Raltegravir Activity In Lymphoid Tissues

HIV Infections Clinical Trial

Official title:

Decay Kinetics of HIV With the Integrase Inhibitor Raltegravir

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT00863668
• Other study ID #: 0901M57887
• Status: Withdrawn
• Phase: N/A
• First received: March 16, 2009
• Last updated: May 14, 2015
• Start date: March 2009
• Est. completion date: March 2011

Study information

• Verified date: May 2015
• Source: University of Minnesota - Clinical and Translational Science Institute
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: March 2011
• Est. primary completion date: March 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• Communicable Diseases
• HIV Infection
• HIV Infections
• Infection

Intervention

Drug:
• Efavirenz + Tenofovir DF/Emtricitabine
600mg QD for 52 weeks + 300mg/200mg QD for 52 weeks
• Raltegravir + Tenofovir DF/Emtricitabine
400mg BID for 52 weeks + 300mg/200mg QD for 52 weeks

Procedure:
• Colonoscopy with biopsies
Day 0, Day 2, Day 7, Day 14, Week 52
• Inguinal Lymph Node Excision
Day 0, Day 2, Day 7, Day 14, Week 52

Locations

Country	Name	City	State
United States	University of Minnesota Medical Center, Division of Infectious Diseases	Minneapolis	Minnesota

Sponsors (2)

Lead Sponsor	Collaborator
University of Minnesota - Clinical and Translational Science Institute	Merck Sharp & Dohme Corp.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rate of HIV mRNA Decline Measured in Peripheral Blood		1 year	No
Primary	Rate of HIV mRNA Expression Decline Measured in Lymphatic Tissues		1 year	No
Primary	CD4+ T Cell Number Increase in Peripheral Blood Over Time		1 year	No
Primary	CD4+ T Cell Increase Quantified in Lymphatic Tissues Over Time		1 year	No
Secondary	Intracellular concentrations of antiretroviral drugs		1 year	No