Expanded Safety and Preliminary Efficacy of Adjuvant 5-Fluorouracil Following Thermal Ablation to Improve HPV Treatment Outcomes in Women with HIV in Africa

ABSTRACT Women in low- and middle-income countries (LMICs) shoulder a disproportionate burden of cervical cancer, accounting for 85% of new cases and 90% of deaths worldwide. Women living with HIV (WWH) -70% of whom reside in Africa – are at especially high risk, with up to 6-fold increased likelihood of developing cervical cancer due to higher incidence and persistence of human papillomavirus (HPV) infection. Consequently, cervical cancer is the leading cause of cancer-related death for WWH in LMICs. Although the World Health Organization (WHO) recommends thermal ablation for treating cervical precancer, recurrence of cervical intraepithelial neoplasia grade 2/3 (CIN2/3) in WWH following ablation alone can reach 33% within a year of treatment. This high recurrence partly stems from thermal ablation’s inability to clear HPV infection in WWH, which is associated with up to 20-fold risk of CIN2/3 recurrence. This is a significant limitation and calls for urgent and accessible solutions to improve cervical precancer treatment outcomes in this population. Drawing on evidence from U.S-based randomized trials and a recent Phase I pilot study in Kenya, we propose to investigate the use of 5-Fluorouracil (5FU), an affordable, widely available chemotherapeutic agent, as a patient-administrated intravaginal therapy following thermal ablation to improve HPV treatment outcomes among WWH in Kenya. While 5FU’s safety and efficacy as a primary and adjuvant cervical precancer treatment have been demonstrated in high-income countries, no randomized trials have investigated its use as an adjuvant therapy following thermal ablation among WWH in LMICs, where the disease burden is greatest. This study will address this gap by conducting a pilot Phase IIa randomized placebo-controlled trial to evaluate the safety, adherence, and preliminary efficacy of self-administered intravaginal 5-fluorouracil (5FU) following thermal ablation in HPV-positive WWH. We will enroll 140 WWH in Kenya and randomize them 1:1 to receive either 5FU or a placebo after undergoing thermal ablation. Our aims are 1) to determine the safety of 5FU, including its effect on genital HIV viral shedding; 2) to evaluate adherence to the self-administered regimen using both self-reported data and ultraviolet light inspection of applicators; and 3) to determine preliminary efficacy by comparing type-specific HPV clearance rates between the two treatment arms at 24 weeks. The trial builds on a successful Phase I single-arm trial of self-administered 5FU in Kenya and leverages well- established partnerships with local healthcare facilities, research institutions, and the Ministry of Health (see letter of support). Findings will inform future Phase IIb or III trials evaluating 5FU as an adjuvant therapy for preventing CIN2/3 recurrence among WWH in Africa and other resource-limited settings. If proven safe, effective, and acceptable, self-administered 5FU could offer a widely scalable approach to improve secondary prevention of cervical cancer for millions of WWH globally, helping to move closer to the global goal of eliminating this preventable cancer.