Tuesday, October 1, 2013

All-Oral Therapy With Sofosbuvir and GS-0938 for 14 Days in Treatment-Naive Geno 1 Hepatitis C (NUCLEAR)

Journal of Viral Hepatitis

All-Oral Therapy With Nucleotide Inhibitors Sofosbuvir and GS-0938 for 14 Days in Treatment-Naive Genotype 1 Hepatitis C (NUCLEAR)

E. J. Lawitz, M. Rodriguez-Torres, J. Denning, A. Mathias, H. Mo, B. Gao, M. T. Cornpropst, M. M. Berrey, W. T. Symonds

J Viral Hepat. 2013;20(10):699-707.

Abstract
Sofosbuvir and GS-0938 are distinct nucleotide analogues with activity against hepatitis C virus (HCV) in vitro. We evaluated the antiviral activity and safety of sofosbuvir and GS-0938 alone and in combination in HCV genotype 1 patients. In this double-blind study, 40 treatment-naïve patients were randomly assigned to 4 treatment cohorts: (i) GS-0938 for 14 days, (ii) GS-0938 for 7 days followed by GS-0938 plus sofosbuvir for 7 days, (iii) sofosbuvir for 7 days followed by GS-0938 plus sofosbuvir for 7 days and (iv) GS-0938 plus sofosbuvir for 14 days. In each arm, 8 patients received active drug and 2 placebo. After 7 days of dosing, patients in all 4 dose groups experienced substantial reductions in HCV RNA, with median declines (Q1, Q3) of −4.50 (−4.66, −4.24) in Cohort 1, −4.55 (−4.97, −4.13) in Cohort 2, −4.65 (−4.78, −4.17) in Cohort 3 and −4.43 (−4.81, −4.13) in Cohort 4; patients receiving placebo had essentially no change in HCV RNA (+0.07 log10 IU/mL). Seven days after the end of treatment, the proportions of patients with HCV RNA <15 IU/mL were 4 (50%), 8 (100%), 7 (88%) and 5 (63%) for Cohorts 1–4, respectively, vs 0 for placebo. No viral breakthrough or resistance mutations were observed. No serious adverse events or Grade 3 or 4 adverse events were reported. Sofosbuvir and GS-0938—alone and in combination—were well tolerated and led to substantial reductions in viral load. Sofosbuvir is undergoing further investigation as a possible backbone of an all-oral regimen for chronic HCV.

Introduction
Adding the protease inhibitors telaprevir or boceprevir to peginterferon and ribavirin has improved rates of sustained virologic response in patients with genotype 1 chronic hepatitis C virus (HCV) by as much as 30% over those seen with peginterferon and ribavirin alone.[1,2] However, these regimens can be challenging for patients to adhere to and tolerate.[3] Peginterferon in particular is associated with a number of onerous side effects, including flulike symptoms, anaemia and depression.[4] Telaprevir, boceprevir and many other direct-acting antivirals cannot be used as monotherapies because of the potential for viral resistance. To minimize the development of resistance, many experimental all-oral regimens involve combination therapy. Recently, it was reported that an all-oral combination therapy with an NS5A replication complex inhibitor and an NS3 protease inhibitor can lead to sustained virologic response in HCV genotype 1 patients who were prior nonresponders to peginterferon and ribavirin,[5,6] suggesting that interferon-free regimens may be a viable treatment strategy.

Sofosbuvir (GS-7977) is a pyrimidine nucleotide analogue inhibitor of the HCV NS5B polymerase. GS-0938 is a purine nucleotide analogue inhibitor of the NS5B polymerase. They both employ unique prodrug components that deliver the monophosphorylated forms of the respective nucleosides. Like other nucleoside or nucleotide analogues, sofosbuvir and GS-0938 appear to have equal antiviral activity against various HCV subtypes as well as high barriers to genetic resistance.[7–10] Phenotypic evaluation of mutations from an in vitro resistance selection experiment with GS-0938 indicated that single amino acid changes were not sufficient to significantly reduce the activity of GS-0938. Among these, the highest fold-shift in EC50 was 3.7 ± 1.4 attributed to C223H.[8] Combinations of three and four amino acid changes were required to confer 17-fold and 20-fold reduced susceptibility to GS-0938. A resistance selection experiment performed with sofosbuvir identified NS5B S282T and M289L as resistance-associated mutations.[9] In vitro, the combination of sofosbuvir and GS-0938 results in additive to synergistic antiviral activity.[11] In patients with HCV genotype 1 infection, 7 days of monotherapy with GS-0938 resulted in HCV RNA reductions of up to 5.35 log10 IU/mL.[12] Before this trial, sofosbuvir had not been administered as monotherapy, but was studied as one of the two diasteromers of the compound GS-9851 (PSI-7851). In a dose-ranging monotherapy study, patients receiving 400 mg of GS-9851 for 3 days experienced a mean maximal reduction in HCV RNA of 1.95 log10 IU/mL.[13] When sofosbuvir was administered to HCV genotype 1 patients in combination with peginterferon and ribavirin for 28 days, the combination resulted in mean HCV RNA reductions of up to 5.3 log10 IU/mL.[14]
                       
Sofosbuvir and GS-0938 have a number of structural differences; they employ different prodrug cleavage pathways, have largely independent phosphorylation pathways, compete with separate endogenous nucleotide pools (purine/pyrimidine) and have complementary resistance profiles.[15–17] This phase 1, placebo-controlled study of sofosbuvir and GS-0938 alone and in combination for 14 days is the first proof-of-concept study of the feasibility of combining two nucleotides for the treatment of patients with genotype 1 HCV and is the first trial characterizing the activity of sofosbuvir administered as monotherapy for 7 days.

Experimental Procedures
Study Design
This was a multicentre, randomized, double-blind, placebo-controlled study of sofosbuvir, GS-0938 and the combination of sofosbuvir and GS-0938 in 4 cohorts of patients infected with HCV genotype 1. Between July 2010 and February 2011, patients were sequestered at 1 of 2 study sites (1 in Texas and 1 in Puerto Rico) the day prior to dosing initiation and stayed for 17 days. Dosing occurred in the mornings on Days 1–14, as follows: GS-0938 300 mg once daily (QD) for all 14 days (Cohort 1); GS-0938 300 mg QD on Days 1–7 followed by GS-0938 300 mg QD and sofosbuvir 400 mg QD on Days 8–14 (Cohort 2); sofosbuvir 400 mg QD on Days 1–7 followed by GS-0938 300 mg QD and sofosbuvir 400 mg QD on Days 8–14 (Cohort 3); and GS-0938 300 mg QD and sofosbuvir 400 mg QD for all 14 days (Cohort 4).

Two patients from each arm were randomized to receive placebo (Cohort 5) (Fig. 1).




Patients fasted 10 h prior to receiving study drug and 4 h postdose on Day 1 in Cohort 4, on Day 7 in Cohorts 2 and 3 and on Day 14 in all cohorts. In all cohorts and on all other study days, patients received the first meal of the morning 2 h after dosing. Each cohort had 10 patients, who were randomly assigned to active drug and placebo in a ratio of 4:1 with a block size of 5. Random allocation sequence was generated by PharStat (Durham, NC, USA). Patients remained in the clinic until Day 17 and then returned on Day 21 for follow-up assessments.

This study was blinded to both investigators and patients through Day 14. Study medication was prepared from bulk supply by an unblinded pharmacist or pharmacist designee and administered by a qualified site staff member who was not otherwise directly involved in this study.
Treatment group sizes were chosen empirically; no formal power or sample size calculations were made. The efficacy endpoint was the change from baseline in plasma HCV RNA, assessed as continuous change from baseline (log10 IU/mL) and as categorical reduction [i.e. <1, ≥1, ≥2, ≥3 log10 IU/mL, or below the lower limit of detection (<15 IU/mL)].

The study protocol was approved by each institution's review board prior to study initiation and was performed in accordance with Good Clinical Practice guidelines outlined by the International Conference on Harmonization. On Day 14 of the study, all patients were offered a full course of standard of care therapy with pegylated interferon and ribavirin. Please see clinical trial protocol, available in the supplementary materials; Appendix S1.

Patients
Eligible patients were men and women between the ages of 18–65 years, chronically infected with HCV genotype 1 (plasma HCV RNA ≥50 000 IU/mL at screening) and had received no prior treatment for HCV infection. Patients had a body mass index of 18–36 kg/m2 inclusive, and were noncirrhotic, as judged by liver biopsy within the prior 3 years. Patients with any of the following were excluded: a chronic liver disease besides hepatitis C; hepatic decompensation; QTc value ≥450 msec; coinfection with HIV or hepatitis A or B virus; creatinine ≥1.5 × ULN; alanine aminotransferase (ALT), aspartate aminotransferase or alkaline phosphatase levels ≥5 × ULN; total bilirubin ≥2 × ULN; haemoglobin <11 g/dL in females and <12 g/dL in males; albumin ≤3 g/dL; serum lipase ≥1.5 × ULN; potassium or magnesium <LLN; creatinine clearance <60 mL/min; or absolute neutrophil count <1500 cells/mm3. Concomitant prescription medications were prohibited during the study unless approved by the investigator and sponsor. Females were required to be surgically sterile or postmenopausal for at least 12 months confirmed by FSH value >35 IU/mL at screening. Where allowed by local regulations, females of child-bearing potential were enrolled provided they used two methods of acceptable contraception. All patients provided written informed consent before undertaking any study-related procedures.

Efficacy Assessments

HCV RNA Blood samples for determining plasma HCV RNA levels were collected at screening; on Days 1–4, 6, 8–11 and 13 prior to study drug dosing; and on Days 15, 17 and 21. Plasma HCV RNA was analysed by Cenetron Central Laboratories (Austin, TX, USA) using the Roche COBAS AmpliPrep/COBAS HCV TaqMan assay (Roche Molecular Systems, Inc., Branchburg, NJ, USA), Research Use Only version, which has a lower limit of quantification of 43 IU/mL and a lower limit of detection of 15 IU/mL.

Resistance Monitoring
Serum samples for NS5B genotypic and phenotypic monitoring were collected on Days 1, 4, 8, 11, 15 and 17 in the morning (before dose on dosing days) and at follow-up on Day 21.

Population sequencing of the HCV NS5B-encoding region of the polymerase of all baseline and end-of-treatment viral samples was performed by the DDL Diagnostic Laboratory (Rijswijk, Netherlands) using standard sequencing technology. Amino acid substitutions in samples taken after baseline were compared with baseline.

Pharmacokinetic Assessments
The pharmacokinetic profiles of sofosbuvir and GS-0938 administered alone and in combination were examined on Days 7 (Cohorts 2 and 3) and 14 (Cohorts 1–4), respectively. Blood samples were drawn at selected time points over the dosing interval. Pharmacokinetic parameters estimated (nonlinear curve-fitting; Phoenix WinNonlin version 6.3; Pharsight Corporation, Mountain View, CA, USA) for sofosbuvir, GS-0938 and GS-331007 (the predominant circulating nucleoside metabolite of sofosbuvir) included maximum observed plasma concentration (Cmax), time to maximum plasma concentration (Tmax), concentration at the end of dosing Ctau, area under the plasma concentration–time curve from 0 h to end of dosing (AUC0-tau) and elimination half-life (t1/2).

Safety Assessments
From baseline through the Day 21 follow-up visit, safety was evaluated on the basis of reported adverse events, physical examinations, clinical laboratory tests, vital signs and ECG recordings. Concomitant medication intake was also recorded. Treatment-emergent adverse events were summarized by treatment, system organ class and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA®), version 14.0. The intensity of an adverse event was graded based on the DAIDS Therapeutic Research Program's 'Table for Grading Severity of Adult Adverse Experiences, August 2009'.

Results
Study Population
Forty patients were randomized and received study drug. Median (Q1, Q3) baseline HCV RNA levels were similar between cohorts and ranged from 5.9 (5.2, 6.7) log10 IU/mL in the placebo group to 7.0 (6.2, 7.5) in the group receiving GS-0938 monotherapy. Between 75% and 100% of patients in each treatment group were infected with genotype 1a HCV. The distribution of IL28B genotypes was uneven across treatment arms; for example, 63% of patients in the GS-0938 monotherapy arm harboured the CC genotype, as compared to no patients in the group that received sofosbuvir plus GS-0938 for 14 days (Table 1). All patients completed treatment and participated in the study through follow-up.

Efficacy Assessments
Antiviral response
Substantial on-treatment reductions in HCV RNA were experienced by patients in all 4 active-therapy cohorts in the first days of treatment (Table 2 and Figs 2 and 3). The initial rapid reductions in HCV RNA were followed by more gradual virologic declines, which continued through the end of dosing on Day 14. After 7 days of dosing, patients receiving active therapy had median HCV RNA declines ranging from −4.43 to −4.65 IU/mL; after 14 days of dosing, declines ranged from −4.99 to −5.21 IU/mL (Table 2). The proportion of patients with HCV RNA <15 IU/mL ranged from 13% to 50% (overall 28%) at Day 7 and 50–100% (overall 75%) at Day 14. Dual therapy with sofosbuvir and GS-0938 did not appear to produce greater median on-treatment reductions in HCV RNA than monotherapy with GS-0938. However, a greater proportion of patients on combination therapy achieved HCV RNA <15 IU/mL by the end of treatment (50% on GS-0938 monotherapy vs 63–100% on combination therapy). All patients with undetectable HCV RNA at the end of dosing still had undetectable HCV RNA 7 days after the end of study treatment (it should be noted that most of these patients elected to continue treatment with peginterferon and ribavirin at the conclusion of the 14 days of study treatment).
 
Figure 2.
Median hepatitis C virus (HCV) RNA changes from baseline.




Figure 3
Individual patient changes in hepatitis C virus (HCV) RNA from baseline.




Resistance Monitoring
The NS5B mutations associated with resistance to either GS-0938 (S15G, R222Q, C223Y, C223H, L320I and V321I) or SOF (S282T and M289L) were not detected in any of these patients at baseline.
No on-treatment viral breakthrough was detected in any patient among the 32 subjects who received active drugs. HCV RNA levels for all patients following a 14-day dosing period were generally very low: <1000 IU/mL at end of treatment Day 15 (HCV RNA levels were below the level of detection in the majority of subjects). With the exception of two subjects who received GS-0938 monotherapy, all subjects had HCV RNA <1000 IU/mL at Day 21 (7 days after the last dose), which precluded them from NS5B population sequencing. Population sequence results were available from one of the two subjects with sufficient HCV RNA for sequencing. At the 21-day follow-up visit, substitutions at NS5B associated with reduced susceptibilities to GS-0938 (S15G, R222Q, C223Y, C223H, L320I and V321I) were not detected in this patient.

Pharmacokinetic Assessments
Plasma pharmacokinetic parameters for sofosbuvir and GS-331007 following administration of sofosbuvir alone are summarized in Table 3. As seen in previous clinical studies, sofosbuvir exhibits low and transient exposure with maximum concentrations achieved within 0.75 h postdose (median Tmax) and a terminal half-life of 0.48 h (median t1/2). The majority of systemic exposure is accounted for by GS-331007, which exhibits a maximum concentration achieved within 2 h postdose (median Tmax) and a longer plasma circulating half-life of 9.4 h (median t1/2).

A direct assessment of drug–drug interactions between GS-0938 and sofosbuvir was made in patients receiving sofosbuvir and GS-0938 combination therapy vs sofosbuvir alone or GS-0938 alone. The data indicate that GS-0938 and sofosbuvir were involved in a modest pharmacokinetic drug interaction upon coadministration that is not considered clinically significant. A modest increase in GS-0938 Cmax (24% increase), but no relevant change in the GS-0938 AUC, was observed on coadministration of the combination. Exposure (AUC0-tau and Cmax) of sofosbuvir was modestly elevated (<60%) by GS-0938, with no effect of GS-0938 on the exposure of GS-331007 (the GLSM ratios and associated 90% CIs of GS-331007 AUC0-tau and Cmax were contained within the equivalence bounds of 70–143%). For sofosbuvir, the increase in exposure observed on coadministration with GS-0938 was within the range of sofosbuvir exposures observed in other clinical trials and does not warrant any dose adjustment.

Safety Assessments
Sofosbuvir and GS-0938 both had favourable safety profiles. No serious adverse events were reported, and no patients interrupted or discontinued dosing because of an adverse event (Table 4 see below). Headache was the most commonly reported adverse event among patients receiving either active therapy or placebo: headache was reported in 4 of 32 patients receiving nucleotides (13%) and in 2 of 8 patients receiving placebo (25%). No Grade 3 or 4 adverse events were reported, and there were no clinically relevant changes in vital signs, ECG or physical examination assessments. Among all cohorts, one treatment-emergent Grade 1 elevation in ALT occurred in a patient receiving placebo.
In the nucleotide-treated groups, all 8 patients who had Grade 1 or higher elevations of ALT at baseline had normalized ALT levels by Day 8, and through Day 14, no patient on active treatment experienced a treatment-emergent elevation in ALT greater than normal. One patient in the placebo group had a Grade 1 or higher elevation in ALT at baseline, and by Day 14, ALT was still abnormally high.

Table 4.  Treatment-emergent adverse events
 
 GS-0938 × 14 days (n = 8)GS-0938 × 7 days, GS-0938 + SOF × 7 days (n = 8)SOF × 7 days, GS-0938 + SOF × 7 days (n = 8)GS-0938 + SOF × 14 days (n = 8)Placebo (n = 8)
Patients with ≥1 adverse event, n (%)2 (25)3 (37.5)3 (37.5)4 (50)4 (50)
Grade 3 or 4 adverse events, n 00000
Adverse event leading to discontinuation, n 00000
Adverse events, n (%)
   Eye pruritus01 (12.5)000
   Constipation0001 (12.5)0
   Diarrhoea0001 (12.5)0
   Nausea001 (12.5)00
   Vomiting001 (12.5)00
   Chills1 (12.5)1 (12.5)001 (12.5)
   Fatigue0001 (12.5)0
   Irritability00001 (12.5)
   Noncardiac chest pain001 (12.5)00
   Pyrexia01 (12.5)000
   Arthralgia01 (12.5)000
   Back pain1 (12.5)0000
   Myalgia1 (12.5)01 (12.5)01 (12.5)
   Dizziness01 (12.5)000
   Headache1 (12.5)003 (37.5)2 (25)
   Nasal congestion01 (12.5)000
   Increased perspiration01 (12.5)000
   Skin pruritus0001 (12.5)1 (12.5)
   Skin rash0001 (12.5)0
   Conjunctival hyperaemia01 (12.5)000
Serious adverse events, n (%)00000


Discussion
In this 14-day phase 1 study, treatment with the nucleotide inhibitors sofosbuvir and GS-0938 alone and in combination resulted in rapid and substantial declines in serum HCV RNA in patients infected with genotype 1 HCV. These reductions in HCV RNA were greater than or comparable with those seen after administration of other direct-acting antiviral agents currently under investigation. After 14 days of monotherapy with the protease inhibitor danoprevir 300 mg to 600 mg, median decreases in HCV RNA of −1.7 to −3.8 (range −0.9 to −5.0) were observed.[18] The combination of the NS3 protease inhibitor asunaprevir and the NS5A replication complex inhibitor daclatasvir provided a median reduction in HCV RNA of 5.1 log10 IU/mL.[5] Patients receiving the macrocyclic protease inhibitor IDX320 200 mg twice daily for 3 days experienced a decline of 3.8 log10 IU/mL.[19] Patients receiving the NS3/4A protease inhibitor TMC435 experienced a median reduction of 3.46 log10 IU/mL in HCV RNA levels after three days of treatment.[20] Data were presented earlier this year on the protease inhibitor ABT-450 in combination with low-dose ritonavir (ABT-450/r). After 3 days of treatment with 3 different doses of ABT-450/r, the mean maximum decreases from baseline in HCV RNA were 3.91–4.11 log10 IU/mL.[21]
                       
Of note, this was the first characterization of the antiviral potency of sofosbuvir given as monotherapy, rather than in the form of GS-9851, of which sofosbuvir is one of the diasteromers. Compared to the earlier results with GS-9851 over 3 days, sofosbuvir produced significantly greater reductions in HCV RNA with 3.69 log10 IU/mL at Day 3 compared with 1.95 log10 IU/mL at Day 3 in the earlier GS-9851 study. Thus, development of sofosbuvir rather than the mixture of diasteromers has resulted in approximately double the antiviral potency at the same mg dose level.

Combining sofosbuvir and GS-0938 did not appear to cause greater on-treatment viral suppression than either agent alone. While both agents show additive to synergistic activity in vitro,[11] no obvious additive activity was observed in this study although a greater proportion of patients on combination therapy achieved undetectable HCV RNA at Day 14 (Table 2 see below). This, however, may have been attributable simply to the higher HCV RNA values at baseline, particularly in the 4 subjects who failed to achieve undetectable HCV RNA in the GS-0938 monotherapy arm (i.e. 6.97–7.49 log10 IU/mL). One possible explanation for the uniformity of response among the arms may be that each drug alone leads to near-maximal suppression of viral replication and adding a second drug of the same class does nothing to further suppress replication as can be measured by currently available HCV RNA assays. However, in this study, treatment lasted only 14 days, and it is possible that combination therapy with 2 nucleotides could confer additional benefits during a longer time course (i.e. prevention of breakthrough, relapse and/or resistance emergence over therapeutic treatment durations).

Table 2.  Summary of antiviral response after 4, 8 and 15 days of treatment
 
 GS-0938 × 14 days (n = 8)GS-0938 × 7 days, GS-0938 + SOF × 7 days (n = 8)SOF × 7 days, GS-0938 + SOF × 7 days (n = 8)GS-0938 + SOF × 14 days (n = 8)Placebo (n = 8)
Day 4
   Median HCV RNA (Q1, Q3)−3.93 (−4.03, −3.50)−3.89 (−4.18, −3.32)−3.69 (−4.05, −3.37)−3.65 (−4.16, −3.56)−0.12 (−0.33, 0.23)
   <15 IU/mL, n (%)1 (13)1 (13)1 (13)00
Day 8
   Median HCV RNA (Q1, Q3)−4.50 (−4.66, −4.24)−4.55 (−4.97, −4.13)−4.65 (−4.78, −4.17)−4.43 (−4.81, −4.13)0.07 (−0.16, 0.19)
   <15 IU/mL, n (%)03 (38)5 (63)00
Day 15
   Median HCV RNA (Q1, Q3)−5.21 (−5.76, −4.71)−5.15 (−5.54, −4.61)−5.02 (−5.37, −4.49)−4.99 (−5.37, −4.66)−0.04 (−0.55, 0.28)
   <15 IU/mL, n (%)4 (50)8 (100)7 (88)5 (63)0

Measurements on Days 4, 8, and 15 are predosing and reflect 3, 7, and 14 days of dosing.

Sofosbuvir with its potent pan-genotypic activity is under development as the cornerstone of multiple regimens across all HCV genotypes including combination with pegylated interferon and ribavirin, ribavirin and with various DAAs with different mechanisms of action, including NS5a inhibitors, NS3 protease inhibitors and a non-nucleoside inhibitor. Sofosbuvir fulfils the major attributes of a cornerstone agent in that it (i) has a high barrier to resistance, (ii) is highly potent, (iii) provides once daily dosing and (iv) is pan-genotypic. Promising results from phase 2 studies suggest that sofosbuvir in combination with ribavirin or peginterferon and ribavirin can provide high rates of SVR in patients with genotype 1, 2, 3, 4 and 6 infections.[22–24] GS-0938 is no longer in clinical development due to safety concerns (elevated ALT levels) that arose in a subsequent phase 2 study; all treatment arms containing GS-0938 were halted.

In conclusion, treatment with the HCV nucleoside inhibitors sofosbuvir and GS-0938—alone and in combination—led to rapid and substantial reductions in viral load without any incidences of viral breakthrough. Sofosbuvir demonstrated potent HCV RNA suppression when administered alone for 7 days, an antiviral effect almost double that observed with GS-9851 at the same dose. Sofosbuvir is currently in phase 3 clinical development as a possible backbone of multiple anti-HCV regimens for chronic hepatitis C.

  • Abstract and Introduction
  • Experimental Procedures
  • Results 
  • Discussion

  • References
    1. McHutchison JG, Lawitz EJ, Shiffman ML et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009; 361: 580–593.
    2. Poordad F, McCone J Jr, Bacon BR et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364: 1195–1206.
    3. H_ezode C. Boceprevir and telaprevir for the treatment of chronic hepatitis C: safety management in clinical practice. Liver Int 2012; 32(Suppl 1): 32–38.
    4. Sulkowski MS, Cooper C, Hunyady B et al. Management of adverse effects of Peg-IFN and ribavirin therapy for hepatitis C. Nat Rev Gastroenterol Hepatol 2011; 8: 212–223.
    5. Lok AS, Gardiner DF, Lawitz E et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med 2012; 366: 216–224.
    6. Chayama K, Takahashi S, Toyota J et al. Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asuna- previr, in hepatitis C virus genotype 1b-infected null responders. Hepatology 2012; 55: 742–748.
    7. Sarrazin C, Zeuzem S. Resistance to direct antiviral agents in patients with hepatitis C virus infection. Gastroenterology 2010; 138: 447–462.
    8. Lam AM, Espiritu C, Bansal S et al. Genotype and subtype profiling of PSI-7977 as a nucleotide inhibitor of hepatitis C virus. Antimicrob Agents Chemother 2012; 56: 3359–3368.
    9. Lam AM, Espiritu C, Bansal S et al. Hepatitis C virus nucleotide inhibitors PSI-352938 and PSI-353661 exhibit a novel mechanism of resistance requiring multiple mutations within replicon RNA. J Virol 2011; 85: 12334–12342.
    10. Lam AM, Espiritu C, Murakami E et al. Inhibition of hepatitis C virus replicon RNA synthesis by PSI- 352938, a cyclic phosphate prodrug of b-D-2'-deoxy-2'-a-fluoro-2'-b-Cmethylguanosine. Antimicrob Agents Chemother 2011; 55: 2566–2575.
    11. Zennou V, Lam A, Keilman M et al. Combination of two complementary nucleotide analogues PSI-7977 and PSI-938 effectively clears wild type and NS5B:S282T HCV replicons - comparisons with combinations of other antiviral compounds. J Hepatol 2010; 52(Suppl 1): S400.
    12. Rodriguez-Torres M, Lawitz E, Denning J et al. PSI-352938, a novel purine nucleotide analog, exhibits potent antiviral activity and no evidence of resistance in patients with HCV genotype 1 over 7 days. J Hepatol 2011; 54(Suppl 1): S488.
    13. Lawitz E, Rodriguez-Torres M, Denning JM et al. Pharmacokinetics, pharmacodynamics, and tolerability of GS-9851, a nucleotide analog polymerase inhibitor, following multiple ascending doses in patients with chronic hepatitis C infection. GS-9381 Antimicrob Agents Chemother 2013; 57: 1209–1217.
    14. Lawitz E, Lalezari J, Rodriguez-Torres M et al. High rapid virologic response (RVR) with PSI-7977 QD plus PEG-IFN/RBV in a 28-day phase 2A trial. Hepatology 2010; 52 (Suppl 1): 181A.
    15. Sofia MJ, Bao D, Chang W et al. Discovery of a b-d-2'-deoxy-2'-a-fluoro- 2'-b-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus. J Med Chem 2010; 53: 7202–7218.
    16. Lam AM, Murakami E, Espiritu C et al. PSI-7851, a pronucleotide of beta-D-2'-deoxy-2'-fluoro-2'-C-methyluridine monophosphate, is a potent and pan-genotype inhibitor of hepatitis C virus replication. Antimicrob Agents Chemother 2010; 54: 3187– 3196.
    17. Reddy PG, Bao D, Chang W et al. 2'-deoxy-2'-a-fluoro-2'-b-C-methyl 3',5'-cyclic phosphate nucleotide prodrug analogs as inhibitors of HCV NS5B polymerase: discovery of PSI-352938. Bioorg Med Chem Lett 2010; 20: 7376–7380.
    18. Forestier N, Larrey D, Guyader D et al. Treatment of chronic hepatitis C patients with the NS3/4A protease inhibitor danoprevir (ITMN- 191/RG7227) leads to robust reductions in viral RNA: a phase 1b multiple ascending dose study. J Hepatol 2011; 54: 1130–1136.
    19. de Bruijne J, van Vliet A, Weegink CJ et al. Rapid decline of viral RNA in chronic hepatitis C patients treated once daily with IDX320: a novel macrocyclic HCV protease inhibitor. Antivir Ther 2012; 17: 633–642.
    20. Reesink HW, Fanning GC, Farha KA et al. Rapid HCV-RNA decline with once daily TMC435: a Phase I study in healthy volunteers and hepatitis C patients. Gastroenterology 2010; 138: 913–921.
    21. Lawitz E, Poordad F, DeJesus E et al. ABT-450/ritonavir (ABT-450/r) combined with pegylated interferon alpha-2a/ribavirin (P/R) after 3-day monotherapy in HCV Genotype 1 (GT1)-infected treatment-naive subjects: 12-week sustained virologic response (SVR12) and safety results. Presented at the 47th Annual European Association for the Study of the Liver meeting from April 18th- 22nd 2012 in Barcelona, Spain.
    22. Kowdley K, Lawitz E, Crespo I et al. ATOMIC: 97% RVY for PSI- 7977 + PEG/RBV 9 12 week regimen in HCV GT1: an end to response-guided therapy? Presented at: 47th Annual Meeting of the European Association for the Study of the Liver (EASL); 2012 April 18– 22; Barcelona, Spain. J Hepatol 2012; 56: S1.
    23. Lawitz E, Lalezari JP, Hassanein T et al. PROTON: PSI-7977 & Peg/RBV in treatment-naive patients with HCV GT1: sustained virologic response. 62nd Annual Meeting of the American Association for the Study of Liver Diseases; 2011 November 4–8; San Francisco, CA.
    24. Gane EJ, Stedman CA, Hyland RH et al. Once daily PSI-7977 plus RBV: pegylated interferon-alfa not required for complete rapid viral response in treatment-naive patients with HCV GT2 or GT3. 62nd Annual Meeting of the American Association for the Study of Liver Disease 2011 November 4–8; San Francisco, CA.

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