Efficacy of Nucleotide Polymerase Inhibitor Sofosbuvir Plus the NS5A Inhibitor Ledipasvir or the NS5B Non-Nucleoside Inhibitor GS-9669 Against HCV Genotype 1 Infection

Gastroenterology 2014;146:736–743

Efficacy of Nucleotide Polymerase Inhibitor Sofosbuvir Plus the NS5A Inhibitor Ledipasvir or the NS5B Non-Nucleoside Inhibitor GS-9669 Against HCV Genotype 1 Infection Edward J. Gane,1 Catherine A. Stedman,2 Robert H. Hyland,3 Xiao Ding,3 Evguenia Svarovskaia,3 G. Mani Subramanian,3 William T. Symonds,3 John G. McHutchison,3 and Phillip S. Pang3 CLINICAL LIVER

1 New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand; 2Gastroenterology Department, Christchurch Hospital and University of Otago, Christchurch, New Zealand; and 3Gilead Sciences, Inc, Foster City, California

BACKGROUND & AIMS: We evaluated an all-oral regimen comprising the nucleotide polymerase inhibitor sofosbuvir (SOF) with the NS5A inhibitor ledipasvir (LDV) or the NS5B non-nucleoside inhibitor GS-9669 in patients with genotype 1 hepatitis C virus (HCV) infection. METHODS: A total of 113 patients were enrolled. Sofosbuvir (400 mg once daily) and LDV (90 mg once daily) plus ribavirin (RBV) were given for 12 weeks to treatment-naïve (TN) patients (n ¼ 25) and those who did not respond to previous therapy (prior null responders, n ¼ 9). Sofosbuvir and GS-9669 (500 mg once daily) plus RBV were given for 12 weeks to TN patients (n ¼ 25) and prior null responders (n ¼ 10). Additionally, prior null responders with cirrhosis were randomly assigned to groups given a fixed-dose combination of SOF and LDV, with RBV (n ¼ 9) or without RBV (n ¼ 10). Finally, a group of TN patients received SOF, LDV, and RBV for 6 weeks (n ¼ 25). The primary efficacy end point was sustained virologic response 12 weeks after therapy (SVR12). RESULTS: SVR12 was achieved by 25 of 25 (100%) TN patients receiving SOF, LDV, and RBV and 23 of 25 (92%) of those receiving SOF, GS-9669, and RBV. Of TN patients receiving 6 weeks of SOF, LDV, and RBV, 17 of 25 (68%) achieved SVR12. All noncirrhotic prior null responders receiving 12 weeks of SOF along with another direct-acting antiviral agent plus RBV achieved SVR12—9 of 9 (100%) of those receiving SOF, LDV, and RBV and 10 of 10 (100%) of those receiving SOF, GS-9669, and RBV. Among cirrhotic prior null responders, SVR12 was achieved by 9 (100%) of those receiving SOF, LDV, and RBV and 7 (70%) of those receiving SOF and LDVD without RBV. The most common reported adverse events were headache, fatigue, and nausea. CONCLUSIONS: The combination of SOF and a second direct-acting antiviral agent is highly effective in TN patients with HCV genotype 1 infection and in patients that did not respond to previous treatment. ClinicalTrials.gov ID NCT01260350.

peginterferon and ribavirin (RBV) for 24 to 48 weeks. Such triple therapy can cure up to 75% of eligible treatmentnaïve (TN) patients; however, these regimens are less effective in treatment-experienced patients, especially in those with advanced liver disease.2–5 Only 14% of prior null responders with cirrhosis achieved sustained virologic response after 12 months of telaprevir combination therapy.6 In post-approval studies in previously treated patients with cirrhosis, there has been a number of cases of serious adverse events and treatment-related serious adverse events, including anemia, rash, serious infection, decompensation, and death.7 In addition, many patients are not eligible for interferon-based regimens because of relative or absolute contraindications to interferon.8,9 Finally, protease inhibitorbased therapy is complex, requiring the treating practitioner to monitor for on-treatment virologic response to provide appropriate response-guided therapy.7,10 A recent review on expanding access to HCV treatment called for a “safer, simpler, and more effective therapy.”11 Sofosbuvir (SOF) is a uridine nucleotide analogue inhibitor of the HCV NS5B polymerase.12–14 In 2 earlier arms of the ELECTRON trial, 25 TN and 10 null responder patients were treated with 12 weeks of SOF and RBV.15 Twenty-one (84%) of the TN patients, but only 1 (10%) of the null responder patients, achieved SVR12 with this regimen. We hypothesized that adding a second directacting antiviral agent (DAA) with a different mechanism of action would enhance rates of response. Ledipasvir (LDV), an inhibitor of the HCV-encoded NS5A protein, which is essential for HCV RNA replication, post-replication assembly, and secretion, has picomolar potency against HCV genotype 1a and 1b.16 GS-9669, a non-nucleoside inhibitor of HCV NS5B binding at thumb site II of the polymerase, has nanomolar potency against HCV genotype 1a and 1b.17

Keywords: DAA; Drug; Clinical Trial; Liver Cirrhosis.

O

f the 6 major genotypes of the hepatitis C virus (HCV), genotype 1 is the most prevalent worldwide and the most difficult to cure.1 The standard of care for patients with genotype-1 infection is an HCV protease inhibitor, either boceprevir or telaprevir, combined with

Abbreviations used in this paper: DAA, direct-acting antiviral; HCV, hepatitis C virus; LDV, ledipasvir; RBV, ribavirin; SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks post therapy; TN, treatment-naïve. © 2014 by the AGA Institute 0016-5085/$36.00 http://dx.doi.org/10.1053/j.gastro.2013.11.007

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Methods Patients and Study Design We enrolled patients at 2 centers in New Zealand during the period from June 2012 to May 2013 (ClinicalTrials.gov ID NCT01260350). Eligible patients were men and women older than 18 years of age, chronically infected with genotype 1 HCV (serum HCV RNA >50,000 IU/mL). There was no upper limit for body mass index or age and opiate substitution therapy was allowed. Patients testing positive for hepatitis B surface antigen, hepatitis B core immunoglobulin M antibodies, or antibodies against human immunodeficiency virus were excluded. SOF, LDV, and GS-9669 (Gilead Sciences, Foster City, CA) were all orally administered once daily at doses of 400 mg, 90 mg, and 500 mg, respectively. Three of the treatment arms used the fixed-dose combination of SOF and LDV. Ribavirin (Ribasphere; Kadmon, New York, NY) was orally administered as a divided dose according to body weight (1000 mg daily in patients with a body weight <75 kg and 1200 mg daily in patients with a body weight 75 kg). Four groups of noncirrhotic, genotype 1 HCV patients were initially enrolled: 25 TN patients and 9 patients with documented null response to prior interferon treatment were enrolled to receive SOF and LDV plus RBV for 12 weeks. Twenty-five TN and 10 patients with documented null response (a decline of <2 log10 IU/mL in HCV RNA after previous treatment with 12 weeks of peginterferon and RBV) to prior interferon treatment were enrolled to receive SOF and GS9669, plus RBV for 12 weeks. Subsequently, 19 patients with documented null response to prior interferon treatment and cirrhosis were randomized 1:1 to receive 12 weeks of either SOF/LDV or SOF/LDV plus RBV. We used a computergenerated randomization sequence; allocation to treatment was done sequentially and communicated to the site by e-mail based on the randomization sequence. Finally, 25 noncirrhotic TN patients were enrolled to receive SOF/LDV plus RBV for 6 weeks (Supplementary Figure 1). All patients provided informed consent. The study was approved by the Institutional Review Boards at both participating sites and was conducted in compliance with the Declaration of Helsinki, Good Clinical Practice guidelines, and local regulatory requirements. The study was designed and conducted by the sponsor in collaboration with the principal investigators. The sponsor collected the data and monitored the study conduct. All authors had access to the study data and had reviewed and approved the final manuscript. The investigators, participating institutions, and sponsor agreed to maintain confidentiality of the data.

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Study Assessments Serum HCV RNA levels were measured with the Roche COBAS AmpliPrep/COBAS TaqMan HCV Test, Research Use Only version with a lower limit of quantification of 43 IU/mL. The assay was validated by the central laboratory with a limit of detection of 15 IU/mL, defined by a 95% hit rate with World Health Organization standards. Serum HCV RNA levels were measured at the time of screening, at baseline, weekly throughout the 8- or 12-week treatment period, and at 2, 4, 8, 12, and 24 weeks post treatment. Serum or plasma samples obtained at each time point were stored for drug-resistance monitoring. Standard population or deep sequencing (assay cut-off at 1%) of the full-length NS5A and/or NS5B region was performed at baseline for all patients, and at viral relapse for patients who did not achieve SVR due to virologic failure or early discontinuation and who had HCV RNA 1000 IU/mL. In cases where amplification of full-length NS5B failed, sequencing of a short-fragmentcontaining coding region for S282 amino acid position was attempted. Phenotypic analyses were performed of select samples using a chimeric replicon encoding the NS5A or NS5B region derived from patient plasma/serum. We measured vital signs and conducted electrocardiograms and symptom-directed physical examinations. In addition, blood and urine samples were taken for laboratory assessments. All adverse events were recorded and graded according to standardized scales.

Statistical Methods This study was not designed to evaluate formal statistical hypotheses, and no sample size calculations were performed. Adverse events, vital signs, laboratory tests, magnitude of HCV RNA decline, and rates of on-treatment and post-treatment virologic response were descriptively compared across the treatment groups. The point estimate and 95% exact confidence interval of the response rates were calculated. This was an open-label study.

Results Patient Characteristics Baseline characteristics are presented in Table 1. Eightythree percent of patients were infected with HCV subtype 1a. A higher prevalence of non-CC IL28B genotype was observed in prior null responders. Because this trial is being conducted in New Zealand, it has enrolled few black and Hispanic patients.

Virologic Response On-treatment virologic response. Patients in all treatment groups experienced rapid viral suppression after initiating treatment (Figure 1), with mean declines across arms ranging from 3.9 to 4.5 IU/mL at the end of week 1. All patients had HCV RNA <15 IU/mL by week 6 of treatment, which they maintained until the end of treatment. Sustained virologic response. Rates of SVR12 by treatment arm are shown in Table 2. Of the 50 TN patients receiving 12 weeks of SOF along with another DAA plus RBV, 48 (96%) achieved SVR12; 25 of 25 (100%) of those

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We report results from 7 arms of the ongoing ELECTRON trial. These arms were designed to evaluate the safety and efficacy of SOF along with LDV or GS-9669 plus RBV in noncirrhotic TN and previously treated HCV genotype 1infected patients, and of the SOF/LDV fixed-dose combination with and without RBV in cirrhotic prior null responders, and of 6 weeks of SOF/LDV with RBV in TN patients. The primary efficacy end point was sustained virologic response, defined as HCV RNA below the limit of detection (15 IU/mL), 12 weeks after the end of therapy (SVR12).

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Table 1.Baseline Characteristics Treatment-naïve patients

Previously treated patients

12 Weeks 12 Weeks 12 Weeks 12 Weeks 12 Weeks SOF þ 6 Weeks 12 Weeks SOF þ SOF/LDVa SOF/LDVa þ a SOF þ LDV þ GS-9669 þ SOF/LDV þ SOF þ LDV þ GS-9669 þ cirrhotic RBV cirrhotic RBV (n ¼ 25) RBV (n ¼ 25) RBV (n ¼ 25) RBV (n ¼ 9) RBV (n ¼ 10) (n ¼ 10) (n ¼ 9)

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Age, y, mean (SD) Patient sex, n (%) Male Female Patient race, n (%) White Asian Pacific Islander Other BMI, mean (SD) HCV RNA, mean (SD) HCV RNA >6 log10, n (%) HCV genotype, n (%) 1a 1b IL28b genotype, n (%) CC CT TT

45 (9.2)

46 (9.3)

51 (9.0)

50 (13.0)

55 (6.0)

61 (4.9)

57 (5.2)

8 (32) 17 (68)

13 (52) 12 (48)

13 (52) 12 (48)

7 (78) 2 (22)

7 (70) 3 (30)

10 (100) 0

8 (89) 1 (11)

23 (92) 0 1 (4) 1 (4) 25.2 (4.3) 5.9 (0.9) 14 (56)

20 (80) 1 (4) 0 4 (16) 26.5 (3.9) 6.3 (0.5) 17 (68)

22 (88) 0 1 (4) 2 (8) 25.9 (4.1) 6.5 (0.6) 19 (76)

20 (80) 5 (20)

21 (84) 4 (16)

21 (84) 4 (16)

8 (89) 1 (11)

9 (90) 1 (10)

8 (80) 2 (20)

7 (78) 2 (22)

9 (36) 14 (56) 2 (8)

7 (28) 14 (56) 4 (16)

5 (20) 15 (60) 5 (20)

0 7 (78) 2 (22)

1 (10) 8 (80) 1 (10)

4 (40) 4 (40) 2 (20)

2 (22) 5 (56) 2 (22)

9 (100) 0 0 0 25.6 (2.3) 6.9 (0.2) 9 (100)

9 (90) 0 0 1 (10) 29.6 (6.1) 7.0 (0.4) 10 (100)

8 (80) 0 0 2 (20) 31.0 (6.8) 6.5 (0.6) 8 (80)

9 (100) 0 0 0 27.3 (5.0) 6.3 (0.8) 6 (67)

BMI, body mass index. a SOF/LDV ¼ fixed-dose combination of sofosbuvir 400 mg and ledipasvir 90 mg.

receiving SOF and LDV plus RBV, and 23 of 25 (92%) of those receiving SOF and GS-9669 plus RBV. Of note, of the 2 TN patients who relapsed, 1 was later found to be a case of reinfection. Enrollment of TN patients to receive 6 weeks of SOF and LDV plus RBV, which had been contingent on patients in the 12-week arm achieving an SVR4 rate of at

least 90%, was conducted and 17 of 25 (68%) of patients achieved SVR12. Among previously treated patients, all noncirrhotic prior null responders receiving 12 weeks of SOF along with another DAA plus RBV achieved SVR12; 9 of 9 (100%) of those receiving SOF and LDV plus RBV, and 10 of 10 (100%) of those receiving SOF and GS-9669 plus RBV.

Figure 1. HCV RNA levels during the first 8 weeks of treatment.

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Table 2.Virologic Response During and After Treatment Treatment-naïve patients

Previously treated patients

RVRa 95% CI SVR4 95% CI SVR12 95% CI Virologic failure On-treatment Relapse a

25 (100) 86 to 100 25 (100) 86 to 100 25 (100) 86 to 100

23 (92) 74 to 99 23 (92) 74 to 99 23 (92) 74 to 99

25 (100) 86 to 100 22 (88) 69 to 97 17 (68) 47 to 85

8 (89) 52 to >99 9 (100) 66 to 100 9 (100) 66 to 100

10 (100) 69 to 100 10 (100) 69 to 100 10 (100) 69 to 100

8 (80) 44 to 98 8 (80) 44 to 98 7 (70) 35 to 93

6 (67) 30 to 93 9 (100) 66 to 100 9 (100) 66 to 100

0 0

0 2 (8)b

0 8 (32)

0 0

0 0

0 3 (30)

0 0

RVR ¼ rapid virologic response, HCV RNA <15 IU/mL at week 4 of treatment. One of the patients classified as having relapsed was in fact reinfected with genotype 3a HCV.

b

Among cirrhotic prior null responders, SVR12 was achieved by 9 (100%) of those receiving SOF/LDV with RBV and 7 (70%) of those receiving SOF/LDV without RBV. The patient numbers across the different arms were not large enough to allow analysis of the impact of traditional baseline predictors of response (age, sex, presence of cirrhosis, IL28B genotype, viral load, HCV subtype) on virologic response rates, but no differences in response by subgroup were evident. Virologic failure. No patient in any treatment group experienced virologic failure when on treatment. A total of 13 patients completed treatment but did not achieve SVR12; 12 had virologic relapse and 1 was reinfected. In none of the 12 patients who relapsed was the S282T mutation detectable at baseline or at time of relapse. The one patient who relapsed after receiving 12 weeks of SOF and GS-9669 plus RBV did not have any detectable non-nucleoside NS5B-resistant variants at either baseline or time of relapse. Of the 3 cirrhotic prior null responders receiving SOF/LDV, 2 had no NS5A-resistant variants at baseline, and 1 had Q30H (>99%) at baseline; all 3 had NS5A-resistant variants at time of relapse. None of the 8 patients receiving 6 weeks of SOF/LDV plus RBV had any NS5Aresistant variant at baseline. Also, NS5A-resistant variants were not detected in 6 of 8 patients at relapse time points. Two subjects had NS5A-resistanceassociated variants detectable at the time of relapse with Q30R (31%) detected in 1 patient and L31M (>99%) detected in the other patient. The patient with confirmed reinfection was a TN patient with HCV genotype 1a receiving 12 weeks of SOF and GS9669 plus RBV. This patient had HCV RNA <15 IU/mL at post-treatment week 2, but had confirmed reinfection with HCV genotype 3a at post-treatment week 4. The presumed route of reinfection was intravenous drug use. Of note, the patient’s partner was infected with HCV genotype 3a.

Safety and Tolerability Overall, 93% of patients experienced at least 1 adverse event during treatment. The most common adverse events

were headache, fatigue, and nausea. The lowest incidence of adverse events (70%) was in the group of null responder patients with cirrhosis receiving 12 weeks of SOF/LDV without RBV (Table 3). Most of the adverse events were mild in severity. Overall, 5 patients experienced severe adverse events: 3 TN patients receiving SOF and LDV plus RBV for 12 weeks and 2 TN patients receiving SOF and GS-9669 plus RBV for 12 weeks. Of these, the only severe event considered related to treatment was grade 3 hemolytic anemia—a known side effect of RBV—in 1 patient from each of the 2 groups. Of the 113 patients treated, 1 discontinued treatment after 7 weeks due to an adverse event. This event—peritonitis secondary to spontaneous perforation of a colonic diverticulum in a TN patient receiving SOF and LDV plus RBV—was judged serious, but was not thought to be related to treatment. Despite discontinuation of all treatment at the time of emergency laparotomy, this patient achieved SVR12 and SVR24. The only other serious adverse event in the study was pyelonephritis in a TN patient receiving 12 weeks of SOF and LDV plus RBV. The only grade 4 laboratory abnormality was prolonged prothrombin time in a patient taking warfarin after mitral valve surgery. The only grade 3 laboratory abnormalities detected were decreased hemoglobin, prolonged prothrombin time, and hematuria (Table 3). All groups receiving RBV experienced mean reductions of hemoglobin of 2.0 IU/mL to 3.5 IU/mL at the end of treatment. Hemoglobin levels in the only group not receiving RBV—cirrhotic prior null responders receiving the SOF/LDV—did not decline during treatment (Figure 2). Four patients—2 TN patients receiving SOF/RBV and RBV and 2 TN patients receiving SOF with GS-9669 and RBV—had grade 3 prolonged prothrombin time, but all 4 events were unconfirmed. Grade 3 microscopic hematuria was detected in 16 patients, 9 TN patients receiving SOF and LDV plus RBV and 7 TN patients receiving SOF and GS-9669 plus RBV. Urinalysis was performed weekly throughout the study and in all cases, the hematuria was an isolated event, not confirmed on subsequent visits. All but one of the patients with

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12 Weeks 12 Weeks 12 Weeks 12 Weeks SOF þ 6 Weeks 12 Weeks 12 Weeks SOF/LDV SOF/LDV þ RBV SOF þ LDV þ GS-9669 þ SOF/LDV þ SOF þ LDV þ SOF þ GS-9669 þ cirrhotic cirrhotic (n ¼ 9) RBV (n ¼ 25) RBV (n ¼ 25) RBV (n ¼ 25) RBV (n ¼ 9) RBV (n ¼ 10) (n ¼ 10)

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Table 3.Adverse Events, Discontinuations Due to Adverse Events, and Laboratory Abnormalities

12 Weeks SOF þ LDV þ RBV (n ¼ 25)

12 Weeks SOF þ GS-9669 þ RBV (n ¼ 25)

6 Weeks SOF/LDV þ RBV (n ¼ 25)

12 Weeks SOF þ LDV þ RBV (n ¼ 9)

12 Weeks SOF þ GS-9669 þ RBV (n ¼ 10)

12 Weeks SOF/LDV cirrhotic (n ¼ 10)

12 Weeks SOF/LDV þ RBV cirrhotic (n ¼ 9)

24 (96) 3 (12) 1 (4)

25 (100) 2 (8) 0

22 (88) 0 0

9 (100) 0 0

10 (100) 0 0

7 (70) 0 0

8 (89) 1 (11) 0

(40) (50) (20) (20) (10) (10) (10) (20) 0 0 1 (10) 0 0 0 0 0 0 1 (10) 0 0 0 0

3 (30) 1 (10) 0 1 (10) 0 0 0 0 0 0 0 0 0 0 1 (10) 0 0 0 0 0 0 2 (22)

2 1 4 1 1 2

11 6 6 9 4 1 4 5

(44) (24) (24) (36) (16) (4) (16) (20) 0 2 (8) 4 (16) 0 5 (20) 4 (16) 3 (12) 3 (12) 4 (16) 2 (8) 1 (4) 2 (8) 0 0

8 4 9 3 3 9 5 2 1 4

2 1 1 1 1 1

1

(32) (16) (36) (12) (12) (36) (20) (8) (4) (16) 0 0 (8) (4) (4) (4) 0 (4) (4) 0 0 (4)

8 6 5 3 6 3 3 1 1 1

(32) (24) (20) (12) (24) (12) (12) (4) (4) (4) 0 0 1 (4) 3 (12) 1 (4) 0 0 3 (12) 0 0 0 0

6 7 3 3 4 1 1 1 1 2 1 1 3 2 3 2 3 2 1

(67) (78) (33) (33) (44) (11) (11) 0 (11) (11) (22) 0 (11) (11) (33) (22) 0 (33) (22) (33) (22) (11)

4 5 2 2 1 1 1 2

2 2 1 2 1

1 2

(22) (11) (44) (11) (11) (22) 0 (22) (22) 0 (11) (22) (11) 0 0 0 (11) 0 (22) 0 0 0

13 (52) 0

12 (48) 1 (4)

9 (36) 0

2 (22) 0

1 (10) 0

0 0

0 0

5 (20)

4 (16)

9 (36)

2 (22)

1 (10)

0

0

2 (8) 0

2 (8) 1 (4)

0 0

0 0

0 0

0 0

0 0

9 (36)

7 (28)*

0

0

0

0

0

NOTE. Data are n (%). AE, adverse event. a Events that occurred in 15% of patients in each cohort.

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Patients with 1 AE Grade 3 or 4 AEs AEs leading to discontinuation from any study drug Most common adverse eventsa Headache Fatigue Nausea Upper respiratory tract infection Insomnia Vomiting Rash Arthralgia Anxiety Diarrhea Depression Conjunctivitis Dry skin Irritability Cough Dizziness Dyspnea Oropharyngeal pain Gastroesophageal reflux disease Myalgia Skin fissures Gastroenteritis Laboratory abnormalities Any grade 3 abnormality Any grade 4 abnormality Hemoglobin Grade 3 Prothrombin time Grade 3 Grade 4 Hematuria Grade 3

Previously treated patients

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Figure 2. The figure shows mean hemoglobin during treatment among prior null responders receiving SOF/ LDVFDC or SOF/LDVFDC plus RBV.

hematuria were women and menstruation is assumed to be the likely cause. One null responder patient with cirrhosis receiving SOF/LDV had grade 3 elevations in lipase during post-treatment follow-up.

Discussion The results of this study demonstrated that 12 weeks of treatment with SOF in combination with another DAA agent has the potential to provide safe and effective treatment of patients with HCV genotype 1, including difficult to cure patients. Rates of SVR were high across all study populations, and factors historically associated with reduced response to treatment—the presence of cirrhosis, null response to prior interferon treatment, non-CC IL28b alleles—did not appear to be associated with reduced response to these combinations. In contrast, the response rate of 68% observed with 6 weeks of therapy with SOF/LDV þ RBV, in TN noncirrhotic subjects suggests that a longer duration of therapy, or additional potency, is required for optimal efficacy. In all clinical studies conducted to date, SOF has been well tolerated without any specific toxicity or safety issues. The adverse event profile for SOF plus RBV appears to be similar to that of RBV monotherapy. In this current study, the addition of either LDV or GS-9669 to SOF did not appear to be associated with any new safety issues. The only arm that did not include RBV—cirrhotic prior null responders receiving 12 weeks of SOF-LDV—had a lower overall rate of adverse events than did the RBV-containing arms (70% vs 92%100%). It is not clear from our results if the possible benefits of RBV outweigh the adverse consequences associated with its use. In this study, we evaluated the nucleotide NS5B polymerase inhibitor SOF in combination with DAA agents from 2 other classes—the NS5A inhibitor LDV or the non-nucleoside NS5B polymerase inhibitor GS-9669. The idea behind

combining 2 or more antiviral agents to treat HCV is based on the assumption that multiple agents with distinct mechanisms of action can provide more comprehensive viral suppression than monotherapy with any single agent.18 In addition, the use of agents with complementary resistance profiles can lessen the likelihood of viral escape and the subsequent development of populations of resistant variants. Both LDV and GS-9669 are active against S282T, the only variant known to reduce susceptibility to SOF.19,20 The high rates of response (and low rates of relapse) observed in some arms of this study appear to support these assumptions, as do recently published results from the LONESTAR trial, in which genotype-1 TN patients receiving 8 weeks of SOF and LDV with and without RBV or 12 weeks of SOF and LDV, and genotype-1 patients who did not achieve SVR with a protease inhibitor regimen (more than half of whom had cirrhosis) receiving 12 weeks of SOF and LDV with and without RBV achieved SVR rates of 95% to 100%.21 To our knowledge, this is one of the first studies of an interferon-free regimen for patients with hepatitis C to include patients with cirrhosis who had shown null response to prior pegylated interferon and RBV treatment; in the LONESTAR study, patients with cirrhosis who were prior treatment failures to protease inhibitor triple therapy were treated with 12 weeks of a SOF/LDV-containing regimen; in the COSMOS study, patients with cirrhosis who had shown null response to prior pegylated interferonþRBV treatment are being treated with 12 and 24 weeks of an SOFþsimeprevir-containing regimen. Cirrhotic patients treated with 12 weeks of SOFþsimeprevir with and without RBV had SVR4 rates of 96% (26 of 27) and 100% (14 of 14), respectively. Such patient groups have been among the most difficult to cure. Prior null responder patients with cirrhosis receiving telaprevir triple therapy for 48 weeks had an SVR rate of only 14%. Other favorable

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features of the SOF regimens evaluated in this study include simplicity and tolerability. Another important benefit of these interferon-free regimens is that they can be extended to the critical population of patients who are not suitable for interferon treatment. The limitations of this study include its small size, openlabel design, and lack of a control arms. These limitations preclude subgroup analysis, comparison among groups, and direct comparison to historical results. The results of this trial appear to lend further support to the potential role of SOF as the backbone of future regimens. Ongoing phase 3 studies with the fixed-dose combination of SOF/LDV will determine the optimal duration of therapy and whether RBV is required when SOF is combined with LDV in TN and treatment-experienced HCV genotype 1infected patients, with and without cirrhosis.

Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Gastroenterology at www.gastrojournal.org, and at http://dx.doi.org/10.1053/ j.gastro.2013.11.007.

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12.

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18. 19.

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from the first experience in a real world setting. PLOS One 2013;8. Aronsohn A, Jensen D. Expanding access to HCV care: a call to deconstruct individualized therapy. Hepatology 2013 Jun 20. http://dx.doi.org/10.1002/hep.26590. [Epub ahead of print]. Lawitz E, Lalezari JP, Hassanein T, et al. Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, doubleblind, phase 2 trial. Lancet Infect Dis 2013;13:401–408. Kowdley KV, Lawitz E, Crespo I, et al. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatmentnaive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. Lancet 2013;381:2100–2107. Lawitz E, Mangia S, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013;368:1878–1887. Gane E, Stedman CA, Hyland RH, et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med 2013;368:34–44. Lawitz EJ, Gruener D, Hill JM, et al. A phase 1, randomized, placebo-controlled, 3-day, dose-ranging study of GS-5885, an NS5A inhibitor, in patients with genotype 1 hepatitis C. J Hepatol 2012;57:24–31. Lawitz E, Hazan L, Gruener D, et al. GS-9669, A novel NS5B non-nucleoside thumb site II inhibitor, demonstrates potent antiviral activity, favorable safety profile and potential for once-daily dosing. J Hepatol 2012;52(Suppl 2):S471. Manns MP, von Hahn T. Novel therapies for hepatitis C—one pill fits all? Nat Rev Drug Disc 2013;12:595–610. Cheng G, Peng B, Corsa A, et al. Antiviral activity and resistance profile of the novel HCV NS5A inhibitor GS5885. 47th Annual Meeting of the European Association for the Study of the Liver, April 1822, 2012, Barcelona, Spain. Dvory-Sobol H, Svarovskaia E, Gontcharova V, et al. Resistance analyses using deep and population sequencing after 3 day monotherapy with GS-9669, a novel non-nucleoside NS5B inhibitor in genotype 1 HCV patients. 48th Annual Meeting Annual Meeting of the European Association for the Study of the Liver, April 2428, 2013, The Netherlands, Amsterdam. Lawitz E, Poordad FF, Pang PS, et al. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naïve and previously treated patients with genotype 1 hepatitis C infection (LONESTAR): an open-label, randomised, phase 2 trial. Lancet, 2013 Nov 1. pii: S0140-6736(13)62121-2, http://dx.doi.org/10. 1016/S0140-6736(13)62121-2. [Epub ahead of print].

Received October 3, 2013. Accepted November 13, 2013. Reprint requests Address requests for reprints to: Edward J. Gane, MBChB, MD, FRACP, MNZM, New Zealand Liver Transplant Unit, Auckland City Hospital, Private Bag 1142, Auckland, New Zealand. e-mail: [email protected]; fax: 649529-4061.

Acknowledgments The authors thank the patients and their families, the research staff at Christchurch Clinical Studies Trust and Auckland Clinical Studies as well as Juan Betular and Ken Imamura of Gilead Sciences. Editorial assistance was provided by David McNeel and Kellie Chu of Gilead Sciences. Conflicts of interest The authors disclose the following: Edward J. Gane has received grants and done research for Gilead, served on the advisory boards of AbbVie,

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Boehringer Ingelheim, Gilead, Janssen, Novartis, Roche, Tibotec; has been a speaker for Gilead, Novartis, Roche, Tibotec; has patents with Gilead. Catherine A. Stedman has received grants and done research for Gilead; served on the advisory boards of Janssen and Roche. Robert H. Hyland, Xiao Ding, Evguenia Svarovskaia, G. Mani Subramanian, William T. Symonds, John G. McHutchison, and Phillip S. Pang are current employees of Gilead Sciences. Funding This trial was supported by Gilead Sciences.

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Supplementary Figure 1. Patient disposition.