The Effects of Cognitive Behavioral Therapy on Insulin Resistance in People With HIV

A Randomized, Controlled Trial Assessing the Effects of Cognitive Behavioral Therapy to Prevent Worsening Insulin Resistance in Depressed, Virologically-Suppressed, Antiretroviral-Treated Adults With HIV

The goal of this clinical trial is to learn if depression treatment improves insulin resistance, or how the body uses insulin to lower blood sugar, in people with HIV on HIV treatment. Researchers will compare an internet-based (online) depression treatment program called cognitive behavioral therapy with depression education. In the online group, participants will undergo 9 weekly treatment sessions. The education group will receive learning materials about depression and will be monitored every month. All participants will have 4 study visits over 12 months.

Study Overview

• Status: Recruiting
• Conditions: Insulin Resistance; HIV; Cognitive Behavior Therapy; Depression in Adults
• Intervention / Treatment: Behavioral: Internet cognitive behavioral therapy (iCBT-D); Behavioral: Active Control (AC)

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Danielle Grounds, RVT; Phone Number: 1-317-278-0255; Email: diground@iu.edu
• Study Contact Backup: Name: Rory Duplantier, ANP-PC; Phone Number: 1-317-274-8473; Email: rldupl@iu.edu

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Recruiting
      • Indiana University Health
      • Contact: Danielle Grounds; Phone Number: 317-278-0255; Email: diground@iu.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• HIV-1 infection, documented as listed clinically in the participant's electronic medical record by any of the following tests: (1) any licensed rapid HIV test, (2) HIV enzyme test kit at any time prior to study entry, (3) at least one detectable HIV-1 antigen, or (4) at least one detectable plasma HIV-1 RNA viral load.
• Age ≥ 18 years.
• Ongoing receipt of stable antiretroviral therapy of any kind for at least 180 days prior to Screening

• Meets the depression definition for this trial:

  • (1) repeat PHQ-9 ≥10100 result at the Screening Visit (suggesting moderate to severe depressive symptoms), AND
  • (2) PHQ-9 depressive disorder diagnosis (2 or more of the 9 depressive symptoms, including depressed mood or anhedonia, present in the past 2 weeks), AND
  • (3) functional impairment (using the tenth PHQ-9 item assessing social/occupational impairment), AND
  • (4) no evidence that the direct physiological effects of a substance, medication, or medical condition clearly account for the depressive symptoms, AND
  • (5) no bipolar or psychotic disorders

NOTE: The use of antidepressant medications is not exclusionary.

• HbA1c < 6.5% at Screening
• HIV-1 RNA level < 75 copies/mL at Screening

NOTE: There are no CD4 cell count eligibility criteria for this trial.

Exclusion Criteria:

• Inability to complete written, informed consent
• Inability to read and understand English as seen on a computer screen
• Diagnosed diabetes mellitus or any previously recorded HbA1c ≥6.5%
• History of bipolar disorder or a psychotic disorder, including schizophrenia

NOTE: Depressive disorders are not exclusionary.

• Incarceration at the time of any study visit
• Active suicidality at Entry, as determined by the patient's HIV provider or social worker following a positive response (1, 2, or 3) to PHQ-9 Item #9 and a positive response (yes) to one or more of the three questions (for Question #3, the previous attempt must be within the past 10 years) on the Patient Suicidality Form (see Appendix).
• Diagnosed disease or process, besides HIV infection, associated with increased systemic inflammation (including, but not limited to, systemic lupus erythematosus, inflammatory bowel diseases, or other collagen vascular diseases).

NOTE: Hepatitis B or C co-infections are NOT exclusionary, but treatment for hepatitis C cannot be provided during study participation

• End stage renal disease requiring renal replacement therapy (dialysis, transplantation).
• Known or suspected malignancy requiring systemic treatment within 180 days of the Entry Visit.

NOTE: Localized treatment for skin cancers is not exclusionary.

• Therapy for serious medical illnesses within 14 days prior to the Entry Visit

NOTE: Therapy for serious medical illnesses that overlaps with a study visit will result in postponement of that study visit until the course of therapy is completed; postponement outside of the allowed study visit timeframe will result in study discontinuation.

• Pregnancy or breastfeeding during the study.
• Receipt of investigational agents, cytotoxic chemotherapy, systemic immunosuppressive therapies, systemic glucocorticoids (of any dose), or anabolic steroids at the Entry Visit

NOTE: Physiologic testosterone replacement therapy or topical steroids is not exclusionary. Inhaled/nasal steroids are not exclusionary as long as the participant is not also receiving HIV protease inhibitors

NOTE: Use of NSAIDS and aspirin are allowed

• Active drug use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Internet Cognitive Behavioral Therapy (iCBT-D); Intervention participants will receive the empirically supported, HIPAA-compliant, therapist-assisted iCBT-D called Good Days Ahead (GDA; MindStreet, Inc.). GDA uses an interactive, multimedia format (including video, exercises, calls to action, newsfeeds, and customized feedback) to deliver nine 45-minute sessions, the structure and content of which mirror traditional face-to-face CBT. Topics include identifying and modifying automatic thoughts, using behavioral activation and other behavioral methods, identifying and modifying schemas, using effective coping strategies, and employing other core CBT methods.	Behavioral: Internet cognitive behavioral therapy (iCBT-D); Intervention participants will receive the empirically supported, HIPAA-compliant, therapist-assisted iCBT-D called Good Days Ahead (GDA; MindStreet, Inc.). GDA uses an interactive, multimedia format (including video, exercises, calls to action, newsfeeds, and customized feedback) to deliver nine 45-minute sessions, the structure and content of which mirror traditional face-to-face CBT. Topics include identifying and modifying automatic thoughts, using behavioral activation and other behavioral methods, identifying and modifying schemas, using effective coping strategies, and employing other core CBT methods.
Active Comparator: Active Control (AC); Our AC comparator will include depression education and depressive symptom monitoring along with usual depression care as provided by the participants HIV clinicians. Trial staff will fist have a 30-minute call with AC participants to review depression materials, including their HIV provider's role in its management and treatment options and also provide a list of local mental health services. There are no care restrictions by the primary HIV clinicians. Trial staff will call AC participants every 4 weeks to assess depressive symptoms (PHQ-9) and will notify clinic staff to encourage additional care when indicated.	Behavioral: Active Control (AC); Our AC comparator will include depression education and depressive symptom monitoring along with usual depression care as provided by the participants HIV clinicians. Trial staff will fist have a 30-minute call with AC participants to review depression materials, including their HIV provider's role in its management and treatment options and also provide a list of local mental health services. There are no care restrictions by the primary HIV clinicians. Trial staff will call AC participants every 4 weeks to assess depressive symptoms (PHQ-9) and will notify clinic staff to encourage additional care when indicated.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in HOMA-IR at 24 weeks	Homeostasis Model Assessment-Insulin, where higher values indicate greater insulin resistance	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in circulating sCD14 at 24 weeks	sCD14 is a blood measure of inflammation, where higher levels indicate greater amounts specifically of monocyte activation	24 weeks
Change from baseline in circulating REG3a at 24 weeks	REG3a is a blood measure of gut integrity, where higher levels indicate greater amounts of gut wall breakdown	24 weeks
Change from baseline in circulating 16S rDNA at 24 weeks	16S rDNA is a measure of small amounts of bacteria in the blood that typically cannot be grown on blood cultures, where higher amounts indicate more bacteria in the bloodstream	24 weeks
Changes from baseline in circulating b-D-glucan at 24 weeks	b-D-glucan is a measure of small amounts of fungus in the blood that typically cannot be grown in fungal cultures, where higher amounts indicate more fungus in the bloodstream	24 weeks
Change from baseline in HOMA-IR at 48 weeks	Homeostasis Model Assessment-Insulin, where higher values indicate greater insulin resistance	48 weeks
Change from baseline in HbA1c at 24 weeks and 48 weeks	HbA1c (hemoglobin A1c) is a measure of average blood sugar control over 3 months	24, 48 weeks
Change from baseline in glycated albumin at 24 weeks and 48 weeks	Glycated albumin is a measure of average blood glucose control over 1 month	24, 48 weeks
Change from baseline in circulating sCD163 at 24 weeks	sCD163 is a measure of inflammation, where higher levels indicate greater macrophage activation	24 weeks
Change from baseline in PC(P-16:0/18:2) levels at 24 weeks	PC(P-16:0/18:2) is a cell metabolite, where higher levels indicate greater insulin resistance	24 weeks

Collaborators and Investigators

• Sponsor: Indiana University
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Samir K Gupta, MD, Indiana University

Publications and helpful links

General Publications

• Bourgi K, Kundu S, Stewart JC, So-Armah K, Freiberg M, Gupta SK. Associations of HIV and Depression with Incident Diabetes Mellitus: Veterans Aging Cohort Study. Clin Infect Dis. 2022 Feb 3;78(2):378-85. doi: 10.1093/cid/ciac085. Online ahead of print.
• Gupta SK, Slaven JE, Liu Z, Polanka BM, Freiberg MS, Stewart JC. Effects of Internet Cognitive-Behavioral Therapy on Depressive Symptoms and Surrogates of Cardiovascular Risk in Human Immunodeficiency Virus: A Pilot, Randomized, Controlled Trial. Open Forum Infect Dis. 2020 Jul 5;7(7):ofaa280. doi: 10.1093/ofid/ofaa280. eCollection 2020 Jul.

Study record dates

Study Major Dates

• Study Start (Actual): April 10, 2026
• Primary Completion (Estimated): June 30, 2031
• Study Completion (Estimated): June 30, 2031

Study Registration Dates

• First Submitted: November 5, 2025
• First Submitted That Met QC Criteria: November 5, 2025
• First Posted (Actual): November 10, 2025

Study Record Updates

• Last Update Posted (Actual): June 2, 2026
• Last Update Submitted That Met QC Criteria: May 31, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: diabetes; depression; cognitive behavioral therapy; insulin resistance; hiv
• Additional Relevant MeSH Terms: Blood-Borne Infections; Urogenital Diseases; Genital Diseases; Endocrine System Diseases; Metabolic Diseases; Immune System Diseases; Behavioral Symptoms; Infections; RNA Virus Infections; Virus Diseases; Glucose Metabolism Disorders; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Slow Virus Diseases; Hyperinsulinism; HIV Infections; Behavior; Nutritional and Metabolic Diseases; Depression; Acquired Immunodeficiency Syndrome; Diabetes Mellitus; Insulin Resistance
• Other Study ID Numbers: 28855 (Regional Committees for Medical and Health Research Ethics); R01DK141366 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All collected IPD
• IPD Sharing Time Frame: Start date: January 1, 2031 End Date: Indefinite
• IPD Sharing Access Criteria: Data and sample requests will be honored after submission of a short proposal that outlines an important scientific question with an appropriate statistical analysis plan that justifies the use of these datasets. In addition, the requests must also verify that confidentiality of the datasets will be ensured. A formal data sharing agreement will be required prior to provision of any datasets.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No