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CROI 2017: Treatment or Watchful Waiting for Cervical Abnormalities in Women with HIV?

Close monitoring of earlier-stage cervical abnormalities (CIN-2) may be preferable to treatment for many women with HIV, a U.S. study suggests. The findings, presented at the Conference on Retroviruses and Opportunistic Infections this week in Seattle, show that CIN-2 regressed in over three-quarters of women taking antiretroviral therapy, without the need for CIN treatment. A higher CD4 count was associated with a lower likelihood that lesions would progress.

[Produced in collaboration with aidsmap.com]

Cervical cancer is one of the most common causes of death and illness in women globally. Women with HIV are at increased risk of developing cervical intraepithelial neoplasia (CIN) -- lesions or changes in the cells of the cervix, sometimes referred to as "pre-cancerous" cell changes. Women with lower CD4 cell counts are more likely to have cervical abnormalities. The risk of developing CIN is associated with human papillomavirus (HPV) infection, which is present in more than 60% of women with HIV.

CIN lesions are graded according to severity. Many grade 1 and some grade 2 lesions will clear up without treatment, but the rate of regression or progression is unclear in women living with HIV. In the general population, CIN-2 is regressive in 30% to 40% of women, but for women with HIV rates of regression tend to be lower. Regardless of HIV status, women over the age of 25 are advised to receive treatment for CIN-2.

Treatment can include removing affected tissue. While this prevents progression to cervical cancer, recent research has suggested such treatment can affect reproductive health, potentially leading to premature birth and complications during pregnancy.

Around 8500 women with HIV give birth annually in the U.S. Presenter Kate Michel from Georgetown University noted that it is important to provide guidance for those HIV-positive women who may delay CIN-2 treatment to improve pregnancy outcomes.  

Michel and colleagues wanted to ascertain the risk of CIN-2 progression in women of reproductive age, including time to progression and factors associated with progression, with CD4 cell count and HIV viral load analyzed as time-dependent covariates. The study included both women who had previously been treated for CIN-2 and those who had not.

Women under the age of 46 were included from the observational Women’s Interagency HIV Study (WIHS). The study, begun in 1993, looks at the impact and progression of HIV in women in clinical sites in 10 U.S. cities. It includes women living with HIV and women identified as being at high risk for HIV.

A total of 116 women with biopsy-confirmed CIN-2 were included in the study. Of these, 102 were HIV-positive (41 had previously had CIN-2 treatment) and 14 were HIV-negative (8 had previously been treated). The mean age was 32 years, the majority of women were black or Hispanic, just over half were smokers, and 72% had 1 male partner. Women with HIV were on average 5 years older than HIV-negative women.

CIN-2 regression, defined as biopsy-confirmed CIN-1 or no abnormalities detected by biopsy or normal Pap tests (cervical screening) across all follow-up visits, was overall the most common prognosis (63%), independent of treatment, occurring in 62% and 71% of HIV-positive and HIV-negative women, respectively.

Combination antiretroviral therapy (ART) was associated with a significant 78% decrease in CIN-2 progression. Similarly, each increase of 100 CD4 cells/mm³ was associated with a significant 26% decrease in progression.

In this study 17% more HIV-negative women were treated for CIN-2 than HIV-positive women. Michel noted that this gap, while not statistically significant, warrants further examination of reproductive health access for women with HIV.

Overall, 18% of women progressed to CIN-3 or dysplasia over a median of 10 years (18% HIV-positive and 21% HIV-negative). Median time to progression in HIV-positive women was 3 years. None of the women progressed to cervical cancer.

Michel concluded that for women with HIV considering pregnancy and with well-controlled viral load on ART, short-term conservative management of CIN-2 with close monitoring provides an alternative to immediate resection.

Treatment for CIN 2/3 in Low-Income Settings

In resource-limited settings where HIV is endemic, treatment for abnormal cervical cells (CIN-2/3) usually takes the form of cryotherapy (freezing cells with a chemical); this technique is cost-effective and feasible, as it can be performed by nurses. 

Findings from observational studies of women with HIV suggest that treating abnormal cervical cells with cryotherapy may be less effective than treatment with LEEP (loop electrosurgical excision procedure), which removes abnormal cells by cutting them away with a thin wire loop heated with an electrical current.

A randomized controlled trial conducted in Kenya found that HIV-positive women with CIN-2/3 treated with cryotherapy had a 64% higher risk of recurrent lesions compared to those treated with LEEP at 24 months follow-up, presenter Sharon Greene from the University of Washington in Seattle reported.

Women with HIV underwent cervical screening with Pap test and confirmatory biopsy. 400 with CIN-2/3 or carcinoma in situ (CIS) were randomized to receive cryotherapy or LEEP and were followed-up every 6 months with a Pap test (and biopsy if indicated) for 2 years.

Age, education, and employment status were balanced between the study arms. 80% of women in both study arms has used ART for longer than 6 months. Median CD4 cell counts were similar in both arms, 404 cells/mm³ and 407 cells/mm³ in the cryotherapy and LEEP arms, respectively. 59% and 63% had CIN-3 in the cryotherapy and LEEP arms, respectively.

Overall, the rate of recurrence of high-grade squamous intraepithelial lesions (HSIL) was 21.1 per 100 woman-years after cryotherapy and 14.0 per 100 women-years after LEEP. At 24 months, while HSIL increased in both arms, it was significantly higher in the cryotherapy arm, 37% vs 26%.

Women with HIV are disproportionately affected by cervical cancer and once cancer is invasive, mortality for HIV-positive women is almost twice as high as for HIV-negative women. The World Health Organization (WHO) guidelines recommend cryotherapy with LEEP as an alternative for women who are not eligible for cryotherapy. Findings from this study, Greene stressed, provide compelling evidence for WHO and national ministries of health to develop a screening and treatment algorithm based on HIV status.

2/15/17

Sources

C Colie, S Massad, C Wang, K Michel, et al. Natural history of cervical intraepithelial neoplasma-2 among HIV-infected women. Conference on Retroviruses and Opportunistic Infections. Seattle, February 13-16, 2017. Abstract 23.

SA Greene, E Nyongesa-alva, BA Richardson, et al. Randomized trial of LEEP vs. cryotherapy to treat CIN2/3 in HIV-infected women. Conference on Retroviruses and Opportunistic Infections. Seattle, February 13-16, 2017. Abstract 22.