Changes in Inflammatory and Coagulation Biomarkers: A Randomized Comparison of Immediate versus Deferred Antiretroviral Therapy in Patients With HIV Infection

Abstract

Ojectives Among a subgroup of participants in the Strategies for Management of Antiretroviral Therapy (SMART) Trial that were naïve to antiretroviral therapy (ART) or off ART (≥6 months) at study entry, risk of AIDS and serious non-AIDS events was increased for participants who deferred ART compared to those randomized to (re)initiate ART immediately. Our objective was to determine whether ART initiation in this group reduced markers of inflammation and coagulation that have been associated with increased mortality risk in SMART. Changes in these biomarkers have been described after stopping ART, but not after starting ART in SMART. Methods Stored specimens for 254 participants (126 DC and 128 VS) who were naïve to ART or off ART (≥6 months) were analyzed for interleukin-6 (IL-6), high sensitivity C-reactive protein (hsCRP) and D-dimer at baseline and months 2 and 6. Results At month 6, 62% of VS group had HIV RNA <400copies/mL and median CD4 count was 190 cells/mm3 higher than for the DC group (590 vs. 400 cells/mm3). Compared with DC, the VS group had 32% (95%CI: 19 to 43%) lower D-dimer levels at month 6 (p<0.001); differences were not significant for hsCRP or IL-6 levels. Conclusions In this randomized comparison of immediate versus delayed ART initiation, D-dimer, but not IL-6 and hsCRP, declined significantly after starting ART. Further studies are needed to determine whether improvements in D-dimer are associated with reduced risk of clinical disease, and whether adjunct treatments used in combination with ART can reduce inflammation among individuals with HIV infection.

Metabolic Effects of Darunavir/Ritonavir Versus Atazanavir/Ritonavir in Treatment-Naive, HIV Type 1-Infected Subjects over 48 Weeks

“…[42][43][44][45] Our findings corroborate another recent analysis, which reported that only d-dimer, and not IL-6 or hs-CRP, is reduced over the short term in those initiating ARV therapy. 46 Additionally, the reductions in LPS observed here are similar in magnitude to those seen in a previous study 47 ; the similar reductions in the DRV/r and ATV/r arms suggest that these ARV agents do not result in differential levels of LPS, a trigger of persistent immune activation in ARV-treated individuals. In contrast, no decreases in hs-CRP were seen in either arm of this study over 48 weeks; this observation is in agreement with the ACTG (AIDS Clinical Trials Group) A5095 study, which demonstrated similar results in subjects receiving efavirenzbased regimens over 96 weeks.…”

Histone Deacetylase Inhibitors for Purging HIV-1 from the Latent Reservoir

“…In patients who delay antiretroviral therapy, there was an expected rise in CD4 + T cells on initiation of antiretroviral therapy. Although there was also a decrease in the level of D-dimer, there was no change in elevated IL-6 or CRP (52). It is presently unclear whether the decrease in D-dimer will reduce clinical disease; however, the continued elevated IL-6 and CRP levels indicate a continued inflammatory state, even in patients being successfully treated with antiretroviral therapy and who sustain an increased risk for non-HIV-1-associated death.…”

Immediate Antiretroviral Therapy Reduces Risk of Infection-Related Cancer During Early HIV Infection

“…Because cART improves immune function, lowers HIV viral load, and reduces inflammation [29], earlier cART initiation had previously been proposed as an approach to reduce cancer risk among HIV-infected persons [2][3][4]. Furthermore, cohort studies had long identified a relationship between immunodeficiency and uncontrolled HIV RNA replication with risk of nonHodgkin lymphoma and Kaposi sarcoma [1,2].…”