Sofosbuvir (formerly known as GS-7977; Gilead Sciences, Foster City, CA, United States) is a nucleotide NS5B inhibitor[16]. Sofosbuvir is converted into a pharmacologically active form (GS-461203) within hepatocytes[17]. GS-461203 inhibits RNA-dependent RNA polymerase activity by competing with uridine and prevents HCV RNA synthesis by acting as “chain terminator”. Because the catalytic site of the NS5B protein is highly conserved, sofosbuvir is believed to have pangenotypic activity[18].

Another favorable characteristic of sofosbuvir is its high genetic barrier. In an HCV replicon study, a S282T substitution in NS5B was reported to impart drug resistance[19]. However, in clinical trials, this NS5B variant was detected in only one patient after treatment with sofosbuvir monotherapy[16,20-22]. Foster et al[23] reported that sofosbuvir treatment led to the emergence of drug-resistant variants in 9/78 (12%) of patients. An L159F variant was present both at baseline and at the time of virologic failure in 1 patient and at the time of virologic failure in 7 additional patients. The V321A variant emerged at the time of virologic failure in 2 patients.

Sofosbuvir also possess a noteworthy safety profile and high tolerability. In phase 3 trials of sofosbuvir, the frequency of serious adverse events ranged from 1% to 8% and the rate of treatment discontinuation because of adverse events range from 0% to 4.4%[24,25].

The results from phase 3 clinical trials evaluating the use of treatment regimens containing sofosbuvir against HCV genotype 1 are shown in Table 1. The NEUTRINO study was the first phase 3 trial to evaluate sofosbuvir-containing therapy[26]. In this single-group, open-label study, 291 treatment-naïve patients infected with HCV genotype 1 were treated with sofosbuvir plus peginterferon and ribavirin for 12 wk. The patients attained a high rate of SVR at 12 wk after completion of therapy (SVR12) (89%) and had a low rate of treatment discontinuation (2%) compared with historical controls. This study demonstrated the efficacy and safety of combining sofosbuvir with peginterferon and ribavirin; however, patients contraindicated for peginterferon or ribavirin were excluded.

Based on high rates of SVR in phase 2 studies, phase 3 ION studies (ION-1, ION-2 and ION-3 studies) were conducted to assess a fixed-dose combination of sofosbuvir and ledipasvir[27-30]. In the ION-1 trial, 865 treatment-naïve patients infected with HCV genotype 1 were randomly divided into four groups and received either 12 or 24 wk of sofosbuvir and ledipasvir with or without ribavirin. High SVR12 rates were attained in all groups (range: 97%-99%), and no patients in either 12-wk group discontinued therapy because of adverse events[28].

The ION-2 trial was conducted to evaluate the combination of sofosbuvir and ledipasvir with or without ribavirin in treatment-experienced patients. In this trial, 440 patients were divided into groups and treated with either 12 or 24 wk of sofosbuvir and ledipasvir with or without ribavirin. As in the ION-1 trial, high SVR12 rates were attained in all treatment groups (range: 94%-99%). No cases of treatment discontinuation owing to adverse events were reported[29].

The ION-3 trial was conducted to evaluate the feasibility of shorter duration therapy in previously untreated patients without cirrhosis. The noninferiority of an 8-wk regimen was demonstrated by the similar SVR12 rates in all groups (range: 93%-95%)[30]. The results from the ION-3 trial also indicated that an 8-wk regimen of sofosbuvir plus ledipasvir is not generally equal to 12 wk of treatment; however, international guidelines recommend that an HCV RNA threshold of 6 million IU/mL is maintained.

Among Asian countries, Mizokami et al[25] reported a phase 3 study conducted to evaluate Japanese patients. In this study, 166 treatment-naïve and 175 treatment-experienced patients received 12 wk of sofosbuvir and ledipasvir with or without ribavirin. High SVR12 rates (range: 96%-100%) were also attained in this study. This is noteworthy, as Japanese patients tend to be older, have more advanced fibrosis and are more frequently treated with previous therapy than patients in other countries. In the above studies, the inclusion of ribavirin in the treatment regimens produced no additional benefit. Furthermore, adverse events were more common in groups treated with ribavirin than in those without ribavirin.

The SOLAR-1 and SOLAR-2 studies showed the usefulness of sofosbuvir plus ledipasvir for decompensated cirrhosis[31,32]. In patients with cirrhosis and moderate or severe hepatic impairment who had not undergone liver transplantation, 86%-89% SVR12 rates were achieved[31]. In patients who had undergone liver transplantation, 96%-98%, 85%-88%, and 60%-75% SVR12 rates were achieved in patients without cirrhosis or with well-compensated cirrhosis, patients with moderate hepatic impairment, and patients with severe hepatic impairment, respectively[31]. All 6 patients with fibrosing cholestatic hepatitis achieved SVR12. Response rates in the 12- and 24-wk treatment groups were similar[31]. The use of sofosbuvir plus simeprevir for 12 and 8 wk in HCV genotype 1-infected patients without cirrhosis resulted in 83% and 97% SVR12 rates, respectively[33]. Likewise, the use of sofosbuvir plus simeprevir for 12 wk resulted in an 83% SVR12 rate in HCV genotype 1 - infected patients with cirrhosis[34].

The results from phase 3 clinical trials evaluating the use of treatments containing sofosbuvir against HCV genotype 2-infected patients are shown in Table 2. Three phase 3 trials have evaluated previously untreated patients (the FISSION, POSITRON and VALENCE studies)[23,29-31]. In the FISSION study, 12 wk of sofosbuvir plus ribavirin treatment and 24 wk of Peg-interferon α-2a (Peg-IFNα2a) plus ribavirin treatment produced comparable results in treatment-naïve patients. The SVR12 rate was 97% in a group of 70 patients who received sofosbuvir plus ribavirin and 78% in a group of 67 patients who received Peg-IFNα2a plus ribavirin. The noninferiority of the sofosbuvir plus ribavirin regimen relative to interferon-based therapy was shown. Furthermore, adverse events were less frequent with the sofosbuvir plus ribavirin regimen[26,35].

In the POSITRON study, 109 patients for whom treatment with Peg-IFN was not an option received 12 wk of sofosbuvir plus ribavirin, and 78% of these patients achieved SVR12[36]. These results were confirmed by the VALENCE study, in which 97% of 32 treatment-naïve patients achieved SVR12[37].

In addition, the FUSION study[36] and the other arm of the VALENCE study evaluated the use of a sofosbuvir plus ribavirin regimen in treatment-experienced patients. In the FUSION study, 103 patients received sofosbuvir plus ribavirin for 12 wk, and 98 patients received the treatment for 16 wk. The rates of SVR12 were 86% and 94% in the 12 and 16-wk groups, respectively[36].

Omata et al[38] reported the efficacy and safety of a 12-wk sofosbuvir plus ribavirin treatment in Japanese patients. The rates of SVR12 were 98% and 95% in treatment-naïve and previously treated patients, respectively. According to these trials, the use of sofosbuvir plus ribavirin has become a standard of care for the treatment of HCV genotype 2-infected patients.

HCV genotype 3 has become the most difficult genotype to cure in the era of interferon-free therapy. Although sofosbuvir is considered to have pangenotypic inhibitory activities, its treatment efficacy against HCV genotype 3 is lower than against the other genotypes. The results from phase 3 clinical trials evaluating treatments containing sofosbuvir to combat HCV genotype 3 are shown in Table 3.

In the FISSION study, SVR12 occurred in 56% of patients who received 12 wk of sofosbuvir plus ribavirin and in 63% of patients who received 24 wk of peginterferon plus ribavirin. These results were poor, as 97% of patients infected with HCV genotype 2 achieved SVR12 following treatment with sofosbuvir plus ribavirin in the same study[26,35].

The results of the POSITRON study were similar to those of the FISSION study. In the FISSION study, 61% patients infected with HCV genotype 3 achieved SVR12 compared to 93% of patients infected with HCV genotype 2. The rate of SVR12 in patients with cirrhosis was especially low in the HCV genotype 3 group (21%)[36].

Although the above results are somewhat disappointing, extending the duration of treatment might improve sofosbuvir’s efficacy against HCV genotype 3. In the FUSION study, 16 wk of sofosbuvir plus ribavirin therapy resulted in higher SVR12 rates than 12 wk therapy (37% vs 63% in patients without cirrhosis; 19% vs 61% in patients with cirrhosis)[36].

In addition, the VALENCE study was conducted to assess the efficacy of 24 wk of sofosbuvir plus ribavirin treatment in 250 HCV genotype 3-infected patients[37]. The rates of SVR12 were 95% and 92% in treatment-naïve patients with and without cirrhosis, respectively, and 87% and 62% in previously treated patients with and without cirrhosis. A longer treatment duration was not associated with a higher frequency of adverse events or treatment discontinuation. However, further studies will be necessary to improve treatment efficacy in previously treated patients with cirrhosis.

Foster et al[23] reported a 93% SVR12 rate following 12 wk of treatment with peginterferon, sofosbuvir and ribavirin vs an 84% SVR12 rate following 24 wk of treatment with sofosbuvir plus ribavirin vs an 88% SVR12 rate following 12 wk of treatment with peginterferon, sofosbuvir and ribavirin in cirrhotic patients. Treatment with daclatasvir plus sofosbuvir for 12 wk led to a 96% SVR12 rate in HCV genotype 3-infected patients without cirrhosis[39].

In the NEUTRINO study, 35 patients infected with HCV genotypes 4 through 6 were treated with sofosbuvir, ribavirin and peginterferon for 12 wk. The rates of SVR12 were 96% and 100% in patients infected with HCV genotypes 4 and 5-6, respectively[26]. A treatment regimen that contains sofosbuvir might therefore be efficient against these genotypes.

The use of a ribavirin- and interferon-free regimen of ledipasvir/sofosbuvir for 12 wk resulted in an SVR4 rate of 93% in genotype 4 and genotype 5 HCV-infected treatment-naïve and treatment-experienced patients with or without cirrhosis[40].

The PHOTON-1 and -2 studies were conducted to evaluate the use of sofosbuvir plus ribavirin therapy to combat HCV-human immunodeficiency virus (HIV) co-infection[41,42]. The results of these trials are summarized in Table 4.

In the PHOTON-1 study, in patients infected with HCV genotype 1, 12 wk of sofosbuvir plus ribavirin led to a 78% SVR12 rate. Extending treatment to 24 wk tended to result in higher rates of SVR (85%)[41].

The use of a longer treatment duration also appeared to be effective in treatment-naïve patients infected with HCV genotype 3. Similar to the results from the study against HCV genotype 3 infection alone, 12 wk of sofosbuvir plus ribavirin therapy attained low rates of SVR12 compared with other genotypes in the PHOTON-1 study (67%)[32]. Extending treatment from 12 to 24 wk improved the rate of SVR12 in the PHOTON-2 study (91%)[42]. Among patients infected with other HCV genotypes, high rates of SVR12 (83%-92%) were attained after 12 wk of sofosbuvir plus ribavirin treatment in treatment-naïve patients and 24 wk of the above treatment in previously treated patients[41,42].

The ALLY-2 study examined the use of daclatasvir plus sofosbuvir in patients co-infected with HIV and HCV genotype 1. The results showed that SVR rates were 96.4% following 12 wk of treatment and 75.6% following 8 wk of treatment in treatment-naïve patients. The SVR12 rate was 97.7% in treatment-experienced patients following 12 wk of treatment with the above regimen[43].

The ION-4 study evaluated the use of ledipasvir plus sofosbuvir for 12 wk in HIV co-infected patients. The SVR12 rates were 96% in HCV genotype 1a-infected patients, 96% in HCV genotype 1b-infected patients, and 100% in HCV genotype 4-infected patients[44].