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Background: With the explosion of newly available direct acting antiviral (DAA) Hepatitis C virus (HCV) treatments that demonstrate 95% sustained virologic response (SVR) rates, evidence-based strategies are urgently needed to achieve real-world effectiveness in challenging patient populations. While HIV is incurable, lessons from over 30 years of experience overcoming obstacles to the HIV treatment cascade could be applied to the HCV context., Methods: Using Institute of Medicine guidelines, we conducted a systematic review of published interventions from PubMed, Medline, GoogleScholar, EmBASE, and PsychInfo bibliographic databases and citation indices. Abstracts were first screened by three independent reviewers and studies were included if they involved original research, described a specific intervention, were published in English in a peer-reviewed journal between 2001 and 2014, and had full text available., Results: Evidence-based interventions to enhance HCV assessment, treatment, and adherence generally fell into one of 4 categories, including those involving: (1) diagnosis or case-finding; (2) linkage to HCV care; (3) pre-therapeutic evaluation or treatment initiation; or (4) treatment adherence. While most available eligible studies described interventions using non-contemporary interferon-based HCV treatments, future research will need to address how these interventions apply to the context of well-tolerated, simple, oral treatment regimens. In some cases, we explored how HIV-specific interventions might be modified to fit the HCV spectrum of care engagement., Conclusions: Evidence-based interventions should be strategically incorporated into HCV treatment implementation efforts to most effectively deliver treatment and maximize treatment outcomes., (Copyright © 2015 Elsevier B.V. All rights reserved.)