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Antiviral Therapy 13 Suppl 1:31–36 Review Future directions in therapy for chronic hepatitis C

Donald M Jensen1* and Antonio Ascione2

1Center for Liver Diseases, University of Chicago Hospitals, Chicago, IL, USA 2Liver Unit, Cardarelli Hospital, Naples, Italy

*Corresponding author: E-mail: [email protected]

The development of new antiviral therapies in the pegylated interferon, particularly in the presence of treatment of hepatitis C virus (HCV) is reviewed, ribavirin, has resulted in significant improvements in including a discussion of the potential advances that antiviral activity. Preliminary studies have confirmed this treatment will bring. Data from new molecules in that the new molecules are well tolerated and further Phase I and II clinical trials, specifically polymerase and clinical studies are underway to evaluate their efficacy. protease inhibitors, will be discussed. The potential for Nevertheless, because of its critical role at all stages of resistance has been reported when these have been used therapy, pegylated interferon is likely to remain the as monotherapy. However, their use in combination with cornerstone of HCV therapy.

Introduction

The combination of pegylated interferon (PEG-IFN) comprises IFN-α2b linked to human albumin. In a plus ribavirin is the current standard of care for randomized, multicentre, Phase II trial, the drug was patients with chronic hepatitis C and is likely to remain combined with ribavirin and was administered at doses the backbone of treatment for this condition for the of 1,000 or 1,200 mg/day at 2- and 4-week intervals foreseeable future [1,2]. Optimizing therapy with the for a total of 48 weeks. There was no significant standard of care is an effective strategy that will improvement in sustained virological response (SVR) improve outcomes over the next few years (see articles rates in patients treated with alb-IFN-α2b plus by Lee and Ferenci and by Berg and Carosi in this ribavirin compared with a control group treated with supplement [3,4]). The development of novel agents the combination of PEG-IFN-α2a (40 kDa; Pegasys®; with enhanced efficacy and/or better tolerability may Roche, Basel, Switzerland) plus ribavirin (Copegus®; lead to considerable improvements in outcomes over the Roche; 51–59% versus 58%) [6]. long term. Therapeutic classes with clinical potential Only after the intent-to-treat population was limited within the next 5 years are shown in Table 1. to those patients with >75 kg bodyweight and >80% adherence could superiority of the alb-IFN-α2b treat- Modified IFNs ment arms over PEG-IFN-α2a be demonstrated. The rate of discontinuations because of adverse events was An avenue that is being actively pursued is enhancing consistently higher in patients treated at 2- and the activity of IFN. One approach is to produce novel 4-week intervals with alb-IFN-α2b (9–18%) than α α IFN- analogues with improved antiviral and Th1- with PEG-IFN- 2a (6%) [6]. inducing activity through ‘gene shuffling’. This approach has led to the development of interferon Specifically targeted antiviral therapy for compounds with more than 10-fold greater antiviral chronic hepatitis C activity than IFN alfacon-1 [5]. Clinical trials in patients with chronic hepatitis C are awaited with great interest. A number of compounds with direct activity against Another ongoing programme is dedicated to hepatitis C virus (HCV) are under clinical develop- producing an IFN with a longer elimination half-life ment. The most advanced compounds are those that than the commercially available PEG-IFNs. target HCV polymerase or HCV protease enzymes. Alb-IFN-α2b (Albuferon®; Human Genome Sciences, Rather than attempting to replace the existing standard Rockville, MD, USA) is a long-acting preparation that of care, the best way to make use of these compounds,

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Table 1. Potential therapies for chronic hepatitis C in active clinical development Potential therapy Specific examples Stage of development

Long-acting interferon preparations Alb-IFN-α2b Phase III Direct-acting antiviral compounds that target HCV Protease inhibitors (for example, telaprevir) Phase II Polymerase inhibitors (for example, R1626) Phase II Ribavirin analogues Taribavirin Phase II Therapeutic vaccines IC41 Phase II GI-5005 Phase IB

Alb-IFN-α2a, albumin-interferon-α2a; HCV, hepatitis C virus.

at least in the near future, is to use them in combination HCV protease inhibitors with PEG-IFN and ribavirin. The main reason for this is to reduce the risk of resistance. Resistance has been The NS3-4A serine protease of HCV is a multifunctional reported with both polymerase and protease protein that is essential for post-translational processing inhibitors when administered as monotherapy [2,7,8]. of viral proteins. This protein is the target of several The ultimate goal is to significantly improve SVR development programmes. Development of BILN 2061 rates and/or enhance patient convenience by (Boehringer Ingelheim, Ingelheim, Germany), the first of decreasing the total duration of treatment required to these agents to show promising antiviral activity and the eradicate the virus. The greatest need is in patients first to enter the clinic, was discontinued because of infected with HCV genotype 1, in whom SVR rates cardiotoxicity in animals [9]. When used alone, are lowest, and in those who have failed previous protease inhibitors promote the emergence of resistant IFN-based therapy because the chance of a cure is variants [10,11]; therefore, all ongoing development <20% with existing therapy. programmes are evaluating protease inhibitors in Resistant variants of the virus have been detected combination with PEG-IFN. in patients treated with protease inhibitors and poly- merase inhibitors. As monotherapy, this resistance Telaprevir would likely develop before viral eradication could Telaprevir (VX-950; Vertex, Cambridge, MA, USA) is in be accomplished. It is unlikely that cross-resistance Phase II of development and is presently the best charac- will occur between agents of different classes because terized protease inhibitor and the furthest down the road of their distinct therapeutic targets, but, at present, to market. An understanding of the efficacy, toxicity and few data are available on which to base combination resistance profile of the drug is emerging. Mutations therapy. Measures to delay or prevent the emergence were detected at four positions in the NS3 serine of resistant HCV variants are mandatory for protease gene in HCV RNA isolated from the serum of ensuring the clinical usefulness of experimental ther- patients after 14 days of monotherapy with oral apies [8]. Potential strategies include administering telaprevir (750 mg every 8 h or 1,250 mg every 12 h). newer antiviral agents with low barriers to genetic One variant conferred high-level resistance with a 781-

resistance against the background of the current stan- fold increase in 50% inhibitory concentration (IC50) dard of care (that is, PEG-IFN plus ribavirin) or in compared with wild-type HCV [8]. After withdrawal of combinations that do not demonstrate cross-resistance. the drug, wild-type virus re-emerged and became The former strategy is currently viable, whereas the predominant; however, variants with low-level resistance

latter will remain theoretical until the efficacy, safety to telaprevir (four- to sevenfold increase in IC50) were and resistance profiles of several agents have been still detectable 3–7 months after treatment [8]. fully characterized. Rapid and sustained reductions in serum HCV The ideal PEG-IFN for use in combination with the RNA levels were obtained in patients with HCV newer agents should have a rapid onset of action and genotype 1 infection given telaprevir three times show consistent activity throughout the dosing daily in combination with PEG-IFN-α2a 180 μg once interval in order to minimize the likelihood of resis- weekly. After 14 days of treatment, median reduc- tance. The agents used in combination with new tions in HCV RNA were greater in patients treated α antivirals have included both PEG-IFN- 2a and with the combination (5.5 log10 IU/ml) than α α PEG-IFN- 2b. The more sustained serum levels of monotherapy with either PEG-IFN- 2a (1.1 log10 α PEG-IFN- 2a are a distinct advantage in achieving IU/ml) or telaprevir (4.0 log10 IU/ml) [12]. steady viral load reduction without fluctuations, Telaprevir has now advanced to Phase II clinical which can give rise to viral rebound. trials in which it is being studied in treatment-naive and

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treatment-experienced patients infected with HCV SVR rates in patients treated with telaprevir and that genotype 1. In the Phase II PROVE-1 trial in treatment- SVR rates of 60–65% may be possible with a 24-week naive patients, telaprevir 750 mg every 8 h has been triple-therapy regimen in genotype 1 patients. combined with a therapeutic backbone of PEG-IFN-α2a (40 kDa) 180 μg/week plus ribavirin 1,000 or 1,200 Boceprevir mg/day [13]. The study involved four treatment groups, Boceprevir (SCH 503034; Schering-Plough three of which were treated with the triple-therapy Corporation, Kenilworth, NJ, USA) is less potent than regimen for 12 weeks followed by 0, 12, or 36 weeks of telaprevir. Mean reductions in serum HCV RNA were α PEG-IFN- 2a plus ribavirin combination therapy. The 1.08 log10 and 1.61 log10 after 1 week of treatment control group was treated with the standard of care: with boceprevir 200 mg and 400 mg three times daily, 48 weeks of treatment with PEG-IFN-α2a plus ribavirin. respectively, in patients with HCV genotype 1 infec- An interim analysis of data collected at the end of tion who had not responded to previous IFN-based the triple-therapy phase of the trial (week 12) showed therapy [17]. The mean maximum reductions in HCV that significantly more patients treated with telaprevir RNA level after 2 weeks of combination therapy with had undetectable HCV RNA at week 12 (<10 IU/ml; PEG-IFN-α2b plus boceprevir 200 mg and 400 mg α 70% versus 39% receiving PEG-IFN- 2a plus three times daily were 2.45 log10 and 2.88 log10, ribavirin; P<0.001; Figure 1) [13]. Corresponding respectively (Figure 2). The effects of the two agents rates of rapid virological response (RVR; undetectable were strictly additive and the addition of boceprevir HCV RNA [<10 IU/ml] at week 4) were 79% and did not abrogate the characteristic fluctuations in 11% (P<0.001). Through the first 12 weeks of the serum HCV RNA levels that occur with PEG-IFN-α2b trial, the discontinuation rate was higher in patients [17]. Boceprevir is in Phase II of clinical development. treated with triple therapy (19/175; 11%) than with the standard of care (2/75; 3%). Rash was the most HCV polymerase inhibitors common cause of withdrawal in patients treated with telaprevir (7/19 patients) [13]. One arm of the trial Most polymerase inhibitors are nucleoside analogues investigated whether 12 weeks of triple therapy that require conversion to an active triphosphate form, would be sufficient to eradicate the virus. At week 20 and cause chain termination when incorporated into a of follow-up, 35% of the intent-to-treat population nascent viral RNA chain. They are active against HCV had undetectable HCV RNA (<10 IU/ml), with the rate rising to 67% of patients who achieved an RVR. Final SVR data are now available for patients in Figure 1. Patients with undetectable HCV RNA after two of the four treatment groups in PROVE-1. 12 weeks of treatment in the PROVE-1 trial Among patients treated for 12 weeks with telaprevir- based triple therapy followed by 12 weeks of Telaprevir + PEG-IFN-α2a + ribavirin (n=175) PEG-IFN-α2a (40 kDa) plus ribavirin (24 weeks total) 61% (48 of 79) achieved an SVR; among those PEG-IFN-α2a + ribavirin (n=75) treated with 12 weeks of triple therapy alone 35% (6 of 17) achieved an SVR [14]. In the European PROVE-2 trial, which is generally P<0.001 100 P<0.001 similar to PROVE-1, SVR rates of 59% were reported in 85% patients treated for a total of 12 weeks with telaprevir- 80 70% based triple therapy and 65% in patients treated for 24 weeks, the first 12 of which comprised telaprevir- 60 based triple therapy followed by 12 weeks of 43% 39% PEG-IFN-α2a (40 kDa) plus ribavirin therapy. The SVR 40

rate in patients treated with telaprevir plus HCV RNA*, % PEG-IFN-α2a (40 kDa) for 12 weeks was 29% [15]. 20

Virological breakthrough during the first 12 weeks of Patients with undetectable therapy occurred in 24 of 78 patients treated with 0 ITT LOCF telaprevir plus PEG-IFN-α2a (40 kDa) and in just 5 of 163 patients treated with triple therapy. A viral sequence analysis showed that breakthrough was associated with *Undetectable hepatitis C virus (HCV) RNA <10 IU/ml. In the PROVE-1 trial, treatment-naive patients infected with HCV genotype 1 were treated with oral selection of telaprevir-resistant mutants [16]. telaprevir 750 mg every 8 h, and subcutaneous pegylated interferon Collectively the results of PROVE-1 and PROVE-2 (PEG-IFN)-α2a 180 μg/week plus oral ribavirin 1,000/1,200 mg/day or PEG-IFN-α2a 180 μg/wk plus ribavirin 1,000/1,200 mg/day [13]. ITT, demonstrate that ribavirin is essential to maximize intent-to-treat; LOCF, last on treatment HCV RNA value carried forward.

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of all genotypes. Non-nucleoside polymerase inhibitors class. Viral load reductions obtained with the drug are are active at non-catalytic sites and do not require the highest reported to date with a polymerase inhibitor, triphosphate conversion. and are of the same order of magnitude as those observed with potent protease inhibitors. The drug R1626 produced dose-dependent reductions in HCV RNA of

R1626 (Roche) is an oral prodrug of the potent and 1.6 log10, 2.6 log10 and 3.7 log10 after 14 days when given selective nucleoside analogue polymerase inhibitor as monotherapy at a twice-daily dose of 1,500 mg, R1479, and is currently in Phase II trials [18]. To date, it 3,000 mg and 4,000 mg, respectively, in an ascending- is currently the most advanced compound in this drug dose Phase IB trial in patients infected with HCV genotype 1 (Figure 3) [18]. Five out of nine patients treated with the highest dose had undetectable HCV RNA (<50 IU/ml) after 14 days of treatment. No Figure 2. The effect of boceprevir in combination with PEG-IFN-α2b on serum HCV levels in previous non-responders evidence of viral resistance was detected during the trial and the drug was well tolerated. Headache was the most PEG-IFN-α2b alone (n=22) common adverse event in each dosage group. Reversible PEG-IFN-α2b + boceprevir 200 mg tid (n=12) reductions in haemoglobin levels and white blood cell PEG-IFN-α2b + boceprevir 400 mg tid (n=12) counts were detected in patients treated with the drug. Phase II trials are now underway in which the drug 0 is being studied in combination with a backbone of -0.5 PEG-IFN-α2a plus ribavirin. An interim analysis -1.0 showed that 4 weeks of treatment with the combina- tion of R1626 1,500 mg twice daily plus PEG-IFN-α2a -1.5 (40 kDa) 180 mg/week plus ribavirin 1,000/1,200 HCV RNA change

10 -2.0 mg/day produced additive or synergistic reductions in from baseline from -2.5 serum HCV RNA levels compared with the combina- α tion of R1626 plus PEG-IFN- 2a (40 kDa; 5.2 log10

Mean log -3.0 α 0 5 10 15 versus 3.6 log10). The standard of care (PEG-IFN- 2a Treatment day [40 kDa] plus ribavirin) produced a 2.4 log10 reduction in HCV RNA over 4 weeks. A total of 81% of patients Serum hepatitis C virus (HCV) RNA levels during treatment with boceprevir plus had undetectable HCV RNA after 4 weeks of treat- pegylated interferon (PEG-IFN)-α2b 1.5 µg/kg/week in patients infected with HCV genotype 1 who were non-responders to PEG-IFN plus ribavirin [17,24]. ment with R1626-based triple therapy. There was no Adapted with permission from The AGA Institute. HCV, hepatitis C virus; tid, evidence of resistance to R1626 during the study [19]. three times daily. Valopicitabine Valopicitibine (NM283; Idenix, Cambridge, MA, USA) is an oral prodrug of an NS5B polymerase inhibitor. Figure 3. Serum HCV RNA levels during treatment with orally administered R1626 in treatment-naive patients with HCV Valopicitibine is being investigated in Phase II trials in genotype 1 infection [18] combination with PEG-IFN-α2a in treatment-naive genotype 1 patients [20] and in patients with HCV genotype 1 infection who are non-responders to previous PEG-IFN plus ribavirin combination therapy Placebo Treatment Follow-up 500 mg bid [21]. The combination of valopicitabine 200 or 1 1,500 mg bid 800 mg/day plus PEG-IFN-α2a 180 μg/week 3,000 mg bid 10 0 produced rapid reductions in serum HCV RNA in 4,500 mg bid treatment-naive patients (Figure 4). The maximum -1 dose of valopicitabine was subsequently reduced -2 Mean decrease =1.2 log10 from 800 mg/day to 400 mg/day because of gastroin- -3 testinal adverse events that occurred during the first Mean decrease =2.6 log10 -4 2 weeks of treatment. After 24, 36 and 48 weeks, Mean decrease =3.7 log10 Mean HCV RNA log change from baseline change from mean reductions in serum HCV RNA were on the -5 0 5 10 15 20 25 30 order of 4 log10 [20]. The combination of valopicitabine plus Study day PEG-IFN-α2a did not produce an SVR in previous non-responders to PEG-IFN plus ribavirin in another Bid, twice daily; HCV, hepatitis C virus. study [21]. This suggests that it is too early to abandon

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Figure 4. Mean reductions in serum HCV RNA levels in Figure 5. Change in serum HCV RNA levels during treatment treatment-naive patients with HCV genotype 1 infection with orally administered HCV-796 plus PEG-IFN-α2b in treated with oral valopicitabine plus subcutaneous treatment-naive patients with HCV infection [22] PEG-IFN-α2a 180 μg/week [20]

PEG-IFN-α2b PEG-IFN-α2a + valopictabine 200 mg HCV-796 100 mg bid + PEG-IFN-α2b* PEG-IFN-α2a + valopictabine 800 mg (pooled) HCV-796 250 mg bid + PEG-IFN-α2b* HCV-796 500 mg bid + PEG-IFN-α2b* 7 HCV-796 1,000 mg bid + PEG-IFN-α2b* 6 1 5 Dose reduction

absolute 4 implemented 0 10 3 -1 2 HCV RNA 10 Mean log

HCV RNA IU/ml 1 -2 0 0 4 8 12 16 20 24 28 32 36 40 44 48 Mean log

change from baseline change from -3 Study week -4 Lower limit of quantification for Amplicor (Roche Molecular Diagnostics, -1 2 5 8 11 14 17 20 23 26 29 Pleasanton, CA, USA) <600 IU/ml and the lower limit of detection for Taqman Study day (Roche) <20 IU/ml. HCV, hepatitis C virus; PEG-IFN, pegylated interferon.

*Pegylated interferon (PEG-IFN)-α2b was administered subcutaneously at a μ ribavirin and that further trials in non-responders dose of 1.5 g/kg/week. Bid, twice weekly; HCV, hepatitis C virus. should involve the addition of an investigational agent together with the current standard of care (PEG-IFN- α2a and ribavirin). The valopicitabine clinical have to take the following two points into consideration: programme has recently been placed on hold in the US the first is whether the high rates of early responses because of a high incidence of severe gastrointestinal (79% of patients treated with telaprevir triple therapy adverse events. achieved an RVR) translate into SVR rates with shorter treatment durations that are comparable to HCV-796 those seen in patients treated with standard of care; HCV-796 (ViroPharma, Exton, PA, USA) produced and the second is that longer treatment durations with additive reductions in HCV RNA levels when admin- small molecules will be necessary for superiority istered orally twice daily at a dose of 100–1,000 mg studies, with higher cost, less convenience, more in combination with once weekly PEG-IFN-α2b drug–drug interactions, less tolerability with higher

(mean reductions of 3.3–3.5 log10 were obtained after discontinuation rates and an enhanced risk of resis- 14 days of treatment) [22]. The intraweek rebounds tance development. Two or more small molecules may in HCV RNA levels, typical of PEG-IFN-α2b, were be required in order to spare the IFN or ribavirin observed during treatment with this combination component of combination therapy, for example, in (Figure 5). Dosing of HCV-796 has recently been patients who are previous non-responders to PEG- discontinued in this Phase II study due to safety IFN-α plus ribavirin. Further studies are needed to issues [23]. define possible strategies for future success, for example, PEG-IFN plus ribavirin plus small molecule, Conclusion a combination of one or several small molecules with PEG-IFN without ribavirin or a combination of Clinical data are still pending in order to define the several small molecules without PEG-IFN. However, best use of small molecules for the treatment of we have a long way to go before these therapeutic chronic hepatitis C. Available data suggest that both options become a reality. protease and polymerase inhibitors produce additive or synergistic effects when given with a PEG-IFN-α Acknowledgements backbone and will need to be used with this combina- tion to prevent the emergence of resistance. A We thank Health Interactions Ltd, UK who provided balanced perspective of these new compounds will editorial support on behalf of Roche.

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Disclosure statement 12. Kieffer TL, Sarrazin C, Miller JS, et al. Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in DMJ serves as a consultant and on the advisory boards patients. Hepatology 2007; 46:631–639. of Hoffmann-La Roche, Boehringer-Ingelheim, 13. McHutchison JG, Everson GT, Gordon S, et al. Results of an interim analysis of a phase 2 study of telaprevir (VX- Abbott and Globeimmune pharmaceutical compa- 950) with peginterferon alpha-2a and ribavirin in nies. He receives research support from previously untreated subjects with hepatitis C. J Hepatol 2007; 46 Suppl 1:S296. Hoffmann-La Roche, Globeimmune, Vertex, Valeant 14. Jacobson IR, Everson GT, Gordon SC, et al. Interim and Bristol-Myers Squibb. He has no stock or other analysis results from a phase 2 study of telaprevir with equity in any company related to hepatitis. AA has peginterferon alfa-2a and ribavirin in treatment-naive subjects with hepatitis C. Hepatology 2007; 46 Suppl no relationship with the manufacturers of PEGASYS 1:315A now, or in the past, and has not received funding 15. Hezode C, Ferenci P, Dusheiko GM, et al. PROVE2: phase from the manufacturers to carry out research. II study of VX950 (telaprevir) in combination with peginterferon alfa 2a with or without ribavirin in subjects with chronic hepatitis C, first interim analysis. Hepatology References 2007; 46 Suppl 1:268A. 16. Kieffer T, Zhou Y, Zhang E, et al. Evaluatiuon of viral 1. Dienstag JL, McHutchison JG. American variants during a phase 2 study (PROVE2) of telaprevir Gastroenterological Association medical position statement with peginterferon alfa-2a and ribavirin in treatment-naive on the management of hepatitis C. Gastroenterology 2006; HCV genotype 1-infected patients. Hepatology 2007; 46 130:225–230. Suppl 1:862A. 2. Pawlotsky JM, Chevaliez S, McHutchison JG. The hepatitis 17. Sarrazin C, Rouzier R, Wagner F, et al. SCH 503034, a C virus life cycle as a target for new antiviral therapies. novel hepatitis C virus protease inhibitor, plus pegylated Gastroenterology 2007; 132:1979–1998. interferon alpha-2b for genotype 1 nonresponders. 3. Lee SS, Ferenci P. Optimizing outcomes in patients with Gastroenterology 2007; 132:1270–1278. hepatitis C virus genotype 1 or 4. Antivir Ther 2008; 13 18. Roberts S, Cooksley G, Dore G, et al. Results of a phase Suppl 1:9–16. 1B multiple dose study of R1626, a novel nucleoside 4. Berg T, Carosi G. Optimizing outcomes in patients with analog targeting HCV polymerase in chronic HCV hepatitis C virus genotype 2 or 3. Antvir Ther 2008; 13 genotype 1 patients. Hepatology 2006; 44 Suppl 1:692A. Suppl 1:17–22. 19. Pockros P, Nelson D, Godofksy E, et al. Robust synergistic 5. Brideau-Andersen A, Huang X, Chang Sun S, et al. antiviral effect of R1626 in combination with peginterferon Directed evolution of novel gene shuffled interferon alphas alfa-2a (40KD) with or without ribavirin - interim analysis for the treatment of hepatitis C. J Hepatol 2006; 44 Suppl results of phase 2a study. Hepatology 2007; 46 Suppl 2:S6. 1:311A. 6. Human Genome Sciences announces positive final results of 20. Lawitz E, Nguyen T, Younes Z, et al. Clearance of HCV Phase 2B trial of albuferon, 7 June 2007. Accessed on 25 RNA with valopicitabine (NM283) plus peg-interferon in July 2007 at: http://www.hgsi.com/news/press/07-06- treatment-naive patients with HCV-1 infection: results at 07_Albuferon_Phase_2B.htm 24 and 48 weeks. J Hepatol 2007; 46 Suppl 1:S9. 7. Villano S, Howe A, Raible D, Harper D, Speth J, Bichier G. 21. Afdhal N, O’Brien C, Godofksy E, et al. Valopicitabine Analysis of HCV NS5B genetic variants following (NM283), alone or with peg-interferon, compared to peg monotherapy with HCV-796, a non-nucleoside polymerase interferon/ribavirin (PEGIFN/RBV) retreatment in patients inhibitor, in treatment-naive HCV-infected patients. with HCV-1 infection and prior non-response to Hepatology 2006; 44 Suppl 1:607A PEGIFN/RBV: one-year results. J Hepatol 2007; 46 Suppl 8. Sarrazin C, Kieffer TL, Bartels D, et al. Dynamic hepatitis 1:S5. C virus genotypic and phenotypic changes in patients 22. Villano SA, Raible D, Harper D, et al. Antiviral activity of treated with the protease inhibitor telaprevir. the non-nucleoside polymerase inhibitor, HCV-796, in Gastroenterology 2007; 132:1767–1777. combination with pegylated interferon alfa-2b in treatment- 9. Hinrichsen H, Benhamou Y, Wedemeyer H, et al. Short- naive patients with chronic HCV. J Hepatol 2007; 46 Suppl term antiviral efficacy of BILN 2061, a hepatitis C virus 1:S24 serine protease inhibitor, in hepatitis C genotype 1 patients. 23. Potential Safety Issue Identified in Ongoing Phase 2 Gastroenterology 2004; 127:1347–1355. Clinical Study of HCV-796, 10 August 2007. Accessed on 10. Lin C, Gates CA, Rao BG, et al. In vitro studies of cross- 14 August 2007 at: http://phx.corporate- resistance mutations against two hepatitis C virus serine ir.net/phoenix.zhtml?c=92320&p=irol-newsArticle&ID=10 protease inhibitors, VX-950 and BILN 2061. J Biol Chem 39323&highlight= 2005; 280:36784–36791. 24. Zeuzem S, Sarrazin C, Wagner F, et al. Combination 11. Lin C, Lin K, Luong YP, et al. In vitro resistance studies of therapy with the HCV protease inhibitor, SCH 503034, hepatitis C virus serine protease inhibitors, VX-950 and plus Peg-Intron in hepatitis C genotype-1 Peg-Intron non- BILN 2061: structural analysis indicates different resistance responders: Phase IB results. Hepatology 2005; 42 Suppl mechanisms. J Biol Chem 2004; 279:17508–17514. 1:276A.

Accepted for publication 27 November 2007

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