Effect of Ruxolitinib on Cardiovascular Disease-Associated Immunomodulatory Biomarkers in People Living With HIV Público

Michael, Amanda (Spring 2024)

Permanent URL: https://etd.library.emory.edu/concern/etds/ks65hd686?locale=pt-BR
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Abstract

People living with HIV (PWH), even with peripheral viral suppression with antiretroviral therapy (ART), are at an increased risk for cardiovascular disease (CVD) and CVD-related comorbidities, including sudden cardiac death and acute myocardial infarction (MI). While PWH may appear virally suppressed in peripheral blood samples, viral reservoirs persist in gut-associated lymphoid tissue (GALT) and are associated with CVD-related morbidity and mortality. This project aimed to determine if Jak 1/2 inhibitor ruxolitinib, which our group and others have demonstrated confers significant reduction in vitro and across ex vivo patient samples and murine models to block HIV-associated inflammatory events, could confer efficacy in treating HIV-driven inflammation associated with CVD development and related comorbidities in PWH. Our team performed an AIDS Clinical Trial Group (ACTG) sponsored Phase 2a human study (n = 60, 2:1 ruxolitinib to open label control), including 5 weeks of ruxolitinib (10 mg BID), with additional follow up through week 12. Mixed effects analysis and a Spearman rho correlation test were performed to determine the impact of ruxolitinib on the following biomarkers known to be associated with CVD: IFN-b, IFN-g, IL-1b, and TNF-a. Significant changes in IFN-b and IFN-g were observed, indicating that a 5-week course of ruxolitinib can confer modulation of these two cytokines, both of which are involved in innate immune control and harnessing of viral persistence. The same biomarkers were also assessed for correlation with HIV reservoir levels, a key barrier to systemic eradication of HIV-1 independent of ruxolitinib treatment. Correlation between the replication competent reservoir (quantified with the integrated proviral DNA assay; IPDA) and IFN-b demonstrated a strong trend towards significance (p=0.088), wherein more IFN-b correlated with a smaller reservoir size. Examining the RUX arm, no significance was observed, collectively underscoring that IFN responses are associated with reservoir control. Ruxolitinib can modulate these responses in PWH, but longer duration treatment is likely needed to observe any meaningful impact on reservoir decline conferred by this mechanism. Future directions include analysis of second-generation Jak inhibitors such as baricitinib for efficacy in treating HIV-driven CVD and related biomarkers in longer duration studies, leveraged from our team’s existing trials.

Table of Contents

Background ... 1

Mechanisms of Viral Persistence ... 1

Immunological Biomarkers ... 4

Selected Biomarkers ... 4

Unmet Clinical Need ... 6

Methods ... 8

Specific Aims ... 8

Study Design ... 8

Statistical Analysis ... 10

Results ... 11

Question 1: Impact of Ruxolitinib on Biomarker Concentration ... 11

Question 2: Correlation Between Reservoir and Cytokine Concentrations ... 16

Supplementary Analysis ... 20

Conclusions ... 20

Impact of Ruxolitinib on Biomarker Concentration ... 20

Correlation Between Reservoir and Cytokine Concentrations ... 21

Discussion ... 21

Future Directions ... 24

References ... 26

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