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A changing paradigm: management and treatment of the HCV/HIV-co-infected patient. Hepatitis C virus (HCV) treatment in HIV/HCV co-infected individuals has renewed relevance given the ongoing opioid crisis and rise of new HIV and HCV infections associated with injection drug use. Patients co-infected with HIV and HCV demonstrate increased rates of hepatic fibrosis, progression to liver failure, and liver-related mortality. HIV co-infection does not impact outcomes of current HCV treatments, and patients should be treated the same as HCV mono-infected persons, though attention to drug:drug interactions is required. In this review, we discuss the mechanisms mediating injury to the liver in HIV mono-infection and HIV/HCV co-infection, and present the landmark trials of HCV treatment in HIV-infected individuals.