DESCRIPTION (provided by applicant): Family planning options, including hormonal contraceptives, are essential for improving reproductive health among HIV-infected women. For these individuals, prevention of unintended pregnancy decreases maternal and child mortality, as well as reduces the risk of mother-to-child HIV transmission. Similarly, antiretroviral therapy (ART) is essential for reducing morbidity and mortality among HIV-infected individuals, in addition to preventing HIV transmission. Thus, it is of critical public health importance to safely combine hormone contraceptives and ART. Millions of HIV-infected women on ART currently use subdermal progestin-releasing implants as a preferred method of long-acting, reversible contraception despite the lack of critically needed pharmacokinetic (PK) drug-interaction data to inform their safe and effective concomitant use. Highlighting this concern, our research team recently demonstrated that combined use of efavirenz (EFV)-based ART, the only preferred first-line ART regimen in low- and middle-income countries, with a levonorgestrel (LNG)-releasing implant for one year reduced LNG plasma concentrations by approximately 50% compared to women not on ART. Importantly, we also observed three unintended pregnancies (15%) in our study group of women on EFV-based ART plus the LNG implant, in contrast to the <1% expected failure rate of the implant for women without drug interactions. Still, subdermal implants remain an essential family planning option and are routinely co-prescribed with ART. Therefore, the overall goal of this proposed study is to build upon and extend our prior work in order to provide comprehensive, evidence-based guidance on the use of LNG implants with ART in HIV-infected women. Overall, we hypothesize that detrimental drug-drug interactions between the LNG implant and EFV-based ART can be overcome by using an increased dose of the LNG implant and/or alternative ART combinations. We will accomplish this through the following three specific aims: Aim 1) determine if increasing the dose of the LNG-releasing subdermal implant effectively overcomes the known PK interaction with EFV- based ART; Aim 2) predict optimal strategies to comprehensively combine LNG implants with ART options using physiologically-based PK (PBPK) modeling; and Aim 3) determine the in vivo PK of LNG released from a subdermal implant over one year in combination with emerging ART strategies. Collectively, these aims significantly extend our preliminary findings to identify a strategy to overcome the drug-drug interaction between LNG and EFV-based ART, advance contraceptive therapeutic options for HIV-infected women, and advance the science of the drug-drug interaction field. Overall, our proposed study will provide an evidence- based approach to safely combine LNG implants with ART regimens spanning the continuum of HIV care. In turn, this collaborative study is strongly expected to improve the management o...