New treatments for chronic hepatitis C virus infection

Médecine et maladies infectieuses 41 (2011) 579–587

General review

New treatments for chronic hepatitis C virus infection Nouveaux traitements de l’infection chronique par le virus de l’hépatite C M. Corouge , S. Pol ∗ Unité d’hépatologie, hôpital Cochin, université Paris-Descartes, AP–HP, Inserm U-1016, 27, institut Cochin, rue du Faubourg-Saint-Jacques, 75679 Paris cedex, France Received 24 February 2011; accepted 6 April 2011 Available online 20 July 2011

Abstract The treatment of hepatitis C virus infection (HCV) by a combination of pegylated interferon and ribavirin, according to early viral kinetics, leads to a sustained virological response (SVR) in more than 50% of patients with chronic infection. This SVR is a complete recovery of the infection but more than 50% of genotype 1-infected patients do not achieve SVR. A better understanding of the viral cycle, and the characterization of viral enzymes which are potential targets, resulted in the development of new molecules, direct acting antivirals (DAA) targeted against HCV, either specific of genotype 1 (protease inhibitors NS3/NS4A and polymerase inhibitors NS5B) or with a wider spectrum (NS5A or entry inhibitors), and non-specific antivirals (new interferons, cyclophilin inhibitors). We describe the results of phase II and III trials which clearly demonstrated a 20 to 30% increase in the SVR rate of genotype 1-infected patients, either naïve or treatment experienced. These new drugs should be approved by the end of 2011, after a temporary approval for compassionate use in cirrhotic patients with previous relapse or partial response to the combination therapy. In the future, the main limitations of triple therapy will be safety (cutaneous rash or anemia which may be controlled), cost, compliance, viral resistance, and drug interactions that must be avoided by educating patients and physicians. © 2011 Elsevier Masson SAS. All rights reserved. Keywords: Hepatitis C virus; Pegylated interferon; Ribavirin; Protease inhibitors

Résumé Le traitement par interféron pégylé et ribavirine, adapté à la réponse virologique précoce permet d’obtenir une virosuppression efficace et durable chez plus de 50 % des patients atteints d’hépatite C chronique. Cette réponse virologique soutenue (RVS) correspond à une véritable guérison mais plus de 50 % des patients infectés par un génotype 1 du virus de l’hépatite C ne sont pas guéris. L’amélioration de la compréhension du cycle de réplication virale et la caractérisation d’enzymes virales, cibles thérapeutiques potentielles, a permis le développement de nouvelles molécules, antiviraux directs spécifiques du virus de l’hépatite C, du génotype 1 (inhibiteurs de la protéase NS3/NS4A et inhibiteurs de la polymérase NS5B) et à plus large spectre (inhibiteurs de la NS5A, inhibiteurs d’entrée) ou antiviraux non spécifiques du virus de l’hépatite C (nouveaux interférons, inhibiteurs de la cyclophiline). Nous détaillerons les études de phase II et III des inhibiteurs de protéases qui ont clairement montré une augmentation de la RVS de 20 à 30 % chez les patients naïfs ou non répondeurs (NR) à la bithérapie et surtout qui auront probablement leur autorisation de mise sur le marché à la fin de 2011 après avoir obtenu une autorisation temporaire d’utilisation pour les cirrhotiques répondeurs partiels ou rechuteurs à la bithérapie. À l’avenir, les principales limites de ces trithérapies seront la tolérance (cutanée ou hématologique, contournable), le coût, l’observance thérapeutique, les résistances virales et les interactions médicamenteuses qu’il nous faudra dépasser par une éducation thérapeutique à la fois des patients mais aussi des cliniciens. © 2011 Elsevier Masson SAS. Tous droits réservés. Mots clés : Virus de l’hépatite C ; Interferon pégylé ; Ribavirine ; Inhibiteurs de protéases

1. Introduction

∗

Corresponding author. E-mail address: [email protected] (S. Pol).

0399-077X/$ – see front matter © 2011 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.medmal.2011.04.003

A combination of pegylated interferon and ribavirin, adapted to the early virological response, induces an effective and sustained suppression of viruses in more than 50% of patients

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presenting with chronic hepatitis C. This sustained virological response (SVR) is a complete virological recovery allowing for the inactivation of necrotic and inflammatory activity leading to reversibility of fibrosis or even of early cirrhosis, provided there is no hepatic co-morbidity. A better understanding of the viral cycle, and the characterization of viral enzymes which are potential targets, resulted in the development of new molecules, direct acting antivirals (DAA) targeted against hepatitis C virus (HCV), and more specifically of genotype 1 (protease inhibitors NS3/NS4A, polymerase inhibitors NS5B) or with a broader spectrum (inhibitors the multiple function protein NS5A, entry inhibitors) and nonspecific HCV antivirals (new interferons, cyclophilin inhibitors). Telaprevir and boceprevir, oral protease inhibitors targeting the NS3/NS4A region of the virus, may now be used in combination with the pegylated bitherapy, in cirrhotic patients infected by a genotype 1, with previous relapse or partial response to this combination therapy. This temporary approval for compassionate use (TAU) was given once phases II and III had clearly proved a 20 to 30% SVR increase in patients either naïve of treatment or not responding (NR) to bitherapy [1–3]. 2. Effectiveness and limits of pegylated bitherapy The reference treatment for patients presenting with chronic hepatitis C is a pegylated interferon (IFN) and ribavirin [4] combination for 24 (genotypes 2 and 3) to 48 weeks (genotypes 1 and 4). The treatment’s main goal is viral eradication, or a sustained virological response (SVR) defined by an undetectable HCV RNA six months after the end of treatment. In 55% of cases (around 45% of genotypes 1, 65% of genotypes 4, 75% of genotypes 3, and more than 85% of genotypes 2), the pegylated IFN and ribavirin combination adapted to the virological response under treatment gives an effective and sustained virus suppression [5–7]; it is a true virological recovery [8,9]. Indeed, when there is no hepatic comorbidity, patients with a SVR not only no longer worsen their hepatic fibrosis but can even present with regression at 0.5 fibrosis units per year [8,10]. Thus, the cirrhotic patients with a SVR present with less carcinomatous or non-carcinomatous complications of cirrhosis and a significantly higher survival rate compared to non-responders (NR) [11,12]. For chronic hepatitis C patients in treatment failure the disease may evolve to cirrhosis, hepatic failure, hepatocellular carcinoma, and death [13]. Few therapeutic options are available for NR or relapsers. The contribution of maintenance treatment with low dose pegylated IFN to delay or prevent evolution to cirrhosis and its complications were assessed by three studies [14–16]. Despite a significant improvement of transaminases, viral load, and necrotic and inflammatory activity, the maintenance treatment did not seem to give any significant clinical benefit except for a sub-group of severely cirrhotic patients [14]. Most chronic hepatitis C patients not having responded to an initial treatment are infected by genotypes 1 or 4, and have a SVR in case of re-treatment with pegylated bitherapy only in 15% of NR and 25% of relapsers [17,18], with several adverse

effects impacting the quality of life. These figures are reduced in case of extensive fibrosis or cirrhosis (less than 10%), or comorbidity (HIV co-infection for example) and stress the need for new treatments. 3. New molecules 3.1. Genome structure The HCV genome contains a single-stranded, positive-sense RNA molecule of 9600 nucleotide bases, with one long open reading frame coding for a large polyprotein of about 3000 amino acids. It undergoes co- and post-translational cleavage by host and viral proteases to yield individual viral proteins. The reading frame is located between two untranslated regions (UTR) located on ends 5’ and 3’. 5’ UTR has a ribosome binding site (Internal Ribosome Entry Site [IRES]), essential for starting the translation of viral RNA. Thus, 5’ UTR plays an essential part in replication of viral RNA at high levels, with sequences located upstream of and in the IRES. 3’ UTR could bind various cellular proteins, and especially Polypyrimidine Tract Binding protein (PTB), whose bond with HCV IRES negatively affects the initiation of translation [19]. 3’ UTR could stimulate IRES activity, suggesting its potentially important part in the synthesis of the negative-strand RNA during replication and in the regulation of viral protein translation. 3.2. Targets of antiviral drugs and direct acting antivirals agents: protease, polymerase, and NS5A inhibitors Maturation of the polyprotein leads to the synthesis of at least ten viral proteins with multiple and different functions: structural proteins (core and capsid protein, glycoprotein E1 and E2, viroporin p7) and non-structural proteins, potential targets for therapy (proteins NS2, NS3, NS4A, NS4B, NS5A, NS5B). NS3A participates in the production of mature viral proteins by cleaving the polyprotein downstream of the following sites: NS3/NS4A, NS4A/NS4B, NS4B/NS5A, and NS5A/NS5B. NS4A has a transmembrane domain in its N-terminal part allowing anchoring of NS3 and of the NS3/4A protein at the endoplasmic reticulum membrane level [20] and thus acts as a cofactor for protein NS3. It also interacts with NS5A by regulating its phosphorylation. NS5A is known to be the protein of resistance to IFN␣. It interacts with protein kinase dsRNA dependent (PKR) and induces the secretion of IL8, a pro-inflammatory cytokine responsible for the inhibition of IFN-␣ antiviral effects. NS5B is the RNA dependent RNA polymerase (RdRp) essential for HCV replication. NS5B proteins are organized in a multimolecular replication complex (because of direct interactions with proteins NS3, NS4A, and through these with NS4B and NS5A) in a functional oligomer at the endoplasmic reticulum membrane level and synthetize RNA in a cooperative manner. These RdRp–RdRp interactions could be implicated in the regulation of replicase activity [21].

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We will describe the recently published results of new molecules, inhibitors of these viral proteins. Finally, two HCV entry inhibitors are currently studied in phase 1 trials. 3.3. Other antiviral strategies Cyclophilins are ubiquitous proteins that exhibit peptidyl prolyl cis-trans isomerization, catalyzing the isomerization of peptide bonds, and facilitate the folding of proteins. The cyclosporine–cyclophilin complex has a part in the immunosuppressive activity of cyclosporine, but cyclophilin B also regulates RdRp. In a recent phase II study, Debio 025, a cyclophilin inhibitor, was tested in patients presenting with chronic hepatitis C naïve of treatment (genotypes 1, 2, 3, and 4). Several doses of Debio 025 combined with pegylated IFN-␣ during four weeks were compared to monotherapy. Reported results were undetectable rates superior to 60% for genotypes 1/4, and superior to 80% for genotypes 2/3, much higher than with monotherapy alone [22]. Nitazoxanide (NTZ) is another interesting therapeutic option; it is used as an antiparasitic against cryptosporidiosis, but its mechanism of action against hepatitis C remains unknown. In a study including naïve genotype 4 patients, the group treated by 12 weeks of NTZ followed by 36 weeks of tritherapy (NTZ and pegylated bitherapy) reached an SVR of 79% versus 50% for the group with pegylated bitherapy only [23]. Nevertheless, the most recent results plus for genotype 1 infection in naïve or NR patients are disappointing. Activation of the TLR-9 receptor, present on the surface of immune cells, induces the stimulation of these cells (activation of NK cells and lymphocytes B, secretion of endogenous IFN-␣ by dendritic cells). Promising results have been reported for some TLR agonists but their development was stopped. The phase I study results of a new agonist of Toll Like Receptors TLR-9 (IMO 21-25) were recently published [24]. The effectiveness of IMO-21-25 was tested for 28 days in 41 patients (40 genotype 1), NR to conventional pegylated bitherapy. This treatment led to the activation of several immunity markers, which in turn increased in an important dose-dependent serum concentration of endogenous IFN-␣. A decrease of the viral load was also noted also in a dose-dependent way, correlated to the intensity of IFN␣ induction. This phase I study suggests that the agonist TLR-9 IMO-21-25 has a limited but positive antiviral effectiveness in NR patients. Concerning immunotherapy, GlobeImmune (GI-5005) is an anti-HCV protein vaccine (NS3-core fusion protein expressed by Saccharomyces cerevisiae) able to induce immune responses anti-HCV CD4+ and CD8+. In a phase II study including 133 patients mostly naïve but also with some partial NR, genotype 1, pegylated bitherapy alone was compared to pegylated bitherapy combined to vaccine therapy [25]. SVR was observed in 59% (vaccine) versus 48% (controls) of naïve patients, and in respectively 11% and 5% of NR (NS). The results became significant by pooling results of naïve patients and NR. Therapeutic vaccination may have a beneficial effect in combination with pegylated bitherapy, but this effect remains limited. The role of this strategy in new therapeutic combinations remains to be determined

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(prevention of relapse? promotion of viral eradication in future combinations without IFN?). Other research options are under development such as taribavirin or pegylated lambda IFN. This is a new type III interferon whose less ubiquitous receptor distribution than type I IFN could bring a better tolerance and even an improved effectiveness [26]. Taribavirin is a ribavirin prodrug that is, with a weight-dependent dose, as effective as ribavirin with less adverse effects, especially for anemia [27]. Other therapeutic strategies are being studied such as inhibitors of HCV morphogenesis with iminosugars: they inhibit the secretion of virions and decrease the infectious power of new viral particles in in vitro models. The interest of these molecules is the absence of in vitro resistant virus emergence. A phase IIa study on celgosivir (migenix) in combination with pegylated bitherapy reported an early virological response at 12 weeks superior to pegylated bitherapy in NR genotype 1 patients [28]. 4. Results for new molecules The most recent and advanced progress concerns antiviral treatments specifically targeting HCV, and agents inhibiting HCV protease or polymerase. The publication of phase II studies and communications in recent congress of phase III studies for HCV protease inhibitors telaprevir (Incivo© ) and boceprevir, should lead to, after temporary approval for use obtained on March 1, 2011, a marketing authorization by the end of 2011. 4.1. Results for telaprevir Telaprevir is a powerful and selective inhibitor of serine protease NS3/4A. Two phase IIb studies were made in naïve genotype 1 non-cirrhotic patients, one in the USA (Prove 1) [1] and the other in Europe (Prove 2) [2]. Both studies proved the superiority of tritherapy over bitherapy. In the Prove 1 study (250 patients), four groups were compared; T12PR12: telaprevir + pegylated IFN-␣-2a + ribavirin for 12 weeks, T12PR24: telaprevir + pegylated IFN-␣-2a + ribavirin for 12 weeks then pegylated IFN-␣-2a + ribavirin for 12 weeks, T12PR48: telaprevir + pegylated IFN-␣-2a + ribavirin for 12 weeks then pegylated IFN-␣-2a + ribavirin for 36 weeks, and the control group PR48: pegylated IFN-␣-2a + ribavirin + placebo for 48 weeks. The SVR rates were respectively: 35%, 61% (P = 0.02 compared to group PR48), 67% (P = 0.002), and 41%. In the Prove 2 European study, 323 patients (56% of patients included in France) were randomized in four arms: PR 48, T12/PR24, T12/PR12, T12/P12: telaprevir + pegylated IFN-␣-2a for 12 weeks. The SVR rates were respectively: 48%, 69% (P = 0.04), 60% (P = 0.12), and 36% (NS) (Fig. 1). Adding telaprevir to pegylated bitherapy clearly increased the SVR and not using ribavirin in the therapeutic scheme decreased it. For patients infected by a genotype 1, relapsers or NR to a previous pegylated bitherapy, the phase II Prove 3 study [29] compared four groups: PR 48, T12/PR24, T24/PR48, and T24/P24. The patients characteristics were: male sex for 65 to 71%, 66% of genotype 1a and 33% of genotype 1b, 60% de NR (true NR and partial NR), 35% of relapsers and 5% of

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Fig. 1. Results of the european Prove 2 trial (phase II, [2]) comparing 12-week tritherapy (telaprevir/pegasys/ribavirin) or bitherapy (telaprevir/pegasys) for 12, 24 or 48 weeks to usual bitherapy in treatment naïve patients infected by genotype 1. Résultats de l’essai européen Prove 2 (phase II, [2]) comparant la trithérapie (telaprevir/pegasys/ribavirine) ou la bithérapie (telaprevir/pegasys) de 12 semaines avec un traitement de 12, 24 ou 48 semaines au total à la bithérapie usuelle chez des patients naïfs de traitement infectés par un génotype 1.

escapers, 11 to 20% of cirrhosis, and 23 to 29% of severe fibrosis. A 48-week long treatment (SVR: 52%) did not seem to bring any benefit for SVR compared to 24 weeks (SVR: 51%), probably because of a higher rate of treatment interruption in this group. The rates of SVR were significantly lower without ribavirin (24% in the T24P24 arm). In NR, the rates of SVR were respectively 39 and 38% in the T12/PR24 arm and T24/PR48 against 9% in the treatment standard arm (P < 0.05). In relapsers, the rates of SVR were respectively 69, 76, and 29%.The effectiveness of telaprevir in triple combination for patients infected by genotype 1 HCV in therapeutic failure after a first treatment with pegylated interferon and ribavirin was also evaluated in study 107, presented at EASL 2010 [30].Hundred and seven patients infected by genotype 1 HCV, included in control groups (standard bitherapy, PR) of phase II studies (Prove-1, 2 and 3), in therapeutic failure, were re-treated with telaprevir in triple combination with pegylated IFN-␣ and ribavirin (TPR) for 12 weeks, then with the standard treatment a specific length according to the virological response at weeks 4 and 12. Patients with undetectable RNA at weeks 4 and 12 were treated for 24 weeks, patients with undetectable RNA at S4 and/or S12, for 48 weeks. Finally, re-treatment by telaprevir in triple combination for patients in therapeutic failure after a first treatment with pegylated interferon and ribavirin, features an important probability of cure (59%), whether with escapers (75%), relapsers (97%), partial responders (55%), or non-responders (37%). For genotypes 2 and 3 patients, a phase IIa study, presented at EASL 2010 [31], compared the three following treatment schemes in 49 naïve patients: telaprevir (T) alone for 14 days, then bitherapy pegylated IFN-␣ 2a and ribavirin for 24 weeks (T2PR24); telaprevir in triple combination for 14 days, then pegylated IFN and ribavirin (TPR2PR22); standard treatment for 24 weeks (PR24). In the T2PR24 arm, the viral load decreased

at two weeks by 3.66 log in genotype 2 patients, and 0.54 log in genotype 3 patients. For genotype 2 patients, the SVR rates were respectively 56, 100, and 89%; and for genotype 3 patients the SVR rates were respectively: 50, 67, and 44%. Telaprevir, in vivo, has a very good activity on genotype 2 HCV strains and a very weak activity on genotype 3 strains. The monotherapy arm in this study confirmed the antiviral activity on genotype 2 patients and the weak activity on genotype 3. In genotype 2 patients, the SVR rate was more important when telaprevir was given in combination with pegylated interferon and ribavirin. For genotype 4 (not present in this study), the results obtained on a small population were between those observed for genotypes 1 and 3, suggesting nevertheless, as for genotype 2, a synergistic action. Three phase III studies assessing the effectiveness of telaprevir are available. The Advance and Illuminate studies were made on naïve genotype 1 patients. The Advance trial included 1088 patients randomized in three groups [32]. One was given telaprevir (750 mg/8 h) combined with pegylated IFN-␣-2a 180 ␮g/week and ribavirin 1000-1200 mg/day for 12 weeks (T12PR), the second group was given the same treatment but for 8 weeks, followed by four weeks of pegylated bitherapy with placebo (T8PR). The length of treatment with pegylated IFN + ribavirin (24 or 48 weeks) was adapted to the response. This is the concept of response guided therapy (RGT): at 12 weeks, patients in arms T12PR and T8PR continued pegylated bitherapy for 12 weeks in case of rapid and extended virological response (eRVR: extended Rapid Virological Response; HCV RNA undetectable at four weeks and 12 weeks) and 36 weeks in the absence of eRVR. The control arm was given pegylated bitherapy for 48 weeks, whatever the response. The two treatments including telaprevir were significantly more effective than standard treatment, whatever the fibrosis stage and the ethnic

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T12PR

PR

P<0.0001

100 90

75

80

% RVS

T8PR

70

P<0.0001 69

60

44

50 40 30 20 10 0

n/N =

271/363

250/364

158/361

SVR Fig. 2. Results of the Advance trial (phase III, [32]) comparing the 12 or 8week tritherapy (telaprevir/pegasys/ribavirin) for 24 or 48 weeks, according to early viral kinetics, to the usual bitherapy in treatment naïve patients infected by genotype 1. Résultats de l’essai « Advance » (phase III, [32]) comparant la trithérapie (telaprevir/pegasys/ribavirine) de 12 ou huit semaines pour des durées de 24 ou 48 semaines selon les cinétiques virales précoces à la bithérapie usuelle chez des patients naïfs de traitement infectés par un génotype 1.

origin. The two courses of telaprevir treatment, respectively 8 (T8) and 12 (T12) weeks in triple combination, tested in this phase III trial gave similar results (SVR 69% versus 75%, control group: 44%) (Fig. 2). In case of eRVR in the telaprevir groups (57.6% of patients), the SVR rate was high, reaching respectively 89% and 83% in groups T12PR and T8PR, and 97% in the control group (8% of patients). But, close to half of the patients with detectable RNA at four weeks and/or 12 weeks had an SVR in the telaprevir patient groups (54% in group T12PR and 50% in group T8PR against 39% in the control group). The rate of virological failure after 12 weeks, during the treatment period with pegylated bitherapy, were higher in the T8/PR arm (10.2%) than in the T12/PR arm (5.0%) and were associated with a wild virus strain and variants with low level of resistance, which stresses the benefit of four more weeks of telaprevir to decrease virological failure. These results confirm that undetectable viral RNA at four weeks is a major prognostic factor for SVR with standard treatment, but also with a triple combination including a protease inhibitor, and in case of eRVR. The difference between an 8-week tritherapy versus a 12-week one seems limited in terms of cure, if tolerance problems require reducing the tritherapy to less than 12 weeks. The Illuminate study assessed telaprevir [750 mg/8 h] combined to standard bitherapy for 12 weeks (IFN-␣ [180 ␮g/week.] and ribavirin [1000 à 1200 mg/day according to weight]), followed by standard bitherapy for a length determined by the virological response at four and 12 weeks [33]. Patients with an eRVR were randomized (at 20 weeks) in two groups, treated for respectively 24 (T12PR24) or 48 weeks (T12PR48). Patients with a detectable RNA at four and/or 12 weeks were treated for 48 weeks. The objectives were to compare the SVR rates for a 24-week and 48-week treatment in patients with an eRVR and to assess tolerance to telaprevir in combination with standard

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bitherapy. In patients with an eRVR (65% of patients), the SVR rates were comparable between the group of patients treated for 24 weeks (T12P/R24) and the group of patients treated for 48 weeks (T12P/R48). If the rate of cure was analyzed according to the degree of fibrosis or the ethnic origin, there was no difference between 24 or 48 weeks of treatment. This study thus confirmed that 24 weeks of treatment did not seem less effective than 48 weeks in case of eRVR. The benefit of a lead-in phase with pegylated bitherapy was assessed in patients infected by genotype 1, non-responders and relapse in the Realize study [34]. Six hundred and fifty patients were randomized in three groups: PR48, T12PR48, and an arm including pegylated bitherapy for four weeks, then 12 weeks of tritherapy, then 32 weeks of pegylated bitherapy. The SVR rates were respectively 16, 64, and 66%; the four weeks did not bring any benefit. The SVR rates were, according to the previous response, 31% (versus 5% for the PR48 arm) for nullresponders, 86% (versus 24%) for relapsers, and 57% (versus 15%) for partial responders. The virological follow-up at three years of part of the Prove 1, 2, 3 and study 107 patients was reported in the Extend trial [35]. The sustainability of virological response in patients with SVR was analyzed as well as the modifications of resistance variants in patients without SVR. Eight hundred and sixty-seven patients were eligible, having received at least one dose of telaprevir in the four studies, and whose HCV sequences were available on inclusion. This intermediate analysis showed that SVR was maintained after telaprevir treatment, for 122 of the 123 patients whose HCV RNA remained undetectable for a median followup of 22 months. For patients without SVR, resistant variants associated to a decreased susceptibility to telaprevir were no longer detected in 89% of the cases during the study period. 4.2. Results for boceprevir Boceprevir is a protease inhibitor that forms a reversible covalent complex with protease NS3 and which has an antiviral activity in replicons, in vitro HCV replication systems [36]. In the Sprint 1 phase II study, the goal was to assess the most effective therapeutic strategy for the management of genotype 1 patients naïve of any treatment, treated by boceprevir in combination with pegylated IFN-␣-2b–ribavirin bitherapy [37]. The length of treatment was 28 or 48 weeks, each arm benefiting or not from pre-treatment with pegylated IFN-␣-2b + RBV (lead-in phase) for four weeks before administration of boceprevir in tritherapy, the control group was treated for 48 weeks by pegylated bitherapy. The lead-in phase objectives were to have pegylated IFN and ribavirin concentrations reach a steady state before introduction of boceprevir and to potentially reduce the emergence of resistance mutations by first decreasing the viral load. The possibility to reduce ribavirin doses was also studied with various doses: standard ribavirin doses (800 à 1400 mg/day) or weak doses (400 to 1000 mg/day) in the second part of the study, knowing protease inhibitors worsen the anemia induced by ribavirin. The SVR was 38% for the standard bitherapy arm against 54 or 56% (with a lead-in) in the two 24-week tritherapy arms, and 67 to 75% (with a lead-in) for the 48-week tritherapy

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Fig. 3. Results of the Sprint 1 trial (phase II, [37]) comparing a 28 or 48-week course of tritherapy (boceprevir/pegintron/ribavirin) with or without a previous four week bitherapy (lead-in phase) to usual bitherapy for treatment naïve patients infected by genotype 1. Résultats de l’essai Sprint 1 (phase II, [37]) comparant la trithérapie (boceprevir/pegintron/ribavirine) précédée ou non d’une bithérapie de quatre semaines (lead-in phase) et pour une durée de 28 ou 48 semaines à la bithérapie usuelle chez des patients naïfs de traitement infectés par un génotype 1.

(Fig. 3). In the first part of the study, the SVR rates were significantly higher in all the tritherapy arms compared to the bitherapy arm. The SVR rate in the weak-dose ribavirin arm was only 36%. The impact of lead-in treatment on SVR remains to be checked since it was present in the 48-week arm, and not in the 24-week arm. A phase II study on NR was made so as to determine the effective dose of boceprevir (Respond I), the length of treatment, tolerance, and the usefulness of ribavirin for the optimization of SVR. 357 genotype 1 patients, non-responders or partial responders, were included. The study, too complex, featured seven arms with different doses of or without boceprevir, and with or without ribavirin. A lead-in phase included pegintron alone. The SVR rates were 2% with pegylated standard bitherapy and up to 14% in the tritherapy group, ribavirin proved necessary for the effectiveness of treatment. The results were difficult to analyze because several arms did not include ribavirin. The phase II trial, Sprint 2 [37], assessing the effectiveness of boceprevir combined with pegylated IFN-␣ and ribavirin for 24 or 44 weeks according to the virological response between weeks 8 and 24, included 1097 genotype 1 naïve patients (including 159 Afro-Americans). The patients were randomized in three groups: PR48 (pegylated bitherapy for 48 weeks), BOCPR48 (pegylated bitherapy for 4 weeks, the lead-in phase, then boceprevir (B = 2400 mg/d three times a day) tritherapy for 44 weeks), BOC/TGR (pegylated bitherapy for four weeks, the lead-in phase then boceprevir tritherapy for 24 weeks), then 20 weeks more of pegylated bitherapy when RNA was detectable between weeks 8 and 24. The Caucasian patient groups treated with BOC/PR had a significantly higher response than the control group (SVR: PR48 = 40%; BOC/TGR = 67%; BOCPR48 = 68%). For Afro-American patient groups (159 patients), boceprevir also significantly improved the chances of cure compared to standard treatment (SVR: PR48 = 23% BOC/TGR = 42%; BOCPR48 = 53%) (Fig. 4). The probability of cure under treatment was significantly higher when virological response was observed at four weeks (decrease ≥ 1 log compared to the pre-treatment ratio) and without decrease of

Fig. 4. Results of the Sprint 2 trial (phase III, [37]) comparing tritherapy (boceprevir/pegintron/ribavirin) for 24 or 44 weeks (according to early viral kinetics) with a previous four week bitherapy (lead-in phase) to the usual bitherapy in treatment naïve patients infected by genotype 1. Résultats de l’essai Sprint 2 (phase III, [37]) comparant la trithérapie (boceprevir/pegintron/ribavirine) de 24 ou 44 semaines (selon les cinétiques virales précoces) précédée d’une bithérapie de quatre semaines (lead-in phase) à la bithérapie usuelle chez des patients naïfs de traitement infectés par un génotype 1.

RNA superior to 1 log, the probability of selecting resistance variants increased. These results stress the importance of the lead-in phase as prognostic marker of response to treatment during tritherapy with boceprevir (contrary to telaprevir). The results observed in group PR48 confirm the importance of response at week 4 for the early definition of non-response (SVR: 52% in case of RVR versus 5% otherwise). And for TGR, shortening the length of treatment from 48 to 24 weeks in patients with an undetectable RNA after eight weeks (around half of these naïve patients) did not seem to lower chances of cure. For NR, boceprevir was assessed in the phase III study Respond 2 [38]: 403 patients in therapeutic failure after treatment with pegylated IFN and ribavirin were included, with 259 relapsers and 144 partial NR, strictly defined during the previous treatment by a viral load decrease at week 12 is superior to 2 log UI/mL but with a persistently detectable HCV RNA after 24 weeks. The patients were randomizes in three arms: control arm with pegylated IFN-␣-2b + ribavirin for 48 weeks; TGR bitherapy arm for four weeks (lead-in phase) followed by tritherapy with boceprevir (BOC) for 32 weeks, with treatment interruption at 36 weeks for rapid responders (RNA undetectable after eight weeks), and 12 more weeks of treatment (up to 48 weeks) for patients without rapid response (HCV RNA detectable after eight weeks); and finally the tritherapy arm with a bitherapy for four weeks (lead-in phase) followed by tritherapy up to 48 weeks. The SVR rates were significantly higher on the two boceprevir arms (59% and 67%, without any significant difference between these two arms) compared to the control group (21%). In the two boceprevir arms, the rates of responders were superior to those of relapsers (69% and 75%) compared to those of non-responders (40% and 52%). As for naïve patients, the response profile at four weeks was highly predictive of SVR. For patients with a viral load decrease superior to 1 log, the SVR rate was 73% in the boceprevir (response guided arm) and 80% (unchanged regimen arm). But for patients with a viral load

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decrease inferior to 1 log after four weeks, the SVR rate were 33% and 34% in both arms. To conclude, this study showed that prolonged virological response may be acquired in two thirds of relapsers and partial NR re-treated by tritherapy. There is no significant difference between 36 and 48 weeks of treatment in responders after eight weeks but for these difficult to treat patients, the length of treatment will certainly be 48 weeks. This study confirmed the importance of the lead-in phase to better predict chances of therapeutic success, lower (one third of patients) when decrease of viral load inferior 1 log after four weeks, with a high risk of developing resistance; the decision to continue treatment or not should be made case by case taking into account the severity of hepatic lesions. 4.3. Adverse effects Telaprevir increases cutaneous manifestations such as pruritis and especially rash. Most of the times these are toxidermia which remain minimal or moderate and regress with topical corticosteroids, applied as soon as the rash develops or at treatment interruption. According to the studies, adverse effects (especially rash, but also anemia) are the cause of treatment interruption in 10 to 20% of cases. This has led to implementation of early management strategies for cutaneous effects which have reduced by half the rate of treatment interruption between phase II (7%) and III (3%) trials. For boceprevir, in the Sprint 2 and Respond 2 studies, anemia (less than 10 g/dL: 40%) and dysgeusia were the only adverse effects, more frequent in the boceprevir arm. 4.4. Intake frequency Another concern was intake every eight hours of treatment. The C-208 European phase II open randomized study in four arms assessed the effectiveness, tolerance, and pharmacokinetics of telaprevir in two (/12 h) or three intakes (/8 h) combined to standard bitherapy for 24 or 48 weeks according to the virological response between weeks 4 and 20. The rates of SVR were comparable whatever the treatment arm (between 80 and 85% of naïve patients treated by 12 weeks of tritherapy and 12 weeks of usual pegylated bitherapy with IFN-␣-2a or 2b). 5. Prospects 5.1. Other protease and polymerase inhibitors Other protease inhibitors are being assessed in phase II studies: danoprevir, vaniprevir, TMC-43575, or ABT450. For vaniprevir, dose-dependent hepatic toxicity has led to using the molecule at lower doses in combination with ritonavir. TMC-43575 seems especially interesting because of its broader antiviral spectrum since it inhibits the viral replication of genotypes 2, 4, 5, and 6 in vitro, but not of genotype 3. RG-7128 is an NS5B nucleoside inhibitor, active on all genotypes. The phase II study having assessed it in tritherapy reported a good tolerance and encouraging results in terms of SVR. Other

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polymerase inhibitors are being assessed in phase II studies: PSI-7977, IDX-184, and ANA598.

5.2. Combinations of new molecules A new treatment for the eradication of HCV without IFN should soon be available, at least for naïve patients and more probably in case of an infection by a genotype 1b than 1a. The combination of several agents with direct antiviral action could, by targeting various steps of viral replication, induce viral suppression while preventing the emergence of viral resistance. The INFORM 1 study [39] thus assessed the combination RG-7128 and danoprevir in 88 genotype 1 non-cirrhotic patients, naïve or NR. The main objective was to decrease the viral load by week 14. The VL median ranged from –3.7 to –5.2 log (vs. +0.1 log in the placebo control group), with good tolerance. Other protease inhibitor/polymerase inhibitor combinations combined with or without ribavirin in naïve patients [40] or combined with or without pegylated bitherapy in NR [41] are being studied, with promising results even if pegylated bitherapy seems necessary in NR to prevent viral escape. To conclude, NS3/NS4 protease inhibitors, telaprevir and boceprevir combined with pegylated bitherapy, increase SVR rates by 20 to 30% in naïve and NR genotype 1 patients and up to 40 to 50% in relapsers. They can lead to a shortened length of treatment in naïve patients with an early virological response (24 instead of 48 weeks), which counterbalances their adverse effects (rash for telaprevir, dysgeusia for boceprevir, and for both increased anemia induced by ribavirin). The French Agency for the Safety of Health Products (AFSSAPS) issued at the end of 2010 a temporary approval for cohort use in patients presenting with chronic genotype 1 hepatitis at cirrhosis stage (stage 4), in therapeutic failure (relapse or partial virological response), patients with very severe fibrosis and in therapeutic failure being considered as needing tritherapy the most. The marketing authorization by the end of 2011 should specify the indications and benefits. The impact of renal or hepatic insufficiency on the metabolism of various drugs or drug/drug interactions (antiretrovirals) remained to be defined. In the future, oral multitherapies should allow avoiding IFN use and its adverse effects. Other direct antiviral proteins are under development for genotype 1 and other genotypes, the combination of several molecules remaining necessary to prevent the early emergence of resistance mutations. It seems that these oral combinations may be associated to a high rate of viral resistance, especially for patients in therapeutic failure with previous standard treatments. In the future, it can be guessed that the main limitations of these tritherapies will be less tolerance (cutaneous or hematological which may be avoided by early treatments including topical corticosteroids or erythropoietin), than cost (which justifies a good definition of therapeutic indication), treatment observance (because of the still too high number of pills or gel tabs), viral resistance (cross for proteases inhibitors for example), and drug/drug interactions with antiretrovirals, anti-calcineurins, but also with common treatments: psychotropics, antihypertensives, anti-diarrheics, antiemetics, etc. In the

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future, these limitations should be avoided by educating patients and physicians. Disclosure of interest Conflicts of interest of Dr Pol: consulting and lecturing fees from Bristol-Myers Squibb, Boehringer Ingelheim, Tibotec, Novartis, Gilead, Roche, Schering-Plough/Merck, Abbott and GlaxoSmithKline, and grants from Bristol-Myers Squibb, Gilead, Roche and Merck/Schering Plough. Dr Corouge: no conflict of interest. References [1] Mc Hutchison JG, Everson GT, Gordon SC, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009;360:1827–38. [2] Hezode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009;360:1839–50. [3] Kwo PY, Lawitz EJ, McCone J, et al. Efficacy of boceprevir, An NS3 protease inhibitor, in combination with peginterferon alpha-2b and ribavirin in treatmen-naïve patients with genotype 1 hepatitis C infection (Sprint-1): an open-label, randomised, multicentre phase 2 trial. Lancet 2010;376:705–16. [4] National Institutes of Health. National Institutes of Health Consensus Development Conference Statement: management of hepatitis C: June 10-12, 2002. Hepatology 2002;36(Suppl. 1):S3–20. [5] Manns MP, Mc Hutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon-␣2b plus ribavirin compared with interferon-␣-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 2001;358:958–65. [6] Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales Jr FL, et al. Peginterferon-␣2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975–82. [7] McHutchison JG, Lawitz EJ, Shiffman ML, et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009;361:580–93. [8] Poynard T, McHutchison J, Davis GL, Esteban-Mur R, Goodman Z, Bedossa P, et al. Impact of interferon ␣-2b and ribavirin on progression of liver fibrosis in patients with chronic hepatitis C. Hepatology 2000;32(5):1131–7. [9] Fontaine H, Chaix ML, Lagneau JL, et al. Recovery from hepatitis C in long-term responders to ribavirin plus interferon alfa. Lancet 2000;356(9223):41. [10] Pol S, CRNAot F, Lagneau JL, et al. Reversibility of hepatitis C virus–related cirrhosis. Hum Pathol 2004;35(1):107–12. [11] Bruno S, Stroffolini T, Colombo M, Bollani S, Benvegnu L, Ascione A, et al. Sustained virologic response to interferon-␣ is associated with outcome in HCV related cirrhosis: a retrospective study. Hepatology 2007;45: 579–87. [12] Veldt BJ, Heathcote EJ, Wedemeyer H, Reichen J, Hofmann WP, Zeuzem S, et al. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Ann Intern Med 2007;147:677–84. [13] Deuffic-Burban S, Deltenre P, Louvet A, Canva V, Dharancy S, Hollebecque A, et al. Impact of viral eradication on mortality related to hepatitis C: a modeling approach in France. J Hepatol 2008;49(2):175–83. [14] Di Bisceglie AM, Shiffman ML, Everson GT, Lindsay KL, Everhart JE, Wright EC, et al. Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon. N Engl J Med 2008;359(23):2429–41. [15] Bruix J, Poynard T, Colombo M, Schiff E, Reichen J, Burak K, et al. Pegintron maintenance therapy in cirrhotic (Metavir F4) HCV patients, who failed to respond to interferon/ribavirin therapy: final results of the EPIC3 cirrhosis maintenance trial. J Hepatol 2008;50(1):S22.

[16] Curry M, Cardenas A, Afdhal NH, et al. Effect of maintenance peginterferon therapy on portal hypertension and its complication result from the copilot study. J Hepatol 2005;42:S40. [17] Poynard T, Colombo M, Bruix J, Schiff E, Terg R, Flamm S, et al. Peginterferon ␣2b and ribavirin: effective in patients with hepatitis C who failed interferon ␣/ribavirin therapy. Gastroenterology 2009;136:1618–28. [18] Jensen DM, Marcellin P, Freilich B, Andreone P, Di Bisceglie A, BrandaoMello CE, et al. Re-treatment of patients with chronic hepatitis C who do not respond to peginterferon ␣2b: a randomized trial. Ann Intern Med 2009;150(8):528–40. [19] Tischendorf JJ, Beger C, Korf M, et al. Polypyrimidine trac-binding protein (PTB) inhibits Hepatitis C virus internal ribosome entry site (HCV IRES)-mediated translation, but does not affect HCV replication. Arch Virol 2004;149(10):1955–70. [20] Wölk B, Sansonno D, Kräusslich HG, et al. Subcellular localization, stability, and trans-cleavage competence of the hepatitis C virus NS3NS4A complex expressed in tetracycline-regulated cell lines. J Virol 2000;74(5):2293–304. [21] Wang QM, Hockman MA, Staschke K, et al. Oligomerization and cooperative RNA synthesis activity of hepatitis C virus RNA-dependent RNA polymerase. J Virol 2002;76(8):3865–72. [22] Flisiak R, Feinman SV, Jablkowski M, et al. Efficacy and safety of increasing doses of the cyclophilin inhibitor Debio 025 in combination with pegylated interferon alfa-2a in treatment naïve chronic HCV patients. J Hepatol 2008;48(Suppl 2):S62. [23] Rossignol JF, Elfert A, El-Gohary Y, et al. Improved virologic response in chronic hepatitis C genotype 4 treated with nitazoxanide, peginterferon, and ribavirin. Gastroenterology 2009;136:856–62. [24] Rodriguez-Torres M, Ghalib RH, Gordon SC, Lawitz E, Patel K, Pruitt R, et al. IMO-2125, a TLR9 agonist, induces immune responses which correlate with reductions in viral load in null responders HCV patients. Hepatology 2010;52(336A) [AASLD 2010]. [25] Pockros P, Jacobson I, Boyer TD, Schiff ER, Everson GT, Lee WM, et al. GI-5005 therapeutic vaccine plus PEG-IFN/Ribavirin improves sustained virologic response versus PEG-IFN/Ribavirin in prior non-responders with genotype 1 chronic HCV infection. Hepatology 2010;52(107A) [AASLD 2010, abstract LB6]. [26] Muir AJ, Lawitz E, Ghalib RH, Sussman NL, Anderson F, Everson GT, et al. Pegylated interferon lambda (PEG-IFN-␭) phase 2 dose-ranging, activecontrolled study in combination with ribavirin (RBV) for treatment-naïve HCV patients (genotype 1, 2, 3 or 4): safety, viral response, and impact of IL-28B host genotype through week 12. Hepatology 2010;52(715A) [AASLD 2010, abstract 821]. [27] Marcellin P, Lurie Y, Rodriguez-Torres M, et al. The safety and efficacy of taribavirin plus pegylated interferon alfa-2a versus ribavirin plus pegylated interferon alfa-2a in therapy-naïve patients infected with HCV: phase 3 results. J Hepatol 2007;47:51–9. [28] Kaita K, Yoshida E, Kunimoto D, et al. PhII Proof of conception study of celgosivir in combination with peginterferon alfa-2b and ribavirin in chronic hepatitis C genotype-1 non responder patients. J Hepatol 2007;46(1):56–7. [29] McHutchison JG, Manns MP, Muir AJ, et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med 2010;362:1292–303. [30] Berg T, Mchutchison JG, Adda N, et al. SVR with telaprevir, peginterferon alfa-2a and ribavirin in HCV patients with well-characterized prior null response, partial response, viral breakthrough or relapse after PR. 45th Annual meeting of the European Association for the Study of the Liver (EASL 2010). Vienna, Austria, 2010. [31] Foster GR, Hezode C, Bronowicki JP, et al. Activity of telaprevir alone or in combination with peginterferon alfa-2an and ribavirin in treatment-naïve genotype 2 et 3 hepatitis-C patients: interim results of study C209. 45th Annual meeting of the European Association for the Study of the Liver (EASL 2010). Vienna, Austria, 2010. [32] Jacobson IM, McHutchison JG, Dusheiko GM, Di Bisceglie AM, Reddy R, Bzowej NH, et al. Telaprevir in combination with peginterferon and ribavirin in genotype 1 HCV treatment-naïve patients: final results of phase 3 Advance study. Hepatology 2010;52(Suppl. 427A) [AASLD 2010, abstract 211].

M. Corouge, S. Pol / Médecine et maladies infectieuses 41 (2011) 579–587 [33] Sherman KE, Flamm SL, Afdhal NH, Nelson DR, Sulkowski MS, Everson GT, et al. Telaprevir in combination with peginterferon alfa-2a and ribavirin for 24 or 48 weeks in treatment-naïve genotype 1 HCV patients who achieved an extended rapid viral response: final results of phase 3 Illuminate study. Hepatology 2010;52(Suppl. 401A) [AASLD 2010, abstract LB-2]. [34] Zeuzem S, Andreone P, Pol S, Lawitz EJ, Diago M, Roberts S, et al. REALIZE trial final results: Telaprevir-based regimen for genotype 1 hepatitis C virus infection in patients with prior null response, partial response or relapse to peginterferon/ribavirin. J Hepatol 2011;54(Suppl 1):S3. [35] Zeuzem S, Sulkowski MS, Zoulim F, Sherman KE, Alberti A, et al. Longterm follow-up of patients with chronic hepatitis C treated with Telaprevir in combination with peginterferon alfa-2A and Ribavirin: interim analysis of the Extend study. Hepatology 2010;52(Suppl. 401A) [AASLD 2010, abstract 227]. [36] Malcolm BA, Liu R, Lahser F, et al. SCH 503034, a mechanism-based inhibitor of hepatitis C virus NS3 protease, suppresses polyprotein maturation and enhances the antiviral activity of alpha interferon in replicon cells. Antimicrob Agents Chemother 2006;50:1013–20. [37] Poordad F, McCone J, Bacon BR, Bruno S, Manns M, Sulkowski MS, et al. Boceprevir (BOC) combined with peginterferon alfa-2B/ribavirin (P/R) for treatment-naïve patients with hepatitis C virus (HCV) genotype

[38]

[39]

[40]

[41]

587

(G) 1: Sprint-2 final results. Hepatology 2010;52(Suppl. 401A) [AASLD 2010, abstract LB4]. Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, et al. HCV RESPOND-2 final results: high sustained virologic response among genotype 1 previous non-responders and relapsers to peginterferon/ribavirin when re-treated with boceprevir plus pegintron (peginterferon alfa-2b)/ribavirin. Hepatology 2010;52(Suppl. 430A) [AASLD 2010, abstract 216]. Gane EJ, Roberts SK, Stedman CAM. Oral combination therapy with a nucleoside polymeraseinhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (Inform-1): a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet 2010;376:1467–75. Zeuzem S, Asselah T, Angus PW, Zarski J-PH, Larrey D, Mullhaupt B, et al. Strong antiviral activity and safety of IFN-sparing treatment with the protease inhibitor BI 201335, the HCV polymerase inhibitor BI 207127 and ribavirin in patients with chronic hepatitis C. Hepatology 2010; 52(Suppl. 223A), [AASLD 2010, abstract LB7]. Lok A, Gardiner DF, Lawitz, Martorell, Everson GT, Ghalib RH, et al. Combination therapy with BMS-790052 and BMS-650032 alone or with PEGIFN/RBV results in undetectable HCV RNA through 12 weeks of therapy in HCV genotype 1 null responders. Hepatology 2010;52(Suppl. 223A) [AASLD 2010, abstract LB8].