RepurPosed AntiretrOviraL ThErapieS to EliminAte Cervical Cancer (POLESA Trial)

项目总结/摘要 随着宫颈癌死亡人数继续上升，特别是在资源匮乏的环境中，我们 正在寻找更有效的预防宫颈癌的方法。在没有 细胞学和HPV为基础的宫颈癌筛查，专家们赞同筛查的 应用醋酸（VIA）后通过目视检查宫颈，以突出癌前病变或 癌症异常如果识别出的乙酰白图案被感知为异常， 子宫颈上皮通过冷冻（冷冻疗法）或加热（热消融）消融， "看和治疗"的方法或切除与大环切除的转化区（LLETZ）。 这种宫颈癌筛查和治疗方法已被广泛采用， 中等收入国家（LMIC），特别是撒哈拉以南非洲（SSA）， 世界上最高的宫颈癌发病率。我们的团队进行了一项最大的随机 在SSA进行的对照试验比较了这些治疗方法。我们的初步 结果表明，这些治疗方法对感染艾滋病毒的妇女的有效性降低了近50 （WLWH）。这些研究结果表明，消除宫颈癌作为一个重要的公众 健康疾病需要采取和实施易于获得的战略， 价格合理，可接受，在WLWH中同样有效。一种潜在的治疗剂， 需要进一步研究的是含有蛋白酶抑制剂（PI）的阴道胶囊 洛匹那韦和利托那韦（LPV/r），具有已知的抗癌和HPV活性。总目标 这项试验的目的是寻找新的、非侵入性的、易于扩展的解决方案， 二次预防宫颈癌，特别是在WLWH中。本研究的主要目的是 评估LPV/r阴道胶囊单独或联合给药的安全性和可接受性 采用热消融治疗符合消融治疗条件的VIA阳性女性。我们将 在宫颈癌预防中心招募了180名接受宫颈癌筛查的妇女 在赞比亚的诊所。受试者（n = 180）将根据HIV状态进行分层， 随机接受1）LPV/r或安慰剂治疗3周，然后在4周时进行热消融 或2）LPV/r或安慰剂单药治疗3周，6个月时重复VIA， 持续性VIA阳性宫颈病变者。180名VIA阳性妇女中有20人将 随机分配至常规治疗的对照队列，如果合格，立即进行TA。预期 这项工作的结果是产生的证据表明，这种新的LPV/r治疗是安全的， 可用于筛选VIA阳性女性的治疗或辅助治疗。结果从这个 这项研究将为在SSA队列中进行LPV/r的大规模研究奠定基础。

Project Summary/Abstract As the death toll from cervical cancer continues to rise, particularly in low-resource settings, we are in search of more effective approaches to cervical cancer prevention. In the absence of cytology- and HPV-based cervical cancer screening, experts have endorsed screening of the cervix by visual inspection after application of acetic acid (VIA) to highlight precancerous or cancerous abnormalities. If the recognized acetowhite pattern is perceived to be abnormal, the cervical epithelium is either ablated by freezing (cryotherapy) or heating (thermal ablation) in a “see and treat” approach or excised with a large loop excision of the transformation zone (LLETZ). This approach to cervical cancer screening and treatment has been widely adopted in low- and middle-income countries (LMICs), notably in sub-Saharan Africa (SSA), which has some of the world’s highest rates of cervical cancer. Our team conducted one of the largest randomized controlled trials ever conducted in SSA comparing these treatment approaches. Our preliminary results suggest that these treatments are almost 50% less effective for women living with HIV (WLWH). As evidenced by these findings, the elimination of cervical cancer as a significant public health disease requires the adoption and implementation of strategies that are easily accessible, affordable, acceptable and are equally efficacious in WLWH. One potential therapeutic agent that warrants further investigation is a vaginal capsule containing the protease inhibitors (PIs) Lopinavir and Ritonavir (LPV/r), which have known anti-cancer and HPV activity. The overall goal of this trial is to find new, non-invasive, easily scalable solutions that address the profound gap in secondary cervical cancer prevention, particularly among WLWH. The central aim of this study is to assess the safety and acceptability of the LPV/r vaginal capsule given alone or in combination with thermal ablation to treat VIA positive women who are eligible for ablative therapy. We will enroll 180 women who present for cervical cancer screening in a Cervical Cancer Prevention Program clinic in Zambia. Participants (n=180) will be stratified based on HIV status and randomized to receive 1) LPV/r or placebo for 3 weeks followed by thermal ablation at 4 weeks or 2) LPV/r or placebo alone for 3 weeks with repeat VIA at 6 months and thermal ablation for those with persistent VIA positive cervical lesions. Twenty of the 180 VIA positive women will be randomized to a comparator cohort of usual care with immediate TA if eligible. The expected outcome of this work is the generation of evidence that this novel LPV/r treatment is safe and acceptable for use as treatment or adjunct in women who screen VIA positive. Results from this study will lay the groundwork for a large-scale study of LPV/r in a SSA cohort.