Randomized clinical trial protocol: Acceptability and feasibility of combination treatment for cervical precancer among South African women living with HIV (ACT 2)

Background: Global efforts to eliminate cervical cancer currently focus on expanding access to human papillomavirus (HPV) vaccination and cervical screening. However, these efforts lack equal investment in the treatment of precancerous cervical intraepithelial neoplasia grade 2/3 (CIN2/3), particularly among women living with human immunodeficiency virus (HIV; WLWH). This gap leaves a generation of WLWH at high risk of persistent/recurrent CIN2/3 and progression to cervical cancer, as standard surgical treatments are less effective in this population. Methods and design: We conducted a randomized, placebo-controlled trial to evaluate the acceptability and feasibility of combination treatment for CIN2/3 among WLWH in South Africa. As part of the trial, 180 WLWH with CIN2/3 were randomly allocated (1:1) to undergo loop electrosurgical excision procedure (LEEP) followed by self-administration of 8 doses of intravaginal 5% 5-fluorouracil (5FU) or placebo cream (one dose every other week for 16 weeks). Women were followed for 24 weeks. The primary outcomes were acceptability and feasibility (safety, tolerability, adherence, retention). Secondary outcomes included (a) regression of cervical disease to cervical intraepithelial neoplasia grade 1 (CIN1) or normal histology and (b) clearance of the high-risk HPV (hrHPV) genotype(s) detected at baseline. Discussion: This feasibility trial was conducted in preparation for a large-scale effectiveness trial of LEEP combined with intravaginal 5FU for CIN2/3 among WLWH. If proven acceptable, feasible, and effective, topical 5FU may be repurposed as a low-cost, self-administered adjuvant treatment to reduce persistent/recurrent CIN2/3 and progression to cervical cancer in this high-risk population. Trial registration: ClinicalTrials.gov, NCT05413811.