The Lymphoid Tissue Pharmacology of Antiretroviral Drugs

HIV Infection Clinical Trial

Official title:

The Lymphoid Tissue Pharmacology of Antiretroviral Drugs

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT02707926
• Other study ID #: 0212-16-ET
• Secondary ID: 1R01AI124965-01
• Status: Withdrawn
• Start date: March 25, 2023
• Est. completion date: August 17, 2023

Study information

• Verified date: August 2023
• Source: University of Nebraska
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: August 17, 2023
• Est. primary completion date: August 17, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• HIV Infection
• HIV Infections

Intervention

Drug:
• Anti-HIV Agents
Therapy to treat HIV infection

Locations

Country	Name	City	State
n/a

Sponsors (3)

Lead Sponsor	Collaborator
University of Nebraska	National Institute of Allergy and Infectious Diseases (NIAID), University of Minnesota

References & Publications (2)

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Lymph node (LN) tissue penetration ratio.	Ratio of antiretroviral drug concentration in lymph node (LN) to peripheral blood mononuclear cells (PBMCs)	6 months
Primary	Lymph node (LN) residual viremia.	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.	6 months