Effect of Isotretinoin on Immune Activation Among HIV-1 Infected Subjects With Incomplete CD4+ T Cell Recovery
Condition: HIV-1 Infection
Intervention: Isotretinoin
Intervention description: Isotretinoin is a drug that is approved for use in the treatment of severe acne. The aim of this study is to evaluate the role of Isotretinoin on immune activation and inflammation.
Intervention MeSH terms: Isotretinoin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Participants were randomized 2:1 to Isotretinoin arm and no study treatment arm. The primary endpoints were compared between the 2 study arms.
Masking: None (Open Label)
Masking description: open label
Enrollment: 76.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Isotretinoin; HIV-1; immunology markers; immune activation; viral suppression

Summary:

      This phase II study was done in HIV-infected participants on antiretroviral therapy to
      evaluate the effects of isotretinoin (a drug that is approved for use in the treatment of
      severe acne) on the immune system. The immune system helps the body fight infections. When
      the immune system is not working well, one may be at greater risk for diseases that are
      common in aging, like heart disease, weaker bones, and kidney disease.
    

Eligibility criteria:

        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.

        NOTE: The term "licensed" refers to a US FDA-approved kit, which is required for all IND
        studies.

        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 (eg, indirect versus competitive), or a Western blot or a plasma HIV-1 RNA
        viral load.

          -  Receiving ART therapy for at least 12 months prior to study entry.

          -  No plans to change the ART regimen in the 6 months after study entry.

          -  HIV-1 RNA below the lower limit of detection using an FDA-approved assay obtained
             within 30 days prior to study entry by any laboratory that has a CLIA certification or
             its equivalent (eg, <50 copies/mL on Roche Amplicor HIV-1 Monitor assay, <75 copies/mL
             on the Versant HIV-1 RNA assay by branched DNA, <40 copies/mL on the Abbott
             m2000sp/m2000rt real-time PCR test, < 20 copies/mL on the COBAS AmpliPrep/TAQMAN HIV-1
             assay).

          -  All measurements of HIV-1 RNA within the 12 months prior to study entry must be below
             the limit of detection with the following exception:

        NOTE A: 1 viral blip (<200 copies/mL) is permitted if it is preceded and followed by viral
        loads below the limits of detection.

        NOTE B: The virologic assay must have a lower limit of detection of ≤ 75 copies/mL.

          -  CD4+ cell count <350 cells/mm3 obtained at screening within 30 days prior to entry at
             any laboratory that has a CLIA (Clinical Laboratory Improvement Amendments)
             certification or its equivalent.

          -  The following laboratory values obtained within 30 days prior to entry by any
             laboratory that has a CLIA certification or its equivalent:

               1. Hemoglobin A1c (HgbA1c) levels ≤ 6.5%

               2. Hemoglobin ≥ 9.0 g/dL

               3. Platelet count ≥ 50,000/mm3

               4. Creatinine ≤1.5 mg/dl

               5. CrCl ≥ 60 mL/min, calculated by the Cockcroft-Gault method

               6. Aspartate aminotransferase (AST) (SGOT) ≤1.5x upper limit of normal (ULN)

               7. Alanine aminotransferase (ALT) (SGPT) ≤1.5x ULN

               8. Serum lipase ≤1.5x ULN

               9. Fasting triglyceride level ≤200 mg/dL

              10. Fasting glucose <126mg/dL

          -  Karnofsky performance score >/=70 within 30 days prior to entry.

          -  Men and post-menopausal females aged ≥ 18 years and ≤ 80 years at entry.

        Note: Post-menopausal is defined as having either:

          1. Appropriate medical documentation (see note) of prior 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 (12 consecutive months or more of amenorrhea) 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 (see note) in the case of suspected
        spontaneous menopause as follows:

          1. If age >54 years and with the absence of normal menses: Serum FSH (Follicle
             Stimulating Hormone) 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: Negative serum or urine HCG
             with concurrently elevated serum FSH (follicle stimulating hormone) 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.

        NOTE: "Appropriate documentation", and "properly documented" means written documentation or
        oral communication from a clinician or clinician's staff documented in source documents of
        an operative report, discharge summary, or

          -  No active hepatitis B or C infection. NOTE: For subjects who have documentation of
             prior infection, but no active hepatitis infection, evidence of clearance must be
             greater than 1 year.

          -  Ability and willingness of subject to provide informed consent.

          -  Willingness to adhere to the iPLEDGE program requirements.

          -  Indication of willingness to participate in the substudy A5330s. NOTE: In the event
             that 12 or fewer subjects have enrolled into A5330s by the time enrollment in the main
             study has reached 50% of the accrual target, A5330s enrollment will be required.

        Exclusion Criteria:

          -  Pre-existing diagnosis of diabetes.

          -  Currently receiving treatment with fibrate, nicotinic acid, tetracycline, fish oil
             >1g/d, or methotrexate.

          -  Known active healing fracture or any severe bone disorders. NOTE: does not include
             healed fractures or history of old fractures.

          -  Receipt of any of the following medications within 30 days prior to entry: systemic
             steroids (including intra-articular steroids; inhaled or nasal steroid therapy is
             permitted), interleukins, systemic interferons (including intra-articular steroid
             injection; local injection of interferon alpha for treatment of human papilloma virus
             is permitted), or systemic chemotherapy.

          -  Known allergy/sensitivity or any hypersensitivity to vitamin A, retinoids, or any of
             their derivatives.

          -  Active drug or alcohol use or dependence that, in the opinion of the site
             investigator, would interfere with adherence to study requirements.

          -  Acute or serious illness requiring systemic treatment and/or hospitalization within 60
             days prior to entry.

          -  Weight < 40 kg or > 150 kg.

          -  History of major depression or suicide attempt requiring hospitalization, or psychotic
             episode requiring medication or hospitalization.

          -  History of inflammatory bowel disease such as Crohn's disease, or Ulcerative colitis.