Surgery for CIN results in high rates of recurrence in HIV-positive women

HIV-positive women who undergo surgery for pre-cancerous lesions of the cervix have high rates of recurrence, French investigators report in the 1^st August edition of The Journal of Acquired Immune Deficiency Syndromes. The study found that recurrence was more common in women with low CD4 cell counts and when the lesions were not completely removed during surgery. However, the use of highly active antiretroviral therapy (HAART) protected against the disease returning.

Cervical intraepithelial neoplasia (CIN) is an abnormality of the cells in the cervix caused by certain forms of the human papilloma virus or wart virus. HIV-positive women are known to be at an elevated risk of developing CIN, which can go on to become cancerous.

The standard treatment for CIN is surgical removal, which has good results in HIV-negative women. However, while recurrence of cervical disease was reported in studies during the pre-HAART era, the success of surgery in HIV-positive women has not been assessed since the advent of HAART.

Researchers from two Paris hospitals wished to update the pre-HAART findings by examining the rates of CIN recurrence in 121 HIV-positive women. All of the women had low- or high-grade CIN, which was removed surgically, with follow-up Papanicolaou (Pap) smears and biopsies at six-monthly intervals.

The investigators found that nine (69%) of the 13 women with low-grade CIN remained free of the disease and 29 (47%) of the 62 with high-grade lesions after a median follow-up of 1.7 years. To ensure the accuracy of their results, the investigators only included the 75 women who did not have any CIN at baseline and who received follow-up assessment after surgery in their calculations.

These levels of recurrence were equivalent to an overall rate of 22.3 per 100 person-years. When they restricted their analysis to the women with high-grade lesions, the rate of recurrence was 8.6 per 100 person-years.

“The present study performed in the era of HAART confirms the results of earlier reports of high recurrence rates of cervical lesions after surgery in HIV-positive women,” the investigators conclude.

The investigators went on to perform a multivariate analysis to discover which factors were linked to recurrence of CIN after surgery. They found that the presence of CIN cells at the edge of the removed tissue - a ‘positive margin’ - was strongly associated with recurrence (relative risk [RR] = 3.5; 95% confidence interval [CI]: 1.2 – 9.8). It was also linked to recurrence when the investigators restricted their analysis to women with high-grade CIN (RR = 9.0; 95% CI: 2.2 – 36.5). A positive margin indicates that the surgery failed to remove the entire lesion.

Other factors significantly associated with recurrence of CIN included having a CD4 cell count below 200 cells/mm³ (RR = 9.4; 95% CI: 2.7 – 32.7), although these two factors were not significantly associated in their analysis of high-grade CIN. In contrast, the use of HAART reduced the risk of recurrence of CIN (RR = 0.3; 95% CI: 0.1 – 0.7) and of high-grade disease (RR = 0.2; 95% CI: 0.1 – 0.7).

“Our study strongly supports the hypothesis that recurrent CIN is the feature of cervical neoplasia most characteristic of HIV disease in the context of immunodeficiency,” the researchers write. “Women with CD4 counts less than 200 cells/mm³ had a nine times higher risk [of] persistence and / or recurrence of CIN, emphasising the role of cellular immune responses in the control of … human papilloma virus-related cervical disease.”

Since HAART use and CD4 cell count may depend on one another, the investigators carried out a further analysis to tease apart their effects. They found that CD4 cell count had a significant influence on the rate of recurrence only in the women who were not taking HAART. In contrast, women taking HAART seemed to be protected against recurrence of CIN regardless of their CD4 cell count.

Whether CIN was low- or high-grade, and the type of surgery performed - laser vaporisation, electrosurgery or loop excisional excision procedure (LEEP) – did not have a significant impact on the likelihood of recurrence. This was despite a trend for the use of LEEP increasing over the ten years of the study, from 1993 to 2003.

However, the investigators admit that larger studies may enable the detection of subtle differences between the success rates of the various approaches.

Despite the relatively high rate of recurrence, the investigators note that most CIN returned at lower grade and that the rate of recurrence of high-grade lesions was lower than the rate for low- and high-grade lesions combined. This could indicate that surgery delays the progression to cervical cancer.

“Although excisional therapy is highly effective for CIN in immunocompetent patients, such treatment seems to be effective only in preventing progression to cancer, at least in the short term, in HIV-infected women,” they explain.

They offer several explanations for the recurrence of CIN in HIV-positive women, including more high-grade lesions, large lesion size, extra ‘satellite’ lesions outside the excised area and persistent infection with human papilloma virus.

However, they do not speculate on whether similar findings may be observed in HIV-positive patients receiving surgical treatment for similar pre-cancerous lesions, particularly in the anus.