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: 1. Fasting glucose less than 180 mg/dL 2. Alanine aminotransferase (ALT) \[serum glutamic pyruvic transaminase (SGPT)\] less than 2 times the upper limit of normal (ULN) 3. Aspartate aminotransferase (AST) \[serum glutamic oxaloacetic transaminase (SGOT)\] less than 2 times the ULN 4. 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. 5. White blood cell (WBC) greater than 3,000/mm\^3 6. Hemoglobin greater than 12.0 g/dL 7. Platelets greater than 150,000/mm\^3 * Female candidates who were postmenopausal (i.e., of non-childbearing potential) were defined as having either: 1. 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 2. 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: 1. 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%. 2. Cerebrovascular disease: prior ischemic stroke of carotid origin, carotid endarterectomy or stenting, or angiographic carotid stenosis of at least 50%. 3. Peripheral arterial disease: prior lower extremity arterial surgical or percutaneous revascularization procedure, or angiographic lower extremity arterial stenosis of at least 50%. OR B) Controlled type II diabetes mellitus (HbA1C less than or equal to 8.0% within the past 90 days prior to study entry, regardless of use of medications) OR C) Any one of the following CVD risk factors below: 1. Current smoking: self-report of smoking at least a half a pack of cigarettes a day, on average, in the past month. 2. Hypertension (HTN): two consecutive blood pressure (BP) readings with either systolic greater than 140 mm Hg or diastolic greater than 90 mm Hg; or on antihypertensive medications. 3. Dyslipidemia: defined as non-high-density lipoprotein (HDL)-C greater than 160 mg/dL or HDL-C less than or equal to 40 mg/dL, regardless of medication use. 4. High-sensitivity C-reactive protein (hsCRP) greater than or equal to 2 mg/L at screening Ability and willingness of candidate to provide informed consent * Completion of the Flow-mediated Vasodilation (FMD) assessments. NOTE: The FMD must be performed at the site and confirmed as acceptable by the University of Wisconsin Atherosclerosis Imaging Research Program (UW AIRP) core lab prior to study entry. If the FMD is deemed unacceptable, a repeat scan must be performed prior to enrollment. * Appropriate documentation from medical records of prior receipt of pneumococcal vaccination (with both the 13-valent conjugant vaccine \[PCV13\] and 23-valent pneumococcal polysaccharide vaccine \[PPV23\]) within the last 5 years. If no documentation is available, then the PCV13 and PPV23 series (PCV13 vaccine followed by PPV23 vaccine at least 8 weeks later) should be completed more than 14 days prior to study entry. Exclusion Criteria: * Acute or serious illness requiring systemic treatment and/or hospitalization within 60 days prior to study entry. NOTE: Treatment should have ended at least 60 days prior to study entry for eligibility. * Documentation of any CDC category C AIDS-indicator condition or oropharyngeal candidiasis (thrush) within 90 days prior to study entry * Receipt of antibiotic therapy within 30 days prior to study entry * Latent tuberculosis (TB) infection (defined as a positive purified protein derivative \[PPD\] greater than or equal to 5 mm, positive interferon-gamma release assay, or positive T-spot test at any time in the past) or evidence of latent TB on the screening chest x-ray that had not been completely treated or was treated within the past 6 months prior to study entry * TB disease that required treatment within 48 weeks prior to study entry * Life-threatening fungal infection requiring treatment, in the opinion of the site investigator, within 48 weeks prior to study entry * Herpes-zoster viral infection that required treatment within 90 days prior to study entry * A history of or current, active hepatitis B infection defined as positive hepatitis B surface antigen (HBsAg) test or positive hepatitis B virus (HBV) DNA in candidates with isolated hepatitis B core antibody (HBcAb) positivity, defined as negative HBsAg, negative hepatitis B surface antibody (HBsAb), and positive HBcAb within 24 weeks prior to study entry. NOTE: Candidates who were positive for hepatitis B surface antigen but who were HBV DNA negative were permitted in the study. * Chronic hepatitis C infection defined as a positive hepatitis C antibody and positive hepatitis C RNA at any time prior to study entry. NOTE: Candidates who were positive for hepatitis C antibody but whowerehepatitis C virus (HCV) RNA negative are permitted in the study. Candidates who had been treated for hepatitis C should be HCV RNA negative for at least 24 weeks after completion of therapy to be eligible for the study. * Previously diagnosed myelodysplasia syndrome * Treated lymphoproliferative disease less than or equal to 5 years prior to study entry * Clinically significant lung disease on the screening chest x-ray that, in the opinion of the site investigator, places the candidate at increased risk of lung toxicity (e.g., history of pulmonary fibrosis, interstitial lung disease, or pulmonary lymphoproliferative disease) * Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 30 days prior to study entry * Change in the ART regimen in the 12 weeks prior to study entry or intended modification of ART during the study. NOTE: Modifications of ART doses during the 12 weeks prior to study entry were permitted. In addition, the change in formulation (e.g., from standard formulation to fixed-dose combination) was allowed within 12 weeks prior to study entry. A within class single drug substitution (e.g., switch from nevirapine to efavirenz or from atazanavir to darunavir) is allowed within 12 weeks prior to study entry, with the exception of a switch from any other nucleoside reverse transcriptase inhibitor (NRTI) to abacavir. No other changes in ART in the 12 weeks prior to study entry were permitted. * Known allergy/sensitivity or any hypersensitivity to components of study drug(s) or their formulation * Average daily consumption of three or more alcoholic beverages for 4 weeks prior to study entry or intention to consume an average of two or more alcoholic beverages a day during the study. NOTE: An alcohol-containing beverage is defined as 12 ounces of beer, 4 ounces of wine, or 1 ounce of spirits. * Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements * Changes in lipid-lowering or antihypertensive medication within 90 days prior to study entry or expected need to modify these medications during the study. NOTE: Lipid-lowering medication includes: statins, fibrates, niacin (dose greater than or equal to 250 mg daily), and fish-oil/omega 3 fatty acids (dose greater than 1000 mg of marine oils daily). * Vaccination (e.g., influenza, pneumococcal polysaccharide) within 14 days prior to study entry * Anticipated need to receive vaccination (e.g., influenza, pneumococcal polysaccharide) within 1 week prior to Week 4, 12, 24, or 36 study visits * Excess extracompartmental fluids including ascites, pericardial fluid, and pleural effusions which, in the opinion of the study investigators, would result in difficulty in monitoring the dose of MTX * Use of drugs that alter folic acid metabolism such as trimethoprim/sulfamethoxazole or reduce tubular excretion such as probenecid within 14 days prior to study entry * New York Heart Association Class IV congestive heart failure * Diabetes mellitus with HbA1C greater than 8.0% within the past 90 days prior to study entry