Women With HIV at Greater Risk for Cervical Cancer

Cervical cancer has a high incidence and is a rapidly progressive illness among human immunodeficiency virus (HIV)-infected women. This cancer has received increasing attention since 1993 following its addition to the list of AIDS-defining illnesses monitored by the Centers for Disease Control and Prevention (CDC).[1] With increased heterosexual transmission of HIV and frequent co-infection with the human papillomavirus (HPV),[1] invasive cervical cancers will appear more often among HIV-infected women.

Increase in HIV/HPV Coinfection

It is estimated that between 120,000 and 160,000 American women are infected with HIV.[2] HIV infection has tripled in incidence among adolescent girls between 1985 and 1998, accounting for nearly a quarter of new HIV cases.[3] Approximately 12,000 to 15,000 new female AIDS cases were reported annually from 1993 to 1997.[4]

The most notable increase in HIV infections in the United States has been among women of African descent and Hispanic ethnicity, who largely acquire the infection through heterosexual activity. In 1998, blacks and Hispanics accounted for 80% of all new AIDS cases among US women.[2]

Women aged 22 to 44 years are also disproportionately affected. Most of the newly infected women have acquired the disease via sexual transmission and are younger than 25 years of age.[2]

HIV-infected women are at high risk of contracting oncogenic strains of HPV and developing cervical intraepithelial neoplasia (CIN), following immunosuppression and risky sexual practices.[1] Unprotected sex beginning at a young age and involving multiple partners has been identified as a risk factor for acquiring HPV and HIV.

Since the introduction of the Pap smear in the United States in 1946, incidence and mortality have been drastically reduced, to 13,700 new cases and 4,900 deaths from cervical cancer in 1998.[5] Nonetheless, cervical cancer accounts for 6% of all cancer cases in the United States,[6] with a disproportionate number occurring among minority women and women of low socioeconomic status.[7,8]

Although disparities in morbidity and mortality of cervical cancer among different ethnic groups have narrowed, significant differences remain (11.8 cervical cancer deaths per 100,000 black women in the population, 10.2 per 100,000 Hispanic women, and 7.2 per 100,000 white women).[5]

Young women and the elderly seem especially at high risk: The incidence of cervical cancer has increased among young women by 3% since 1986,[7] and elderly women account for one quarter of cervical cancer cases and 41% of cervical cancer deaths.[6]

Etiology of Cervical Cancer

HPV infections are recognized as the main cause of cervical cancer.[5] More than 80 HPV types have been identified, although only a fraction have been linked to the development of precancerous

lesions or CIN. The HPV types most frequently associated with high-grade lesions include HPV 16, 18, 31, 33, and 51.[5] As many as 95% of precancerous lesions on the cervix are associated with high-risk oncogenic strains of HPV.

(See box for an explanation of the mechanisms by which HPV is thought to initiate cervical cancer[1,5,9,10], as well as possible interactions between HIV and HPV that may account for the increased risk of cervical cancer in women who are coinfected.)

How HPV Induces Cervical Cancer

HPV is one of the most common sexually transmitted diseases in the United States. Women acquire the virus during vaginal sex with an infected individual, resulting in infection of the top layers of skin.

When the virus’ DNA is integrated into the infected individual, the E2 gene is disrupted, which results in the transcription of the E6 and E7 genes. The product of the E6 gene inactivates the p53 tumor suppressor gene, while the E7 gene product binds to the Rb gene product, inactivating it and initiating cell cycle activation and proliferation.[5,9] The loss of tumor suppression and induction of proliferation results in an increased likelihood of malignant carcinoma development.[9]

It is also possible that HPV interacts with HIV in ways that increase HPV or even HIV gene expression.[10] In one possible interaction, the HIV-1 tat protein may induce additional HPV regulatory expression.[1,10]

Changes in paracrine and autocrine factors induced by HIV-infection may also influence HPV gene expression.[1]

Detection of HPV in HIV-positive women who reported discontinued sexual activity may reflect reactivation or persistence of preexisting HPV types rather than a recent HPV acquisition. History of an abnormal Pap smear is an independent risk factor for HPV infection among HIV-positive women, which may indicate prior exposure to HPV.[11]

 Cervical Abnormalities in HIV

Women with HIV have high rates of cervical abnormalities (30% to 60%) and cervical dysplasia (11% to 60%)[1,12] that are more difficult to treat.[11] HIV-infected women have a fivefold risk of developing CIN, compared with unin-fected women.[13] Once these women develop cervical cancer, the cancer may be aggressive, and treatment may be ineffective,[10] accounting for high rates of CIN recurrence.[14]

The risk of developing cervical carcinoma seems to vary with the extent of immunosuppression.[12] Risk of HPV is highest in HIV-infected women with CD4-positive lymphocyte counts less than 200 cells/mm³.[11] This association can be linked to the prevalence of HPV infection among HIV-positive women, especially immunocompromised women.

In one study of 1,778 HIV-positive and 500 HIV-negative women, low CD4-positive lymphocyte counts and high HIV viral loads were predictors of HPV infection among HIV-positive women.[11] In a study of 285 HIV-infected women, immunodeficiency and HPV infection were independent risk factors for developing abnormal cytology results, and HPV oncogenic type was the only independent predictor for developing CIN.[14]

Recurrence appears to be related to the degree of immunosuppression—patients with CD4-positive counts less than 500 cells/mm3 have an extremely high recurrence rate.[15]

Since an inexpensive diagnostic test exists for easy diagnosis of precancerous cervical lesions, most mortality related to cervical cancer is avoidable.[6] Unfortunately, one third of adult women have not been screened in the past 3 years, with higher rates among rural women (40%), women living in poverty (43%), and women aged 50 to 64 (47%).

Screening for cervical cancer with Pap smears can be successful only when patients with abnormal results return for follow-up evaluation. Attrition rates have been estimated to be between 30% and 50%.[7] While most low-grade precancerous lesions regress, a portion will progress to higher-grade lesions and eventually invasive cervical cancer.[6]

Depending on the severity of abnormalities in the specimen, women may need repeated Pap smear screening and/or colposcopy or other, more aggressive treatments, including the loop electrosurgical excision procedure (LEEP) or cervical conization.[6]

Patients may be more likely to return after initial colposcopy when the required treatment was more intensive and was administered shortly after colposcopy.[16] As a consequence, not taking into consideration nonadherence to follow-up recommendations will overestimate the effectiveness of screening. Collection of information on Pap smear follow-up rates with different treatment approaches and monitoring intervals is essential in determining and improving the success of cervical cancer screening.

The American Cancer Society, National Cancer Institute, American College of Obstetricians and Gynecologists, and American Medical Association recommend annual Pap smears for women aged 18 and older, or from the onset of sexual activity.[17]

Unless the woman is at high risk for cervical abnormalities, physicians may screen less frequently once they have obtained three consecutive negative Pap smears.[17] According to the CDC, once women with HIV have obtained two negative Pap smears 6 months apart, they can be screened on an annual basis.[12]

In a study of 253 HIV-infected women and 220 uninfected women, the authors found that without performing routine colposcopy and biopsy in addition to obtaining Pap smears, 38% of all CIN in 13% of patients would have gone undetected.[14]

Similar concerns over the sensitivity and specificity of Pap smears in populations with high rates of cervical abnormalities have led to recommendations of more frequent screening for HIV-infected women with Pap smears and/or colposcopy.[12,14] However, increased frequency of screening, especially with routine colposcopy, is costly.[12,17]

Cervical cancer screening recommendations among HIV-positive women are further complicated by frequent vaginal infections that result in inflammation or bleeding that obscures the specimen and limits the accuracy of the reading.[1]

The incidence of invasive cervical cancer is likely to rise with increasing numbers of HIV-infected women or with high-risk oncogenic types of HPV, especially since many of these women are poor and do not receive adequate health care.

Improvements in antiretroviral therapy have dramatically reduced HIV-related mortality from common opportunistic infections, such as Pneumocystis carinii pneumonia.[18] As a consequence, malignancies, including cervical cancers, are likely to be an increasing cause of death among HIV-infected women.

Prevention of invasive cervical cancer requires a three-pronged approach, focusing on education efforts directed at young girls and women, appropriate and regular cytologic and sexually transmitted disease (STD) screening, and adherence to follow-up recommendations.

Explicit discussion of the etiology of cervical cancer and ways in which women can prevent most cases of invasive cervical cancer through abstinence, condom usage, or topical microbicides could also help women reduce their odds of becoming HIV- and/or HPV-infected.

As a result of the Breast and Cervical Cancer Mortality Act (Public Law 101-354, Title XV, Public Health Service Act 1990), a number of public health initiatives have been established to improve screening rates, especially among under-served populations.[8]

Current screening efforts should be continued to establish regular screening of all women and more intensive screening of those at high risk for developing cervical cancer, especially HIV-infected women with high-risk oncogenic types of HPV. Screening initiatives also need to integrate follow-up treatment and monitoring following detection of cytologic abnormalities.

In addition to screening for precancerous lesions, the introduction of HPV typing in community settings will be crucial in identifying viral strains associated with invasive cervical cancers. It is hoped that new technologies under investigation will provide effective anti-HPV vaccines, further reducing morbidity and mortality from cervical cancer.[9] w

References:

1. Maiman M et al: Management of cervical neoplasia in human immunodeficiency virus-infected women. Monogr Natl Cancer Inst 23:43-49, 1998.

2. Centers for Disease Control and Prevention Report: HIV/AIDS Among US Women: Minority and Young Women at Continuing Risk, 1999.

3. Fauci AS et al: The AIDS epidemic: Considerations for the 21st century. N Engl J Med 341:1046-1050, 1999.

4. Centers for Disease Control and Prevention: Special data run, 1998.

5. Schoell WMJ et al: Epidemiology and biology of cervical cancer. Semin Surg Oncol 16:203-211, 1999.

6. National Institutes of Health Consensus Development Conference Statement on Cervical Cancer. Gynecol Oncol 66:351-361, 1996.

7. Marcus AC et al: A review of cervical cancer screening intervention research: Implications for public health programs and future research. Prev Med 27:13-31, 1998.

8. Lawson HW et al: Cervical cancer screening among low-income women: Results of a national screening program, 1991-1995. Obstet Gynecol 92:745-752, 1998.

9. Lowy DR et al: Papillomaviruses and cervical cancer: Pathogenesis and vaccine development. Monogr Natl Cancer Inst 23:27-30, 1998.

10. Palefsky JM et al: Human papillomavirus infection and anogenital neoplasia in human immunodeficiency virus-positive men and women. Monogr Natl Cancer Inst 23:15-20, 1998.

11. Palefsky JM et al: Cervicovaginal human papillomavirus infection in HIV-positive and high-risk HIV-negative women. J Natl Cancer Inst 91:226-236, 1999.

12. Goldie SJ et al: The costs, clinical benefits, and cost-effectiveness of screening for cervical cancer in HIV-infected women. Ann Intern Med 130:97-107, 1999.

13. Boccalon M et al: Intra-epithelial and invasive cervical neoplasia during HIV-infection. Eur J Cancer 32A:2212-2217, 1996.

14. Maiman M et al: Prevalence, risk factors, and accuracy of cytologic screening for cervical intraepithelial neoplasia in women with the human immunodeficiency virus. Gynecol Oncol 68:233-239, 1998.

15. Mitsuyasu R: Oncological complications of the human immunodeficiency virus disease and hematologic consequences of their treatment. Clin Infect Dis 29:35-43, 1999.

16. Massad LS et al: Predicting compliance with follow-up recommendations after colposcopy among indigent urban women. Obstet Gynecol 94:371-376, 1999.

17. Walsh JME et al: Cervical cancer: Developments in screening and evaluation of the abnormal Pap smear. West J Med 169:304-310, 1998.

18. Pallela FJ et al: Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 338:853-860, 1998.