Adis evaluation of ledipasvir/sofosbuvir in chronic hepatitis C

Single-tablet regimen administered once daily, with potential for improved treatment adherence

Achieves high sustained virological response rates 12 weeks’ post-treatment in treatment-naïve and -experienced patients with chronic HCV genotype 1 infection

Data support its use in chronic HCV genotype 4 infection and in HCV and HIV co-infection

Data support its use, in combination with ribavirin, in chronic HCV genotype 1 or 4 infection with decompensated cirrhosis or liver transplantation, or in chronic HCV genotype 3 infection

Generally well tolerated

Cost may represent a barrier to treatment

What is the rationale for developing ledipasvir/sofosbuvir?

Combination therapy with peginterferon-α and ribavirin was the mainstay of treatment in chronic hepatitis C for a number of years [1]. However, peginterferon-α is often poorly tolerated and a large proportion of patients are not eligible or willing to receive it [2]. Recently, the treatment of chronic hepatitis C has been transformed by direct-acting antiviral agents, with interferon-free regimens now a reality. Interferon-free treatment with the direct-acting antiviral agents ledipasvir and sofosbuvir is now available in the EU as a single-tablet regimen (ledipasvir/sofosbuvir; Harvoni®) [3].

How do ledipasvir and sofosbuvir work?

Ledipasvir inhibits the hepatitis C virus (HCV) NS5A protein and sofosbuvir inhibits HCV NS5B RNA-dependent RNA polymerase; both NS5A and NS5B RNA-dependent RNA polymerase are essential for viral replication [3]. Ledipasvir has potent antiviral activity against HCV genotypes 1a and 1b, with lower activity against HCV genotypes 4a, 4d, 5a and 6a, and substantially lower activity against HCV genotypes 2a, 2b, 3a and 6e [3]. Sofosbuvir has pangenotypic antiviral activity [4].

In cell culture, reduced ledipasvir susceptibility was associated with certain NS5A amino acid substitutions (e.g. Y93H in HCV genotypes 1a and 1b and Q30E in HCV genotype 1a) [3]. Among patients with chronic HCV genotype 1 infection who received ledipasvir/sofosbuvir in the pivotal 3 ION trials [5–7], some of the patients who qualified for resistance testing had at least one NS5A resistance-associated variant as determined by deep sequencing [3].

In cell culture, reduced sofosbuvir susceptibility was associated with the primary NS5B substitution S282T in multiple HCV genotypes [3]. However, sofosbuvir has a high genetic barrier to resistance; the NS5B S282T variant was not detected during the ION trials [5–7] in patients with chronic HCV genotype 1 infection who received ledipasvir/sofosbuvir [3]. No cross resistance was seen between ledipasvir and sofosbuvir [3].

For whom is ledipasvir/sofosbuvir indicated?

Ledipasvir/sofosbuvir is indicated in the EU for the treatment of adults with chronic hepatitis C [3]. A summary of the EU prescribing information for ledipasvir/sofosbuvir is shown in Table 1.

Table 1 Prescribing summary of ledipasvir/sofosbuvir 90/400 mg (Harvoni®) in chronic hepatitis C in the EU [3]
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What is the clinical efficacy of ledipasvir/sofosbuvir?

A ledipasvir/sofosbuvir dosage of 90/400 mg once daily was administered to patients in the trials discussed in this section. A number of trials included treatment arms in which patients also received ribavirin. Some of the trials/analyses discussed in this section are only available as abstracts, posters and/or slide presentations [9–19].

In chronic HCV genotype 1 infection

The pivotal, phase 3 ION-1 [5], ION-2 [6] and ION-3 [7] trials examined the efficacy of ledipasvir/sofosbuvir in patients aged ≥18 years with chronic HCV genotype 1 infection. These randomized, open-label, multicentre trials included patients who were treatment-naïve (ION-1 [5] and ION-3 [7]) or had experienced virological failure after treatment with peginterferon-α plus ribavirin with or without a NS3/4A protease inhibitor (ION-2 [6]). Approximately 20 % of patients in ION-1 [5] and ION-2 [6] could have compensated cirrhosis, whereas ION-3 enrolled patients without cirrhosis [7]. The primary endpoint was the rate of sustained virological response (SVR) 12 weeks’ post-treatment (SVR12) [5–7]; SVR12 has been shown to be an appropriate measure of durable response to ledipasvir/sofosbuvir [9].

SVR12 rates were ≥97 % in treatment-naïve patients in ION-1, regardless of whether ledipasvir/sofosbuvir was administered for 12 or 24 weeks or administered with or without ribavirin (Table 2) [5].

Table 2 Efficacy of ledipasvir/sofosbuvir 90/400 mg once daily in treatment-naïve [5, 7] or -experienced [6] patients with chronic hepatitis C virus genotype 1 infection
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In ION-3, an SVR12 rate of 94 % was achieved in treatment-naïve patients without cirrhosis who received ledipasvir/sofosbuvir for 8 weeks (Table 2) [7]. The 8-week regimen of ledipasvir/sofosbuvir was noninferior to the 12-week regimen of ledipasvir/sofosbuvir or to the 8-week regimen of ledipasvir/sofosbuvir plus ribavirin in terms of SVR12 (Table 2) [7]. Moreover, post hoc analysis of ION-3 demonstrated that an 8-week regimen of ledipasvir/sofosbuvir appeared sufficient in treatment-naïve patients without cirrhosis who had a baseline HCV RNA level of <6 million IU/mL, with an SVR12 rate of 97 % (Table 2) and a relapse rate of 2 % [10].

High SVR12 rates were seen across various patient subgroups in ION-1 and ION-3, including in patients with traditional predictors of poor response [5, 7]. For example, across the four treatment groups in ION-1, SVR12 rates were 94–100 % in patients with cirrhosis, 97–99 % in patients with chronic HCV genotype 1a infection, 97–99 % in those with non-CC IL28B and 91–100 % in Black patients [5]. Thus, factors that traditionally predicted a poor response to interferon-based therapy do not predict response to ledipasvir/sofosbuvir treatment [10].

Among patients who had failed prior peginterferon-α-based treatment, high SVR12 rates were seen with ledipasvir/sofosbuvir administered for 12 or 24 weeks, with or without ribavirin, in the ION-2 trial (Table 2) [6]. In ION-2, ledipasvir/sofosbuvir achieved high SVR12 rates regardless of whether patients had no response to prior treatment or prior virological breakthrough or relapse, and regardless of whether patients had failed previous treatment with an HCV protease inhibitor plus peginterferon-α and ribavirin or with peginterferon-α plus ribavirin [6].

In the ION trials, ledipasvir/sofosbuvir was effective regardless of the degree of liver fibrosis or the method of fibrosis determination [11]. In addition, among patients achieving SVR12, improvements in patient-reported outcomes were seen regardless of fibrosis stage (e.g. early or advanced hepatic fibrosis) [20].

Significant (p < 0.001 vs. baseline) improvements in most patient-reported outcomes occurred as early as week 2 of treatment with ledipasvir/sofosbuvir without ribavirin, and were maximized by the end of treatment in the ION trials [21]. Changes in measures of health-related quality of life, fatigue and work productivity significantly (p < 0.0001) favoured ledipasvir/sofosbuvir over ledipasvir/sofosbuvir plus ribavirin on the last day of treatment [21].

A randomized, open-label, multicentre, phase 3 Japanese trial included treatment-naïve or treatment-experienced patients with chronic HCV genotype 1 infection who received ledipasvir/sofosbuvir (n = 171) or ledipasvir/sofosbuvir plus ribavirin (n = 170) for 12 weeks; 76 patients (22 %) had compensated cirrhosis at baseline [22]. The SVR12 rate (primary endpoint) was 100 % in ledipasvir/sofosbuvir recipients and 98 % in ledipasvir/sofosbuvir plus ribavirin recipients, with SVR12 rates of 100 and 96 % in treatment-naïve patients and 100 and 100 % in treatment-experienced patients [22].

In patients with chronic HCV genotype 1 infection and compensated cirrhosis who have failed prior treatment with a regimen including peginterferon-α and an HCV protease inhibitor (n = 155), the SVR12 rate (primary endpoint) was 96 % in patients receiving ledipasvir/sofosbuvir plus ribavirin for 12 weeks and 97 % in patients receiving ledipasvir/sofosbuvir for 24 weeks, according to a randomized, double-blind, multicentre phase 2 trial (SIRIUS) [23].

A post hoc, integrated analysis of phase 2/3 trial data also support the use of a 24-week regimen of ledipasvir/sofosbuvir or a 12-week regimen of ledipasvir/sofosbuvir plus ribavirin in treatment-experienced patients with chronic HCV genotype 1 infection who have compensated cirrhosis, including those who have failed prior treatment with an HCV protease inhibitor-containing regimen [24].

In HCV and HIV co-infection

The open-label, multicentre, phase 3 ION-4 trial examined the efficacy of 12 weeks’ therapy with ledipasvir/sofosbuvir in 335 treatment-naïve or -experienced patients co-infected with HCV genotype 1 or 4 and HIV-1 [12]. At baseline, 20 % of patients had compensated cirrhosis and 55 % of patients had not responded to prior anti-HCV therapy; all patients were receiving stable antiretroviral therapy. The overall SVR12 rate (primary endpoint) was 96 %, with SVR12 rates of 94 % in treatment-naïve patients, 97 % in treatment-experienced patients, 96 % in patients without cirrhosis and 94 % in patients with cirrhosis [12].

Results of the open-label, single-centre ERADICATE trial also support the use of ledipasvir/sofosbuvir in patients co-infected with HCV genotype 1 and HIV [25]. ERADICATE included 50 patients without cirrhosis who had not received prior treatment for chronic HCV infection and were antiretroviral naïve or experienced. The SVR12 rate (primary endpoint) was 100 % in antiretroviral-naïve patients and 97 % in antiretroviral-experienced patients following 12 weeks of ledipasvir/sofosbuvir [25].

In HCV genotype 1 or 4 infection following liver transplantation or with decompensated cirrhosis

The open-label, multicentre SOLAR-1 trial included a cohort of treatment-naïve or -experienced patients with recurrence of HCV genotype 1 or 4 infection following liver transplantation (223 evaluable patients) [13]. SVR12 rates (primary endpoint) in patients receiving ledipasvir/sofosbuvir plus ribavirin for 12 or 24 weeks were 96 and 98 % in patients with a fibrosis score of F0–F3 (n = 111), 96 and 96 % in Child-Pugh-Turcotte (CPT) class A cirrhosis, 85 and 83 % in CPT class B cirrhosis and 60 and 67 % in CPT class C cirrhosis [13].

SOLAR-1 also included a cohort of treatment-naïve or -experienced patients with chronic HCV genotype 1 or 4 infection who had decompensated cirrhosis and had not undergone liver transplantation (n = 108) [14]. SVR12 rates (primary endpoint) in patients receiving ledipasvir/sofosbuvir plus ribavirin for 12 or 24 weeks were 87 and 89 % overall, 87 and 89 % in CPT class B cirrhosis and 86 and 90 % in CPT class C cirrhosis [14].

In the open-label, multinational SOLAR-2 trial, treatment-naïve or -experienced patients with HCV genotype 1 or 4 infection who had decompensated cirrhosis (n = 107) or HCV recurrence following liver transplantation (n = 220) were randomized to receive ledipasvir/sofosbuvir plus ribavirin for 12 or 24 weeks [18]. The SVR rate 4 weeks’ post-treatment (SVR4) in patients with decompensated cirrhosis who had not undergone liver transplantation and had received 12 or 24 weeks’ therapy was 86 and 100 % in those with CPT class B cirrhosis and 88 and 50 % in those with CPT class C cirrhosis. SVR4 in patients with HCV recurrence post-liver transplantation who had received 12 or 24 weeks’ therapy was 94 and 100 % in those with a fibrosis score of F0–F3, 97 and 92 % in those with CPT class A cirrhosis, 100 and 100 % in those with CPT class B cirrhosis and 100 and 50 % in those with CPT class C cirrhosis [18].

In chronic HCV genotype 3, 4 or 5 infection

Results of the ELECTRON-2 trial support the efficacy of ledipasvir/sofosbuvir in patients with chronic HCV genotype 3 infection. This trial included treatment arms in which treatment-naïve patients received ledipasvir/sofosbuvir (n = 25) or ledipasvir/sofosbuvir plus ribavirin (n = 26) for 12 weeks [15] and treatment-experienced patients received ledipasvir/sofosbuvir plus ribavirin for 12 weeks (n = 50) [16]. In treatment-naïve patients, SVR12 was seen in 64 % of ledipasvir/sofosbuvir recipients and in 100 % of ledipasvir/sofosbuvir plus ribavirin recipients [15]. In treatment-experienced patients, SVR12 was seen in 82 % of patients overall, with an SVR12 rate of 89 % in patients without cirrhosis and 73 % in patients with cirrhosis [16].

In the open-label SYNERGY trial, treatment-naïve or -experienced patients with chronic HCV genotype 4 infection (n = 21) received ledipasvir/sofosbuvir for 12 weeks, with an SVR12 rate of 95 % [17].

An open-label, multicentre study included treatment-naïve or -experienced patients with chronic HCV genotype 4 (n = 44) or 5 (n = 41) infection who received ledipasvir/sofosbuvir for 12 weeks [19]. SVR4 rates in patients with chronic HCV genotype 4 or 5 infection were 93 and 93 % [19].

What is the tolerability profile of ledipasvir/sofosbuvir?

Oral ledipasvir/sofosbuvir was generally well tolerated in patients with chronic hepatitis C. In a pooled analysis of the ION-1, -2 and -3 trials in patients with chronic HCV genotype 1 infection who received ledipasvir/sofosbuvir (n = 1080) or ledipasvir/sofosbuvir plus ribavirin (n = 872), the incidence of adverse events was 74 versus 85 % and the incidence of treatment-related adverse events was 45 versus 71 % [26].

In patients receiving ledipasvir/sofosbuvir (without ribavirin) for 8–24 weeks, the most commonly reported adverse events were fatigue (21–24 % of patients), headache (14–24 %), nausea (7–11 %), diarrhoea (7–10 %), insomnia (5–9 %), arthralgia (4–8 %), irritability (1–6 %), rash (1–6 %), cough (1–6 %) and pruritus (1–4 %) [26]. Most adverse events were of mild to moderate severity [5, 6]. Adverse drug reactions attributed to ledipasvir/sofosbuvir were headache and fatigue [3, 23].

The incidence of adverse events known to be associated with ribavirin was numerically higher in patients receiving ledipasvir/sofosbuvir plus ribavirin than in patients receiving ledipasvir/sofosbuvir [26]. For example, with ledipasvir/sofosbuvir plus ribavirin for 8–24 weeks versus ledipasvir/sofosbuvir for 8–24 weeks, fatigue occurred in 35–40 % versus 21–24 % of patients and insomnia occurred in 12–20 % versus 5–9 %. Anaemia was reported in 7 % of ledipasvir/sofosbuvir plus ribavirin recipients versus 0.09 % of ledipasvir/sofosbuvir recipients [26].

Across the ION-1, -2 and -3 trials, serious adverse events were reported in 0–8 % of patients receiving ledipasvir/sofosbuvir for 8–24 weeks and in 0–3 % of patients receiving ledipasvir/sofosbuvir plus ribavirin for 8–24 weeks [5–7]; no deaths were reported [26]. Discontinuation of ledipasvir/sofosbuvir because of adverse events occurred in 0–3 % of patients [5–7], and dose modification or interruption of treatment because of adverse events occurred in 0.6 % of ledipasvir/sofosbuvir recipients versus 14 % of ledipasvir/sofosbuvir plus ribavirin recipients [26].

The tolerability profile of ledipasvir/sofosbuvir in patients with compensated cirrhosis appeared similar to that in patients without cirrhosis [24]. In the SOLAR trials, ledipasvir/sofosbuvir plus ribavirin was generally well tolerated in patients with recurrence of HCV post-transplantation [13, 18] or in those with decompensated cirrhosis [14, 18].

Ledipasvir/sofosbuvir was also generally well tolerated in patients co-infected with HCV and HIV in the ION-4 [12] and ERADICTAE [25] trials, with no discontinuations because of adverse events. In general, there were no clinically significant changes in CD4 + cell counts [25], HIV RNA levels [12, 25] or renal function [25].

What is the current positioning of ledipasvir/sofosbuvir?

The single-tablet regimen of ledipasvir/sofosbuvir represents a significant advance in the treatment of chronic hepatitis C. A 12-week regimen of ledipasvir/sofosbuvir achieves high SVR12 rates in treatment-naïve patients, with no additional benefit conferred by the addition of ribavirin or extending the treatment duration to 24 weeks. Moreover, an 8-week regimen also achieves high SVR12 rates, with a low relapse rate, in patients with a baseline HCV RNA level of <6 million IU/mL. High SVR12 rates are seen in treatment-experienced patients who receive ledipasvir/sofosbuvir for 12 or 24 weeks. Data also support the use of ledipasvir/sofosbuvir in chronic HCV genotype 4 infection, in HCV and HIV co-infection and, in combination with ribavirin, in patients with chronic HCV genotype 1 or 4 infection who have decompensated cirrhosis or are liver transplant recipients and in chronic HCV genotype 3 infection. Ledipasvir/sofosbuvir plus ribavirin also shows efficacy in the retreatment of patients with chronic HCV genotype 1 infection who did not achieve SVR with prior sofosbuvir-containing therapy [27]. Oral ledipasvir/sofosbuvir is generally well tolerated.

The low pill burden associated with once-daily administration of the single-tablet regimen of ledipasvir/sofosbuvir and shorter treatment durations have the potential to improve treatment adherence. However, ledipasvir/sofosbuvir is an expensive therapy and its acquisition cost represents a barrier to treatment. Analyses of its cost effectiveness in the European setting would be of interest.

Ledipasvir/sofosbuvir is included in recently updated treatment guidelines from the European Association for the Study of the Liver (EASL) [1]. These guidelines recommend ledipasvir/sofosbuvir in a number of settings, including the following:

  • Patients with chronic HCV genotype 1a or 1b infection without cirrhosis who are treatment naïve or treatment experienced should be treated with ledipasvir/sofosbuvir for 12 weeks. Treatment may be shortened to 8 weeks in treatment-naïve patients without cirrhosis who have a baseline HCV RNA level of <6 million IU/mL (this should be done with caution).

  • Patients with chronic HCV genotype 1a or 1b infection and compensated cirrhosis who are treatment naïve or treatment experienced should be treated with ledipasvir/sofosbuvir plus ribavirin for 12 weeks. Patients who cannot receive ribavirin because of contraindications or tolerability issues should receive ledipasvir/sofosbuvir for 24 weeks. Treatment with ledipasvir/sofosbuvir plus ribavirin can be extended to 24 weeks in treatment-experienced patients with negative predictors of response.

  • Patients with chronic HCV genotype 4, 5 or 6 infection without cirrhosis who are treatment naïve or treatment experienced should be treated with ledipasvir/sofosbuvir for 12 weeks.

  • Patients with chronic HCV genotype 4, 5 or 6 infection and compensated cirrhosis who are treatment naïve or treatment experienced should be treated with ledipasvir/sofosbuvir plus ribavirin for 12 weeks. Patients who cannot receive ribavirin because of contraindications or tolerability issues should receive ledipasvir/sofosbuvir for 24 weeks. Treatment with ledipasvir/sofosbuvir plus ribavirin can be extended to 24 weeks in treatment-experienced patients with negative predictors of response.

  • Patients co-infected with HCV and HIV should receive the same treatment as those with HCV monoinfection (taking into account potential drug interactions).

EASL guidelines also discuss the use of ledipasvir/sofosbuvir in patients who have failed treatment with a regimen containing a direct-acting antiviral agent (including sofosbuvir), in patients with decompensated cirrhosis and in patients with recurrent HCV infection following liver transplantation [1].