CC-11050 in Human Immunodeficiency Virus-1-Infected Adults With Suppressed Plasma Viremia on Antiretroviral Therapy (APHRODITE)

CC-11050 is a novel anti-inflammatory compound with potential to treat a variety of chronic inflammatory conditions and cytokine storms associated with infectious diseases. CC-11050 is a selective phosphodiesterase-4 inhibitor (PDE4) that is active in several in vivo models of inflammatory disease, inhibiting systemic TNF- production, colitis symptoms of the colon, psoriasiform features in the skin, arthritogenic swelling in the joints, neutrophilia and eosinophilia in the lung, and reducing choroidal neovascularization. These data suggest that CC-11050 may have therapeutic potential for chronic inflammatory conditions and/or as an antiangiogenic treatment. The safety profile of CC-11050 has been investigated in healthy males and in subjects with cutaneous lupus erythematosus; the most frequently reported adverse events were fatigue, headache, upper respiratory infection and pruritus; there were no deaths or serious adverse events. Inflammation is an important contributor to HIV pathogenesis both prior to and after ART initiation. Inflammatory responses can occur abruptly upon ART initiation (known as immune reconstitution inflammatory syndrome or IRIS) and can be chronic in persons with suppressed plasma HIV viremia who are treated with ART, and has been linked to an excess risk of non-AIDS serious events such as cardiovascular, liver and kidney disease and accelerated bone loss. Corticosteroids to reduce levels of inflammatory cytokines in plasma are a standard therapeutic intervention for IRIS, however a more targeted anti-inflammatory and less broadly immunosuppressive intervention is desirable. We propose a double-blind, randomized trial to assess the safety of CC-11050 in adults with HIV infection who have taken ART for at least 1 year and have suppressed plasma viremia. Enrolled subjects will be randomized 2:1 to 200 mg CC-11050 or placebo twice daily for 12 weeks. Participants will be evaluated at weeks 0, 2, 4, 8, 12 and 16. Changes in in plasma HIV-1 RNA levels (by clinical assay), CD4+ T cell counts and percentages, and the effect on markers of systemic inflammation (e.g., TNF, IL-6, CRP, IFNg, sCD14, D-dimer) will be measured. The effect of CC-11050 on cellular immune activation (T cells and monocytes), and on viral reservoirs (cell associated HIV DNA and RNA) will also be assessed.