Human Papilloma Virus (HPV)

Introduction

Human Papilloma Virus (HPV) typically infects the cells of the skin and results in warts. These may occur at any location on the skin, and even on mucous membranes, such as genitalia. Warts are generally benign and harmless. Some HPVs may however, result in cancer formation. It has been shown that cervical cancers are a result of HPV infection.

Incidence

Cutaneous warts are a relatively common problem. While exact figures of its incidence are unavailable, it was reported in one study that 22% of school students had warts. Not all were aware of it, and only some were receiving treatment. Similar information of the adult population is limited.

Cervical cancer rates in developed countries such as Australia have decreased significantly. Breast cancer is now the most common cancer in women. An incidence of 7.4:100,000 and mortality rate of 2.0:100,000 have been reported for cervical cancers. This is considerably less than figures reported regarding developing countries.

Causes

Even though transmission occurs mainly through direct contact, normal skin is quite resistant to inoculation. As such, a deficit in skin integrity is usually required. Individuals with known warts are generally advised not to scratch them; doing so may result in localized spread and worsening of the condition. It has also been suggested that warts can be spread by inanimate objects; this is due to HPV resistance to inactivation by environmental factors (e.g. heat/ cold). Objects in public places such as toilet seats may be able to spread the virus. Frequent visits to public swimming pools may also predispose to HPV infection.

Genital warts are spread via genital contact. As such, it is its incidence rises with increasing sexual activity. The use of condoms has been suggested to reduce spread; however, this form of prevention is not completely protective.

Cancers (in particular cervical cancers) result when normal cellular growth regulations are disrupted beyond recovery. Excessive proliferation of cells results in cancerous change.

Symptoms

Most patients may not even notice their own warts until they have reached a relatively large size. Warts are generally slow growing, and as such are not readily obvious. In addition, no other symptoms such as pain or itch alert the patient of its presence. These symptoms may rarely occur.

Patient complaints are generally for cosmetic reasons. Warts come in all shapes and sizes. Some are flat while others are more nodular. Spindle-shaped warts may also occur.

Under current screening regimens, cervical cancers are generally detected prior to their symptomatic stage. It is recommended that all women who are (or have been) sexually active receive regular pap smears (once every one to two years). Symptoms that may occur may include abnormal bleeding (i.e. between menstrual cycles; during or after sexual intercourse), or pelvic pain.

Treatments

A number of treatments are available for warts depending on their size, type, and location.

Topical Medications:

• Topical salicylic acid
• Retinoids
• Podophyllum

Physical Treatment (i.e. removal, destruction of the wart):

• Surgical removal
• Cryotherapy
• Cautery

Treatment for cervical cancer also varies, but depending on the staging of the cancer. In general, surgical management is used with adjunct chemotherapy and/or radiotherapy where necessary. Staging of the tumour depends on the extent of its growth. Early detection via screening greatly improves survivability.

A new vaccine against HPVs has just been made available in recent years. They are available for free for young women and girls between the age of 14 and 26. These vaccines do not confer complete immunity against cervical cancer and warts; they only provide immunity against some of the more common virus strains.

Introduction

The Human Papilloma Virus (HPV) is the causative agent of warts. Warts are an abnormal skin growth on the skin, taking on a variety of different appearances, and in any region of skin. Warts are generally benign, and the most common complaints are for cosmetic reasons. In some cases, pain, pruritus, or local irritation may occur.

While most HPV infection is benign and is not immediately life-threatening, dysplastic change or tumours may form. The most common of these are cervical and anal cancers resulting from genital or anal HPV infection.

Epidemiology and prevalence

Surveillance data of cutaneous warts in the community is limited. One report from a sample of 2491 students in Victoria indicated an overall prevalence of cutaneous warts of 22%. The incidence of warts in the community (i.e. among adults is not available). However, one study described occupations involved with meat, poultry, and fish processing to be associated with increased risk of getting warts.

Data on genital warts is also lacking. Indigenous Australian women in the Northern Territory were reported to have a HPV prevalence of 42%. In a study of 69,147 women from Denmark, Iceland, Norway, and Sweden, 10.6% were reported to have had genital warts. Note that, infection with HPV does not necessarily result in warts. Genetic material from HPV has been isolated from individuals without clinically evident warts.

Risk factors for acquiring genital warts include:

• Younger age,
• Number of lifetime sexual partners
• Smoking
• Lack of or inconsistent condom use

HPV infections also have a causal relationship with cervical cancer. Not all HPV infections result in warts. As such, cervical cancer may develop in a woman without ever having had genital warts. Similarly, not all HPV infections result in dysplastic transformation. Some HPV types have a higher propensity to develop into cancers. HPV 16 was isolated in 53.8% of patients with cervical cancer in Australia; HPV 18 was isolated in 17.2%. An association was also found between HPV 18 and adenocarcinomas. A meta-analysis also support that the commonest HPV types associated with cervical cancer are HPV16 and HPV18. Regional variation exists; HPV 58 and HPV 52 were more frequently identified in Asia.

There were an estimated 493,000 new cases of cervical cancer and 274,000 mortalities worldwide in 2002. The incidence and mortality rates are higher in developing countries than developed countries; in Australia, the incidence is 7.40 per 100,000, and mortality rate is 2.0 per 100,000 persons. Screening programs have resulted in decline; cervical cancer was previously the most common cancer in women in developed nations. It is now the second most common cancer in women, and seventh most common in the world.

Clinical features

Warts are generally persistent, slow growing skin lesions, and are often scaly or hyperkeratotic. They generally occur within one region: the appearance of new warts nearby is supportive of the diagnosis. However, infection at multiple sites may occur.

The appearance of warts varies considerably. They may be papular or nodular, with either a flat or rounded surface. Some may be spindle shaped, or even take the appearance of cutaneous horns. The presence of scale or hyperkeratosis is also variable. Pedunculated warts also exist. The size of warts may vary considerably.

Several commonly seen warts have been described such as:

• Common warts
• Flat warts
• Filiform warts
• Mosaic warts
• Plantar warts
• Genital warts

In-depth descriptions are available on the Better Health Channel (State of Victoria, 2007).

Etiology and pathogenesis

Human papilloma viruses (HPVs) belong to the Papillomavirus family. Their genetic material consists of circular deoxyribonucleic acid (DNA). This genetic material is contained within a protein capsid. However, unlike some viruses, this virus does not have a lipid membrane. This lack of lipid membrane gives the virus more resistance to environmental factors. Over 100 genotypes of HPV exist.

HPV transmission usually occurs via direct contact. Direct transmission to skin usually requires the integrity of skin to be compromised. Abrasions and excoriations are generally required. In addition, because of the resistance of the virus to the environment, a virus particle on an inanimate object may in theory result in an infection.

The virus typically invades the basal cells of the skin. Viral particles are produced as the basal cells proliferate into keratinocytes and migrate to the superficial skin. These particles are contained within the skin cells and are released as the cells slough off. Because the viral genes do not code for its own DNA polymerase, HPV relies heavily on host cell mechanisms to reproduce. This renders the virus resistant to drug treatments; fewer drug-specific proteins are available as drug targets to hinder virus production.

The proteins coded for by the HPV DNA are generally divided into two categories: E for early-phase proteins and L for late-phase proteins. Early phase proteins are involved in interfering with normal cell function, in order to promote abnormal cell growth and proliferation. In particular, E6 and E7 disrupt tumour suppressor genes (such as p53 and retinoblastoma) resulting in irregular growth patterns. The late stage proteins are expressed when infected cells have migrated closer to the skin surface. L1 and L2 form the protein capsid. These proteins are important in the pathogenicity of the virus. Because L1 and L2 are expressed only in the late stages, they are unable to stimulate the immune system to effectively remove the virus. By the time these proteins are expressed, the cells are relatively distant from the blood supply and are have thus effectively evaded the immune system. While antibodies against L1 and L2 are still produced, they are not manufactured in sufficient amounts. It is also on the basis of these proteins that the vaccine against HPV was developed. The vaccines consist of L1 and L2 proteins of specific HPV types (Androphy & Lowy, 2008). These assemble into virus-like-particles (VLPs) which when injected into humans, stimulating a more effective immune response. The body is then able to produce higher numbers of antibodies sufficient to combat the infection.

E6 and E7 proteins are important in the pathogenesis of cervical cancer. The genes encoding these proteins are retained or incorporated into cellular DNA. The inactivation of tumour suppressor genes over long periods of time results in dysplastic change and eventual cancer development. By this stage, L1 and L2 proteins are no longer expressed. Antibodies against L1 and L2 are no longer effective. Thus, the vaccines are only valid for preventative measures, and are not used for treatment.

Prevention

Cutaneous HPV may be avoided by minimizing contact with individuals who have warts. However, because of the resistance of the virus to environmental agents, there is a theoretical risk that HPV infection can be acquired from inanimate objects. Genital HPV infection could be minimized by consistent condom use in sexual activity. Despite this, HPV infection is still likely to occur.

A HPV vaccine has just been released. The vaccine is a quadrivalent vaccine and protects against HPV 16 and 18 (two most common causes of cervical cancer), & HPV 6 and 11. Because there is a range of various other HPV types that may cause genital warts and cervical cancer, no one is fully protected. The vaccine only protects against the HPV types that are the most common causes of cervical cancer and genital warts. Because prevention is not 100% effective, active surveillance is still required. It is recommended that women who have had the vaccine continue to receive regular pap smears to ensure that any malignant change is detected early with appropriate follow-up treatment(s) initiated.

In Australia, the National HPV Vaccination Program began in April 2007. Under this program, young girls aged 12-13 whose parents consent will be provided the HPV vaccine for free. Girl and young women between the age of 14 and 26 are also eligible for free vaccine. The vaccine can be provided at school for school-goers, and at general practice surgeries or community immunization clinics for non-school-goers. The free vaccination is only available for females aged 14-26 until the end of June 2009.

The vaccination course occurs over a six month period:

• First dose at an elected date
• Second dose two months following first dose
• Third dose six months following first dose

The HPV vaccine does not have Therapeutic Goods Administration (TGA) approval for women over the age of 26.

TGA approval has been obtained for males aged between 9 to 15 years. However, evidence supporting the effectiveness of providing the vaccine for men is limited. As such, the free vaccine is not available for men.

Other nations have also incorporated the HPV vaccine into their vaccination programs. The vaccine is available for free in the United Kingdom , and in select provinces/territories in Canada. The vaccine is available but not publicly funded in some countries such as New Zealand.

Treatment

Cutaneous and Genital Warts

Treatment options for warts vary with location (Therapeutic Guidelines Ltd, 2004a):

Common Warts:

• Topical keratolytics (i.e. salicylic acid, Upton’s paste)
• Cryotherapy
• Ablative therapy (ie. Cautery)
• Bleomycin
• Immune modulators (i.e. imiquimod)
• Immunotherapy (topical sensitizers, dinitrochlorobenzene, diphencyprone)

Plane Warts:

• Retinoids
• Cryotherapy
• Keratolytics (i.e. salicylic acid, Upton’s paste)

Genital Warts:

• Periodic cryotherapy
• Podophyllotoxin
• Immune modulators (i.e. imiquimod)
• Podophyllum
• Hydocortisone (to reduce irritation/ symptomatic relief)

Subungual warts:

• Keratolytics (i.e. salicylic acid, Upton’s paste)
• Cryotherapy

Topical salicylic acid has been regarded as one of the more effective therapies against warts. Pooled data from multiple trials suggests a cure rate of 75%. Side effects such as cellulitis and minor skin irritation have been reported. Other major side effects are generally not seen.

Cryotherapy involves the use of liquid nitrogen to freeze warts, effectively killing the cells. Trials have suggested its effectiveness to be similar to the use of topic salicylic acid. However, severe side effects may result. The most common complaints are pain and blistering (up to 64%), particularly with more aggressive therapy. Several participants have withdrawn from studies due to these side effects.

The use of topical imiquimod for genital or perianal warts has been supported by multiple studies. The most common side effect was skin irritation. Imiquimod is believed to stimulate the immune system, in particular by increasing the production of interferon. This typically results in localized inflammation, and may be related to irritation reported by some users.

Retinoids are analogues of Vitamin A and functions by inhibiting growth and differentiation of the epidermis. The effectiveness of retinoids in children has been reported in two separate trials. In one group of 25 participants, 42.3% experienced skin erythema and peeling. Similar data involving adults is not available.

Podophyllotoxin and Podophyllum are used to treat warts due to their anti-mitotic activity (Therapeutic Guidelines, 2004b). While treatment of warts with these agents have had some success, other forms of treatments are generally more effective.

Resistant warts may be treated with diphencyprone. 60% of patients in a study responded positively to treatment. Topical dinitrochlorobenzene may also be used; a cure rate of 80% has been reported.

Several trials on the effectiveness of intra-lesional bleomycin have produced inconsistent findings. Cure rates in these studies ranged between 16 and 94%. Localized skin reactions such as an erythematous rash, hyperpigmentation, and tenderness may result. However, more serious side effects such as anaphylactoid reactions and even pulmonary fibrosis have been reported.

The use of duct tape has also bee proposed. One study found the use of duct tape to be more efficacious than cryotherapy. Duct tape was applied on the warts for six days, and was replaced if displaced. Following the end of this period, the duct tape was removed. The site of the wart was soaked in water, and then debrided with either an emery board or pumice stone. The duct tape was replaced the next day. This treatment continued for a maximum of two months or until the wart had resolved. Complete resolution was seen in 85% of participants treated with duct tape as compared to 60% in patients treated with cryotherapy.

Cervical cancer

A number of general treatment options are available for treatment. This may vary depending on the staging or severity and specific type of cancer (U.S. National Cancer Institute).

Surgical treatment:

• Conization – removal of a section of the cervix and cervical canal; this sample may be used as part of staging and/or grading the cancer
• Hysterectomy – removal of the cervix and the uterus
• Radical hysterectomy – removal of the uterus, cervix, and part of the vagina; the ovaries, fallopian, and local lymph nodes may also be removed
• Pelvic exenteration – removal of cervix, vagina, ovaries, and local lymph nodes, as well as lower colon, rectum, and bladder
• Cryosurgery
• Laser surgery

Radiation therapy:

• X-rays are used to irradiate the cancer cells to kill them or minimize growth

Chemotherapy:

• Drugs are used to kill the cancer cells. The mechanism of action of different drugs varies. However, because of the similarities between cancer cells and normal cells, severe side effects may result

Prognosis

The prognosis of cutaneous warts is generally good. A variety of therapies are available with relatively good success rates. Some warts may eventually disappear even without treatment. Those that are refractory to treatment are generally benign.

The mortality rate from cervical cancer is relatively low. The prognosis of the cervical cancer is variable depending on the staging of the cancer. This includes factors such as:

• The size of the tumour
• The extent of invasion into the cervix
• Invasion to local or neighbouring structures
• Metastases to local lymph nodes
• Metastases to other solid organs
• Specific histopathological findings

References

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Online resources:

• Guidelines for the management of cutaneous warts
• The National HPV Prevention Program
• The National HPV Vaccination Program Register
• HealthInsite: Cervical Cancer
• HealthInsite: Genital Warts