International Hepatology

Realize the advance in HCV treatment, but remain cautious

Tarik Asselah⇑

Service d’Hépatologie, Hôpital Beaujon, Clichy, France; INSERM, U773, Centre de Recherche Bichat-Beaujon CRB3, University Paris Diderot, France

COMMENTARY ON: rashes occurred at a higher incidence among patients receiving

Telaprevir for previously untreated chronic hepatitis C virusinfection. Jacobson IM, McHutchison JG, Dusheiko G, Di BisceglieAM, Reddy KR, Bzowej NH, Marcellin P, Muir AJ, Ferenci P, Fli-siak R, George J, Rizzetto M, Shouval D, Sola R, Terg RA, YoshidaEM, Adda N, Bengtsson L, Sankoh AJ, Kieffer TL, George S, Kauff-man RS, Zeuzem S; ADVANCE Study Team. N Engl J Med. 2011Jun 23;364(25):2405–2416. Copyright (2011). Abstract rep-rinted with permission of the Massachusetts Medical Society.

http://www.ncbi.nlm.nih.gov/pubmed/21696307

Abstract. Background: In phase 2 trials, telaprevir, a hepatitis Cvirus (HCV) genotype 1 protease inhibitor, in combination withpeginterferon-ribavirin, as compared with peginterferon-ribavirinalone, has shown improved efficacy, with potential for shorteningthe duration of treatment in a majority of patients.Methods: In this international, phase 3, randomized, double-blind,placebo-controlled trial, we assigned 1088 patients with HCV geno-type 1 infection who had not received previous treatment for theinfection to one of three groups: a group receiving telaprevir com-bined with peginterferon alfa-2a and ribavirin for 12 weeks (T12PRgroup), followed by peginterferon-ribavirin alone for 12 weeks ifHCV RNA was undetectable at weeks 4 and 12 or for 36 weeks ifHCV RNA was detectable at either time point; a group receivingtelaprevir with peginterferon-ribavirin for 8 weeks and placebowith peginterferon-ribavirin for 4 weeks (T8PR group), followedby 12 or 36 weeks of peginterferon-ribavirin on the basis of thesame HCV RNA criteria; or a group receiving placebo with peginter-feron-ribavirin for 12 weeks, followed by 36 weeks of peginterfer-on-ribavirin (PR group). The primary end point was theproportion of patients who had undetectable plasma HCV RNA24 weeks after the last planned dose of study treatment (sustainedvirologic response).Results: Significantly more patients in the T12PR or T8PR groupthan in the PR group had a sustained virologic response (75% and69%, respectively, vs. 44%; p <0.001 for the comparison of theT12PR or T8PR group with the PR group). A total of 58% of thepatients treated with telaprevir were eligible to receive 24 weeksof total treatment. Anemia, gastrointestinal side effects, and skin

Journal of Hepatology 20

Keywords: Telaprevir; Boceprevir; Pegylated interferon; Ribavirin; Protease inh-ibitors; Polymerase inhibitors; Interferon lambda; IL28B.Received 27 July 2011; received in revised form 29 July 2011; accepted 30 July 2011⁄

Address: Service d’Hépatologie, Hôpital Beaujon, Clichy, France. Tel.: +33 (0)140875338, fax: +33 (0) 147309440.E-mail address: tarik.asselah@bjn.aphp.frAbbreviations: DAAs, direct acting antivirals; SVR, sustained virological response;RVR, rapid virological response; PEG-IFN, pegylated-interferon; RBV, ribavirin.

telaprevir than among those receiving peginterferon-ribavirinalone. The overall rate of discontinuation of the treatment regimenowing to adverse events was 10% in the T12PR and T8PR groupsand 7% in the PR group.Conclusions: Telaprevir with peginterferon-ribavirin, as comparedwith peginterferon-ribavirin alone, was associated with significantlyimproved rates of sustained virologic response in patients with HCVgenotype 1 infection who had not received previous treatment, withonly 24 weeks of therapy administered in the majority of patients.(Funded by Vertex Pharmaceuticals and Tibotec; ADVANCE Clinical-Trials.gov number, NCT00627926)

AND

Telaprevir for retreatment of HCV infection. Zeuzem S, AndreoneP, Pol S, Lawitz E, Diago M, Roberts S, Focaccia R, Younossi Z,Foster GR, Horban A, Ferenci P, Nevens F, Müllhaupt B, PockrosP, Terg R, Shouval D, van Hoek B, Weiland O, Van Heeswijk R,De Meyer S, Luo D, Boogaerts G, Polo R, Picchio G, Beumont M;REALIZE Study Team. N Engl J Med. 2011 Jun 23;364(25):2417–28. Copyright (2011). Abstract reprinted with permissionof the Massachusetts Medical Society.

http://www.ncbi.nlm.nih.gov/pubmed/21696308

Abstract. Background: Up to 60% of patients with hepatitis C virus(HCV) genotype 1 infection do not have a sustained virologic responseto therapy with peginterferon alfa plus ribavirin.Methods: In this randomized, phase 3 trial, we evaluated the addi-tion of telaprevir to peginterferon alfa-2a plus ribavirin in patientswith HCV genotype 1 infection who had no response or a partialresponse to previous therapy or who had a relapse after an initialresponse. A total of 663 patients were assigned to one of threegroups: the T12PR48 group, which received telaprevir for 12 weeksand peginterferon plus ribavirin for a total of 48 weeks; the lead-in T12PR48 group, which received 4 weeks of peginterferon plusribavirin followed by 12 weeks of telaprevir and peginterferon plusribavirin for a total of 48 weeks; and the control group (PR48),which received peginterferon plus ribavirin for 48 weeks. The pri-mary end point was the rate of sustained virologic response, whichwas defined as undetectable HCV RNA 24 weeks after the lastplanned dose of a study drug.Results: Rates of sustained virologic response were significantlyhigher in the two telaprevir groups than in the control group amongpatients who had a previous relapse (83% in the T12PR48 group, 88%in the lead-in T12PR48 group, and 24% in the PR48 group), a partialresponse (59%, 54%, and 15%, respectively), and no response (29%,33%, and 5%, respectively) (p <0.001 for all comparisons). Grade 3

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Control

12 24 48 weeks

Peg-IFN/RBV

0 8

Peg-IFN/RBV TVR/Peg-IFN/RBV T12/PR

Peg-IFN/RBV TVR/Peg/RBV T8/PR

eRVR: Stop at Week 24

No eRVR: Treat to Week 48

eRVR: Stop at Week 24

No eRVR: Treat to Week 48

B

A

SVR

p <0.001

p <0.001

271/363 250/364 158/361 n/N =

75 69

44

0

20

40

60

80

100 T12PR T8PR PR

Fig. 1. Advance study design and results. (A) N = 350 planned subjects per arm(1050 planned subjects total). Treatment arms were (a) Telaprevir 750 mg q8 h incombination with PEG-IFN alfa-2a and RBV for 8 weeks, followed by additionalweeks of standard of care; (b) Telaprevir 750 mg q8 h in combination with PEG-IFN alfa-2a and RBV for 12 weeks, followed by additional weeks of standard ofcare; (c) PEG-IFN alfa-2a and RBV for 48 weeks (control arm). Patients intelaprevir arms achieving an extended rapid viral response (eRVR, undetectableHCV RNA at weeks 4 and 12) received a total of 24 weeks of therapy while thosewho did not received a total of 48 weeks of therapy [5]. (B) A significantly greaterproportion of patients achieved SVR with 12-week and 8-week telaprevir-basedcombination regimens (75% and 69%, respectively) compared with PEG-IFN alfa-2a and RBV 48 weeks control arm (44%, p <0.001) [5].

International Hepatology

adverse events (mainly anemia, neutropenia, and leukopenia) weremore frequent in the telaprevir groups than in the control group(37% vs. 22%).Conclusions: Telaprevir combined with peginterferon plus ribavirinsignificantly improved rates of sustained virologic response inpatients with previously treated HCV infection, regardless of whetherthere was a lead-in phase. (Funded by Tibotec and Vertex Pharma-ceuticals; REALIZE ClinicalTrials.gov number, NCT00703118.)

� 2011 European Association for the Study of the Liver. Publishedby Elsevier B.V. All rights reserved.

New direct acting antivirals (DAA), such as protease and poly-merase inhibitors, are currently under development [1]. Forthe treatment of genotype 1 chronic hepatitis C, in both treat-ment-naïve and treatment-experienced patients, two NS3/4Aprotease inhibitors, telaprevir, and boceprevir, were approvedin Europe and the United States in 2011 for use in combinationwith pegylated interferon and ribavirin. In a previous article, wediscussed results obtained with Boceprevir (developed by thecompanies Merk/Schering Plough) in both treatment-naïve andtreatment-experienced patients [2–4]. Interesting data werereported with Telaprevir (developed by the companies Vertexand Tibotec) in both treatment-naïve [5–6] and treatment-expe-rienced patients [7]. This article is discussing the two majorphase III clinical trials published recently (Advance [5] and Real-ize [7]).

The Advance study (Fig. 1A and B) is a 3-arm double-blind, ran-domized, placebo-controlled Phase 3 study assessing efficacy andsafety of two telaprevir-based response-guided regimens com-pared with PEG-IFN alfa-2a and RBV in treatment-naïve patientswith chronic genotype 1 HCV infection [5]. The trial design is pre-sented in Fig. 1A. A significantly greater proportion of patientsachieved SVR with the 12-week and 8-week telaprevir-basedcombination regimens (75% and 69%, respectively) comparedwith the PEG-IFN alfa-2a and RBV 48 weeks control arm (44%,p <0.001) (Fig. 1B).

The most common (>25%) adverse events in the telaprevirarms were fatigue, pruritus, nausea, headache, anemia, rash,influenza-like illness, insomnia, pyrexia, and diarrhea. Discontin-uation of treatment due to adverse events occurred in 7% and 8%in telaprevir regimens and 4% in PEG-IFN alfa-2a and RBV; it wascaused by rash in 0.5%, 1.4%, and 0.0%, and it was due to anemiain 3.3%, 0.8%, and 0.6% in telaprevir 8 weeks in combination withPEG-IFN alfa-2a and RBV, telaprevir 12 weeks with PEG-IFN alfa-2a and RBV; and control arms, respectively.

Finally, the telaprevir-based therapy improved SVR rates ingenotype 1 treatment-naive patients. A 12-week telaprevir-basedregimen demonstrated a better benefit:risk profile than an8-week regimen. With response guided therapy, nearly two-thirds naïve patients were eligible for a 24-week treatment, andattained high rates of SVR. Discontinuation of the treatmentregimen due to rash was minimized by stopping medicationsequentially.

The Illuminate study is a Phase 3 open-label study evaluatingpatients randomized to two durations of therapy among thosewho achieved extended rapid viral response (eRVR) [6].

Five hundred and forty HCV genotype 1 treatment-naïvepatients were treated with telaprevir (12 weeks, 750 mg poq8 h) with PEG-IFN alfa2a and RBV. Patients who achievedeRVR (undetectable HCV RNA at weeks 4 and 12) were ran-domized at week 20 to continue receiving PEG-IFN alfa2a

1458 Journal of Hepatology 2011

and RBV for 24 or 48 weeks of total treatment. Patients notachieving eRVR were assigned 48 weeks of treatment [6]. 72%(n = 389) of patients achieved RVR; 65.2% (n = 352) of patientsachieved eRVR. 322 (59.6%) patients were randomized (1:1) toeither a 24- or 48-weeks arm. SVR was 92% among patientsrandomized to 24 weeks (n = 162) and 87.5% (D4.5%, 2-sided95% C.I. = �2.1% to +11.1%) among patients randomized to48 weeks (n = 160). Overall, SVR was 71.9% (ITT analysis). SVRwas 92% among patients randomized to 24 wks (n = 162).SVR was 87.5% (D4.5%, 2-sided 95% C.I. = �2.1% to +11.1%)among patients randomized to 48 weeks (n = 160). 36 patients(6.7%) discontinued treatment due to virologic failure. 94patients (17.4%) had permanent discontinuation of all studydrugs for adverse events. Fatigue (n = 22) and anemia (n = 12)were the most common adverse events leading to discontinua-tion. Treatment discontinuation due to anemia and rash were 3(0.6%) and 6 (1.1%) patients, respectively, during the telaprevirtreatment phase.

Finally, among patients who achieved eRVR, a 24-week tela-previr-based regimen was non-inferior to 48-week telaprevir-based regimen (92% SVR compared to 87.5%). Response-guidedtreatment led to 71.9% SVR overall and nearly two-thirds of thepatients were eligible for shorter duration of treatment. Perma-nent discontinuation of all study drugs due to adverse eventsoccurred in 17.4% of patients. These results support response-guided therapy for telaprevir-based regimens in treatment-naïvepatients.

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48 4 16 0 12 8 Weeks

72

T12/PR48 n = 266

SVRassessment

LI T12/ PR48n = 264

Pbo/PR48

(control)n = 132

TVR + Peg-IFN + RBV Pbo + Peg-IFN + RBV Peg-IFN + RBV Follow-up

B

A

0

20

40

60

80

100

SVR

(%)

Prior relapsers

Prior partial responders

Prior nullresponders

83*

59*

29* 33*

5

54*

15

88*

24

Pbo/PR48 LIT12/PR48 T12/PR48

121/145

124/141

16/68

29/49

26/48

4/27

21/72

25/75

2/37

n/N =

ig. 2. Realize study design and results. (A) There were two telaprevir-basedrms (simultaneous and delayed start) and one control arm. Patients werendomized 2:2:1 to the two telaprevir arms and the control arm, respectively. Asall Phase 3 studies of telaprevir, patients received no more than 12 weeks of

laprevir given in combination with pegylated interferon and ribavirin. In thisudy, the telaprevir arms included 12 weeks of telaprevir in combination withegylated-interferon and ribavirin with 36 weeks of pegylated-interferon andbavirin alone for a total of 48 weeks of treatment. One of the telaprevireatment arms was designed to evaluate whether there was any furtherprovement in viral cure rates when delaying the start of telaprevir by four

eeks, during which time, patients received four weeks of pegylated-interferonnd ribavirin alone, compared to a simultaneous start [7]. Randomization wasratified by viral load and prior response. Stopping rules applied for TVR (Weeks, 6, and 8 for T12/PR48; Weeks 8, 10, and 12 for Li T12/PR48) and Peg-IFN/RBV

eeks 12, 24, and 36 for T12/PR48; Weeks 16, 24 and 36 for Li T12/PR48) Peg-N: Peg-IFN alfa-2a = 180 lg/week; RBV = 1000–1200 mg/day; TVR = 750 mg

very 8 h. (B) SVR rates for the telaprevir simultaneous start arm and the delayedart arm were 64% and 66%, respectively, overall, based on an intent-to-treatTT) analysis. For the primary analysis, the SVR rates for the telaprevirmultaneous start arm, delayed start arm and control arm, respectively, were3%, 88%, and 24% in relapsers (p <0.001); 59%, 54%, and 15% in partial responders,

<0.001); and 29%, 33%, and 5% in null responders, (p <0.001) [7].

JOURNAL OF HEPATOLOGY

What have we learned?

First, duration of therapy should be shortened in naive genotype 1patients who achieved eRVR

A major information from the telaprevir studies, is that approxi-mately two-thirds of patients achieved RVR and remain HCV RNAnegative through 24 weeks and benefit from 24 weeks of treat-ment. Treatment-naïve patients with cirrhosis who have unde-tectable HCV-RNA at weeks 4 and 12 may benefit from anadditional 36 weeks of peginterferon alfa and ribavirin (48 weekstotal).

Second, knowledge of the stopping rules is important

Discontinuation of therapy is recommended in all patients withHCV-RNA levels of greater than or equal to 1000 IU/ml at treat-ment week 4 or 12; or confirmed detectable HCV-RNA levels attreatment Week 24. Patients may develop treatment-emergentresistance substitutions.

Can either interferon be utilized with either protease inhibitor?

Probably yes. In a prospective, multicenter, randomized, open-label, phase 2 clinical trial study, including 161 HCV genotype 1patients, a high proportion (>80%) of patients achieved an SVRregardless of the telaprevir dosing frequency (q8 h or q12 h) ortype of peginterferon alfa used (alfa-2a or alfa-2b) [8]. Each pegy-lated interferon provides approximately the same SVR (4). Itmight be that either interferon could be utilized with either pro-tease inhibitor; however we need more information regardingthis issue.

The Realize study is a phase 3, randomized, double-blind, pla-cebo-controlled study conducted in 662 genotype 1 chronic hep-atitis C patients who did not achieve an SVR after at least oneprior treatment with IFN-based therapy [7]. Trial design is pre-sented in Fig. 2A. There were two telaprevir-based arms (simulta-neous and delayed start) and one control arm. As in all Phase 3studies of telaprevir, patients received no more than 12 weeksof telaprevir given in combination with pegylated interferonand ribavirin. One of the telaprevir treatment arms was designedto evaluate whether there was any further improvement in viralcure rates when delaying the start of telaprevir by four weeks,during which time patients received four weeks of pegylated-interferon and ribavirin alone, compared to a simultaneous start.The SVR rates between these two arms were similar and therewas no clinical benefit to the telaprevir delayed start treatmentarm in any of the subgroups of patients. SVR rates for the telapre-vir simultaneous start arm and the delayed start arm were 64%and 66%, respectively, overall, based on an intent-to-treat (ITT)analysis (Fig. 2B). For the primary analysis, the SVR rates forthe telaprevir simultaneous start arm, delayed start arm and con-trol arm, respectively, were 83%, 88%, and 24% in relapsers(p <0.001); 59%, 54%, and 15% in partial responders, (p <0.001);and 29%, 33%, and 5% in null responders, (p <0.001) (Fig. 2B).

Prior relapsers might be treated for a duration of 24 weeks ifthey achieved eRVR. Among prior relapsers, 76% (218/286)achieved an eRVR and of those 95% (208/218) achieved an SVR.Partial responders and non responders will be treated for48 weeks. Null responders may wait for future combinationtreatment. The mechanisms of non response to interferon are

Journal of Hepatology 2011

Faraintestpritrimwast4(WIFest(Isi8(p

not well understood, and the addition of a protease inhibitormight partially restore IFN responsiveness [9].

Finally, a major breakthrough has been achieved with tripletherapy when telaprevir is added to pegylated interferon andribavirin. Realize the Advance in HCV treatment, but remain cau-tious. In genotype 1 naïve and experienced patients, standard ofcare is currently the triple therapy with telaprevir or boceprevir,with PEG-IFN plus ribavirin.

This led to major expectancies but also caution. There will bemajor educational needs to achieve good clinical use of treat-ment. First, knowledge of treatment response predictors willinclude genotype 1 subtype, and also all previously knownpredictors (RVR, etc.). Power of IL28B polymorphisms testing to

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International Hepatology

predict SVR for triple therapy is not completely evaluated cur-rently and cannot be recommended at this time. Naïve patientswho achieved eRVR benefit from a shorter duration treatment.Treatment has to be well explained and simplified. Second, it willbe important to focus on compliance. In addition to PEG-IFN andribavirin, telaprevir is administered orally at a dose of 750 mgthree times daily (to be taken with food and at an interval of7–9 h between doses) in two capsules of 375 mg each. Compli-ance will be an issue, since poor compliance is associated withfailure and resistance.

Third, management of side effects and treatment dose adapta-tion will be important. The main side effects observed with tela-previr are skin lesions, including rash and pruritus, and anemia.In the Advance study, rash was more frequently observed in the12-week telaprevir arm than in the control arm (56% vs. 37%,respectively) [5]. Rash was also more frequent in the telaprevirarm in the REALIZE study (37% and 36% in the telaprevir armsvs. 19% in the control arm) [7]. Approximately 90% of all rasheswere mild or moderate (grades 1 and 2), whereas 6% of patientsexperienced severe (grade 3) rash, leading to telaprevir discontin-uation [5]. Grade 3 to 4 cutaneous lesions require immediatetreatment discontinuation and immediate consultation withexperienced dermatologists. Frequent physical examinationstogether with laboratory testing for anemia to adapt dosing willbe needed. Last but not least, measurements of HCV RNA formonitoring drug resistance will be mandatory. HCV RNA assaysbased on real-time PCR will have to be done frequently. A viralbreakthrough in a compliant patient is very likely to be drugresistance and is a stopping rule.

In the future, we do hope that once several DDAs becomeavailable, treatment strategies will include a combination ofseveral drugs with different mechanisms of action (protease

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inhibitors plus polymerase inhibitors) that could hopefully resultin IFN- and/or ribavirin sparing regimens leading to additivepotency, lacking cross resistance and with a good safety profile.

Conflict of interest

Tarik Asselah is a speaker and/or investigator for Abbott, Boehrin-ger-Ingelheim, BMS, Gilead, Janssen, Merck, Novartis and Roche.

References

[1] Asselah T, Marcellin P. New direct-acting antivirals’ combination for thetreatment of chronic hepatitis C. Liver Int 2011;31:68–77.

[2] Asselah T. A sprint to increase response to HCV treatment: expectancies butcaution. J Hepatol 2011;55:1154–1158.

[3] Poordad F, McCone Jr J, Bacon BR, et al. Boceprevir for untreated chronic HCVgenotype 1 infection. N Engl J Med 2011;364:1195–1206.

[4] Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronicHCV genotype 1 infection. N Engl J Med 2011;364:1207–1217.

[5] Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previouslyuntreated chronic hepatitis C virus infection. N Engl J Med 2011;364:2405–2416.

[6] Sherman KE, Flamm SL, Afdhal NH, et al. Telaprevir in Combination withPeginterferon Alfa2a and Ribavirin for 24 or 48 weeks in Treatment-NaïveGenotype 1 HCV Patients who Achieved an Extended Rapid Viral Response.Hepatology 2010;52:LB–2, [AASLD, abstract].

[7] Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection.N Engl J Med 2011;364:2417–2428.

[8] Marcellin P, Forns X, Goeser T, et al. Telaprevir Is Effective Given Every 8 or 12Hours With Ribavirin and Peginterferon Alfa-2a or -2b to Patients WithChronic Hepatitis C. Gastroenterology 2011;140:459–468.

[9] Asselah T, Bièche I, Sabbagh A, Bedossa P, Moreau R, Valla D, et al. Geneexpression and hepatitis C virus infection. Gut 2009;58:846–858.

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