The availability of direct-acting antiviral (DAA) therapy has launched a new era 
in the management of chronic hepatitis C. Sofosbuvir, a uridine nucleotide 
analog that inhibits the hepatitis C RNA-dependent RNA polymerase, is the 
backbone of chronic hepatitis C therapy. Acting at the catalytic site of the 
polymerase, sofosbuvir is highly potent in suppressing viral replication and has 
a high genetic barrier to resistance. Sofosbuvir is effective across all 
hepatitis C genotypes, and is a mainstay of interferon-free combination therapy. 
In Phase II and III studies, genotype 1 patients who took sofosbuvir in 
combination with another DAA such as the NS3-4A protease inhibitor, simeprevir, 
or the NS5A replication complex inhibitors, ledipasvir or daclatasvir, achieved 
a sustained virologic response rate of over 90%. Harvoni(®), a combination 
tablet of sofosbuvir and ledipasvir, dosed once daily is recommended for 24 
weeks for treatment-experienced genotype 1 patients with cirrhosis, but 12 weeks 
of therapy is sufficient for all other populations. While genotype 2 (12 weeks 
or 16 weeks) and treatment-naïve genotype 3 patients (24 weeks) have excellent 
response rates with sofosbuvir and ribavirin, treatment-experienced cirrhotic 
genotype 3 patients may need the addition of another DAA such as daclatasvir. 
Sofosbuvir is efficacious in special populations such as HIV-hepatitis C 
virus-coinfected patients and liver transplant recipients and has already made a 
profound impact in these groups. Since it is renally eliminated, patients with 
advanced kidney disease or on dialysis must await dosing recommendations. 
Sofosbuvir-based regimens appear to be well tolerated with headache and fatigue 
being the most common side effects. The opportunity to cure patients with 
hepatitis C with sofosbuvir combination therapy is likely to change the future 
for our patients, particularly if the emphasis shifts to identifying those 
patients unaware that they are infected and providing affordable access to 
treatment.