PET/CT Imaging Companion Study To ACTG A5314

1\. Inclusion Criteria: 1.1 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. NOTE: The term "licensed" refers to a US FDA-approved kit, which is required for all IND studies. WHO (World Health Organization) and CDC (Centers for Disease Control and Prevention) guidelines mandate that confirmation of the initial test result must use a test that is different from the one used for the initial assessment. A reactive initial rapid test should be confirmed by either another type of rapid assay or an E/CIA that is based on a different antigen preparation and/or different test principle (e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral load. 1.2 Currently on continuous ART for ≥24 weeks prior to study entry. This is 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. 1.3 CD4+ T-cell count ≥400 cells/mm3 obtained within 60 days prior to study entry by any US laboratory that has a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent. 1.4 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 can be performed by any US laboratory that has a CLIA certification or its equivalent. NOTE: Single determinations that are between the assay quantification limit and 200 copies/mL are allowed as long as the preceding and subsequent determinations are below the level of quantification. 1.5 The following laboratory values obtained within 60 days prior to study entry by any US laboratory that has a CLIA certification or its equivalent; * Fasting glucose \<180 mg/dL * ALT \[serum glutamic pyruvic transaminase (SGPT)\] \<2 times upper limit of normal (ULN) * AST \[serum glutamic oxaloacetic transaminase (SGOT)\] \<2 x ULN * Estimated creatinine clearance (CrCl) ≥50 mL/min by Cockcroft-Gault (see section 6.3.5 for CrCl instructions) NOTE: Candidates who are taking TDF as part of their ART regimen must have an estimated CrCl ≥60 mL/min. * White blood cell (WBC) \>3000/mm3 * Hemoglobin \>12.0 g/dL * Platelets \>150,000/mm3 1.6 Females subjects who are postmenopausal (i.e., of non-childbearing potential), 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"). Hormonal deficiency should be properly documented in the case of suspected spontaneous menopause as follows: 1. If age \>54 years and with the absence of normal menses for at least 24 consecutive months: serum follicle stimulating hormone (FSH) level elevated to within the post-menopausal range based on the laboratory reference range where the hormonal assay is performed; 2. If age ≤ 54 years and with the absence of normal menses for at least 24 consecutive months: Negative serum or urine (β-HCG) performed within 48 hours prior to study entry with concurrently elevated serum FSH level in the post-menopausal range, depressed estradiol (E2) level in the post-menopausal range, and absent serum progesterone level, based on the laboratory reference ranges where the hormonal assays are performed. 1.7 Male subjects 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 subject must agree to the use of TWO reliable forms of contraceptives simultaneously while on study and for a minimum of 3 months after therapy. At least TWO of the following contraceptives MUST be used appropriately by male subjects and their female partners: * Condoms (male or female) with or without a spermicidal agent * Diaphragm or cervical cap with spermicide * Intrauterine device (IUD) * Tubal ligation * Hormone-based contraceptive NOTES: Sexual activity that could lead to pregnancy is not applicable to sexual activity with an infertile partner. Acceptable documentation for the use of two methods of contraceptives is the male subject's report of use of a second form of contraceptive by his female partner. 1.8 Subjects who are not of reproductive potential (defined as women who have been postmenopausal for at least 24 consecutive months or men who have documented vasectomy) are eligible for the study without requiring the use of contraceptives. In order to verify lack of reproductive potential, written documentation or verbal communication by the clinician or clinician's staff of one of the following must be in the source documents: * Physician report/letter. * Operative report or other source documentation in the patient record. * Discharge summary. * Follicle-stimulating hormone (FSH) measurement elevated into the menopausal range as established by the reporting laboratory. NOTES: Any statement of self-reported sterility or infertility (or that of a partner's) should be entered into the source document. Females who report being postmenopausal for at least 24 consecutive months but who do not have documentation of postmenopausal status from a clinician will have the hormonal assessments performed prior to study entry. 1.9 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 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 ≤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: subject report of smoking at least a half a pack of cigarettes a day, on average, in the past month. 2. Hypertension (HTN): two consecutive BP readings with either systolic \>140 mmHg or diastolic \>90 mmHg; or on antihypertensive medications. 3. Dyslipidemia: defined as non-HDL-C \>160 mg/dL, regardless of medication use. 4. hsCRP ≥2mg/L 1.10 Men and women age ≥40 years. 1.11 Ability and willingness of subject to provide informed consent. 1.12 For subjects taking tenofovir (TFV) as part of their ART regimen, willingness to conside participate in the PK component of the study. NOTE: Participation in the PK component is optional but strongly encouraged. 1.13 Completion of the pre-entry FMD assessment. NOTE: At least one 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. 1.14 Additional Inclusion criteria for the Imaging sub-study: To be eligible for the PET/CT Imaging sub-study, the subject must: A) Be a participant in the Parent Study B) Not yet have received study drug C) Be able to undergo imaging prior to randomization 2\. Exclusion Criteria: 2.1 Acute or serious illness requiring systemic treatment and/or hospitalization within 60 days prior to study entry. NOTE: Treatment must have ended at least 60 days prior to study entry for eligibility. 2.2 Documentation of any CDC category C AIDS-indicator condition \[78\] or oropharyngeal candidiasis (thrush) within 90 days prior to study entry. 2.3 Receipt of antibiotic therapy within 30 days prior to study entry. 2.4 Latent TB infection (defined as a positive PPD ≥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 has not been completely treated or was treated within the past 6 months prior to study entry . 2.5 TB disease requiring treatment within 48 weeks prior to study entry. 2.6 Life-threatening fungal infection requiring treatment, in the opinion of the site investigator, within 48 weeks prior to study entry. 2.7 Herpes-zoster viral infection requiring treatment within 90 days prior to study entry. 2.8 A history of or current, active hepatitis B infection defined as positive hepatitis B surface antigen test or positive HBV DNA in subjects with isolated HBcAb positivity, defined as negative HBsAg, negative HBsAb, and positive HBcAb within 24 weeks prior to study entry. NOTE: Subjects who are positive for hepatitis B surface antigen but who are HBV DNA negative are permitted in the study. 2.9 Chronic hepatitis C infection defined as a positive hepatitis C antibody and positive hepatitis C RNA at any time prior to study entry. NOTE: Subjects who are positive for hepatitis C antibody but who are HCV RNA negative are permitted in the study. 2.10 Previously diagnosed myelodysplasia syndrome. 2.11 Treated lymphoproliferative disease ≤5 years prior to study entry. 2.12 Clinically significant lung disease on the screening chest x-ray that, in the opinion of the site investigator, places the subject at increased risk of lung toxicity (e.g., history of pulmonary fibrosis, interstitial lung disease, or pulmonary lymphoproliferative disease). 2.13 Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 30 days prior to study entry. 2.14 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 are permitted. In addition, the change in formulation (e.g., from standard formulation to fixed-dose combination) is 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 NRTI to abacavir. No other changes in ART in the 12 weeks prior to study entry are permitted. 2.15 Known allergy/sensitivity or any hypersensitivity to components of study drug(s) or their formulation. 2.16 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. 2.17 Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements. 2.18 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 ≥250 mg daily), and fish-oil/omega 3 fatty acids (dose \>1000 mg of marine oils daily). 2.19 Vaccination (e.g., influenza, pneumococcal polysaccharide) within 14 days prior to study entry. 2.20 Anticipated need to receive vaccination (e.g., influenza, pneumococcal polysaccharide) within 1 week prior to week 4, 12, 24, or 36 study visits. 2.21 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. 2.22 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. 2.23 New York Heart Association Class IV congestive heart failure. 2.24 Diabetes mellitus with HbA1C \>8.0% within the past 90 days prior to study entry. 2.25 Patients who report any significant radiation exposure over the course of the year prior to randomization. Significant exposure is defined as: i) More than 2 PCI within 12 months of randomization ii) More than 2 myocardial perfusion studies within the past 12 months iii) More than 2 CT angiograms within the past 12 months iv) Any subjects with history of radiation therapy. 2.26 Current daily use of insulin.