Randomised trial of HPV vaccination for the control of HPV-related diseases in HIV-positive African populations: Preparatory phase (PH01/14-39)

针对高危致癌人类乳头瘤病毒（HPV）的二价、四价和非价疫苗的开发和推广为控制并可能根除非洲女性人群中发病率最高的癌症提供了巨大的机会。目前，建议在性经验不足的妇女中使用人乳头瘤病毒疫苗，通常是14岁或以下的年轻女孩，使大量女性人口得不到保护，并面临患宫颈癌和其他人乳头瘤病毒相关疾病（生殖器疣、其他生殖器和口咽癌）的风险，在资源贫乏的环境中，很少有负担得起和可实施的筛查选择。人乳头瘤病毒疫苗对其目标类型提供高度保护，对其他基因型具有一定的交叉保护，但假设如果受试者被一种疫苗类型感染，则不会提供保护。艾滋病毒阳性妇女感染和持续感染HPV的风险增加，从而导致宫颈癌和其他生殖器疾病的发展。我们进行了一项研究（称为HARP），评估了南非（SA）和布基纳法索（BF） 1200名艾滋病毒阳性妇女的宫颈癌筛查策略的表现，其中包括HPV筛查。我们发现宫颈癌前病变（SA占20%，BF占5%）和高危HPV感染（SA占70%，BF占55%）的负担很大。我们记录了单独的HPV检测或结合细胞学检测这些病变的良好表现。我们希望在这一丰富的数据源基础上，通过开发临床试验平台来成功实施这项研究，以开发HARP的下一阶段，该阶段将以通过筛查和疫苗接种控制HPV的作用为中心。我们建议在HIV阳性妇女中进行HPV疫苗接种的随机试验，以预防宫颈癌病变。目前还没有关于HPV疫苗在HIV阳性女性中的有效性的数据，尽管一些试验已经显示了二价HPV疫苗在HIV阳性人群中的安全性和免疫原性，包括在SA女性中的一项试验。南非政府最近宣布在全国范围内引入HPV疫苗接种，这为探索HPV疫苗接种在不同亚群体中的作用提供了机会。在准备疫苗试验的过程中，拟议的研究将评估纳入HPV筛查规划的HPV疫苗接种在降低目标人群中HPV相关感染和疾病（CIN，无生殖器疣）发生率方面的潜在有效性和成本效益。它将根据艾滋病毒相关因素（血浆病毒载量/CD4计数/抗逆转录病毒治疗状态）和HPV相关因素（当前感染由生殖道中存在HPV确定，或先前暴露由HPV血清学确定）对各种试验结果（组织学，细胞学和病毒学）调查疫苗接种的反应。最后，它将调查这种试验的潜在可接受性。具体而言，PHINDS提案将通过以下方式为南非HIV+妇女中HPV疫苗研究的发展提供信息：1)估计在基于HPV检测（HARP研究）的宫颈癌筛查计划中招募的HIV+妇女中进行疫苗接种研究的潜在影响和所需样本量。将采用统计和建模方法，使用HARP和另一个基于约翰内斯堡的研究数据集。2)通过结合HPV基因分型（已完成）和类型特异性HPV血清学（待完成）的结果，评估研究人群对HPV疫苗类型的真实暴露。3)评估目标人群、服务提供者和其他国家利益相关者接种HPV疫苗的可行性、可接受性和成本。4)建立一个研究网络，通过最近在约翰内斯堡威特沃特斯兰德大学设立的美国国立卫生研究院临床试验单位来实施这项研究

The development & rollout of bivalent, quadrivalent and nonavalent vaccines against high-risk oncogenic human papillomavirus (HPV) affords a tremendous opportunity to control and possibly eradicate the cancer with the highest incidence among female populations in Africa. Currently, HPV vaccines are recommended for use among sexually unexperienced women, typically young girls aged 14 years or younger, leaving a huge female population unprotected and at risk of developing cervical cancer and other HPV related diseases (genital warts, other genital & oropharyngeal cancers), for which few affordable and implementable screening options are available in resource-poor settings. The HPV vaccines afford high protection against the types they target, with some element of cross-protection against other genotypes, but it is assumed that no protection is offered if subjects have been infected by a vaccine type.HIV+ women are at increased risk of acquisition and persistence of HPV leading on to the development of cervical cancer and other genital disease. We have conducted a study (called HARP) evaluating the performance of cervical cancer screening strategies among 1200 HIV+ women in South Africa (SA) and Burkina Faso (BF), which included HPV screening. We have found a huge burden of cervical precancer lesions (20% in SA, 5% on BF) and of high-risk HPV infection (>70% in SA, 55% in BF). We have recorded a good performance of HPV testing alone or in combination with cytology to detect these lesions. We would like to build upon this rich data source and the successful implementation of this study through the development of a clinical trial platform to develop the next phase of HARP, which will centre on the role of HPV control through screening and vaccination. We propose to develop a proposal for a randomised trial of HPV vaccination among HIV+ women to prevent cervical cancer lesions. There is currently no data on the efficacy of an HPV vaccine among HIV+ women, although a few trials have shown the safety and immunogenicity of the bivalent HPV vaccine in HIV+ populations, including one trial among SA women. The recent announcement by the SA government of the introduction of HPV vaccination countrywide offers the opportunity to explore the role of HPV vaccination in various sub groups.The proposed study, in preparation of the vaccine trial, will assess the potential effectiveness and cost-effectiveness of HPV vaccination embedded in an HPV screening programme in reducing the incidence of HPV-related infection and disease (CIN, ano-genital warts) in the target populations. It will investigate the response to vaccination depending on HIV related factors (plasma viral load/CD4 count/antiretroviral therapy status) and HPV related factors (current infection as determined by presence of HPV in the genital tract, or prior exposure as determined by HPV serology) on various trial outcomes (histological, cytological and virological). Finally, it will investigate the potential acceptability of such trial.Specifically, the PHINDS proposal will inform the development of an HPV vaccine study among HIV+ women in SA by:1) Estimating the potential impact and sample size required for a vaccination study among HIV+ women recruited within a cervical cancer screening programme based on HPV testing (HARP study). Statistical & modelling methodology will be employed, using HARP & another Johannesburg based study datasets.2) Evaluating the true exposure of the study population to HPV vaccine types by combining results of HPV genotyping (already done) & type-specific HPV serology (to be done).3) Evaluating the feasibility, acceptability & costs of HPV vaccination in the target population, service providers & other national stakeholders.4) Setting up a research network to implement the study through the recently awarded NIH Clinical Trials Unit at University of Witwatersrand, Johannesburg