Abstract
Oral human papillomavirus (HPV) is associated with oropharyngeal cancer (OPC). Although OPC incidence is increasing globally, knowledge of oral HPV infection rates is limited. Here we carried out an observational epidemiological analysis of oral HPV incidence in 3,137 men enrolled from the United States, Mexico and Brazil between 2005 and 2009. Individuals were followed for new HPV infection for a median of 57 months. Cumulative incidence and factors associated with acquisition were also assessed. The incidence rate of oral oncogenic HPV was 2.4 per 1,000 person-months, did not vary with age and was constant throughout the study period. Risk of oral HPV acquisition was significantly associated with alcohol consumption, having male sexual partners, more lifetime female sexual partners, more oral sex given and higher educational attainment. These data indicate that men are at risk of acquiring oral HPV throughout their lifetime, suggesting that catch-up vaccination may reduce new infection incidence.
Human papillomavirus (HPV) is the cause of multiple cancers among men, including oropharyngeal cancer (OPC)1. OPC incidence is increasing in both men and women globally2, with the highest incidence (2.5/100,000) in high-resource countries of Northern Europe and North America where it reaches up to 8/100,000 in males3. OPC incidence is significantly higher among men than in women (4.0 vs 0.79 per 100,000)4, with the burden shifting towards older white men5. Increases in OPC may be driven by increases in HPV-associated OPC, especially among middle-aged and older adults. The United States has reported significant increases in HPV-associated OPC incidence from 2002–2006 to 2014–2018; 17.1 to 22.0 per 100,000, among vaccine ineligible men aged 45–64 years and 17.5–28.4 per 100,000 among men aged over 65 years6.
While it is known that oral HPV infection is a primary cause of OPC and that HPV-16 is present in ~90% of HPV-associated OPC cases in the United States7, little is known about the natural history of oral HPV infection7. The few studies that report incidence of oral HPV have limited sample size8, short follow-up periods9,10, or focused on high-risk populations such as men who have sex with men (MSM)11,12. Furthermore, no study has estimated oral HPV incidence across multiple countries over multiple years. Understanding the incidence of oral HPV is important for appropriate design of prevention strategies, early detection and public health awareness. Therefore, we aimed to estimate the incidence and associated risk factors of acquiring oral HPV in a large multinational population of men from the United States, Mexico and Brazil. We report that the incidence rate of oral oncogenic HPV did not vary with age and was constant throughout the study period. Risk of oral HPV acquisition was significantly associated with alcohol consumption, having male sexual partners, more lifetime female sexual partners, more oral sex given and higher education attainment.
Results
Study design and demographic factors
A total of 3,137 men aged 18–70 years, recruited from the HPV Infection in Men (HIM) Study cohort who had at least two oral gargle samples that were valid for HPV DNA testing were included in the study (United States, 881; Brazil, 1,235; and Mexico, 1,021). All demographic and sexual behavioural variables were significantly different (P < 0.001) among countries (Table 1). The median age was 24, 34 and 35 years for men from the United States, Brazil and Mexico, respectively. The racial and ethnic distribution was largely white and non-Hispanic among men from Brazil (60.7% and 76.9% respectively) and the United States (68.1% and 83.9%, respectively), and mostly other (91.5%) and Hispanic (99.6%) among men from Mexico. A higher proportion of men from the United States (83.8%) completed at least 13 years of education compared with those from Brazil (43.1%) and Mexico (36.0%). Most men reported only having sex with women: 88.2%, 79.5% and 87.7% for the United States, Brazil and Mexico, respectively (Table 1). Characteristics of participants with and without incident oral HPV infection are described in Supplementary Table 1.
Table 1 |.
Baseline sociodemographic and sexual behavioural characteristics of participants from the HIM Study oral subcohort, stratified by country
| Country of residence | |||
|---|---|---|---|
| United States (n = 881) | Brazil (n = 1,235) | Mexico (n = 1,021) | |
| Age | |||
| Median (range) | 24 (18–81a) | 34 (18–72) | 35 (a17–72) |
| Mean (s.d.) | 30.6 (13.2) | 35.1 (10.0) | 35.9 (10.0) |
| 18–24 | 445 (50.5) | 196 (15.87) | 124 (12.16) |
| 25–32 | 135 (15.3) | 345 (27.9) | 308 (30.2) |
| 33–41 | 120 (13.6) | 369 (29.9) | 316 (31.0) |
| 42+ | 181 (20.5) | 325 (26.3) | 272 (26.7) |
| Marital Status | |||
| Divorced/Separated/Widowed | 105 (12.0) | 119 (9.7) | 51 (5.0) |
| Married/Cohabiting | 204 (23.3) | 614 (50.0) | 763 (75.5) |
| Single | 565 (64.7) | 495 (40.3) | 197 (19.5) |
| Race b | |||
| White | 599 (68.1) | 749 (60.7) | 56 (5.5) |
| Black | 154 (17.5) | 357 (28.9) | 1 (0.10) |
| Asian/PI | 50 (5.7) | 20 (1.6) | 0 (0.0) |
| Other | 71 (8.1) | 94 (7.6) | 932 (91.5) |
| Refused | 6 (0.7) | 14 (1.1) | 30 (2.9) |
| Ethnicity b | |||
| Hispanic | 122 (15.4) | 267 (21.6) | 1,015 (99.6) |
| Non-Hispanic | 665 (83.9) | 949 (76.9) | 2 (0.2) |
| Refused | 6 (0.76) | 18 (1.5) | 2 (0.2) |
| Education duration | |||
| Completed 12years or less | 142 (16.2) | 697 (56.94) | 645 (63.99) |
| 13–15years | 482 (55.0) | 181 (14.8) | 80 (7.9) |
| Completed at least 16years | 253 (28.9) | 346 (28.3) | 283 (28.1) |
| Number of drinks of any alcoholic beverage consumed in the past 1 month b | |||
| 0 | 181 (20.7) | 318 (26.2) | 257 (25.7) |
| 1–30 | 361 (41.4) | 511 (42.0) | 531 (53.1) |
| 31–60 | 126 (14.4) | 138 (11.4) | 86 (8.6) |
| >60 | 191 (21.9) | 225 (18.5) | 97 (9.7) |
| Refused | 14 (1.6) | 24 (2.0) | 29 (2.9) |
| Smoking status b | |||
| Current | 156 (18.3) | 212 (17.5) | 304 (30.4) |
| Former | 213 (25.0) | 273 (22.5) | 264 (26.4) |
| Never | 482 (56.6) | 726 (59.9) | 428 (42.8) |
| Refused | 1 (0.1) | 1 (0.1) | 3 (0.3) |
| Sexual orientation | |||
| MSW | 723 (88.2) | 946 (79.5) | 830 (87.7) |
| MSWM | 23 (2.8) | 127 (10.7) | 48 (5.1) |
| MSM | 17 (2.1) | 91 (7.7) | 14 (1.5) |
| Never had sex | 57 (7.0) | 26 (2.2) | 54 (5.7) |
| Lifetime number of female sex partners | |||
| Median (range) | 6 (0–320) | 10 (0–400) | 5 (0–350) |
| Mean (s.d.) | 15.4 (29.0) | 23.1 (42.0) | 9.0 (16.1) |
| 0–2 | 225 (25.6) | 213 (17.3) | 224 (22.0) |
| 3–7 | 219 (24.9) | 204 (16.6) | 384 (37.7) |
| 8–19 | 185 (21.0) | 300 (24.3) | 244 (24.0) |
| >19 | 205 (23.3) | 391 (31.7) | 108 (10.6) |
| Refused | 46 (5.2) | 125 (10.1) | 58 (5.7) |
| Number of female sex partners in past 6 months | |||
| Median (range) | 1(0–25) | 1 (0–50) | 1 (0–12) |
| Mean (s.d.) | 1.4 (1.8) | 1.9 (3.3) | 1.1 (1.1) |
| 0 | 210 (23.8) | 308 (24.9) | 288 (28.23) |
| 1 | 436 (49.5) | 472 (38.2) | 458 (45.0) |
| 2+ | 226 (25.7) | 430 (34.8) | 232 (22.8) |
| Refused | 9 (1.0) | 25 (2.0) | 40 (3.9) |
| Lifetime number of male sex partners | |||
| Median (range) | 0 (0–300) | 0 (0–300) | 0 (0–200) |
| Mean (s.d.) | 0.71 (10.6) | 5.6 (25.8) | 0.56 (6.6) |
| 0–2 | 839 (96.0) | 1,005 (81.6) | 974 (95.7) |
| 3–7 | 16 (1.8) | 73 (5.9) | 17 (1.7) |
| 8–19 | 6 (0.69) | 41 (3.3) | 11 (1.1) |
| >19 | 6 (0.69) | 83 (6.7) | 5 (0.49) |
| Refused | 7 (0.80) | 30 (2.4) | 11 (1.1) |
| Number of male sex partners in past 6 months b | |||
| Median (range) | 0 (0–10) | 0 (0–40) | 0 (0–6) |
| Mean (s.d.) | 0.07 (0.54) | 0.44 (2.0) | 0.05 (0.39) |
| 0 | 847 (97.2) | 1057 (86.2) | 979 (97.4) |
| 1 | 12 (1.4) | 67 (5.5) | 8 (0.80) |
| 2+ | 12 (1.4) | 94 (7.7) | 13 (1.3) |
| Refused | 0 (0.0) | 9 (0.73) | 5 (0.50) |
| Ever had oral sex b | |||
| No | 82 (9.3) | 96 (7.8) | 162 (16.0) |
| Yes | 792 (90.2) | 1,130 (92.0) | 839 (83.1) |
| Refused | 4 (0.46) | 2 (0.16) | 9 (0.89) |
| Ever had oral sex with a man | |||
| No | 740 (91.2) | 786 (68.2) | 836 (90.5) |
| Yes | 71 (8.8) | 367 (31.8) | 88 (9.5) |
| Number of times gave oral sex in the past 6 months | |||
| Median (range) | 2 (0–200) | 3 (0–500) | 2 (0–300) |
| Mean (s.d.) | 11.1 (22.8) | 12.9 (30.1) | 8.57 (20.0) |
| 0 | 330 (38.6) | 364 (31.8) | 402 (39.7) |
| 1–6 | 222 (26.0) | 333 (29.1) | 294 (29.0) |
| 7–24 | 163 (19.1) | 247 (21.6) | 185 (18.3) |
| 25+ | 111 (13.0) | 145 (12.7) | 85 (8.4) |
| Refused | 29 (3.4) | 57 (5.0) | 47 (4.6) |
| Days since last gave oral sex | |||
| Never | 82 (9.6) | 96 (8.4) | 162 (16.1) |
| 0–3 | 140 (16.5) | 211 (18.5) | 137 (13.6) |
| 4–10 | 133 (15.6) | 196 (17.2) | 168 (16.7) |
| 11–30 | 165 (19.4) | 206 (18.0) | 191 (19.0) |
| >30 | 320 (37.6) | 400 (35.0) | 317 (31.5) |
| Refused | 11 (1.3) | 33 (2.9) | 32 (3.2) |
| Ever had gingivitis | |||
| No | 728 (90.8) | 1,031 (88.4) | 935 (94.5) |
| Yes | 74 (9.2) | 136 (11.7) | 54 (5.5) |
| Number of teeth lost due to oral disease | |||
| =0 | 613 (76.3) | 614 (52.7) | 663 (68.4) |
| ≥1 | 190 (23.7) | 551 (47.3) | 307 (31.7) |
| Consistent bleeding of gums after brushing teeth or presence of swollen gums | |||
| No | 778 (96.9) | 1,029 (88.0) | 868 (87.8) |
| Yes | 25 (3.1) | 140 (12.0) | 121 (12.2) |
All variables were significantly different by country of residence with the same P value of <0.001. P values were calculated using ANOVA for numerical covariates and chi-square test for categorical covariates, using 95% CI. Kruskal-Wallis test was used when numeric variables were skewed. All statistical tests were two-sided. Column statistics are presented in this table. P < 0.05 was used as the measure of statistical significance.
Age recorded is at time of oral HPV recruitment, after recruitment into the main HIM study, therefore some men included in the oral subcohort were aged just over 72 years and only one participant aged 81 was outside the 18–70 range.
For these variables, ‘Refused’ responses were not included in subsequent analyses.
Oral oncogenic HPV incidence was constant with time and age
Overall, 19.6% of study participants had a prevalent oral HPV infection with any genotype detected at baseline, with 14.2%, 17.3% and 27.0% prevalence among men in the United States, Brazil and Mexico, respectively (Table 2). The baseline prevalence of oral oncogenic HPV was 5.9%, and HPV-16 was the most prevalent genotype at 1.6%. The incidence rate of any oral oncogenic HPV was 2.4 per 1,000 person-months, with higher incidence among men from the United States compared with men from Brazil and Mexico (3.5, 2.1 and 2.1 per 1,000 person-months, respectively). Incidence rates for HPV-16 were 0.62 per 1,000 person-months overall, and 1.03, 0.53 and 0.41 per 1,000 person-months among men in the United States, Brazil and Mexico, respectively. Among the combined cohort, HPV-52 was the most frequently acquired HPV type at 0.87 per 1,000 person-months. However, HPV-52 incidence was only higher than HPV-16 incidence among men from Brazil and Mexico, not among those from the United States (Table 2). When analysing oral HPV acquisition by age category, HPV-16 incidence rates were 0.72, 0.54, 0.50 and 0.73 per 1,000 person-months among men aged 18–24, 25–32, 33–41 and 42+ years, respectively. Oncogenic HPV incidence rates among the same age categories were 2.9, 2.2, 2.2 and 2.5 per 1,000 person-months, respectively (Supplementary Table 2).
Table 2 |.
Oral HPV prevalence and incidence by country of residence in the HIM Study oral subcohort
| HPV type | All men | United States | Brazil | Mexico | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Prevalence | Incident infections (No.) | Person-months | Incidence per 1,000 person-months (95% CI) | Prevalence | Incident infections (No.) | Person-months | Incidence per 1,000 person-months (95% CI) | Prevalence | Incident infections (No.) | Person-months | Incidence per 1,000 person-months (95% CI) | Prevalence | Incident infections (No.) | Person-months | Incidence per 1,000 person-months (95% CI) | |
| Any HPV | 615 (19.6%) | 614 | 124,009 | 5.0 (4.6,5.4) | 125 (14.2%) | 234 | 31,967 | 7.3 (6.4,8.3) | 214 (17.3%) | 225 | 53,746 | 4.2 (3.7,4.8) | 276 (27.0%) | 155 | 38,297 | 4.1 (3.5,4.7) |
| Oncogenic | 186 (5.9%) | 387 | 158,820 | 2.4 (2.2,2.7) | 47 (5.3%) | 138 | 39,911 | 3.46 (2.9,4.1) | 66 (5.3%) | 139 | 67,157 | 2.1 (1.8,2.4) | 73 (7.2%) | 110 | 51,751 | 2.1 (1.8,2.6) |
| 16 | 51 (1.6%) | 111 | 179,329 | 0.62 (0.51,0.75) | 13 (1.5%) | 47 | 45,529 | 1.03 (0.78,1.4) | 20 (1.6%) | 40 | 75,317 | 0.53 (0.39,0.72) | 18 (1.8%) | 24 | 58,482 | 0.41 (0.28,0.61) |
| 18 | 14 (0.45%) | 49 | 183,414 | 0.27 (0.20,0.35) | 2 (0.23%) | 8 | 47,538 | 0.17 (0.08,0.3) | 7 (0.57%) | 21 | 76,677 | 0.27 (0.18,0.2) | 5 (0.49%) | 20 | 59,199 | 0.34 (0.22,0.52) |
| 52 | 23 (0.73%) | 155 | 178,219 | 0.87 (0.74,1.0) | 7 (0.79%) | 39 | 45,967 | 0.85 (0.62,1.2) | 11 (0.89%) | 64 | 73,736 | 0.87 (0.68,1.1) | 5 (0.49%) | 52 | 58,515 | 0.89 (0.68,1.2) |
| Non-oncogenic | 105 (3.4%) | 239 | 170,012 | 1.4 (1.2,1.6) | 22 (2.5%) | 70 | 44,421 | 1.6 (1.2,2.0) | 52 (4.2%) | 97 | 69,487 | 1.4 (1.1,1.7) | 31 (3.0%) | 72 | 56,103 | 1.3 (1.0,1.6) |
| 6 | 30 (0.96%) | 51 | 182,095 | 0.28 (0.21,0.37) | 4 (0.45%) | 15 | 47,116 | 0.32 (0.19,0.53) | 14 (1.1%) | 25 | 75,824 | 0.33 (0.22,0.49) | 12 (1.2%) | 11 | 59,155 | 0.19 (0.10,0.34) |
| 11 | 8 (0.26%) | 27 | 184,640 | 0.15 (0.10,0.21) | 0 (0%) | 4 | 47,679 | 0.08 (0.03,0.22) | 2 (0.16%) | 20 | 76,863 | 0.33 (0.22, 0.49) | 6 (0.59%) | 3 | 60,098 | 0.05 (0.02,0.15) |
| 4vHPV | 100 (3.2%) | 191 | 172,649 | 1.1 (0.96,1.3) | 19 (2.2%) | 64 | 44,674 | 1.4 (1.1,1.8) | 42 (3.4%) | 82 | 71,952 | 1.1 (0.92,1.4) | 39 (3.8%) | 45 | 56,023 | 0.80 (0.60,1.1) |
| All 9vHPV | 143 (4.6%) | 327 | 164,016 | 2.0 (1.8,2.2) | 32 (3.6%) | 107 | 42,128 | 2.5 (2.1,3.1) | 57 (4.6%) | 128 | 68,199 | 1.9 (1.6,2.2) | 54 (5.3%) | 92 | 53,689 | 1.7 (1.4,2.1) |
| HR-HPV of 9vHPV | 110 (3.5%) | 306 | 167,335 | 1.8 (1.6,2.1) | 28 (3.2%) | 101 | 42,585 | 2.4 (2.0,2.9) | 43 (3.5%) | 113 | 69,896 | 1.6 (1.3,1.9) | 39 (3.8%) | 92 | 54,854 | 1.7 (1.4,2.1) |
| Untypable | 341 (10.9%) | 459 | 149,226 | 3.1 (2.8,3.4) | 59 (6.7%) | 150 | 39,430 | 3.8 (3.2,4.5) | 105 (8.5%) | 170 | 64,456 | 2.6 (2.3,3.1) | 177 (17.3%) | 139 | 45,341 | 3.1 (2.6,3.6) |
Oral HPV prevalence and incidence by country of residence (United States, Brazil and Mexico) in the HIM Study oral subcohort. Overall incidence calculated at 60 months. An incident oral HPV infection was defined as the first acquired oral HPV genotype that was not present at baseline. Person-time for incident oral HPV infection was calculated from the date of the baseline oral visit to the date of the first detection of HPV DNA. Incidence rates and 95% CIs were estimated using Poisson models.
When analysing incidence over time, the incidence rate of a new oral oncogenic HPV was constant over time at 2.9, 3.4, 3.1, 2.8 and 2.6 per 1,000 person-months at 12, 24, 36, 48 and 60 months, respectively (Table 3). There were no significant changes in incidence across time periods for individual oncogenic genotypes (HPV-16, HPV-18 and HPV-52) or HPV genotype categories (oncogenic, non-oncogenic, 4vHPV, all 9vHPV and HR-HPV of 9vHPV), as detailed in Table 3. HPV-16 incidence was 0.68 and 0.69 per 1,000 person-months at 12 and 24 months, and 0.63, 0.62 and 0.58 per 1,000 person-months at 36, 48 and 60 months, respectively. Incidence of HPV-18 remained at ~0.3 per 1,000 person-months across all time periods. The cumulative incidence and risk of oral oncogenic and HPV-16 was significantly different by country (P < 0.001) (Fig. 1a,b). Using men from Mexico as the reference group, men from the United States had a higher risk of acquiring oral HPV for any oncogenic HPV type (hazard ratio (HR): 1.58; 95% confidence interval (CI): 1.23–2.03; Fig. 1a) and HPV-16 (HR: 2.38; 95% CI: 1.45–3.90; Fig. 1b). There was no difference in oncogenic HPV and HPV-16 acquisition among men from Brazil compared to those from Mexico (Fig. 1a,b). However, the cumulative incidence and risk of oncogenic HPV and HPV-16 acquisition did not significantly differ by age group among all men (Fig. 1c,d) and within each of the three countries (Extended Data Fig. 1).
Table 3 |.
Annual oral HPV incidence rate over 60 months in the HIM Study oral subcohort
| HPV type | 12-month | 24-month | 36-month | 48-month | 60-month | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Incident infections (No.) | Person-months | Incidence per 1,000 person-months (95% CI) | Incident infections (No.) | Person-months | Incidence per 1,000 person-months (95% CI) | Incident infections (No.) | Person-months | Incidence per 1,000 person-months (95% CI) | Incident infections (No.) | Person-months | Incidence per 1,000 person-months (95% CI) | Incident infections (No.) | Person-months | Incidence per 1,000 person-months (95% CI) | |
| Any HPV | 151 | 29,588 | 5.1 (4.4, 6.0) | 347 | 54,403 | 6.4 (5.7, 7.1) | 458 | 74,667 | 6.1 (5.6, 6.7) | 527 | 90,969 | 5.8 (5.3, 6.3) | 554 | 103,341 | 5.4 (4.9, 5.8) |
| Oncogenic | 101 | 34,916 | 2.9 (2.4, 3.5) | 222 | 65,722 | 3.4 (3.0, 3.9) | 284 | 91,700 | 3.1 (2.8, 3.5) | 320 | 113,357 | 2.8 (2.5, 3.2) | 337 | 130,127 | 2.6 (2.3, 2.9) |
| 16 | 25 | 36,907 | 0.68 (0.46, 1.00) | 49 | 70,879 | 0.69 (0.52, 0.91) | 63 | 100,222 | 0.63 (0.49, 0.80) | 77 | 125,187 | 0.62 (0.49, 0.77) | 84 | 144,845 | 0.58 (0.47, 0.72) |
| 18 | 10 | 37,416 | 0.27 (0.14, 0.50) | 24 | 72,082 | 0.33 (0.22, 0.50) | 30 | 102,042 | 0.29 (0.21, 0.42) | 34 | 127,617 | 0.27 (0.19, 0.37) | 41 | 147,825 | 0.28 (0.20, 0.38) |
| 52 | 44 | 37,172 | 1.2 (0.88, 1.6) | 95 | 71,011 | 1.3 (1.1 1.6) | 117 | 100,160 | 1.2 (0.97, 1.4) | 134 | 124,821 | 1.1 (0.91, 1.3) | 140 | 144,241 | 0.97 (0.82, 1.2) |
| Non-oncogenic | 58 | 36,061 | 1.6 (1.3, 2.1) | 125 | 68,792 | 1.8 (1.5, 2.2) | 168 | 96,669 | 1.8 (1.5, 2.0) | 198 | 120,007 | 1.7 (1.4, 1.9) | 207 | 138,236 | 1.5 (1.3, 1.7) |
| 6 | 14 | 37,190 | 0.38 (0.22, 0.64) | 28 | 71,611 | 0.39 (0.27, 0.57) | 37 | 101,364 | 0.37 (0.26, 0.50) | 41 | 126,716 | 0.32 (0.24, 0.44) | 42 | 146,736 | 0.29 (0.21, 0.39) |
| 11 | 3 | 37,518 | 0.08 (0.03, 0.25) | 13 | 72,362 | 0.18 (0.10, 0.31) | 24 | 102,516 | 0.23 (0.16, 0.35) | 25 | 128,247 | 0.19 (0.13, 0.29) | 26 | 148,621 | 0.17 (0.12, 0.26) |
| 4vHPV | 45 | 36,208 | 1.2 (0.93, 1.7) | 97 | 69,200 | 1.4 (1.2, 1.7) | 129 | 97,443 | 1.3 (1.1, 1.6) | 146 | 121,323 | 1.2 (1.0, 1.4) | 158 | 140,046 | 1.1 (0.97, 1.3) |
| All 9vHPV | 85 | 35,529 | 2.4 (1.9, 2.7) | 183 | 67,160 | 2.7 (2.4, 3.2) | 234 | 93,968 | 2.5 (2.2, 2.8) | 265 | 116,412 | 2.3 (2.0, 2.6) | 279 | 133,894 | 2.1 (1.9, 2.3) |
| HR-HPV of 9vHPV | 79 | 35,964 | 2.20 (1.76, 2.74) | 168 | 68,127 | 2.5 (2.1, 2.9) | 216 | 95,488 | 2.3 (2.0, 2.6) | 248 | 118,442 | 2.1 (1.9, 2.4) | 263 | 136,345 | 1.9 (1.7, 2.2) |
| Untypable | 89 | 33,164 | 2.68 (2.18, 3.30) | 214 | 62,399 | 3.4 (3.0, 3.9) | 304 | 86,854 | 3.5 (3.1, 3.9) | 366 | 107,003 | 3.4 (3.1, 3.8) | 390 | 122,606 | 3.2 (2.9, 3.5) |
Annual oral HPV incidence rate over 60 months in the HIM Study oral subcohort. An incident oral HPV infection was defined as the first acquired oral HPV genotype that was not present at baseline. Person-time for incident oral HPV infection was calculated from the date of the baseline oral visit to the date of the first detection of HPV DNA within the 12-month cumulative intervals. Incidence rates and 95% CIs were estimated using Poisson models.
Fig. 1 |. Kaplan–Meier estimates of cumulative incidence of oral oncogenic HPV and HPV-16 infections.
Estimates stratified by country (a,b) and age group (c,d) in the HIM Study oral subcohort. log-rank test was conducted to test differences among groups, using 95% CI and two-sided P < as the measure of statistical significance. Number of unique participants for oncogenic HPV incidence analysis (with a total of 2,951) by country: 1,169 from Brazil (BZ), 948 from Mexico (MX) and 834 from the United States (US); by age: 742 from the 18–24 age group, 737 from the 25–32 age group, 741 from the 33–41 group and 731 from the 42+ age group. Number of unique participants for HPV-16 incidence analysis (with a total of 3,086) by country: 1,215 from BZ, 1,003 from MX and 868 from the US; by age: 757 from the 18–24 age group, 774 from the 25–32 age group, 785 from the 33–41 group and 770 from the 42+ age group.
Factors associated with oral oncogenic HPV infection
Factors independently associated with acquisition of oral oncogenic HPV infection, based on the reference groups listed in Table 4, were education duration of 13–15 years (adjusted hazard ratios (aHR): 1.36; 95% CI: 1.04–1.78) and 16+ years (aHR: 1.52; 95% CI: 1.13–2.04), >60 alcoholic beverages in the past month (aHR: 1.43; 95% CI: 1.02–2.01), only having male sexual partners (aHR: 2.37; 95% CI: 1.14–4–94), reporting a history of three or more female sexual partners in their lifetime (3–7 [aHR: 3.03; 95% CI: 1.26–7.32], 8–19 [aHR: 2.84; 95% CI: 1.17–6.92] and >19 [aHR: 3.06; 95% CI: 1.25–7.49] lifetime female sex partners, respectively), and having given oral sex at least seven times in the past 6 months before recruitment (7–24 times [aHR: 1.55; 95% CI: 1.14–2.13] and 25+ times [aHR: 1.65; 95% CI: 1.16–2.35]). Marginally elevated risk was observed among men who lost one or more teeth to oral disease (aHR: 1.31; 95% CI: 0.95–1.81). Importantly, in adjusted HR models, risk of acquiring a new oral oncogenic HPV infection was not independently associated with country of residence or age (Table 4).
Table 4 |.
Factors associated with the first acquisition of an oncogenic oral HPV infection over 60 months of follow-up in the HIM Study oral subcohort
| Oncogenic HPV | ||
|---|---|---|
| Univariate crude HR (95% CI) | Multivariate aHR (95% CI) | |
| Country of residence | ||
| Mexico | Reference | Reference |
| United States | 1.56 (1.21–2.01) | 1.29 (0.94–1.77) |
| Brazil | 0.98 (0.76–1.26) | 0.84 (0.63–1.12) |
| Age | ||
| 42+ | Reference | Reference |
| 18–24 | 1.07 (0.82–1.41) | 0.87 (0.62–1.22) |
| 25–32 | 0.85 (0.64–1.13) | 0.79 (0.58–1.07) |
| 33–41 | 0.89 (0.67–1.17) | 0.95 (0.71–1.28) |
| Marital status | ||
| Single | Reference | Reference |
| Divorced/Separated/Widowed | 1.20 (0.87–1.67) | N/A |
| Married/Cohabiting | 0.77 (0.62–0.95) | N/A |
| Education duration | ||
| Completed 12years or less | Reference | Reference |
| 13–15years | 1.47 (1.16–1.88) | 1.36 (1.04–1.78) |
| Completed at least 16years | 1.84 (1.44–2.34) | 1.52 (1.13–2.04) |
| Number of drinks of any alcoholic beverage consumed in the past Imonth | ||
| 0 | Reference | Reference |
| 1–30 | 1.16 (0.89–1.52) | 1.04 (0.78–1.39) |
| 31–60 | 1.22 (0.84–1.76) | 0.98 (0.66–1.46) |
| >60 | 1.63 (1.20–2.22) | 1.43 (1.02–2.01) |
| Smoking status | ||
| Never | Reference | Reference |
| Current | 1.27 (0.99–1.61) | 1.15 (0.87–1.51) |
| Former | 0.90 (0.69–1.16) | 0.80 (0.60–1.05) |
| Sexual orientation | ||
| MSW | Reference | Reference |
| MSWM | 1.24 (0.86–1.79) | 1.31 (0.88–1.96) |
| MSM | 1.06 (0.66–1.70) | 2.37 (1.14–4.94) |
| Never had sex | 0.49 (0.25–0.95) | 1.11 (0.38–3.24) |
| Lifetime number of female sex partners | ||
| 0 | Reference | Reference |
| 1–2 | 1.07 (0.60–1.91) | 1.44 (0.63–3.31) |
| 3–7 | 1.91 (1.15–3.18) | 3.03 (1.26–7.32) |
| 8–19 | 1.75 (1.04–2.94) | 2.84 (1.17–6.92) |
| >19 | 2.11 (1.27–3.53) | 3.06 (1.25–7.49) |
| Refused | 1.85 (1.02–3.37) | 3.51 (1.38–8.91) |
| Female sex partners in past 6months | ||
| 0 | Reference | Reference |
| 1 | 1.31 (1.00–1.71) | N/A |
| 2+ | 1.62 (1.22–2.14) | N/A |
| Refused | 1.35 (0.68–2.69) | N/A |
| Lifetime number of male sex partners | ||
| 0 | Reference | Reference |
| 1–2 | 1.16 (0.80–1.68) | N/A |
| 3–7 | 1.33 (0.83–2.14) | N/A |
| 8–19 | 1.27 (0.67–2.38) | N/A |
| >19 | 1.16 (0.66–2.02) | N/A |
| Ever had oral sex | ||
| No | Reference | Reference |
| Yes | 2.22 (1.43–3.45) | N/A |
| Ever had oral sex with a man | ||
| No | Reference | Reference |
| Yes | 1.19 (0.93–1.53) | N/A |
| Number of times gave oral sex in the past 6months | ||
| 0 | Reference | Reference |
| 1–6 | 1.36 (1.03–1.79) | 1.21 (0.89–1.64) |
| 7–24 | 1.81 (1.37–2.41) | 1.55 (1.14–2.13) |
| 25+ | 2.03 (1.47–2.81) | 1.65 (1.16–2.35) |
| Refused | 1.74 (1.08–2.81) | 1.32 (0.74–2.36) |
| Days since last gave oral sex | ||
| Never | Reference | Reference |
| 0–3 | 2.57 (1.58–4.18) | N/A |
| >3–10 | 2.79 (1.72–4.51) | N/A |
| 11–30 | 2.19 (1.35–3.57) | N/A |
| >30 | 1.91 (1.20–3.04) | N/A |
| Refused | 2.13 (1.00–4.51) | N/A |
| Ever had gingivitis | ||
| No | Reference | Reference |
| Yes | 1.03 (0.73–1.46) | N/A |
| Number of teeth lost due to oral disease | ||
| =0 | Reference | Reference |
| ≥1 | 0.98 (0.79–1.21) | 1.31 (0.95–1.81) |
| Consistent bleeding of gums after brushing teeth or presence of swollen gums | ||
| No | Reference | Reference |
| Yes | 0.82 (0.56–1.19) | N/A |
| Agea | 1.00 (0.99–1.01) | |
Factors associated with the first acquisition of oncogenic oral HPV infection over 60 months of follow-up in the HIM Study oral subcohort. Factors associated with oral oncogenic HPV acquisition were assessed in crude and adjusted Cox proportional hazard models with backward elimination (P < 0.20). Two-sided tests were conducted. Only men who had infection with an HPV genotype under investigation at the baseline visit were excluded from the analyses. As country and age were cohort design factors, they were included as predictors in the models. When a man had multiple oral oncogenic HPV infections acquired through follow-up, only the first oncogenic infection was modelled. P < 0.05 was used as the measure of statistical significance. All hazard ratios with P < 0.05 are presented in bold font. After removing 186 men who had prevalent oral HPV infections at baseline, the number of observations in the original dataset was 2,951. N/A denotes variables that were not included in the multivariate model after backward selection.
Analysed as a continuous variable.
Discussion
Our study reports incidence of oral HPV among a large cohort (n = 3,137) of healthy men across multiple countries over years of follow-up (median follow-up 57 months; maximum 104 months). We observed significant differences in the incidence of oral oncogenic and HPV-16 by country, both of which were highest among men in the United States compared with Mexico and Brazil. Although there could be additional factors that may lead to OPC development, our oral HPV findings are consistent with GLOBOCAN 2020 estimates that have reported higher OPC incidence rates in the United States compared with Brazil and Mexico3. While the cumulative incidence of oral oncogenic HPV-16 increased over time in all countries, the incidence rate estimated per year remained relatively stable over 5 years of follow-up. In all countries, acquisition of new oral HPV infections did not differ by age, indicating that men may remain susceptible to acquiring cancer-causing HPV types at the oral epithelium throughout their lifetime.
Previously, we reported oral HPV incidence among a subgroup of men from the HIM Study cohort. Although there was no difference in oral HPV by age, our inferences were limited by a smaller sample size, shorter follow-up period and less sensitive HPV genotyping platform13. Oral HPV incidence has been previously reported in only a few other studies9,14. However, as most of these studies included sample sizes that were relatively small and focused on high-risk populations, it remains unclear whether this lack of association with age would be observed with a larger sample size, or among a more general population. As our study included a large sample size of men from the general population of three countries and had multiple years of follow-up, we are able to report with high confidence a steady acquisition rate of oral oncogenic HPV per year that did not differ by age. Furthermore, we report relatively constant incidence rates across age groups for both HPV-16 and oncogenic HPV, with slightly higher rates among young men (18–24 years) and older men (≥42 years), compared with men aged 25–41 years. Previously, among men and women at high risk for HIV,14 no difference in oral HPV acquisition by age was reported. The incidence rate they reported for oral oncogenic HPV infection was slightly higher than observed in our study as would be expected for a higher-risk population (4.6 vs 3.5 per 1,000 person-months, respectively)14. In another study among those at high risk for HIV, MSM reporting for care to a sexually transmitted infections (STI) clinic in the Netherlands, an oral HPV-16 incidence rate of 0.90 per 1,000 person-months was reported9, higher than the 0.62 per 1,000 person-months observed in our study. Similar to our study and that of Beachler and colleagues14, oral HPV incidence was not significantly associated with age among HIV uninfected men in a study from the Netherlands9. It is important to note that the United States and the Netherlands studies report oral HPV-16 as the most common genotype, similar to our observation for the HIM Study men from the United States. However, in Mexico and Brazil, HPV-52 was the most common oncogenic HPV type detected and was a driver of the overall oral oncogenic HPV incidence in these countries. HPV-16 and 52 are among the genotypes prevented by the Gardasil 9 vaccine. However, as OPC incidence and the proportion due to HPV continues to increase in medium and high-resource countries, it will be important to assess the proportion of tumours due to HPV-16 and 52 in the Americas and Europe prospectively in the future.
Men appear to remain susceptible to acquiring HPV infection over time at all the anatomic sites where HPV causes cancer. The current study of oral HPV incidence adds to our previous observation that the genital15 and anal16 HPV incidence rate among men does not differ by age. The constant rate of HPV acquisition among men throughout their lifetime can probably be explained by the relatively low prevalence of antibodies to HPV in men17,18 in comparison with genital HPV in women19. When comparing oral HPV infections, men and women both have low concordance of HPV antibodies prevalence, 0.8% vs 0.2% respectively20. However, only a small proportion of men develop natural immunity (<5%), and these antibodies do not confer protection against future genital or oral infections with the same HPV type18,21,22. Our previous observation of recurrent same-type HPV infections23 further support that natural immunity is not sufficient. In contrast, HPV vaccination has been shown to significantly reduce anogenital HPV vaccine type infection in men in Phase III trials24 and oral HPV in effectiveness studies in the United States25,26.
It is important to note that HPV-related OPC occurs among men at relatively older ages (median age at OPC diagnosis ~60 years)27,28. This raises the question as to the age at which the causative HPV type was acquired. Our data indicate that the causative oral HPV infection in men may be equally acquired at both older and younger ages and may probably differ from what is known regarding cervical cancer, in which the majority of the causal HPV infections are thought to occur by age 30 years29,30. Previously, we reported that almost 20% of oral HPV-16 infections persisted for >24 months, thus potentially increasing the risk of OPC development31. We also previously reported that 12-month persistence of oral HPV infections significantly increases with age32; thus, men who acquire oral HPV at an older age are potentially at increased risk of developing OPC. In addition, ref. 8 reported a significantly longer time to clearance in older men and women aged 60–79 years compared with ages <40 and 40–49 years. The time to clearance was significantly longer among men compared with women8. These observations support the benefit of HPV vaccination among men regardless of age, given that those men who acquire oral HPV at an older age are potentially at increased risk of developing OPC.
Recently, a microsimulation-based model concluded that 70% of oral HPV-16 infections that cause OPC in men occur by age 26 years33. The model results, which were primarily dependent on cross-sectional prevalence data and did not have the benefit of data from prospective oral HPV natural history studies, are not consistent with the observed rate of oral HPV acquisition by age observed in the HIM Study. Our findings on oral HPV in men differ from data on cervical HPV in women, 75% of whom acquire their causal HPV infections by age 30 years34.
In addition to sexual behaviour, which has been associated with oral HPV incidence in previous studies35–37, we observed several distinct factors independently associated with the risk of acquiring oral oncogenic HPV in men. High consumption of alcoholic beverages and higher educational attainment were both independently associated with oral oncogenic HPV acquisition. Related to alcohol consumption, findings from the present study are in line with other studies that show that alcohol intake is associated with increased risk of OPC in the Americas, Asia and Europe38. Men with fewer years of schooling are less likely to have adequate knowledge on genital HPV infection39. However, there is still a lack of awareness on the risks of oral sex and development of oral cancers40, with misperceptions that oral sex transmits fewer infections than vaginal and anal sex41,42. Our findings on the association of longer duration of education with new infections require further examination.
While our study has several strengths, there are limitations that should be acknowledged. First, lifestyle and behavioural variables were self-reported and therefore, a reporting bias might have occurred. To minimize this bias, the surveys were self-administered via computer in a private room. While we attempted to control for confounding in our multiple variable analyses, it is possible that there remained residual confounding. Second, the oral rinse and gargle sample collection method does not target the exact cancer site of interest, the oropharynx. However, this is the method of choice across multiple studies8,43,44, thus allowing direct comparison to the literature. Lastly, men were not followed after 2016, therefore we do not report data post 2016. Our study had notable strengths, such as the large sample size, which increased our statistical power to examine incidence of specific HPV types and grouped HPV types. We utilized a common protocol for sample collection, processing, archiving and HPV genotype analyses across the populations and time points. The sensitive and robust SPF10 PCR-DEIA-LIPA25 assay was utilized to genotype all oral specimens in the same laboratory. Furthermore, the representation of healthy men from three different geographic regions increased the generalizability of our findings.
In conclusion, our study found that men are at risk of acquiring oral HPV infections regardless of country of residence and age, with higher rates of acquisition in men from the United States compared with Brazil and Mexico. These data should inform interventions to prevent OPC, such as gender-neutral vaccination and catch-up vaccination of mid-adult-aged men who missed the opportunity for vaccination earlier in life. Awareness of the risks of oral oncogenic HPV acquisition should highlight the association of sexual behaviours and alcohol consumption. The association of longer duration of education with new infections requires further investigation to guide prevention strategies and awareness campaigns. Given the increasing incidence of HPV-related OPC with increasing age in men, the results of our study highlight the importance of preventing oral HPV, the precursor to HPV-associated OPC.
Methods
Study design
Ethics approval was received from the Institutional Review Boards at the University of South Florida (Tampa, United States), Ludwig Institute for Cancer Research (São Paulo, Brazil), Hospital das Clinicas da Faculdade de Medicina da USP (HC FMUSP) (São Paulo, Brazil) and Instituto Nacional de Salud Pública de México (Cuernavaca, Mexico). The approval numbers for these institutions are IRB00000335, IRB00001650 and IRB00001022, respectively. Eligible men who provided written informed consent were included in the study.
This was a cohort study nested within the larger HIM Study, an HPV natural history study consisting of 4,123 men aged 18–70 years who were human immunodeficiency virus (HIV) negative, enrolled from 2005 to 2009 and followed for HPV acquisition through 201615,45. Participants were recruited from three sites: Tampa (United States), São Paulo (Brazil) and Cuernavaca (Mexico).
Men who provided at least two oral gargle samples were included in the HIM Study oral subcohort44,46 and the current analyses. Data on sociodemographic characteristics and behavioural history were collected using a computer-assisted self-interview (CASI) at every visit. Behavioural variables included alcohol consumption, smoking status, lifetime number of sexual partners, oral sex debut, recent oral sex performed and measures of oral health. Oral samples were collected prospectively from November 2007 to September 2016 every 6 months with a median follow-up time of 57 (6–104) months.
Sample collection and HPV DNA testing
Participants rinsed their mouths and gargled for 30 s using 15 ml of locally available mouthwash (Brazil, PLAX; Mexico, Oral-B; United States, Target Brand)47. The collected oral gargle specimens were stored at −80 °C following processing. DNA was extracted from all archived oral specimens using the robotic MDx Media kit (Qiagen), as instructed by the manufacturer. HPV was detected and genotyped with the SPF10 PCR-DEIA-LiPA25 (DDL Diagnostic Laboratory, Rijswik, the Netherlands) line probe assay system that detects 25 HPV genotypes48,49. This assay was used for the ability to detect 20% more HPV infections than other marketed assays, even in oral gargle samples where HPV target cells are diluted44. For quality control, amplification of the beta-globin gene was performed.
Statistics and reproducibility
All men from the HIM Study oral HPV substudy with at least two oral gargles were included in the study, and no additional statistical method was used to predetermine sample size. An incident oral HPV infection was defined as the first acquired oral HPV genotype that was not present at baseline. Person-time for incident oral HPV infection was calculated from the date of the baseline oral visit to the date of the first detection of HPV DNA. Genotype-specific HPV infections were reported using any 1 of 25 HPV types and further grouped as follows: oncogenic types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68), non-oncogenic types (6, 11, 34, 40, 42, 43, 44, 53, 54, 70 and 74), 9-valent (HPV-6, 11, 16, 18, 31, 33, 45, 52 and 58) and quadrivalent (HPV-6, 11, 16 and 18) vaccine types.
Characteristics of the study population were compared across country of residence (United States, Brazil and Mexico) using analysis of variance (ANOVA) for continuous variables and chi-square test for categorical variables. The Kruskal–Wallis test was used when numeric variables were skewed. Incidence rates and 95% CIs were estimated using Poisson models. Time to first oral HPV acquisition during follow-up was estimated using the Kaplan–Meier method, with the log-rank test conducted to test differences among groups.
Factors associated with oral oncogenic HPV acquisition (listed in Table 1) were assessed in crude and adjusted Cox proportional hazard models with backward elimination (P < 0.20). Only men who had infection with an HPV genotype under investigation at the baseline visit were excluded from the analyses. Demographic and clinical factors independently associated with HPV-16 acquisition alone were not modelled because of the relatively low number of infections. As country and age were cohort design factors, these were included as predictors in the models. When a man had multiple oral oncogenic HPV infections acquired through follow-up, only the first oncogenic infection was modelled. Similarly, for all other HPV infection groups, the first infection with an HPV genotype from the group was modelled. For variables with ‘refused’ as a category, the category was retained when the sample size was sufficient (>20 men refused). If not, then ‘refused’ was treated as missing and excluded from the analysis. All analyses were conducted with SAS v.9.4 and statistical significance was defined as two-sided P < 0.05.
Extended Data
Extended Data Fig. 1 |. Kaplan Meier estimates of cumulative incidence of oral HPV infections within each country [US, Brazil (BZ) and Mexico (MX)] stratified by age group in the HIM Study oral sub cohort (A-I).
Log-rank test was conducted to test differences among groups, using 95% confidence interval and two-sided p < 0.05 as the measure of statistical significance. The cumulative incidence and risk of oncogenic HPV and HPV 16 acquisition did not significantly differ by age group, within each of the three countries. A-C: Number of unique participants for any types of HPV incidence analysis (with a total of 756) in US by age: 401 from 18–24 age group, 113 from 25–32 age group, 94 from 33–41 group and 148 from 42+ age group. Number of unique participants for oncogenic HPV types of incidence analysis (with a total of 834) in US by age: 433 from 18–24 age group, 121 from 25–32 age group, 106 from 33–41 group and 174 from 42+ age group. Number of unique participants for HPV type 16 incidence analysis (with a total of 868) in US by age: 443 from 18–24 age group, 132 from 25–32 age group, 116 from 33–41 group and 177 from 42+ age group. D-F: Number of unique participants for any types of HPV incidence analysis (with a total of 1021) in BZ by age: 178 from 18–24 age group, 290 from 25–32 age group, 302 from 33–41 group and 251 from 42+ age group. Number of unique participants for oncogenic HPV types of incidence analysis (with a total of 1169) in BZ by age: 189 from 18–24 age group, 326 from 25–32 age group, 346 from 33–41 group and 308 from 42+ age group. Number of unique participants for HPV type 16 incidence analysis (with a total of 1215) in BZ by age: 191 from 18–24 age group, 339 from 25–32 age group, 362 from 33–41 group and 323 from 42+ age group. G-I: Number of unique participants for any types of HPV incidence analysis (with a total of 745) in MX by age: 104 from 18–24 age group, 226 from 25–32 age group, 229 from 33–41 group and 186 from 42+ age group. Number of unique participants for oncogenic HPV types of incidence analysis (with a total of 948) in MX by age: 120 from 18–24 age group, 290 from 25–32 age group, 289 from 33–41 group and 249 from 42+ age group. Number of unique participants for HPV type 16 incidence analysis (with a total of 1003) in MX by age: 123 from 18–24 age group, 303 from 25–32 age group,307 from 33–41 group and 270 from 42+ age group.
Supplementary Material
Acknowledgements
We thank the HIM Study teams and participants in the United States (Moffitt Cancer Center, Tampa), Brazil (Centro de Referência e Treinamento em DST/AIDS, Fundação Faculdade de Medicina Instituto do Câncer do Estado de São Paulo, Ludwig Institute for Cancer Research, São Paulo) and Mexico (Instituto Mexicano del Seguro Social, Instituto Nacional de Salud Pública, Cuernavaca). Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health (NIH) under Award Number R01CA214588 (A.R.G.). This work was supported in part by the Biostatistics and Bioinformatics Shared Resource at the H. Lee Moffitt Cancer Center and Research Institute, a National Cancer Institute (NCI) designated Comprehensive Cancer Center (P30-CA076292). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Additional support was provided by an American Cancer Society Clinical Research Professor Award to A.R.G.
Footnotes
Competing interests
A.R.G. reports grants and personal fees from Merck & Co. outside of the submitted work. L.L.V. is an occasional speaker for HPV prophylactic vaccines of Merck, Sharp & Dohme. All other authors report no competing interests.
Reporting summary
Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.
Code availability
No custom code was developed for the analysis of data in this manuscript.
Additional information
Extended data is available for this paper at https://doi.org/10.1038/s41564-024-01824-5.
Supplementary information The online version contains supplementary material available at https://doi.org/10.1038/s41564-024-01824-5.
Data availability
All data relevant to this manuscript are included in the Article or uploaded as supplementary material. The authors have also prepared a minimal de-identified dataset, necessary to interpret, replicate and build on the findings reported in the paper. Analyses and scripts have also been prepared on SAS version 9.4 for future referencing. Both the dataset and scripts are stored at Moffitt Cancer Center’s internal HIM Study cohort data repository. Due to the sensitive nature of the data, interested parties may request access to the de-identified data and SAS scripts by contacting the corresponding author. Kindly anticipate a response within 3–4 weeks.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
All data relevant to this manuscript are included in the Article or uploaded as supplementary material. The authors have also prepared a minimal de-identified dataset, necessary to interpret, replicate and build on the findings reported in the paper. Analyses and scripts have also been prepared on SAS version 9.4 for future referencing. Both the dataset and scripts are stored at Moffitt Cancer Center’s internal HIM Study cohort data repository. Due to the sensitive nature of the data, interested parties may request access to the de-identified data and SAS scripts by contacting the corresponding author. Kindly anticipate a response within 3–4 weeks.