PET/CT Imaging Companion Study To ACTG A5314 — PET/CTMTX  

HIV Clinical Trial

Official title: Imaging Companion Study To ACTG A5314: Effect of Reducing Inflammation With Low Dose Methotrexate on Inflammatory Markers and Endothelial Function in Treated and Suppressed HIV Infection

Status Completed

Clinical Trial Summary

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) may reduce CVD risk in people with rheumatoid arthritis, who like those with HIV, have increased levels of inflammation. The NHLBI is funding a clinical trial targeting the excess inflammation in HIV. That "Parent Study" is a randomized, double-blind, placebo-controlled trial (NCT01949116) 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. In this imaging sub-study, the overall goal is to determine if treating virologically suppressed, HIV-infected individuals with LDMTX will reduce inflammation within the arterial wall.

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.

Clinical Trial Description

HIV infection is associated with a substantially increased risk of CVD that is not fully accounted for by traditional risk factors. Several lines of evidence suggest that chronic immune cell activation may be complicit. In support of this concept, we recently used 18F-FDG-PET/CT to demonstrate that HIV-infected individuals have increased arterial inflammation compared to non-HIV, FRS-matched controls and that the degree of arterial inflammation is related to markers of monocyte activation. Further, we and others have shown that increased arterial FDG uptake predicts future CVD events in non-HIV cohorts. Together, these observations support the concept that targeting arterial inflammation may provide benefit for HIV infected individuals.

The NHLBI recently provided funding for a clinical trial targeting the excess inflammation in HIV. The "Parent Study" is being performed as a collaboration with the National Institute of Allergy and Infectious Diseases (NIAID) AIDS Clinical Trials Group and the NHLBI. That randomized, double-blind, placebo-controlled trial will assess whether 24-week treatment with very low-dose methotrexate (LDMTX): i) is safe, ii) reduces levels of circulating inflammatory biomarkers and activated immune cells and iii) improves brachial artery reactivity (BART). However, neither the biomarkers nor the BART studies measured as part of 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 Parent Study.

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. FDG-PET/CT imaging has been employed in several multi-center trials to measure changes in arterial inflammation in response to anti-inflammatory treatments. Accordingly, we propose a time sensitive ancillary imaging study to determine if treating virologically suppressed, HIV-infected individuals with LDMTX reduces atherosclerotic inflammation, assessed by FDG-PET/CT. Our central hypothesis is that persistent immune cell activation results in chronic arterial inflammation, which subsequently 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, and (ii) identify the immune cell subtypes whose changes (with LDMTX) are associated with changes in arterial inflammation. Accordingly, the proposed ancillary study would provide unique and highly complementary information that would greatly increase the knowledge and mechanistic insights gained from the Parent Study. The ancillary study has two specific aims:

Specific Aim 1: 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. [Primary and secondary outcomes]

Knowledge Gap/Need: The parent study does not provide for assessment of the target pathology (arterial inflammation) hence insights regarding effects of LDMTX treatment on arterial inflammation are needed.

Hypothesis 1: LDMTX therapy will reduce arterial inflammation (to a greater extent than placebo).

To test hypothesis 1: We will determine in 91 patients (a subset of the parent study) if arterial inflammation (measured with PET/CT at 0 and 24 weeks) is reduced by LDMTX (relative to placebo).

Specific Aim 2: To evaluate the cellular and biochemical mediators associated with arterial inflammation in HIV and to explore the potential mechanism of the effect of LDMTX therapy on arterial inflammation in HIV. [Exploratory outcomes]

Knowledge Gap/Need: The parent study, on its own, does not provide the tools to directly evaluate arterial inflammation in HIV. Evaluation of the relationships between circulating inflammatory mediators and arterial inflammation in the context of this study would yeild mechanistic insights regarding atherosclerotic disease in HIV and provide a greater understanding of the effect of LDMTX on arterial inflammation in HIV.

Hypothesis 2.1:At baseline, arterial inflammation is closely associated with measures of activated immune cells (CD14+/CD16+ monocytes). Additional relationships might be seen between arterial inflammation and other cellular subsets (e.g. T-cells), inflammatory cytokines, and endothelial function.

Hypothesis 2.2: Post-treatment changes in arterial inflammation are positively correlated with changes in measures of activated immune cells (especially activated monocytes).

To test these hypotheses: We will evaluate if arterial inflammation (by PET) correlates with inflammatory cell activation and other measured biomarkers separately. We will then compare the strength of the associations and test their independence. The evaluation of associations will be performed: comparing baseline measurements (SA 2.1), and comparing post-randomization changes (SA2.2).

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. 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. ;

Related Conditions & MeSH terms

• Atherosclerosis
• HIV
• Inflammation

• NCT number: NCT02312219
• Study type: Observational
• Source: Massachusetts General Hospital
• Status: Completed
• Start date: November 2014
• Completion date: December 8, 2016