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Inflammation and Coagulation Markers Askew in Children With Higher HIV RNA
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9th International Congress on Drug Therapy in HIV Infection, November 9-13, 2008, Glasgow
Mark Mascolini
Levels of the thrombosis marker D-dimer were significantly higher in children and adolescents with an HIV load above 1000 copies than in those with lower loads [1]. Protein C and S anticoagulant activity and antithrombin activity were lower in youngsters with high viral loads.
HIV researchers started pondering D-dimer when SMART trial investigators charted significantly rising levels of that marker in people randomized to intermittent antiretrovirals compared with steady therapy [2]. The SMART analysis also disclosed climbing concentrations of IL-6, an inflammation marker, in treatment interrupters. Higher SMART baseline levels of both D-dimer and IL-6 raised the risk of all-cause mortality.
A cross-sectional ("slice-of-time") study at Rome's Bambino Gesu Children's Hospital involved 88 children, adolescents, and young adults seen between December 2007 and June 2008. Their ages averaged 13.6 years and ranged from 3 to 25. Fifty-two cohort members (59%) were female, and 76 (86%) were taking antiretrovirals. The investigators measured the thrombosis marker D-dimer and several inflammation markers--antithrombin, protein C anticoagulant, protein S anticoagulant, and C-reactive protein.
Sixty-three youngsters (72%) had a viral load below 1000 copies, and 25 had a higher load. Sixty-eight people (77%) had a CD4% above 25% and 20 were under 25%. Sixty-one (70%) had CDC class B or C (symptomatic) HIV infection and 27 did not. Defining protein C and S activity deficiency as below 70% activity, the investigators found deficient C activity in 7 people (8%) and deficient S activity in 45 (51%). Antithrombin activity deficiency, defined as below 75% activity, affected only 1 person.
D-dimer levels were significantly higher in cohort members with a viral load above 1000 than in those with lower loads. In contrast, activity of protein C anticoagulant, protein S anticoagulant, and antithrombin was significantly lower in the group with a high viral load. C-reactive protein did not vary significantly by viral load, CD4%, or disease stage. None of the markers correlated with age or duration of HIV infection.
D-dimer
<1000 copies: mean 206 (+/- 100 standard deviation [SD]) ng/mL
>1000 copies: mean 341 (+/- 253 SD) ng/mL
P = 0.024
Protein C activity
<1000 copies: mean 101.9% (+/- 26.0% SD)
>1000 copies: mean 92.0% (+/- 14.7% SD)
P = 0.007
CDC class N/A: 89.9% (+/- 20.4% SD)
CDC class B/C: 103.1% (+/- 24.1% SD)
P = 0.02
Protein S activity
<1000 copies: mean 75.3% (+/- 18.2% SD)
>1000 copies: mean 57.6% (+/- 21.7% SD)
P = 0.0003
CD4% >25: 74.1% (+/- 19.5% SD)
CD4% <25: 57.2% (+/- 20.0% SD)
P = 0.001
Antithrombin activity
< 1000 copies: mean 115.5% (+/- 13.6% SD)
>1000 copies: mean 107.5% (+/- 9.2% SD)
P = 0.005
CDC class N/A: mean 107.2% (+/- 9.2% SD)
CDC class B/C: mean 116.15% (+/- 13.6% SD)
P = 0.002
CD4% >25: 114.6% (+/- 13.2% SD)
CD4% <25: 108.9% (+/- 11.5% SD)
P = 0.024
The SMART analysis of D-dimer and IL-6 factored in age, race, use of antiretrovirals, viral load, CD4 count, smoking status, body mass index (BMI), prior cardiovascular disease, diabetes, use of antihypertensives or lipid-lowering drugs, total-to-HDL cholesterol ratio, and coinfection with hepatitis B or C [2]. The Italian study excluded people with hepatitis but did not specify which variables they weighed in their analysis, other than those noted above.
The investigators speculated that the better protein C and anticoagulant activity in children and adolescents with symptomatic HIV infection could reflect antiretroviral treatment of these children compared with those who had less advanced infection. But none of the markers studied varied significantly by antiretroviral treatment status. The 1000-copy cutoff for good viral control may strike some as arbitrary.
The researchers acknowledged that "further studies are necessary to correlate such alterations with clinical events and to investigate the protective role of therapy in this particular population." This line of research bears watching since treatment interruptions remain high on the research agenda for children, who otherwise face several decades of continuous antiretroviral therapy. But if coagulation and inflammation markers signal a higher risk of non-AIDS diseases in children with higher loads while interrupting therapy (as they do in adults [2]), treatment breaks may not be worth the risk even in children.
References
1. Pontrelli G, Tchidjou H, Citton R, et al. D-dimer and anticoagulation activity markers in children and adolescents with HIV infection. 9th International Congress on Drug Therapy in HIV Infection, November 9-13, 2008, Glasgow. Abstract P213.
2. Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 2008;5(10):e203.
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