Alcohol Drinking, HIV-1-infection
Conditions
Keywords
HIV infection, alcohol, brain, inflammation
Brief summary
This study will examine whether moderate alcohol use in the context of HIV infection exacerbates inflammatory signaling in the immune system and brain. The study will recruit healthy individuals and people living with HIV infection who are otherwise in good health to participate. Participants will complete an experimental protocol that involves controlled alcohol administration and magnetic resonance imaging (MRI). Primary outcomes are plasma biomarkers of inflammation and MRI markers correlated with neuroinflammation. Results will advance understanding of the effects of alcohol use in people living with HIV infection.
Detailed description
A sample of 56 participants, to include equal numbers of people living with HIV and uninfected controls, will be recruited to complete the experimental protocol. Participants will be randomized to one of the two beverage conditions (0.60 g/kg alcohol beverage, 0.00 g/kg placebo beverage). Blood samples will be collected at baseline (prior to beverage administration) and for three hours afterward. Cognitive performance and subjective intoxication will be assessed using standardized measures. MRI scans will be collected 4-5 hours after beverage consumption to capture neurobiological outcomes on the descending limb of blood alcohol.
Interventions
OTHERAlcohol, ethyl, moderate dose
Moderate oral dose of ethyl alcohol
OTHERPlacebo
Placebo beverage
Sponsors
National Institute of General Medical Sciences (NIGMS)
The Miriam Hospital
Brown University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
General Inclusion Criteria: 1. 21-60 years old; 2. Able to speak and read English at least at 8th grade level; 3. Alcohol use ≥.60 g/kg at least once in past year. In standard drinks, this amount translates to 1.9-3.0 drinks for an average-weight female and 2.4-3.9 drinks for an average-weight male. 4. Body mass index of 18.5-34.9 kg/m2; 5. Lab tests obtained in past year showing no evidence of acute/chronic Hepatitis B or C infection; 6. HIV-1 serostatus (positive or negative, depending on group) confirmed by standard clinical testing; 7. Able to consume soy and nuts safely (in order to consume the standardized meal). General
Exclusion criteria
1. History of heavy drinking on a weekly or more frequent basis, with heavy drinking defined per NIAAA guidelines (≥4 drinks for women, ≥5 drinks for men on a given day), in the past two years; 2. More than five heavy drinking episodes in past 90 days; 3. Seeking or receiving treatment for alcohol/drug use, with exception of smoking cessation treatment; 4. Antibiotic use in past 1 month; 5. Daily use of non-steroidal anti-inflammatory drugs, which are known to increase gut permeability; 6. Disorder of the lower GI tract (e.g., inflammatory bowel disease, ulcerative colitis); 7. Positive urine test for amphetamine, cocaine, methamphetamine, opioids, or benzodiazepines (cannabis use will be assessed but is not an exclusion criterion); 8. Positive screening for past 12-month drug use disorder, indicated by Drug Abuse Screening Test-10 score \>2; 9. Current major psychiatric disorder (current major depressive episode, bipolar disorder, psychotic disorder); 10. History of fainting, weakness, infection, excessive bruising, or extreme distress from blood draw; 11. Safety contraindication for MRI (e.g., metal implant); Note: copper intrauterine devices (IUDs) continue to be excluded due to Brown MRI research facility regulations but other non-metal IUDs are allowed; 12. Head trauma with loss of consciousness \>10 min; 13. Inability to abstain from nicotine for 8 hours in-session; 14. For cannabis users: inability to abstain for 48 hours prior to study; 15. Pregnant, breastfeeding, or not using effective birth control; 16. Any other clinical condition or therapy that, in the physician's opinion, would make subject unsuitable for study or unable to comply with dosing requirement. HIV-Specific Inclusion Criteria: 1. On antiretroviral therapy (ART) for ≥6 mos; 2. Labs in past 6 mos showing viral load \<100 copies/mL, hemoglobin ≥10.0 g/dL, neutrophil count ≥1,000 cells/μL, and platelet count ≥150,000/μL; 3. No active AIDS diagnosis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Biomarker of Microbial Translocation | 0-3 hours | Lipopolysaccharide (LPS), measured in pg/ml |
| Plasma Biomarkers of Immune Activation | 0-3 hours | soluble cluster of differentiation 163 (sCD163), measured in ng/ml |
| Cerebral Metabolites | 5 hours | Magnetic resonance spectroscopy will be used quantify cerebral metabolites in brain regions of interest, specifically frontal lobe. Primary metabolites of interest include the summed peak of glutamate and glutamine; choline. |
| White Matter Diffusivity | 5 hours | Diffusion-weighted MRI will be used to quantify diffusivity metrics in brain white matter. Primary outcome is fractional anisotropy (measured on a scale of 0-1, where 1 reflects total anisotropy). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Subjective Intoxication | 0-5 hours | Intoxication rating scale (0-10), where a higher rating indicates greater subjective feelings of alcohol intoxication. Participants rate their maximum level of intoxication during the study. |
| Cognitive Functioning | 0-2 hours | Repeatable Battery for Assessment of Neuropsychological Status standardized scores; Note: this measure was unable to be administered to due coronavirus (COVID-19) pandemic restrictions related to social distancing. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited via online platforms (e.g., social media) and from The Miriam Hospital Infectious Diseases and Immunology Center, the largest outpatient provider of infectious disease treatment in Rhode Island.
Pre-assignment details
Participants are considered enrolled when they provide informed consent for initial screening. However, there is a further eligibility assessment at which participants may be found ineligible for a variety of reasons. Therefore the total number of individuals completing the study is lower than the number of individuals enrolled.
Participants by arm
| Arm | Count |
|---|---|
| HIV Seropositive - Placebo Group Individuals with confirmed HIV infection who received the placebo condition | 5 |
| HIV Seronegative - Placebo Group Individuals confirmed negative for HIV infection who received the placebo condition | 15 |
| HIV Seropositive - Alcohol Group Individuals with confirmed HIV infection who received the alcohol condition | 6 |
| HIV Seronegative - Alcohol Group Individuals confirmed negative for HIV infection who received the alcohol condition | 12 |
| Total | 38 |
Baseline characteristics
| Characteristic | HIV Seropositive - Placebo Group | Total | HIV Seronegative - Alcohol Group | HIV Seropositive - Alcohol Group | HIV Seronegative - Placebo Group |
|---|---|---|---|---|---|
| Age, Continuous | 41.4 years STANDARD_DEVIATION 11.1 | 35.9 years STANDARD_DEVIATION 10.9 | 31.8 years STANDARD_DEVIATION 9.4 | 40.0 years STANDARD_DEVIATION 12.3 | 35.73 years STANDARD_DEVIATION 11.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 9 Participants | 5 Participants | 2 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 29 Participants | 7 Participants | 4 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 5 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 5 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 24 Participants | 7 Participants | 4 Participants | 10 Participants |
| Region of Enrollment United States | 5 participants | 38 participants | 12 participants | 6 participants | 15 participants |
| Sex: Female, Male Female | 0 Participants | 13 Participants | 5 Participants | 0 Participants | 8 Participants |
| Sex: Female, Male Male | 5 Participants | 25 Participants | 7 Participants | 6 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 15 | 0 / 6 | 0 / 12 |
| other Total, other adverse events | 0 / 5 | 0 / 15 | 0 / 6 | 0 / 12 |
| serious Total, serious adverse events | 0 / 5 | 0 / 15 | 0 / 6 | 0 / 12 |
Outcome results
Primary
Cerebral Metabolites
Magnetic resonance spectroscopy will be used quantify cerebral metabolites in brain regions of interest, specifically frontal lobe. Primary metabolites of interest include the summed peak of glutamate and glutamine; choline.
Time frame: 5 hours
Population: One participant's data was lost due to computational/technical factors.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| HIV seropositive - placebo group | Cerebral Metabolites | Glutamate+glutamine | 13.0 mmol/kg of tissue water | Standard Deviation 1.5 |
| HIV seropositive - placebo group | Cerebral Metabolites | Choline | 1.9 mmol/kg of tissue water | Standard Deviation 0.29 |
| HIV seronegative - placebo group | Cerebral Metabolites | Choline | 1.8 mmol/kg of tissue water | Standard Deviation 0.38 |
| HIV seronegative - placebo group | Cerebral Metabolites | Glutamate+glutamine | 14.6 mmol/kg of tissue water | Standard Deviation 5 |
| HIV seropositive - alcohol group | Cerebral Metabolites | Glutamate+glutamine | 12.3 mmol/kg of tissue water | Standard Deviation 2.8 |
| HIV seropositive - alcohol group | Cerebral Metabolites | Choline | 1.75 mmol/kg of tissue water | Standard Deviation 0.22 |
| HIV seronegative - alcohol group | Cerebral Metabolites | Glutamate+glutamine | 14.4 mmol/kg of tissue water | Standard Deviation 3.2 |
| HIV seronegative - alcohol group | Cerebral Metabolites | Choline | 1.7 mmol/kg of tissue water | Standard Deviation 0.33 |
Comparison: Test of group by condition interaction on choline.p-value: 0.987ANOVA
Comparison: Test of group by condition interaction on summed peak of glutamate plus glutaminep-value: 0.836ANOVA
Primary
Plasma Biomarker of Microbial Translocation
Lipopolysaccharide (LPS), measured in pg/ml
Time frame: 0-3 hours
Population: Data from one participant in the HIV seronegative - alcohol group arm was not returned from the analytic laboratory and so this group had 11 rather than 12 participants for the LPS analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| HIV seropositive - placebo group | Plasma Biomarker of Microbial Translocation | Hour 0 | 58.562 pg/ml | Standard Deviation 26.2243 |
| HIV seropositive - placebo group | Plasma Biomarker of Microbial Translocation | Hour 1 | 52.421 pg/ml | Standard Deviation 18.2908 |
| HIV seropositive - placebo group | Plasma Biomarker of Microbial Translocation | Hour 2 | 64.928 pg/ml | Standard Deviation 24.6054 |
| HIV seropositive - placebo group | Plasma Biomarker of Microbial Translocation | Hour 3 | 66.267 pg/ml | Standard Deviation 25.6505 |
| HIV seronegative - placebo group | Plasma Biomarker of Microbial Translocation | Hour 1 | 91.230 pg/ml | Standard Deviation 45.7622 |
| HIV seronegative - placebo group | Plasma Biomarker of Microbial Translocation | Hour 2 | 96.092 pg/ml | Standard Deviation 54.8184 |
| HIV seronegative - placebo group | Plasma Biomarker of Microbial Translocation | Hour 3 | 94.090 pg/ml | Standard Deviation 50.1699 |
| HIV seronegative - placebo group | Plasma Biomarker of Microbial Translocation | Hour 0 | 99.285 pg/ml | Standard Deviation 48.2314 |
| HIV seropositive - alcohol group | Plasma Biomarker of Microbial Translocation | Hour 2 | 88.037 pg/ml | Standard Deviation 31.6958 |
| HIV seropositive - alcohol group | Plasma Biomarker of Microbial Translocation | Hour 1 | 81.651 pg/ml | Standard Deviation 31.7415 |
| HIV seropositive - alcohol group | Plasma Biomarker of Microbial Translocation | Hour 3 | 67.979 pg/ml | Standard Deviation 14.8 |
| HIV seropositive - alcohol group | Plasma Biomarker of Microbial Translocation | Hour 0 | 77.232 pg/ml | Standard Deviation 31.6189 |
| HIV seronegative - alcohol group | Plasma Biomarker of Microbial Translocation | Hour 3 | 95.877 pg/ml | Standard Deviation 50.5859 |
| HIV seronegative - alcohol group | Plasma Biomarker of Microbial Translocation | Hour 1 | 98.079 pg/ml | Standard Deviation 47.9421 |
| HIV seronegative - alcohol group | Plasma Biomarker of Microbial Translocation | Hour 0 | 97.343 pg/ml | Standard Deviation 42.995 |
| HIV seronegative - alcohol group | Plasma Biomarker of Microbial Translocation | Hour 2 | 107.312 pg/ml | Standard Deviation 47.1446 |
Comparison: Linear mixed model testing the three-way interaction of HIV serostatus (positive/negative), beverage condition (alcohol/placebo), and time (hour 0, 1, 2, 3).p-value: 0.343Mixed Models Analysis
Primary
Plasma Biomarkers of Immune Activation
soluble cluster of differentiation 163 (sCD163), measured in ng/ml
Time frame: 0-3 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| HIV seropositive - placebo group | Plasma Biomarkers of Immune Activation | Hour 0 | 323.50 ng/ml | Standard Deviation 28.333 |
| HIV seropositive - placebo group | Plasma Biomarkers of Immune Activation | Hour 1 | 261.77 ng/ml | Standard Deviation 41.248 |
| HIV seropositive - placebo group | Plasma Biomarkers of Immune Activation | Hour 2 | 261.51 ng/ml | Standard Deviation 45.48 |
| HIV seropositive - placebo group | Plasma Biomarkers of Immune Activation | Hour 3 | 303.82 ng/ml | Standard Deviation 43.385 |
| HIV seronegative - placebo group | Plasma Biomarkers of Immune Activation | Hour 1 | 304.71 ng/ml | Standard Deviation 100.36 |
| HIV seronegative - placebo group | Plasma Biomarkers of Immune Activation | Hour 2 | 298.80 ng/ml | Standard Deviation 107.154 |
| HIV seronegative - placebo group | Plasma Biomarkers of Immune Activation | Hour 3 | 300.68 ng/ml | Standard Deviation 105.172 |
| HIV seronegative - placebo group | Plasma Biomarkers of Immune Activation | Hour 0 | 301.22 ng/ml | Standard Deviation 94.12 |
| HIV seropositive - alcohol group | Plasma Biomarkers of Immune Activation | Hour 2 | 410.52 ng/ml | Standard Deviation 117.886 |
| HIV seropositive - alcohol group | Plasma Biomarkers of Immune Activation | Hour 1 | 412.88 ng/ml | Standard Deviation 95.823 |
| HIV seropositive - alcohol group | Plasma Biomarkers of Immune Activation | Hour 3 | 405.28 ng/ml | Standard Deviation 111.696 |
| HIV seropositive - alcohol group | Plasma Biomarkers of Immune Activation | Hour 0 | 376.36 ng/ml | Standard Deviation 80.593 |
| HIV seronegative - alcohol group | Plasma Biomarkers of Immune Activation | Hour 3 | 275.30 ng/ml | Standard Deviation 82.67 |
| HIV seronegative - alcohol group | Plasma Biomarkers of Immune Activation | Hour 1 | 276.51 ng/ml | Standard Deviation 80.02 |
| HIV seronegative - alcohol group | Plasma Biomarkers of Immune Activation | Hour 0 | 271.79 ng/ml | Standard Deviation 85.204 |
| HIV seronegative - alcohol group | Plasma Biomarkers of Immune Activation | Hour 2 | 262.46 ng/ml | Standard Deviation 87.451 |
Comparison: Linear mixed model testing the three-way interaction of HIV serostatus (positive/negative), beverage condition (alcohol/placebo), and time (hour 0, 1, 2, 3).p-value: 0.026Mixed Models Analysis
Primary
White Matter Diffusivity
Diffusion-weighted MRI will be used to quantify diffusivity metrics in brain white matter. Primary outcome is fractional anisotropy (measured on a scale of 0-1, where 1 reflects total anisotropy).
Time frame: 5 hours
Population: 2 participants were lost to analysis due to technical/computational reasons.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HIV seropositive - placebo group | White Matter Diffusivity | .560 units on a scale | Standard Deviation 0.011 |
| HIV seronegative - placebo group | White Matter Diffusivity | .570 units on a scale | Standard Deviation 0.009 |
| HIV seropositive - alcohol group | White Matter Diffusivity | .562 units on a scale | Standard Deviation 0.007 |
| HIV seronegative - alcohol group | White Matter Diffusivity | .574 units on a scale | Standard Deviation 0.009 |
Comparison: Test of group by condition interaction on fractional anisotropy (FA).p-value: 0.846ANOVA
Secondary
Cognitive Functioning
Repeatable Battery for Assessment of Neuropsychological Status standardized scores; Note: this measure was unable to be administered to due coronavirus (COVID-19) pandemic restrictions related to social distancing.
Time frame: 0-2 hours
Population: Data cannot be reported because this test was not performed. Due to restrictions on human subjects research implemented during the COVID-19 pandemic, researchers were not allowed in the same room as participants for \>15 mins total during visits. This test (RBANS) was standardized with the administrator seated at a table across from the test taker. The test takes 20-30 mins to administer. Thus, due to COVID-19 rules, this test could not be administered as standardized.
Secondary
Subjective Intoxication
Intoxication rating scale (0-10), where a higher rating indicates greater subjective feelings of alcohol intoxication. Participants rate their maximum level of intoxication during the study.
Time frame: 0-5 hours
Population: Full sample
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HIV seropositive - placebo group | Subjective Intoxication | 1.6 score on a scale | Standard Deviation 2.1 |
| HIV seronegative - placebo group | Subjective Intoxication | 1.3 score on a scale | Standard Deviation 1.5 |
| HIV seropositive - alcohol group | Subjective Intoxication | 6.0 score on a scale | Standard Deviation 1.5 |
| HIV seronegative - alcohol group | Subjective Intoxication | 5.5 score on a scale | Standard Deviation 1.9 |
Comparison: Test of interaction of group by beverage condition.p-value: 0.894ANOVA