Chapter 193: Human Papillomavirus Infections

Interest in human papillomavirus (HPV) infection began in earnest in the 1980s after Harold zur Hausen postulated that infection with these viruses was associated with cervical cancer. It is now recognized that HPV infection of the human genital tract is extremely common and causes clinical conditions ranging from asymptomatic infection to genital warts (condylomata acuminata); dysplastic lesions and invasive cancers of the anus, penis, vulva, vagina, and cervix; and a subset of oropharyngeal cancers. This chapter describes the epidemiology of HPV as a virus and a pathogen, the natural history of HPV infections and associated cancers, strategies to prevent infection and HPV-associated disease, and treatment modalities for some conditions caused by HPV.

Overview

HPV is an icosahedral, nonenveloped, 8000-base-pair, double-stranded DNA virus with a diameter of 55 nm. Like the genomes of other papillomaviruses, HPV’s genome consists of an early (E) gene region, a late (L) gene region, and a noncoding region, which contains regulatory elements. The E1, E2, E5, E6, and E7 proteins are expressed early in the growth cycle and are necessary for viral replication and cellular transformation. The E6 and E7 proteins are responsible for malignant transformation, targeting the human cell-cycle regulatory molecules p53 and Rb (retinoblastoma protein) for degradation, respectively. Translation of the L1 and L2 transcripts and splicing of an E1^E4 transcript occur later. The L1 gene encodes the 54-kDa major capsid protein that makes up the majority of the virus shell; the 77-kDa L2 minor protein contributes a smaller percentage of the capsid mass.

More than 125 HPV types have been identified and are numerically designated on the basis of a unique L1 gene sequence. Approximately 40 HPV types are regularly identified in the anogenital tract; these types are subdivided into high-risk and low-risk categories depending on the associated risk of cervical cancer. For example, HPV types 6 and 11 cause genital warts and ~10% of low-grade cervical lesions and are thus designated low risk. HPV types 16 and 18 cause dysplastic lesions and a high percentage of invasive cancers of the cervix and are therefore considered high risk.

HPV targets basal keratinocytes after microtrauma allows exposure of these cells to the virus. The HPV replication cycle is completed as keratinocytes undergo differentiation. Virions are assembled in the nuclei of differentiated keratinocytes and can be detected by electron microscopy. Infection is transmitted by contact with virus contained in these desquamated keratinocytes (or with free virus) from an infected individual.

The Immune Response to HPV Infection

Unlike many viral infections, HPV infection has no viremic phase. This lack of viremia may account for the incomplete antibody response to HPV infection. Natural HPV infection of the genital tract gives rise to a serum antibody response in 60–70% of individuals. Significant, although incomplete, protection against type-specific reinfection is associated with the presence of neutralizing antibodies. Serum antibodies likely reach the cervical epithelium and secretions by transudation and exudation. Therefore, protection against infection relates to the amount of neutralizing antibody at the site of infection and lasts as long as sufficient levels of neutralizing antibodies are present.

A cell-mediated immune response plays an important role in controlling progression of HPV infection. Histologic examination of lesions in individuals who experience regression of genital warts demonstrates infiltration by T cells and macrophages. CD4+ T cell regulation is particularly important in controlling HPV infections, as evidenced by the higher rates of infection and disease in immunosuppressed individuals, particularly those who are infected with HIV. Specific T-cell responses may be measured against HPV proteins, the most important of which appear to be the E2 and E6 proteins. In women with HPV type 16 cervical infection, a strong T-cell response to type 16–derived E2 protein is associated with a lack of progression of cervical disease. However, measurable changes occur in the innate and adaptive immune systems of patients with HPV-associated cancers. There is suppression of the antigen-presentation process as well as suppression of antitumor activity. The end result is a reduction of HPV-specific antitumor immune responses and an increase in immunosuppressive cellular responses.

HPV is transmitted by vaginal or anal intercourse, oral sex, and probably by touching a partner’s genitalia. In cross-sectional and longitudinal studies, ~40% of young women demonstrate evidence of HPV infection, with peaks during the teens and early twenties, soon after first coital experience. The number of lifetime sexual partners correlates with the likelihood of HPV infection and the subsequent risk of HPV-associated malignancy. HPV infection may occur in a monogamous person if that person’s partner is infected.

Most HPV infections become undetectable after 6–9 months, a phenomenon known as “clearance.” However, with prolonged follow-up and frequent sampling, the same HPV types may again be detected months or even years later. It is still debated whether such episodic detection indicates viral latency followed by reactivation or represents reinfection with an identical HPV type.

While HPV is the causative agent of several cancers, most attention has focused on cervical cancer, which is the second most common cancer in women worldwide. More than 500,000 women are diagnosed and 275,000 die from invasive cervical cancer annually. More than 85% of all cervical cancer cases, as well as deaths, occur in women living in low-income countries, especially countries in sub-Saharan Africa, Asia, and South and Central America.

Twenty-five years of evidence shows that HPV causes nearly 100% of cervical cancers. Persistent HPV infection is the most significant risk factor for cervical cancer; relative risks range from 10 to 20 and exceed 100 in prospective and case–control studies, respectively. The time from HPV infection to cervical cancer may exceed 20 years. Cervical cancer peaks in the fifth and sixth decades of life for women living in developed countries and as much as a decade earlier for women living in resource-poor countries. Persistent carriers of oncogenic HPV types are at greatest risk for high-grade cervical dysplasia and cancer.

Why HPV infections in some women but not others eventually lead to malignancy is not clear. Although oncogenic HPV infection is necessary for the development of cervical malignancy, only ~3–5% of infected women will ever develop this cancer, even in the absence of cytologic screening. Biomarkers that can predict which women will develop cervical cancer are not available. Immunosuppression in general plays a significant role in redetection/reactivation of HPV infections, while other factors, such as smoking, hormonal changes, chlamydial infection, and nutritional deficits, have an impact on viral persistence and cancer.

The International Agency for Research on Cancer has concluded that HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59 are carcinogenic in the uterine cervix. HPV type 16 is particularly virulent and causes 50% of cervical cancers. Worldwide, HPV types 16 and 18 cause at least 70% of cervical squamous cell carcinomas and 85% of cervical adenocarcinomas. Oncogenic types other than 16 or 18 cause the remaining 30% of cervical cancers. HPV types 16 and 18 also cause nearly 90% of anal cancers worldwide.

In addition to cervical and anal cancer, other HPV-associated cancers include vulvar and vaginal cancer (caused by HPV in 50–70% of cases), penile cancer (caused by HPV in 50% of cases), and at least 65% of oropharyngeal squamous cell carcinomas (OPSCCs). Over the past two decades, an epidemic of OPSCC related to oncogenic HPV infection, primarily HPV type 16, has developed. Rates of OPSCC in the United States have been increasing in men from a low of 0.27 case per 100,000 in 1973 to 0.57 case per 100,000 per year in 2004; rates in women have remained relatively stable at ~0.17 per 100,000 per year. The greatest increase in the incidence of OPSCC is among white men 40–50 years of age. Nearly 14,000 new cases were diagnosed in the United States in 2013. OPSCCs of the base of the tongue and tonsil cancer have increased annually by rates of 1.3 and 0.6%, respectively. Few data are available from developing countries about OPSCC.

HIV infection accelerates the natural history of HPV infections. HIV-infected individuals are more likely than other individuals to develop genital warts, and their lesions are more recalcitrant to treatment. HIV infection has been consistently associated with precancerous cervical lesions, including low-grade cervical intraepithelial lesions (CIN) and CIN 3, the immediate precursor to cervical cancer. Women with HIV/AIDS have significantly higher rates of cervical cancer as well as subsets of some vulvar, vaginal, and oropharyngeal tumors than women in the general population. Studies indicate a direct relationship between low CD4+ T lymphocyte count and the risk of cervical cancer. Some studies show a reduced likelihood of HPV infection and precancerous lesions of the cervix in HIV-infected women given antiretroviral therapy (ART). However, the incidence of cervical cancer in HIV-infected women has not changed significantly since ART was introduced, possibly because of preexisting oncogenic HPV infections that occurred before ART was initiated.

The burden of HPV-associated cancers is expected to increase in HIV-infected patients, given the prolonged life expectancies provided with ART. For women living in developing countries where cervical cancer screening is not widely available, this trend will have significant consequences. Thus, elucidating the interactions of HIV infection and cervical cancer with cofactors such as diet, other sexually transmitted infections, and environmental exposures is an important focus of research that impacts women living in low- and middle-income countries.

Similar to that of cervical cancer, the incidence of anal cancer is strongly influenced by HIV infection. HIV-infected men who have sex with men (MSM) and HIV-infected women have much higher rates of anal cancer than HIV-uninfected populations. Specifically, the incidence among HIV-infected MSM has been found to be as high as 130 cases per 100,000, as opposed to 5 cases per 100,000 among HIV-negative MSM. The advent of ART has not impacted the incidence of anal cancer and high-grade anal intraepithelial neoplasia in the HIV-infected patient population.

More information regarding screening, prevention, and treatment in the HIV-infected population can be found at the Department of Health and Human Services website (aidsinfo.nih.gov/guidelines).

HPV infects the male urethra, penis, and scrotum and the female vulva, vagina, and cervix. Perianal, anal, and oropharyngeal infections occur in both genders. Genital warts are caused primarily by HPV type 6 or 11 and appear as soft sessile growths with a surface that is either smooth or rough with multiple finger-like projections. Penile genital warts are usually 2–5 mm in diameter and often occur in groups. A second type of penile lesion, the keratotic plaque, is slightly raised above normal epithelium and has a rough, often pigmented surface. Figs. 193-1, 193-2, 193-3 show vulvar and vaginal, penile, and perianal warts, respectively.

Vulvar warts are soft, whitish papules that are either sessile or have multiple fine, finger-like projections. These lesions are most often located in the introitus and labia. In nonmucosal areas, vulvar lesions are similar in appearance to those in men: dry and keratotic. Vulvar lesions can appear as smooth, sometimes pigmented papules that may coalesce. Vaginal lesions appear as multiple areas of elongated papillae. Biopsy of vulvar or vaginal lesions may reveal malignancy; differentiation based on clinical exam is not always reliable.

Subclinical cervical HPV infections are common, and the cervix may appear normal on examination. Cervical lesions often appear as papillary proliferations near the transformation zone. Irregular vascular loops are present beneath the surface epithelium. Patients who develop cervical cancer from HPV infection may present with a variety of symptoms. Early carcinomas appear eroded and bleed easily. More advanced carcinomas present as ulcerated lesions or as an exophytic cervical mass. Some cervical carcinomas are located in the cervical canal and may be difficult to see. Bleeding, symptoms of a mass lesion in late stages, and metastatic disease that may manifest as bowel or bladder obstruction due to direct extension of the tumor have also been described.

Patients with squamous cell cancer of the anus have more variable presentations. The most common presentations include rectal bleeding and pain or a mass sensation. Twenty percent of patients who are diagnosed with anal cancer may not present with any specific symptoms at the time of diagnosis, and the lesion is found fortuitously.

Behaviors That Can Reduce Exposure to HPV

HPV infections are transmitted through direct contact with infected genital skin or mucosal surfaces and secretions. Does abstinence reduce HPV infections? For both men and women, numerous studies indicate that HPV infection and HPV-associated diseases correlate with the number of lifetime sexual partners, and people with no history of sexual intercourse have a lower detection rate of HPV. Fewer studies look at nonpenetrative sex and the risk of HPV infection and disease, but several studies indicate that HPV can be spread by any sexual intimacy, including touching, oral sex, or use of sex toys. It is therefore possible that individuals who have not partaken in penetrative sex can become infected.

Use of latex condoms reduces the risk of HPV infection and HPV-associated disease, such as genital warts and cervical precancers. Correct and consistent condom use has also been associated with regression of CIN in women and regression of HPV-associated penile lesions in men. As a preventive measure, condom use should be considered partially effective at best, not a substitute for cervical cancer screening or vaccination against HPV.

HPV Vaccines

The development of HPV vaccines effective in preventing infection and HPV-associated disease represents a major development in the last decade. The vaccines use virus-like particles (VLPs) that consist of the HPV L1 major capsid protein. The L1 protein self-assembles into VLPs when expressed in eukaryotic cells (i.e., yeast for the Merck vaccine or insect cells for the GlaxoSmithKline vaccine). These VLPs contain the same epitopes as the HPV virion. However, they do not contain genetic material and cannot transmit infection. The immunogenicity of the HPV vaccines relies on development of conformational neutralizing antibodies to epitopes displayed on viral capsids.

Several large vaccine trials have been completed and demonstrate the high degree of safety and efficacy of HPV vaccines. The evidence to date shows high and sustained efficacy against disease caused by those HPV types represented in the vaccines (HPV types 6, 11, 16, and 18 in the Merck vaccine and HPV types 16 and 18 in the GlaxoSmithKline vaccine). However, no therapeutic effect of either vaccine against active infection or disease has been documented.

BIVALENT VACCINE (CERVARIX)

The bivalent L1 VLP vaccine (HPV types 16 and 18) marketed under the name Cervarix (GlaxoSmithKline) is administered by intramuscular injection at months 0, 1, and 6. This vaccine was tested in 18,644 women 15–25 years of age who resided in the United States, South America, Europe, and Asia. The primary endpoints of the study included vaccine efficacy against persistent infections with HPV types 16 and 18. Investigators also assessed vaccine efficacy against CIN grade 2 or higher due to HPV 16 and 18 in women who had no evidence of HPV 16 or 18 infection at baseline. Vaccine efficacy related to HPV type 16 or 18 was 94.9% (95% confidence interval [CI], 87.7–98.4) against CIN 2 or worse; 91.7% (95% CI, 66.6–99.1) against CIN 3 or worse; and 100% (95% CI, –8.6 to 100) against adenocarcinoma in situ (AIS). Adverse events associated with the bivalent vaccine were evaluated in phase 3 trials in a subset of 3077 women who received vaccine and 3080 women who received hepatitis A vaccine. Injection-site adverse events (pain, redness, and swelling) and systemic adverse events (fatigue, headache, and myalgia) were reported more frequently in the HPV vaccine group than in the control group. Serious adverse events, new-onset chronic disease, or medically significant conditions occurred in the same proportion (3.5%) of HPV vaccine recipients and control vaccine recipients. The bivalent vaccine is approved in the United States for prevention of cervical cancer, CIN 2 or worse, AIS, and CIN 1 caused by HPV types 16 and 18. This vaccine is approved for females 9–25 years of age.

QUADRIVALENT VACCINE (GARDASIL)

The quadrivalent L1 VLP vaccine (HPV types 6, 11, 16, and 18) marketed under the name Gardasil (Merck) is administered intramuscularly at months 0, 2, and 6. A combined efficacy analysis based on data from four randomized double-blind clinical studies including >20,000 participants was performed; results demonstrated that vaccine efficacy against external genital warts was 98.9% (95% CI, 93.7–100). Vaccine protective efficacy was 95.2% (95% CI, 87.2–98.7) against CIN; 100% (95% CI, 92.9–100) against type 16– or 18–related CIN 2/3 or AIS; and 100% (95% CI, 55.5–100.0) against type 16– or 18–related vulvar intraepithelial neoplasia (VIN) grades 2 and 3 and against vaginal intraepithelial neoplasia (VaIN) grades 2 and 3.

Safety data on the quadrivalent HPV vaccine are available from seven clinical trials including nearly 12,000 women 9–26 years of age who received the vaccine and ~10,000 women who received aluminum-containing or saline placebo. A larger proportion of young women reported injection-site adverse events in the vaccine groups than in the placebo groups. Systemic adverse events were reported by similar proportions of vaccine and placebo recipients and were described as mild or moderate for most participants. The types of serious adverse events reported were similar for the two groups. Ten persons who received the quadrivalent vaccine and seven persons who received placebo died during the trials; no deaths were considered to be vaccine related.

During the course of studies on the quadrivalent vaccine, surveillance data on the development of new medical conditions were collected for up to 4 years after vaccination. No statistically significant differences in the incidence of any medical conditions between vaccine and placebo recipients were demonstrated; this result indicated a very high safety profile for the vaccine. A recent safety review by the U.S. Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) examined events related to Gardasil that had been reported to the Vaccine Adverse Events Reporting System (VAERS). The adverse events were consistent with what was seen in previous safety studies of the vaccine. Of note, rates of syncope and venous thrombotic events were higher with Gardasil than those usually observed with other vaccines.

The quadrivalent vaccine is approved for (1) vaccination of girls and women ages 9–26 years of age to prevent genital warts and cervical cancer caused by HPV types 6, 11, 16, and 18; (2) vaccination of the same population to prevent precancerous or dysplastic lesions, including cervical AIS, CIN 2/3, VIN 2/3, VaIN 2/3, and CIN 1; (3) vaccination of boys and men 9–26 years of age to prevent genital warts caused by HPV types 6 and 11; and (4) vaccination of people 9–26 years of age to prevent anal cancer and associated precancerous lesions due to HPV types 6, 11, 16, and 18. While the duration of protection has not been established, no evidence of waning protection has been found after a three-dose series of quadrivalent HPV vaccine, even after 10 years of follow-up from clinical trials.

NINE-VALENT VACCINE (GARDASIL-9)

HPV types 16 and 18 together cause up to 80% of all cervical cancers worldwide, and worldwide data show that HPV types 31, 33, 35, 45, 52, and 58 are the next most frequently detected types in invasive cervical cancers. In 2014, the FDA approved a new nine-valent L1 VLP vaccine that targets HPV types 6, 11, 16, and 18 (the types also targeted by the quadrivalent HPV vaccine) as well as five additional oncogenic HPV types (31, 33, 45, 52, and 58). The nine-valent vaccine is marketed under the name Gardasil-9 (Merck) and is administered intramuscularly at months 0, 2, and 6.

In clinical studies of girls and women 16–26 years of age, the nine-valent HPV vaccine generated a noninferior antibody response to HPV types 6, 11, 16, and 18 compared to the quadrivalent vaccine. Bridging immunologic studies in male and female vaccine recipients 9–15 years of age and in boys and men 16–26 years of age indicated that the lower bound of the 95% CIs of the geometric mean titer ratio and seroconversion rates met criteria for noninferiority for all HPV types represented in the vaccine. In female recipients 16–26 years of age, vaccine efficacy against the combined endpoint of high-grade cervical, vulvar, or vaginal disease caused by any of the five additional oncogenic HPV types was 96.7% (95% CI, 80.9–99.8%). Like the other available HPV vaccines, the nine-valent HPV vaccine is safe and extremely well tolerated.

Mathematical models estimate that the level of protection conferred by the nine-valent HPV vaccine against all HPV-associated squamous cell cancers worldwide could be raised to 90%. However, the true impact will depend on vaccine uptake, especially in poor countries where cervical cancer is common and the vaccine is currently prohibitively expensive.

CROSS-PROTECTION OF HPV VACCINES

Women who receive any of the available HPV vaccines produce neutralizing antibodies to virus types that are closely related to type 16 or 18. Analyses of data from clinical trials suggest that the HPV vaccines may offer limited cross-protection against nonvaccine virus types. Over short periods, the bivalent vaccine appears more efficacious against HPV types 31, 33, and 45 than the quadrivalent vaccine, but differences in study design make direct comparisons difficult, if not impossible. In addition, in the bivalent vaccine trials, vaccine efficacy against persistent infections with HPV types 31 and 45 waned over time, whereas efficacy against persistent infection with HPV type 16 or 18 remained stable. These results suggest that cross-protection is likely to be shorter lived than efficacy against infection and disease caused by vaccine types.

TWO-DOSE VERSUS THREE-DOSE SCHEDULE FOR HPV VACCINATION

In an effort to simplify the dosing schedule and potentially reduce costs and improve vaccine uptake, a two-dose schedule has been considered. In several randomized vaccine trials among adolescent girls, geometric mean concentrations (GMCs) of antibodies to HPV types 16 and 18 were shown to be noninferior up to 24 months after a two-dose schedule to GMCs after a three-dose schedule. Numerous countries have adopted a two-dose HPV vaccination schedule. In the United States, the CDC now recommends two doses of HPV vaccine (at 0 and 6–12 months) for persons starting the vaccination series before the 15th birthday, as the immunologic response is rigorous in this age group. Three doses of HPV vaccine (at 0, 1–2, and 6 months) are recommended for persons starting the vaccination series on or after the fifteenth birthday and for persons with certain immunocompromising conditions, including HIV/AIDS.

RECOMMENDATIONS FOR HPV VACCINATION

The most recent guidelines for HPV vaccination from the Advisory Committee on Immunization Practices (ACIP) are summarized below and provided in detail at https://www.cdc.gov/mmwr/volumes/65/wr/mm6549a5.htm.

For both girls and boys, the ACIP recommends that routine HPV vaccination be initiated at age 11 or 12 years, although the vaccination series can be started beginning at age 9 years. An individual can begin a vaccines series with one HPV vaccine and then complete the series with another.

For female recipients, vaccination is recommended through 26 years of age with the bivalent, quadrivalent (if still available), or nine-valent HPV vaccine. Papanicolaou (Pap) smear testing and screening for HPV DNA are not recommended before vaccination. After vaccination, cervical cancer screening should be conducted according to age-specific guidelines (see below).

For male recipients, vaccination with either the bivalent vaccine or (as long as this formulation is available) the nine-valent vaccine is recommended through 21 years of age to those who have not been vaccinated previously or who have not completed the three-dose series. Men 22–26 years of age may also be vaccinated.

Once HPV infection occurs, prevention of HPV-associated disease relies on screening. At present, screening for cervical cancer is widely accepted as cost-effective in preventing cervical cancer, and anal screening is accepted for screening in high-risk groups. In resource-rich countries, the primary method of cervical cancer screening is cytology via Pap smear. The American Society of Colposcopy and Cervical Pathology guidelines recommend initiation of cervical cancer screening at age 21, no matter the age of sexual debut. Women 21–29 years old should have a Pap smear every 3 years if their initial and subsequent Pap smears are normal. Although adolescent and young women often test positive for HPV DNA, they are at very low risk of cervical cancer. Because the presence of HPV DNA does not correlate with the presence of high-grade squamous intraepithelial neoplasia, co-testing (testing for HPV DNA at the time of Pap smear) is not recommended for women in this age group.

As a method of determining the need for colposcopy, HPV DNA co-testing is recommended for women 25–29 years of age in whom cytology detects abnormal squamous cells of undetermined significance. Women 30–65 years of age should have a Pap smear every 3 years if testing for HPV DNA is not performed. The screening interval for women in this age group can be extended to every 5 years if HPV DNA co-testing is performed and results are negative. HPV testing is not recommended for partners of women with HPV or for screening of conditions other than cervical cancer.

The role of HPV DNA testing as a primary screen for cervical cancer is changing. In 2014, the FDA approved the Roche Cobas HPV test for primary screening of cervical cancer. This test can be used to detect HPV DNA in specimens obtained from the cervix without cervical cytology for women ≥25 years of age. A positive result for HPV type 16 or 18 has a high enough positive predictive value in the general population that these women should have colposcopy performed. If high-risk HPV types other than 16 or 18 are detected, then cytology can be used. Ongoing studies of other HPV DNA testing methods are evaluating their use as a primary screening tool. The complete set of algorithms for appropriate age-specific screening guidelines, HPV DNA testing, and the management of abnormal Pap smears is available through the American Society of Colposcopy and Cervical Pathology at http://www.asccp.org/asccp-guidelines.

For women ≤30 years of age who are infected with HIV, cervical cytology is the preferred method of cervical cancer screening, and HPV DNA co-testing is not recommended. Cervical cancer screening should begin within 1 year of diagnosis of HIV infection, regardless of the mode of HIV transmission. If the first Pap smear is normal, then subsequent Pap smears should be performed annually until three negative tests are obtained. Cytology can then be conducted every 3 years. For women >30 years old, Pap testing is performed in the same manner as for younger women. However, HPV DNA co-testing can be used in women of this age group. If cytology and HPV DNA co-testing are negative, the next exam can be performed in 3 years. Positive results of HPV DNA co-testing are treated in the same manner as in HIV-uninfected women.

Women residing in developing countries with a lack of access to cervical screening programs have a higher rate of cervical cancer and poorer cancer-specific survival. Approximately 75% of women living in developed countries have been screened in the past 5 years, as opposed to ~5% of women living in developing countries. Economic and logistic obstacles likely impede routine cervical cancer screening for these populations. Many poor countries rely on an alternative method—visual inspection with acetic acid (VIA)—for cervical cancer screening. While some studies show a reduction in cervical cancer mortality in communities where VIA is widely used, other studies do not. In addition, the low specificity of VIA is problematic. As newer methods that use detection of oncogenic HPV DNA become available, even resource-limited countries may be able to replace VIA with these methods and achieve a reduction in cervical cancers as a result.

Currently, there is no broad consensus regarding screening for anal cancer and its precursors, including high-grade anal intraepithelial lesions. The reason is a lack of understanding of optimal treatment for low- or high-grade anal dysplasia found during cytologic screening. Current HIV treatment guidelines suggest that there may be a benefit to screening, but an effect on the associated morbidity and mortality of anal squamous cell cancer has not been consistently demonstrated.

Most sexually active adults will be infected with HPV during their lives. The only way to avoid acquiring an HPV infection is to abstain from sexual activity, including intimate touching and oral sex. Practicing safe sex (partner reduction, use of condoms) may help reduce HPV transmission. Most HPV infections will be controlled by the immune system and cause no symptoms or disease. Some infections lead to genital warts and cervical precancers. Genital warts can be treated for cosmetic reasons and to prevent spread of infection to others. Even after resolution of genital warts, latent HPV may persist in normal-appearing skin or mucosa and thus theoretically may be transmitted to uninfected partners. Precancerous cervical lesions should be treated to prevent progression to cancer.

Additional Online References