Acceptability and feasibility of combination treatment for cervical precancer among South Africa women living with HIV

摘要 癌症发病率、死亡率和贫富差距预计将以惊人的速度上升。它是 例如，据估计，到2030年，癌症每年将导致100万非洲人死于宫颈癌 占非洲女性癌症死亡人数最多的原因。全球根除宫颈癌的努力目前正在进行 重点是扩大HPV疫苗接种和宫颈癌筛查的机会。然而，这些努力缺乏 平等投资治疗宫颈上皮内瘤变前病变2/3级(CIN2/3)，特别是 在感染艾滋病毒的妇女中。这一差距使一代感染艾滋病毒的妇女面临着高风险 持续/复发的CIN2/3和进展为宫颈癌，因为CIN2/3的标准治疗(切除 或消融)在这一人群中效果要差得多。对艾滋病毒中CIN2/3的新的治疗方法的需要- 因此，受感染的妇女人数很多。我们建议的中心假设是外用5-氟尿嘧啶 (5FU)，一种广泛获得的低成本仿制药，可以重新用于患者控制的辅助治疗 对于手术切除后的CIN2/3，以降低持续/复发CIN2/3和进展到宫颈的风险 艾滋病毒感染妇女中的癌症。我们的首要目标是在美国功效研究的基础上，测试 CIN2/3联合治疗的可接受性和可行性(即手术切除后自我治疗 在低资源环境中应用佐剂5FU)。首先，我们将探讨南非对当前 宫颈癌预防策略，找出当地联合治疗的障碍和促进者 背景。我们将通过一系列焦点小组和对不同群体的深入采访来实现这一目标 利益攸关方(感染艾滋病毒的妇女、男性伴侣、卫生保健人员)。第二，并由我们的 形成研究，我们将进行联合治疗策略的可行性试验，以确定安全性， 耐受性、坚持性和保持性。我们将随机选择180名患有CIN2/3的HIV感染女性，她们将接受 环切(LEEP)后自我应用5FU与安慰剂(8剂，每2周一次)。女性将会成为 随访24周。第三，更好地了解联合治疗对艾滋病毒感染者的免疫反应 女性，我们将评估与手术相关的生殖器HIV-1脱落和局部免疫激活的变化 切除后5FU/安慰剂。我们的研究将在南非进行，那里有400多万女性 都是艾滋病毒携带者，妇女患宫颈癌的终身风险是世界上最高的之一。如果成功， 我们的发现将对资源丰富和资源贫乏地区的艾滋病毒感染妇女具有广泛的相关性 全球，包括美国农村和偏远地区。

ABSTRACT Cancer incidence, mortality, and disparities between rich and poor are projected to rise at staggering rates. It is estimated, for example, that cancer will kill one million Africans each year by 2030, with cervical cancer accounting for the most cancer deaths in African women. Global efforts to eliminate cervical cancer are currently focused on expanding access to HPV vaccination and cervical cancer screening. However, these efforts lack equal investment in treatment of precancerous cervical intraepithelial neoplasia grade 2/3 (CIN2/3), particularly among HIV-infected women. This gap leaves a generation of HIV-infected women at high risk of persistent/recurrent CIN2/3 and progression to cervical cancer because standard treatment for CIN2/3 (excision or ablation) is far less effective in this population. The need for novel treatment approaches for CIN2/3 in HIV- infected women is therefore substantial. The central hypothesis of our proposal is that topical 5-fluorouracil (5FU), a widely available low-cost generic drug, can be repurposed as a patient-controlled, adjuvant treatment for CIN2/3 after surgical excision to reduce the risk of persistent/recurrent CIN2/3 and progression to cervical cancer among HIV-infected women. Our overarching goal is to build on U.S. efficacy studies and test the acceptability and feasibility of combination treatment for CIN2/3 (i.e., surgical excision followed by self- applied adjuvant 5FU) in a low-resource setting. First, we will explore South African perspectives on current cervical cancer prevention strategies and identify barriers to and facilitators of combination treatment in the local context. We will accomplish this through a series of focus groups and in-depth interviews with diverse stakeholders (HIV-infected women, male partners, healthcare personnel). Second, and informed by our formative research, we will conduct a feasibility trial of the combination treatment strategy to determine safety, tolerability, adherence, and retention. We will randomize 180 HIV-infected women with CIN2/3 who will undergo loop excision (LEEP) followed by self-apply 5FU versus placebo (8 doses, once every 2 weeks). Women will be followed for 24 weeks. Third, to better understand the immune response to combination treatment in HIV-infected women, we will assess changes in genital HIV-1 shedding and local immune activation associated with surgical excision followed by 5FU/placebo. Our study will be conducted in South Africa, where more than 4 million women are living with HIV and women’s lifetime risk of cervical cancer is among the highest in the world. If successful, our findings will have broad relevance for HIV-infected women in both resource-rich and resource-poor regions worldwide, including rural and remote areas of the U.S.