Suppression of Dualtropic Human Immunodeficiency Virus Type 1 by the CXCR4 Antagonist AMD3100 Is Associated with Efficiency of CXCR4 Use and Baseline Virus Composition

ABSTRACT In a phase I/II evaluation of the CXCR4 antagonist AMD3100, human immunodeficiency virus RNA levels were significantly reduced in a single study subject who harbored CXCR4 (X4)-tropic virus, but not in subjects who harbored either dual/mixed (DM)-tropic or CCR5 (R5)-tropic virus (C. W. Hendrix et al., J. Acquir. Immune Defic. Syndr. 37:1253-1262, 2004). In this study, we analyzed the envelope clones of DM-tropic virus in baseline and treated virus populations from 14 subjects. Ten subjects exhibited significant reductions in CXCR4-mediated infectivity after 10 days of AMD3100 therapy relative to baseline (X4 suppressor group), while four subjects had no reduction of CXCR4-mediated infectivity (X4 nonsuppressor group). The baseline viruses of the X4 suppressor group infected CXCR4-expressing cells less efficiently than those of the X4 nonsuppressor group. Clonal analysis indicated that the baseline viruses from the X4 suppressor group contained a higher proportion of R5-tropic variants mixed with CXCR4-using variants, while the X4 nonsuppressor group was enriched for CXCR4-using variants. AMD3100 suppressed X4-tropic variants in all subjects studied, but not all dualtropic variants. Furthermore, dualtropic variants that used CXCR4 efficiently were suppressed by AMD3100, while dualtropic variants that used CXCR4 poorly were not. This study demonstrated that AMD3100 has the ability to suppress both X4-tropic and certain dualtropic variants in vivo. The suppression of CXCR4-using variants by AMD3100 is dependent on both the tropism composition of the virus population and the efficiency of CXCR4 usage of individual variants.

Thrombocytopenia Is a Strong Predictor of All-Cause and AIDS-Specific Mortality in Women with HIV: The Women’s Interagency HIV Study.

Background: Thrombocytopenia is a common condition among HIV-infected individuals, however its significance is unclear, particularly among women. Two previous studies, one consisting mostly of men (Sullivan PS, et al. J Acquir Immune Defic Syndr.1997;14:374–379) and one of hemophiliacs (Ehmann WC, et al. Am J Hematol.1997; 54:296–300), have suggested that low platelet count is associated with decreased survival. Methods: The Women’s Interagency HIV Study (WIHS) is a long-term prospective cohort study of HIV-infected women and HIV-negative women that is being conducted at six urban sites across the United States. 1,990 HIV-infected women and 553 HIV-negative women are included in this report. These women are seen every six months; the median follow-up time is 7.5 years. We conducted extensive multivariate analysis using both generalized estimating equations and Cox proportional hazards models in order to determine the predictors of thrombocytopenia and the role of platelet count in mortality among women being followed as part of this study. Results: At baseline, 15% of HIV-positive women were thrombocytopenic versus 1.6% of HIV-negative women (p<0.001). Factors associated with increased risk of thrombocytopenia included HIV infection, low CD4 cells, increasing viral load, and smoking. African-American women were significantly protected against thrombocytopenia when compared to Whites, as reported by others (Sloand EM, et al. Eur J Haematol. 1992; 48:168–72; Sullivan PS, et al. J Acquir Immune Defic Syndr.1997;14:374–379 ). Resolution of thrombocytopenia was associated with highly-active antiretroviral therapy (p<0.001), especially that containing zidovudine (<0.0001). On multivariate analysis, thrombocytopenia was a significant predictor of mortality, with women having a platelet count <50,000 cells/mm3 being at more than 5-fold increased risk of dying due to any cause, and at 3-fold increased risk of death due to AIDS compared to women with a platelet count in the normal range. Only CD4+ lymphocyte count <200 cells/mm3 was similar in the magnitude of its effect on mortality. The reasons for decreased survival associated with low platelet count in the context of HIV-infection are unclear and further study is needed. Conclusions: (1) Thrombocytopenia is associated with HIV infection (p<0.001), and with parameters of more advanced HIV disease in women; (2) African American HIV + women are protected from thrombocytopenia compared to HIV + white women (p<0.0001); (3) HAART is associated with resolution of thrombocytopenia, especially those regimens including AZT (p<0.001); (4) Thrombocytopenia is an independent risk factor for decreased survival in HIV infected women.