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

• Sponsor: AIDS Clinical Trials Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT01969058
• Collaborator: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Enrollment: 76
• Locations: 15
• Arms: 2
• Actual Duration (Months): 28
• Patients Per Site: 5.1
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
HIV-1 Infection	Drug: Isotretinoin	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 76 participants
• 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.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
• Primary Purpose: Treatment
• Official Title: 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)
• Actual Study Start Date: Jul 2, 2014
• Actual Primary Completion Date: Aug 1, 2016
• Actual Study Completion Date: Nov 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 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.	Drug: Isotretinoin; 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.; Other Names: 13-cis-retinoic acid
No Intervention: No study treatment Arm No Isotretinoin treatment

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

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.

17. 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.

18. 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.)

19. 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.)

20. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	31788 Alabama CRS	Birmingham	Alabama	United States	35294
2	601 University of California, Los Angeles CARE Center CRS	Los Angeles	California	United States	90035
3	801 University of California, San Francisco HIV/AIDS CRS	San Francisco	California	United States	94110
4	101 Massachusetts General Hospital (MGH) CRS	Boston	Massachusetts	United States	02114
5	107 Brigham and Women's Hosp. ACTG CRS	Boston	Massachusetts	United States	02115
6	2101 Washington University Therapeutics (WT) CRS	Saint Louis	Missouri	United States	63110
7	31786 New Jersey Medical School Clinical Research Center CRS	Newark	New Jersey	United States	07103
8	31787 University of Rochester Adult HIV Therapeutic Strategies Network CRS	Rochester	New York	United States	14642
9	3201 Chapel Hill CRS	Chapel Hill	North Carolina	United States	27516
10	3203 Greensboro CRS	Greensboro	North Carolina	United States	27401
11	2401 Cincinnati CRS	Cincinnati	Ohio	United States	45267-0405
12	2951 The Miriam Hospital (TMH) ACTG CRS	Providence	Rhode Island	United States	02906
13	3652 Vanderbilt Therapeutics (VT) CRS	Nashville	Tennessee	United States	37204
14	31473 Houston AIDS Research Team (HART) CRS	Houston	Texas	United States	77030
15	5401 Puerto Rico AIDS Clinical Trials Unit CRS	San Juan		Puerto Rico	00931

Sponsors and Collaborators

• AIDS Clinical Trials Group
• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Study Chair: Douglas Kwon, MD, PhD, Massachusetts General Hospital
• Study Chair: Nina Lin, MD, Harvard Medical School (HMS and HSDM)

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: AIDS Clinical Trials Group
• ClinicalTrials.gov Identifier: NCT01969058
• Other Study ID Numbers: ACTG A5325; UM1AI068636
• First Posted: Oct 25, 2013
• Last Update Posted: Aug 3, 2021
• Last Verified: Mar 1, 2019

• Keywords provided by AIDS Clinical Trials Group: Isotretinoin; HIV-1; immunology markers; immune activation; viral suppression
• Additional relevant MeSH terms: Isotretinoin

Study Results

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 Detail	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.

Arm/Group Title	Isotretinoin Arm	No Study Treatment Arm
Arm/Group Description	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.	No Isotretinoin treatment
Period Title: Overall Study
STARTED	50	26
COMPLETED	47	26
NOT COMPLETED	3	0

Baseline Characteristics

Arm/Group Title	Isotretinoin Arm	No Study Treatment Arm	Total
Arm/Group Description	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.	No Isotretinoin treatment	Total of all reporting groups
Overall Participants	50	26	76
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	49	51	49
Age, Customized (Count of Participants)
18-39 years	14 28%	7 26.9%	21 27.6%
40-59 years	31 62%	16 61.5%	47 61.8%
>=60 years	5 10%	3 11.5%	8 10.5%
Sex: Female, Male (Count of Participants)
Female	4 8%	1 3.8%	5 6.6%
Male	46 92%	25 96.2%	71 93.4%
Race/Ethnicity, Customized (Count of Participants)
Non-Hispanic White	18 36%	12 46.2%	30 39.5%
Non-Hispanic Black	21 42%	9 34.6%	30 39.5%
Hispanic (Regardless of Race)	11 22%	5 19.2%	16 21.1%
Region of Enrollment (Count of Participants)
Puerto Rico	1 2%	0 0%	1 1.3%
United States	49 98%	26 100%	75 98.7%
HIV-1 RNA (Count of Participants)
>= Assay lower limit (40 copies/mL)	0 0%	1 3.8%	1 1.3%
< Assay lower limit (40 copies/mL)	50 100%	25 96.2%	75 98.7%
CD4+ Cell Count (cells/mm^3) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [cells/mm^3]	549	556	552
BMI (kg/m^2) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [kg/m^2]	27.1	26.9	27.1
CD8+ T-cell Activation Percent (percentage of cells) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [percentage of cells]	13.67	13.40	13.66

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	Isotretinoin Arm	No Study Treatment Arm
Arm/Group Description	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.	No Isotretinoin treatment
Measure Participants	39	26
Median (Inter-Quartile Range) [percentage of cells]	3.24	0.52

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Isotretinoin Arm, No Study Treatment Arm
	Comments	Null hypothesis: There is no difference between the two arms in the change in T-cell activation from baseline to week 14/16.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.030
	Comments	Not adjusted for multiple comparisons.
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Secondary Outcome

Title	Change in CD8+ T-cell Activation
Description	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.
Time Frame	baseline, week 14/16, week 28

Outcome Measure Data

Analysis Population Description

The 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/Group Title	Isotretinoin Arm	No Study Treatment Arm
Arm/Group Description	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.	No Isotretinoin treatment
Measure Participants	39	26
Change from week 14/16 to week 28	-3.58	-0.91
Change from baseline to week 28	-0.69	0.03

3. Secondary Outcome

Title	Change in sCD14
Description	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.
Time Frame	baseline, week 14/16, week 28

Outcome Measure Data

Analysis Population Description

The 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/Group Title	Isotretinoin Arm	No Study Treatment Arm
Arm/Group Description	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.	No Isotretinoin treatment
Measure Participants	39	26
Change from baseline to week 14/16	0.02	-0.02
Change from week 14/16 to week 28	-0.06	0.02
Change from baseline to week 28	-0.02	0.00

4. Secondary Outcome

Title	Change in I-FABP
Description	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.
Time Frame	baseline, week 14/16, week 28

Outcome Measure Data

Analysis Population Description

The 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/Group Title	Isotretinoin Arm	No Study Treatment Arm
Arm/Group Description	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.	No Isotretinoin treatment
Measure Participants	39	26
Change from baseline to week 14/16	-0.03	0.04
Change from week 14/16 to week 28	0.09	-0.05
Change from baseline to week 28	0.07	-0.07

5. Secondary Outcome

Title	Change in IL-6
Description	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.
Time Frame	baseline, week 14/16, week 28

Outcome Measure Data

Analysis Population Description

The 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/Group Title	Isotretinoin Arm	No Study Treatment Arm
Arm/Group Description	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.	No Isotretinoin treatment
Measure Participants	39	26
Change from baseline to week 14/16	0.10	-0.04
Change from week 14/16 to week 28	-0.08	0.01
Change from baseline to week 28	0.02	-0.01

6. Secondary Outcome

Title	Change in hsCRP
Description	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.
Time Frame	baseline, week 14/16, week 28

Outcome Measure Data

Analysis Population Description

The 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/Group Title	Isotretinoin Arm	No Study Treatment Arm
Arm/Group Description	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.	No Isotretinoin treatment
Measure Participants	39	26
Change from baseline to week 14/16	0.20	-0.08
Change from week 14/16 to week 28	-0.24	0.11
Change from baseline to week 28	-0.09	-0.05

7. Secondary Outcome

Title	Change in sTNF-r1
Description	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.
Time Frame	baseline, week 14/16, week 28

Outcome Measure Data

Analysis Population Description

The 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/Group Title	Isotretinoin Arm	No Study Treatment Arm
Arm/Group Description	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.	No Isotretinoin treatment
Measure Participants	39	26
Change from baseline to week 14/16	0.00	0.01
Change from week 14/16 to week 28	0.00	0.00
Change from baseline to week 28	0.00	0.02

8. Secondary Outcome

Title	Change in sTNF-r2
Description	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.
Time Frame	baseline, week 14/16, week 28

Outcome Measure Data

Analysis Population Description

The 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/Group Title	Isotretinoin Arm	No Study Treatment Arm
Arm/Group Description	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.	No Isotretinoin treatment
Measure Participants	39	26
Change from baseline to week 14/16	0.03	0.01
Change from week 14/16 to week 28	-0.02	0.00
Change from baseline to week 28	0.00	0.02

9. Secondary Outcome

Title	Change in D-dimer
Description	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.
Time Frame	baseline, week 14/16, week 28

Outcome Measure Data

Analysis Population Description

The 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/Group Title	Isotretinoin Arm	No Study Treatment Arm
Arm/Group Description	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.	No Isotretinoin treatment
Measure Participants	39	26
Change from baseline to week 14/16	0.10	0.02
Change from week 14/16 to week 28	-0.04	0.00
Change from baseline to week 28	0.01	0.09

10. Secondary Outcome

Title	Change in TF
Description	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.
Time Frame	baseline, week 14/16, week 28

Outcome Measure Data

Analysis Population Description

The 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/Group Title	Isotretinoin Arm	No Study Treatment Arm
Arm/Group Description	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.	No Isotretinoin treatment
Measure Participants	39	26
Change from baseline to week 14/16	-0.01	0.01
Change from week 14/16 to week 28	0.00	0.01
Change from baseline to week 28	-0.02	0.03

11. Secondary Outcome

Title	Change in sCD163
Description	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.
Time Frame	baseline, week 14/16, week 28

Outcome Measure Data

Analysis Population Description

The 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/Group Title	Isotretinoin Arm	No Study Treatment Arm
Arm/Group Description	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.	No Isotretinoin treatment
Measure Participants	39	26
Change from baseline to week 14/16	0.15	-0.01
Change from week 14/16 to week 28	-0.14	-0.01
Change from baseline to week 28	-0.02	0.04

12. Secondary Outcome

Title	Change in CD4+ T-cell Count
Description	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.
Time Frame	baseline, week 14/16, week 28

Outcome Measure Data

Analysis Population Description

The 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/Group Title	Isotretinoin Arm	No Study Treatment Arm
Arm/Group Description	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.	No Isotretinoin treatment
Measure Participants	39	26
Change from baseline to week 14/16	17	-39
Change from week 14/16 to week 28	31	21
Change from baseline to week 28	27	-14

13. Secondary Outcome

Title	Change in Cell-associated HIV-1 RNA
Description	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.
Time Frame	baseline, week 14/16, week 28

Outcome Measure Data

Analysis Population Description

The 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 have cell-associated HIV-1 RNA data

Arm/Group Title	Isotretinoin Arm	No Study Treatment Arm
Arm/Group Description	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.	No Isotretinoin treatment
Measure Participants	37	26
Change from baseline to week 14/16	-0.09	-0.02
Change from week 14/16 to week 28	-0.03	-0.20
Change from baseline to week 28	-0.08	-0.18

14. Secondary Outcome

Title	Cell-associated HIV-1 DNA
Description	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.
Time Frame	baseline, week 14/16, week 28

Outcome Measure Data

Analysis Population Description

The 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 have cell-associated HIV-1 DNA data

Arm/Group Title	Isotretinoin Arm	No Study Treatment Arm
Arm/Group Description	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.	No Isotretinoin treatment
Measure Participants	39	26
baseline	2.55	2.72
week 14/16	2.52	2.66
week 28	2.64	2.55

15. Secondary Outcome

Title	Change in Treg Frequency (%FoxP3+/CD25hi+/CD39+/CD127-(CD4+))
Description	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.
Time Frame	baseline, week 14/16, week 28

Outcome Measure Data

Analysis Population Description

The 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/Group Title	Isotretinoin Arm	No Study Treatment Arm
Arm/Group Description	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.	No Isotretinoin treatment
Measure Participants	39	26
Change from baseline to week 14/16	0.00	-0.03
Change from week 14/16 to week 28	0.00	0.02
Change from baseline to week 28	-0.03	0.11

16. Secondary Outcome

Title	Change in Th17 Frequency (%IFNg-/IL17+(CD161+/CCR6+))
Description	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.
Time Frame	baseline, week 14/16, week 28

Outcome Measure Data

Analysis Population Description

The 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/Group Title	Isotretinoin Arm	No Study Treatment Arm
Arm/Group Description	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.	No Isotretinoin treatment
Measure Participants	39	26
Change from baseline to week 14/16	-0.04	0.01
Change from week 14/16 to week 28	0.02	-0.07
Change from baseline to week 28	-0.05	-0.01

17. Secondary Outcome

Title	Pharmacokinetics - Endogenous Levels of Retinoid Metabolites for Isotretinoin Arm
Description	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.
Time Frame	weeks 0, 20, 28

Outcome Measure Data

Analysis Population Description

Included only Isotretinoin arm participants who were on Isotretinoin for 8 weeks of more.

Arm/Group Title	Isotretinoin Arm
Arm/Group Description	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.
Measure Participants	39
Retinol	2.4
Total Retinyl Ester	0.5

18. Secondary Outcome

Title	Pharmacokinetics - Steady-state Trough Concentrations of Isotretinoin for Isotretinoin Arm
Description	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.
Time Frame	weeks 8, 12, 16

Outcome Measure Data

Analysis Population Description

Included only Isotretinoin arm participants who were on Isotretinoin for 8 weeks of more and have steady state troughs available.

Arm/Group Title	Isotretinoin Arm
Arm/Group Description	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.
Measure Participants	30
All	205
With EFV	228
No EFV	202

19. Secondary Outcome

Title	Pharmacokinetics - Trough Concentrations of TDF for Isotretinoin Arm
Description	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.)
Time Frame	weeks 0, 8, 12, 16, 20

Outcome Measure Data

Analysis Population Description

Included only Isotretinoin arm participants who were on TDF and on Isotretinoin for 8 weeks of more, and with available TDF trough.

Arm/Group Title	Isotretinoin Arm
Arm/Group Description	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.
Measure Participants	15
With Isotretinoin	82
Without Isotretinoin	63

20. Secondary Outcome

Title	Pharmacokinetics - 12-hour Levels of EFV for Isotretinoin Arm
Description	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.)
Time Frame	weeks 0, 8, 12, 16, 20

Outcome Measure Data

Analysis Population Description

Included only Isotretinoin arm participants who were on EFV and on Isotretinoin for 8 weeks of more, and with available EFV 12-hour levels.

Arm/Group Title	Isotretinoin Arm
Arm/Group Description	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.
Measure Participants	11
With Isotretinoin	2607
Without Isotretinoin	2665

21. Secondary Outcome

Title	Primary Targeted Adverse Events
Description	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.
Time Frame	from study entry to end of study (week 28)

Outcome Measure Data

Analysis Population Description

all enrolled participants

Arm/Group Title	Isotretinoin Arm	No Study Treatment Arm
Arm/Group Description	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.	No Isotretinoin treatment
Measure Participants	50	26
Count of Participants [Participants]	18 36%	6 23.1%

Adverse Events

Time Frame	Adverse Events (AEs) reported from study enrollment until study completion at 28 weeks
Adverse Event Reporting Description	Expedited adverse event (EAE) reporting followed the Division of AIDS (DAIDS) EAE Manual under the SAE Reporting Category and including fetal losses. Events were graded (1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death) according to the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, Clarification Aug 2009.
Arm/Group Title	Isotretinoin		No Study Treatment
Arm/Group Description	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.		No Isotretinoin treatment
All Cause Mortality
	Isotretinoin		No Study Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/50 (0%)		0/26 (0%)
Serious Adverse Events
	Isotretinoin		No Study Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/50 (4%)		0/26 (0%)
Infections and infestations
Meningitis viral	1/50 (2%)		0/26 (0%)
Pyelonephritis	1/50 (2%)		0/26 (0%)
Other (Not Including Serious) Adverse Events
	Isotretinoin		No Study Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	41/50 (82%)		18/26 (69.2%)
Infections and infestations
Upper respiratory tract infection	0/50 (0%)		2/26 (7.7%)
Investigations
Alanine aminotransferase increased	0/50 (0%)		4/26 (15.4%)
Aspartate aminotransferase increased	0/50 (0%)		3/26 (11.5%)
Blood alkaline phosphatase increased	3/50 (6%)		2/26 (7.7%)
Blood bicarbonate decreased	3/50 (6%)		1/26 (3.8%)
Blood bilirubin increased	7/50 (14%)		2/26 (7.7%)
Blood cholesterol increased	20/50 (40%)		11/26 (42.3%)
Blood creatinine increased	3/50 (6%)		2/26 (7.7%)
Blood glucose decreased	3/50 (6%)		1/26 (3.8%)
Blood glucose increased	10/50 (20%)		5/26 (19.2%)
Blood potassium decreased	3/50 (6%)		2/26 (7.7%)
Blood sodium decreased	3/50 (6%)		1/26 (3.8%)
Lipase abnormal	3/50 (6%)		2/26 (7.7%)
Low density lipoprotein increased	18/50 (36%)		8/26 (30.8%)
Neutrophil count decreased	2/50 (4%)		2/26 (7.7%)
Platelet count decreased	2/50 (4%)		2/26 (7.7%)
Nervous system disorders
Headache	3/50 (6%)		0/26 (0%)
Respiratory, thoracic and mediastinal disorders
Nasal congestion	0/50 (0%)		2/26 (7.7%)
Skin and subcutaneous tissue disorders
Dry skin	3/50 (6%)		0/26 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

In accordance with the Clinical Trials Agreement between NIAID (DAIDS) and company collaborators, NIAID (DAIDS) provides companies with a copy of any abstract, press release, or manuscript prior to submission for publication with sufficient time for company review and comment. The publication/other disclosure can be delayed for up to 30 additional business days for manuscripts and five (5) business days for abstracts, to preserve U.S. or foreign patent or other intellectual property rights.