November 19, 2013

Journal of Hepatology
Volume 59, Issue 6 , Pages 1342-1345, December 2013

Tarik Asselah

Received 23 May 2013; received in revised form 8 July 2013; accepted 10 July 2013. published online 26 July 2013.

Abbreviations: DAA, direct-acting antivirals, IFN, interferon, PegIFN, pegylated interferon, RBV, ribavirin, SVR, sustained virological response, eRVR, extended rapid virological response, RVR, rapid virologic response

Keywords: Direct-acting antivirals, Sustained virological response, Chronic hepatitis C, NS5A inhibitors, Gilead, Safety, Resistance

COMMENTARY ON:

Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, Hindes RG, Berrey MM. N Engl J Med. 2013 Jan 3;368(1):34–44. doi: 10.1056/NEJMoa1208953. Copyright © 2013. Abstract reprinted with permission from Massachusetts Medical Society.

http://www.ncbi.nlm.nih.gov/pubmed/23281974

Abstract: Background: The standard treatment for hepatitis C virus (HCV) infection is interferon, which is administered subcutaneously and can have troublesome side effects. We evaluated sofosbuvir, an oral nucleotide inhibitor of HCV polymerase, in interferon-sparing and interferon-free regimens for the treatment of HCV infection.

Methods: We provided open-label treatment to eight groups of patients. A total of 40 previously untreated patients with HCV genotype 2 or 3 infection were randomly assigned to four groups; all four groups received sofosbuvir (at a dose of 400mg once daily) plus ribavirin for 12weeks. Three of these groups also received peginterferon alfa-2a for 4, 8, or 12weeks. Two additional groups of previously untreated patients with HCV genotype 2 or 3 infection received sofosbuvir monotherapy for 12weeks or sofosbuvir plus peginterferon alfa-2a and ribavirin for 8weeks. Two groups of patients with HCV genotype 1 infection received sofosbuvir and ribavirin for 12weeks: 10 patients with no response to prior treatment and 25 with no previous treatment. We report the rate of sustained virologic response 24weeks after therapy.

Results: Of the 40 patients who underwent randomization, all 10 (100%) who received sofosbuvir plus ribavirin without interferon and all 30 (100%) who received sofosbuvir plus ribavirin for 12weeks and interferon for 4, 8, or 12weeks had a sustained virologic response at 24weeks. For the other patients with HCV genotype 2 or 3 infection, all 10 (100%) who received sofosbuvir plus peginterferon alfa-2a and ribavirin for 8weeks had a sustained virologic response at 24weeks, as did 6 of 10 (60%) who received sofosbuvir monotherapy. Among patients with HCV genotype 1 infection, 21 of 25 previously untreated patients (84%) and 1 of 10 with no response to previous therapy (10%) had a sustained virologic response at 24weeks. The most common adverse events were headache, fatigue, insomnia, nausea, rash, and anemia.

Conclusions: Sofosbuvir plus ribavirin for 12weeks may be effective in previously untreated patients with HCV genotype 1, 2, or 3 infection. (Funded by Pharmasset and Gilead Sciences; ClinicalTrials.gov number, NCT01260350).

For the treatment of HCV infection, several direct-acting antivirals (DAAs), including NS3 protease inhibitors, nucleoside/nucleotide analogues and non-nucleoside inhibitors of the RNA-dependent RNA polymerase, and NS5A inhibitors, are under development [1]. Among them, sofosbuvir is a potent HCV-specific nucleotide analog (chain terminator). It is given orally, once daily, without food effect. So far, no safety signal in preclinical/clinical studies has been observed with this compound. Sofosbuvir has a high barrier to resistance with no virologic breakthrough to date. It has a pangenotypic antiviral effect, although it might be less efficient in genotype 3 (G3).

The ELECTRON study goal was to evaluate the safety and efficacy of sofosbuvir as a backbone of combination antiviral therapy in patients with chronic HCV genotype 1, 2, and 3 infections, including both treatment-naïve and treatment-experienced patients [2]. The design of the trial and the results are provided in Fig. 1. Sofosbuvir combined with ribavirin (RBV) for 12weeks was associated with sustained virological response (SVR) in 100% of G2/G3 HCV infected patients. For G1 HCV infected patients, 12-week sofosbuvir plus RBV provided SVR12 in 84% of treatment-naïve, but only in 10% of null responders. For G2/3, when sofosbuvir was given alone, SVR rate was 60%.

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Fig. 1. Electron trial design and results [2]. ELECTRON is an open-label study with eight groups of patients. A total of 40 previously untreated patients with HCV genotype 2 or 3 infection were randomly assigned to four groups; all four groups received sofosbuvir (at a dose of 400mg once daily) plus ribavirin for 12weeks. Three of these groups also received PegIFNα-2a for 4, 8, or 12weeks. Two additional groups of previously untreated patients with HCV genotype 2 or 3 infection received sofosbuvir monotherapy for 12weeks or sofosbuvir plus PegIFNα-2a and ribavirin for 8weeks. Two groups of patients with HCV genotype 1 infection received sofosbuvir and ribavirin for 12weeks: 10 patients with no response to prior treatment and 25 with no previous treatment. The rate of sustained virologic response 24weeks after therapy is reported.

The authors concluded that sofosbuvir plus RBV may be an effective treatment in all previously untreated patients with G2 or G3 HCV infections and also in the majority of G1 HCV naïve infected patients.

What have we learned and what are the questions raised?

First, can we predict relapse with early viral kinetics with sofosbuvir based regimen? No, unfortunately. Previous studies with pegylated-interferon (PegIFN) based therapy demonstrated that early kinetics may help predict SVR [3]. However, in this sofosbuvir plus RBV trial, HCV RNA levels in all patients declined rapidly after the initiation of treatment (Fig. 2). By week-2 of treatment, the majority of patients from all groups had an undetectable level of HCV-RNA. By week-4 of treatment, all 95 patients in the study had an undetectable level of HCV RNA, which was maintained until the end of treatment.

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Fig. 2. Mean change from baseline in hepatitis C virus (HCV) RNA level during treatment. All patients with HCV genotype 2 or 3 infection completed the 12weeks of treatment. All patients had an HCV RNA level below the limit of detection (i.e., <15IU/ml) from week 4 until the end of treatment. Reprinted from [2].

Second, is RBV useful? Yes. Results from the 10 patients with G2 or G3 HCV infection who received sofosbuvir alone strongly suggest a role for RBV in the maintenance of an antiviral response. The exact mechanism by which RBV acts remains unknown.

Third, can we extrapolate these data to phase 3 data or real-world practice?

No, we still have to be cautious for several reasons: the number of patients is limited; they are selected as they have no cirrhosis, no comorbidities. We have to wait for more data, with a larger number of patients, including difficult-to-cure patients with cirrhosis and previous non-response.

For G1, since sofosbuvir and ribavirin are not a reasonable option, two strategies have been developed: (1) 12-week sofosbuvir, PegIFN/RBV and (2) new IFN-free regimens with sofosbuvir and ledipasvir (NS5A inhibitor).

Interestingly, several phase 3 studies with sofosbuvir based regimen have been published since then.

The NEUTRINO trial was a single-group, open-label study of sofosbuvir plus PegIFN/RBV in 327 patients infected with HCV genotype 1, 4, 5, or 6 [4]. All patients received sofosbuvir, PegIFNα-2a for 12weeks. Most of the patients who were included in the study had HCV G1 (89%); 9% had G4, and 2% had G5 or 6. Sofosbuvir was given orally at a dose of 400mg, once a day, along with RBV, also given orally in a dose based on body weight. Patients who weighed less than 75kg received 1000mg/d, and heavier patients received 1200mg/d. Patients received PegIFNα-2a subcutaneously once a week at a dose of 180μg.

A total of 295 of the 327 patients (90%) reached SVR after 12weeks of treatment. According to the HCV genotype: 89% of patients with G1 (92% for G1a and 82% for G1b) and 96% (27/28) of those with G4 had SVR. The single patient with G5 and all six patients with G6 in this trial had an SVR.

The FISSION trial was a randomized, open-label, active-control study of sofosbuvir plus RBV in patients with G2 or G3 HCV infection; patients with the two genotypes were enrolled in an approximately 1:3 ratio, respectively [4]. Patients were randomly assigned to a 1:1 ratio to receive either 12weeks of sofosbuvir plus RBV or 24weeks of PegIFN/RBV. The doses of sofosbuvir and RBV were the same as those administered in the Neutrino trial. The dose of RBV for patients in the PegIFN/RBV group was 800mg daily. Sofosbuvir–RBV was shown to be non-inferior to PegIFN/RBV. At 12weeks, the rates of SVR for patients receiving 12weeks of sofosbuvir–RBV and those receiving 24weeks of PegIFN/RBV were each 67%. An SVR occurred in 97% of patients with G2 and in 56% of those with G3 in the group receiving sofosbuvir–RBV, as compared with response rates of 78% and 63%, respectively, in the group receiving PegIFN/RBV. Among patients with cirrhosis at baseline, 47% of those receiving sofosbuvir–RBV had an SVR, as compared with 38% of those receiving PegIFN/RBV.

The POSITRON trial was a double blinded, placebo-controlled study that compared 12weeks of treatment with sofosbuvir and RBV with matching placebo in patients who had previously discontinued IFN-therapy owing to unacceptable adverse events, who had a concurrent medical condition precluding therapy with an IFN-containing regimen, or who had decided against treatment with an IFN-containing regimen [5]. The most common reasons that IFN treatment was not an option were clinically significant psychiatric disorders (in 57% of patients) and autoimmune disorders (in 19%).

The rate of SVR at 12weeks after treatment was 78% among patients receiving sofosbuvir-RBV, as compared with 0% among those receiving placebo (p<0.001). Among patients who received sofosbuvir-RBV, 93% of patients with G2 HCV infection had an SVR, as compared with 61% of those with G3 HCV infection. Likewise, 81% of patients without cirrhosis (92% of patients with G2 HCV infection and 68% of those with G3 HCV infection) had an SVR, as compared with 61% of patients with cirrhosis (94% of patients with G2 HCV infection and 21% of those with G3 HCV infection).

The FUSION study was a blinded, active-control study involving patients who had not had a response to prior treatment with an IFN-containing regimen [5]. Approximately 75% of the previously treated patients enrolled had either virologic breakthrough during the prior treatment or virologic relapse afterward; the remainder did not have a response. The rates of SVR achieved were superior to the historical control rate of 25%, with rates of 50% in the 12-week group and 73% in the 16-week group (p<0.001 for each comparison). Rates of SVR between the groups showed that patients receiving 16weeks of treatment had a significantly higher rate of SVR than patients receiving 12weeks of treatment (p<0.001). The rates of SVR among patients with G2 HCV infection who received 12weeks of treatment and those who received 16weeks of treatment were 86% and 94%, respectively, as compared with 30% and 62% for 12 and 16weeks of treatment, respectively, among patients with G3 HCV infection.

Cirrhosis was associated with a decreased rate of SVR, particularly among patients with G3 HCV infection who received 12weeks of treatment. Among patients with cirrhosis who received 12weeks of treatment, the rate of SVR was 31% (60% with G2 HCV infection and 19% with G3 HCV infection), as compared with 61% among patients without cirrhosis (96% with G2 HCV infection and 37% with G3 HCV infection). Among patients with cirrhosis who received 16weeks of treatment, the rate of SVR was 66% (78% with G2 HCV infection and 61% with G3 HCV infection) as compared with 76% among patients without cirrhosis (100% with G2 HCV infection and 63% with G3 HCV infection).

So can we summarize these data? Yes, we can (Table 1). What are the key messages?

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P/R, PegIFN/RBV; sof, sofosbuvir.

First, for G1 HCV naïve patients, sofosbuvir with PegIFN-RBV triple therapy appears a reasonable option. Of course, we will need to increase the number of patients with cirrhosis; and also data from genotype 1 experienced patients. There are ongoing phase 3 studies to investigate the efficacy and safety of sofosbuvir/ledipasvir fixed-dose combination with or without RBV for 8 or 12weeks in treatment-naive G1 HCV chronic infection. Ledipasvir is an NS5A replication complex inhibitor ledipasvir (previously GS-5885).

Second, for G4 naïve patients, the data are excellent but limited (n=28 patients) and we need larger studies for this specific G4 HCV population. There is a major medical need since standard of care remains PegIFN-RBV for 48weeks with low SVR in “difficult-to-cure” patient populations (IFNL3 non CC; patients with cirrhosis, experienced patients, etc.) [6]. We urge for studies in G4 HCV, naïve but also experienced patients.

Third, for G2 HCV naïve patients, sofosbuvir-RBV provides excellent results. We have to recall obvious evidence: G2 HCV is not G3, and we need separate studies. In past PegIFN/RBV dual therapy, for statistical issues, HCV G1 and G4, and HCV G2 and G3, were respectively pooled [6]. For DAAs, we need an individual study for each genotype. For G2 HCV treatment experienced and cirrhosis, we need more data.

Four, data were disappointing regarding G3 HCV naïve patients, in particular those with cirrhosis. The question is how to treat HCV G3 infected patients in the near future. There will be several options:

(1)PegIFN plus RBV, with satisfactory results, but with IFN side effects.

(2)Sofasbuvir plus RBV for 16weeks: (better tolerated, possible in case of IFN contra-indication, but not better than PegIFN plus RBV, and even worse in cirrhotics).

(3)Sofosbuvir plus RBV for 24weeks; however, SVR results will be given by the ongoing VALENCE study.

(4)Triple therapy (Sofosbuvir plus PegIFN-RBV) with a short duration of 12weeks, using the neutrino regimen, but without data with G3!

Moreover, it is believed that clinical trials provide best evidence when they are randomized to controlled arms with large number of patients [7]. Several of the trials discussed here lack controlled arms or large number of patients. It may be argued that controlled arms are not necessary when they expose patients to side effects. Furthermore, we need data for «difficult-to-cure» patients, those with cirrhosis, previous non response, comorbidities, etc.

Impressive data have been reported with sofosbuvir based therapy, with high SVR rates and a favorable safety profile so far. A pilot study demonstrated that addition of ledipasvir increased efficacy of sofosbuvir plus RBV, without additional safety issues, and without virologic failures. Gilead recently initiated the first Phase 3 trial (ION-I) evaluating a fixed-dose combination of sofosbuvir and lepidasvir in treatment-naïve G1 HCV infected patients. This four-arm study is evaluating the fixed-dose combination with and without RBV for 12-and 24-week durations in 800 patients, 20 percent of whom have evidence of cirrhosis.

Finally, there is a realistic hope for patients with HCV infection, since several IFN-free trials are ongoing with promising early data [8], [9], [10], [11]. We do hope that the majority of patients with HCV infection will become «easy-to-cure», and there will be increase in access to treatment.

Conflict of interest

Tarik Asselah is a speaker and investigator for BMS, Boehringer-Ingelheim, Janssen, Gilead, Roche and MSD.

References

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PII: S0168-8278(13)00534-5
doi:10.1016/j.jhep.2013.07.023
© 2013 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.

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