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Thursday, April 12, 2012

Human Papillomavirus (HPV)

Human papillomavirus (HPV) is a virus from the Papillomaviridae family that is capable of infecting humans. Like all Papillomaviruses (PVs), HPVs establish productive infections only in keratinocytes of the skin or mucosal tissue. While the majority of the known types of HPV cause no symptoms in most people, some types can cause verrucae (warts), while others can, in a minority of cases, lead to cancers of the cervix, vulva, vagina, penis, oropharynx (the middle part of the throat), and anus.  Recently, HPV has been linked with an increased risk of cardiovascular disease.  In addition, HPV 16 and 18 infections are strongly associated with an increased odds ratio of developing orophanyngeal (throat) cancer.

More than 30 to 40 types of HPV are typically transmitted through sexual contact and infect the anogenital region. Some sexually transmitted HPV types may cause genital warts. Persistent infection with "high-risk" HPV types, different from the ones that cause skin warts, may progress to precancerous lesions and invasive cancer.  HPV infection is a cause of nearly all cases of cervical cancer.  However, most infections with these types do not cause disease.

Pathology: EM: Papilloma Virus (HPV) Electron micrograph of a negatively stained human papilloma virus (HBV) which occurs in human warts. Warts on the hands and feet have never been known to progress to cancer. However, after many years cervical warts can become cancerous. Source: NIH-Visuals Online# AV-8610-3067 http://visualsonline.cancer.gov/details.cfm?imageid=2255. Author: Unknown photographer/artist. Source: Laboratory of Tumor Virus Biology. Permission: PD-USGov-HHS-NIH (No- This image is in the public domain and can be freely reused. This image is a work of the National Institutes of Health http://www.nih.gov/, part of the United States Department of Health and Human Services. As a work of the U.S. federal government, the image is in the public domain.

Most HPV infections in young females are temporary and have little long-term significance.  70% of infections are gone in 1 year and 90% in 2 years.  However, when the infection persists, in 5% to 10% of infected women, there is high risk of developing precancerous lesions of the cervix, which can progress to invasive cervical cancer.  This process usually takes 10 to 15 years, providing many opportunities for detection and treatment of the precancerous lesion.  Progression to invasive cancer can be almost always prevented when standard prevention strategies are applied, but the lesions still cause considerable burden necessitating preventive surgeries, which do in many cases involve loss of fertility.

In more developed countries, cervical screening using a Papanicolaou (Pap) test, also called a pap smear or cervical cytology, is used to detect abnormal cells that may develop into cancer.  If abnormal cells are found, women are invited to have a colposcopy.  During a colposcopic inspection, biopsies can be taken and abnormal areas can be removed with a simple procedure, typically with a cauterizing loop or, more commonly in the developing world — by cryotherapy (freezing). Treating abnormal cells in this way can prevent them from developing into cervical cancer.

Pap smears have reduced the incidence and fatalities of cervical cancer in the developed world, but even so there were 12,280 women diagnosed with cervical cancer and over 4,021 deaths in the U.S. in 2007. According to the latest global estimates, 493,000 new cases of cervical cancer occur each year among women, and 274,000 women die of the disease annually.  HPV vaccines (Cervarix® and Gardasil®), which prevent infection with the HPV types 16 and 18 that cause 70% of cervical cancer, may lead to further decreases.

Signs and Symptoms

Notable HPV Types and Associated Diseases

Over 100 HPV types have been identified and are referred to by number.  Types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82 are carcinogenic "high-risk" sexually transmitted HPVs and may lead to the development of cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN), penile intraepithelial neoplasia (PIN), and/or anal intraepithelial neoplasia (AIN).


Disease                                              HPV type
Common warts                                  2, 7
Plantar warts                                      1, 2, 4, 63
Flat warts                                            3, 10, 8
Anogenital warts                                 6, 11, 42, 44 and others
Anal lesions                                        6, 16, 18, 31, 53, 58
Genital cancers                                  Highest risk: 16, 18, 31, 45
                                                           Other high-risk: 33, 35, 39, 51, 52, 56, 58, 59
                                                            Probably high-risk: 26, 53, 66, 68, 73, 82


Epidermodysplasia verruciformis            more than 15 types
Focal epithelial hyperplasia (oral)            13, 32
Oral papillomas                                         6, 7, 11, 16, 32
Oropharyngeal cancer                             16
Laryngeal papillomatosis                           6, 11


Cancer

HPV-induced cancers often have viral sequences integrated into the cellular DNA.  Some of the HPV "early" genes, such as E6 and E7, are known to act as oncogenes that promote tumor growth and malignant transformation. Oral infection with HPV increased the risk of HPV-positive oropharyngeal cancer independent of tobacco and alcohol use.  In the United States, HPV is expected to replace tobacco as the main causative agent for oropharyngeal cancer.

The p53 protein, also known as protein 53 or tumor protein 53, is a tumor suppressor protein that arrests the cell cycle when there is DNA damage.  The abscence or mutation of this protein is a primary event in the formation of many types of cancer.  The p53 also upregulates the p21 protein, which blocks the formation of the Cyclin D/Cdk4 complex, thereby preventing the phosphorylation of RB and, in turn, halting cell cycle progression by preventing the activation of E2F.  E6 has a close relationship with the cellular protein E6-AP (E6-associated protein).  E6-AP is involved in the ubiquitin ligase pathway, a system that acts to degrade proteins.  E6-AP binds ubiquitin to the p53 protein, thereby flagging it for proteosomal degradation.

Most HPV infections are cleared rapidly by the immune system and do not progress to cervical cancer. 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).

Sexually-transmitted HPVs also cause a major fraction of anal cancers and approximately 25% of oropharynx cancers.  The latter commonly present in the tonsil area, and HPV is linked to the increase in oral cancers in non-smokers.  Engaging in anal sex or oral sex with an HPV-infected partner may increase the risk of developing these types of cancers.

Studies show a link between HPV infection and penile and anal cancer, and the risk for anal cancer is about 17 times higher among gay, bisexual, and HIV-positive males than among heterosexual males.  It has been suggested that anal pap test screening for anal cancer might benefit some sub-populations of men or women engaging in anal sex.  There is no consensus that such screening is beneficial, or who should get an anal pap test.  Further studies have also shown a link between a wide range of HPV types and squamous cell carcinoma of the skin. In vitro studies suggest that the E6 protein of the HPV types implicated may inhibit apoptosis induced by ultraviolet light.


Papilloma. Human papillomavirus (HPV). Author: George Chernilevsky http://commons.wikimedia.org/wiki/User:George_Chernilevsky. Permission: Public domain. I, the copyright holder of this work, release this work into the public domain. This applies worldwide.
 Skin Warts

Some HPV infections can cause verrucae (warts), which are noncancerous skin growths. Infection with these types of HPV causes a rapid growth of cells on the outer layer of the skin.  Types of warts include:

  • Common warts: Some "cutaneous" HPV types cause common skin warts. Common warts are often 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 warts are found on the soles of the feet. Plantar warts grow inward, generally causing pain when walking.
  • Subungual or periungual warts form under the fingernail (subungual), around the fingernail or on the cuticle (periungual). They may be more difficult to treat than warts in other locations.
  • Flat warts: 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.
  • Genital warts are quite contagious, while common, flat, and plantar warts are much less likely to spread from person to person.

Genital Warts

Genital or anal warts (condylomata acuminata or venereal warts) are the most easily recognized sign of genital HPV infection. Although a wide variety of HPV types can cause genital warts, types 6 and 11 account for about 90% of all cases.  Most people who acquire genital wart-associated HPV types clear the infection rapidly without ever developing warts or any other symptoms. People may transmit the virus to others even if they do not display overt symptoms of infection.

HPV types that tend to cause genital warts are not those that cause cervical cancer.  Since an individual can be infected with multiple types of HPV, the presence of warts does not rule out the possibility of high-risk types of the virus also being present.  The types of HPV that cause genital warts are usually different from the types that cause warts on other parts of the body, such as the hands or inner thighs.

Respiratory Papillomatosis

HPV types 6 and 11 can cause a rare condition known as recurrent respiratory papillomatosis, in which warts form on the larynx or other areas of the respiratory tract.  These warts can recur frequently, may require repetitive surgery, may interfere with breathing, and in extremely rare cases can progress to cancer.

In the Immunocompromised

In very rare cases, HPV may cause epidermodysplasia verruciformis in immunocompromised individuals. The virus, unchecked by the immune system, causes the overproduction of keratin by skin cells, resulting in lesions resembling warts or cutaneous horns.  For instance, Dede Koswara, an Indonesian man developed warts that spread across his body and became root-like growths. Attempted treatment by both Indonesian and American doctors included surgical removal of the warts.

Transmission

Prenatal

Although genital HPV types can be transmitted from mother to child during birth, the appearance of genital HPV-related diseases in newborns is rare. Perinatal 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

Since cervical and female genital infection by specific HPV types is highly associated with cervical cancer, those types of HPV infection have received most of the attention from scientific studies.  HPV infections in that area are transmitted primarily via sexual activity.  At least 40 identified HPV types infect the genital tract. If a college-aged woman has at least one different partner per year for four years, the probability that she will leave college with an HPV infection is greater than 85%.  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.

Shared Objects

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

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 tissues through micro-abrasions or other epithelial trauma that exposes segments of the basement membrane.  The infectious process is slow, taking 12 to 24 hours for initiation of transcription.  It is believed that involved antibodies play a major neutralizing role while the virions still reside on the basement membrane and cell surfaces.

HPV lesions are thought to arise from the proliferation of infected basal keratinocytes.  Infection typically occurs when basal cells in the host are exposed to 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. The HPV virus 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.

The HPV life cycle strictly follows the differentiation program of the host keratinocyte. It is thought that the HPV virion infects epithelial tissues through micro-abrasions, whereby the virion associates with putative receptors such as alpha integrins and laminins, leading to entry of the virions into basal epithelial cells through clathrin-mediated endocytosis and/or caveolin-mediated endocytosis depending on the type of HPV. At this point, the viral genome is transported to the nucleus by unknown mechanisms and establishes itself at a copy number between 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.

E6/E7 Proteins

E6 and E7 are the HPV proteins associated with cancer. The HPV genome is composed of six early (E1, E2, E4, E5, E6, and E7) genes, two late (L1 and L2) genes, and a non-coding long control region (LCR).  After the host cell is infected E1 and E2 are expressed first.  High E2 levels repress expression of the E6 and E7 proteins. When the host and HPV genomes integrate, E2 function is disrupted, preventing repression of E6/E7.

Role in Cancer

The E6/E7 proteins inactivate two tumor suppressor proteins, p53 (inactivated by E6) and pRb (inactivated by E7).  The viral oncogenes 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 (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 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 study has found that  E6 and E7 are involved in beta-catenin nuclear accumulation and activation of Wnt signaling in HPV-induced cancers.

Latency Period

Once an HPV viron 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.

Prevention

HPV infection is the most frequent sexually transmitted disease in the world.  Methods of prevention include abstinence, condoms, vaccination and microbicides.

Vaccines: HPV vaccine

Two vaccines are available to prevent infection by some HPV types: Gardasil®, licensed and marketed by Merck & Co, is a vaccine shown to be 98% effective against HPV types 6, 11, 16 and 18.  Cervarix®, developed by GlaxoSmithKline has been shown to be 92% effective in preventing HPV strains 16 and 18, and is effective for more than four years.  Both vaccines provide protection 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.  According to a 2011 essay published in the Annals of Medicine, researchers from the University of British Columbia, in Vancouver, point out that "there is a major discrepancy in claims regarding the safety and efficacy of Gardasil® and Cervarix®"".

The vaccines provide little benefit to women having already been infected with HPV types 16 and 18, which includes most sexually active females.  For this reason, the vaccine is recommended primarily for those women not yet having been exposed to HPV during sex. The World Health Organization (WHO) position paper on HPV vaccination (pages. 118-131) clearly outlines appropriate, cost-effective strategies for using HPV vaccine in public sector programs.

Both vaccines are delivered in three shots over six months.  In most countries, they are approved only for female use, but are approved for male use in countries like the USA and the UK. 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, while in comparison around two-thirds of teens have gotten shots for meningitis and DPT vaccine.

Women should continue to seek cervical screening, such as pap smear testing, even after receiving the vaccine. Cervical cancer screening recommendations have not changed for females who receive the HPV vaccine.  Without continued screening, the number of cervical cancers preventable by vaccination alone is less than the number of cervical cancers prevented by regular screening alone.  Both men and women are carriers of HPV.  The Gardasil® vaccine also protects men against anal cancers and warts and genital warts.

No efficacy trials for children under 15 have been performed.  Duration of vaccine efficacy is not yet answered by rigorous methodologic trials. Cervarix® efficacy is proven for 7.4 years with published data through 6.4 years while Gardasil® efficacy is proven for 5 years.  Age of vaccination is less important than the duration of efficacy.

Condoms

The Centers for Disease Control and Prevention (CDC) says that male "condom use may reduce the risk for HPV-associated diseases (e.g., genital warts and cervical cancer) and may mitigate the other adverse consequences of infection with HPV; condom use has been associated with higher rates of regression of cervical intraepithelial neoplasia (CIN) and clearance of HPV infection in women, and with regression of HPV-associated penile lesions in men. A limited number of prospective studies have demonstrated a protective effect of condoms on the acquisition of genital HPV".  Female condoms provide somewhat greater protection than male condoms, as the female condom allows for less skin contact.  Studies have suggested that regular condom use can effectively limit the ongoing persistence and spread of HPV to additional genital sites in individuals already infected.

Microbicides for Sexually Transmitted Diseases (STD's)

Ongoing research has suggested that several inexpensive chemicals might serve to block HPV transmission if applied to the genitals prior to sexual contact.  These candidate agents, known as topical microbicides, are currently undergoing clinical efficacy testing.  A study indicates that some sexual lubricant brands that use a gelling agent called carrageenan can inhibit the papillomavirus infection.  Clinical trial results announced at the 2010 International Papillomavirus Conference indicate that a carrageenan-based personal lubricant called Carraguard® is effective for preventing HPV infection in women.  The results suggest that use of carrageenan-based personal lubricant products, such as Divine No 9®, Bioglide® and Oceanus Carrageenan®, may likewise be effective for preventing HPV infection.

Oral Infection

A review of scientific studies in healthy subjects has found carcinogenic HPV in 3.5% of the studies subjects and HPV16 in 1.3%.  Men have higher prevalence of oral HPV than women.  Oral HPV infection is associated with HPV-positive oropharyngeal cancer. Odds of oral HPV infection increases with the number of recent oral sex partners or open-mouthed kissing partners.  Nonsexual oral infection through salivary or cross transmission is also plausible.

Diagnosis

Cervical Testing

In 2009, the U.S. Food and Drug Administration (FDA) approved two assays (screening tests) Cervista® HPV HR (high risk) and Cervista® HPV 16/18 for use in cervical cancer screening.  According to the National Cancer Institute, "testing samples of cervical cells is an effective way to identify high-risk types of HPV that may be present. The FDA has approved an HPV test as a follow-up for women who have an ambiguous pap smear test and, for women over the age of 30, for general cervical cancer screening. This HPV test can identify at least 13 of the high-risk types of HPV associated with the development of cervical cancer. The test can detect high-risk types of HPV even before there are any conclusive visible changes to the cervical cells".

The recent outcomes in the identification of molecular pathways involved in cervical cancer provide helpful information about novel bio- or oncogenic markers that allow monitoring of these essential molecular events in cytological smears, histological, or cytological specimens. These bio- or onco- markers are likely to improve the detection of lesions that have a high risk of progression in both primary screening and triage settings.  E6 and E7 mRNA detection PreTect HPV-Proofer, (HPV OncoTect) or p16 cell-cycle protein levels are examples of these new molecular markers.  According to published results, these markers, which are highly sensitive and specific, allow to identify cells going through malignant transformation.

Other Testing

In 2011 the US Food and Drug Administration approved Gen-Probe's APTIMA® HPV Assay, New Molecular Test to Detect Virus that Causes Cervical Cancer. 

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.  Currently, there are no tests approved by the US Food and Drug Administration (FDA) to detect HPV in males.

Treatment

There is currently no cure for HPV infection, but there are some treatment options.   According to the Centers for Disease Control and Prevention (CDC), the body’s healthy immune system clears HPV naturally within two years for 90% of cases.  However, experts do not agree on whether the virus is completely eliminated or reduced to undetectable levels, and it is difficult to know when it is contagious.

HPV Treatments for Tissue Changes

If the HPV infection has caused abnormal cell changes that could lead to cervical cancer, there are four main treatment options:

  • Watch and wait. Sometimes the cell changes, called cervical dysplasia, precancerous cell changes, or cervical intraepithelial neoplasia, will heal on their own.
  • Cryotherapy. This involves freezing the abnormal cells with liquid nitrogen.
  • Conization. This procedure, also known as a cone biopsy, removes the abnormal areas.
  • LEEP or Loop Electrosurgical Excision Procedure. The abnormal cells are removed with an electrical current.
The goal is to remove all the abnormal cells and thus remove most or all of the cells with HPV.

HPV Treatment options for Genital Warts

According to the Mayo Clinic the HPV treatment options include:

Medications
  • Imiquimod® (Aldara®, Zyclara®).
  • Podophyllin® and Podofilox® (Condylox®).
  • 5-fluorouracil® (Efudix®), which is also known as 5FU.
  • Trichloroacetic acid (TCA).

Surgery
  • Cryotherapy (freezing with liquid nitrogen).
  • Surgical excision.
  • Electrocautery.
  • Laser treatments.

Surgical removal may cure the problem in a single visit. Success rates for the other techniques range from about 80% to 90%.

Epidemiology

Cutaneous HPV's

Little is known about the risk factors for cutaneous human papillomavirus infection.  Certain HPV types have a preference for cutaneous epithelium and are found in common warts, flat warts, plantar warts, and butcher's warts. Those HPV types associated with common and plantar include types 1, 2, and 4, respectively.  HPV types 3 and 10 most often cause flat warts, while butcher's warts, which are common warts that tend to occur in meat, poultry and fish handlers, are most often associated with HPV types 2 and 7.  Bowen's Disease (BD), which is also called ‘squamous cell carcinoma in situ’, is a superficial precancerous, slow growing or early stage, skin malignancy. The lesions may occur anywhere on the skin surface or on mucosal surfaces. Multiple HPV types have been isolated from these lesions; including HPV types 16, 18, 31, 32, 34, and others. Freezing, cauterization or diathermy coagulation is often effective treatment. Causes of BD include long-term overexposure to the sun, chronic exposure to arsenic (very rare nowadays), people who have to take drugs that lower their immunity (for example, AIDS or after receiving an organ transplant), genital warts (human papillomavirus), previous radiotherapy (for a different cancer) in the affected area, chronic skin injury, and dermatoses.

All HPVs are believed to be capable of establishing long-term "latent" infections in small numbers of stem cells 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 that an individual may become resistant to one HPV type while remaining susceptible to other types.

Lung Cancer

There has been evidence linking HPV to benign and malignant tumors of the upper respiratory tract. The International Agency for Research on Cancer (IARC) have found that Lung Cancer Risk Rises in the Presence of HPV Antibodies.  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 non-cancer patients did, and among lung cancer patients, the chances of having eight types of serious HPV were significantly increased.  In addition, there has been expression of HPV structural proteins by immunohistochemistry and in vitro studies that suggests HPV presence in bronchial cancer and its precursor lesions.  Another study detected HPV in the 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 non-small 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 US, respectively, and the mean number of HPV in Asian lung cancer samples was 35.7%, with a considerable heterogeneity between certain countries and regions.

Throat Cancer

In recent years, the United States has experienced an increase in the number of cases of throat cancer caused by the human papillomavirus (HPV) Type 16. According to The National Cancer Institute (NCI), throat cancers associated with HPV have been estimated to have increased by 225% between 1988 and 2004.  NCI estimates there were approximately 6,700 cases of HPV-positive oropharynx cancers in 2010, up from 4,000 to 4,500 in 2004, and cases are projected to increase 27% to 8,500 in 2020.

Researchers explain this recent data by an increase in oral sex. Moreover, findings indicate this type of cancer is much more prevalent in men than in women, something that needs to be further explored.  Currently, two vaccines, Gardasil® and Cervarix®, are recommended to girls to prevent HPV related cervical cancer but not as a precaution against HPV related throat cancer.

Genital HPV's

A large increase in the incidence of genital HPV infection occurs at the age when individuals begin to engage in sexual activity. The great majority of genital HPV infections never cause any overt symptoms and are cleared by the healthy immune system in a matter of months.  As with cutaneous HPVs, immunity is believed to be HPV type-specific. Some infected individuals may fail to bring genital HPV infection under immunological control. Lingering infection with high-risk HPV types, such as HPVs 16, 18, 31, and 45, can lead to the development of cervical cancer or other types of cancer.  In addition to persistent infection with high-risk HPV types, epidemiological and molecular data suggest that co-factors such as the cigarette smoke carcinogen benzo[a]pyrene (BaP) enhance development of certain HPV-induced cancers.

High-risk HPV types 16 and 18 are together responsible for over 65% of cervical cancer cases.  Type 16 causes 41 to 54% of cervical cancers, and accounts for an even greater majority of HPV-induced vaginal/vulvar cancers, penile cancers, anal cancers, and head and neck cancers.

Prevalance of HPV infection among females in the United States - [JAMA 2007] PubMed
Prevalance of Oral HPV infection in the United States, 2009-2010 - JAMA 2012
Global prevalance of HPV and Related Cancers - World Health Organization (WHO)

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 reported estimates that about 20 million people are currently infected with HPV.  Approximately 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.  Over 4,000 American women die of cervical cancer each year.

It was estimated that, in the year 2000, there were approximately 6.2 million new HPV infections among Americans aged 15 to 44; of these, an estimated 74% occurred in people between the ages of 15 and 24.  Of the STDs studied, genital HPV was the most commonly acquired.

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. However, only 3.4% were infected with one or more of the four types prevented by the Gardasil vaccine, which was lower than previous estimates.

The prevalence for high-risk and low-risk types is roughly similar over time.  The overall prevalence of high- and low-risk HPV types was 15.2% and 17.8%, respectively.  Note that prevalence decreases with age. This may be due to the HPV infections being naturally cleared by the healthy immune system, or sinking to undetectable levels while still present in the body.

History

"Characterization of two types of human papillomaviruses in lesions of epidermodysplasia verruciformis" was proposed by Stefania Jablonska, Chairman, Professor Emeritus, Department of Dermatology, Warsaw School of Medicine, Poland.  Jablonska and Gerard Orth, director of The Papillomavirus Unit at Institut Pasteur, discovered HPV-5 in skin cancer.  In the 1970s Professor Harald zur Hausen postulated a role for, and then found HPV-DNA in cervical cancers, and in the 1980s, Proffessor zur Hausen and his colleagues were the first to isolate HPV-16 and HPV-18 from cervical cancer tissues.  In 2008 Professor Harald zur Hausen was joint winner of the Nobel Prize for medicine.

The mutant HeLa cell line contains extra DNA in its genome that originated from HPV.


External Links

HPV Fact sheets - Centers for Disease Control and Prevention (CDC).
Myths and Misconceptions about HPV – American Social Health Association.
The HPV Connection - The Oral Cancer Foundation.
Human Papilloma Virus (HPV) - Young and Healthy - Canadian Association for Adolescent Health.
Human Papillomavirus (HPV) Vaccines - National Cancer Institute Fact Sheet - US National Institutes of Health (NIH).
Cervical Cancer: The Preventable Gynecologic Cancer - Centers for Disease Control and Prevention CDC).
HPV and Cancer - Centers for Disease Control and Prevention (CDC).
HPVs and Cancer - National Cancer Institute.
Recurrent Respiratory Papillomatosis or Laryngeal Papillomatosis - National Institute on Deafness and Other Communication Disorders.
STD Facts: HPV and Men - Centers for Disease Control and Prevention (CDC).
HPV Vaccine and Pregnancy - Organization of Teratology Information Specialists (OTIS) (pdf).
Teens Health: HPV Vaccine - Nemours Foundation.

Treatment
Human Papillomavirus (HPV) and Genital Warts: Treatment - National Institute of Allergy and Infectious Diseases.

Prevention/Screening
Condoms - Mayo Foundation for Medical Education and Research (MFMER).
Frequently Asked Questions about HPV Vaccine Safety - Centers for Disease Control and Prevention (CDC).
HPV Prevention - Centers for Disease Control and Prevention (CDC).
HPV Vaccine - Cervarix - Centers for Disease Control and Prevention (CDC).
HPV Vaccine - Gardasil - Centers for Disease Control and Prevention (CDC).
Understanding Abnormal Pap Test Results - American College of Obstetricians and Gynecologists.
Understanding Cervical Changes: A Health Guide for Women - National Cancer Institute.

Clinical Trials
ClinicalTrials.gov: Papillomavirus Infections - National Institutes of Health (NIH).

Research
Clinical Trial Shows Potential Benefit of HPV Vaccine for Anal Cancer - National Cancer Institute.
Second HPV Vaccine Shows Early Positive Results - National Cancer Institute.
Cancer Advances: Study Shows Dramatic Rise in Oral (Oropharyngeal) Cancer Linked to HPV - American Society of Clinical Oncology.
Vaccine Reduces HPV Infections in Young Men - National Cancer Institute.

Statistics
HPV-Associated Cancers Statistics - Centers for Disease Control and Prevention (CDC).
Human Papillomavirus - Prevalence of High-risk and Low-risk Types among Females Aged 14-59 Years, National Health and Nutrition Examination Survey, 2003-2006 - Centers for Disease Control and Prevention (CDC).

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