HIV InfectionsPLUSNCT00884793
Pilot Study on the Effect of Adding Raltegravir +/- a Second Drug on HIV Levels in the Gut
A study testing raltegravir, Study NNRTI and Study PI in people with HIV Infections, run by University of California, San Francisco at 2 sites in United States.
Trial summary
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"). Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- HIV Infections
- What is being tested?
- raltegravir, Study NNRTI and Study PI
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 8 participants
- Where
- 2 sitesUnited States
- Study dates
- Sep 2008to Dec 2010
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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.
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- 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
Trial locations and contacts
2 sites in 1 country.
United States2 sites
San Francisco General Hospital
San Francisco, California, 94110
San Francisco VA Medical Center (SFVAMC)
San Francisco, California, 94121
About this study
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
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) .
Read the 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.
- Conditions
- HIV Infections
- Being tested
- raltegravir, Study NNRTI, Study PI
- Keywords
- HIV, persistence, reservoirs, residual replication, gut, gut-associated lymphoid tissue, treatment experienced
- Medical subject headings
- HIV Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
raltegravirDrug
Also called Isentress
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).
Study NNRTIDrug
Also called efavirenz (Sustiva), etravirine (Intelence
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).
Study PIDrug
Also called atazanavir (Reyataz, ATV), fosamprenavir (Lexiva, FPV, Telzir), lopinavir/ritonavir (Kaletra, LPV/r)
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.
| Study group | Role | What they receive |
|---|---|---|
| intensification with raltegravir +/- NNRTI or PI | Experimental | Intensification with raltegravir 400mg PO BID +/- a study PI or NNRTI Receives: Drug: raltegravir; Drug: Study NNRTI; Drug: Study PI |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Subjects Who Had a Decrease in HIV RNA Per Million CD4+ T Cells in the Ileum
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
Measured: 12 weeks
Secondary outcomes (3)
Number of Subjects Who Experienced an Increase in CD4+ T Cells (as a % of All Cells) in the Ileum.
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.
Measured: 12 weeks
Number of Subjects Who Experienced an Increase in CD4% in the Ileum.
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
Measured: 12 weeks
Average Change in "Activated" (CD38+HLADR+) CD8+ T Cells in the Ileum
Average of changes(week 0-week 12) in the % of CD8+ T cells that are CD38+HLA-DR+, by flow cytometry
Measured: 12 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Apr 2009 (estimated)
- Study startSep 2008
- Primary completionDec 2009
- Study completionDec 2010
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for HIV InfectionsStudies of the same condition, open and under way.
- More trials run by University of California, San FranciscoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 8 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of California, San Francisco
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Diane Havlir, MD, Principal investigator, San Francisco General Hospital (SFGH) and University of California San Francisco (UCSF)Joseph K Wong, MD, Principal investigator, San Francisco VA Medical Center (SFVAMC) and University of California, San Francisco (UCSF)Steven Yukl, MD, Principal investigator, SFVMAC and UCSF
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00884793
- Sponsor's protocol ID
- PLUS1
- Acronym
- PLUS
- Status last verified
- Jun 2012
- First submitted
- 20 Apr 2009
- Last updated
- 23 Jul 2012
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
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.
PubMed 20939732Yukl 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.
PubMed 20827162
Study at a glance
From the registry record, last updated by the sponsor on 23 Jul 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT00884793
- Acronym / sponsor ID
- PLUS / PLUS1
- Conditions
- HIV Infections
- Keywords
- HIV, persistence, reservoirs, residual replication, gut, gut-associated lymphoid tissue, treatment experienced
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 8 participants (actual)
- Lead sponsor
- University of California, San FranciscoUniversity, hospital or other
- Study start
- Sep 2008
- Primary completion
- Dec 2009 (actual)
- Study completion
- Dec 2010 (actual)
- First posted
- 21 Apr 2009 (estimated)
- Results
- Posted 23 Jul 2012
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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) .
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 design
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| intensification with raltegravir +/- NNRTI or PI | Experimental | Drug: raltegravir, Drug: Study NNRTI, Drug: Study PIIntensification with raltegravir 400mg PO BID +/- a study PI or NNRTI |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- 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.
Key exclusion criteria (23 listed)
- 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:
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| raltegravirAlso: IsentressThe 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). | Drug | intensification with raltegravir +/- NNRTI or PI |
| Study NNRTIAlso: efavirenz (Sustiva), etravirine (IntelenceSubjects 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). | Drug | intensification with raltegravir +/- NNRTI or PI |
| Study PIAlso: atazanavir (Reyataz, ATV), fosamprenavir (Lexiva, FPV, Telzir), lopinavir/ritonavir (Kaletra, LPV/r)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. | Drug | intensification with raltegravir +/- NNRTI or PI |
Primary outcome
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
3 secondary outcomes
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% in the Ileum.
Time frame: 12 weeks
Average Change in "Activated" (CD38+HLADR+) CD8+ T Cells in the Ileum
Time frame: 12 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Jul 2012.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 20939732Yukl 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.
- Results publication: PubMed 20827162Yukl 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Diane Havlir, MD principal investigator
San Francisco General Hospital (SFGH) and University of California San Francisco (UCSF)
Joseph K Wong, MD principal investigator
San Francisco VA Medical Center (SFVAMC) and University of California, San Francisco (UCSF)
Steven Yukl, MD principal investigator
SFVMAC and UCSF
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing raltegravir, Study NNRTI and Study PI in people with HIV Infections, run by University of California, San Francisco at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 23 Jul 2012. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 23 Jul 2012). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Subjects Who Had a Decrease in HIV RNA Per Million CD4+ T Cells in the Ileum (time frame: 12 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00884793, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Jul 2012.