Incidence and clearance of oral human papillomavirus infection in men: the HIM cohort study

doi:10.1016/S0140-6736(13)60809-0

The Lancet

Volume 382, Issue 9895, 7–13 September 2013, Pages 877-887

https://doi.org/10.1016/S0140-6736(13)60809-0 Get rights and content

Summary

Background

Oral human papillomavirus (HPV) infection causes a subset of oropharyngeal cancers. These cancers disproportionately affect men, are increasing in incidence, and have no proven prevention methods. We aimed to establish the natural history of oral HPV infection in men.

Methods

To estimate incidence and clearance of HPV infections, men residing in Brazil, Mexico, and the USA who were HIV negative and reported no history of anogenital cancer were recruited into the HPV Infection in Men (HIM) cohort study. A subset of the cohort who provided two or more oral rinse-and-gargle samples with valid HPV results and who completed a minimum of 2 weeks of follow-up were included in this analysis. Oral rinse-and-gargle samples and questionnaire data were obtained every 6 months for up to 4 years. Samples were analysed for the presence of oncogenic and non-oncogenic HPV infections by the linear array method.

Findings

1626 men aged 18–73 years and with a median follow-up of 12·7 months (IQR 12·1–14·7) were included in the analysis. During the first 12 months of follow-up, 4·4% (95% CI 3·5–5·6; n=115 incident infections) of men acquired an incident oral HPV infection, 1·7% (1·2–2·5; n=53 incident infections) an oral oncogenic HPV infection, and 0·6% (0·3–1·1; n=18 incident infections) an oral HPV 16 infection. Acquisition of oral oncogenic HPV was significantly associated with smoking and not being married or cohabiting, but was similar across countries, age groups, and reported sexual behaviours. Median duration of infection was 6·9 months (95 % CI 6·2–9·3; n=45 cleared infections) for any HPV, 6·3 months (6·0–9·9; n=18 cleared infections) for oncogenic HPV, and 7·3 months (6·0–not estimable; n=5 cleared infections) for HPV 16. Eight of the 18 incident oral HPV 16 infections persisted for two or more study visits.

Interpretation

Newly acquired oral oncogenic HPV infections in healthy men were rare and most were cleared within 1 year. Additional studies into the natural history of HPV are needed to inform development of infection-related prevention efforts.

Funding

US National Cancer Institute, Merck Sharp & Dohme.

Introduction

Human papillomavirus type 16 (HPV 16) is associated with the rapid increase in incidence of oropharyngeal cancer in some world regions, most notably in the USA, Sweden, and Australia, where it causes more than 50% of cases.1, 2, 3, 4 However, no proven methods exist to prevent or detect these cancers at an early stage. Detection of prevalent infection with HPV 16 in oral exfoliated cells is significantly associated with oropharyngeal cancer.⁵ However, prevalent oral HPV 16 infection is rare, present in only 1·0% of cancer-free individuals.6, 7 In recent population-based studies of oral HPV infection in the USA,6, 7 prevalence was three times higher in men than in women, which is a similar gender ratio to that reported for oropharyngeal cancer.⁸ A bimodal age distribution in HPV infection has been noted,⁷ with peak prevalence at ages 30–34 and 60–64 years. Whether these peaks are caused by increased duration of infection over an individual's lifespan or by an increase in acquisition at older ages (a pattern contrary to that established for cervical HPV infection) is an important epidemiological question.

Because prevalence is the product of acquisition and duration of infection, some oral HPV 16 infections detected cross-sectionally are likely to have persisted for some time. Persistent oral HPV 16 infection might be a precursor to oropharyngeal cancer, similar to how persistent cervical HPV infections lead to cervical precancer and, in the absence of screening, to cancer.9, 10 Although understanding the rates of HPV acquisition and persistence in the oral region is essential to inform potential prevention efforts for HPV-related oropharyngeal cancers, to do a prospective oral HPV infection study with oropharyngeal cancer as an endpoint is not feasible, since oral HPV 16 infection and the resultant HPV-induced oropharyngeal cancer are rare (1·8 per 100 000 women and 8·2 per 100 000 men),3, 11, 12 and a long latency period typically occurs between infection and cancer (at least 10–20 years).¹³ Thus, we made use of the HPV Infection in Men (HIM) study—a prospective cohort study to assess the natural history of genital HPV infections in healthy men residing in Brazil, Mexico, and the USA—to examine the acquisition and clearance of oral HPV infection, the presumed obligate precursor to HPV-related oropharyngeal cancer.

Section snippets

Study population

This work was nested within the HIM study, which is in progress and has been previously described.14, 15 Briefly, men were recruited from Brazil, Mexico, and the USA beginning in 2005; the oral component of this research was started in 2007.¹² The complete HIM study cohort consists of 4072 men aged 18–70 years who reported no previous diagnosis of penile or anal cancers, had never been diagnosed with genital or anal warts, and reported no symptoms of or treatment for a sexually transmitted

Results

The analysed cohort consisted of 1626 men (499 from Brazil, 557 from Mexico, and 570 from the USA) who were the first to have provided oral rinse-and-gargle samples at two or more study visits. These men completed a minimum of 2 weeks of follow-up (median 12·7 months, IQR 12·1–14·7; range 0·5–37·2). 161 (10%) men completed two follow-up visits, 953 (59%) completed three visits, 485 (30%) completed four visits, and 27 (2%) completed five visits. Men in the analysed cohort were similar to men in

Discussion

Our findings show that acquisition of an oral oncogenic HPV infection in healthy men is a rare event (2·5 per 1000 person-months) compared with genital (22·2 per 1000 person-months)¹⁵ and, to a lesser extent, anal (3·7 per 1000 person-months)²⁰ HPV infection, and that incidence is fairly stable across countries and age groups. We have also shown that, similar to patterns of clearance in the genital epithelium in men and women, most newly acquired oral oncogenic HPV infections in men clear

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Surveillance of human papillomavirus through salivary diagnostics - A roadmap to early detection of oropharyngeal cancer men
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Human papillomavirus (HPV) is the most common sexually transmitted disease. Certain strains have the potential to cause malignancy in multiple anatomical sites if not cleared by the immune system. In most infected people, HPV is cleared within two years. However, HPV may persist in susceptible individuals with certain risk factors, eventually leading to malignancy. New evidence suggests that over 75% of all oropharyngeal cancers (OPC) are directly attributable to HPV. It is estimated that prophylactic HPV vaccination alone may take at least 25 years to have a significant impact on reducing the incidence of OPC. The temporal link between detection of oral HPV, persistence of the infection and the subsequent development of OPC have been well established. Moreover, men have threefold higher risk than women for acquiring HPV-OPC. This comprehensive review focuses on OPC development in men, highlighting the risk factors associated with malignant transformation of HPV-OPC. Current evidence is insufficient to determine whether early identification of at-risk demographics, screening, and prompt diagnosis result in improved outcomes. Hitherto, the effectiveness of an oral HPV screening program in this regard has not been investigated. Nevertheless, the potential to emulate the success of the cervical screening program remains a very real possibility.
Impact of HPV vaccination on HPV-related oral infections
2023, Oral Oncology
Human papillomavirus (HPV) is one of the most common sexually transmitted infections worldwide. Although the efficacy of the HPV vaccine in preventing the development of cervical pre-malignant lesions has been well demonstrated, the efficacy of the HPV vaccine in preventing HPV infection in the upper respiratory tract has been poorly studied.
In the context of the IARC cohort study of two versus three doses of HPV vaccine in India, we compared the HPV type prevalence in the oral cavity of women vaccinated with three doses, two doses, or a single dose of quadrivalent HPV vaccine with that of unvaccinated women. A total of 997 oral samples, from 818 vaccinated women and 179 unvaccinated women, were collected at three study sites. All the participants were sexually active at the time of sample collection.
The age-standardized proportion (ASP) of HPV16/18 infections was 2.0 % (95 % CI, 1.0–3.0 %) in vaccinated women and 4.2 % (95 % CI, 1.2–7.2 %) in unvaccinated women. HPV16 was detected in 3.5 % of single-dose recipients, 1.2 % of two-dose recipients (days 1 and 180), and 1.5 % of three-dose recipients (days 1, 60, and 180), whereas 3.3 % of the unvaccinated women tested positive for HPV16. The same trend was observed for HPV18.
Our findings agree with those of previous studies on the efficacy of HPV vaccination in reducing oral HPV infections and provide indications that a single vaccine dose may be less efficient than two or three doses in preventing oral HPV infection.
Human papillomavirus detection in oral rinses and history of tonsillectomy in U.S. adults
2022, American Journal of Otolaryngology - Head and Neck Medicine and Surgery
This study aims to elucidate any relationship between prior tonsillectomy and the presence of oropharyngeal HPV DNA found in screening mouth rinses.
A cross sectional study was conducted using the 2011–2014 National Health and Nutrition Examination Survey (NHANES). Participants between 40 and 69 were included in the study and medical, surgical, and sexual health history were recorded. Multivariable analyses were conducted to examine factors associated with HPV prevalence in oral rinse samples.
A total of 4825 participants were recorded with 21.1 % having a history of tonsillectomy. In the no tonsillectomy group, 8.6 % of respondents had a positive oral rinse for HPV, while 7.2 % of those with a tonsillectomy had a positive rinse sample. There was no association between age and HPV prevalence (OR = 1.04, 95 % CI: [1.00–1.07]). When controlling for demographics, medical history, and sexual behaviors, tonsillectomy history was not shown to have an association with HPV (OR = 0.86, 95 % CI: [0.53–1.40]). However, men, Hispanics, smokers, and those with higher lifetime sexual partners had increased odds of having a positive HPV oral rinse sample which was statistically significant.
Our data showed that a history of tonsillectomy was not significantly associated with the presence of HPV in an oral rinse. However, a significant relationship was seen between the presence of HPV in oral rinses and certain demographic factors such as male gender, Hispanic race, smoking history, and increased sexual partners.
Oral human papillomavirus prevalence, persistence, and risk-factors in HIV-positive and HIV-negative adults
2022, Tumour Virus Research
HIV has been shown to increase the likelihood of oral HPV infection. In this study, we evaluated the risk of oral HPV in HIV infected patients compared with HIV-negative controls.
101 healthy adult volunteers (HIV-) and 245 adults living with HIV infection (HIV+) were recruited from 5 academic medical centers. Questionnaires and saliva samples were obtained every 3–8 months over a period of 2 years (2015–2017). DNA was isolated from the saliva samples and tested for 18 high- and low-risk genotypes.
Oral HPV was detected in 23% of HIV + vs. 10% of HIV- participants (p < 0.0001). Men had a higher oral HPV prevalence than women (27% vs. 15% HIV+, p = 0.03, 16% vs. 5% HIV-, p = 0.01). Risk factors among HIV + participants included more lifetime deep kissing and oral sex partners, and history of AIDS. Persistent oral HPV was detected in 23% of HIV + vs. 5% of HIV- participants (p < 0.001). Among 8 HIV + participants with CD4 counts <200 cell/μL none had cleared their HPV infection during the study.
Risk of oral HPV infection and persistence was significantly higher in HIV + adults with a history of poorly controlled HIV, which may put them at increased risk of HPV-associated cancer.
Long-term impact of HPV vaccination and COVID-19 pandemic on oropharyngeal cancer incidence and burden among men in the USA: A modeling study
2022, The Lancet Regional Health - Americas
Oropharyngeal cancer (OPC) incidence is rising rapidly among men in the United States of America (USA). We aimed to project the impact of maintaining the current HPV vaccination uptake and achieving 80% national (Healthy People) goal on OPC incidence and burden.
We developed an open-cohort micro-simulation model of OPC natural history among contemporary and future birth cohorts of men, accounting for sexual behaviors, population growth, aging, and herd immunity. We used data from nationally representative databases, cancer registries from all 50 states, large clinical trials, and literature. We evaluated the status quo scenario (the current HPV vaccination uptake remained stable) and alternative scenarios of improvements in uptake rates in adolescents (aged 9-17 years) and young adults (aged 18-26 years) by 2025 to achieve and maintain the 80% goal. The primary outcome was to project OPC incidence and burden from 2009 to 2100. We also assessed the impact of disruption in HPV vaccine uptake during the COVID-19 pandemic.
OPC incidence is projected to rise until the mid-2030s, reaching the age-standardized incidence rate of 9·8 (95% uncertainty interval [UI] 9·5-10·1) per 100 000 men, with the peak annual burden of 23 850 (UI, 23 200-24 500) cases. Under the status quo scenario, HPV vaccination could prevent 124 000 (UI, 117 000-131 000) by 2060, 400 000 (UI, 384 000-416 000) by 2080, and 792 000 (UI, 763 000-821 000) by 2100 OPC cases among men. Achievement and maintenance of 80% coverage among adolescent girls only, adolescent girls and boys, and adolescents plus young adults could prevent an additional number of 100 000 (UI, 95 000-105 000), 118 000 (UI, 113 000-123 000), and 142 000 (UI, 136 000-148 000) male OPC cases by 2100. Delayed recovery of the HPV vaccine uptake during the COVID-19 pandemic could lead to 600 (UI, 580-620) to 6200 (UI, 5940-6460) additional male OPC cases by 2100, conditional on the decline in the extent of the national HPV vaccination coverage and potential delay in rebounding.
Oropharyngeal cancer burden is projected to rise among men in the USA. Nationwide efforts to achieve the HPV vaccination goal of 80% coverage should be a public health priority. Rapid recovery of the declined HPV vaccination uptake during the COVID-19 pandemic is also crucial to prevent future excess OPC burden.
National Cancer Institute and National Institute on Minority Health and Health Disparities of the USA.
Prevalence and characteristics of tonsillar human papillomavirus infection in tumor-free patients undergoing tonsillectomy
2022, Auris Nasus Larynx
Citation Excerpt :
In this study, the most prevalent type of HPV infection was HPV 16, represented in 6 (75%) out of 8 patients with tonsillar HPV infection, and this result was also comparable to those of meta-analysis involving 2520 healthy pediatric patients reporting 78.6% of HPV 16 in 28 patients with HPV infections [5]. Even when including studies involving adult individuals and those that used oral rinse and gargle samples, there is no controversy that HPV 16 deemed the most prevalent type of HPV infection in the oral and tonsil tissues, regardless age and sample collection methods [7,8,10,22,26]. Interestingly, HPV types other than HPV 16 (HPV 52 and 58) detected in this study were high-risk.
This study evaluated the prevalence and characteristics of tonsillar human papillomavirus (HPV) infection in tumor-free patients undergoing tonsillectomy.
We prospectively enrolled healthy patients who underwent tonsillectomy for tumor-free tonsillar disease. Their tonsillar HPV infections were evaluated using CLART HPV2, and subsequent p16 immunohistochemistry was performed in patients with positive HPV infection. Moreover, the results of tonsillar HPV infection were analyzed according to sex, age, and indication of tonsillectomy.
A total of 362 patients were included. HPV test was positive in 8 patients, with an overall prevalence of 2.2%. All detected HPV types were high-risk, including HPV 16 in six patients, HPV 52 in one patient, and HPV 58 in one patient. P16 was negative in all 8 patients with HPV infection. The prevalence of tonsillar HPV infection in males and females was 2.4% (6/246) and 1.7% (2/116), respectively (P > 0.999), and in pediatric and adult patients, 2.2% (5/228) and 2.2% (3/134), respectively (P > 0.999). The prevalence showed a bimodal peak at 1st and 6th decades, with the prevalence of 2.6% (5/194) and 7.9% (3/38), respectively. The prevalence of tonsillar HPV infection in tonsillitis and non-tonsillitis groups were 0.0% (0/104) and 3.1% (8/258), respectively (P = 0.111).
The prevalence of tonsillar HPV infection in tumor-free patients was low, but all detected HPV infections were high-risk types. Our results support using a 9-valent vaccine which covers all high-risk HPV types found in this study

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^†: Contributed equally

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ArticlesIncidence and clearance of oral human papillomavirus infection in men: the HIM cohort study

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study population

Results

Discussion

Vaccine

Lancet Oncol

Lancet

Lancet

Lancet Oncol

J Multivar Anal

J Autoimmun

Human papillomavirus and rising oropharyngeal cancer incidence in the United States

J Clin Oncol

Annual report to the nation on the status of cancer, 1975–2009, featuring the burden and trends in human papillomavirus (HPV)-associated cancers and HPV vaccination coverage levels

J Natl Cancer Inst

Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma?

Int J Cancer

Case-control study of human papillomavirus and oropharyngeal cancer

N Engl J Med

National prevalence of oral HPV infection and related risk factors in the U.S. adult population

Oral Dis

Prevalence of oral HPV infection in the United States, 2009–2010

JAMA

Persistent genital human papillomavirus infection as a risk factor for persistent cervical dysplasia

J Natl Cancer Inst

Oral human papillomavirus in healthy individuals: a systematic review of the literature

Sex Transm Dis

Articles
Incidence and clearance of oral human papillomavirus infection in men: the HIM cohort study