Clinical trial NCT00735072: Maraviroc as an Immunomodulatory Drug for Antiretroviral-treated HIV Infected Patients Exhibiting Immunologic Failure
Official title: Maraviroc as an Immunomodulatory Drug for Antiretroviral-treated HIV Infected Patients Exhibiting Immunologic Failure
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: HIV Infection
Keywords: HIV infection
T cell activation
Antiretroviral Therapy
CCR5
Maraviroc
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: Pfizer
name: amfAR, The Foundation for AIDS Research
name: Stanford University
name: Case Western Reserve University
name: Rush University
First posted: 2008-08-14
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Many people with HIV fail to regain normal CD4 counts despite effectively suppressing HIV replication with medications. Blocking the "co-receptor" for HIV might decrease inflammation of the immune system, potentially providing an immune benefit. The goal of the current trial is to determine whether adding maraviroc, a new CCR5 "co-receptor" blocker, decreases inflammation, providing an immune benefit for patients with low CD4 counts despite undetectable viral loads on HIV medications.

In this study, HIV-infected patients who are receiving antiretroviral therapy for HIV will receive either maraviroc or a placebo (sugar pill) each day for 24 weeks. After 24 weeks, the study medication will be stopped and all subjects will be followed for 12 more weeks. Blood tests measuring the extent of inflammation, low-level viremia, and immune function will be measured throughout the trial and compared between treatment arms.

Detailed description: Our primary hypothesis is that CCR5 inhibitors may have protective immunomodulatory effects independent of their impact on HIV replication. Specifically, we predict that maraviroc will reduce the persistent T cell activation that prevents normal immune reconstitution during HAART-mediated viral suppression. This hypothesis will be tested in the context of a placebo controlled pilot study assessing the impact of maraviroc in antiretroviral-treated patients with a CD4+ T cell count less than 350 cells/mm3. In order to address the immunologic activity of this drug independent of plasma HIV RNA levels, we will study individuals who have undetectable viral loads (\< 75 copies RNA/mL). Subjects will be randomized to maraviroc for 24 weeks or matching placebo for 24 weeks, followed by a 12 week washout period. We will use as our primary endpoint the proportion of CD8+ T cells that co-expresses CD38 and HLA-DR, as these outcomes have been well validated in prior studies. The primary outcome will be change in the percentage of activated CD8+ T cells at week 24. Change in CD4+ T cell counts, HIV RNA levels (using ultra-sensitive techniques), and other more experimental immunologic measurements will be assessed as secondary outcomes.

Eligibility criteria: Inclusion Criteria:

1. HIV-1 infection, as documented by any licensed ELISA test kit and confirmed by Western blot at any time prior to study entry. HIV-1 culture, HIV-1 antigen, plasma HIV-1 RNA, or a second antibody test by a method other than ELISA is acceptable as an alternative confirmatory test.
2. Stable antiretroviral therapy for at least 12 months
3. Screening CD4+ T cell count below 350 cells/mm3
4. All available CD4+ T cell counts in the last year and at screening \< 350 cells/mm3
5. Screening plasma HIV RNA levels below level of detection (\< 50 copies RNA/mL using Roche Amplicor or \< 75 copies/mL using Bayer bDNA)
6. All available plasma HIV RNA levels within past year below the level of detection. Isolated values that are detectable but \< 500 copies will be allowed as long as the plasma HIV RNA levels before and after this time point are undetectable.
7. \> 90% adherence to therapy within the preceding 30 days, as determined by self-report.
8. Both male and female subjects are eligible. Females of childbearing potential must have a negative serum pregnancy test at screening and agree to use a double-barrier method of contraception throughout the study period.
9. Ability and willingness of subject or legal guardian/representative to provide informed consent

Exclusion Criteria:

1. Increase in CD4 count of \> 100 cells/mm3 in past year.
2. Patients who are intending to modify antiretroviral therapy in the next 24 weeks for any reason.
3. Serious illness requiring hospitalization or parental antibiotics within preceding 3 months.
4. Concurrent treatment with immunomodulatory drugs, or exposure to any immunomodulatory drug in past 16 weeks.
5. HBVsAg+ or active hepatitis C or hepatitis B which will require treatment in the subsequent 24 weeks.
6. Prior exposure to CCR5 inhibitors
7. Screening absolute neutrophil count \<1,000 cells/mm3, platelet count \<50,000 cells/mm3, hemoglobin \< 8mg/dL, estimated creatinine clearance \<40 mL/minute.
8. Pregnant or breastfeeding women
9. Use of both Tenofovir and Didanosine in current antiretroviral therapy regimen.

Primary outcomes:
measure: Week 24 Change in Percentage of CD8+ T Cells That Co-express CD38 and HLA DR (Week 24 %CD38+HLA-DR+ CD8+ T Cells Minus Baseline %CD38+HLA-DR+ CD8+ T Cells)
timeFrame: Baseline and Week 24
Secondary outcomes:
measure: Change in CD4+ T Cell Count
timeFrame: Baseline and Week 24
measure: Change in Ultra-sensitive Plasma HIV RNA Level (Single Copy/ml Assay)
timeFrame: Baseline and Week 24
measure: Change in Brachial Artery Flow-mediated Dilatation (UCSF Site Only)
timeFrame: Baseline and Week 24
measure: Change in Gut-associated Lymphoid Tissue HIV RNA Level (UCSF Site Only)
timeFrame: Baseline and Week 24
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California San Francisco - San Francisco General Hospital
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Chicago
country: United States
facility: Rush University - Stroger Hospital of Cook County
state: Illinois
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
Study officials:
affiliation: University of California, San Francisco
name: Peter W Hunt, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Francisco
name: Steven G Deeks, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Stanford University
name: Nancy Shulman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Stanford University
name: Robert Shafer, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Case Western Reserve University
name: Michael Lederman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Rush University
name: Toyin Adeyemi, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hunt PW, Shulman NS, Hayes TL, Dahl V, Somsouk M, Funderburg NT, McLaughlin B, Landay AL, Adeyemi O, Gilman LE, Clagett B, Rodriguez B, Martin JN, Schacker TW, Shacklett BL, Palmer S, Lederman MM, Deeks SG. The immunologic effects of maraviroc intensification in treated HIV-infected individuals with incomplete CD4+ T-cell recovery: a randomized trial. Blood. 2013 Jun 6;121(23):4635-46. doi: 10.1182/blood-2012-06-436345. Epub 2013 Apr 15.