Treatment or watchful waiting for cervical abnormalities in HIV women?

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Close monitoring of earlier-stage cervical abnormalities (CIN-2) may be preferable to treatment for many women with HIV, a US study suggests.

The findings, presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2017) in Seattle, show that CIN-2 regressed in over three-quarters of women taking antiretroviral therapy (ART), without the need for treatment. A higher CD4 count was associated with a lower likelihood that the lesion would progress.

Around 8,500 women with HIV give birth annually in the US. Dr Kate Michel at Georgetown University, Washington DC presenting, noted that it is important to provide guidance for those women with HIV who may delay CIN-2 treatment to improve pregnancy outcomes.

Abstract 1
Therapy for cervical intraepithelial neoplasia-2 (CIN2), a potential precursor of invasive cervical cancer, can include resection of affected tissue which can prevent progression but result in cervical incompetence and complications during pregnancy. We sought to characterize the natural history of CIN2 among HIV-positive women of childbearing age.
126 biopsy-confirmed CIN2-diagnosed women under age 46 (109 HIV-positive and 17 HIV-negative) were included from the multi-site, observational Women’s Interagency HIV Study. Kaplan-Meier curves and Cox proportional hazards models were used to assess time to CIN2 progression (CIN3+) with CD4+ T cell and HIV RNA levels analyzed as time dependent covariates (SASv9.3).
CIN2-diagnosed women were primarily Black (56.4%), current smokers (51.6%), with a median age of 32 years and contributed 2,558 semi-annual visits over a median of 10 years. Among 109 HIV-positive women with CIN2, 66 (60.6%) did not receive CIN2 treatment during follow-up. CIN2 treated and untreated HIV-positive women did not differ in median follow-up time, colposcopy findings, age, CD4+ count, HIV RNA level, or combination antiretroviral therapy (cART) use. Only 21% of HIV-positive women showed CIN2 progression within the median 10-year follow-up. Three untreated women progressed to cancer. CIN2 progression rates were not significantly different in HIV-positive women treated versus untreated for CIN2 at 2 years (11.1% vs. 5.2%) or 5 years (14.8% vs. 16.2%) post-CIN2 diagnosis. Propensity weighting did not affect findings. Median time to CIN2 progression was not significantly different between treated and untreated HIV-positive women (5.8 vs. 9.0 years, p=0.14). Use of cART was associated with ~ 80% decrease in CIN2 progression (hazard ratio (aHR) 0.20; 95% CI 0.05, 0.71), adjusting for CIN2 treatment, CD4+ count, and HIV RNA levels. Similarly, each increase of 100 CD4+ T cells was associated with ~ 30% decrease in CIN2 progression (aHR=0.68; 95% CI 0.53, 0.85), adjusting for CIN2 treatment, cART use, and HIV RNA levels.
Progression of CIN2 is uncommon in HIV-positive women, regardless of treatment. For HIV-positive women of childbearing age who are well controlled on cART and considering pregnancy, short-term conservative management of CIN2 with close monitoring may be an alternative to immediate resection. Further studies are planned to determine the role of HPV type on cervical disease progression.

Authors
Christine Colie, L Stewart Massad, Cuiwei Wang, Kate Michel, Gysamber D’Souza, Joel Palefsky, Howard Minkoff, Howard D Strickler, Seble Kassaye

 

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 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 randomised controlled trial conducted in Kenya found that HIV-positive women with cervical lesions (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, Sharon Greene of the University of Washington in Seattle, told the conference.

Abstract 2
Cervical screening and treatment using visual inspection with acetic acid (VIA) and cryotherapy (screen-and-treat) is often implemented in resource-limited settings with high HIV-1 endemicity; however, cryotherapy may be less effective than loop electrosurgical excisional procedure (LEEP) among HIV-infected women. We randomized 400 HIV-infected women to cryotherapy or LEEP and examined the recurrence of cervical disease over a 2-year follow-up.
From June 2011 to July 2014, HIV-infected women enrolled at the Coptic Hope Center for Infectious Diseases in Nairobi, Kenya underwent cervical screening with Pap smear and confirmatory biopsy. Four hundred women with cervical intraepithelial neoplasia (CIN)2/3 or carcinoma in situ (CIS) disease were randomized 1:1 to receive cryotherapy or LEEP, and were followed every 6 months with a Pap smear for 2 years. Recurrence was defined as high grade squamous intraepithelial lesions (HSIL) or greater on cytology, and outcomes were compared between arms using Chi-square tests and Cox proportional hazards regression.
Sociodemographic and biological factors were balanced between arms. Median age was 37 years [interquartile range (IQR): 31-43], most women were on ART (89%) at the time of intervention, and median CD4 was 380 cells/μl (IQR: 215-524). Among women randomized to cryotherapy: 71 (35.5%) had CIN2 at baseline, 107 (53.5%) CIN3, 11 (5.5%) CIS, and 11 (5.5%) no dysplasia/CIN1. In the LEEP arm: 59 women (29.5%) had CIN2, 116 (58%) CIN3, 10 (5%) CIS, and 15 (7.5%) no dysplasia/CIN1. Median follow-up was 2.1 years in both arms and 341 (85%) women completed all 4 follow-up visits. At 12-months, more women treated with cryotherapy experienced recurrent HSIL than those who underwent LEEP (27% vs 18%; P=0.031). At 24 months, HSIL increased in both arms and remained significantly higher in the cryotherapy arm (37% vs 26%; P=0.018). Overall, the rate of recurrence of HSIL+ was 21.1 per 100 woman-years after cryotherapy and 14.0 per 100 woman-years after LEEP. Women treated with cryotherapy were 52% more likely to experience recurrence (hazard ratio (HR): 1.52, 95% confidence interval [CI]: 1.07-2.17; P=0.020) compared to LEEP.
Treatment with cryotherapy was associated with significantly higher risk of recurrent pre-cancerous cervical disease among HIV-infected women compared to LEEP. In high HIV-burden settings, a screen-and-treat approach coupled with HIV testing and referral for LEEP may be more effective than cryotherapy alone.

Authors
Sharon A Greene, Evans Nyongesa-Malava, Barbra A Richardson, Grace John-Stewart, Hugo De Vuyst, Nelly Yatich, Catherine Kiptinness, Sameh Sakr, Nelly Mugo, Michael H Chung

Aidsmap material
CROI 2017 abstract 1 (23)
CROI 2017 abstract 2 (22)


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