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

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.

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