HIV type 1 chemokine coreceptor use among antiretroviral-experienced patients screened for a clinical trial of a CCR5 inhibitor: AIDS Clinical Trial Group A5211.
BACKGROUND
Chemokine coreceptor use impacts both the natural history of human immunodeficiency virus type 1 (HIV-1) disease and the potential use of a new class of antiretroviral agents, the CCR5 inhibitors.


METHODS
We analyzed HIV-infected patients who were screened for participation in Acquired Immunodeficiency Syndrome (AIDS) Clinical Trial Group protocol A5211, a phase 2b study of the investigational CCR5 inhibitor vicriviroc involving antiretroviral-experienced subjects. Screening CD4(+) cell count, HIV-1 plasma RNA level, HIV-1 genotype, and chemokine coreceptor use phenotype were determined. The univariate and multivariate association of subject characteristics with coreceptor use was assessed by logistic regression.


RESULTS
Coreceptor use was determined for 391 subjects: 197 (50%) had virus that used the CCR5 coreceptor (the R5 group), 178 [corrected] (46%) had dual-tropic or mixed HIV-1 populations that used both CCR5 and CXCR4 coreceptors (the D/M group), and 16 (4%) had virus that used the CXCR4 coreceptor (the X4 group). The D/M group had a significantly lower median CD4(+) cell count than the R5 virus group (103 cells/ micro L vs. 170 cells/ mu L; P<.001). No other characteristics were independently associated. Among 118 subjects who entered A5211 having R5 virus, 12 (10%) had D/M virus according to the results of a second coreceptor test conducted prior to starting treatment with the study drug.


CONCLUSIONS
Infection with dual-tropic or mixed HIV-1 populations that use both CCR5 and CXCR4 is common among highly treatment-experienced patients, but infection with virus using CXCR4 alone is uncommon. Subjects in the D/M group had significantly lower CD4(+) cell counts than subjects in the R5 group. Evaluating coreceptor use will be important in the clinical development of CCR5 and CXCR4 inhibitors.
Wilkin
Timothy J
TJ
Division of International Medicine and Infectious Diseases, Weill-Cornell Medical College, New York, NY, USA. tiw2001@med.cornell.edu
Su
Zhaohui
Z
Kuritzkes
Daniel R
DR
Hughes
Michael
M
Flexner
Charles
C
Gross
Robert
R
Coakley
Eoin
E
Greaves
Wayne
W
Godfrey
Catherine
C
Skolnik
Paul R
PR
Timpone
Joseph
J
Rodriguez
Benigno
B
Gulick
Roy M
RM
D000163:Acquired Immunodeficiency Syndrome / Q000175:diagnosis / Q000188:drug therapy*; D000328:Adult; D000704:Analysis of Variance; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D065100:CCR5 Receptor Antagonists; D015704:CD4 Antigens / Q000032:analysis; D002986:Clinical Trials as Topic; D003430:Cross-Sectional Studies; D005260:Female; D005838:Genotype; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D018579:Patient Selection; D011336:Probability; D019713:Receptors, CCR5 / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019562:Viral Load
D044966:Anti-Retroviral Agents; D065100:CCR5 Receptor Antagonists; D015704:CD4 Antigens; D019713:Receptors, CCR5; D019718:Receptors, CXCR4