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). With increased heterosexual transmission of HIV and
frequent co-infection with the human papillomavirus (HPV),
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. HIV infection has tripled in incidence among
adolescent girls between 1985 and 1998, accounting for nearly a
quarter of new HIV cases. Approximately 12,000 to 15,000 new
female AIDS cases were reported annually from 1993 to 1997.
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.
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.
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.
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. Nonetheless,
cervical cancer accounts for 6% of all cancer cases in the United
States, 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
Young women and the elderly seem especially at high risk: The
incidence of cervical cancer has increased among young women by 3%
since 1986, and elderly women account for one quarter of cervical
cancer cases and 41% of cervical cancer deaths.
Etiology of Cervical Cancer
HPV infections are recognized as the main cause of cervical
cancer. 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. 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
When the virus DNA is integrated into the infected individual,
It is also possible that HPV interacts with HIV in ways that increase
Changes in paracrine and autocrine factors induced by HIV-infection
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
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. HIV-infected women have a fivefold risk of developing CIN,
compared with unin-fected women. Once these women develop
cervical cancer, the cancer may be aggressive, and treatment may be
ineffective, accounting for high rates of CIN recurrence.
The risk of developing cervical carcinoma seems to vary with the
extent of immunosuppression. Risk of HPV is highest in
HIV-infected women with CD4-positive lymphocyte counts less than 200
cells/mm³. This association can be linked to the prevalence
of HPV infection among HIV-positive women, especially
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. 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
Recurrence appears to be related to the degree of
immunosuppressionpatients with CD4-positive counts less than
500 cells/mm3 have an extremely high recurrence rate.
Since an inexpensive diagnostic test exists for easy diagnosis of
precancerous cervical lesions, most mortality related to cervical
cancer is avoidable. 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%.
While most low-grade precancerous lesions regress, a portion will
progress to higher-grade lesions and eventually invasive cervical cancer.
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.
Patients may be more likely to return after initial colposcopy when
the required treatment was more intensive and was administered
shortly after colposcopy. 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.
Unless the woman is at high risk for cervical abnormalities,
physicians may screen less frequently once they have obtained three
consecutive negative Pap smears. 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.
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.
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.
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. 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.
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. w
1. Maiman M et al: Management of cervical neoplasia in human
immunodeficiency virus-infected women. Monogr Natl Cancer Inst
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
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
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.