Burden of HPV virus, Carcinogenesis and Prevention

Human papillomavirus (HPV) infection is the most common sexually transmitted infection in men and women across the world. Most sexually active persons will acquire HPV in their lifetime. Recent data indicate that approximately 79 million persons are currently infected with HPV, and 14 million persons are newly infected each year in the United States.[1]Most infections cause no symptoms and are not clinically significant, but persistent infection can lead to disease or cancer.
Professor Harald zur Hausen, the recipient of the 2008 Nobel Prize is known as the ‘Father of HPV Virology’. He identified for the first time the connection between HPV and cervical cancer. Development of this cancer is dependent on a number of other risk factors such as smoking, number of sexual partners, sexual practices and how effective your immune system is working. People with HIV or AIDs and those on medications that suppresses the immune system, e.g. taken following organ transplants, are at higher risk. The greater the number of risk factors present, the higher the chance of developing HPV related cancer.
The Virus:
HPV is a small, tightly coiled circular DNA virus with approximately 8000 base pairs. It has a specific predilection for infecting the cutaneous epithelium (skin) and mucous membranes. The HPV genome is composed of six early proteins (E1, E2, E4, E5, E6, and E7), two late (L1 and L2) proteins, and a non-coding long control region (LCR). The “E” designation indicates that these two proteins are expressed early in the HPV life cycle, while the \”L\” designation indicates late expression. The two primary proteins which leads to cancer development (oncoproteins) in high risk HPV types are E6 and E7.
More than 100 HPV types have been identified so far and are named on the basis of genetic sequencing of the outer capsid protein L1. Most HPV types infect the cutaneous epithelium and cause common skin warts. Approximately 40 types are transmitted through sexual contact and infect the anogenital region and other mucosal sites of the body. Mucosal HPV types are classified as either high-risk HPV (oncogenic) (e.g., most commonly types 16 and 18) or low-risk HPV (e.g., types 6 and 11). Other less common high-risk types include types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 69, 73, 82.
Electron microscopy of HPV Virus
HPV Genome
Clinical spectrum:
HPV types which infects skin can cause warts and verrucas, which are common on the hands (type 2) , feet (type 1) , genital areas and around the anus (types 6 and 11) , although they can arise anywhere else in the body. These cutaneous types are spread through any type of skin contact and they do not usually cause cancer.
Approximately 40 types that infect mucous membranes are divided into high risk or low risk types depending on potential for causing cancer. These are transmitted sexually and can occur through all sexual practices where mucous membrane is present. Low-risk HPV causes anogenital warts, sometimes called condyloma acuminata. They are soft, moist or flesh colored appearing in the genital area within weeks or months after infection. Sometimes they can appear in clusters and are either raised or flat, small or large. In women they appear in the vulva, cervix, vagina and anus, on the scrotum or penis in men. Rarely, warts can develop in throat and airways, especially in babies of infected mothers. High-risk HPV causes many cancers of the cervix, vagina, vulva, penis, anus and oral cavity. Most commonly, they cause abnormal changes in the cells of cervix which is picked up on smear test and persistent infection with high risk HPV causes cervical cancer.
HPV Clinical FeaturesMost HPV infections are asymptomatic and result in no clinical diseaseClinical presentation of HPV infection include:- anogenital warts- recurrent laryngeal warts- cervical cancer precursors (cervical intraepithelial neoplasia)- cancer (cervical, anal, vaginal, vulvar, penile, and some head and neck cancer)
HPV and Cancer:
There are now number of studies to confirm that high risk HPV causes cancer, through the expression of early proteins. E6 and E7 which destroy natural defences (p53 and pRb) against cancer. P53 and pRb (retinoblastoma gene) are tumour suppressor genes that normally control the cell cycle, prevent excessive proliferation and allow programmed cell death (apoptosis) at the end of their differentiation. E6 binds with p53 and E7 binds with pRb, with loss of effect from normal protective genes.
Normally, HPV early protein E2 keeps E6 and E7 under control, but once the viral DNA is integrated with host DNA, E2 loses controls over E6 and E7. There is much evidence to confirm the role of E6 and E7 in producing cancer.
p53 Action
How does ‘high risk’ HPV cause cancer?
► Virus enters through minor abrasions in skin and mucous membranes.
► Attaches itself to receptors and enters into the basal epithelial cells (where new cells are formed) by a process of endocytosis.
► The virus genome is transported to the nucleus by unknown mechanism.
► Establishes 10-200 copies of viral genome in each host cell.
► Numerous cellular transcription factors interact with the non-coding viral regulatory region (LCR) with expression of early viral proteins.
► Integration of viral DNA into host genome damages the Gatekeeper gene E2.
► A sophisticated cascade of transcription occurs as the host cell begins to divide.
► Loss of control of oncogenic viral proteins E6 and E7.
► E6 and E7 binds with naturally occurring tumour suppressor genes p53 and pRb (E6 with p53 and E7 with pRb) and renders them inactive.
► Due to altered DNA driven by E6 and E7, normal cell cycle is disrupted.
► Host cells continue to replicate without apoptosis (programmed cell death) with increased rate of mutation.
► Uncontrolled cellular proliferation with malignant transformation.
Cancer of cervix :
Cervical (neck of the womb) cancer is the third most common cancer in women worldwide. It is estimated that in 2008, approximately 530,000 women developed cervical cancer and that 275,000 died from the disease. Eighty-six per cent of cervical cancer cases occur in developing countries. In contrast to many other malignancies, cervical cancer primarily affects younger women, with the majority of cases appearing between the ages of 35 and 50 years.
Cervical cancer was known to be sexually transmitted since 1800 but it was after Professor Hausen’s discovery in 1980’s that the primary role HPV was recognised in the development of cervical cancer. High-risk HPV types are detected in 99% of cervical cancers. Type 16 is the cause of approximately 50% of cervical cancers worldwide, and types 16 and 18 together account for about 70% of cervical cancers. Infection with a high-risk HPV type is considered necessary for the development of cervical cancer, but it is not sufficient, because the vast majority of women with HPV infection do not develop cancer.
The natural history of HPV infection is long and 80% of those infected will develop antibodies against HPV spontaneously, with resolution within 18 months. Less than 20% will not be able to mount adequate immune response and hence the virus will persist to cause cancer-related changes.
Because of the risk of cervical cancer in women who are sexually active, screening is performed by carrying out regular smear tests of the cervix. Infection with high risk HPV can be detected due to cells showing abnormal nuclei containing dense chromatin. This is termed as ‘dyskaryosis’, with degrees of abnormality described as mild, moderate or severe dyskaryosis. These days, the smear test also checks for presence of high risk HPV. Women with abnormal smear test results are referred to a specialist clinic called ‘Colposcopy’ where biopsy is taken. Precancerous changes, which can be seen in the cervical tissue, are called Cervical Intra-epithelial Neoplasia (CIN) and when corresponding to the smear test, are termed as CIN 1, 2 or 3. CIN 2 and 3 are considered precursors for cervical cancer and require treatment. Treatment only gets rid of any visible signs of the HPV infection, such as CIN or warts, but there is no treatment that can eradicate the HPV virus. The body normally clears the virus on its own after around 18 months.
HPV infection in cervix
Since the start of cervical screening in 1970’s, deaths from cervical cancers has significantly dropped worldwide due to effective treatment of pre-cancerous cells. Cervical cancer is preventable, and it is therefore very important for women to have regular smear tests.
Cervical Cancer (C53): 1971-2011
European Age-Standardised Mortality Rates per 100,000 Population, Females, UK
HPV and other cancers:
Recent U.S. population-based studies conducted by CDC show that 66% of cervical cancers, 55% of vaginal cancers, 79% of anal cancers, and 62% of oropharyngeal cancers are attributable to HPV types 16 or 18. Each year in the United States, an estimated 26,000 new cancers are attributable to HPV, about 17,000 in women and 9,000 in men.
Vaginal and vulval cancers are rare and seen in older women. Just like cervical cancer, both have precancerous stages which can be detected and treated. Anal cancer is also a rare cancer with just under 1,200 people diagnosed each year in the UK. Anal cancer is slightly more common in women, especially in those who have HPV related changes in cervix, vagina and vulva. Men who have anal intercourse, or who have genital warts are also at higher risk.
Cancer of penis is also a rare cancer in Western countries. Around 550 men are diagnosed each year in the UK, usually in men over 60 years of age. It is more common in men who live in Asia, Africa or South America. The exact cause of penile cancer is not known but men with human papilloma virus have an increased risk of developing cancer of the penis. A number of research studies have tried to establish the link between penile cancer and HPV. These studies showed that up to 79% of men with penile cancer have evidence of HPV infection. The main types of HPV found in men with penile cancer are HPV 16 and 18, although other types may also be related. HPV 16 and 18 do not usually cause genital warts but there is evidence that men with a history of genital warts have an increased risk of penile cancer.
In a Danish study, men who had never used condoms had more than double the risk of penile cancer compared to men who had used condoms. This may be because condoms reduce the risk of HPV infection. Men who have two or more sexual partners before the age of 20 have a 4 to 5 increased risk of penile cancer. This may also be due to HPV infection.
Men who smoke may be more likely to develop cancer of the penis. There are chemicals that cause cancer (benzyrene) in cigarettes. Researchers believe that these may damage the DNA of cells in the penis and increase the risk of developing cancer. Cells in the lining of the penis, called Langerhans cells, help fight disease. These cells do not work so well in smokers and can’t fight off viruses as well as they do in non-smokers. Men who have undergone circumcision, especially at a younger age seem to have a reduced risk of HPV infection of the penis, but this factor is not as important as smoking.
Cancer of the mouth (oral cavity) and throat (pharynx) are together known as Oro-pharyngeal cancer. Cancer can start anywhere in the mouth including lip and tongue up to the throat and then quickly spreads to lymph nodes in the neck. These cancers are relatively rare and mostly occur in older people, but the number of younger and middle-aged men developing them is increasing. The exact cause is not known but a number of risk factors contribute to its development. The main risk factors are those that cause chronic irritation of the skin and mucous membrane, namely smoking, alcohol and chewing tobacco. This is because cigarettes and alcohol contain nitrosamines, along with other chemicals, which cause cancers.A study in 2011 estimated that more than half of mouth and throat cancers in the UK are caused by smoking. Pipe smokers, or people who hold the cigarette for a long time on the lip, have an increased risk of cancer of the lip. People exposed to secondhand smoke at home or in the workplace also have a small increase in their risk of mouth or oropharyngeal cancer.
Other factors include high risk HPV infection, especially HPV type 16, which causes genetic changes in the cells. The combination of HPV infection with smoking and alcohol intake is likely to be the cause of rising incidence of mouth cancer in younger generation. Currently, there are a number of clinical trials on the effectiveness of a new HPV vaccine for people with oral cancers. People with rare genetic disorders called Fanconi’s anemia and dyskeratosis congenita are at higher risk of developing oral cancers.
HPV quadrivalent Vaccine
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Prevention of HPV:
One can do several things to lower the chances of getting HPV related infections.
Use of latex condoms during sex. This lowers the chances of getting HPV but HPV can still infect areas that are not covered by a condom.Being in a mutually monogamous relationship and having healthy sexual practices.Stopping smoking.For women, regular screening for cervical cancer – between 25 to 65 years of age.
HPV vaccines are safe and effective. They can protect males and females against diseases (including cancers) caused by HPV when given in the recommended age groups. HPV vaccines are given in three shots (recently changed to 2 doses) over six months; it is important to get all doses.
The HPV vaccine contains viral like particles (VLP) obtained from L1 surface protein with no viral DNA. The VLPs are non-pathogenic and cannot infect cells since they do not have a viral genome. The vaccines induce a high titre of antibodies against the respective HPV types, which are secreted in the cervico-vaginal secretion and are also exuded from the micro-abrasions in the epithelium. Presence of the antibodies at the point of viral entry ensures the neutralization of the virus before it gets an opportunity to bind to infect the basal keratinocytes. Occasional cases of severe allergic reactions to the vaccines have been reported, but otherwise they are considered safe.
Two type of HPV vaccines (bivalent and quadrivalent) are licensed by the Food and Drug Administration (FDA). Both vaccines are directed against HPV16 and HPV18, types that cause cervical cancers and other HPV-associated cancers. Quadrivalent vaccine (Gardasil) is also directed against HPV6 and HPV11, types that cause anogenital warts. The Advisory Committee on Immunization Practices (ACIP) recommends that girls and boys be routinely vaccinated at age 11 or 12 years; vaccine may be given starting at age 9 years. In addition, for those who were not vaccinated when they were younger, all girls/young women through to age 26 years and all boys/young men through to age 21 years should be vaccinated. ACIP recommends that men who have sex with other men also be vaccinated through to age 26 years. ACIP considered data on vaccine efficacy and safety, disease burden attributable to HPV, cost-effectiveness of vaccination, and programmatic issues to develop recommendations.
The HPV vaccine is covered by most private health insurance and government insurance programs in USA, and the quadrivalent one is most commonly used. Within the NHS, HPV vaccination programme was started in 2007 for girl aged between 12-13 years, with a catch up vaccination for girls up to 18 for a period of 2 years. Unfortunately, the current NHS vaccination program does not routinely include boys since this is not considered cost-effective. Vaccines may be offered to boys and men at higher risk of HPV infection, e.g. those who are gay, bisexual, suffering from immunosuppressant disease, such as HIV/AIDS or on immunosuppressant drugs.
There are a lot of unknown variables regarding the vaccination program and nothing has changed with the cervical screening programme yet. Data from clinical trials show that both vaccines, when given as a 3-dose series, have very high efficacy for prevention of vaccine type–associated cervical precancers. Quadrivalent HPV vaccine has been shown to prevent HPV16- and HPV18-associated vaginal, vulvar, and anal precancer and HPV6- and HPV11-associated anogenital warts. The vaccines are prophylactic and do not prevent progression of existing infection to disease or treat existing disease. No clinical trial data are currently available to demonstrate efficacy for prevention of oropharyngeal or penile cancers. However, because many of these are attributable to HPV16, the HPV vaccine is likely to offer protection against these cancers as well.
HPV Vaccine Mechanism
HPV is a modern challenge, affecting mainly the younger generation, but with long lasting effects. The burden and cost of HPV-associated disease and cancer is therefore an important public health problem. Reducing the burden of HPV-associated cancer and disease through vaccination requires an integrated approach that includes clinical medicine, public health, and public policy at a global level. Within the NHS, since HPV vaccination is currently offered only to girls to prevent cervical cancer, there is a general tendency amongst young boys and men to think that HPV is a women’s problem. Therefore, there is a strong need to:
Promote awareness of HPV as being the commonest sexually transmitted infection.
Instil a sense of responsibility amongst boys and men to protect women and also to educate them about the increasing risk of other HPV cancers which are on the rise.
Educate regarding the use of condoms to prevents HPV and other infection (in addition to other contraception).
Increase awareness of the importance of reducing the number of risk factors, such as smoking and alcohol, related to the development of cancer.
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