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Futility of antiviral treatments for hepatitis C: An evolving concept entering the direct antiviral agents era
Digestive and Liver Disease 45 (2013) 356–361
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Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Review Article
Futility of antiviral treatments for hepatitis C: An evolving concept entering the direct antiviral agents era夽 Savino Brunoa,∗ , Alessandra Mangiab,1 a b
A.O. Fatebenefratelli e Oftalmico, Milan, Italy I.R.C.C.S. Casa del Sollievo e della Sofferenza, S Giovanni Rotondo, Italy
a r t i c l e
i n f o
Article history: Received 6 August 2012 Accepted 23 September 2012 Available online 24 October 2012 Keywords: DAA First generation of protease inhibitors HCV treatment
a b s t r a c t Two first-generation non-specific protein 3/4A protease inhibitors (Boceprevir and Telaprevir) have been approved in the U.S. and in Europe in combination with the standard of care for treatment of both previously untreated and prior non responder genotype 1 chronic hepatitis C, based on the results of 5 large phase III trials. With these drugs, futility-stopping rules at weeks 4, 8 and 12 have been provided in order to avoid ineffective therapy and dangerous adverse events. However, despite several guidelines that have been published, a main question remains: how we can identify patients in whom triple therapy will be useless or ineffective? Based on the available data, this review proposes three algorithms to optimize triple antiviral therapy for chronic hepatitis C, to aid physicians avoid prescription of unnecessary treatment, given its substantial side effects and costs. © 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction The goal of antiviral treatment in patients with chronic hepatitis C virus (HCV) infection is the achievement of persistent viral clearance. The attainment of this short-term outcome is the only way to ensure that, in patients with chronic liver damage, the underlying liver disease can stabilize and decrease liver-related mortality [1]. When this goal is unlikely to be achieved or treatment is very costly, in terms of side effects and quality of life, it is important to make the right decision, including not to treat or to discontinue therapy early. Several factors must be considered when deciding to treat a patient with HCV infection, first of all the efficacy of treatment. In the past 10 years, treatment of chronic hepatitis C (CHC) has been exclusively based on Peg-Interferon (Peg-IFN) alpha and ribavirin (RBV) (standard of care, SoC) which allows in naïve patients the attainment of viral eradication in approximately 40–50% of genotype 1 and 80% of genotype 2–3 infected, respectively [1]. Among prior non-responders this combination leads to viral clearance in no more than 6–20% of patients [1]. Recently, several new antiviral drugs (direct acting antivirals, DAA) capable of inhibiting different targets of the viral lifecycle
夽 The contents of the manuscript represent the author’s personal opinion and do not reflect any position of current guidelines provided by Society or Health Organization. ∗ Corresponding author. Tel.: +39 2 63632489/2596; fax: +39 2 63632714. E-mail address: [email protected] (S. Bruno). 1 In alphabetical order.
have been developed. Among them, based on the results of 5 large phase 3 trials, two first-generation NS3/4A protease inhibitors (Boceprevir, BOC and Telaprevir, TVR) in combination with SoC have been approved in the U.S. and in Europe for treatment of both previously untreated and prior non-responder genotype 1 (HCV-1) CHC infection [2–5,7]. According to these studies, a new lexicon to interpret the results achieved has been developed (Table 1). With the addition of these drugs, a two- and threefold SVR rate increase was achieved in previously untreated and treatment-experienced patients, respectively. It appears evident that the benefit progressively decreased across relapsers, partial and null responders with rates of viral clearance in the last category not higher than 30% [5]. With these drugs, baseline predictors to be taken into account in the treatment decision making process include: the stage of liver disease, patient age, complexity of the treatment regimen/strategy and, as suggested very recently, the genetic predisposition to respond to IFN-based treatment according to IL28B gene variability. Treatment responses at weeks 4, 8 and 12 have been identified during Peg-IFN and RBV double therapy, as key milestones to predict either response or treatment duration [6]. These milestones maintain a main role during triple treatment. Although all HCV-infected patients, with the only exception of those with decompensated cirrhosis, should be offered treatment, the most recent treatment guidelines released in 2011 by EASL and focused on the association of Peg-IFN and RBV combination prioritize treatment of patients with significant fibrosis (METAVIR score F2–F4) [1]. Has anything changed in the era of triple therapy? A main question remains: how to identify patients in which triple therapy using BOC and TVR would be either useless or ineffective?
1590-8658/$36.00 © 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.dld.2012.09.011
S. Bruno, A. Mangia / Digestive and Liver Disease 45 (2013) 356–361 Table 1 New lexicon adopted for protease inhibitors triple therapy. BOCEPREVIR Lead-in phase (LI) Rapid virologic response (RVR) Responsive to IFN Poorly responsive to IFN Early response (ER) Late response (LR) TELAPREVIR Extended-RVR (eRVR)
PegIFN plus RBV for 4 weeks before Boceprevir addition Undetectable HCV RNA at week 4a HCV RNA drop from baseline >1 log10 after Lead In HCV RNA drop from baseline <1 log10 after Lead In Undetectable HCV RNA at week 8 after Boceprevir addition Detectable HCV RNA at week 8 after Boceprevir addition Undetectable HCV RNA at weeks 4 and 12
PegIFN, peginterferon alpha; RBV, ribavirin. a Assay sensitivity: 50 IU/ml.
2. Treatment naïve 2.1. Boceprevir The SPRINT-2 Phase III study compared efficacy and safety of Boceprevir-based regimens, fixed (Boceprevir plus PegIFN-RBV for 48 weeks, BOC PR48) and response-guided (BOC RGT), with SoC in treatment-naïve patients infected with HCV genotype 1 [2]. Overall, SVR rates were 63% in BOC RGT and 66% in BOC PR48 compared with 38% in the control group, respectively. 2.1.1. Baseline predictors of SVR Genetic polymorphism of IL-28B, was tested in approximately 60% of patients enrolled in the SPRINT-2 study who gave their consent. No differences were found between patients who carried IL-28B CC treated by BOC-regimen or SoC (80% in BOC PR48, 82% in BOC RGT, 78% in PR); while, among subjects with IL28b TT and IL28b CT, SVR was achieved in 59%, 55% and 27%, and in 71%, 65% and 28%, respectively. Higher SVR rates were found in genotype 1b than 1a (73% and 62%) and in patients with low viral load (<800,000 UI/ml) than high viral load at baseline (85% and 63%) treated by BOC-regimen. The stage of liver fibrosis was also found to be a determinant factor for treatment success with BOC. In patients with mild fibrosis (METAVIR F0–F2), SVR rate was 67% in BOC-regimen compared to 38% SVR rate in the control group. Among patients with advanced fibrosis/cirrhosis (METAVIR F3/4) SVR was achieved in 52% and 41% of BOC-regimen (BOC PR48 and RGT, respectively) compared to 38% of SoC. In patients with established cirrhosis (F4) SVR rates were 38% (BOC RGT and BOC PR48 regimens combined) [2]. 2.1.2. On-treatment predictors of SVR 2.1.2.1. Treatment week 4 (TW4). The strategy adopted in BOC studies was based on 4 weeks lead-in phase, which consists of an induction phase with Peg-IFN alpha 2b 1.5 mcg/kg/week and weight-based 800–1400 mg/qd RBV therapy prior to the introduction of the protease inhibitor. Approximately 9–10% of patients had Rapid Virologic Response (RVR, HCV-RNA undetectable at week 4). SVR was achieved in 89%, 90% and 97% of these patients in the three treatment arms (BOC RGT, BOC PR48 and SoC, respectively). Twenty-five percent of patients had poor interferon response (HCV-RNA decline <1 log). Overall, this group of patients showed both lower probability of SVR and higher rates of resistance associated variants (RAV), when compared to those with >1 log decline, defined poor responsive. Between patients with advanced fibrosis/cirrhosis who achieved a ≥1 log10 decline in HCV RNA after the 4 weeks
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lead-in, SVR rates were 77% after completion of 44 weeks of triple therapy, compared with 50% in those treated for 48 weeks with PR alone. Moreover, despite the carriage of IL28B CC was significantly associated to the likelihood to achieve SVR at multiple logistic regression analysis (MLR) which included only baseline predictors, when 4-week response was included in the analysis, lead-in became the strongest predictor of SVR and IL28B lost its predictive value. 2.1.2.2. Treatment week 8 (TW8). 56% of patients had undetectable HCV RNA (early responders, ER) after addition of BOC. This group of patients achieved 89% of SVR in BOC RGT group with 24 weeks of treatment and 91% of SVR in BOC PR48 (48 weeks of treatment); IL-28B CC carriage was significantly associated with the likelihood of achieving ER. This may enable us to identify those patients who are candidates to a short course of triple treatment. Despite the presence of advanced fibrosis/cirrhosis, patients with undetectable HCV RNA at week 8 had SVR rates of 79–93% (BOC RGT and BOC PR48 arms, respectively) [8], while among Poor IFN Responders, no patients with <3 log decline at TW8 achieved SVR [9]. 2.1.2.3. Treatment week 12 (TW12). Recently, a retrospective analysis of data form SPRINT-2 has been conducted using different HCV RNA thresholds as stopping rules at week 8, 12 and 24. The threshold of HCV RNA ≥100 UI/ml at week 12 predicted failure to achieve SVR without sacrificing any SVR (specificity of 100%) [10]. 2.2. Telaprevir The ADVANCE phase III registration study [3] evaluated two TVR-regimens: 8 weeks and 12 weeks of TVR in combination with Peg-IFN alpha 2a 180 mcg/week and RBV 1000–1200 mg/qd, followed by response-guided SoC. SVR was achieved in 75% in the group treated with TVR for 12 weeks and PR for 24/48 weeks (T12PR) and in 69% in the group treated with TVR for 8 weeks and PR for 24/48 weeks (T8PR) compared with 44% in the SoC group. As observed in SPRINT 2, among patients included in the PR control arm who achieved RVR, the rate of SVR was very high 94%. Of interest this rate was significantly higher compared to that achieved by patients who achieved RVR starting with triple therapy (78 and 84%, respectively, p < 0.033) [3]. 2.2.1. Baseline predictors Genetic polymorphism of IL-28b was tested in approximately 40% of patients enrolled in the ADVANCE study who gave their consent. Higher SVR rates were demonstrated across all genotypes in TVR-regimen compared with SoC, with more evident differences in CT and TT genotypes than CC. According to fibrosis stage, naïve patients with advanced fibrosis and cirrhosis (METAVIR F3/F4) achieved SVR in 62% and 53% in T12PR and T8PR TVR arms, respectively, compared with 78% and 73% SVR in patients with no/or moderate fibrosis (METAVIR F0–F2) included in the same arms. 2.2.2. On-treatment predictors of SVR 2.2.2.1. Treatment week 4–12. In group T12PR 68% of patients attained RVR and 58% of them achieved an extended Rapid Virological Response (e-RVR, HCV RNA undetectable at week 4 through 12). In group T8PR, RVR was 67% and eRVR 57%. Patients with eRVR were assigned to 24 weeks of treatment according to RGT, and SVR rates were 89% (T12PR) and 83% (T8PR). Patients who did not achieve eRVR had SVR rates of 54%, 50% and 39% in the T12PR, T8PR and SoC arms, respectively. The second phase III trial ILLUMINATE [4] confirmed the safety and efficacy of a short TVR-regimen for eRVR patients. Of all
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randomized patients 72% had an RVR, 65% were eRVR, and they achieved 92% and 88% SVR rates irrespective of RGT (24 weeks) or fixed (48 weeks) regimens, respectively. 3. Treatment-experienced 3.1. Boceprevir The RESPOND-2 Phase III study evaluated efficacy of BOCregimen in treatment-experienced patients. The study focused on relapsers (previous HCV RNA undetectable at the end of treatment, but detectable 24 weeks after discontinuation of therapy) and previous partial responders (patients with >2 log drop at week 12 in comparison to baseline, but never undetectable). Null responders, defined as patients with <2 log viral load decline at week 12 in a previous treatment course were not included in this study, but were investigated in a single roll-over survey named PROVIDE which is not yet published as a full paper [11]. Even in this group of patients SVR rates were higher in all BOC-regimens (RGT and BOC PR48) than in SoC (66% and 59% vs. 21%) [5]. After 4 weeks lead-in, patients were randomized to triple therapy or to SoC. Triple therapy were administered as fixed 44 weeks or as RGT. Strikingly, the RGT offered in patients without cirrhosis the opportunity to receive BOC triple therapy for 32 weeks after 4 weeks lead-in. By contrast, in patients with detectable HCV RNA at week 8, a tail of 12 weeks of Peg-IFN and RBV was required for an overall duration of 48 weeks of treatment [5]. SVR was achieved in 72% of relapsers, and in 35% of partial responders [5]. As for treatment-naïve patients, early responders achieved 86% and 88% of SVR both in RGT regimen and in fixed regimen. 3.1.1. Baseline predictors of SVR The stage of liver fibrosis was less significant compared to naïve patients in predicting SVR with BOC. In patients with mild fibrosis (Metavir F0–F2) SVR rates were 68% and 66% in BOC-regimen (BOC PR48 and RGT respectively) compared to 23% in the control group; among patients with advanced fibrosis (Metavir F3 and 4) SVR rate was 68% and 44% for Boceprevir-regimen (BOC PR48 and RGT, respectively) compared to 13% SVR for SoC However, it should be highlighted that only 47 patients with F4 and 29 patients with bridging fibrosis were included in the RESPOND-2 study. Genetic polymorphism of IL-28b was tested in approximately 60% of patients enrolled in the RESPOND2 study who gave their consent. No differences were seen based genotype. 3.1.2. On-treatment predictors of SVR 3.1.2.1. Treatment week 4 (TW4). In treatment-experienced, as in naïve patients, the strongest predictive factor of a favourable response was an HCV RNA decline >1 log at week 4. The definition of treatment response at week 4 after lead-in used in BOC-regimen led to a redefinition of the historical response to SoC. Irrespective of the old definition of response, patients with <1 log drop decline had lower SVR rates compared to those who achieved >1 log decline after lead-in. Interestingly, the majority of patients (60%) previously defined as partial responders experienced >1 log HCV RNA decline at week 4, with high probability of SVR, while among previous relapsers 35% had <1 log decline, with low chance of SVR. 3.1.2.2. Treatment week 8 (TW8). 49% of patients had undetectable HCV RNA (early responders, ER) after addition of BOC. This group of patients achieved 86% of SVR in BOC RGT group with 24 weeks of treatment and 88% of SVR in BOC PR48 (48 weeks of treatment) [5].
3.1.2.3. Treatment week 12 (TW12). As for SPRINT-2 a retrospective analysis was conducted using different HCV RNA thresholds as stopping rules at week 8, 12 and 24. According to the findings of this analysis, the proposal of a futility threshold of HCV RNA ≥100 UI/ml at week 12 instead of detectable HCV RNA seems to be reasonable. Although this choice needs to be validated in a larger population, it enables us to minimize premature discontinuation in patients who might achieve SVR [10]. 3.1.3. Null responders As previously reported, null responders were evaluated in the PROVIDE study [11]. In this study, 47 patients with less than 2 log HCV RNA drop at week 12 were included in the control arms of SPRINT-2 and RESPOND-2, who received 44 weeks triple therapy, and obtained 40% SVR. Accordingly, the FDA and European Regulatory authorities allowed null responders to be treated with BOC triple therapy [11]. 3.1.4. SVR in poorly responsive patients after lead-in: combining SPRINT-2 and RESPOND-2 Based on concordance, correlation, and CART analyses of the IDEAL study, TW4 viral load decline of <1 log approximates to that of <2 log at TW12 and is an earlier predictor of null response with a negative predictive value (NPV) of 96% [12]. This data was recently confirmed in patients who were included in the control arms of both the SPRINT2 and RESPOND 2 studies, in which the agreement between those subjects with <1 log drop at week 4 and those with <2 log drop at week 12 were 89% (293/329) and 91% (68/75), respectively (data on file). Therefore, a post hoc analysis which included all patients from both studies who had shown a poor response to IFN was carried out. In these patients no subject with <3 log decline at week 8 achieved SVR, NPV = 100% [9]. In the subgroup of 46 patients with F3/F4 fibrosis, the overall SVR rate (G1a and 1b pooled) was 17%; and this rate was no higher than 6% (4% in G1a and 14% in G1b, respectively) when baseline levels of HCV RNA were >2,000,000 IU/ml [8]. Finally, combining both studies, only 3 out of 25 (12%) patients with cirrhosis (F4) achieved SVR (BOC RGT, 10% and BOC PR48 14%, respectively) while the corresponding SVR rate in 51 cirrhotics with TW4 viral load decline of >1 log was 67% [8]. 3.2. Telaprevir The phase III REALIZE study included patients who failed a previous SoC treatment and evaluated 2 different TVR-regimens (T12PR48 and lead-in T12PR48) compared to SoC. This is the only TVR-based study that investigated the utility of a lead-in phase (Peg-IFN alpha 2a 180 mcg/week and RBV 1000–1200 mg/qd) prior to the addition of TVR for 12 weeks. Overall, SVR rate was 65% in TVR group and 17% in controls, with no significant difference between patients treated with or without lead-in phase (66% vs. 64%, respectively). However, SVR rates were 33% in those with <1 log HCV RNA drop and 82% among patients with >1 log drop. As expected, SVR rates were higher among prior relapser patients compared to partial or null responders (83%, 59% and 29%) [7]. As mentioned above, despite no differences in SVR rates with or without the lead-in phase, week 4 response after lead-in caused a redefinition of the historical response to SoC. Of interest, only 10% of relapsers (who are clearly interferon sensitive) had <1 log HCV RNA drop at week 4, compared to 59% among null responders and 40% among partial responders. In the two latter groups of patients, the corresponding rates of SVR were 15% and 56%, respectively. Furthermore partial and null responders experienced >1 log HCV RNA decline at week 4 in approximately 50% of cases, irrespective of the “old” definition of response. The reliability of lead-in in better recognizing the likelihood to achieve SVR appears to be more relevant in relapsers and
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null responders; in fact overall SVR rates were 62% in those with <1 log decline vs. 94% in those with >1 log decline among relapsers and 15% vs. 54% in null responders, respectively [12]. Unfortunately, data on SVR rates of patients included in REALIZE according to both lead-in and fibrosis stages have not been provided. This result indicates that also with TVR, the real time response to IFN may be used in patients with previous treatment failure to identify lower/higher likelihood of achieving SVR. This is particularly useful given the fact that in many treatment-experienced patients there is difficulty in obtaining documentation of on-treatment response during the previous antiviral regimen.
3.2.1. Baseline predictors In treatment-experienced patients, retrospective analysis of the REALIZE trial found no association between IL28B genotypes and SVR rates in TVR-regimen. As for treatment-naïve patients, the stage of liver fibrosis was found to be a determinant factor for treatment success with TVR. In patients with advanced fibrosis (Metavir F3/4) SVR rates were 58% and 53% (with and without lead-in, respectively) compared to 75% in F0–F2. However, in previous relapsers, SVR rate was 84% regardless of fibrosis stage; in previous partial and null responders SVR rates decrease from 72% to 41% in F0–F2 fibrosis, from 56% to 39% in F3 fibrosis and from 34% to 14% (both TVR12 and lead-in arms combined) in F4 fibrosis, respectively. Regrettably, in the REALIZE study [7] there has not yet been a post hoc analysis in patients with partial and null response according to week 4 response, exclusively dedicated to patients with advanced fibrosis and cirrhosis in the lead-in arm. Similarly, the effect of week 4 response in predicting SVR in patients with F4 fibrosis included in the lead-in arm was not tested by multiple logistic regression analysis [13].
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4. Futility rules Despite the improvement in treatment efficacy, there are patients who might develop a breakthrough even after an early response. In order to prevent the onset of resistant mutants in patients with continuous replication during treatment, futility rules were introduced for both drugs. In case of HCV RNA >100 IU/ml at week 12, EMA recommends all BOC-based triple treatments to be discontinued. Treatment had to be discontinued also in case of detectable HCV RNA at week 24 in patients receiving BOC with HCV RNA <100 IU/ml at week 12. The stopping rules suggested by the label for TVR state that in case of HCV RNA >1000 IU/ml at week 4, and 12, TVR should be discontinued. This should also be done in case of HCV RNA above the threshold of 15 IU/ml at week 24 or 36 on-treatment. It should be highlighted that single European countries have published their own guidelines for the use of triple therapy with protease inhibitors, and different sensitivity thresholds of HCV RNA assays have been selected by each country [14–16]. 5. Conclusive remarks In summary, BOC and TVR in combination with SOC, may cure approximately two-thirds of patients with CHC genotype 1, either previously untreated or treatment-experienced. However, the rate of SVR in patients with advanced fibrosis and especially in F4 cirrhotics treated with BOC who are not responsive at the end of lead-in is, disappointingly, very modest, while no information has been provided in the same group of patients treated with TVR. Lead-in phase also allows the identification of naïve patients with RVR who may avoid triple therapy, and enables us to more reliably redefine the likelihood of achieving SVR in
Fig. 1. Suggested algorithm for treatment-naïve patients, METAVIR F0–F3. TW, treatment week; BOC, boceprevir: TVR, telaprevir; PegIFN, peginterferon alpha; RBV, ribavirin; PR, peginterferon alpha plus ribavirin; SoC, standard of care; RVR, rapid virological response; eRVR, extended rapid virolgical response.
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S. Bruno, A. Mangia / Digestive and Liver Disease 45 (2013) 356–361
Fig. 2. Suggested algorithm for treatment-experienced patients, METAVIR F0–F3. Relapsers using lead-in who achieves rapid virological response could be managed as naïve patients. TW, treatment week; BOC, boceprevir: TVR, telaprevir; PegIFN, peginterferon alpha; RBV, ribavirin; PR, peginterferon alpha plus ribavirin.
treatment-experienced subjects, regardless of or in combination with the previous definition of response. Furthermore, lead-in helps to identify patients in whom the benefit of treatment is poor and risks very high.
In this latter group (namely cirrhotics, poorly responsiveness to IFN), physicians need to very critically assess whether patients with these characteristics should be treated with triple therapy, balancing both the likelihood to attain SVR and the risk of
Fig. 3. Suggested algorithm for cirrhotic patients, METAVIR F4 (both naïve and treatment-experienced). BOC: PR 4 weeks + PR BOC 44 weeks. TVR: PR 4 weeks + PRTVR 12 weeks + PR 32 weeks. TW, treatment week; BOC, boceprevir: TVR, telaprevir; PegIFN, peginterferon alpha; RBV, ribavirin; PR, peginterferon alpha plus ribavirin.
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developing severe side effects with the known increased survival rates observed in patients with cirrhosis who achieve HCV clearance [17,18]. Therefore, the choice of stopping therapy after lead-in without adding DAA could be carefully considered in order to avoid a potential ineffective and hazardous expensive treatment. 6. Suggested algorithm On the basis of the above considerations, lead-in phase represents the most reliable tool to recognize those patients in whom triple therapy is useless or poorly effective. Therefore, irrespective of on-label with first generations PI’s indications, we suggest three simple algorithms (Figs. 1–3) that may optimize lead-in use with both drugs. The possibility to avoid lead-in is admitted in noncirrhotic relapsers, because in this subset of patients the rate of those with either RVR or with less than1000 IU/ml and HCV RNA >100 IU/ml, respectively, is justified, in our opinion, by the conceivable high risk of RAV emergence; these patients have a very low probability to achieve SVR given the threshold of residual viremia and, conversely, the suggestion matches both the futility rule indicated on the label and EMA recommendations. Regarding cirrhotic patients, despite the lack of TVR data, the futility rule at week 4 for poorly responsive patients is recommended with both molecules, because it enables recognition IFN hyposensitivity, thus avoiding the equivalent of a functional monotherapy. This choice minimizes the risk of developing serious, life-threatening adverse events, as observed in real-life settings [19] in patients who have a low chance to attain SVR [8]. Finally, the indications given for the proposed futility rules are based on Authors’ opinion and should not be considered as formal recommendations. Conflict of interest statement None declared.
List of abbreviations BOC, Boceprevir; CHC, chronic hepatitis C; DAA, direct acting antivirals; ER, early responders; eRVR, extended rapid virological response; MLR, multiple logistic regression analysis; NPV, negative predictive value; PegIFN, peginterferon; PI’s, protease inhibitors; PR, Peg-IFN and RBV; RAV, resistance associated variants; RBV, ribavirin; RGT, response-guided therapy; SoC, standard of care; SVR, sustained virological response; TVR, Telaprevir; TW, treatment week; TW4, treatment week 4; TW8, treatment week 8; TW12, treatment week 12.
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Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Review Article
Futility of antiviral treatments for hepatitis C: An evolving concept entering the direct antiviral agents era夽 Savino Brunoa,∗ , Alessandra Mangiab,1 a b
A.O. Fatebenefratelli e Oftalmico, Milan, Italy I.R.C.C.S. Casa del Sollievo e della Sofferenza, S Giovanni Rotondo, Italy
a r t i c l e
i n f o
Article history: Received 6 August 2012 Accepted 23 September 2012 Available online 24 October 2012 Keywords: DAA First generation of protease inhibitors HCV treatment
a b s t r a c t Two first-generation non-specific protein 3/4A protease inhibitors (Boceprevir and Telaprevir) have been approved in the U.S. and in Europe in combination with the standard of care for treatment of both previously untreated and prior non responder genotype 1 chronic hepatitis C, based on the results of 5 large phase III trials. With these drugs, futility-stopping rules at weeks 4, 8 and 12 have been provided in order to avoid ineffective therapy and dangerous adverse events. However, despite several guidelines that have been published, a main question remains: how we can identify patients in whom triple therapy will be useless or ineffective? Based on the available data, this review proposes three algorithms to optimize triple antiviral therapy for chronic hepatitis C, to aid physicians avoid prescription of unnecessary treatment, given its substantial side effects and costs. © 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction The goal of antiviral treatment in patients with chronic hepatitis C virus (HCV) infection is the achievement of persistent viral clearance. The attainment of this short-term outcome is the only way to ensure that, in patients with chronic liver damage, the underlying liver disease can stabilize and decrease liver-related mortality [1]. When this goal is unlikely to be achieved or treatment is very costly, in terms of side effects and quality of life, it is important to make the right decision, including not to treat or to discontinue therapy early. Several factors must be considered when deciding to treat a patient with HCV infection, first of all the efficacy of treatment. In the past 10 years, treatment of chronic hepatitis C (CHC) has been exclusively based on Peg-Interferon (Peg-IFN) alpha and ribavirin (RBV) (standard of care, SoC) which allows in naïve patients the attainment of viral eradication in approximately 40–50% of genotype 1 and 80% of genotype 2–3 infected, respectively [1]. Among prior non-responders this combination leads to viral clearance in no more than 6–20% of patients [1]. Recently, several new antiviral drugs (direct acting antivirals, DAA) capable of inhibiting different targets of the viral lifecycle
夽 The contents of the manuscript represent the author’s personal opinion and do not reflect any position of current guidelines provided by Society or Health Organization. ∗ Corresponding author. Tel.: +39 2 63632489/2596; fax: +39 2 63632714. E-mail address: [email protected] (S. Bruno). 1 In alphabetical order.
have been developed. Among them, based on the results of 5 large phase 3 trials, two first-generation NS3/4A protease inhibitors (Boceprevir, BOC and Telaprevir, TVR) in combination with SoC have been approved in the U.S. and in Europe for treatment of both previously untreated and prior non-responder genotype 1 (HCV-1) CHC infection [2–5,7]. According to these studies, a new lexicon to interpret the results achieved has been developed (Table 1). With the addition of these drugs, a two- and threefold SVR rate increase was achieved in previously untreated and treatment-experienced patients, respectively. It appears evident that the benefit progressively decreased across relapsers, partial and null responders with rates of viral clearance in the last category not higher than 30% [5]. With these drugs, baseline predictors to be taken into account in the treatment decision making process include: the stage of liver disease, patient age, complexity of the treatment regimen/strategy and, as suggested very recently, the genetic predisposition to respond to IFN-based treatment according to IL28B gene variability. Treatment responses at weeks 4, 8 and 12 have been identified during Peg-IFN and RBV double therapy, as key milestones to predict either response or treatment duration [6]. These milestones maintain a main role during triple treatment. Although all HCV-infected patients, with the only exception of those with decompensated cirrhosis, should be offered treatment, the most recent treatment guidelines released in 2011 by EASL and focused on the association of Peg-IFN and RBV combination prioritize treatment of patients with significant fibrosis (METAVIR score F2–F4) [1]. Has anything changed in the era of triple therapy? A main question remains: how to identify patients in which triple therapy using BOC and TVR would be either useless or ineffective?
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S. Bruno, A. Mangia / Digestive and Liver Disease 45 (2013) 356–361 Table 1 New lexicon adopted for protease inhibitors triple therapy. BOCEPREVIR Lead-in phase (LI) Rapid virologic response (RVR) Responsive to IFN Poorly responsive to IFN Early response (ER) Late response (LR) TELAPREVIR Extended-RVR (eRVR)
PegIFN plus RBV for 4 weeks before Boceprevir addition Undetectable HCV RNA at week 4a HCV RNA drop from baseline >1 log10 after Lead In HCV RNA drop from baseline <1 log10 after Lead In Undetectable HCV RNA at week 8 after Boceprevir addition Detectable HCV RNA at week 8 after Boceprevir addition Undetectable HCV RNA at weeks 4 and 12
PegIFN, peginterferon alpha; RBV, ribavirin. a Assay sensitivity: 50 IU/ml.
2. Treatment naïve 2.1. Boceprevir The SPRINT-2 Phase III study compared efficacy and safety of Boceprevir-based regimens, fixed (Boceprevir plus PegIFN-RBV for 48 weeks, BOC PR48) and response-guided (BOC RGT), with SoC in treatment-naïve patients infected with HCV genotype 1 [2]. Overall, SVR rates were 63% in BOC RGT and 66% in BOC PR48 compared with 38% in the control group, respectively. 2.1.1. Baseline predictors of SVR Genetic polymorphism of IL-28B, was tested in approximately 60% of patients enrolled in the SPRINT-2 study who gave their consent. No differences were found between patients who carried IL-28B CC treated by BOC-regimen or SoC (80% in BOC PR48, 82% in BOC RGT, 78% in PR); while, among subjects with IL28b TT and IL28b CT, SVR was achieved in 59%, 55% and 27%, and in 71%, 65% and 28%, respectively. Higher SVR rates were found in genotype 1b than 1a (73% and 62%) and in patients with low viral load (<800,000 UI/ml) than high viral load at baseline (85% and 63%) treated by BOC-regimen. The stage of liver fibrosis was also found to be a determinant factor for treatment success with BOC. In patients with mild fibrosis (METAVIR F0–F2), SVR rate was 67% in BOC-regimen compared to 38% SVR rate in the control group. Among patients with advanced fibrosis/cirrhosis (METAVIR F3/4) SVR was achieved in 52% and 41% of BOC-regimen (BOC PR48 and RGT, respectively) compared to 38% of SoC. In patients with established cirrhosis (F4) SVR rates were 38% (BOC RGT and BOC PR48 regimens combined) [2]. 2.1.2. On-treatment predictors of SVR 2.1.2.1. Treatment week 4 (TW4). The strategy adopted in BOC studies was based on 4 weeks lead-in phase, which consists of an induction phase with Peg-IFN alpha 2b 1.5 mcg/kg/week and weight-based 800–1400 mg/qd RBV therapy prior to the introduction of the protease inhibitor. Approximately 9–10% of patients had Rapid Virologic Response (RVR, HCV-RNA undetectable at week 4). SVR was achieved in 89%, 90% and 97% of these patients in the three treatment arms (BOC RGT, BOC PR48 and SoC, respectively). Twenty-five percent of patients had poor interferon response (HCV-RNA decline <1 log). Overall, this group of patients showed both lower probability of SVR and higher rates of resistance associated variants (RAV), when compared to those with >1 log decline, defined poor responsive. Between patients with advanced fibrosis/cirrhosis who achieved a ≥1 log10 decline in HCV RNA after the 4 weeks
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lead-in, SVR rates were 77% after completion of 44 weeks of triple therapy, compared with 50% in those treated for 48 weeks with PR alone. Moreover, despite the carriage of IL28B CC was significantly associated to the likelihood to achieve SVR at multiple logistic regression analysis (MLR) which included only baseline predictors, when 4-week response was included in the analysis, lead-in became the strongest predictor of SVR and IL28B lost its predictive value. 2.1.2.2. Treatment week 8 (TW8). 56% of patients had undetectable HCV RNA (early responders, ER) after addition of BOC. This group of patients achieved 89% of SVR in BOC RGT group with 24 weeks of treatment and 91% of SVR in BOC PR48 (48 weeks of treatment); IL-28B CC carriage was significantly associated with the likelihood of achieving ER. This may enable us to identify those patients who are candidates to a short course of triple treatment. Despite the presence of advanced fibrosis/cirrhosis, patients with undetectable HCV RNA at week 8 had SVR rates of 79–93% (BOC RGT and BOC PR48 arms, respectively) [8], while among Poor IFN Responders, no patients with <3 log decline at TW8 achieved SVR [9]. 2.1.2.3. Treatment week 12 (TW12). Recently, a retrospective analysis of data form SPRINT-2 has been conducted using different HCV RNA thresholds as stopping rules at week 8, 12 and 24. The threshold of HCV RNA ≥100 UI/ml at week 12 predicted failure to achieve SVR without sacrificing any SVR (specificity of 100%) [10]. 2.2. Telaprevir The ADVANCE phase III registration study [3] evaluated two TVR-regimens: 8 weeks and 12 weeks of TVR in combination with Peg-IFN alpha 2a 180 mcg/week and RBV 1000–1200 mg/qd, followed by response-guided SoC. SVR was achieved in 75% in the group treated with TVR for 12 weeks and PR for 24/48 weeks (T12PR) and in 69% in the group treated with TVR for 8 weeks and PR for 24/48 weeks (T8PR) compared with 44% in the SoC group. As observed in SPRINT 2, among patients included in the PR control arm who achieved RVR, the rate of SVR was very high 94%. Of interest this rate was significantly higher compared to that achieved by patients who achieved RVR starting with triple therapy (78 and 84%, respectively, p < 0.033) [3]. 2.2.1. Baseline predictors Genetic polymorphism of IL-28b was tested in approximately 40% of patients enrolled in the ADVANCE study who gave their consent. Higher SVR rates were demonstrated across all genotypes in TVR-regimen compared with SoC, with more evident differences in CT and TT genotypes than CC. According to fibrosis stage, naïve patients with advanced fibrosis and cirrhosis (METAVIR F3/F4) achieved SVR in 62% and 53% in T12PR and T8PR TVR arms, respectively, compared with 78% and 73% SVR in patients with no/or moderate fibrosis (METAVIR F0–F2) included in the same arms. 2.2.2. On-treatment predictors of SVR 2.2.2.1. Treatment week 4–12. In group T12PR 68% of patients attained RVR and 58% of them achieved an extended Rapid Virological Response (e-RVR, HCV RNA undetectable at week 4 through 12). In group T8PR, RVR was 67% and eRVR 57%. Patients with eRVR were assigned to 24 weeks of treatment according to RGT, and SVR rates were 89% (T12PR) and 83% (T8PR). Patients who did not achieve eRVR had SVR rates of 54%, 50% and 39% in the T12PR, T8PR and SoC arms, respectively. The second phase III trial ILLUMINATE [4] confirmed the safety and efficacy of a short TVR-regimen for eRVR patients. Of all
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randomized patients 72% had an RVR, 65% were eRVR, and they achieved 92% and 88% SVR rates irrespective of RGT (24 weeks) or fixed (48 weeks) regimens, respectively. 3. Treatment-experienced 3.1. Boceprevir The RESPOND-2 Phase III study evaluated efficacy of BOCregimen in treatment-experienced patients. The study focused on relapsers (previous HCV RNA undetectable at the end of treatment, but detectable 24 weeks after discontinuation of therapy) and previous partial responders (patients with >2 log drop at week 12 in comparison to baseline, but never undetectable). Null responders, defined as patients with <2 log viral load decline at week 12 in a previous treatment course were not included in this study, but were investigated in a single roll-over survey named PROVIDE which is not yet published as a full paper [11]. Even in this group of patients SVR rates were higher in all BOC-regimens (RGT and BOC PR48) than in SoC (66% and 59% vs. 21%) [5]. After 4 weeks lead-in, patients were randomized to triple therapy or to SoC. Triple therapy were administered as fixed 44 weeks or as RGT. Strikingly, the RGT offered in patients without cirrhosis the opportunity to receive BOC triple therapy for 32 weeks after 4 weeks lead-in. By contrast, in patients with detectable HCV RNA at week 8, a tail of 12 weeks of Peg-IFN and RBV was required for an overall duration of 48 weeks of treatment [5]. SVR was achieved in 72% of relapsers, and in 35% of partial responders [5]. As for treatment-naïve patients, early responders achieved 86% and 88% of SVR both in RGT regimen and in fixed regimen. 3.1.1. Baseline predictors of SVR The stage of liver fibrosis was less significant compared to naïve patients in predicting SVR with BOC. In patients with mild fibrosis (Metavir F0–F2) SVR rates were 68% and 66% in BOC-regimen (BOC PR48 and RGT respectively) compared to 23% in the control group; among patients with advanced fibrosis (Metavir F3 and 4) SVR rate was 68% and 44% for Boceprevir-regimen (BOC PR48 and RGT, respectively) compared to 13% SVR for SoC However, it should be highlighted that only 47 patients with F4 and 29 patients with bridging fibrosis were included in the RESPOND-2 study. Genetic polymorphism of IL-28b was tested in approximately 60% of patients enrolled in the RESPOND2 study who gave their consent. No differences were seen based genotype. 3.1.2. On-treatment predictors of SVR 3.1.2.1. Treatment week 4 (TW4). In treatment-experienced, as in naïve patients, the strongest predictive factor of a favourable response was an HCV RNA decline >1 log at week 4. The definition of treatment response at week 4 after lead-in used in BOC-regimen led to a redefinition of the historical response to SoC. Irrespective of the old definition of response, patients with <1 log drop decline had lower SVR rates compared to those who achieved >1 log decline after lead-in. Interestingly, the majority of patients (60%) previously defined as partial responders experienced >1 log HCV RNA decline at week 4, with high probability of SVR, while among previous relapsers 35% had <1 log decline, with low chance of SVR. 3.1.2.2. Treatment week 8 (TW8). 49% of patients had undetectable HCV RNA (early responders, ER) after addition of BOC. This group of patients achieved 86% of SVR in BOC RGT group with 24 weeks of treatment and 88% of SVR in BOC PR48 (48 weeks of treatment) [5].
3.1.2.3. Treatment week 12 (TW12). As for SPRINT-2 a retrospective analysis was conducted using different HCV RNA thresholds as stopping rules at week 8, 12 and 24. According to the findings of this analysis, the proposal of a futility threshold of HCV RNA ≥100 UI/ml at week 12 instead of detectable HCV RNA seems to be reasonable. Although this choice needs to be validated in a larger population, it enables us to minimize premature discontinuation in patients who might achieve SVR [10]. 3.1.3. Null responders As previously reported, null responders were evaluated in the PROVIDE study [11]. In this study, 47 patients with less than 2 log HCV RNA drop at week 12 were included in the control arms of SPRINT-2 and RESPOND-2, who received 44 weeks triple therapy, and obtained 40% SVR. Accordingly, the FDA and European Regulatory authorities allowed null responders to be treated with BOC triple therapy [11]. 3.1.4. SVR in poorly responsive patients after lead-in: combining SPRINT-2 and RESPOND-2 Based on concordance, correlation, and CART analyses of the IDEAL study, TW4 viral load decline of <1 log approximates to that of <2 log at TW12 and is an earlier predictor of null response with a negative predictive value (NPV) of 96% [12]. This data was recently confirmed in patients who were included in the control arms of both the SPRINT2 and RESPOND 2 studies, in which the agreement between those subjects with <1 log drop at week 4 and those with <2 log drop at week 12 were 89% (293/329) and 91% (68/75), respectively (data on file). Therefore, a post hoc analysis which included all patients from both studies who had shown a poor response to IFN was carried out. In these patients no subject with <3 log decline at week 8 achieved SVR, NPV = 100% [9]. In the subgroup of 46 patients with F3/F4 fibrosis, the overall SVR rate (G1a and 1b pooled) was 17%; and this rate was no higher than 6% (4% in G1a and 14% in G1b, respectively) when baseline levels of HCV RNA were >2,000,000 IU/ml [8]. Finally, combining both studies, only 3 out of 25 (12%) patients with cirrhosis (F4) achieved SVR (BOC RGT, 10% and BOC PR48 14%, respectively) while the corresponding SVR rate in 51 cirrhotics with TW4 viral load decline of >1 log was 67% [8]. 3.2. Telaprevir The phase III REALIZE study included patients who failed a previous SoC treatment and evaluated 2 different TVR-regimens (T12PR48 and lead-in T12PR48) compared to SoC. This is the only TVR-based study that investigated the utility of a lead-in phase (Peg-IFN alpha 2a 180 mcg/week and RBV 1000–1200 mg/qd) prior to the addition of TVR for 12 weeks. Overall, SVR rate was 65% in TVR group and 17% in controls, with no significant difference between patients treated with or without lead-in phase (66% vs. 64%, respectively). However, SVR rates were 33% in those with <1 log HCV RNA drop and 82% among patients with >1 log drop. As expected, SVR rates were higher among prior relapser patients compared to partial or null responders (83%, 59% and 29%) [7]. As mentioned above, despite no differences in SVR rates with or without the lead-in phase, week 4 response after lead-in caused a redefinition of the historical response to SoC. Of interest, only 10% of relapsers (who are clearly interferon sensitive) had <1 log HCV RNA drop at week 4, compared to 59% among null responders and 40% among partial responders. In the two latter groups of patients, the corresponding rates of SVR were 15% and 56%, respectively. Furthermore partial and null responders experienced >1 log HCV RNA decline at week 4 in approximately 50% of cases, irrespective of the “old” definition of response. The reliability of lead-in in better recognizing the likelihood to achieve SVR appears to be more relevant in relapsers and
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null responders; in fact overall SVR rates were 62% in those with <1 log decline vs. 94% in those with >1 log decline among relapsers and 15% vs. 54% in null responders, respectively [12]. Unfortunately, data on SVR rates of patients included in REALIZE according to both lead-in and fibrosis stages have not been provided. This result indicates that also with TVR, the real time response to IFN may be used in patients with previous treatment failure to identify lower/higher likelihood of achieving SVR. This is particularly useful given the fact that in many treatment-experienced patients there is difficulty in obtaining documentation of on-treatment response during the previous antiviral regimen.
3.2.1. Baseline predictors In treatment-experienced patients, retrospective analysis of the REALIZE trial found no association between IL28B genotypes and SVR rates in TVR-regimen. As for treatment-naïve patients, the stage of liver fibrosis was found to be a determinant factor for treatment success with TVR. In patients with advanced fibrosis (Metavir F3/4) SVR rates were 58% and 53% (with and without lead-in, respectively) compared to 75% in F0–F2. However, in previous relapsers, SVR rate was 84% regardless of fibrosis stage; in previous partial and null responders SVR rates decrease from 72% to 41% in F0–F2 fibrosis, from 56% to 39% in F3 fibrosis and from 34% to 14% (both TVR12 and lead-in arms combined) in F4 fibrosis, respectively. Regrettably, in the REALIZE study [7] there has not yet been a post hoc analysis in patients with partial and null response according to week 4 response, exclusively dedicated to patients with advanced fibrosis and cirrhosis in the lead-in arm. Similarly, the effect of week 4 response in predicting SVR in patients with F4 fibrosis included in the lead-in arm was not tested by multiple logistic regression analysis [13].
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4. Futility rules Despite the improvement in treatment efficacy, there are patients who might develop a breakthrough even after an early response. In order to prevent the onset of resistant mutants in patients with continuous replication during treatment, futility rules were introduced for both drugs. In case of HCV RNA >100 IU/ml at week 12, EMA recommends all BOC-based triple treatments to be discontinued. Treatment had to be discontinued also in case of detectable HCV RNA at week 24 in patients receiving BOC with HCV RNA <100 IU/ml at week 12. The stopping rules suggested by the label for TVR state that in case of HCV RNA >1000 IU/ml at week 4, and 12, TVR should be discontinued. This should also be done in case of HCV RNA above the threshold of 15 IU/ml at week 24 or 36 on-treatment. It should be highlighted that single European countries have published their own guidelines for the use of triple therapy with protease inhibitors, and different sensitivity thresholds of HCV RNA assays have been selected by each country [14–16]. 5. Conclusive remarks In summary, BOC and TVR in combination with SOC, may cure approximately two-thirds of patients with CHC genotype 1, either previously untreated or treatment-experienced. However, the rate of SVR in patients with advanced fibrosis and especially in F4 cirrhotics treated with BOC who are not responsive at the end of lead-in is, disappointingly, very modest, while no information has been provided in the same group of patients treated with TVR. Lead-in phase also allows the identification of naïve patients with RVR who may avoid triple therapy, and enables us to more reliably redefine the likelihood of achieving SVR in
Fig. 1. Suggested algorithm for treatment-naïve patients, METAVIR F0–F3. TW, treatment week; BOC, boceprevir: TVR, telaprevir; PegIFN, peginterferon alpha; RBV, ribavirin; PR, peginterferon alpha plus ribavirin; SoC, standard of care; RVR, rapid virological response; eRVR, extended rapid virolgical response.
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Fig. 2. Suggested algorithm for treatment-experienced patients, METAVIR F0–F3. Relapsers using lead-in who achieves rapid virological response could be managed as naïve patients. TW, treatment week; BOC, boceprevir: TVR, telaprevir; PegIFN, peginterferon alpha; RBV, ribavirin; PR, peginterferon alpha plus ribavirin.
treatment-experienced subjects, regardless of or in combination with the previous definition of response. Furthermore, lead-in helps to identify patients in whom the benefit of treatment is poor and risks very high.
In this latter group (namely cirrhotics, poorly responsiveness to IFN), physicians need to very critically assess whether patients with these characteristics should be treated with triple therapy, balancing both the likelihood to attain SVR and the risk of
Fig. 3. Suggested algorithm for cirrhotic patients, METAVIR F4 (both naïve and treatment-experienced). BOC: PR 4 weeks + PR BOC 44 weeks. TVR: PR 4 weeks + PRTVR 12 weeks + PR 32 weeks. TW, treatment week; BOC, boceprevir: TVR, telaprevir; PegIFN, peginterferon alpha; RBV, ribavirin; PR, peginterferon alpha plus ribavirin.
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developing severe side effects with the known increased survival rates observed in patients with cirrhosis who achieve HCV clearance [17,18]. Therefore, the choice of stopping therapy after lead-in without adding DAA could be carefully considered in order to avoid a potential ineffective and hazardous expensive treatment. 6. Suggested algorithm On the basis of the above considerations, lead-in phase represents the most reliable tool to recognize those patients in whom triple therapy is useless or poorly effective. Therefore, irrespective of on-label with first generations PI’s indications, we suggest three simple algorithms (Figs. 1–3) that may optimize lead-in use with both drugs. The possibility to avoid lead-in is admitted in noncirrhotic relapsers, because in this subset of patients the rate of those with either RVR or with less than
List of abbreviations BOC, Boceprevir; CHC, chronic hepatitis C; DAA, direct acting antivirals; ER, early responders; eRVR, extended rapid virological response; MLR, multiple logistic regression analysis; NPV, negative predictive value; PegIFN, peginterferon; PI’s, protease inhibitors; PR, Peg-IFN and RBV; RAV, resistance associated variants; RBV, ribavirin; RGT, response-guided therapy; SoC, standard of care; SVR, sustained virological response; TVR, Telaprevir; TW, treatment week; TW4, treatment week 4; TW8, treatment week 8; TW12, treatment week 12.
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