human papillomavirus

Papillomaviruses are a diverse group of DNA-based viruses that infect the skin and mucous membranes of humans and a variety of animals. More than 100 different human papillomavirus (HPV) types have been characterized. Some HPV types cause benign skin warts, or papillomas, for which the virus family is named. HPVs associated with the development of such "common warts" are transmitted environmentally or by casual skin-to-skin contact.

A group of about 30-40 HPVs are typically transmitted through sexual contact and infect the anogenital region. Some sexually transmitted HPVs, such as types 6 and 11, can cause genital warts. However, most HPV types that infect the genitals tend not to cause noticeable symptoms.

Persistent infection with a subset of about a dozen so-called "high-risk" sexually transmitted HPVs, including types 16, 18, 31, 33, 35, 39, 45, 51 and 52 -- different from the ones that cause warts -- can lead to the development of cervical dyskaryosis, which may in turn lead to cancer of the cervix. HPV infection is a necessary factor in the development of nearly all cases of cervical cancer.^[1]

Cervical Pap smear testing is used to detect HPV-induced cellular abnormalities. This allows targeted surgical removal of pre-cancerous lesions prior to the development of invasive cervical cancer. In the absence of Pap testing or treatment, about 1% of women with genital HPV infections will eventually go on to develop 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 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.^[2]

Prevalence

Quoted statistics of HPV infection vary wildly, with one review finding reported values anywhere from 14% to 90%.^[3] The major reason numbers conflict is simply a lack of context. A quote of the number of women that have ever been infected by any strain will be much higher than the number that are currently infected by one of the high-risk strains. 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".^[4][5] 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 strain of HPV (including those that are harmless). This was higher than previous estimates. Of the four strains prevented by the Gardasil vaccine, however, only 3.4% were infected, which was lower than previous estimates. Of the high-risk strains that cause cancer, 15.2% were infected. Prevalence (of any type) was significantly higher (44.8%) in women aged 20-24, while younger and older age brackets were all below 28%.^[6]

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.^[7]

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.^{citation needed]} Studies show that HPV infection is much more prevalent in the gay community.^{citation needed]}

HPV-induced diseases

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 closely resemble common warts.
• 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.^[8][9]

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 possiblity of high risk strains of the virus also being present.

Cancer

About a dozen HPV types (including types 16, 18, 31 and 45) are called "high-risk" types because they can cause cervical cancer, as well as anal cancer, vulvar cancer, head and neck cancers, and penile cancer.^[10] 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.^[11][12]

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.^[13][14] 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.^[15][12]

These warts can recur frequently, may require repetitive surgery, may interfere with breathing, and in extremely rare cases can progress to cancer.^[16][12]

Epidemiology

Cutaneous HPVs

Infection with cutaneous HPVs is ubiquitous.^[17] 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.^[18]

High-risk HPV types 16 and 18 are together responsible for over 70% of cervical cancer cases.^[19][7]

Type 16 causes 41 to 54% of cervical cancers, ^[20][7] and accounts for an even greater majority of HPV-induced vaginal/vulvar cancers,^[21] penile cancers, anal cancers and head and neck cancers.^[22]

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.^[12] 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%.

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

Main article: Pap smear

Papanicolaou screening, colloquially known as "Pap" smear testing, is an effective strategy for reducing the risk of invasive cervical cancer. In March 2003, the US FDA approved HPV DNA testing as a primary screening tool for detecting high-risk HPV infections that may lead to cervical cancer. Pap smear testing has proven to be one of the most successful screening tests in the history of medicine, but ACOG states the even the newer liquid based cytology methods (Thinprep and Surepath) may miss 15-35% of CIN3's and cancer. By adding the HPV test to all women over the age of thirty, it improves the sensitivity of the cytology test to nearly 100%. The HPV DNA test, which is marketed by Digene, can also serve as an adjunct to Pap smear testing, and may be ordered in response to abnormal Pap smear results. It is the gold standard for the resolution of ASCUS pap results, as detailed in the ALTS trial. Detailed inspection of the cervix by colposcopy may be indicated if abnormal cells are detected by routine Pap smear.

It has been suggested that Pap smear screening for anal cancer might be of benefit for some sub-populations of gay men.^[23]

HPV testing

An HPV test detects certain human papillomaviruses (HPVs), depending on the test. 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 screening or "Pap test." More recently a method for detecting the DNA of high-risk HPVs has been added to the range of clinical options for cervical cancer screening. The US FDA has approved this "hybrid-capture" test, marketed by Digene, for use as an alternative or adjunct to Pap testing.

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. 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. 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.

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.

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. 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.^[24]

Vaccine

Main article: HPV vaccine

On June 8, 2006, the FDA approved Gardasil, a prophylactic HPV vaccine which is marketed by Merck. The vaccine trial,^[25] 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. The Centers for Disease Control and Prevention (CDC) recommend vaccinating a woman who has already been diagnosed with HPV (October 2006)^[26]. As much as the vaccine is recomended, the administration techniques are still some what primitive. The vaccine must be injected into the largest tissue source on the human body. The point of vaccination will be sore from 1-5 days found in some studies, but results are optimal.

Avoiding risky sexual behavior

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.^[27] It remains clear that people with greater numbers of sexual partners are at increased risk of developing genital HPV-related diseases. Co-infection with other sexually transmitted pathogens, such as HIV, may also increase the risk of developing HPV-related diseases.

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.^[28][29]

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.^[30][31]

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.^[29] Both Planned Parenthood and the Centers for Disease Control recommend condom use to reduce the risk of contracting HPV.^{citation needed]}

Microbicides

Ongoing research has suggested that several inexpensive chemicals might serve to block HPV transmission if applied to the genitals prior to sexual contact.^[32]

These candidate agents, which are 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.^[33]

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

Avoiding smoking

Tobacco smoking increases the risk of developing invasive cervical cancer, as well as other HPV-induced cancers. Smoking decreases the ability to absorb folic acid, and taking folic acid is a respected way of treating cervical dysplasia, an extremely common symptom of HPV.

Treatment

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