Human Immunodeficiency Virus Infection
Conditions
Keywords
HIV, cardiovascular risk, systemic immune activation
Brief summary
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.
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.
Interventions
DRUGdarunavir with ritonavir and fixed-dose viread+emtricitabine daily
Sponsors
University of California, Davis
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Baseline, 12 months | CD4+ T-cells in the lamina propria/mm2 before and after 12 months of therapy compared to age-matched control volunteers without HIV. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Percentage of Total Artery Diameter | Baseline, 12 months | computerized axial tomography angiography of the coronary arteries (CT-angio) before and after 12-months of Darunavir therapy |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Systemic Immune Activation | Baseline, 12 months | Change in systemic immune activation, as measured by change in plasma cytokine levels (IL-6). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
darunavir with ritonavir and fixed-dose viread+emtricitabine daily | 18 |
| 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. | 17 |
| Total | 35 |
Baseline characteristics
| Characteristic | Normal Control Volunteers | HIV Positive Naive to ART | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants | 18 Participants | 35 Participants |
| Age, Continuous | 37 years | 40 years | 37 years |
| CD4+ T-cells | 460 cells/mm^3 | 215 cells/mm^3 | 310 cells/mm^3 |
| HIV viral load | 0 copies/ml | 41032 copies/ml | 41032 copies/ml |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 6 Participants | 5 Participants | 11 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 7 Participants | 15 Participants |
| Region of Enrollment United States | 17 participants | 18 participants | 35 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 17 Participants | 18 Participants | 35 Participants |
| weight | 194 lbs | 187 lbs | 191 lbs |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 18 | 0 / 17 |
| serious Total, serious adverse events | 0 / 18 | 0 / 17 |
Outcome results
Primary
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.
Time frame: Baseline, 12 months
Population: HIV negative participants underwent the procedures only once at Screening (entry). In the HIV group the comparison between before and after ART was done using a Wilcoxon signed-rank test.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| HIV Positive Naive to ART | 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 | Entry | 80 cells / mm^2 |
| HIV Positive Naive to ART | 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 | 12-months after ART | 213 cells / mm^2 |
| Normal Control Volunteers | 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 | Entry | 478 cells / mm^2 |
Comparison: Comparison between HIV positive naïve to ART before and after ART has been done.p-value: 0.0025Sign test
Secondary
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
Time frame: Baseline, 12 months
Population: We compare wall thickness between HIV+ infected individuals and in the HIV group before and after 12-months of ART.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| HIV Positive Naive to ART | Change in Percentage of Total Artery Diameter | 57 % of total artery diameter |
| Normal Control Volunteers | Change in Percentage of Total Artery Diameter | 53 % of total artery diameter |
p-value: 0.032Wilcoxon (Mann-Whitney)
Comparison: Comparison of coronary artery wall thickness before and after ART in the HIV infected participants.p-value: 0.826Sign test
Other Pre-specified
Change in Systemic Immune Activation
Change in systemic immune activation, as measured by change in plasma cytokine levels (IL-6).
Time frame: Baseline, 12 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| HIV Positive Naive to ART | Change in Systemic Immune Activation | 1.74 pg/ml |
| Normal Control Volunteers | Change in Systemic Immune Activation | 0.66 pg/ml |
Comparison: comparison between groups (HIV+ vs HIV-)p-value: <0.001Wilcoxon (Mann-Whitney)
Comparison: Changes in systemic immune activation through IL6p-value: 0.807Sign test