Why Human Papillomavirus (HPV) Is Most Deadly

Human papillomavirus (HPV) is a DNA virus capable of infecting humans. HPVs establish productive infections only in the skin or mucous membranes.


Most HPV infections are subclinical and will cause no physical symptoms; however, in some people subclinical infections will become clinical and may cause warts [verrucae] or squamous cell papilloma), or cancers of the cervix, vulva, vagina, penis, oropharynx and anus.  In particular, HPV16 and HPV18 are known to cause around 70% of cervical cancer cases.




Over 170 types are known and more than 40 types of HPV are typically transmitted through sexual contact and infect the anogenital region (anus and genitals).

HPV types 6 and 11 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.

High-risk HPV infection is a cause of nearly all cases of cervical cancer. However, most infections do not cause disease. New vaccines have been developed to protect against infection with HPV.

70% of clinical HPV infections, in young men and women, may regress to subclinical in one year and 90% in two years. However, when the subclinical infection persists in 5% to 10% of infected women there is high risk of developing precancerous lesions of the vulva and cervix, which can progress to invasive cancer. Progression from subclinical to clinical infection may take years, providing opportunities for detection and treatment of pre-cancerous lesions.

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.

In 2012, it was estimated that there were 528,000 cases of cervical cancer, and 266,000 deaths. It is estimated that there will be 12,900 diagnosed cases of cervical cancer and 4,100 deaths in the U.S. in 2015. There are 48,000 cases of genital warts in UK men each year. HPV causes cancers of the throat, anus and penis as well as causing genital warts.

Signs and symptoms

Over 170 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 cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN), penile intraepithelial neoplasia (PIN), and/or anal intraepithelial neoplasia (AIN).

"high-risk" sexually transmitted HPVs and may lead to the development of

Disease	HPV type
Common warts	2, 7, 22
Plantar warts	1, 2, 4, 63
Flat warts	3, 10, 8
Anogenital warts	6, 11, 42, 44 and others
Anal dysplasia (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
Verrucous cyst	60
Laryngeal papillomatosis	6, 11

Cancer

In August 2012, the Medscape website released a slides presentation about HPV and cancer risk. The following table shows the incidence of HPV associated cancers in the period of 2004-2008 in the US.^[22]

Cancer area	Average Annual Number of cases	HPV Attributable (Estimated)	HPV 16/18 Attributable (Estimated)
Cervix	11,967	11,500	9,100
Vulva	3,136	1,600	1,400
Vagina	729	500	400
Penis	1,046	400	300
Anus (woman)	3,089	2,900	2,700
Anus (men)	1,678	1,600	1,500
Oropharynx (woman)	2,370	1,500	1,400
Oropharynx (men)	9,356	5,900	5,600
Total (women)	21,291	18,000	15,000
Total (men)	12,080	7,900	7,600

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.

Furthermore, HPV can induce a tumorigenic process by integration in host genome associated with alterations in DNA copy number, no functional alternative splicing, inter- and intrachromosomal rearrangements and changes in patterns of DNA methylation, the latter also produced by the virus extrachromosomal.

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 oral cancer.

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 cancers of the mouth and upper throat (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.

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.

It has been suggested that anal Pap smear 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 smear.


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.


The mutational profile of HPV+ and HPV- head and neck cancer has been reported, further demonstrating that they are fundamentally distinct diseases.

Skin warts

All HPV infections can cause warts (verrucae), which are noncancerous skin growths. Infection with these types of HPV causes a rapid growth of cells on the outer layer of the skin. In a study, HPV types 2, 27 and 57 were most frequently observed with warts, while HPV 1, 2, 63, 27 were commonly observed on clinically normal 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.

Transmission

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 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.
Of the 120 known human papillomaviruses, 51 species and three subtypes infect the genital mucosa. 15 are classified as high-risk types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82), 3 as probable high-risk (26, 53, and 66), and 12 as low-risk (6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, and CP6108).
If a 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.

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 couples every other month for an average of 7 months. She found 2 couples where the man's genitals infected the woman's hand with high risk HPV, 2 where her hand infected his genitals, 1 where her genitals infected his hand, 2 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 2 years) as their genitals (48%). Winer reports 14% of fingertip samples from sexually active women were positive. None of these studies reports whether participants were asked to wash or not wash their hands before testing.
Non-sexual hand contact seems to have little or no role in HPV transmission. Winer found all 14 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 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 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. 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 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 and other Red Cross societies do not presently appear to disallow HPV-positive individuals from donating blood.

Treatment

There is currently no specific treatment for HPV infection. However, the viral infection, more often than not, clears to undetectable levels by itself. According to the Centers for Disease Control and Prevention, 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 completely eliminated or reduced to undetectable levels, and it is difficult to know when it is contagious.
The DRACO (antiviral) drug is currently in the early stages of research, and may offer a generic HPV treatment if it proves successful. Novirin and Gene- Eden- VIR are natural antiviral supplements backed by clinical studies followed by FDA guidelines. They are designed to help the immune system target the latent form of HPV.
Alferon N, a drug against genital warts, is set to go back on the market in late 2015. It is used to treat genital warts that occur on the outside of the body and is for use only in people who are at least 18 years old.
A 2014 study indicates that lopinavir is effective against the human papilloma virus (HPV). The study used the equivalent of one tablet twice a day applied topically to the cervices of women with high-grade and low-grade precancerous conditions. After three months of treatment, 82.6% of the women who had high-grade disease had normal cervical conditions, confirmed by smears and biopsies.