Clinical trial NCT00709111: Adding Maraviroc to Antiretroviral Therapy for Suboptimal CD4 T-Cell Recovery Despite Sustained Virologic Suppression
Official title: A Pilot Trial of Maraviroc for Treatment of Subjects on Antiretroviral Therapy With Suboptimal CD4 T-cell Count Recovery Despite Sustained Virologic Suppression
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: HIV Infections
Keywords: CCR5 antagonist
CD4 T-cell count
immune activation
treatment experienced
Lead sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Sponsor class: NETWORK
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2008-07-03
Enrollment: 34
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Despite viral suppression, antiretroviral therapy (ART) does not restore CD4+ T-cell counts in some subjects. The purpose of this study is to assess whether adding maraviroc (MVC) to a suppressive ART will result in a significant CD4+ T-cell count increase over 24 weeks in subjects with suboptimal CD4+ T-cell recovery despite sustained virologic suppression.

Detailed description: The majority of HIV-infected subjects with virologic suppression on antiretroviral therapy (ART) have a marked increase in CD4+ T-cell counts over the first year on treatment. However, a portion of these individuals show a suboptimal immune response and remain at an elevated risk for disease progression. The use of the CCR5 inhibitor maraviroc (MVC) is associated with enhanced CD4+ T-cell recovery in subjects who initiate ART. AIDS Clinical Trials Group (ACTG) A5256 studied the effect of ART intensification with MVC on CD4+ T-cell counts in subjects with suboptimal CD4 recovery despite sustained virologic suppression. Eligible subjects added MVC to their ART regimen, and continued MVC for 24 weeks. At week 24, subjects discontinued MVC and were followed for an additional 24 weeks off MVC.

Subjects were seen through week 48 for clinical and laboratory evaluations, including plasma HIV-1 RNA, CD4+ T-cell count, and safety laboratories. Subjects had 2 baseline visits prior to starting MVC. Study visits were scheduled at weeks 4, 8, 12, 16, 22, 24, 36, 46, and 48. CD4+ T-cell counts were measured at every study visit and HIV-1 RNA at weeks 12, 24, 36, and 48, regardless of treatment status. Measures of activation, T-cell maturation, and apoptosis were performed at all weeks except 4, 8, and 16. At the end of the study, the pre-entry, entry, week 12, 22, 24, and 36 samples for the HIV-1 RNA by single-copy assay (SCA) were run. The week 46 and 48 samples were not run.

Eligibility criteria: Inclusion Criteria:

* HIV-1 infection
* On ART for at least 48 weeks prior to study entry with a regimen that includes three or more antiretroviral medications
* No change in ART regimen for at least 24 weeks prior to study entry
* Screening CD4+ T-cell count less than 250 obtained within 60 days prior to study entry
* Stable CD4+ T-cell count for at least 48 weeks prior to study entry (as assessed by an estimated CD4+ T-cell count slope between -20 and +20 cells/year)
* Screening HIV-1 RNA below the limit of detection using an FDA-approved assay obtained within 60 days prior to study entry
* All other plasma HIV-1 RNA measurements in the 48 weeks prior to study entry must be below the limit of detection
* Laboratory values obtained within 60 days prior to study entry:

  * Absolute neutrophil count (ANC) \>=750/µL
  * Hemoglobin \>=9.0 g/dL for female subjects and \>=10.0 g/dL for male subjects
  * Platelet count \>=50,000/ µL
  * Calculated creatinine clearance (CrCl) \>=30 mL/min
  * Aspartate aminotransferase (serum glutamic oxaloacetic transaminase), alanine aminotransferase (serum glutamic pyruvic transaminase), and alkaline phosphatase \<=5 X Upper Limit of Normal (ULN)
  * Direct bilirubin \<=2.5 X ULN
* Females of reproductive potential will need a negative serum or urine pregnancy test within 48 hours prior to study entry
* Agree not to participate in the conception process, and if participating in sexual activity that could lead to pregnancy, the subject/partner must use at least two reliable forms of contraceptives while receiving study treatment and for 6 weeks after stopping study treatment.

Exclusion Criteria:

* Unstable clinical condition
* Currently breast-feeding or pregnant
* Use of immunomodulators or cancer chemotherapy or radiation treatment within 12 months prior to study entry
* An acute AIDS-defining illness within 60 days prior to study entry
* Known allergy/sensitivity or hypersensitivity to components of MVC, including allergy or hypersensitivity to soya lecithin, soya or peanuts
* Active drug or alcohol abuse that, in the opinion of the investigator, would interfere with adherence to study regimens
* Serious illness requiring systemic treatment and/or hospitalization within 60 days prior to study entry
* Receipt of a vaccine within 30 days prior to study entry
* Current or previous use of a CCR5 inhibitor
* Plan to change background ART regimen within 24 weeks after study entry
* Receipt of experimental or non-experimental medications for the purpose of raising CD4+ T-cell counts within 6 months prior to study entry

Primary outcomes:
measure: Change in CD4+ T-cell Count
timeFrame: From baseline to week 24
Secondary outcomes:
measure: Proportion of Participants Achieving a 50-cell Increase in CD4+ T-cell Count
timeFrame: From baseline to week 24
measure: Within-subject CD4+ T-cell Count Slopes
timeFrame: From baseline through week 24
measure: Change From Within-subject Pre-treatment CD4+ T-cell Count Slopes to Corresponding Within-subject CD4+ T-cell Count Slopes From Baseline Through Week 24
timeFrame: From pre-treatment through week 24
measure: Change in CD4+ T-cell Count
timeFrame: From week 24 to week 36
measure: Change in CD4+ T-cell Count
timeFrame: From week 24 to week 48
measure: Change in CD4 Percentage
timeFrame: From baseline to week 24
measure: Within-subject CD4 Percentage Slopes
timeFrame: From baseline through week 24
measure: Change From Within-subject Pre-treatment CD4 Percentage Slopes to Corresponding Within-subject CD4 Percentage Slopes From Baseline Through Week 24
timeFrame: From pre-treatment through week 24
measure: Change in CD4 Percentage
timeFrame: From week 24 to week 36
measure: Change in CD4 Percentage
timeFrame: From week 24 to week 48
measure: Number of Subjects Who Experience a Grade 2, 3 or 4 Signs and Symptoms, Grade 3 or 4 Laboratory Abnormalities, or Death.
timeFrame: From baseline through week 24
measure: Change in Percentage of CD4+ T-cells That Are: naïve (%CD45RA+CCR7+), Central Memory (%CD45RA-CCR7+), Effector Memory (%CD45RA-CCR7-), Effector (%CD45RA+CCR7-), %HLA-DR+CD38+, %CD38+, %Ki67+, %caspase3+, %Bcl-2-, and %CD57+
timeFrame: From baseline to week 24
measure: Change in Percentage of CD8+ T-cells That Are: naïve (%CD45RA+CCR7+), Central Memory (%CD45RA-CCR7+), Effector Memory (%CD45RA-CCR7-), Effector (%CD45RA+CCR7-), %HLA-DR+CD38+, %CD38+, %Ki67+, %caspase3+, %Bcl-2-, and %CD57+
timeFrame: From baseline to week 24
measure: Change in Percentage of CD4+ T-cells That Are: naïve (%CD45RA+CCR7+), Central Memory (%CD45RA-CCR7+), Effector Memory (%CD45RA-CCR7-), Effector (%CD45RA+CCR7-), %HLA-DR+CD38+, %CD38+, %Ki67+, %caspase3+, %Bcl-2-, and %CD57+
timeFrame: From week 24 to week 36
measure: Change in Percentage of CD8+ T-cells That Are: naïve (%CD45RA+CCR7+), Central Memory (%CD45RA-CCR7+), Effector Memory (%CD45RA-CCR7-), Effector (%CD45RA+CCR7-), %HLA-DR+CD38+, %CD38+, %Ki67+, %caspase3+, %Bcl-2-, and %CD57+
timeFrame: From week 24 to week 36
measure: Change in Percentage of CD4+ T-cells That Are: naïve (%CD45RA+CCR7+), Central Memory (%CD45RA-CCR7+), Effector Memory (%CD45RA-CCR7-), Effector (%CD45RA+CCR7-), %HLA-DR+CD38+, %CD38+, %Ki67+, %caspase3+, %Bcl-2-, and %CD57+
timeFrame: From week 24 to week 48
measure: Change in Percentage of CD8+ T-cells That Are: naïve (%CD45RA+CCR7+), Central Memory (%CD45RA-CCR7+), Effector Memory (%CD45RA-CCR7-), Effector (%CD45RA+CCR7-), %HLA-DR+CD38+, %CD38+, %Ki67+, %caspase3+, %Bcl-2-, and %CD57+
timeFrame: From week 24 to week 48
measure: Change in Soluble CD14
timeFrame: From baseline to week 24
measure: Change in Soluble CD14
timeFrame: From week 24 to week 36
measure: Change in Soluble CD14
timeFrame: From week 24 to week 48
measure: Change in High Sensitivity C-reactive Protein (Hs-CRP)
timeFrame: From baseline to week 24
measure: Change in Interleukin (IL)-6, Monocyte Chemoattractant Protein (MCP)-1, MCP-2, and Plasma CD40 Ligand (CD40L)
timeFrame: From baseline to week 24
measure: Change in Intercellular Cell Adhesion Molecule (ICAM)-1, Plasma P-selectin, Soluble TNFRII (sTNFRII), and Matrix Metalloproteinase (MMP)-9
timeFrame: From baseline to week 24
measure: Change in D-dimer
timeFrame: From baseline to week 24
measure: Change in Hs-CRP
timeFrame: From week 24 to week 36
measure: Change in IL-6, MCP-1, MCP-2, and Plasma CD40L
timeFrame: From week 24 to week 36
measure: Change in ICAM-1, Plasma P-selectin, sTNFRII, and MMP-9
timeFrame: From week 24 to week 36
measure: Change in D-dimer
timeFrame: From week 24 to week 36
measure: Change in Hs-CRP
timeFrame: From week 24 to week 48
measure: Change in IL-6, MCP-1, MCP-2, and Plasma CD40L
timeFrame: From week 24 to week 48
measure: Change in ICAM-1, Plasma P-selectin, sTNFRII, and MMP-9
timeFrame: From week 24 to week 48
measure: Change in D-dimer
timeFrame: From week 24 to week 48
measure: Proportion of Participants With Detectable HIV-1 Viremia as Measured by Single Copy Assay (SCA)
timeFrame: At weeks -1 (pre-entry), 0 (entry), 12, 22, 24, and 36
measure: Drug Adherence Assessed as Number of Missed Doses Over a 4-day Recall
timeFrame: At weeks 4, 12, and 24
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Alabama Therapeutics CRS (5801)
state: Alabama
city: Los Angeles
country: United States
facility: UCLA CARE Center CRS (601)
state: California
city: Palo Alto
country: United States
facility: Stanford CRS (501)
state: California
city: San Diego
country: United States
facility: Ucsd, Avrc Crs (701)
state: California
city: San Francisco
country: United States
facility: Ucsf Aids Crs (801)
state: California
city: Washington
country: United States
facility: Georgetown University CRS (GU CRS) (1008)
state: District of Columbia
city: Miami
country: United States
facility: Univ. of Miami AIDS CRS (901)
state: Florida
city: Atlanta
country: United States
facility: The Ponce de Leon Ctr. CRS (5802)
state: Georgia
city: Chicago
country: United States
facility: Northwestern University CRS (2701)
state: Illinois
city: Baltimore
country: United States
facility: IHV Baltimore Treatment CRS (4651)
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Adult AIDS CRS (201)
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital ACTG CRS (101)
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hosp. ACTG CRS (107)
state: Massachusetts
city: Boston
country: United States
facility: Boston Medical Center ACTG CRS (104)
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University CRS (2101)
state: Missouri
city: New York
country: United States
facility: Cornell CRS (7804)
state: New York
city: New York
country: United States
facility: NY Univ. HIV/AIDS CRS (401)
state: New York
city: Rochester
country: United States
facility: AIDS Care CRS (1108)
state: New York
city: Rochester
country: United States
facility: Univ. of Rochester ACTG CRS (1101)
state: New York
city: Chapel Hill
country: United States
facility: Unc Aids Crs (3201)
state: North Carolina
city: Durham
country: United States
facility: Duke Univ. Med. Ctr. Adult CRS (1601)
state: North Carolina
city: Cincinnati
country: United States
facility: Univ. of Cincinnati CRS (2401)
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth CRS (2503)
state: Ohio
city: Columbus
country: United States
facility: The Ohio State Univ. AIDS CRS (2301)
state: Ohio
city: Philadelphia
country: United States
facility: Hosp. of the Univ. of Pennsylvania CRS (6201)
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Pittsburgh CRS (1001)
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt Therapeutics CRS (3652)
state: Tennessee
city: Dallas
country: United States
facility: Peabody Health Ctr. CRS (31443)
state: Texas
city: Houston
country: United States
facility: Houston AIDS Research Team CRS (31473)
state: Texas
Study officials:
affiliation: Cornell Clinical Research Site
name: Timothy J. Wilkin, MD, MPH
role: STUDY_CHAIR
affiliation: Cornell HIV Clinical Trials Unit
name: Roy Gulick, MD, MPH
role: STUDY_CHAIR
References:
citation: Fadel H, Temesgen Z. Maraviroc. Drugs Today (Barc). 2007 Nov;43(11):749-58. doi: 10.1358/dot.2007.43.11.1131763.
citation: MacArthur RD, Novak RM. Reviews of anti-infective agents: maraviroc: the first of a new class of antiretroviral agents. Clin Infect Dis. 2008 Jul 15;47(2):236-41. doi: 10.1086/589289.
citation: Wilkin T, Lalama C, Tenorio A, Landay A, Ribaudo H, McKinnon J, Gandhi R, Mellors J, Currier J, and Gulick R. Maraviroc Intensification for Suboptimal CD4+ Cell Response Despite Sustained Virologic Suppression: ACTG 5256. 17th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, February 16-19, 2010.
citation: Wilkin T, Lalama C, Tenorio A, Landay A, Fox L, McKinnon J, Gandhi R, Mellors J, Currier J, Gulick R. ACTG 5256: Effect of adding and removing maraviroc (MVC) on immune activation in participants on suppressive antiretroviral therapy (ART). 18th Conference on Retroviruses and Opportunistic Infections, Boston, MA, February 27-March 02, 2011.
citation: Hilldorfer B, Lalama C, McKinnon J, Coombs B, Tenorio A, Fox L, Gandhi R, Ribaudo H, Currier J, Gulick R, Wilkin TJ, Mellors J. Effects of Maraviroc (MVC) on Residual Low-Level Viremia in Patients on Suppressive Antiretroviral Therapy (ART): Results from ACTG 5256. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Rome, Italy, July 17-20, 2011.
citation: Wilkin TJ, Lalama CM, McKinnon J, Gandhi RT, Lin N, Landay A, Ribaudo H, Fox L, Currier JS, Mellors JW, Gulick R, Tenorio AR. A pilot trial of adding maraviroc to suppressive antiretroviral therapy for suboptimal CD4(+) T-cell recovery despite sustained virologic suppression: ACTG A5256. J Infect Dis. 2012 Aug 15;206(4):534-42. doi: 10.1093/infdis/jis376. Epub 2012 Jun 27.