IL-1β Inhibitor Lowers Arterial Inflammation in Adults With Controlled HIV
March 6, 2017
One subcutaneous dose of canakinumab, a monoclonal antibody to IL-1β, significantly reduced arterial inflammation in 10 individuals with well-controlled HIV. A larger placebo-controlled trial of canakinumab in people with HIV infection is under way.
People with HIV infection have higher rates of cardiovascular disease than the general population, partly because of ongoing atherosclerotic inflammation even after attaining an undetectable viral load with antiretroviral therapy (ART). IL-1 lies at an early point on the pathogenic pathway to inflammation. IL-1β binding to IL-1 stimulates atherogenesis and HIV disease pathogenesis.
Canakinumab, a human monoclonal antibody to IL-1β, is licensed for treatment of inflammatory disorders, including cryopyrin-associated periodic syndromes (CAPS), at a subcutaneous dose of 150 mg every eight weeks. Treatment has a rapid and sustained anti-inflammatory effect with a minimal impact on lipids. Researchers at the University of California, San Francisco, and other centers conducted this pilot study of canakinumab in 10 adults with well-controlled HIV infection.
Related: Classic Risk Factors Drive Heart Attack Rates More Than HIV Variables
This open-label study enrolled HIV-positive people at least 40 years old, all taking effective ART and all with established cardiovascular disease or at least one cardiovascular risk factor. Participants received a single 150-mg subcutaneous dose of canakinumab. Researchers measured inflammatory markers in plasma and used fluorodeoxyglucose positron emission tomography (FDG-PET) imaging to track changes in arterial inflammation from before treatment to eight weeks after treatment.
The 10 participants had a median age of 59 years (interquartile range [IQR] 55 to 65). Nine were men and eight Caucasian. All had an undetectable viral load with ART. Eight participants were taking a statin. Cardiovascular risk factors included hypertension in nine, elevated cholesterol in eight, family history of cardiovascular disease in four, personal history of cardiovascular disease in three and current smoking in two. Median CD4 count stood at 638 cells/mm3 (IQR 570 to 1,142) and median HIV infection duration at 24 years (IQR 22 to 27).
Absolute neutrophil count declined by 28% at weeks two and three then rebounded by week four. Shingles developed in one person and resolved within the usual recovery period. Shingles have not emerged as a risk of canakinumab therapy in the 10,000-person CANTOS trial, which is testing canakinumab to reduce rates of myocardial infarction, stroke and cardiovascular death. CD4 count, CD4/CD8 ratio and HIV RNA did not change significantly during the 10-person pilot trial.
Levels of the inflammation marker IL-6 fell by 30% from baseline to week eight (P = .003). Over the same time, levels of the inflammation marker high-sensitivity C-reactive protein fell by 41% (P = .039) and levels of the inflammation and activation markers sCD163 dropped by 9% (P = .015). Neither T-cell activation phenotypes nor monocyte subsets changed significantly through eight weeks, except for a significant decrease in CCR5-positive monocytes (P = .002). Consistent with inflammatory marker changes, lipopolysaccharide stimulation showed less production of IL-1β and IL-6 from baseline to week eight (P = .006).
Eight weeks after canakinumab administration, FDG-PET scans indicated significant reductions in aortic inflammation and bone marrow metabolic activity. Arterial inflammation declined by 10% (P = .046) and bone marrow activity by 11% (P < .001).
A placebo-controlled trial of canakinumab in 100 people with HIV is recruiting participants, who will receive two doses of the monoclonal antibody separated by 12 weeks. Enrollees must be 40 years old or older and taking a stable antiretroviral regimen with an undetectable viral load for 52 weeks. Participants must have high risk for coronary artery disease.
Mark Mascolini writes about HIV infection.
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