Increased risk of treatment failure in HIV-infected women with CIN

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Women living with HIV are more likely than HIV-negative women to have residual or recurring abnormal cells after treatment for pre-cancerous cervical lesions, according to research. This systematic review and meta-analysis found that treatment for cervical intraepithelial neoplasia (CIN), or abnormal cells that could progress to cancer, was nearly three times more likely to be unsuccessful in HIV-positive women. However, the study was unable to classify women according to CD4 cell count, so it does not shed much light on outcomes among women on antiretroviral therapy with well-preserved immune function.

Several types of human papillomavirus (HPV) can cause cervical, anal, oral and other cancers. Cervical cancer is a major cause of cancer-related death for women worldwide, but it usually is not fatal in industrialised countries thanks to regular HPV screening and Pap tests, which allow for early treatment before abnormal cells progress to cancer.

Studies have shown that women with HIV are more likely than HIV-negative women to have persistent HPV infection and to develop CIN and invasive cervical cancer. Those with lower CD4 counts, indicating greater immune suppression, are at higher risk.

CIN lesions are graded according to severity. Many grade 1 lesions will clear up on their own. Treatment is usually recommended for women with grade 2 or 3 pre-cancerous lesions (also known as high-grade squamous intraepithelial lesions, or HSIL). This may involve destroying the abnormal cells by freezing (cryotherapy) or heat, or cutting out a cone-shaped section of the cervix using a cold knife or heated wire (loop electrosurgical excision procedure, or LEEP).

Pierre Debeaudrap of Université Paris Descartes and colleagues performed a systematic review and meta-analysis of studies looking at outcomes of cervical pre-cancer treatment in women with HIV.

Searching MEDLINE, HIV conference abstracts and other sources in any language from January 1980 to May 2018, the researchers identified 40 eligible studies in which HIV-positive women with confirmed cervical abnormalities were followed for at least six months post-treatment. Four were clinical trials, 16 were observational cohort studies and 20 were retrospective studies.

Two-thirds of the studies were conducted in high-income countries (mostly the US) and 13 in low- and middle-income countries (mostly in Africa); however, the low-income country studies were larger and accounted for a majority of total participants. Altogether, the studies included 3975 HIV-positive women. Some also included HIV-negative women as a comparison group (total 3638). LEEP was the most common treatment approach.

A meta-analysis of the data found that the pooled prevalence of treatment failure among HIV-positive women – defined as the continued presence of residual grade 2 or higher CIN, or recurrence of high-grade CIN after treatment – was 21.4%. Half of the women had residual or recurrent cervical abnormalities of any grade.

There was no difference in the likelihood of treatment failure using cryotherapy (13.9%) versus LEEP (13.8%). Failure was more likely, at 47.2%, in women with positive margins, meaning some precancerous cells were found at the edges of the surgically removed tissue, compared to those with negative margins (19.4% failure). Of note, the treatment failure rate was higher in high-income (27.9%) compared with low-income countries (14.4%).

In the ten studies that included both HIV-positive and HIV-negative women, the women with HIV had more than a twofold higher risk of treatment failure with grade 2 or higher CIN (23.4% versus 9.5%, respectively; odds ratio 2.7). Further, HIV-positive women had a fivefold higher likelihood of having post-treatment cervical abnormalities of any grade.

“This meta-analysis provides evidence that, even after cervical screening and treatment, women infected with HIV remain at high risk of CIN2+/HSIL cervical lesions,” the researchers wrote in their discussion. “In the context of increasing effort to scale up cervical cancer screening in limited-resource settings, these findings highlight the importance of reflecting upon the appropriate post-treatment follow-up of this population.”

A limitation of this analysis is that the studies did not always include information about the women’s CD4 counts, which are known to affect cervical pre-cancer outcomes in women with HIV. However, some of the individual studies did show significantly more treatment failure in women with lower current or nadir (lowest-ever) CD4 levels. Also, the studies did not consistently distinguish between residual abnormalities – which suggest pre-cancerous cells were not completely destroyed or removed – and relapse.

Based on these findings, the researchers concluded, “There is strong evidence for increased risk of treatment failure in HIV-infected women in comparison to their HIV-negative counterparts. The only significant predictor of treatment failure in HIV-infected women was positive margin status, but further data is needed on long-term outcomes after ablative treatment in HIV-infected women.”

Abstract
Background: Screening and treating premalignant cervical lesions (CIN2+) is an effective way to prevent cervical cancer, and recommendations exist for monitoring of treatment success. Yet, there is no specific recommendation for HIV-infected women, who are at known increased risk of cervical cancer.
Methods: A systematic review was performed by searching MEDLINE, EMBASE and Web of Science from January 1980 through May 2018. Eligible studies described prevalence of histologically and/or cytologically-defined lesions in HIV-infected women, at least 6 months post-treatment. Primary endpoint was treatment failure, defined as the presence of residual and/or recurrent high-grade CIN2+/HSIL+ lesions post-treatment. Pooled prevalence in HIV-infected women, and odds ratios (OR) for HIV-infected compared to HIV-uninfected women were estimated using random-effects models.
Results: Among 40 eligible studies, pooled prevalence of treatment failure in HIV-infected women was 21.4% (95%CI 15.8–27.0). There was no significant difference in treatment failure for cryotherapy (13.9%, 95%CI 6.1–21.6) versus LEEP (13.8%, 95%CI 8.9–18.7,p=0.9), but it was significantly higher in women with positive (47.2%, 95%CI 22.0–74.0) than with negative (19.4%, 95%CI 11.8–30.2) margins (OR 3.4, 95%CI 1.5–7.7). Treatment failure was significantly increased in HIV-infected versus HIV-uninfected women, both overall (OR 2.7, 95%CI 2.0–3.5) and in all sub-group analyses.
Conclusion: There is strong evidence for increased risk of treatment failure in HIV-infected women in comparison to their HIV-negative counterparts. The only significant predictor of treatment failure in HIV-infected women was positive margin status, but further data is needed on long-term outcomes after ablative treatment in HIV-infected women.

Authors
Pierre Debeaudrap, Joelle Sobngwi, Pierre-Marie Tebeu, Gary M Clifford

Aidsmap material
Clinical Infectious Diseases abstract


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