Telaprevir for the treatment of chronic hepatitis C infection
Telaprevir is an NS3/4A protease inhibitor that has recently received US FDA approval for the treatment of chronic HCV infection.
Telaprevir is given in combination with peg-IFN- and ribavirin and is indicated for both treatment-naive and treatment-experienced patients with genotype 1 infection. Along with the other first generation NS3/4A protease inhibitor boceprevir, these combination regimens have immediately become the standard of care for genotype 1 patients. The adverse event profile for the combination regimen remains dominated by peg-IFN- and ribavirin, but there is additional anemia and rash with telaprevir. Owing to telaprevir’s metabolism by the CYP3/4A pathway, drug–drug interactions could lead to toxicity from other medications or decreased efficacy of telaprevir. Viral resistance can develop during treatment with telaprevir, and patients will need to be educated on their role in adherence to minimize the risk of resistance and improve their chances of cure of HCV infection.
HCV has infected more than 170 million people worldwide [1]. Chronic infection leads to sig- nificant morbidity and mortality through the increased risk of cirrhosis and the resulting com- plications of ascites, variceal bleeding, hepatic encephalopathy and hepatocellular carcinoma [2,3]. The predominant risk factors for HCV transmission are transfusion of infected blood and percutaneous exposure to infected blood that most commonly takes place through injec- tion drug use [4]. Due to the shared transmission routes, prevalence is increased among patients with HIV infection [5].
For the last decade, standard of care has been treatment with a combination of peg-IFN- and ribavirin [6,7]. The standard definition of treatment response is sustained virologic response (SVR), which occurs when the patient has undetectable HCV RNA in their serum at least 6 months after cessation of therapy. This combination of peg-IFN- and ribavi- rin is extremely effective in genotypes 2 and 3 with SVR rates of approximately 81–84% with 24 weeks of therapy [8]. Genotype 1 infection is more difficult to treat, requiring 48 weeks of peg-IFN- and ribavirin with response rates of 40–52% [8,9]. Genotype 1 infection is common throughout the world and is the most frequent genotype present in the USA and Europe [10]. As a result, genotype 1 infection has been a significant unmet medical need and led to efforts to improve the response rate through the use of direct-acting antiviral medications.
Among patients with genotype 1 infection, factors associated with lower rates of SVR include male gender, older age, Black/African American race, high viral load (HCV RNA>600,000 IU/ml), advanced fibrosis (bridging fibrosis or cirrhosis), hepatic steatosis and insu- lin resistance [9]. Lower response rates are also observed in patients with HIV–HCV coinfec- tion and patients treated after liver transplanta- tion [5,11]. Recently, a genome-wide association study of patients in the IDEAL trial was per- formed and determined that a single nucleotide polymorphism (SNP) rs12979860, near the IL-28B gene, was the strongest baseline predic- tor of treatment response to peg-IFN- and riba- virin [12]. Caucasian patients with the favorable CC genotype at the SNP near IL-28B were much more likely to achieve SVR (69% vs 33% and 27%; p < 0.0001) compared with CT and TT [13]. African–Americans are much less likely to have the CC genotype and this finding explains a significant portion of the lower response rate for this group. The accepted definition of treatment response in HCV has been SVR. Given the long natural history of HCV, it has been difficult to dem- onstrate the clinical benefit of curing patients of HCV and impacting long-term clinical outcomes. A recent analysis from the US Department of Veterans Affairs evaluated all patients with genotypes 1, 2 or 3 HCV treated between 2001 and 2008 [14]. Using multivariate survival models controlling for demographic factors and comorbidities, SVR was associated with substantially reduced mortality for all three genotypes. These data only further support the hope that improved response rates with protease inhibitors will improve the health of the population of patients with HCV infection. Overview of the market HCV treatment has evolved over the last three decades but has consistently had a backbone of IFN-. Most recently, stan- dard treatment was a combination of peg-IFN- and ribavirin [6,7]. Peg-IFN- is available in two versions with peg-IFN -2a (Pegasys®, Hoffman-La Roche Inc., Nutley, NJ, USA) and peg-IFN -2b (Pegintron®, Merck, Whitehouse Station, NJ, USA). Both of these preparations are administered once weekly in combination with ribavirin that is dosed twice daily. The HCV lifecycle presents a number of targets, and the first generation of direct-acting antivirals focus on the NS3/4A pro- tease. Recently, the first generation protease inhibitors telaprevir (Incivek®) and boceprevir (Victrelis®, Merck) received approval from the US FDA for the treatment of chronic HCV infection in combination with peg-IFN- and ribavirin. Both agents received approval for use in previously untreated patients and in patients who had failed previous therapy. Telaprevir is manufactured by Vertex Pharmaceuticals (Cambridge, MA, USA) and is marketed under the trade name Incivek. Telaprevir and boceprevir represent a major step for- ward in the treatment of chronic HCV infection with improved response rates [15–18]. However, these treatments have limitations and many patients are not eligible for treatment that includes IFN-. The adverse event profile of IFN- includes significant influenza-like symptoms, bone marrow suppression and neuro- psychiatric adverse events including depression [7]. Many patients discontinue therapy due to these adverse events [9]. Other direct- acting antivirals are in development with the hope of improving response rates. Other goals of these combination regimens are to reduce the duration of treatment with IFN- or to offer inter- feron-free regimens. These compounds include the next genera- tion of protease inhibitors, NS-5B polymerase inhibitors, NS-5A inhibitors and cyclophilin inhibitors [19]. Introduction to the drug Telaprevir is an orally bioavailable NS3/4A protease inhibitor that was approved by the FDA in 2011 [20]. Telaprevir is approved only in combination with peg-IFN- and ribavirin for genotype 1 patients who are treatment-naive or have been previously treated with interferon-based treatment. These treatment-experienced patients can include prior null responders (less than 2-log10 reduc- tion in HCV RNA by week 12), partial responders (greater than 2-log10 reduction in HCV RNA by week 12 but detectable at week 24) and relapsers (undetectable HCV RNA at the end of treat- ment but reappeared after therapy was discontinued). Telaprevir is not recommended for patients who have previously failed a regimen that includes telaprevir or boceprevir. The recommended dosage in adult patients is 750 mg every 8 h. Telaprevir is currently not approved for use in pediatric patients. Telaprevir combination treatment is not recommended for pregnant women due to the teratogenic effects of ribavirin. Telaprevir is approved for patients with compensated cirrhosis but not Child-Pugh B or C cirrhosis. The algorithm for treatment with telaprevir varies according to patient history and on-treatment virologic response. All patients receive 12 weeks of triple combination treatment with telapre- vir, peg-IFN- and ribavirin followed by varying durations of peg-IFN- and ribavirin. Patients who have never been treated or relapsed during prior peg-IFN- and ribavirin treatment will receive response-guided therapy. If these patients are undetectable at weeks 4 and 12, they will receive a total of 24 weeks of therapy. For these measurements, use of a sensitive real-time PCR assay for HCV RNA levels during treatment is recommended with a lower limit of quantification equal to or less than 25 IU/ml and a limit of detection of 10–15 IU/ml. Patients who have detect- able HCV RNA levels at 4 weeks but pass futility rules (greater than 1000 IU/ml at week 4 and 12 or detectable at week 24) will receive 48 weeks total of treatment. It is also recommended to consider 48 weeks of treatment for these patients with cirrhosis. For prior partial and null responders, response-guided therapy is not recommended. These patients will receive 12 weeks of triple combination with telaprevir, peg-IFN- and ribavirin followed by 36 weeks of peg-IFN- and ribavirin. The same futility rules for treatment-naive patients also apply to prior partial and null responders. The combination regimen with telaprevir includes peg-IFN- and ribavirin, and therefore the recommended dose modifications and discontinuation rules for adverse events for both peg-IFN- and ribavirin should also be followed. In the event of adverse events, telaprevir must never be dose reduced. If discontinued for an adverse event, telaprevir cannot be restarted. Chemistry Telaprevir is a white to off-white powder with solubility in water of 0.0047 mg/ml [20]. It is available as a purple, capsule-shaped, film-coated tablet for oral administration containing 375 mg of telaprevir. It has a molecular formula of C36H53N7O6 with a molecular weight of 679.85. The structural formula of telaprevir is shown in FIGURE 1. Pharmacodynamics Resistance Early in the development program of telaprevir, resistance was observed within 14 days of monotherapy [21]. Using samples from 34 patients in the Phase Ib study of telaprevir with doses of 450–1250 mg every 8 h, sequencing was performed to iden- tify mutations in the NS3 protease catalytic domain. Mutations conferring low-level resistance (V36A/M, T54A, R155K/T and A156S) and high-level resistance (A156V/T, 36+155, 36+156) to telaprevir were detected. These resistant variants correlated with telaprevir exposure and virologic response. When evaluated following cessation of telaprevir, the majority of resistant variants were replaced by wild-type virus within 3–7 months. In this early development period, further study of telaprevir with or without peg-IFN -2a revealed more insight into the develop- ment of resistance [22]. In a report of 16 patients, four patients developed viral rebound with monotherapy. The R155K/T and A156V/T variants were detected during the initial decline in HCV RNA, but these were replaced in the rebound phase by V36(M/A)/R155(K/T) double mutant variants. In the remain- ing 12 patients given telaprevir alone or with peg-IFN -2a, the A156V/T variant was detected in some patients, but the combi- nation of peg-IFN -2a and telaprevir inhibited both wild-type and resistant variants. This study demonstrated that the initial antiviral response to telaprevir targets wild-type virus and then uncovers pre-existing telaprevir-resistant variants and ultimately leads to selection of variants with greater fitness. This early finding in the telaprevir program led to ongoing evaluation of sequencing among patients receiving telaprevir in combination with peg-IFN- and ribavirin [17,18]. In the Phase III studies with telaprevir, the FDA analyzed the development of resistant substitutions in the NS3 protease among patients who did not achieve SVR, and these results are detailed in TABLE 1 [20]. This analysis demonstrated the different pattern of treatment- emergent substitutions between genotypes 1a and 1b with the high-level resistance V36M/R155K double mutation present only in the genotype 1a patients. In order to better understand the course of resistance, patients who developed resistance have been followed. In a recent report, patients who did not achieve SVR in the Phase III trials were evaluated by population sequencing with a median follow-up of 11 months [23]. 60% of telaprevir-resistant variants were no longer detectable at the last assessment. The impact of persistence of telaprevir-resistant variants on the natural history of the virus or future treatment is unknown and warrants further study. Pharmacokinetics & metabolism Telaprevir is orally available and appears to be absorbed in the small intestine. The maximum plasma concentrations after a single dose of telaprevir are achieved after 4–5 h. There is a significant food effect with telaprevir. The systemic exposure was increased by 237% when telaprevir was administered with a standard fat meal (533 kcal, 21 g fat) compared with fasting conditions. Exposure was increased more when telaprevir was administered with a high-fat meal (928 kcal, 56 g fat ) at 330% compared with a low-fat meal (249 kcal, 3.6 g fat) at 117%. As a result, telaprevir should be taken with food that is not low fat [20]. In vitro studies have found that telaprevir is 59–76% bound to plasma proteins, predominantly 1-acid glycoprotein and albumin. The volume of distribution was estimated to be 252 l with inter- individual variability of 72%. Telaprevir is metabolized in the liver and cytochrome P450 3A4 is the major isoform responsible for its metabolism. As a result, there are extensive drug–drug interactions to consider prior to prescribing telaprevir. Drugs that are highly dependent on CYP3A for clearance with a narrow therapeutic index are contraindicated with telaprevir due to the risk of severe adverse events related to elevated plasma concentrations. These medications include 1-adrenoreceptor antagonists, ergot derivatives, HMG CoA reductase inhibitors, PDE5 inhibitors when given at doses for pulmonary hypertension, and orally administered midazolam and triazolam. A detailed list of other drug–drug interactions is included in the package insert in detail, and providers will need to evaluate drug–drug interactions for all patients. The most recent develop- ment in this area is the concerning report of the effect on cyclo- sporine and tacrolimus, which are common immunosuppressants used in patients undergoing liver transplantation [24]. In a study of healthy volunteers, coadministration with telaprevir increased cyclosporine exposure by 4.6-fold and increased tacrolimus expo- sure by approximately 70-fold. Telaprevir increased the terminal elimination half-life of cyclosporine from 12 to 42.1 h and of tacroli- mus from 40.7 to 196 h. These findings have major implications on the treatment of patients post-liver transplant and warrant further study to understand the best approach for these patients. Figure 1. Telaprevir. Following a single dose of telaprevir, 82% was recovered in the feces. The mean elimination half-life after a single dose of telaprevir 750 mg ranged from 4.0 to 4.7 h. At steady state, the effective half-life is 9–11 h [20].Patients with compensated cirrhosis were included in the Phase III trials with telaprevir, and subjects with cirrhosis had similar pharmacokinetic parameters compared with those without cirrhosis [20]. In studies of HCV-negative subjects, steady-state exposure to telaprevir was reduced by 15% in Child-Pugh class A and 46% in Child-Pugh class B. Treatment with telaprevir is not recommended for Child-Pugh class B and C patients. For patients with renal impairment, no dose adjustment is necessary. However, combination therapy with telaprevir has not been studied in HCV patients with creatinine clearance less than 50 ml/min due to the contraindication for ribavirin. Population pharmacokinetic studies showed no differences in telaprevir pharmacokinetics according to gender or race. There was also no clear difference in exposure to telaprevir within the age range studied of 19 to 70 years, but only 25 subjects over the age of 65 were included. The pharmacokinetics of telaprevir in pediatric patients have not been evaluated. Clinical efficacy Phase I studies of telaprevir for chronic HCV infection The initial Phase I study in patients with HCV evaluated mul- tiple dose levels of telaprevir monotherapy [25]. In this placebo- controlled, double-blind study, 34 patients with genotype 1 chronic HCV infection were randomized to receive placebo or telaprevir at doses of 450 or 750 mg every 8 h or 1250 mg every 12 h for 14 days. Of the 34 participants, 27 (79%) had failed prior treatment. Among the 28 patients receiving telaprevir, 28 (100%) had at least a 2-log10 reduction in HCV RNA by day 14, and 26 (93%) had a 3-log10 or greater reduction. The 750-mg dose group had the highest trough plasma drug concentrations, and the median reduction of HCV RNA was 4.4 log10 after 14 days. The following study evaluated the safety and antiviral effects of telaprevir in combination with peg-IFN -2a and ribavirin in treatment-naive patients with genotype 1 chronic HCV [26]. Twelve patients received telaprevir 750 mg every 8 h, peg-IFN -2a 180 µg per week and ribavirin (1000 or 1200 mg/day) for 28 days. All patients achieved rapid virologic response (undetectable HCV RNA at week 4). Patients were offered to continue peg-IFN -2a and ribavirin combination therapy for an additional 44 weeks. Of the eight patients who did agree to this treatment course, all eight achieved SVR. Phase II studies of telaprevir for chronic HCV infection The Phase II studies with telaprevir explored a number of issues to find the appropriate combination in both treatment-naive and -experienced patients (TABLE 2). The early studies with telaprevir had demonstrated resistance with monotherapy and the need for combination with IFN-α, but the role of ribavirin was unknown. PROVE-1 was a randomized, placebo-controlled trial of 263 treatment-naive patients at 37 centers in the USA [27]. The control arm patients received peg-IFN -2a 180 µg weekly plus ribavirin (1000–1200 mg daily in divided dose). The patients in all three experimental arms received the triple combination, of telapre- vir 750 mg every 8 h plus peg-IFN -2a and ribavirin, for 12 weeks. Patients in one of these experimental arms (T12PR12) only received 12 weeks of therapy. Patients in the other two experimental arms received either 12 more weeks (T12PR24) or 36 more weeks (T12PR48) of peg-IFN -2a and ribavirin. Compared with 41% SVR observed in the control arm, SVR rates were 61% (p = 0.02) in the T12PR24 arm and 67% (p = 0.002) in the T12PR48 arm. The arm with only 12 weeks of the triple combination achieved SVR of only 35% and therefore did not continue into Phase III. PROVE-2 was a similar study to PROVE-1 in treatment-naive genotype 1 patients in Europe [28]. The control arm patients again received peg-IFN -2a 180 µg weekly plus ribavirin (1000– 1200 mg daily in divided dose). The T12PR12 and T12PR24 groups followed the same regimen as PROVE-1. This study also specifically evaluated the role of ribavirin with a group that received telaprevir and peg-IFN -2a without ribavirin for 12 weeks. SVR was achieved in 46% of patients in the control group. Among the telaprevir arms, 69% of patients in the T12PR24 group (p = 0.004 vs control group) and 60% in the T12PR12 group (p = -0.12 vs control group) achieved SVR. Only 36% of patients in the T12P12 group achieved SVR with unacceptable rates of viral resistance and relapse. This study highlighted the importance of ribavirin in treatment regimens with telaprevir. PROVE-3 was a Phase II study in North America and Europe to evaluate the safety and efficacy of combination therapy with telaprevir among patients who had failed peg-IFN- and ribavirin therapy [29]. The control group received peg-IFN- and ribavirin. The telaprevir arms included the T12PR24 group with the triple combination for 12 weeks followed by 12 weeks of peg-IFN- and ribavirin. The T24PR48 group received the triple combination for 24 weeks followed by 48 weeks of peg-IFN- and ribavirin. The T12P24 group received telaprevir and peg-IFN- but not ribavirin for 24 weeks and again performed poorly with a SVR rate of 24%. The SVR rates of 51% in the T12PR24 group and 53% in the T24PR48 group were significantly higher than the control group at 14%. In looking at the T12PR24 and T24PR48 arms more closely, patients who previously relapsed had higher SVR rates (69 and 76%) compared with patients with prior nonresponse (39 and 38%). Another Phase II study examined retreatment among patients who did not achieve SVR in the control arms of the other Phase II studies [30]. Known as the 107 study, this open-label, nonran- domized trial was conducted in 28 sites in North America and Europe and had the benefit of the virological results from the previous studies, to aid characterization of patients in terms of nonresponder or relapser status. The initial plan for treatment was 12 weeks of the triple regimen; telaprevir, peg-IFN- and ribavirin, followed by 12 more weeks of peg-IFN- and ribavirin. During the study, the protocol was amended to extend the peg- IFN- and ribavirin course to a 48-week regimen for patients with previous null response. Patients with prior partial response, viral breakthrough or relapse were assigned to the 24-week regi- men if they had undetectable HCV RNA levels at weeks 4 and 12, or the 48-week regimen if they had detectable HCV RNA at week 4 or 12. Overall, the SVR rate was 59% (69/117). When evaluated according to prior treatment response, the rates were 37% (19/51) in prior null responders, 55% (16/29) in partial responders, 75% (6/8) in prior viral breakthroughs and 97% (28/29) in relapsers. PROVE-3 and the 107 study established the role for telaprevir in improving the likelihood of SVR for prior treatment failure patients but also noted the disparity between nonresponders and relapsers. Phase III studies of telaprevir for chronic HCV infection The Phase III program for telaprevir included three international trials. Two of these studies, ADVANCE and ILLUMINATE, enrolled genotype 1 patients who had not been previously treated, and REALIZE enrolled genotype 1 patients who had failed peg-IFN- and ribavirin treatment [17,18,20]. The ADVANCE trial was a randomized, double-blind, pla- cebo-controlled trial of 1088 patients with HCV genotype 1 infection and who had received no previous treatment for the infection [17]. A major question addressed by the study was the optimal duration of telaprevir therapy. The two telaprevir arms had either 8 weeks (T8PR) or 12 weeks (T12PR) of telaprevir in combination with peg-IFN- and ribavirin followed by con- tinued therapy with peg-IFN- and ribavirin. The other major question was the role of response-guided therapy. If patients had undetectable HCV RNA at weeks 4 and 12, the total treatment course was 24 weeks versus 48 weeks if they had slower virologic response. Overall, both the T12PR and T8PR groups had higher SVR when compared with the control group of peg-IFN- and ribavirin (75 and 69%, respectively, vs 44%). Both telaprevir arms were statistically significantly higher (p < 0.001) for the comparison to the control arm. The study also demonstrated the success of the 24 week duration for patients undetectable HCV RNA at week 4 and 12 with SVR rates of 89% in the T12PR group and 83% in the T8PR group. In comparison, patients with detectable HCV RNA at weeks 4 or 12 had SVR rates of 54% in the T12PR group and 50% in the T8PR group with 48 weeks of therapy. In addition, subgroup analysis demonstrated that groups with historically low response rates to treatment benefited from the addition of telaprevir. These results are summarized in TABLE 3. The other Phase III naive study was called ILLUMINATE and was a randomized, open-label trial in 540 treatment-naive patients [31]. The main research question for this study was the optimal duration of peg-IFN- and ribavirin following the triple combina- tion of telaprevir, peg-IFN- and ribavirin. All patients received 12 weeks of the triple combination. Patients who experienced extended rapid virological response (eRVR; undetectable HCV RNA at weeks 4 and 12) were then randomized to 12 (T12PR24) or 36 (T12PR48) more weeks of peg-IFN- and ribavirin. Patients who did not achieve eRVR received the T12PR48 course. The SVR rate for all subjects enrolled in the trial was 74%. Among patients who did not achieve eRVR and received the T12PR48 course, the SVR rate was 64%. Of the 322 (60%) subjects who achieved eRVR and were randomized, the SVR rates were similar at 92% (T12PR24) and 90% (T12PR48), respectively. As a result, this study confirmed that the 24-week regimen was adequate for patients with strong initial response to treatment. REALIZE was a randomized, double-blind, placebo-controlled trial conducted in 663 subjects who did not achieve SVR with peg-IFN- and ribavirin [18]. The study population included relaps- ers and nonresponders, the nonresponders were further divided into prior partial responders and prior null responders. In addition to learning more about the treatment-experienced population, the major research question for this study was the role of a lead-in ther- apy. The regimen for the other recently approved protease inhibitor, boceprevir, includes 4 weeks of lead-in therapy with peg-IFN- and ribavirin prior to starting the protease inhibitor. In addition to the control group of peg-IFN- and ribavirin, patients were random- ized to receive telaprevir, peg-IFN- and ribavirin for 12 weeks followed by peg-IFN- and ribavirin for an additional 36 weeks (T12PR48); or 4 weeks of peg-IFN- and ribavirin lead-in followed by 12 weeks of the triple combination and then an additional 32 weeks of peg-IFN- and ribavirin (lead-in T12PR48). SVR rates are summarized in TABLE 4 and demonstrate no clear advantage for the lead-in strategy. Once again, prior relapsers had the highest rates of SVR, while patients with prior null response had approximately 30% chance of SVR. One question that has emerged is the role of the rs12979860 genotype or IL-28B genotype in the outcome of treatment in combination with telaprevir. The IL-28B genotype was origi- nally found among patients treated with peg-IFN- and riba- virin. This remains important given the role of peg-IFN- and ribavirin in the successful treatment with telaprevir. The IL-28B genotype was evaluated in a subset of Caucasian patients in the ADVANCE trial, and the results are displayed in TABLE 5. While it appears that CC patients continue to have the highest response rates to treatment, all IL-28B genotype groups have much higher response rates compared with standard of care. Similar results are observed among patients from the REALIZE trial in TABLE 5. Another way to examine this question is to look at patients who achieved RVR, as these patients have demonstrated IFN- responsiveness. Among patients in the ADVANCE study achiev- ing RVR, 206 out of 246 (84%) achieved SVR compared with 32/34 (94%) receiving peg-IFN- and ribavirin [17]. These results have raised questions as to whether such patients need the addi- tion of a protease inhibitor given the cost of the medications. Few patients achieve RVR with peg-IFN- and ribavirin, and patients receiving telaprevir received only 24 weeks of treatment compared with 48 weeks with peg-IFN- and ribavirin. A meta-analysis [31] reported reasonable result rates with 24 weeks of peg-IFN- and ribavirin for genotype 1 patients with low viral load. The optimal approach for these interferon- responsive patients needs further study and likely economic analysis. Safety & tolerability Treatment with telaprevir combination carries risk of considerable side effects, with many related to the backbone of peg-IFN- and ribavirin including: influenza-like symptoms, fatigue, bone marrow suppression, hemo- lytic anemia, thyroid dysfunction and neuropsychiatric symptoms including depression [4]. In addition, a number of new adverse events are contributed by telaprevir. The common adverse events in the ADVANCE trial are listed in TABLE 6. Beyond the common peg-IFN- and ribavirin adverse events, telaprevir brings added risk of rash, anemia and anorectal symp- toms. The combination was generally well tolerated in comparison to peg-IFN- and ribavirin. In the ADVANCE trial, 10% of the patients in the T12PR group and 7% in the control group discontinued all treatment at some time during the study due to adverse events [17]. Discontinuation of telaprevir/placebo in the ADVANCE trial was 11% in the T12PR group and 1% in the control group. In the initial Phase I combination study, five of 12 patients developed rash within the first 4 weeks [26]. In the Phase II stud- ies, severe rashes were reported leading to discontinuation of all treatment [27,28]. In the Phase III studies, 56% of patients devel- oped rash with the telaprevir combination regimen. Severe rash was defined as generalized rash or rash with vesicles, bullae or ulcerations and occurred in 4% of patients receiving the tela- previr combination compared with 1% among patients receiv- ing peg-IFN- and ribavirin. The severe rash was noted to be eczematous. A rash management plan was developed for the Phase III studies in which telaprevir was discontinued in the event of significant rash and this led to less events of discontinuation of all treatment. In the ADVANCE study, 7% of patients in the T12PR group discontinued telaprevir due to rash, but only 1.4% discontinued all treatment due to rash [17]. Among all patients treated with telaprevir, less than 1% developed Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) and Stevens– Johnson syndrome [20]. These reports highlight the need for close monitoring of rash during treatment. If a patient develops a rash during telaprevir combination treat- ment, mild-to-moderate rashes should be followed closely. Good skin hydration is recommended. Oral antihistamines and topi- cal corticosteroids may improve symptoms but systemic cortico- steroids are not recommended. If the rash progresses and becomes severe or if systemic symptoms develop, telaprevir should be dis- continued. Peg-IFN- and ribavirin may be continued, but the patient should continue to be monitored. If improvement is not observed within 7 days of stopping telaprevir, discontinu- ation of ribavirin should be considered. If telaprevir is discontinued due to rash, it should not be restarted. Dose reduction is never appropriate in managing a telaprevir adverse event. Anemia is common with HCV therapy due to the bone marrow suppression of peg-IFN- and the hemolysis from ribavi- rin [4]. A recent genome-wide-association study reported polymorphisms associated with inosine triphosphatase (ITPA) defi- ciency protected against anemia [32]. ITPA deficiency is a benign red cell enzymopa- thy characterized by the accumulation of ITP in erythrocytes and increased toxicity of purine analogue drugs. Reduced ITPA activity has been reported with a mis- sense variant in exon 2 (rs1127354) and a splicing-altering SNP located in the second intron (rs7270101). Further studies have suggested that ITP confers protection against ribavirin-induced ATP reduction by substituting for erythrocyte GTP, which is depleted by ribavirin in the biosynthesis of ATP [33]. The addi- tion of telaprevir is associated with increased rates of anemia, although the mechanism is unknown [20]. Recent studies with rs1127354 have reported that patients with the ribavirin-sen- sitive polymorphism (CC) had significantly lower hemoglobin levels as early as week 2 and required ribavirin dose reductions earlier during treatment when compared with patients with the ribavirin-resistant ITPA genotypes [34,35]. In the clinical stud- ies, hemoglobin less than 10 g/dl occurred in 36% of patients receiving the telaprevir regimens compared with 17% of patients receiving peg-IFN- and ribavirin. Anemia was the reason for discontinuation in 4% of patients receiving telaprevir compared with 1% of patients receiving peg-IFN- and ribavirin. Anemia led to dose modification in 32% of patients receiving telaprevir compared with 12% of patients receiving peg-IFN- and riba- virin. In the clinical studies, anemia was effectively managed through dose reduction of ribavirin and peg-IFN-. Use of erythropoietin-stimulating agents was not allowed in the clini- cal trials. In the event ribavirin is permanently discontinued, telaprevir should be discontinued due to the poor treatment outcomes and increased resistance without ribavirin. A variety of anorectal signs and symptoms were reported in the clinical studies including: hemorrhoids, anorectal discomfort, anal pruritus and rectal burning. These events occurred in 29% of subjects in the telaprevir groups compared with 7% of those treated with peg-IFN- and ribavirin. These events were gener- ally mild to moderate in severity and rarely led to treatment dis- continuation. The etiology for these symptoms is unknown [20]. Regulatory affairs Telaprevir is currently approved in the USA for combination therapy with peg-IFN- and ribavirin for genotype 1 patients who are treatment naive or failed prior treatment. Telaprevir has also recently gained regulatory approval in the EU. Conclusion Treatment with telaprevir in combination with peg-IFN- and ribavirin offers a remarkable step forward for patients with genotype 1 infection. This combination has led to substantial increases in SVR rates for a number of patient groups. The highest response rates are observed in treatment-naive and prior-relapse patients and these patients are eligible to receive 24 weeks of treatment in a response-guided algorithm. Patients with compensated cirrhosis have substantial increases in SVR rates as well but may benefit from 48 weeks of treatment. Patients with prior-partial response and especially prior null response have lower response rates to telaprevir combination treatment. Patients who fail the telaprevir combination treat- ment have the risk of developing drug-resistant viral infection. Although most of these patients return to the wild-type as the dominant strain, the long-term implications of resistance development and the effect on future treatment regimens are unknown and will need to be studied. Telaprevir is an inhibitor of the cytochrome P450 enzyme 3A, and drug– drug interactions have led to a number of contraindications and precautions. Providers will need to review concomitant medications in detail before prescribing telaprevir. Treatment with the telaprevir combination carries the well-known adverse events of peg-IFN- and ribavirin but brings additional ane- mia and rash. The development of mild-to-moderate rash is common with the telaprevir combination and providers will need to monitor these patients closely to monitor for progres- sion to severe rash that requires discontinuation of telaprevir. Although rare, DRESS and Stevens–Johnson syndrome have been reported. These new algorithms, drug–drug interac- tions, resistance and adverse events will be the challenges to providers successfully prescribing treatment with telaprevir combination. Patients will need to be educated on their role in adherence to avoid resistance and maximize likelihood of successful treatment. Expert commentary The addition of both boceprevir and telaprevir to the armamentar- ium for HCV treatment is a landmark time for the field. Both these medications lead to substantial increases in SVR overall for patients with HCV infection and we are unlikely to see such a dramatic increase in response rates again. The improved response rates for a number of groups with traditionally low response rates, including African–Americans and patients with cirrhosis, are very important. While there is reason for enthusiasm for many patients, these medications will not be the final solution to HCV treatment due to some inherent weaknesses. They are dosed three times daily, which will be challenging for many patients. These medications also have no role in monotherapy due to the risk of resistance, and it was disappointing to learn that they required not only peg-IFN- but also ribavirin to be effective. As a result, the side effects of these medications remain an issue for patients under- going treatment. In addition, many patients are not candidates for treatment due to their contraindications to peg-IFN- and ribavirin. Patients with significant psychiatric disease, decompen- sated cirrhosis and renal failure have no options for treatment at this time. Concerns about drug–drug interactions have become heightened with the finding of dramatic increases in cyclospo- rine and tacrolimus exposure when administered with telaprevir. Recurrent HCV following liver transplantation remains a major clinical challenge with poor response rates to peg-IFN- and ribavirin, and telaprevir will not be an easy solution there. These results from the telaprevir program only continue to highlight the segmentation of patients with HCV infection. Patients are clearly separated into those who are more or less dif- ficult to treat. The requirement for peg-IFN- in the combina- tion with telaprevir highlights the role of the IL-28B genotype. With telaprevir combination, we now see impressive response rates among treatment-naive and prior relapsers but disappoint- ing results among null responders. Null responders are one of the major challenges for this field. Although potent direct-acting antivirals are under investigation, these medications will not be available soon. In the meantime, clinicians will need to work with the medications available. Null responders have the lowest response rates and the highest risk of resistance. We can expect many null responders, especially those with advanced fibrosis, to receive treatment with protease inhibitors. With the unknown clinical impact of the development of resistance, null responders with early fibrosis should perhaps consider deferring therapy until more potent therapies are available. The other challenge for this field is the complexity of the treat- ment regimen. Boceprevir and telaprevir have different response- guided therapy algorithms with varying treatment durations and different futility rules. Resistance is a new phenomenon to most HCV providers. These medications also carry new concerns about drug–drug interactions and adverse events including rash with telaprevir. One concern will be if some previous providers of peg-IFN- and ribavirin will want to participate in treatment with protease inhibitors. Another concern is the quality of HCV treatment. In the era of peg-IFN- and ribavirin, analyses of quality of care are rather alarming, with poor compliance with treatment algorithms [36]. The additional complexity of these protease inhibitor algorithms will require new approaches for more successful treatment. Five-year view In the next few years, we can anticipate refinements in the use of the current medications and continued development of other direct-acting antivirals for patients with genotype 1 infection. These changes will likely take place within the segmentation of the patient population. This current segmentation is largely defined by responsiveness to IFN-, which can also be catego- rized according to the IL-28B genotype. For IL-28B CC patients or those who are responsive to IFN-, the optimal regimen is unclear. These patients may not need a protease inhibitor to achieve reasonable response rates. They may instead require shorter durations of IFN- with the current protease inhibitors or will perhaps respond well to initial attempts at all oral regi- mens. Null responders will remain the most challenging group of patients while IFN- is part of the regimen, these patients need more potent direct-acting antivirals to achieve reasonable response rates. The ultimate goal for HCV treatment is oral regimens that avoid the side effects of peg-IFN- but these regimens are a number of years away. The proof-of-concept study that SVR was possible with an all oral regimens was presented at the 2011 International Liver Congress. In this study of prior null respond- ers, four of eleven patients achieved SVR when treated with a protease inhibitor and an NS5A inhibitor [37]. This small study also demonstrated that most patients did not respond to the oral combination and all null responders achieved SVR with a quadru- ple therapy regimen made up of the two direct-acting antivirals plus peg-IFN- and ribavirin. This study provides a reasonable road map with quad regimens initially but later combinations of multiple oral medications to achieve high SVR rates. Information resources In addition to the manuscripts from the key studies highlighted in this review, guidelines have been developed by two major societies: • American Association for the Study of Liver Diseases (www. aasld.org) • European Association for the Study of the Liver (www.easl.eu) Financial & competing interests disclosure AJ Muir has served as a consultant and also received research grants from Vertex Pharmaceuticals. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Key issues • Telaprevir is available orally and was designed to target the NS3 protease for genotype 1 chronic hepatitis C infection. • Telaprevir was approved in combination with peg-IFN- and ribavirin for treatment-naive and treatment-experienced patients. • Telaprevir monotherapy leads to HCV resistance within the first 2 weeks. • The recommended dose of telaprevir is 750 mg every 8 h, no dose reductions are recommended. If telaprevir is discontinued, it should not be restarted. • Patients receive 12 weeks of triple combination of telaprevir, peg-IFN- and ribavirin followed by 12–36 weeks of peg-IFN- and ribavirin. • Treatment-naive patients and previous relapsers are eligible for 24 weeks of therapy in a response guided therapy algorithm. • Previous partial responders, null responders and patients with cirrhosis require 48 weeks of treatment. • Side effects related to peg-IFN- and ribavirin are common with telaprevir along with increased rates of rash, anemia and anorectal symptoms. • Mild-to-moderate rash is common in the telaprevir combination regimen, and patients need to be monitored closely to discontinue telaprevir if the rash becomes severe. 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