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Prospective Longitudinal Pilot Study on the Effect of Intensification With Raltegravir +/- PI or NNRTI on HIV in the GALT (PLUS)
This study is currently recruiting participants.
Verified by University of California, San Francisco, March 2009
First Received: April 20, 2009   Last Updated: May 14, 2009   History of Changes
Sponsored by: University of California, San Francisco
Information provided by: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT00884793
  Purpose

The "PLUS" study is a pilot study to measure the effect of therapy intensification (with raltegravir and optional second agent) on HIV levels in the gut and blood in patients on antiretroviral therapy (ART) with viral load < 50 copies/mL (herein referred to as "suppressed"). We hypothesize that there is ongoing replication in the gut despite suppressive ART and that this replication can be inhibited by the addition of one or two new antiretroviral drugs whose activity affects a distinct part of the viral life cycle. All study participants will have upper and lower endoscopy at baseline (before intensification) and after intensification.

These endoscopies will be used to obtain gut tissue and single cells (for CD4+ cells) .


Condition Intervention
HIV Infections
Drug: raltegravir

Study Type: Interventional
Study Design: Non-Randomized, Open Label, Uncontrolled, Single Group Assignment
Official Title: A Prospective Longitudinal Pilot Study to Measure the Effect of Therapy Intensification With Raltegravir +/- a Protease Inhibitor or Non-Nucleoside Reverse Transcriptase Inhibitor on HIV-1 DNA and RNA in the Gut-Associated Lymphoid Tissue (GALT) in Patients on Suppressive Antiretroviral Therapy

Resource links provided by NLM:


Further study details as provided by University of California, San Francisco:

Primary Outcome Measures:
  • The primary outcome is a comparison of cell-associated HIV levels in the GALT before and after intensification. [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Comparison of HIV levels from different sites of GALT (rectum, right colon, terminal ileum, and duodenum) [ Time Frame: Baseline, 12 weeks ] [ Designated as safety issue: No ]
  • Comparison of pre- and post-intensification levels of peripheral blood (plasma and PBMC) HIV, immunologic markers, and secondary markers of gut barrier function [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]

Estimated Enrollment: 12
Study Start Date: September 2008
Estimated Study Completion Date: June 2010
Estimated Primary Completion Date: December 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
1: Experimental
intensification with raltegravir +/- PI or NNRTI
Drug: raltegravir
The baseline ART regimen will be intensified with raltegravir 400mg PO BID (all participants) +/- a study NNRTI or PI (at the option of the participant and the study clinical team).

Detailed Description:

The "PLUS" study is a prospective, longitudinal pilot study to measure the effect of therapy intensification (with raltegravir and possible addition of a study PI or NNRTI) on HIV-1 DNA/RNA levels in the gut-associated lymphoid tissue (GALT) and blood in patients on ART with viral load (VL) < 50 copies/mL (herein referred to as "suppressed"). We hypothesize that there is ongoing replication in the GALT despite suppressive ART and that this replication can be inhibited by the addition of one or two new antiretroviral drugs whose activity affects a distinct part of the viral life cycle. All study participants will have a colonoscopy and esophagogastroduodenoscopy (EGD) at baseline (before intensification) and a second colonoscopy with EGD 12 weeks after intensification. These endoscopies will be used to obtain GALT mononuclear cells (for CD4+ lymphocytes) as well as tissue for in situ hybridization and immunohistochemical studies.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age 18 to 65 years
  2. Infection with HIV-1, as documented by a licensed ELISA and confirmed by a Western blot or HIV-1 RNA at any time prior to study entry
  3. On ART for at least 12 months prior to study entry with a regimen that includes at least two NRTIs and either an NNRTI or PI
  4. No change in ART for at least 3 months prior to study entry.
  5. CD4+ T cell count of 200 or greater within 30 days prior to study entry.
  6. HIV-1 RNA level consistently below the limit of detection of commercial ultrasensitive assays (<50 copies/mL) for at least 6 months before study entry.
  7. Women of reproductive potential (those who have not undergone surgical sterilization via hysterectomy, bilateral oophorectomy, or tubal ligation and who have had menses in the preceding 24 months) must have a negative urine or serum pregnancy test within 48 hours prior to study entry.
  8. All subjects must agree not to participate in the process of conception (such as active attempts to impregnate or become pregnant, sperm or egg donation, in vitro fertilization) while receiving study drugs and for 6 weeks after stopping study drugs. If participating in sexual activity that could lead to pregnancy, the subject and/or partner should use at least two reliable methods of contraception, including oral contraceptive pills, an intrauterine device (IUD), condoms, and a diaphragm or cervical cap with spermicide.
  9. Ability and willingness to provide informed consent.

Exclusion Criteria:

  1. Any condition that, in the opinion of the GI specialist, would either be a contraindication to endoscopy or would increase the risk from sedation, endoscopy, or mucosal biopsies. These conditions may include, but are not limited to:

    • Significant complication (such as perforation) from prior endoscopy
    • Known bleeding diathesis
    • Platelet count < 100,000 per microliter
    • INR > 1.6
    • Current use of antiplatelet agents (aspirin, other NSAIDS, clopidogrel (Plavix), other antiplatelet agents) or anticoagulants (heparin, low molecular weight heparin, warfarin, lepirudin, or other anticoagulants) and inability to temporarily hold such medications for endoscopy.
    • Active angina, unstable angina, or MI within 2 months prior to study entry
    • Decompensated CHF
    • Respiratory insufficiency with FEV1 < 1L, resting hemoglobin saturation of <92%, or need for oxygen supplementation
    • OSA requiring CPAP
    • Ongoing substance abuse
    • Peripheral glucose > 350 mg/dL
  2. Prior use of raltegravir
  3. Any condition that, in the opinion of the infectious disease (ID) specialist, would be a contraindication to raltegravir. These conditions may include, but are not limited to: unstable clinical condition (such as recent hospitalization, cancer with need for chemotherapy or radiation); severe hepatic insufficiency; need for contraindicated medicines; breastfeeding; or high risk for myopathy or rhabdomyolysis.
  4. Calculated creatinine clearance (CrCl) < 50 mL/min, as estimated by the Cockcroft-Gault equation
  5. AST (SGOT), ALT (SGPT), alkaline phosphatase, or bilirubin > 3x the upper limit of normal (ULN).
  6. LDL > 200 mg/dL or TG > 400 mg/dL in fasting lipids, as measured within three months prior to screening or at the time of screening
  7. Plan to change the background ART within 16 weeks after study entry
  8. Receipt of any HIV vaccine
  9. Receipt of a non-HIV vaccine within 30 days prior to study entry
  10. An opportunistic infection within 60 days prior to study entry
  11. Use of significant immunosuppressive medications (such as systemic corticosteroids, tacrolimus, sirolimus, mycophenolate, azathioprine, interferon, and cancer chemotherapy) within 60 days prior to study entry.
  12. Active drug or alcohol abuse that, in the opinion of the investigator, would interfere with adherence to the requirements of the study
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00884793

Contacts
Contact: Steven Yukl, MD 415-221-4810 ext 3930 steven.yukl@ucsf.edu

Locations
United States, California
San Francisco VA Medical Center (SFVAMC) Recruiting
San Francisco, California, United States, 94121
Contact: Steven Yukl, MD            
Principal Investigator: Joseph K Wong, MD            
Principal Investigator: Steven Yukl, MD            
San Francisco General Hospital Recruiting
San Francisco, California, United States, 94110
Contact: Steven Yukl, MD            
Principal Investigator: Diane V Havlir, MD            
Sponsors and Collaborators
University of California, San Francisco
Investigators
Principal Investigator: Diane Havlir, MD San Francisco General Hospital (SFGH) and University of California San Francisco (UCSF)
Principal Investigator: Joseph K Wong, MD San Francisco VA Medical Center (SFVAMC) and University of California, San Francisco (UCSF)
Principal Investigator: Steven Yukl, MD SFVMAC and UCSF
  More Information

No publications provided

Responsible Party: SFGH and UCSF ( Diane V. Havlir )
Study ID Numbers: PLUS1
Study First Received: April 20, 2009
Last Updated: May 14, 2009
ClinicalTrials.gov Identifier: NCT00884793     History of Changes
Health Authority: United States: Institutional Review Board

Keywords provided by University of California, San Francisco:
HIV
persistence
reservoirs
residual replication
gut
gut-associated lymphoid tissue
treatment experienced

Study placed in the following topic categories:
Virus Diseases
Anti-Infective Agents
Sexually Transmitted Diseases, Viral
Anti-Retroviral Agents
HIV Infections
Sexually Transmitted Diseases
Acquired Immunodeficiency Syndrome
Antiviral Agents
Retroviridae Infections
Immunologic Deficiency Syndromes
Protease Inhibitors
Reverse Transcriptase Inhibitors

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

ClinicalTrials.gov processed this record on August 24, 2009