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T Cell Activation Is Inversely Associated with CD4+ T Cell Increase after HAART, and Predicts CD4 Gains at 48 Weeks after Controlling for Baseline CD4 Count and Plasma HIV RNA Level
Benigno Rodriguez*1, J Spritzler2, E Chan2, R Gandhi3, P Skolnik4, D Defreitas5, D Asmuth5, G Robbins3, R Pollard5, and the ACTG 384 Study Team
1Case Western Reserve Univ, Ctr for AIDS Res, Cleveland, OH, US; 2Harvard Sch of Publ Hlth, Boston, MA, US; 3Massachusetts Gen Hosp, Boston, US; 4Boston Univ Med Ctr, MA, US; and 5Univ of California, Davis Med Ctr, Sacramento, US
Background: Immune activation, especially of CD8+
T cells, is associated with HIV disease progression, but its role in predicting
CD4 rise after HAART is unclear.
Methods: We included 623 treatment-naïve participants
in the multicenter ART trial ACTG384 (of a total of 980
subjects), who underwent advanced flow cytometry
studies. We analyzed CD4 count, HIV RNA, and markers of immune activation at
baseline and at weeks 24, 48, 72, 96, 120, and 144. Immune activation was
defined as CD38 and HLA-DR co-expression on CD4 and CD8 T cells. Treatment
exposure was calculated as the proportion of time during which a patient was
receiving the study regimen. Multiple linear regression
was used to assess association of the covariates of interest with CD4 cell
increase; Spearman’s rank correlation was used for univariate
comparisons. AIC stepwise logistic regression was used to assess predictors of
CD4 cell gain ≥100/mm3 by week 48.
Results: Median baseline CD4 and HIV RNA level were 280
cells/mm3 and 4.9 log10 copies/mL,
respectively. As expected, the magnitude of CD4 gain was greater with
increasing time on treatment. Change in immune activation percentage of both
CD4 and CD8 was inversely associated with magnitude of CD4 increase from week
48 to week 144. This association held at most time points when restricting to
subjects receiving treatment up to that point. In multiple linear regression
analyses, CD8 activation change was strongly and independently associated with
CD4 increase from week 48 to week 120, after controlling for treatment
exposure. In logistic regression analyses, week 48 CD8 activation was
negatively associated with a CD4 cell gain ≥100 at week 48, after
controlling for baseline CD4 T cell count and plasma HIV RNA level, as well as
treatment exposure. In this model, each 10% decrease in CD8 activation at week
48 was associated with an odds ratio of 1.3 (95% CI, 1.1-1.5)
of achieving a ≥100 CD4 cell count increase.
Conclusions: In treatment-naïve patients, HAART-induced decline
in CD8 T cell activation is associated with the degree of CD4 rise after HAART,
even after accounting for treatment exposure. A negative association of CD4 reconstitution
with CD8 T cell activation at week 48 can be demonstrated even after
controlling for baseline CD4 count, plasma HIV RNA level and treatment exposure.
These findings suggest that the ability to reduce immune activation may be an
important independent determinant of the immunologic outcome of HAART.
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