Real-world effectiveness of HPV vaccine in women living with HIV and its impact on cervical cancer screening accuracies

项目摘要/摘要 世界卫生组织制定了通过全球接种HPV疫苗消除宫颈癌(CC)的目标 和宫颈癌筛查(CCS)。不幸的是，现实世界中的HPV疫苗既没有效果也没有效率 已经为感染艾滋病毒(WWH)的妇女建立了CCS，她们受到CC的影响不成比例。我们的 小组报告称，接种HPV疫苗的年轻女性围产期感染艾滋病毒(WWPHIV)的比例很高 与HIV[-]妇女相比，宫颈细胞学异常的比率表明疫苗有效性降低。 而用于筛查的一次HPV检测(PHS)和分流测试是CCS在 在美国的普通人群中，疾控中心不建议将其用于WWH，因为缺乏科学的 支持。我们小组最近的一项研究表明，在WWH中进行16/18分型的PHS减少了 在不降低敏感性的情况下将不必要的镜检查减半(与HPV/细胞学联合检测相比)；然而，阳性 预测价值仍然较低。此外，最近FDA批准的双重免疫细胞化学染色 P16/Ki67以及使用扩展HPV基因分型和DNA甲基化的新型生物标记物显示出巨大的前景 但在WWH上的研究还远远不够。我们有一个特殊的机会来检查两种HPV疫苗 与儿童HIV/AIDS队列合作在WWH中的有效性和PHS筛查分流策略 部分由我们的调查团队领导的研究(PHACS)。PHAC包括超过2400 WWH的队列，包括 WWPHIV和WWH，水平感染(WWHH)，他们与他们接触艾滋病毒的孩子一起登记。我们 据估计，90%的WWPHIV感染者和50%的41岁妇女至少感染过一种HPV 剂量。在WWH中，我们的目标是：1)检查由3年定义的HPV疫苗的有效性 I)疫苗接种的累积风险--持续12个月或更长时间的HPV类型，以及ii)组织学(H)宫颈 上皮内瘤变(CIN)-2+；2a)检测并比较敏感性(Se)、特异性(Sp)、阳性(PPV) 和阴性预测值(NPV)，以检测hCIN-2+立即或3年后在PHS[+]妇女使用4 反射策略：(I)细胞学，(Ii)HPV扩展基因分型，(Iii)p16/ki-67双重染色细胞学，(Iv) HPV/宿主甲基化水平；2b)检查自收集的PHS[+}样本中的Se、Sp、PPV和NPV HCIN2+检测侧重于甲基化和HPV基因分型分型测试，因为这两种测试适用于 自己采集的样本。我们计划使用自采样工具包筛选约810个WWH--现在是一种被广泛接受的模式 筛查--PHS检测(罗氏眼镜蛇)和那些PHS[+](~570)将参加临床访问的人 阴道镜/活检和4项分诊试验。WWH和&lt；CIN 2+被要求每年回来做阴道镜检查和 HPV基因分型时间长达3年。存在含Cin2+的WWH。WWH PHS[-]将被要求在第二年返回 重新筛选。这些PHS[+]将如上所述，PHS[-]将被要求获得自收集的阴道 连续3年每年采集标本进行HPV基因分型。冲击力。了解HPV疫苗的有效性和 WHH的最佳CCS战略将为减轻全球CC的负担做出重大贡献。

PROJECT SUMMARY/ABSTRACT The World Health Organization has set goals for cervical cancer (CC) elimination through global HPV vaccination and cervical cancer screening (CCS). Unfortunately, neither real-world HPV vaccine effectiveness nor efficient CCS have been established for women living with HIV (WWH) who are disproportionately affected by CC. Our group reported that HPV-vaccinated young women living with perinatal HIV infection (WWPHIV) had very high rates of abnormal cervical cytologic compared with HIV [-] women suggesting reduced vaccine effectiveness. While primary HPV testing used for screening (PHS) with a triage test is the preferred method for CCS in the general population in the U.S., the CDC has not recommended it for WWH because of the lack of scientific support. A recent study by our group showed that PHS with triage 16/18 genotyping in WWH cut the number of unnecessary colposcopies in half without reducing sensitivity (vs HPV/cytology co-testing); however, the positive predictive value remained low. Furthermore, the recently FDA-approved dual immunocytochemistry staining for p16/ki67 as well as novel biomarkers using extended HPV genotyping and DNA methylation show great promise but are vastly understudied in WWH. We have an exceptional opportunity to examine both HPV vaccine effectiveness and PHS screening triage strategies in WWH by partnering with the Pediatric HIV/AIDS Cohort Study (PHACS) led, in part, by our investigative team. PHACS includes a cohort of over 2400 WWH, including WWPHIV and WWH, horizontally (WWHH) infected, who are enrolled along with their HIV exposed children. We estimated that 90% of the WWPHIV and 50% of the WWHH <41 years of age have received at least one HPV dose. Among WWH, we aim to: 1) examine the effectiveness of the HPV vaccine defined by the 3-year cumulative risk of i) vaccine-HPV types that persist 12 months or longer and, ii) histologic (h) cervical intraepithelial neoplasia (CIN)-2+; 2a) examine and compare the sensitivity (Se), specificity (Sp), positive (PPV) and negative predictive values (NPV) to detect hCIN-2+ immediately or in 3 years in PHS[+] women using 4 reflex strategies: (i) cytology, (ii) HPV extended genotyping, (iii) p16/Ki-67 dual staining cytology, and (iv) HPV/host methylation levels; 2b) examine the Se, Sp, PPV, and NPV in self-collected PHS[+} samples for hCIN2+ detection focusing on methylation and HPV genotyping triage tests since these 2 tests are suitable for self-collected samples. We plan to screen ~810 WWH using a self-sampling kit--now a well-accepted mode for screening-- for PHS testing (Roche Cobas) and those who PHS[+] (~570) will attend a clinical visit to have colposcopy/biopsy and the 4 triage tests. WWH with <CIN 2+ are asked to return annually for colposcopy and HPV genotyping for up to 3 yrs. WWH with CIN 2+ are exited. WWH PHS[-] will be asked to return in Year 2 for rescreening. Those PHS[+] will be followed as above and PHS[-] will be asked to obtain self-collected vaginal samples for HPV genotyping annually for 3 years. Impact. Understanding HPV vaccine effectiveness and optimal CCS strategies in WHH will make a significant contribution to decreasing the worldwide burden of CC.