New Approaches to CIN in HIV-Positive Women Reported

SAN FRANCISCO—Women infected with the human immunodeficiency virus (HIV) are at increased risk for cervical abnormalities, including cervical intraepithelial neoplasia (CIN), and these problems may not be eradicated by conventional approaches such as conization.

Research reported at the 30th Annual Meeting of the Society of Gynecologic Oncologists pointed to new approaches to managing CIN and highlighted the inadequacy of conventional Pap smears for monitoring potential problems in HIV-positive women.

Maintenance 5-FU

Mitchell Maiman, MD, reported that HIV-infected women are at high risk for recurrence of CIN after standard therapy, and this risk can be significantly reduced by maintenance therapy with topical 5-fluorouracil (5-FU). Adjunctive vaginal 5-FU was “particularly effective in reducing the rate of high-grade CIN,” he said.

Dr. Maiman and his colleagues at Staten Island University Hospital, New York, conducted a phase III, randomized, non-blinded study comparing topical vaginal 5-FU with observation in 101 HIV-positive women after standard excisional or ablative cervical treatment of grade II or III CIN.

Fluorouracil treatment consisted of 2 g of 5% cream biweekly. Pap smears and colposcopy were done at regular intervals over 18 months of follow-up.

Dr. Maiman reported that, overall, 38% of women developed recurrence: 14 of 50 (28%) on the 5-FU arm vs 24 of 51 (47%) on the observation arm. Treatment with 5-FU was significantly associated with prolonged time to CIN (P = .04), and patients who did not receive 5-FU were more likely to develop high-grade recurrences.

Patients with more profound immu-nosuppression (CD4 counts under 200/mm³) were significantly more likely to have a recurrence, regardless of treatment (46% vs 33%, P = .04).

In an interview, Dr. Maiman said that multicovariate analysis with patients stratified by CD4 count showed that the treatment effect was significant at P = .08.

He noted that use of topical 5-FU could be easily incorporated into ordinary clinical practice and that “compliance was, in general, excellent.”

False-Negative Pap Smears

Conventional Pap smears have false-negative rates of 20% to 37% in women with high sexual risk factors and should probably be replaced by regular colposcopic screening in women with atypical squamous cells of undetermined significance (ASCUS) , according to data presented by Annekathryn Goodman, MD, and her colleagues at Massachusetts General Hospital, Boston.

“HIV-positive women, especially those who have high sexual risk factors such as multiple sexual partners, have a higher incidence of cervical dysplasia and a higher rate of false-negative Pap smears. They need to be screened carefully, perhaps more than once a year, and those who have atypical squamous Pap smears probably need colposcopy as opposed to just repeating the Pap smear,” Dr. Goodman said in an interview.

Dr. Goodman studied 184 women recruited from a sexually transmitted disease (STD) clinic or a women’s prison. Of these, 82 were HIV-negative, and 102 were HIV-positive. All underwent Pap smear, colposcopy-directed biopsies, and endocervical curettage.

False-negative Pap smear rates were 21% in HIV-negative and 37% in HIV-positive women (P = NS), indicating that HIV infection did not significantly increase the risk of false-negative Pap smears in this already high-risk population. [The false-negative rate in women without HIV who do not have other sexual risk factors is about 10%.]

Dr. Goodman said that women with patches of ASCUS comprised the majority of false negatives among HIV-positive women. “That is a very important category in HIV-positive women but much less so in HIV-negative women,” she concluded.

Kevin M. Holcomb, MD, and his associates at the State University of New York Health Science Center, Brooklyn, also studied ASCUS in HIV-infected women and concluded that “given the 29% risk of associated CIN, all HIV-positive women with ASCUS cytology should undergo colposcopic evaluation.”

This study included 261 HIV-positive women who underwent 761 Pap smears during the study; 209 (27%) of these smears were diagnosed as ASCUS.

“The incidences of human papilloma virus (HPV, 35%), CIN I and II (26%), and CIN III and carcinoma in situ (2.9%) were similar to those observed in previous studies of ASCUS in HIV-untested populations,” Dr. Holcomb said. There were no cases of invasive cancer, and there was no significant difference in the incidence or severity of CIN in patients with severe immunosuppression.

The researchers concluded that a cytologic diagnosis of ASCUS in HIV-positive women identifies a group at significant risk because a majority of such patients will be diagnosed with HPV or CIN I or II. In an interview, Dr. Holcomb said, “I do recommend colposcopy for HIV-positive women with ASCUS. A 6-month interval for colposcopy and Pap is probably adequate.”

Cervical Conization

In related work, Dr. Holcomb’s group evaluated the efficacy of cervical conization in the treatment of CIN in HIV-positive women. “Although conization was not effective in eradicating CIN in this population, it was successful in preventing progression to cervical cancer,” Dr. Holcomb told Oncology News International. No cases of invasive cancer were found during the study period.

This study included 158 cone biopsies performed on 117 HIV-positive patients. Eighty-seven of the biopsies had adequate follow-up information to be included in the analysis. Patients were stratified based on cone margin status and endocervical curettage (ECC) status, and the rate of histologically proven recurrent CIN was calculated for each group.

Dr. Holcomb reported that “54% of patients with negative margins and ECC experienced recurrence, most within 36 months. There was no significant difference in recurrence rates for patients with positive margins, positive ECC, or positive margins and positive ECC, when compared to patients with complete excision of dysplasia.” Mean CD4 count also did not affect risk of recurrence.

The degree of dysplasia was the most important predictor of recurrence, and most patients had recurrence despite complete excision of dysplasia. “Although multiple procedures were necessary in some patients, cone biopsy was effective in preventing progression to invasive cancer in all cases,” Dr. Holcomb reported.