Systemic Inflammation, Coagulation, and Clinical Risk in the START Trial

Abstract

Background: The Strategic Timing of AntiRetroviral Treatment (START) trial demonstrated that immediate (at CD4+ >500 cells/µL) vs deferred (to CD4+ <350 cells/µL or AIDS) antiretroviral therapy (ART) initiation reduced risk for AIDS and serious non-AIDS (SNA). We investigated associations of inflammation, coagulation, and vascular injury biomarkers with AIDS, SNA or death, and the effect of immediate ART initiation.

Methods: Biomarkers were measured from stored plasma prior to randomization and at month 8. Associations of baseline biomarkers with event risk were estimated with Cox regression, pooled across groups, adjusted for age, gender, and treatment group, and stratified by region. Mean changes over 8 months were estimated and compared between the immediate and deferred ART arms using analysis of covariance models, adjusted for levels at entry.

Results: Baseline biomarker levels were available for 4299 START participants (92%). Mean follow-up was 3.2 years. Higher levels of IL-6 and D-dimer were the only biomarkers associated with risk for AIDS, SNA or death, as well as the individual components of SNA and AIDS events (HRs ranged 1.37-1.41 per 2-fold higher level), even after adjustment for baseline CD4+ count, HIV RNA level, and other biomarkers. At month 8, biomarker levels were lower in the immediate arm by 12%-21%.

Conclusions: These data, combined with evidence from prior biomarker studies, demonstrate that IL-6 and D-dimer consistently predict clinical risk across a broad spectrum of CD4 counts for those both ART-naïve and treated. Research is needed to identify disease-modifying treatments that target inflammation beyond the effects of ART.

Keywords: HIV disease; coagulation; comorbidities; end-organ disease; inflammation risk.

Figure 1.

Flow diagram for availability of biomarker data among START participants. ^*Of 4487 participants who consented to storing specimens for future research. Of the 319 participants (149 in the immediate group and 170 in the deferred group) who had biomarker data at baseline but not month 8, 7 had died and 44 were lost to follow-up prior to month 8, 145 missed the month 8 visit, 65 attended the visit but no specimen was collected, and for 59 participants the specimen could not be analyzed. The distribution of reasons was similar in the immediate and deferred groups.

Figure 2.

Hazard ratios (HRs) with 95% confidence intervals (CIs) for the risk of clinical events associated with 2× higher baseline biomarker levels in START (n = 4299). HRs were estimated in separate proportional hazards models, pooled across treatment groups, adjusted for age, gender, and treatment group, and stratified by geographic location. HRs are per 2× higher biomarker(s). Biomarker associations with event risk were homogeneous across treatment groups, except for sVCAM with AIDS (higher HR in the deferred group) and sICAM with SNA (higher HR in the immediate group). Abbreviations: IL = interleukin; hsCRP = high-sensitivity C-reactive protein; SAA = serum amyloid A; sICAM = soluble intercellular adhesion molecule; sVCAM = soluble vascular cellular adhesion molecule.

Figure 3.

Kaplan-Meier (KM) estimates for the cumulative percentage of participants experiencing AIDS, serious non-AIDS, or death in START (4299). (A) Kaplan-Meier estimates for the cumulative percentage of participants experiencing an AIDS or AIDS-death (top row) and serious non-AIDS or non-AIDS death (bottom row) pooled over study groups by quartiles of D-dimer and IL-6 at baseline (first quartile = blue; second quartile = green; third quartile = orange; fourth quartile = red). The number at risk at each year of follow-up is presented below the x-axis. (B) Kaplan-Meier estimates for the cumulative percentage of participants experiencing the composite outcome of AIDS, serious non-AIDS or death in the immediate (red lines) and deferred (blue lines) ART groups in START, separately by whether baseline level of D-dimer and IL-6 were above (solid lines) or below (dashed lines) their median at baseline.

Figure 4.

Biomarker changes from baseline to month 8 with immediate vs deferred art initiation in START (n = 3980). The percentage change (95% CI) from baseline to month 8 for each of the 7 biomarkers, adjusted for baseline level, is plotted for both the immediate (red circles) and deferred (blue squares) ART groups. The absolute difference between immediate and deferred groups for the percentage change from baseline to month 8 is presented below the x-axis (with P-values) for each of the biomarkers. Abbreviations: CI = confidence interval; hsCRP = high-sensitivity C-reactive protein; IL = interleukin; sICAM = soluble intercellular adhesion molecule, sVCAM = soluble vascular cellular adhesion molecule.