Human papillomavirus

Overview
Papillomaviruses are a diverse group of DNA-based viruses that infect the skin and mucous membranes of humans and a variety of animals. Over 100 different human papillomavirus (HPV) types have been identified.

Some HPV types may cause condylomas (skin warts) while others may cause a subclinical infection resulting in precancerous lesions. All HPVs are transmitted by skin-to-skin contact.

A group of about 30-40 HPVs is typically transmitted through sexual contact and infect the anogenital region. Some sexually transmitted HPVs -- types 6, 11, may cause genital warts. However, other HPV types which may infect the genitals do not to cause any noticeable signs of infection.

Persistent infection with a subset of about 13 so-called "high-risk" sexually transmitted HPVs, including types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68 — different from the ones that cause warts — may lead to the development of cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN), penile intraepithelial neoplasia (PIN), and/or anal intraepithelial neoplasia (AIN). These are precancerous lesions and can progress to invasive cancer. HPV infection is a necessary factor in the development of nearly all cases of cervical cancer.

A cervical Pap smear with HPV DNA testing is used to detect cellular abnormalities and the presence of HPV. This allows targeted surgical removal of condylomatous and/or pre-cancerous lesions prior to the development of invasive cervical cancer. Although the widespread use of Pap testing has reduced the incidence and lethality of cervical cancer in developed countries, the disease still kills several hundred thousand women per year worldwide. A recently approved HPV vaccine, Gardasil, that blocks initial infection with several of the most common sexually transmitted HPV types may lead to further decreases in the incidence of HPV-induced cancer.

History of discovering link between virus and cancer
The fact that prostitutes have much higher rates of cervical cancer than nuns was a key early observation leading researchers to speculate about a causal link between sexually transmitted HPVs and cervical cancer.

Genital HPV prevalence in the United States
Quoted statistics of HPV infection vary, with one review finding reported values anywhere from 14% to 90%. The major reason numbers conflict is simply a lack of context. A report of the number of women that have ever been infected by any type will be much higher than the number that are currently infected by one of the high-risk types. The confusion surrounding the issue is highlighted by news coverage of a comprehensive study published in February 2007. Some headlines read "more women than expected have HPV", while others said that infection was "rarer than first estimated". Both are actually true, in context:

The 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. Of the four types prevented by the Gardasil vaccine, however, only 3.4% were infected, which was lower than previous estimates. Of the high-risk types that cause cancer, 15.2% were infected.

Genital HPV infection is very common, with estimates suggesting that more than 50% of women will become infected with one or more of the sexually transmitted HPV types at some point during adulthood.

The American Social Health Association projections in 2006 were yet more pessimistic, predicting that about 75% of the reproductive population will have been infected with genital HPV infection in their lifetime. Studies show that HPV infection is much more prevalent in the gay community. Studies show a link between HPV infection and penile and anal cancer, and the risk for anal cancer is 17 to 31 times higher among gay and bisexual men than among heterosexual men.

Although it is possible to test for HPV DNA in men, there are no FDA-approved tests for general screening, since the testing is inconclusive and considered medically unnecessary.

"There is no screening test for HPV infection in men. However, although there are no formal guidelines, some experts believe that men who receive anal sex should have a routine anal Pap test, especially if they also have HIV infection. Ask your health professional whether and how often you should be tested."

Information from the CDC
According to the Centers for Disease Control (CDC), by the age of 50 more than 80% of American women will have contracted at least one strain of genital HPV. All women are encouraged to get a yearly pap smear solely to detect cellular abnormalities caused by HPV.

Genital HPV is the most common sexual transmitted infection in the United States. About 6.2 million Americans will get infected with genital HPV this year. According to the National Cervical Cancer Coalition (NCCC), 11% of American women do not have regular cervical cancer screenings; women who do not have cervical cancer screenings on a regular basis dramatically increase their chances of developing cervical cancer. About 14,000 women in the United States are diagnosed with cervical cancer disease each year, and more than 3,900 women die in the United States each year from this disease.

Information from the AMA
According to the Journal of the American Medical Association (Dunne, Eileen F. et al, 2007) the prevalence of HPV infection among females in the United States is as follows:


 * 24.5% prevalence of HPV among females 14 to 19 years old
 * 44.8% prevalence of HPV among females 20 to 24 years old
 * 27.4% prevalence of HPV among females 25 to 29 years old
 * 27.5% prevalence of HPV among females 30 to 39 years old
 * 25.2% prevalence of HPV among females 40 to 49 years old
 * 19.6% prevalence of HPV among females 50 to 59 years old

HPV lifecycle
The HPV lifecycle 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. 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 amiable to the amplification of viral genome replication and consequent late gene expression. In the upper layers of the host epithelium, the late genes L1 and L2 are transcribed/translated and serve as structural proteins which encapsidate the amplified viral genomes. Virions can then be sloughed off in the dead squames of the host epithelium and the viral lifecycle continues.

Skin warts

 * Common warts: Some "cutaneous" HPV types, such as HPV-1 and HPV-2, 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 do not usually cause genital warts and 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
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 don't display overt symptoms of infection. However, in the vast majority of cases, this is not a cause for concern if proper tests are routinely administered.

HPV types that tend to cause genital warts are not the same ones that cause cervical cancer. However, 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.

Condyloma accumulata is another form of genital warts.

Cancer
About a dozen HPV types (including types 16, 18, 31 and 45) are called "high-risk" types because they can lead to cervical cancer, as well as anal cancer, vulvar cancer, and penile cancer. Several types of HPV, particularly type 16, have been found to be associated with oropharyngeal squamous-cell carcinoma, a form of head and neck 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.

The p53 protein prevents cell growth in the presence of DNA damage primarily through the BAX domain, which blocks the anti-apoptotic effects of the mitochondrial BCL-2 receptor. In addition, 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. In short, p53 is a tumor suppressor gene that arrests the cell cycle when there is DNA damage. The E6 and E7 proteins work by inhibiting tumor suppression genes involved in that pathway: E6 inhibits p53, while E7 inhibits p53, p21, and RB.

A history of infection with one or more high-risk HPV types is believed to be a prerequisite for the development of cervical cancer (the vast majority of HPV infections are not high risk); according to the American Cancer Society, women with no history of the virus do not develop this type of cancer. However, 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 who have been infected with HPV for a long time, usually over a decade or more.

Sexually transmitted HPVs also cause a major fraction of anal cancers and approximately 25% of cancers of the mouth and upper throat (known as the oropharynx) (see figure). 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.

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.

Cutaneous HPVs
Infection with cutaneous HPVs is ubiquitous. Some HPV types, such as HPV-5, may establish infections that persist for the lifetime of the individual without ever manifesting any clinical symptoms. Like remora suckerfish that hitchhike harmlessly on sharks, these HPV types can be thought of as human commensals. Other cutaneous HPVs, such as HPV types 1 or 2, may cause common warts in some infected individuals. Skin warts are most common in childhood and typically appear and regress spontaneously over the course of weeks to months. About 10% of adults also suffer from recurring skin warts. 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 likely HPV type-specific, meaning that an individual may become immunologically resistant to one HPV type while remaining susceptible to other types.

Genital HPVs
A large increase in the incidence of genital HPV infection occurs at the age when individuals begin to engage in sexual activity (see figure). The great majority of genital HPV infections never cause any overt symptoms and are cleared by the immune system in a matter of months. As with cutaneous HPVs, immunity is believed to be HPV type-specific. A subset of 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.

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.

Public health and genital HPVs
According to the Centers for Disease Control, by the age of 50 more than 80% of American women will have contracted at least one strain of genital HPV. All women are encouraged get a yearly pap smear solely to detect cellular abnormalities caused by HPV.

The HPV vaccine, Gardasil, protects against the two strains of HPV that cause 70% of cervical cancer cases, and two strains of HPV that cause 90% of genital warts.

The CDC recommends that girls and women between the ages of 11 and 26 be vaccinated.

Perinatal transmission
Although genital HPV types are sometimes 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%.

Cervical cancer detection and prevention
Most people become infected with various cutaneous HPV types during childhood. Papillomaviruses have a sturdy outer protein shell or "capsid" that renders them capable of lingering in the environment for long periods of time. Avoiding contact with contaminated surfaces, such as the floors of communal showers or airport security lines, might reduce the risk of cutaneous HPV infection. Treating common warts soon after they first appear may also reduce the spread of the infection to additional sites.

Genital HPV infections may be distributed widely over genital skin and mucosal surfaces, and transmission can occur even when there are no overt symptoms. Several strategies should be employed to minimize the risk of developing diseases caused by genital HPVs:

Pap smear
Certain types of sexually transmitted HPVs can cause cervical cancer. Persistent infection with one or more of about a dozen of these "high-risk" HPV types is an important factor in nearly all cases of cervical cancer. The development of HPV-induced cervical cancer is a slow process that generally takes many years. During this development phase, pre-cancerous cells can be detected by annual or semi-annual cervical cytology Papanicolaou screening, colloquially known as "Pap" smear testing. The Pap test is an effective strategy for reducing the risk of invasive cervical cancer. The Pap test involves taking cells from the cervix and putting them on a small glass slide and examining them under a microscope to look for abnormal cells. This method is 70% to 80% effective in detecting HPV-caused cellular abnormalities. A more sensitive method is a “Thin Prep,” in which the cells from the cervix are placed in a liquid solution. This test is 85% to 95% effective in detecting HPV-caused cellular abnormalities. The last Pap test method is mainly used on women over 30. It is a combination Pap-HPV DNA test. If this test comes back negative women can usually wait 3 years before having the test done again. Detailed inspection of the cervix by colposcopy may be indicated if abnormal cells are detected by routine Pap smear. A frequently occurring example of an abnormal cell found in association with HPV is the koilocyte. (See figure.)

The Center for Disease Control (CDC) recommends that women get a Pap test no later than 3 years after their first sexual encounter and no later than 21 years of age. Women should have a Pap test every year until age 30. After age 30, women should discuss risk factors with their health care provider to determine whether a Pap test should be done yearly. If risk factors are low and previous Pap tests have been negative, most women only need to have tests every 2-3 years until 65 years of age (Centers for Disease Control 2005). Since these screening tools have been developed there has been a 70% decrease in cervical cancer deaths over the last 50 years. Pap smear testing has proven to be one of the most successful screening tests in the history of medicine, but the American College of Obstetricians and Gynecologists states the even the newer liquid based cytology methods (Thinprep and Surepath) may miss 15-35% of CIN3's and cancer.

A study published in April 2007 suggested the act of performing a Pap smear produces an inflammatory cytokine response, which may initiate immunologic clearance of HPV, therefore reducing the risk of cervical cancer. Women who had even a single Pap smear in their history had a lower incidence of cancer. "A statistically significant decline in the HPV positivity rate correlated with the lifetime number of Pap smears received."

It has been suggested that Pap smear screening for anal cancer might be of benefit for some sub-populations of gay men.

HPV testing
An HPV test detects certain types of human papillomavirus (HPVs), depending on the test. A method for detecting the DNA of high-risk HPVs has recently been added to the range of clinical options for cervical cancer screening. In March 2003, the US FDA approved a "hybrid-capture" test, marketed by Digene, as a primary screening tool for detecting high-risk HPV infections that may lead to cervical cancer. This test was also approved for use as an adjunct to Pap testing, and may be ordered in response to abnormal Pap smear results.

Adding the HPV test for all women over thirty improves the sensitivity of the cytology test alone to nearly 100% and gives the clinician the option to extend the pap smear screening interval out to three years.

According to the CDC there is currently no test commercially available to determine infection in men. Genital warts are the only visible sign of HPV in men, and can be identified with a visual check of the genital area. These visible growths, however, are usually the result of non-carcinogenic HPV types. Vinegar solutions have been used to identify flat warts by making them more distinct, but most providers have found this technique helpful only in moist areas, such as the female genital tract.

Vaccine
On June 8, 2006, the FDA approved Gardasil, a prophylactic HPV vaccine which is marketed by Merck. The vaccine trial, conducted in adult women with a mean age of 23, showed protection against initial infection with HPV types 16 and 18, which together cause 70 percent of cervical cancers. HPV types 16 and 18 also cause anal cancer in men and women.

The trial also showed 100% efficacy against persistent infections, not just incident infections. The vaccine also protects against HPV types 6 and 11, which cause 90 percent of genital warts. Women aged nine through twenty-six can be vaccinated, though the trial did not test minors. GlaxoSmithKline is expected to seek approval for a prophylactic vaccine targeting HPV types 16 and 18 early in 2007, known as Cervarix. Since the current vaccine will not protect women against all the HPV types that cause cervical cancer, it will be important for women to continue to seek Pap smear testing, even after receiving the vaccine. In addition, the Centers for Disease Control and Prevention (CDC) recommends vaccinating women who have already been diagnosed with HPV.

The vaccine has no side effects with the exception of soreness around the injection area. The FDA and CDC consider the vaccine to be completely safe. It does not contain mercury, thimerosal or live virus (only dead virus). Merck, the manufacturer of Gardasil, will continue to test women who have received the vaccine to determine the vaccine's efficacy over the period of a lifetime.

Both men and women are carriers of HPV. To eradicate the disease, men will eventually need to be vaccinated. Studies are being conducted now to determine the efficacy of vaccinating boys with the current vaccine.

The vaccine (commonly known as Gardasil) is delivered in a series of three shots over six months at a cost of approximately $360 (US dollars). The CDC recommends that girls and women between the ages of 11 and 26 be vaccinated, though girls as young as 9 may benefit.

Condoms
Although condoms are highly effective for preventing the transmission of other sexually transmitted diseases (STDs), recent studies have concluded that condoms only offer partial protection, at best, against the transmission of genital HPVs.

This may be due to the fact that HPVs can infect genital skin areas that are not covered by condoms. On the other hand, some studies have suggested that regular condom use can effectively limit the ongoing persistence and spread of HPV to additional genital sites in individuals who are already infected.

Thus, condom use may reduce the risk that infected individuals will progress to cervical cancer or develop additional genital warts. A 2006 study of 82 college students suggests that condoms can be up to 70% effective for preventing genital HPV infection if used for every sexual encounter. Planned Parenthood recommends condom use to reduce the risk of contracting HPV, but the Centers for Disease Control and Prevention maintain that "While the effect of condoms in preventing HPV infection is unknown, condom use has been associated with a lower rate of cervical cancer, an HPV-associated disease."

Microbicides
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 recent study indicates that some sexual lubricant brands that use a gelling agent called carrageenan can inhibit papillomavirus infection in vitro. See Carrageenan for details.

Clinical trials are needed to determine whether carrageenan-based sexual lubricant gels are effective for blocking the sexual transmission of HPVs in vivo.

Vitamin A
In a clinic-based case-control study to assess serum micronutrients as risk factors for cervical dysplasia, subjects in the lowest serum retinol quartile were at increased risk of CIN I compared with women in the highest quartile.

Vitamin C
Risk of type-specific, persistent HPV infection was lower among women reporting intake values of vitamin C in the upper quartile compared with those reporting intake in the lowest quartile.

Vitamin E
HPV clearance time was significantly shorter among women with the highest compared with the lowest serum levels of tocopherols, but significant trends in these associations were limited to infections lasting 120 days) was not significantly associated with circulating levels of tocopherols. Results from this investigation support an association of micronutrients with the rapid clearance of incident oncogenic HPV infection of the uterine cervix.

A statistically significantly lower level of alpha-tocopherol was observed in the blood serum of HPV-positive patients with cervical intraepithelial neoplasia. The risk of dysplasia was four times higher for an alpha-tocopherol level < 7.95 mumol/l.

Folic acid
Higher folate status was inversely associated with becoming HPV test-positive. Women with higher folate status were significantly less likely to be repeatedly HPV test-positive and more likely to become test-negative. Studies have shown that lower levels of antioxidants coexisting with low levels of folic acid increases the risk of CIN development. Improving folate status in subjects at risk of getting infected or already infected with high-risk HPV may have a beneficial impact in the prevention of cervical cancer.

Carotenoids
Higher circulating levels of carotenoids were associated with a significant decrease in the clearance time of type-specific HPV infection, particularly during the early stages of infection (120 days) was not significantly associated with circulating levels of carotenoids.

The likelihood of clearing an oncogenic HPV infection is significantly higher with increasing levels of lycopenes. A 56% reduction in HPV persistence risk was observed in women with the highest plasma [lycopene] concentrations compared with women with the lowest plasma lycopene concentrations. These data suggests that vegetable consumption and circulating lycopene may be protective against HPV persistence.

CoQ10
Women who had either CIN or cervical cancer had markedly lower levels of CoQ10 in their blood and in their cervical cells than the women who were healthy.

Fruits and vegetables
Higher levels of vegetable consumption were associated with a 54% decrease risk of HPV persistence. Consumption of papaya at least once a week was inversely associated with persistent HPV infection.

Fish oil
In a 1999 study, Docosahexaenoic acid inhibited growth of HPV16 immortalized cells.

Treatment
Many sufferers of HPV warts report success using organic Apple Cider Vinegar (acidity 5%). A paper towel soaked in ACV is applied onto the infected areas, and can be secured with duct tape. Those reporting the best results leave the soaked paper towel on for hours, or even all night during sleep. The result is that the wart turns bright white in color, and after several treatments, begins to turn black and die, eventually peeling off. Many users report success mixing the ACV with small amounts of garlic and Tea Tree Oil as well when preparing the solution. The ACV can also be swallowed orally when mixed with water. Because the ACV can irritate sensitive skin area, some users report alternating treatments with a paper towel soaked in castor oil, which moisturizes skin while assisting in the removal of HPV warts. 

Therapies are addressed in main articles covering the various HPV-related diseases.