Einstein/Rwanda/DRC Consortium for Research in HIV/HPV Malignancies

摘要： 宫颈癌是全球第四大常见癌症和女性癌症相关死亡原因; 在许多资源较少的地区，特别是撒哈拉以南非洲（SSA），这是最常见的。几乎所有 宫颈癌和癌前病变是由高危型人乳头瘤病毒（hrHPV）引起的。HPV 16引起~55- 60%和HPV 18引起约10-15%的宫颈癌，而其余的约12种HPV类型引起其余的宫颈癌。 25-30%的宫颈癌。hrHPV，主要是HPV 16，也引起大多数肛门，外阴，阴道和阴茎 癌症和相当大比例的口咽癌。预防性HPV疫苗已被 已被证明对偶发感染和相关异常有近100%的保护作用 针对一般人群中的目标HPV类型。然而，有效性的证据 预防性HPV疫苗在感染人类免疫缺陷病毒（HIV）（WLWH）的妇女中的作用尚不清楚。 HIV感染会增加宫颈癌的风险，因为对HPV的免疫反应受损。 2011年，卢旺达是东非宫颈癌高负担国家，艾滋病毒流行率为100%。 3.3%的成年女性实施了国家HPV疫苗接种计划，其中Gardasil®可保护 针对HPV 16和HPV 18，这两种HPV类型导致约70%的宫颈癌，以及HPV 6和HPV 11， 这两种类型导致约90%的肛门生殖器疣（HPV 6/11/16/18）。他们的计划实现了>90% 每年覆盖目标人口，主要是12岁的女孩。实施一个高度 成功的HPV疫苗接种计划和艾滋病毒的高流行率，除了研究和医疗 阿尔伯特·爱因斯坦医学院（爱因斯坦）帮助卢旺达军事医院建立的能力 (RMH)和卢旺达大学（UR），使卢旺达成为研究HPV长期影响的理想场所 在WLWH接种疫苗。 为了回答有关卢旺达WLWH HPV疫苗有效性和免疫力的问题，合作者 在爱因斯坦，RMH和UR将对WLWH和HIV阴性（HIV[-]）妇女进行观察性研究， WLWH没有接受HPV疫苗接种（1997年及以后的出生队列），WLWH没有接受HPV疫苗接种（1997年以前的出生队列）。我们 将比较757例宫颈、肛门和口腔的HPV 6/11/16/18流行和6个月持续感染， HPV疫苗接种的WLWH与757名未接种疫苗的WLWH相比。我们还将比较HPV免疫 548名接种HPV疫苗的WLWH对548名接种HPV疫苗的HIV[-]妇女的反应以及转换的影响 从2015年的3剂加德西增加到2剂我们还将验证一种低成本、简单的即时检测方法， HPV 16抗体作为验证/确定HPV疫苗接种状态的方法。最后，我们将调查风险 包括宫颈阴道微生物组在内的因素，导致WLWH中HPV持续存在。我们的长期目标是 建立一个WLWH队列，我们可以在其中检查HPV疫苗接种的长期有效性， WLWH现在和未来。这一贡献是重要的，因为它将确定人口的有效性， HPV疫苗接种的WLWH生活在SSA，妇女在宫颈癌的风险最高， 缺乏证据。拟议的研究是创新的，因为它利用和扩大了当地的研究， 卢旺达的医疗能力，以研究关于HPV疫苗的一个关键的未回答的问题， 在世界卫生组织呼吁全球控制子宫颈癌的背景下，

Abstract: Cervical cancer is the 4th most common cancer and cause of cancer-related death in women globally; in many lower-resource settings, especially sub-Saharan Africa (SSA), it is the most common. Virtually all cervical cancer and precancer are caused by high-risk human papillomavirus (hrHPV). HPV16 causes ~55- 60% and HPV18 causes ~10-15% of cervical cancer while the remaining ~12 HPV types cause the remaining 25-30% of cervical cancer. hrHPV, predominately HPV16, also causes most anal, vulvar, vaginal, and penile cancers and a significant proportion of oropharyngeal cancers. Prophylactic HPV vaccines have been developed and have shown to be nearly 100% protective against incident infection and related abnormalities against the target HPV types in the general population. However, the evidence for the effectiveness of prophylactic HPV vaccines in women living with human immunodeficiency virus (HIV) (WLWH) is less clear. HIV infection increases the risk of cervical cancer due to an impaired immune response to HPV. In 2011, Rwanda, a high-burden cervical cancer country in East Africa that has an HIV prevalence in adult women of 3.3%, implemented a national HPV vaccination program with Gardasil®, which protects against HPV16 and HPV18, the two HPV types that cause ~70% of cervical cancer, and HPV6 and HPV11, the two types that cause ~90% of anogenital warts (HPV6/11/16/18). Their program has achieved >90% coverage of the target population, primarily girls aged 12 years, annually. The implementation of a highly successful HPV vaccination program and the high prevalence of HIV, in addition to the research and medical capacity that Albert Einstein College of Medicine (Einstein) has helped to build at the Rwanda Military Hospital (RMH) and University of Rwanda (UR), makes Rwanda the ideal locale to study the long-term effects of HPV vaccination in WLWH. To answer questions about HPV vaccine effectiveness and immunity in Rwanda WLWH, collaborators at Einstein, RMH, and UR will conduct an observational study of WLWH and HIV-negative (HIV[-]) women who did (birth cohorts 1997 and later) and WLWH did not receive HPV vaccination (birth cohorts before 1997). We will compare the cervical, anal, and oral prevalent and 6-month persistent HPV6/11/16/18 infections in 757 HPV-vaccinated WLWH to those in 757 unvaccinated WLWH. We will also compare the HPV immune response in 548 HPV-vaccinated WLWH to 548 HPV-vaccinated HIV[-] women and the impact of switching from 3 doses to 2 doses of Gardasil in 2015. We also will validate a low-cost, simple point-of-care test for HPV16 antibodies as method to verify/determine HPV vaccination status. Finally, we will investigate the risk factors, including the cervicovaginal microbiome, for HPV persistence in WLWH. Our (long-term) goal is to establish a cohort of WLWH in whom we can examine the long-term effectiveness of HPV vaccination in WLWH now and in the future. This contribution is significant as it will establish the population effectiveness of HPV vaccination in WLWH living in SSA, the women at the highest risk of cervical cancer, for which there is a dearth of evidence. The proposed research is innovative as it leverages and expands the local research and medical capacity in Rwanda to examine one of the critically unanswered questions about HPV vaccine effectiveness in the context of the World Health Organization call for the global control of cervical cancer.