Feasibility of artesunate to improve HPV and cervical precancer treatment outcomes among HIV positive women in LMICs

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ABSTRACT Women living in low- and middle-income countries (LMICs) face a disproportionate burden of incidence and mortality from cervical cancer, accounting for 85% of incident cases and 90% of mortality globally. Women living with HIV (WLWH), the majority of whom live in LMICs, bear the greatest burden with up to 6 times increased risk of cervical cancer due to higher incidence and persistence of human papillomavirus (HPV) infection. The World Health Organization (WHO) recommends the use of ablation or excisional treatment for suspected or confirmed cervical precancer in LMICs, in a 'screen & treat' strategy to limit loss to follow-up. However, among WLWH, both treatment methods experience high failure rates, with a 30% recurrence of cervical intraepithelial neoplasia (CIN2/3) at two years following thermal ablation. Treatment failure rates are driven partly by high rates of persistent HPV infection following both ablation and excisional treatment in WLWH. High treatment failures are a significant limitation of the current cervical cancer secondary prevention strategy among WLWH and call for studies on feasible, innovative, yet accessible therapies to improve HPV clearance and reduce precancer treatment failure in WLWH. I will build on ongoing U.S-based trials that demonstrate safety and possible efficacy of artesunate, a semi-synthetic derivative of artemisinin for treatment of HPV-associated anogenital lesions. My proposed study will generate preliminary data on the feasibility of using self-administered artesunate vaginal inserts as adjuvant therapy following thermal ablation to improve treatment outcomes among HPV+ WLWH in LMICs. I will leverage my decade-plus collaboration with Ministry of Health-supported HIV clinics in Western Kenya, the Kenya Medical Research Institute (KEMRI), and new and established collaborators to conduct this study successfully. In this planning grant, I propose a pilot, randomized, placebo-controlled trial to investigate the following specific aims: 1) evaluate uptake and acceptability of self-administered artesunate vaginal inserts as adjuvant treatment following thermal ablation in HPV+ WLWH in an LMIC, 2) test and evaluate three methods of assessing adherence to self-administered artesunate to inform a future study protocol, and 3) perform a preliminary comparison of type-specific hrHPV clearance at six months following randomization in the artesunate and matched placebo arms as a statistical planning aim to obtain effect sizes to power a future trial. This study will be the first to evaluate the feasibility of artesunate vaginal inserts for improving the current ‘screen & treat’ cervical cancer prevention strategy among WLWH in LMICs. If found to be feasible and effective, artesunate, which is included in the WHO’s Essential Medications List, could be repurposed in this highly scalable approach to impact a significant global public health problem.