Paper # 285 
Maraviroc Intensification for Suboptimal CD4+ Cell Response Despite Sustained Virologic Suppression: ACTG 5256
Timothy Wilkin1, C Lalama2, A Tenorio3, A Landay3, H Ribaudo2, J McKinnon4, R Gandhi5, J Mellors4, J Currier6, and R Gulick1
1Weill Cornell Med Coll, New York, NY, US; 2Harvard Sch of Publ Hlth, Boston, MA, US; 3Rush Univ Med Ctr, Chicago, IL, US; 4Univ of Pittsburgh Sch of Med, PA, US; 5Massachusetts Gen Hosp, Boston, US; and 6Univ of California, Los Angeles, US
Background: Despite viral suppression, ART does not
restore CD4 counts in some patients. Maraviroc (MVC) use is associated with
enhanced CD4 recovery in patients who initiate ART. We therefore studied the
effect of ART intensification with MVC on CD4 counts in patients with
suboptimal CD4 recovery.
Methods: Single-arm pilot trial in subjects with a
CD4 count <250/µL, a calculated CD4 slope between -20 and +20 cells/µL/year
and undetectable plasma HIV-1 RNA for the 48 weeks prior to entry. Subjects
added MVC, a CCR5 antagonist, to their existing ART regimen for 24 weeks. The
primary endpoint was the change in CD4 counts from the average of the 2
baseline counts to the average of the week 22 and 24 counts on MVC. Extensive
immunophenotyping was also performed at baseline, week 22 and 24. With a
planned sample size of 32, MVC intensification would be considered successful
if a CD4-count increase of <20 cells/µL was excluded based on a one-sided
Wilcoxon signed-rank test.
Results: There were 34 subjects enrolled in this
study. The median age was 50; 10 (29%) were non-white; 2 (6%) were women; the
median baseline CD4 count was 153/µL. The median duration of HIV-1 RNA
suppression was 3 years prior to entry. Two subjects discontinued MVC for
virologic failure and were excluded per protocol. A CD4 count increase of
<20 cells/µL was not excluded for the primary endpoint (P =0.97).
The mean increase in CD4 count to week 22/24 was 11 cells/µL [90% CI 4 to
19]. Only 2 subjects had a CD4 increase of ³50
cells/µL. The median baseline immune activation and apoptosis markers in the
CD4+ and CD8+ subsets and the change to week 22/24 are
shown below. The change in %CD38+ was not associated with CD4 gain.
|
|
Baseline (CD4+
subset)
|
Change to week 22/24 [90%
CI]
|
Baseline (CD8+
subset)
|
Change to week 22/24 [90%
CI]
|
|
%CD38+
|
45%
|
-15% [-20, -9]
|
30%
|
-14% [-20, -9]
|
|
%HLA-DR+/CD38+
|
5.3%
|
-1.3% [-1.8, -0.3]
|
8.7%
|
-1.4% [-3, -0.3]
|
|
%Ki67+
|
2.9%
|
-1.0% [-1.5, -0.5]
|
0.9%
|
-0.1% [-0.3, 0.1]
|
|
%caspase3+
|
1.7%
|
-1.1% [-1.4, -0.6]
|
1.1%
|
-0.7% [-0.9, -0.4]
|
|
%Bcl-2-
|
1.7%
|
0.7% [0, 1.3]
|
1.3%
|
0.5% [-0.1, 0.8]
|
Conclusions: Adding MVC to a suppressive
antiretroviral regimen was not associated with the hypothesized increase in CD4
counts. MVC intensification was associated with decreased immune activation as
evidenced by reduced %CD38+, % HLA-DR+/CD38+,
and improvement in markers of apoptosis. The clinical significance of these
findings is unknown. Further studies of CCR5 antagonists to dampen immune
activation associated with HIV infection are warranted.
|
