- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00884793
Pilot Study on the Effect of Adding Raltegravir +/- a Second Drug on HIV Levels in the Gut (PLUS)
June 18, 2012 updated by: University of California, San Francisco
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
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) .
Study Overview
Status
Completed
Conditions
Intervention / Treatment
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.
Study Type
Interventional
Enrollment (Actual)
8
Phase
- Not Applicable
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
-
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California
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San Francisco, California, United States, 94110
- San Francisco General Hospital
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San Francisco, California, United States, 94121
- San Francisco VA Medical Center (SFVAMC)
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Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years to 65 years (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
Inclusion Criteria:
- Age 18 to 65 years
- 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
- 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
- No change in ART for at least 3 months prior to study entry.
- CD4+ T cell count of 200 or greater within 30 days prior to study entry.
- 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.
- 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.
- 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.
- Ability and willingness to provide informed consent.
Exclusion Criteria:
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
- Prior use of raltegravir
- 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.
- Calculated creatinine clearance (CrCl) < 50 mL/min, as estimated by the Cockcroft-Gault equation
- AST (SGOT), ALT (SGPT), alkaline phosphatase, or bilirubin > 3x the upper limit of normal (ULN).
- 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
- Plan to change the background ART within 16 weeks after study entry
- Receipt of any HIV vaccine
- Receipt of a non-HIV vaccine within 30 days prior to study entry
- An opportunistic infection within 60 days prior to study entry
- Use of significant immunosuppressive medications (such as systemic corticosteroids, tacrolimus, sirolimus, mycophenolate, azathioprine, interferon, and cancer chemotherapy) within 60 days prior to study entry.
- Active drug or alcohol abuse that, in the opinion of the investigator, would interfere with adherence to the requirements of the study
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: intensification with raltegravir +/- NNRTI or PI
Intensification with raltegravir 400mg PO BID +/- a study PI or NNRTI
|
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 Names:
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:
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:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of Subjects Who Had a Decrease in HIV RNA Per Million CD4+ T Cells in the Ileum
Time Frame: 12 weeks
|
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
|
12 weeks
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of Subjects Who Experienced an Increase in CD4+ T Cells (as a % of All Cells) in the Ileum.
Time Frame: 12 weeks
|
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.
|
12 weeks
|
Number of Subjects Who Experienced an Increase in CD4% in the Ileum.
Time Frame: 12 weeks
|
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
|
12 weeks
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Average Change in "Activated" (CD38+HLADR+) CD8+ T Cells in the Ileum
Time Frame: 12 weeks
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Average of changes(week 0-week 12) in the % of CD8+ T cells that are CD38+HLA-DR+, by flow cytometry
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12 weeks
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
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
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
- Yukl SA, Gianella S, Sinclair E, Epling L, Li Q, Duan L, Choi AL, Girling V, Ho T, Li P, Fujimoto K, Lampiris H, Hare CB, Pandori M, Haase AT, Gunthard HF, Fischer M, Shergill AK, McQuaid K, Havlir DV, Wong JK. Differences in HIV burden and immune activation within the gut of HIV-positive patients receiving suppressive antiretroviral therapy. J Infect Dis. 2010 Nov 15;202(10):1553-61. doi: 10.1086/656722. Epub 2010 Oct 12.
- Yukl SA, Shergill AK, McQuaid K, Gianella S, Lampiris H, Hare CB, Pandori M, Sinclair E, Gunthard HF, Fischer M, Wong JK, Havlir DV. Effect of raltegravir-containing intensification on HIV burden and T-cell activation in multiple gut sites of HIV-positive adults on suppressive antiretroviral therapy. AIDS. 2010 Oct 23;24(16):2451-60. doi: 10.1097/QAD.0b013e32833ef7bb.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start
September 1, 2008
Primary Completion (Actual)
December 1, 2009
Study Completion (Actual)
December 1, 2010
Study Registration Dates
First Submitted
April 20, 2009
First Submitted That Met QC Criteria
April 20, 2009
First Posted (Estimate)
April 21, 2009
Study Record Updates
Last Update Posted (Estimate)
July 23, 2012
Last Update Submitted That Met QC Criteria
June 18, 2012
Last Verified
June 1, 2012
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- RNA Virus Infections
- Virus Diseases
- Infections
- Blood-Borne Infections
- Communicable Diseases
- Sexually Transmitted Diseases, Viral
- Sexually Transmitted Diseases
- Lentivirus Infections
- Retroviridae Infections
- Immunologic Deficiency Syndromes
- Immune System Diseases
- HIV Infections
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Antiviral Agents
- Reverse Transcriptase Inhibitors
- Nucleic Acid Synthesis Inhibitors
- Enzyme Inhibitors
- Anti-HIV Agents
- Anti-Retroviral Agents
- Protease Inhibitors
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Enzyme Inducers
- Cytochrome P-450 CYP3A Inducers
- HIV Integrase Inhibitors
- Integrase Inhibitors
- HIV Protease Inhibitors
- Viral Protease Inhibitors
- Cytochrome P-450 CYP2B6 Inducers
- Cytochrome P-450 CYP2C9 Inhibitors
- Cytochrome P-450 CYP2C19 Inhibitors
- Raltegravir Potassium
- Ritonavir
- Lopinavir
- Etravirine
- Atazanavir Sulfate
- Efavirenz
- Fosamprenavir
Other Study ID Numbers
- PLUS1
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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