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The approval of the first direct-acting antivirals (DAAs) against the hepatitis C virus (HCV) has been eagerly expected for treating chronic hepatitis C in HIV individuals given that progression to cirrhosis and end-stage liver disease occurs faster in the co-infected population. The appropriate and judicious use of DAAs may provide cure to a large number of HIV–HCV patients. On the contrary, the widespread use of DAAs will occasionally be off-label or under unsatisfactory medical conditions, which may result in undesirable toxicities, drug interactions or selection of drug resistance in HCV. As a result of using first-generation DAAs in HIV–HCV-co-infected patients, a growing proportion of the remaining hepatitis C individuals will be those harboring non-HCV 1 genotypes or drug-resistant HCV variants. Over time, the largest reservoir of HCV genotype 1 patients will accumulate in resource-poor nations where access to hepatitis C therapy has been elusive and HIV treatment remains the primary health issue for the co-infected population.