Inflammation and coagulation are associated with disease risk among persons with HIV. ART reduces inflammation, but whether time of initiation during infection affects this reduction has not been studied experimentally. We report on the interleukin-6 (IL-6) and D-dimer trajectories in the immediate versus deferred arms of the START trial
In participants randomized to immediate (CD4>500 cells/µL) vs. deferred (CD4 <350 cells/µL) ART initiation, IL-6 and D-dimer levels were measured from stored plasma specimens at baseline, month 8, and annually up to 7 years. Mean change from entry and from start of ART in log2-transformed levels were compared between the deferred versus immediate groups using longitudinal mixed models adjusted for age, sex, geographic region, baseline biomarker levels and visit. Results were presented as percent change
Among 2209 participants (median age 36 years, 20% female, 67% enrolled in high-income countries), the median levels at entry of IL-6 were 1.47 pg/mL, D-dimer 0.31 µg/mL, and CD4 counts 649 cells/µL. In the immediate group, 94-97% had viral load <200 cp/mL at all annual visits, whereas the deferred group suppression rates increased over time: 18%, 61%, 89%, and 95% at years 1, 3, 5, 7, respectively. In the deferred group, IL-6 and D-dimer levels remained significantly higher than the immediate group through 5 years (Fig). Over the follow-up period, treatment difference in IL-6 was 10.3% (95%CI: 7.6 to 12.9, p<0.001), and D-dimer 14.0% (95%CI: 11.5 to 16.5, p<0.001). When comparing treatment groups based on the time from ART start, biomarker levels were higher in the deferred compared to the immediate group over at least the first 2 years of ART. At 2 years on ART est. diff. 9.9% (95% CI: 4.0 to 15.8; p<0.001) for IL-6 and 10.0% (95% CI: 6.4 to 13.6, p<0.001) for D-dimer, and >96% in each group had HIV RNA <200 cp/mL
Compared to immediate ART, deferral of ART was associated with higher levels of IL-6 and D-dimer over at least 5 years. During the first 2 years of ART treatment, despite viral suppression in both groups, biomarker levels were higher in the deferred compared to immediate group. Follow-up continues in START to determine the clinical consequences of excess inflammation from delayed diagnosis and treatment