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

摘要 生活在低收入和中等收入国家的妇女面临着不成比例的发病率和 宫颈癌死亡率占全球发病病例的85%和死亡率的90%。活着的女性 艾滋病毒携带者(WLWH)，其中大多数生活在低收入国家，承受着最大的负担，风险增加了6倍 由于人类乳头瘤病毒(HPV)感染的较高发病率和持久性，宫颈癌的发病率较高。世界 世界卫生组织(WHO)建议对疑似或确诊的患者使用消融或切除治疗 LMICs中的宫颈癌前病变，采取“筛查和治疗”策略，以限制随访的损失。然而，在WLWH中， 这两种治疗方法的失败率都很高，宫颈上皮内瘤变的复发率为30% (CIN2/3)在热消融后两年。治疗失败率在一定程度上是由较高的 WLWH消融和切除治疗后持续的HPV感染。严重的治疗失败是 WLWH当前宫颈癌二级预防策略的一个重大局限性，并呼吁 研究可行的、创新的、但可获得的治疗方法以促进HPV清除和减少癌前病变 WLWH治疗失败。我将在正在进行的美国试验的基础上，证明安全性和可能的有效性 青蒿琥酯是青蒿素的半合成衍生物，用于治疗HPV相关性肛门生殖器病变。我的 拟议的研究将产生关于使用自我给药青蒿琥酯阴道的可行性的初步数据 作为热消融后辅助治疗的插入物以改善HPV+WLWH的治疗结果 LMIC。我将利用我十多年来与卫生部支持的西部艾滋病诊所的合作 肯尼亚、肯尼亚医学研究所(KEMRI)以及新的和现有的合作者进行这项工作 学习成功。在这项计划拨款中，我提出了一项试点、随机、安慰剂对照试验来研究 具体目的如下：1)评价自身给药青蒿琥酯阴道埋植剂的摄取和可接受性 作为LMIC中HPV+WLWH热消融后的辅助治疗，2)测试和评价三种方法 评估自身给药青蒿琥酯的依从性，以告知未来的研究方案，以及3)进行 青蒿琥酯随机治疗后6个月型特异性hrHPV清除的初步比较 作为一项统计计划，匹配的安慰剂组的目的是获得效果大小，为未来的试验提供动力。本研究 将第一个评估青蒿琥酯阴道插入物用于改善目前的筛查和治疗的可行性。 低分子肝病患者子宫颈癌预防策略。如果被发现是可行有效的，青蒿琥酯， 包括在世界卫生组织的基本药物清单中，可以在这种高度可扩展的方法中重新使用 来影响一个重大的全球公共卫生问题。

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.