HIV-infected individuals on antiretroviral therapy (ART) are at increased risk for cardiovascular disease (CVD), likely due to chronically increased inflammation. Low-dose methotrexate (LDMTX) appears to reduce CVD risk in people with rheumatoid arthritis, who like those with HIV, have increased levels of inflammation. The NHLBI recently provided funding for a clinical trial targeting the excess inflammation in HIV. That "Parent Study" is a randomized, double-blind, placebo-controlled trial that will assess whether 24-week treatment with LDMTX: i) is safe, ii) reduces circulating inflammatory biomarkers and levels of immune cell activation and iii) improves brachial artery reactivity. However, neither the biomarkers nor endothelial function tests measured as part of the parent study will report on atherosclerotic inflammation, (the desired pathobiological target of LDMTX therapy in HIV). As such, the direct evaluation of arterial inflammation would substantially enhance the scientific value of the trial. We propose to conduct a time sensitive ancillary imaging study whose overall goal is to determine if treating virologically suppressed, HIV-infected individuals with LDMTX will reduce inflammation within the arterial wall. Atherosclerotic inflammation can be non-invasively and reproducibly measured with FDG-PET/CT imaging, a well-validated quantitative technique that can sensitively detect changes in atherosclerotic inflammation and which has been employed in several multi-center trials to measure changes in arterial inflammation in response to anti-inflammatory treatments. Our central hypothesis is that persistent immune activation results in chronic arterial inflammation, which contributes to the CVD risk observed in HIV. This fully integrated ancillary study would, in a subset of patients enrolled in the parent trial: (i) assess the impact of LDMTX on arterial inflammation, (ii) evaluate mechanisms responsible for arterial inflammation in HIV and iii) explore mechanisms responsible for actions of LDMTX on the artery wall. Accordingly, the proposed study would provide unique and highly complementary information that would greatly increase the knowledge and mechanistic insights gained from Parent Study. The ancillary study has two specific aims1) To determine the impact of anti-inflammatory treatment with LDMTX on arterial inflammation, as assessed by FDG-PET/CT imaging, in virally suppressed HIV-infected individuals., and 2) To evaluate the cellular and biochemical basis of the effect of LDMTX therapy on arterial inflammation in HIV. We expect that LDMTX therapy will improve arterial inflammation and that this mechanistic, proof-of-concept study will demonstrate the importance of inflammation and immune activation in HIV-associated CVD. This would thus form the basis for event-driven trials to evaluate whether anti-inflammatory strategies reduce CVD risk in individuals with treated HIV infection. Accordingly, the study has the potential to shift the paradigm in the approach to treating atherosclerosis in HIV-infected individuals, and potentially in other populations as well.
HIV-infected individuals on effective antiretroviral therapy are at increased cardiovascular disease (CVD) risk because of persistent inflammation. This study will test the hypothesis that inflammation drives CVD risk in HIV infection by evaluating the effects of reducing inflammation using low-dose methotrexate on arterial inflammation and immune activation in treated HIV-infected individuals. (End of abstract)
|Figueroa, Amparo L; Takx, Richard A P; MacNabb, Megan H et al. (2016) Relationship Between Measures of Adiposity, Arterial Inflammation, and Subsequent Cardiovascular Events. Circ Cardiovasc Imaging 9:e004043|
|Joseph, Philip; Ishai, Amorina; MacNabb, Megan et al. (2016) Atrial fibrillation is associated with hematopoietic tissue activation and arterial inflammation. Int J Cardiovasc Imaging 32:113-9|
|Takx, Richard A P; MacNabb, Megan H; Emami, Hamed et al. (2015) Increased arterial inflammation in individuals with stage 3 chronic kidney disease. Eur J Nucl Med Mol Imaging :|
|Tawakol, Ahmed; Singh, Parmanand; Mojena, Marina et al. (2015) HIF-1Î± and PFKFB3 Mediate a Tight Relationship Between Proinflammatory Activation and Anerobic Metabolism in Atherosclerotic Macrophages. Arterioscler Thromb Vasc Biol 35:1463-71|