Safety and Effectiveness of Low-Dose Methotrexate for Reducing Inflammation in HIV-Infected Adults on ARV Medications

Inclusion Criteria

• HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load.
• Had to be on continuous ART for greater than or equal to 24 weeks prior to study entry. This was defined as continuous active therapy for the 24-week period prior to study entry with no treatment interruption longer than 7 consecutive days and a total duration off treatment of no more than 14 days in the 90 days prior to study entry.
• CD4 T-cell count greater than or equal to 400 cells/mm^3 obtained within 60 days prior to study entry by any U.S. laboratory that has a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent
• HIV-1 RNA level below the limit of quantification using a FDA-approved assay for at least 24 weeks prior to study entry and confirmed within 60 days prior to study entry. The assay used for eligibility could be performed by any U.S. laboratory that had a CLIA certification or its equivalent. NOTE: Single determinations that are between the assay quantification limit and 200 copies/mL were allowed as long as the preceding and subsequent determinations are below the level of quantification.
• The following laboratory values obtained within 60 days prior to study entry by any U.S. laboratory that has a CLIA certification or its equivalent:
• Fasting glucose less than 180 mg/dL
• Alanine aminotransferase (ALT) [serum glutamic pyruvic transaminase (SGPT)] less than 2 times the upper limit of normal (ULN)
• Aspartate aminotransferase (AST) [serum glutamic oxaloacetic transaminase (SGOT)] less than 2 times the ULN
• Estimated creatinine clearance (CrCl) greater than or equal to 50 mL/min by Cockcroft-Gault. NOTE: Candidates who were taking tenofovir disoproxil fumarate (TDF) as part of their ART regimen should have an estimated CrCl greater than or equal to 60 mL/min.
• White blood cell (WBC) greater than 3,000/mm^3
• Hemoglobin greater than 12.0 g/dL
• Platelets greater than 150,000/mm^3
• Female candidates who were postmenopausal (i.e., of non-childbearing potential) were defined as having either:
• Appropriate medical documentation of prior hysterectomy and/or complete bilateral oophorectomy (i.e., surgical removal of the ovaries, resulting in "surgical menopause" and occurring at the age at which the procedure was performed), OR
• Permanent cessation of previously occurring menses as a result of ovarian failure with documentation of hormonal deficiency by a certified healthcare provider (i.e., "spontaneous menopause").
• Male candidates must agree not to participate in a conception process (i.e., active attempt to impregnate, sperm donation). If participating in sexual activity that could lead to pregnancy, the male participant must agree to the use of TWO reliable forms of contraceptives simultaneously while on study and for a minimum of 3 months after therapy.
• Candidates who were not of reproductive potential (defined as women who have been postmenopausal for at least 24 consecutive months or men who have documented vasectomy) were eligible for the study without requiring the use of contraceptives.
• Moderate or high CVD risk defined as:

A) Documented CVD as assessed by meeting at least 1 of 3 criteria below:

• Coronary artery disease (CAD): prior myocardial infarction (MI) due to atherosclerosis, coronary artery bypass graft surgery, percutaneous coronary intervention, or angiographic CAD with luminal diameter stenosis of at least one coronary artery at least 50%.
• Cerebrovascular disease: prior ischemic stroke of carotid origin, carotid endarterectomy or stenting, or angiographic carotid stenosis of at least 50%.
• Peripheral arterial disease: prior lower extremity arterial surgical or percutaneous revasculari