INTRODUCTION:

Hepatocellular carcinomaa, cirrhosis, and chronic hepatitis are all brought on by a persistent hepatitis C virus (HCV) infection. Interferon-based therapy has been the mainstay of HCV treatment for the past 20 years, but even when paired with ribavirin, its effectiveness has been constrained by poor tolerability and unsatisfactory sustained virological response (SVR) rates. In 2011, boceprevir and telaprevir, the first direct-acting antiviral (DAA) medications authorized for the treatment of HCV, increased SVR rates in treatment of HCV, increased SVR rates in treatment-naïve patients with genotype 1 HCV from roughly 40-44% to 68-75%.^12,23

However, protease inhibitor monotherapy only works when combination with peginterferon and ribavirin as triple therapy due to the quick acquisition of viral resistance. Thus, the adverse event profile of peginterferon with ribavirin is increased by the use of these NS3/4 protease inhibitors, especially in cirrhosis patient where cytopenia’s and other severe adverse event pose a considerable safety risk.³ NS3/4A protease inhibitors, NS5A inhibitors, and NS5B polymerase inhibitors are the three main groups of DAA medications presently undergoing phase III clinical studies. These treatment can be further classified as either nucleoside inhibitor or nonnucleoside inhibitors. Since the catalytic region of the NS5B protein is highly conserved across the many HCV genotypes, nucleotide inhibitors that target this protein are an attractive therapeutic approach. The NS5B polymerase is in charge of viral RNA replication. By causing a chain termination event and disrupting the transcription of the viral polyprotein, the nucleoside analogues disrupt the viral lifecycle.²⁵ They also have a barrier to viral resistance and a comparatively high potency overall. Nonnucleoside inhibitors that target NS5B’s allosteric regions, on the other hand, typically exhibit reduced effectiveness and a low barrier to viral resistance. This review will look at the clinical potential of sofosbuvir, commonly known as GS-7977 (formally PSI-7977), a nucleotide inhibitor of NS5B that shows promise as a therapy for HCV infection.

Pharmacology of Sofosbuvir:

When the viral genotype replicates, sofosbuvir, a prodrug of 2’-deoxy-2’-fluoro-2’-C-methyluridine monophosphate, is transformed in a hepatocyte into its active uridine triphosphate form, resulting in chain termination.²² The active triphosphate exhibits broad activity across HCV genotypes in vitro, inhibiting recombinant NS5B polymerases from genotypes 1-4 with comparable half maximal inhibitory concentration values for each genotype.¹⁵ The chemistry of sofosbuvir has previously been reviewed¹⁰ and will not be reviewed in detailed in this paper.

The kidney is the main organ through which sofosbuvir is removed from the body as the inactive nucleoside metabolite GS-331007 (formerly known as PSI-6206). Sofosbuvir single-dose pharmacokinetics were examined in patients with mild (eGFR 50-80ml/min), moderate (eGFR 30-49ml/min), severe (eGFR<30ml/min), and normal renal function (estimated glomerular filtration rate [eGFR]>80ml/min). Reduced renal status was associated with an increase in the area under the curve (AUC) of GS-331007 and to a lesser degree, sofosbuvir. The renal clearance of GS-331007 and creatinine clearance were linearly correlated. The GS-331007 AUC was roughly 56%, 90% and 456% higher in persons with mild, moderate and sever renal impairment, respectively, then in the patients with normal renal function.¹ To ascertain the safe use of sofosbuvir in patients with severe renal impairment, more research is necessary.

In a hepatic impairment study, 400mg QD of sofosbuvir was given for seven days to HCV-infected participants with mild hepatic impairment; sofosbuvir was typically well tolerated and produced a systemic exposure to GS-331007 comparable to that of noncirrhotic subjects. After seven days of dosage, all individuals showed significant decreases in HCV RNA.¹⁹ Consequently, in cases of hepatic impairment, dose adjustments are not necessary.

Sofosbuvir does not interact clinically with meals or with the concurrent use of tacrolimus, cyclosporine, or methadone.^2,20

Clinical trial data:

Sofosbuvir was assessed in conjunction with peginterferon and ribavirin (PEG/RBV) in the first phase II trials. 64 patients were randomly assigned to receive one of three once-daily doses of oral sofosbuvir (100, 200, or 400mg) or a placebo plus peginterferon and ribavirin for 28 days. Following this, all patients continued to receive peginterferon and ribavirin for an additional 44 weeks in a 28-days dose-ranging trial in subjects infected with genotype 1 HCV [clinicalTrials.govidentifier:NCT01054729]. After 28 days, the mean HCV RNA reductions for patients in the sofosbuvir/peginterferon/ribavirin groups were >5log10IU/ml for all doses, compared to 2.8 log10IU/ml for placebo/peginterferon/ribavirin. While all three sofosbuvir groups showed nearly identical responses during the 28-days sofosbuvir/placebo phase of the study, differences surfaced during the peginterferon and ribavirin phase of dosing, with the 100 mg groups SVR24 being 56% compared to 83% and 80% for 200 and 400mg groups, respectively.²⁴ Thus, the 200 and 400 mg dosages were chosen for additional assessment in phase IIb trials.

Proton:

Sofosbuvir was shown to be highly effective against genotype 1, 2 and 3 HCV when used in combination with peginterferon and ribavirin as a 12-weeks triple therapy, followed by additional peginterferon and ribavirin in the genotype 1 patients. Proton was a double-blind, randomized, placebo-controlled, dose-ranging phase II study. SVR12 results were greater than 90%in all sofosbuvir-containing arms of the study.¹⁷ (Table 1).

Atomic:

316 treatment-naïve patients with genotype 1 HCV were randomly assigned to one of three treatment arms in the Atomic study, which investigated shorter treatment durations of sofosbuvir-based triple therapy. One arms received sofosbuvir triple therapy for 12 weeks, and subjects were randomized to receive an additional 12 weeks of sofosbuvir alone or with ribavirin.¹³ The other two treatment arms included sofosbuvir 400mg plus peginterferon and ribavirin therapy for 12 or 24 weeks. Cohort B of study also comprised with 5 patients with genotype 6 and 11 individuals with genotype 4 (Table 1).

Table 1: Phase II studies of sofosbuvir.

Study	Design	Genotype	RVR	EDT (%)	SVR4	SVR12
PROTON [ClinicalTrials.gov identifier: NCT01188772] [Lawitz et al.2013c]	SOF 200mg/PEG/RBV 12wk + 12-36wk PEG/RBV [RGT] [n=48]	1	98	94		90
	SOF 400mg/PEG/RBV 12wk + 12-36wk PEG/RBV [RGT] [n=47]	1	98	100		91
	Placebo/PEG/RBV 12wk + 36wk PEG/RBV [n=26]	1	19	62		58
	SOF 400mg/PEG/RBV 12wk [n=25]	2 and 3	96	100		91
ATOMIC [ClinicalTrial.gov identifier: NCT01329978] [Kowdley et al. 2013]	SOF 400mg/RBV/PEG 12wk [n=52]	1	94	98	94	90
	SOF 400mg/RBV/PEG 24wk [n=125]	1, 4 and 6	98	99	94	93
	SOF 400mg/RBV/PEG 12wk + SOF 400mg/RBV 12wk or SOF 400mg 12wk [n=155]	1	97	99	93	91
ELECTRON [ClinicalTrial.gov identifier: NCT01260350] Part 1 [randomized] [Gane et al. 2013c]	1. SOF 400mg/RBV 12wk [n=10]	2 and 3	100	100	100	100
	2. SOF 400mg/RBV 12wk+ PEG [wk 1-4] [n=9]	2 and 3	100	100	100	100
	3. SOF400mg/RBV 12wk+ PEG [wk 1-8] [n=10]	2 and 3	100	100	100	100
	4. SOF 400mg/RBV/PEG 12wk [n=11]	2 and 3	100	100	100	100
Part 2 [Gane et al. 2013c]	5. SOF 400mg 12wk [n=10]	2 and 3	100	100	60	60
	6. SOF 400mg/RBV/PEG 8wk [n=10]	2 and 3	100	100	100	100
	7. SOF 400mg/RBV 12wk [n=10 null responders]	1	100	100	10	10
Part 3 [Gane et al. 2013c]	8. SOF 400mg/RBV 12wk[n=25; naïve]	1	100	100	88	84
[Gane et al. 2012]	9. SOF 400mg/RBV 12wk [n=25; treatment experienced]	2 and 3	100	100	80	68
Part 4	10. SOF 400mg/RBV 8wk [n=25]	2 and 3, naïve				64
Part 4	11. SOF 400mg/RBV 800mg 12wk [n=10]	2 and 3, naïve
[Gane et al. 2013a, 2013b]	12. SOF/ledipasvir 90mg/RBV 12wk [n=9]	1; null	89	100	100	100
[Gane et al. 2013a, 2013b]	13. SOF/ledipasvir 90mg/RBV 12wk [n=25]	1; naive	100	100	100	100
Part 5 [Gane et al. 2013a, 2013b]	14. SOF/GS9669 500mg/RBV 12wk [n=10]	1; null	100	100	100	100
[Gane et al. 2013a, 2013b]	15. SOF/GS9669 500mg/RBV [n=25]	1; naive	92	100	92	92
COSMOS [Lawitz et al. 2013b]	1. Simeprevir 150mg/SOF 400mg ± RBV 12wk; SMV/SOF/RBV [n=27]	1, noncirrhotic null responders	85	100	96	96% SVR 8
	SMV/SOF [n=14]		57	100	93	93% SVR 8
	24wk; SMV/SOF/RBV [n=24]		82	83
	SMV/SOF [n=15]		67	90
[Medivir, 2013]	2. 12wk; SMV/SOF/RBV [n=27]	1, naïve and null responders with advanced fibrosis			96
[Medivir, 2013]	SMV/SOF [n=14] 24wk;SMV/SOF/RBV SMV/SOF				100
LONESTAR [Gilead Sciences, 2013]	SOF/ledipasvir FDC 8wk [n=20]	1, naïve				95% SVR8
	SOF/ledipasvir FDC + RBV 8wk [n=21]	1, naïve				100% SVR8
	SOF/ledipasvir FDC 12wk[n=19]	1, naïve			100
	SOF/ledipasvir FDC 12wk [n=19]	1, protease inhibitor experienced			95
	SOF/ledipasvir FDC + RBV 12wk [n=21]	1, protease inhibitor experienced			95
Daclatasvir plus Sofosbuvir [Sulkowaski et al. 2012]	SOF 400mg/daclatasvir 60mg ± RBV; SOF for 7 days then DCV/SOF 23wk [n=15] or	1; noncirrhotic, naive	100	100	100	100
	DCV/SOF 24wk [n=14] or		100	100	100	100
	DCV/SOF/RBV 24wk [n=15]		100	100	100	100
	SOF for 7 days then DCV/SOF 23wk [n=16] or	2 or 3 noncirrhotic, naive	100	94	88	88
	DCV/SOF 24wk [n=14] or		100	100	100	100
	DCV/SOF/RBV 24wk [n=14]		100	100	86	86
[Sulkowaski et al. 2013]	Daclatasvir 60mg/SOF 400mg 24wk [n=21]	1; previous failed TVT or	100	100	100	100
[Sulkowaski et al. 2013]	Daclatasvir 60mg/SOF 400mg/RBV 24wk [n=20]	BOC; noncirrhotic	95	100	100	95

PEG=Peginterferon, RBV=Ribavirin, SOF=Sofosbuvir, FDC=Fixed-Dose Combination, EOT=End of Therapy, RVR=Rapid Virological Response [viral load undertectable by week 4 on treatment], SVR=Sustained Virological Response, TVT=Telaprevir-based Triple Therapy, BOC=Boceprevir-based Triple Therapy, wk=Week, Blank spaces in the table represent incomplete or unpublished data.

All the study arms had SVR rates above 90%, and patients with characteristics typically linked to a lower response to interferon-based therapy, such as a high baseline viral load, patients with non-CC IL28B genotypes, or bridging fibrosis on liver biopsy, showed only slight variations in SVR.¹³ The results also indicated that prolonging sofosbuvir triple therapy past 12 weeks did not provide any extra advantages.

Electron:

The Electron research assessed sofosbuvir in interferon-sparing and interferon-free regimens for the treatment of HCV infection in noncirrhotic patients, building on the findings of proton and atomic (Table 1). Forty treatment-naïve patients with genotypes 2 or 3 HCV were randomly assigned to four groups in the initial cohort. Each group received weight-based ribavirin and 400mg/day of sofosbuvir. Peginterferon was also administered to three of the groups for four, eight, or twelve weeks. Regardless of whether they received peginterferon or not, all 40 patients had an SVR at week 24.⁸ For 12 weeks, two more groups of patients with genotype 2 or 3 infection received sofosbuvir monotherapy, which produced a 60% SVR24, or for 8 weeks, sofosbuvir-based triple treatment, which produced a 100% SVR24.

For 12 weeks without peginterferon, two groups of patients with HCV genotype 1 infection-25 treatment-naïve patients and 10 previous peginterferon null responders-were additionally given sofosbuvir and ribavirin. In this interferon-free treatment, SVR24 was attained by 10% of prior null responders and 84% of previously untreated patients with genotype 1 infection. Once more, a significant percentage of patients had a non-CC IL28B genotype, and 89% had genotype 1a infection, which has been linked to poorer response rates to other DAA treatments such triple therapy based on telaprevir or boceprevir. This study showed that sofosbuvir-based, interferon-free regimens can achieve SVR in patients with genotypes 1, 2 and 3 HCV infection. They also showed that ribavirin continues to have a part in preventing relapse following treatment.

Weight-based ribavirin dosing has been used for ongoing clinical development with sofosbuvir-dual therapy, and later cohorts of electron investigated sofosbuvir/ribavirin in treatment-experienced patients with genotypes 2 and 3 as well as cohorts with shorter treatment durations and lower doses of ribavirin [ClinicalTrials.gov identifier: NCT01260350]. However, these results have only been partially published in abstract from.⁷ Triple therapy combination of sofosbuvir/ribavirin and other DAA medications, such as the HCV NS5B nonnucleoside inhibitor GS9669 or the NS5A inhibitor ledipasvir (LDV; GS-5885) in a once daily fixed dose combination, were also used to treat patients with genotype 1 HCV. Both treatment-naïve patients and null responders who are typically resistant to other forms of DAA triple therapy with first-generation protease inhibitor have shown excellent SVR rates with both of these triple therapy combinations^5,6 (Table 1).

Lonestar:

In patients with genotype 1 HCV, the Lonestar research proceeded to assess various treatment during (8 or 12 weeks) using the fixed-dose combination of sofosbuvir and ledipasvir with or without ribavirin (Table 1). Cohort comprised 40 patients who had previously failed therapy with an HCV-specific protease inhibitor-based regimen in addition to GT1 patients who were new to treatment. Compensated cirrhosis was present in half of these patients. Phase III trials using the fixed-dose combination of sofosbuvir and ledipasvir are planned and a recent Gilead press release⁹ indicated SVR4 rates of at least 95% in all cohorts.

Daclatasvir and Sofosbuvir:

Sofosbuvir and the NS5A inhibitor daclatasvir have been tested together in two clinical trials. Treatment-naïve patients with HCV genotypes 1, 2 and 3 were randomized to receive daclatasvir plus sofosbuvir with or without ribavirin for a total treatment duration of 24 weeks, albeit some arms had a 1-week sofosbuvir lead-in phase prior to the addition of daclatasvir. This was the first experiment that was published. 100% of patients with genotype 1 and 86-100% of patients with genotype 2/3 cohort attained SVR12.¹¹

41 HCV genotype 1 patients who had previously failed protease-inhibitor-based triple therapy with either telaprevir or boceprevir were also evaluated for the combination of daclatasvir and sofosbuvir. These patients received 24 weeks of sofosbuvir plus daclatasvir, with or without ribavirin.²⁶ Remarkably, SVR12 rates of 95-100% were achieved with or without ribavirin, indicating that sofosbuvir plus an NS5A inhibitor is a successful treatment even for patients resistant to NS3A protease inhibitors.

Cosmos:

For 12 or 24 weeks, patients with HCV genotype 1 are being evaluated in the Cosmos trial using a once-daily regimen of the NS3/4A protease inhibitor simeprevir (TMC435) plus sofosbuvir with or without ribavirin (Table 1). According to recent early results from the 12-week cohort, SVR4 rates for patients with and without ribavirin were 96% and 93%, respectively, for cohort 1, which is made up of patients with mild to moderate fibrosis who had previously shown no response to peginterferon.¹⁶ Peginterferon null responders and treatment-naïve patients with severe fibrosis are included in cohort 2, and according to a recent press release, the 12-week groups SVr4 results ranges from 96% to 100%.²¹

Phase III trials of sofosbuvir:

Sofosbuvir 400mg + ribavirin (weight-based dosage) for at least 12 weeks in patients with chronic HCV has been the subject of four published phase III trials to far (Table 2). 499 treatment-naïve patients with genotype 2 or 3 HCV were randomly assigned to either peginterferon with ribavirin for 24 weeks or sofosbuvir 400mg plus ribavirin for 12 weeks in the Fission study, which was a noninterferiority trial. Although the RVR rates in this experiment differed significantly (From 99% to 67%, respectively), the SVR12 rates were the same at 67%¹⁸ (Table 2). Notably, response rate in this research varied significantly between patients with genotype 2 (97% SVR 12) and genotype 3 patients (56% SVR 12) HCV, as well as between patients who were cirrhotic (47% SVR 12) and those who were not (72% SVR 12).

IN the 12-week open-label NEUTRINO study, patients with HCV genotypes 1, 4, 5, or 6 (of whom 98% had genotype 1 or 4) who had never received treatment were given sofosbuvir + ribavirin. Overall SVR12 rates were 90%, with genotype 1 cirrhosis patients showing 81% response rates. Additionally, just 2% of these cirrhotic individuals stopped their therapy, indicating that this combination is safe and very well tolerated even in cirrhotic patients.¹⁸

In patients with genotypes 2 and 3 HCV for whom interferon was not an option (previously intolerant of interferon, unwilling or unable to take interferon), POSITRON compared sofosbuvir plus ribavirin versus a placebo. The sofosbuvir/ribavirin groups overall SVR12 rates were greater than those of FISSION (78%), presumably as a result of a larger percentage of genotype 2 patients who once more showed noticeably higher SVR12 rates (92%) than genotype 3(68%). In genotype 2 patients, the degree of liver fibrosis did not seem to have a major impact on outsides (94% SVr12, even in cirrhosis patients); however, in genotype 3 patients, SVR12 rates were low, at 21% in cirrhosis patients.¹¹

Table 2: Phase III studies of sofosbuvir.

Study	Design	Genotype	RVR	EDT (%)	SVR4	SVR12
FISSION [ClinicalTrials.gov identifier: NCT01497366] [Lawitz et al. 2013d]	SOF 400mg/RBV 12wk [n=253] or PEG/RBV [n=243]	2 and 3; naïve	99 67	98 89	74 74	67(G2 97: G3 56) 67
NEUTRINO [ClinicalTrial.gov identifier: NCT01641640] [Lawitz et al. 2013d]	SOF 400mg/RBV/PEG 12wk [n=327]	1, 4, 5, 6; naïve [98% G1 or 4]	99	99	92	90 [G1a 92; G1b 82; G4 96]
POSITRON [ClinicalTrials.gov identifier: NCT01542788]	SOF 400mg/RBV [n=207] or placebo [n=71] 12wk	2 and 3; naïve [IFN not an option]	99	100	83	78 [G2 93: G3 61]
FUSSION [ClinicalTrials.gov identifier: NCT01604850] [Jacobson et al. 2013]	SOF 400mg/RBV	2 and 3: previous treatment failure
	12wk [n=103] or		97	100	56	50 [G2 86; G3 30]
	16wk [n=98]		98	100	77	73 [G2 94; G3 62]

PEG=Pegylated Interferon Alpha, RBV=Ribavirin, SMV=Simeprevir, [TMC435], SOF=Sofosbuvir [GS7977], DCV=Daclatasvir, RGT=Response Guided Therapy, EOT=End of Therapy, SVR=Sustained Virological Response.

Fusion:

Patients with genotypes 2 or 3 HCV who had not responded to previous treatment with an interferon-containing regimen were included in the blinded, active-control FUSION trial. Patients were randomized to receive either 16 weeks of sofosbuvir and ribavirin or 12 weeks of sofosbuvir and ribavirin followed by 4 weeks of a matching placebo. A third of those who took part had cirrhosis. According to Jacobson et al. (2013), the 16-week arm had significantly higher overall SVR rates (73%) than the 12-week arm (50%). Additionally, genotype 2 patients had higher SVR rates (86% and 94% for 12 and 16 weeks, respectively) then genotype 3 patients (30% and 62% for 12 and 16 weeks). A lower rate of SVR was linked to cirrhosis, especially in genotype 3 patients who received therapy for 12 weeks as opposed to 16 weeks (SVR 19% versus 61%). SVR rates for genotype 2 individuals who received 16 weeks of treatment varied from 60% to 78% for cirrhosis patients and up to 100% for noncirrhotic patients who did not have cirrhosis.

Potential for sofosbuvir in liver transplantation:

Data on the safety and effectiveness of sofosbuvir in patients with decompensated chronic liver disease who are peri- or post-liver transplant is clearly needed in clinical settings. Sofosbuvir is a desirable option to be investigated in these groups due to its good safety record thus far and the absence of notable medication interactions. One case report of a patients with severe recurrent cholestatic hepatitis C, six months after transplantation, has been reported to far. The patient was successfully saved and obtained SVR with a combination of sofosbuvir and daclatasvir.⁴ This is encouraging, and the outcomes of upcoming sofosbuvir trials in these patients populations are eagerly anticipated.

Adverse events:

In these sofosbuvir-based interferon-free therapy regimens, treatment discontinuations due to adverse events have been rare. Treatment discontinuation rates in phase III studies were 1-2% for sofosbuvir plus ribavirin cohort and 11% for patients receiving peginterferon-ribavirin for 24 weeks. Fatigue, sleeplessness, anemia and headaches were among the prevalent adverse effects linked to ribavirin medication that were recorded. In FUSSION and ELECTRON, hematologic problems were more prevalent in patients who received interferon than in those who did not.^8,18 In groups that did not get interferon, neutropenia and thrombocytopenia were not typically observed. In contrast to 5% of individuals getting sofosbuvir + ribavirin, depression, a typical side effect of interferon therapy, occurred in 14% of patients receiving peginterferon in the FISSION research. Sofosbuvir plus ribavirin was linked to a higher health-related quality of life than peginterferon plus ribavirin in the FISSION and POSITRON trials, and it was comparable to patients not undergoing active therapy, according to a recent review of the effects of HCV treatment on quality of life. Improvements in health-related quality of life were similarly linked to achieving SVR on sofosbuvir + ribavirin.²⁷

Concordance data: SVR at weeks 4, 12 and 24:

SVR24 has historically been defined as the lack of detectable virus 24 weeks following the end of treatment with interferon-based therapy for HCV. With positive predictive values of 98% for SVR12 and 91% for SVR4, recent analysis have indicates that SVR12 and SVR24 are consistent across treatments that include peginterferon/ribavirin as well as peginterferon/ribavirin triple therapy, which includes telaprevir and boceprevir. In the sofosbuvir phase II program, which included 590 individuals, the concordance of SVR4, SVR12, and SVR24 was evaluated. Positive predictive values and sensitivity of SVR for SVR12 and SVR24 was higher than 98.5% and there was high concordance between SVR4 and subsequent time points. Drug development is most likely accelerated as a result of greater reliance on these early SVR4 and SVR12 time points to predict outcomes.

Viral resistance:

Even people with an untreated HCV infection may have viral alterations in the NS3 and NS5B regimens, which have been linked to resistance to protease and nonnucleoside inhibitors. In sofosbuvir replicon studies, the S282T mutation has been found to be the most frequently selected mutation. This mutation can confer resistance to sofosbuvir,¹⁵ but it is not typically found in untreated HCV patients and very poor replicative fitness.¹⁴ The S282T mutation was not found on deep-sequencing assays in any of the patients receiving sofosbuvir in the first large phase II and III studies involving the drug. This stands in stark contrast to the quick emergence of viral resistance that has been noted with other classes of DAA in patients who experienced a breakthrough during treatment or relapse after therapy was finished.^8,11,18 Positively, new research indicates that even in patients with protease inhibitor resistance, sofosbuvir/NS5A inhibitor combination therapy is quite successful in NS3A protease-inhibitor-experienced individuals.²⁶

CONCLUSION AND FUTURE DIRECTIONS:

Despite not being among the first DAA medications to advance to phase III clinical trials, sofosbuvir’s combined trial results do mark a substantial paradigm shift in the way HCV infection is treated. Effective interferon-free treatment of HCV is now possible for a variety of genotypes thanks to sofosbuvir-based regimens; nonetheless, distinct patterns of genotypic response to treatment have surfaced in contrast to those observed with conventional interferon-based therapy. Given that SVR rates in genotype 3 patients are substantially lower than those in genotype 2, it is now evident that genotypes 2 and 3 should be assessed very independently in the current DAA era.^11,18 Even in individuals with developed cirrhosis, genotype 2 is an easily curable strain of HCV that exhibits excellent SVR rates with sofosbuvir/ribavirin dual therapy. On the other hand, when a 12-week regimen is employed, the presence of extensive liver fibrosis significantly lowers SVR rates in genotype 3 patients. The FUSION statistics clearly indicate that the dual sofosbuvir/ribavirin combination requires at least 16 weeks of therapy for this patients population. The outcomes of upcoming trials assessing a 24-week course of treatment are eagerly anticipated. Although adding another DAA to the regimen is an alternative approach, there may be a role for continuing to use peginterferon in conjunction with sofosbuvir in this patient group until more information is available to determine the best interferon-free treatment for genotype 3 HCV patients with advanced fibrosis or prior treatment failure.

In contrast to the continuously developing data regarding the safety of protease inhibitor/peginterferon-based triple therapy, the NEUTRINO data have demonstrated the highest SVR rates yet documented for patients with genotype 1 HCV and cirrhosis when treated with sofosbuvir/ribavirin dual therapy. This is especially noteworthy for the absence of significant adverse events. However, for the genotype 1 null responder group, this dual therapy is insufficient. New phase II data in genotype 1 patients on triple therapy regimens of sofosbuvir plus ribavirin plus an NS5A inhibitor, either daclatasvir or ledipasvir, show SVR rates near 100% in both treatment-naïve and null-responder patients. This triple therapy approach, which uses a fixed-dose once-daily regimen of sofosbuvir/ledipasvir, may further reduce the length of therapy to 8 weeks. We are awaiting information on how well this combination works in cirrhotic genotype 1 null responders. Sofosbuvir is probably going to be the cornerstone of the new era of effective interferon-free DAA therapy for HCV, which has the potential to expand treatment of HCV to patient groups that have either shunned or were not a good fit for earlier interferon-based therapy.

REFERENCES:

1. Cornpropst, M., et al. The effect of renal impairment and stage renal disease on the single-dose pharmacokinetics of PSI-7977. Hepatol. 56 (Suppl. 2): 2012: Abstract 1101.

2. Denning, J., et al. Lack of effect of the nucleoside analog polymerase inhibitor PSI-7977 on methadone PK and PD. Hepatology. 54(4): 2011: Abstract 372.

3. Fontaine, H., et al. SVR12 rates and safety of triple therapy including telaprevir or boceprevir in 221 cirrhotic non responders treated in the French early access program (ANRS C020-CUPIC). Hepatol. 58 (S25-S44): 2013: A60.

4. Fontana, R., et al. Sofosbuvir and daclatasvir combination therapy in a liver transplant recipient with severe recurrent cholestatic hepatitis C. Am f Transplant. 13: 2013: 1601-1605.

5. Gane, E., et al. Efficacy of Nucleotide Polymerase Inhibitor Sofosbuvir plus the NS5A Inhibitor GS-9669 Against HCV Genotype 1 Infection. Gastroenterology. 2013a: DOI: 10.1053/j.gastro.2013.11.007.

6. Gene, E., et al. All-oral sofosbuvir-based 12-week regimens for the treatment of chronic HCV infection: the ELECTRON study. F Hepatol. 58(S1-S24): 2013b: A14.

7. Gane, E., et al. Once daily sofosbuvir (GS-7977) plus ribavirinin patients with HCV genotypes 1, 2 and 3: the ELECTRON trial. Hepatology. 56(4 Suppl.): 2012: A229.

8. Gane, E., et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl f Med. 368: 2013c: 34-44.

9. Gilead Sciences, Gilead reports interim data from phase 2 LONESTAR study: 2013: Available at: http://www.gilead.com/news/press-releases/2013/5/gilead-reports-interim-data-from-phase-2-lonestar-study.

10. Herbest, D., et al. Sofosbuvir, a nucleotide polymerase inhibitor, for the treatment of chronic hepatitis C virus infection. Expert Opin Investing Drugs 22: 2013: 527-536.

11. Jacobson, I., et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl f Med 368: 2013: 1867-1877.

12. Jacobson, I., et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl f Med. 364: 2011: 2405-2416.

13. Kowdly, K., et al. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naïve patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomized, multicenter phase 2 trial. Lancet. 381: 2013: 2100-2107.

14. Kuntzen, T., et al. Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naïve patients. Hepatology. 48: 2008: 1769-1778.

15. Lam, A., et al. Genotype and subtype profiling of PSI-7977 as a nucleotide inhibitor of hepatitis C virus. Antimicrob Agents Chemother. 56: 2012: 3359-3368.

16. Lawitz, E., et al. COSMOS Study: SVR4 results of a once daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in HCV genotype 1 null responders In: Proceedings of the CROI: 20^th Conference on Retroviruses and Opportunistic Infections, Atlanta, GA: 2013b.

17. Lawitz, E., et al. Sofosbuvir in combimation with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naïve patients with genotypes 1, 2, and 3 hepatitis C infection: a randomized, double-blind, phase 2 trial. Lancet Infect Dis 13: 2013c: 401-408.

18. Lawitz, E., et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl f Med. 368: 2013d: 1878-1887.

19. Lawitz, E., et al. The effect of hepatic impairment on the pharmacokinetics and antiviral antiviral activity of PSI-7977 in hepatitis C infected subjects treated for seven days. F Hepatol. 56 (Suppl. 2): 2012: Abstract 1130.

20. Mathias, A., et al. No clinically significant pharmacokinetic drug-drug interactions between sofosbuvir (GS-7977) and the immunosuppressants, cyclosporine A or tacrolimus in healthy volunteers. Hepatology. 56 (4 Suppl.): 2012: Abstract 1869.

21. Medivir, Medivir announces interim results from cohort 2 of the COSMOS study evaluating Simeprevir and Sofosbuvir in HCV patients with METAVIr scores F3-F4, Press Release: 2013: Available at: http://www.medivir.se/v5/en/uptodate/pressrelease.cfm?releaseid=FEBC5055C8C2C046andyear=2013.

22. Murakami, E., et al. Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. F Biol Chem 285: 2010: 34337-34347.

23. Poordad, F., et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl f Med 364: 2011: 1195-1206.

24. Rodriguez-Torres, M., et al. Sofosbuvir (GS-7977) plus peginterferon/ribavirin in treatment-naïve patients with HCV genotype 1: A randomized, 28-days, dose-ranging trial. F Hepatol 58: 2013: 663-668.

25. Sofia, M., et al. Discovery of a beta-d-2’-deoxy-2’-alpha-fluoro-2’-beta-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus. F Med Chem 53: 2010: 7202-7218.

26. Sulkowski, M., et al. Sustained virological response with daclatasvir, plus sofosbuvir +- ribavirin (RBV) in chronic HCV genotype (GT) 1-infected patients who previously failed telaprevir (TVR) or boceprevir (BOC). F Hepatol. 58 (S567-S577): 2013: Abstract 1417.

27. Younossi, Z., St et al. Minimal impact of sofosbuvir + ribavirin on health related quality of life (HRQL) compared to pegylated interferon + ribavirin for chronic hepatitis C: results from FISSION + POSITRON trials. F Hepato; 58(S567-S577): 2013: Abstract 1431.

Received on 31.03.2025 Revised on 04.06.2025

Accepted on 27.07.2025 Published on 06.10.2025

Available online from October 13, 2025

Asian J. Pharm. Res. 2025; 15(4):411-417.

DOI: 10.52711/2231-5691.2025.00064

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.