Telaprevir: A novel, protease inhibitor for the treatment of hepatitis C virus

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Chronic hepatitis C virus affects more than 170 million people worldwide and is the most common chronic blood-borne infection in the United States. Telaprevir is a member of a new class of specifically targeted antiviral therapies for HCV.

Key Points

Abstract

The World Health Organization estimates that about 3% of the world's population, approximately 130 to 210 million people, has been infected with hepatitis C virus (HCV) and that 170 million people are chronic carriers.1 In the United States, HCV infection is the most common chronic blood-borne infection, accounting for 60% to 70% of chronic hepatitis cases.2 Chronic HCV infection can lead to serious complications such as cirrhosis, liver failure, and hepatocellular carcinoma. HCV is becoming a major healthcare challenge; the costs associated with the disease and its complications are staggering, with an estimated $10.7 billion in direct medical expenditures for HCV between 2010 and 2019.3

The current standard of care for chronic HCV infection is weekly administration of pegylated interferon (peginterferon) alfa in combination with daily ribavirin. Duration of treatment depends on the viral genotype-a 24-week course of combination therapy in patients with genotypes 2 and 3 versus a 48-week treatment course for patients with genotype 1. Response rate to treatment is measured by sustained virologic response (SVR), which is defined as an absence of detectable HCV RNA 24 weeks after the end of treatment. SVR rates range between 70% and 80% in patients with genotypes 2 and 3 compared with 40% to 45% in patients with genotype 1. Patients who fail to achieve early virologic response (defined as ≥2 log decrease or better after 12 weeks of therapy) have a <3% chance of achieving SVR.4,5

The combination of peginterferon alfa and ribavirin is associated with significant side effects leading to delays in starting therapy, dose reductions, and early discontinuation. Major toxicities include flu-like symptoms, myelosuppression, neuropsychiatric disorders, primarily depression, and ribavirin-induced hemolytic anemia. Novel therapies that address these limitations are urgently needed.

Telaprevir (VX-950), a member of a new class of specifically targeted antiviral therapies for HCV, is a reversible, selective inhibitor of the HCV nonstructural (NS) 3-4A protease, an enzyme required for viral replication. The NDA for telaprevir was supported by data from 3 phase 3 studies, known as ADVANCE (A New Direction in HCV Care: A Study of Treatment-Naive Hepatitis C Patients with telaprevir), ILLUMINATE (Illustrating the Effects of Combination Therapy with Telaprevir) , and REALIZE (Re-treatment of Patients with Telaprevir-based Regimen to Optimize Outcomes). The drug was approved by FDA on May 23, 2011.

CHEMISTRY AND PHARMACOLOGY

HCV is an enveloped, single-stranded RNA virus. The viral genome encodes a precursor polyprotein that is processed by host and HCV proteases to release 10 individual viral proteins, 3 structural proteins (Core [C], E1, E2), and 7 NS proteins (p7, NS2-3, NS3, NS4A, NS4B, NS5A, and NS5B). The NS proteins are processed by 2 viral proteases, the NS2–3 protease and the NS3–4A serine protease. Proteolytic release of the NS proteins from the polyprotein is essential for viral replication to occur, making them an attractive target for antiviral drug development.4,6

Resistance to antiviral drugs is inevitable because of the error-prone nature of the RNA-dependent RNA polymerases. In vitro and in vivo resistance mutations against telaprevir have been identified. This resistance is caused by specific mutations in the viral enzyme.

The combination of telaprevir and peginterferon alfa-2a inhibited resistant variants in patients with a viral rebound on telaprevir alone.7-9

PHARMACOKINETICS

Animal studies demonstrate that telaprevir is orally available, with a half-life of 0.8 to 3.2 hours. It undergoes first-pass metabolism, resulting in higher concentrations in the liver than in plasma.10 The pharmacokinetic parameters of telaprevir have been evaluated in healthy volunteers, in patients with mild or moderate hepatic impairment, and in patients with renal impairment, but none of these studies has been published.

Telaprevir is approximately 59% to 76% bound to plasma proteins, and it has a large apparent volume of distribution. Telaprevir maximum concentration and area under the curve increase after multiple dosing. When administered as 750 mg every 8 hours, steady state was reached after 3 to 7 days, and the half-life was approximately 9 to 11 hours. Drug absorption and therefore exposure increases with food; systemic exposure was increased by 237% when telaprevir was administered with a standard fat meal compared to dosing under fasting state. The type of meal also effects exposure with an increase of 117% with low fat meal versus 330% with a high fat meal relative to fasting.11

Telaprevir is a substrate and inhibitor of CYP3A and a substrate of P-glycoprotein (P-gp). Hepatic metabolism is a major route of telaprevir elimination; it is extensively metabolized through CYP3A4 oxidation to its weak and inactive metabolites.12

Elimination in the feces is the predominant route of excretion for telaprevir and its metabolites, with minimal renal excretion. The results of a single-dose (750 mg) pharmacokinetic study in subjects with severe renal impairment showed an increase in telaprevir exposure by 21%, which was not considered clinically significant.13 Steady state exposure was reduced by 15% in subjects with mild hepatic impairment and by 46% in subjects with moderate hepatic impaiment compared to healthy volunteers.11 The pharmacokinetics of telaprevir are not affected by sex, age, race, or body weight.

CLINICAL TRIALS

The ADVANCE study included treatment-naïve subjects with HCV genotype 1 infection who were stratified based on HCV RNA (<800,000 IU/mL and >800,000 IU/mL) and genotype (1a vs 1b) into 1 of 3 treatment arms. Randomization occurred in a 1:1:1 ratio to the following treatment arms:

(a) T12PR: telaprevir (T) plus peginterferon alfa-2a (P) plus ribavirin (R) for 12 weeks followed by an additional 12 to 24 weeks of PR depending on whether the patient achieved eRVR;

(b) T8PR: TPR for 8 weeks followed by 4 weeks of placebo plus PR followed by an additional 12 to 24 weeks of PR depending on whether the patient achieved an eRVR;

(c) Control group: PR for 48 weeks.

Patients who achieved eRVR received therapy for a total of 24 weeks whereas those who did not achieve eRVR received therapy for a total of 48 weeks. The primary end point was SVR.

SVR was significantly greater in the T12PR (75%) and T8PR (69%) arms versus the control arm (44%). The difference between the 12-week and 8-week telaprevir-based combination regimens was not statistically significant. More patients who received telaprevir-based therapy achieved eRVR (58% in T12PR and 57% in T8PR) than those in the control arm (8%). Similarly, the T12PR group had higher rates of SVR among all races and fibrosis stages compared with the other 2 arms. The relapse rate in the telaprevir-based arms (8%) was much lower than in the control arm (28%).15

ILLUMINATE, the second phase 3 trial, was designed to evaluate the duration of therapy in treatment-naïve patients with the HCV genotype 1 who achieved eRVR. All patients enrolled in the study received TPR for the first 12 weeks followed by PR. Patients achieving eRVR were randomized in a 1:1 ratio at week 20 to receive a total 24 or 48 weeks of therapy whereas patients who did not achieve eRVR received 48 weeks of total therapy. A total of 540 patients were enrolled using an intent-to-treat analysis with the primary end point of SVR.

Overall, 65.2% of patients achieved eRVR. Patients who achieved eRVR and received 24 weeks of therapy had a noninferior SVR compared with those who received 48 weeks of therapy, 92% versus 87.5%. Patients who did not achieve eRVR had an SVR of 64%. Overall SVR, however, was 71.9% based on early response-driven treatment plans.16

REALIZE, the third phase 3 trial, evaluated the efficacy and safety of telaprevir in patients with HCV genotype 1 who did not achieve SVR on previous peginterferon alfa-2a and ribavirin therapy. Patients were stratified by HCV RNA level and previous response (relapse, partial response, null response) in a 2:2:1 ratio to 1 of 3 arms. The first arm, with no lead-in phase, was TPR for 12 weeks, followed by 4 weeks of placebo plus PR, and then 32 weeks of PR. The second arm, including a lead-in phase, was placebo plus PR for 4 weeks, TPR for 12 weeks, and then 32 weeks of PR. The control arm regimen consisted of placebo plus PR for 16 weeks followed by 32 weeks of PR. The primary objective was to evaluate the SVR rates with telaprevir-containing therapy based on previous response.

Primary data show that previous relapsers had a SVR rate of 83% in the no lead-in arm, 88% in the lead-in arm, and 24% in the control arm. Nonresponders (partial response or null response) had an SVR rate of 41%, 41%, and 9% in the no lead-in arm, lead-in arm, and control arm, respectively. SVR rates are significantly higher with telaprevir-containing regimens in patients with previous treatment failure. In addition, higher SVR rates were seen with the telaprevir-containing regimen in a subanalysis of patients grouped by HCV subtype and baseline fibrosis stage. On-treatment virological failure in the telaprevir-containing arm was seen mostly in previous nonresponders rather than in those who had relapsed. A secondary end point was to determine the impact of PR lead in before initiation of telaprevir. The study found no difference in SVR rate, virological failure, or relapse rate between the lead-in and no lead-in groups (66% vs 64%).17

Of note, a phase 2 open-label study explored the efficacy and safety of telaprevir administered every 12 hours (q12h) compared with every 8 hours (q8h). Treatment-naïve patients received either telaprevir 750 mg q8h or 1,125 mg q12h with standard-dose PR for 12 weeks followed by 12 to 36 weeks of PR depending on their eRVR. No difference was noted in the SVR rate between the q8h (82.9%) and q12h (82.3%) groups (P=.997). A phase 3 trial is further examining the dosing intervals.18

ADVERSE EVENTS

Full manuscripts of the phase 3 trials have not yet been published, but given the larger patient population in these trials, they will likely provide additional insight into adverse events expected during the telaprevir phase of the triple-combination therapy regimen (telaprevir, peginterferon, and ribavirin). Until the detailed data from the phase 3 trials are available, results of the phase 2b PROVE trials published in The New England Journal of Medicine provide the most comprehensive information on adverse events.

Rash and pruritus. Rash is the main adverse effect noted in clinical trials, occurring in roughly half of patients (52%, 389 of the 755 patients receiving telaprevir in the phase 2b PROVE trials). In 5.2% (39 of 755) of patients, the rash was categorized as grade 3 (severe) compared to 0.4% (1 of 271) of patients receiving the standard of care. The rashes noted in the PROVE trials were maculopapular and classified as those typically observed in drug-induced reactions.19-21 The median time to rash appearance was between 9 and 12 days in PROVE 2 and 7 and 28 days in PROVE 3.20 The FDA advisory committee briefing document on telaprevir states that a dermatology expert panel (DEP) observed the rashes to be indistinguishable from a peginterferon/ribavirin rash. In addition, the DEP noted that rashes involved less than 30% of the body surface area and were primarily pruritic and eczematous, and not consistent with a typical hypersensitivity reaction. The DEP also noted that telaprevir-induced rashes were both clinically and histologically different from common drug rashes. Telaprevir-induced rashes were greater in severity, occurred at any time during treatment, and took weeks to resolve after drug discontinuation.12 The mechanism leading to the rash has not been identified.

After it became apparent in PROVE 1 that rash was a main factor in discontinuation of telaprevir, guidelines for the categorization of grade 3 and 4 rashes and management of the rash were incorporated into all clinical trials. Medical management of the rashes included steroids and antiallergic agents.19-21 Pooled data from phase 2 and 3 trials in the telaprevir briefing document indicate that 77% of patients were prescribed a medication for rash treatment. This included 53.7% receiving topical steroids, 39.5% receiving systemic antihistamines, and 6.2% requiring systemic corticosteroids.12

Of note, a case report published in Dermatology documents a drug rash with eosinophilia and systemic symptoms (DRESS) attributed to telaprevir.22 The patient was enrolled in the control group of PROVE 2, was treated with peginterferon alfa-2a and ribavirin for 12 months, and then 7 months later enrolled in a phase 2 rollover study, which included treatment with telaprevir, peginterferon alfa-2a, and ribavirin. Six weeks later, the patient developed a generalized pruritic maculopapular exanthema with malaise, fever, dyspnea, and lymph node swelling. Symptoms resolved within a month after treatment with topical and oral steroids. The DEP also identified 11 cases suggestive of DRESS and 3 suggestive of Stevens-Johnson syndrome. One of these 3 cases was considered definite for Stevens-Johnson syndrome, but it was not classified as drug-related because it occurred 11 weeks after the last dose of telaprevir.12

Pruritus was also a common occurrence in clinical trials. Approximately 45% (342 of 755) of patients experienced pruritus in the PROVE trials, either concurrently with rash or in the absence of rash.19-21 Like the rash associated with telaprevir, pruritus regressed after withdrawal of the drug.12

Anemia. Anemia is the other clinically significant adverse event associated with the use of telaprevir. Patients receiving telaprevir had a 23% (171 of 755) incidence of anemia compared with 16% (43 of 271) of control patients in the PROVE trials.19-21 In PROVE 1, the hemoglobin for the control group declined by 3 g/dL at week 12 (end of administration of telaprevir), and in patients receiving telaprevir, it declined an additional 0.5 to 1.0 g/dL.19 The FDA briefing document on telaprevir reports a 44-day median time to onset and 85-day median duration of anemia. The incidence of anemia was greatest during the second month of therapy. In combined data from phase 2 and 3 trials, hemoglobin nadir levels below 8.5 g/dL occurred in 8.3% of patients receiving telaprevir compared with 2.3% of patients receiving the standard of care.12 Treatment of anemia with ribavirin dose reductions was allowed; in the clinical trials, however, use of erythropoietin-stimulating agents was not permitted during the first 12 weeks when patients were receiving telaprevir. After the telaprevir phase of the regimen was over, hemoglobin levels increased and were similar to the levels in the control group for the remainder of the regimen.19 The FDA briefing document suggests that telaprevir may be associated with a mild bone marrow suppressive effect that resolves on drug discontinuation.12

Anemia led to discontinuation of therapy in 1.17% (6 of 514) of patients receiving telaprevir compared with 0.53% (1 of 189) in the control group during the PROVE 1 and 3 trials.19,21 Treatment discontinuation at a higher rate in the telaprevir group compared with the control group due to anemia is consistent with available data from the phase 3 clinical trials.15-17 The briefing document for telaprevir reports a higher treatment discontinuation rate of 2.7% in telaprevir patients compared with 0.5% of patients receiving standard of care when results from some of the phase 3 trials were added in. The telaprevir package insert recommends monitoring patients on a telaprevir-containing regimen for anemia prior to and at least every 4 weeks during therapy.11 Because telaprevir is given for only 12 weeks, it is unclear whether there will be a role for erythropoietin-stimulating agents, especially considering that the anemia resolves on treatment discontinuation.

DRUG INTERACTIONS

Only limited published data regarding drug-drug interactions are available. Given that telaprevir is categorized as a substrate of CYP3A and P-gp and is an inhibitor of CYP3A, the potential for a wide range of drug-drug interactions exists between substrates, inducers, and inhibitors of these systems. A significant impact of telaprevir on other liver isoenzymes besides CYP3A has not been identified.12

Data from a study presented at the 2011 Conference on Retroviruses and Opportunistic Infections demonstrated that there were drug interactions between telaprevir and all of the ritonavir-boosted protease inhibitors (combinations of ritonavir with atazanavir, darunavir, fosamprenavir, and lopinavir), which are substrates and inhibitors of CYP3A4. Atazanavir had the least impact on telaprevir metabolism compared with the other protease inhibitor and ritonavir combinations. The abstract also included data regarding efavirenz, an inducer of CYP3A4, administered with higher doses of telaprevir to overcome the drug-drug interaction. The authors concluded that higher doses, such as telaprevir 1,125 mg q8h, may be required to offset the interaction with efavirenz.23 Additional studies and dosing recommendations will be essential to ensure safe use of telaprevir, avoid significant drug-drug interactions, and ensure that the clinical benefit of telaprevir is maintained.

The recently available prescribing information in the package insert for telaprevir states that telaprevir is contraindicated when co-administered with medications that are highly dependent on CYP3A for clearance and where elevated plasma concentrations are associated with serious and/or life-threatening events, or medications that strongly induce CYP3A which may result in lower exposure and loss of efficacy of telaprevir. Specific medications referenced include: alfuzosin, rifampin, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, St. John's wort, atorvastatin, lovastatin, simvastatin, pimozide, sildenafil, tadalafil, oral midazolam and triazolam. Extensive tables addressing the established and potentially significant interactions with telaprevir are included in the package insert.11

DOSING AND ADMINISTRATION

Telaprevir (Incivek) is formulated as a 375-mg film-coated tablet and is best administered with food for improved absorption.11 Consistent with the dosing used in the three phase 3 trials, telaprevir, for the treatment of patients with chronic HCV genotype 1, is approved to be dosed at 750 mg (two 375-mg tablets) 3 times a day orally for 12 weeks only when used in combination with peginterferon alfa-2a 180 µg/wk injection, and ribavirin 1,000 to 1,200 mg/d orally based on body weight (1,000 mg/d for body weight <75 kg and 1,200 mg/d for body weight ≥75 kg), with the latter 2 medications continued for a total treatment duration up to 48 weeks.11,15-17 Based on early results from a phase 1 trial using telaprevir as monotherapy, in which selection of viral mutants with decreased sensitivity to telaprevir was found, treatment with telaprevir as monotherapy is not recommended.24

The phase 3 trial ILLUMINATE provided the basis for the recommendation for treatment response- guided therapy. Results from ILLUMINATE support the need to check viral status at week 4 and 12 and determine whether treatment-naïve and prior-relapse patients will benefit from a shorter 24-week duration of total therapy if the HCV-RNA is undetectable.16 Patients who do not achieve early undetectable viral levels (HCV-RNA of 1,000 IU/mL or less at week 4 or 12) or are prior partial and null responders qualify for the full 48-week therapy duration. In addition, it is recommended to discontinue the triple therapy regimen at week 4 or 12 if the HCV-RNA is greater than 1,000 IU/mL or discontinuation of peginterferon and ribavirin at week 24 if HCV-RNA is detectable.11

Of note, a shorter 8-week duration of telaprevir therapy in the ADVANCE trial had a better response rate compared with the control arm, but the best results were achieved with 12 weeks of telaprevir.15 In clinical practice, use of the shorter regimen may be necessary in patients who are unable to tolerate the potential adverse events from this medication, however consistent with many of the clinical trials, telaprevir was approved for 12 weeks of therapy.

Also investigated in clinical trials was an alternative dosing regimen of 1,125 mg twice daily in a small study (n=161).18 Theoretically, twice-daily dosing would have the potential for better patient compliance and less development of resistance. The trial demonstrated no difference in SVR rates between the 2 groups and comparable adverse events. With further clinical data, this may be an alternative dosing regimen option.

Due to the hepatic metabolism of telaprevir and the exclusion of patients with severe hepatic impairment from clinical trials, the FDA approval recommends against use of telaprevir in patients with Child-Pugh score greater than or equal to 7 as safety and efficacy has not yet been established. In addition, the safety and efficacy has not been established in pediatrics or in patients undergoing solid organ transplant. Adjustments for renal insufficiency are not necessary, although the medication has not been studied in patient with a creatinine clearance less than 50 mL/min. A dosing regimen for patients coinfected with HIV and specific recommendations for dose adjustments with concomitant CYP3A4 inhibitors, inducers, and substrates are not available at this time. Telaprevir has a pregnancy category rating of B. However, the triple drug therapy regimen with peginterferon alfa and ribavirin has a pregnancy category of X.11

Use of telapavir in patients infected with genotypes other than type 1 will require further evaluation in clinical trials. Some data suggest that telaprevir has some activity against genotype 2 and potentially type 4 and limited activity against type 3.25,26 Data for type 5 and 6 are not available. Therefore, the standard of care for treatment of all non-type 1 HCV will likely remain a combination of peginterferon alfa and ribavirin until further data are available.

FORMULARY CONSIDERATIONS

The telaprevir approval will likely change the current standard of care for HCV genotype 1 infection. The advantages of telaprevir include specifically targeting the virus, potential to decrease treatment duration, and proven efficacy in treatment-naïve patients and those who have not responded to previous therapies. Telaprevir was well tolerated in clinical trials; however, clinically significant side effects include rash, pruritus, and anemia. Unfortunately, this will potentiate the adverse events associated with peginterferon and ribavirin. Appropriate strategies will need to be used to manage these adverse events and avoid early treatment discontinuation and, therefore, avoid poor outcomes. Telaprevir is a substrate of the CYP3A isoenzyme and P-gp. As an inhibitor of CYP3A there is a potential for a wide range of drug-drug interactions. This is of concern in this patient population, who is often coinfected and use other medications metabolized by these systems. Telaprevir has a low genetic barrier for resistance, and optimal therapy will likely require use of multiple protease inhibitors, similar to HIV therapy. No clinical trials have yet evaluated the combination of protease inhibitors in the treatment of HCV infection. It is anticipated that telaprevir will be priced like other protease inhibitors on the market, which will significantly increase the cost of hepatitis therapy. This increase in cost may be offset by the potential for a decrease in duration of therapy. Also, an increase in response rate will reduce the number of patients requiring further treatment.

Finally, telaprevir will have to compete with other protease inhibitors for market share; boceprevir, which has a similar safety and efficacy profile, was approved by FDA on May 14, 2011. Formulary decisions will be influenced by price, patient-specific characteristics, and postmarketing safety reports. The efficacy of telaprevir in patients who have previously not responded to therapy with the protease inhibitors has not been established. F

Dr Patel is PGY-2 oncology pharmacy resident, Yale New Haven Hospital, New Haven, Conn. Dr Pauli is pharmacy clinical specialist, Yale New Haven Hospital. Dr Abdelghany is coordinator, Investigational Drug Service, Yale New Haven Hospital.

Disclosure Information: The authors report no financial disclosures as related to products discussed in this article.

In each issue, the "Focus on" feature reviews a newly approved or investigational drug of interest to pharmacy and therapeutics committee members. The column is coordinated by Robert A. Quercia, MS, RPh, medical editor, University of Connecticut/Hartford Hospital, Evidence-based Practice Center, Hartford, Conn., and adjunct associate professor, University of Connecticut School of Pharmacy, Storrs, Conn; and by Craig I. Coleman, PharmD, associate professor of pharmacy practice, University of Connecticut School of Pharmacy, and director, Pharmacoeconomics and Outcomes Studies Group, Hartford Hospital.

EDITORS' NOTE: The clinical information provided in "Focus on" articles is as current as possible. Due to regularly emerging data on developmental or newly approved drug therapies, articles include information published or presented and available to the author up until the time of the manuscript submission.

REFERENCES

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11. Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.

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13. Van Heeswijk R, Vandevoorde A, Boogaerts, et al. The effect of severe renal impairment on the pharmacokinetics of the investigational HCV protease inhibitor telaprevir. Presented at the 46th Annual Meeting of the European Association for the Study of the Liver; March 30-April 3, 2011. Berlin, Germany. Abstract # 1245.

14. Pawlotsky JM. The results of phase III clinical trials with telaprevir and boceprevir presented at the Liver Meeting 2010: a new standard of care for hepatitis C virus genotype 1 infection, but with issues still pending. Gastroenterology. 2011;140(3):746–754. Epub 2011 Jan 18.

15. Jacobson IM, McHutchison JG, Dusheiko GM, et al. Telaprevir in combination with peginterferon and ribaviron in genotype 1 HCV treatment-naïve patients: final results of phase 3 ADVANCE study. Hepatology. 2010;52(suppl):427A.

16. Sherman KE, Flamm SL, Afdhai NH, et al. Telaprevir in combination with peg-interferon alfa-2a and ribavirin for 24 or 48 weeks in treatment-naïve genotype 1 HCV patients who achieved an extended rapid viral response: final results of phase 3 ILLUMINATE study. Hepatology. 2010;52(suppl):401A.

17. Zeuzem S, Andreone P, Pol S, et al. REALIZE trial final results: telaprevir-based regimen for genotype I hepatitis virus infection in patients with prior null response, partial response or relapse to peginterferon/ribavirin. Presented at the 46th Annual Meeting of the European Association for the Study of the Liver; March 30-April 3, 2011. Berlin, Germany. Oral Presentations.

18. Marcellin P, Forns X, Goeser T, et al. Telaprevir is effective given every 8 or 12 hours with ribavirin and peginterferon alfa-2a or alfa2-2b in patients with chronic hepatitis C. Gastroenterology. 2010;140(2):459–468.

19. McHutchison JG, Everson GT, Gordon SC, et al; for the PROVE 1 Study Team. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med. 2009;360(18):1827–1838.

20. Hézode C, Forestier N, Dusheiko G, et al; for the PROVE 2 Study Team. Telepavir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med. 2009;360(18):1839–1850.

21. McHutchison JG, Manns M, Muir A, et al; for the PROVE 3 Study Team. Telaprevir for previously reated chronic HCV infection. N Engl J Med. 2010;362(14):1292–1303.

22. Montaudie H, Passeron T, Cardot-Leccia N, Sebbag N, Lacour JP. Drug rash with eosinophilia and systemic symptoms due to telaprevir. Dermatology. 2010;221(4):303–305.

23. van Heeswijk R, Vandevoorde A, Boogaerts G, et al. Pharmacokinetic interactions between ARV agents and the investigational HCV protease inhibitor TVR in healthy volunteers. Presented at the 18th Conference of Retroviruses and Opportunistic Infections. February 27-March 2, 2011; Boston, Massachusetts. Abstract No. 119.

24. Reesink HW, Zeuzem S, Weegink CJ, et al. Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase 1b placebo-controlled, randomized study. Gastroenterology. 2006;131(4):997–1002.

25. Benhamou Y, Moussali J, Ratziu V, et al. Results of a proof of concept study (C210) of telaprevir monotherapy and in combination with peginterferon alfa-2a and ribavirin in treatment-naïve genotype 4 HCV patients. J Hepatol. 2009;50(suppl 1):S6.

26. Foster GR, Hezode C, Bronowicki JP, et al. Activity of telaprevir alone or in combination with peginterferon alfa-2a and ribavirin in treatment-naïve genotype 2 and 3 hepatitis C patients: interim results of study C209. J Hepatol. 2009;50(suppl 1):S22.

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