.9) | 33 | 18.0 (11.3–27.4) | 1 | |
| 30–39 | 1769 (19.4) | 20 | 16.4 (10.5–24.7) | 0.89 (0.41–1.93) | 0.770 |
| 40–49 | 1783 (21.1) | 28 | 17.6 (10.4–28.2) | 0.97 (0.51–1.87) | 0.932 |
| 50–59 | 1646 (20.3) | 37 | 24.1 (17.2–32.6) | 1.45 (0.79–2.67) | 0.227 |
| 60–69 | 1644 (14.3) | 36 | 21.2 (14.1–30.7) | 1.23 (0.56–2.72) | 0.602 |
| Sex | |||||
| Female | 4656 (50.1) | 22 | 12.1 (6.5–21.4) | 1 | |
| Male | 4601 (49.9) | 132 | 22.0 (18.3–26.3) | 2.06(1.02–4.14) | 0.043 |
| Race/ethnicity | |||||
| White, non-Hispanic | 3516 (65.0) | 52 | 18.6 (14.0–24.4) | 1 | |
| Mexican American | 1495 (9.0) | 13 | 11.1 (7.2–16.8) | 0.55 (0.33–0.90) | 0.018 |
| Other Hispanic | 1003 (6.1) | 17 | 20.9 (12.7–32.3) | 1.15 (0.58–2.28) | 0.673 |
| Black, non-Hispanic | 2163 (12.1) | 62 | 25.9 (20.7–31.8) | 1.53 (0.95–2.44) | 0.077 |
| Other race | 1080 (7.8) | 10 | 25.8 (11.8–47.5) | 1.52 (0.56–4.14) | 0.401 |
| Education | (0.655) | ||||
| Less than high school | 2297 (16.8) | 44 | 20.2 (12.8–30.3) | 1 | |
| High school or equivalent | 2053 (21.3) | 41 | 21.8 (15.7–29.4) | 1.11 (0.61–2.02) | 0.738 |
| Some college or higher | 4898 (61.9) | 69 | 18.5 (13.8–24.3) | 0.90 (0.45–1.80) | 0.756 |
| Income-to-poverty ratio‡ | (0.044) | ||||
| < 1.0 | 2174 (17.2) | 43 | 22.1 (16.5–28.9) | 1 | |
| ≥ 1.0 to <2.0 | 2214 (19.8) | 55 | 25.8 (19.1–33.9) | 1.23 (0.75–2.01) | 0.398 |
| ≥ 2.0 to <3.0 | 1084 (13.8) | 19 | 26.7 (17.8–38.0) | 1.29 (0.80–2.09) | 0.292 |
| ≥ 3.0 | 2987 (49.2) | 26 | 14.3 (9.2–21.6) | 0.59 (0.30–1.16) | 0.124 |
| Marital status | |||||
| Never married | 1985 (21.4) | 39 | 27.4 (19.0–37.9) | 1 | |
| Married/living with partner | 5129 (63.1) | 66 | 14.7 (9.8–21.3) | 0.46 (0.23–0.91) | 0.026 |
| Widowed/divorced/separated | 1574 (15.5) | 48 | 27.6 (19.7–37.3) | 1.01 (0.48–2.11) | 0.978 |
| Cigarette smoking§ | |||||
| Never/former | 5294 (72.2) | 43 | 12.4 (8.3–18.2) | 1 | |
| Current | 2154 (27.8) | 77 | 26.3 (20.5–33.1) | 2.52 (1.39–4.57) | 0.003 (0.931) |
| Alcohol use in past year, average no. drinks/week | |||||
| 0 | 2282 (22.6) | 32 | 19.9 (11.6–32.0) | 1 | |
| > 0 to <1 | 2561 (30.3) | 31 | 20.5 (14.4–28.2) | 1.02 (0.52–2.00) | 0.944 |
| 1 to <7 | 2081 (29.2) | 42 | 22.8 (14.9–33.2) | 1.19(0.48–2.95) | 0.704 |
| 7 to <14 | 665 (9.9) | 19 | 19.6 (11.2–32.0) | 1.10(0.40–2.99) | 0.849 |
| ≥ 14 | 610 (8.0) | 20 | 20.9 (10.4–37.6) | 0.98(0.31–3.05) | 0.965 |
| Marijuana use¶ | (0.553) | ||||
| Never | 3206 (41.4) | 31 | 14.6 (9.4–21.9) | 1 | |
| Former | 2553 (44.5) | 50 | 23.7 (17.3–31.6) | 1.83 (0.91–3.66) | 0.088 |
| Current | 1010(14.1) | 26 | 18.0 (10.2–29.6) | 1.28(0.53–3.11) | 0.569 |
| Sexual orientation|| | |||||
| Never had sex | 471 (5.0) | 3 | 26.4 (8.2–59.1) | 1.49 (0.36–6.21) | 0.572 |
| Homosexual/bisexual | 294 (4.4) | 8 | 25.8 (9.2–54.5) | 1.45 (0.39–5.37) | 0.570 |
| Heterosexual | 5954 (90.6) | 95 | 19.4 (15.3–24.2) | 1 | |
| Ever performed oral sex | |||||
| No | 1914(15.4) | 18 | 17.4 (10.1–28.4) | 1 | |
| Yes | 6322 (84.6) | 123 | 20.7 (17.0–24.9) | 1.24 (0.65–2.36) | 0.512 |
| No. lifetime oral sex partners** | (0.054) | ||||
| 0 | 1914(17.4) | 18 | 17.4 (10.1–28.4) | 1 | |
| 1−3 | 3157(45.9) | 23 | 13.6 (7.9–22.6) | 0.75 (0.30–1.86) | 0.519 |
| 4–10 | 1546 (24.8) | 36 | 19.9 (14.1–27.3) | 1.18 (0.64–2.16) | 0.595 |
| ≥ 11 | 711 (11.9) | 38 | 26.3 (18.6–35.8) | 1.69 (0.77–3.69) | 0.182 |
| No. oral sex partners in past year||** | (0.231) | ||||
| 0 | 3171 (38.0) | 35 | 20.2 (12.4–31.1) | 1 | |
| 1 | 3300 (51.5) | 42 | 15.6 (10.8–22.0) | 0.73 (0.34–1.56) | 0.404 |
| ≥ 2 | 823 (10.5) | 35 | 29.9 (20.7–41.1) | 1.69 (0.79–3.61) | 0.172 |
| Barrier use during oral sex in past year||†† | |||||
| No oral sex in previous year | 3171 (38.2) | 35 | 20.2 (12.4–31.1) | 1.03 (0.51–2.08) | 0.926 |
| Never/rarely | 3580 (56.7) | 66 | 19.7 (15.1–25.3) | 1 | |
| Usually/always | 470 (5.1) | 11 | 18.9 (10.3–32.1) | 0.95 (0.48–1.88) | 0.876 |
| No. lifetime any-sex partners | (0.053) | ||||
| 0 | 454 (4.2) | 2 | 19.4 (4.5–54.8) | 1 | |
| 1−3 | 2480 (30.0) | 13 | 10.3 (4.9–20.2) | 0.48 (0.09–2.55) | 0.375 |
| 4–10 | 2954 (37.6) | 41 | 16.4 (10.6–24.5) | 0.82 (0.16–4.29) | 0.804 |
| ≥ 11 | 2273 (28.2) | 82 | 23.8 (18.2–30.5) | 1.30(0.24–6.98) | 0.750 |
| No. any-sex partners in past year|| | (0.249) | ||||
| 0 | 1143 (15.8) | 10 | 23.3 (10.8–43.1) | 1 | |
| 1 | 4267 (67.2) | 57 | 17.3 (12.3–23.7) | 0.69 (0.24–2.00) | 0.481 |
| ≥ 2 | 1340 (17.0) | 40 | 26.8 (19.1–36.4) | 1.21 (0.47–3.09) | 0.683 |
| Had a new any-sex partner in past year|| | |||||
| No | 4553 (82.7) | 64 | 16.9 (12.5–22.4) | 1 | |
| Yes | 1084 (17.3) | 34 | 27.0 (18.5–37.5) | 1.82(1.01–3.29) | 0.049 |
| History of genital herpes/genital warts|| | |||||
| No | 5951 (91.9) | 94 | 18.8 (14.5–24.0) | 1 | |
| Yes | 434 (8.1) | 10 | 27.3 (13.1–48.3) | 1.62 (0.57–4.63) | 0.357 |
| Current use of birth control or female hormones‡‡ | |||||
| No | 3663 (85.14) | 13 | 8.8 (3.7–19.7) | 1 | |
| Yes | 494 (14.86) | 6 | 36.0 (13.6–66.7) | 5.81 (1.19–28.51) | 0.031 |
| Overall oral health§§ | |||||
| Good-excellent | 5202 (72.6) | 71 | 17.4 (13.2–22.7) | 1 | |
| Poor-fair | 2639 (27.4) | 67 | 26.5 (21.3–32.3) | 1.70(1.12–2.61) | 0.015 |
| No. teeth lost¶¶ | (0.003) | ||||
| 0 | 608 (6.8) | 5 | 8.5 (3.2–20.9) | 1 | |
| 1−5 | 4037 (55.6) | 45 | 16.2 (11.3–22.8) | 2.09 (0.69–6.32) | 0.185 |
| ≥ 6 | 3345 (37.6) | 87 | 26.3 (21.4–31.7) | 3.84(1.19–12.32) | 0.025 |
| HPV vaccination|||| | |||||
| Never | 5014(93.8) | 66 | 19.3 (14.1–25.9) | 1 | (0.418) |
| Completed 1−2 doses | 168 (2.3) | 3 | 28.9 (7.2–68.1) | 1.70 (0.33–8.64) | 0.513 |
| Completed 3 doses | 214 (3.9) | 3 | 32.7 (6.7–76.6) | 2.02(0.29–14.00) | 0.463 |
| HIV | |||||
| Negative | 7065 (99.6) | 103 | 19.6 (16.0–23.9) | 1 | |
| Positive | 38 (0.4) | 3 | 29.9 (7.6–68.9) | 1.74 (0.33–9.16) | 0.500 |
Multitype oral HPV infection is infection with any two or more HPV genotypes.
Analyses were restricted to individuals aged 18–69 years, for whom data on oral HPV results were available except otherwise specified (unweighted n = 9257).
Index for the ratio of family income-to-poverty threshold, specific to family size, year, and state. Avalue <1 denotes a family income below the poverty threshold.
Current smokers included those who had smoked a cigarette in the past 30 days.
Current marijuana users included those who had used it at least once in the past 30 days.
Analyses were restricted to individuals aged 18–59 years, for whom data on sexual behaviors were available.
Included partners of both sexes.
Original responses on a 4-point Likert scale were dichotomized.
Analyses were restricted to females aged 18–69 years, for whom data on birth control/hormone use were available (unweighted n = 6081).
Self-rated overall oral health was measured by the question, “Overall, how would you rate the health of your teeth and gums?” The original response on a 5-point Likert scale, from 1, excellent to 5, poor, was dichotomized into poor-fair and good-excellent.
Analysis was restricted to participants aged 18–69 years who underwent oral examination (unweighted n = 9257) by registered dental hygienists (cohort 2009–2010) or a dentist (cohort 2011–2012). A tooth was counted as lost if it was recorded as “dental implant,” “tooth not present,” or “permanent dental root fragment present.”
Analyses were restricted to females aged 18–59 years, for whom data on HPV vaccination were available (unweighted n = 7613).
Factors Associated With Multitype Oral HPV Infection in Multivariable Nominal Logistic Regression Models
In the model with reference to the group of single-type oral HPVinfection (Table 4), being male (RRR, 3.69; 95%CI, 1.57–8.65), current cigarette smoking (RRR, 2.57; 95% CI, 1.23–5.36), and having a new any-sex partner in the past year (RRR, 2.10; 95% CI, 1.03–4.28) were associated with multitype oral HPV infection after controlling for cohort and age, whereas self-rated overall oral health was not (P = .805). There was no interaction between sex and any other variables in this model (P values for interaction were .108 for smoking and > 0.350 for other variables; see Supplementary Table 2, http://links.lww.com/OLQ/A145). In the model with reference to the group of no oral HPV infection, men were much more likely than females to have oral multitype HPV infection (RRR, 11.19; 95% CI, 4.64–26.99); also, older age, smoking, and having a new any-sex partner in the past year were associated with increased odds of multitype oral HPV infection.
TABLE 4.
Adjusted Associations Between Oral HPV Infection and Demographic or Behavioral Factors in the US Population Aged 18 to 59 Years, Unweighted n = 4515
| Single-Type vs No Infection | Multitype* vs No Infection | Multitype* vs Single-Type | ||||
|---|---|---|---|---|---|---|
| Variables | RRR (95% CI) | P (for Trend) | RRR (95% CI) | P (for Trend) | RRR (95% CI) | P (for Trend) |
| Cohort | ||||||
| 2009–2010 | 1 | 1 | 1 | |||
| 2011–2012 | 0.92(0.63–1.33) | 0.639 | 1.43 (0.88–2.34) | 0.145 | 1.57(0.91–2.69) | 0.102 |
| Age | (0.188) | (0.023) | (0.237) | |||
| 18–29 | 1 | 1 | 1 | |||
| 30–39 | 1.30(0.68–2.49) | 0.419 | 1.54 (0.54–4.39) | 0.408 | 1.19(0.37–3.85) | 0.771 |
| 40–49 | 1.13 (0.54–2.38) | 0.736 | 1.70 (0.85–3.41) | 0.130 | 1.50(0.61–3.73) | 0.368 |
| 50–59 | 1.62(0.95–2.74) | 0.073 | 2.65 (0.89–7.89) | 0.079 | 1.64 (0.51–5.31) | 0.398 |
| Sex | ||||||
| Female | 1 | 1 | 1 | |||
| Male | 3.04 (2.05–4.51) | <0.001 | 11.19(4.64–26.99) | <0.001 | 3.69(1.57–8.65) | 0.004 |
| Cigarette smoking† | ||||||
| Never/former | 1 | 1 | 1 | |||
| Current | 2.11 (1.59–2.80) | <0.001 | 5.42 (2.43–12.13) | <0.001 | 2.57(1.23–5.36) | 0.013 |
| Had a new any-sex partner in past year | ||||||
| No | 1 | 1 | 1 | |||
| Yes | 1.16 (0.68–1.98) | 0.587 | 2.43 (1.45–4.07) | 0.001 | 2.10(1.03–4.28) | 0.042 |
| Overall oral health‡ | ||||||
| Poor-fair | 0.78 (0.58–1.06) | 0.84(0.47–1.52) | 1.08(0.59–1.99) | |||
| Good-excellent | 1 | 0.108 | 1 | 0.560 | 1 | 0.805 |
Multitype oral HPV infection is infection with any 2 or more genotypes.
Current smokers included those who had smoked a cigarette in the past 30 days.
Self-rated overall oral health was measured by the question, “Overall, how would you rate the health of your teeth and gums?” The original response on a 5-point Likert scale, from 1, excellent to 5, poor, was dichotomized into poor-fair and good-excellent.
DISCUSSION
To our knowledge, this is the first population-based study to report the prevalence of oral HPV infection with multiple types in the United States. Compared with the multitype genital HPV prevalence in HPV-positive women that ranged from 18.5% to 46.0% in the United States and worldwide,6,7 multitype oral HPV infection in the US appears less prevalent (22.0% in HPV-positive men and 12.1% in HPV-positive women). However, most multitype oral HPV infection includes at least one high-risk type. Our analysis showed no evidence that multitype oral HPV infection occurred more commonly than would be expected by chance alone. However, as noted by Plummer et al,19 this result has little meaning for interpretation because the expected number of multitype infection cases was calculated from a simplistic Poisson probability model that assumes that all HPV types are independent even though they actually share common risk factors for transmission.
Although a systematic review of literature worldwide showed that the prevalence of any-type oral HPV was nearly the same for men and women,20 the prevalence of oral HPV infection in the US was significantly higher in men than in women.3 Our study showed that men were approximately 3.7 times more likely than women to have multitype oral HPV infection. It seems that men are not only more susceptible to getting oral HPV infection but also more likely than women to get multiple oral HPV genotypes. As explained by Gillison et al,3 a higher oral HPV prevalence in men could be plausibly due to a higher probability of HPV transmission from women through oral sex, differences in sex hormones that might influence the duration of oral HPV infection, or the protective effect of seroconversion in women after responding to genital infection. The increased likelihood of having any-type or multitype oral HPV infection in men might explain why the incidence of oropharyngeal cancers in men was approximately 3–4 times higher than that in women.2 An implication of the higher prevalence of multitype oral HPV in men is a message for promoting HPV vaccination in boys and young men. Some data have suggested that HPV vaccination offers protection against oral HPV infection with vaccine-target types.21 Thus, this information can be used to encourage parents to vaccinate their boys to prevent oral HPV infection and subsequent HPV-related oropharyngeal cancers.
Although older ages is an important risk factor for HPV-related cancers, age groups did not have a clear association with multitype oral HPV infection. People at older ages might have had a reduced immune response to clear HPV, while younger people might have had more sexual partners or activities and thus more likely to expose to different types of HPV.
In univariate models, ever performed oral sex, a higher number of lifetime oral-sex partners, and a higher number of lifetime any-sex partners were associated with the increased likelihood of single-type and multitype oral HPV infection in reference to the group with no HPV infection; however, these variables did not increase the risk of multitype oral HPV infection over single-type oral HPV infection. This result is not surprising. Although oral sexual behaviors have been thought to be the main route of oral HPV acquisition, this association was found in some studies3,4 but not in some others.5,22 This result is also similar to a finding in a pooled analysis of genital multiple HPV infection in women from 11 areas worldwide, which showed that the lifetime number of sexual partners was associated with HPV positivity, but the association was not statistically significant when comparing multitype versus single-type infection.23 These results suggest that sexual behaviors, albeit being important risk factors for vaginal HPV infection, may not be a strong risk factor for oral HPV infection.
Having a new any-sex partner in the past year was associated with multitype oral HPV infection. With a new sex partner, the participant might have been exposed to 1 or more HPV genotypes. However, given the cross-sectional nature of the survey, it should be noted that the detection of these multiple genotypes did not guarantee established infections (i.e., one or more genotypes might be a contamination from the new partner).
Besides its direct carcinogenic effect, smoking has widely been associated with oral HPV infection3,5,24 and oral HPV persistence24 in oral HPV literature. In a cohort study of 1626 men in 3 countries, including the US, smoking was significantly associated with the new acquisition of oral oncogenic HPV, whereas age and reported sexual behaviors were not.25 In our analysis, not only did being a current smoker increase the risk of overall oral HPV infection (ie, single-type or multitype infection versus no infection), it also increased the risk of multitype oral HPV infection over single-type oral HPV infection. These associations were statistically significant after adjusting for other demographic or behavioral factors, suggesting that the effect of smoking is independent from other factors such as sex or sexual behaviors. The mechanism by which HPV infection at different body sites is related to cigarette smoking is not well understood. Cigarette smoking has been shown to have both systemic and local immunosuppressive effects26,27 and thus may facilitate oral HPV acquisition and persistence. Smoking may also increase cellular proliferation and turnover, which subsequently increase HPV replication, or may lead to an increase of proinflammatory factors that alter the function of immune cells.28
In the oral and oropharyngeal areas, poor oral health could be a risk factor for oral HPV infection, independently or possibly as a result of smoking. Strong clinical evidence shows that cigarette smokers are at a significantly higher risk of oral diseases, such as inflammatory damage to periodontal tissues or chronic periodontitis,29 that possibly increase the susceptibility of the epithelium to HPV infection. In our previous study using a related data set, poorer self-rated oral health and a higher number of teeth lost were associated with any-type oral HPV infection, independent from the effect of smoking.30 In the current analysis, although poorer self-rated oral health was associated with oral HPV infection in general (ie, when compared with the no-infection group), it did not increase the risk of multitype oral HPV infection compared with single-type oral HPV infection.
The cross-sectional nature of this population-based data precludes causal inferences. However, about 70% of cervical HPV infections clear within 1 year and 90% clear within 2 years; similar clearance rates have been observed for oral HPV infections.31 Thus, it is reasonable to presume that most detected oral HPV infections were recent. Oral swish might not be the best method for collecting samples (eg, compared with oral gargle or swab), particularly when HPV shedding was low. Therefore, oral HPV prevalence might have been underestimated. The recall biases and misclassification might occur in self-reporting behaviors. Despite the large number of NHANES participants in this analysis, the sample sizes for some subgroup analyses were moderate, particularly when comparing multitype infection with single-type infection. This might limit statistical power to assess associations and interactions. Given the small number of cases of each pair of type-specific HPV infection, we could not examine the cooperative or competitive effects in oral multitype HPV infection (ie, the tendency that infection of one HPV type would increase or decrease the likelihood of the infection of another type) that have been suggested in cervical HPV studies.6,7,11 Future studies with a larger number of multitype oral HPV infection should perhaps examine this clustering pattern in depth, particularly for oncologic types. Further research is also needed to identify risk factors of multitype oral HPV persistence, as well as the associations between multitype oral HPV infection or persistence and potentially malignant disorders in the oral or oropharyngeal areas.
Supplementary Material
Acknowledgements:
Thanh C. Bui was supported by a faculty fellowship from The University of Texas MD Anderson Cancer Center, Duncan Family Institute for Cancer Prevention and Risk Assessment. Thanh C. Bui, Damon J. Vidrine, and the preparation of this article is also supported in part by a grant from the Oklahoma Tobacco Settlement Endowment Trust, 092-016-0002 (PI: Vidrine). Thuy N. Thai is supported by the Vietnam Education Foundation Fellowship. The content of the article is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.
Footnotes
Conflict of interest: None declared.
Abstract presented: 30th International Papillomavirus Conference and Clinical and Public Health Workshops, Lisbon, Portugal, 17–21 September 2015.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (http://www.stdjournal.com).
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