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Evaluating the impact of HPV-related diseases: cervical cancer and genital warts.

Natural course of HPV infection and oncogenesis

Human papillomavirus (HPV) is a nonenveloped, double-stranded DNA virus. During intercourse, microabrasions occur in the genital mucosal and keratinized epithelial tissues. Breaches in the epithelium allow HPV to invade and infect basal keratinocytes. (1) In the nucleus, low-risk HPV DNA remains separated from the host DNA and uses host cell machinery to replicate. Subsequently, as HPV-infected basal cells divide, HPV uses the host cell's machinery to produce new virus particles. Basal cells remain infected while the new cell begins to divide, carrying HPV with it to the more superficial layers of the epithelium. If the body is able to clear HPV from the basal cells, the infection regresses. Unlike low-risk HPV types, intermediate- and high-risk HPV types may become integrated into the host cell DNA, leading to cell-cycle dysregulation and immortalization of the cell. With HPV, the outcome of the infection is variable. Uncontrolled cell division leads to cervical intraepithelial neoplasia (CIN), or cancer, in some women. The normal cervical transformation zone is the main target of HPV and its oncogenic effects. The infection either is cleared or persists. Proliferation of the epithelium can occur and can result in a clinical condyloma (low-risk HPV types), CIN or invasive cancer (high-risk HPV types), or a latent infection with no clinically apparent signs. (1,2)

Many factors play a role in how the body deals with an HPV infection and the ultimate outcome of that infection. HPV infections are thought to be cleared by the immune system or are at least halted by it, making them clinically latent fie, a small number of cells remain infected with a low viral copy number). (1) It is unclear how long latency can last. Persistence can be defined as detection of the same HPV type 2 or more times over a span of several months. (1) This latency can help explain why some patients can have condylomata that resolve spontaneously or after treatment, only to have them reoccur when the woman is pregnant or her immune system becomes compromised (eg, because of diabetes or an HIV infection). Long-term viral persistence in the absence of precancer is uncommon. (2)

There are currently more than 100 different HPV types, with 30 types primarily infecting the genital epithelium. Approximately 15 types of HPV infection cause virtually all cases of cervical cancer. (3,4) High-risk types are 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82; probable high-risk types are 26, 53, and 66. (4) Together causing more than 60% of cervical cancer cases, the 2 most prevalent HPV types are 16 and 18. HPV 16 is the major oncogenic type, accounting for approximately 50% of cases of cervical cancer, (2) while HPV 18 accounts for the other 10% to 12%. (5) Low-risk HPV types include 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, and CP6108. (4) Types 6 and 11 are the most frequently detected low-risk types and can often be detected in cases of genital warts. (6) Infection with oncogenic HPV types is strongly predictive of subsequent development of CIN 3 (odds ratio [OR] = 17.2). (7) Persistence of oncogenic HPV may be more sensitive and specific than cytology for early detection of CIN 3 and invasive cancer. (7)

In addition to differences in oncogenic progression between low- and high-risk HPV types, there can be differences in aggressiveness with variants of the same high-risk HPV types. Xi et al (8) demonstrated differences in the biologic behavior with HPV 16, with non-prototype-like variants being 6.5 times more likely to lead to the development of CIN 2/3 compared with those with prototype-like variant infections.

During a 45-month period of follow-up, Sherman et al (9) showed that the cumulative incidence of CIN 3, or cancer, was 4.54% (95% confidence interval [CI], 3.61%-5.46%) among women with a Pap test result indicating atypical squamous cells or worse, a positive HPV test, or both, compared with 0.16% (95% CI, 0.08%-0.24%) among women with negative Pap and HPV test results. A strong relationship exists between persistent HPV infections and squamous intraepithelial lesion (SIL) incidence, particularly for HPV types 16 and 18. (10) Having an infection with oncogenic HPV, however, does not mean a woman is destined to develop CIN or cancer. There is a long time gap between the development of CIN 3 and progression to cancer; but between one third and two thirds of women with CIN 3 will eventually develop invasive cancer if left untreated? Infection with oncogenic HPV types can reduce the time required for progression from low-grade CIN to high-grade CIN, and from high-grade CIN to cervical cancer. In uninfected women, the mean time to progression from atypical squamous cells of undetermined significance (ASCUS) to low-grade squamous intraepithelial lesions (LSIL), or worse, is approximately 88 months; however; lesions infected with oncogenic HPV types show marked progression within 67 months. Mean time for progression from LSIL to high-grade squamous intraepithelial lesion (HSIL), or worse, is also shortened, from 83.5 to 73.3 months. (11) Furthermore, the risk for abnormal cervical cytology is significantly increased with persistent HPV infection with high-risk types, and regression of lesions is often delayed by persistence of infection. (12)

The body is able to clear HPV infection, including high-risk HPV. Ho et al followed 608 college women for 36 months and demonstrated a cumulative infection rate of 43%. The median duration of HPV infection was 8 months, and by 24 months only 9% continued to be infected. (12)

Risk factors for HPV infection

Primary risk factors for HPV infection are directly related to the number of sexual partners, the risk status of the various partners, use of barrier contraceptives, the presence of other sexually transmitted diseases, high frequency of vaginal sex, not being in school, not living with the partner; and alcohol consumption. Other possible risk factors for the acquisition of genital HPV infection include oral contraceptive (OC) use, pregnancy, smoking, nutritional factors, and impairment of cell-mediated immunity. (1,2,12-19) Others have reported high parity and early menopause as being significantly associated with cervical cancer. (20) Infection in virgins is rare, but any type of nonpenetrative sexual contact (ie, "outercourse") is associated with an increased risk for HPV infection. (14)

Unlike recent HPV DNA-based investigations, a study based on the use of HPV-seropositive controls showed that OC use was unrelated to the risk for cervical cancer; and multiparity was only weakly related to risk. (16) Some have even shown that current use of OCs can have a protective effect against the development of low-grade CIN.(15)

HIV-positive status is a significant risk factor for HPV infection (OR = 3.3) and SIL (OR = 4.7). (21) Herpes simplex 2 (HSV-2) and Chlamydia trachomatis infections increase the risk for cervical cancer and its precursor. (3) Infection with HSV-2 may act in conjunction with HPV infection to increase the risk for invasive cervical carcinoma (ICC). (19) Seropositivity of HSV-2 is 44% among patients with squamous-cell carcinoma compared with 25.6% in HSV-2 seronegative controls. (19) Chlamydia trachomatis is a possible cofactor with HPV in the etiology of squamous cervical cancer, increasing the risk for squamous cervical cancer among HPV-positive women (OR = 2.1). It is thought that this increased risk is mediated by a chronic inflammation of the cervix and may be a cofactor for high-grade cervical lesions or cancer development in women infected with oncogenic HPV types. (22,23) This cervical inflammation could lead to damage of the cellular DNA via reactive oxidative metabolites. (3) Overt cervicitis is associated with a 1.9-fold increase in risk for high-grade lesions. (22) Poorly defined immunologic factors are the major determinants of viral outcome) The lower prevalence of HPV infection among older women compared with younger women has been found to be independent of sexual behavior. These results suggest that a biologic effect, such as HPV immunity acquired over time and with multiple exposures, may mediate the inverse relationship between age and HPV prevalence. (17)

Often the lower genital tract is infected with several different types of HPV. Baseline predictors of HPV coinfection include younger age, high number of recent sexual partners, a history of condyloma but not of other STDs, and younger age at first sexual intercourse. (24) The prevalence of HPV coinfections is 3% among cytologically normal women, 10% among women with ASCUS, 23% among those with LSIL, and 7% among those with HSIL. Higher grade lesions and cancers are most often associated with a single high-risk HPV type rather than the multiple infections seen typically in low-grade lesions. The incidence of coinfection declines markedly with age. (25) Circumcision reduces the likelihood of HPV infection, probably because of the decreased amount of noncornified epithelium present. (2)

Cigarette smoking is a risk specific to low-grade CIN, supporting the role of tobacco in neoplastic development. (15,16) Smoking is also associated with an increased risk for ICC and CIN 2/3 in women who are infected with oncogenic HPV. (26) Smoking 10 or more cigarettes per day is associated with CIN 2/3 (OR: 2.6) and CIN 1 (OR: 2.5). (27) Former smokers, women who smoked fewer than 1 pack of cigarettes per day, and women who smoked 1 or more packs per day had crude relative risks for CIN 3 or cervical cancer of 2.1, 2.2, and 2.9 respectively, for the entire follow-up period compared with women who never smoked. (26)

The role of the male partner as a vector for HPV infection is clear, while the role the male partner plays in persistence of infection in the female partner is a subject of controversy. Use of condoms by the male with a new partner is not protective against HPV infection. (14) However, one study showed that regression of flat penile HPV lesions is accelerated by condom use and is attributed to blocking viral transmission between sexual partners. (28) The influence of circumcision on subsequent cervical carcinoma in situ and cervical cancer rates was the topic of a study in a multinational analysis of 1913 couples. (29) Penile HPV was detected more than 3 times as often in uncircumcised men (19.6%) compared with circumcised men (5.5%). After adjustment for confounding factors, circumcised men were found to be less likely than uncircumcised men to have HPV infection (OR: 0.37). (29) Male circumcision is associated with a reduced risk for penile HPV infection and, in the case of men with a history of multiple sexual partners, a reduced risk for cervical cancer in their current female partners. (29)

Detection of gross condylomata is straightforward. Genital warts can be painful and pruritic, but more often they are asymptomatic. (30) There are generally 5 to 15 lesions of 1 to 10 mm in diameter, and at times the condylomata can form confluent plaques. (30,31) They can manifest as papular warts of the keratinized epithelium, flat lesions, or cauliflower-type acuminate warts, (FIGURE 1, FIGURE 2). (31)

[FIGURES 1-2 OMITTED]

Condylomata are usually red to gray in color and can occasionally be pigmented if located on the external keratinized tissues or if associated with high-grade intraepithelial neoplasia. (31) A condyloma can occur anywhere in the lower genital tract in women and men. The most common sites for men are the penile shaft and foreskin if uncircumcised. In women, lesions affect the labia, vagina, perianal area, and cervix. Perianal warts can occur in both women and men, and do not specifically imply a history of anal intercourse, but rather may be secondary to autoinoculation. Checking the perianal area at the time of examination can help a clinician detect a reservoir of HPV that could lead to persistent infection if not treated. Warts can also occur in the mouth if patients have condyloma and participate in oral-genital sex. (30) Biopsy of a genital condylomata is usually not needed unless the lesion is pigmented (FIGURE 3) or not responding to treatment, or if the diagnosis is uncertain. (30,31)

[FIGURE 3 OMITTED]

HPV screening and DNA testing procedures

Both the American Cancer Society (ACS) and the American College of Obstetricians and Gynecologists (ACOG) recommend that cytologic screening for cervical cancer should begin 3 years after the onset of vaginal intercourse. (41,42) While cervical cytologic screening (the Papanicolaou smear) has been the norm for decades, new technologies have become available in recent years that hold the potential to further reduce the incidence of cervical cancer. One of these technologies, HPV testing, has become the cornerstone of new triage guidelines for the management of cytologic and histologic diagnoses.

There are 3 main types of HPV technology in current use, with only 1 (Hybrid Capture 2 [HC2], Digene, Gaithersburg, MD) approved by the US Food and Drug Administration (FDA) for triage of ASCUS cytology and primary screening; HC2 tests for a panel of 13 high- and intermediate-risk HPV types, including 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. Although there is a low-risk HPV panel available, it is not clinically useful in the triage of ASCUS cytology. All mention of HPV testing is speaking of high-risk panels only. The HC2 test is reproducible even among cytologically normal women with low test values. (43)

The other technologies available are an in situ hybridization test called Inform HPV (Ventana Medical Systems, Tucson, AZ) and a test using polymerase chain reaction (PCR) technology called Amplicor HPV (Roche, Switzerland). HPV testing can be done using residual cellular material obtained by liquid cytology or from a separate collection device obtained at the time of the cytologic sampling. Some have even proposed patient self-collection of HPV samples. A comparison study of the performance of these tests for HPV testing in self-collected vaginal specimens and clinician-collected cervical specimens showed that more cases of CIN 2/3, or cervical cancer, were detected using HPV assays than using a Pap smear alone. (44)

Serologic tests for HPV are not particularly clinically useful, because seropositivity to HPV 16, HPV 18, or HPV 31 was not associated with a statistically significant decrease in risk for infection with the homologous HPV type. (45) In one study, seropositivity did not lead to observed immunity, although a protective effect from natural infection could not be excluded. (45) HPV serology is not very sensitive, with many women who are HPV infected being serologically negative. (2) The HC2 test is reliable for detecting clinically relevant oncogenic HPV DNA. (46)

Summary of guidelines for screening and testing

Low-grade SIL regression in young women is common, occurring in up to 91% of women after 36 months. (47) Low-grade squamous intraepithelial lesions can be monitored rather than treated in adolescent women. Furthermore, negative HPV status was associated with regression, suggesting that HPV testing may be helpful in monitoring LSIL. (47) While HPV DNA testing is more sensitive for detecting high-grade cervical lesions than is traditional cytologic testing, many women who are HPV positive are normal on cytologic testing. (48) Therefore, performing traditional cytology in addition to HPV DNA testing will remain essential for the protection of women from precancerous lesions and cervical cancer. Precursor lesions of the cervix persist longer and progress more quickly in women with oncogenic HPV infections than in women with nononcogenic infections or without HPV. Testing cervical lesions for oncogenic HPVs may help clinicians identify those that are likely to progress rapidly. (11)

In 2001, a multiorganizational consensus panel hosted by the American Society for Colposcopy and Cervical Pathology (ASCCP) published guidelines for the management of cervical cytologic abnormalities. (49,50) The cumulative risk for CIN 2/3 is equivalent for LSIL (27.6%) and HPV-positive ASCUS (26.7%); therefore, LSIL and HPV-positive ASCUS are clinically equivalent. (51) LSIL cytology usually mandates colposcopy, as does that of HSIL, cancer, or atypical glandular cells (AGCs). HPV testing with a sensitive molecular test was incorporated into many aspects of evaluation of abnormal cervical cytology, particularly with ASCUS. The preferred method to evaluate ASCUS cytology is reflex HPV testing. Reflex testing simply means that if a smear is interpreted as ASCUS, the laboratory automatically performs HPV testing on the remaining liquid-based cellular material. If conventional cytology is performed, the patient would need to return for specific HPV sampling. The advantages of reflex testing for ASCUS are that it saves the patient an additional visit, and if the HPV test is negative, she can return for her annual cytologic follow-up. A publication in 2002 dealt with the issue of histologic management and post-CIN treatment follow-up. HPV testing once again plays a major role in these guidelines, often supplanting colposcopy as the preferred method of follow-up. (49,52) In women who have CIN 1 or lower on colposcopy and directed biopsy, the risk for subsequent CIN 2/3 is approximately 12% over 2 years. (51) Therefore, even if the result of colposcopic biopsy is negative, follow-up is needed.

About 15% of women in annual screening programs who concurrently have a negative Pap test result and a positive oncogenic HPV result will have a subsequent abnormal Pap smear within 5 years. (48) Negative baseline Pap and HPV test results were associated with a low risk for CIN 3 in the subsequent 45 months. (9) Negative combined test results should provide added reassurance for lengthening the screening interval among low-risk women, whereas positive results identify a relatively small subgroup that requires more frequent surveillance. (26) As HPV testing began to be more commonly used, clarification of expanded use of HPV testing became an issue. To help provide guidance to clinicians and patients when using HPV DNA testing as an adjunct to cervical cell screening, a workshop was cosponsored by the National Cancer Institute, ASCCP, and the ACS. The conclusions of the workshop were that DNA testing for HPV may be added to cervical cytology for screening in women aged 30 years or more (called primary screening). This is different from reflex HPV testing, which takes effect only when a smear is interpreted as ASCUS. Women whose results are negative by both DNA testing for HPV and cytology should not be rescreened for 3 years. (50) Women whose results are negative by cytology, but are high-risk HPV DNA positive, are at a relatively low risk for high-grade cervical neoplasia, and colposcopy should not be performed routinely in this setting. Instead, HPV DNA testing along with cervical cytology should be repeated in these women at 6 to 12 months. If both tests' results are negative, she should have routine rescreening again in 3 years. If either test result is abnormal, colposcopy should then be performed. (50)

The ACOG recognizes HPV testing for 2 main purposes--triage of the ASCUS Pap smears and primary screening. For ASCUS triage, HPV DNA testing will reduce the number of women who are unnecessarily referred for colposcopy. If ASCUS Pap results are negative for high-risk HPV types, it is equivalent to a negative Pap smear and the patient is returned to annual cytology. If HC2 HPV is positive, it is equivalent to an LSIL Pap smear, and colposcopy is indicated. For primary screening, the only FDA-approved test is HC2, and the test is called DNAwithPap. It is the same test as HC2 for reflex testing, but because it has a new indication, the FDA required Digene to give the test a different name. Primary screening is cytology and HPV testing in women aged 30 years or more. If both of these test results are negative, the woman should be rescreened no more frequently than every 3 years. (41) If the Pap smear is abnormal, management is per the ASCCP Consensus Guidelines. (50)

The role of HPV DNA testing in men is more difficult to assess. Because HPV infection in men is typically asymptomatic and the optimal anatomic site to harvest HPV DNA from the male genitalia is largely unknown, HPV testing in men is not typically recommended. Nonetheless, it remains to be determined whether HPV DNA testing will become beneficial for diagnosing anal dysplasias and anal cancer, since HPV DNA is found in more than 85% of anal cancers.

Summary

Sexual activity, especially with multiple or high-risk male partners, places a woman at a significantly increased risk for acquiring an HPV infection. Once in the host, an HPV infection may be latent, subclinical, or overtly manifested. Low-risk HPV types commonly present as condylomata, while high-risk HPV types are associated with precancerous and cancerous changes in the cervix. Recent consensus guidelines have given clinicians evidenced-based recommendations for the evaluation and management of HPV-associated cytologic and histologic changes in the cervix. Detection of a condyloma is generally straightforward, and it can be treated. However, some HPV infections can persist over time without clinical manifestation (ie, with high-risk HPV types). Both condylomata and cervical cancer pose significant public health issues. Furthermore, HPV-associated lower-genital-tract infections are prevalent, result in very high healthcare dollar expenditures, and pose a tremendous burden of suffering for women. Future development of preventive vaccines will be a great help in reducing the frequency of this all too common STD.

Prevalence, incidence, onset, and transmission of HPV

Human papillomavirus (HPV) is a ubiquitous genital epithelial infection that is highly prevalent among adolescent girls and young women, and may be associated with substantial morbidity and mortality. (32) Infection with HPV can manifest as overt condylomata, as cervical intraepithelial neoplasia (CIN) or cancer, or as a latent infection with no clinically visible presence. Genital condylomata are present in approximately 1% of sexually active adults in the United States. Additionally, at least another 15% have subclinical HPV infection. (13) Outpatient office visits for the diagnosis and treatment of genital warts is very common, accounting for 264,000 initial visits to physicians' offices in 2003. (33) The incidence of condylomata is increasing; in 2001, an evaluation of health care claims from more than 5 million patients showed that the incidence of genital warts is on the rise, increasing from 117 cases per 100,000 persons in 1998 to 205 per 100,000 persons in 2001 (FIGURE 4). (34) The age of those treated for condylomata peaks between 20 and 39 years, with more than 70% of patients being in this age category. (35)

HPV incurs the highest direct medical costs of all sexually transmitted diseases (STD) other than HIV, at $1.6 billion annually. This cost includes the direct annual costs for treatment of genital warts, CIN, and cervical cancer. (36) An observational study of records for more than 100,000 female health maintenance organization (HMO) enrollees determined that the average annual cost for cervical HPV-related treatment and prevention was $26,415 per 1000 enrollees. Peak costs were $51,863 for 20- to 29-year-olds, nearly double those for women aged 50 to 69 years. Routine cervical cancer screening accounted for 63.4% of the costs. (37) A study of estimated direct medical costs per complete clearance associated with different treatment options for condylomata acuminata demonstrated, surprisingly, that surgical options such as excision, electrodessication, loop electrosurgical excision, and laser surgery were low-cost options. The mean direct cost per complete clearance was $285 for surgical excision, $316 for loop electrosurgical excision procedure, and $416 for carbon dioxide laser. Destructive treatments were higher-cost modalities, with cryotherapy at $951, trichloroacetic acid at $986, imiquimod at $1255, and podophyllin at $1632. (38) Screening and treatment of HPV and cervical cancer are costly endeavors.

HPV infections are frequent occurrences. Ho et al followed 608 college women at 6-month intervals for 3 years. (12) The cumulative 36-month incidence of HPV infection was 43%. Winer et al followed 603 university women in the state of Washington at 4-month intervals between 1990 and 2000. At each visit, a sexual and health questionnaire was completed and cervical and vulvovaginal samples were collected to be tested for HPV DNA. At 24 months, the cumulative incidence of first-time infection was 32.3% (95% CI: 28.0-37.1). (14) Another study showed that 54 incident HPV infections occurred in 105 females who were HPV-negative at study entry. (15) The prevalence of HPV, including oncogenic types, usually diminishes significantly over a 1- to 2-year period of time. (16) In a cohort study of 439 sexually active inner-city women between the ages of 18 and 50 years, the prevalence of HPV infection ranged from 36% in women younger than 25 years to just 2.8% in women aged 45 years or more. (17) The prevalence of oncogenic HPV at entry declined from 19% among women younger than 25 years to fewer than 3% in women aged 40 years or more. (17) Persistent HPV infections are more likely to progress to cervical precancer and cancer. (3)

Virtually all cervical cancer cells contain HPV DNA, which suggests that HPV infection is a prerequisite to cervical neoplasia. (39) Munoz et al found that HPV DNA was detected in 1739 of 1918 (90.7%) women with cervical cancer compared with 259 of 1928 (13.4%) controls (FIGURE 5). (4) HPV infection was detected in all but one invasive cervical cancer (ICC) case and in 27.7% of controls (odds ratio [OR] = 498). Twenty-three different HPV types were found. The most common type in either cases or controls was HPV 16, followed by HPV 18 and 33. (20) If we can prevent HPV infection from occurring or help the body clear an established infection, the burden of suffering caused by cervical cancer will be dramatically reduced. In developing countries without cervical cancer screening programs, cervical cancer is still the second leading cause of cancer-related deaths in women. In 1999, there were 371,000 new cases of cervical cancer diagnosed worldwide and 190,000 cervical cancer deaths. (40) In the United States in 2004, there were 10,500 cervical cancers and 3900 cervical cancer-related deaths. (18)

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FIGURE 4

Increase in incidence of
genital warts--1998 and 2001

Number Per 100,000 Persons

1998    117
2001    205

FIGURE 5

Detection of HPV DNA in women
with cervical cancer compared with control

Women With NPV DNA (%)

Control                        13.4
Women With Cervical Cancer     90.7


Gregory L. Brotzman, MD

Department of Family and Community Medicine

Medical College of Wisconsin

Columbia-St. Mary's Family Medicine Residency Program

Milwaukee, WI
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Title Annotation:human papillomavirus
Author:Brotzman, Gregory L.
Publication:Journal of Family Practice
Article Type:Disease/Disorder overview
Geographic Code:1USA
Date:Jul 15, 2005
Words:5888
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