Strategies to Predict Success on Long-Acting Therapy in Real-World Settings for HIV (SPLASH)

About This Grant

PROJECT SUMMARY/ABSTRACT Long-acting (LA) antiretroviral therapy (ART) has emerged as a paradigm-shifting approach for treating HIV by addressing adherence challenges, a critical barrier to achieving viral suppression (VS). While clinical trials demonstrated high efficacy among people with HIV with VS on oral ART, real-world implementation has expanded to include those with active viremia and adherence difficulties. The UCSF Ward 86 Clinic and the Emory Ponce de Leon Clinic pioneering LA ART programs have shown remarkably high rates of VS on LA ART, even among initially viremic patients with significant comorbidities, informing recent guideline changes in the U.S. that now permit LA ART for those with viremia. However, critical knowledge gaps remain regarding predictors of treatment outcomes in real-world populations, including pharmacokinetics (PK) and the reservoir. This study will establish the relationship between LA ART drug concentrations and virologic outcomes in a real- world clinical setting with a focus on populations not well-represented in clinical trials (e.g. those with initial viremia and adherence challenges). We hypothesize that specific threshold levels of cabotegravir, rilpivirine, and lenacapavir in hair and plasma will predict blips, persistent low-level viremia, and virologic success, with other patient-level factors, such as body mass index (BMI), age, sex, modifying these relationships. Finally, the frequency of blips on LA ART has raised concerns that these drugs may fail to achieve complete VS, meriting deep investigation of how LA ART affects the active and latent viral reservoirs. Ward 86 in San Francisco and Ponce Clinic in Atlanta have now collaborated in this application due to having the two largest LA ART programs in the country (~1100 on LA ART combined). We will: 1) enroll patients from our two LA ART programs into a cohort with PK sampling, demographic data, and clinical outcomes (Aim 1); 2) assess the relationship between drug levels and viral suppression using validated assays for cabotegravir, rilpivirine, and lenacapavir in both hair and plasma (Aim 2); and 3) compare the active and latent viral reservoir among those starting LA ART with or without viremia, and compare this reservoir data to a contemporaneous cohort of people on oral ART (Aim 3). Our two sites are well poised to conduct these aims and the inclusion of a site in the South will allow for sex differences to be evaluated due to the higher prevalence of women in the region. The UCSF Hair Analytical Laboratory has performed drug level monitoring for two decades, and our team is experienced in measurement of the HIV viral reservoir within a large preexisting cohort on oral ART. By study completion, we will have determined factors that predict virologic success on LA ART and established drug levels necessary for VS in real-world settings so that LA ART can be optimally dosed for individuals and intensified, depending on reservoir findings. Our findings will address the 33% gap in viral suppression in the U.S. and provide guidance for optimizing LA ART implementation. These results will directly inform clinical practice and interventions to optimize LA ART outcomes, particularly among those with adherence challenges.