Atorvastatin on Biomarkers of Inflammation, Coagulopathy, Angiogenesis & T-cells
Condition: HIV-1 Infection
MeSH terms: Inflammation
Intervention: atorvastatin; atorvastatin; placebo for atorvastin
Intervention description: 10 mg daily for 4 weeks, if no symptoms or lab findings suggestive of atorvastatin toxicity, dose increase to 20 mg daily from week 4- week 20; Starting at week 24, 10 mg daily for 4 weeks. If no symptoms or lab findings suggestive of atorvastatin toxicity were found, 20 mg daily from week 28- week 44.; One tablet once daily for 4 weeks. If no symptoms or lab findings suggestive of toxicity were found, then increase the dose to two tablets once daily.
Intervention MeSH terms: Atorvastatin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Enrollment: 98.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      ACTG A5275 was a prospective, double-blind, randomized, placebo-controlled cross-over design
      pilot study evaluating the effect of atorvastatin on biomarkers of inflammation,
      coagulopathy, angiogenesis, and T-lymphocyte activation in HIV-1 infected individuals with
      suppressed HIV-1 RNA on stable protease inhibitor based antiretroviral therapy with fasting
      LDL cholesterol < 130 mg/dL.

      Atorvastatin is a drug approved by the Food and Drug Administration (FDA) for treating high
      cholesterol. Atorvastatin has also been able to lower the level of inflammation blood tests
      in certain other diseases but has not been studied for this purpose in people who have HIV.
      The main goal of this experimental study is to see how taking atorvastatin affects
      inflammation blood tests in people infected with HIV who do not need to take medicine for
      high cholesterol. In addition to observing the effects of atorvastatin on the level of
      inflammation measured in the blood, this study evaluated if atorvastatin is safe for people
      with HIV who are also taking medication for HIV.
    

Eligibility criteria:

        Inclusion Criteria:

          -  HIV-1 infected

          -  Combination ART that includes any boosted PI regimen for at least 6 months prior to
             study entry

          -  No plans to change the antiretroviral regimen in the next year

          -  Must have been on the same HAART regimen for at least 12 weeks with no change prior to
             study entry. More information on this criterion can be found in the study protocol.

          -  If on vitamin D replacement therapy, must have been on stable regimen for ≥ 1 mo.
             prior to study entry.

          -  CD4+ T-cell count obtained within 45 days prior to study entry at any laboratory that
             has a Clinical Laboratory Improvement Amendments (CLIA) certification or its
             equivalent.

          -  Screening HIV-1 RNA < 40 copies/mL by Abbott RealTime PCR at a laboratory certified by
             the DAIDS Virology Quality Assurance (VQA) program within 45 days prior to study
             entry.

          -  All known HIV-1 RNA levels obtained within 180 days prior to study entry are below the
             limits of quantification on all tests, with documentation of at least 1 test by any
             FDA-approved assay at a CLIA-certified laboratory obtained between 90 to 180 days
             prior to study entry. A single RNA "blip" of < 500 copies/mL during this time period
             was permissible if RNA levels immediately before and after were below the limits of
             quantification for the assay.

          -  Laboratory values obtained within 45 days prior to study entry- Absolute neutrophil
             count (ANC) 750/mm3, Hemoglobin ≥ 9.0 g/dL for female subjects,10.0 g/dL for male
             subjects, Platelet count ≥ 100,000/mm3, Calculated creatinine clearance (CrCl) 30
             mL/min, as estimated by the Cockcroft-Gault equation, Creatine kinase (CK) < 3 x ULN,
             AST ≤ 2.0 x ULN, ALT ≤ 2.0 x ULN, Total bilirubin ≤ 2.5 x ULN. If the subject was
             taking an indinavir- or atazanavir-containing regimen at the time of screening, a
             total bilirubin of ≤ 5 x ULN is acceptable, Fasting LDL cholesterol ≥ 70 mg/dL and <
             130 mg/dL, Fasting triglycerides < 400 mg/dL, Fasting glucose < 110 mg/dL

          -  Screening plasma D-dimer > 0.34 μg/mL from a sample obtained within 45 days prior to
             study entry was the original D-dimer criterion. It was revised to ≥ 0.25 ug/mL four
             months after the first enrollment, and subsequently the D-dimer eligibility criterion
             was completely cut off a year later.

          -  For females of reproductive potential (women who had not been post-menopausal for at
             least 24 consecutive months, i.e., who had menses within 24 months prior to study
             entry), or women who had not undergone surgical sterilization, specifically
             hysterectomy or bilateral oophorectomy or tubal ligation) required a negative serum or
             urine pregnancy test within 48 hours prior to entry. More information on this
             criterion can be found in the study protocol.

          -  Must agree not to participate in the conception process (e.g., active attempt to
             become pregnant or to impregnate, sperm donation, in vitro fertilization), and if
             participating in sexual activity that could lead to pregnancy, the subject/partner
             must use at least 2 reliable methods of contraception, (condoms, without a spermicidal
             agent; a diaphragm or cervical cap without spermicide; an IUD; or hormone-based
             contraceptive), for 2 weeks before study treatment, while receiving study treatment,
             and for 6 weeks after receiving study treatment. As hormone-based contraceptives
             (oral, transdermal, or subdermal) can affect coagulopathy biomarkers, subjects who
             plan on using such a contraceptive during the study must be taking the same product
             for ≥ 4 weeks prior to screening and be encouraged to continue throughout the duration
             of the study if medically feasible.

          -  Karnofsky performance score ≥ 70 on at least one occasion within 45 days prior to
             study entry

          -  Confirmation of the availability of the stored pre-entry fasting plasma, serum, and
             cell samples. The site had to confirm that these samples had entered into the
             Laboratory Data Management System (LDMS).

        Exclusion Criteria:

          -  Current or past malignancy (except non-melanoma cancer of the skin)

          -  Coronary artery disease (CAD) or CAD equivalent including diabetes mellitus or
             National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III)
             calculated 10-year coronary heart disease (CHD) risk of > 20%.

          -  Known cirrhosis.

          -  Known chronic active hepatitis B or C.

          -  Thyroid-stimulating hormone (TSH) < 1.0 x lower limit of normal or > 1.0 x ULN.

          -  Known inflammatory conditions, such as, but not limited to, rheumatoid arthritis (RA),
             systemic lupus erythematosus (SLE), sarcoidosis, inflammatory bowel disease (IBD),
             chronic pancreatitis, autoimmune hepatitis, myositis, or myopathy.

          -  Pregnant or breast-feeding.

          -  Previous intolerance to any statin or any of its components.

          -  Use of any lipid-lowering therapies including all statin drugs, Omega 3 fatty
             acids/fish oil, red yeast rice, and niacin products ≥ 1 g/day (e.g., niacin, nicotinic
             acid, vitamin B3) taken within 45 days prior to study entry. More information on this
             criterion can be found in the study protocol.

          -  Immunosuppressant use, such as, but not limited to, systemic or potentially systemic
             glucocorticoids (including nasal or inhaled steroids), azathioprine, tacrolimus,
             mycophenolate, sirolimus, rapamycin, or cyclosporine within 45 days prior to study
             entry.

          -  Use of any systemic antineoplastic or immunomodulatory treatment, investigational
             vaccines, interleukins, interferons, growth factors, or intravenous immunoglobulin
             (IVIG) within 45 days prior to study entry. More information on this criterion can be
             found in the study protocol.

          -  Concurrent use of prohibited medications. More information on this criterion can be
             found in the study protocol.

          -  Heavy alcohol use as defined by the National Institute on Alcohol Abuse and Alcoholism
             (NIAAA)
             (http://pubs.niaaa.nih.gov/publications/Practitioner/pocketguide/pocket_guide3.htm)
             and alcohol or drug use or dependence that, in the opinion of the site investigator,
             would interfere with adherence to study requirements.

          -  Current use of anticoagulation therapy other than ≤ 325 mg of daily aspirin.

          -  Known coagulopathy, deep venous thrombosis, pulmonary embolism within 6 months prior
             to study entry.

          -  Known active or recent (not fully resolved within 4 weeks prior to study entry)
             bacterial, fungal, parasitic, or viral infections.

          -  Known history of recurrent rectal and/or genital herpes simplex virus (HSV) or
             varicella zoster virus (VZV) infection within 12 weeks prior to study entry.

          -  Serious illness or trauma requiring systemic treatment and/or hospitalization within 4
             weeks prior to study entry.

          -  History of stroke.