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  Conference on Retroviruses
and Opportunistic Infections (CROI)
Boston, Massachusetts
March 4-7, 2018
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Methotrexate Reins in CD8 Cells But Does Not Improve Endothelial Function
  25th Conference on Retroviruses and Opportunistic Infections (CROI), March 4-7, 2018, Boston
Mark Mascolini
In older HIV-positive people with or at risk of cardiovascular disease, 24 weeks of low-dose methotrexate (LDMTX) reduced CD8-cell numbers and activation but did not quell other markers of inflammation or improve endothelial function [1]. This placebo-controlled AIDS Clinical Trials Group (ACTG) study found high adverse event rates in both study arms, although less than 15% increase in probability of key safety events. . Authors concluded LDMTX at 15mg/week was tolerated without hematologic/renal/hepatic side effects. This was among the first and the largest studies of an immunomodulatory agent in HIV. During Q&A question by Jens Lundgren raised the question that under powering may not have detected benefits, Hsue said when we designed the study safety was the primary endpoint, although we also wanted to look at the impact on inflammation, and because of the greater variability in IL-6 measurement and FMD we may have been underpowered to assess the impact on these single biomarker measurements. Also in Q&A Michael Lederman made the point that activation of CD8+ T-cells appear relevant to CVD and is worth investigating in HIV as he has observed from his research and that of others, this was in response to question by Jason Baker that in this study there was a decline in CD8 activation so perhaps this might provide a protective affect in HIV for CVD.
Much work ties methotrexate to reduced risk of cardiovascular disease in people taking the antiinflammatory for rheumatoid arthritis [2]. CIRT, a 7000-person placebo-controlled trial, is exploring the impact of LDMTX in people with a prior myocardial infarction and either type 2 diabetes or the metabolic syndrome [3].
Ongoing inflammation despite effective antiretroviral therapy predicts cardiovascular risk. Because strategies to control this inflammation have had mixed results, Priscilla Hsue (University of California, San Francisco) and ACTG investigators conducted this placebo-controlled trial of LDMTX. They hypothesized (1) that LDMTX would cause no more than a 15% increase in probability of "safety events" (including drops in CD4 count and virologic failure) compared with the background rate, and (2) that reducing inflammation would improve endothelial function assessed by flow-mediated vasodilation of the brachial artery.
ACTG A5314 enrolled men and women at least 40 years old who had maintained viral control with antiretroviral therapy for at least 24 weeks. Everyone had a CD4 count of 400 or more, and everyone had documented atherosclerotic cardiovascular disease or one cardiovascular risk factor--diabetes, smoking, hypertension, abnormal lipids, or high-sensitivity C-reactive protein (hsCRP, an inflammation marker) above 2 mg/dL.
The investigators randomized 86 people to LDMTX and 90 to placebo for 24 weeks. Follow-up continued for another 12 weeks. More than 90% of participants had 100% LDMTX adherence throughout the study. Most participants, 90%, were men, 42% were white, 42% black, and 15% Hispanic. Median age stood at 54 (interquartile range [IQR] 49 to 59), making this the oldest group ever enrolled in an ACTG trial. More than half of participants, 59%, were already taking a statin, and 40% took aspirin.
After 24 weeks the LDMTX and placebo groups did not differ in lipid, kidney, liver, or hematologic test results. There were no virologic failures or lymphoproliferative malignancies with LDMTX. Eleven people in the LDMTX arm (12.8%) and 5 in the placebo arm (5.6%) had one or more primary safety events, including 3 confirmed CD4-cell declines in the LDMTX group and 7 pneumonias (4 with LDMTX, 3 with placebo). One person taking LDMTX died of pneumococcal pneumonia. The LDMTX group stayed within the safety event target: less than a 15% higher safety event rate than placebo.
Median CD4 count fell by 58 cells in the LDMTX group at week 24 (IQR -163 to +47, P = 0.016) and rebounded after treatment stopped. CD4-cell activation dropped modestly with LDMTX but the change reached significance at week 24 (P = 0.007). Levels of CD8 cells, an inflammation indicator, fell significantly more with LDMTX than with placebo at weeks 8, 12, and 24 (-103 versus -2 cells, P = 0.001). The CD8 count rebounded in the 12 weeks after LDMTX stopped (-50 versus -16 cells, P = 0.13). Compared with people taking placebo, those taking LDMTX had significantly decreased CD8-cell activation (CD8+ CD38+ HLA-DR+) at weeks 4, 12, and 24 (all P < 0.001). In a subset of 28 participants who had FDG-PET/CT at weeks 0 and 24, those randomized to LDMTX (versus placebo) had significantly reduced arterial inflammation [4]. LDMTX in a small amount of individuals appeared to reduce arterial SUV compared to placebo, and the reduction observed in this study in cycling CD8+ T-cells correlated with this reduction in arterial inflammation.
No other markers of inflammation or coagulation changed significantly with LDMTX (hsCRP, IP-10, IL-6, sCD14, sCD163, D-dimer, fibrinogen, or sVCAM). The inflammation marker IL-6 rose over time in both study arms, with no significant difference between groups. Flow-mediated vasodilation showed no change in endothelial function with LDMTX. Related secondary endpoints--brachial artery diameter and hyperemic flow velocity--did not change over time.
Viral persistence and more detailed imaging of the brachial artery studies are ongoing. Future studies in HIV will partly depend on the clinical trial looking at low dose methotrexate in the general population.
The ACTG investigators suggested that CD8 cells may mediate the immunomodulatory effect of LDMTX. They noted that CD8 parameters independently predict non-AIDS events, including cardiovascular disease. The researchers surmised that "pathways of inflammation in HIV may be distinct from other chronic inflammatory conditions such as rheumatoid arthritis." They proposed that justification of future LDMTX studies in people with HIV will partly depend on results of the CIRT trial [3].
This was among the first and the largest studies of an immunomodulatory agent in HIV. The median age of 54 makes it among the oldest HIV population studied in the ACTG and we noted that infectious complications were common even in the placebo arm of the study suggesting that antiretroviral therapy does not fully restore health in this patient population. Immunomodulatory impact of LDMTX may be mediated through CD8+ T-cells and T-cell activation. these markers are independently predictive of CVD and non-AIDS events, and may represent a therapeutic target for cure. As noted in the talk by Jason Baker on inflammation markers (reported by NATAP) these pathways of inflammation in HIV are clearly very complex and may be distinct from other chronic inflammatory conditions such as RA.
WEBCAST: http://www.croiwebcasts.org/console/player/37178?mediaType=slideVideo&&crd_fl=1&ssmsrq=1520775525555&ctms=5000&csmsrq=757
1. Hsue P, Ribaudo H, Deeks SG, et al. Impact of LDMTX on immune activation and endothelial function in treated HIV. 25th Conference on Retroviruses and Opportunistic Infections (CROI). March 4-7, 2018. Boston. Abstract 79.
2. Westlake SL, Colebatch AN, Baird J, et al. The effect of methotrexate on cardiovascular disease in patients with rheumatoid arthritis: a systematic literature review. Rheumatology (Oxford). 2010;49:295-307.
3. Everett BM, Pradhan AD, Solomon DH, et al. Rationale and design of the Cardiovascular Inflammation Reduction Trial: a test of the inflammatory hypothesis of atherothrombosis. Am Heart J. 2013;166:199-207.
4. Tawakol A, Ribaudo H, Isha AE, et al. Impact of methotrexate on arterial inflammation in persons with treated HIV. Conference on Retroviruses and Opportunistic Infections (CROI). March 4-7, 2018. Boston. Abstract 684LB.