August 25, 2013

Accepted Manuscript

International hepatology

Tarik Asselah

PII: S0168-8278(13)00534-5
DOI: http://dx.doi.org/10.1016/j.jhep.2013.07.023
Reference: JHEPAT 4806

To appear in: Journal of Hepatology

Received Date: 23 May 2013
Revised Date: 8 July 2013
Accepted Date: 10 July 2013

Please cite this article as: Asselah, T., Sofosbuvir-based interferon-free therapy for patients with HCV infection, Journal of Hepatology (2013), doi: http://dx.doi.org/10.1016/j.jhep.2013.07.023

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Sofosbuvir-based interferon-free therapy for patients with HCV infection

Tarik Asselah

Service d'Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy; Inserm Unité 773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, Clichy and Paris; and Université Paris Diderot-Paris 7, Paris, France.

Keywords: Direct-acting antivirals; Sustained virological response; Chronic hepatitis C; NS5A inhibitors; Gilead; Safety, Resistance.
Corresponding author: Hepatology Department, AP-HP, University, Paris Diderot 7 and
INSERM U773, CRB3, Hospital Beaujon, 100 Bd du Général Leclerc, 92110 Clichy, France.
Tel.: +33(0) 140875579; fax: +33(0) 147309440.
E-mail address: tarik.asselah@bjn.aphp.fr
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.

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 interferonsparing 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 400 mg once daily) plus ribavirin for 12 weeks. Three of these groups also received peginterferon alfa-2a for 4, 8, or 12 weeks. Two additional groups of previously untreated patients with HCV genotype 2 or 3 infection received sofosbuvir monotherapy for 12 weeks or sofosbuvir plus peginterferon alfa-2a and ribavirin for 8 weeks. Two groups of patients with HCV genotype 1 infection received sofosbuvir and ribavirin for 12 weeks: 10 patients with no response to prior treatment and 25 with no previous treatment. We report the rate of sustained virologic response 24 weeks 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 12 weeks and interferon for 4, 8, or 12 weeks had a sustained virologic response at 24 weeks. For the other patients with HCV genotype 2 or 3 infection, all 10 (100%) who received sofosbuvir plus peginterferon alfa-2a and ribavirin for 8 weeks had a sustained virologic response at 24 weeks, 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 24 weeks. The most common adverse events were headache, fatigue, insomnia, nausea, rash, and anemia.

CONCLUSIONS: Sofosbuvir plus ribavirin for 12 weeks 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)

© European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved

For the treatment of HCV infection, several direct-acting antivirals (DAAs), including NS3 protease inhibitors, nucleoside/nucleotide analogue 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 trials and the results are provided in Fig. 1. Sofosbuvir combined with ribavirin (RBV) for 12 weeks was associated with sustained virological response (SVR) in 100% of G2/G3 HCV infected patients. For G1 HCV infected patients, 12 weeks 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%. 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 to predict SVR [4]. However, in this sofosbuvir plus RBV trial, HCV RNA levels in all patients declined rapidly after the initiation of treatment (Fig. 2B). 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.

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 is not a reasonable option, two strategies have been developed (1) 12 weeks 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 [5]. All patients received sofosbuvir, PegIFNα-2a for 12 weeks. 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 400 mg, once a day, along with RBV, also given orally in a dose based on body weight. Patients who weighed less than 75 kg received 1000 mg/d, and heavier patients received 1200 mg/d. Patients received PegIFNα-2a subcutaneously once a week at a dose of 180 μg. A total of 295 of the 327 patients (90%) reached SVR after 12 weeks of treatment. According to the HCV genotype: 89% for patients with G1 (92% for G1a and 82% for G1b) and 96% (27/28) for those with G4 had SVR. The single patient with G5 and all six patients with G6 in this trial had a 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 [5]. Patients were randomly assigned in a 1:1 ratio to receive either 12 weeks of sofosbuvir plus RBV or 24 weeks 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 800 mg daily. Sofosbuvir–RBV was shown to be non-inferior to PegIFN/RBV. At 12 weeks, the rates of SVR for patients receiving 12 weeks of sofosbuvir–RBV and those receiving 24 weeks of PegIFN/RBV were each 67%. A 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 a SVR, as compared with 38% of those receiving PegIFN/RBV.

The POSITRON trial was a double blinded, placebo-controlled study that compared 12 weeks 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 [6]. 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 12 weeks 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 a 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 a 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. 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 16 weeks of treatment had a significantly higher rate of SVR than patients receiving 12 weeks of treatment (p <0.001). The rates of SVR among patients with G2 HCV infection who received 12 weeks of treatment and those who received 16 weeks of treatment were 86% and 94%, respectively, as compared with 30% and 62% for 12 and 16 weeks 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 12 weeks of treatment. Among patients with cirrhosis who received 12 weeks 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 16 weeks 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?

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 12 weeks 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 48 weeks with low SVR in “difficult-to-cure” patients population (IL28B non CC; patients with cirrhosis, experienced patients, etc;..). We urge for studies in G4 HCV, naïve but also experienced patients.

Third, for G2 HCV naïve patients, sofosbuvir-RBV provide 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. For DAAs, we need 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 16 weeks: (better tolerated, possible in case of IFN contraindication,
    but not better than PegIFN plus RBV, and even worse in cirrhotics).
  3. Sofosbuvir plus RBV for 24 weeks; however, SVR results will be given by the ongoing VALENCE study
  4. Triple therapy (Sofosbuvir plus PegIFN-RBV) with a short duration of 12 weeks, 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 argue 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 fixeddose 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 [8-10]. 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.

Reference

[1] Asselah T, Marcellin P. Interferon-free therapy with direct acting antivirals for HCV. Liver Int. 2013; 33 Suppl 1:93-104.

[2] Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med. 2013;368:34-44.

[3] Estrabaud E, Vidaud M, Marcellin P, Asselah T. Genomics and HCV infection: progression of fibrosis and treatment response. J Hepatol 2012;57:1110–1125.

[4] Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013 Apr 23.

[5] Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, Sulkowski MS, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment option. N Engl J Med. 2013 Apr 23.

[6]. Asselah T, De Muynck S, Broet P, Masliah-Planchon J, Blanluet M, Bieche I, et al. IL28B Hepatol, 2011;56:527-532.

[7] Sacks H, Chalmers TC, Smith H Jr. Randomized versus historical controls for clinical trials. Am J Med. 1982;72:233-240.

[8] Poordad F, Lawitz E, Kowdley KV, Cohen DE, Podsadecki T, Siggelkow S, et al. Exploratory study of oral combination antiviral therapy for hepatitis C. N Engl J Med. 2013;368:45-53.

[9] Kowdley KV, Lawitz E, Poordad F, Cohen DE, Nelson D, Zeuzem S, et al. Safety and efficacy of interferon-free regimens of ABT- 450/R, ABT-267, ABT-333 +/- ribavirin in patients with chronic HCV GT1 infection : results from the Aviator study. . J Hepatol, 2013; 58 (Suppl 1): A3.

[10] Zeuzem S, Asselah T, Angus P, Zarski JP, Larrey D, Mullhaupt B, et al. Efficacy of the protease inhibitor BI201335, polymerase inhibitor BI 207127, and ribavirin in patients with chronic HCV infection. Gastroenterology 2011;141:2047–2055.

Fig.s Legend

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 400 mg once daily) plus ribavirin for 12 weeks. Three of these groups also received PegIFNα-2a for 4, 8, or 12 weeks. Two additional groups of previously untreated patients with HCV genotype 2 or 3 infection received sofosbuvir monotherapy for 12 weeks or sofosbuvir plus PegIFNα-2a and ribavirin for 8 weeks. Two groups of patients with HCV genotype 1 infection received sofosbuvir and ribavirin for 12 weeks: 10 patients with no response to prior treatment and 25 with no previous treatment. The rate of sustained virologic response 24 weeks after therapy is reported.

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 12 weeks of treatment. All patients had an HCV RNA level below the limit of detection (i.e., <15 IU/ml) from week 4 until the end of treatment.

To view Figures and Tables please go to PDF (pp11-13) …..

Accepted Manuscript

Review

A.J. van der Meer, H. Wedemeyer, J.J. Feld, B.E. Hansen, M.P. Manns, S. Zeuzem, H.L.A. Janssen

PII: S0168-8278(13)00598-9
DOI: http://dx.doi.org/10.1016/j.jhep.2013.07.043
Reference: JHEPAT 4835

To appear in: Journal of Hepatology

Received Date: 7 May 2013
Revised Date: 17 June 2013
Accepted Date: 15 July 2013

Please cite this article as: van der Meer, A.J., Wedemeyer, H., Feld, J.J., Hansen, B.E., Manns, M.P., Zeuzem, S., Janssen, H.L.A., Is there sufficient evidence to recommend antiviral therapy in hepatitis C?, Journal of Hepatology (2013), doi: http://dx.doi.org/10.1016/j.jhep.2013.07.043

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

TITLE PAGE

Title
Is there sufficient evidence to recommend antiviral therapy in hepatitis C?

Authors
A.J. van der Meer, MD1 - a.vandermeer@erasmusmc.nl
H. Wedemeyer, MD, PhD2 - Wedemeyer.Heiner@mh-hannover.de
J.J. Feld, MD, PhD3 - Jordan.Feld@uhn.ca
B.E. Hansen, PhD1 - b.hansen@erasmusmc.nl
M.P. Manns, MD, PhD2 - Manns.Michael@mh-hannover.de
S. Zeuzem, MD, PhD4 - Zeuzem@em.uni-frankfurt.de
H.L.A. Janssen, MD, PhD1,3 - harry.janssen@uhn.ca

Affiliations
1 Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center
Rotterdam, Rotterdam, the Netherlands
2 Department of Gastroenterology, Hepatology, and Endocrinology, Medical School Hannover,
Hannover, Germany
3 Liver Centre, Toronto Western Hospital, University Health Network, Toronto, Ontario,
Canada
4 Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main,
Germany

Corresponding author
Adriaan J. van der Meer, MD
Erasmus MC, University Medical Center
Department of Gastroenterology and Hepatology
‘s Gravendijkwal 230, Room Ha 206
3015 CE Rotterdam, The Netherlands

Tel: +31 10 703 3038
Fax: +31 10 436 5916
Email: a.vandermeer@erasmusmc.nl

List of abbreviations in order of appearance
HCV, hepatitis C virus; SVR, sustained virological response; HALT-C, Hepatitis C Antiviral
Long-term Treatment Against Cirrhosis; HCC, hepatocellular carcinoma; RCT, randomized
controlled trial; OR, odds ratio; CI, confidence interval; MELD, Model for End-stage Liver
Disease; HVPG, hepatic venous pressure gradient; HR, hazard ratio.

Keywords Chronic hepatitis C, antiviral therapy, clinical efficacy, mortality

Word count manuscript 3313 (excluding references)

MANUSCRIPT

Summary

While patients with chronic hepatitis C virus (HCV) infection are treated in order to prevent liver-related morbidity and mortality, we rely on sustained virological response (SVR) as a virological biomarker to evaluate treatment efficacy in both clinical practice as well as in drug development. However, conclusive evidence for the clinical benefit of antiviral therapy or validity of SVR as surrogate marker, as derived from trials randomizing patients to a treatment or control arm, is lacking. In fact, the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) trial recently showed an increased mortality rate among interferon-treated patients compared to untreated controls. Consequently, the recommendation to treat patients with chronic HCV infection was challenged.

Here, we argue that the possible harmful effect of long-term low-dose pegylated interferon mono therapy, as was observed in the HALT-C trial cohort, cannot be extrapolated to potentially curative short-term treatment regimens. Furthermore, we discuss SVR as a surrogate biomarker, based on numerous studies which indicated an association between SVR and improvements in health-related quality of life, hepatic inflammation and fibrosis, and portal pressure as well as a reduced risk for hepatocellular carcinoma (HCC), liver failure and mortality.

Introduction

For the treatment of HCV infection we currently rely on interferon-based antiviral regimens. These therapies are very effective to prevent chronification of the acute infection, and also have good potential to eradicate HCV in those chronically infected [1-4]. Sustained virological response (SVR) is defined as absence of viremia 24 weeks after cessation of antiviral therapy, which showed long-term durability [5]. Consequently, antiviral therapy is considered successful and patients are usually considered ‘cured’ upon achievement of SVR. Although SVR may be the most widely used endpoint to evaluate antiviral treatment efficacy, it remains an indirect outcome measure. Indeed, the main reason to treat patients with chronic HCV infection is to improve their prognosis, by preventing cirrhosis-related morbidity and mortality. Are we convinced that the currently available treatment regimens achieve this goal so that we are right to recommend antiviral therapy to our patients?

Findings of a recent Cochrane meta-analysis

Recently, this discussion flared up due to the Cochrane review of Dr. Koretz and colleagues which aimed to assess the efficacy of interferon-based retreatment on solid clinical endpoints [6]. Their study included only randomized controlled trials (RCT) in which patients with chronic HCV infection and nonresponse or relapse to a prior interferon-based treatment course were randomized to interferon re-treatment or no treatment. Extensive literature searches resulted in seven eligible trials for meta-analyses. For each endpoint of interest a subset of these trials was used, depending on the described endpoints in the original study reports. Only three trials reported on clinical outcomes, with all-cause mortality as most definite endpoint [7-10]. These three studies solely included patients with significant hepatic fibrosis or cirrhosis, so that the meta-analyses on clinical outcomes focused on a difficult-to-treat subgroup of patients with advanced liver disease and prior treatment failure. Combining the results of these trials indicated a higher mortality rate among interferon retreated patients as compared to patients who did not receive further antiviral therapy, although this difference was not statistically significant (Odds Ratio [OR] 1.30, 95% Confidence Interval [CI] 0.95-1.79). However, in a sensitivity analysis including only the two largest trials with a low risk of bias, the disadvantage for patients who received interferon did reach statistical significance (OR 1.41, 95%CI 1.02-1.95). With respect to the other clinical endpoints, the occurrence of liver-related mortality, encephalopathy, ascites, spontaneous bacterial peritonitis, and hepatocellular carcinoma (HCC) was not found to differ significantly between re-treated patients and controls. An exception was variceal bleeding, which occurred significantly less often among the patients who were randomized to interferonbased therapy (OR 0.26, 95%CI 0.09-0.71).

A secondary aim was to assess the validity of SVR as a surrogate endpoint of antiviral therapy. Although four studies reported on this virological efficacy measure, only two trials included patients that actually attained SVR [8, 10]. However, because of the difficultto- treat patient population and the assessment of suboptimal treatment regimens for HCV eradication, the number of patients with SVR was very low. Nevertheless, and as expected, SVR occurred more often among the patients treated with interferon (OR 14.73, 95%CI 2.78- 77.97). The meta-analyses thus found a discrepancy between the effect of interferon therapy on the surrogate outcome measure SVR and the clinical outcome measure all-cause mortality, as both occurred more frequently among actively treated patients.

The harmful effect of interferon-based therapy on survival, which was found within clinical scenario of the included trials, led to the conclusion that (pegylated) interferon is not an effective treatment option for patients with chronic HCV infection who failed a previous antiviral treatment course. Since this negative effect of interferon-based therapy was not captured by suppression of HCV RNA, SVR failed the criteria to be considered as a valid surrogate endpoint [11-14]. Based on these findings, the authors subsequently stated that their results caution physicians to stop advocating antiviral interventions of any kind. Extrapolating their recommendation to anti-HCV therapy in general was thus not discouraged by the fact that their meta-analyses regarding all-cause mortality and SVR were almost exclusively based on the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALTC) trial. However, this important limitation warrants more careful interpretation of the results of this review in order to prevent unbalanced statements with potentially major consequences for the HCV-infected population.

HALT-C trial

In brief, the HALT-C trial included 1050 patients with chronic HCV infection and advanced hepatic fibrosis, who were randomized to receive 3.5 years of 90 μg pegylated interferon alfa-2a weekly or no treatment. Interferon maintenance therapy was not found to slow down clinical and/or histological liver disease progression [8]. In fact, a post-hoc analysis after prolonging the follow-up in this cohort indicated a poorer survival among patients in the interferon maintenance arm, as the cumulative 7-year mortality rate was 20% in treated and 15% in control patients (p=0.049) [9]. This impaired overall survival was predominantly caused by deaths of non-liver-related origin among patients with advanced hepatic fibrosis (but not yet cirrhosis). Based on this study, there is reasonable consensus that interferon maintenance therapy has no regular place in the treatment of chronic HCV infection. The findings of the recent Cochrane meta-analysis further underline this general perception.

There are, however, several reasons not to withhold short-term interferon-based therapy with the potential to eradicate the chronic HCV infection based on the HALT-C trial results. First, the patients in the control arm of the HALT-C trial were not treatment naive. All included patients showed an insufficient virological response to a full–dose pegylated interferon a nd ribavirin treatment course just prior to randomization. The survival among patients who received interferon maintenance therapy for 3.5 years was thus significantly reduced compared to that of patients who received short-term interferon-based treatment, indicating that the possible harmful effects of long-term pegylated interferon mono therapy cannot be projected onto standard 24-48 week regimens. Second, the increase in mortality only began to arise after 3 years of pegylated interferon therapy, suggesting that the possible off-target treatment effects require long-term continuous interferon stimulation. Third, patients in the control arm of the HALT-C more frequently underwent liver transplantation, which can substantially prolong the survival. Consequently, the survival also becomes dependent on non-patient-related factors such as the availability of donor livers. In fact, allocation of donor liver grafts based on the Model for End-stage Liver Disease (MELD score) favors those patients with poorest prognosis [15-17]. In the HALT-C trial, the 7-year cumulative rate of allcause mortality or liver transplantation as a combined endpoint was similar among the patients who received maintenance therapy (25%) versus those who did not (24%, p=0.45) [9]. Last, as mentioned in the Cochrane review, the excess mortality in a subgroup of the treated patients in the HALT-C study could be a chance finding. A significant increase in mortality due to interferon-based therapy was neither confirmed in another large RCT evaluating 5 years of maintenance therapy (Evaluation of PegIntron in Control of Hepatitis C trial), nor in smaller RCTs with shorter durations of interferon treatment [7, 10, 18-24].

Furthermore, it can be questioned whether it is legitimate to assess the validity of SVR as a surrogate marker with a trial that did not aim to induce SVR and in fact assessed an interferon regimen almost unable to result in this virological endpoint. Indeed, the power was limited as less than 4% of the treatment-experienced patients with advanced hepatic fibrosis attained SVR with the low-dose pegylated interferon maintenance regimen. Surely, these few patients could not significantly affect the clinical outcome in the treated arm as a whole, whether or not a harmful effect would have been present.

SVR as surrogate endpoint

Currently, many clinical development trials aim to increase the SVR rate of anti-HCV therapy. In support, there are numerous arguments to consider SVR as a relevant endpoint. Treatment-induced viral clearance is important to prevent transmission of HCV and, even with the risk for re-infection among injecting drug users, antiviral therapy will decrease the prevalence of chronic HCV infection and the incidence of its sequelae [25, 26]. Achieving SVR before liver transplantation in patients with advanced cirrhosis showed to eliminate the risk for post-transplant HCV recurrence, which is known to limit graft and overall survival [27- 29].

The majority of patients with chronic HCV infection are fortunate not to develop cirrhosis and the need for liver transplantation [30]. Although clinical outcome is often focused on solid cirrhosis-related endpoints such as hepatocellular carcinoma and mortality, it should be noted that the health-related quality of life is also impaired among patients with chronic HCV infection in absence of end stage liver disease [31]. Indeed, extrahepatic symptoms including fatigue, headaches, nausea, musculoskeletal and abdominal pain, and neuropsychiatric symptoms like depression and irritability can accompany the chronic infection [32]. Multiple studies indicated that the health-related quality of life, although further diminished for the duration of interferon-based treatment, improved compared to baseline in patients who attained SVR [31, 33-37]. As the total burden of chronic HCV infection extends beyond the liver, the impact of SVR on patient-reported outcome measures covering physical, social as well as mental health should be appreciated.

Still, the predominant consequences of infection with HCV should be sought in the liver, where continuous inflammation can lead to fibrosis. Relevant are thus the many histological studies which showed regression of hepatic inflammation and fibrosis, as assessed by semi-quantitative grading and staging scores (Ishak and METAVIR), after interferon-induced eradication of HCV as the causative agent [38-45]. These histological improvements were frequently observed among patients who had already developed cirrhosis as well. In addition, the quantitatively measured total liver collagen content was also described to reduce upon achievement of SVR [38, 46, 47]. In fact, among patients with cirrhosis who did not show an improved METAVIR score in their post-SVR liver biopsy, the total amount of fibrosis was still significantly reduced [38]. Two prior Cochrane metaanalyses indicated that, compared to no treatment, interferon significantly improved liver histology, and that regression of hepatic fibrosis was more often achieved with interferon and ribavirin combination therapy compared to interferon therapy alone [48, 49]. An important study by Mallet et al. linked the histological improvement following antiviral therapy to a favorable clinical outcome, as the ‘regression of cirrhosis’ was associated with reduced occurrence of cirrhosis-related morbidity and prolonged overall survival [40].

Improved histology could explain the reduction in portal pressure among patients with SVR, as measured by the hepatic venous pressure gradient (HVPG) [50-52]. Importantly, the HVPG is one of the best validated surrogate markers within the field of hepatology, as higher HVPG levels are associated with worse clinical outcome and RCTs have indicated that interventions to reduce the portal pressure resulted in both decreased HVPG levels as well as improved clinical outcome [12, 53-55]. Indeed, cirrhotic patients with chronic HCV infection who attained SVR did not develop esophageal varices or variceal bleeding, the most direct clinical complication of portal hypertension which is associated with substantial mortality [50, 56].

Several Western cohort studies assessed the relation between SVR and the occurrence of solid clinical endpoints such as liver failure, hepatocellular carcinoma, liver transplantation and death [56-61]. Our group was one of the first to show that patients with chronic HCV infection and advanced hepatic fibrosis had a reduced risk for liver failure as well as liver-related mortality already shortly after SVR [62]. Studies with longer follow-up confirmed that these events remained rare among successfully treated patients, and also indicated a strong association between SVR and reduced occurrence of HCC (hazard ratios [HR] varying from 0.19 to 0.38) [56-60]. A partially prospective study with up to 7.5 years of follow-up found that all-cause mortality or liver transplantation, as a combined endpoint, occurred significantly less often among patients with SVR compared to those with virological nonresponse (HR 0.17, 95%CI 0.06-0.46, p<0.001). In a multicenter study from Spain, which included 1599 patients with chronic HCV and human immunodeficiency virus coinfection who were followed for a median of approximately 5 years, SVR was independently associated with a reduced risk for non-liver-related, non-AIDS-related deaths (HR 0.35, 95%CI 0.13-0.93, p=0.036) [63]. Population-based studies indicated a favorable overall survival among HCVexposed patients without detectable HCV RNA. A study expected to include over 90% of all Danish patients tested for HCV RNA, found a significantly lower 5-year survival among patients with chronic HCV infection compared those who cleared HCV RNA (86% versus 92%, respectively) [61]. Recent data from the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer (R.E.V.E.A.L.)-HCV study, a prospective natural history study from Taiwan including 19,636 HBsAg-seronegative patients, indicated that the cumulative 18-year all-cause mortality rate was similar among anti-HCV seropositive patients with undetectable HCV RNA (12.4%) and anti-HCV seronegative patients (12.8%) [64]. In contrast, the mortality rate was substantially higher among anti-HCV seropositive patients with detectable HCV RNA (30.1%; p<0.001). Recently, important data have emerged regarding the association between SVR and reduced all-cause mortality as well. Multivariate analyses, stratified for HCV genotype, indicated SVR was independently associated with reduced risk for death of any cause (HR 0.51-070, p<0.01 for HCV genotypes 1, 2 and 3) among almost 17,000 American veterans with chronic HCV infection and varying stages of liver disease [65]. An update of our cohort, including 530 patients with HCV-induced advanced hepatic fibrosis or cirrhosis, resulted in a median follow-up duration of 8.4 years, and showed a 10-year cumulative all-cause mortality rate of 9% among patients with SVR compared to 26% among patients without SVR (p<0.001) [56]. Multivariate analyses indicated that SVR was the most important factor that was independently associated with improved survival, as patients with SVR had an approximately four-fold lower mortality risk compared those without SVR (HR 0.26, 95%CI 0.14-0.49, p<0.001). Together these large follow-up studies provide the most important data to endorse SVR as a relevant endpoint, as all showed similar and conclusive findings with strong adjusted hazard ratios for the association between SVR and improved clinical outcome.

Randomized controlled trials reporting on clinical outcome

It should, however, be recognized that cohort studies suggesting a clinical benefit of SVR share a similar limitation. Despite extensive multivariate analyses, the association between SVR and improved clinical outcome remains potentially influenced by unmeasured confounding factors [66]. In other words, observational studies cannot rule out the possibility that patients who have attained SVR are merely a selection of patients who would have a favorable natural history if left untreated as well. Indeed, several host and viral factors were related to a favorable long-term clinical outcome as well as to an adequate virological response to interferon-based therapy [56, 58, 59, 67, 68]. Thus, the frequently reported association between SVR and improved clinical outcome from cohort studies neither validates SVR as a surrogate endpoint nor confirms that antiviral therapy has clinical benefit. This requires RCTs to indicate that interferon therapy positively affects SVR as well as clinical outcome [11-14]. As discussed, this was not the case in latest Cochrane metaanalysis [6].

Since RCTs on solid clinical endpoints usually require long and costly prospective follow-up, especially in a slowly progressive disease as chronic hepatitis C, it is not surprising that only few have been performed. The trials that have been performed all exclusively included patients with advanced liver disease, probably because these patients are at highest risk for clinical events. Due to the restriction to interferon retreatment, not all RCTs reporting on clinical outcome events were included in the recent Cochrane review. Unfortunately, however, most of the additional trials are limited by a low number of included patients and the use of interferon-based regimens with relatively low antiviral efficacy [10, 18- 24]. Especially among patients with cirrhosis, SVR rates of the early interferon-based antiviral regimens have been poor [69]. Although several trials did report a clinical benefit of interferon-based antiviral therapy, the results varied and not all positive trials were without controversy [10, 18, 22, 23]. Therefore, definite evidence for the clinical efficacy of interferon therapy was never established and SVR was never formally validated. The use of SVR as surrogate outcome measure thus remains with some uncertainty. Nevertheless, another recent Cochrane meta-analysis did indicate that the combination of interferon and ribavirin significantly reduced morbidity plus mortality, as a composite clinical endpoint, compared to interferon mono therapy [49]. This finding is in line with the increase in SVR rate due to the addition of ribavirin to interferon therapy [70, 71].

Presently, new treatment regimens and the introduction of protease inhibitors have substantially increased the antiviral efficacy of interferon-based therapy. Also for patients with cirrhosis, pegylated interferon and ribavirin combination therapy (with the addition of a protease inhibitor for those with HCV genotype 1) is likely to increase SVR rates to above 50% [2-4, 72-76]. None of the RCTs on clinical efficacy have assessed a full-dose pegylated interferon and ribavirin treatment course, however, while this has been the standard of care over the last decade. Future interferon-free regimens are even expected to further enhance antiviral efficacy, while simultaneously reducing treatment duration and improving side-effect profiles [77, 78]. Thus, assuming the biologically plausible causal relation between HCV eradication and improved clinical outcome, RCTs with current antiviral regimens would have higher power to show a clinical benefit of antiviral therapy as well as to validate SVR as surrogate endpoint. However, the accumulated data suggesting patients benefit from SVR impedes justification of trials in which patients are denied a chance to eradicate their chronic HCV infection. Ethical concerns thus prevent us from performing the trials which could bring conclusive evidence regarding the clinical efficacy of antiviral therapy. Such trials should thus not be awaited for the decision to initiate antiviral therapy in the individual patient.

Conclusion

To conclude, we are aware that definite proof for the surrogacy of SVR and clinical benefit of interferon-based antiviral therapy is lacking. Nevertheless, SVR has been repeatedly associated with improvements in health-related quality of life, hepatic inflammation and fibrosis, and portal pressure as well as with a reduced occurrence of solid clinical endpoints such as hepatocellular carcinoma, liver failure and death. Collectively, this strongly argues that SVR is a patient-relevant endpoint and reasonably likely to predict clinical benefit [13]. Furthermore, there is no clear evidence to suggest a long-term harmful effect of 24-48 weeks of interferon-based therapy by which we usually attempt to achieve this virological outcome measure in our patients. With future triple therapy, a treatment duration of 12 weeks might even be sufficient [79]. The increased mortality rate in a subgroup of patients who received long-term interferon maintenance therapy is not representative for short-term antiviral therapy with the potential to result in SVR. Nevertheless, we do acknowledge that interferon-based therapy is accompanied by substantial side-effects, which was also highlighted again by the recent meta-analysis [6]. Thus, careful patient selection remains a necessity at this time, and better tolerated interferon-free treatment regimens with combinations of direct-acting antiviral agents are urgently required. We oppose, however, that the results of the recent Cochrane meta-analysis, or more specifically the HALT-C study, should discourage physicians from treating their patients with chronic HCV infection in general.

Key Points

1. The recommendation to treat hepatitis C was recently challenged because patients receiving interferon maintenance therapy within the HALT-C trial had an increased mortality rate as compared to controls, despite attaining SVR more frequently.

2. The possible increase in mortality due to long-term interferon maintenance therapy cannot be extrapolated to the commonly applied short-term interferon-based regimens with the potential to eradicate the HCV infection.

3. Achievement of SVR has been repeatedly associated with regression of hepatic fibrosis, reduction of portal pressure, a lower risk for liver failure and hepatocellular carcinoma, as well as with an improved overall survival.

4. As viral eradication is likely to improve their prognosis, physicians should continue to treat their patients with chronic HCV infection.

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