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CD8 Activation and Naive CD4s Predict
CD4 Gains Through 10 to 15 Years of ART
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19th Conference on Retroviruses and Opportunistic Infections, March 5-8, 2012, Seattle
Mark Mascolini
Lower levels of activated CD8 T cells 3 to 5 years after starting antiretroviral therapy (ART) predicted significantly greater CD4 gains in years 10 to 15 of treatment among people with consistently well-controlled viremia, according to results of an observational AIDS Clinical Trials Group (ACTG) study [1]. Higher naive CD4 percentages in the first years of ART also predicted greater CD4 gains over the next decade in people with good viral control.
Previous research linked higher CD8-cell activation before starting ART to worse CD4 recovery and determined that persistent CD8 activation during ART raises the risk of death [2]. But whether long-term consequences of persistent CD8-cell activation--or naive CD4-cell levels--predict CD4 restoration had not been determined.
The new analysis involved 120 adults in the ACTG ALLRT observational study who never had consecutive viral loads above 1000 copies/mL while taking ART. Everyone had data available on CD8-cell activation (defined as percentage of CD38+/HLA-DR+ CD8s) and naive CD4 levels (defined as percentage of CD45RA+/CD62L+ CD4s). The ACTG team compared average CD4 counts in people with activated CD8 and naive CD4 levels above versus below the group medians from 3 to 15 years after starting indinavir-based ART.
The study group began indinavir-based ART with a median CD4 count of 89, a median viral load of 4.8 log (about 65,000 copies), and a median age of 40. Most study participants (91%) were men, and most (70%) were non-Hispanic white. Follow-up extended for a median of 14 years (interquartile range 10 to 15).
Lower CD8-cell activation levels predicted significantly greater CD4 gains through 15 years of follow-up after ART began. Specifically, people with a CD8 activation level at or below 18.5% (the group median) gained an average 403 CD4s cells to the average determined in years 10 to 15, compared with an average gain of 345 during that period in people with a higher CD8 activation level (P = 0.002). At years 10 and 15, CD4 counts averaged 583 in the low CD8-activation group and 479 in the high CD8-activation group (P = 0.003).
The cutoff between low and high naive CD4 percentages during suppressive ART was 32%. People with a high naive CD4 percent had an average CD4 count of 586 at treatment years 10 and 15, compared with an average count of 493 for people with a lower naive CD4 percent in those years (P = 0.010). People in the high naive-CD4 group gained an average 475 CD4 cells to years 10 to 15, compared with an average gain of 354 in the low naive-CD4 group (P = 0.001).
Both CD8-cell activation and naive CD4 percentage remained significant predictors of long-term CD4 gains in (1) an analysis that included both markers and (2) an analysis that included only 52 study participants who kept their viral load below 50 copies throughout follow-up.
In the model that included both CD8 activation and naive CD4 percentage, every 5% higher CD8 activation level lowered CD4 counts by an average 27 cells at year 10, and every 5% higher naive CD4 percent raised CD4 counts by an average 22 cells at year 10. Younger people had greater CD4 gains even after statistical adjustment for CD8 activation and naive CD4 percent.
The investigators believe their findings "support research efforts to identify new approaches to reduce immune activation and enhance naive T-cell survival in treated HIV disease."
References
1. Zhang X, Hunt P, Hammer S, Cespedes M, Patterson K, Bosch R. Immune activation while on potent ART can predict subsequent CD4+ T cell increases through 15 years of treatment. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 274.
2. Hunt PW, Cao HL, Muzoora C, et al. Impact of CD8+ T-cell activation on CD4+ T-cell recovery and mortality in HIV-infected Ugandans initiating antiretroviral therapy. AIDS. 2011;25:2123-2131.
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