Interventions for anal canal intraepithelial neoplasia.

Abstract

Background: Anal intraepithelial neoplasia (AIN) is a dysplasia of the anal transitional epithelium that is associated with human papillomavirus (HPV) infection. High-grade lesions have the potential to develop into anal cancer. The incidence and prevalence of AIN and anal cancer has been increasing over the last decades. Certain groups - including people living with HIV, men who have sex with men (MSM), and those with suppressed immune systems - are at high risk of developing AIN. Targeted excisions using ablative treatments such as electrocauterisation, infrared coagulation, or cryotherapy have been used as first-line therapeutic strategies. Other options include topical treatment with immunomodulators such as imiquimod or cytostatics such as fluorouracil. Ideally, treatment of AIN should have a low risk of complications and result in a low risk of recurrence. This is the first update of a review originally published in 2012.

Objectives: To assess the effects of any therapeutic intervention for anal intraepithelial neoplasia, regardless of gender, age, and comorbidity.

Search methods: We used CENTRAL, MEDLINE, Embase, and five trials registers, together with reference checking, citation searching and contact with study authors to identify the studies that are included in the review. The latest search date was 16 April 2025.

Selection criteria: We included randomised controlled trials (RCTs) that assessed any type of intervention for AIN. We excluded cluster-randomised and cross-over trials. We excluded people with a histological diagnosis of anal carcinoma, Paget's disease, or Bowenoid papulosis.

Data collection and analysis: We used standard methodological procedures expected by Cochrane. Our primary outcomes of interest were: AIN eradication (defined by the absence of histologic criteria OR the presence of a normal epithelium or scarring OR the complete absence of dysplasia); development of anal cancer; and human papillomavirus (HPV) eradication. We assessed the certainty of the evidence using GRADE.

Main results: Five RCTs met our inclusion criteria, randomising a total of 4907 participants. All included participants were adults living with HIV with a CD4 cell count above 300 cells/μL. The median participant age ranged from 45 to 51 years. Most participants were male. Two studies were multicentre, both conducted in the USA. The remaining studies were conducted in outpatient clinics in Spain, the Netherlands, and the UK. We considered the overall risk of bias as high in one study and moderate in four. The main reasons for concerns of bias were open-label design and high dropout rates. All studies had different interventions and outcomes, precluding meta-analysis. The inclusion of two multi-armed studies means that we synthesised evidence for nine separate comparisons. Here, we summarise only the results from the largest study, with 4459 randomised participants, comparing high-resolution anoscopy-guided treatment to active monitoring. We summarise results from the other studies in the main review. The study comparing high-resolution anoscopy (HRA)-guided treatment to active monitoring did not assess four of the review's outcomes of interest: AIN eradication, HPV eradication, histological downgrading of AIN lesions, and recurrence of AIN. Results for the three remaining outcomes - development of anal cancer, quality of life, and adverse events - are as follows. In the HRA-guided treatment group, four per 1000 (0.4%) participants developed anal cancer, while in the active monitoring group, nine per 1000 (0.9%) participants developed anal cancer, with a median follow-up of 25 to 28 months (risk ratio (RR) 0.43, 95% confidence interval (CI) 0.20 to 0.93; P = 0.03; 1 study, 4446 participants; very low-certainty evidence). In the active monitoring group, there was an increased impact on psychological functions from inclusion to 28 days after inclusion. In the treatment group, there was no difference in physical symptoms, impact on physical functioning, or impact on psychological functioning from inclusion to 28 days after inclusion. Two per cent of participants in the treatment arm and 0.2% in the active monitoring arm reported adverse events. Most adverse events were mild pain (RR 10.7, 95% CI 3.85 to 29.79; P < 0.001; 1 study, 4446 participants; very low-certainty evidence).

Authors' conclusions: All included studies focused on people living with HIV. This may limit the applicability of the results to HIV-negative people. We assessed the certainty of evidence as very low for all outcomes across all nine comparisons, highlighting a lack of high-quality evidence on interventions for AIN. Our findings suggest that HRA-guided treatment may lower anal cancer risk, but the evidence is very uncertain. We evaluated the efficacy of cidofovir, sinecatechins, infrared coagulation, HRA-guided electrocautery, imiquimod, and fluorouracil in eradicating AIN. With eradication rates between 14% and 62% and follow-up periods ranging from four weeks to 33 months, the evidence on the effectiveness of these treatments is very uncertain. Further studies on interventions for AIN with sufficient power and duration are required to determine the efficacy of interventions. Studies addressing treatments in HIV-negative cohorts are also needed.