treatment failure with new hepatitis c drugs

1. Introduction

2. New antivirals for hepatitis C

3. HCV treatment failure

modalities

4. HCV drug resistance

5. HCV rescue therapies

6. Expert opinion

Review

Treatment failure with newhepatitis C drugsVincent Soriano†, Eugenia Vispo, Eva Poveda, Pablo Labarga &Pablo BarreiroHospital Carlos III, Infectious Diseases Department, Madrid, Spain

Introduction: The combination of pegylated interferon-a plus ribavirin

(pegIFNa--RBV) has been the only therapeutic option for patients with chronic

hepatitis C virus (HCV) infection during the last decade. Unfortunately, it pro-

vides cure to less than a half of individuals infected with HCV genotype 1,

which is by far the most prevalent worldwide. The recent introduction of

new direct-acting antivirals (DAA) has revolutionized the hepatitis C field.

The addition of any of the two recently approved HCV protease inhibitors,

boceprevir or telaprevir, to pegIFNa--RBV results in the cure for two-thirds

of HCV genotype 1, interferon-naive patients.

Areas covered: This paper reviews new antivirals for hepatitis C and HCV

treatment failures, along with HCV drug resistance and rescue therapies.

Expert opinion: The application of early stopping rules may reduce the enrich-

ment of drug-resistant viruses in patients failing first-generation HCV prote-

ase inhibitors, potentially allowing more chances of response to rescue

interventions with other compounds within the same class in the near future.

On the other hand, the advent of DAA belonging to distinct drug families

may provide further opportunities for clearing definitively HCV in patients

currently failing first-generation HCV protease inhibitors. Thus, hepatitis C

has entered a new era that hopefully will end with its eradication. In

the meantime, a wise use of DAA is warranted, including adequate selection

of candidates for therapy, close monitoring of drug adherence, proper

management of side effects and early application of stopping rules.

Keywords: boceprevir, DAA, drug resistance, HCV, HIV, telaprevir

Expert Opin. Pharmacother. (2012) 13(3):313-323

1. Introduction

Chronic hepatitis C virus (HCV) infection affects around 175 million peopleworldwide. In the absence of successful therapy, nearly one-third of these patientswill go on to develop hepatic complications lifelong [1]. Until recently, the combi-nation of pegylated interferon-a plus ribavirin (pegIFNa--RBV) was the onlytherapeutic option for these patients. Unfortunately, overall only 40% of thoseharboring HCV genotype 1 infection, which by far is the most prevalent world-wide, responded to therapy [2,3]. The discovery and recent approval of the firstdirect-acting antivirals (DAA) for the treatment for chronic hepatitis C is acutting-edge event in infectious diseases [4-8]. What is happening in year 2011 inhepatitis C reminds what occurred in year 1996 in the HIV/AIDS field, whentriple-combination antiretroviral therapy using the first HIV protease inhibitorsalong with a nucleoside analog backbone allowed to achieve undetectable viremiaand rapid CD4 gains in most patients.

The recent therapeutic advances in hepatitis C have been concurrent with majorimprovements in diagnostic tools, what has further accelerated and shift paradigmsin the treatment of hepatitis C. The widespread use of noninvasive tools to assessliver fibrosis is rapidly replacing liver biopsy in many clinics [9,10]. As a consequence,

10.1517/14656566.2012.653341 © 2012 Informa UK, Ltd. ISSN 1465-6566 313All rights reserved: reproduction in whole or in part not permitted

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a larger number of HCV carriers are being found to exhibitsignificant or advanced liver fibrosis, and, therefore, requirestreatment consideration. On the other hand, the fascinatingdiscovery of the impact of interleukin 28B (IL28B) gene poly-morphisms on treatment outcomes in late 2009 [11-15] hasprovided a new tool to predict treatment response in chronichepatitis C patients. For all these reasons, year 2011 should beviewed as the birth of a new era for hepatitis C [16].

2. New antivirals for hepatitis C

Efforts in developing new compounds against HCV havebeen hampered until recently by difficulties in replicatingthe virus in cell culture and the lack of suitable animal models.However, advances in the understanding of the HCV geno-mic organization and life cycle, and the development ofHCV replicons and infectious viral particles in tissue culturesystems have enabled the rational design of agents that specifi-cally inhibit HCV replication. The goal of future HCV treat-ment is to develop interferon-free combinations that are lesstoxic, more potent and allow shorter duration of therapythan the current standard of care. Ideally, the aim is a regimengiven for no longer than 24 weeks, including a combinationof oral compounds that will result in the cure of most chronichepatitis C patients.Three viral enzymes are currently the most promising

targets for the design of specific anti-HCV inhibitors, andseveral compounds have already been tested against theNS3/4A protease, the NS5B polymerase and the NS5A

protein [17]. Table 1 records the list of drugs already marketedor in clinical development, which have entered Phase II -- IIItrials. In May 2011, the first two HCV protease inhibitors,telaprevir and boceprevir, obtained FDA approval.

Table 2 summarizes the major differential features of dis-tinct HCV antiviral drug families [8]. Nucleos(t)ide analogpolymerase inhibitors characteristically exhibit pan-genotypicactivity and high barrier to resistance. More than four groupsof compounds have been found to inhibit allosterically theNS5B polymerase. They are non-nucleoside analogs and areactive only against HCV genotype 1. They uniformly displaylow barrier to resistance and may be inactive in the presence ofnaturally occurring polymorphisms [18].

Besides DAA, other compounds that inhibit cellular pro-teins critically involved in the HCV replication cycle arealso showing promising results and may soon expand thespectrum of the HCV armamentarium. This is the case of alis-porivir (DEB-025), a cyclophilin inhibitor with activityagainst all HCV genotypes, which is currently being testedin Phase III trials [19].

Two major classes of HCV protease inhibitors againstHCV genotype 1 have been developed so far. The first groupis represented by covalent inhibitors, such as telaprevir andboceprevir, which are linear a-ketoamide derivatives. The sec-ond is constituted by non-covalent inhibitors, which are splitout into two groups: the first contains a carboxylic acid and islinear (e.g., BI-1335) while the second group is acidsulfonamide derivatives and can be either linear (e.g.,asunaprevir) or macrocyclic compounds (e.g., danoprevirand simeprevir) [8].

2.1 TelaprevirIn the ADVANCE trial [6], 1088 HCV genotype 1 patientswere randomized to triple therapy or standard of care, withtwo arms on telaprevir one giving the drug for 8 weeks andanother for 12 weeks. The length of therapy was dependentof the achievement of extended rapid virological response(eRVR), defined as viral undetectability from weeks 4 to 12.Then, duration of therapy was 24 weeks for patients witheRVR and 48 weeks for the rest. Patients with triple therapyfor 12 weeks achieved 75% sustained virological response(SVR) while it was significantly lower (69%) in the 8-weektriple arm. The ILLUMINATE trial [20] was designed to spe-cifically demonstrate that treating HCV genotype 1 IFNa-naive patients for 24 weeks was not inferior compared withtreating them for 48 weeks if they achieved eRVR. A totalof 540 patients were recruited in the trial, of whom 65%achieved eRVR and were randomized to complete 24 or48 weeks of pegIFNa--RBV therapy. Using this response-guided therapy (RGT) approach, no significant differenceswere seen comparing the two arms (92 vs 88%, respectively).

In the REALIZE study [7], patients with prior nullresponse, partial response or relapse to pegIFNa--RBVreceived triple therapy with telaprevir for the first 12 weeksfollowed by 36 weeks of pegIFNa--RBV. Significantly higher

Article highlights.

. Treatment with peginterferon-a/ribavirin cures less thana half of patients infected with hepatitis C virus (HCV)genotype 1. Failure is more frequent in specialsubpopulations, as individuals with unfavorable IL28Balleles, infection with HCV subtype 1a, HIV coinfectionor prior null response to interferon-based treatment.

. The arrival of new direct-acting antivirals (DAA) hasbeen eagerly awaited for the treatment of hepatitis C.However, suboptimal drug adherence, development ofside effects (anemia, rash, etc.) and/or selection of drug-resistant viruses may all lead to failure in at least onequarter of interferon-naive patients who receive triplecombination therapy. This rate is even higher in patientswith advanced liver fibrosis and those with priorinterferon null response.

. Application of early stopping rules may reduce theenrichment of drug-resistant viruses in patients failingDAA, potentially allowing more chances of response torescue interventions with other compounds within thesame class in the near future.

. The advent of new DAA belonging to distinct drugfamilies may provide further opportunities for clearingdefinitively HCV in patients currently failingfirst-generation HCV protease inhibitors.

This box summarizes key points contained in the article.

Treatment failure with new hepatitis C drugs

314 Expert Opin. Pharmacother. (2012) 13(3)

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SVR rates were obtained with triple therapy compared withstandard of care, especially in prior relapsers (86 vs 24%).However, treatment failure and selection of drug resistancewere common in prior null responders and in patientswith cirrhosis.

2.2 BoceprevirThe SPRINT-2 study [4] examined triple therapy in IFNa-naive HCV genotype 1 patients while the RESPOND-2 trial [5]tested triple therapy in patients with prior IFNa experience. Inall cases, boceprevir was preceded by a lead-in period of 4 weeksof pegIFNa--RBV alone aimed to reduce viral load and the like-lihood of selecting boceprevir resistance. In the SPRINT-2 trial,there was a prespecified enrollment goal for blacks that exceedthe expected proportion that would have occurred with a ran-dom enrollment, to power the study to show the SVR responsein both blacks and whites. The overall SVR in the trial was 66%,with no significant differences between patients treated for 1 yearand those treated for shorter periods according to RGT (only24 weeks if they had achieved and sustained undetectabilityfrom week 4 of triple therapy). Overall, whites responded betterthan blacks. Anemia and gastrointestinal intolerance were themajor dose-limiting side effects of boceprevir. However, only15% of patients discontinued therapy prematurely due to seri-ous adverse events.

While telaprevir is administered for only 12 weeks as2 pills/8 h and hopefully will soon be dosed twice a day [21],boceprevir has to be provided as 4 pills/8 h for the wholelength of therapy in most cases (24, 36 or 48 weeks). Bothdrugs use the RGT principle, allowing a shortened duration

of therapy based on early viral responses. Table 3 records themost relevant differences between telaprevir and boceprevir.

A lead-in phase of pegIFNa--RBV therapy is recommendedusing boceprevir but not with telaprevir. While this strategymay increase the complexity of treatment, it may allow to iden-tify a subset of patients with unresponsiveness to IFNa (< 1 logHCV-RNA decline at week 4), in whom therapy might bedeferred given the low chances of cure. If therapy is otherwiseindicated, as it may be preferred in patients with advanced liverfibrosis, the selection of drug resistance is a major concern.However, up to 30% of these patients may respond to DAAtherapy. On the other hand, achievement of undetectable vire-mia at week 4 only with pegIFNa--RBV therapy may identify asubset of individuals in whom the chances of response to dualtherapy alone are above 80% (Figure 1). In this group ofpatients, the addition of boceprevir may only slightly increaseSVR rates, although it may allow a shortened length of therapy.This latest consideration may be particularly relevant in cir-rhotics. Altogether, there is uniform opinion that while theintroduction of DAA is a major breakthrough in hepatitis Ctherapeutics, it adds significant complexity and introducesimportant challenges.

3. HCV treatment failure modalities

Despite the attractiveness of high response rates achieved withtriple therapy, it is worth to consider that treatment failure isnot rare. Figure 2 records the rate of treatment failure in themajor registrational trials with telaprevir and boceprevir.Triple therapy was tested in interferon-naive patients in the

Table 1. Hepatitis C virus antivirals in more advanced stages of clinical development.

Protease inhibitors Polymerase inhibitors NS5A inhibitors

Nucleoside analogs Non-nucleside analogs

TelaprevirBoceprevirSimeprevirMK-5172BI-1335DanoprevirGS-9256ABT-450

MericitabinePSI-7977PSI-7851

TegobuvirFilibuvirBI-7127SetrobuvirVX-222VCH-759ABT-072

DaclatasvirIDX-184

Table 2. Main differential features of new hepatitis C virus antivirals agents.

NS3 protease inhibitors NS5B polymerase

nucleos(t)ide analogs

NS5B polymerase

non-nucleoside analogs

NS5A inhibitors

Mechanism of inhibition Inhibitory competition Inhibitory competition Allosteric ?Genotype activity G1 (G1b > G1a) Across all G1 (G1b > G1a) Across all

(G1b > G1a)Resistance barrier Low High Low LowCross-resistance High Low Split out in 4--5 families ?Drug interactions Pharmacokinetic Pharmacodynamic Pharmacokinetic ?

Soriano, Vispo, Poveda, Labarga & Barreiro

Expert Opin. Pharmacother. (2012) 13(3) 315

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ADVANCE [6] and SPRINT-2 [4] trials, while it was evaluatedin prior interferon-experienced patients in the REALIZE [7]

and RESPOND-2 [5] trials. It is noteworthy that treatmentfailure occurred in 25 -- 31% of telaprevir and in 32 -- 33%of boceprevir (higher in blacks) interferon-naive patients.These figures were higher in interferon-experienced patients,with rates of 41 -- 46% and 48 -- 60% in prior non-relapsers.Patients treated with DAA-based regimens may fail within

three categories (Table 4). A subset of individuals is just notready and stops therapy soon after beginning it. Voluntarystop of the medication may go with or without patient’s lostto follow-up. It occurs more often in the absence of appropri-ate information about side effects of the medication and whenaccess to care provider doctors/nurses is difficult.Treatment failure may also occur as a result of early discon-

tinuation of therapy this time mandated by the doctor incharge due to serious adverse events. Interestingly, prematuredrug discontinuation due to side effects in patients respond-ing to hepatitis C therapy is not universally followed byHCV rebound, and a few are cured with quite short coursesof therapy (e.g., 12 weeks). Therefore, viral load testing ismandatory in these individuals to confirm treatment failure.

Persistence of viral replication under drug therapy leads totreatment failure. There are two different scenarios. First,when there is insufficient viral suppression early on therapy.Second, when there is a viral breakthrough in patients whoalready had achieved undetectable viremia. In any of thesesituations, the presence of drug resistance mutations at base-line as natural polymorphisms in some viral strains, a limitedpotency of the chosen drug combination and/or poor drugadherence [22,23] may all contribute to suboptimal viral sup-pression under pressure. A further reason for virological fail-ure within this category, either as early on therapy or as viralbreakthrough, may result from drug interactions resultingto suboptimal DAA exposure. This situation should be espe-cially considered when treating special populations, such asHIV-coinfected patients on antiretroviral agents [24-26].

Finally, treatment failure in hepatitis C may occur as aresult of viral rebound upon completion of the plannedlength of therapy. This situation is one of the most disap-pointing in hepatitis C therapy. It occurred in arounda quarter of HCV genotype 1 patients treated withpegIFNa--RBV [2,3] but still is observed in 10% of thosetreated with DAA [4,6]. The current evidence suggests that

Add DAA

Continue pegIFNα–RBVUndetectable

Consider stop<1 log reduction

Baseline HCV-RNA at week 4 Therapy

Figure 1. Proposed treatment strategy with a lead-in phase of peginterferon--ribavirin for the first 4 weeks.

Table 3. Main differences between first-generation hepatitis C virus protease inhibitors.

Boceprevir Telaprevir

Potency ++ +++Tolerability Anemia and dysgeusia Rash and anemiaConvenience 4 capsules/8 h for 6 -- 9 -- 12 months 2 pills/8 h for 3 monthsComplexity Lead-in.

Response-guided therapy for shorteninglength of therapy

Response-guided therapy for shorteninglength of therapy

Cost ~ 16,000 to 30,000 euros, dependingon prescription for 6, 9 or 12 monthsConsider additional erythropoietin usein a substantial number of patients

~ 25,000 euros for 3 months

Drug access Merck worldwide Vertex in the USA (Janssen in the restof the world)



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prolonging the length of therapy in these patients shouldconsolidate HCV suppression leading to become HCV-RNA negative lifelong.

Efforts to minimize the rate of treatment failure with DAAwill require the collection of information from special patientpopulations, especially from those particularly prone at riskfor selection of drug resistance, which was generally excludedor minimally represented in registrational trials. This is the

case for prior null responders to pegIFNa--RBV therapy, cir-rhotics, HIV--HCV coinfected individuals [24] and pre- andpost-transplant patients.

4. HCV drug resistance

HCV replicates at very high rates with the production of morethan 1012 particles per day in chronically infected individuals,

25

T12PR TBPR PR

31

56%

ADVANCE*n = 1088

17

41

71

46

12

6776

85

REALIZE§

n = 663RESPOND-2¶

n = 403

95

31

%

%

%

48

47

32 33

58 60

SPRINT-2‡

n =9388 77

60

71

93

25

BPR43T12PR Li-T12PR PR BPRRGT PR

BPR43 BPRRGT PR

Relapsers

Partial responders

Whites

Blacks

Null responders

Figure 2. Treatment failure rate using telaprevir and boceprevir in registrational trials.*ADVANCE, telaprevir (T) in interferon-naıve patients.zSPRINT-2, boceprevir (B) in interferon-naıve HCV genotype 1 patients (black and whites).§REALIZE, T in prior peginterferon-ribavirin (PR) failures (relapsers, partial responders & null responders).{RESPOND-2, B in prior PR failures (relapsers and partial responders).

Table 4. Treatment failure using direct-acting antivirals for hepatitis C.

Modalities Major causes Prevention and management

Premature drug discontinuation Voluntary stop Improve patient’s information and make easieraccess to doctors/nurses

Serious adverse events Proper management of side effects (i.e., use of EPO)

Virological failure under treatment Early virological failure Exclude baseline drug resistance polymorphismsAvoid drug regimens with low potencyCheck for poor drug adherenceAvoid drug--drug interactions

Viral breakthrough

Relapse after completion of therapy Short length of therapy Extend the duration of treatment



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in whom the total estimated virus population may approach1013 particles at any given time point [27]. The HCV genomecomprises nearly 104 base pairs. The error rate of the viralpolymerase during HCV replication approaches 1 per 104

base pairs, so each day viruses with genomes that harbor oneor two mutations at each position are generated, includingthose that may confer drug resistance. The constellation ofdistinct but closely related viral genomes in a given infectedcarrier is known as quasi-species. Under drug pressure, viruseswith preexisting drug resistance mutations are preferentiallyselected and expanded progressively, replacing the whole viruspopulation. Once drugs are discontinued and pressure disap-pears, the more fit viruses, which generally are those lackingdrug resistance mutations, reappear and become again themajor viral population [28].In contrast with HIV, the replication of HCV within the

infected cells does not involve any integration into chro-mosomes. HCV replicates exclusively in the cytoplasmaof hepatocytes. Thus, while proviral DNA acts as a lifelongreservoir in HIV infection, there is no stable HCV reser-voir. Indeed, using sensitive techniques, resistance muta-tions can be found in almost all HIV-infected individualsthat failed drugs in the past. By contrast, selection ofdrug-resistant variants in HCV may occur in the presenceof drug pressure and vanish upon drug removal. Thetime to disappear or return to baseline levels will be

determined by the fitness of drug-resistant mutants andthe accumulation of compensatory changes [29]. Althoughearly reports suggested an average half-life of 2 years fordisappearance of drug resistance mutations upon drugremoval using bulk sequencing, more recent data suggestthat it happens more rapidly (weeks to months). However,it is important to highlight that DAA should be discontin-ued as soon as virological failure is confirmed. This rulewill prevent the accumulation of compensatory changesthat restore the impaired fitness of viruses with primaryresistance mutations [30].

Figure 3 records the major changes at positions that result inloss of susceptibility to DAA. Interestingly, mutations atcodon 155 are the most frequently selected using first-generation HCV protease inhibitors in HCV subtype 1a [31].Patients infected with HCV subtype 1b select more oftenchanges at positions 36, 54, 55, 156 and 170 [32-34]. Muta-tions at codon 168 are the most common in patients failingsecond-generation HCV protease inhibitors. It is noteworthythat more than a quarter of HCV subtype 1a strains harborpolymorphisms at codon 80 that may reduce the activity ofsome second-generation HCV protease inhibitors, such assimeprevir [18,35]. It is worth to exam the clinical consequencesof this observation, and if proven, baseline drug resistancetesting might be considered before empirically prescribingthis drug.

V

36 54 55TelaprevirBoceprevir

Proteaseinhibitors

Nucleosideinhibitors

Mericitabine

Tegobuvir

BI-7127

Filibuvir

Non-nucleosideinhibitors

ABT-333

VHC-759

M/V

Y/N

C

M

F H P

495 496 499

P V

C Y Y

445 448 452

C/H

S/L/A/T A/S A

316L

T

423

419

282

S

T

DanoprevirBI-1335TMC-435

V

A T/K T/S/V A/T/L

170156155

168

V/A/T/H

DQF

43

S R/K

80

A/M A/V/S

R A VT

Figure 3. Main drug resistance mutations to direct-acting antivirals.



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Resistance to nucleoside analog NS5B polymerase inhibitors(e.g., mericitabine) occurs as a result of selection of changes atposition 282, which is within the catalytic site of the viralenzyme [36]. It is interesting to note that mutation S282T hasbeen selected in vitro but so far it has not been identified inpatients failing on mericitabine, most likely because it severelycompromises the activity of the viral enzyme. This explainsthe seemingly high barrier to resistance of this drug family [37].

Along with the active site, the HCV polymerase shows fourand potentially five distinct binding sites for compounds thatmay block its activity allosterically. These pockets are located atthe thumb (sites 1 and 2) and palm (sites 3 and 4) of a righthand-modeled HCV polymerase enzyme. The fifth site (E) isthe B-hairpin region.Non-nucleoside inhibitors, NS5B polymer-ase inhibitors, are noncompetitive blockers and accordingly canbe grouped into distinct families, which generally select for differ-ent resistance changes [38] (Figure 3). At least twomutations, how-ever, may compromise the activity of more than one drug class.This is the case for C316Y/N, which reduces the activity of sites3 and 4 compounds. Likewise, Y448H reduces the activity of3 and 5 site inhibitors. Overall, non-nucleoside inhibitors displaythe lowest genetic barrier for resistance among DAA. As showninTable 5, natural polymorphisms inHCVvariantsmay compro-mise the activity of some of these compounds in subjects not pre-viously exposed to any of these drugs [18,35,39-44]. If thisobservation is confirmed, baseline drug resistance testing, as in

HIV, might be considered before prescription of non-nucleosideHCV polymerase inhibitors.

NS5A inhibitors represent the newest promising class ofDAA to fight HCV [45]. They do not exhibit cross-resistancewith either protease or polymerase inhibitors [46]. Changesat positions Q30R, L31V/M and Y93C/N are the most fre-quently selected in patients failing NS5A replication complexinhibitors. As with first-generation HCV protease inhibitorsand non-nucleoside HCV polymerase inhibitors, the barrierfor resistance to daclatasvir (BMS-052) is lower in HCVsubtype 1a than 1b [47]. The impact of naturally occurringpolymorphisms on the activity of NS5A inhibitors warrantsfurther investigation [48].

5. HCV rescue therapies

Given that the HCV armamentarium is rapidly evolving,concerns about cross-resistance in patients failing first-generation HCV protease inhibitors should not precludetheir use. Next-generation HCV protease inhibitors andcompounds belonging to different drug classes (e.g., poly-merase inhibitors or NS5A inhibitors) most likely willsoon be part of salvage regimens recommended to patientswho have failed triple combination regimens based onfirst-generation HCV protease inhibitors on top of thepegIFNa--RBV backbone.

Table 5. Baseline polymorphisms that may influence direct-acting antivirals susceptibility.

GenBank

Database

Bartels

et al. [39]

Kuntzen

et al. [40]

Gaudieri

et al. [41]

Sun

et al. [42]

Bae

et al. [35]

Trevino

et al. [18]

Trimoulet

et al. [43]

Plaza

et al. [44]

NS3 ProteaseNo. tested

3197-3328 570 507* 192z - 39 55§ 76 -

V36A/M/L/G 0.03% 0.9% 1.6%# 1% 0 0 4%T54S/A 1.4% - 1.8% 3%{ 5% 0 3%V55A - - - - 0 3.6% 0Q80R/K 47%# - - - 28% 16%{ 0R109K 0.21% 0.2% 0 1% 0 0 0R155K/T/I/M/G/L/S 0.03% 0.7% 0.6%# 0.5% 0 0 1%A156S/T/V/I - - 0 0 0 0 0D168A/V/E - - 0.2% 1%{ 0 0 0V170A 0.12% 0.2% 0 5%{ 0 0 0

NS5B PolymeraseNo. tested

- - - 212z 55 - 47 - 61§

S282T/R 0.4% 0 2% 0L314F 0 - 0 0C316Y/N/F/S 2% 2% 11% 13%#

M411S 0 0 0 0M423T/I 1.4% 0 0 0V499A 75%{ - 51%{ 100%S556N/G 0 6% 0 0

*Overall 28% coinfected with HIV.zOverall 42% coinfected with HIV.§All HIV and HCV coinfected.{Significantly more frequent in HCV subtype 1a than 1b.#All HCV subtype 1b.



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Table 6 summarizes the major differences between first- andsecond-generation HCV protease inhibitors. New drugs willovercome most of the disadvantages of recently marketedtelaprevir and boceprevir, including their inconvenientdosing, side effects, genotype specificity and low barrier toresistance [49].Once several anti-HCVoral compounds belonging to distinct

drug families will become available, then combination DAAtherapy sparing interferon will eagerly be pursued. The firstproof of concept that DAA combinations may work derivesfrom preliminary results obtained in the INFORM-1 studythat reported week 4 virological results with a combination ofdanoprevir and mericitabine [50]. Table 7 records ongoing trialstesting interferon-free regimens [51-53].

6. Expert opinion

The advent of DAA for the treatment of chronic hepatitis C isa major breakthrough in the fight against HCV infection,which currently affects around 175 million people worldwideand represents the first cause of liver transplantation in devel-oped countries. In contrast with HIV or HBV, successfulHCV therapy results in definitive virus clearance, so hepatitisC is the only major chronic viral disease that can be eradicated

from infected carriers. However, the proper use of DAA issurrounded by unprecedented complexities and requires sig-nificant expertise by care providers. Moreover, current DAAtherapy is very demanding in terms of dosing and drug adher-ence, and is often associated with unpleasant side effects, all ofwhich require a high patient commitment.

Lifelong liver-related complications of chronic hepatitis Coccurs only in a third of patients. For this reason, the indi-cation of therapy so far has mainly been restricted to indi-viduals with significant liver fibrosis (i.e., Metavir F2 orabove). Following the introduction of DAA, it is clear thatthis paradigm would shift. More potent drugs providecure to more than 70% of patients within 6 months. More-over, besides liver-related complications, several studies arenow emerging pointing out that chronic HCV infection isassociated with metabolic complications, neurocognitivedysfunction, kidney disease, inflammatory and autoimmuneconditions and so on [54]. So if there is any chance to limitthe consequences of extrahepatic manifestations of HCV,treatment will be considered for all persons chronicallyinfected with HCV, regardless of liver fibrosis stage. How-ever, the limited efficacy and poor tolerability of first-generation HCV protease inhibitors may still favor aprioritization of therapy for those with more advanced liver

Table 6. Main characteristics of hepatitis C virus protease inhibitors.

First-generation PIs

(telaprevir, boceprevir)

Second-generation PIs (simeprevir,

MK-5172, BI-1335, danoprevir)

Mechanism of inhibition Covalent Non-covalentDosing Q8h/t.i.d. q.d.Genotype activity HCV-1 mainly (1b > 1a) Pan-genotypicSafety Rash, anemia GIShortened treatment duration 40 -- 60% 80 -- 90%SVR ~ 70% Potential for > 80%

GI: Gastrointestinal; PI: Protease inhibitor; SVR: Sustained virological response.

Table 7. Trials testing interferon-free direct-acting antivirals (DAA) combination regimens.

Company DAA-1 DAA-2

Roche Danoprevir* Mericitabinez

Boehringer BI-1335* BI-7127{

Vertex VX-950* VX-222{

Gilead GS-9526* Tegobuvir{

BMS BMS-65032* BMS-790052§

Idenix IDX-320* IDX-184§

Abbott ABT-450* ABT-072{

Pharmasset PSI-938# PSI-7977#

NOTE: On November 2011, Pharmasset was bought by Gilead.

*Protease inhibitors.zNucleoside analog polymerase inhibitor.§NS5A inhibitor.{Non-nucleoside analog polymerase inhibitor.#Nucleotide analog polymerase inhibitor.



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disease. However, with the advent of more active and con-venient drugs, HCV therapy will progressively be given toall carriers.

In most places, hepatologists have been so far the physiciansgenerally providing care to hepatitis C patients. This was inpart due to the late presentation of liver disease in mostpatients, often with manifestations of decompensatedcirrhosis (e.g., ascites, encephalopathy, variceal bleeding orliver cancer), for which liver doctors were the best trained.The introduction of DAA, however, has changed this sce-nario, as antiviral therapy is now mainly considered forasymptomatic individuals, in whom a virological assessment(including viral load and genotyping) provides the mostimportant piece of information for treatment decision mak-ing. The way of managing DAA therapy, considering earlyviral kinetics and eventually selection of drug-resistant mutant

viruses, is becoming more within the area of expertise of infec-tious diseases specialists, mainly clinical virologists. It must behighlighted, however, that the complexity of combinationDAA therapy, which further requires knowledge on druginteractions, and on how to manage frequent and potentiallylife-threatening adverse events, requires particular expertise(Figure 4). It would be the case that this is time for the birthof a new specialist, the ‘HCV doctor.’

Declaration of interest

The author declares no conflict of interest. This work wassupported in part by grants from the European AIDSTreatment Network (NEAT, LSHP-CT-2006-037570), theSpanish AIDS Network (RIS, ISCIII-RETIC RD06), andFundacion Investigacion y Educacion en SIDA (F-IES).

VirusLiver

Hepatologist Infectologist

The HCV doctor

Figure 4. The shift in care providers for hepatitis C.



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AffiliationVincent Soriano†, Eugenia Vispo, Eva Poveda,

Pablo Labarga & Pablo Barreiro†Author for correspondence

Hospital Carlos III,

Department of Infectious Diseases,

Calle Sinesio Delgado 10,

Madrid 28029, Spain

Tel: +34 91 4532500; Fax: +34 91 7336614;

E-mail: [email protected]



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treatment failure with new hepatitis c drugs

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