ITIH4 and substance abuse: Multiple factors have been suggested to contribute to the increased neuroinflammation: (a) The persistent expression of HIV proteins, such as Tat and gp120; (b) low levels of HIV replication in brain macrophages owing to reduced penetrance of some cART regimens; (c) co-morbid conditions, including hepatitis C co-infection and substance abuse; and (d) direct CNS toxicity of cART.