HEPATITIS 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. Over170 million people are infected with HCV worldwide and this number grows as moreand 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 rib­avirin (RBV). Success rates for viral eradication—sustained virological response (SVR),for patients infected with HCV genotype 1 (G1), the most common HCV genotype in theUnited 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 andtelaprevir, both protease inhibitors, have just been FDA approved (May 2011). TreatingHCV with the addition of protease inhibitors to SoC is very promising with SVRs ofapproximately 70–75% in recent studies. This article, the first in this series, will reviewthe burden of hepatitis C, the HCV lifecycle, and the studies behind the new therapiesin an effort to preview how patients will likely be treated in the near future.


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

Figure 1: Targets for Protease and Polymerase Inhibition (5)


ering the number of deaths from cirrhosis and its com­plications, and on reducing the numbers of hospital­izations due to HCV-related disease, which ultimatelywill dramatically reduce healthcare spending.
THE HEPATITIS C VIRUS LIFECYCLE
In order to understand how the new protease inhibitorswork against HCV, one must first understand the struc­ture of the virus and its lifecycle. The HCV genomeconsists of 9600 bases, which encode a single polypro­tein of 3,000 amino acids (4). This polyprotein con­sists of four structural and six nonstructural proteins(see Figure 1) (5). The nonstructural proteins areessential for the virus to replicate and have thereforebeen the target of new antiviral medications.
When a patient is infected with the hepatitis C virusit attaches to plasma lipid particles in the blood andmigrates to the liver. The viral particles have proteins ontheir surface that bind to receptors on the surface ofliver cells, making the liver its target organ. Once thereceptors are engaged, the liver cell internalizes thevirus. Inside the liver, the outer coating of the virus dis­solves and the genetic material is released. A single pos­itive RNA containing strand remains and containsenough information to replicate itself. In order to do so,

the viral RNA travels to the endoplasmic reticulumwhere proteins are made. The viral RNA then interactswith the ribosome on the outer surface of the endoplas­mic reticulum and translates genetic information to pro­duce viral proteins 3000 amino acids long (6).
Here the four structural proteins (Core, E1, E2,and p7) attach to liver cell receptors. The structuralproteins are freed from the chain by liver enzymes.The remaining nonstructural proteins are freed by viralproteases. Then NS2 cysteine protease interacts withNS3 serine protease to separate from the polyprotein.NS3 works with NS4A to separate and NS3 acts like aknife cleaving the four remaining proteins leavingthem free to perform their specific roles. NS4B andNS5A form the site for HCV viral replication in amembranous web. NS5B the viral polymerase plays akey role and is therefore the other area being studiedto develop polymerase inhibitors. During replicationnegative RNA is produced from positive RNA to formthe double stranded intermediate, which then serves asa copier producing thousands of copies of the genome.The virus is then packaged into new viral particles andthese are transported out of the cell to infect new livercells. The cycle is repeated and up to 1 trillion copiesof the virus can be made each day (7).
(continued on page 16)


 

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 thelandscape of HCV treatment.
Although there are currently over 50 drugs in clinicaltrials aimed at increasing HCV cure rates, the mostsuccessful drug class to date is the protease inhibitor.TELAPREVIR Telaprevir and boceprevir are two orally effectiveThis drug was studied in a series of trials titled PROVEDAA inhibitors of the nonstructural NS3/NS4A HCV1-3. PROVE stands for PROtease inhibition for Viral serine protease. Understanding the life cycle of theEvaluation. PROVE 1 was a phase 2b randomized, dou­hepatitis C virus as described above is essential toble blind, placebo controlled trial involving 250 treatmentunderstanding 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-

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


 


(8). This study took place across 37 centers in the US andcompared telaprevir based therapy groups of 12, 24, and48 week durations with a standard 48 week Peg-IFN alfa-2a/RBV control group (see Figure 2). The objectives ofthe study were threefold: 1. Assess the SVR rate intelaprevir-based therapy. 2. Evaluate whether or not telaprevir could shorten the duration of current therapy. 3.Assess the safety and efficacy of therapy with telaprevir.
Patients in the 24 and 48 week telaprevir basedtreatment groups achieved 61% and 67% SVR respec­tively while those in the standard care group achievedjust 41%.
PROVE 2 was a multicenter, randomized, partiallydouble blind, placebo controlled phase 2b clinical trialinvolving 323 treatment naïve patients with chronicgenotype 1 HCV infection (9). This study was doneacross 28 centers in Europe to compare telaprevirbased therapy groups of 12 and 24-week durationswith and without ribavirin against a standard 48 weekcontrol group (see Figure 3).
In the 24-week telaprevir based regimen there wasa significantly higher SVR rate (69%) with a shortenedtreatment duration compared with the control group(46%). Also, this study showed that ribavirin is a nec­essary part of the treatment regimen.
All PROVE studies cite pruritus, rash, and anemiaas the most common adverse events in the telaprevirbased groups. In PROVE 2, rash led to discontinuationof all study drugs in 7% of patients. PROVE 3 will bediscussed below as its population involved both nonre­sponders and relapsers.
Two additional large phase III trials have con­firmed the results of the PROVE 1 and 2 studies. More importantly, these trials determined that patients whoachieved 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 RNAbecomes undetectable, the higher the likelihood ofachieving SVR. A new Direction in HCV Care: aStudy of Treatment Naïve Hepatitis C Patient withTelaprevir (ADVANCE) trial evaluated two differenttelaprevir based treatment regimens compared withSoC in approximately 1050 previously untreated geno­type 1 patients (Figure 4a) (10). The SVR was the highest, 75%, in patients receiving 12 weeks of tripletherapy followed by another 12 weeks of SoC.(T12PR24). The Illustrating the Effects of Combina­tion Therapy with Telaprevir (ILLUMINATE) studywas designed to compare 24 to 48 weeks of SoC treat­ment after beginning with an initial 12 weeks tripletherapy, utilizing RGT. This trial enrolled 540 geno­type 1 patients and did not have a SOC arm (Figure 4b)(11). The results demonstrated that SVR rates in thepatients with an eRVR who were randomized intoeither the T12PR24 or T12 PR48 were virtually thesame—92% and 88% respectively.
BOCEPREVIR
This drug has been studied in the SPRINT 1 and 2 stud­ies along with the RESPOND 1 and 2 trials. The SerinePRotease INhibitor Therapy-1 study was a phase II trialthat investigated an 800mg dose of boceprevir in com-

Week 4 Week 28 Week 48


PR48
PR4/PRB24
Part 1
PR4/PRB44


PRB28
PRB48
 PRB48 Part 2
Low-dose PRB48
Text Box: Peginterferon alfa-2b 1.5 µg/kg+ 24-week ribavirin 800–1400 mg per day follow-up

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


Peginterferon alfa-2b 1.5 µg/kg+ ribavirin 800–1400 mg per day+ boceprevir 800 mg three times per day
Peginterferon alfa-2b 1.5 µg/kg+ ribavirin 800–1400 mg per day+ boceprevir 800 mg three times per day
Peginterferon alfa-2b 1.5 µg/kg+ ribavirin 400–1000 mg per day+ 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 previousuntreated HCV genotype 1 patients (12). The studyincluded four boceprevir based treatment regimens ofdifferent treatment duration, including a 4-week pegIFN-ribavirin lead- in and a low dose ribavirin armcompared with SOC (Figure 5). The highest SVR rateof 75% was observed with the pegIFN/RBV lead-inwhich is followed by 44 weeks of triple therapy. Inpatients receiving 48 weeks of triple therapy with nolead-in, SVR was 66% therefore showing a lead inphase with PegIFN and RBV may be beneficial. Safetydata from the study indicated that the most commonadverse events reported were fatigue, anemia, nausea, and headache. Treatment discontinuation owing toadverse events was between 9 and 19% in the bocepre­vir arms compared to only 8% in the control arm.
SPRINT 2 divided patients into 2 cohorts by race:black and nonblack (see Figure 6). There were 316,311, and 311 nonblack patients in the Boceprevir RGT,boceprevir/PR48, and 48/PR (control) arms respec­tively, and there were 52, 55, and 52 black patients inthose groups (13). All groups had a 4-week lead-inwith Peg/RBV. SVR achieved in the nonblack cohortwas 68% in the boceprevir/PR48 group vs. 40% in thecontrol arm. In the group with African Americanpatients, the highest SVR was 53% achieved in the

Figure 6: SPRINT-2 Study Design (13). (P) = Peg-IFN = pegy-lated interferon alfa-2b, (R) = RBV = ribavirin, (B) = boceprevir



Boceprevir/PR48 group compared to 23% in the con­trol arm. 44% of patients received the shorter 28-weekcourse of therapy. In general, the boceprevir-contain­ing arms had more patients with anemia (49% vs.29%). Erythropoietin was allowed in the study andwas used in 43% of the cases. 2% of the patients dis­continued treatment due to anemia.
HOW TO APPROACH PREVIOUS RELAPSERS OR NONRESPONDERS
Each of the new protease inhibitors has at least onelarge study already looking into this topic and many more are sure to follow. Patients who have been previ­ously treated for at least 12 weeks and did not achievean early virologic response (EVR) defined as a > 2-logdecrease in viral load from the pretreatment level aretermed nonresponders Those who achieved an unde­tectable HCV RNA at end of treatment (EOT) but thenhad detectable HCV RNA during follow up (did notachieve SVR) are known as relapsers. The PROVE 3trial was a randomized, partially placebo controlled,partially double blind phase 2 clinical trial whichlooked at 453 HCV genotype 1 infected patients whodid not achieve SVR with an initial full course of Peg-IFN/RBV treatment (14). This study was done across41 centers in the U.S., 6 in Canada, 3 in the Nether­lands, and 3 in Germany (see Figure 7).
Overall SVR rates in the telaprevir based groupsof 12 and 24 weeks were 51% and 53% vs. 14% in the control group. In previous nonresponders 39% ofpatients achieved an SVR in 24 weeks of total treat­ment, and in relapsers this went up to 69%. Currentstandard of care leads to only a 9% SVR in nonre­sponders and 20% SVR in relapsers. The ReTreatmentof Patients with Telaprevir Based Regimen to Opti­mize Outcomes (REALIZE) (Figure 8) study was atrial of telaprevir-based treatment for patients withgenotype 1 HCV infection who failed to achieve SVRwith prior therapy with pegIFN and ribavirin. Therewere 662 patients were enrolled in this trial and SVR
(continued on page 26)



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



Figure 8: Realize (15). (P) = Peg-IFN = pegylated interferon alfa-2b, (R) = RBV = ribavirin, (B) = boceprevir


rates were 86% in prior relapsers, 57% in partialresponders, and 31% in null responders in the telapre­vir groups (compared with 24%, 15%, and 5% in thecontrol arm) (15). A lead in phase did not appear to bebeneficial in this study. RESPOND 1 evaluated the safety and efficacy ofboceprevir with pegIFN in genotype 1 patients whohad been null responders to prior peg-IFN/ribavirin.This study evaluated varying doses of boceprevir butthe drug safety monitoring board recommended that allpatients who showed a response be switched toboceprevir 800 mg PO TID because lower dosesappeared less effective and there was more resistanceto boceprevir when ribavirin wasn’t given (16). Thisstudy suggested that in patients with prior treatment failures an SVR could be achieved using boceprevirand that a lead in period of initial therapy with just P/Rmight provide additional benefit.
Figure 9: RESPOND—2 Study Design (17). (P) = Peg-IFN = pegylated interferon alfa-2b, (R) = RBV = ribavirin, (B) = boceprevir


RESPOND 2 excluded null responders from thetrial (those who did not achieve a >2 log HCV RNAdecrease from baseline at week 12 during the firstcourse of therapy). SVR rates here were 59%, 66%, and21% in the boceprevir/RGT, Boceprevir/PR48, and con­trol arms respectively (17). Again previous relapsersresponded better than previous nonresponders, definedin this study as patients who achieved a >2 log drop butkept detectable HCV RNA throughout therapy, alsoknown as a partial responder. The main side effects seenin this trial were anemia and dysgeusia (Figure 9).
THE FUTURE OF HEPATITIS C TREATMENT
Researchers continue to examine ways to make hepati­tis C treatment more effective and feasible. Most experts agree that eventually a combination of drugs:protease inhibitors, polymerase inhibitors, and rib­avirin may replace the need for interferon for at leastsome patients, and these trials are already in their earlystages. In the meantime, a protease inhibitor combinedwith PegIFN plus RBV is now the new SOC. Infec­tious disease physicians, primary care physicians,gastroenterologists, dermatologists, hematologists,psychiatrists, and hepatologists will need to work out anew system of caring for and monitoring these patientswho will be on complex treatment regimens. Theunderstanding of the hepatitis C virus lifecycle hasallowed treatment options to grow tremendously overthe last 10 years. The fruit of this research and devel­opment has finally come to the market and the man­agement of hepatitis C will be changed forever. ■
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 Associationfor the Study of Liver Diseases. Diagnosis, management, andtreatment of hepatitis C: an update. Hepatology, 2009;49(4): 1335-1374.
  3. Mallet V, Vallet-Pichard A, Pol S. New trends in hepatitis C man­agement. Presse Med, 2010;39(4):446-51.
  4. Kronenberger B, Zeuzem S. Current and future treatment optionsfor HCV. Ann Hepatol, 2009;8(2):103-12.
  5. Reiser M, Timm J. Serine protease inhibitors as anti-hepatitis Cvirus agents. Expert Rev Anti Infect Ther, 2009;7(5):537-47.

 


 

  1. Asselah T, Benhamou Y, Marcellin P. Protease and polymeraseinhibitors for the treatment of hepatitis C. Liver Int, 2009;29Suppl 1:57-67.
  2. Qureshi SA. Hepatitis C virus—biology, host evasion strategies,and promising new therapies on the horizon. Med Res Rev,2007;27(3):353-73.
  3. McHutchison JG et al. Telaprevir with Peginterferon and Rib­avirin for Chronic HCV Genotype 1 Infection. N Engl J Med,2009;360(18): 1827-1838.
  4. Hezode C et al. Telaprevir and Peginterferon with or without Rib­avirin for Chronic HCV Infection. N Engl J Med, 2009;360(18):1839-1850.
  5. Jacobson IM, McHutchison JG, Dusheiko GM, et al. Telaprevirin combination with peginterferon and ribavirin in genotype 1HCV treatment-naïve patients: final results of Phase 3 ADVANCE study. Hepatology, 2010;52(suppl):427A.
  6. Sherman KE, Flamm SL, Afdhal NH, et al. Telaprevir in combi­nation with peginterferon alfa2a and ribavirin for 24 or 48 weeksin treatment-naïve genotype 1 HCV patients who achieved anextended rapid viral response: final results of Phase 3 ILLUMI­NATE study. Hepatology, 2010;52(suppl):401A.
  7. Kwo PY, Lawitz EJ, McCone J, et al. Efficacy of boceprevir, anNS3 protease inhibitor, in combination with peginterferon alfa-2band ribavirin in treatment-naïve patients with genotype 1 hepati­tis C infection (SPRINT-1): an open label, randomized, multi-centre phase 2 trial. Lancet, 2010;376: 705-716.

 
  1. F Poordad, J McCone, BR Bacon, et al. (SPRINT-2 Investiga­tors). Boceprevir for Untreated Chronic HCV Genotype 1 Infec­tion. New England Journal of Medicine 364: 1195-1206 (abstract). March 31, 2011. C
  2. McHutchison JG et al. Telaprevir for Chronic HCV Infection Pre­viously Treated with Peginterferon and Ribavirin N Engl J Med,2010;362(14): 1292-1303.
  3. Zeuzem S, et al “REALIZE trial final results: telaprevir-basedregimen for genotype 1 hepatitis C virus infection in patients withprior null response, partial response or relapse to peginterferon/ribavirin” EASL 2011; Abstract 192
  4. Chary A, Holodniy M. Recent advances in hepatitis C virus treat­ment: review of HCV protease inhibitor clinical trials. Rev Recent Clin Trials, 2010;5(3):158-73.
  5. Bacon BR, Gordon SC, Lawitz E, et al. HCV RESPOND-2 finalresults: high sustained virologic response among genotype 1 pre­vious nonresponders and relapsers to peginterferon/ribavirinwhen retreated with boceprevir plus PegIntron (peginterferonalfa-2b)/ribavirin. Hepatology, 2010; 52(suppl) 430A.