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

青蒿琥酯改善中低收入国家 HIV 阳性女性 HPV 和宫颈癌前治疗结果的可行性

• 批准号: 10762866
• 负责人: Chemtai Mungo
• 金额: $ 24.7万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-06 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10762866
• 关键词: Ablation; Accounting; Adherence; Adjuvant; Adjuvant Therapy; Anus; Apoptosis; Area; Artemisinins; Biopsy; Cell Death; Cells; Cervical; Cervical Intraepithelial Neoplasia; Clinic; Clinical Trials; Collaborations; Coupled; Data; Dyes; Enrollment; Epithelial Cells; Excision; Exhibits; Face; Failure; Feasibility Studies; Free Radicals; Future; Genotype; Grant; HIV; HIV Seronegativity; HIV Seropositivity; HPV-High Risk; Health; Hela Cells; Histologic; Human Papillomavirus; Human papilloma virus infection; Incidence; Individual; Intervention; Interview; Investigation; Iron; Kenya; Laboratories; Laboratory Finding; Lesion; Malaria; Malignant neoplasm of cervix uteri; Measures; Medical Research; Men' s Role; Methods; Normal Cell; Oncoproteins; Participant; Patient Self-Report; Pharmaceutical Preparations; Phase; Pilot Projects; Placebos; Population; Prevention strategy; Protocols documentation; Public Health; Randomized; Reaction; Recommendation; Recurrence; Research Institute; Risk; Safety; Secondary Cancer Prevention; Secondary Prevention; Self Administration; TFRC gene; Testing; Thermal Ablation Therapy; Topical application; Treatment Failure; Treatment outcome; Trypan Blue; Ultraviolet Rays; Vagina; Vulva; Woman; Work; World Health Organization; arm; artesunate; cancer cell; cervical cancer prevention; co-infection; cost effective; cytotoxic; cytotoxicity; efficacy study; efficacy trial; eligible participant; experience; follow-up; high risk population; improved; in vivo; innovation; low and middle-income countries; mortality; overexpression; oxidative damage; participant enrollment; phase I trial; premalignant; randomized placebo controlled trial; recruit; screening; uptake

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.

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负担， 子宫颈癌的死亡率占全球发病病例的85%和死亡率的90%。生活的妇女 艾滋病毒感染者（WLWH），其中大多数生活在中低收入国家，承受着最大的负担，风险增加了6倍 人乳头瘤病毒（HPV）感染是导致宫颈癌的主要原因。世界 世界卫生组织（WHO）建议使用消融或切除治疗疑似或确诊的 宫颈癌前病变的LMIC，在一个“筛选和治疗”的战略，以限制损失的后续行动。然而，在WLWH中， 两种治疗方法都有很高的失败率，30%的宫颈上皮内瘤变复发 (CIN2/3）热消融后2年。治疗失败率的部分原因是 WLWH中消融和切除治疗后的持续HPV感染。高治疗失败率是 WLWH中目前宫颈癌二级预防策略的重大局限性，并呼吁 研究可行、创新且可行的疗法，以提高HPV清除率并减少癌前病变 WLWH治疗失败。我将以正在进行的美国试验为基础，这些试验证明了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相关的肛门生殖器病变。我 拟议的研究将产生关于使用自我管理青蒿琥酯阴道的可行性的初步数据， 插入物作为热消融后的辅助治疗，以改善HPV+ WLWH患者的治疗结局 中低收入国家。我将利用我与卫生部支持的艾滋病毒诊所在西部的十多年合作， 肯尼亚，肯尼亚医学研究所（KEMRI），以及新的和建立的合作者进行这项工作 学习成功。在这份计划补助金中，我提议进行一项试验性、随机、安慰剂对照试验， 以下具体目的：1）评价自我施用青蒿琥酯阴道插入物的摄取和可接受性 作为LMIC中HPV+ WLWH热消融术后的辅助治疗，2）测试和评价三种方法 评估对自我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 青蒿琥酯组随机分组后6个月时特异性hrHPV清除率的初步比较 并匹配安慰剂组作为统计规划目标，以获得效应量，为未来的试验提供动力。本研究 将是第一个评估青蒿琥酯阴道插入物改善当前“筛查和治疗”的可行性的人。 在中低收入国家妇女和妇女健康中心实施宫颈癌预防战略。如果发现青蒿琥酯是可行和有效的， 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。