Case 2: Emerging Therapeutic Options in Hepatitis C Virus Infection (CE)

Physician Credit

Accreditation Statement

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the University of Cincinnati. The University of Cincinnati is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation

The University of Cincinnati designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

If you have any questions, please contact Deborah Cole - coledr@uc.edu at 513-558-2016.

Pharmacy Credit

Pharmacy Times Office of Continuing Professional Education is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. This program is approved for 1.0 contact hour (0.1 CEU) under the ACPE universal program number of 0290-9999-11-026-H01-P. This program is available for CE credit through April 8, 2012.

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This activity is supported by an educational grant from Merck & Co, Inc.

Case 2: Emerging Therapeutic Options in Hepatitis C Virus Infection

F red Poordad, MD

Department of Medicine

CedarsSinai Medical Center

Los Angeles, California

Fred Poordad has disclosed the following:Consultant/advisory board: Abbott, Achillion, Anadys, Gilead, Merck, Novartis, Pfizer, Vertex; Grants: Abbott, Achillion, Anadys, Bristol-Myers Squibb, Gilead, Merck, Novartis, Pfizer, Pharmasset, Vertex; Lecturer: Gilead, Roche; Speakers’ Bureau: Gilead, Roche, Vertex The planning staff from the University of Cincinnati, The American Journal of Managed Care, and the Pharmacy Times Office of Continuing Professional Education have no relevant financial relationships to disclose.

Activity Overview

This activity discusses the efficacy of standard-of-care therapies in the management of HCV infection, emerging therapeutic strategies for improving treatment response, and efforts to optimize viral eradication in HCV-infected patients thereby reducing disease burden and improving treatment outcomes.

Please note the case presentation and supporting material have been created to be an engaging CE activity, and as such the case and questions will appear throughout. These questions are provided for your reference to be able to relate material presented back to a patient case presentation, and are not answerable on the case page. To answer the questions you will need to go to the posttest section, which will again reiterate the questions and provide you the opportunity to answer them.How to Obtain Credit

To receive your CE certificate, participants must view the entire activity online, complete the online 10‐ question posttest with a score of 70% or better, and complete the evaluation form. After successful completion of the online posttest and evaluation form, participants may immediately print their certificates.

Release Date: April 8, 2011

Expiration Date: April 8, 2012

Estimated time to complete: 1 hour

Type of Activity: Application

Targeted Audience

This activity is designed for medical directors, pharmacy directors, and other managed care professionals who oversee the care of patients with HCV infection.

Educational Objectives

After completing this activity, the participant should be able to:·

• Evaluate the efficacy of standard-of-care therapies in the management of HCV infection and efforts to optimize viral eradication in HCV-infected patients, thereby reducing disease burden
• Identify predictors of treatment outcomes, including the impact of genotype and adherence, to select and apply strategies to improve treatment response
• Assess the potential of emerging HCV infection therapeutic strategies for improving treatment response and outcomes in HCV-infected patients, including available efficacy and safety data

Introduction

Chronic hepatitis C virus (HCV) infection affects approximately 170 million people. The disease often leads to cirrhosis (and sometimes hepatocellular carcinoma) and it is becoming an increasingly significant health burden in the United States.^1,2

The current standard of care for patients with chronic HCV infection is pegylated interferon alfa (PEG) in combination with ribavirin (RBV). Two forms of PEG are currently approved by the US Food and Drug Administration for treating hepatitis C: PEG alfa-2a and PEG alfa-2b.

Treatment duration and efficacy depend on HCV genotype. The most common genotype in the United States, genotype 1, is also the most difficult to treat. It usually requires 48 weeks of therapy, and only approximately 40% of patients achieve a sustained viral response (SVR), regardless of which type of PEG/RBV combination is used.³ Meanwhile, up to 80% of black patients with HCV genotype 1 do not respond to currently available therapy.⁴ HCV genotypes 2 and 3, however, which comprise 30% of US infections, usually require 24 weeks of therapy and have SVR rates up to 85%.⁵

In addition, the side effects associated with current HCV treatments make adherence to therapy difficult, further reducing the chance for an SVR.⁶ Interferons can also exacerbate autoimmune conditions. Given the growing number of patients in the United States with chronic HCV requiring treatment, there is a significant need for therapies with greater efficacy and fewer adverse effects.

CASE STUDY

MD is a 52-year-old black male who presents with jaundice and complains of fatigue. Clinical laboratory results reveal elevated liver enzymes. He was diagnosed 20 years ago with HCV infection, which likely occurred during a blood transfusion for a ruptured spleen resulting from an automobile accident at age 28.

1) What patient-related factor can determine response to treatment for HCV?

a) HCV genotype

b) Years of infection

c) Age

d) Ethnicity

2) What is the most important consideration for HCV treatment duration?

a) Viral genotype

b) Level of fibrosis

c) Patient sex

d) Patient age

3) What is the most common HCV genotype in the United States?

a) Type 1

b) Type 2

c) Type 3

d) Type 4

Emerging Therapies For HCV Infection

A new era of direct acting antiviral (DAA) compounds is underway. The first 2 new compounds, boceprevir and telaprevir, are protease inhibitors expected to reach the US market in 2011. It is anticipated that they will be used as add-on therapy to current PEG/RBV regimens in treatment-naïve patients and those who do not respond to IFN/RBV or have a relapse.

In the SPRINT (Serine Protease Inhibitor Therapy)-2 trial of 1100 treatment-naïve patients, boceprevir achieved SVR rates of 66% overall (68% in non-black patients, 53% in blacks, vs 40% and 23%, respectively, in controls; P = .004 and P = .044), with a regimen incorporating a 4-week lead-in of PEG/RBV, followed by the addition of boceprevir for 24 weeks.⁷ Based on viral response at 8 weeks and beyond, nearly half of patients qualified for a shortened duration of 28 weeks of therapy. Approximately 25% of patients required the full 48-week protocol of PEG/RBV, with boceprevir added for 24 weeks, while the remaining patients discontinued therapy (due to lack of viral response at week 24 or adverse events).⁸

In RESPOND (Retreatment with HCV Serine Protease Inhibitor Boceprevir and Peginteron/Rebetol)-2, a trial in 404 previously treated patients who received the same protocol of boceprevir 24 weeks and IFN/RBV for 24 to 48 weeks, 66% of patients in the 48-week arm and 59% in the response-guided arm achieved SVR (both significantly higher than the 21% SVR rate in the control arm).⁹ The study included previous relapsers and patients who exhibited some responsiveness to IFN. Patients who demonstrated little response in the 4-week lead-in with IFN/RBV only were most likely to have resistance-associated variants of HCV.

The predominant adverse event in SPRINT and RESPOND was anemia, defined as a hemoglobin level below 10 g/dL, which occurred in 50% of patients receiving boceprevir. Discontinuations due to anemia, however, occurred in less than 2% of patients.

CASE STUDY (continued)

Based on CD’s history, you order a panel of tests, including those for sexually transmitted diseases and HCV infection. She tests positive for anti-HCV.

4) Given the patient’s previous treatment, what do you recommend as the next step in managing the patient’s HCV infection?

a) Another 48-week course of PEG/RBV

b) A 24-week course of PEG/RBV

c) Maintenance therapy with PEG/RBV

d) None of the aboverder an HCV RNA test

Telaprevir was assessed in treatment-naïve patients in the phase 3 ADVANCE (A New Direction in HCV Care: A Study of Treatment-naïve Hepatitis C Patients with Telaprevir) trial, which studied telaprevir in combination with PEG/RBV. Patients received 12 weeks of telaprevir with 24 or 48 weeks of PEG/RBV based on response-guided parameters of viral negativity between weeks 4 and 12. Nearly 60% of patients qualified for the shorter duration of treatment. Patients in the telaprevir arm achieved SVR rates of 75% compared with 44% with control. The primary adverse event was rash, which occurred in 56% of patients, but only resulted in the discontinuation of 7% of patients given telaprevir. Forty percent of patients experienced anemia.¹⁰

Treatment-naïve patients were also studied in the ILLUMINATE (Illustrating the Effects of Combination Therapy with Telaprevir) trial. Patients in the telaprevir arm achieved a 72% SVR rate, with no additional benefit noted beyond 24 weeks in those who had an extended rapid virologic response at 24 weeks.¹¹

REALIZE (Re-treatment of Patients with Telaprevir-based Regimen to Optimize Outcomes) evaluated telaprevir in treatment-resistant patients. Recently presented results reveal SVR rates of 64% compared with 17% in the control group.¹² Although a 4-week lead-in arm did not reveal differences in SVR rates, complete data regarding predictability of SVR and resistance based on PEG/RBV response has not been presented. Patients with a previous relapse had SVR rates of 86% (24% with control), partial responders had an SVR of 57% (15% with control), and nonresponders had a SVR of 31% (5% with control).

Both boceprevir and telaprevir are oral agents that are administered 3 times daily. The incidence of anemia with both agents is approximately 40% to 50%. Rash is common with telaprevir, and dysguesia occurs with boceprevir, raising concerns about their effects on patient adherence to treatment.

CASE STUDY (continued)

In 2010, MD underwent a percutaneous liver biopsy that showed significant fibrosis. He has come to you to ask about other options, particularly because he recently learned that 2 new medications have been approved for treating HCV infection: telaprevir and boceprevir.

5) If you choose to treat the patient with telaprevir triple therapy, what side effect is most likely to occur?

a) Rash

b) Dysgeusia

c) Nausea

d) Headache

6) If you choose to treat the patient with boceprevir triple therapy, what side effect is most likely to occur?

a) Rash

b) Anemia

c) Nausea

d) Headache

7) If you choose to treat the patient with a 48-week trial of triple therapy with 24 weeks of boceprevir, what is the likelihood that he will achieve an SVR based on the results of the RESPOND trial?

a) 20%

b) 50%

c) 65%

d) 75%

8) You’ve decided to treat the patient with the triple therapy regimen recommended for boceprevir. However, he shows little change in viral levels after the 4-week lead-in with IFN/RBV. What does this mean?

a) That he will be resistant to boceprevir.

b) That he will need at least 48 weeks of boceprevir.

c) That he likely has a resistance-associated variant of HCV.

d) That he will likely develop anemia.

9) You’ve decided to treat the patient with triple therapy using boceprevir. Regardless of response, you will keep him on it for 48 weeks.

a) True

b) False

10) You’ve decided to treat the patient with triple therapy using telaprevir. Based on the REALIZE trial, what is the likelihood that he will achieve a SVR?

a) 15%

b) 30%

c) 65%

d) 85%

Other protease compounds include TMC-435, which demonstrated a 90% SVR rate in study participants who received 24 weeks of response-guided therapy. Rash and anemia occurred at similar rates compared with control.¹³

In a phase 2 trial, treatment-naïve patients received vaniprevir (MK-7009) with PEG/RBV for 28 days, then continued PEG/RBV only for 44 weeks.¹⁴ Vaniprevir was associated with rapid viral response rates ranging from 68.8% to 82.4% (compared with 5.6% with placebo). Primary side effects included nausea, headache, and flu-like symptoms.

Other Agents Under Investigation for Chronic HCV Infection

Several polymerase inhibitors are also under investigation. Nucleoside analog inhibitors bind to the active site of the NS5B RNA-dependent polymerase and non-nucleoside inhibitors bind to various other sites. PSI-7977, a uridine nucleotide analog, is one of the most potent compounds in this class. In a phase 2b study of 125 treatment-naïve patients dosed once daily with 1 of 3 doses of PSI-7977 and PEG/RBV for 4 weeks followed by PEG/RBV for 36 more weeks, 75% to 94% of patients achieved viral negativity at day 28 and week 12, respectively.¹⁵

A similar compound, RG-7128, is dosed twice daily and also showed comparable efficacy.¹⁶ It achieved proof of concept when given in conjunction with a protease inhibitor (R7227/ITMN-191) over a 2-week period, demonstrating that potent viral suppression can be achieved with no viral breakthrough when 2 DAAs that act on different targets are administered.

Non-nucleoside inhibitors are a heterogeneous class of compounds that can bind to at least 4 different sites on the virus. They have a lower potency compared with other classes, but will likely have value as part of combination regimens with other DAAs (rather than in combination with PEG/RBV).

Other classes under investigation include NS5A inhibitors, which inhibit theNS5A protein. They are now being assessed as pan-genotypic agents that can be used with PEG/RBV or in combination with other DAAs.

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Continuing professional education (CPE) activities sponsored by Pharmacy Times Office of CPE are offered solely for educational purposes and do not constitute any form of professional advice or referral. Discussions concerning drugs, dosages, and procedures may reflect the clinical experience of the author(s) or they may be derived from the professional literature or other sources and may suggest uses that are investigational in nature and not approved labeling or indications. Participants are encouraged to refer to primary references or full prescribing information resources.

The author(s), reviewer(s), and editor(s) have made extensive efforts to ensure that the information including treatments, drugs, and dosage regimens are accurate and conform to the standards accepted at the time of publication. However, health care professionals should always consult additional sources of information and exercise their best professional judgment before making clinical decisions of any kind. In particular, the reader is advised to check the product information provided by the manufacturer of a drug product before prescribing or administering it, especially if the drug is unfamiliar or is used infrequently.

Instructions

After reading “Case 2: Emerging Therapeutic Options in Hepatitis C Virus Infection,” select the 1 best answer to each of the posttest questions.

A statement of continuing education hours will be provided to those physicians and pharmacists who successfully complete and return the answer form and program evaluation and receive a passing grade of 70% or higher.

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References

1. Alter MJ. Epidemiology of hepatitis C virus infection. World J Gastroenterol. 2007; 13:2346-2441.
2. Forns X, Ampurdanes S, Sanchez-Tapias T et al. Long-term follow-up of chronic hepatitis C in patients diagnosed at a tertiary care center. J Hepatol 2001; 35:265-271.
3. McHutchison JG, Lawitz EJ, Shiffman ML et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009 Aug 6;361(6):580-93.
4. Muir AJ, Bornstein JD, Killenberg PG. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-hispanic whites. N Engl J Med. 2004;350:2265-2271.
5. Hadziyannis SJ, Sette H Jr, Morgan TR et al. Peginterferon-alpha 2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004; 140:346-355.
6. Fried MW. Side effects of therapy of hepatitis C and their management. Hepatology. 2002; 36:S237-S244.
7. Poordad F, McCone J, Bacon BR, et al. Boceprevir (BOC) Combined with Peginterferon alfa-2b/Ribavirin (P/R) for Treatment-Naïve Patients with Hepatitis C Virus (HCV) Genotype (G) 1: SPRINT-2 Final Results. Hepatology 2010;52 (4 Suppl):LB-4.)
8. Bronowicki J, McCone J, Bacon BR, et al. Response-guided therapy (RGT) with boceprevir (BOC) + peginterferon alfa-2b/ribavirin (P/R) for treatment-naïve patients with hepatitis C virus (HCV) genotype (G) 1 was similar to a 48-wk fixed-duration regimen with BOC+P/R in SPRINT-2. Hepatology 2010;52(4 Suppl):LB-15.)
9. Bacon BR, Gordon SC, Lawitz E et al. HCV RESPOND-2 final results: high sustained virologic response among genotype 1 previous non-responders and relapsers to peginterferon/ribavirin when re-treated with boceprevir plus pegintron (peginterferon alfa-2b)/ribavirin. Hepatology 2010;52(4 Suppl):A216.
10. Jacobson IR, McHutchison JG, Dusheiko GM, et al. Telaprevir in combination with Peginterferon and Ribavirin in genotype 1 HCV Treatment-naïve patients: final results of phase 3 ADVANCE Study. Hepatology 2010;52(4 Suppl):A211.
11. Sherman KE, Flamm SL, Afdhal NH et al. Telaprevir in combination with peginterferon Alfa2a 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(4 Suppl):LB-2.
12. Foster GR, Zeuzem S, Andreone P, et al. Telaprevir-based therapy in G1 HCV-infected patients with prior null response, partial response or relapse to peginterferon/ribavirin: REALIZE trial final results. Hepatology International 2011;5(1): PS02-4.
13. Fried MW, Buti M, Dore GJ, et al. Efficacy and safety of TMC435 in combination with pegintereron alfa 2a and ribavirin in treatment-naïve genotype-1 HCV patients: 24-week interim results from the PILLAR study. Hepatology 2010;52(4 Suppl):LB-5.
14. Manns M et al. MK-7009 significantly improves rapid viral response (RVR) in combination with pegylated interferon alfa-2a and ribavirin in patients with chronic hepatitis C (CHC) genotype 1 infection. J Hepatol 2009; 50:S384.
15. Lawitz EJ, Lalezari J, Rodriguez-Torres M, et al. High Rapid Virologic Response (RVR) with PSI-7977 daily dosing plus PEG-IFN/RBV in a 28-day Phase 2a trial. Hepatology 2010;52(4 Suppl):A806.
16. Jensen DM, Wedemeye RH, Herring RW, et al. High rates of early viral response, promising safety profile and lack resistance-related breakthrough in HCV GT1/4 patients treated with RG7128 plus pegIFN alfa-2a (40KD)/RBV: planned week 12 interim analysis from the PROPEL study. Hepatology 2010;52(4 Suppl):A81.