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Immune Activators Stay High Despite Long-Term HIV Suppression With Antiretrovirals: affects CD4 recovery
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16th Conference on Retroviruses and Opportunistic Infections, February 8-11, 2009, Montreal
Mark Mascolini
Levels of lipopolysaccharide (LPS) and sCD14, two immune activators, dropped significantly during antiretroviral therapy but did not return to normal levels after up to 11 years of treatment in a study by Reena Rajasuriar and Melbourne colleagues [1]. They also found that a higher pretreatment CD4 count and IL-7R-alpha haplotype GTA predicted CD4 gains exceeding 500 cells/mm(3).
Because IL-7R-alpha polymorphisms could influence antiretroviral-induced CD4-cell recovery, Rajasuriar and coworkers examined the role of these genetic shifts, as well as gut microbial translocation and immune activation, on long-term CD4 gains in people taking a suppressive regimen. They included people who began treatment with a potent combination at a CD4 count under 500 whose viral load became undetectable within 6 months of starting therapy. Everyone had at least three CD4 counts in the first 12 months of therapy.
IL-7R-alpha polymorphisms may impair T-cell reconstitution by altering the soluble/membrane receptor expression ratio of T cells. The GTA polymorphism is associated with more membrane-bound than soluble receptor expression. In theory, that could increase IL7 signal transduction and thus lead to better CD4 recovery in people with HIV infection.
The study group included 83 men and 13 women with a median age of 39.5 years (interquartile range [IQR] 33-47) when they began therapy. Median pretreatment CD4 count stood at 199 (IQR 92 to 304), and follow-up lasted a median of 4 years (IQR 3 to 7). Twenty-seven people (28%) had AIDS before beginning therapy, and 47 (49%) were taking myelosuppressive therapy when they started their antiretrovirals. Two thirds took a nonnucleoside-based regimen, 30% began with a protease inhibitor, and 3% started with three nucleosides. IL-7R-alpha haplotypes were fairly evenly distributed in the study group--32% GTG, 25% GTA, 16% TTA, and 27% GCA.
LPS concentration dropped significantly after these people started therapy (P < 0.001) but remained elevated when compared with HIV-negative controls (P = 0.026). sCD14 also dropped significantly with treatment (P < 0.001) but stayed significantly higher than in uninfected people (P < 0.001). LPS levels correlated positively and significantly with sCD14 levels (R = 0.361, P < 0.001).
LPS and sCD14 concentrations measured for up to 132 months of treatment in 30 study participants dropped slowly but continuously over that time (P = 0.005 for LPS, P = 0.011 for sCD14) but remained well above concentrations in people without HIV. People with the IL-7R-alpha GTA haplotype regained CD4 cells significantly faster than those with other haplotypes (P = 0.007).
Multivariate analysis to uncover independent predictors of long-term CD4 reconstitution above the 500 mark considered baseline and lowest-ever CD4 count, baseline viral load, age, type of antiretroviral regimen, use of myelosuppressive drugs, LPS and sCD14 before and during treatment and fold change in each, previous AIDS, duration of follow-up, gender, hepatitis B or C coinfection, mode of HIV transmission, and IL-7R-alpha haplotype. Only two factors independently predicted CD4 gains: higher pretreatment CD4 count (hazard ratio 1.007, 95% confidence interval 1.005 to 1.009, P < 0.001) and GTA versus other haplotypes (hazard ratio 1.60, 95% confidence interval 1.10 to 2.33, P = 0.019).
The Melbourne team proposed that genetic factors such as IL-7R-alpha haplotype may prove useful as prognostic markers to suggest the best time to begin antiretroviral therapy.
Reference
1. Rajasuriar R, Jones G, Solomon A, et al. Biological determinants of immune reconstitution following long-term HAART. 16th Conference on Retroviruses and Opportunistic Infections. February 8-11, 2009. Montreal. Abstract 390.
(The poster is online at http://www.retroconference.org/2009/PDFs/390.pdf.)
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