Risk Of Developing Liver Cancer After HCV Treatment

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Thursday, September 6, 2012

Directly acting antivirals for the treatment of chronic hepatitis C: Unresolved topics from registration trials

Digestive and Liver Disease

DOI: 10.1016/j.dld.2012.05.002

Article in Press

Directly acting antivirals for the treatment of chronic hepatitis C: Unresolved topics from registration trials

Alessio Aghemo , Elisabetta Degasperi , Massimo Colombo Department of Medicine, AM Migliavacca Center for Liver Diseases and First Division of Gastroenterology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy

Received 6 April 2012; accepted 3 May 2012. published online 13 June 2012.

Corrected Proof

Abstract
The Food and Drug Administration and European Medicines Agency approval of first generation directly acting antivirals NS3 protease inhibitors boceprevir and telaprevir opens a new era in the treatment of patients with chronic hepatitis C virus genotype 1 infection. Indeed telaprevir and boceprevir registration trials clearly showed a substantial improvement in rates of sustained virological response both in naive and in treatment-experienced patients, with the possibility of shortened regimens in a consistent subset of patients, through the optimization of treatment algorithms. Phases 2 and 3 studies also provided the basis for the management of side effects in order to maximize the safety profile of directly acting antivirals. However, the entry of triple therapy in current clinical practice comes with some unresolved topics, such as relevance of IL28B genetic testing and other pretreatment predictors in patient selection, use of the 4-week pretreatment lead-in phase with dual therapy, safety of triple therapy in some high-risk patient categories and specific management of directly acting antivirals-induced anaemia. As a consequence of these open issues, clinical practice guidelines on triple therapy released by American and European associations provide slightly different recommendations, effectively leaving these “grey” areas wide open for individual interpretation in everyday clinical practice.

1. Introduction
The decade long development of the first generation directly acting antivirals (DAAs) NS3 protease inhibitors boceprevir and telaprevir for the treatment of patients with chronic hepatitis C virus (HCV) genoptype 1 infection, has been a roller coaster ride in terms of emotions and knowledge for the community of hepatologists. Indeed every single step of development added in equal measure lights and shadows on the efficacy and safety of the two drugs (Table 1). The Phase 1 data showed us the potent antiviral activity of both compounds but also unfortunately wiped away any idea we had of achieving a sustained virological response (SVR) with a DAA monotherapy [1], [2]. The Phase 2 data bedazzled us with never before seen SVR rates in both naive patients and relapsers, but also worried us for the outcome of previous non-responders to pegylated interferon plus ribavirin (PR), as well as for the less than optimal tolerability profile of both regimens [3], [4]. Finally, the Phase 3 studies inspired the algorithms to maximize efficacy and safety of the two regimens, but left us with some unanswered questions on the management of specific clinical issues. Although some of these questions have been at least in part answered by subsequent sub-analyses performed both by the manufacturers of the drugs as well as by regulatory agencies, the fact that these post hoc analyses mostly rely on small numbers of patients and in some cases were ultimately driven more by commercial than scientific interests, effectively leaves us with some areas of uncertainty in the management of patients receiving a boceprevir- or telaprevir-based regimen.

Table 1. Lessons from registration trials of direct acting antivirals.

Positive dataNegative data
Phase 1-Steep decrease in HCV RNA in monotherapy
-Well-tolerated		-Rapid selection of resistant variants (RAVs)
-Need for peginterferon (ribavirin)
Phase 2-High SVR rates in naive and relapsers
-High RVR rates
-Low relapse rates
-Response-guided therapy (RGT)		-Side effects
-Need for Ribavirin
-Low SVR rates in previous non-responders
Phase 3-High SVR rates with RGT
-RAVs disappearance
-Rash management plan
-Definition of stopping rules		-Negative impact of fibrosis stage
-Areas of uncertainty: lead-in
IL28B
Management of anaemia


SVR, sustained virological response; RVR, rapid virological response; RGT, response-guided therapy; RAVs, resistant antiviral variants.

2. Lessons from registration trials
In Phase 1 studies, monotherapy with both DAAs led to a rapid decline of viraemia in the first days of dosing as a consequence of suppressed replication of DAA sensitive virions, which was however followed by either a plateau or a rebound of viraemia between days 3 and 14 of dosing, due to the rapid selection of DAA resistant variants (RAV) that naturally occur in all HCV-infected individuals [5]. Upon DAA withdrawal, a couple of weeks only were enough to have the initial HCV RNA viraemia completely restored, as a consequence of the emergence of wild type HCV virions no longer exposed to the suppressive activity of DAA. Fortunately, the co-administration of PR led to the full suppression of DAA-related RAVs and consequently made serum HCV RNA undetectable in all treated patients [6]. This was the proof of concept that the anti-HCV activity of DAA can be granted by the association with a PR backbone only, thereby providing the foundation for the Phases 2 and 3 studies in both naive and treatment-experienced patients.

In Phase 2 studies, telaprevir-based triple therapy with PR caused higher rates of rapid virological response (RVR) and lowered the rates of relapse driving higher rates of SVR in both naive and treatment-experienced patients [7], [8], [9]. These studies also built the foundation for exploration of the efficacy for response-guided therapy (RGT) in Phase 3 studies, having established that a 12-week triple therapy followed by a tail of PR was enough to ensure a cure of hepatitis C in most patients, whereas in treatment-experienced patients, a 24-week triple therapy regimen appeared to be toxic causing high rates of drop-outs. All in all, Phase 2 studies confirmed that ribavirin was necessary to prevent the occurrence of breakthroughs in DAA treated patients, particularly those infected by the HCV genotype 1a. Last but not least, registration studies depicted the side effects profile for telaprevir, mainly represented by eczematous pruritus and rash, anaemia and gastrointestinal symptoms.

The lesson from Phase 2 studies with boceprevir was more or less the same as with telaprevir, except for boceprevir regimens being built on a 4-week lead-in phase with PR preceding DAA administration. The lead-in treatment phase was found to reduce the risk of a relapse or a breakthrough to triple therapy by reducing initial viraemia in patients being exposed to boceprevir [10]. These studies provided also thoughtful insights on optimal dosing of boceprevir, clearly demonstrating in parallel the need for high doses of ribavirin to prevent viral breakthroughs. In analogy with telaprevir studies, Phase 2 studies with boceprevir provided the foundation for exploring efficacy of RGT in Phase 3 studies. Finally, the side effect profile for boceprevir regimens was defined in terms of anaemia, dysgeusia and gastrointestinal symptoms.

Following the Phase 3 studies in naive patients, ADVANCE and ILLUMINATE, efficacy of telaprevir was set at 75% SVR rate (44% in controls treated with PR) that climbed to 89% in patients who cleared the virus at week 4 and remained serum HCV RNA negative at week 12 (eRVR) [11], [12]. The clinical relevance of these observations was that these patients could be treated for 24weeks only, as shown by the ILLUMINATE trial, without compromising SVR rates. telaprevir was definitively superior to PR in the retreatment of patients with a previous failure to the standard of care too, providing however preliminary evidence for the existence of a relationship between SVR rates and the pattern of a previous response to PR. The rates of SVR, in fact, were 86% in prior relapsers, 57% in prior partial responders and 31% in prior null responders (i.e. those with a ≤2log decline of the initial viraemia following PR), the SVR in patients receiving triple therapy being higher than in controls receiving PR (65% vs 17%). Although the side effect profile was similar to that reported in Phase 2 studies, thanks to the introduction of a rash management plan as well as a learning curve effect in the management of telaprevir-related adverse events, there was a sharp decrease in the number of patients discontinuing treatment for non-virological reasons [13].

In the Phase 3 boceprevir SPRINT-2 trial conducted in naives, the rate of SVR was 66% in the patient population receiving a lead-in of 4weeks with PR prior to 44weeks of triple therapy [14], but it climbed to 96% in the set of patients with an extended RVR, who could shorten treatment duration to 28weeks. This happened in 44% of the overall population in study. In treatment-experienced patients included in RESPOND-2, the rates of SVR were clearly dependent upon the pattern of a previous response to PR, i.e. 72% in prior relapsers and 46% in prior partial responders, compared to 29% and 7% in controls, respectively [15]. Noticeably, exclusion of experienced patients with a prior null response to PR aimed to minimize the risk of boceprevir-associated RAVs, whereas the adoption of a lead-in phase aimed to assess responsiveness of patients with respect to the sensitivity to interferon using the criterion of 1log decline at week 4 of PR therapy. Poorly responsive to interferon patients, i.e. those with less than 1log decline of serum HCV RNA at week 4 of the lead-in phase, had 33% and 34% SVR rates to boceprevir RGT and boceprevir 48weeks therapy, respectively. Instead, interferon-responsive patients who had ≥1log decline of HCV RNA during lead-in showed higher responses rates to boceprevir, i.e. 73% and 79% SVR rates, respectively.

While the general profile of efficacy and safety of both telaprevir and boceprevir was clearly depicted by the above cited registration trials, several aspects of triple therapy which relate to pretreatment patient selection and therapeutic algorithm need to be elucidated.

3. Areas of uncertainty
Following post hoc analyses of both registration and confirmatory studies, evidence has emerged that both the outcome and duration of triple therapy with DAA can be substantially modified by a number of virological, clinical and constitutional predictors of treatment response, including fibrosis stage, sensitivity to interferon, and to some extent, genetic polymorphisms of the IL28B gene. Whether these predictors should be used to identify patients who should be better served by dual therapy rather than by a DAA-based regimen, is a matter of debate. By the same token, the lead-in pretreatment phase with dual therapy before starting triple therapy with DAA, is now perceived as a means to identify interferon-sensitive patients who may satisfactorily be treated with dual therapy only.
Another key area of uncertainty with regard to the safety of both boceprevir and telaprevir in patients with cirrhosis, as a limited number of patients with histologically documented cirrhosis (7–25%), were indeed enrolled in Phase 3 studies. By the same token, registration trials provided little opportunity to test real safety of DAA-based regimens in patients with significant portal hypertension, who are at the same time most in need of treatment and exposed to an increased risk of clinical decompensation following treatment-related toxicity.

On the other hand, Phases 2 and 3 studies have limited the fears associated with the emergence of detectable levels of RAVs in patients failing a DAA-based regimen, that were fuelled by the previous experience with first generation anti-hepatitis B virus (HBV) nucleos(t)ide analogues and anti-human immunodeficiency virus (HIV) retroviral regimens. Current understanding is that RAVs have minor clinical implications in the immunocompetent patients since they are not archived and in most cases actually removed by the immune system following DAA withdrawal [16], [17], [18]. As a consequence, guidelines in Europe and the U.S.A. do not recommend testing for RAVs in the immunocompetent patient, except for those who are enrolled in studies with next generation protease inhibitors or other DAA-based regimens.


4. How are treatment outcome and safety affected by the stage of liver fibrosis?
Field practice studies have provided conclusive evidence that the rates of SVR to dual therapy with PR are reduced in hepatitis C patients with advanced fibrosis compared to patients with mild or moderate liver fibrosis, yet the mechanisms behind this are poorly understood [19], [20]. Interplay between hepatitis stage and treatment efficacy was also obvious in the registration studies of both treatment-naive and treatment-experienced patients receiving triple therapy with DAA (Fig. 1). In the Phase 3 studies of telaprevir in naive patients that enrolled a limited number of patients with advanced (F3 or F4) fibrosis, the cumulative rates of SVR to telaprevir-based therapy were 14% lower than in patients with F0–F2 stage of fibrosis (65% vs 79%), yet significantly higher than those provided by dual therapy to similar patients (49% vs 36%) [21], [22]. Further highlighting the adverse role of liver fibrosis was a post hoc analysis of 30 patients with cirrhosis enrolled in the ILLUMINATE study, showing higher rates of SVR following a 36-week tail of PR to complete 12weeks of triple therapy with telaprevir in patients with an eRVR, compared to a shorter consolidation tail of 12weeks with PR only (92% vs 67%). With all the caveats of the limited sample size, this subanalysis suggested that patients with advanced fibrosis may require prolonged exposure to PR in order to efficiently clear all infected hepatocytes [23]. These findings, while calling for confirmation in a larger series of patients, provided the rationale for recommending an extended tail of PR in naive patients with advanced fibrosis receiving telaprevir-based regimens. The relevant impact of fibrosis on a response to DAA regimens was also apparent in the retreatment of patients who had had either a partial or a null response to a prior treatment with PR, as shown by the post hoc analysis of the patients enrolled in REALIZE [24]. In this study, in contrast to relapsers to a previous course of PR (who in fact achieved very high rates of SVR to triple therapy independently from the stage of fibrosis – 86% and 85%), the SVR rates to triple therapy in F3/F4 patients with a previous null or partial response to PR were only 25% and 42%, respectively. Though the rates of SVR in these latter patients were four- to fivefold higher than in similar patients retreated with dual PR, the success rates were definitively lower than in F0–F2 patients receiving triple therapy with telaprevir (41% and 72%, respectively).




 Fig. 1.
Sustained virological response rates in patients receiving a direct acting antiviral-based regimen in registration trials of telaprevir (ADVANCE and REALIZE) and boceprevir (SPRINT-2 and RESPOND-2) stratified by degree of fibrosis. SVR, sustained virological response; TVR, telaprevir; BOC, boceprevir.
 
This was also the message of the studies with boceprevir regimens in both treatment-naive and treatment-experienced patients [14], [15]. In the SPRINT-2 study, the gain in SVR rates provided by triple therapy in comparison to dual therapy was definitively greater in F0–F2 patients than in those with more advanced fibrosis (29% vs 14%), even when overall duration of treatment was extended to 48weeks. Further suggesting the interplay between disease severity and treatment outcome, were the higher rates of SVR in patients with a previous relapse to PR who received 48weeks of triple therapy (F0–F2 75% vs F3, F4 83%) compared to patients receiving RGT with boceprevir (75% vs 50%). The same was true for patients with a prior partial response to PR, however resulting in lower rates of SVR, i.e. 55% in F0–F2 and 46% in F3–F4 receiving 48weeks of therapy, but differed between RGT patients with F0–F2 (30%) and F3–F4 (47%). While the mechanisms responsible for attenuated rates of SVR in patients with advanced fibrosis remain elusive and not necessarily associated in all cases to cytopenia-related PR dose adjustment, failure of achieving optimal response rates in patients with cirrhosis in general has somehow mitigated the initial enthusiasm for the DAA-based regimens while raising doubts on effectiveness and safety of DAAs in the more difficult-to-treat subgroup of patients with significant portal hypertension [25]. Unfortunately we still miss detailed data on the safety of both regimens in patients with cirrhosis, quite frankly this is a bit worrisome as these patients are more likely to develop serious adverse events (AEs), such as a rapid and pronounced anaemia, grade III thrombocytopenia and concurrent infections, given they are also more often aged >55years [26]. Suggesting caution in these patients is the interim analysis of an expanded programme of telaprevir/boceprevir in patients with cirrhosis in France (CUPIC), where 129 patients (41%) had severe AEs, 9% had to discontinue triple due to AEs and 4 (1%) died as a consequence of severe AEs [27].
 
5. Should IL28B enter the standard pretreatment algorithm?
In both hemispheres, testing for IL28B polymorphisms allows to identify patients with HCV genotype 1 chronic infection who have an increased likelihood of SVR to dual therapy with PR [28], [29]. Indeed, the SVR rates to PR are higher in patients with the CC genotype of IL 28B compared to those carrying the T allele (80% vs 40%) being the direct consequence of higher rates of RVR which reflect increased interferon sensitivity as documented by studies of interferon-stimulated gene expression [30], [31]. While across all IL28B genotypes triple therapy was shown to be superior to dual therapy in terms of SVR rates, success rates with triple therapy were however attenuated in carriers of the T allele compared to CC patients.

With all the caveats of a post hoc analysis of patients pre-stratified for different variables, where only a subgroup of patients agreed to genetic testing, IL28B polymorphisms study of treatment-naive patients exposed to telaprevir and boceprevir provided interesting and to some extent, complementary information (Fig. 2A and B). In the telaprevir scenario of the ADVANCE study, CC patients showed, in fact, the highest rates of SVR with respect to CT and TT carriers (90% vs 71% and 73%) that were consistently superior to the SVR rates provided by PR (64% vs 25% and 23%) [32]. Interestingly enough, this was not the case for patients in the SPRINT-2 study where the CC patients treated with RGT and fixed 48-week boceprevir regimens had SVR rates as high as patients treated with PR (82% and 80% vs 78%). In the same study the rates of SVR to triple therapy were lower among CT and TT patients than among CC patients (65% and 71%; 59% and 55%) [33]. One interesting finding of both telaprevir and boceprevir scenarios was that patient stratification by IL28B polymorphisms might have the added clinical value of predicting a successful outcome of shortened treatment algorithms. The reanalysis of the PROVE-2 study, in fact, which also included 82 patients receiving a total of 12weeks triple therapy with telaprevir, demonstrated 100% success rates in IL28B CC patients compared to less than 50% SVR rates in carriers of the T allele [34]. In the boceprevir scenario of the SPRINT study, CC patients were more likely than T allele carriers to undergo a RGT of 28weeks’ duration as a result of higher rates of RVR (89% vs 52%), thereby providing an additional insight for improving pretreatment patient selection and cost effectiveness of triple therapy. Conversely, in the scenario of treatment-experienced patients, which includes many patients with a partial or null response to a previous course of PR, a genetic predictor such as the IL28B polymorphism will predictably help little to improve algorithms based on triple therapy. Indeed, the post hoc analysis of the REALIZE study confirmed that testing for IL28B polymorphism was less predictive for SVR to triple therapy than the pattern of a previous response to PR, which however might not to be available in all referred patients with previous exposure to PR therapy. The SVR rates in CC patients with a previous relapse or partial response to PR were 85% and 71% respectively, compared to less than 31% in null responders, only [35]. The boceprevir counterpart RESPOND-2 substantially provided similar preliminary insights on the limited usefulness of IL28B polymorphisms, however with the additional caveat of the absence of the null responder subset together with many patients missing genetic testing [34].
 
 
 
Fig. 2.
(A and B) Sustained virological response rates in ADVANCE and SPRINT-2 registration trials, stratified by IL28B genotype. SVR, sustained virological response; TVR, telaprevir; BOC, boceprevir; PR, peginterferon plus ribavirin.
 
6. Do we need a lead-in phase?
The reanalysis of 3 registration trials of PR, clearly demonstrated that achievement of an RVR as determined by PCR assays with a limit sensitivity of 50IU/ml, was associated with greater than 85% rates of SVR in patients with chronic infection independently of HCV genotype [36]. In patients with genotype 1 HCV, the rates of RVR have been found to be substantially influenced by ethnicity, disease severity, IL28B polymorphisms and sensitivity of the HCV RNA PCR assay. The rates of RVR in a series of Italian patients with genotype 1 HCV were 30% using a PCR assay with a lower limit of detection of 50IU/ml, falling however to 10% when an assay with a limit of 5IU/ml was used to re-test samples [37]. This notwithstanding, the clinical importance of rapid clearance of serum HCV RNA clinically stands alone, as remarkable rates of SVR to PR achievable in genotype 1 patients with an RVR was the foundation for a RGT to dual therapy with PR. The ability of RVR to predict patient sensitivity to PR has inflated the argument about treating genotype 1 patients with an RVR with sole dual therapy during the lead-in phase, with the ultimate goal of sparing adverse events and costs related to DAA-based regimens. Although using the lead-in for this endpoint may have an added value, it is important to remember that RVR patients require 48weeks of dual therapy to achieve high SVR rates and that therapy can be truncated at 24weeks only in those with baseline HCV RNA values <600,000IU/ml [38]. On the contrary, when adding boceprevir in patients with RVR, extremely high SVR rates can be achieved with only 24 further weeks of treatment [14]. Another issue is that approximately 20% of patients with RVR and favourable predictors of response to PR ultimately will not achieve SVR, thereby requiring a costly retreatment with triple therapy as well. Clearly these issues need to be discussed with the patient and decisions must be made on a case-by-case basis.

Obviously the lead-in phase can be used the other way around, which is to identify poor candidates to boceprevir or telaprevir add-on therapy. The argument in favour of lead-in to select candidates for dual therapy is that interferon sensitivity itself is a relevant prerequisite of efficacy of boceprevir/telaprevir-based therapy, since it permits prevention of boceprevir/telaprevir associated RAVs. The lead-in phase investigated in the REALIZE, SPRINT-1 and -2 and RESPOND-2 studies used the cut-off of a 1log decline of baseline viraemia to separate interferon-sensitive from interferon-refractory patients; this cut-off has the ability of identifying patients with very low SVR rates (less than 15%) that could effectively stop treatment at week 4 and be observed until more potent DAAs are available.

Following Phase 3 trials there is conclusive evidence to support that original idea for which the lead-in phase was introduced, that is to reduce HCV RNA levels whilst achieving peginterferon and ribavirin steady state kinetics when the DAA is introduced, is more theoretical than reality. The study REALIZE revealed no benefits in terms of SVR or virological breakthroughs in patients pre-treated with a lead-in with PR [39].

7. Comparing clinical practice guidelines
These areas of uncertainty on the use and management of DAAs-based regimens explain why European and North American guidelines present small but significant differences in their recommendations on key issues, such as patient selection, use of the lead-in phase as well as management of specific side effects. In this analysis we will compare the American Association for the Study of Liver Diseases (AASLD) guidelines, the Italian position paper [Associazione Italiana per lo Studio del Fegato (AISF)], the French guidelines [Association Francaise pour l’Etude du Foie (AFEF)], The Swedish Consensus Guidelines, the German Expert Opinion on boceprevir and telaprevir-based Triple Therapies of Chronic Hepatitis C, the UK Consensus Guidelines for the use of protease inhibitors in genotype 1 chronic hepatitis C infected patients and the Spanish Propuesta de Recomendaciones de la Sociedad Catalana de Digestivo en relacion al tratamiento triple del la hepatitis cronica C genotipo 1 [40], [41], [42], [43], [44], [45], [46] (Table 2).

Table 2. U.S.A. and European clinical practice guidelines on triple therapy with telaprevir/boceprevir.

CountryDual therapyStopping rules TVR, BOCAnaemia treatmentHCV RNA assessment
USAIndividualizedLabelRibavirin DRLabel
ItalyIL28B CC
Fibrosis ≤2		>100IU/ml RNA
Label+wk4		Ribavirin DR in RNA (−)
Epo RNA (+)
Transfusion		Monthly+week 8 TVR
Week 6 BOC
<10IU/mla
SpainIL28B CC
Fibrosis ≤2		LabelRibavirin DR
Epo
Transfusion		Label
FranceLI responders
IL28B CC
Fibrosis ≤2		LabelRibavirin DR in RNA (−)
Epo
Transfusion		Monthly+week 2
<15IU/mla
SwedenLI responders
IL28B CC
Fibrosis ≤2
Low VL, BMI		LabelEpo 2-week pretreatment
In high-risk patients (renal impairment, cardiac disease, solid organ transplants)		TVR weeks 4, 8, 12, 24
BOC same+wk16
<10–15IU/mla
UKLI responders
IL28B CC
Fibrosis ≤2
Low VL, BMI		LabelRibavirin DR
Epo
Transfusion		Label
<15IU/mla
Germany
Austria
Switzerland		IL28B CC
Fibrosis ≤2
Individualized		LabelRibavirin DR
Transfusion		Monthly→RNA (−)
<10–15IU/mla

TVR, telaprevir; BOC, boceprevir; DR, dose reduction; LI, Lead-in with peginterferon+ribavirin; VL, viral load; BMI, body mass index; Epo, erythropoietin.


aLimit sensitivity of the PCR assay.
 
8. Is there still a role for dual therapy?
Although all guidelines are unanimous in defining triple therapy with boceprevir/telaprevir plus PR, the optimal treatment for adult HCV-1 patients, most European guidelines suggest considering some highly responsive groups of patients for PR dual therapy. The baseline factors consider including fibrosis stage, IL28B genotype and initial HCV RNA values, with some guidelines suggesting using the week 4 lead-in response as an additional factor to decide who to keep on dual therapy. This obviously relies on the assumption that there are subgroups of patients where triple therapy is unlikely to be more effective and could result in an increase in health care costs and side effects that do not warrant its prescription [47]. However, we should acknowledge that we do not have randomized controlled studies comparing the efficacy of dual therapy versus triple therapy in these sub-populations, nor do we have definite evidence that telaprevir can be safely and effectively used following a 4week PR lead-in phase. Interestingly the AASLD as well as the German guidelines do not recommend PR dual therapy in any subgroup of patients, effectively considering boceprevir/telaprevir triple therapy as the first line choice in all treatment categories.

9. Monitoring and management of anaemia
Anaemia represents one of the most common side effects of boceprevir/telaprevir-based regimens, with a 20% increase in incidence compared to PR. The correct management includes ribavirin dose reductions, addition of erythroid stimulating agents (ESA) as well as blood transfusions [48]. However, the regulatory rules for the use of ESA differ from country to country, with ESA still being off-label in the U.S.A. while they are reimbursable by the National health systems in most European countries. Moreover, some European countries such as Italy require demonstration of a virological response to allow the use of ESA. Further complicating matters, is the fact that ESA were not allowed in telaprevir Phase 3 studies, while they were commonly used in boceprevir studies. Lastly but not least, it is still unknown if maintained optimal ribavirin dosing is as crucial for the efficacy of boceprevir/telaprevir-based regimens as it was for PR dual therapy. Indeed, sub-analyses of both DAA-based regimens seem to suggest that ribavirin dose reduction for anaemia does not negatively impact on SVR rates, although it is still unclear whether the timing of ribavirin dose reduction does play any role [49].
As a consequence of this further area of uncertainty as well as the different local regulations in the use of ESA, available guidelines differ significantly in terms of anaemia management recommendations.

10. Conclusions
The first generation DAAs boceprevir and telaprevir have entered the hepatitis C market following a rigorous development plan by both manufacturers, which has provided clinicians with detailed efficacy and safety data, validated stopping rules and management plans for specific side effects. Unfortunately, some “grey” areas still remain, especially in terms of patient selection, role of the lead-in phase, utility of the IL28B genotype and optimal management of treatment-related anaemia. Given that second generation HCV protease inhibitors are expected to enter the market in 2014–2015, it is highly improbable that any of these issues will be completely solved by rigorous studies, and that recommendations coming from clinical practice guidelines will be based on a relatively low grade of evidence [50], [51]. This will effectively make the individual clinical skill of the treating physician the limiting step to translate the efficacy of DAAs seen in clinical trials into effectiveness in real world clinical practice. This might cause an unequal access to treatment for HCV-1 patients, with small volume centres shying away from the prescription of these drugs, and with many patients being denied the chance of eradicating the virus. For this reason is it our opinion that the creation of a local network, where small volume centres are clustered around a large volume centre could effectively allow equal access to boceprevir/telaprevir treatment, partially resolving the remaining areas of uncertainties in the management of these drugs and hence replicating the success already obtained by the network model in the PR era [52].

Conflict of interest statement
MC acknowledge the research grant obtained from Merck, Roche, BMS, Gilead Science and also thank the advisory committees such as Merck, Roche, Novartis, Bayer, BMS, Gilead Science, Tibotec, Vertex, Achillion. Besides, he was supported by Tibotec, Roche, Novartis, Bayer, BMS, Gilead Science, Vertex for his Speaking and Teaching; AA was supported by Roche, Gilead Sciences for his grant research, and also acknowledges Roche, Janssen Travel support: BMS, Glaxo Smith-Kline, Bayer, Janssen, Roche, Merck for the help towards Speaking and Teaching; ED declared that no conflict of interest exist.

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