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Multicenter Study
. 2011 Jan 28;25(3):303-14.
doi: 10.1097/QAD.0b013e32834273ad.

Effect of highly active antiretroviral therapy on biomarkers of B-lymphocyte activation and inflammation

Deborah L Regidor  1 , Roger Detels, Elizabeth C Breen, Daniel P Widney, Lisa P Jacobson, Frank Palella, Charles R Rinaldo, Jay H Bream, Otoniel Martínez-Maza
Affiliations
Multicenter Study

Effect of highly active antiretroviral therapy on biomarkers of B-lymphocyte activation and inflammation

Deborah L Regidor et al. AIDS. .

Abstract

Objective: Chronic inflammation and B-cell hyperactivation are seen in HIV infection, contributing to an increased risk for the accrual of genetic errors that may result in B-cell lymphoma. The primary objective of this study was to determine the effect of highly active antiretroviral therapy (HAART) on serum levels of molecules that are associated with immune activation and/or inflammation, including several that are associated with B-cell activation, specifically IL-6, sCD30, sCD27, IgG, IgA, CXCL13 (B lymphocyte chemoattractant, BLC), a B-lymphocyte chemokine involved in B-cell trafficking, as well as C-reactive protein, an acute-phase protein.

Design: We used a retrospective cohort study design, measuring serum levels of these markers at each of four 1-year intervals, 2 years before and 2 years after HAART initiation, in a subgroup of 290 HIV-infected men enrolled in the Multicenter AIDS Cohort Study (MACS).

Methods: Serum levels of immune activation-associated molecules were measured by ELISA and multiplexed immunometric assays. Reference values were determined by the 5th to 95th percentiles from a sample of 109 HIV-uninfected MACS men.

Results: HAART use was associated with a reduction, but not normalization, of most biomarkers tested. Serum levels of IL-6 and C-reactive protein appeared to be unaffected by HAART.

Conclusions: These results suggest a partial normalization of serum cytokine levels post HAART. However, a chronic state of B-cell hyperactivation continues 2-3 years after HAART initiation. These findings may explain, in part, the excess incidence of lymphoma still occurring in HIV-infected persons in the post-HAART era.

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Figures

Fig. 1
Fig. 1. Biomarker levels pre and post-HAART
Levels of cytokines and molecules associated with inflammation and immune activation were assessed as described in the Methods section, in sera collected at two MACS study visits prior to, and two visits after, the initiation of HAART. The pre-HAART study visits were at −3.0 to −1.5 years (T1) (n = 270), or −1.5 to −0.5 years (T2) (n = 236), preceding HAART initiation. Post-HAART visits were at 0.5 to 1.5 years (T3) (n = 261), or 1.5 to 3.0 years (T4) (n = 266), post-HAART initiation. The characteristics of these participants and visits are outlined in Table 3. Serum levels of these same biomarkers, assessed in a reference group of HIV-negative MACS participants also is provided (HIV−) (n = 109). Average levels of all of the biomarkers shown in this figure were significantly decreased post-HAART (P < 0.001), except IL-6 and CRP, which were not significantly decreased post-HAART. CRP, C-reactive protein; HAART, highly active antiretroviral therapy; MACS, Multicenter AIDS Cohort Study.
Fig. 2
Fig. 2. Effect of HAART on biomarkers of inflammation and immune activation
(a) Total population, (b) stratified by HIV viral response, and (c) stratified by ART exposure at HAART initiation. HAART, highly active antiretroviral therapy.
Fig. 3
Fig. 3. Distribution of CD4 lymphocytes over time by HIV viral response
T1: −3.0 to −1.5 years pre-HAART (n = 270), T2: −1.5 to −0.5 years pre-HAART (n = 236), T3: 0.5 to 1.5 years post-HAART (n = 261), T4: (1.5 to 3.0 years post-HAART) (n = 266).
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