The Lymphoid Tissue Pharmacology of Antiretroviral Drugs

• Sponsor: University of Nebraska (Other)
• Overall Status: Not yet recruiting
• CT.gov ID: NCT02707926
• Collaborator: University of Minnesota (Other)
• Enrollment: 18
• Anticipated Duration (Months): 9

Study Details

Study Description

Brief Summary

Hypothesis:

Antiretroviral drugs (ARVs) with enhanced LT penetration characteristics in vitro and in macaques will translate into an ARV regimen with increased LN and GALT concentrations and a faster decay and more potent suppression of HIV replication in LT in HIV-infected persons.

Objectives:

1. Determine lymph nodes (LN) and gut-associated lymphoid tissue (GALT) pharmacokinetics (PK) in HIV-infected persons on an antiretroviral drug (ARV) regimen.

2. Determine virological responses of antiretroviral therapy in plasma, peripheral blood mononuclear cells (PBMCs) and lymphoid tissue (LT).

Condition or Disease	Intervention/Treatment	Phase
HIV Infection	Drug: Anti-HIV Agents

Detailed Description

This is a single-center study of 18 ARV naïve, HIV infected persons to assess impact of an ARV regimen on lymph node (LN) and (GALT) virus reservoirs.

All participants will give informed consent. At baseline, plasma and PBMCs will be obtained and all subjects will have an incisional biopsy of an inguinal LN and pinch biopsy of ileum and rectum via colonoscopy. The selected LT-enhanced ARV regimen will be initiated. Participants will return to the clinic at weeks 2 and 4 and then monthly for safety evaluations, CD4 T cell counts, plasma HIV-RNA and ARV drug concentrations in plasma and PBMCs. An intensive PK study will be performed at week 2. At months 3 and 6, the inguinal LN biopsy and pinch biopsies of ileum and rectum will be repeated.

Study Design

• Study Type: Observational
• Anticipated Enrollment: 18 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: The Lymphoid Tissue Pharmacology of Antiretroviral Drugs
• Anticipated Study Start Date: Jul 1, 2022
• Anticipated Primary Completion Date: Jan 1, 2023
• Anticipated Study Completion Date: Apr 1, 2023

Outcome Measures

Primary Outcome Measures

1. Lymph node (LN) tissue penetration ratio. [6 months]

   Ratio of antiretroviral drug concentration in lymph node (LN) to peripheral blood mononuclear cells (PBMCs)

2. Lymph node (LN) residual viremia. [6 months]

   Quantification of residual viremia in lymph node (LN) at 6 months of therapy as measured by digital droplet polymerase chain reaction (PCR), which can quantify as low as 50 copies/million cells.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Antiretroviral drug (ARV)-naive, HIV-infected individuals

2. Aged 18 years or over

3. Agree to initiating ARV therapy

4. BMI ≤ 30

5. Inguinal lymph node(s) identifiable by ultrasound at enrollment

6. Screening plasma HIV RNA > 40,000 copies/mL

7. Screening CD4 count > 200 cells/mm3

8. Women of child bearing potential must agree to use effective contraception while on the study.

9. Screening viral isolates demonstrate genotype sensitivity to chosen antiretroviral therapy (ART) regimen.

10. Able to provide voluntary written consent

Exclusion Criteria:

1. Previous ARV therapy

2. Contraindications to ARV regimen (e.g., comorbid conditions or drug interactions), or study procedures as determined by the principal investigator.

3. Planning or current pregnancy or breastfeeding

4. History and/or presence of any clinically significant disease or disorder, such as cardiovascular, pulmonary, renal, hepatic, neurological, gastrointestinal and psychiatric/mental disease/disorder, which, in the opinion of the enrolling physician, may put the participant at risk because of participation in the study, influence the results of the study, or affect the participant's ability to participate in the study.

5. Inability to comply with study procedures per enrolling physician discretion

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• University of Nebraska
• University of Minnesota

Investigators

• Principal Investigator: Tim Schacker, MD, University of Minnesota
• Principal Investigator: Courtney V Fletcher, PharmD, University of Nebraska

Study Documents (Full-Text)

None provided.

More Information

Publications

• Fletcher CV, Staskus K, Wietgrefe SW, Rothenberger M, Reilly C, Chipman JG, Beilman GJ, Khoruts A, Thorkelson A, Schmidt TE, Anderson J, Perkey K, Stevenson M, Perelson AS, Douek DC, Haase AT, Schacker TW. Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues. Proc Natl Acad Sci U S A. 2014 Feb 11;111(6):2307-12. doi: 10.1073/pnas.1318249111. Epub 2014 Jan 27.
• Lorenzo-Redondo R, Fryer HR, Bedford T, Kim EY, Archer J, Pond SLK, Chung YS, Penugonda S, Chipman J, Fletcher CV, Schacker TW, Malim MH, Rambaut A, Haase AT, McLean AR, Wolinsky SM. Persistent HIV-1 replication maintains the tissue reservoir during therapy. Nature. 2016 Feb 4;530(7588):51-56. doi: 10.1038/nature16933. Epub 2016 Jan 27.

• Responsible Party: Courtney Fletcher, Professor and Director, Antiviral Pharmacology Laboratory, University of Nebraska
• ClinicalTrials.gov Identifier: NCT02707926
• Other Study ID Numbers: 1601M83126
• First Posted: Mar 14, 2016
• Last Update Posted: Oct 7, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: HIV Infections; Anti-HIV Agents

Study Results

No Results Posted as of Oct 7, 2021