Screening for cervical cancer in HIV-infected women

Author
William R Robinson, MD
Section Editor
Barbara Goff, MD
Deputy Editor
Sandy J Falk, MD, FACOG
Disclosures: William R Robinson, MD Nothing to disclose. Barbara Goff, MD Nothing to disclose. Sandy J Falk,
MD, FACOG Nothing to disclose.
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Literature review current through: Jun 2015. | This topic last updated: Aug 19, 2014.
INTRODUCTION The availability of cervical cytology to screen for cervical cancer often permits
diagnosis at the preinvasive stage, when treatment can almost always prevent progression to
invasive cancer. For this reason, screening for cervical cancer is important in all women. Screening
for cervical cancer is of particular concern to HIV-infected women and adolescents, since the
incidence of cervical intraepithelial neoplasia (CIN), as confirmed by colposcopy, is four to five times
higher in HIV-positive women and adolescents compared to HIV-negative women and adolescents
with high-risk sexual behaviors [1-3].
CIN is common in HIV-infected women because [4-8]:
Both HIV and human papillomavirus (HPV) are sexually transmitted, and
HIV-infected women are more likely to have persistent HPV infection, and
Persistent infection with one or more oncogenic HPV subtypes is a major factor in the
pathogenesis of premalignant and malignant cervical disease
A study has reported that, unfortunately, as many as one-fourth of HIV-infected women do not get
an annual pap smear despite seeing a primary care provider during that time period, underscoring
the need for continued emphasis on cervical cancer screening in this population [9].
Specific issues regarding screening for cervical cancer in HIV-infected women will be reviewed
here. Evaluation and management of women with abnormal screening results and general issues
regarding screening for cervical cancer are discussed separately. (See "Preinvasive and invasive
cervical neoplasia in HIV-infected women"and "Cervical cancer screening tests: Techniques for
cervical cytology and human papillomavirus testing".)
CERVICAL CYTOLOGY The performance of cervical cytology assessment alone as a screening
tool for cervical intraepithelial neoplasia (CIN)/cancer in women with HIV has been controversial,
with some studies reporting a low sensitivity for the detection of cytological abnormalities [10-13],
while other studies have been more reassuring about the reliability of this technique [1,14-18].
Either conventional Pap smears or liquid-based cervicovaginal preparations may be employed for

screening [19,20]. (See "Cervical cancer screening tests: Techniques for cervical cytology and
human papillomavirus testing".)
Cervical cytology appears to be reliable as a primary screening tool for cervical neoplasia:
In one study, 391 HIV-seropositive and 103 seronegative women with atypical squamous
cells (ASC) or low-grade squamous intraepithelial lesions (LSIL) on cervical cytology and
negative colposcopy were followed for a mean of four years with cytology at six-month
intervals [21]. HIV-infected women had a slightly higher risk of progression than HIV-negative
women, but the absolute risk was low and did not justify further therapy.
In another study, the HIV Epidemiology Research (HER) Study group followed 189 HIVinfected women for six years [22]. Agreement between cytologic findings and colposcopic and
histologic findings was high, which led them to conclude that the routine use of colposcopy in
these individuals was not necessary.
A multicenter study conducted in Europe and South Africa attempted to follow 1534 HIVpositive women using cytology, HPV testing, and colposcopy (with histopathology when
indicated) at six-month intervals [17]. Median follow-up was about two years. Cytology
(ASCUS) and colposcopy had equivalent sensitivity for detecting women with CIN 2 or worse
(100 and 98 percent, respectively). HPV testing had similar sensitivity (91 percent), but was
much less specific (50 percent versus 65 percent for cytology and 63 percent for colposcopy).
Based on these findings, the authors concluded cytology was preferable to HPV testing or
colposcopy for screening HIV-positive women for cervical cancer.
Guidelines from the American College of Obstetricians and Gynecologists and the United States
Preventive Services Task Force recommend that women who are infected with HIV (or otherwise
immunocompromised) should undergo cervical cytology for cancer screening twice in the first year
after diagnosis of HIV infection and then annually, provided the test results are normal [23,24]. Two
cervical screening assessments initially is prudent for HIV-infected women, since intraepithelial
neoplasia is not uncommon and can develop rapidly in these women [2,25], and because highgrade lesions may be missed with a single smear [13]. The efficacy of annual cervical cytology after
consistently negative results was illustrated in a study of 942 HIV-infected women [26]. After three
consecutive negative cytology results, after 15 months, there were no cases of precancer (CIN 2,3,
atypical glandular cells favor neoplasia, or adenocarcinoma in situ), and after 39 months, precancer
was found in 2 percent of women.
A cost-effectiveness analysis using a simulated clinical practice in the United States also supports
this recommendation [27]. This report compared six screening strategies in HIV-infected women: no
screening, annual Pap smear, annual Pap smear after two negative smears obtained six months
apart, semiannual Pap smears, annual colposcopy, and semiannual colposcopy. Annual Pap smear
after two negative smears obtained six months apart offered quality adjusted life expectancy
benefits at a cost comparable to other clinical preventive interventions. Semiannual Pap smear
screening provided additional quality adjusted life years (QALYs) but at significantly greater cost,
while colposcopy added significant cost but provided no further benefit.
Women with advanced HIV disease (particularly those controlled with highly active antiretroviral
therapy) appear to be more likely to have persistent HPV and CIN than those with early HIV
infections; however, there are no objective data showing that more aggressive screening is
indicated for these women or affects outcome.

It has been suggested that the use of highly active antiretroviral therapy (HAART) may reverse or
lessen the severity of cervical neoplasia in HIV-infected women, as is the case with other AIDSrelated malignancies [28-30]. However, multiple studies of this hypothesis have yielded mixed
results, and the incidence of invasive cervical neoplasia appears to be unchanged in the HAART
era [31-33].
Follow-up of normal results For women with two consecutive normal cytological examinations,
we recommend that annual follow-up include a thorough visual inspection of the anus, vulva, and
vagina, as well as the cervix [34,35].
Evaluation of abnormal results The American Society for Colposcopy and Cervical Pathology
2006 consensus guidelines advise that immunosuppressed women, including women who are HIV
positive, with atypical squamous cells of undetermined significance (ASC-US) may be managed the
same as women in the general population [36,37]. Women in this population do not appear to be at
increased risk of CIN 2,3 or HPV positivity [38,39]. Other cytologic abnormalities in women infected
with HIV should also be evaluated in the same manner as in other women. (See "Cervical cytology:
Evaluation of atypical squamous cells (ASC-US and ASC-H)", section on 'Immunocompromised
women'.)
Although rates of cytologic glandular abnormalities appear to increase with degree of
immunosuppression in HIV-positive women, glandular neoplasia is rare. This was illustrated in a
large cohort study that included almost 50,000 Pap tests [40]. Rates of glandular abnormalities on
cervical cytology did not differ significantly in HIV-positive (0.8 percent) compared with HIV-negative
women (0.6 percent). Among HIV-positive women, on the other hand, the rate of cytologic glandular
abnormalities increased significantly with decreasing CD4 lymphocyte count (>500/mm3: 0.6
percent; 250 to 500/mm3: 0.8 percent; <250/mm3: 1.0 percent). Ultimately, cervical biopsy found
only one HIV-positive woman with cervical adenocarcinoma and one HIV-negative woman with
glandular atypia; other women had negative histology or squamous abnormalities and showed no
significant difference by HIV serostatus.
Screening after hysterectomy There is little information about the prevalence of vaginal
intraepithelial neoplasia in HIV-infected women who have undergone hysterectomy and how best to
follow these women. Uninfected women with no history of CIN who undergo hysterectomy for
benign disease have a near zero risk of developing vaginal intraepithelial neoplasia, so periodic
vaginal cytological screening is not recommended. Uninfected women with a history of CIN who
undergo hysterectomy for CIN or other benign disease have about a 1 percent risk of developing
vaginal intraepithelial neoplasia [41,42]; therefore, periodic cytology has been advised for these
women until three consecutive negative results have been obtained subsequent to the diagnosis of
CIN. (See "Screening for cervical cancer".)
By comparison, a study of 102 HIV-infected women who underwent hysterectomy for a variety of
indications reported 16 developed vaginal intraepithelial neoplasia within the first few years after
their surgery [43]. Nineteen of these women were known to have CIN or cervical cancer at the time
of hysterectomy, seven were known not to have any CIN, and there was no information on the other
76 patients. Of note, the seven women without CIN had normal vaginal cytology during median
follow-up of three years. Although the number of patients in this series is small and data are
incomplete, the high rate of vaginal intraepithelial neoplasia suggests that annual vaginal cytology
screening in HIV-infected women is a reasonable approach.

HUMAN PAPILLOMAVIRUS TESTING A cost-effectiveness study evaluated the role of human

papillomavirus (HPV) testing for cervical cancer screening in HIV-infected women [44]. For HIVinfected women on antiretroviral therapy, adding HPV testing to the two cervical cytology smears
obtained in the first year and then modifying subsequent screening based upon these results
(cervical cytology screening every six months for women with detectable HPV DNA and annual
screening for all others) was more effective and cost effective than annual screening alone.
Others have also found a low risk of cytological abnormalities in immunocompromised women who
test negative for high-risk subtypes of HPV and have normal CD4 counts. A cohort study showed
that HIV-infected women (mean age 37 years) with CD4 counts over 500/mcL, normal cervical
cytology, and HPV-negative test results at baseline were at low risk of developing cervical
intraepithelial neoplasia (CIN) in the next three years, and their risk was equivalent to that of HIVnegative women [20].
On the other hand, a study of 103 women who were HIV positive and had CD4 counts less than 500
reported that the presence of a high-risk HPV subtype, although strongly associated with the
presence of any CIN, only slightly improved the sensitivity and predictive value of baseline
screening when compared to cytologic screening alone [15]. The lack of substantial benefit was
most likely due to the high prevalence of HPV infection in HIV-infected women. It appears that HIVinfected women are more likely than other women to be infected with high-risk HPV subtypes other
than 16 and 18 and are likely to have persistent infection [45,46].
We feel the use of HPV testing to determine the frequency of subsequent screening in HIV-infected
women is a reasonable approach; women who test negative for HPV and have two negative initial
cervical cytology results could undergo cytological screening yearly (as discussed above), while
those with high-risk HPV DNA would have cervical cytology every six months. This is different from
the recommendation for HIV-negative women in whom prolongation of the screening interval to not
less than three years is recommended if both cytology and HPV results are normal. (See "Cervical
cancer screening tests: Techniques for cervical cytology and human papillomavirus testing", section
on 'HPV testing'.)
The US Food and Drug Administration (FDA) approved the cobas HPV test for use in co-testing or
as a standalone method of screening for women over age 24. This was based on a study of over
40,000 women, which showed that the test was safe and effective for the new indication for use
[47]. However, this study included no known HIV-infected subjects. As discussed above, historical
cervical screening techniques may be less effective in HIV-infected women. We therefore cannot
currently endorse the use of the cobas HPV test as a standalone screening technique for this
population. Additional large clinical trials are needed to determine whether subgroups of HIVpositive women, such as those who are HPV negative and/or have normal CD4 counts, can be
screened for cervical cancer at screening intervals longer than one year. In the meantime, annual
screening with more frequent evaluation of those with abnormal cytology or high-risk HPV types is
recommended.
COLPOSCOPY Many clinicians perform routine colposcopy in HIV-infected women, either with
the initial cervical cytology or annually. The rationale for this approach is:

These women are usually seen in the health care system more often than once a year for
other reasons, so they would not require an additional visit (with its associated costs and
inconvenience) just for screening.
The rate of noncompliance is high, thus, the potential need for a return visit for colposcopy is
eliminated.
A higher rate of concurrent vulvar, vaginal, and anal neoplasias occurs in this group [34,35].
Even mildly abnormal smears are associated with a high rate of histologic CIN (38 percent in
one series) [14].
Colposcopic examination of the vagina and vulva, as well as the cervix, should be included in the
evaluation because of the higher risk of multifocal disease [34,35]. (See"Colposcopy".)
We recommend a screening colposcopy at initial evaluation. We base the need for subsequent
examinations on cervical cytology results. (See 'Evaluation of abnormal results' above.).
SUMMARY AND RECOMMENDATIONS
Women who are infected with HIV (or otherwise immunocompromised) should undergo
cervical cancer screening twice in the first year after diagnosis of HIV infection and then
annually, provided the test results are normal. (See 'Cervical cytology' above.)
For women with two consecutive normal cytological examinations, we recommend that
annual follow-up include a thorough visual inspection of the anus, vulva, and vagina, as well
as the cervix. (See 'Follow-up of normal results' above.)
There is no consensus as to whether human papillomavirus (HPV) testing should be
performed routinely on HIV-infected women. We suggest the use of HPV testing to determine
the frequency of subsequent cervical cancer screening in these women; women who test
negative for HPV and have two negative initial cervical cytology results could undergo
cytological screening yearly, while those with high-risk HPV DNA should have cervical cytology
every six months. (See'Human papillomavirus testing' above.)
We recommend a screening colposcopy at initial evaluation. The need for subsequent
examinations is based upon cervical cytology results. (See 'Colposcopy'above.)
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