Best Practice & Research Clinical Gastroenterology 26 (2012) 455–462

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Best Practice & Research ClinicalGastroenterology

8

Triple therapy with boceprevir or telaprevir for prior HCVnon-responders

Tarik Asselah, MD, PhD, Professor *

Service d’hépatologie, Hôpital Beaujon, APHP, University Paris-Diderot and INSERM CRB3, 100 Bd du Général Leclerc,92110 Clichy, France

Keywords:NS5A inhibitorsPegylated-interferonPolymerase inhibitorsProtease inhibitorsRibavirin

Abbreviations: DAA, direct acting antivirals; ETR,interferon; RBV, ribavirin; RVR, rapid virological resp

* Corresponding author. Tel.: þ33 0 140875579;E-mail address: tarik.asselah@bjn.aphp.fr.

1521-6918/$ – see front matter � 2012 Publishedhttp://dx.doi.org/10.1016/j.bpg.2012.09.003

a b s t r a c t

Approximately 170 million people are infected with hepatitisC virus (HCV) worldwide. Sustained virological response (SVR) isequivalent to viral eradication and associated with a reduction inthe risk of cirrhosis and hepatocellular carcinoma. The treatmentfor genotype 1 HCV chronic infection is the addition of a proteaseinhibitor (telaprevir or boceprevir) to the pegylated-interferon(PEG-IFN) plus ribavirin (RBV) regimen. Treatment of genotype 1naïve chronic hepatitis C with PEG-IFN and ribavirin (RBV) for 48weeks results in SVR in approximately 40% of patients. Retreat-ment of previous relapsers to PEG-IFN/RBV therapy with tripletherapy, a protease inhibitor (telaprevir or boceprevir), plus PEG-IFN and RBV results in SVR in more than 70% of cases. However,retreatment of previous non-responders to PEG-IFN/RBV therapywith these triple therapies, results in SVR in less than 30% of cases.The aim of this review is to summarize results obtained withBoceprevir or Telaprevir triple therapy for prior HCV experiencedpatients (non-responders and relapsers).

� 2012 Published by Elsevier Ltd.

Definition of different pattern of responses (SVR, relapse, non-response)

The primary goal of treatment is achievement of sustained virologic response (SVR) traditionallydefined as undetectable serum or plasma HCV RNA 24 weeks following completion of treatment [1,2].

end-of-treatment response; EVR, early virological response; PEG-IFN, pegylated-onse; SVR, sustained virological response.

fax: þ33 0 147309440.

by Elsevier Ltd.

T. Asselah / Best Practice & Research Clinical Gastroenterology 26 (2012) 455–462456

The SVR corresponds to a cure of infection and histological improvement [3]. Twelve-week post-treatment follow-up appears as relevant as 24 weeks to define SVR [4].

Treatment endpoints have a strict definition (Fig. 1 and Table 1).Classically, the non-response to previous PEG-IFN/RBV is defined by a less than 2 log10 HCV RNA

level decrease at 12 weeks of treatment, or a less than 1 log10 HCV RNA level decrease at week 4, HCVRNA detectable during and at the end of therapy.

It has been shown that some IFN-stimulated genes were highly expressed in non-responders priorto treatment, thus pre-activation of the IFN system appears to limit the effect of IFN therapies [5].

During therapy, HCV RNA levels should be monitored ideally with a real-time PCR method witha lower limit of detection of the order of 10–15 IU/mL. Flat non-responders show no variation ofthe HCV RNA. Patients achieving an early virological response (more than 2 log10 reduction in HCVRNA load compared with the baseline or HCV RNA negative, at week 12) or a rapid virologicalresponse (RVR) (HCV RNA negative at treatment week 4) have a better chance of maintaining anSVR [6].

Triple therapy with boceprevir, PEG-IFN plus RBV, for treatment-experienced genotype 1

Boceprevir is a linear peptidomimetic ketoamide serine protease inhibitor that binds reversibly tothe HCV non-structural 3 (NS3) active site.

The final results of the Respond 2 study trial showed that Boceprevir triple therapy resulted inhigher SVR rates in patients with HCV genotype 1 who did not respond to or relapsed after treatmentwith PEG-IFN and RBV [7]. In this trial, three arms were randomly defined from 403 HCV genotype 1patients who previously failed treatment–partial/non-responders or relapsers. The SVR was signifi-cantly higher in the two boceprevir groups (group 2, 59%; group 3, 66%) than in the PEG-IFN/RBVcontrol group (21%) (Fig. 2). The SVR in patients with undetectable HCV RNA levels at week 8 was86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. The SVR in the 102patients whose HCV RNA levels decreased by less than 1 log10 IU/ml at treatment week 4 were 0%, 33%,and 34% in groups 1, 2, and 3 respectively. Anaemia was significantly more common in the boceprevirgroups than in the control group, and erythropoietinwas administered to 41–46% of boceprevir-treatedpatients and 21% of controls.

The SVR in patients with prior relapse was 29% in group 1, vs. 69% and 75% in groups 2 and 3respectively. The corresponding rates in patients with a prior non-response were 7% vs. 40% and 52%respectively. A total of 102 patients (15%, 28%, and 27% in groups 1, 2 and 3 respectively) had a poorresponse to IFN, defined as a decrease in HCV RNA levels of less than 1 log10 IU/ml after the four-week

Relapse

Null response

vel

Partial response

V R

NA

le

Detection limit

HC

Treatment0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72

Weeks

Fig. 1. Different patterns of response to HCV therapy. Rapid virologic response (RVR): HCV RNA undetectable at week 4 of treatment.Early virological response (EVR): �2 log10 reduction from baseline HCV RNA at week 12 of treatment. End-of-treatment response (ETR):undetectable HCV RNA at the end of treatment. Sustained virologic response (SVR): undetectable HCV RNA at week 24 after the end oftreatment. Relapse: undetectable viraemia during and at the end of treatment but virus is detectable after treatment is stopped. Non-response: detectable HCV RNA throughout treatment.

Table 1. Endpoints for chronic hepatitis C virus (HCV) treatment.

End-point Definition Time point for measuring HCV RNA

Rapid virologic response (RVR) HCV RNA undetectable four weeks after treatmentEarly virologic response (EVR) �2 log10 reduction in HCV RNA 12 weeks after treatmentEnd-of-treatment response (ETR) HCV RNA undetectable End of treatmentSustained virologic response (SVR) HCV RNA undetectable 24 weeks after end of treatment

T. Asselah / Best Practice & Research Clinical Gastroenterology 26 (2012) 455–462 457

lead-in. None of the patients in group 1 of this subgroup achieved an SVR, although 33% and 34%achieved an SVR in groups 2 and 3 respectively. The SVR in patients with a response to IFN (a decreasein HCV RNA level of at least 1 log10 IU/ml at week 4), was 25%, 73% and 79% in groups 1, 2 and 3respectively.

An assessment for amino acid variants associated with reduced susceptibility to boceprevir wasperformed in 114 patients in groups 2 or 3 who did not achieve an SVR. Post-baseline data wereavailable for 98 of the 114 patients (86%) and variants were detected in 43 (44%). The rate of amino acidvariants associated with reduced susceptibility to boceprevir was higher in patients with a poorresponse to IFN than in those with a good response.

The EVR (i.e., undetectable HCV RNA at week 8) was associated with a high SVR rate in all threegroups. The proportion of patients with undetectable HCV RNA levels at week 8 in the boceprevirgroups was approximately six times that in group 1. The factors associated with SVR were: receivingboceprevir, previous relapse, low viral load at baseline and the absence of cirrhosis. When the decline

Prior relapsers Prior partial

responders

)S

VR

(%

)

PR48 BOC44/

PR48

BOC

RGT

PR48 BOC44/

PR48

BOC

RGT

2/29 30/5823/57n/N= 15/51 77/10372/105

Fig. 2. RESPOND 2 study: this phase III randomized trial demonstrated that combination therapy with boceprevir yields higher SVRrates in patients with HCV genotype 1 who did not respond to or relapsed after treatment with PEG-IFN/RBV. In this trial, three armswere randomly selected from 403 HCV genotype 1 patients who previously failed treatment–partial/non-responders or relapsers.The control arm received PEG-IFNalfa-2b/RBV for 48 weeks. The second arm received four weeks of PEG-IFNalfa-2b/RBV lead-infollowed by RGT with PEG-IFNalfa-2b/RBV and 800 mg of boceprevir three times a day. The third arm received four weeks ofPEG-IFNalfa-2b/RBV lead-in followed by 44 weeks of PEG-IFNalfa-2b/RBV and 800 mg of boceprevir. At 24 weeks after the end oftreatment, the control arm achieved an SVR of 21%. Adding boceprevir to treatment increased SVR to 59% for the second arm and 67%for the third arm. It was noted that the SVR rate was better in previous relapsers than in non-responders in all arms. Adapted fromRef. [7].

T. Asselah / Best Practice & Research Clinical Gastroenterology 26 (2012) 455–462458

in viral load at week 4 was added to the model, the week 4 response was a stronger predictor of SVRthan the historical response.

There was a higher incidence of anaemia in the boceprevir groups (43–46%) than in the controlgroup (20%). However, discontinuation owing to anaemiawas infrequent. Dysgeusia, rash, and dry skinwere more frequent in the boceprevir than in the control groups.

The SVR rate in patients with undetectable HCV RNA levels at treatment week 8 was similarwhether boceprevir was taken for 32 or 44 weeks. Thus, an early response identified patients whocould benefit from shorter treatment.

The authors identified 102 patients with a poor response to IFN, defined as a decrease in HCV RNAof less than 1 log10 IU/ml at week 4. This is important to identify changes over time in patients whohave previously been treated and are awaiting retreatment. The possible explanations for thesechanges include an increase in body weight, development of glucose intolerance, an increase inhepatic steatosis and the progression of fibrosis, all of which could decrease the responsiveness toPEG-IFN/RBV. In particular SVR was achieved after boceprevir was added to PEG-IFN/RBV in 33–34%of patients with a poor response to IFN, compared to 0% of patients who were retreated with PEG-IFN/RBV alone.

Furthermore, certain IFN-stimulated genes were shown to be highly expressed in non-responders,thus pre-activation of the IFN system in patients appears to limit the effect of IFN antiviraltherapy. Failure to respond to exogenous PEG-IFN in non-responders could indicate a blunted responseto IFN [5].

Triple therapy with telaprevir, PEG-IFN plus RBV, for treatment-experienced genotype 1

Telaprevir (VX-950) inhibits the HCV NS3-4A serine protease, leading to the block of viral poly-protein processing and subsequent decrease of viral RNA replication.

The Realize study was a phase 3, randomized, double-blind, placebo-controlled study in 662genotype 1 experienced chronic hepatitis C patients [8].

SVR rates for the telaprevir simultaneous start arm and the delayed start arm were 64% and 66%respectively, based on an intent-to-treat analysis. Primary analysis showed that the SVR rates for thetelaprevir simultaneous start arm, delayed start arm and control arm respectively, were 83%, 88% and24% in relapsers; 59%, 54% and 15% in partial responders; and 29%, 33% and 5% in non-responders(Fig. 3). Prior relapsers could be treated for 24 weeks if they achieved an eRVR. About 76% of prior

Fig. 3. The REALIZE study was a phase 3, randomized, double-blind, placebo-controlled study in 662 genotype 1 chronic HCV non-responder patients with at least prior treatment with IFN-based therapy. There were two telaprevir-based arms (simultaneous anddelayed start) and one control arm. SVR rates for the telaprevir simultaneous start arm and the delayed start arm were 64% and 66%respectively, overall, based on an intent-to-treat (ITT) analysis. For the primary analysis, the SVR rates for the telaprevir simultaneousstart arm, delayed start arm and control arm, respectively, were 83%, 88% and 24% in relapsers (P < 0.001); 59%, 54% and 15% inpartial responders, (P < 0.001); and 29%, 33% and 5% in non-responders, (P < 0.001). Adapted from Ref. [8].

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relapsers achieved an eRVR and 95% of these achieved an SVR. Partial responders and non-respondersshould be treated for 48 weeks. Non-responders could wait for future combination treatments.Although the mechanisms of non-response to IFN are not well understood the addition of a proteaseinhibitor could partially restore IFN responsiveness [9].

Rash is one of the most prominent side effects of telaprevir. Approximately 90% of all rasheswere mild or moderate (grades 1 and 2), although severe rash (grade 3) developed in 6% ofpatients, leading to discontinuation of telaprevir [8]. Grade 3–4 skin lesions require immediatetreatment discontinuation and consultation with an experienced dermatologist. Frequent physicalexaminations and laboratory testing for anaemia must be performed to adapt dosing inthese regimens. HCV RNA must be measured frequently with real-time PCR to monitor drugresistance. A viral breakthrough in a compliant patient is very likely to be drug resistance and isa stopping rule.

Resistance issues

Viral resistance to DAAs is defined by the selection of viral variants bearing amino-acid substi-tutions that alter the drug target and thereby confer reduced susceptibility to the drug’s inhibitoryactivity. The genetic barrier to resistance is defined as the number of nucleotide changes required forthe targeted viral protein to acquire an amino-acid substitution that imparts resistance. Selection ofresistant variant is under the influence of a number of factors including viral, pharmacological andhost-related factors. Adherence to therapy should be investigated to optimize response. Antiviraldrug potency also plays a major role for resistance and DAAs against different viral targets induceda significant viral suppression. The selection of resistance is mainly due to the combination of the highreplication rate of HCV and the poor fidelity of its NS5B RNA-dependent RNA polymerase (RdRp) thatproduce numerous variant during HCV replication. Without antiviral drugs, resistance mutationsfrequently impairs viral fitness, but when a DAA is administrated, pre-existent drug-resistant variantshave a fitness advantage and can be selected to become the dominant viral population. Indeed,monotherapy studies with DAA like NS3/4A PI, NS5B RdRp or NS5A inhibitors revealed that thesecompounds have a low or intermediate genetic barrier to resistance. Other classes of drugs, like thenucleoside/nucleotide analogues inhibitors of the RdRp, seem to have a higher genetic barrier toresistance [2].

The main amino-acid changes associated to resistance to telaprevir and boceprevir havebeen described [10,11]. Overall, the genetic barrier to resistance of PI is lower in subtype 1a than 1b [11].For example, to select the mutation R155K, only one nucleotide change in subtype 1a strain is required,whereas two nucleotide changes are required to achieve this mutation in subtype 1b strain. As a result,a higher rate of virologic failure is observed in subtype 1a infection versus subtype 1b [10,11].Therefore, HCV subtype may be considered when treating with NS3/4A PI.

It appears that resistant-variant to PI acquired additional mutations on order toimprove their fitness. Therefore, it is important to follow the stopping rules when resistanceoccurs and to stop treatment. We can also recall that virus resistant to DAAs may remain sensitiveto IFN.

Genetics to predict treatment response

SNPs, near the IL-28B (IFN-3k) region, have been associated with a treatment response, thusopening a window for personalized medicine [12]. A strong association was reported betweenrs12979860 and SVR in genotype 1 treatment-naive patients treated with PEG-IFNalfa-2a/RBV.Although all the identified variants lie in or near the IL-28B gene, none of them has an obviouseffect on gene function [13]. The power of IL-28B testing to predict SVR to triple therapy has not beensufficiently evaluated and cannot be recommended at this time. Moreover, IL28B may have limitedpredictive value in patients with prior failure to PEG-IFN/RBV. In experienced patients, the mostimportant predictors of response are the type of previous failure (relapse, partial response, null-response) and the presence of cirrhosis.

Fig. 4. Virologic response. (Group A) Four patients on oral dual combination therapy (with the non-structural protein 5A inhibitor,daclatasvir, and the non-structural protein 3 protease inhibitor, asunaprevir) (36%) had an SVR at 12 weeks after the end of thetreatment period, and all four also had an SVR at week 24 after treatment. Six patients (all with HCV genotype 1a) had a viralbreakthrough while receiving therapy; one patient had a viral response at the end of treatment but relapsed after the treatmentperiod. (Group B) (1) ten of ten patients had undetectable HCV RNA by week 6 of therapy with no viral breakthrough; (2) ten of tenpatients achieved SVR12 and nine of ten achieved SVR24; (3) one patient <LLOQ at week 24 post-treatment was undetectable onretesting, one and three months later. Adapted from Ref. [16].

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Perspectives for non-responders

Proof of concept for IFN free regimen has been provided [14,15]. Recent data on future new DAAscombination therapy for previous null-responders are promising. One study included 21 non-responders to PEG-IFN/ribavirin re-treated for 24 weeks with NS5A inhibitor daclatasvir and NS3/4API asunaprevir alone or in combination with PEG-IFN-ribavirin [16]. Nine of the ten patients achievedSVR (Fig. 4). Interestingly, the potential to eradicate HCV in this difficult-to-treat patient populationwith IFN-free regimen was demonstrated with 36% of SVR. The remaining patients experienced viralbreakthrough caused bymulti-drug resistant virus. The frequency of resistance was higher in genotype1a patients than 1b. A similar study conducted in Japan with ten HCV genotype 1b prior null-responders to PEG-IFN/RBV assessed the efficacy of 24 weeks of daclatasvir and asunaprevir combi-nation [17]. Nine of the ten patients achieved SVR. Studies with daclatasvir and asunaprevir have beendiscussed recently [18].

Conclusion

Major breakthroughs have been achieved in the treatment of chronic HCV infection. Currently,the standard of care of treatment of HCV genotype 1 is the addition of a DAA protease inhibitor(telaprevir or boceprevir) to the PEG-IFN plus RBV regimen. Retreatment of previous relapsers toPEG-IFN/RBV therapy with triple therapy, a protease inhibitor (telaprevir or boceprevir), plus PEG-IFN and RBV results in SVR in more than 70% of cases. However, retreatment of previous non-responders to PEG-IFN/RBV therapy with these triple therapies, results in SVR in less than 30% ofcases. The future management of patients with these new molecules will require good clinicalpractice, knowledge of indications, management of side effects and monitoring for antiviral resis-tance. Certain major medical needs are still unmet requiring studies in special populations (e.g. HIV–HCV coinfected patients, transplanted patients) in HCV genotypes non-1 patients and in non-responders.

Second generation protease inhibitors and new classes of DAA are under development inclinical trials. Preliminary results of DAA combinations show increased antiviral efficacy, reducedresistance and a good safety profile. It is important to note that some of these drugs have pan-genotypic activity. This rapid progress strongly suggests that in the near future, IFN-free shortduration DAA combinations will make HCV the first chronic viral infection to be eradicatedworldwide.

Practice points

1 The primary goal of treatment is achievement of sustained virologic response (SVR) tradi-tionally defined as undetectable serum or plasma HCV RNA 24weeks following completion oftreatment.

2 The treatment for genotype 1 HCV chronic infection (naïve and experienced patients) is theaddition of a protease inhibitor (telaprevir or boceprevir) to the pegylated-interferon (PEG-IFN) plus ribavirin (RBV) regimen.

3 Non-response to previous PEG-IFN/RBV is defined by a less than 2 log10 HCV RNA leveldecrease at 12 weeks of treatment, or a less than 1 log10 HCV RNA level decrease at week 4, orHCV RNA detectable during and at the end of therapy.

4 Retreatment of previous relapsers to PEG-IFN/RBV therapy with triple therapy, a proteaseinhibitor (telaprevir or boceprevir), plus PEG-IFN and RBV results in SVR in more than 70% ofcases.

5 Retreatment of previous non-responders to PEG-IFN/RBV therapy with these triple therapies,result in SVR in less than 30% of cases.

6 In experienced patients, the most important predictors of response to triple therapy are thetype of previous failure (relapse, partial response, null-response) and the presence ofcirrhosis.

Research agenda

1 The mechanisms of non-response to triple therapy need a better understanding (IFN non-response, resistance to DAAs).

2 Clinical trials on special populations (HIV–HCV coinfected patients, transplanted patients,etc.) in HCV genotypes non-1 patients and in non-responders.

3 Second generation protease inhibitors and new classes of DAA are under development inclinical trials. Preliminary results of DAA combinations show increased antiviral efficacy,reduced resistance and a good safety profile. It is important to note that some of these drugshave pan-genotypic activity. This rapid progress strongly suggests that in the near future, IFN-free short duration DAA combinations will make HCV the first chronic viral infection to beeradicated worldwide.

4 Safety profiles of new DAAs will be a major issue.

T. Asselah / Best Practice & Research Clinical Gastroenterology 26 (2012) 455–462 461

Conflicts of interest

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

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