Congenital CMV infection in the era of Option B in South Africa

 描述(申请人提供)：先天性巨细胞病毒感染(CCMV)是世界上最常见的先天性感染，也是导致感音神经性听力损失的主要非遗传原因。CCMV的出生流行率与母亲CMV血清阳性水平成正比，在高血清阳性人群中观察到的发病率显著更高。在非洲人口中观察到CCMV感染率的增加，有证据表明，艾滋病毒等孕产妇共同感染在这些国家作为CCMV的驱动因素发挥了关键作用。尽管撒哈拉以南非洲的艾滋病毒感染负担很重，但尚未系统地评估产妇艾滋病毒对巨细胞病毒宫内传播、出生时症状感染和长期后遗症的影响。我们最近对南非西开普省HIV感染的新生儿进行了首次CCMV出生流行率的研究，发现在产前抗逆转录病毒预防的时代，CCMV的发生率很高(2.93%；95%可信区间1.73-4.13)。婴儿巨细胞病毒感染广泛与艾滋病毒疾病进展和死亡风险增加有关，并对感染艾滋病毒但未受感染的赞比亚婴儿的生长、发育和总体发病率产生不利影响。这些发现表明，巨细胞病毒感染(宫内或出生后获得)对未感染艾滋病毒的儿童的总体发病率和死亡率有不利影响。我们假设母体HIV感染增加了CMV在宫内传播的风险，并使CMV感染的婴儿即使在备选方案B的时代也容易出现不良后果。拟议的研究将在三重抗逆转录病毒治疗的背景下，对撒哈拉以南非洲艾滋病毒暴露和未暴露的新生儿先天性CMV感染的出生流行率提供可靠的估计，以及关于婴儿出生后感染CMV的频率和时间以及婴儿时期获得的CMV感染对儿童发病率的影响的初步数据。在这项研究中，我们将对Mshiyeni王子纪念医院的4200名新生儿进行筛查，这是一家提供补贴医疗服务的地区医院，40%的孕妇感染了艾滋病毒。新生儿巨细胞病毒筛查将通过检测干燥的唾液样本进行，方法是使用我们实验室开发的实时荧光聚合酶链式反应方法。将实施婴儿听力筛查和诊断听力测试方案，以确定巨细胞病毒相关性听力损失的患病率。本研究的目的是：1)确定HIV感染和非HIV感染的新生儿先天性巨细胞病毒感染的出生流行率；2)确定HIV感染和未暴露的先天性CMV感染新生儿的新生儿疾病和CMV相关后遗症的患病率；3)探讨CMV感染(包括先天和出生后)对儿童总体发病率和死亡率的影响。拟议的研究利用具有相似兴趣和动机的调查小组的经验、专业知识和承诺，以确定母亲艾滋病毒感染对巨细胞病毒宫内传播的影响，巨细胞病毒相关性听力损失，以及在婴儿早期获得的巨细胞病毒感染是否影响儿童总体发病率。

 DESCRIPTION (provided by applicant): Congenital CMV infection (cCMV) is the most common congenital infection and a leading non-genetic cause of sensorineural hearing loss worldwide. The birth prevalence of cCMV is directly proportional to maternal CMV seroprevalence levels, with substantially higher rates observed in highly seropositive populations. Increased rates of cCMV are observed in African populations, with evidence for a key role for maternal co-infections, such as HIV, as a driver of cCMV in these countries. Despite a high burden of HIV infection in sub-Saharan Africa, the impact of maternal HIV on the frequency of in utero CMV transmission, symptomatic infection at birth and long-term sequelae has not been systematically evaluated. We recently conducted the first study of cCMV birth prevalence among HIV-exposed newborns in the Western Cape, South Africa, and demonstrated a high rate of cCMV (2.93%; 95% CI 1.73-4.13) in the era of prenatal antiretroviral prophylaxis. Infant CMV infection has been widely associated with an increased risk of HIV disease progression and mortality, as well as an adverse impact on growth, development and overall morbidity in HIV-exposed but uninfected Zambian infants. These findings suggest that CMV infection (intrauterine or postnatal acquisition) has an adverse impact on overall childhood morbidity and mortality in children not infected with HIV. We hypothesize that maternal HIV infection increases the risk of intrauterine CMV transmission, and predisposes CMV-infected infants to adverse outcomes even in the era of option B. The proposed study will provide reliable estimates of the birth prevalence of congenital CMV infection in HIV-exposed and HIV-unexposed newborns in sub-Saharan Africa in the context of triple antiretroviral therapy, as well as preliminary data on the frequency and timing of postnatal CMV acquisition during infancy and the impact of CMV infection acquired in infancy on childhood morbidity. In this study, we will screen ~4,200 newborns at the Prince Mshiyeni Memorial Hospital, a regional hospital that provides subsidized health care where 40% of pregnant women are HIV-infected. Newborn CMV screening will be carried out by testing dried saliva specimens using a real-time PCR method developed in our laboratory. Hearing screening of infants and diagnostic audiology testing protocols will be implemented to determine the prevalence of CMV-associated hearing loss. The objectives of the study are: 1) To determine the birth prevalence of congenital CMV infection among HIV-exposed and HIV-unexposed newborns, 2) To determine the prevalence of newborn disease and CMV-associated sequelae in HIV-exposed and unexposed newborns with congenital CMV infection, and 3) To explore the impact of CMV infection (both congenital and postnatal) on overall childhood morbidity and mortality. The proposed studies take advantage of the experience, expertise and commitment of the investigative team with similar interests and motivation to determine the impact of maternal HIV infection on in utero transmission of CMV, CMV-associated hearing loss and whether CMV infection acquired in early infancy affects overall childhood morbidity.