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Emergence of X4 Virus at High CD4 Counts in MACS Cohort
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Mark Mascolini
XVI International AIDS Conference, Toronto
August 16, 2006
HIV that can use the CXCR4 (X4) coreceptor on CD4 cells--considered a sign of worsening disease--appeared in men with a high median CD4 count of 484 cells/mm3 [1]. This analysis of the US Multicenter AIDS Cohort Study (MACS) spotted X4 virus in 4 men within 2 years of HIV infection, and all 4 had AIDS or a CD4 count under 200 cells/mm3 within 3.5 years.
Researchers have known for years that X4 virus begins to infiltrate a person's CCR5-(R5)-using viral population as HIV infection progresses. Understanding the timing and correlates of X4 emergence has gained urgency with the imminent licensing of CCR5 antagonists, which some fear will drive HIV to switch from R5 to X4 use.
MACS enrolls gay men at risk for HIV infection and tracks them regularly whether or not they become infected. This analysis scrutinized 685 blood samples from 67 men who did become infected. The MACS team tested virus in the blood with an assay for R5 or X4 use. This assay cannot distinguish between individual viruses that use both coreceptors (called dual-tropic virus) and viral populations including both R5- and X4-using virus (called mixed-tropic virus).
The study group was 87% white and had a median age of 32 years when infected with HIV; 1986 was their median year of infection.
Two men had R5/X4 virus at their first visit after picking up HIV infection, and their virus remained mixed-tropic throughout follow-up. Of the 65 men with an exclusive R5-using population after infection, 33 (51%) later had R5/X4-using virus.
Half of the men in whom X4 use arose had R5/X4 virus before an AIDS diagnosis or before their CD4 count dropped below 200 cells/mm3. Median time from X4 emergence to AIDS or fewer than 200 CD4 cells/mm3 measured 1 year. And the median CD4 count at X4 emergence stood at 484 cells/mm3 (interquartile range 299 to 718 cells/mm3).
Earlier work in the MACS cohort defined a point when the T-cell population of HIV-infected men shifts from relative stability to a progressively downward course [2]. The new analysis figured how this so-called inflection point correlates with the change in R5 and X4 use. The MACS researchers found that X4 virus appeared in 54% of men with a defined inflection point compared with 24% of those without a defined inflection point, a significant difference (P = 0.048). Among men with a defined inflection point who later had X4-using virus, the X4 virus appeared a median of 9 months after they passed the inflection point.
HIV infection did progress to AIDS in some men who never had evidence of X4 virus, a finding confirming earlier research. But the MACS study challenges the assumption that X4 virus appears only in people with advanced HIV infection. The MACS results add weight to the belief that people should be tested for R5 and X4 use before starting CCR5 antagonists, which do nothing to control replication of X4-using virus but can have some impact on mixed R5/X4 viral populations.
References
1. Shepherd J, Jacobson L, Qiao W, et al. Analysis of the timing of CXCR4-tropic HIV emergence in the MACS cohort. XVI International AIDS Conference. August 13-18. Toronto. Abstract TUPE0001.
2. Gange SJ, Munoz A, Chmiel JS, et al. Identification of inflections in T-cell counts among HIV-1-infected individuals and relationship with progression to clinical AIDS. Proc Natl Acad Sci USA 1998;95:10848-10853.
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