Project 1: Urine sampling for HPV infection and methylation testing for cervical cancer screening among women living with HIV in Malawi and South Africa

摘要：项目1：HPV感染尿样和宫颈癌甲基化检测 马拉维和南非艾滋病毒携带者妇女的筛查 癌症发病率、死亡率和差异预计将以惊人的速度上升。据估计， 例如，到2030年，癌症每年将导致100万非洲人死亡，并患有浸润性宫颈癌(ICC) 占非洲女性癌症死亡人数最多的原因。尽管全球政策寻求迅速扩张 在未来十年获得人类乳头瘤病毒(HPV)疫苗接种和宫颈癌筛查， 在低收入和中等收入国家消除宫颈癌的实际努力仍然有限。这 GAP使几代妇女面临不必要的ICC风险，尤其是艾滋病毒阳性(HIV+)妇女 很脆弱。需要具有成本效益和可扩展的筛查和治疗战略，以减少ICC 因此，这是非常重要的。还迫切需要直接适用于艾滋病毒+妇女的高质量证据。 LMIC，面临最高的HPV感染风险、宫颈癌前病变(CIN2/3)和ICC。 我们建议的中心假设是，使用自我收集的样本来检测HPV感染 在不进行盆腔检查的临床环境中增加宫颈筛查覆盖率的潜力 例行公事。我们将在接受宫颈治疗的HIV+女性中验证尿液HPV检测 在马拉维和南非的两个强大的研究地点筛查诊所。因为主要的HPV筛查是 高度敏感但仅对CIN2/3和ICC中等特异性，我们还将验证一种新的S5甲基化 对HPV筛查呈阳性的妇女进行分流测试。 在目标1中，我们将招募925名艾滋病毒阳性妇女，并评估自己收集的尿液中高危HPV检测 宫颈阴道和提供者采集的宫颈样本用于检测CIN2/3和ICC(CIN2+)。我们会 报告3种样本中的HPV阳性，并比较其敏感性、特异性以及阳性和阴性 样本类型之间CIN2+检测的预测值(PPV和NPV)。在目标2中，我们将评估S5 甲基化作为HPV阳性的HIV阳性妇女的分诊检测。对于每种样本采集方法 (尿液、自身和提供者)，我们将计算CIN2+的PPV、NPV、灵敏度和特异度。 我们还将报告在使用和不使用S5分流的情况下，每个CIN2+病例检测到的阴道镜转诊数量。 我们提议的项目将是第一个在HIV阳性妇女中验证尿液HPV检测的项目，也是第一个 使用尿液、自身和提供者收集的样本比较S5分流测试的临床性能 LMIC设置。如果成功，我们的发现将对艾滋病毒+女性在资源丰富和 全球资源贫乏地区，包括美国农村和偏远地区。

ABSTRACT: PROJECT 1: Urine sampling for HPV infection and methylation testing for cervical cancer screening among women living with HIV in Malawi and South Africa Cancer incidence, mortality, and disparities are projected to rise at staggering rates. It is estimated, for example, that cancer will kill one million Africans each year by 2030, with invasive cervical cancer (ICC) accounting for the most cancer deaths in African women. Although global policy seeks to rapidly expand access to human papillomavirus (HPV) vaccination and cervical cancer screening in the coming decade, practical efforts to eliminate cervical cancer in low- and middle-income countries (LMICs) remain limited. This gap leaves generations of women needlessly at risk for ICC, with HIV-positive (HIV+) women particularly vulnerable. The need for cost-effective and scalable screening and treatment strategies to reduce ICC is therefore substantial. There is also an urgent need for quality evidence directly applicable to HIV+ women in LMICs, who face the highest risk of HPV infection, cervical precancer (CIN2/3), and ICC. The central hypothesis of our proposal is that the use of self-collected samples to test for HPV infection has the potential to increase cervical screening coverage in clinical settings where pelvic examinations are not routinely performed. We will validate urine-based HPV testing among HIV+ women attending cervical screening clinics at two strong research sites in Malawi and South Africa. As primary HPV screening is highly sensitive but only moderately specific for CIN2/3 and ICC, we will also validate a novel S5 methylation test for triage of women who screen positive for HPV. In Aim 1, we will enroll 925 HIV+ women and evaluate high-risk HPV testing in urine, self-collected cervicovaginal, and provider-collected cervical samples for the detection of CIN2/3 and ICC (CIN2+). We will report HPV positivity in the 3 sample types and compare the sensitivity, specificity, and positive and negative predictive values (PPV and NPV) for CIN2+ detection between the sample types. In Aim 2, we will evaluate S5 methylation as a triage test for HIV+ women with HPV positive results. For each sample collection method (urine, self, and provider), we will calculate PPV, NPV, sensitivity, and specificity of S5 triage testing for CIN2+. We will also report the number of colposcopy referrals per CIN2+ case detected with and without S5 triage. Our proposed project will be the first to validate urine-based HPV testing among HIV+ women and the first to compare the clinical performance of S5 triage testing using urine, self, and provider-collected samples in an LMIC setting. If successful, our findings will have broad relevance for HIV+ women in both resource-rich and resource-poor regions worldwide, including rural and remote areas of the U.S.