Relationship of Tenofovir With HIV-1 Suppression in ex Vivo Tissue in Adolescents
Information source: University of California, Los Angeles
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Human Immunodeficiency Virus
Intervention: flexible sigmoidoscopy or colonoscopy with biopsies (Device)
Phase: Phase 1
Status: Recruiting
Sponsored by: University of California, Los Angeles Official(s) and/or principal investigator(s): Sue McDiarmid, MD, Principal Investigator, Affiliation: University of California, Los Angeles, Departments of Pediatrics and Surgery
Overall contact: Kathy Kordy, MD, Phone: (310) 794-7195, Email: kkordy@mednet.ucla.edu
Summary
Microbicides are topical medicines that can prevent infection by Human Immunodeficiency
Virus (HIV). Microbicide medicine has yet to be studied in adolescents, a key group that is
becoming infected with HIV all over the world. From past research, we know that at
different ages people experience age-related changes in their bodies that can cause
differences in how they process medications. In this study, gut tissue samples (or gut
biopsies) from 12 HIV-negative volunteers will be collected. These pieces of tissue will
be infected with HIV in the laboratory to develop a model that can be used to test certain
drugs against the HIV infection. We can use this tissue to test a drug called tenofovir
against HIV infection. We will determine whether this drug can decrease HIV infection in
the gut biopsies. In this study, we will also measure HIV levels and the levels of
tenofovir in gut and blood samples in 12 people who are already taking this drug. This
information can determine whether levels of drug found in the gut can protect it from HIV.
The results can be compared to other age groups of adolescents and adults. Subjects will
undergo a common procedure called a lower endoscopy (this can be a colonoscopy or a flexible
sigmoidoscopy) to obtain gut biopsy samples.
The central hypothesis is that tissue drug profiles of tenofovir (TFV) and its active
component, tenofovir disoproxil fumarate (TDF), and tissue infectibility vary between
younger (10-14 years old) versus older adolescents (18-21 years old), and that both differ
from adults (>21 years). Specifically, younger HIV positive adolescents will have lower
levels of tissue tenofovir compared to older HIV positive adolescents and adults in an
age-dependent manner. Additionally, biopsies from younger HIV negative adolescents will
have: 1) higher rates of infection compared to biopsies from older HIV negative adolescents
infected with a lower dose of virus; and 2) lower percent suppression of tissue infectivity
compared to biopsies from older HIV negative adolescents using low dose tenofovir.
Clinical Details
Official title: Dose-response Relationship of Tenofovir With HIV-1 Suppression in ex Vivo Model of Tissue Infectibility in Adolescents
Study design: Observational Model: Cohort, Time Perspective: Cross-Sectional
Primary outcome: Measure Cmax of tenofovir (TFV) in plasma (ng/ml) & tissue (ng/mg), tenofovir-diphosphate (TFV-DP) in tissue (fmol/mg) and PBMC (fmol/million), HIV quantified PCR (copies/ml) from tissue & plasma.establish ex vivo infectibility assay as measured by HIV-1 p24 (pg/ml) in HIV-negative biopsies infected with R5 HIV-1BaL low 10^2 TCID50 or high 10^4 TCID50 concentration Assess differences in percent suppression of tissue infectivity (measured by HIV-1 p24 (pg/ml)) in biopsies from younger vs older adolescents pretreated with low dose tenofovir.
Secondary outcome: Measures of tenofovir drug efficacy predicting drug levels (tissue TFV ng/mg, TFV-DP fmol/mg) necessary to suppress 50%, 90%, 95% of biopsy HIV-1 p24 (pg/ml) (EC50,90,95) will be calculated by interpolation of the dose response curve.
Eligibility
Minimum age: 10 Years.
Maximum age: 21 Years.
Gender(s): Both.
Criteria:
Inclusion Criteria:
1. Age >/= 10 years and = 14 years and age = 18 years and = 21 years.
2. Willing and able to communicate in English.
3. Willing and able to provide written informed consent or assent to take part in the
study (where required, parent/guardian must provide consent).
4. Willing and able to provide adequate information for locator purposes.
5. Understand and agree to local sexually transmitted infections (STI) reporting
requirements.
6. HIV-negative or - positive as documented in prior serologic testing or per report, and
willing to undergo repeat HIV testing.
7. Willing and able to not take aspirin, any aspirin containing medications, or
non-steroidal anti-inflammatory drugs for at least 72 hours before and 72 hours after
flexible sigmoidoscopy.
8. All female patients of childbearing potential (post-menarche) must be willing to
undergo urine pregnancy testing at screening.
9. Must be in general good health, including normal renal function.
10. Subjects <18 years old must be scheduled for a clinically indicated colonoscopy or
flexible sigmoidoscopy with biopsies.
11. HIV-positive participants only (Aim 1):
- Must have recent HIV polymerase chain reaction (PCR) documented in the last 6-12
months by verbal report
- Must have tenofovir in chronic cART regimen (>/= 1 month).
- Be reportedly compliant.
- CD4 T cells >250/cmm
Exclusion Criteria:
1. Known history of inflammatory bowel disease.
2. Abnormalities of the colorectal mucosa, or significant colorectal symptom(s) which in
the opinion of the clinician represents a contraindication to biopsy (including but
not limited to presence of any unresolved injury, inflammatory condition of the local
mucosa, and presence of symptomatic external hemorrhoids).
3. Evidence of any known enteric infection at the time of study visit.
4. Participant-reported symptoms and/or clinical or laboratory diagnosis of active and
symptomatic rectal infection (gonorrhea, Chlamydia, syphilis, clinically active
perineal HSV).
- Note: Allow one re-screening after documented treatment (30 days) in cases of
gonorrhea/chlamydia (GC/CT) identified at screening.
5. Pregnancy.
6. Subjects with other poorly controlled medical conditions (e. g. diabetes, congestive
heart failure).
7. Chronic renal disease (BUN and serum creatinine >1. 5 times the upper normal limit).
8. History or presence of impaired gastrointestinal motility, or history of extensive
small bowel resection (greater than half the length of the small intestine).
9. Use of warfarin or heparin.
10. Use of systemic immunomodulatory medications within 4 weeks of screening.
11. Use of any investigational products within 4 weeks of screening.
12. Fever at time of endoscopy. Subjects can be re-scheduled at a later point after the
fever is resolved.
13. Any other clinical condition or prior therapy that, in the opinion of the
investigator, would make the patient 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 sever, progressive, or uncontrolled renal, hepatic,
hematological, gastrointestinal, endocrine, pulmonary, neurological, or cerebral
disease.
Locations and Contacts
Kathy Kordy, MD, Phone: (310) 794-7195, Email: kkordy@mednet.ucla.edu
UCLA Clinical and Translational Research Center (CTRC), Los Angeles, California 90095, United States; Recruiting Stephanie Okimoto, BA, CCRC, Phone: 310-267-1040, Email: sokimoto@mednet.ucla.edu
Additional Information
Starting date: May 2014
Last updated: December 3, 2014
|