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 居住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 宫颈癌的死亡率占事件病例的85％，全球死亡率的90％。妇女生活 大多数生活在LMIC中的艾滋病毒（WLWH）拥有最大风险的最高6倍的Burnen 由于人乳头瘤病毒（HPV）感染的发病率和持久性而导致的宫颈癌。世界 卫生组织（WHO）建议使用消融或省份治疗进行可疑或确认 LMIC中的宫颈预科剂，在“屏幕和治疗”策略中，将损失限制为随访。但是，在wlwh中， 两种治疗方法均具有较高的衰竭率，宫颈上皮内肿瘤复发30％ （CIN2/3）热消融后两年。治疗失败率部分由高率驱动 在WLWH中消融和散布治疗后，持续的HPV感染。高治疗失败是 WLWH中当前宫颈癌二级预防策略的显着限制并要求 研究可行，创新但可访问的疗法，以提高HPV清除并减少预科剂 WLWH的治疗失败。我将建立正在进行的美国试验，以证明安全性和可能的​​效率 青蒿酯是青蒿素的半合成衍生物，用于治疗与HPV相关的肛门生殖器病变。我的 拟议的研究将生成有关使用自我管理的敏捷阴道的可行性的初步数据 在热消融后插入作为调整疗法的插入，以改善HPV+ WLWH的治疗结果 LMICS。我将利用我的十年以上与西方卫生支持的艾滋病毒诊所的合作 肯尼亚，肯尼亚医学研究所（Kemri）和新的和成熟的合作者来进行此事 成功学习。在这项计划赠款中，我提出了一个飞行员，随机，安慰剂对照试验，以调查 以下具体目的：1）评估自我管理的敏捷阴道插入物的摄取和可接受性 在LMIC中的HPV+ WLWH中进行热消融后的调整处理，2）测试并评估三种方法 评估遵守自我管理的敏捷以告知未来研究方案的依从性，3）执行 在青霉素中随机化后六个月时，特定类型的HRHPV清除率的初步比较 并匹配安慰剂武器作为统计计划，旨在获得效果大小，以便为以后的试验提供动力。这项研究 将是第一个评估敏捷的阴道插入物来改善当前“屏幕和治疗”的可行性的人 LMIC中WLWH中的宫颈癌预防策略。如果发现是可行和有效的，则是敏锐的， 该方法包括在WHO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 影响重大的全球公共卫生问题。