Elsevier

The Lancet

Volume 383, Issue 9916, 8–14 February 2014, Pages 515-523
The Lancet

Articles
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

https://doi.org/10.1016/S0140-6736(13)62121-2Get rights and content

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, 2012. 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 ledipasvir for 8 weeks (group 1), sofosbuvir plus ledipasvir and ribavirin for 8 weeks (group 2), or sofosbuvir plus ledipasvir for 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 ledipasvir for 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 NCT01726517.

Findings

In cohort A, SVR12 was achieved by 19 (95%) of 20 patients (95% CI 75–100) 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.

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 contraindications and other reasons for ineligibility, including the unwillingness 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)—24–48 weeks of peginterferon and ribavirin with 12–44 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, 5, 6, 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 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.11, 12, 13, 14, 15 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 ledipasvir with ribavirin 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 protease-inhibitor-containing regimen, half of whom had compensated cirrhosis.

Section snippets

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, 2012. Eligible patients were at least 18 years of age and had chronic genotype-1 HCV infection with serum HCV RNA concentrations of 10 000 IU/mL or greater. Exclusion criteria included hepatic decompensation (as evidenced by the presence of ascites,

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

Discussion

In this randomised, open-label study, treatment with the fixed-dose combination of sofosbuvir and ledipasvir with and without ribavirin was well tolerated and resulted in high rates of SVR12 (95–100%) in both treatment-naive and previously treated patients with genotype-1 HCV. Patients in the 12-week group of cohort A had a similar response to patients in the 8-week groups, suggesting that 8 weeks of treatment might be sufficient for non-cirrhotic patients who have not previously been treated

References (31)

  • IM Jacobson et al.

    Telaprevir for previously untreated chronic hepatitis C virus infection

    N Engl J Med

    (2011)
  • F Poordad et al.

    Boceprevir for untreated chronic HCV genotype 1 infection

    N Engl J Med

    (2011)
  • S Zeuzem et al.

    Telaprevir for retreatment of HCV infection

    N Engl J Med

    (2011)
  • BR Bacon et al.

    Boceprevir for previously treated chronic HCV genotype 1 infection

    N Engl J Med

    (2011)
  • B Maasoumy et al.

    Eligibility and safety of triple therapy for hepatitis C: lessons learned from the first experience in a real world setting

    PLoS ONE

    (2013)
  • Cited by (473)

    View all citing articles on Scopus
    View full text