Nucleotide compounds like sofosbuvir, acyclovir, and tenofovir have proven to be 
amongst the most potent orally available antiviral treatments. These drugs 
exhibit high efficacy and a wide therapeutic index, with demonstrated utility in 
a number of chronic viral infections. The approval of Sovaldi™, brand name for 
sofosbuvir, by the U.S. Food and Drug Administration heralded improvements in 
chronic hepatitis C virus (HCV) treatment. Sofosbuvir was originally discovered 
by Pharmasset Corporation and named PSI-7977. It was subsequently acquired and 
advanced through phase 3 development by Gilead Sciences, Inc. In Sofosbuvir both 
a unique pharmacology and a high specificity for the HCV ribonucleic acid 
polymerase are present in a molecule that is well tolerated and highly 
efficacious. Phase 2 and 3 clinical trials have consistently demonstrated 
durable and high rates of sustained virologic response (SVR), curing patients in 
excess of 80% in all genotypes and >90% in treatment-naïve subjects being 
administered combination therapy with other agents. Harvoni(®) is the 
combination of sofosbuvir and the NS5A inhibitor ledipasvir in a fixed-dose oral 
tablet, and it has demonstrated high SVR rates in patients infected with HCV 
genotype 1, without the need for exogenous interferon and/or ribavirin. Here, we 
discuss the discovery, development, pharmacologic characterization, and results 
from the phase 3 trials of sofosbuvir. Hepatitis C is a chronic disease, for 
which most patients have been undiagnosed, are unwilling to start treatment, or 
are ineligible for treatment because of the high toxicity and low efficacy of 
interferon and ribavirin-based therapy. Clinical studies with sofosbuvir have 
demonstrated significant improvement over the prior standard of care, thus 
ushering in a new paradigm of HCV treatment and an update of treatment 
guidelines.