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：宫颈癌的HPV感染和甲基化检测的尿液采样 在马拉维和南非对感染艾滋病毒的妇女进行筛查 预计癌症发病率、死亡率和差距将以惊人的速度上升。据估计，由于 例如，到2030年，这种癌症每年将导致100万非洲人死亡，其中包括浸润性宫颈癌（ICC） 是非洲女性癌症死亡的主要原因。尽管全球政策寻求迅速扩大 在未来十年获得人乳头瘤病毒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 这一差距使几代妇女不必要地面临ICC的风险，特别是艾滋病毒阳性（HIV+）妇女 脆弱需要具有成本效益和可扩展的筛查和治疗策略，以减少ICC， 因此是实质性的。还迫切需要直接适用于艾滋病毒阳性妇女的高质量证据， LMIC，他们面临HPV感染，宫颈癌前病变（CIN 2/3）和ICC的最高风险。 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子宫颈筛查覆盖率的潜力 常规执行。我们将在接受宫颈检查的HIV阳性妇女中验证基于尿液的HPV检测 在马拉维和南非的两个强有力的研究基地进行筛查诊所。HPV初筛是 高度敏感，但只有中等特异性的CIN 2/3和ICC，我们也将验证一个新的S5甲基化 测试谁筛选HPV阳性的妇女分流。 在目标1中，我们将招募925名HIV+女性，并评估自我收集的尿液中的高危HPV检测。 宫颈阴道和提供者收集的宫颈样本用于检测CIN 2/3和ICC（CIN 2+）。我们将 报告3种样本类型的HPV阳性，并比较敏感性、特异性和阳性与阴性 样本类型之间CIN 2+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阳性结果的HIV+女性的分诊测试。对于每种样品采集方法 （尿液、自身和提供者），我们将计算PPV、NPV、灵敏度和特异性S5分类检测CIN 2+。 我们还将报告每例CIN 2+病例的阴道镜转诊数量，包括S5分诊和未分诊的情况。 我们提出的项目将是第一个在HIV+妇女中验证尿液HPV检测的项目，也是第一个 比较使用尿液、自身和提供者收集的样本进行S5分诊检测的临床性能， LMIC设置。如果成功，我们的研究结果将对资源丰富和 全球资源贫乏的地区，包括美国的农村和偏远地区。

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.