Eric Lawitz, Fred F Poordad, Phillip S Pang, Robert H Hyland, Xiao Ding, Hongmei Mo, William T Symonds, John G McHutchison, Fernando E Membreno

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Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised,
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Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial Eric Lawitz, Fred F Poordad, Phillip S Pang, Robert H Hyland, Xiao Ding, Hongmei Mo, William T Symonds, John G McHutchison, Fernando E Membreno Summary Background Interferon-based treatment is not suitable for many patients with hepatitis C virus (HCV) infection because of contraindications such as psychiatric illness, and a high burden of adverse events. We assessed the efficacy and safety of an interferon-free regimen a fixed-dose combination of the nucleotide polymerase inhibitor sofosbuvir (400 mg) and the HCV NS5A inhibitor ledipasvir (90 mg), with and without ribavirin in patients with genotype-1 hepatitis C infection who were treatment-naive or previously treated with a protease-inhibitor regimen. Methods For this open-label study, we enrolled 100 adult patients ( 18 years) with HCV infection at a centre in the USA between Nov 2, 2012, and Dec 21, In cohort A, we used a computer-generated sequence to randomly assign (1:1:1; stratified by HCV genotype [1a vs 1b]) 60 non-cirrhotic, treatment-naive patients to receive sofosbuvir plus 8 weeks (group 1), sofosbuvir plus ledipasvir and ribavirin for 8 weeks (group 2), or sofosbuvir plus 12 weeks (group 3). In cohort B, we randomly allocated (1:1; stratified by genotype and presence or absence of cirrhosis) 40 patients who previously had virological failure after receiving a protease inhibitor regimen to receive sofosbuvir plus 12 weeks (group 4) or sofosbuvir plus ledipasvir and ribavirin for 12 weeks (group 5). 22 (55%) of 40 patients in cohort B had compensated cirrhosis. The primary endpoint was sustained virological response 12 weeks after treatment (SVR12), analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT Findings In cohort A, SVR12 was achieved by 19 (95%) of 20 patients (95% CI ) in group 1, by 21 (100%) of 21 patients (84 100) in group 2, and by 18 (95%) of 19 patients (74 100) in group 3. In cohort B, SVR12 was achieved by 18 (95%) of 19 patients (74 100) in group 4 and by all 21 (100%) of 21 patients (84 100) in group 5. Two patients had viral relapse; one patient was lost to follow-up after achieving sustained virological response 8 weeks after treatment. The most common adverse events were nausea, anaemia, upper respiratory tract infection, and headache. One patient in group five had a serious adverse event of anaemia, thought to be related to ribavirin treatment. Lancet 2014; 383: Published Online November 5, S (13) See Comment page 491 Texas Liver Institute and the University of Texas Health Science Center, San Antonio, TX, USA (Prof E Lawitz MD, Prof F F Poordad MD, F E Membreno MD); and Gilead Sciences Inc, Foster City, CA, USA (P S Pang MD, R H Hyland DPhil, X Ding PhD, H Mo PhD, W T Symonds PharmD, J G McHutchison MD) Correspondence to: Prof Eric Lawitz, Texas Liver Institute, University of Texas Health Science Center, 607 Camden Street, San Antonio, TX 78215; USA Interpretation These findings suggest that the fixed-dose combination of sofosbuvir-ledipasvir alone or with ribavirin has the potential to cure most patients with genotype-1 HCV, irrespective of treatment history or the presence of compensated cirrhosis. Further clinical trials are needed to establish the best treatment duration and to further assess the contribution of ribavirin. Funding Gilead Sciences. Introduction The treatment of patients with chronic hepatitis C virus (HCV) infection has evolved substantially since results from the first clinical trial of recombinant human interferon alfa for this disorder were published in 1986, 1 but one element of treatment has remained constant: regular injections of recombinant interferon alfa for durations of 6 months to 1 year. The disadvantages of interferon treatment are well known, from its onerous side-effects (asthenia, myalgia, influenza-like symptoms, cytopenia, and depression) to the inconvenience of weekly injections, and the many potential medical contra indications and other reasons for ineligibility, including the unwilling ness of many patients to receive interferon treatment because of side-effects. 2,3 Although protease inhibitor-containing regimens for patients with genotype 1 HCV (both approved in 2011) weeks of peginterferon and ribavirin with weeks of a protease inhibitor have achieved high rates of sustained virological response (SVR) in clinical trials, these trials excluded, by definition, the population of patients for whom interferon is not an option because of contraindications or intolerability. 4 7 Moreover, HCV protease inhibitors can sometimes cause additional and specific adverse events. In their wider clinical use outside of clinical trials, they have been shown to exacerbate the side-effects normally seen with peginterferon and ribavirin treatment. Serious adverse events associated Vol 383 February 8, with these regimens, especially in patients with cirrhosis, can also lead to premature treatment discontinuation. 8,9 Other limitations of protease inhibitors include their low barrier to the development of resistance, high pill burden, complex response-guided regimens, and drug drug interactions. Overall, less than half of diagnosed patients are eligible to receive protease inhibitor regimens. Those who do not achieve SVR with a protease inhibitor regimen have no treatment options at present. 10 Sofosbuvir (formerly known as GS-7977; Gilead Sciences, Foster City, CA, USA) is a nucleotide analogue inhibitor of the HCV NS5B polymerase that has been extensively studied in combination with peginterferon and ribavirin, as well as with other direct-acting antiviral agents in treatment-naive patients with genotype-1 HCV infection Ledipasvir (formerly known as GS-5885; Gilead Sciences) is a novel HCV NS5A inhibitor that has shown potent antiviral activity against genotypes 1a and 1b HCV infection, 16 and is active against HCV with the S282T mutation, the only variant known to reduce susceptibility to sofosbuvir. 17 Findings from a drug interaction study showed no clinically significant pharmacokinetic interactions between sofosbuvir and ledipasvir, with the investigators concluding that the two drugs could be given together without any dose adjustments. 18 The combination of sofosbuvir and was first assessed in treatment-naive and prior null responder patients with genotype-1 infection in the ELECTRON trial. 19 All 25 treatment-naive patients and all nine prior null responder patients who received 12 weeks of sofosbuvir and ledipasvir plus ribavirin in ELECTRON achieved SVR 12 weeks after discontinuation of treatment (SVR12). However, none of these patients had cirrhosis. The primary objective of the LONESTAR study was to assess the antiviral efficacy of a fixed-dose single-tablet combination of sofosbuvir and ledipasvir (sofosbuvir plus ledipasvir) with and without ribavirin, for 8 weeks or 12 weeks in treatment-naive patients with genotype-1 HCV, and for 12 weeks in patients with genotype 1 HCV who had not achieved SVR after receiving a proteaseinhibitor-containing regimen, half of whom had compensated cirrhosis. Methods Study design and participants For this two-cohort study, we enrolled patients with chronic genotype-1 HCV infection at one clinical site in the USA (Texas Liver Institute, San Antonio, TX). Screening for the trial began on Nov 2, 2012, with the last patient enrolled on Dec 21, Eligible patients were at least 18 years of age and had chronic genotype-1 HCV infection with serum HCV RNA concentrations of IU/mL or greater. Exclusion criteria included hepatic decompensation (as evidenced by the presence of ascites, encephalopathy, or a history of variceal haemorrhage), a body-mass index of 18 kg/m² or lower, or co-infection with hepatitis B virus or HIV. Patients in cohort A had not received any previous treatment for HCV. Patients in cohort B had had virological failure after treatment with an approved or investigational protease inhibitor regimen (which included peginterferon and ribavirin), but had not discontinued treatment due to an adverse event. About 50% of patients enrolled in cohort B could have compensated cirrhosis. We established the presence of cirrhosis by liver biopsy (eg, a Metavir score of 4 or an Ishak score of 5). For all patients, IL28B was determined by PCR amplification and sequencing of the rs singlenucleotide polymorphism. Before enrolment and before any study procedures were undertaken, written informed consent was obtained from all patients. The study was done in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Randomisation and masking We used a computer-generated randomisation sequence; allocation to treatment was done sequentially and communicated to the site by based on the randomisation sequence. XD (Gilead Sciences) generated the randomisation sequence and remained on the study as lead statistician. In cohort A, in which treatment-naive patients with HCV genotype-1 were randomly allocated in a 1:1:1 ratio to treatment groups 1, 2, or 3, randomisation was stratified by HCV genotype (1a vs 1b). In cohort B, in which patients with HCV genotype-1 who had failed a previous protease inhibitor regimen were randomly allocated in a 1:1 ratio to groups 4 or 5, randomisation was stratified by HCV genotype (1a vs 1b) and presence or absence of compensated cirrhosis. This was an openlabel study, so patients and investigators were not masked to treatment allocation. Procedures Patients in all treatment groups received a fixed-dose combination tablet containing 400 mg of sofosbuvir and 90 mg of ledipasvir ledipasvir) once daily with or without food. Ribavirin was given orally as a divided, weight-based daily dose (ie, patients weighing 75 kg received 1000 mg and those weighing 75 kg received 1200 mg). In cohort A, patients in group 1 received sofosbuvir plus 8 weeks; those in group 2 received sofosbuvir plus ledipasvir and ribavirin for 8 weeks; patients in group 3 received sofosbuvir plus 12 weeks. In cohort B, patients in group 4 received sofosbuvir plus ledipasvir without ribavirin for 12 weeks and those in group 5 received sofosbuvir plus for 12 weeks. After completion or early discontinuation of treatment, we followed-up patients for 24 weeks. We measured plasma HCV RNA concentrations using the COBAS TaqMan HCV Test (version 2.0) for use with the High Pure System (Roche; Indianapolis, IN, USA) with a lower limit of quantification for HCV RNA of less 516 Vol 383 February 8, 2014 116 patients screened 16 screened but not randomised 12 did not meet eligibility criteria 2 study enrolment had closed 2 withdrew consent 60 allocated to cohort A 40 allocated to cohort B 20 to group 1 8 weeks) 21 to group 2 ledipasvir and ribavirin for 8 weeks) 19 to group 3 12 weeks) 19 to group 4 12 weeks) 21 to group 5 ledipasvir and ribavirin for 12 weeks) 1 discontinued treatment and lost to follow-up* 20 completed treatment 21 completed treatment 18 completed treatment 19 completed treatment 21 completed treatment 20 returned for posttreatment 21 returned for posttreatment 18 returned for posttreatment 19 returned for posttreatment 21 returned for posttreatment Figure 1: Trial profile *This patient, who discontinued treatment due to withdrawal of consent, had HCV RNA LLOQ at post-treatment weeks 4 and 8, but was lost to follow-up after week 8. than 25 IU/mL. We defined virological breakthrough as the presence, during treatment, of HCV RNA concentrations greater than 25 IU/mL in serum samples after previous documentation of on-treatment concentrations of HCV RNA concentrations less than 25 IU/mL. We defined relapse as the presence of HCV RNA concentrations greater than 25 IU/mL at any time during the post-treatment follow-up period after documentation of HCV RNA less than 25 IU/mL in a serum sample at the end of treatment. Deep sequencing of the NS3 and NS5A regions of the HCV RNA was done for all patients at baseline. We established the presence of baseline resistance-associated variants (RAVs) by comparison with wild-type reference sequences (1a-H77 for genotype 1a samples and 1b-Con-1 for genotype 1b samples). NS3 protease RAVs for genotypes 1a and 1b were assessed at aminoacid positions 36, 54, 55, 155, 156, 168, and 170. We also assessed the presence of Q80 polymorphisms. NS5A RAVs was assessed at aminoacids 28, 30, 31, 58, and 93 for genotype 1a, and at positions 31 and 93 for genotype 1b. For all patients who had virological failure, deep sequencing of the NA5A and NS5B regions was done with samples obtained at the time of failure. We compared the resulting sequences with sequences from baseline samples to detect emergent RAVs. We reported RAVs present at greater than 1% of sequence reads. Patients allocated to groups 1 or 2 who completed 8 weeks of treatment and had post-treatment virological failure at or before the post-treatment were offered a 24-week regimen of sofosbuvir plus ledipasvir with weight-based ribavirin. We encouraged all patients who achieved SVR 24 weeks after discontinuation of treatment to enrol in the SVR Registry Study (NCT ), which is intended to assess durability of SVR for up to 3 years post-treatment. Patients who did not achieve SVR were eligible to enrol in the Sequence Registry Study (NCT ), for the purpose of monitoring the persistence of HCV-resistant mutations for up to 3 years post-treatment. Safety was assessed by review of adverse events and concomitant drugs, blood samples for clinical laboratory testing including haematological assessments, and physical examinations. Patients in groups 2 and 5 (ie, those receiving ribavirin) with decreases in haemoglobin concentrations to lower than 100 g/l during treatment had the option to reduce the daily dose of ribavirin. The use of erythropoiesis-stimulating agents was not permitted. Statistical analysis The primary efficacy endpoint of the study was the proportion of patients achieving SVR12, analysed by intention to treat. We did the primary analysis after all patients had been followed-up through 12 weeks posttreatment or after premature discontinuation from the study. The SVR12 rate was calculated for each treatment group along with the 2-sided 95% CI using the exact Vol 383 February 8, See Online for appendix binomial distribution (the Clopper-Pearson method). The study was exploratory and not powered to allow for comparisons among groups. Therefore, we did no statistical hypothesis testing. With a sample size of 20 patients in each treatment group, a two-sided 95% exact CI will extend at most 46% in length. We used SAS (version 9.2) for all statistical analyses. This study is registered with ClinicalTrials.gov, number NCT Role of the funding source The study sponsor oversaw trial management, data collection, statistical analyses, and the writing and review of the report. The corresponding author had full access to all data in the study and had final responsibility for the decision to submit for publication. Results We screened 116 patients, of whom 100 were deemed eligible and enrolled in the study (figure 1, appendix). Baseline characteristics of patients within each of the two cohorts were similar among groups (table 1). Most patients were non-black. In cohort A, 53 (88%) of 60 patients had HCV genotype 1a, and 40 (80%) had non-cc IL28B genotypes. A similar proportion of patients in cohort B (34 [85%] of 40 patients) had genotype 1a infection, but a larger proportion (37 patients [93%]) carried non-cc IL28B genotypes, as would be expected Cohort A: treatment-naive patients Cohort B: patients previously treated with protease inhibitors 8 weeks (n=20) for 8 weeks (n=21) Age (years) 48 (10 7) 50 (11 1) 46 (11 6) 54 (6 6) 52 (9 8) Men 14 (70%) 12 (57%) 11 (58%) 15 (79%) 14 (67%) Race Black 4 (20%) 0 1 (5%) 2 (11%) 2 (10%) Non-black 16 (80%) 21 (100%) 18 (95%) 17 (89%) 19 (90%) Ethnic origin Hispanic or Latino 3 (15%) 12 (57%) 9 (47%) 6 (32%) 10 (48%) Non-Hispanic 17 (85%) 9 (43%) 10 (53%) 13 (68%) 11 (52%) Body-mass index (kg/m 2 ) 28 7 (6 9) 29 8 (5 5) 28 1 (5 8) 31 4 (4 7) 31 5 (7 3) Log 10 HCV RNA (IU/mL) 6 1 (0 8) 6 0 (0 8) 6 1 (0 8) 6 3 (0 5) 6 2 (0 4) HCV genotype 1a 17 (85%) 19 (90%) 17 (89%) 18 (95%) 16 (76%) 1b 3 (15%) 2 (10%) 2 (11%) 1 (5%) 5 (24%) IL28b) CC 4 (20%) 7 (33%) 1 (5%) 2 (11%) 1 (5%) CT 12 (60%) 11 (52%) 14 (74%) 13 (68%) 11 (52%) TT 4 (20%) 3 (14%) 4 (21%) 4 (21%) 9 (43%) Cirrhosis No 20 (100%) 21 (100%) 19 (100%) 8 (42%) 10 (48%) Yes (58%) 11 (52%) Previous treatment Boceprevir 11 (58%) 11 (52%) Telaprevir 8 (42%) 10 (48%) Response to previous treatment Non-responder 12 (63%) 15 (71%) Breakthrough or relapse 7 (37%) 6 (29%) Baseline resistance-associated variants NS5A 2 (10%) 1 (5%) 3 (16%) 1 (5%) 2 (10%) NS3 PI Any PI 4* (20%) (68%) 16 (76%) R155K (47%) 10 (48%) Q80K 7 (35%) 10 (48%) 12 (63%) 9 (47%) 7 (33%) for 12 weeks (n=21) Data are mean (SD) or n (%) unless otherwise stated. HCV=hepatitis C virus. PI=protease inhibitor. *One patient had A155D/A156T/D168E triple protease inhibitor variants at baseline. Table 1: Baseline characteristics 518 Vol 383 February 8, 2014 given their failure to respond to previous interferon-based treatment com bined with a protease inhibitor. More than half of patients (22 patients [55%]) in cohort B had compensated cirrhosis. At baseline, 22 patients with cirrhosis had mean total bilirubin of 0 9 mg/dl, mean albumin of 3 8 g/dl, mean platelet count of ³, and mean prothrombin time international normalised ratio of Most patients in cohort B had shown non-response to previous treatment with protease inhibitor regimens (27 [68%] of 40 patients) whereas about a third (13 patients [33%]) had had virological breakthrough or relapse. All patients had rapid reductions in serum HCV RNA after beginning treatment, with most having serum HCV RNA reductions of about four logs by the end of week 1 of treatment (figure 2). By the end of the second week of dosing, 90 [90%] of 100 patients had HCV RNA below the limit of quantification, and by the end of the fourth week of dosing 99 (99%) of these patients had concentrations below the limit of quantification (appendix). Most patients in all dose groups achieved SVR12 (table 2), irrespective of previous treatment history (treatment naive vs previously treated), the presence or absence of ribavirin in the regimen, the presence or absence of cirrhosis, or race (black vs non-black). Early viral response during treatment was not predictive of the likelihood of SVR12 achievement. Post-treatment week 24 data are available for all of 97 patients who achieved SVR12. All 97 patients also achieved SVR24. No patient in any treatment group had virological breakthrough during study treatment. Of the 100 patients enrolled and treated, two (2%) had virological relapse after receiving a full course of treatment: one noncirrhotic 60-year-old white man with genotype 1a infection and the CT IL28b genotype in treatment group 1 relapsed between post-treatment weeks 4 and 8, and one cirrhotic 54-year-old white woman with genotype 1a infection and the CT IL28b genotype in treatment group 4 relapsed between post-treatment weeks 2 and 4 this patient was a non-responder to prior treatment with boceprevir-peginterferon-ribavirin triple therapy. At baseline, NS3 protease inhibitor RAVs were detected in 33 patients: four (7%) of 60 treatment-naive patients and 29 (73) of 40 previously treated patients (table 1). R155K, the most prevalent protease inhibitor RAV, was detected in 19 patients (all of whom were previously treated with protease inhibitors). All 33 patients with baseline NS3 RAVs achieved SVR12. At baseline, NS5A RAVs were detected in nine patients, seven of whom achieved SVR12. Two patients, one each in groups 1 and 4, had virological
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