Effect of Isotretinoin on Immune Activation Among HIV-1 Infected Subjects With Incomplete CD4+ T Cell Recovery

Isotretinoin was administered to participants in the Isotretinoin arm at approximately 0.5
mg/kg PO once daily for 4 weeks, then increased to approximately 1.0 mg/kg PO once daily for
12 weeks. Follow-up continues to week 28 to evaluate the duration of effect. Randomization
was stratified by willingness to participate in the gut biopsy substudy, A5330s. The study
population included HIV-1 infected adults whose virus was suppressed on ART, excluding women
of child bearing potential.

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.