Raltegravir Activity In Lymphoid Tissues

NCT00863668 | Withdrawn DMC

• 1 other identifier: 0901M57887
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

HIV Infection; HIV Infections

Keywords

Infection; HIV 1; HIV; treatment naive

Outcome Measures

Primary Outcomes (4)

• Rate of HIV mRNA Decline Measured in Peripheral Blood

  1 year

• Rate of HIV mRNA Expression Decline Measured in Lymphatic Tissues

  1 year

• CD4+ T Cell Number Increase in Peripheral Blood Over Time

  1 year

• CD4+ T Cell Increase Quantified in Lymphatic Tissues Over Time

  1 year

Secondary Outcomes (1)

• Intracellular concentrations of antiretroviral drugs

  1 year

Study Arms (2)

Efavirenz

ACTIVE COMPARATOR

Drug: Efavirenz + Tenofovir DF/Emtricitabine; Procedure: Colonoscopy with biopsies; Procedure: Inguinal Lymph Node Excision

Raltegravir

EXPERIMENTAL

Drug: Raltegravir + Tenofovir DF/Emtricitabine; Procedure: Colonoscopy with biopsies; Procedure: Inguinal Lymph Node Excision

Interventions

Efavirenz + Tenofovir DF/Emtricitabine DRUG

600mg QD for 52 weeks + 300mg/200mg QD for 52 weeks

Also known as: Sustiva, EFV, Tenofovir, Tenofovir Disoproxil Fumarate, TDF, Emtriva, FTC, Truvada, Atripla, Nucleoside Reverse Transcriptase Inhibitor, NRTI, Non-Nucleoside Reverse Transcriptase Inhibitor, NNRTI

Efavirenz

Raltegravir + Tenofovir DF/Emtricitabine DRUG

400mg BID for 52 weeks + 300mg/200mg QD for 52 weeks

Also known as: Isentress, MK-0518, Tenofovir, Tenofovir Disoproxil Fumarate, TDF, Emtriva, FTC, Truvada, Integrase Inhibitor, Nucleoside Reverse Transcriptase Inhibitor, NRTI

Raltegravir

Colonoscopy with biopsies PROCEDURE

Day 0, Day 2, Day 7, Day 14, Week 52

Also known as: Colonoscopy, Biopsy, Secondary, Lymphatic, Tissue, Gastrointestinal, GALT, Peyers, Patch, Lamina, Propria

Efavirenz; Raltegravir

Inguinal Lymph Node Excision PROCEDURE

Day 0, Day 2, Day 7, Day 14, Week 52

Also known as: Secondary, Lymphatic, Tissue, Inguinal, Lymph, Node, LN, Excision, Biopsy

Efavirenz; Raltegravir

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Minnesota: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (1)

University of Minnesota Medical Center, Division of Infectious Diseases

Minneapolis, Minnesota, 55455, United States

Location

MeSH Terms

Conditions

HIV Infections; Infections

Interventions

efavirenz; Tenofovir; Emtricitabine; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Raltegravir Potassium; Integrase Inhibitors; Colonoscopy; Biopsy; Histocompatibility Testing; Transdermal Patch

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Drug Combinations; Pharmaceutical Preparations; Oxazines; Pyrrolidinones; Pyrrolidines; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Endoscopy, Gastrointestinal; Endoscopy, Digestive System; Diagnostic Techniques, Digestive System; Diagnostic Techniques and Procedures; Diagnosis; Endoscopy; Diagnostic Techniques, Surgical; Digestive System Surgical Procedures; Surgical Procedures, Operative; Minimally Invasive Surgical Procedures; Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Specimen Handling; Investigative Techniques; Immunologic Tests; Immunologic Techniques; Equipment and Supplies

Study Officials

• Timothy W Schacker, M.D.

  University of Minnesota

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 16, 2009
• First Posted: March 18, 2009
• Study Start: March 1, 2009
• Primary Completion: March 1, 2010
• Study Completion: March 1, 2011
• Last Updated: May 18, 2015

Record last verified: 2015-05

Locations

US (1)