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

NCT00884793 | Completed Results DMC

• 1 other identifier: PLUS1
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 2

Brief 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"). 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) .

Conditions

HIV Infections

Keywords

HIV; persistence; reservoirs; residual replication; gut; gut-associated lymphoid tissue; treatment experienced

Outcome Measures

Primary Outcomes (1)

• 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

  12 weeks

Secondary Outcomes (3)

• Number of Subjects Who Experienced an Increase in CD4+ T Cells (as a % of All Cells) in the Ileum.

  12 weeks

• Number of Subjects Who Experienced an Increase in CD4% in the Ileum.

  12 weeks

• Average Change in "Activated" (CD38+HLADR+) CD8+ T Cells in the Ileum

  12 weeks

Study Arms (1)

intensification with raltegravir +/- NNRTI or PI

EXPERIMENTAL

Intensification with raltegravir 400mg PO BID +/- a study PI or NNRTI

Drug: raltegravir; Drug: Study NNRTI; Drug: Study PI

Interventions

raltegravir DRUG

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).

Also known as: Isentress

intensification with raltegravir +/- NNRTI or PI

Study NNRTI DRUG

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).

Also known as: efavirenz (Sustiva), etravirine (Intelence

intensification with raltegravir +/- NNRTI or PI

Study PI DRUG

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.

Also known as: atazanavir (Reyataz, ATV), fosamprenavir (Lexiva, FPV, Telzir), lopinavir/ritonavir (Kaletra, LPV/r)

intensification with raltegravir +/- NNRTI or PI

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of California, San Francisco: lead

Study Sites (2)

San Francisco General Hospital

San Francisco, California, 94110, United States

Location

San Francisco VA Medical Center (SFVAMC)

San Francisco, California, 94121, United States

Location

Related Publications (2)

• 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.

  PMID: 20939732 RESULT

• 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.

  PMID: 20827162 RESULT

MeSH Terms

Conditions

HIV Infections

Interventions

Raltegravir Potassium; efavirenz; etravirine; Atazanavir Sulfate; fosamprenavir; Lopinavir; Ritonavir; lopinavir-ritonavir drug combination

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pyrrolidinones; Pyrrolidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyridines; Oligopeptides; Peptides; Amino Acids, Peptides, and Proteins; Pyrimidinones; Pyrimidines; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles

Limitations and Caveats

1\) relatively small number of participants; 2) intensification may have been too short; 3)the biopsies themselves can cause inflammation/microbial leakage; 4) sampling may miss viral replication if it occurs in temporally and spatially-discrete foci

Results Point of Contact

• Title: Steven Yukl
• Organization: UCSF

steven.yukl@ucsf.edu

415-221-4810

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 20, 2009
• First Posted: April 21, 2009
• Study Start: September 1, 2008
• Primary Completion: December 1, 2009
• Study Completion: December 1, 2010
• Last Updated: July 23, 2012
• Results First Posted: July 23, 2012

Record last verified: 2012-06

Locations

US (2)