Mechanisms of Immune Reconstitution & Reduced Immune Activation Following Darunavir-based ART

Potent HIV suppression with Darunavir-based antiretroviral therapy (ART) will lead to repopulation of gastrointestinal-associated lymphoid tissue (GALT) cluster of differentiation (CD)4+ T-cell populations, normalization of systemic immune activation, and improved HIV-associated cardiovascular disease (CVD) risk.

Study Overview

• Status: Completed
• Conditions: Human Immunodeficiency Virus Infection
• Intervention / Treatment: Drug: darunavir with ritonavir and fixed-dose viread+emtricitabine daily

Detailed Description

Rationale Infection with HIV causes significant morbidity and mortality, even among individuals who are virologically suppressed with combination anti-retroviral therapy (ART). ART is effective in prolonging life and enabling individuals who are HIV positive to live near-normal life spans. However, these individuals are increasingly developing a number of chronic diseases of aging, such as atherosclerotic cardiovascular disease (ASCVD). The proposed studies will examine the role of highly active antiretroviral therapy in restoring the mucosal immunity and the systemic effect on immune activation, bacterial translocation, and change in HIV-associated cardiovascular disease risk.

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • Sacramento, California, United States, 95617
      • University of California Davis

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Willing to sign consent form
• Naïve to ART (remote ART use >5 years will be considered on a case by case basis)
• No known GI or cardiovascular disease
• Between the ages of 18 and 60
• No active opportunistic infections or therapy for acute OI within 30 days of entry. Subjects can be on secondary prophylaxis with a history of AIDS defining illness.
• All women of childbearing potential (WCBP) must have a negative urine pregnancy test before any of the invasive or radiation exposure study procedures.
• Normal population should be free of chronic metabolic conditions such as diabetes, hypercholesterolemia, or coronary artery disease
• There are no CD4+ T-cell count or HIV plasma viral load restrictions.

Exclusion Criteria:

• Abnormal coagulation parameters (PT>1.2 upper limit of normal (ULN))
• Thrombocytopenia (platelet count <50.000 within 6 weeks)
• Contra-indications to upper endoscopy or conscious sedation
• Anemia (>grade 1 [appendix 1])
• Aspirin, ibuprofen, warfarin or other agents that interfere with the coagulation cascade are prohibited within 1 week of endoscopy.
• Renal insufficiency (serum Creatinine >1.2 ULN)
• History of chronic proteinuria that could impact viread use.
• Allergy to contrast used for CT angiography
• Requirement to take medications that are contraindicated with study ART regimen.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: HIV positive naive to ART; HIV subjects will receive open-label darunavir 800 mg in combination with ritonavir 100 mg tablets and fixed-dose combination viread + emtricitabine (Truvada®) to be taken once daily without regard to food. Subjects will undergo upper endoscopy, CT cardiac angiogram, intimal-medial thickening, and peripheral blood collection before and after 12 months of ART.	Drug: darunavir with ritonavir and fixed-dose viread+emtricitabine daily; Other Names: darunavir (Prezista®) 800 mg with ritonavir 100 mg and Truvada® to be taken once daily
No Intervention: normal control volunteers; HIV negative age-matched controls will undergo the same interventions and procedures without receiving ART at study entry and after 12 months.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of CD4+ T-cells in the Lamina Propria/mm2 Before and After 12 Months of Therapy Compared to Age-matched Control Volunteers Without HIV	CD4+ T-cells in the lamina propria/mm2 before and after 12 months of therapy compared to age-matched control volunteers without HIV.	Baseline, 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Percentage of Total Artery Diameter	computerized axial tomography angiography of the coronary arteries (CT-angio) before and after 12-months of Darunavir therapy	Baseline, 12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Systemic Immune Activation	Change in systemic immune activation, as measured by change in plasma cytokine levels (IL-6).	Baseline, 12 months

Collaborators and Investigators

• Sponsor: University of California, Davis

Study record dates

Study Major Dates

• Study Start: June 1, 2013
• Primary Completion (Actual): December 1, 2016
• Study Completion (Actual): December 1, 2016

Study Registration Dates

• First Submitted: June 1, 2013
• First Submitted That Met QC Criteria: June 1, 2013
• First Posted (Estimate): June 5, 2013

Study Record Updates

• Last Update Posted (Actual): March 4, 2020
• Last Update Submitted That Met QC Criteria: February 24, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: HIV; cardiovascular risk; systemic immune activation
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Emtricitabine; Ritonavir; Darunavir
• Other Study ID Numbers: 394080; IIS RFA _Asmuth:TMC114HIV2029 (Other Identifier: Other)