Acceptability and Feasibility of Combination Treatment for Cervical Precancer Among Women Living with HIV in South Africa: Primary Outcomes from the ACT 2 Randomized Trial

ObjectiveDetermine acceptability and feasibility of loop electrosurgical excision procedure (LEEP) combined with adjuvant intravaginal 5-fluorouracil (5FU) for treatment of cervical intraepithelial neoplasia grade 2/3 (CIN2/3) in women living with HIV (WLWH). DesignDouble-blind, randomized, placebo-controlled Phase 2b feasibility trial. SettingPublic-sector hospital in Johannesburg, South Africa. Population180 WLWH aged 18+ years with CIN2/3 confirmed by LEEP and on antiretroviral therapy for [≥]60 days. MethodsParticipants underwent LEEP and were randomly assigned (1:1) to receive 8 doses of adjuvant 5FU or placebo cream every other week and followed for 24 weeks. Main Outcome MeasuresThe primary outcomes were acceptability and feasibility (adherence, retention, safety, tolerability). ResultsBetween March 2023 and January 2025, we randomized 180 WLWH. Median age was 41 years (interquartile range [IQR]: 35-45), median CD4+ count was 636 cells/mm3 (IQR: 376-873), and 98.9% were virologically suppressed. Acceptability (>94%) and adherence (>91%) were high and comparable between arms. Retention exceeded 92% in both arms, although Week 24 attendance was lower in the 5FU arm (92.2% vs. 98.9%, probability difference [PD] -6.7%, 95% confidence interval [CI] -14.4%, -0.5%). Safety events were mild, more common with 5FU, and primarily reported as Grade 1 or 2 cervical inflammation (49.2% vs. 26.7%, risk difference [RD] 22.5%, 95% CI 8.6%, 36.4%). One Grade 3 adverse event (an allergic reaction to 5FU) resulted in treatment discontinuation. ConclusionsLEEP plus adjuvant intravaginal 5FU is acceptable and feasible among WLWH in South Africa, supporting progression to a Phase 3 trial. Clinical Trial RegistrationNCT05413811. FundingUnited States National Institutes of Health (R01CA250850).