Pilot Study on the Effect of Adding Raltegravir +/- a Second Drug on HIV Levels in the Gut (PLUS)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
University of California, San Francisco
ClinicalTrials.gov Identifier:
NCT00884793
First received: April 20, 2009
Last updated: June 18, 2012
Last verified: June 2012
  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
Drug: Study NNRTI
Drug: Study PI

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Official Title: A Prospective Longitudinal Pilot Study to Measure the Effect of Intensification With Raltegravir +/- a Protease Inhibitor (PI) or Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) on HIV-1 Levels in the Gut

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Number of Subjects Who Had a Decrease in HIV RNA Per Million CD4+ T Cells in the Ileum [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    Number of subjects who had a decrease from week 0 to week 12 in unspliced cell-associated HIV RNA per million CD4+ T cells in the ileum


Secondary Outcome Measures:
  • Number of Subjects Who Experienced an Increase in CD4+ T Cells (as a % of All Cells) in the Ileum. [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    Number of subjects who experienced an increase in CD4+ T cells (as a % of all cells) in the ileum (by flow cytometry) from week 0 to week 12.

  • Number of Subjects Who Experienced an Increase in CD4% in the Ileum. [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    Number of subjects who experienced an increase from week 0 to week 12 in CD4+ T cells (as a % of T cells, by flow cytometry) in the ileum

  • Average Change in "Activated" (CD38+HLADR+) CD8+ T Cells in the Ileum [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    Average of changes(week 0-week 12) in the % of CD8+ T cells that are CD38+HLA-DR+, by flow cytometry


Enrollment: 8
Study Start Date: September 2008
Study Completion Date: December 2010
Primary Completion Date: December 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: intensification with raltegravir +/- NNRTI or PI
Intensification with raltegravir 400mg PO BID +/- a study PI or NNRTI
Drug: raltegravir
The baseline ART regimen will be intensified with raltegravir 400mg orally (PO) twice daily (BID) (all participants) +/- a study NNRTI or protease inhibitor (PI) (at the option of the participant and the study clinical team).
Other Name: Isentress
Drug: Study NNRTI
Subjects who are not already on an NNRTI and who are suitable candidates will have the option of adding a study NNRTI (either efavirenz or etravirine).
Other Names:
  • efavirenz (Sustiva)
  • etravirine (Intelence
Drug: Study PI
Subjects who are not on a PI and who are suitable candidates will have the option of adding a study PI. PIs used as study drugs will include atazanavir (+/- ritonavir), fosamprenavir (+/-ritonavir), lopinavir/ritonavir, and darunavir/ritonavir.
Other Names:
  • atazanavir (Reyataz, ATV)
  • fosamprenavir (Lexiva, FPV, Telzir)
  • lopinavir/ritonavir (Kaletra, LPV/r)

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-Non-Nucleoside Reverse Transcriptase Inhibitor) 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
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: NCT00884793

Locations
United States, California
San Francisco VA Medical Center (SFVAMC)
San Francisco, California, United States, 94121
San Francisco General Hospital
San Francisco, California, United States, 94110
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

Publications:
Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT00884793     History of Changes
Other Study ID Numbers: PLUS1
Study First Received: April 20, 2009
Results First Received: August 8, 2011
Last Updated: June 18, 2012
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

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

ClinicalTrials.gov processed this record on August 21, 2014