HIV-1 coreceptor usage and CXCR4-specific viral load predict clinical disease progression during combination antiretroviral therapy.
BACKGROUND
Although combination antiretroviral therapy (cART) dramatically reduces rates of AIDS and death, a minority of patients experience clinical disease progression during treatment.


OBJECTIVE
To investigate whether detection of CXCR4(X4)-specific strains or quantification of X4-specific HIV-1 load predict clinical outcome.


METHODS
From the Swiss HIV Cohort Study, 96 participants who initiated cART yet subsequently progressed to AIDS or death were compared with 84 contemporaneous, treated nonprogressors. A sensitive heteroduplex tracking assay was developed to quantify plasma X4 and CCR5 variants and resolve HIV-1 load into coreceptor-specific components. Measurements were analyzed as cofactors of progression in multivariable Cox models adjusted for concurrent CD4 cell count and total viral load, applying inverse probability weights to adjust for sampling bias.


RESULTS
Patients with X4 variants at baseline displayed reduced CD4 cell responses compared with those without X4 strains (40 versus 82 cells/microl; P = 0.012). The adjusted multivariable hazard ratio (HR) for clinical progression was 4.8 [95% confidence interval (CI) 2.3-10.0] for those demonstrating X4 strains at baseline. The X4-specific HIV-1 load was a similarly independent predictor, with HR values of 3.7 (95% CI, 1.2-11.3) and 5.9 (95% CI, 2.2-15.0) for baseline loads of 2.2-4.3 and > 4.3 log10 copies/ml, respectively, compared with < 2.2 log10 copies/ml.


CONCLUSIONS
HIV-1 coreceptor usage and X4-specific viral loads strongly predicted disease progression during cART, independent of and in addition to CD4 cell count or total viral load. Detection and quantification of X4 strains promise to be clinically useful biomarkers to guide patient management and study HIV-1 pathogenesis.
Weiser
Barbara
B
Division of Infectious Diseases, Wadsworth Center, New York State Department of Health, Albany, New York 12208, USA. weiser@wadsworth.org
Philpott
Sean
S
Klimkait
Thomas
T
Burger
Harold
H
Kitchen
Christina
C
Bürgisser
Philippe
P
Gorgievski
Meri
M
Perrin
Luc
L
Piffaretti
Jean-Claude
JC
Ledergerber
Bruno
B
D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D018450:Disease Progression; D004812:Epidemiologic Methods; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology; D015497:HIV-1; D006801:Humans; D008297:Male; D019718:Receptors, CXCR4 / Q000378:metabolism*; D016896:Treatment Outcome; D019562:Viral Load
D019718:Receptors, CXCR4