Adding Maraviroc to Antiretroviral Therapy for Suboptimal CD4 T-Cell Recovery Despite Sustained Virologic Suppression

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Pilot Trial of Maraviroc for Treatment of Subjects on Antiretroviral Therapy With Suboptimal CD4 T-cell Count Recovery Despite Sustained Virologic Suppression

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Maraviroc


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Maraviroc<br>Maraviroc (MVC) was taken for 24 weeks, in addition to the subject's current antiretroviral therapy (ART) drug regimen. At week 24, subjects discontinued MVC and were followed for an additional 24 weeks off MVC, but still on current ART drug regimen. | Drug: Maraviroc<br>* The maraviroc doses were 150 mg orally twice daily, 300 mg orally twice daily, or 600 mg orally twice daily, depending on the pharmacokinetic interaction with a subject's pre-study ART and non-ART drug regimen according to the package insert.<br>* Other names: Selzentry;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in CD4+ T-cell Count | Change was calculated as the week 24 CD4+ T-cell count (average of the week 22 and week 24 values) minus the baseline CD4+ T-cell count (average of pre-entry and entry values). | From baseline to week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants Achieving a 50-cell Increase in CD4+ T-cell Count | Baseline was defined as the average of pre-entry and entry values. Week 24 was defined as the average of the week 22 and week 24 values. | From baseline to week 24 | 
| Within-subject CD4+ T-cell Count Slopes | The estimated mean slope was summarized across the population by using generalized estimating equations. Baseline was defined as the average of pre-entry and entry values. Week 24 was defined as the average of the week 22 and week 24 values. | From baseline through week 24 | 
| 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 | The estimated mean change in slopes was summarized across the population by using generalized estimating equations. Pre-treatment CD4+ T-cell counts (from at least 48 weeks prior to study entry) were recorded at screening from patient source documentation. Baseline was defined as the average of pre-entry and entry values. Week 24 was defined as the average of the week 22 and week 24 values. | From pre-treatment through week 24 | 
| Change in CD4+ T-cell Count | Change was calculated as week 36 CD4+ T-cell count minus the week 24 CD4+ T-cell count (average of the week 22 and week 24 values). | From week 24 to week 36 | 
| Change in CD4+ T-cell Count | Change was calculated as week 48 CD4+ T-cell count (average of week 46 and week 48) minus the week 24 CD4+ T-cell count (average of the week 22 and week 24 values). | From week 24 to week 48 | 
| Change in CD4 Percentage | Change was calculated as the week 24 CD4 percentage (average of the week 22 and week 24 values) minus the baseline CD4 percentage (average of pre-entry and entry values). | From baseline to week 24 | 
| Within-subject CD4 Percentage Slopes | The estimated mean slope was summarized across the population by using generalized estimating equations. Baseline was defined as the average of pre-entry and entry values. Week 24 was defined as the average of the week 22 and week 24 values. | From baseline through week 24 | 
| Change From Within-subject Pre-treatment CD4 Percentage Slopes to Corresponding Within-subject CD4 Percentage Slopes From Baseline Through Week 24 | The estimated mean change in slopes was summarized across the population by using generalized estimating equations. Pre-treatment CD4 percentage (from at least 48 weeks prior to study entry) were recorded at screening from patient source documentation. Baseline was defined as the average of pre-entry and entry values. Week 24 was defined as the average of the week 22 and week 24 values. | From pre-treatment through week 24 | 
| Change in CD4 Percentage | Change was calculated as week 36 CD4 percentage minus the week 24 CD4 percentage (average of the week 22 and week 24 values). | From week 24 to week 36 | 
| Change in CD4 Percentage | Change was calculated as week 48 CD4 percentage (average of week 46 and week 48) minus the week 24 CD4 percentage (average of the week 22 and week 24 values). | From week 24 to week 48 | 
| Number of Subjects Who Experience a Grade 2, 3 or 4 Signs and Symptoms, Grade 3 or 4 Laboratory Abnormalities, or Death. | Events with date of onset or specimen date prior to first dose of MVC or after the last dose of MVC were excluded. Signs and symptoms with a date of onset the same as the first dose of MVC were excluded if confirmed by the site to be before the first dose. Lab abnormalities with the date of specimen the same as the date of the first dose of MVC were excluded on the assumption that the specimen was drawn before the first dose. Grading used the Division of AIDS (DAIDS) 2004 Severity of Adverse Events Tables, where Grade 1=Mild, 2=Moderate, 3=Severe, 4=Potentially life-threatening. | From baseline through week 24 | 
| 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+ | Change was calculated as the week 24 result (average of the week 22 and week 24 values) minus the baseline result (average of pre-entry and entry values). | From baseline to week 24 | 
| 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+ | Change was calculated as the week 24 result (average of the week 22 and week 24 values) minus the baseline result (average of pre-entry and entry values). | From baseline to week 24 | 
| 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+ | Change was calculated as week 36 result minus the week 24 result (average of the week 22 and week 24 values). | From week 24 to week 36 | 
| 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+ | Change was calculated as week 36 result minus the week 24 result (average of the week 22 and week 24 values). | From week 24 to week 36 | 
| 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+ | Change was calculated as week 48 result (average of week 46 and week 48) minus the week 24 result (average of the week 22 and week 24 values). | From week 24 to week 48 | 
| 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+ | Change was calculated as week 48 result (average of week 46 and week 48) minus the week 24 result (average of the week 22 and week 24 values). | From week 24 to week 48 | 
| Change in Soluble CD14 | Change was calculated as the week 24 result (average of the week 22 and week 24 values) minus the baseline result (average of pre-entry and entry values). Soluble CD14 is a marker of gut microbial translocation. | From baseline to week 24 | 
| Change in Soluble CD14 | Change was calculated as week 36 result minus the week 24 result (average of the week 22 and week 24 values). Soluble CD14 is a marker of gut microbial translocation. | From week 24 to week 36 | 
| Change in Soluble CD14 | Change was calculated as week 48 result (average of week 46 and week 48) minus the week 24 result (average of the week 22 and week 24 values). Soluble CD14 is a marker of gut microbial translocation. | From week 24 to week 48 | 
| Change in High Sensitivity C-reactive Protein (Hs-CRP) | Change was calculated as the week 24 result (average of the week 22 and week 24 values) minus the baseline result (average of pre-entry and entry values). | From baseline to week 24 | 
| Change in Interleukin (IL)-6, Monocyte Chemoattractant Protein (MCP)-1, MCP-2, and Plasma CD40 Ligand (CD40L) | Change was calculated as the week 24 result (average of the week 22 and week 24 values) minus the baseline result (average of pre-entry and entry values). | From baseline to week 24 | 
| Change in Intercellular Cell Adhesion Molecule (ICAM)-1, Plasma P-selectin, Soluble TNFRII (sTNFRII), and Matrix Metalloproteinase (MMP)-9 | Change was calculated as the week 24 result (average of the week 22 and week 24 values) minus the baseline result (average of pre-entry and entry values). | From baseline to week 24 | 
| Change in D-dimer | Change was calculated as the week 24 result (average of the week 22 and week 24 values) minus the baseline result (average of pre-entry and entry values). | From baseline to week 24 | 
| Change in Hs-CRP | Change was calculated as week 36 result minus the week 24 result (average of the week 22 and week 24 values). | From week 24 to week 36 | 
| Change in IL-6, MCP-1, MCP-2, and Plasma CD40L | Change was calculated as week 36 result minus the week 24 result (average of the week 22 and week 24 values). | From week 24 to week 36 | 
| Change in ICAM-1, Plasma P-selectin, sTNFRII, and MMP-9 | Change was calculated as week 36 result minus the week 24 result (average of the week 22 and week 24 values). | From week 24 to week 36 | 
| Change in D-dimer | Change was calculated as week 36 result minus the week 24 result (average of the week 22 and week 24 values). | From week 24 to week 36 | 
| Change in Hs-CRP | Change was calculated as week 48 result (average of week 46 and week 48) minus the week 24 result (average of the week 22 and week 24 values). | From week 24 to week 48 | 
| Change in IL-6, MCP-1, MCP-2, and Plasma CD40L | Change was calculated as week 48 result (average of week 46 and week 48) minus the week 24 result (average of the week 22 and week 24 values). | From week 24 to week 48 | 
| Change in ICAM-1, Plasma P-selectin, sTNFRII, and MMP-9 | Change was calculated as week 48 result (average of week 46 and week 48) minus the week 24 result (average of the week 22 and week 24 values). | From week 24 to week 48 | 
| Change in D-dimer | Change was calculated as week 48 result (average of week 46 and week 48) minus the week 24 result (average of the week 22 and week 24 values). | From week 24 to week 48 | 
| Proportion of Participants With Detectable HIV-1 Viremia as Measured by Single Copy Assay (SCA) | A subject was considered detectable at a specific week if HIV-1 RNA by SCA >=1 copy/ml. | At weeks -1 (pre-entry), 0 (entry), 12, 22, 24, and 36 | 
| Drug Adherence Assessed as Number of Missed Doses Over a 4-day Recall | Self-reported MVC adherence data were based on a four-day (8 expected doses) recall. Based on the wording of the Self Report case report form (CRF), participants reporting that they were currently taking MVC that then failed to complete the record of the number of missed doses were assumed to have no missed doses to report. Missing adherence assessments at a time point of interest were ignored and only those participants completing an adherence assessment at least one time point of interest were included. | At weeks 4, 12, and 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CCR5 antagonist, CD4 T-cell count, immune activation, treatment experienced