INTRODUCTION — Papillomaviruses are double-stranded deoxyribonucleic acid (DNA) viruses that constitute the Papillomavirus genus of the Papillomaviridae family. These viruses are highly species specific; human papillomaviruses (HPVs) infect only humans. There are more than 200 types of HPVs, which can be subdivided into cutaneous or mucosal categories based upon their tissue tropism.
The epidemiology and disease associations of HPV infections will be reviewed here. The role of HPV in the pathogenesis of epithelial cancers is discussed elsewhere. (See "Virology of human papillomavirus infections and the link to cancer".)
The clinical manifestations, diagnosis, and management of HPV-associated diseases are discussed in the dedicated topic reviews.
Vaccination to prevent HPV infection and its associated diseases is also discussed elsewhere. (See "Human papillomavirus vaccination".)
Replication cycle — HPVs are small, nonenveloped, capsid viruses with an eight kilobase circular genome that encodes eight genes, including two encapsulating structural proteins, L1 and L2 . The L1 protein, expressed recombinantly in a cell-culture system, self-assembles in the absence of the viral genome to form a virus-like particle (VLP). The L1 VLP is the immunogen used in the HPV vaccines. L2 is the minor capsid protein that along with L1 mediates HPV infectivity [1,2].
The replication cycle of the virus is integrally linked to epithelial differentiation (ie, the maturation of the keratinocyte). Initial infection of the basal stem cell occurs as the result of microscopic breaks in the epithelium [3,4]. The infecting HPV virions appear to attach to the basal stem cell via tissue-specific heparan sulfate proteoglycans [5-7].
Specific gene products are transcribed at every level of differentiation of the squamous keratinocyte . At the most superficial level, the genes for the L1, L2, and E4 genes are transcribed for assembly of the viral capsid into which the HPV genome is packaged. Upon desquamation of this short-lived cell, infectious HPV virions are released for the next round of infection.
Natural history — Most HPV infections, including those with carcinogenic HPV genotypes, typically resolve within 12 months [8,9]. During productive cervical HPV infection, low-grade cytological abnormalities may be clinically detectable in screening, but are usually transient. However, carcinogenic HPV infections that persist beyond 12 months increase the likelihood of precancerous or cancerous lesions, although not all persistent infections progress. In the United States, the median age of cytologically detected precancerous cervical lesions occurs approximately 10 years after the median age of sexual debut .
HPV can enter a latent state [11-13]. Additionally, there is evidence of cervical viral reactivation in some populations, including females with human immunodeficiency virus (HIV) and older females [11,14,15]. However, it is unknown whether all or only a subset of HPV infections become latent and whether re-emergent HPV infections carry a significant cancer risk.
●Cutaneous – Certain HPV types have a predilection for cutaneous epithelium and are found in plantar warts, common warts, flat warts, and butcher's warts (common warts that tend to occur in meat, poultry, and fish handlers) . HPV types associated with plantar and common warts include types 1, 2, and 4. Flat warts are most often caused by HPV types 3 and 10, while butcher's warts are most often associated with HPV types 7 and 2 . (See 'Nongenital warts' below.)
●Anogenital epithelium – HPV types with a predilection for anogenital keratinized skin and mucous membrane infection also exist. Common sites for infection include the penis, scrotum, perineum, anal canal, perianal region, vaginal introitus, vulva, and cervix. Over 40 mucosal HPV genotypes can infect the genital tract. Anogenital disease manifestations differ by HPV type:
•Squamous intraepithelial lesions and/or carcinoma of the vagina, vulva, cervix, anus, or penis – Approximately 15 HPV types are associated with cancer and are known as high risk, carcinogenic, or cancer associated . HPV 16 is the most common and is associated with the highest risk of progression to cancer [17,18,21-24]. (See 'Cervical cancer' below and 'Vulvar and vaginal cancer' below and 'Anal cancer' below and 'Penile cancer and precursor lesions' below.)
The presence of a cervical transformation zone is not necessary for oncogenic HPV to infect the female genital tract. As a result, the prevalence of oncogenic HPV subtypes in the vagina is similar in females who have and have not undergone hysterectomy . Similarly, HPV may infect not only the anal canal in the anal transformation zone, but also more distal sites, including the keratinized skin of the anal verge and perianal region [26,27]. (See "Virology of human papillomavirus infections and the link to cancer".)
●Other mucosal surfaces – HPV type 16 can infect the oral mucosa and has been associated with squamous cell carcinoma of the oral cavity. Infection of the respiratory mucosa with HPV types 6 and 11 also occurs, particularly but not exclusively in young children and infants . (See 'Oropharyngeal cancer' below and 'Recurrent respiratory papillomatosis' below.)
HPV-related disease in females
Cervical cancer — Worldwide, cervical cancer is the fourth most common cancer among females, with approximately 570,000 cases of invasive cervical carcinoma diagnosed and 311,000 cervical cancer deaths annually . (See "Virology of human papillomavirus infections and the link to cancer" and "Cervical intraepithelial neoplasia: Terminology, incidence, pathogenesis, and prevention" and "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis".)
Evidence linking HPV to cervical carcinoma is extensive [17,21,22,29]. Virtually all cases of cervical cancer are attributable to HPV infection, with HPV 16 accounting for approximately 50 percent of cases and HPV 18 for 20 percent . HPV types 31, 33, 45, 52, and 58 are estimated to cause an additional 19 percent . The epidemiology of high-risk types can be illustrated by the following observations:
●A pooled analysis of 11 case-control studies from nine countries involving 1918 females with histologically confirmed squamous cell cervical cancer and 1928 controls was performed to better determine the risk associated with various HPV genotypes . HPV DNA was found in 90 percent of the females with cervical cancer and 13 percent of controls. Fifteen HPV types were classified as high risk (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82).
●A study of paraffin-embedded samples representing 10,575 cases of invasive cervical cancer from 38 countries spanning five continents demonstrated that the most common HPV types were 16, 18, 31, 33, 35, 45, 52, and 58; HPV types 16 and 18 represented 71 percent of the cases overall .
A detailed discussion of other risk factors for cervical cancer is found elsewhere. (See "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis", section on 'Epidemiology'.)
Vulvar and vaginal cancer — Vulvar and vaginal cancer are uncommon globally. Unlike cervical cancer, not all cancers of the external genitalia are associated with HPV infection. The attributable fraction due to HPV infection has been estimated to be 29 to 43 percent for vulvar cancer, 87 percent for vulvar intraepithelial neoplasia, 70 percent for vaginal cancer, and 69 to 100 percent for vaginal intraepithelial neoplasia [33-37]. HPV types 16 and 18 cause approximately 35 to 77 percent of HPV-positive vulvar cancer, 75 to 80 percent of HPV-positive precancerous vulvar lesions, and 60 percent of HPV-positive vaginal cancer and precancerous vaginal lesions [34,35].
In contrast to HPV-negative cancers of the external genitalia, HPV-associated vulvar cancers occur at a younger age, exhibit basaloid instead of keratinizing pathology, do not have p53 mutations, and are associated with sexual risk factors [38,39]. HPV-associated vaginal cancers have similar features, but overall, vaginal cancer is more likely to be HPV-associated [37,40].
The epidemiological link of HPV infection to these cancers is discussed in detail elsewhere. (See "Vulvar cancer: Epidemiology, diagnosis, histopathology, and treatment", section on 'Epidemiology' and "Vaginal cancer", section on 'Epidemiology and risk factors'.)
HPV-related disease in females and males
Nongenital warts — HPV is spread from skin surface to skin surface, and cutaneous HPV infections are widespread throughout the general population. Warts occur in 10 percent of children, with a peak incidence between the ages of 12 and 16 . Nongenital warts are not confined solely to the pediatric population; as many as 3.5 percent of adults have nongenital warts at any given time . Common warts represent up to 71 percent of all cutaneous warts followed in frequency by plantar warts and flat warts (34 and 4 percent, respectively) . Close personal contact is assumed to be of importance for the transmission of cutaneous warts . (See "Cutaneous warts (common, plantar, and flat warts)".)
Genital warts — Population-based studies in sexually active individuals suggest a prevalence ranging from 1 percent in the United States to approximately 10 percent in Scandinavian countries [41-44]. The peak prevalence occurs in persons between the ages of 17 and 33 years of age, and the peak incidence is in those aged 20 to 24 years. (See "Condylomata acuminata (anogenital warts) in adults: Epidemiology, pathogenesis, clinical features, and diagnosis", section on 'Epidemiology'.)
HPV types 6 and 11 cause approximately 90 percent of genital warts. In a study of 8800 females who were enrolled in the placebo arms of two HPV vaccine trials, approximately 3 percent developed genital warts over four years, and the vast majority were associated with HPV 6 or 11 infection .
In children, anogenital warts are associated with HPV types typically isolated from common warts (types 1 and 2). (See "Condylomata acuminata (anogenital warts) in children".)
Anal cancer — Anal cancer is relatively uncommon among the general global population, although its incidence has been increasing in some resource-rich settings, including the United States [46-49]. HPV types 16 and 18 cause nearly 90 percent of anal cancers and precancerous anal lesions (ie, high-grade squamous intraepithelial lesions) [48-52].
Females have a higher incidence of anal cancer than males, although incidence is particularly high among men who have sex with men, particularly those with HIV [53,54].
The epidemiologic link of HPV infection to anal cancer is discussed in detail elsewhere. (See "Classification and epidemiology of anal cancer", section on 'Human papillomavirus infection'.)
Oropharyngeal cancer — HPV infection plays a role in the pathogenesis of squamous cell carcinomas of the head and neck. Like penile and vulvar cancer, oropharyngeal cancers consist of two broad categories of disease: HPV-associated and non-HPV-associated. HPV-associated oropharyngeal cancers are primarily found in the oropharynx and base of the tongue and tonsil [55-57]. HPV has also been linked to cancer of the larynx . (See "Epidemiology, staging, and clinical presentation of human papillomavirus associated head and neck cancer".)
HPV-related oropharyngeal cancers occur in a younger population than the non-HPV-associated cancers and are associated with sexual risk factors [59,60]. In contrast, non-HPV-associated cancers are associated primarily with alcohol and tobacco use and often have p53 mutations. In the United States, the incidence of HPV-associated oropharyngeal cancers has been rising and the incidence of non-HPV-associated cancers has been declining, so that the incidence of the former now exceeds that of the latter [47,60]. In 2015, oropharyngeal squamous cell carcinoma was the most common HPV-associated cancer .
In an age- and sex-matched case-control study of 130 patients with newly diagnosed squamous cell carcinoma of the head and neck, oropharyngeal malignancy was associated with high-risk sexual behaviors, oropharyngeal HPV infection, and HPV 16 seropositivity .
The prevalence and incidence of oropharyngeal HPV infection is discussed below. (See 'Epidemiology of oropharyngeal infection' below.)
Recurrent respiratory papillomatosis — Recurrent respiratory papillomatosis is the most common benign laryngeal tumor in children and is thought to be caused by HPV acquired during passage through the birth canal of an infected mother . HPV 6 and 11 are the types most commonly involved. The incidence is uncertain but has been estimated at 4.5 per 100,000 children and 1.8 per 100,000 adults in the United States. Although benign, substantial morbidity arises from obstruction of the larynx by the warts, and many affected children require multiple ablative procedures [62,63]. In addition, the papillomatous lesions can, rarely, grow aggressively, spread into the lungs, and undergo malignant transformation.
This condition is discussed in further detail elsewhere. (See "Common causes of hoarseness in children", section on 'Papillomatosis'.)
Other cutaneous diseases
●Bowen's disease, a form of high-grade intraepithelial neoplasia, has both genital and extragenital forms . It can occur on the fingers, toes, palms, feet, and on the genital mucosa. Multiple HPV types have been isolated from these lesions, including HPV types 16, 18, 31, 32, 34, and others [16,21,64]. (See "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis", section on 'Cutaneous squamous cell carcinoma in situ (Bowen's disease)'.)
●Epidermodysplasia verruciformis is a rare, probably autosomal recessive condition characterized by the appearance of HPV-induced wart-like lesions early in childhood, with malignant transformation in approximately half of patients during adulthood, often in skin surfaces with sun exposure. Multiple HPV types have been isolated from these lesions, but HPV types 5 and 8 appear to have the most malignant potential in these individuals . (See "Epidermodysplasia verruciformis".)
HPV-related diseases in males
Penile cancer and precursor lesions — Penile cancer is uncommon globally, although in some parts of Africa, South America, and Asia, it accounts for up to 10 percent of male cancers . Unlike cervical cancer, not all cancers of the external genitalia are associated with HPV infection. HPV types 16 and 18 cause approximately 35 to 40 percent of penile cancers overall and 70 to 80 percent of HPV-positive penile cancers . In contrast to HPV-negative cancers of the external genitalia, HPV-associated penile cancers occur at a younger age, exhibit basaloid instead of keratinizing pathology, do not have p53 mutations, and are associated with sexual risk factors [38,39].
The epidemiological link of HPV infection to these cancers is discussed in detail elsewhere. (See "Carcinoma of the penis: Epidemiology, risk factors, and pathology", section on 'HPV'.)
DETECTION OF HPV — The clinical application of HPV detection is limited to testing of cervical specimens as part of cervical cancer screening and testing of oropharyngeal cancer biopsy specimens to inform appropriate staging and prognosis. These and the techniques for HPV detection are discussed in detail elsewhere. (See "Cervical cancer screening tests: Techniques for cervical cytology and human papillomavirus testing", section on 'HPV testing' and "Epidemiology, staging, and clinical presentation of human papillomavirus associated head and neck cancer", section on 'Confirming HPV 16 positivity'.)
Although HPV testing of other sites (vaginal, penile, and anal swabs, as well as oral rinses) has been used for surveillance and research purposes and is used clinically in special situations in some countries, such as the Netherlands and Australia, it is not approved for routine use in the United States. HPV testing in order to determine appropriateness of HPV vaccination is also not warranted.
In the United States, there are no Food and Drug Administration (FDA)-approved tests clinically available to detect HPV infection of oropharyngeal, anal, or male genital specimens. There are also no FDA-approved serological or blood tests to detect HPV infection.
The detection of HPV is facilitated by advances in molecular biology. HPV DNA testing was the first approach developed for routine clinical testing. Many studies showed that the addition of HPV DNA testing to cervical cytology improved the sensitivity for detection of cervical cancer precursors, such as cervical intraepithelial neoplasia (CIN) 2 and 3. However, this may come at the cost of decreased specificity with the potential for unnecessary referral of some females for colposcopy. Several different HPV DNA detection assays have been validated and are approved for clinical use in screening . (See "Cervical cancer screening tests: Techniques for cervical cytology and human papillomavirus testing", section on 'HPV testing'.)
HPV ribonucleic acid (RNA) testing, looking for expression of E6 and/or E7 RNA, may be performed with the expectation that active HPV oncogene expression would provide similar sensitivity and slightly better specificity than HPV DNA testing . RNA-based testing has received FDA approval for cervical HPV testing .
Cellular marker detection uses a different approach to diagnosing HPV-associated disease. The HPV E7 protein disrupts cell cycling, leading to an increase in cellular p16 protein expression. Per the recommendations of the Lower Anogenital Tract Terminology project , CIN 2 or anogenital biopsy specimens classified as grade 2 can be stained with p16 immunostain. Those that are positive are classified along with CIN 3 biopsies as high-grade squamous intraepithelial lesions. CIN 2 biopsies negative for p16 are classified as low-grade squamous intraepithelial lesions. p16 immunostaining of cervical biopsies is also used to help distinguish between high-grade CIN and immature squamous metaplasia, which is not associated with HPV and is not precancerous.
p16 staining, along with Ki-67 staining, is also used in cytology specimens. A large study investigating the combination p16/Ki-67 dual-stained cytology has demonstrated superior sensitivity and noninferior specificity over conventional liquid-based or slide-based cervical cytology to detect cervical high-grade squamous intraepithelial lesions dysplasia . A p16/Ki-67 cytology-based test is FDA approved for screening at this time and is typically used in conjunction with HPV testing to determine the need for referral for colposcopy and to guide other management decisions. (See "Cervical cancer screening: The cytology and human papillomavirus report", section on 'Management of results'.)
Several other methods of screening are under active investigation, including detection of HPV E6 oncoproteins  and host and HPV methylation assays [72-74]. The goal of incorporating these assays is to use them in combination with HPV testing or cytology to maximize the sensitivity and specificity and negative and positive predictive value of screening algorithms designed to identify females in need of colposcopy or other forms of further evaluation. The exact indication and the order of use of these tests are still under investigation in different populations. In addition, the various testing methods are being assessed for use in self-sampling specimens, since self sampling may allow females to participate in screening programs more easily than provider-collected sampling allows .
EPIDEMIOLOGY OF ANOGENITAL INFECTION — Globally, anogenital HPV is the most common sexually transmitted infection. Like all sexually transmitted infections, peak prevalence of HPV infection typically occurs within the first decade after sexual debut, typically between the ages of 15 to 25 years in most western countries.
It has been estimated that at least 80 percent of sexually active individuals are exposed to HPV once in their lifetime . However, many experts believe that virtually all sexually active adults have been infected by HPV for the following reasons:
●Most HPV infections are transient and can come and go in the interval between HPV testing [8,77].
●There are more than 40 HPV types that infect the entire lower genital tract, including the vagina [4,5,78,79].
Impact of HPV vaccine — Routine HPV immunization is recommended in many countries for adolescents and young adults. Many studies have reported declining prevalence and incidence of HPV infection as well as HPV-related disease following the introduction of HPV vaccination [80-96]. As an example, in the United States, the prevalence of quadrivalent HPV vaccine types 6, 11, 16, and 18 in cervical samples from females from the prevaccine (2003 to 2006) and post-vaccine (2013 to 2016) eras decreased by 88 percent (from 11.5 to 1.1 percent) among those aged 14 to 19 years and by 81 percent (from 18.5 to 3.3 percent) among those aged 20 to 24 years . This observation was made despite suboptimal vaccine coverage, with only an estimated 55 percent of adolescent females receiving at least one vaccine dose. Similarly in another study of participants within a large United States health care system, HPV vaccine type prevalence decreased 78 percent among 20- to 24-year-olds and 38 percent in 25- to 29-year-olds within 9 to 10 years of vaccine introduction . In these and other studies, declines in vaccine-type HPV infections have been observed in both vaccinated and unvaccinated individuals, showing evidence of direct and herd protection [94,95,99-102]. Several studies have documented the direct effect of HPV vaccination on reduction of cervical cancer in vaccinated populations [103,104]. (See "Human papillomavirus vaccination", section on 'Cervical, vaginal, and vulvar disease'.)
Vaccine effects on the prevalence of the five additional HPV types included in the 9-valent HPV vaccine are also expected to become evident once enough time has passed since the introduction of that vaccine.
The impact of HPV vaccination on HPV-associated disease is discussed in detail elsewhere. (See "Human papillomavirus vaccination", section on 'Efficacy'.)
United States — In the United States, anogenital HPV infection is common in young sexually active females, with an estimated prevalence of 20 million infections and annual incidence of 5.5 million infections [105-109]. Introduction of HPV vaccination has been associated with declines in HPV prevalence and incidence. (See 'Impact of HPV vaccine' above.)
The prevalence of genital HPV infection in the United States has been assessed by the National Health and Nutrition Examination Survey (NHANES), for which female participants submit vaginal swabs for HPV DNA testing. Between 2013 and 2014, the prevalence among females aged 18 to 59 years was 40 percent for all HPV types and 20 percent for high-risk HPV types . In an earlier, prevaccine era NHANES survey that included 2603 females aged 14 to 59 years, 30 percent had serologic evidence of prior infection with one of the seven high-risk HPV types included in the 9-valent vaccine . This proportion is thought to be an underestimation of the true exposure burden, as natural infection does not always result in detectable antibody levels, which additionally may wane with age. Furthermore, these are only point-prevalence estimates; lifetime risk of genital HPV infection is much higher.
The incidence of HPV infection is also high among young sexually active females soon after their sexual debut [106,108,112]. One study of female college students reported a 29 percent one-year cumulative incidence of HPV infection following their first male sexual partner; this increased to almost 50 percent after three years . Many sexually active young females have sequential infections with different oncogenic types of HPV. These infections are usually detected transiently, although they frequently produce reversible cytologic changes.
There may be racial differences in the type and turnover of HPV infection in females [113-115]. These differences are illustrated by the findings of a longitudinal study of 467 college-age females in the United States . The overall incidence of HPV infection was similar between Black and White females, but Black females had a slightly higher incidence of infection with high-risk HPV types. Two years after the incident high-risk HPV infection, more Black females had persistent infection (56 versus 24 percent of White females). These findings might partially explain the higher incidence of cervical cancer in Black females in the United States. (See "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis", section on 'Incidence and mortality'.)
Worldwide — A meta-analysis of studies including over 150,000 females with normal cervical cytology demonstrated that the worldwide point-prevalence of HPV is approximately 10 percent . The highest regional prevalence was in Africa, where 22 percent of females had evidence of HPV infection.
The most common types worldwide are HPV types 16 and 18, both of which are preventable by vaccination; however, there appears to be geographic variation in the distribution of HPV genotypes. As an example, in an HPV prevalence study from 11 countries that included over 15,000 sexually active females with normal cervical cytology, females in Europe with HPV infection were more likely to be infected with HPV type 16 compared with those in Sub-Saharan Africa (odds ratio [OR] 2.6) .
In a study of 1275 females aged 12 to 24 years seeking health services in Uganda, the prevalence HPV and HIV infections was 75 and 9 percent, respectively . Among high-risk types, the most frequently detected were HPV types 52 (13 percent), 51 (12 percent), 18 (11 percent), and 16 (11 percent).
In contrast, in a study of 2185 sexually active females recruited from universities in the United Kingdom, the prevalence of high-risk HPV infection, detected by testing of self-collected vaginal swabs, was 19 percent . Among those with high-risk HPV infection, HPV type 16 was the single most common type detected, but most of the females were infected with at least one non-16, non-18 HPV type.
Older females — The prevalence of cervical HPV infection decreases sharply in females after the age of 25 . A secondary, minor peak of HPV prevalence has been observed in some populations after menopause [20,121]. In China and Africa, the prevalence of HPV remains uniformly high at all ages . The cause of this is unknown.
Among older females, the prevalence of HPV detection might be related to persistence or reactivation of previously acquired infection rather than new, recent infections. In a cohort of over 800 females aged 35 to 60 years, the attributable risk for high-risk HPV detection associated with a history of more than five lifetime sexual partners was greater than that associated with a new sexual partner among females older than 50 years (87 versus 8 percent) . In contrast, among females 35 to 49 years of age, the attributable risks associated with lifetime and recent sexual partners were the same (28 percent). That this reflects reactivation of infection in older females is only one interpretation of the data, but raises important questions about the cause and importance of reactivation HPV [11,13,124]. Reactivation has also been proposed as a major source of newly detected HPV infection among females with HIV. In a prospective study of 1848 females with HIV (the Women's Interagency HIV Study), more than half of the females with newly detected cervical HPV infection had reported no new sexual partners since the prior visit .
Anal infections — Studies of anal HPV infection in females suggest that it is far more common than originally thought [126-130]. In studies of high-risk females, including females with HIV and females with a history of commercial sex work or injection drug use, anal HPV infection is more common than cervical HPV infection [131,132]. In studies of lower-risk females, the prevalence and incidence of anal HPV infection is similar to that of cervical HPV infection, and longitudinal studies have demonstrated that acquisition of cervical HPV infection predicts acquisition of anal HPV infection [127,133-135]. Similarly, in a systematic review of studies involving over 13,000 females with paired cervical and anal samples, there was a strong relationship between cervical HPV infection and anal HPV infection . Females with a history of vulvar or cervical high-grade, squamous intraepithelial lesions or cancer are also at increased risk of anal HPV infection and HPV-related disease .
Despite the frequency of anal HPV infections in females, they are often transient [126,136]. In one study of 431 sexually active females , half of whom had incident anal HPV infections, more than 58 percent became HPV DNA test-negative over a 15-month period of follow-up . This observation may help explain why the incidence of anal cancer is much lower than that of cervical cancer .
Risk factors for infection — Genital and cervical HPV infections are primarily transmitted by genital-genital or anal-genital contact . The most consistent predictor of genital HPV infection has been sexual activity . Most studies have been performed in young females in whom the following findings have been noted:
●As with other sexually transmitted infections, sex with a new partner is a stronger risk factor than sex with a long-term partner [106,142]. In a prospective cohort study of young females in San Francisco, for example, the relative hazard was 10.1 per new partner per month .
Both vaginal and anal intercourse are major risk factors for HPV infection . Although penetrating vaginal intercourse is not required for transmission , the prevalence of HPV infection is much lower among virgins (4 versus 22 percent in sexually active females in a report from Sweden) . In one study of adolescent females with no reported history of sex, genital HPV infection was noted in 8 percent and was associated with intravaginal cleansing, but this observation could simply reflect unreported or nonpenetrating sexual activity [144,145].
Anal intercourse is likely an efficient means of spread of HPV to the anal canal, but it is similarly not required for transmission; other types of contact may also play a role in transmission, such as spread through fingers or toys, or from other genital organs infected with HPV [106,146,147]. In one study from Australia, anal HPV infection was associated with post-toilet wiping from front to back, implying that direct spread of HPV from one genital site to another through wiping could account for some cases of anal HPV infection not associated with anal intercourse .
Among heterosexual couples, type-specific concordance (ie, both partners infected with the same HPV type) is common, almost 25 percent in one series . Additionally, among discordant heterosexual couples, female to male transmission may occur at a higher rate than male to female transmission . Transmission in either direction is typically asymptomatic [42,151].
In several studies of females, the presence of anti-HPV antibodies, indicative of prior infection, has been associated with a decreased risk of subsequent infection with HPV of the same type, particularly for type 16, suggesting the potential for protective immunity following natural infection [152-155]. However, the extent and duration of such protection is unknown, and many females do not develop antibodies following infection [156-158].
Correct and consistent condom use reduces the risk of HPV infection . However, condoms do not completely prevent transmission of HPV because the virus is spread through skin-to-skin contact.
Although use of an intrauterine device has been associated with a lower risk of cervical cancer, it does not appear to be associated with either the acquisition or clearance of genital HPV infection . (See "Intrauterine contraception: Candidates and device selection", section on 'Infection risk'.)
Males — In a systematic review of articles published from 1990 to 2006, HPV prevalence in males ranged from 1 to 73 percent . This wide range of prevalence was attributed to a combination of factors, including the anatomic sites sampled, number of specimens processed, and methods of detection used. A consistent finding among demographic groups is an association of increased sexual activity and high-risk HPV genotypes. Among males in the United States, based on data collected from participants in the 2013 to 2014 NHANES, for which male participants would submit penile swabs for HPV DNA testing, the prevalence of genital HPV infection was estimated to be 45 percent for all types and 25 percent for high-risk types . These are only point-prevalence estimates; lifetime risk of genital HPV infection is much higher.
Factors associated with prevalent HPV infection in males include HIV infection, current and past sexual behavior, number of sex partners, absence of condom use, prior sexually transmitted infection, race, ethnicity, and circumcision status [161-168]. Natural history studies demonstrate that uncircumcised males have slower rates of HPV clearance compared with circumcised males .
Men who have sex with men — The burden of anogenital HPV infection among men who have sex with men (MSM) is high [165,167,170], including among teenaged and young MSM under 30 years [171-173]. In a meta-analysis of 53 observational studies, the pooled prevalence for anal infection with any HPV type and any high-risk HPV type in MSM without HIV was 64 and 37 percent, respectively . The largest of these studies evaluated 1218 MSM without HIV between the ages of 18 and 89 years in four American cities . Demographic data and information on sexual practices were collected, and specimens from the anal canal were tested for the presence of HPV infection by polymerase-chain reaction. The following findings were noted:
●The overall prevalence of anal HPV infection was 57 percent
●Prevalence did not vary across age groups
●The most common HPV type was HPV 16, a high-risk type for anal cancer
In a multivariate analysis, anal HPV infection was independently associated with a history of receptive anal intercourse (OR 2) and with more than five sex partners during the preceding six months (OR 1.5). Another study that assessed the baseline prevalence of penile, scrotal, perineal, and intra-anal HPV infections among 602 MSM without HIV found anal infections to be the most common site of involvement (42 percent) . Published data from the placebo arm of an HPV vaccine study show that the prevalence of HPV 6, 11, and the 7 most common high-risk HPV infections was 37.9 percent, among MSM aged 16 to 26 years . Risk factors for HPV seropositivity in this group included younger age at sexual debut, higher number of receptive anal sex partners, and less frequent condom use.
Among males with HIV, the prevalence of anal HPV infection appears to be even higher. (See 'Effect of HIV infection on HPV' below.)
Heterosexual males — HPV genital infection is common among heterosexual males, as shown by the findings of several studies, including the human papillomavirus in men (HIM) study, which follows a large prospective cohort of males without HIV from the United States, Mexico, and Brazil:
●Among 3326 heterosexual males, the prevalence of genital HPV of any type was 53 percent . Almost one-third of study participants were infected with oncogenic HPV types. Factors associated with oncogenic HPV infection included smoking, heavy alcohol use, and a higher numbers of female sexual partners, whereas condom use was associated with a reduced likelihood of HPV infection.
●The 12-month incidence of genital HPV among 1159 males (about 90 percent of whom were heterosexual) was 39 and 27 percent for any type and oncogenic types, respectively . The overall median time to clearance of HPV infection was 7.5 months, although it was one year for HPV type 16.
Other, smaller studies of males in the United States have shown comparable HPV rates and associated factors [177-179]. These rates may differ in various regions of the world. A study of 776 heterosexual males without HIV in rural Uganda reported a high incidence of oncogenic genital HPV infection (33 cases per 100 person-years) . The risk of infection decreased with age, married status, and circumcision; condom use had no association. In another study of 3463 heterosexual males from Latin America, North America, Africa, Europe, and Asia, the prevalence of genital HPV was 21 percent for any type, although fewer types were tested for in this study . Neither condom use nor circumcision was associated with HPV infection. The prevalence of HPV was lowest in Asia and highest in Africa. Published data from the placebo arm of a HPV vaccine study show that the prevalence of HPV 6, 11, and the 7 most common high-risk HPV infections was 13.1 percent among heterosexual males aged 16 to 26 years .
Few studies have evaluated the frequency of anal HPV infection in heterosexual males, but it appears to be less than that of genital HPV infection. In a study that included 1305 heterosexual males, anal infection with any HPV type was detected in 12 percent, over half of whom carried an oncogenic type . Approximately 50 percent of the heterosexual males with anal HPV infection had the same HPV type detected on genital sampling. Risk factors for anal HPV infection included increased lifetime number of female sex partners, shorter duration of relationship with the current sex partner, prior genital HPV infection, and past diagnosis of hepatitis B virus infection [163,181].
The high rates of infection in these study populations suggest that strategies for the prevention of HPV infection also need to target males. (See "Human papillomavirus vaccination", section on 'Males'.)
Effect of circumcision — A meta-analysis of 23 studies was performed to assess the association between circumcision and HPV DNA . Circumcised males were less likely to have prevalent genital HPV infection than uncircumcised males (OR 0.57, 95% CI 0.45-0.71). There was weak evidence that circumcision was associated with decreased HPV incidence or increased HPV clearance.
Effect of HPV sampling sites — The epidemiology of HPV may also be affected by the specific genital sites that are sampled within studies; this issue is most controversial among males because of conflicting data on optimal HPV detection.
A systematic analysis of optimal HPV sampling in a prevalence study evaluated the site-specific prevalence of infection (eg, urethra, glans penis/coronal sulcus, penile shaft/prepuce, scrotum, perianal region, anal canal, semen, and urine) . HPV detection was highest at the penile shaft (50 percent) and lowest in the urethra and in semen (10 and 5 percent, respectively). Another prevalence study of 379 males also demonstrated a wide range of infection rates depending on the site sampled (eg, 6 percent in semen to 52 percent on the penile shaft) .
The findings were different in the incidence study . Sampling of the glans, penile shaft, and scrotum demonstrated that genital infection in males is multifocal and that there is no clear preferential site for infection. HPV DNA was also detected under fingernails; however, it is unclear as to whether this observation has significant implications for transmission.
EPIDEMIOLOGY OF OROPHARYNGEAL INFECTION — The prevalence of oropharyngeal human papillomavirus (HPV) is generally lower than that of anogenital HPV infection [57,110,185-188]. Also, consistent with the observed sex distribution for HPV-associated oropharyngeal cancer, the prevalence of oropharyngeal HPV infection in males is higher than in females. In a cross-sectional study of males and females who provided an oral rinse sample for HPV DNA sampling, the prevalence of oropharyngeal infection among 4493 males was 11.5 percent for any HPV type and 7.3 percent for high-risk HPV types; among the 4641 females, the prevalence was 3.2 and 1.4 percent, respectively . The prevalence of high-risk HPV infection was especially high (22.2 percent) among males reporting two or more lifetime same-sex oral sex partners.
Oropharyngeal HPV prevalence has been associated with a greater number of sexual (including oral sex) and open-mouthed kissing partners in both males and females, as well as with older age and smoking (both tobacco and marijuana) [57,185,188-190].
The incidence of oropharyngeal HPV is also lower than that of anogenital HPV infection. In a study of 1626 males aged 18 to 70 years (88 percent men who have sex with women only) without a prior history of HPV-associated disease and with a median follow-up of 13 months, 4.4 percent acquired an oropharyngeal infection with any HPV type, and 1.7 percent with an oncogenic HPV type . The incidence of oropharyngeal HPV infection was 5.6 and 2.5 cases per 1000 person-months for any and oncogenic types, respectively, and was constant across all age groups. In multivariate analysis, acquisition of a new oncogenic oropharyngeal HPV infection was associated with former or current smoking and being unmarried, but not with number of sexual partners or oral sex partners. Of the infections with enough longitudinal follow-up, 45 of 81 (56 percent) oral infections with any type and 18 of 24 (75 percent) infections with oncogenic types spontaneously cleared, at a median of six to seven months.
There is evidence that upper aerodigestive tract (nasal and oropharyngeal) HPV infection may be acquired in the health care setting through exposure to HPV in aerosols produced during surgical excision or ablation of HPV-associated lesions, although the magnitude of this risk is unknown . HPV DNA has been detected in surgical smoke generated following laser or electrocoagulation treatment of cutaneous and cervical lesions [193,194]. Smoke generated during laser ablation of bovine fibropapillomas caused new cutaneous lesions when injected into calves, suggesting the viability of infectious papillomavirus in surgical smoke , but this has not yet been specifically demonstrated for HPV. Clinical evidence also supports the possibility of transmission of HPV through surgical smoke. As an example, in a study of 700 gynecologists in China who underwent nasal swab testing for HPV, self-report of performing electrosurgery or loop electrosurgical excision procedures (LEEPs) was associated with a higher prevalence of HPV (9 to 10 percent compared with 2 to 3 percent) . However, none of those gynecologists with an initial positive test subsequently had detectable nasal HPV DNA over 24 months of follow-up, and none were diagnosed with HPV-associated upper aerodigestive tract disease. Nevertheless, HPV-associated upper aerodigestive tract disease has been reported in several surgeons with long histories of treating HPV-related lesions and no other clear risk factors [197,198]. Potential interventions to prevent occupational exposure to HPV are discussed elsewhere. (See "Human papillomavirus vaccination", section on 'Health care workers at risk for occupational exposure' and "Cervical intraepithelial neoplasia: Diagnostic excisional procedures", section on 'Health care workers at risk for occupational exposure'.)
There is emerging evidence that HPV vaccination can protect against oropharyngeal HPV infection [199-201]. (See "Human papillomavirus vaccination", section on 'Oral disease'.)
INTERACTIONS BETWEEN HIV AND HPV — There is a bidirectional epidemiologic interaction between HIV and HPV infections.
Effect of HIV infection on HPV — Several studies have shown that HPV infection is more common among individuals with HIV than in those without HIV [130,167,202-205].
Infection with multiple HPV types is also more common among individuals with HIV. In a study of 486 heterosexual South African couples followed for up to 24 months, new HPV infection was detected more frequently in females with HIV (57 versus 27 events per 1000 person-months) and males with HIV (80 versus 52 events per 1000 person-months) compared to individuals without HIV . Furthermore, HIV infection was independently associated with a decreased likelihood of clearance of HPV infection over time.
Another study evaluated the concordance of HPV infection among 254 heterosexually active couples and the impact of HIV coinfection on the prevalence of HPV . The following observations were made:
●HPV detection was significantly more common among females with HIV than among females without HIV (68 versus 31 percent, respectively).
●Similarly, HPV detection was significantly more common among males with HIV than among males without HIV (72 versus 43 percent, respectively).
●HIV coinfection in one partner had a significant impact on the prevalence of HPV infection in the other partner. For example, HIV-uninfected male partners of females with HIV had a greater prevalence of HPV than did HIV-uninfected male partners of females without HIV (58 versus 32 percent, respectively).
●Concordance of the same HPV genotypes was more commonly found among couples when one or both partners had HIV, compared with couples without HIV.
Among men who have sex with men (MSM), HPV prevalence is similarly increased in the setting of HIV infection [167,206-209]. In a meta-analysis of 53 studies, the pooled prevalence of anal HPV infection was considerably higher in males with HIV (93 and 74 percent for any type and any high-risk type, respectively, compared with 64 and 37 percent in MSM without HIV) .
The use of effective antiretroviral therapy (ART) may attenuate the risk of HPV infection and persistence among patients with HIV [205,210-212], although data are conflicting . As an example, in a study of 652 females with HIV, among whom the baseline prevalence of high-risk HPV was 42 percent, ART use and HIV RNA suppression for more than two years were each independently associated with a lower risk of high-risk HPV infection . Sustained HIV RNA suppression was also marginally associated with clearance of high-risk HPV infection (odds ratio 1.02, 95% CI 1.001-1.04). Other studies have not shown an association between ART use and decreased HPV risk . The effect of ART on the risk of HPV-associated neoplasia is discussed elsewhere. (See "Preinvasive and invasive cervical neoplasia in patients with HIV infection", section on 'Antiretroviral therapy' and "Anal squamous intraepithelial lesions: Epidemiology, clinical presentation, diagnosis, screening, prevention, and treatment", section on 'HIV'.)
Effect of HPV on HIV acquisition — HPV infection is associated with an increased risk for HIV acquisition. Whether HPV infection itself predisposes to subsequent HIV infection or is simply a marker of increased HIV risk remains unknown. It is also unclear whether prevalent HPV infection or the immune response associated with clearing that HPV infection, or both, plays a role in potentiating HIV acquisition.
The first evidence for an association between HPV infection and increased risk of HIV acquisition came from studies of MSM. In a cohort of MSM without HIV, infection with more than one anal HPV type was significantly associated with HIV seroconversion (adjusted hazard ratio [HR] 3.5; 95% CI 1.2–10.6) . Subsequent studies suggest that penile HPV infection is also a risk factor for subsequent HIV infection . Males without HIV in Kenya (n = 2168) who were participating in a randomized trial of male circumcision underwent HPV DNA sampling of their glans/coronal sulcus and were followed up for 42 months for evidence of HIV acquisition . Approximately 50 percent of the males had evidence of HPV DNA at baseline. After controlling for subsequent circumcision status, baseline herpes simplex virus type 2 serostatus, and other sexual risk factors, those males who were infected with HPV at baseline had a significantly higher risk of HIV acquisition compared with males without HPV infection (HR 1.8; 95% CI 1.1-2.9).
In contrast, in a case-control study of 44 males who acquired HIV and 787 males without HIV who had been followed in a circumcision trial, penile HPV acquisition was not associated with HIV acquisition after controlling for other HIV transmission risks . However, an association between clearance of HPV infection and subsequent HIV infection was observed in this study and postulated to be related to changes in local immune responses that might predispose to HIV infection.
The presence of HPV infection also appears to be associated with an increased risk of HIV acquisition among females. In a meta-analysis of prospective studies of females who underwent HPV testing, HIV acquisition was associated with baseline HPV infection of any type and high-risk type (HRs 2.06 [95% CI 1.44-2.94] and 1.99 [95% CI 1.54-2.56], respectively) when compared with no baseline HPV infection . Of note, several included studies did not assess or adjust for sexual behavior or other coincident sexually transmitted infections, which are significant potential confounders in the association between HPV and HIV. In a separate study of females from Zimbabwe, clearance of cervical HPV infection was associated with risk of HIV acquisition , similar to the association with clearance of penile HPV infection described in the study above. Similarly, in a clinical trial of HIV chemoprophylaxis among cisgender women in sub-Saharan Africa, HPV infection was associated with an increased risk of HIV seroconversion .
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Human papillomavirus (HPV) vaccine (Beyond the Basics)" and "Patient education: Genital warts in women (Beyond the Basics)" and "Patient education: Cervical cancer screening (Beyond the Basics)")
●Microbiology − Human papillomaviruses (HPV) are double-stranded DNA viruses that only infect humans. There are more than 200 types of HPV, which differ in their tissue tropism (table 1). HPV can be transmitted from one epithelial surface to another. Most infections typically resolve within 12 months. However, persistent infection with high-risk HPV types can increase the risk of precancerous or cancerous lesions. (See 'Microbiology' above.)
●Genotypes and disease associations − Cutaneous infection with HPV types 1 and 2 is associated with plantar or common hand warts. Mucocutaneous infection with HPV types 6, 11, 16, and 18 is associated with genital warts and precancerous and cancerous lesions of the cervix, vulva, vagina, penis, anus, and oropharynx. Evidence linking HPV to cervical carcinoma is extensive, with HPV 16 accounting for approximately 50 percent of invasive cervical cancers, and HPV 18 for 20 percent. (See 'Genotypes and tissue tropism' above and 'Disease associations' above.)
●Detection of HPV − Clinical application of HPV detection is limited to testing cervical specimens and oropharyngeal cancer biopsy specimens. Although HPV testing of other sites has been used for surveillance and research purposes, there is no clinical utility to such testing, and we do not recommend it. (See 'Detection of HPV' above.)
●Anogenital infections − Anogenital HPV is the most common sexually transmitted infection. Peak prevalence of HPV infection typically occurs within the first decade after sexual debut. The worldwide prevalence of genital HPV infection among females is approximately 10 percent, and HPV type 16 is the most common high-risk type. Penile HPV infection is also highly prevalent among males, and anal infection is common among females and men who have sex with men. Persons with multiple sex partners are at greater risk for HPV infection compared with those in a monogamous relationship, and individuals with a new sex partner are at greater risk than those with a long-term sex partner. (See 'Epidemiology of anogenital infection' above.)
●Oropharyngeal HPV − The prevalence of oropharyngeal HPV infection is higher in males than in females but is overall lower than that of anogenital infection. Oropharyngeal HPV infection is also associated with sexual risk factors. (See 'Epidemiology of oropharyngeal infection' above.)
●Interaction between HIV and HPV − HPV detection is more common among individuals with HIV than among those without HIV. HPV infection is associated with an increased risk of HIV acquisition. Whether HPV infection itself predisposes to subsequent HIV infection or is simply a marker of increased HIV risk remains unknown. (See 'Interactions between HIV and HPV' above.)
●Impact of HPV vaccine − The introduction of routine HPV vaccination of adolescents and young adults has been associated with a decline in the burden of HPV infection as well as HPV-associated disease. (See 'Impact of HPV vaccine' above and "Human papillomavirus vaccination", section on 'Efficacy'.)
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