Menstrual cups, maturation of the adolescent vaginal microbiome, and STI/HIV risk

A disproportionate number of new HIV infections occur in adolescent girls in sub-Saharan Africa (SSA). In parts of western Kenya, HIV prevalence rises from 1.3% in 13-14 year-olds to 12.8% by age 18 years. Bacterial vaginosis (BV), which doubles the risk of HIV acquisition and transmission, affects 20-50% of general population women in SSA and Kenya. For adolescent girls, the HIV/STI epidemic overlaps with broader reproductive health concerns. Menstrual hygiene management (MHM) is a pervasive problem across low- and middle-income countries and a lack of MHM materials negatively impacts girls' health and schooling. To attend school and obtain necessities such as sanitary products, soap and underwear, girls consequently often engage in exchange sex. To tackle these challenges, Co-Investigator Phillips-Howard conducted a cluster randomized controlled feasibility study following 644 girls aged 14-16 years old: after one year, menstrual cup use resulted in 35% lower (p=0.034) BV prevalence and 52% lower (p=0.039) STI prevalence compared to control condition of menstrual hygiene counseling. Based on our and others' research, we hypothesize menstrual cups protect against STIs by preserving or promoting a Lactobacillus-dominant vaginal microbiome (VMB). Numerous studies associated a Lactobacillus-dominant VMB with reduced risk of STI and HIV acquisition. We propose to study this proposed microbiome-related mechanism to understand how menstrual cup use leads to reduced BV and STIs, and the effect of menstrual cup use on evolution of the adolescent VMB. We will:Aim 1 : Determine the influence of menstrual cup use on the VMB and how this is related to risk of BV and STIs; Aim 2 : Identify the change in VMB as girls initiate sexual activity, and whether this is modified by menstrual cup use, and Aim 3: Augment trial pharmacovigilance through detection of E. coli on cups and correlation with VMB. The proposed study will be a longitudinal sub-study of 440 girls aged 14-16 years nested within a recently funded cluster randomized controlled trial to examine menstrual cup use versus cash transfer or control condition among 3,864 secondary school girls in Siaya County, Kenya (DfID/MRC/Wellcome Trust; PI: Phillips-Howard). To achieve our aims, we will characterize the VMB using high throughput amplicon sequencing of portions of the bacterial 16S rRNA gene. Participants (220 cup users, 220 controls) will be asked to provide a self-collected vaginal swab at baseline prior to allocation and at each semi-annual visit, for a maximum of 6 samples per subject (BL, 6-, 12-, 18-, 24-, 30-months). BV will be assessed at baseline at each semi-annual visit, and STIs (C. trachomatis, T. vaginalis, N. gonorrhoeae) at baseline and annually. HIV and HSV-2 are assessed at baseline and annually by the larger trial. Results from this study will provide understanding of whether microbiome modulating interventions being tested for adult women are applicable for adolescent girls. Menstrual cups could be a low-cost, multipurpose intervention to add to the prevention toolkit not just for girls, but for sex workers and women at high risk for HIV and STIs.

撒哈拉以南非洲（sub-Saharan Africa, SSA）的少女群体新发HIV感染占比远超其他群体。在肯尼亚西部部分区域，HIV感染率从13至14岁群体的1.3%攀升至18岁时的12.8%。细菌性阴道病（bacterial vaginosis, BV）可使HIV感染与传播风险翻倍，在撒哈拉以南非洲及肯尼亚的普通女性人群中，其患病率达20%至50%。对于少女而言，HIV/性传播感染（sexually transmitted infection, STI）的流行态势与更广泛的生殖健康问题相互交织。月经卫生管理（menstrual hygiene management, MHM）在中低收入国家是普遍存在的公共卫生难题，缺乏合格的月经卫生用品会对少女的健康与学业造成负面影响。为获取卫生巾、肥皂、内衣等生活必需品，不少少女往往会通过性交易换取所需物资。为应对上述多重挑战，联合研究员Phillips-Howard开展了一项整群随机对照可行性研究，对644名14至16岁少女进行了为期1年的随访。研究结果显示，与仅接受月经卫生咨询的对照组相比，使用月经杯可使细菌性阴道病患病率降低35%（p=0.034），性传播感染患病率降低52%（p=0.039）。基于本团队及其他学者的已有研究，我们提出假说：月经杯可通过维持或促进以乳杆菌属为主导的阴道微生物组（vaginal microbiome, VMB），从而发挥预防性传播感染的作用。多项已发表研究证实，以乳杆菌属为主导的阴道微生物组可显著降低性传播感染与HIV感染的风险。本研究拟深入探究这一与微生物组相关的潜在机制，以明确月经杯使用如何减少细菌性阴道病与性传播感染的发生，同时考察月经杯使用对少女阴道微生物组演化的影响。本研究设定三项核心目标：目标1：明确月经杯使用对阴道微生物组的调控作用，及其与细菌性阴道病和性传播感染风险的关联；目标2：探明少女首次发生性行为后阴道微生物组的动态变化，以及月经杯使用是否会对该变化产生调节效应；目标3：通过检测月经杯表面定植的大肠杆菌（E. coli）并分析其与阴道微生物组的相关性，强化试验的药物警戒工作。本研究为一项纵向子研究，嵌套于一项新近获得资助的整群随机对照试验。该大型试验将在肯尼亚西亚亚县的3864名中学女生中开展，对比月经杯使用、现金补助与常规对照三种干预方案（资助方：DfID/MRC/Wellcome Trust；首席研究员：Phillips-Howard），本子研究将纳入440名14至16岁少女。为达成研究目标，我们将通过对细菌16S rRNA基因片段进行高通量扩增子测序，来全面表征阴道微生物组的组成与结构。研究对象（220名月经杯使用者、220名对照者）需在分组前的基线阶段，以及每半年一次的随访中提供自行采集的阴道拭子样本，每名受试者最多可提供6份样本（基线、6个月、12个月、18个月、24个月、30个月）。细菌性阴道病将在基线及每半年的随访中进行评估，性传播感染（沙眼衣原体、阴道毛滴虫、淋病奈瑟菌）则在基线及每年的随访中进行检测。大型试验将在基线及每年对HIV与单纯疱疹病毒2型（HSV-2）进行血清学检测。本研究的结果将有助于明确针对成年女性的微生物组调控干预手段是否适用于少女群体。月经杯有望成为一种低成本、多用途的公共卫生干预手段，不仅可纳入少女的疾病预防工具包，也可应用于性工作者及HIV与性传播感染高风险女性人群。