HAART-Induced HIV Suppression and Markers of Inflammation
HAART-Induced HIV Suppression and Markers of Inflammation
Objectives To investigate the impact of HAART-induced HIV suppression on levels of 24 serological biomarkers of inflammation and immune activation.
Design A prospective cohort study.
Methods Biomarkers were measured with multiplex assays in centralized laboratories using stored serum samples contributed by 1697 men during 8903 person-visits in the Multicenter AIDS Cohort Study (MACS) from 1984 to 2009. Using generalized gamma models, we compared biomarker values across three groups, adjusting for possible confounders: HIV-uninfected (NEG); HIV-positive, HAART-naive (NAI); and HAART-exposed with HIV RNA suppressed to less than 50 copies/ml plasma (SUP). We also estimated changes in biomarker levels associated with duration of HIV suppression, using splined generalized gamma regression with a knot at 1 year.
Results Most biomarkers were relatively normalized in the SUP group relative to the NAI group; however, 12 biomarkers in the SUP group were distinct (P < 0.002) from NEG values: CXCL10, C-reactive protein (CRP), sCD14, sTNFR2, tumour necrosis factor-alpha (TNF-α), sCD27, sGP130, interleukin (IL)-8, CCL13, BAFF, GM-CSF and IL-12p70. Thirteen biomarkers exhibited significant changes in the first year after viral suppression, but none changed significantly after that time.
Conclusion Biomarkers of inflammation and immune activation moved towards HIV-negative levels within the first year after HAART-induced HIV suppression. Although several markers of T-cell activation returned to levels present in HIV-negative men, residual immune activation, particularly monocyte/macrophage activation, was present. This residual immune activation may represent a therapeutic target to improve the prognosis of HIV-infected individuals receiving HAART.
The introduction of HAART led to greatly increased survival of HIV-infected individuals. Although HAART dramatically reduces HIV viral load, individuals receiving HAART face higher risks than HIV-uninfected individuals of serious non-AIDS related morbidities, AIDS-defining cancers and all-cause mortality, depending upon the stage of HIV disease at which HAART was initiated. Although the cause of these risks remains unclear, persistent dysregulation of inflammatory processes causing chronic immune activation is likely important. For example, T-cell activation among HIV-suppressed individuals receiving HAART is negatively associated with immune reconstitution. HIV-induced dysregulation of inflammatory processes occurs via multiple pathways, possibly including microbial translocation.
The effect of HAART on immune activation and inflammation is incompletely understood. There is evidence that HAART-induced HIV suppression reduces some measures of HIV-induced immune activity, but not necessarily to levels present in HIV-uninfected individuals. In the Multicenter AIDS Cohort Study (MACS), elevated levels of B cell stimulatory cytokines and other immune activation markers did not normalize following HAART initiation. In the Women's Interagency HIV Study (WIHS), however, serum levels of both inflammatory and anti-inflammatory biomarkers normalized following HAART initiation, though tumour necrosis factor (TNF)-α remained elevated in women despite undetectable HIV RNA. In the Strategies for Management of Antiretroviral Treatment trial, participants with HIV suppression still had higher levels of interleukin (IL)-6, D-dimer and C-reactive protein (CRP) than HIV-negative individuals from other cohorts.
Most studies examining changes in inflammatory biomarker levels in HIV-infected individuals have been limited by small study populations, cross-sectional designs and/or small numbers of biomarkers. Recent technical advances, especially the development of multiplexed assays, have enabled the more efficient measurement of multiple inflammatory biomarkers. In this study, we compared levels of 24 such biomarkers in stored serum samples from HIV-infected participants in the MACS before and after HAART initiation, and from HIV-uninfected MACS participants who had similar ages and racial profiles to the HIV-infected men studied.
Abstract and Introduction
Abstract
Objectives To investigate the impact of HAART-induced HIV suppression on levels of 24 serological biomarkers of inflammation and immune activation.
Design A prospective cohort study.
Methods Biomarkers were measured with multiplex assays in centralized laboratories using stored serum samples contributed by 1697 men during 8903 person-visits in the Multicenter AIDS Cohort Study (MACS) from 1984 to 2009. Using generalized gamma models, we compared biomarker values across three groups, adjusting for possible confounders: HIV-uninfected (NEG); HIV-positive, HAART-naive (NAI); and HAART-exposed with HIV RNA suppressed to less than 50 copies/ml plasma (SUP). We also estimated changes in biomarker levels associated with duration of HIV suppression, using splined generalized gamma regression with a knot at 1 year.
Results Most biomarkers were relatively normalized in the SUP group relative to the NAI group; however, 12 biomarkers in the SUP group were distinct (P < 0.002) from NEG values: CXCL10, C-reactive protein (CRP), sCD14, sTNFR2, tumour necrosis factor-alpha (TNF-α), sCD27, sGP130, interleukin (IL)-8, CCL13, BAFF, GM-CSF and IL-12p70. Thirteen biomarkers exhibited significant changes in the first year after viral suppression, but none changed significantly after that time.
Conclusion Biomarkers of inflammation and immune activation moved towards HIV-negative levels within the first year after HAART-induced HIV suppression. Although several markers of T-cell activation returned to levels present in HIV-negative men, residual immune activation, particularly monocyte/macrophage activation, was present. This residual immune activation may represent a therapeutic target to improve the prognosis of HIV-infected individuals receiving HAART.
Introduction
The introduction of HAART led to greatly increased survival of HIV-infected individuals. Although HAART dramatically reduces HIV viral load, individuals receiving HAART face higher risks than HIV-uninfected individuals of serious non-AIDS related morbidities, AIDS-defining cancers and all-cause mortality, depending upon the stage of HIV disease at which HAART was initiated. Although the cause of these risks remains unclear, persistent dysregulation of inflammatory processes causing chronic immune activation is likely important. For example, T-cell activation among HIV-suppressed individuals receiving HAART is negatively associated with immune reconstitution. HIV-induced dysregulation of inflammatory processes occurs via multiple pathways, possibly including microbial translocation.
The effect of HAART on immune activation and inflammation is incompletely understood. There is evidence that HAART-induced HIV suppression reduces some measures of HIV-induced immune activity, but not necessarily to levels present in HIV-uninfected individuals. In the Multicenter AIDS Cohort Study (MACS), elevated levels of B cell stimulatory cytokines and other immune activation markers did not normalize following HAART initiation. In the Women's Interagency HIV Study (WIHS), however, serum levels of both inflammatory and anti-inflammatory biomarkers normalized following HAART initiation, though tumour necrosis factor (TNF)-α remained elevated in women despite undetectable HIV RNA. In the Strategies for Management of Antiretroviral Treatment trial, participants with HIV suppression still had higher levels of interleukin (IL)-6, D-dimer and C-reactive protein (CRP) than HIV-negative individuals from other cohorts.
Most studies examining changes in inflammatory biomarker levels in HIV-infected individuals have been limited by small study populations, cross-sectional designs and/or small numbers of biomarkers. Recent technical advances, especially the development of multiplexed assays, have enabled the more efficient measurement of multiple inflammatory biomarkers. In this study, we compared levels of 24 such biomarkers in stored serum samples from HIV-infected participants in the MACS before and after HAART initiation, and from HIV-uninfected MACS participants who had similar ages and racial profiles to the HIV-infected men studied.
Source...