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。是 例如，据估计，到2030年，癌症每年将导致100万非洲人死亡，其中包括宫颈癌 是非洲女性癌症死亡的主要原因。目前，全球努力消除宫颈癌， 重点是扩大获得人乳头瘤病毒疫苗接种和宫颈癌筛查的机会。然而，这些努力缺乏 对2/3级宫颈上皮内瘤变（CIN 2/3）的治疗进行同等投资， 感染艾滋病毒的妇女。这一差距使一代感染艾滋病毒的妇女面临高风险， 持续性/复发性CIN 2/3和进展为宫颈癌，因为CIN 2/3的标准治疗（切除 或消融术）在这一人群中的效果要差得多。对HIV感染者CIN 2/3新型治疗方法的需求- 因此，受感染的妇女人数很多。我们建议的中心假设是局部5-氟尿嘧啶 (5FU)作为一种广泛使用的低成本仿制药， 对于手术切除后的CIN 2/3，以降低持续/复发CIN 2/3和进展至宫颈癌的风险 艾滋病毒感染妇女中的癌症。我们的首要目标是在美国疗效研究的基础上， CIN 2/3联合治疗的可接受性和可行性（即，手术切除后， 应用佐剂5 FU）。首先，我们将探讨南非对当前 宫颈癌预防策略，并确定当地联合治疗的障碍和促进因素 上下文我们将通过一系列焦点小组和深入采访不同的人来实现这一目标。 利益攸关方（感染艾滋病毒的妇女、男性伴侣、保健人员）。第二，根据我们的 形成性研究，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、依从性和保留性。我们将随机选择180名CIN 2/3的HIV感染女性， 环切除术（LEEP），然后自我应用5 FU与安慰剂（8剂，每2周一次）。妇女将被 随访24周。第三，为了更好地了解艾滋病毒感染者对联合治疗的免疫反应， 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，然后是5 FU/安慰剂。我们的研究将在南非进行，那里有400多万妇女， 妇女感染艾滋病毒的风险是世界上最高的，妇女一生中患宫颈癌的风险是世界上最高的。如果成功， 我们的研究结果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 包括美国的农村和偏远地区。

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.