RepurPosed AntiretrOviraL ThErapieS to EliminAte Cervical Cancer (POLESA Trial)

R37CA284033 In the absence of cytology- and HPV-based cervical cancer screening, screening of the cervix by visual inspection after application of acetic acid (VIA) to highlight precancerous or cancerous abnormalities is recommended. During VIA, if a visible acetowhite pattern is perceived to be abnormal, the cervical epithelium is either ablated (by freezing or heat) or excised. This ‘see and treat’ approach to cervical cancer prevention has been widely adopted in sub-Saharan Africa (SSA), which has some of the world’s highest cervical cancer rates. Our team conducted one of the largest randomized controlled trials in SSA comparing these treatment approaches and determined they are almost 50% less effective in women living with HIV (WLWH). As evidenced by these findings, the elimination of cervical cancer as a significant public health disease requires the adoption and implementation of strategies that are easily accessible, affordable, acceptable and are equally efficacious in WLWH. One potential therapeutic agent that warrants further investigation is a vaginal application of the protease inhibitors (PIs) Lopinavir and Ritonavir (LPV/r), which have known anti-cancer and HPV activity. The overall goal of this trial is to find new, non-invasive, easily scalable solutions for secondary cervical cancer prevention, particularly among WLWH. The central aim of this study is to assess the safety and acceptability of vaginal LPV/r given alone or in combination with thermal ablation (TA) to treat VIA positive women, eligible for ablative therapy. The initial phase of this study has three components: 1) through surveys and interviews, assess the impact of social, behavioral and environmental factors on current treatment outcomes, 2) evaluate biological factors such as the vaginal microenvironment as contributors to poorer treatment response in WLWH, and 3) assess barriers, facilitators, and acceptability of the proposed treatment strategy with key stakeholders. For the intervention phase, we will enroll 180 VIA positive women from designated cervical cancer screening clinics in Lusaka, Zambia. Participants will be stratified based on HIV status and randomized to receive 1) LPV/r or placebo for 3 weeks followed by thermal ablation at 4 weeks or 2) LPV/r or placebo alone for 3 weeks with repeat VIA at 6 months and thermal ablation for those with persistent VIA positive abnormalities. Twenty of the 180 VIA positive women will be randomized to a comparator cohort of usual care with immediate TA if eligible. The expected outcome of this work is the generation of evidence that this novel LPV/r treatment is safe and acceptable for use as treatment or adjunct in women who screen VIA positive and identify potential contributors to overall treatment response. Results from this study will lay the groundwork for a large-scale study of LPV/r in additional SSA cohorts.