Comparison of imiquimod, topical fluorouracil, and electrocautery for the treatment of anal intraepithelial neoplasia in HIV-positive men who have sex with men: an open-label, randomised controlled trial

Summary

Background

Anal cancer is an increasing issue in HIV-positive men who have sex with men (MSM). Screening for its precursor, anal intraepithelial neoplasia (AIN), is subject of discussion. Current treatment options are suboptimum and have not been compared in a prospective trial. We compared efficacy and side-effects of imiquimod, topical fluorouracil, and electrocautery for the treatment of AIN.

Methods

In this open-label randomised trial, we included HIV-positive MSM older than 18 years visiting the HIV outpatient clinic of the Academic Medical Center, Amsterdam, Netherlands. Patients with histologically confirmed AIN were randomly assigned to receive either 16 weeks of imiquimod (three times a week), 16 weeks of topical fluorouracil (twice a week), or monthly electrocautery for 4 months. Randomisation was done with random block sizes of three and six, stratified for AIN grade (AIN grades 1, 2, or 3) and AIN location (peri-anal or intra-anal). Participants were assessed by high-resolution anoscopy 4 weeks after treatment. Responding patients returned for follow-up 24 weeks, 48 weeks, and 72 weeks after treatment. The primary endpoint was histological resolution of AIN measured 4 weeks after treatment and AIN recurrence at week 24, week 48, and week 72 after treatment. The primary analysis was done in a modified intention-to-treat population, including all patients who had received their assigned treatment at least once. The trial is registered at the Netherlands Trial Register, number NTR1236.

Findings

Between Aug 12, 2008, and Dec 1, 2010, we screened 388 HIV-positive MSM for AIN by high resolution anoscopy. Of the 246 (63%) patients who had AIN, 156 (63%) were randomly assigned to either receive imiquimod (54 patients), topical fluorouracil (48 patients), or electrocautery (46 patients) following withdrawing of consent by eight patients. Modified intention-to-treat analysis showed a complete response in 13 (24%, 95% CI 15–37) patients in the imiquimod group, eight (17%, 8–30) of patients in the fluorouracil group, and 18 (39%, 26–54) of patients in the electrocautery group (p=0·027). At week 24, 11 (22%) of 50 responders had recurrence; at week 48, 22 (46%) of 48 had recurred; and at week 72, 30 (67%) of 45 had recurred. Recurrence was observed at 72 weeks in 10 (71%) of 14 patients treated with imiquimod, seven (58%) of 12 patients treated with fluorouracil, and 13 (68%) of 19 patients treated with electrocautery. Grade 3–4 side-effects were noted in 23 (43%) of 53 patients in the imiquimod group, 13 (27%) of 48 patients in the fluorouracil group, and eight (18%) patients in the electrocautery group (p=0·019). The most common side-effects were pain, bleeding, and itching. Seven serious adverse events occurred, all not related to the study.

Interpretation

Electrocautery is better than imiquimod and fluorouracil in the treatment of AIN, but recurrence rates are substantial.

Funding

Anna Maurits de Cock foundation provided funding for the video colposcope.

Introduction

The incidence of anal cancer is increasing in patients with HIV.1, 2 In particular, men who have sex with men (MSM) who are HIV positive are at risk, with incidence rates of 65–109 per 100 000 person-years.³ As in cervical cancer, oncogenic human papillomavirus (HPV) has an important role, and anal cancer is likewise preceded by a precursor lesion: anal intraepithelial neoplasia (AIN), graded from 1 to 3.⁴ AIN of grade 1 is referred to as low-grade AIN and AIN of grades 2 and 3 as high-grade AIN. A study in HIV-positive men before the introduction of combination antiretroviral therapy (cART) showed a progression rate of 52% from low to high grade dysplasia during a follow-up period of 4 years.⁵ Progression rates from high-grade AIN to anal cancer have been reported to be around 15% for HIV-positive MSM, during median follow-up periods of 2 and 5 years.6, 7 By way of comparison, malignant progression of inadequately treated cervical intraepithelial neoplasia 3 is 30% in 30 years.⁸

Since anal cancer incidence in HIV-positive MSM is substantially higher than the incidence of cervical cancer before the introduction of standard cytological screening,⁹ and screening for cervical intraepithelial neoplasia is effective in preventing cervical cancer, AIN screening is subject of discussion. However, the efficacy of known treatment options for AIN is poor and the recurrence rate is high. Moreover, most studies of AIN treatment are retrospective single-arm case series. At present, infrared coagulation and electrocautery seem to be the best options for treatment of AIN, with moderate response rates.10, 11 However, electrocautery and infrared coagulation require an outpatient setting and, given the high recurrence rates, often need to be repeated. Therefore, topical therapies, which can be applied by the patient at home, could be an attractive alternative. A prospective study¹² on imiquimod showed a complete response rate of 61% for (mainly peri-anal) AIN. In a more recent, placebo-controlled study¹³ the complete response rate of imiquimod treatment for intra-anal AIN was 14% after 4 months of treatment. Another topical option is fluorouracil. Results from a study¹⁴ from our group showed a complete response rate of 39% for intra-anal AIN.

Since, to our knowledge, electrocautery and topical therapies have not yet been compared, we did a randomised trial comparing efficacy and tolerability of imiquimod, topical fluorouracil, and electrocautery for the treatment of AIN in HIV-positive MSM.