HPV - Human Papillomavirus

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INTRODUCTION — Human papilloma virus (HPV) causes more than 99 percent of cases of cervical cancer and genital warts. Persistent infection with certain types of HPV can lead to cancer of the cervix. The virus less commonly causes cancer of the anus, vagina, vulva, penis, mouth, or sinuses.

WHAT IS HPV? — Human papilloma virus (HPV) is a virus that is spread by direct skin-to-skin contact, including sexual intercourse, oral sex, anal sex, or any other contact involving the genital area (eg, hand to genital contact). Condoms do not provide complete protection from HPV infection, because condoms do not cover all exposed genital skin. It is not possible to become infected with HPV by touching an object, such as a toilet seat, because the virus can only be passed from one skin surface to another.

The risk of HPV exposure increases with the number of sexual partners. It has been estimated that 75 to 80 percent of sexually active adults will acquire a genital tract HPV infection before the age of 50. A majority of women become infected with HPV for the first time between ages 15 and 25 years. Most people who are infected with HPV have no signs or symptoms and clear the infection within two years, often without treatment.

In 10 to 20 percent of patients, however, the infection persists. In this situation, there is a higher likelihood of developing cervical cell abnormalities or cancer. However, it usually takes several years for HPV infection to cause cervical cancer. Thus, regular pap smears are important in detecting cervical abnormalities early, before cancer develops.

Over 100 different types of HPV have been identified; 40 of these are known to infect the cervix and 15 are known to cause most cases of cervical cancer. Researchers have labeled the HPV types as being high or low risk for causing cervical cancer. HPV types 6 and 11 can cause warts and are low-risk types because they do not cause cervical cancer. Types 16 and 18 are the high-risk types that cause most cases of cervical cancer.

RISK FACTORS FOR TRANSMISSION — Close personal contact is assumed to be of importance for the transmission of cutaneous warts, while anogenital warts and HPV infection of the cervix are primarily transmitted by genital contact, usually sexual intercourse. However, HPV types typically isolated from common warts (types 1 and 2) have been isolated from anogenital warts in children and infection of the respiratory tract mucosa is thought to occur during passage of the fetus through an infected birth canal.

The most consistent predictor of genital HPV infection has been sexual activity. Most studies have shown:

• The risk of HPV infection in women is directly related to the number of male sex partners and to the male partners' number of female sex partners.
• As with other sexually transmitted diseases, sex with a new partner is a stronger risk factor than sex with a steady partner.
• Vaginal and anal intercourse are major risk factors for HPV infection. Although penetrating vaginal intercourse is not required, the prevalence of HPV infection is much lower among virgins.
• The source of transmission (male to female) is usually asymptomatic and does not known that he is infected.

Natural History of HPV Infection

Most HPV infections are subclinical and transient (>90% clear within 2 years), resolving spontaneously presumably due to the development of a cellular immune response. In some individuals, HPV infection may produce benign genital warts and low-grade lesions of the cervix. However, in others, certain types of HPV may persist and possibly progress over a number of years to high-grade precancerous lesions and invasive cervical cancer.

Subclinical Infection

Following infection, HPV enters a period of quiescence that lasts about 2-12 months. Most HPV infections resolve without symptoms (subclinical) at this stage, presumably due to the emergence of the host’s cell-mediated immune response beginning approximately 3 months after infection. This immune response either eradicates the virus or suppresses it to non-detectable levels. Therefore, it is not yet known whether an HPV infection that appears to have cleared clinically is really eradicated or simply remains below the sensitivity level for detection with current molecular techniques.

Some HPV infections are thought to be suppressed and their genomes maintained in a long-term latent state (i.e., subclinical infection with a very small group of cells presumably maintaining infection at low DNA copy numbers). Support for a latent state for HPV infection comes from the observation that in some women genital warts can resolve spontaneously only to recur (i.e., reactivate) during pregnancy or when the immune system becomes compromised (e.g., HIV infection). It is not yet clear how commonly latency occurs in immunocompetent hosts, its ultimate duration, the circumstances and mechanisms that trigger re-emergence of HPV into a detectable state, whether latent HPV infection is ultimately eliminated in most individuals, or whether latent infection can persist, possibly leading to cervical cancer.

Clinically-evident Infection

Low-grade Lesions

If the host immune system can not adequately contain the virus, then beginning 3-6 months after infection, HPV can lead to genital warts and low-grade lesions of the cervix. The latter consist of mild changes in the cellular structure and organization of the basal portion of the cervical epithelium caused by abnormal proliferation of cells infected by either high- or low-risk types of HPV. These low-grade lesions are known pathologically as cervical intraepithelial neoplasia (CIN) 1 or cytologically as low-grade squamous intraepithelial lesions (LSIL); koilocytes are often present.

HPV types 6 and 11, the most common low-risk HPV types account for >90% of all cases of genital warts. Previously, it was thought that low-risk HPV types cause low-grade cervical lesions and high-risk HPV types cause high-grade cervical lesions (CIN 2/3). HPV 6 and 11, the most common low-risk HPV types, account for ~25% of CIN 1 lesions; however, ~75% of CIN 1 lesions are caused by high-risk types, with ~25% of CIN 1 lesions caused by the most common high-risk HPV types HPV 16 and HPV 18 . At this stage of HPV infection, viral clearance and regression of cytologic abnormalities occurs in over 85% of these HPV infections.

Persistence vs. Clearance

Beginning about 9 months after infection, the natural history of HPV infection reaches a “crossroads”; certain infections remain subclinical (latent or clear) while approximately 10-20% of patients who still have clinically-evident infection or who “recur” after a lesion-free interval develop persistent HPV infection. Viral persistence is the consistent detection of the same HPV type two or more times over a 6-12 month interval. Long-term viral persistence is required in order for HPV infection to progress to cervical precancer and invasive cervical carcinoma.

High-grade Lesions

Progression to Precancer/Cancer

Beginning approximately 4-5 years after initial HPV infection, persistent infection can lead to the development of precancerous (high-grade) lesions of the cervix known as CIN 2/3. High-grade lesions most often evolve from low-grade lesions; however, in some cases they appear to progress directly from HPV infection. If left untreated, high-grade lesions may progress to invasive carcinoma.

Persistent infection with high-risk HPV types is crucial for the progression of HPV infection to precancer and cancer. Results from one study, for example, showed that the risk for developing cervical cancer precursors was 14 times higher for women who had at least 3 positive tests for high-risk HPV types compared with women who had negative tests for high-risk HPV types. In contrast to low-risk HPV types, the DNA of high-risk HPV types (e.g., HPV 16 and HPV 18) is capable of integrating into host cell DNA, leading to cell-cycle dysregulation and, over time, cell immortalization.

In addition to persistent infection with high-risk HPV types, other viral co-factors that may be associated with persistence and progression include concurrent infection with multiple HPV types (e.g., HPV 16 and another HPV type), high viral load, and certain unique variant HPV types (e.g., HPV 16 non-European variants).

Even the majority of infections with high-risk HPV types generally clear within 2 years, failing to persist or progress to cervical cancer. This suggests that HPV infection alone is not sufficient for cervical cancer; rather, an interaction between high-risk HPV types and other host or environmental co-factors (e.g. smoking, oral contraceptive use) appears to play a role in disease progression.

Given the importance of cellular immune responses in the resolution of HPV infection, it is not surprising that deficiencies in cell-mediated immunity increase the likelihood of disease expression (persistence or progression) in groups such as older women (waning immunity), transplant recipients, patients with HIV, and those receiving immunosuppressive drugs (steroid therapy and chemotherapy).

Certain host genetic factors have been implicated in the natural history of HPV infection; some increase the risk of HPV persistence by several fold, whereas others are associated with a reduced risk of persistent HPV infections.

Progression to Invasive Cervical Carcinoma

Usually about 9-15 years after initial HPV infection, untreated HPV infection in certain circumstances can progress to invasive squamous cell carcinoma.

The peak prevalence of CIN 1 occurs at approximately 28 years of age, CIN 2/3 at 42 years of age, and cervical cancer at approximately 50 years of age. This suggests that there may be a sequenced evolution of stages for cervical cancer over time, beginning with infection with high-risk HPV types, viral persistence, and progression from CIN 1 through CIN 3, ultimately to invasive cervical cancer. However, some studies contradict the hypothesis that stages of HPV-related disease are sequential; for example, development of CIN 2/3 may occur in the absence of known previous CIN 1.

VACCINE TIMING AND DOSE — The HPV vaccine is given by injection and requires three doses; the first injection is followed by a second and third dose two and six months later, respectively.

Who should be vaccinated? — In the United States, Gardasil® is recommended for all girls and women who are between ages nine and 26 years. It is important to be vaccinated before becoming sexually active since the vaccine does not help to eliminate HPV infection after it has occurred.

Duration of protection — While it is not known exactly how long the vaccine protects against HPV infection, clinical trials demonstrate protection for at least five years [2] . Further studies are in progress to determine whether a booster dose of Gardasil® would be of benefit to extend its duration of protection.

Need for Pap smear — Girls and women do not require a screening test for cervical cancer (eg, Pap smear) before the HPV vaccine is given. Cervical cancer screening (Pap smear) is recommended, starting by age 21 or within three years of becoming sexually active. HPV immunization does not eliminate the need for careful follow-up since other HPV types, which are not prevented by the vaccine, can also cause cervical cancer.

VACCINE SIDE EFFECTS AND PRECAUTIONS — The HPV vaccine may cause a mild injection site reaction (redness, tenderness, swelling) in some individuals. The vaccine is not currently recommended during pregnancy, although there are no known risks to a fetus if a woman is vaccinated inadvertently. There are no known long-term side effects of the HPV vaccine.

VACCINE EFFECTIVENESS — Results from the Gardasil® vaccine studies showed that the vaccines are highly effective.

In the trials of Gardasil, the following results were seen:

• 98 percent of women who were given the vaccine were protected against cervical pre-cancers caused by HPV for at least three years.
• 100 percent of women who were given the vaccine were protected against external genital warts caused by HPV types 6 and 11 for at least three years..

The additional benefit of vaccinating boys and men in reducing the risk of cervical cancer is unknown. Studies are currently underway to address this question. It is also not known if the vaccine is effective if fewer than three doses are given.

OTHER SEXUALLY TRANSMITTED INFECTIONS — The HPV vaccine is not perfect, meaning that some women will still develop an HPV infection despite having being vaccinated. In addition, other sexually transmitted infections (STIs), including HIV, chlamydia, gonorrhea, are not prevented by the vaccine.

It is important to follow guidelines to reduce the risk of all STIs. Use of a male or female condom with every sexual act, and limiting the number of sexual partners, are critical in reducing the risk of STIs.