Articles
Ledipasvir-sofosbuvir in patients with hepatitis C virus genotype 5 infection: an open-label, multicentre, single-arm, phase 2 study

https://doi.org/10.1016/S1473-3099(15)00529-0Get rights and content

Summary

Background

Data about the response of hepatitis C virus (HCV) genotype 5 to approved and experimental treatment regimens are scarce. We assessed the efficacy and safety of combination therapy with the NS5A inhibitor ledipasvir and the NS5B polymerase inhibitor sofosbuvir in patients with HCV genotype 5.

Methods

We did this open-label, multicentre, single-arm, phase 2 trial at five hospitals in France. Eligible patients were at least 18 years old and had chronic infection with HCV genotype 5, with plasma HCV RNA of at least 10 000 IU/mL. We used BLAST analyses of NS5B partial sequences to establish the genotype and subtype at screening. Patients were given a fixed-dose combination tablet of 90 mg ledipasvir and 400 mg sofosbuvir orally once per day for 12 weeks. The primary endpoint was the proportion of patients with a sustained viral response, defined as HCV RNA concentration less than 15 IU/mL at 12 weeks after the end of treatment (SVR12). We analysed efficacy and safety in all patients who received at least one dose of ledipasvir-sofosbuvir. This trial is registered with EudraCT, number 2013-003978-27, and with ClinicalTrials.gov, number NCT02081079.

Findings

From March 7 to June 10, 2014, we recruited 41 patients, including 21 who were treatment naive and 20 who were treatment experienced. All patients were of white ethnic origins. All 41 patients who started treatment completed the full 12 weeks of treatment and had undetectable HCV RNA at their final treatment visit. In the overall study population, 39 (95%, 95% CI 83–99) of 41 patients achieved SVR12. SVR12 was achieved by 20 (95%, 76–100) of the 21 patients who were treatment naive and 19 (95%, 75–100) of the 20 patients who were treatment experienced. Eight (89%) of nine patients with cirrhosis achieved SVR12, whereas 31 (97%) of the 32 patients without cirrhosis achieved SVR12. The two patients who did not reach SVR12 both had IL28B TT genotype and had viral relapse within 4 weeks of the end of treatment. The most common adverse events were asthenia (16 [39%] patients), headache (11 [27%] patients), and fatigue (four [10%] patients). One patient had a serious adverse event, worsening depression, which we judged to be unrelated to study treatment.

Interpretation

The oral regimen of ledipasvir-sofosbuvir is an effective and well-tolerated treatment for patients with HCV genotype 5 infection who are treatment naive or treatment experienced.

Funding

Gilead Sciences.

Introduction

Hepatitis C virus (HCV) genotype 5 accounts for about 1·4 million cases of HCV infection globally.1 Although more than 80% of cases occur in southern and eastern sub-Saharan Africa,1 clusters of HCV genotype 5 exist in regions of Belgium, France, Spain, Greece, and Syria.2, 3 For example, in France, the overall prevalence of HCV genotype 5 infection is estimated to be 1–3% of HCV infections,4 but in the Clermont-Ferrand area of central France, 14% of patients infected with HCV were identified as having genotype 5 infection.5, 6 In this area of central France, HCV genotype 5 was spread locally by unsafe injections before 1972 and more widely by transfusions, with the eventual infection of hundreds of patients. Although data about the natural history of HCV genotype 5 infection are scarce, some evidence suggests that patients with genotype 5 HCV are generally older than are those with other genotypes of HCV, usually have high viral loads, and frequently have cirrhosis.2, 3, 4, 7

The eradication of HCV with antiviral drugs reduces liver-related complications and improves short-term survival.8, 9 Patients with HCV genotype 5 have had relatively low rates of response to pegylated interferon-alfa and ribavirin, with about 60% achieving sustained virological response (SVR) after 48 weeks of therapy.10 The development of antivirals that directly target HCV (ie, directly acting antivirals) has increased available treatment options and success of treatment for many patients with chronic HCV,11, 12, 13 but these new regimens have been assessed in very few patients with HCV genotype 5. Provision of an all-oral regimen for HCV genotype 5 infection could expand access to treatment globally, especially in regions with limited resources such as Africa, where the most genotype 5 HCV infections are found.

Combination therapy with the NS5A inhibitor ledipasvir and the NS5B polymerase inhibitor sofosbuvir shows efficacy in several HCV genotypes. In patients with HCV genotype 1 infection in the ION-1 and ION-2 studies, treatment with ledipasvir-sofosbuvir for 12 weeks resulted in SVR in 99% of patients who were treatment naive and 94% of patients who were treatment experienced.14, 15 In the SYNERGY study of 21 patients with HCV genotype 4 infection who were treatment naive or experienced, 12 weeks of ledipasvir-sofosbuvir resulted in SVR at 12 weeks after treatment in 95% of patients.16 Furthermore, in the ELECTRON2 study, 24 (96%) of 25 patients with HCV genotype 6 infection achieved SVR after 12 weeks of ledipasvir-sofosbuvir.17 However, no data have been available about the efficacy and safety of all-oral HCV regimens for patients with HCV genotype 5 infection. Consequently, we did a trial to assess the efficacy and safety of a fixed-dose combination of ledipasvir-sofosbuvir in patients with HCV genotype 5.

Research in context

Evidence before this study

In April, 2013, we did a search of PubMed for all papers published in English between January, 1990, and April, 2013, using the keywords “HCV genotype 5”, “HCV genotype 5 treatment”, and “HCV genotype 5 epidemiology”. This study was designed in the first half of 2013, before any all-oral regimens for hepatitis C virus (HCV) infection had been approved. At the time of study design, many reports had described the use of directly acting antivirals as part of interferon-based or all-oral regimens for HCV, but very few patients with HCV genotype 5 were included. The recommendation in the American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America and the European Association for the Study of the Liver (EASL) guidelines for patients with HCV genotype 5 infection to receive 12 weeks of triple therapy with sofosbuvir, ribavirin, and pegylated interferon-alfa was based on data from a single patient with HCV genotype 5 in the NEUTRINO trial.

Added value of this study

To our knowledge, this study is the first to assess a treatment regimen consisting entirely of directly acting antivirals in patients with HCV genotype 5 infection. 12 weeks of a fixed-dose combination tablet of ledipasvir-sofosbuvir once per day resulted in sustained viral responses in 39 (95%) of 41 patients at 12 weeks after the end of treatment. Treatment was equally successful irrespective of whether patients were treatment naive or treatment experienced.

Implications of all the available evidence

Based on the results of this study, the AASLD treatment guidelines have been modified such that ledipasvir-sofosbuvir for 12 weeks is now the recommended treatment for patients with HCV genotype 5 infection who are treatment naive or treatment experienced. EASL treatment guidelines also recommend treatment with ledipasvir-sofosbuvir for 12 weeks in patients with HCV genotype 5 infection.

Section snippets

Study design and participants

This was an open-label, multicentre, single-arm, phase 2 trial. Patients with genotype 5 HCV infection were enrolled and treated at five hospitals in France (two in suburban Paris, two in central France, and one in the southwest). The study protocol was approved by each institution's ethics committee before the start of the study. The study was done in accordance with the International Conference on Harmonization Good Clinical Practice Guidelines and the Declaration of Helsinki.

Study details

Results

From March 7, to June 10, 2014, we enrolled 41 patients (figure). All patients were white, 21 (51%) were men (table 1), and 39 (95%) self-identified as being white European. Information about the source of HCV infection was not collected. The numbers of patients who were treatment naive (n=21) and treatment experienced (n=20) were similar. Of the patients who were treatment experienced, six (30%) had cirrhosis, compared with three (14%) of the patients who were treatment naive. For 39 (95%)

Discussion

This prospective, open-label study is the first to assess a regimen consisting of only directly acting antivirals in patients with HCV genotype 5 infection. The study population of 41 patients is large for a study of HCV genotype 5, which is rare worldwide but is more concentrated in regions of Africa and Europe. All patients in this study were enrolled in France, including 17 (41%) in Clermont-Ferrand, which has a documented cluster of mainly iatrogenic HCV genotype 5 infections.5, 6

In this

References (20)

  • C Henquell et al.

    Evolutionary history of hepatitis C virus genotype 5a in France, a multicenter ANRS study

    Infect Genet Evol

    (2011)
  • X Forns et al.

    C-salvage: grazoprevir (GZR; MK-5172), elbasvir (EBR; MK-8742) and ribavirin (RBV) for chronic hcv-genotype 1 (GT1) infection after failure of direct-acting antiviral (DAA) therapy

    J Hepatol

    (2015)
  • JP Messina et al.

    Global distribution and prevalence of hepatitis C virus genotypes

    Hepatology

    (2015)
  • N Antaki et al.

    The unexpected discovery of a focus of hepatitis C virus genotype 5 in a Syrian province

    Epidemiol Infect

    (2009)
  • N Antaki et al.

    HCV genotype 5: an orphan virus

    Antivir Ther

    (2013)
  • F Legrand-Abravanel et al.

    Hepatitis C virus genotype 5: epidemiological characteristics and sensitivity to combination therapy with interferon-alpha plus ribavirin

    J Infect Dis

    (2004)
  • A Abergel et al.

    The epidemiology and virology of hepatitis C virus genotype 5 in central France

    Aliment Pharmacol Ther

    (2007)
  • C Bonny et al.

    Effectiveness of interferon plus ribavirin combination in the treatment of naive patients with hepatitis C virus type 5. A French multicentre retrospective study

    Aliment Pharmacol Ther

    (2006)
  • LI Backus et al.

    A sustained virologic response reduces risk of all-cause mortality in patients with hepatitis C

    Clin Gastroenterol Hepatol

    (2011)
  • AJ van der Meer et al.

    Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis

    JAMA

    (2012)
There are more references available in the full text version of this article.

Cited by (71)

  • 2020 Taiwan consensus statement on the management of hepatitis C: part (I) general population

    2020, Journal of the Formosan Medical Association
    Citation Excerpt :

    In EXPEDITION-8 that included treatment-naïve patients with cirrhosis, the 8-week glecaprevir/pibrentasvir regimen yielded SVR12 of 100% in both GT5-infected (1/1) and GT6-infected (9/9) patients.71 An open-label, multicenter, single-arm, phase II trial that enrolled 41 GT5-infected patients (treatment-naïve: 51%; cirrhosis: 22%) yielded an SVR12 rate of 95% (39/41) following 12 weeks of sofosbuvir/ledipasvir.132 As for GT6-infected patients, the efficacy of sofosbuvir/ledipasvir for 12 weeks was demonstrated in an open-label, phase II trial that included 25 patients (treatment-naïve: 92%; cirrhosis: 8%).

  • Efficacy and safety of glecaprevir/pibrentasvir in patients with chronic hepatitis C virus genotype 5 or 6 infection (ENDURANCE-5,6): an open-label, multicentre, phase 3b trial

    2019, The Lancet Gastroenterology and Hepatology
    Citation Excerpt :

    HCV treatment guidelines established by the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD) recommend pangenotypic glecaprevir/pibrentasvir for the treatment of chronic HCV genotype 5 or 6 infection (8-week glecaprevir/pibrentasvir for those without cirrhosis, and 12-week glecaprevir/pibrentasvir for those with compensated cirrhosis).21,22 Other regimens for this population recommended by both associations include 12-week pangenotypic sofosbuvir/velpatasvir and (for treatment-naive patients) 12-week sofosbuvir/ledipasvir, which yield SVR12 rates between 95% and 100%.23–25 Lastly, AASLD, but not EASL, recommends 12 weeks of sofosbuvir/velpatasvir/voxilaprevir for treatment of direct-acting-antiviral-experienced patients with HCV genotype 5 or 6 infection, which yielded a 100% SVR12 rate in seven such patients (one with genotype 5 and six with genotype 6 infection).26

  • Hepatitis C

    2019, The Lancet
    Citation Excerpt :

    Similarly high proportions of patients who were co-infected with genotype 1 or 4 and HIV achieved an SVR.94 Less data have been accrued in patients infected with genotypes 4, 5, and 6, but the proportion attaining SVR is similar.95–97 Ledispavir has reduced in-vitro activity against genotype 6e, but there are some data to show that this activity does not affect the SVR12.98

View all citing articles on Scopus
View full text