The Strategies for the Management of AntiRetroviral Therapy (SMART) trial has transformed HIV research by unambiguously demonstrating the link between viral replication, inflammation and clinical outcomes. A detailed sub-study in SMART found that, in adults, particular coagulation and inflammatory biomarkers (specifically D-dimer and IL-6) were very strongly associated with mortality risk, and levels of these biomarkers increased in association with HIV viral load when study participants interrupted ART. In the new issue of the journal AIDS, a group of Italian researchers describe results of a study designed to provide insight into whether the findings of SMART are relevant to children and adolescents with HIV.
The researchers divided a cohort of 88 individuals (mean age 13.5 years) into high and low HIV viral load groups using a cut-off of 1,000 copies of HIV RNA/mL. Higher viral load levels were associated with significantly lower levels of protein S, a substance involved in blood coagulation; low levels of protein S are known to be associated with an increased risk of excessive blood clotting (thrombophilia). Levels of D-dimer were also significantly elevated in the high viral load group and showed a statistically significant correlation with HIV RNA levels (R2 0.37, P<0.001). D-dimer is a small protein fragment that is produced when blood clots are degraded in the body. Levels of C-reactive protein (CRP), which increased in SMART participants after ART interruption, showed no differences between the high and low viral load groups. IL-6 levels were not measured in this study.
In discussing their findings, the researchers state: “The study, given the low mean age of the cohort, highlights the direct role of HIV replication on coagulation disorders excluding the possible confounding role of major known risk factors for thrombosis and CVD, like hypertension, diabetes, and history of clinical thrombotic event. Furthermore, our analysis took into account the putative confounding action of other factors associated with an increased risk of thrombosis and CVD disease both in the general population (smoke, age, dyslipidaemia), and HIV-infected population (cumulative use of cART and protease inhibitor, actual use of ABC and ddI, dyslipidaemia). Nevertheless the study has some limitations since it is a cross-sectional study and the power for analysis of all variables considered has been limited by the relative small amount of observations. Prospective studies are needed to confirm and investigate the clinical implications of our observations.”
AIDS. 24(8):1145-1151, May 15, 2010.
Pontrelli, Giuseppe; Martino, Alessandra M; Tchidjou, Hyppolite K; Citton, Rita; Mora, Nadia; Ravà, Lucilla; Tozzi, Alberto E; Palma, Paolo; Muraca, Maurizio; Franco, Elisabetta; Rossi, Paolo; Bernardi, Stefania
Background and objective: Atherosclerosis and other cardiovascular diseases associated with thrombosis appear more relevant and anticipated in HIV-infected patients after combination antiretroviral therapy (cART) has reduced AIDS-related diseases and has improved survival. The association between viral replication and coagulation abnormalities in a cohort of HIV-infected children and adolescents was investigated here.
Methods: Protein S, protein C anticoagulant and antithrombin activity, together with fibrinogen, D-dimer, high-sensitive C-reactive protein and homocysteine were assayed in a cross-sectional study among a cohort of HIV-infected children and adolescents. Results in patients with high viral load (HVL, HIV-RNA > 1000 copies/ml) were compared with those in patients with a lower replication (LVL), adjusting for other demographic, clinical and therapeutic covariates.
Results: Eighty-eight patients (mean age 13.5 years, CD4 30%, 72% with LVL) were enrolled. A prevalence of protein S and protein C deficiency of 51 and 8% was, respectively, found. HVL group compared to LVL showed a significant reduction of protein S, protein C and antithrombin activities, and an increase of D-dimer levels. The independent association of HVL with decreased protein S activity (-11.2%, P = 0.04) and increased D-dimer levels (+0.13 [mu]g/ml, P = 0.004) was confirmed in the multivariate model.
Conclusions: HIV-infected children and adolescents present high prevalence of thrombophilic abnormalities. The multivariate model confirmed that high viral replication is independently associated with decrease of protein S and increase of D-dimer, suggesting the advantage of suppressive therapy on coagulation homeostasis and the opportunity of an active control of cardiovascular risk factors starting at a younger age.