Raltegravir Activity In Lymphoid Tissues

This study has been withdrawn prior to enrollment.
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Timothy W. Schacker, University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier:
NCT00863668
First received: March 16, 2009
Last updated: October 24, 2011
Last verified: October 2011
  Purpose

The reduction with antiretroviral therapy (ART) of HIV RNA in blood, and HIV RNA in infected cells and in viruses associated with the follicular dendritic cell (FDC) network in lymphatic tissues, typically follows a two-phase pattern of decline. The half-life of the first-phase is about 1 day and that of the second phase is about 14 days, with comparable estimates for first-phase decay in SIV-infected rhesus macaques.

While substantial evidence supports the current view that first-phase decay reflects the death of activated CD4+ T cells infected before ART was begun, the sources of viral RNA in the second phase have not as yet been conclusively established. Possible sources of viral RNA that have been invoked in mathematical models, or for which there is experimental evidence, include longer-lived infected cells such as macrophages and resting CD4+ T cells, dissociation of virus from the FDC network, and productively infected CD4+ T cells that are not subject to clearance by host immune responses because of waning levels of HIV antigen.

Raltegravir (MK-0518) belongs to a new class of integrase inhibitors that potently suppress HIV and SIV replication, and reportedly markedly alters the second phase HIV decline in a way that challenges the current view that longer-lived infected cells are the source of virus in this phase. While mathematical modeling of decay of HIV RNA in blood was most consistent with 1) cells newly infected by long-lived cells, or 2) from activation of latently infected cells with full-length unintegrated HIV DNA as a source of second phase virus, we think the data are also quite consistent with the greater efficacy of integrase inhibitors in a particular cell type and/or anatomic site such as the gut.

In this protocol we will test the hypothesis that the rapid decrease in HIV replication associated with raltegravir is due to a more complete suppression of viral replication in lymphatic compartments such as lymph nodes and gastrointestinal lymphatic tissue. We will also investigate compartment-specific intracellular levels of raltegravir to potentially explain differences in changes in these compartments.


Condition Intervention
HIV Infection
HIV Infections
Drug: Efavirenz + Tenofovir DF/Emtricitabine
Drug: Raltegravir + Tenofovir DF/Emtricitabine
Procedure: Colonoscopy with biopsies
Procedure: Inguinal Lymph Node Excision

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Decay Kinetics of HIV With the Integrase Inhibitor Raltegravir

Resource links provided by NLM:


Further study details as provided by University of Minnesota - Clinical and Translational Science Institute:

Primary Outcome Measures:
  • Rate of HIV mRNA Decline Measured in Peripheral Blood [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • Rate of HIV mRNA Expression Decline Measured in Lymphatic Tissues [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • CD4+ T Cell Number Increase in Peripheral Blood Over Time [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • CD4+ T Cell Increase Quantified in Lymphatic Tissues Over Time [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Intracellular concentrations of antiretroviral drugs [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Estimated Enrollment: 10
Study Start Date: March 2009
Estimated Study Completion Date: March 2011
Estimated Primary Completion Date: March 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Efavirenz Drug: Efavirenz + Tenofovir DF/Emtricitabine
600mg QD for 52 weeks + 300mg/200mg QD for 52 weeks
Other Names:
  • Sustiva
  • EFV
  • Tenofovir
  • Tenofovir Disoproxil Fumarate
  • TDF
  • Emtriva
  • FTC
  • Truvada
  • Atripla
  • Nucleoside Reverse Transcriptase Inhibitor
  • NRTI
  • Non-Nucleoside Reverse Transcriptase Inhibitor
  • NNRTI
Procedure: Colonoscopy with biopsies
Day 0, Day 2, Day 7, Day 14, Week 52
Other Names:
  • Colonoscopy
  • Biopsy
  • Secondary
  • Lymphatic
  • Tissue
  • Gastrointestinal
  • GALT
  • Peyers
  • Patch
  • Lamina
  • Propria
Procedure: Inguinal Lymph Node Excision
Day 0, Day 2, Day 7, Day 14, Week 52
Other Names:
  • Secondary
  • Lymphatic
  • Tissue
  • Inguinal
  • Lymph
  • Node
  • LN
  • Excision
  • Biopsy
Experimental: Raltegravir Drug: Raltegravir + Tenofovir DF/Emtricitabine
400mg BID for 52 weeks + 300mg/200mg QD for 52 weeks
Other Names:
  • Isentress
  • MK-0518
  • Tenofovir
  • Tenofovir Disoproxil Fumarate
  • TDF
  • Emtriva
  • FTC
  • Truvada
  • Integrase Inhibitor
  • Nucleoside Reverse Transcriptase Inhibitor
  • NRTI
Procedure: Colonoscopy with biopsies
Day 0, Day 2, Day 7, Day 14, Week 52
Other Names:
  • Colonoscopy
  • Biopsy
  • Secondary
  • Lymphatic
  • Tissue
  • Gastrointestinal
  • GALT
  • Peyers
  • Patch
  • Lamina
  • Propria
Procedure: Inguinal Lymph Node Excision
Day 0, Day 2, Day 7, Day 14, Week 52
Other Names:
  • Secondary
  • Lymphatic
  • Tissue
  • Inguinal
  • Lymph
  • Node
  • LN
  • Excision
  • Biopsy

Detailed Description:

The study will evaluate rates of HIV elimination in peripheral blood in comparison to secondary lymphatic tissues, including inguinal lymph nodes (LN) and gastrointestinal lymphatic tissues (GALT). HIV-infected patients who are antiretroviral therapy (ART) naive and fit criteria to initiate ART will be randomized to either Truvada (tenofovir/emtricitabine) + Sustiva (efavirenz - 600mg qDAY orally - standard of care) or Truvada + Isentress (raltegravir - 400mg BID orally).

Patients will have a blood draw, a colonoscopy with biopsies, and inguinal lymph node excision at days 0, 2, 7, 14, and week 52. Plasma HIV RNA and CD4+ T cell quantitation will be performed conventionally. HIV mRNA will be quantitated in LN and GALT using in-situ hybridization (ISH). Immunohistochemistry (IHC) will be performed to quantitate changes in CD4+ cell numbers over time in tissues from each respective ART regimen.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • HIV positive (proven serologically at the time of screen, unless evidence for seroconversion)
  • Evidence of recent (proven seroconversion within 4 months) or acute infection (HIV antibody negative, HIV RNA positive), or CD4 T Cells > 350 in peripheral blood and plasma viral load > 100,000 copies/ml
  • Antiretroviral therapy naive (no prior history of antiretroviral therapy)
  • Negative pregnancy test for eligible women of childbearing potential

Exclusion Criteria:

  • Contraindication to surgical and endoscopic procedures (as judged by the principal investigator)
  • Psychiatric or psychological illness that would make adherence to protocol procedures unlikely
  • Pregnancy
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00863668

Locations
United States, Minnesota
University of Minnesota Medical Center, Division of Infectious Diseases
Minneapolis, Minnesota, United States, 55455
Sponsors and Collaborators
University of Minnesota - Clinical and Translational Science Institute
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Timothy W Schacker, M.D. University of Minnesota - Clinical and Translational Science Institute
  More Information

No publications provided

Responsible Party: Timothy W. Schacker, Professor of Medicine, University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier: NCT00863668     History of Changes
Other Study ID Numbers: 0901M57887
Study First Received: March 16, 2009
Last Updated: October 24, 2011
Health Authority: United States: Institutional Review Board

Keywords provided by University of Minnesota - Clinical and Translational Science Institute:
Infection
HIV 1
HIV
treatment naive

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
Communicable Diseases
HIV Infections
Infection
Immune System Diseases
Immunologic Deficiency Syndromes
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Sexually Transmitted Diseases
Sexually Transmitted Diseases, Viral
Slow Virus Diseases
Virus Diseases
Efavirenz
Emtricitabine
Integrase Inhibitors
Reverse Transcriptase Inhibitors
Tenofovir
Tenofovir disoproxil
Anti-HIV Agents
Anti-Infective Agents
Anti-Retroviral Agents
Antiviral Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 22, 2014