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

Clin Infect Dis. 2019 May 17;68(11):1877-1886. doi: 10.1093/cid/ciy781.


Background: Chronic inflammation in treated 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.

Methods: This was a phase 2 randomized, double-blind, multicenter trial in adults ≥40 years old with treated HIV, with CD4+ T-cell count ≥400 cells/μL and with/at increased risk for ASCVD. Participants received LDMTX (5-15 mg/week) or placebo (plus folic acid) for 24 weeks and were followed for an additional 12 weeks. Primary endpoints were safety and brachial artery flow-mediated dilation (FMD).

Results: 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 vs 5 (5.6%) in placebo (Δ = 7.2%, upper 1-sided 90% CI, 13.4%; Pnoninferiority = .037). Week 24 change in FMD was 0.47% with LDMTX and 0.09% with placebo (P = .55). No inflammatory markers changed differentially with LDMTX compared to placebo.

Conclusions: Adults with HIV and increased ASCVD risk treated with LDMTX had more safety events than with placebo, but the prespecified noninferiority 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.

Clinical trials registration: NCT01949116.

Keywords: endothelial function; human immunodeficiency virus; inflammation.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Anti-Inflammatory Agents / administration & dosage*
  • Antiretroviral Therapy, Highly Active
  • Atherosclerosis / etiology
  • CD4 Lymphocyte Count
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Endothelium / drug effects*
  • Endothelium / physiology
  • Female
  • HIV Infections / complications*
  • HIV Infections / drug therapy
  • HIV-1
  • Humans
  • Inflammation / drug therapy*
  • Inflammation / etiology
  • Male
  • Methotrexate / administration & dosage*
  • Middle Aged


  • Anti-Inflammatory Agents
  • Methotrexate

Associated data