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Despite guideline recommendations, access to hepatitis C virus (HCV) treatment is frequently restricted, with some payers approving therapy for only those with advanced disease or cirrhosis. However, delaying potentially curative treatment until the development of advanced liver disease may have costly consequences in terms of both hepatic complications and extrahepatic manifestations (EHMs) of HCV. Using a large claims database from the United States, we measured the risks and medical costs of 20 EHMs and investigated the role of treatment in different stages of liver fibrosis for mitigating the clinical and economic burden of these EHMs. After adjusting for potential confounders, including comorbid liver disease, patients with HCV had a significantly higher risk for any EHM (adjusted odds ratio, 2.23;  P  < 0.05) and higher EHM‐related annual medical costs (adjusted medical cost difference, $6,458;  P <  0.05) compared to matched patients without HCV. HCV treatment can offset the higher medical costs in patients with HCV by saving ∼$25,000 in all‐cause medical costs per patient per year, with a large proportion attributable to savings in EHM‐related medical costs (adjusted cost difference $12,773,  P <  0.05). Finally, additional EHM‐related medical costs could be saved by initiating HCV therapy in early stage fibrosis as opposed to late‐stage fibrosis (adjusted medical cost difference, $10,409;  P <  0.05).  Conclusion : The clinical and economic burden of EHMs is substantial and can be reduced through viral eradication, especially if treatment is initiated early and not delayed until fibrosis advances. Considering that the wholesale acquisition cost of a 12‐week course of therapy ranges from $55,000 to $147,000, the results of the current study suggest the cost of these treatments could be offset within 3 to 6 years by savings in all‐cause medical costs. ( Hepatology Communications  2017;1:439–452)

Prevalence and economic burden of extrahepatic manifestations of hepatitis C virus are underestimated but can be improved with therapy