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Clin Infect Dis. 2018 Sep 14. doi: 10.1093/cid/ciy781. [Epub ahead of print]

Safety and Impact of Low-Dose Methotrexate on Endothelial Function and Inflammation in Individuals with Treated Human Immunodeficiency Virus: AIDS Clinical Trials Group Study A5314.

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Department of Medicine, University of California - San Francisco School of Medicine; San Francisco, CA, United States.
Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health; Boston, MA, United States.
University of Texas Health Science Center at Houston, McGovern Medical School; Houston, TX, United States.
Cardiology Division, Brigham and Women's Hospital and Harvard Medical School; Boston, MA.
University of Cincinnati College of Medicine; Cincinnati, OH, United States.
David Geffen School of Medicine at University of California - Los Angeles; Los Angeles, CA, United States.
Cardiology Division, Massachusetts General Hospital and Harvard Medical School; Boston, MA, United States.
Case Western Reserve University School of Medicine; Cleveland, OH, United States.
University of Wisconsin School of Medicine and Public Health; Madison, WI, United States.



Chronic inflammation in treated human immunodeficiency virus (HIV) infection is associated with mortality and atherosclerotic cardiovascular disease (ASCVD). We evaluated the safety and potential efficacy of low-dose methotrexate (LDMTX) in treated HIV.


This was a phase II randomized, double-blind, multi-center trial in adults with treated HIV ≥40 years old with CD4+ T-cells ≥400 cells/mm 3 and with or at increased risk for ASCVD. Participants received LDMTX (5 to15 mg/week) or placebo (+ folic acid) for 24 weeks and were followed for an additional 12 weeks. Primary endpoints were safety and brachial artery flow-mediated dilation (FMD).


The 176 participants (90% male) had a median (Q1, Q3) age of 54 (49, 59) years. LDMTX was associated with decreases in CD4+ T-cells at week 24 and CD8+ T-cells at weeks 8, 12, and 24. Eleven participants (12.8%) experienced safety events in the LDMTX group versus 5 (5.6%) in the placebo group (=7.2%, upper 1-sided 90% CI=13.4%; pnon-inferiority=0.037). Week 24 change in FMD was 0.47% with LDMTX and 0.09% with placebo (p=0.55). No inflammatory markers changed differentially with LDMTX compared to placebo.


In adults with HIV with or at increased risk for ASCVD, participants treated with LDMTX had more safety events than with placebo but the pre-specified non-inferiority margin of 15% was not exceeded. LDMTX had no significant effect on endothelial function or inflammatory biomarkers but was associated with a significant decrease in CD8+ T-cells. The balance of risks and potential benefits of LDMTX in this population will require additional investigation.


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