HCV NS3 Protease Inhibitors Telaprevir and Boceprevir

Antiviral Therapy 2012; 17:1119–1131 (doi: 10.3851/IMP2424)

Review The first wave: HCV NS3 protease inhibitors telaprevir and boceprevir

Kristen M Marks1*, Ira M Jacobson2

1Division of Infectious Diseases, Weill Cornell Medical College, New York, NY, USA 2Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY, USA

*Corresponding author e-mail: [email protected]

Boceprevir and telaprevir are peptidomimetic serine and treatment-experienced patients and shortens the protease inhibitors that have been recently approved duration of treatment for over half of treatment-naive for the treatment of HCV chronic infection. The addi- patients. This review describes the clinical data support- tion of these drugs to the prior standard of care, ing the approval and use of telaprevir and boceprevir, pegylated interferon and ribavirin, improves sus- the algorithm for the use of these drugs, their adverse tained virological response rates for treatment-naive effects, as well as their important drug–drug interactions.

Introduction

Although agents targeting several sites in the HCV their use in clinical practice (Figure 1) based on their viral life cycle are in development, to date, only tel- FDA-approved indications and the latest American aprevir and boceprevir (drugs that inhibit the NS3/4a Association for the Study of Liver Diseases (AASLD) serine protease) have been FDA-approved for treat- guidelines for the treatment of HCV [1]. Lastly, the ment of chronic hepatitis C. The year 2011 witnessed review characterizes the adverse event and drug–drug a dramatic development in the field of therapy for interaction profiles (Table 4) to help guide safe and chronic HCV infection with the approval of two pro- appropriate use of these medications. tease inhibitors (PIs), telaprevir and boceprevir. These drugs represent the first of an anticipated wave of Overview of serine protease inhibitors direct-acting antiviral agents (DAAs) representing sev- telaprevir and boceprevir eral mechanisms of action undergoing ongoing study. Both of the available PIs must be used in combination Mechanism and spectrum of action with pegylated interferon (PEG-IFN) and ribavirin Both boceprevir and telaprevir are peptidomimetic (RBV) and are approved, at this time, only for geno- inhibitors that bind reversibly to the active site of the type 1 infection. Pivotal clinical trials demonstrated NS3/4a serine protease enzyme active site [2,3]. They two important benefits from the addition of these drugs prevent the cleavage of the portion of the genome- to PEG-IFN and RBV: improved rates of sustained derived polypeptide required for the generation of the virological response (SVR) and shortened duration of individual non-structural proteins essential to the HCV treatment for a substantial proportion of patients with viral life cycle. Exposure to either drug results in potent the use of response-guided therapy (RGT). inhibition of viral replication in vitro and in vivo. This review describes the clinical trial data support- However, monotherapy results in the rapid emergence ing the approval and use of telaprevir and boceprevir of resistant variants (further described in Resistance), for patients with chronic HCV infection, including resulting in the need for concomitant administration of important findings from early phase studies, results PEG-IFN and RBV. Although approved only for treat- of the pivotal Phase III studies (Tables 1 and 2), and ment of HCV genotype 1 and clearly not pangenotypic available data related to treatment of historically dif- in their spectrum of activity, variable degrees of sup- ficult to cure patients. In addition, this review com- pression of other genotypes may occur, as demonstrated pares the similarities and differences between the for telaprevir in a recent study in patients with HCV two drugs (Table 3) and provides an algorithm for genotype 2 but not genotype 3 [4].

Resistance Interferon retains the capacity to suppress all resistant NS3/4a protease polymorphisms/substitutions that variants and clinical studies have also shown a clear confer reduced susceptibility to the drugs can be benefit for RBV in preventing the emergence of resist- detected prior to treatment by population-based ance despite lingering questions about its mechanisms of sequencing in 5% of subjects from telaprevir studies action [11,12]. In clinical studies, mutations associated of treatment-naive patients and 7% from boceprevir with resistance occur more readily with HCV genotype studies of treatment-naive patients [5,6]. The presence 1a compared with 1b due to a lower genetic barrier to of these viral variants did not appear to preclude SVR, resistance: for two of the amino acid substitutions capa- although this requires further study, particularly in ble of impairing viral sensitivity to either drug, genotype poorly interferon responsive patients [7,8]. 1a requires one base pair mutation, whereas 1b requires Viral variants with mutations in the area of the active two to confer resistance [13]. The most common muta- drug binding site can also be selected using both drugs tions (observed in >10% of subjects with virological fail- in vitro and in vivo [9]. These result in resistance to the ure in clinical trials) include the following: V36M, T54S, drugs, but at the expense of decreased viral fitness [10]. R155K for genotype 1a subjects who received boceprevir,

Table 1. Efficacy results of Phase III studies for HCV treatment-naivepatients Study/arm Subjects, n RVR, % eRVR, % SVR if eRVR, % SVR, % Relapse, %

Boceprevir SPRINT-2 non-Black cohort 938 – – – – – SOC PEG-IFN/RBV 350 18a 13 93 40 23 RGT arm 316 60a 47 97 67 9 FD arm 311 59a 46 96 68 8 Boceprevir SPRINT-2 Black cohort 159 – – – – – SOC PEG-IFN/RBV 52 8a 6 100 23 14 RGT arm 52 35a 29 87 42 12 FD arm 55 40a 37 95 53 17 Telaprevir ADVANCE 1,095 – – – – – SOC PEG-IFN/RBV 361 9 8 97 44 28 T8PR RGT arm 364 66 57 83 69 9 T12PR RGT arm 363 68 58 89 75 9 Telaprevir ILLUMINATE eRVR+24 week arm 162 NA NA 92 NA 6 eRVR+48 week arm 160 NA NA 88 NA 3 All subjects 540 72 65 As above 72 8

Data from [17,27,28]. aWeek 8: after 4 weeks of triple therapy. eRVR, extended rapid virological response; FD, fixed duration; NA, not applicable; PEG-IFN, pegylated interferon; RBV, ribavirin; RGT, response-guided therapy; RVR, rapid virological response; SOC, standard of care; SVR, sustained virological response; T8PR, triple therapy for 8 weeks; T12PR, triple therapy for 12 weeks.

Table 2. Efficacy results of Phase III studies for HCV treatment-experienced patients Overall RVR (RVR Overall SVR (SVR by Relapse (relapse by by relapse, partial prior replase, partial prior relapse, partial Study/arm Subjects, n response, null response), % SVR if RVR, % response, null response), % response, null response), %

Boceprevir RESPOND-2 403 – – – – SOC PEG-IFN/RBV 80 9a (Un, Un, NA) 100 21 (29, 7, NA) 32 (Un, Un, NA) RGT arm 162 46a (Un, Un, NA) 86 59 (69, 40, NA) 15 (Un, Un, NA) FD arm 161 52a (Un, Un, NA) 88 66 (75, 52, NA) 12 (Un, Un, NA) Telaprevir REALIZE 833 – – – – SOC PEG-IFN/RBV 133 2b (3, 0, 3) Un 17 (24, 15, 5) 25 (65, 0, 60) 48 week arm 266 57b (89, 65, 26) Un 64 (85, 59, 29) 10 (7, 21, 27) Lead-in 48 week arm 264 59b (70, 65, 41) Un 66 (88, 54, 33) 10 (7, 25, 25)

Data from [31,33]. aTreatment week 8 (after 4 weeks triple therapy). bTreatment week 8 for lead-in arm, week 4 for others. FD, fixed duration; NA, not applicable; PEG-IFN, pegylated interferon; RBV, ribavirin; RGT, response-guided therapy; RVR, rapid virological response; SOC, standard of care; SVR, sustained virological response; Un, unavailable.

T54A/S, V55A, A156S and I/C170A for genotype 1b sub- Treatment-naive patients jects who received boceprevir, V36M and R155K for genotype 1a subjects who received telaprevir, and V36A/L, Clinical trial data and recommended use of T54A/S and A156S/T for genotype 1b subjects who boceprevir for treatment-naive patients received telaprevir [5,6]. These mutations confer cross- Boceprevir early phase study findings resistance of telaprevir and boceprevir to each other as Initial Phase I and II studies to explore the safety and well as to several other investigational HCV PIs [14]. dosing of boceprevir were actually conducted in treatment-experienced subjects. They established the most Clinical trial data and recommended use of effective dose of boceprevir (800 mg three times daily) boceprevir and telaprevir and showed that boceprevir yielded greater reductions in viral load when given with PEG-IFN [15,16]. Because there has been no clinical trial comparing the Monotherapy resulted in viral breakthrough related to efficacy of telaprevir and boceprevir head-to-head, the the selection of resistant viral mutants [15] and RBV clinical data regarding these two drugs will be reviewed use improved outcomes [16]. It was also observed separately for treatment-naive and treatment-experi- that a rapid response to treatment predicted SVR enced patients. The limited available data related to and that subjects who demonstrated some interferon- treatment of historically difficult to cure patients, such responsiveness (that is, 1–2 log decrease during PEG- as those of Black race or those with HIV or advanced IFN/RBV dual therapy) were more likely to achieve fibrosis, will be discussed. Limited or no data exist SVR with triple therapy [16]. In the Phase II study, a about telaprevir’s and boceprevir’s safety and efficacy 1–2 g/ dl incremental increase in anaemia was observed in paediatric and geriatric patients or in patients with with boceprevir use [16]. end stage renal disease or on haemodialysis, moder- Incorporating lessons learned from that study, ate to severe hepatic impairment, solid organ trans- SPRINT-1 was an international, multicentre rand- plantation, HBV coinfection, or in patients who failed omized clinical trial in treatment-naive genotype 1 therapy with other HCV PIs. Use of boceprevir and patients that compared multiple boceprevir treatment telaprevir in these populations is therefore not recom- strategies with PEG-IFN-a2b plus RBV standard of care mended at this time, although studies in some of these (SOC). This study explored 28- versus 48-week treat- groups are planned or ongoing. ment durations, utilization of a PEG-IFN/RBV lead-in

Table 3. Comparison between boceprevir- and telaprevir-based HCV treatment

Boceprevir Telaprevir

Mechanism of action Serine protease inhibitor Serine protease inhibitor Metabolism Aldo-keto reductase, CYP3A, CYP3A, P-glycoprotein P-glycoprotein Dosing 800 mg (four 200 mg capsules) 750 mg (two 375 mg tablets) 3 times daily (every 7–9 h) 3 times daily (every 7–9 h) Food restrictions With meal or light snack With meal or snack containing approximately 20 g of fat PEG-IFN/RBV dual 4 Weeks None therapy lead-in Duration triple therapy 24–44 Weeks depending on 12 Weeks response, cirrhosis status and prior treatment statusa Total treatment duration 28–48 Weeks depending on 24–48 Weeks depending on response, response, cirrhosis status and cirrhosis status and prior treatment statusa prior treatment statusa Groups approved for Treatment-naive, relapsersb, Treatment-naive, relapsers response-guided therapy partial respondersb Rules for stopping treatment HCV RNA>100 IU/ml at 12 weeks, HCV RNA>1,000 IU/ml at 4 or 12 weeks, based on futility detectable at 24 weeks detectable at 24 weeks Side effects seen in excess Anaemia, neutropaenia, Rash, fatigue, pruritis, gastrointestinal effects, of PEG-IFN/RBV in controlled gastrointestinal effects, dysgeusia, chills anaemia, anorectal symptoms, dysgeusia clinical trials

Data from [5,6]. aSee Figure 1 for algorithm that depicts duration of treatment accounting for response, cirrhosis status and prior treatment status. bUS only. PEG-IFN, pegylated interferon; RBV, ribavirin.

Antiviral Therapy 17.6 Pt B 1121 KM Marks & IM Jacobson

Figure 1. Recommended treatment algorithms that incorporate response during treatment, cirrhosis status and prior treatment status

A RGT decision: HCV RNA detected Boceprevir for treatment-naive patients without known cirrhosis week 8? No PEG-IFN/RBV + boceprevir PEG-IFN/ PEG-IFN/ RBV RBV + lead-in boceprevir

Ye PEG-IFN/RBV + boceprevir PEG-IFN/RBV s

Week 12 Week 24 HCV RNA HCV RNA ≥100 detected IU/ml Week 48 12 24 36 48

RGTa decision: Boceprevir for prior relapsers and partial responders without known cirrhosisa HCV RNA detected week 8? No PEG-IFN/RBV + boceprevir PEG-IFN/ PEG-IFN/ RBV RBV + lead-in boceprevir

Ye PEG-IFN/RBV + boceprevir PEG-IFN/RBV s

Week 12 Week 24 HCV RNA HCV RNA ≥100 detected IU/ml

RGT decision: Telaprevir for treatment-naive patients and prior relapsers without known cirrhosis HCV RNA detected week 4 or 12?

No PEG-IFN/RBV

PEG-IFN/RBV + telaprevir Ye

s PEG-IFN/RBV

Week 4 Week 12 Week 24 HCV RNA HCV RNA HCV RNA >1,000 >1,000 detected IU/ml IU/ml Week 4122448

Duration of pegylated interferon (PEG-IFN)/ribavirin (RBV) dual therapy is depicted in light grey, duration of triple therapy including protease inhibitor in dark grey and stopping rules are in clear hexagons. (A) Treatment algorithms for patients eligible for response-guided therapy (RGT). (B) Treatment algorithms for patients not eligible for RGT. aRGT approach approved by the FDA not the EMA.

Figure 1. Continued

B Boceprevir for prior null responders, patients with cirrhosis, or <1 log drop week 4

PEG-IFN/ PEG-IFN/RBV + boceprevir RBV lead-in

Week 12 Week 24 HCV RNA HCV RNA ≥100 detected IU/ml

Week 4122448

Telaprevir for prior partial or null responders or patients with cirrhosis

PEG-IFN/RBV + telaprevir PEG-IFN/RBV

Week 4 Week 12 Week 24 HCV RNA HCV RNA HCV RNA ≥1,000 ≥1,000 detected IU/ml IU/ml

versus simultaneous start of all three drugs and, as a RBV and provided support for the use of RGT (28–48 way of minimizing side effects, low dose versus stand- weeks determined by treatment response; Table 1) [17]. ard RBV. SPRINT-1 showed that adding boceprevir This randomized, double-blind, placebo-controlled improved SVR rates compared with SOC PEG-IFN/ trial, compared triple therapy with boceprevir (800 mg RBV, but that SVR rates were substantially higher with three times daily) plus PEG-IFN/RBV, given for either 48 weeks treatment compared with 28 weeks and with a duration to be determined by treatment response standard versus low dose RBV [12]. The rationale for (RGT) or a fixed duration (FD), to SOC PEG-IFN/ using a 4-week PEG-IFN/RBV dual therapy lead-in RBV in both a Black and non-Black cohort of patients prior to adding boceprevir was to establish steady-state (n=938 non-Black and n=159 Black). Subjects ran- and reduce HCV viral load, thus decreasing the odds of domized to RGT all received 4 weeks PEG-IFN/RBV subsequent development of boceprevir resistance. The lead-in followed by 24 weeks of triple therapy. At this 48-week arms had higher SVR rates than the shorter point, those subjects who had achieved a rapid viro- duration arms, and the 48-week arm with the lead-in logical response (RVR; defined as undetectable HCV phase had the highest SVR rate (75%). It was addition- RNA after 4 weeks triple therapy (week 8 treatment) ally observed that the degree of virological response and maintained undetectable HCV RNA stopped treat- during the lead-in was predictive of SVR [12]. Moreo- ment. Those with detectable HCV RNA during that ver, there was a trend toward lower rates of virologi- period continued on PEG-IFN/RBV for an additional cal breakthrough in the lead-in arms. This strategy of 20 weeks unless HCV RNA was detectable at treatment treating with a PEG-IFN/RBV lead-in prior to adding week 24, which comprised a stopping rule. FD subjects boceprevir was incorporated into all arms of the Phase received 4-week lead-in PEG-IFN/RBV followed by 44 III studies. weeks of boceprevir/PEG-IFN/RBV. SVR rates achieved in both the boceprevir RGT and FD groups were supe- Boceprevir Phase III study data rior to PEG-IFN/RBV with respective SVR rates of 67% The Phase III study, SPRINT-2, confirmed the superior and 68% versus 41% in the non-Black cohort and 42% efficacy of boceprevir plus PEG-IFN/RBV to PEG-IFN/ and 53% versus 23% in the Black cohort. Notably,

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in the RGT arms, 60% of the non-Black and 35% of results. In the boceprevir arm, 61% of subjects achieved the Black cohort were undetectable at week 8 (RVR), SVR12 compared with 27% with PEG-IFN/RBV [20]. with those who remained undetectable qualifying for Although this study excluded efavirenz use and did not shortened therapy. Of these subjects with RVR, 89% of evaluate RGT, a Phase III study will explore the use of patients in the non-Black cohort and 78% of patients boceprevir in HIV treatment-naive and treatment-expe- in the Black cohort achieved SVR. Overall, SVR rates rienced subjects, including RGT for treatment-naive were 36% in subjects without an RVR [17]. Although patient without cirrhosis. not powered to determine non-inferiority of RGT to FD, the FDA concluded RGT was justified based on this Boceprevir treatment strategy recommended for data and recommend RGT in treatment-naive patients treatment-naive patients without cirrhosis. Boceprevir has been FDA- and European Medical Predictors of response to treatment included base- Agency (EMA)-approved for treatment of HCV geno- line HCV RNA<400,000 IU/ml, age ≤40 years, absence type 1 only in combination with PEG-IFN and RBV. of cirrhosis and statin use. The lead-in phase was The algorithm in Figure 1 demonstrates the recom- also observed to be a valuable predictor of treatment mended strategy for using boceprevir including deci- response: 79–81% of subjects with a >1 log decrease sion points and stopping rules. After giving a 4-week during the lead-in phase achieved SVR compared with lead-in treatment with PEG-IFN/RBV, boceprevir 800 28–38% SVR in those who did not [17]. Subsequent mg three times a day (every 7–9 h) is added. Treatment analyses also showed a more favourable response in sub- duration is then guided by response. Those with unde- jects with genotype 1b versus 1a and host IL28B (genetic tectable HCV RNA at week 8 receive a total duration polymorphism on chromosome 19, rs 12979860) geno- of 28 weeks (4 weeks PEG-IFN/RBV followed by 24 type CC versus CT or TT [18]. However, boceprevir weeks triple therapy), and those with detectable HCV therapy sharply decreased the differential rates of SVR RNA at week 8 that becomes undetectable by week 24 between CC patients and those with the T allele. receive 48 weeks total treatment (4 weeks PEG-IFN/ RBV followed by 32 weeks triple therapy and then 12 Boceprevir for difficult to cure populations: Black/ weeks PEG-IFN/RBV). The latter regimen differs from African American the regimen used in clinical studies described above, As described above, Black patients benefited from the as it contains an extra 8 weeks of boceprevir. This addition of boceprevir with SVR rates of 42% with RGT was based upon the findings that in patents with late and 53% with FD compared with 23% in the SOC arm response across both the non-Black and Black cohorts, [17]. When the intent-to-treat analysis was limited to SVR occurred in 66% of those receiving RGT (with non-cirrhotic Black subjects, more similar response rates 24 weeks of boceprevir and a 20-week PEG-IFN/RBV were observed with RGT and FD (50% versus 54%) ‘tail’) and in 75% of those receiving a full 44 weeks of [19]. In addition, with a modified intent-to-treat analysis boceprevir after the PEG-IFN/RBV lead-in. RGT is not evaluating only patients who received at least one dose recommended for patients with cirrhosis, who should of boceprevir, the SVR rates in the boceprevir arms were receive 48 weeks of therapy. Also different from the piv- 47% and 53% for RGT and FD, respectively. otal trial is the stopping rule of detectable HCV RNA at week 24 in the SPRINT-trial, the recommended stop- Boceprevir for difficult to cure populations: advanced fibrosis ping rule in clinical practice is HCV RNA≥100 IU/ml at Subgroup analyses of the Phase III study revealed week 12 or detectable HCV RNA at week 24. that triple therapy including boceprevir was also Clinicians should be aware that the basis for the superior to SOC in the 10% of Caucasian patients application of RGT is complete undetectability of HCV with advanced fibrosis (Metavir score 3 or 4), with RNA at week 8 and beyond. If HCV RNA is detectable SVR rates of 50% with boceprevir versus 39% with but below the lower limit of quantification, the oppor- SOC [17]. In subjects with cirrhosis, higher response tunity for RGT does not apply. rates were observed with FD (43%) versus RGT (31%). Although numbers of subjects were small, this Clinical trial data and recommended use of telaprevir resulted in the FDA recommending 48-week treat- for treatment-naive patients ment (no RGT) for subjects with cirrhosis. Telaprevir early phase findings Phase I studies established telaprevir dosing (750 mg Boceprevir for difficult to cure populations: HIV coinfection every 8 h), demonstrated the potency of telaprevir as SVR rates in patients with HIV coinfection have not monotherapy (all subjects given 750 mg dosing had a yet been published, but a study comparing 48 weeks >3 log decrease in HCV RNA) and revealed that viro- of boceprevir/PEG-IFN/RBV with PEG-IFN/RBV logical breakthrough with selection of viral mutations for patients with HIV showed promising preliminary with decreased susceptibility to telaprevir would occur

with monotherapy [21–23]. They also established that side effects (for example, rash) while preserving effi- these resistant variants could be cleared subsequently cacy. Unlike the Phase II studies, ADVANCE included with PEG-IFN and RBV, thereby confirming the neces- patients with advanced fibrosis (bridging fibrosis or sity of combination therapy [22–24]. compensated cirrhosis) and took a response-guided Two Phase II multicentre, randomized, double-blind, approach to the duration of therapy for all subjects. placebo-controlled studies, PROVE1 and PROVE2, Subjects in the telaprevir arms with undetectable HCV established the safety of telaprevir in combination with RNA from weeks 4 to 12, referred to as an extended PEG-IFN and RBV and superior efficacy over PEG-IFN/ rapid virological response (eRVR), received 24 weeks RBV for treatment-naive subjects in the US and Europe of treatment, whereas those who took longer to become [11,25]. In addition to establishing superiority over undetectable received 48 weeks. SVR rates were 69% PEG-IFN/RBV, PROVE1 established the foundation for and 75% in the two telaprevir groups and were supe- what has become known as RGT by showing that in rior to SOC (44%). In addition, 57% and 58% of those with RVR, SVR rates with 24 weeks were similar T8PR and T12PR subjects met the criteria for eRVR to that of 48 weeks. It also showed that relapse rates and received 24 weeks of total treatment resulting in were unacceptably high if PEG-IFN/RBV was discon- SVR rates of 89% and 83%, respectively. Although a tinued as early as 12 weeks, leading to a recommended lower incidence of rash was observed in the T8PR arm, treatment duration of at least 24 weeks [25]. In addition the T12PR arm experienced a higher SVR rate that was to establishing superiority over SOC, PROVE2, which consistent among subgroup analysis as well as a lower contained a RBV-free arm of equivalent size to the other incidence of virological failure during the dual therapy treatment arms, demonstrated that RBV was essential to phase of treatment. For these reasons, 12 weeks of tri- combination therapy and that baseline HCV RNA was ple therapy became the approved treatment strategy. predictive of response to triple therapy [11]. PROVE1 The other Phase III study of telaprevir conducted and PROVE2 showed that virological breakthrough dur- in treatment-naive subjects, ILLUMINATE (n=540), ing telaprevir treatment was associated with selection of sought to establish the non-inferiority of RGT by ran- resistance mutants and demonstrated that subjects with domizing subjects with eRVR to 24 versus 48 weeks. genotype 1a were more likely to develop resistance than In this supportive, multicentre, randomized, open-label 1b given its lower genetic barrier to resistance. In both clinical trial, 65% of subjects achieved an eRVR with studies, anaemia and a potentially treatment-limiting SVR rates of 92% and 88% in the 24 and 48 week rash emerged as important side effects that occurred groups, respectively – meeting the statistical criteria for more frequently with triple therapy than SOC [11,25]. non-inferiority and providing firm evidence to support Another Phase II study explored whether telaprevir the approach of RGT in treatment-naive patients [28]. could be administered every 12 h as the three times a day dosing was chosen based on monotherapy and not Telaprevir for difficult to cure populations: Black/African on studies of telaprevir combined with PEG-IFN/RBV. American In this open-label study, which also evaluated PEG- Although Black patients represented only 9% of sub- IFN-a2a versus PEG-IFN-a2b, no significant differ- jects in ADVANCE and 15% in ILLUMINATE, a ence in SVR rates were observed between subjects who pooled analysis of subjects assigned to receive 12 weeks received telaprevir every 12 or every 8 h and were simi- of triple therapy as part of either RGT or FD in these lar regardless of PEG-IFN. However, telaprevir every studies was conducted to examine the effect of race on 12 h dosing needs to be explored further in larger stud- treatment response and resistance rates [29]. It revealed ies before being considered as SOC and such studies are overall SVR rates of 62% in 127 Black subjects ver- in progress [26]. sus 77% in 1,124 non-Black subjects. In the 46% of Black subjects with eRVR, 85% achieved SVR, whereas Telaprevir Phase III study data the rate was 90% in the 65% of non-Black patients Two pivotal Phase III studies established the safety and with eRVR. Because this analysis included subjects efficacy of telaprevir for purposes of FDA registration assigned to either RGT or FD, it cannot answer if RGT and informed the current use of telaprevir (Table 1). The is non-inferior to FD for Black patients in particular. randomized, double-blind, placebo-controlled, FDA However, in support of RGT, SVR rates were similar registration trial, ADVANCE (n=1,088), studied two for Black subjects with eRVR in ILLUMINATE (88% telaprevir dosing strategies, triple therapy for 8 (T8PR) and 94% achieving SVR in the 24-week and 48-week or 12 (T12PR) weeks followed by response-guided arms, respectively [28]). Although the numbers were PEG-IFN/RBV, and compared them with PEG-IFN/ small, on-treatment virological failure and relapse both RBV [27]. The goal of studying two different durations occurred more frequently in Black patients compared of telaprevir dosing was to determine whether a shorter with non-Black patients (virological failure in 11% ver- duration of telaprevir would decrease the frequency of sus 7% and relapse in 7% versus 3%, respectively) [29].

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Telaprevir for difficult to cure populations: advanced fibrosis Treatment-experienced patients In ADVANCE, SVR rates were superior to SOC in telaprevir-treated subjects with advanced fibrosis When considering treatment-experienced patients, the with 62% achieving SVR versus 33% in SOC. How- most important predictor of treatment response is prior ever, in ILLUMINATE, although numbers were small, treatment response. Patients for whom treatment failed SVR rates appeared diminished in cirrhotic subjects previously are typically categorized as one of the fol- assigned to 24 weeks compared with 48 weeks, with lowing: relapsers (HCV RNA became undetectable 12/18 (67%) versus 11/12 (92%) achieving SVR, during treatment but detectable HCV RNA recurred respectively. Although data is insufficient to conclude after cessation of treatment), partial responders (HCV the inferiority of RGT in this population, guidelines RNA decreased ≥2 log IU/ml at week 12 but did not recommend strong consideration of 48 weeks dura- become undetectable by 24 weeks) or null responders tion of therapy for previously treatment-naive cir- (HCV RNA decreased <2 log IU/ml at week 12). Sub- rhotics with eRVR. jects were stratified by these categories in the Phase III studies described below. Telaprevir for difficult to cure populations: HIV coinfection Preliminary data from a Phase II study of HIV– Clinical trial data and recommended use of HCV-coinfected patients revealed promising SVR 12 boceprevir for treatment-experienced patients responses of 74% in telaprevir-treated compared to Boceprevir clinical trial data 45% with PEG-IFN/RBV alone [30]. Subjects were on RESPOND-2 (n=403), the Phase III, randomized, no antiretroviral therapy or on antiretroviral regimens double-blind, parallel group, study of boceprevir including the combination of tenofovir/emtricitabine with PEG-IFN/RBV for treatment-experienced sub- plus either ritonavir-boosted atazanavir or efavirenz. jects included patients with prior partial response Intensive week 4 pharmacokinetic (PK) evaluation or relapse, but not null response to prior PEG-IFN/ showed that telaprevir exposure was comparable RBV treatment (Table 2). It was designed similar across these antiretroviral regimens and that only mod- to the treatment-naive study in that the boceprevir est changes occurred in the PK of the antiretrovirals. arms included a 4-week lead-in of PEG-IFN/RBV and Phase III studies for treatment-naive and treatment- compared RGT and FD with SOC PEG-IFN/RBV. experienced HIV–HCV-infected persons that include However, in this study, the regimens for the RGT arm RGT for treatment-naive are underway. differed from the treatment-naive study with subjects achieving an eRVR completing 32 weeks of triple Telaprevir treatment strategy recommended for therapy (36 weeks of total treatment), whereas those treatment-naive patients still detectable at week 8 completed 32 weeks of triple Based on the data presented above, telaprevir has been therapy followed by an additional 12 weeks of PEG- FDA- and EMA-approved for treatment of chronic IFN/RBV (48 weeks total therapy). Boceprevir triple HCV genotype 1 only in combination with PEG-IFN therapy arms were superior to SOC PEG-IFN/RBV and RBV. Telaprevir 750 mg three times a day (every with 66%, 59% and 21% achieving SVR in the FD, 7–9 h) plus PEG-IFN/RBV is given for 12 weeks fol- RGT, SOC arms, respectively [31]. SVR rates were lowed by PEG-IFN/RBV for 12 or 36 weeks duration highest amongst subjects who were relapsers (69– as determined by treatment response. Those having 75%) compared with partial responders (40–52%). an eRVR defined as HCV RNA undetectable at weeks Again, undetectable HCV RNA after 4 weeks of tri- 4 and 12, receive a total duration of 24 weeks (12 ple therapy was highly predictive of SVR; 86–88% of weeks triple therapy followed by 12 weeks PEG-IFN/ subjects with RVR in the boceprevir arms achieved RBV) and those without an eRVR receive 48 weeks SVR compared with 40% in subjects without RVR. total treatment (12 weeks triple therapy followed by Other predictors of response included lower base- 36 weeks PEG-IFN/RBV). RGT is not recommended line HCV RNA and absence of cirrhosis. A <1 log for patients with cirrhosis who should receive 48 decrease during the lead-in also predicted a poorer weeks of therapy. The algorithm in Figure 1 demon- response to treatment; however, even these subjects strates the recommended strategy for using telaprevir had improved response rates compared with SOC including decision points and futility stopping rules. PEG-IFN/RBV (33–34% versus 0%) [31]. Thus, it is Of note, these stopping rules differ from those applied not recommended that the lead-in response be used as in Phase III trials, with an HCV RNA level of >1,000 a rationale to discontinue treatment. IU/ml at weeks 4 and 12 mandating discontinuation Although RESPOND-2 did not include prior null of all therapy. Again, complete HCV RNA undetect- responders, a subsequent, single arm rollover study ability at weeks 4 and 12 is required for application (PROVIDE) enrolled null responders from the Phase of RGT. III treatment studies. An interim assessment of data

from 45 of 48 subjects (3 were not dosed with including 4 weeks PEG-IFN/RBV followed by 44 weeks boceprevir) revealed that 16 (36%) achieved SVR triple therapy, is recommended. Similarly, 48 weeks of with boceprevir [32]. The number of cirrhotics in treatment is recommended for patients with poor inter- this open-label study was small. This rate is similar feron response (defined as <1 log at end of PEG-IFN/ to that observed in RESPOND-2 subjects with poor RBV lead-in phase) or, as above, cirrhosis. The stopping interferon responsiveness (<1 log decrease at week rules for futility of treatment are identical to those for 4). When treatment failed, resistance mutations were treatment-naive subjects (Figure 1). present frequently; 44% of tested subjects without SVR had resistant variants detected. Clinical trial data and recommended use of telaprevir for treatment-experienced patients Boceprevir for difficult to treat populations: Black/ Telaprevir clinical trial data African American REALIZE (n=662), the Phase III study of telaprevir Of the 49 Black patients enrolled in RESPOND-2, for treatment-experienced subjects, differed from the 53–61% achieved SVR with boceprevir. This was simi- boceprevir Phase III treatment-experienced study in lar to the study population as a whole and far superior that no RGT regimen was studied (Table 2). REAL- to the 8% who achieved SVR with PEG-IFN/RBV [31]. IZE also included patients with null response as well as partial response and relapse to SOC PEG-IFN/ Boceprevir for difficult to treat populations: RBV. REALIZE utilized a randomized, double-blind, advanced fibrosis placebo-controlled study design to compare two regi- Subgroup analysis showed benefit in subjects with mens of telaprevir in combination with PEG-IFN/ cirrhosis re-treated with boceprevir compared with RBV to SOC PEG-IFN/RBV. Both telaprevir-based SOC, where none achieved SVR. However, in compar- treatments lasted 48 weeks and consisted of 12 weeks ing RGT versus FD strategies, the SVR rate was noted of triple therapy followed by 36 weeks of PEG-IFN/ to be much lower in the RGT arm (35% versus 77%) RBV. One arm utilized a 4-week lead-in treatment of [31]. This, along with the small number of patients PEG-IFN/RBV treatment, whereas the other started studied and the importance of ‘erring’ on the side of all drugs simultaneously. The overall SVR rates were optimizing therapy in cirrhotics, has contributed to superior in both telaprevir-containing arms (65% the package insert guideline that cirrhotics, whether combined arms) compared with the SOC arm (17%). treatment-naive or treatment-experienced, should In subjects who received telaprevir, response corre- receive a full 48 weeks of therapy with a 4-week lead- lated to prior interferon responsiveness, with 86% of in period of PEG-IFN/RBV and 44 weeks of triple relapsers, 57% of partial responders and 31% of null therapy with boceprevir. responders achieving SVR [33]. However, among 50 null responder cirrhotics, the SVR rate was only 7/50 Boceprevir treatment strategy recommended for (14%). By contrast, the presence of cirrhosis had no treatment-experienced patients significant effect on rates of SVR in prior relapsers and The FDA approved RGT for relapsers and partial a more modest effect in partial responders. responders without cirrhosis (Figure 1). This entails The majority of subjects (76%) in triple therapy giving a 4-week PEG-IFN/RBV lead-in followed by 32 arms with virological failure or relapse developed weeks of triple therapy for patients with undetectable mutations associated with reduced susceptibility to HCV RNA at week 8. Patients without detectable HCV telaprevir [33]. No difference was observed between RNA at week 8 in whom HCV RNA becomes unde- the two strategies of telaprevir, lead-in or simulta- tectable by week 24, and are therefore eligible for com- neous start (66% versus 64%, respectively). Simi- pletion of therapy, require an additional 12 weeks of lar to boceprevir studies, <1 log IU/ml HCV RNA PEG-IFN/RBV from weeks 36 to 48. The EMA did not decrease during the 4-week PEG-IFN/RBV lead-in approve RGT for these patients, instead endorsing a predicted lower likelihood of SVR. A subsequent fixed 48-week duration of treatment for all relapsers and analysis revealed that among null responders, a <1 log partial responders (4-week PEG-IFN/RBV lead-in, fol- reduction in HCV RNA at week 4 of lead-in therapy lowed by 32 weeks of triple therapy and then 12 weeks resulted in an SVR rate of 15% compared with 54% of PEG-IFN/RBV). For null responders, limited clini- in those with a better response at week 4. This has cal data exists regarding boceprevir use. As described led some clinicians to adopt the ‘off-label’ approach of above, a recent small open-label study of null respond- a 4-week PEG-IFN/RBV lead-in when treating prior ers derived from the control arms of the boceprevir tri- null responders, and discontinuing therapy in the face als showed an SVR rate of approximately 36%, with of a poor interferon response. The rationale for this the analysis nearly completed [32]. If boceprevir is cho- approach is to minimize the risk of emergent resist- sen for a prior null responder, 48 weeks of treatment, ance in the face of a poor likelihood of success and,

Antiviral Therapy 17.6 Pt B 1127 KM Marks & IM Jacobson

at centres where clinical trials are performed, to pre- PEG-IFN/RBV-treated subjects experienced the fol- serve the eligibility of such patients for trials of novel lowing side effects: anaemia, neutropaenia, dysgeusia, agents in null responder populations. Other predictors vomiting and chills (experienced by >10% of subjects of response to telaprevir-based treatment include low- and ≥5% more than SOC) [5,6]. Data from combined, density lipoprotein, HCV genotype subtype, alanine controlled clinical trials of telaprevir showed that rash, aminotransferase and aspartate aminotransferase lev- anaemia, pruritis, anorectal complaints (described var- els, HCV RNA and fibrosis stage [34]. iously as hemorrhoids, discomfort and pruritis), nau- sea, diarrhoea, vomiting and dysgeusia occurred in at Telaprevir for difficult to cure populations: Black/ least 5% more of telaprevir-treated subjects compared African American with PEG-IFN/RBV-treated subjects [5,6]. Although only 4% of subjects in REALIZE were Black, The two common side effects of greatest potential they had similar response rates as the group as a whole concern include anaemia and rash. Although anaemia (63% overall SVR). Further study is needed to accu- during treatment is primarily driven by RBV through rately determine response rates for treatment-experi- its effect on red blood cell haemolysis, both boceprevir enced Black patients. and telaprevir contribute to anaemia. Both drugs induce an incremental degree of haemoglobin decrease Telaprevir for difficult to cure populations: advanced fibrosis of 1–1.5 g beyond that observed with PEG-IFN/RBV. Subgroup analysis of REALIZE revealed that more In treatment-naive studies SPRINT-1 and SPRINT-2, advanced fibrosis predicted poorer response to treat- haemoglobin levels <10 g/dl and <8.5 g/dl occurred ment, particularly in the patients with poorer interferon more frequently in the boceprevir-treated patients responsiveness during past treatment. In the combined (49% and 6%) compared with SOC (29% and 3%) telaprevir arms, 34% of prior partial responders with [6]. Erythropoetin (EPO) use and dose modifications cirrhosis and only 14% of prior null responders with of RBV due to anaemia occurred approximately twice cirrhosis achieved SVR. as frequently in boceprevir arms in Phase II and III studies, but treatment discontinuations due to anae- Telaprevir treatment strategy recommended for mia were rare with or without boceprevir (1%) [6]. treatment-experienced patients Preliminary data suggested that the anaemia manage- As with treatment-naive subjects, telaprevir for ment strategy (EPO versus dose reduction) did not treatment-experienced subjects is administered in com- affect SVR rates with boceprevir use. However, sub- bination with PEG-IFN/RBV for 12 weeks followed by jects with anaemia did experience higher SVR rates PEG-IFN/RBV with the duration depending on prior [36]. In Phase III telaprevir studies, haemoglobin <10 treatment history and on treatment response. Although g/dl and <8.5 g/dl also occurred more frequently with not explicitly studied, the FDA and EMA endorse a rec- 12 weeks of telaprevir (36% and 14%) compared with ommendation that prior relapsers may be considered SOC (17% and 5%) [5]. The telaprevir studies did not for RGT similar to treatment-naive patients (Figure permit EPO use, so RBV dose reduction was the pre- 1). This recommendation is based on the high degree ferred strategy. RBV dose reductions due to anaemia of interferon responsiveness in relapsers, by definition, occurred in 36% but, as with boceprevir, were not and the high actual SVR rates in relapsers, including associated with reduced rates of SVR (76% if reduc- Phase II studies in which subjects with rapid response tion versus 72% without) [37]. The package insert for received 24 weeks of treatment [35]. RGT is not rec- boceprevir recommends dose reduction of RBV for ommended for partial and null responders. They haemoglobin <10 g/dl and discontinuation of RBV for should be given 48 total weeks of treatment including haemoglobin <8.5 g/dl, whereas the telaprevir pack- 12 weeks of triple therapy followed by 36 weeks of age insert recommends dose reduction in the event of PEG-IFN/RBV. The stopping rules for futility of treat- anaemia as per the RBV prescribing information [5,6]. ment are identical to those for treatment-naive subjects In Phase II/III studies, approximately half of telaprevir- (Figure 1). treated patients developed a rash with >90% being of mild-to-moderate severity and commonly resolv- Side effects of boceprevir and telaprevir ing after telaprevir discontinuation. Rash was judged severe in these trials if it involved >50% of body surface Not surprisingly, because both telaprevir and area in the judgment of the investigator. Approximately boceprevir are given in addition to PEG-IFN and RBV 50% of rashes occurred within the first 4 weeks and the in the studies described above, the frequency of adverse other 50% between weeks 5–12 with median onset at events was greater in the arms that included these PIs. day 25 [38]. In Phase III studies, the implementation of Combined data from controlled treatment-naive stud- a rash management plan resulted in less PEG-IFN/RBV ies revealed that more boceprevir-treated subjects than discontinuations due to rash (1% in Phase III versus

6% in Phase II). The plan involves sequential discon- Table 4. Medications contraindicateda for use during tinuation of telaprevir initially, followed by observation treatment with telaprevir and boceprevir and subsequent of RBV and possibly PEG-IFN as well Contraindicateda with both telaprevir and boceprevir if the problem became more severe or failed to abate. Alfuzosin Serious forms of rash such as drug-related eosinophilia Rifampin with systemic symptoms (DRESS) or Stevens–Johnson Dihydroergotamine and other ergot derivatives syndrome have been reported rarely (<1% of patients). St John’s Wort (hypericum perforatum) The package insert and other product guides provide Lovastatin comprehensive rash management strategies. Simvastatin Sildenafil and tadalafil (when used for the treatment of pulmonary arterial hypertension) Drug–drug interactions Pimozide Triazolam Attention to drug–drug interactions with HCV PIs is Contraindicateda with boceprevir only essential for the clinician who may be unaccustomed Carbamazepine to this concern after years of experience with PEG-IFN/ Phenobarbital RBV therapy. Both telaprevir and boceprevir are potent Phenytoin inhibitors of cytochrome p450 3A4/5 (CYP3A) and Cisapride P-glycoprotein. Other medications that rely on these Drosperinone pathways for clearance require increased monitoring Orally administered midazolam for adverse events if coadministered, or they are con- Contraindicateda with telaprevir only traindicated for use with boceprevir and telaprevir if Atorvastatin increased drug levels are associated with serious or life- Data from [5,6]. aAlthough this table contains medications that are threatening events. Of additional concern, boceprevir contraindicated for use with boceprevir and telaprevir, many additional medications metabolized by CYP3A cytochrome interact with boceprevir and and telaprevir are also metabolized by pathways includ- telaprevir. The package insert and additional drug interaction software should be ing CYP3A (Table 3), thus leading to the potential for used to assess their compatibility. coadministered medications that induce these enzymes to lower their levels and effectiveness. Table 4 includes medications and supplements that are known to be con- inhibit, induce or are metabolized by the CYP3A traindicated for use during treatment with boceprevir pathway. The antiretroviral regimen in use may and/or telaprevir for these reasons. Some commonly ultimately dictate the particular HCV PI and the used drug classes concerning for interactions with dose of the PI that is most suitable for the patient. boceprevir and telaprevir include, but are not limited For instance, telaprevir is not recommended for use to, antiretrovirals, anticonvulsants, antiarrhythmics, with lopinavir/ritonavir, darunavir or fosamprenavir, calcium channel blockers, HMG-CoA reductase inhibi- and may require an increased dose when coadmin- tors, oral contraceptives, immunosuppressants, PDE5 istered with efavirenz [5]. The FDA and EMA also inhibitors, sedatives and inhaled corticosteroids. A small recently released warnings about coadministration of study of subjects on stable methadone replacement boceprevir with HIV PIs due to drug–drug interac- revealed about a 20% decrease in unbound methadone tions. Additional information on drug interactions levels with coadministration of telaprevir, although not with antiretrovirals is expected from ongoing and generally necessary dose adjustments may be needed in planned clinical trials. Because the safety and efficacy some patients [39]. Both boceprevir and telaprevir may of these drugs has not yet been established for HIV- compromise the effectiveness of hormonal contracep- infected persons, treatment through a clinical trial is tion, with decreased exposure to ethinyl estradiol and advisable and early data do suggest favourable on- increased exposure to drosperinone [5,6,40]. Because treatment response rates [20,30]. If a clinical trial is these drugs are always given with RBV, a known terato- not available, recently published guidelines may be gen, two forms of non-hormonal contraception should helpful in determining the appropriateness of their be used by women of childbearing capacity until at least off-label use [41]. 2 weeks after discontinuation of the PI, whereupon the longstanding requirement of two methods of contracep- Conclusions tion (including hormonal) until 6 months after cessation of RBV is still in effect. Additional information on Clinical trial evidence supports and guidelines now drug interactions can be found in the package inserts or endorse a PI, either telaprevir or boceprevir, along with through online drug interaction software. PEG-IFN/RBV as the new SOC for both treatment- For HIV-infected patients, drug–drug interactions naive and treatment-experienced adults with genotype are of particular concern as many antiretrovirals 1 chronic HCV infection. However, guidelines do not

Antiviral Therapy 17.6 Pt B 1129 KM Marks & IM Jacobson

address prioritization of patients to receive telaprevir- References or boceprevir-based treatment based on predictors of 1. Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB. response. For instance, a PI-based regimen offers a An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American treatment-naive patient a high likelihood of cure as Association for the Study of Liver Diseases. Hepatology well as being eligible for shorter treatment. By con- 2011; 54:1433–1444. trast, for a patient with a prior null response together 2. Perni RB, Almquist SJ, Byrn RA, et al. Preclinical profile of VX-950, a potent, selective, and orally bioavailable with cirrhosis, SVR rates are quite low with approved inhibitor of hepatitis C virus NS3-4A serine protease. PIs and failure is likely to result in the development Antimicrob Agents Chemother 2006; 50:899–909. of resistance. This latter patient may benefit from a 3. Malcolm BA, Liu R, Lahser F, et al. SCH 503034, a mechanism-based inhibitor of hepatitis C virus NS3 regimen including more than one DAA, available only protease, suppresses polyprotein maturation and enhances through clinical trials currently. the antiviral activity of alpha interferon in replicon cells. With the use of telaprevir and boceprevir, some Antimicrob Agents Chemother 2006; 50:1013–1020. 4. Foster GR, Hezode C, Bronowicki JP, et al. Telaprevir common themes have emerged including those related alone or with peginterferon and ribavirin reduces HCV to RGT, interferon responsiveness, drug resistance, RNA in patients with chronic genotype 2 but not genotype adverse events and drug–drug interactions. With both 3 infections. Gastroenterology 2011; 141:881–889.e1. telaprevir and boceprevir, treatment duration is guided 5. Incivek (Telaprevir). Package insert 2011. Vertex Pharmaceuticals, Cambridge, MA, USA. by response for treatment-naive and relapsers, and 6. Victrelis (Boceprevir). Package insert 2011. Schering results in shorter duration of therapy for half or more Corporation, a subsidiary of Merck & Co, Inc, Whitehouse of patients. For treatment-experienced subjects, the Station, NJ, USA. highest SVR rates occur in prior relapsers, followed 7. Vierling JM, Lawitz EJ, Poordad F, et al. Four-week therapy with peginterferon alfa-2b/ribavirin effectively predicts by partial and then null responders. The majority of sustained virologic response in treatment-naive and patients in whom treatment fails develop mutations previous-treatment-failure patients with HCV-1 treated with boceprevir plus peginterferon alfa-2b/ribavirin. J Hepatol associated with resistance, with failure occurring most 2011; 54 Suppl 1:S197. frequently in prior null responders, especially cirrhot- 8. Kieffer T, De MS, Bartels DJ, et al. Clinical virology ics. The long-term implications of drug resistance findings from treatment-naive and treatment-experienced genotype 1 HCV patients receiving telaprevir/ remain unclear, but available data show a reassuring peginterferon/RBV in Phase 3 clinical trials. Antivir Ther tendency toward decrease in resistant viral variants 2011; 16 Suppl 1:A27. over time [42–45]. This provides a rationale for not 9. Hiraga N, Imamura M, Abe H, et al. Rapid emergence of telaprevir resistant hepatitis C virus strain from wildtype categorically denying therapy to patients with nega- clone in vivo. Hepatology 2011; 54:781–788. tive prognostic factors, although the decision to re- 10. Sarrazin C, Kieffer TL, Bartels D, et al. Dynamic hepatitis C treat certain patients, such as null responders with virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology cirrhosis, should be individualized. 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GT-1a or GT-1b subtype-specific resistance profiles for Disclosure statement hepatitis C virus inhibitors telaprevir and HCV-796. Antimicrob Agents Chemother 2009; 53:2129–2132. IMJ has received grant/research support from 14. Halfon P, Locarnini S. Hepatitis C virus resistance to protease inhibitors. J Hepatol 2011; 55:192–206. Achillion, Anadys, Boehringer Ingelheim, Bristol– 15. Sarrazin C, Rouzier R, Wagner F, et al. SCH 503034, a Myers Squibb, Gilead, GlobeImmune, Novartis, Pfizer, novel hepatitis C virus protease inhibitor, plus pegylated Pharmasset, Roche/Genentech, Schering/Merck, Tibo- interferon alpha-2b for genotype 1 nonresponders. Gastroenterology 2007; 132:1270–1278. tec/Janssen, Vertex and Zymogenetics; is on speakers’ 16. Schiff E, Poordad F, Jacobson I, et al. Boceprevir (B) bureaus for Bristol–Myers Squibb, Gilead, Roche/ combination therapy in null responders (NR): response Genentec, Schering/Merck and Vertex; and acts as a dependent on interferon responsiveness. J Hepatol 2011; 48 Suppl 2:S46. consultant/advisor for Abbott, Achillion, Boehringer 17. Poordad F, McCone J, Jr., Bacon BR, et al. Boceprevir for Ingelheim, Bristol–Myers Squibb, Gilead, GlaxoS- untreated chronic HCV genotype 1 infection. N Engl J Med mithKline, GlobeImmune, Inhibitex, Idenix, Kadmon, 2011; 364:1195–1206. Novartis, Pharmasset, Presidio, Roche/Genentech, 18. Poordad F, Bronowicki JP, Gordon SC, et al. IL28b polymorphism predicts virologic response in patients with Schering/Merck, Tibotec/Janssen and Vertex. KMM hepatitis c genotype 1 treated with boceprevir (BOC) declares no competing interests. combination therapy. J Hepatol 2011; 54 Suppl 1:S190.

19. McCone J, Jacobson I, Bacon B, et al. Treatment-naive 34. Berg T, Andreone P, Pol S, et al. Predictors of virologic Black patients treated with boceprevir (BOC) combined response with telaprevir-based combination treatment in with peginterferon alfa-2b + ribavirin (PR): results from HCV genotype 1-infected patients with prior peginterferon/ HCV SPRINT-2. 62nd Annual Meeting of the American ribavirin treatment failure: post-hoc analysis of the Phase Association for the Study of Liver Diseases. 5–9 November III REALIZE study. 62nd Annual Meeting of the American 2011, San Francisco, CA, USA. Abstract 981. Association for the Study of Liver Diseases. 5–9 November 20. Sulkowski M, Pol S, Cooper C, et al. Boceprevir + 2011, San Francisco, CA, USA. Abstract 1138547. peginterferon + ribavirin for the treatment of HCV/HIV 35. McHutchison JG, Manns MP, Muir AJ, et al. Telaprevir for co-infected patients: end of treatment (week-48) interim previously treated chronic HCV infection. N Engl J Med results. 19th Conference on Retroviruses and Opportunistic 2010; 362:1292–1303. Infections. 5–8 March 2012, Seattle, WA, USA. Abstract 47. 36. Sulkowski MS, Poordad F, Manns MP, et al. Anemia during 21. Reesink HW, Zeuzem S, Weegink CJ, et al. Rapid decline treatment with peginterferon alfa-2b/ ribavirin with or of viral RNA in hepatitis C patients treated with VX-950: without boceprevir is associated with higher SVR rates: a phase Ib, placebo-controlled, randomized study. analysis of previously untreated and previous-treatment- Gastroenterology 2006; 131:997–1002. failure patients. J Hepatol 2011; 54 Suppl 1:S194–S195. 22. Kieffer TL, Sarrazin C, Miller JS, et al. Telaprevir and 37. Sulkowski MS, Reddy R, Afdhal NH, et al. Anemia had pegylated interferon-alpha-2a inhibit wild-type and no effect on efficacy outcomes in treatment-naive patients resistant genotype 1 hepatitis C virus replication in patients. who received telaprevir-based regimen in the ADVANCE Hepatology 2007; 46:631–639. and ILLUMINATE Phase 3 studies. J Hepatol 2011; 54 23. Forestier N, Reesink HW, Weegink CJ, et al. Antiviral Suppl 1:S195. activity of telaprevir (VX-950) and peginterferon alfa-2a in 38. Cacoub P, Bourliere M, Lubbe J, et al. Dermatological side patients with hepatitis C. Hepatology 2007; 46:640–648. effects of hepatitis C and its treatment: Patient management 24. Lawitz E, Rodriguez-Torres M, Muir AJ, et al. Antiviral in the era of direct-acting antivirals. J Hepatol 2012; effects and safety of telaprevir, peginterferon alfa-2a, and 56:455–463. ribavirin for 28 days in hepatitis C patients. J Hepatol 39. Van Heeswijk R, Vandevoorde A, Verboven P, et al. The 2008; 49:163–169. pharmacokinetic interaction between methadone and the 25. McHutchison JG, Everson GT, Gordon SC, et al. Telaprevir investigational HCV protease inhibitor telaprevir. J Hepatol with peginterferon and ribavirin for chronic HCV genotype 2011; 54 Suppl 1:S491–S492. 1 infection. N Engl J Med 2009; 360:1827–1838. 40. Garg V, van Heeswijk R, Yang Y, Kauffman R, Smith F, 26. Marcellin P, Forns X, Goeser T, et al. Telaprevir is effective Adda N. The pharmacokinetic interaction between given every 8 or 12 hours with ribavirin and peginterferon an oral contraceptive containing ethinyl estradiol and alfa-2a or -2b to patients with chronic hepatitis C. norethindrone and the HCV protease inhibitor telaprevir. Gastroenterology 2011; 140:459–468.e1. J Clin Pharmacol 2011; doi: 10.1177/0091270011419855. 27. Jacobson IM, McHutchison JG, Dusheiko G, et al. 41. Thomas DL, Bartlett JG, Peters MG, Sherman KE, Telaprevir for previously untreated chronic hepatitis C virus Sulkowski M, Pham PA. Provisional guidance on the use infection. N Engl J Med 2011; 364:2405–2416. of hepatitis C virus protease inhibitors for treatment of hepatitis C in HIV-infected persons. Clin Infect Dis 2012; 28. Sherman KE, Flamm SL, Afdhal NH, et al. Response-guided 54:979–983. telaprevir combination treatment for hepatitis C virus infection. N Engl J Med 2011; 365:1014–1024. 42. Susser S, Vermehren J, Forestier N, et al. Analysis of long- term persistence of resistance mutations within the hepatitis 29. Muir AJ, Sullivan JC, Dusheiko GM, et al. Treatment effect C virus NS3 protease after treatment with telaprevir or and resistance profiles were similar between Black/African boceprevir. J Clin Virol 2011; 52:321–327. American and non-Black/African American patients treated with a telaprevir combination regimen. American College of 43. Zeuzem S, Sulkowski M, Zoulim F, et al. Long-term Gastroenterology Annual Scientific Meeting. 28 October–2 follow-up of patients with chronic hepatitis C treated with November 2011, Washington, DC, USA. Abstract 4. telaprevir in combination with peginterferon alfa-2a and ribavirin: interim analysis of the EXTEND Study. 61st 30. Dieterich DT, Soriano V, Sherman KE, et al. Telaprevir in Annual Meeting of the American Association for the Study combination with peginterferon alfa-2a/ribavirin in HCV/ of Liver Diseases (AASLD). 29 October–2 November 2010, HIV co-infected patients: SVR12 interim analysis. 19th MA, Boston, USA. Abstract 227. Conference on Retroviruses and Opportunistic Infections. 5–8 March 2012, Seattle, WA, USA. Abstract 46. 44. Vierling JM, Ralston R, Lawitz E, et al. Long-term outcomes following combination treatment with boceprevir 31. Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for plus Peg-Intron/ribavirin (P/R) in patients with chronic previously treated chronic HCV genotype 1 infection. hepatitis C, genotype 1 (CHC-G1). 45th Annual Meeting of N Engl J Med 2011; 364:1207–1217. the European Association for the Study of the Liver. 14–18 32. Vierling JM, Flamm S, Gordon S, et al. Efficacy of April 2010, Vienna, Austria. Abstract 2016. boceprevir in prior null responders to peginterferon/ 45. Sherman KE, Sulkowski M, Zoulim F, et al. Follow-up of ribavirin: the PROVIDE study. 62nd Annual Meeting of the SVR durability and viral resistance in patients with chronic American Association for the Study of Liver Diseases. 5–9 hepatitis C treated with telaprevir-based regimens: interim November 2011, San Francisco, CA, USA. Abstract 931. analysis from the EXTEND study. 62nd Annual Meeting of 33. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for the American Association for the Study of Liver Diseases. 5–9 retreatment of HCV infection. N Engl J Med 2011; November 2011, San Francisco, CA, USA. Abstract 1126934. 364:2417–2428.

Accepted 18 March 2012; published online 5 October 2012

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