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.

抽象的 生活在低收入和中等收入国家 (LMIC) 的妇女面临着不成比例的发病率和负担 宫颈癌死亡率占全球发病病例的 85% 和死亡率的 90%。女性生活 HIV 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，风险增加多达 6 倍 由于人乳头瘤病毒（HPV）感染的较高发病率和持续性，宫颈癌的发病率较高。世界 卫生组织（WHO）建议对疑似或确诊病例采用消融或切除治疗 中低收入国家的宫颈癌前病变，采用“筛查和治疗”策略，以限制随访损失。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高达 30% (CIN2/3) 热消融后两年。治疗失败率的部分原因是治疗失败率高 WLWH 消融和切除治疗后持续 HPV 感染。治疗失败率较高 当前 WLWH 中宫颈癌二级预防策略存在重大局限性，并呼吁 研究可行、创新且易于使用的疗法，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，证明安全性和可能的​​功效 青蒿琥酯，一种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 插入作为热消融后的辅助治疗，以改善 HPV+ WLWH 的治疗结果 中低收入国家。我将利用与卫生部支持的西部艾滋病毒诊所十多年的合作 肯尼亚、肯尼亚医学研究所 (KEMRI) 以及新老合作者开展此项研究 学习成功。在这项规划拨款中，我提出了一项试点、随机、安慰剂对照试验来调查 以下具体目标： 1) 评估自我给药青蒿琥酯阴道塞剂的吸收和可接受性 作为 LMIC 中 HPV+ WLWH 热消融后的辅助治疗，2) 测试和评估三种方法 评估自我给药青蒿琥酯的依从性，为未来的研究方案提供信息，以及 3) 进行 青蒿琥酯随机分组后 6 个月时类型特异性 hrHPV 清除率的初步比较 并匹配安慰剂组作为统计规划，旨在获得效应大小，为未来的试验提供动力。这项研究 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”可行性的人 中低收入国家 WLWH 的宫颈癌预防策略。如果发现可行且有效，青蒿琥酯， 它被列入世界卫生组织的基本药物清单，可以在这种高度可扩展的方法中重新利用 影响重大的全球公共卫生问题。