C: A NEW ERA OF TREATMENT, SERIES #1

Melissa Palmer, M.D., Series Editor Change Has Arrived: Treating Hepatitis C with Protease Inhibitors— the New Standard of Care

J. Reggie Thomas Sherri Thomas Rakesh Nanda Melissa Palmer

Treating patients with the hepatitis C virus (HCV) is about to be changed forever. Over 170 million people are infected with HCV worldwide and this number grows as more and more patients are diagnosed with hepatitis C daily. Current standard of care (SoC) treatment for chronic hepatitis C consists of pegylated interferon (Peg IFN) and rib- avirin (RBV). Success rates for viral eradication—sustained virological response (SVR), for patients infected with HCV genotype 1 (G1), the most common HCV genotype in the United States are less than 50%. New drugs, known as direct acting antivirals (DAAs), have been in development for over a decade, and the initial two of these, boceprevir and telaprevir, both protease inhibitors, have just been FDA approved (May 2011). Treating HCV with the addition of protease inhibitors to SoC is very promising with SVRs of approximately 70–75% in recent studies. This article, the first in this series, will review the burden of hepatitis C, the HCV lifecycle, and the studies behind the new therapies in an effort to preview how patients will likely be treated in the near future.

INTRODUCTION with hepatitis C worldwide (1). While some patients he wait for new drugs in the fight against hepati- have achieved a sustained virologic response (SVR), tis C (HCV) is finally over. It is estimated that defined as a nondetectable HCVRNA 24 weeks after T over 170 million people are chronically infected treatment termination, also synonymous with a cure, many have failed to achieve SVR or have simply put off treatment feeling that a less than 50% chance for a J. Reggie Thomas, DO, Sherri Thomas, DO, Rakesh cure is not worth the potential side effects. Current Nanda MD, FACP, Banner Good Samaratin Medical treatment of naïve hepatitis C patients with pegylated Center, Phoenix VA Health Care System, Phoenix, AZ. Melissa Palmer, M.D., Clinical Professor of Medicine, interferon and ribavirin yields an SVR of approxi- Director of , NYU Hepatology Associates, mately 45% (2). New treatments have been shown to Plainview, New York. E-mail: [email protected] increase SVR to approximately 75% (3). This break- for any further discussion or reprint requests. through is expected to have a profound effect on low-

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Figure 1: Targets for Protease and Polymerase Inhibition (5) ering the number of deaths from and its com- the viral RNA travels to the endoplasmic reticulum plications, and on reducing the numbers of hospital- where proteins are made. The viral RNA then interacts izations due to HCV-related disease, which ultimately with the ribosome on the outer surface of the endoplas- will dramatically reduce healthcare spending. mic reticulum and translates genetic information to pro- duce viral proteins 3000 amino acids long (6). Here the four structural proteins (Core, E1, E2, THE HEPATITIS C VIRUS LIFECYCLE and p7) attach to cell receptors. The structural In order to understand how the new protease inhibitors proteins are freed from the chain by liver enzymes. work against HCV, one must first understand the struc- The remaining nonstructural proteins are freed by viral ture of the virus and its lifecycle. The HCV genome proteases. Then NS2 cysteine protease interacts with consists of 9600 bases, which encode a single polypro- NS3 serine protease to separate from the polyprotein. tein of 3,000 amino acids (4). This polyprotein con- NS3 works with NS4A to separate and NS3 acts like a sists of four structural and six nonstructural proteins knife cleaving the four remaining proteins leaving (see Figure 1) (5). The nonstructural proteins are them free to perform their specific roles. NS4B and essential for the virus to replicate and have therefore NS5A form the site for HCV viral replication in a been the target of new antiviral medications. membranous web. NS5B the viral polymerase plays a When a patient is infected with the hepatitis C virus key role and is therefore the other area being studied it attaches to plasma lipid particles in the blood and to develop polymerase inhibitors. During replication migrates to the liver. The viral particles have proteins on negative RNA is produced from positive RNA to form their surface that bind to receptors on the surface of the double stranded intermediate, which then serves as liver cells, making the liver its target organ. Once the a copier producing thousands of copies of the genome. receptors are engaged, the liver cell internalizes the The virus is then packaged into new viral particles and virus. Inside the liver, the outer coating of the virus dis- these are transported out of the cell to infect new liver solves and the genetic material is released. A single pos- cells. The cycle is repeated and up to 1 trillion copies itive RNA containing strand remains and contains of the virus can be made each day (7). enough information to replicate itself. In order to do so, (continued on page 16)

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(continued from page 14)

Figure 2: PROVE 1 Study Design (8). (P) = Peg-IFN = pegylated interferon alfa-2a, (R) = RBV = ribavirin, (T) = TVR = telaprevir

PROTEASE INHIBITORS ical trials that led to FDA approval, and changed the Although there are currently over 50 drugs in clinical landscape of HCV treatment. trials aimed at increasing HCV cure rates, the most successful drug class to date is the protease inhibitor. TELAPREVIR Telaprevir and boceprevir are two orally effective This drug was studied in a series of trials titled PROVE DAA inhibitors of the nonstructural NS3/NS4A HCV 1-3. PROVE stands for PROtease inhibition for Viral serine protease. Understanding the life cycle of the Evaluation. PROVE 1 was a phase 2b randomized, dou- hepatitis C virus as described above is essential to ble blind, placebo controlled trial involving 250 treatment understanding how these drugs can halt viral replica- naïve, genotype 1 patients with chronic HCV infection tion. This section provides a review of the pivotal clin- (continued on page 21)

Figure 3: PROVE 2 Study Design (9). (P) = Peg-IFN = pegylated interferon alfa-2a, (R) = RBV = ribavirin, (T) = TVR = telaprevir

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(continued from page 16)

(8). This study took place across 37 centers in the US and highest, 75%, in patients receiving 12 weeks of triple compared telaprevir based therapy groups of 12, 24, and therapy followed by another 12 weeks of SoC. 48 week durations with a standard 48 week Peg-IFN alfa- (T12PR24). The Illustrating the Effects of Combina- 2a/RBV control group (see Figure 2). The objectives of tion Therapy with Telaprevir (ILLUMINATE) study the study were threefold: 1. Assess the SVR rate in was designed to compare 24 to 48 weeks of SoC treat- telaprevir-based therapy. 2. Evaluate whether or not ment after beginning with an initial 12 weeks triple telaprevir could shorten the duration of current therapy. 3. therapy, utilizing RGT. This trial enrolled 540 geno- Assess the safety and efficacy of therapy with telaprevir. type 1 patients and did not have a SOC arm (Figure 4b) Patients in the 24 and 48 week telaprevir based (11). The results demonstrated that SVR rates in the treatment groups achieved 61% and 67% SVR respec- patients with an eRVR who were randomized into tively while those in the standard care group achieved either the T12PR24 or T12 PR48 were virtually the just 41%. same—92% and 88% respectively. PROVE 2 was a multicenter, randomized, partially double blind, placebo controlled phase 2b clinical trial involving 323 treatment naïve patients with chronic BOCEPREVIR genotype 1 HCV infection (9). This study was done This drug has been studied in the SPRINT 1 and 2 stud- across 28 centers in Europe to compare telaprevir ies along with the RESPOND 1 and 2 trials. The Serine based therapy groups of 12 and 24-week durations PRotease INhibitor Therapy-1 study was a phase II trial with and without ribavirin against a standard 48 week that investigated an 800mg dose of boceprevir in com- control group (see Figure 3). In the 24-week telaprevir based regimen there was a significantly higher SVR rate (69%) with a shortened treatment duration compared with the control group (46%). Also, this study showed that ribavirin is a nec- essary part of the treatment regimen. All PROVE studies cite pruritus, rash, and anemia as the most common adverse events in the telaprevir based groups. In PROVE 2, rash led to discontinuation of all study drugs in 7% of patients. PROVE 3 will be discussed below as its population involved both nonre- sponders and relapsers. A Two additional large phase III trials have con- firmed the results of the PROVE 1 and 2 studies. More importantly, these trials determined that patients who achieved an undetectable HCVRNA at both weeks 4 and 12, known as an extended rapid viral response (eRVR) are eligible for a shortened course of therapy. This is known as “response guided therapy” (RGT) and utilizes the concept that the earlier HCV RNA becomes undetectable, the higher the likelihood of achieving SVR. A new Direction in HCV Care: a Study of Treatment Naïve Hepatitis C Patient with B Telaprevir (ADVANCE) trial evaluated two different telaprevir based treatment regimens compared with Figure 4: ADVANCE and ILLUMINATE, Study Designs (10,11). SoC in approximately 1050 previously untreated geno- (P) = Peg-IFN = pegylated interferon alfa-2a, (R) = RBV = type 1 patients (Figure 4a) (10). The SVR was the ribavirin, (T) = TVR = telaprevir

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Week 4 Week 28 Week 48

Peginterferon alfa-2b 1.5 µg/kg+ 24-week PR48 ribavirin 800–1400 mg per day follow-up

Peginterferon alfa-2b 1.5 µg/kg+ 24-week PR4/PRB24 Lead-in ribavirin 800–1400 mg per day+ follow-up boceprevir 800 mg three times per day

Peginterferon alfa-2b 1.5 µg/kg+ 24-week Part 1 PR4/PRB44 Lead-in ribavirin 800–1400 mg per day+ follow-up boceprevir 800 mg three times per day

Peginterferon alfa-2b 1.5 µg/kg+ 24-week ribavirin 800–1400 mg per day+ PRB28 follow-up boceprevir 800 mg three times per day

Peginterferon alfa-2b 1.5 µg/kg+ 24-week ribavirin 800–1400 mg per day+ PRB48 follow-up boceprevir 800 mg three times per day

Peginterferon alfa-2b 1.5 µg/kg+ 24-week PRB48 ribavirin 800–1400 mg per day+ follow-up boceprevir 800 mg three times per day Part 2 Peginterferon alfa-2b 1.5 µg/kg+ Low-dose 24-week ribavirin 400–1000 mg per day+ PRB48 follow-up boceprevir 800 mg three times per day

Figure 5: SPRINT-1 Study Design (12). (P) = Peg-IFN = pegylated interferon alfa-2b, (R) = RBV = ribavirin, (B) = boceprevir bination with PegIFN and ribavirin in 595 previous and headache. Treatment discontinuation owing to untreated HCV genotype 1 patients (12). The study adverse events was between 9 and 19% in the bocepre- included four boceprevir based treatment regimens of vir arms compared to only 8% in the control arm. different treatment duration, including a 4-week SPRINT 2 divided patients into 2 cohorts by race: pegIFN-ribavirin lead- in and a low dose ribavirin arm black and nonblack (see Figure 6). There were 316, compared with SOC (Figure 5). The highest SVR rate 311, and 311 nonblack patients in the Boceprevir RGT, of 75% was observed with the pegIFN/RBV lead-in boceprevir/PR48, and 48/PR (control) arms respec- which is followed by 44 weeks of triple therapy. In tively, and there were 52, 55, and 52 black patients in patients receiving 48 weeks of triple therapy with no those groups (13). All groups had a 4-week lead-in lead-in, SVR was 66% therefore showing a lead in with Peg/RBV. SVR achieved in the nonblack cohort phase with PegIFN and RBV may be beneficial. Safety was 68% in the boceprevir/PR48 group vs. 40% in the data from the study indicated that the most common control arm. In the group with African American adverse events reported were fatigue, anemia, nausea, patients, the highest SVR was 53% achieved in the

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more are sure to follow. Patients who have been previ- ously treated for at least 12 weeks and did not achieve an early virologic response (EVR) defined as a > 2-log decrease in viral load from the pretreatment level are termed nonresponders Those who achieved an unde- tectable HCV RNA at end of treatment (EOT) but then had detectable HCV RNA during follow up (did not achieve SVR) are known as relapsers. The PROVE 3 trial was a randomized, partially placebo controlled, partially double blind phase 2 clinical trial which looked at 453 HCV genotype 1 infected patients who did not achieve SVR with an initial full course of Peg- IFN/RBV treatment (14). This study was done across Figure 6: SPRINT-2 Study Design (13). (P) = Peg-IFN = pegy- 41 centers in the U.S., 6 in Canada, 3 in the Nether- lated interferon alfa-2b, (R) = RBV = ribavirin, (B) = boceprevir lands, and 3 in Germany (see Figure 7). Overall SVR rates in the telaprevir based groups Boceprevir/PR48 group compared to 23% in the con- of 12 and 24 weeks were 51% and 53% vs. 14% in the trol arm. 44% of patients received the shorter 28-week control group. In previous nonresponders 39% of course of therapy. In general, the boceprevir-contain- patients achieved an SVR in 24 weeks of total treat- ing arms had more patients with anemia (49% vs. ment, and in relapsers this went up to 69%. Current 29%). Erythropoietin was allowed in the study and standard of care leads to only a 9% SVR in nonre- was used in 43% of the cases. 2% of the patients dis- sponders and 20% SVR in relapsers. The ReTreatment continued treatment due to anemia. of Patients with Telaprevir Based Regimen to Opti- mize Outcomes (REALIZE) (Figure 8) study was a trial of telaprevir-based treatment for patients with HOW TO APPROACH PREVIOUS RELAPSERS genotype 1 HCV infection who failed to achieve SVR OR NONRESPONDERS with prior therapy with pegIFN and ribavirin. There Each of the new protease inhibitors has at least one were 662 patients were enrolled in this trial and SVR large study already looking into this topic and many (continued on page 26)

Figure 7: PROVE 3 Study Design (14). (P) = Peg-IFN = pegylated interferon alfa-2a, (R) = RBV = ribavirin, (T) = TVR = telaprevir

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(continued from page 23)

failures an SVR could be achieved using boceprevir and that a lead in period of initial therapy with just P/R might provide additional benefit. RESPOND 2 excluded null responders from the trial (those who did not achieve a >2 log HCV RNA decrease from baseline at week 12 during the first course of therapy). SVR rates here were 59%, 66%, and 21% in the boceprevir/RGT, Boceprevir/PR48, and con- trol arms respectively (17). Again previous relapsers responded better than previous nonresponders, defined in this study as patients who achieved a >2 log drop but kept detectable HCV RNA throughout therapy, also Figure 8: Realize (15). (P) = Peg-IFN = pegylated interferon known as a partial responder. The main side effects seen alfa-2b, (R) = RBV = ribavirin, (B) = boceprevir in this trial were anemia and dysgeusia (Figure 9). rates were 86% in prior relapsers, 57% in partial responders, and 31% in null responders in the telapre- THE FUTURE OF HEPATITIS C TREATMENT vir groups (compared with 24%, 15%, and 5% in the Researchers continue to examine ways to make hepati- control arm) (15). A lead in phase did not appear to be tis C treatment more effective and feasible. Most beneficial in this study. experts agree that eventually a combination of drugs: RESPOND 1 evaluated the safety and efficacy of protease inhibitors, polymerase inhibitors, and rib- boceprevir with pegIFN in genotype 1 patients who avirin may replace the need for interferon for at least had been null responders to prior peg-IFN/ribavirin. some patients, and these trials are already in their early This study evaluated varying doses of boceprevir but stages. In the meantime, a protease inhibitor combined the drug safety monitoring board recommended that all with PegIFN plus RBV is now the new SOC. Infec- patients who showed a response be switched to tious disease physicians, primary care physicians, boceprevir 800 mg PO TID because lower doses gastroenterologists, dermatologists, hematologists, appeared less effective and there was more resistance psychiatrists, and hepatologists will need to work out a to boceprevir when ribavirin wasn’t given (16). This new system of caring for and monitoring these patients study suggested that in patients with prior treatment who will be on complex treatment regimens. The understanding of the hepatitis C virus lifecycle has allowed treatment options to grow tremendously over the last 10 years. The fruit of this research and devel- opment has finally come to the market and the man- agement of hepatitis C will be changed forever. n

References 1. Alter MJ. Epidemiology of hepatitis C virus infection. World J Gastroenterol, 2007;13(17):2436-2441. 2. Ghany MG, Strader DB, Thomas DL, et al. American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology, 2009;49(4): 1335-1374. 3. Mallet V, Vallet-Pichard A, Pol S. New trends in hepatitis C man- agement. Presse Med, 2010;39(4):446-51. Figure 9: RESPOND—2 Study Design (17). (P) = Peg-IFN 4. Kronenberger B, Zeuzem S. Current and future treatment options = pegylated interferon alfa-2b, (R) = RBV = ribavirin, (B) = for HCV. Ann Hepatol, 2009;8(2):103-12. 5. Reiser M, Timm J. Serine protease inhibitors as anti-hepatitis C boceprevir virus agents. Expert Rev Anti Infect Ther, 2009;7(5):537-47.

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6. Asselah T, Benhamou Y, Marcellin P. Protease and polymerase 13. F Poordad, J McCone, BR Bacon, et al. (SPRINT-2 Investiga- inhibitors for the treatment of hepatitis C. Liver Int, 2009;29 tors). Boceprevir for Untreated Chronic HCV Genotype 1 Infec- Suppl 1:57-67. tion. New England Journal of Medicine 364: 1195-1206 7. Qureshi SA. Hepatitis C virus—biology, host evasion strategies, (abstract). March 31, 2011. C and promising new therapies on the horizon. Med Res Rev, 14. McHutchison JG et al. Telaprevir for Chronic HCV Infection Pre- 2007;27(3):353-73. viously Treated with Peginterferon and Ribavirin N Engl J Med, 8. McHutchison JG et al. Telaprevir with Peginterferon and Rib- 2010;362(14): 1292-1303. avirin for Chronic HCV Genotype 1 Infection. N Engl J Med, 15. Zeuzem S, et al “REALIZE trial final results: telaprevir-based 2009;360(18): 1827-1838. regimen for genotype 1 hepatitis C virus infection in patients with 9. Hezode C et al. Telaprevir and Peginterferon with or without Rib- prior null response, partial response or relapse to peginterferon/ avirin for Chronic HCV Infection. N Engl J Med, 2009;360(18): ribavirin” EASL 2011; Abstract 192 1839-1850. 16. Chary A, Holodniy M. Recent advances in hepatitis C virus treat- 10. Jacobson IM, McHutchison JG, Dusheiko GM, et al. Telaprevir ment: review of HCV protease inhibitor clinical trials. Rev Recent in combination with peginterferon and ribavirin in genotype 1 Clin Trials, 2010;5(3):158-73. HCV treatment-naïve patients: final results of Phase 3 17. Bacon BR, Gordon SC, Lawitz E, et al. HCV RESPOND-2 final ADVANCE study. Hepatology, 2010;52(suppl):427A. results: high sustained virologic response among genotype 1 pre- 11. Sherman KE, Flamm SL, Afdhal NH, et al. Telaprevir in combi- vious nonresponders and relapsers to peginterferon/ribavirin nation with peginterferon alfa2a and ribavirin for 24 or 48 weeks when retreated with boceprevir plus PegIntron (peginterferon in treatment-naïve genotype 1 HCV patients who achieved an alfa-2b)/ribavirin. Hepatology, 2010; 52(suppl) 430A. extended rapid viral response: final results of Phase 3 ILLUMI- NATE study. Hepatology, 2010;52(suppl):401A. 12. Kwo PY, Lawitz EJ, McCone J, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b CALL FOR PAPERS and ribavirin in treatment-naïve patients with genotype 1 hepati- tis C infection (SPRINT-1): an open label, randomized, multi- ANNOUNCING AN EXCITING centre phase 2 trial. Lancet, 2010;376: 705-716. NEW DIRECTION FOR PRACTICAL GASTROENTEROLOGY Academic Gastroenterologist We are launching a new series on original digestive diseases research. Research can be prospective or The University of Tennessee Health Science retrospective as well as clinical in nature. Outcomes Center in Memphis is actively recruiting a clinically or population based research is also welcome. Please provide a cover letter that briefly summarizes oriented academic gastroenterologist for a faculty the important aspects of the manuscript with position in its Division of Gastroenterology. recommendations for up to three reviewers who are Candidates are expected to be accomplished in qualified in the field as well as three reviewers who may have a conflict of interest with your study. their area of expertise and have a desire to Please send manuscripts electronically to Dr. Uma provide outstanding clinical gastroenterology Sundaram, attention Cristin Murphy (telephone: patient care. Excellence in teaching medical 304.293.4123) to the following e-mail address: students, residents and fellows. [email protected] Candidates must be eligible for Tennessee licensure and be board certified in Internal Medicine and (by 2012) Gastroenterology. Please forward letter of interest and C.V. to PRACTICAL the attention of Toan Nguyen, M.D., Chief of Gastroenterology, Department of Medicine, GASTROENTEROLOGY University of Tennessee Health Science Center, via fax at 901-448-7091. The University of REPRINTS Tennessee is an EEO/AA/title VI/Title IX/Section For further details on rates or to place 504/ADA/ADEA institution in the provision of its an order, visit our website at: education and employment program and services. www.practicalgastro.com

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