Aging, HIV Infections
Conditions
Keywords
tenofovir, pharmacokinetic, cellular kinase
Brief summary
The goal of this clinical study is to learn about the effect of aging on certain enzymes, or proteins, in the blood and colon. The study involves collection of blood and colon tissue biopsies using a flexible sigmoidoscope or colonoscope. This study is also investigating how medications tenofovir and emtricitabine interact with certain enzymes. The investigators will compare the difference in enzyme activity between people taking tenofovir and emtricitabine, to those who are not taking tenofovir and emtricitabine.
Detailed description
This project involves obtaining peripheral blood mononuclear cells (PBMCs) and colorectal tissue samples from study participants in order to measure adenylate kinase 2 (AK2) and muscle-type creatine kinase (CKM) enzyme levels in various age populations. Both AK2 and CKM has been demonstrated to be vital enzymes in converting the prodrug tenofovir (TFV) into its active form, tenofovir diphosphate (TFV-DP). However, no study has yet investigated the effect of aging on AK2 or CKM in tissues relevant to HIV infection and prevention. This study will investigate the AK2 and CKM variability in individuals from various age groups and how the pharmacokinetics (PK) of tenofovir (TFV) vary with altering levels of cellular enzymes in different age populations
Interventions
OTHERbiopsy
colorectal biopsy for tissue acquisition
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
National Institute on Aging (NIA)
Johns Hopkins University
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
Yes
Inclusion criteria
1. English speaking male or female volunteers between the ages of 18-50 for younger adults or 65-80 for older adults 2. Willing to provide written informed consent 3. Willing to abstain from insertion of anything in rectum for 72 hours before and 72 hours after the endoscopic procedure for colorectal tissue collection. 4. Not currently participating in other research studies involving drugs and/or medical devices. For participants not infected with HIV (Control Cohort A) 1. No known risk for HIV exposure or a documented negative HIV-1/HIV-2 Ag/Ab test in the past 3 months (HIV risk, but not on PrEP) 2. Documented negative HBsAg in those taking study TFV (i.e. cohort B) For participants not infected with HIV, but taking or willing to take TFV (PrEP Cohort B) 1. Currently taking TFV-based oral PrEP daily or willing to take oral TFV-containing PrEP for one week 2. Documented negative HIV-1/HIV-2 Ag/Ab test in the past 3 months 3. Documented negative HBsAg For participants infected with HIV (ARV Cohort C) 1. Virologically suppressed HIV for at least 6 months prior to screening. 2. Taking tenofovir disoproxil fumarate or tenofovir alafenamide containing regimen to treat HIV
Exclusion criteria
1. History of inflammatory bowel disease or active inflammatory condition of the GI tract 2. History of significant gastrointestinal bleeding 3. Current medically-indicated use of warfarin or heparin or other anticoagulant medications associated with increased risk for bleeding following mucosal biopsy (e.g., daily high dose aspirin \[\>81 mg\], non-steroidal anti-inflammatory drugs \[NSAIDs\], or Pradaxa®) 4. Use of systemic immunomodulatory medications within 4 weeks of enrollment 5. Use of rectally administered medications within 4 weeks of enrollment 6. Use of product containing nonoxynol-9 within 4 weeks of enrollment 7. Use of any investigational products within 4 weeks of enrollment 8. Any other clinical condition or prior therapy that, in the opinion of the investigator, would make the participant unsuitable for the study or unable to comply with the study requirements. Such conditions may include, but are not limited to, current or recent history of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, neurological, or cerebral disease. 9. Active rectal infection (GC, Chlamydia, HSV). Participants screening positive for GC/CT at the time of endoscopy will be excluded from analysis (and replaced). For participants not undergoing a concurrent endoscopic procedure for indication unrelated to this study: 10. Hct \<36% 11. Platelet count \<150/mm3 12. International normalised ratio blood test \> 1.2
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Concentration of AK2 in Colorectal Tissue | Once within one month | Concentration in nanometers (nm) of AK2 in colorectal tissue. |
| Concentration of CKM in Colorectal Tissue | Once within one month | Concentration in nanometers (nm) of CKM in colorectal tissue |
| Concentration of AK2 in Peripheral Blood Mononuclear Cells | Once within one month | Concentration in nanometers (nm) of AK2 in peripheral blood mononuclear cells |
Countries
United States
Participant flow
Recruitment details
Three cohorts of participants will be recruited, with younger adults (18-50 years old) and older adults (65-80 years old) in each cohort.
Participants by arm
| Arm | Count |
|---|---|
| HIV Negative, Not Taking Tenofovir (TFV) Based PrEP (18 - 50 Years) biopsy: colorectal biopsy for tissue acquisition | 11 |
| HIV Positive Taking Tenofovir (TFV) and Emtricitabine (FTC) Based HIV Treatment (18 - 50 Yrs) biopsy: colorectal biopsy for tissue acquisition | 1 |
| HIV Negative, Steady State Tenofovir (TFV) Based Regimen (18 - 50 Years) biopsy: colorectal biopsy for tissue acquisition | 0 |
| HIV Negative, Not Taking Tenofovir (TFV) Based PrEP (65 - 80 Years) biopsy: colorectal biopsy for tissue acquisition | 3 |
| HIV Positive Taking Tenofovir (TFV) and Emtricitabine (FTC) Based HIV Treatment (65 - 80 Yrs) biopsy: colorectal biopsy for tissue acquisition | 6 |
| HIV Negative, Steady State Tenofovir (TFV) Based Regimen (65 - 80 Years) biopsy: colorectal biopsy for tissue acquisition | 0 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | ineligble laboratory | 1 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | ineligible vital signs | 0 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | HIV Positive Taking Tenofovir (TFV) and Emtricitabine (FTC) Based HIV Treatment (18 - 50 Yrs) | HIV Negative, Steady State Tenofovir (TFV) Based Regimen (18 - 50 Years) | HIV Negative, Not Taking Tenofovir (TFV) Based PrEP (65 - 80 Years) | HIV Negative, Not Taking Tenofovir (TFV) Based PrEP (18 - 50 Years) | HIV Positive Taking Tenofovir (TFV) and Emtricitabine (FTC) Based HIV Treatment (65 - 80 Yrs) | HIV Negative, Steady State Tenofovir (TFV) Based Regimen (65 - 80 Years) |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 9 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 6 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 1 Participants | 0 Participants | 0 Participants | 11 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 | 0 Participants | — | 0 Participants | 1 Participants | 0 Participants | — |
| Race (NIH/OMB) Black or African American | 5 Participants | 1 Participants | — | 1 Participants | 1 Participants | 2 Participants | — |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | — | 0 Participants | 0 Participants | 0 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 | 0 Participants | — | 0 Participants | 0 Participants | 0 Participants | — |
| Race (NIH/OMB) White | 15 Participants | 0 Participants | — | 2 Participants | 9 Participants | 4 Participants | — |
| Region of Enrollment United States | 21 Participants | 1 Participants | — | 3 Participants | 11 Participants | 6 Participants | — |
| Sex: Female, Male Female | 7 Participants | 1 Participants | 0 Participants | 2 Participants | 4 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 14 Participants | 0 Participants | 0 Participants | 1 Participants | 7 Participants | 6 Participants | 0 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 / 11 | 0 / 1 | 0 / 3 | 0 / 6 |
| other Total, other adverse events | 0 / 11 | 0 / 1 | 0 / 3 | 0 / 6 |
| serious Total, serious adverse events | 0 / 11 | 0 / 1 | 0 / 3 | 0 / 6 |
Outcome results
Primary
Concentration of AK2 in Colorectal Tissue
Concentration in nanometers (nm) of AK2 in colorectal tissue.
Time frame: Once within one month
Population: Only participants who completed the rectal tissue biopsy are included in the analysis population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| HIV Negative, Not Taking Tenofovir (TFV) Based PrEP (18-50 Years) | Concentration of AK2 in Colorectal Tissue | 12232 nm |
| HIV Negative, Not Taking Tenofovir (TFV) Based PrEP (65-80 Years) | Concentration of AK2 in Colorectal Tissue | 12975 nm |
| HIV Positive Taking Tenofovir (TFV) and Emtricitabine (FTC) Based HIV Treatment (65-80 Yrs) | Concentration of AK2 in Colorectal Tissue | 13173 nm |
Primary
Concentration of AK2 in Peripheral Blood Mononuclear Cells
Concentration in nanometers (nm) of AK2 in peripheral blood mononuclear cells
Time frame: Once within one month
Population: Only participants who completed the rectal tissue biopsy are included in the analysis population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| HIV Negative, Not Taking Tenofovir (TFV) Based PrEP (18-50 Years) | Concentration of AK2 in Peripheral Blood Mononuclear Cells | 2035 nm |
| HIV Negative, Not Taking Tenofovir (TFV) Based PrEP (65-80 Years) | Concentration of AK2 in Peripheral Blood Mononuclear Cells | 1175 nm |
| HIV Positive Taking Tenofovir (TFV) and Emtricitabine (FTC) Based HIV Treatment (65-80 Yrs) | Concentration of AK2 in Peripheral Blood Mononuclear Cells | 1740 nm |
Primary
Concentration of CKM in Colorectal Tissue
Concentration in nanometers (nm) of CKM in colorectal tissue
Time frame: Once within one month
Population: Only participants who completed the rectal tissue biopsy are included in the analysis population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| HIV Negative, Not Taking Tenofovir (TFV) Based PrEP (18-50 Years) | Concentration of CKM in Colorectal Tissue | 4143 nm |
| HIV Negative, Not Taking Tenofovir (TFV) Based PrEP (65-80 Years) | Concentration of CKM in Colorectal Tissue | 3236 nm |
| HIV Positive Taking Tenofovir (TFV) and Emtricitabine (FTC) Based HIV Treatment (65-80 Yrs) | Concentration of CKM in Colorectal Tissue | 4176 nm |