RepurPosed AntiretrOviraL ThErapieS to EliminAte Cervical Cancer (POLESA Trial)

As the death toll from cervical cancer continues to rise, particularly in low-resource settings, we are in search of more effective approaches to cervical cancer prevention. In the absence of cytology- and HPV-based cervical cancer screening, experts have endorsed screening of the cervix by visual inspection after application of acetic acid (VIA) to highlight precancerous or cancerous abnormalities. If the recognized acetowhite pattern is perceived to be abnormal, the cervical epithelium is either ablated by freezing (cryotherapy) or heating (thermal ablation) in a “see and treat” approach or excised with a large loop excision of the transformation zone (LLETZ). This approach to cervical cancer screening and treatment has been widely adopted in low- and middle-income countries (LMICs), notably in sub-Saharan Africa (SSA), which has some of the world’s highest rates of cervical cancer. Our team conducted one of the largest randomized controlled trials ever conducted in SSA comparing these treatment approaches. Our preliminary results suggest that these treatments are almost 50% less effective for 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 capsule containing 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 that address the profound gap in secondary cervical cancer prevention, particularly among WLWH. The central aim of this study is to assess the safety and acceptability of the LPV/r vaginal capsule given alone or in combination with thermal ablation to treat VIA positive women who are eligible for ablative therapy. We will enroll 180 women who present for cervical cancer screening in a Cervical Cancer Prevention Program clinic in Zambia. Participants (n=180) 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 cervical lesions. 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. Results from this study will lay the groundwork for a large-scale study of LPV/r in a SSA cohort.