Project Summary/Abstract: Preventing HIV among young women is key to ending the HIV epidemic. However, prevention strategies have been hampered by poor adherence to oral pre- exposure prophylaxis (PrEP) in women and difficult implementing PrEP for young healthy women who have limited interaction with the healthcare system. The recent announcement that injectable long-acting cabotegravir (CAB-LA) is associated with a 9-fold decrease in the incidence of HIV infection in women compared with oral PrEP has the potential to transform the course of the HIV epidemic if CAB-LA can be effectively implemented. In addition to identifying strategies to efficiently reach young women at risk for HIV, breastfeeding safety data for CAB- LA are needed to achieve widespread use in women. Countries with high HIV prevalence also have high fertility and women spend up to 1/3 of their reproductive years pregnant and breastfeeding. Additionally, HIV acquisition risk is 2-4 times higher during the post-partum period, and preventing HIV during breastfeeding also prevents pediatric HIV infection. We propose to address both implementation challenges and lack of breastfeeding safety data by evaluating a strategy of starting CAB-LA PrEP in high risk women who are admitted to the post- partum ward after delivery, and co-locating follow up PrEP services with post-partum and pediatric care, in a primarily breastfeeding population in Botswana. The immediate post-partum period is a unique time to reach young women with PrEP because they are engaged in regular healthcare and highly motivated to stay healthy. In addition to assessing feasibility, uptake, acceptability and retention of this approach, we will also measure HIV incidence with CAB-LA PrEP in a real-world, high HIV prevalence setting. This will be the first large study to evaluate the pharmacokinetics of CAB-LA in breastfeeding women without HIV (and their infants), and this study will perform additional important safety evaluations related to use of integrase inhibitors, including the impact of CAB on maternal weight and cardiometabolic outcomes, post- partum depression and infant growth. We expect this innovative strategy will be easily scalable, influence HIV prevention guidelines and result in the advancement of HIV prevention strategies for women around the world.