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

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)

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01969058

Enrollment

Registered

2013-10-25

Start date

2014-07-02

Completion date

2016-11-30

Last updated

2024-10-15

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

HIV-1 Infection

Keywords

Isotretinoin, HIV-1, immunology markers, immune activation, viral suppression

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.

Interventions

DRUGIsotretinoin

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.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Masking description

open label

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.

Eligibility

Sex/Gender

ALL

Age

18 Years to 80 Years

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Change in CD8+ T-cell Activation From Baseline to Week 14/16	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

Measure	Time frame	Description
Change in CD8+ T-cell Activation	baseline, week 14/16, week 28	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 week 14/16 to week 28 (week 28 - week 14/16) and from baseline to week 28 (week 28 - baseline). 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 in sCD14	baseline, week 14/16, week 28	sCD14 (soluble cluster of differentiation 14) is a marker of gut microbial translocation and monocyte activation. The outcome measures are changes in log10 transformed sCD14 from baseline to week 14/16 (week 14/16 - baseline), from week 14/16 to week 28 (week 28 - week 14/16), and from baseline to week 28 (week 28 - baseline). Levels measured at pre-entry and entry were averaged for baseline, levels measured at week 14 and week 16 were averaged for week 14/16.
Change in IL-6	baseline, week 14/16, week 28	IL-6 (Interleukin-6) is a marker of systemic inflammation. The outcome measures are changes in log10 transformed IL-6 from baseline to week 14/16 (week 14/16 - baseline), from week 14/16 to week 28 (week 28 - week 14/16), and from baseline to week 28 (week 28 - baseline). Levels measured at pre-entry and entry were averaged for baseline, levels measured at week 14 and week 16 were averaged for week 14/16.
Change in hsCRP	baseline, week 14/16, week 28	hsCRP (high-sensitivity C-reactive protein) is a marker of inflammation. Change in log10 transformed hsCRP from baseline to week 14/16 (week 14/16 - baseline), from week 14/16 to week 28 (week 28 - week 14/16), and from baseline to week 28 (week 28 - baseline). Levels measured at pre-entry and entry were averaged for baseline, levels measured at week 14 and week 16 were averaged for week 14/16.
Change in sTNF-r1	baseline, week 14/16, week 28	sTNF-r1 (soluble tumour necrosis alpha receptor 1) is a marker of inflammation. Change in log10 transformed sTNF-r1 from baseline to week 14/16 (week 14/16 - baseline), from week 14/16 to week 28 (week 28 - week 14/16), and from baseline to week 28 (week 28 - baseline). Levels measured at pre-entry and entry were averaged for baseline, levels measured at week 14 and week 16 were averaged for week 14/16.
Change in sTNF-r2	baseline, week 14/16, week 28	sTNF-r2 (soluble tumour necrosis alpha receptor 2) is a marker of inflammation. Change in log10 transformed sTNF-r2 from baseline to week 14/16 (week 14/16 - baseline), from week 14/16 to week 28 (week 28 - week 14/16), and from baseline to week 28 (week 28 - baseline). Levels measured at pre-entry and entry were averaged for baseline, levels measured at week 14 and week 16 were averaged for week 14/16.
Change in D-dimer	baseline, week 14/16, week 28	D-dimer (or D dimer) is a marker of coagulation activation. Change in log10 transformed D-dimer from baseline to week 14/16 (week 14/16 - baseline), from week 14/16 to week 28 (week 28 - week 14/16), and from baseline to week 28 (week 28 - baseline). Levels measured at pre-entry and entry were averaged for baseline, levels measured at week 14 and week 16 were averaged for week 14/16.
Change in TF	baseline, week 14/16, week 28	TF (Tissue Factor) is a marker of Coagulation. Change in log10 transformed TF from baseline to week 14/16 (week 14/16 - baseline), from week 14/16 to week 28 (week 28 - week 14/16), and from baseline to week 28 (week 28 - baseline). Levels measured at pre-entry and entry were averaged for baseline, levels measured at week 14 and week 16 were averaged for week 14/16.
Change in sCD163	baseline, week 14/16, week 28	sCD163 (soluble CD 163) is a marker of macrophage activation Change in log10 transformed sCD163 from baseline to week 14/16 (week 14/16 - baseline), from week 14/16 to week 28 (week 28 - week 14/16), and from baseline to week 28 (week 28 - baseline). Levels measured at pre-entry and entry were averaged for baseline, levels measured at week 14 and week 16 were averaged for week 14/16.
Change in I-FABP	baseline, week 14/16, week 28	I-FABP (intestinal-fatty acid binding protein) is a marker of intestinal cell damage and turnover. The outcome measures are changes in log10 transformed I-FABP from baseline to week 14/16 (week 14/16 - baseline), from week 14/16 to week 28 (week 28 - week 14/16), and from baseline to week 28 (week 28 - baseline). Levels measured at pre-entry and entry were averaged for baseline, levels measured at week 14 and week 16 were averaged for week 14/16.
Change in Cell-associated HIV-1 RNA	baseline, week 14/16, week 28	Cell-associated HIV-1 RNA in blood from baseline to week 14/16(week 14/16 - baseline), from week 14/16 to week 28 (week 28 - week 14/16), and from baseline to week 28 (week 28 - baseline). Levels measured at pre-entry and entry were averaged for baseline, levels measured at week 14 and week 16 were averaged for week 14/16. For cell-associated HIV-1 RNA results below the assay limit, the lowest value of the sample was imputed to these results (1.32 log10 copies/10\^6 CD4 cells). Since there are only a few results below the assay limit, it is still reasonable to summarize the absolute changes for cell-associated HIV-1 RNA, where changes were calculated based on the imputed values (described above) for below assay limit results.
Cell-associated HIV-1 DNA	baseline, week 14/16, week 28	Cell-associated HIV-1 DNA in blood at baseline, week 14/16, and week 28. Levels measured at pre-entry and entry were averaged for baseline, levels measured at week 14 and week 16 were averaged for week 14/16. For cell-associated HIV-1 DNA results below the assay limit, the lowest value of the sample was imputed to these results and considered lowest ranks (1.62 log10 copies/10\^6 CD4 cells). It was originally planned to summarize the absolute changes for cell-associated HIV-1 DNA. However, since there are many results below limit of detection, analyzing the absolute changes would be inappropriate in this case. Instead, the baseline, week 14/16, and week 28 levels were summarized.
Change in Treg Frequency (%FoxP3+/CD25hi+/CD39+/CD127-(CD4+))	baseline, week 14/16, week 28	Treg (T Regulatory) Cells are a subpopulation of T cells which modulate the immune system. The outcome measure is the change in percent FoxP3+/CD25hi+/CD39+/CD127-(CD4+) from baseline to week 14/16 (week 14/16 - baseline), from week 14/16 to week 28 (week 28 - week 14/16), and from baseline to week 28 (week 28 - baseline). Levels measured at pre-entry and entry were averaged for baseline, levels measured at week 14 and week 16 were averaged for week 14/16.
Change in Th17 Frequency (%IFNg-/IL17+(CD161+/CCR6+))	baseline, week 14/16, week 28	Th17 (T-helper 17) cells are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17). The outcome is the change in percent IFNg-/IL17+(CD161+/CCR6+) from baseline to week 14/16 (week 14/16 - baseline), from week 14/16 to week 28 (week 28 - week 14/16), and from baseline to week 28 (week 28 - baseline). Levels measured at pre-entry and entry were averaged for baseline, levels measured at week 14 and week 16 were averaged for week 14/16.
Pharmacokinetics - Endogenous Levels of Retinoid Metabolites for Isotretinoin Arm	weeks 0, 20, 28	Isotretinoin Arm (Arm A) only. Endogenous retinoid metabolites are defined as the average concentrations of Retinol, and Total Retinyl Ester from weeks 0, 20, and 28.
Pharmacokinetics - Steady-state Trough Concentrations of Isotretinoin for Isotretinoin Arm	weeks 8, 12, 16	Isotretinoin arm (Arm A) only, steady-state trough concentrations of Isotretinoin is defined as the average of 'eligible' concentrations at weeks 8, 12, and 16, where 'eligible' means the time from the previous dose to the blood draw of the sample must have been in the 14-to-30 hour range, and the participant must have taken at least 3 doses in the prior 4 days.
Pharmacokinetics - Trough Concentrations of TDF for Isotretinoin Arm	weeks 0, 8, 12, 16, 20	Isotretinoin arm (Arm A) only, trough concentrations of TDF (Tenofovir) is defined as the average of 'eligible' concentrations, where 'eligible' means the time from the previous dose to the blood draw of the sample must have been in the 20-to-28 hour range, and the participant must have taken at least 3 doses in the prior 4 days. TDF trough during Isotretinoin administration is the average of 'eligible' concentrations from weeks 8, 12, and 16; TDF trough without Isotretinoin administration is the average of 'eligible' concentrations from weeks 0 and 20. (Week 28 data is not available.)
Pharmacokinetics - 12-hour Levels of EFV for Isotretinoin Arm	weeks 0, 8, 12, 16, 20	Isotretinoin arm (Arm A) only, 12-hour levels of EFV (Efavirenz) is defined as the average of 'eligible' concentrations, where 'eligible' means the time from the previous dose to the blood draw of the sample must have been in the 9-to-15 hour range, and the participant must have taken at least 3 doses in the prior 4 days. EFV trough during Isotretinoin administration is the average of 'eligible' concentrations from weeks 8, 12, and 16; EFV trough without Isotretinoin administration is the average of 'eligible' concentrations from weeks 0 and 20. (Week 28 data is not available.)
Primary Targeted Adverse Events	from study entry to end of study (week 28)	Targeted events for A5325 include: events that meet the International Conference on Harmonization (ICH) definitions for a serious adverse event, post-entry signs/symptoms and laboratory abnormalities of Grade ≥3 or that lead to a change in treatment regardless of grade, and any diagnoses.
Change in CD4+ T-cell Count	baseline, week 14/16, week 28	Change in peripheral total CD4 cell count from baseline to week 14/16 (week 14/16 - baseline), from week 14/16 to week 28 (week 28 - week 14/16), and from baseline to week 28 (week 28 - baseline). Levels measured at pre-entry and entry were averaged for baseline, levels measured at week 14 and week 16 were averaged for week 14/16.

Countries

Puerto Rico, United States

Participant flow

Recruitment details

First participant was enrolled on July 2, 2014. Accrual to the study closed on May 5, 2016, with 15 U.S and Puerto Rico sites registered and enrolled participants

Pre-assignment details

Participants were randomized 2:1 to Isotretinoin and no study treatment arms. Randomization was stratified by willingness to participate in the gut biopsy substudy, A5330s.

Participants by arm

Arm	Count
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.	50
No Study Treatment Arm No Isotretinoin treatment	26
Total	76

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	1	0
Overall Study	Withdrawal by Subject	2	0

Baseline characteristics

Characteristic	Isotretinoin Arm	No Study Treatment Arm	Total
Age, Continuous	49 years	51 years	49 years
Age, Customized 18-39 years	14 Participants	7 Participants	21 Participants
Age, Customized 40-59 years	31 Participants	16 Participants	47 Participants
Age, Customized >=60 years	5 Participants	3 Participants	8 Participants
BMI	27.1 kg/m^2	26.9 kg/m^2	27.1 kg/m^2
CD4+ Cell Count	549 cells/mm^3	556 cells/mm^3	552 cells/mm^3
CD8+ T-cell Activation Percent	13.67 percentage of cells	13.40 percentage of cells	13.66 percentage of cells
HIV-1 RNA < Assay lower limit (40 copies/mL)	50 Participants	25 Participants	75 Participants
HIV-1 RNA >= Assay lower limit (40 copies/mL)	0 Participants	1 Participants	1 Participants
Race/Ethnicity, Customized Hispanic (Regardless of Race)	11 Participants	5 Participants	16 Participants
Race/Ethnicity, Customized Non-Hispanic Black	21 Participants	9 Participants	30 Participants
Race/Ethnicity, Customized Non-Hispanic White	18 Participants	12 Participants	30 Participants
Region of Enrollment Puerto Rico	1 Participants	0 Participants	1 Participants
Region of Enrollment United States	49 Participants	26 Participants	75 Participants
Sex: Female, Male Female	4 Participants	1 Participants	5 Participants
Sex: Female, Male Male	46 Participants	25 Participants	71 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 50	0 / 26
other Total, other adverse events	41 / 50	18 / 26
serious Total, serious adverse events	2 / 50	0 / 26

Outcome results

Primary

Change in CD8+ T-cell Activation From Baseline to 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).

Time frame: baseline, week 14/16

Population: The primary analysis is complete case as-treated, and is limited to participants who:~* have data for both baseline and week 14/16~* (for the Isotretinoin arm) completed treatment (allowing ≤8 missed doses)~* did not use prohibited medications~* did not experience virologic failure from baseline to week 16

Arm	Measure	Value (MEDIAN)
Isotretinoin Arm	Change in CD8+ T-cell Activation From Baseline to Week 14/16	3.24 percentage of cells
No Study Treatment Arm	Change in CD8+ T-cell Activation From Baseline to Week 14/16	0.52 percentage of cells

Comparison: Null hypothesis: There is no difference between the two arms in the change in T-cell activation from baseline to week 14/16.p-value: 0.03Wilcoxon (Mann-Whitney)

Secondary

Cell-associated HIV-1 DNA

Cell-associated HIV-1 DNA in blood at baseline, week 14/16, and week 28. Levels measured at pre-entry and entry were averaged for baseline, levels measured at week 14 and week 16 were averaged for week 14/16. For cell-associated HIV-1 DNA results below the assay limit, the lowest value of the sample was imputed to these results and considered lowest ranks (1.62 log10 copies/10\^6 CD4 cells). It was originally planned to summarize the absolute changes for cell-associated HIV-1 DNA. However, since there are many results below limit of detection, analyzing the absolute changes would be inappropriate in this case. Instead, the baseline, week 14/16, and week 28 levels were summarized.