655
Co-receptor Tropism in Patients Screening for ACTG 5211, a Phase 2 Study of Vicriviroc, a CCR5 Inhibitor
Timothy Wilkin*1, Z Su2, D Kuritzkes3, M Hughes2, C Flexner4, R Gross5, E Coakley6, W Greaves7, C Godfrey8, and R Gulick1
1Weill-Cornell Med Coll, New York, NY, US; 2Harvard Sch of Publ Hlth, Boston, MA, US; 3Brigham and Women's Hosp, Boston, MA, US; 4Johns Hopkins Univ, Baltimore, MD, US; 5Univ of Pennsylvania, Philadelphia, US; 6Monogram Biosci, South San Francisco, CA, US; 7Schering-Plough Res Inst, Kenilworth, NJ, US; and 8NIAID, NIH, DHHS, Bethesda, MD, US
Background: The
epidemiology of co-receptor tropism in treatment-experienced patients using
contemporary recombinant virus assays merits further study.
Methods:
Participants were screened for ACTG 5211, a phase 2b study of vicriviroc. Eligibility requirements included prior 3-class
antiretroviral treatment, plasma HIV-1 RNA >5,000 copies/ml, and current use
of a ritonavir-boosted PI. Participant
demographics and nadir CD4 count were assessed. Screening CD4 cell count, HIV-1
plasma RNA, genotypic and phenotypic resistance tests, and co-receptor tropism
phenotype (Monogram) were performed. The
association of predictive factors for co-receptor tropism was determined by
chi-square or Wilcoxon rank sum test,
and multivariate analysis by logistic regression.
Results: 368 subjects had a co-receptor tropism result
available. 177 (48%) were CCR5-tropic
only (R5), 175 (48%) had dual or mixed co-receptor tropism for CCR5 and CXCR4
(R5/X4), and 16 (4%) were CXCR4-tropic only (X4). Matched screening data were available on 279
(76%) subjects and genotypic resistance data were available for 245 (67%)
subjects. The prevalence of R5 only was
similar in women (16/31, 52%) and men (126/248, 51%). The prevalence of R5 only in Hispanics,
Non-Hispanic Whites, and Non-Hispanic Blacks was 20/30 (67%), 88/169 (52%), and
31/74 (42%) (p=.06).
Univariate Predictors of Co-receptor Tropism (median [interquartile
range])
|
|
R5 only group
|
R5/X4 and X4 groups
|
p-value
|
|
Age
|
46 [41-53]
|
45 [41-50]
|
.25
|
|
Nadir CD4 count (cells/mm3)
|
58 [22-143]
|
40 [8-118]
|
.05
|
|
Screening CD4 count (cells/mm3)
|
169 [65-280]
|
113 [21-231]
|
.003
|
|
HIV-1 RNA (log10
copies/ml)
|
4.6 [4.1-5.0]
|
4.7 [4.2-5.2]
|
.21
|
|
Number of
resistance mutations
NRTI
NNRTI
PI
|
6 [4-7]
1 [1-2]
8 [7-9]
|
6 [4-7]
1 [1-2]
8 [7-10]
|
>0.5
>0.5
>0.5
|
On multivariate analysis, CD4 cell count remained
significantly associated with R5 tropism (p=.03), but nadir CD4 cell count did
not (p>0.5). Differences among
race/ethnicity groups approached significance (p=0.1).
Conclusions:
Infection with HIV utilizing CXCR4 and CCR5 is common among highly
treatment-experienced subjects, but presence of CXCR4-tropic virus alone was uncommon. Treatment-experienced patients with R5/X4 or
X4 had significantly lower screening CD4 cell counts than those with R5
only. The potential relationship of
race/ethnicity to co-receptor tropism deserves further study.
|
