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

Purpose

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.

Condition	Intervention	Phase
Human Immunodeficiency Virus Infection	Drug: darunavir with ritonavir and fixed-dose viread+emtricitabine daily	Phase 4


Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Bio-equivalence Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Mechanisms of Immune Reconstitution & Reduced Immune Activation Following Darunavir-based ART

Resource links provided by NLM:

MedlinePlus related topics: HIV/AIDS

Drug Information available for: Emtricitabine Tenofovir Ritonavir Tenofovir Disoproxil Fumarate Darunavir Darunavir ethanolate

U.S. FDA Resources

Further study details as provided by University of California, Davis:

Primary Outcome Measures:

Recovery of CD4 T-lymphocytes in GALT [ Time Frame: 12 months ] [ Designated as safety issue: No ]
To quantify restoration of GALT Lymphocyte Populations following Darunavir Therapy as measured by CD4+ T-cells in the lamina propria/mm2 before and after 12 months of therapy compared to age-matched control volunteers without HIV.

Secondary Outcome Measures:

To measure the change in cardiovascular risk [ Time Frame: 12 months ] [ Designated as safety issue: No ]
To measure the change in CVD risk as determined by Intimal Medial Thickness (IMT), Brachial Artery Reactivity (BAR), and computerized axial tomography angiography of the coronary arteries (CT-angio) before and after 12-months of Darunavir therapy and in comparison to age-matched and traditional CVD risk parameters-matched control volunteers without HIV.

Other Outcome Measures:

changes in systemic immune activation [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
To determine correlations between Immune Activation and Metabolic Profile as measured by CD38/HLA-DR co-expression on CD4+ and CD8+ lymphocytes in the PBMC's, and duodenal GALT and inflammatory cytokines in plasma and tissue before and after 12-months of Darunavir therapy and in comparison to age-matched control volunteers without HIV.


Estimated Enrollment:	40
Study Start Date:	June 2013
Estimated Study Completion Date:	December 2016
Estimated Primary Completion Date:	December 2015 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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 Name: 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.

Arms

Assigned Interventions

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 Name: 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.

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.

Eligibility


Ages Eligible for Study:	21 Years and older (Adult, Senior)
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

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.

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01869634

Contacts


Contact: Tammy Yotter, RN	916-914-6261	tammy.yotter@ucdmc.ucdavis.edu
Contact: David M Asmuth, MD	916-734-8695	david.asmuth@ucdmc.ucdavis.edu

Locations


United States, California
University of California Davis	Recruiting
Sacramento, California, United States, 95617
Contact: Tammy Yotter, RN 916-914-6261 tammy.yotter@ucdmc.ucdavis.edu
Principal Investigator: David M Asmuth, MD

Sponsors and Collaborators

David Asmuth, MD

More Information


Responsible Party:	David Asmuth, MD, Professor, University of California, Davis
ClinicalTrials.gov Identifier:	NCT01869634 History of Changes
Other Study ID Numbers:	IIS RFA _Asmuth:TMC114HIV2029 394080-2
Study First Received:	June 1, 2013
Last Updated:	June 1, 2013
Health Authority:	United States: Food and Drug Administration United States: Institutional Review Board Sponsor-Investigator: David M Asmuth, MD, Professor, University of California Davis Medical Center, Sacramento, CA, USA

Keywords provided by University of California, Davis:


HIV cardiovascular risk systemic immune activation

Additional relevant MeSH terms:


Immunologic Deficiency Syndromes Acquired Immunodeficiency Syndrome HIV Infections Virus Diseases Immune System Diseases Lentivirus Infections Retroviridae Infections RNA Virus Infections Sexually Transmitted Diseases, Viral Sexually Transmitted Diseases Slow Virus Diseases Ritonavir Darunavir Emtricitabine	Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination Tenofovir HIV Protease Inhibitors Protease Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Anti-HIV Agents Anti-Retroviral Agents Antiviral Agents Anti-Infective Agents Cytochrome P-450 CYP3A Inhibitors Cytochrome P-450 Enzyme Inhibitors Reverse Transcriptase Inhibitors Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on September 27, 2016