Clinical Pharmacology Approaches towards Accelerating HIV Cure Initiatives

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Project Summary/Abstract For the nearly 37 million people living with HIV (PLWH), functional cure, or antiretroviral (ART)-free remission, is rapidly becoming an attainable target. While extensive research on the mechanisms underlying immune dysfunction and viral persistence present promising opportunities for novel therapeutic modalities, a modest understanding of how pharmacology (pharmacokinetics, PK, and pharmacodynamics, PD) contributes to clinical variability in reservoir reduction and immune modulation has frequently resulted in marginal clinical trial outcomes. This career development award will provide Dr. Amelia Deitchman, a pharmacist-researcher with a PhD in PK/PD, with the essential mentorship and training to develop her independent research program to bridge this gap in translational HIV cure research by harnessing heterogeneity in drug response and mismatched clinical translation to further the HIV cure agenda and develop robust and targeted treatments for all patients. Numerous novel therapeutic approaches are being investigated as components of durable HIV cure, including immunosuppressants targeting chronic immune dysfunction and inflammation associated with HIV persistence, as well as broadly neutralizing antibodies (bNAbs) that clear virus and HIV-infected cells. This research investigates the use of sirolimus alone and with Shingrix (recombinant varicella zoster virus, rVZV vaccine) in two clinical trials, and two bNAbs in a combination clinical trial. Using data and samples from these trials in PLWH on virally suppressive ART, and state-of-the-art viral, immune, and pharmacological approaches, the candidate will 1) establish exposure-response of sirolimus and rVZV vaccine on HIV reservoirs, immune function and safety, 2) define predictors of sirolimus and rVZV vaccine response variability attributable to PK and PD heterogeneity, and 3) determine if systemic bNAb levels can predict time to viral rebound after ART interruption in the context of other curative strategies. We hypothesize that changes in outcomes (reservoir size, immune phenotype, inflammatory markers, and for bNAbs, reservoir size and time to viral rebound post ART interruption) are directly related to drug exposure. For sirolimus, these PK/PD relationships may be entirely distinct from those used for other therapeutic indications. Furthermore, we hypothesize that drug-drug interactions, and differences in immune genetics, and patient demographic, clinical, and disease-related traits account for observed variability in clinical drug exposure and response. Ultimately, this award will be the cornerstone for a career in HIV cure clinical pharmacology research through hands-on and didactic training in HIV pharmacology, immunology and virology, clinical trials, and grant writing by an expert team of mentors. These mentors will foster the candidate's development of an independent academic research career answering clinical pharmacology questions in the setting of HIV cure. The research performed as part of this award will support a future R01 submission investigating PK/PD relationships to accelerate drug development, identify novel therapeutic approaches, and deliver precision care to patients.