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High Inflammation/Activation Markers
Before and During ART Predict Death in MACS
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20th International AIDS Conference, July 20-25, 2014, Melbourne
Mark Mascolini
High levels of immune activation and inflammation markers before men started antiretroviral therapy (ART) and during suppressive therapy predicted death in the Multicenter AIDS Cohort Study (MACS). Greater on-treatment declines in certain markers forecasted a lower risk of death.
Persistent immune-cell activation and ongoing inflammation in antiretroviral-treated people with an undetectable viral load may contribute to higher mortality in HIV-positive than negative populations, suggested MACS investigators who conducted this study. Activation and inflammation markers become elevated with HIV infection and often return toward normal levels in people who reach an undetectable viral load with ART. But marker levels often do not return completely to normal despite years of viral suppression. To assess the prognostic significance of abnormal marker levels and their change during ART, the MACS team conducted this study.
MACS is an ongoing study of HIV-positive and at-risk men who have sex with men in Baltimore, Chicago, Los Angeles, and Pittsburgh. For this study researchers measured marker levels in stored serum samples from visits immediately before and after HIV-positive men began ART and at 2-year intervals after that.
The MACS investigators ran two analyses with different starting dates--when ART began (ART initiation group) and when a participant achieved viral suppression (HIV suppression group). A third analysis focused on 10-fold change in the value of each marker from the last antiretroviral-naive visit to the first visit with viral suppression (change at HIV suppression group). The researchers defined higher levels as those above the 75th percentile for the study group. Follow-up continued until death or January 1, 2012. Models were adjusted for age, nonwhite race, chronic hepatitis B or C infection, viral load, and CD4 count below 200 when ART began.
The analysis included 667 men in the ART initiation group, 570 in the HIV suppression group, and 499 in the change at HIV suppression group. Median baseline ages were similar across the three groups: 42.9, 43.6, and 43.6. CD4 count when ART began was lower in the ART initiation group (332) than in the suppression group (466) or the change at suppression group (470). About 20% in each group were nonwhite. During follow-up 111 men (16.6%) in the ART initiation group, 47 (8.2%) in the HIV suppression group, and 35 (7.0%) in the change at suppression group died of any cause.
ART initiation group results: Elevated levels of six markers before ART began were independently associated with a higher risk of all-cause mortality: sCD14, sGP130, IL-6, sTNFR2, BAFF, and sIL-2R-alpha (P < 0.002 for first three, P < 0.05 for last three).
HIV suppression group results: Elevated levels of seven markers after ART-induced suppression were independently associated with a higher risk of all-cause mortality: IL-6, sCD14, sIL-2R-alpha, CXCL13, sCD27, sTNFR2, and TNF-alpha (P < 0.002 for first three, P < 0.05 for last four)
Change at HIV suppression group results: Every 10-fold lower biomarker decline after ART began through HIV suppression was independently associated with a lower risk of all-cause mortality for seven markers: sCD14, sGP130, sTNFR2, BAFF, IL-6, C-reactive protein, and IL-2 (P < 0.002 for sCD14, IL-6, and C-reactive protein; P < 0.05 for the others)
Biomarkers with significant associations in all three analyses were sCD14 (P < 0.002), IL-6 (P < 0.002), and sTNFR2 (P < 0.05).
The MACS team proposed that measuring these markers "may provide valuable prognostic utility for clinical outcomes such as mortality among cART-treated individuals, particularly since biomarker levels appear to be stable more than one year after HIV suppression." They called for further study of the biomarkers identified in this analysis, including "the underlying biologic processes for which these markers serve as proxies."
Reference
1. Wada N, Bream J, Martinez-Maza O, Macatangay B, Galvin S, Jacobson L. Associations between biomarkers of inflammation and mortality among cART initiators in the Multicenter AIDS Cohort Study. AIDS 2014. 20th International AIDS Conference. July 20-25, 2014. Melbourne. Abstract WEPE015.
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