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Sofosbuvir and velpatasvir for the treatment of hepatitis C. INTRODUCTION: Direct acting antivirals are revolutionizing the treatment of chronic hepatitis C. Specifically, the combination therapy sofosbuvir and velpatasvir offers a pangenotypic regimen with high sustained viral response (SVR). Areas covered: Reviewed here are the clinical trials that led to the FDA approval of sofosbuvir and velpatasvir combination therapy, the adverse events during registration trials, and drug-drug interactions. Sofosbuvir and velpatasvir is a fixed dose regimen that is both interferon- and ribavirin-free. It is administered for 12 weeks as a once-a-day pill, covers all genotypes of hepatitis C, and achieves SVR >95% in non-cirrhotic patients and patients with compensated cirrhosis. Addition of ribavirin is recommended for patients with decompensated cirrhosis (CTP B or C). Baseline resistance-associated substitutions do not appear to impair ability to achieve SVR with an initial course of treatment. Expert commentary: Availability of this highly efficacious, well tolerated, all oral regimen formulated as a single pill, can potentially simplify hepatitis C treatment. Its utility as a pangenotypic regimen additionally limits resource utilization.