Clinical trial NCT02707926: The Lymphoid Tissue Pharmacology of Antiretroviral Drugs
Official title: The Lymphoid Tissue Pharmacology of Antiretroviral Drugs
Study type: OBSERVATIONAL
Overall status: WITHDRAWN
Conditions: HIV Infection
Lead sponsor: University of Nebraska
Sponsor class: OTHER
Collaborators: name: University of Minnesota
name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2016-03-14
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Eighteen (18) antiretroviral drug (ARV)-naive, HIV-infected persons who are going to initiate ARV therapy will be recruited at the University of Minnesota. Study entry is open to adults regardless of race or ethnic background. While there will be every effort to seek out and include minority participants from both genders, the patient population is expected to be no different than that of the HIV infected population in Minnesota.

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).

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.

Eligibility criteria: 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

Primary outcomes:
measure: Lymph node (LN) tissue penetration ratio.
timeFrame: 6 months
measure: Lymph node (LN) residual viremia.
timeFrame: 6 months
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
affiliation: University of Minnesota
name: Tim Schacker, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Nebraska
name: Courtney V Fletcher, PharmD
role: PRINCIPAL_INVESTIGATOR
References:
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.
citation: 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.