A Prospective Randomized Controlled Study to Evaluate the Effect of Isotretinoin on Immune Activation Among HIV-1 Infected Subjects With Incomplete CD4+ T Cell Recovery on Suppressive Antiretroviral Therapy (ART)

Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections15 sites in 2 countries76 target enrollmentJuly 2, 2014

ConditionsHIV-1 Infection

InterventionsIsotretinoin

Overview

Phase: Phase 2
Intervention: Isotretinoin
Conditions: HIV-1 Infection
Sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Enrollment: 76
Locations: 15
Primary Endpoint: Change in CD8+ T-cell Activation From Baseline to Week 14/16
Status: Completed
Last Updated: last year

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief 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.

Detailed Description

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.

Registry

clinicaltrials.gov

Start Date

July 2, 2014

End Date

November 2016

Last Updated

last year

Study Type

Interventional

Study Design

Parallel

Sex

All

Investigators

Sponsor

Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections

Responsible Party

Sponsor

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.

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.

Arms & Interventions

Isotretinoin Arm

Participants received Isotretinoin at approximately 0.5 mg/kg orally once daily for 4 weeks, then increased to approximately 1.0 mg/kg orally once daily for 12 weeks.

Intervention: Isotretinoin

Outcomes

Primary Outcomes

Change in CD8+ T-cell Activation From Baseline to Week 14/16

Time Frame: baseline, week 14/16

Level of CD8+ T-cell activation was determined by measuring the percentage of CD8+ T-cells that expressed both the activation marker CD38+ and Human leukocyte antigen (HLA)-DR+. The endpoint is measuring the change from baseline to week 14/16, where baseline is defined as the average of pre-entry and entry, and week 14/16 is defined as the average of week 14 and week 16. Change = (week 14/16 - baseline).

Secondary Outcomes

Change in sTNF-r2(baseline, week 14/16, week 28)
Change in sCD163(baseline, week 14/16, week 28)
Change in sTNF-r1(baseline, week 14/16, week 28)
Change in CD4+ T-cell Count(baseline, week 14/16, week 28)
Cell-associated HIV-1 DNA(baseline, week 14/16, week 28)
Change in IL-6(baseline, week 14/16, week 28)
Change in hsCRP(baseline, week 14/16, week 28)
Change in D-dimer(baseline, week 14/16, week 28)
Change in TF(baseline, week 14/16, week 28)
Change in Cell-associated HIV-1 RNA(baseline, week 14/16, week 28)
Change in Treg Frequency (%FoxP3+/CD25hi+/CD39+/CD127-(CD4+))(baseline, week 14/16, week 28)
Change in Th17 Frequency (%IFNg-/IL17+(CD161+/CCR6+))(baseline, week 14/16, week 28)
Change in CD8+ T-cell Activation(baseline, week 14/16, week 28)
Change in sCD14(baseline, week 14/16, week 28)
Change in I-FABP(baseline, week 14/16, week 28)
Pharmacokinetics - 12-hour Levels of EFV for Isotretinoin Arm(weeks 0, 8, 12, 16, 20)
Pharmacokinetics - Trough Concentrations of TDF for Isotretinoin Arm(weeks 0, 8, 12, 16, 20)
Pharmacokinetics - Endogenous Levels of Retinoid Metabolites for Isotretinoin Arm(weeks 0, 20, 28)
Pharmacokinetics - Steady-state Trough Concentrations of Isotretinoin for Isotretinoin Arm(weeks 8, 12, 16)
Primary Targeted Adverse Events(from study entry to end of study (week 28))