ACT 2 Clinical Trial Design: Acceptability and Feasibility of Combination Treatment for Cervical Precancer Among South African Women Living with HIV.

Background: Global efforts to eliminate cervical cancer currently focus on expanding access to HPV vaccination and cervical screening. However, these efforts lack equal investment in treatment of precancerous cervical intraepithelial neoplasia grade 2/3 (CIN2/3), particularly among women with HIV (WWH). This gap leaves a generation of WWH at high risk of persistent/recurrent CIN2/3 and progression to cervical cancer, as standard surgical treatments alone are far less effective in this population. Methods and Design: After randomization, WWH with CIN2/3 (N=180) are randomly allocated 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 will be followed for 24 weeks. The primary outcomes are acceptability and feasibility (safety, tolerability, adherence, retention). Secondary outcomes include (a) regression of cervical disease to CIN1 or normal histology and (b) clearance of the hrHPV genotype(s) identified in baseline cervical ThinPrep samples. Discussion: We hypothesize that topical 5FU, a widely available low-cost generic drug, can be repurposed as an adjuvant treatment for CIN2/3 to be self-administered after surgical excision (or ablation) to reduce the risk of persistent/recurrent CIN2/3 and progression to cervical cancer among WWH. In preparation for a large-scale trial to test the effectiveness of combination treatment for CIN2/3 in WWH, we are conducting a Phase 2b feasibility trial of LEEP combined with intravaginal 5FU. Trial Registration: ClinicalTrials.gov , NCT05413811 .