Leveraging Epigenetic Clocks to Evaluate and Predict Drug Response in HIV Patients - Varun Dwaraka

Recent advancements in precision medicine have highlighted epigenetic clocks, DNA methylation-based biomarkers of biological aging, as powerful tools for assessing the impact of pharmacological interventions. This presentation details findings from two clinical studies conducted by our group, focusing on patients living with HIV—a population known for accelerated biological aging and increased morbidity. The first study examined the impact of Pitavastatin on epigenetic aging among HIV-positive participants within the REPRIEVE trial. Utilizing the PCGrimAge and DunedinPACE clocks, significant findings demonstrated that Pitavastatin treatment stabilized the rate of biological aging over a 24-month period, compared to placebo. This effect underscores the potential for statins to serve as geroprotective agents in populations with chronic inflammatory conditions. The second study assessed the effect of Semaglutide, a GLP-1 receptor agonist, on epigenetic age markers in HIV patients. Analysis indicated that baseline epigenetic age measures significantly predicted the therapeutic response, including changes in BMI and inflammatory markers post-treatment. Higher epigenetic age acceleration at baseline correlated with greater responsiveness to Semaglutide, suggesting that DNA methylation patterns may predict patient outcomes and therapeutic efficacy. While epigenetic clocks offer a crucial starting point, the true utility lies in their application beyond aging metrics alone. By integrating DNA methylation signals with clinical outcomes, we have also developed examples of companion diagnostics—predictive tools that can help identify which patients are most likely to benefit from specific therapies. These diagnostics provide clinicians with actionable insights that extend far beyond traditional biomarkers, guiding individualized treatment plans with greater accuracy and efficacy. For clinicians, these results have important implications. Understanding which patients are more likely to benefit from specific therapies allows for more personalized treatment strategies, minimizes unnecessary exposure to drugs, and optimizes resource allocation. Importantly, this approach can be applied not only to HIV-positive populations but also to broader patient groups facing age-related comorbidities. This presentation will showcase the development, understanding, and clinical application of these epigenetic-based diagnostics—providing attendees with a framework for how DNA methylation insights can be leveraged in their own practices. The insights shared aim to empower clinicians to move beyond traditional clinical assessments and adopt cutting-edge molecular diagnostics to guide therapeutic decision-making, ultimately improving patient care and healthspan outcomes. Understand the utility of epigenetic clocks in evaluating pharmacological effects on biological aging. ● Learn how DNA methylation patterns can be used to predict therapeutic response to GLP-1 receptor agonists and statins. ● Recognize the potential of companion diagnostics to guide precision medicine approaches. ● Identify opportunities to integrate epigenetic biomarkers into routine clinical decision-making. ● Explore implications for targeting aging-related morbidity through geroscience-guided interventions.