Human papillomavirus
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Human papillomavirus infection (HPV infection) is caused by a
DNA virus A DNA virus is a virus that has a genome made of deoxyribonucleic acid (DNA) that is replicated by a DNA polymerase. They can be divided between those that have two strands of DNA in their genome, called double-stranded DNA (dsDNA) viruses, and ...
from the ''
Papillomaviridae ''Papillomaviridae'' is a family of non- enveloped DNA viruses whose members are known as papillomaviruses. Several hundred species of papillomaviruses, traditionally referred to as "types", have been identified infecting all carefully inspected ...
'' family. Many HPV infections cause no symptoms and 90% resolve spontaneously within two years. In some cases, an HPV infection persists and results in either
wart Warts are typically small, rough, hard growths that are similar in color to the rest of the skin. They typically do not result in other symptoms, except when on the bottom of the feet, where they may be painful. While they usually occur on the ...
s or precancerous lesions. These lesions, depending on the site affected, increase the risk of cancer of the cervix,
vulva The vulva (plural: vulvas or vulvae; derived from Latin for wrapper or covering) consists of the external sex organ, female sex organs. The vulva includes the mons pubis (or mons veneris), labia majora, labia minora, clitoris, bulb of vestibu ...
,
vagina In mammals, the vagina is the elastic, muscular part of the female genital tract. In humans, it extends from the vestibule to the cervix. The outer vaginal opening is normally partly covered by a thin layer of mucosal tissue called the hymen ...
,
penis A penis (plural ''penises'' or ''penes'' () is the primary sexual organ that male animals use to inseminate females (or hermaphrodites) during copulation. Such organs occur in many animals, both vertebrate and invertebrate, but males do n ...
, anus, mouth, tonsils, or throat. Nearly all
cervical cancer Cervical cancer is a cancer arising from the cervix. It is due to the abnormal growth of cells that have the ability to invade or spread to other parts of the body. Early on, typically no symptoms are seen. Later symptoms may include abnormal ...
is due to HPV and two strains – HPV16 and HPV18 – account for 70% of cases. HPV16 is responsible for almost 90% of
HPV-positive oropharyngeal cancer Human papillomavirus-positive oropharyngeal cancer (HPV-positive OPC or HPV+OPC), is a cancer ( squamous cell carcinoma) of the throat caused by the human papillomavirus type 16 virus (HPV16). In the past, cancer of the oropharynx (throat) was as ...
s. Between 60% and 90% of the other cancers listed above are also linked to HPV. HPV6 and HPV11 are common causes of
genital wart Genital warts are a sexually transmitted infection caused by certain types of human papillomavirus (HPV). They are generally pink in color and project out from the surface of the skin. Usually they cause few symptoms, but can occasionally be pai ...
s and
laryngeal papillomatosis Laryngeal papillomatosis, also known as recurrent respiratory papillomatosis (RRP) or glottal papillomatosis, is a rare medical condition in which benign tumors (papilloma) form along the aerodigestive tract. There are two variants based on the ag ...
. An HPV infection is caused by ''human papillomavirus'', a DNA virus from the papillomavirus family. Over 170 types have been described. An individual can become infected with more than one type of HPV, and the disease is only known to affect humans. More than 40 types may be spread through sexual contact and infect the anus and
genitals A sex organ (or reproductive organ) is any part of an animal or plant that is involved in sexual reproduction. The reproductive organs together constitute the reproductive system. In animals, the testis in the male, and the ovary in the female, a ...
. Risk factors for persistent infection by sexually transmitted types include early age of first
sexual intercourse Sexual intercourse (or coitus or copulation) is a sexual activity typically involving the insertion and thrusting of the penis into the vagina for sexual pleasure or reproduction.Sexual intercourse most commonly means penile–vaginal penetrat ...
, multiple sexual partners, smoking, and
poor immune function Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reacti ...
. These types are typically spread by sustained direct skin-to-skin contact, with
vaginal In mammals, the vagina is the elastic, muscular part of the female genital tract. In humans, it extends from the vestibule to the cervix. The outer vaginal opening is normally partly covered by a thin layer of mucosal tissue called the hyme ...
and anal sex being the most common methods. HPV infection can also spread from a mother to baby during pregnancy. There is no evidence that HPV can spread via common items like toilet seats, but the types that cause warts may spread via surfaces such as floors. HPV is not killed by common hand sanitizers and disinfectants, increasing the possibility of the virus being transferred via non-living infectious agents called
fomite A fomite () or fomes () is any inanimate object that, when contaminated with or exposed to infectious agents (such as pathogenic bacteria, viruses or fungi), can transfer disease to a new host. Transfer of pathogens by fomites A fomite is any ina ...
s. HPV vaccines can prevent the most common types of infection. To be most effective, inoculation should occur before the onset of sexual activity, and are therefore recommended between the ages of 9–13 years. Cervical cancer screening, such as the
Papanicolaou test The Papanicolaou test (abbreviated as Pap test, also known as Pap smear (AE), cervical smear (BE), cervical screening (BE), or smear test (BE)) is a method of cervical screening used to detect potentially precancerous and cancerous processes in t ...
("pap smear"), or examination of the cervix after applying
acetic acid Acetic acid , systematically named ethanoic acid , is an acidic, colourless liquid and organic compound with the chemical formula (also written as , , or ). Vinegar is at least 4% acetic acid by volume, making acetic acid the main component ...
, can detect both early cancer and abnormal cells that may develop into cancer. Screening allows for early treatment which results in better outcomes. Screening has reduced both the number of cases and the number of deaths from cervical cancer. Genital warts can be removed by
freezing Freezing is a phase transition where a liquid turns into a solid when its temperature is lowered below its freezing point. In accordance with the internationally established definition, freezing means the solidification phase change of a liquid ...
. Nearly every sexually active individual is infected by HPV at some point in their lives. HPV is the most common sexually transmitted infection (STI), globally. Worldwide in 2018, an estimated 569,000 new cases of cervical cancer occurred, with 311,000 deaths. Around 85% of these cervical cancers occurred in low- and middle-income countries. In the United States, about 30,700 cases of cancer due to HPV occur each year. Roughly 1% of sexually active adults have genital warts. Cases of skin warts have been described since the time of
ancient Greece Ancient Greece ( el, Ἑλλάς, Hellás) was a northeastern Mediterranean civilization, existing from the Greek Dark Ages of the 12th–9th centuries BC to the end of classical antiquity ( AD 600), that comprised a loose collection of cult ...
, but that they were caused by a virus was not determined until 1907.


Signs and symptoms

Some HPV types, such as HPV-5, may establish infections that persist for the lifetime of the individual without ever manifesting any clinical symptoms. HPV types 1 and 2 can cause common warts in some infected individuals. HPV types 6 and 11 can cause genital warts and
laryngeal papillomatosis Laryngeal papillomatosis, also known as recurrent respiratory papillomatosis (RRP) or glottal papillomatosis, is a rare medical condition in which benign tumors (papilloma) form along the aerodigestive tract. There are two variants based on the ag ...
. Many HPV types are carcinogenic. The table below lists common symptoms of HPV infection and the associated strains of HPV.


Warts

Skin infection ("
cutaneous Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal coverings, such as the arthropod exoskeleton, have different d ...
" infection) with HPV is very widespread. Skin infections with HPV can cause noncancerous skin growths called
warts Warts are typically small, rough, hard growths that are similar in color to the rest of the skin. They typically do not result in other symptoms, except when on the bottom of the feet, where they may be painful. While they usually occur on the ...
(verrucae). Warts are caused by a rapid growth of cells on the outer layer of the skin. While cases of warts have been described since the time of ancient Greece, their viral cause was not known until 1907. Skin warts are most common in childhood and typically appear and regress spontaneously over the course of weeks to months. Recurring skin warts are common. All HPVs are believed to be capable of establishing long-term "latent" infections in small numbers of
stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...
s present in the skin. Although these latent infections may never be fully eradicated, immunological control is thought to block the appearance of symptoms such as warts. Immunological control is HPV type-specific, meaning an individual may become resistant to one HPV type while remaining susceptible to other types. Types of warts include: * Common warts are usually found on the hands and feet, but can also occur in other areas, such as the elbows or knees. Common warts have a characteristic cauliflower-like surface and are typically slightly raised above the surrounding skin. Cutaneous HPV types can cause genital warts but are not associated with the development of cancer. *
Plantar wart A plantar wart, or verruca vulgaris, is a wart occurring on the bottom of the foot or toes. Its color is typically similar to that of the skin. Small black dots often occur on the surface. One or more may occur in an area. They may result in pa ...
s are found on the soles of the feet; they grow inward, generally causing pain when walking. * Subungual or
periungual wart Periungual warts are warts that cluster around the fingernail or toenail. They appear as thickened, fissured cauliflower-like skin around the nail plate. Periungual warts often cause loss of the cuticle and paronychia. Nail biting increases su ...
s form under the
fingernail A nail is a claw-like plate found at the tip of the fingers and toes on most primates. Nails correspond to the claws found in other animals. Fingernails and toenails are made of a tough protective protein called alpha-keratin, which is a polymer ...
(subungual), around the fingernail, or on the cuticle (periungual). They are more difficult to treat than warts in other locations. * Flat warts are most commonly found on the arms, face, or forehead. Like common warts, flat warts occur most frequently in children and teens. In people with normal immune function, flat warts are not associated with the development of cancer. Common, flat, and plantar warts are much less likely to spread from person to person.


Genital warts

HPV infection of the skin in the genital area is the most common sexually transmitted infection worldwide. Such infections are associated with genital or anal warts (medically known as condylomata acuminata or venereal warts), and these warts are the most easily recognized sign of genital HPV infection. The strains of HPV that can cause genital warts are usually different from those that cause warts on other parts of the body, such as the hands or feet, or even the inner thighs. A wide variety of HPV types can cause genital warts, but types 6 and 11 together account for about 90% of all cases. However, in total more than 40 types of HPV are transmitted through sexual contact and can infect the skin of the anus and genitals. Such infections may cause genital warts, although they may also remain asymptomatic. The great majority of genital HPV infections never cause any overt symptoms and are cleared by the immune system in a matter of months. Moreover, people may transmit the virus to others even if they do not display overt symptoms of infection. Most people acquire genital HPV infections at some point in their lives, and about 10% of women are currently infected. A large increase in the incidence of genital HPV infection occurs at the age when individuals begin to engage in sexual activity. As with cutaneous HPVs, immunity to genital HPV is believed to be specific to a specific strain of HPV.


Laryngeal papillomatosis

In addition to genital warts, infection by HPV types 6 and 11 can cause a rare condition known as recurrent
laryngeal papillomatosis Laryngeal papillomatosis, also known as recurrent respiratory papillomatosis (RRP) or glottal papillomatosis, is a rare medical condition in which benign tumors (papilloma) form along the aerodigestive tract. There are two variants based on the ag ...
, in which warts form on the
larynx The larynx (), commonly called the voice box, is an organ in the top of the neck involved in breathing, producing sound and protecting the trachea against food aspiration. The opening of larynx into pharynx known as the laryngeal inlet is about ...
or other areas of the respiratory tract. These warts can recur frequently, may interfere with breathing, and in extremely rare cases can progress to cancer. For these reasons, repeated surgery to remove the warts may be advisable.


Cancer


Virus types

About a dozen HPV types (including types 16, 18, 31, and 45) are called "high-risk" types because persistent infection has been linked to cancer of the
oropharynx The pharynx (plural: pharynges) is the part of the throat behind the mouth and nasal cavity, and above the oesophagus and trachea (the tubes going down to the stomach and the lungs). It is found in vertebrates and invertebrates, though its struc ...
,
larynx The larynx (), commonly called the voice box, is an organ in the top of the neck involved in breathing, producing sound and protecting the trachea against food aspiration. The opening of larynx into pharynx known as the laryngeal inlet is about ...
,
vulva The vulva (plural: vulvas or vulvae; derived from Latin for wrapper or covering) consists of the external sex organ, female sex organs. The vulva includes the mons pubis (or mons veneris), labia majora, labia minora, clitoris, bulb of vestibu ...
,
vagina In mammals, the vagina is the elastic, muscular part of the female genital tract. In humans, it extends from the vestibule to the cervix. The outer vaginal opening is normally partly covered by a thin layer of mucosal tissue called the hymen ...
, cervix,
penis A penis (plural ''penises'' or ''penes'' () is the primary sexual organ that male animals use to inseminate females (or hermaphrodites) during copulation. Such organs occur in many animals, both vertebrate and invertebrate, but males do n ...
, and anus. These cancers all involve sexually transmitted infection of HPV to the stratified epithelial tissue. Individuals infected with both HPV and HIV have an increased risk of developing cervical or anal cancer. HPV type 16 is the strain most likely to cause cancer and is present in about 47% of all cervical cancers, and in many vaginal and vulvar cancers, penile cancers, anal cancers, and cancers of the head and neck.


Case statistics

An estimated 561,200 new cancer cases worldwide (5.2% of all new cancers) were attributable to HPV in 2002, making HPV one of the most important infectious causes of cancer. HPV-associated cancers make up over 5% of total diagnosed cancer cases worldwide, and this incidence is higher in developing countries where it is estimated to cause almost half a million cases each year. In the United States, about 30,700 cases of cancer due to HPV occur each year.


Cancer development

In some infected individuals, their immune systems may fail to control HPV. Lingering infection with high-risk HPV types, such as types 16, 18, 31, and 45, can favor the development of cancer. Co-factors such as cigarette smoke can also enhance the risk of such HPV-related cancers. HPV is believed to cause cancer by integrating its genome into
nuclear DNA Nuclear DNA (nDNA), or nuclear deoxyribonucleic acid, is the DNA contained within each cell nucleus of a eukaryotic organism. It encodes for the majority of the genome in eukaryotes, with mitochondrial DNA and plastid DNA coding for the rest. I ...
. Some of the early genes expressed by HPV, such as E6 and E7, act as
oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.
s that promote tumor growth and
malignant transformation Malignant transformation is the process by which cells acquire the properties of cancer. This may occur as a primary process in normal tissue, or secondarily as ''malignant degeneration'' of a previously existing benign tumor. Causes There are ...
. HPV genome integration can also cause
carcinogenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...
by promoting genomic instability associated with alterations in DNA copy number. E6 produces a protein (also called E6) that simultaneously binds to two host cell proteins called
p53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
and E6-Associated Protein ( E6-AP). E6AP is an E3
Ubiquitin ligase A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquit ...
, an enzyme whose purpose is to tag proteins with a
post-translational modification Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribos ...
called Ubiquitin. By binding both proteins, E6 induces E6AP to attach a chain of
ubiquitin Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
molecules to p53, thereby flagging p53 for proteosomal degradation. Normally, p53 acts to prevent cell growth and promotes
cell death Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as d ...
in the presence of DNA damage. p53 also upregulates the p21 protein, which blocks the formation of the cyclin D/Cdk4 complex, thereby preventing the phosphorylation of
retinoblastoma protein The retinoblastoma protein (protein name abbreviated pRb; gene name abbreviated ''Rb'', ''RB'' or ''RB1'') is a proto-oncogenic tumor suppressor protein that is dysfunctional in several major cancers. One function of pRb is to prevent excessive ...
(RB), and in turn, halting cell cycle progression by preventing the activation of E2F. In short, p53 is a tumor-suppressor protein that arrests the cell cycle and prevents cell growth and survival when DNA damage occurs. Thus, the degradation of p53, induced by E6, promotes unregulated cell division, cell growth and cell survival, all characteristics of cancer. It is important to note, that while the interaction between E6, E6AP and p53 was the first to be characterized, there are multiple other proteins in the host cell which interact with E6 and assist the induction of cancer.


Squamous cell carcinoma of the skin

Studies have also shown a link between a wide range of HPV types and
squamous cell carcinoma of the skin Squamous-cell skin cancer, also known as cutaneous squamous-cell carcinoma (cSCC), is one of the main types of skin cancer along with basal cell cancer and melanoma. It usually presents as a hard lump with a scaly top but can also form an ulcer. O ...
. In such cases, ''in vitro'' studies suggest that the E6 protein of the HPV virus may inhibit
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
induced by
ultraviolet light Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nanometer, nm (with a corresponding frequency around 30 Hertz, PHz) to 400 nm (750 Hertz, THz), shorter than that of visible light, but longer than ...
.


Cervical cancer

Nearly all cases of
cervical cancer Cervical cancer is a cancer arising from the cervix. It is due to the abnormal growth of cells that have the ability to invade or spread to other parts of the body. Early on, typically no symptoms are seen. Later symptoms may include abnormal ...
are associated with HPV infection, with two types, HPV16 and HPV18, present in 70% of cases. In 2012, twelve HPV types were considered carcinogenic for cervical cancer by the
International Agency for Research on Cancer The International Agency for Research on Cancer (IARC; french: Centre International de Recherche sur le Cancer, CIRC) is an intergovernmental agency forming part of the World Health Organization of the United Nations. Its role is to conduct and ...
: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59. HPV is necessary for cervical cancer to occur. Persistent HPV infection increases the risk for developing cervical carcinoma. Individuals who have an increased incidence of these types of infection are women with HIV/AIDS, who are at a 22-fold increased risk of cervical cancer. The carcinogenic HPV types in cervical cancer belong to the
alphapapillomavirus ''Alphapapillomavirus'' is a genus of viruses, in the family ''Papillomaviridae''. Human and monkeys serve as natural hosts. There are 14 species in this genus. Diseases associated with this genus include: warts, papilloma, malignant tumours. G ...
genus and can be grouped further into HPV
clade A clade (), also known as a monophyletic group or natural group, is a group of organisms that are monophyletic – that is, composed of a common ancestor and all its lineal descendants – on a phylogenetic tree. Rather than the English term, ...
s. The two major carcinogenic HPV clades, alphapapillomavirus-9 (A9) and alphapapillomavirus-7 (A7), contain
HPV16 ''Papillomaviridae'' is a family of non- enveloped DNA viruses whose members are known as papillomaviruses. Several hundred species of papillomaviruses, traditionally referred to as "types", have been identified infecting all carefully inspected ...
and HPV18, respectively. These two HPV clades were shown to have different effects on tumour molecular characteristics and patient prognosis, with clade A7 being associated with more aggressive pathways and an inferior prognosis. In 2012, about 528,000 new cases and 266,000 deaths from cervical cancer occurred worldwide. Around 85% of these occurred in the
developing world A developing country is a sovereign state with a lesser developed industrial base and a lower Human Development Index (HDI) relative to other countries. However, this definition is not universally agreed upon. There is also no clear agreem ...
. Most HPV infections of the cervix are cleared rapidly by the immune system and do not progress to cervical cancer (see below the Clearance subsection in Virology). Because the process of transforming normal cervical cells into cancerous ones is slow, cancer occurs in people having been infected with HPV for a long time, usually over a decade or more (persistent infection). Furthermore, both the HPV infection and cervical cancer drive metabolic modifications that may be correlated with the aberrant regulation of enzymes related to metabolic pathways. Non-European (NE) HPV16 variants are significantly more carcinogenic than European (E) HPV16 variants.


Anal cancer

Studies show a link between HPV infection and anal cancers. Sexually transmitted HPVs are found in a large percentage of anal cancers. Moreover, the risk for anal cancer is 17 to 31 times higher among HIV-positive individuals who were coinfected with high-risk HPV, and 80 times higher for particularly HIV-positive men who have sex with men. Anal Pap smear screening for anal cancer might benefit some subpopulations of men or women engaging in anal sex. No consensus exists, though, that such screening is beneficial, or who should get an anal Pap smear.


Penile cancer

HPV is associated with approximately 50% of penile cancers. In the United States, penile cancer accounts for about 0.5% of all cancer cases in men. HPV16 is the most commonly associated type detected. The risk of penile cancer increases 2- to 3-fold for individuals who are infected with HIV as well as HPV.


Head and neck cancers

Oral infection with high-risk carcinogenic HPV types (most commonly HPV 16) is associated with an increasing number of
head and neck cancer Head and neck cancer develops from tissues in the lip and oral cavity (mouth), larynx (throat), salivary glands, nose, sinuses or the skin of the face. The most common types of head and neck cancers occur in the lip, mouth, and larynx. Symptoms ...
s.Ridge JA, Glisson BS, Lango MN, et al
"Head and Neck Tumors"
in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds
Cancer Management: A Multidisciplinary Approach
. 11 ed. 2008.
This association is independent of
tobacco Tobacco is the common name of several plants in the genus '' Nicotiana'' of the family Solanaceae, and the general term for any product prepared from the cured leaves of these plants. More than 70 species of tobacco are known, but the ...
and alcohol use. Sexually transmitted forms of HPV account for about 25% of cancers of the mouth and upper throat (the oropharynx) worldwide, but the local percentage varies widely, from 70% in the United States to 4% in Brazil. Engaging in anal or oral sex with an HPV-infected partner may increase the risk of developing these types of cancers. In the United States, the number of newly diagnosed, HPV-associated head and neck cancers has surpassed that of cervical cancer cases. The rate of such cancers has increased from an estimated 0.8 cases per 100,000 people in 1988 to 4.5 per 100,000 in 2012, and, as of 2015, the rate has continued to increase. Researchers explain these recent data by an increase in oral sex. This type of cancer is more common in men than in women. The mutational profile of HPV-positive and HPV-negative head and neck cancer has been reported, further demonstrating that they are fundamentally distinct diseases.


Lung cancer

Some evidence links HPV to benign and malignant tumors of the upper respiratory tract. The International Agency for Research on Cancer has found that people with lung cancer were significantly more likely to have several high-risk forms of HPV antibodies compared to those who did not have lung cancer. Researchers looking for HPV among 1,633 lung cancer patients and 2,729 people without the lung disease found that people with lung cancer had more types of HPV than noncancer patients did, and among lung cancer patients, the chances of having eight types of serious HPV were significantly increased. In addition, expression of HPV structural proteins by immunohistochemistry and ''in vitro'' studies suggest HPV presence in bronchial cancer and its precursor lesions. Another study detected HPV in the
exhaled breath condensate Exhaled breath condensate (EBC) is the exhalate from breath, that has been condensed, typically via cooling using a collection device (commonly to 4 °C or subzero temperatures using a refrigerating device). EBC reflects changes in the respira ...
(EBC), bronchial brushing and neoplastic lung tissue of cases, and found a presence of an HPV infection in 16.4% of the subjects affected by nonsmall cell lung cancer, but in none of the controls. The reported average frequencies of HPV in lung cancers were 17% and 15% in Europe and the Americas, respectively, and the mean number of HPV in Asian lung cancer samples was 35.7%, with a considerable heterogeneity between certain countries and regions.


Skin cancer

In very rare cases, HPV may cause
epidermodysplasia verruciformis Epidermodysplasia verruciformis (EV), also known as treeman syndrome, is an extremely rare autosomal recessive hereditary skin disorder associated with a high risk of skin cancer. It is characterized by abnormal susceptibility to human papillo ...
(EV) in individuals with a
weakened immune system Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that a ...
. The virus, unchecked by the immune system, causes the overproduction of
keratin Keratin () is one of a family of structural fibrous proteins also known as ''scleroproteins''. Alpha-keratin (α-keratin) is a type of keratin found in vertebrates. It is the key structural material making up scales, hair, nails, feathers, ho ...
by
skin cells Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal coverings, such as the arthropod exoskeleton, have different de ...
, resulting in lesions resembling warts or
cutaneous horn Cutaneous horns, also known by the Latin name ''cornu cutaneum'', are unusual keratinous skin tumors with the appearance of horns, or sometimes of wood or coral. Formally, this is a clinical diagnosis for a "conical projection above the surface of ...
s which can ultimately transform into
skin cancer Skin cancers are cancers that arise from the skin. They are due to the development of abnormal cells that have the ability to invade or spread to other parts of the body. There are three main types of skin cancers: basal-cell skin cancer (BCC) ...
, but the development is not well understood. The specific types of HPV that are associated with EV are HPV5, HPV8, and HPV14.


Cause


Transmission

Sexually transmitted HPV is divided into two categories: low-risk and high-risk. Low-risk HPVs cause warts on or around the genitals. Type 6 and 11 cause 90% of all genital warts and recurrent respiratory papillomatosis that causes benign tumors in the air passages. High-risk HPVs cause cancer and consist of about a dozen identified types. Types 16 and 18 are responsible for causing most of HPV-caused cancers. These high-risk HPVs cause 5% of the cancers in the world. In the United States, high-risk HPVs cause 3% of all cancer cases in women and 2% in men. Risk factors for persistent genital HPV infections, which increases the risk for developing cancer, include early age of first sexual intercourse, multiple partners, smoking, and immunosuppression. Genital HPV is spread by sustained direct skin-to-skin contact, with vaginal, anal, and oral sex being the most common methods. Occasionally it can spread from a mother to her baby during pregnancy. HPV is difficult to remove via standard hospital disinfection techniques, and may be transmitted in a healthcare setting on re-usable gynecological equipment, such as vaginal ultrasound transducers. The period of communicability is still unknown, but probably at least as long as visible HPV lesions persist. HPV may still be transmitted even after lesions are treated and no longer visible or present.


Perinatal

Although genital HPV types can be transmitted from mother to child during birth, the appearance of genital HPV-related diseases in newborns is rare. However, the lack of appearance does not rule out asymptomatic latent infection, as the virus has proven to be capable of hiding for decades.
Perinatal Prenatal development () includes the development of the embryo and of the fetus during a viviparous animal's gestation. Prenatal development starts with fertilization, in the germinal stage of embryonic development, and continues in fetal devel ...
transmission of HPV types 6 and 11 can result in the development of juvenile-onset recurrent respiratory papillomatosis (JORRP). JORRP is very rare, with rates of about 2 cases per 100,000 children in the United States. Although JORRP rates are substantially higher if a woman presents with genital warts at the time of giving birth, the risk of JORRP in such cases is still less than 1%.


Genital infections

Genital HPV infections are transmitted primarily by contact with the genitals, anus, or mouth of an infected sexual partner. Of the 120 known human papilloma viruses, 51 species and three subtypes infect the genital mucosa. Fifteen are classified as high-risk types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82), three as probable high-risk (26, 53, and 66), and twelve as low-risk (6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, and 89). Condoms do not completely protect from the virus because the areas around the genitals including the inner thigh area are not covered, thus exposing these areas to the infected person's skin.Egendorf, Laura. Sexually Transmitted Diseases (At Issue Series). New York: Greenhaven Press, 2007.


Hands

Studies have shown HPV transmission between hands and genitals of the same person and sexual partners. Hernandez tested the genitals and dominant hand of each person in 25 heterosexual couples every other month for an average of seven months. She found two couples where the man's genitals infected the woman's hand with high-risk HPV, two where her hand infected his genitals, one where her genitals infected his hand, two each where he infected his own hand, and she infected her own hand. Hands were not the main source of transmission in these 25 couples, but they were significant. Partridge reports men's fingertips became positive for high risk HPV at more than half the rate (26% per two years) as their genitals (48%). Winer reports 14% of fingertip samples from sexually active women were positive. Non-sexual hand contact seems to have little or no role in HPV transmission. Winer found all fourteen fingertip samples from virgin women negative at the start of her fingertip study. In a separate report on genital HPV infection, 1% of virgin women (1 of 76) with no sexual contact tested positive for HPV, while 10% of virgin women reporting non-penetrative sexual contact were positive (7 of 72).


Shared objects

Sharing of possibly contaminated objects, for example, razors, may transmit HPV. Although possible, transmission by routes other than sexual intercourse is less common for female genital HPV infection. Fingers-genital contact is a possible way of transmission but unlikely to be a significant source.


Blood

Though it has traditionally been assumed that HPV is not transmissible via blood – as it is thought to only infect cutaneous and mucosal tissues – recent studies have called this notion into question. Historically, HPV DNA has been detected in the blood of cervical cancer patients. In 2005, a group reported that, in frozen blood samples of 57 sexually naive pediatric patients who had
vertical Vertical is a geometric term of location which may refer to: * Vertical direction, the direction aligned with the direction of the force of gravity, up or down * Vertical (angles), a pair of angles opposite each other, formed by two intersecting s ...
or transfusion-acquired HIV infection, 8 (14.0%) of these samples also tested positive for HPV-16. This seems to indicate that it may be possible for HPV to be transmitted via
blood transfusion Blood transfusion is the process of transferring blood products into a person's circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used whole blood, but mo ...
. However, as non-sexual transmission of HPV by other means is not uncommon, this could not be definitively proven. In 2009, a group tested
Australian Red Cross The Australian Red Cross, formally the Australian Red Cross Society, is a humanitarian aid and community services charity in Australia. Tracing its history back to 1923 and being incorporated by royal charter in 1941, the Australian Red Cros ...
blood samples from 180 healthy male donors for HPV, and subsequently found DNA of one or more strains of the virus in 15 (8.3%) of the samples. However, it is important to note that detecting the presence of HPV DNA in blood is not the same as detecting the virus itself in blood, and whether or not the virus itself can or does reside in blood in infected individuals is still unknown. As such, it remains to be determined whether HPV can or cannot be transmitted via blood. This is of concern, as blood donations are not currently screened for HPV, and at least some organizations such as the
American Red Cross The American Red Cross (ARC), also known as the American National Red Cross, is a non-profit humanitarian organization that provides emergency assistance, disaster relief, and disaster preparedness education in the United States. It is the desi ...
and other Red Cross societies do not presently appear to disallow HPV-positive individuals from donating blood.


Surgery

Hospital transmission of HPV, especially to surgical staff, has been documented. Surgeons, including urologists and/or anyone in the room, is subject to HPV infection by inhalation of noxious viral particles during
electrocautery Cauterization (or cauterisation, or cautery) is a medical practice or technique of burning a part of a body to remove or close off a part of it. It destroys some tissue in an attempt to mitigate bleeding and damage, remove an undesired growth, o ...
or laser ablation of a condyloma (wart). There has been a case report of a laser surgeon who developed extensive laryngeal papillomatosis after providing laser ablation to patients with anogenital condylomata.


Virology

HPV infection is limited to the basal cells of stratified epithelium, the only tissue in which they replicate. The virus cannot bind to live tissue; instead, it infects
epithelial Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercell ...
tissues through micro-abrasions or other epithelial trauma that exposes segments of the
basement membrane The basement membrane is a thin, pliable sheet-like type of extracellular matrix that provides cell and tissue support and acts as a platform for complex signalling. The basement membrane sits between Epithelium, epithelial tissues including mesot ...
. The infectious process is slow, taking 12–24 hours for initiation of transcription. It is believed that involved antibodies play a major neutralizing role while the
virion A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Since Dmitri Ivanovsky's ...
s still reside on the basement membrane and cell surfaces. HPV lesions are thought to arise from the proliferation of infected basal
keratinocytes Keratinocytes are the primary type of cell found in the epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells. Basal cells in the basal layer (''stratum basale'') of the skin are sometimes referre ...
. Infection typically occurs when basal cells in the host are exposed to the infectious virus through a disturbed epithelial barrier as would occur during sexual intercourse or after minor skin abrasions. HPV infections have not been shown to be cytolytic; rather, viral particles are released as a result of degeneration of desquamating cells. HPV can survive for many months and at low temperatures without a host; therefore, an individual with plantar warts can spread the virus by walking barefoot. HPV is a small double-stranded circular DNA virus with a genome of approximately 8000 base pairs. The HPV life cycle strictly follows the differentiation program of the host keratinocyte. It is thought that the HPV
virion A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Since Dmitri Ivanovsky's ...
infects
epithelial Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercell ...
tissues through micro-abrasions, whereby the virion associates with putative receptors such as alpha
integrin Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...
s,
laminin Laminins are a family of glycoproteins of the extracellular matrix of all animals. They are major components of the basal lamina (one of the layers of the basement membrane), the protein network foundation for most cells and organs. The laminins ...
s, and annexin A2 leading to entry of the virions into basal epithelial cells through
clathrin Clathrin is a protein that plays a major role in the formation of coated vesicles. Clathrin was first isolated and named by Barbara Pearse in 1976. It forms a triskelion shape composed of three clathrin heavy chains and three light chains. When ...
- mediated endocytosis and/or caveolin-mediated endocytosis depending on the type of HPV. At this point, the viral
genome In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...
is transported to the nucleus by unknown mechanisms and establishes itself at a copy number of 10-200 viral genomes per cell. A sophisticated transcriptional cascade then occurs as the host keratinocyte begins to divide and become increasingly differentiated in the upper layers of the epithelium.


Evolution

The phylogeny of the various strains of HPV generally reflects the migration patterns of ''Homo sapiens'' and suggests that HPV may have diversified along with the human population. Studies suggest that HPV evolved along five major branches that reflect the ethnicity of human hosts, and diversified along with the human population. Researchers initially identified two major variants of HPV16, European (HPV16-E), and Non-European (HPV16-NE). More recent analyses based on thousands of HPV16 genomes show that indeed two major clades exist, that are further subdivided into four lineages (designated A-D) and even further subdivided into 16 sublineages (A1–4, B1–4, C1–4 and D1–4). The A1-A3 sublineages constitute the European variant, A4 the Asian variant, B1-B4 the African type I variant, C1–C4 the African type II variant, D1 the North American variant, D2 the Asian American type I variant, D3 the Asian American type II variant. The various lineages and sublineages have different oncogenic capacity, where overall, the non-European lineages are considered to increase the risk for cancer. Although HPV16 is a DNA virus, there are signs of recombination among the different lineages. Based on an analysis of more than 3600 genomes, between 0.3 and 1.2% of them could be recombinant. Thus, ideally, genotyping (for cancer-risk assessment) of HPV16 should not be based only on certain genes, but on all genes from the entire genome. A bioinformatics tool named HPV16-Genotyper performs i) HPV16 lineage genotyping, ii) it detects potential recombination events, iii) it identifies, within the submitted sequences, mutations/SNPs that have been reported (in literature) to increase the risk for cancer.


E6/E7 proteins

The two primary oncoproteins of high risk HPV types are E6 and E7. The "E" designation indicates that these two proteins are
early protein The classification of viral proteins as early proteins or late proteins depends on their relationship with genome replication. While many viruses (such as HIV) are described as expressing early and late proteins, this definition of these terms i ...
s (expressed early in the HPV life cycle), while the "L" designation indicates that they are late proteins (late expression). The HPV genome is composed of six early (E1, E2, E4, E5, E6, and E7)
open reading frame In molecular biology, open reading frames (ORFs) are defined as spans of DNA sequence between the start and stop codons. Usually, this is considered within a studied region of a prokaryotic DNA sequence, where only one of the six possible readin ...
s (ORF), two late (L1 and L2) ORFs, and a non-coding long control region (LCR). After the host cell is infected viral early promoter is activated and a polycistronic primary RNA containing all six early ORFs is transcribed. This polycistronic RNA then undergoes active RNA splicing to generate multiple isoforms of
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...
s. One of the spliced isoform RNAs, E6*I, serves as an E7 mRNA to translate E7 protein. However, viral early transcription subjects to viral E2 regulation and high E2 levels repress the transcription. HPV genomes integrate into host genome by disruption of E2 ORF, preventing E2 repression on E6 and E7. Thus, viral genome integration into host DNA genome increases E6 and E7 expression to promote cellular proliferation and the chance of malignancy. The degree to which E6 and E7 are expressed is correlated with the type of cervical lesion that can ultimately develop. ;Role in cancer The E6/E7 proteins inactivate two tumor suppressor proteins,
p53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
(inactivated by E6) and
pRb The retinoblastoma protein (protein name abbreviated pRb; gene name abbreviated ''Rb'', ''RB'' or ''RB1'') is a proto-oncogenic tumor suppressor protein that is dysfunctional in several major cancers. One function of pRb is to prevent excessive ...
(inactivated by E7). The viral
oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.
s E6 and E7 are thought to modify the cell cycle so as to retain the differentiating host keratinocyte in a state that is favourable to the amplification of viral genome replication and consequent late gene expression. E6 in association with host E6-associated protein, which has ubiquitin ligase activity, acts to ubiquitinate p53, leading to its proteosomal degradation. E7 (in oncogenic HPVs) acts as the primary transforming protein. E7 competes for
retinoblastoma protein The retinoblastoma protein (protein name abbreviated pRb; gene name abbreviated ''Rb'', ''RB'' or ''RB1'') is a proto-oncogenic tumor suppressor protein that is dysfunctional in several major cancers. One function of pRb is to prevent excessive ...
(pRb) binding, freeing the transcription factor E2F to transactivate its targets, thus pushing the cell cycle forward. All HPV can induce transient proliferation, but only strains 16 and 18 can immortalize cell lines ''in vitro''. It has also been shown that HPV 16 and 18 cannot immortalize primary rat cells alone; there needs to be activation of the
ras Ras or RAS may refer to: Arts and media * RAS Records Real Authentic Sound, a reggae record label * Rundfunk Anstalt Südtirol, a south Tyrolese public broadcasting service * Rás 1, an Icelandic radio station * Rás 2, an Icelandic radio stati ...
oncogene. In the upper layers of the host epithelium, the late genes L1 and L2 are transcribed/translated and serve as structural proteins that encapsidate the amplified viral genomes. Once the genome is encapsidated, the capsid appears to undergo a redox-dependent assembly/maturation event, which is tied to a natural redox gradient that spans both suprabasal and cornified epithelial tissue layers. This assembly/maturation event stabilizes virions, and increases their specific infectivity. Virions can then be sloughed off in the dead squames of the host epithelium and the viral lifecycle continues. A 2010 study has found that E6 and E7 are involved in
beta-catenin Catenin beta-1, also known as beta-catenin (β-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene. Beta-catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcrip ...
nuclear accumulation and activation of
Wnt signaling The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling ...
in HPV-induced cancers.


Latency period

Once an HPV virion invades a cell, an active infection occurs, and the virus can be transmitted. Several months to years may elapse before squamous intraepithelial lesions (SIL) develop and can be clinically detected. The time from active infection to clinically detectable disease may make it difficult for epidemiologists to establish which partner was the source of infection.


Clearance

Most HPV infections are cleared up by most people without medical action or consequences. The table provides data for high-risk types (i.e. the types found in cancers). Clearing an infection does not always create immunity if there is a new or continuing source of infection. Hernandez' 2005-6 study of 25 couples reports "A number of instances indicated apparent reinfection rom partnerafter viral clearance."


Diagnosis

Over 170 types of HPV have been identified, and they are designated by numbers. They may be divided into "low-risk" and "high-risk" types. Low-risk types cause warts and high-risk types can cause lesions or cancer.


Cervical testing

Guidelines from the
American Cancer Society The American Cancer Society (ACS) is a nationwide voluntary health organization dedicated to eliminating cancer. Established in 1913, the society is organized into six geographical regions of both medical and lay volunteers operating in more than ...
recommend different screening strategies for cervical cancer based on a woman's age, screening history, risk factors and choice of tests. Because of the link between HPV and cervical cancer, the ACS currently recommends early detection of cervical cancer in average-risk asymptomatic adults primarily with cervical cytology by Pap smear, regardless of HPV vaccination status. Women aged 30–65 should preferably be tested every 5 years with both the HPV test and the Pap test. In other age groups, a Pap test alone can suffice unless they have been diagnosed with atypical squamous cells of undetermined significance (ASC-US). Co-testing with a Pap test and HPV test is recommended because it decreases the rate of false-negatives. According to the National Cancer Institute, "The most common test detects DNA from several high-risk HPV types, but it cannot identify the types that are present. Another test is specific for DNA from HPV types 16 and 18, the two types that cause most HPV-associated cancers. A third test can detect DNA from several high-risk HPV types and can indicate whether HPV-16 or HPV-18 is present. A fourth test detects RNA from the most common high-risk HPV types. These tests can detect HPV infections before cell abnormalities are evident. "Theoretically, the HPV DNA and RNA tests could be used to identify HPV infections in cells taken from any part of the body. However, the tests are approved by the FDA for only two indications: for follow-up testing of women who seem to have abnormal Pap test results and for cervical cancer screening in combination with a
Pap test The Papanicolaou test (abbreviated as Pap test, also known as Pap smear (AE), cervical smear (BE), cervical screening (BE), or smear test (BE)) is a method of cervical screening used to detect potentially precancerous and cancerous processes in t ...
among women over age 30."


Mouth testing

Guidelines for oropharyngeal cancer screening by the Preventive Services Task Force and American Dental Association in the U.S. suggest conventional visual examination, but because some parts of the oropharynx are hard to see, this cancer is often only detected in later stages. The diagnosis of oropharyngeal cancer occurs by biopsy of exfoliated cells or tissues. The
National Comprehensive Cancer Network National Comprehensive Cancer Network (NCCN) is an alliance of 32 cancer centers in the United States, most of which are designated by the National Cancer Institute (one of the U.S. National Institutes of Health) as comprehensive cancer centers. It ...
and
College of American Pathologists The College of American Pathologists (CAP) is a member-based physician organization founded in 1946 comprising approximately 18,000 board-certified pathologists. It serves patients, pathologists, and the public by fostering and advocating ...
recommend testing for HPV in oropharyngeal cancer. However, while testing is recommended, there is no specific type of test used to detect HPV from oral tumors that is currently recommended by the FDA in the United States. Because HPV type 16 is the most common type found in oropharyngeal cancer, p16
immunohistochemistry Immunohistochemistry (IHC) is the most common application of immunostaining. It involves the process of selectively identifying antigens (proteins) in cells of a tissue section by exploiting the principle of antibodies binding specifically to an ...
is one test option used to determine if HPV is present, which can help determine course of treatment since tumors that are negative for p16 have better outcomes. Another option that has emerged as a reliable option is HPV DNA
in situ hybridization ''In situ'' hybridization (ISH) is a type of hybridization that uses a labeled complementary DNA, RNA or modified nucleic acids strand (i.e., probe) to localize a specific DNA or RNA sequence in a portion or section of tissue (''in situ'') o ...
(ISH) which allows for visualization of the HPV.


Testing men

There is not a wide range of tests available even though HPV is common; most studies of HPV used tools and custom analysis not available to the general public. Clinicians often depend on the vaccine among young people and high clearance rates (see Clearance subsection in Virology) to create a low risk of disease and mortality, and treat the cancers when they appear. Others believe that reducing HPV infection in more men and women, even when it has no symptoms, is important (herd immunity) to prevent more cancers rather than just treating them. Where tests are used, negative test results show safety from transmission, and positive test results show where shielding (condoms, gloves) is needed to prevent transmission until the infection clears. Studies have tested for and found HPV in men, including high-risk types (i.e. the types found in cancers), on fingers, mouth, saliva, anus, urethra, urine, semen, blood, scrotum and penis. The Qiagen/Digene kit mentioned in the previous section was used successfully off label to test the penis, scrotum and anus of men in long-term relationships with women who were positive for high-risk HPV. 60% of them were found to carry the virus, primarily on the penis. Other studies used cytobrushes and custom analysis. In one study researchers sampled subjects' urethra, scrotum and penis. Samples taken from the urethra added less than 1% to the HPV rate. Studies like this led Giuliano to recommend sampling the glans, shaft and crease between them, along with the scrotum, since sampling the urethra or anus added very little to the diagnosis. Dunne recommends the glans, shaft, their crease, and the foreskin. In one study the subjects were asked not to wash their genitals for 12 hours before sampling, including the urethra as well as the scrotum and the penis. Other studies are silent on washing – a particular gap in studies of the hands. One small study used wet cytobrushes, rather than wet the skin. It found a higher proportion of men to be HPV-positive when the skin was rubbed with a 600 grit emery paper before being swabbed with the brush, rather than swabbed with no preparation. It's unclear whether the emery paper collected the virions or simply loosened them for the swab to collect. Studies have found self-collection (with emery paper and Dacron swabs) as effective as collection done by a clinician, and sometimes more so, since patients were more willing than a clinician to scrape vigorously. Women had similar success in self-sampling using tampons, swabs, cytobrushes and lavage. Several studies used cytobrushes to sample fingertips and under fingernails, without wetting the area or the brush. Other studies analyzed urine, semen, and blood and found varying amounts of HPV, but there is not a publicly available test for those yet.


Other testing

Although it is possible to test for HPV DNA in other kinds of infections, there are no FDA-approved tests for general screening in the United States or tests approved by the Canadian government, since the testing is inconclusive and considered medically unnecessary. Genital warts are the only visible sign of low-risk genital HPV and can be identified with a visual check. These visible growths, however, are the result of non-carcinogenic HPV types. Five percent acetic acid (vinegar) is used to identify both warts and squamous intraepithelial neoplasia (SIL) lesions with limited success by causing abnormal tissue to appear white, but most doctors have found this technique helpful only in moist areas, such as the female genital tract. At this time, HPV tests for males are used only in research. Research into testing for HPV by antibody presence has been done. The approach is looking for an immune response in blood, which would contain antibodies for HPV if the patient is HPV positive. The reliability of such tests has not been proven, as there has not been a FDA approved product as of August 2018; testing by blood would be a less invasive test for screening purposes.


Prevention

The HPV vaccines can prevent the most common types of infection. To be effective they must be used before an infection occurs and are therefore recommended between the ages of nine and thirteen. Cervical cancer screening, such as with the
Papanicolaou test The Papanicolaou test (abbreviated as Pap test, also known as Pap smear (AE), cervical smear (BE), cervical screening (BE), or smear test (BE)) is a method of cervical screening used to detect potentially precancerous and cancerous processes in t ...
(pap) or looking at the cervix after using
acetic acid Acetic acid , systematically named ethanoic acid , is an acidic, colourless liquid and organic compound with the chemical formula (also written as , , or ). Vinegar is at least 4% acetic acid by volume, making acetic acid the main component ...
, can detect early cancer or abnormal cells that may develop into cancer. This allows for early treatment which results in better outcomes. Screening has reduced both the number and deaths from cervical cancer in the developed world. Warts can be removed by
freezing Freezing is a phase transition where a liquid turns into a solid when its temperature is lowered below its freezing point. In accordance with the internationally established definition, freezing means the solidification phase change of a liquid ...
.


Vaccines

Three vaccines are available to prevent infection by some HPV types:
Gardasil Gardasil is an HPV vaccine for use in the prevention of certain strains of human papillomavirus (HPV). Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledge ...
,
Gardasil 9 Gardasil is an HPV vaccine for use in the prevention of certain strains of human papillomavirus (HPV). Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledg ...
and
Cervarix Cervarix is a vaccine against certain types of cancer-causing human papillomavirus (HPV). Cervarix is designed to prevent infection from HPV types 16 and 18, that cause about 70% of cervical cancer cases. These types also cause most HPV-induced ...
; all three protect against initial infection with HPV types 16 and 18, which cause most of the HPV-associated cancer cases. Gardasil also protects against HPV types 6 and 11, which cause 90% of genital warts. Gardasil is a recombinant quadrivalent vaccine, whereas Cervarix is bivalent, and is prepared from virus-like particles (VLP) of the L1
capsid protein A capsid is the protein shell of a virus, enclosing its genetic material. It consists of several oligomeric (repeating) structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or ma ...
. Gardasil 9 is nonavalent, it has the potential to prevent about 90% of cervical, vulvar, vaginal, and anal cancers. It can protect for HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58; the latter five cause up to 20% of cervical cancers which were not previously covered. The vaccines provide little benefit to women already infected with HPV types 16 and 18. For this reason, the vaccine is recommended primarily for those women not yet having been exposed to HPV during sex. The
World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...
position paper on HPV vaccination clearly outlines appropriate, cost-effective strategies for using HPV vaccine in public sector programs. There is high-certainty evidence that HPV vaccines protect against precancerous cervical lesions in young women, particularly those vaccinated aged 15 to 26. HPV vaccines do not increase the risk of serious adverse events. Longer follow-up is needed to monitor the impact of HPV vaccines on cervical cancer. The CDC recommends the vaccines be delivered in two shots at an interval of least 6 months for those aged 11–12, and three doses for those 13 and older. In most countries, they are funded only for female use, but are approved for male use in many countries, and funded for teenage boys in Australia. The vaccine does not have any therapeutic effect on existing HPV infections or cervical lesions. In 2010, 49% of teenage girls in the US got the HPV vaccine. Following studies suggesting that the vaccine is more effective in younger girls than in older teenagers, the United Kingdom, Switzerland, Mexico, the Netherlands and Quebec began offering the vaccine in a two-dose schedule for girls aged under 15 in 2014. Cervical cancer screening recommendations have not changed for females who receive HPV vaccine. It remains a recommendation that women continue cervical screening, such as Pap smear testing, even after receiving the vaccine, since it does not prevent all types of cervical cancer. Both men and women are carriers of HPV. The Gardasil vaccine also protects men against anal cancers and warts and genital warts. Duration of both vaccines' efficacy has been observed since they were first developed, and is expected to be longlasting. In December 2014, the
FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
approved a nine-valent Gardasil-based vaccine, Gardasil 9, to protect against infection with the four strains of HPV covered by the first generation of Gardasil as well as five other strains responsible for 20% of cervical cancers (HPV-31, HPV-33, HPV-45, HPV-52, and HPV-58).


Condoms

The
Centers for Disease Control and Prevention The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georgi ...
says that male "
condom A condom is a sheath-shaped barrier device used during sexual intercourse to reduce the probability of pregnancy or a sexually transmitted infection (STI). There are both male and female condoms. With proper use—and use at every act of in ...
use may reduce the risk for genital human papillomavirus (HPV) infection" but provides a lesser degree of protection compared with other sexual transmitted diseases "because HPV also may be transmitted by exposure to areas (e.g., infected skin or mucosal surfaces) that are not covered or protected by the condom." The strict correlation between
chlamydia Chlamydia, or more specifically a chlamydia infection, is a sexually transmitted infection caused by the bacterium '' Chlamydia trachomatis''. Most people who are infected have no symptoms. When symptoms do appear they may occur only several we ...
infection and HPV infection observed in cervical cancer screening, however, suggests that using condoms provides adequate protection for women in this respect.


Disinfection

The virus is unusually hardy, and is immune to most common disinfectants. It is the first virus ever shown to be resistant to inactivation by
glutaraldehyde Glutaraldehyde is an organic compound with the formula . The molecule consists of a five carbon chain doubly terminated with formyl (CHO) groups. It is usually used as a solution in water, and such solutions exists as a collection of hydrates, c ...
, which is among the most common strong disinfectants used in hospitals. Diluted
sodium hypochlorite Sodium hypochlorite (commonly known in a dilute solution as bleach) is an Inorganic chemistry, inorganic chemical compound with the chemical formula, formula NaOCl (or NaClO), comprising a sodium cation () and a hypochlorite anion (or ). It may ...
bleach is effective, but cannot be used on some types of re-usable equipment, such as ultrasound transducers. As a result of these difficulties, there is developing concern about the possibility of transmitting the virus on healthcare equipment, particularly reusable gynecological equipment that cannot be
autoclave An autoclave is a machine used to carry out industrial and scientific processes requiring elevated temperature and pressure in relation to ambient pressure and/or temperature. Autoclaves are used before surgical procedures to perform sterilizati ...
d. For such equipment, some health authorities encourage use of
UV disinfection Ultraviolet germicidal irradiation (UVGI) is a disinfection method that uses short-wavelength ultraviolet (ultraviolet C or UV-C) light to kill or inactivate microorganisms by destroying nucleic acids and disrupting their DNA, leaving them unabl ...
or a non-hypochlorite "oxidizing‐based high‐level disinfectant
leach Leach may refer to: * Leach (surname) * Leach, Oklahoma, an unincorporated community, United States * Leach, Tennessee, an unincorporated community, United States * Leach Highway, Western Australia * Leach orchid * Leach phenotype, a mutation in ...
with label claims for non‐enveloped viruses", such as a strong
hydrogen peroxide Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscous than water. It is used as an oxidizer, bleaching agent, and antiseptic, usually as a dilute solution (3% ...
solution or
chlorine dioxide Chlorine dioxide is a chemical compound with the formula ClO2 that exists as yellowish-green gas above 11 °C, a reddish-brown liquid between 11 °C and −59 °C, and as bright orange crystals below −59 °C. It is usually ...
wipes. Such disinfection methods are expected to be relatively effective against HPV.


Management

There is currently no specific treatment for HPV infection. However, the viral infection is usually cleared to undetectable levels by the immune system. According to the
Centers for Disease Control and Prevention The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georgi ...
, the body's immune system clears HPV naturally within two years for 90% of cases (see Clearance subsection in Virology for more detail). However, experts do not agree on whether the virus is eliminated or reduced to undetectable levels, and it is difficult to know when it is contagious. Follow up care is usually recommended and practiced by many health clinics. Follow-up is sometimes not successful because a portion of those treated do not return to be evaluated. In addition to the normal methods of phone calls and mail, text messaging and email can improve the number of people who return for care. As of 2015 it is unclear the best method of follow up following treatment of
cervical intraepithelial neoplasia Cervical intraepithelial neoplasia (CIN), also known as cervical dysplasia, is the abnormal growth of cells on the surface of the cervix that could potentially lead to cervical cancer. More specifically, CIN refers to the potentially precancerou ...
.


Epidemiology

Globally, 12% of women are positive for HPV DNA, with rates varying by age and country. The highest rates of HPV are in younger women, with a rate of 24% in women under 25 years. Rates decline in older age groups in Europe and the Americas, but less so in Africa and Asia. The rates are highest in Sub-Saharan Africa (24%) and Eastern Europe (21%) and lowest in North America (5%) and Western Asia (2%). The most common types of HPV worldwide are HPV16 (3.2%), HPV18 (1.4%), HPV52 (0.9%), HPV31 (0.8%), and HPV58 (0.7%). High-risk types of HPV are also distributed unevenly, with HPV16 having a rate around 13% in Africa and 30% in West and Central Asia. Like many diseases, HPV disproportionately affects low-income and resource-poor countries. The higher rates of HPV in Sub-Saharan Africa, for example, may be related to high exposure to
human immunodeficiency virus The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immun ...
(HIV) in the region. Other factors that impact the global spread of disease are sexual behaviors including age of sexual debut, number of sexual partners, and ease of access to barrier contraception, all of which vary globally.


United States

HPV is estimated to be the most common sexually transmitted infection in the United States. Most sexually active men and women will probably acquire genital HPV infection at some point in their lives. The
American Social Health Association The American Sexual Health Association (ASHA), formally known as the American Social Hygiene Association and the American Social Health Association, is an American nonprofit organization established in 1914, that cites a mission to improve the heal ...
estimates that about 75–80% of sexually active Americans will be infected with HPV at some point in their lifetime. By the age of 50 more than 80% of American women will have contracted at least one strain of genital HPV. It was estimated that, in the year 2000, there were approximately 6.2 million new HPV infections among Americans aged 15–44; of these, an estimated 74% occurred to people between ages of 15 and 24. Of the STDs studied, genital HPV was the most commonly acquired. In the United States, it is estimated that 10% of the population has an active HPV infection, 4% has an infection that has caused cytological abnormalities, and an additional 1% has an infection causing genital warts. Estimates of HPV prevalence vary from 14% to more than 90%. One reason for the difference is that some studies report women who currently have a detectable infection, while other studies report women who have ever had a detectable infection. Another cause of discrepancy is the difference in strains that were tested for. One study found that, during 2003–2004, at any given time, 26.8% of women aged 14 to 59 were infected with at least one type of HPV. This was higher than previous estimates; 15.2% were infected with one or more of the high-risk types that can cause cancer. The prevalence for high-risk and low-risk types is roughly similar over time. Human papillomavirus is not included among the diseases that are typically reportable to the
CDC The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georgi ...
as of 2011.


Ireland

On average 538 cases of HPV-associated cancers were diagnosed per year in Ireland during the period 2010 to 2014. Cervical cancer was the most frequent HPV-associated cancer with on average 292 cases per year (74% of the female total, and 54% of the overall total of HPV-associated cancers). A study of 996 cervical cytology samples in an Irish urban female, opportunistically screened population, found an overall HPV prevalence of 19.8%, HPV 16 at 20% and HPV 18 at 12% were the commonest high-risk types detected. In Europe, types 16 and 18 are responsible for over 70% of cervical cancers. Overall rates of HPV-associated invasive cancers may be increasing. Between 1994 and 2014, there was a 2% increase in the rate of HPV-associated invasive cancers per year for both sexes in Ireland. As HPV is known to be associated with ano-genital warts, these are notifiable to the Health Protection Surveillance Centre (HPSC). Genital warts are the second most common STI in Ireland. There were 1,281 cases of ano-genital warts notified in 2017, which was a decrease on the 2016 figure of 1,593. The highest age-specific rate for both male and female was in the 25–29 year old age range; 53% of cases were among males.


Sri Lanka

In Sri Lanka, the prevalence of HPV is 15.5% regardless of their cytological abnormalities.


Inner Mongolia

In the Autonomous Region of
Inner Mongolia Inner Mongolia, officially the Inner Mongolia Autonomous Region, is an autonomous region of the People's Republic of China. Its border includes most of the length of China's border with the country of Mongolia. Inner Mongolia also accounts for a ...
overall HPV prevalence is 14.5% but shows substantial ethnical disparity, the prevalence in Mongolian women (14.9%) being much higher than that of Han participants (4.3%). Urbanization, the number of sex partners, and PAP history appear as risk factors for HPV infection in Han, but not in Mongolian women. The region is thus an important example that epidemiology of HPV is more related to cultural and ethnical factors and not to geography per se.


History

In 1972, the association of the human papillomaviruses with
skin cancer Skin cancers are cancers that arise from the skin. They are due to the development of abnormal cells that have the ability to invade or spread to other parts of the body. There are three main types of skin cancers: basal-cell skin cancer (BCC) ...
in
epidermodysplasia verruciformis Epidermodysplasia verruciformis (EV), also known as treeman syndrome, is an extremely rare autosomal recessive hereditary skin disorder associated with a high risk of skin cancer. It is characterized by abnormal susceptibility to human papillo ...
was proposed by Stefania Jabłońska in Poland. In 1978, Jabłońska and Gerard Orth at the
Pasteur Institute The Pasteur Institute (french: Institut Pasteur) is a French non-profit private foundation dedicated to the study of biology, micro-organisms, diseases, and vaccines. It is named after Louis Pasteur, who invented pasteurization and vaccines f ...
discovered HPV-5 in
skin cancer Skin cancers are cancers that arise from the skin. They are due to the development of abnormal cells that have the ability to invade or spread to other parts of the body. There are three main types of skin cancers: basal-cell skin cancer (BCC) ...
. In 1976
Harald zur Hausen Harald zur Hausen NAS EASA APS (; born 11 March 1936) is a German virologist and professor emeritus. He has done research on cervical cancer and discovered the role of papilloma viruses in cervical cancer, for which he received the Nobe ...
published the hypothesis that human papilloma virus plays an important role in the cause of
cervical cancer Cervical cancer is a cancer arising from the cervix. It is due to the abnormal growth of cells that have the ability to invade or spread to other parts of the body. Early on, typically no symptoms are seen. Later symptoms may include abnormal ...
. In 1983 and 1984 zur Hausen and his collaborators identified HPV16 and HPV18 in cervical cancer. The
HeLa HeLa (; also Hela or hela) is an immortalized cell line used in scientific research. It is the oldest and most commonly used human cell line. The line is derived from cervical cancer cells taken on February 8, 1951, named after Henrietta ...
cell line contains extra DNA in its
genome In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...
that originated from HPV type 18.


Research

The Ludwig-McGill HPV Cohort is one of the world's largest longitudinal studies of the natural history of
human papillomavirus Human papillomavirus infection (HPV infection) is caused by a DNA virus from the ''Papillomaviridae'' family. Many HPV infections cause no symptoms and 90% resolve spontaneously within two years. In some cases, an HPV infection persists and res ...
(HPV) infection and
cervical cancer Cervical cancer is a cancer arising from the cervix. It is due to the abnormal growth of cells that have the ability to invade or spread to other parts of the body. Early on, typically no symptoms are seen. Later symptoms may include abnormal ...
risk. It was established in 1993 by
Ludwig Cancer Research Ludwig Cancer Research is an international community of scientists focused on cancer research, with the goal of preventing and controlling cancer. It encompasses the Ludwig Institute for Cancer Research, an international non-profit organization f ...
and
McGill University McGill University (french: link=no, Université McGill) is an English-language public research university located in Montreal, Quebec, Canada. Founded in 1821 by royal charter granted by King George IV,Frost, Stanley Brice. ''McGill Universit ...
in Montreal, Canada.


References


External links

*
Information Centre on HPV and Cancer
– ICO
HPV Fact sheets
at the
Centers for Disease Control and Prevention The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georgi ...

"Human Papillomavirus (HPV) Vaccines"
National Cancer Institute The National Cancer Institute (NCI) coordinates the United States National Cancer Program and is part of the National Institutes of Health (NIH), which is one of eleven agencies that are part of the U.S. Department of Health and Human Services. ...
Fact Sheet, US National Institutes of Health, 22 October 2009. {{DEFAULTSORT:Human Papillomavirus Carcinogens Carcinogenesis Papillomavirus Infectious causes of cancer Wikipedia medicine articles ready to translate Vaccine-preventable diseases Papillomavirus-associated diseases