Background: In SMART, CD4-guided intermittent antiretroviral treatment (ART) as compared to continuous ART resulted in an increased risk of cardiovascular disease (CVD) and of all-cause mortality, the latter primarily due to non-AIDS diagnoses.  To explore reasons for these increased risks, we evaluated four inflammatory (high sensitivity-C reactive protein [hsCRP], interleukin-6 [IL-6], amyloid A, and amyloid P) and two coagulation (D-dimer and prothrobmin fragment 1+2 [F1.2]) markers that have high laboratory and biological reproducibility and that have been associated with mortality and CVD in the general population. 

Methods: Patients with CD4+ count >350 cells/mm³ were randomized to viral suppression (VS) (continuous ART) (N=2,752) or to drug conservation (DC) (CD4-guided intermittent ART) (N=2,720).  To assess the short-term effect of intermittent ART on the biomarkers, stored plasma samples at baseline and one month after randomization for a random subset of DC (N=249) and VS (N=250) patients were analyzed.  In addition, a nested case control study was carried out in which two controls were matched (age, gender, country, date of randomization) to each death (N=85) and case of CVD (N=136).  Adjusted odds ratios (ORs) for the 4^th versus 1^st quartile of each biomarker at baseline were estimated using logistic regression. 

Results:  IL-6 and D-dimer levels increased by 30% and 16%, respectively, one month after randomization in the DC group and changed little in the VS group (5% and 0%) (P<0.0001 for treatment difference for each biomarker).  For DC patients, increases in IL-6 and D-dimer after one month were related in a graded manner to the increases in HIV RNA at month 1 (P<0.0001 for each biomarker).  IL-6 and D-dimer determined at baseline were strongly related to mortality with ORs greater than 12 for those in 4^th versus 1^st quartile.  Associations with CVD were more modest and were significant for IL-6 and amyloid P.  ORs are summarized in the table below.

Associations of baseline levels of the biomarkers with all-cause mortality and with CVD were similar for DC and VS patients.

Conclusions:   ART interruption results in significant increases in IL-6 and D-dimer.  Elevated levels of D-dimer and IL-6 identify a subgroup of HIV-infected patients at high risk of death in both treatment groups.  Increases in IL-6 and D-dimer may explain, in part, the increased risk of mortality and CVD in the DC group.