16th International AIDS Conference Toronto, Canada - August 13 - 18, 2006

CXCR4-SPECIFIC VIRAL LOAD PREDICTS CLINICAL HIV-1 DISEASE PROGRESSION DURING HAART

Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. ThAa0201

Philpott S.¹, Ledergerber B.², Klimkait T.³, Burger H.¹, Kitchen C.⁴, Bürgisser P.⁵, Gorgievski M.⁶, Joller H.⁷, Perrin L.⁸, Piffaretti J.-C.⁹, Schmid P.¹⁰, Gormley A.¹, Schroeder T.¹, Weiser B.¹, Swiss HIV Cohort Study
¹ New York State Department of Health, Wadsworth Center, Albany, United States, ² Universitätsspital Zurich, Abteilung Infektionskrankheiten und Spitalhygiene, Zurich, Switzerland, ³ Universität Basel, Institut für Medizinische Mikrobiologie, Basel, Switzerland, ⁴ University of California, Department of Biostatistics, Los Angeles, United States, ⁵ Centre Hospitalier Universitaire Vaudois, Service d'Immunologie et Allergie, Lausanne, Switzerland, ⁶ Universität Bern, Institut für Infektionskrankheiten, Bern, Switzerland, ⁷ Universitätsspital Zurich, Klinische Immunologie, Zurich, Switzerland, ⁸ Hôpitaux Universitaires de Genéve, Laboratoire Central de Virologie, Geneva, Switzerland, ⁹ Istituto Cantonale di Microbiologia, Bellinzona, Switzerland, ¹⁰ Kantonsspital St. Gallen, Fachbereich Infektiologie, St. Gallen, Switzerland

BACKGROUND: Although HAART has led to dramatic reductions in HIV-1-related disease progression and death, a minority of patients deteriorate during treatment. Predictors of progression are not completely understood, and HIV-1 coreceptor usage may play a role. CCR5 (R5) viruses initiate infection, whereas CXCR4 (X4) variants are associated with advanced disease. We investigated whether quantification of coreceptor usage and X4-specific HIV-1 load predicts response to HAART.

METHODS: We selected 96 participants in the Swiss HIV Cohort Study who initiated HAART at baseline and subsequently progressed to a new AIDS-defining illness or death. These participants were compared to 84 contemporaneous non-progressors, applying inverse probability weights to adjust for sampling bias. We developed a sensitive heteroduplex tracking assay to quantify the fraction of virus in plasma using R5 and X4, validating it by performing functional assays. QXR (Quantity of X4 and R5) expresses the proportion of virus using R5. If all variants use R5, QXR=1; if all use X4, QXR=0. For R5 and X4 mixtures, QXR<1. QXR and coreceptor-specific HIV-1 loads at baseline and at 6 months were analyzed as cofactors of clinical progression in multivariate Cox models adjusted for concurrent CD4 count and total viral load.

RESULTS: Patients with baseline QXR<1 experienced reduced CD4 cell responses to HAART compared to those with QXR=1 (40 vs. 82 cells, p=0.012); this finding also occurred with QXR<1 at follow-up (35 vs. 90 cells, p=0.049). Adjusted hazard ratios (HR) for clinical progression were 4.00 (95% CI: 1.83 – 8.72) for baseline QXR<1 and 10.3 (2.78 – 38.5) for QXR<1 at the 6-month follow-up. X4-specific viral load was a similarly independent predictor, with a HR of 1.33 (1.11 – 1.60).

CONCLUSIONS: QXR and X4-specific viral loads were strong predictors of disease progression during HAART, independent of and in addition to CD4 count or total viral load. They promise to be useful for clinical management of HIV-1 infection.

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2006-08-13
ThAa0201

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