Effect of Copper versus Levonorgestrel Intrauterine Devices on Mucosal Microbiota and Barrier Function: A Randomized Trial among Young African Women living with and at Risk for HIV

For women with HIV and those at risk for HIV, access to safe prevention of unintended pregnancy is essential. Intrauterine devices (IUD) and systems (IUS) prevent pregnancy for >5 years with an efficacy of >99% and a nearly immediate return to fertility upon removal, making them highly desired tools for contraception by women worldwide. For copper (Cu)-IUDs, side effects often include heavy menses and cramping, which are alleviated with the more recently developed hormone-based devices that deliver a very small amount of hormone locally. Still for many women, preference for a non-hormonal IUD and/or lack of availability of hormonal IUS drive their decision to rely on Cu-IUD for their contraceptive needs. However, Cu-IUD use may inadvertently lead to adverse reproductive outcomes. In our recent randomized analysis of the Cu-IUD and other highly effective contraceptive methods, we found that HIV negative women living in high HIV burden settings using Cu-IUD had more non- optimal vaginal microbiota. This state was associated with high levels of genital inflammation and reduced genital mucosal barrier integrity, all of which are associated with increased risk for sexually transmitted infections (STIs) and adverse reproductive outcomes in both women living with HIV (WLWH) and those without, and a decrease in women's quality of life. Recently, we found significantly higher incident human papilloma virus (HPV) infections in women randomized to Cu-IUD than in women using other methods. WLWH have a high risk of progression to cervical cancer from HPV. Other studies have also noted that women using Cu-IUD had higher incidence of bacterial vaginosis, as well as bacterial STIs. In in vitro studies to assess potential mechanisms, we found that copper had a greater inhibitory effect on growth of lactobacilli than other bacteria. Altogether, these preliminary results suggest that Cu-IUD use might cause undesired health outcomes through metal-ion induced changes in the vaginal microbiota, leading to impaired barrier integrity and increased susceptibility to STIs. Whether hormone-based devices offer contraceptive benefits without the potentially adverse outcomes of Cu-IUD is a major knowledge gap needing exploration for WLWH and those at risk for HIV. Herein, we will conduct a randomized clinical trial among South African WLWH and without HIV to determine whether women assigned to Cu-IUD vs. levonorgesterol (LNG) IUS have differences in vaginal microbial diversity after 1 year of use. We will also determine whether women randomized to Cu-IUD have reduced genital mucosal barrier integrity and greater incidence of high-risk HPV or curable STIs, relative to LNG IUS. Finally, we will explore mechanisms supporting the association between Cu-IUD-induced changes in vaginal microbiota composition and mucosal barrier integrity using an in vitro system. This project will answer critical questions regarding the effects of IUD-based contraceptives in women with and without HIV and may inform product development and policy to make IUDs safer and more available globally. Project Number: 1R01HD118913-01A1 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Heather Jaspan (+1 co-PI) | Institution: SEATTLE CHILDREN'S HOSPITAL, SEATTLE, WA | Award Amount: $751,405 | Activity Code: R01 | Study Section: HIV Coinfections and HIV Associated Cancers Study Section[HCAC] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HD11891301A1