Presentation on theme: "Management of Chronic Hepatitis C in 2013"— Presentation transcript:
1Management of Chronic Hepatitis C in 2013 John M. Vierling, M.D., F.A.C.P. Professor of Medicine and Surgery Chief of Hepatology Director of Advanced Liver Therapies Baylor College of Medicine St. Luke’s Medical Center Houston, TexasHCC, hepatocellular carcinoma; SVR, sustained virologic response.
2Management of Chronic Hepatitis C in 2013 I would rather donate all of my organs right now than hear another talk about currently approved therapies for chronic hepatitis C.TrueFalseHCC, hepatocellular carcinoma; SVR, sustained virologic response.
3HCV Infection a Global Problem: 170 M Persons Hepatitis C Death Rates Per 100,000
4Chronic Hepatitis C: A Treatable Disease HCV infectionChronic in 70-85% and progressive in substantial proportionComplications increasingly common[1,2]Decompensated cirrhosisHepatic failureHCC 3-7% per year in cirrhoticsTreatment resulting in SVREradication of HCV infection (cure)Results in histologic improvement and regression of fibrosisReduces risk of hepatic failure and HCCImproves survival[4,5]HCC, hepatocellular carcinoma; SVR, sustained virologic response.1. Kanwal F, et al. Gastroenterology. 2011;140:2. Shaw JJ, et al. Expert Rev Gastroenterol Hepatol. 2011;5:3. Poynard T, et al. Gastroenterology. 2002;122:4. Craxi A, et al. Clin Liver Dis. 2005;9: Shiratori Y, et al. Ann Intern Med. 2005;142:
5Cirrhosis: Treat Before Decompensation! Survival ProbabilityCompensated100After first major complication8060Patients (%)4020HCV, hepatitis C virus.1224364860728496108120Mos384 65342 21288 11236 7165 4126 479 352 339 225 1Pts at Risk, nFattovich G, et al. Gastroenterology. 1997;112:
6Patients With Liver Complications (%) Liver-Related Complications Decrease Following SVR in Cirrhotic PatientsNo SVR100SVR8060Patients With Liver Complications (%)4020SVR, sustained virologic response.24487296120144168Mos345 70207 4134 12Pts at Risk, nBruno S, et al. Hepatology. 2007;45:
7Probability of decompensation Compensated Cirrhosis: HVPG 10 mmHg is the strongest predictor of decompensation0.20.40.60.81.0Probability of decompensation(ascites, VH, HE)80201004060MonthsBaseline HVPG ≥10mmHgBaseline HVPG <10mmHgLog rank test: p<0.01HR 3.95 (2.29–6.83)Ripoll et al (Timolol Study Group). Gastroenterology 2007; 133:
8* Almost immediately after completing AVT HCV Antiviral Therapy Decreases HVPG in Patients with Advanced Fibrosis or Cirrhosis with Portal Hypertension (n=20)9/11 patients with HVPG ≥ 12 mmHghad a reduction >20% or to <12 mmHgHVPG reduction superior in virological and biochemical responders at EOT** Almost immediately after completing AVTRincon et al. Am J Gastroenterol 2006;101:2269–2274.
9Compensated Cirrhosis: Reduction in HVPG >10% at one-year prevents development of varices12602472 HVPG > 10% HVPG 10%% Free of varicesMonths1008040203648p=0.014Groszmann, Garcia-Tsao, Bosch et al. N Engl J Med 2005, 353:
10SVR is Meaningful Clinical Endpoint SVR= endpoint of successful HCV treatmentDefined as undetectable serum HCV RNA levels 24 wks after end of treatmentRepresents a cureSVR associated with significant reductions of HCV-associated complications and mortality[1,2]SVR betterNo SVR betterGenotype 1P < .0001Genotype 2P = .004Genotype 3P < .00010.20.40.60.81.01.21.41.61.82.0All-Cause Mortality HR (95% CI)Morgan TR, et al. Hepatology. 2010;52:2. Backus L, et al AASLD. Abstract 213.
11Management of Chronic Hepatitis C in 2013 SVR after antiviral therapy for HCV infection:Represents a cureReduces liver-related mortalityReduces all-cause mortalityNeeds to be better understood by Dr. GossAll of the aboveHCC, hepatocellular carcinoma; SVR, sustained virologic response.
12For HCV Genotype 2 or 3, PegIFN/RBV Current Standard of Care Higher SVR rates than genotype 124 wks of therapy recommended[1,2]Patients with RVR and low baseline HCV RNA can be treated for 16 wksRelapse rates may be higherFuture regimens may offer further improvements, such asShorter durationsAll-oral therapyFewer adverse eventsPegIFN, peginterferon; RBV, ribavirin; RVR, rapid virologic response.1. Ghany MG, et al. Hepatology. 2011;54: EASL. J Hepatol. 2011;55:
13Addition of BOC or TVR to Peg-IFN/RBV Improved SVR in Genotype 1 Patients BOC and TVR each indicated in combination with pegIFN/RBV for genotype 1 HCV patients who are previously untreated or who have failed previous therapy100PegIFN + RBV69-8380BOC/TVR + pegIFN* + RBV63-7540-5960SVR (%)38-4429-404024-29BOC, boceprevir; pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response; TVR, telaprevir.207-155Treatment Naive[1,2]Relapsers[3,4]Partial Responders[3,4]Null Responders[4,5]*BOC was administered with pegIFN-α2b; TVR was administered with pegIFN-α2a in these trials.1. Poordad F, et al. N Engl J Med. 2011;364: Jacobson IM, et al. N Engl J Med. 2011;364: Bacon BR, et al. N Engl J Med. 2011;364: Zeuzem S, et al. N Engl J Med. 2011;364: Bronowicki JP, et al. EASL Abstract 11.
14BOC and TVR Potential for Multiple Drug–Drug Interactions Strong inhibitor of CYP3A4/5Partly metabolized by CYP3A4/5Potential inhibitor of and substrate for P-gpMost drug–drug interactions can be overcome by careful survey of the patient’s medications and judicious substitutions during HCV therapy (or just during the period of PI-based triple therapy)TVRSubstrate of CYP3AInhibitor of CYP3ASubstrate and inhibitor of P-gpBOC, boceprevir; P-gp, P-glycoprotein; PI, protease inhibitor; TVR, telaprevir.
15SPRINT-2: Influence of Baseline Patient and Virus Factors on SVR With BOC/PR BOC + pegIFN-α2b/RBV RGTBOC + pegIFN-α2b/RBV 48 wks93/ 13389/ 134100501b aGenotype7066≤ 800, > 800,000HCV RNA (IU/mL)8576F F3/F4Fibrosis67SVR (%)752541/ 5445/ 53213/ 319211/ 313n/ N =6359614152118/ 187106/ 17914/ 3422/ 42192/ 314197/ 31344/ 5582/ 11526/ 44CC CT TT8071IL28BBOC, boceprevir; HCV, hepatitis C virus; pegIFN, peginterferon; RBV, ribavirin; RGT, response-guided therapy; SVR, sustained virologic response.1. Poordad F, et al. N Engl J Med. 2011;364: Poordad F, et al. Gastroenterology. 2012;143:
16ADVANCE: Influence of Baseline Patient and Virus Factors on SVR With TVR Data from TVR12 + pegIFN-α2a/RBV arm only10090797878747371717562SVR (%)5025HCV, hepatitis C virus; pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response; TVR, telaprevir.n/ N =118/ 149152/ 21364/ 82207/ 281226/ 29045/ 7345/ 5048/ 6816/ 221b aGenotype< 800,000 ≥ 800,000HCV RNA (IU/mL)F F3/F4FibrosisCC CT TTIL28B**IL28B testing was in whites only.1. Jacobson IM, et al. N Engl J Med. 2011;364: Jacobson IM, et al. EASL Abstract 1369.
17Challenging Patients with Suboptimal Current Treatment Options Cirrhosis (all genotypes)Decompensated cirrhosisNull respondersPre-transplantationPost-transplantationChronic Renal failureImpaired renal functionDialysisRenal transplantation recipientsInjection-drug usersMethadone substitutionThalassemicsChildrenIFN contraindicatedIFN intolerantThose with poor social supportPsychiatric comorbiditiesHCV, hepatitis C virus; IV, intravenous; PI, protease inhibitor.
18HCV Antivirals New Studies Using Current Therapies
19CONCISE: Telaprevir + P/R for Patients with HCV GT 1 and IL28B CC Interim analysis of ongoing, multicenter, randomized, active-controlled, exploratory phase IIIb studyWk 12Wk 24T12/PR12Stop all treatment(n = 107)Treatment-naive patients or previous relapsers with GT 1 HCV, IL28B CC genotype, and no cirrhosis(N = 239)Telaprevir +P/R2:1 randomization*BOC, boceprevir; GT, genotype; HCV, hepatitis C virus; P/R, peginterferon/ribavirin; RVR, rapid virologic response; T, telaprevir.Stefan Zeuzem, MD:The CONCISE study is part of the phase IIIb program for telaprevir. This interim analysis of the ongoing, multicenter, randomized, active-controlled, exploratory study is evaluating whether noncirrhotic patients with the IL28B CC genotype who are infected with genotype 1 HCV can receive a shortened therapy duration of a total of 12 weeks. This trial was based on a retrospective post hoc analysis of the large phase II PROVE-2 study, which showed that patients with the IL28B CC genotype had high SVR rates with telaprevir plus peginterferon/ribavirin for 12 weeks.Reference1. Hézode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med. 2009;360:T12/PR24Continue P/R alone(n = 52)*Patients with RVR randomly assigned 2:1 to T12/PR12 or T12/PR24.Nelson DR, et al. EASL Abstract 881.
20CONCISE: Virologic Responses TVR12/PR12 vs. TVR12/PR24 after eRVR T12/PR12T12/PR2499981009710089878060Patients (%)4020105/ 10651/ 5293/ 10438/ 3874/ 8529/ 30n/N =eRVR, extended rapid virologic response; GT, genotype; HCV, hepatitis C virus; PR, peginterferon/ribavirin; RVR, rapid virologic response; SVR, sustained virologic response; T, telaprevir; TVR, telaprevir.Stefan Zeuzem, MD:The interim efficacy data from CONCISE show that a 12-week regimen of telaprevir plus peginterferon/ribavirin in patients with the IL28B CC genotype resulted in an SVR rate of 87%. Among patients randomized to the standard of care—24 weeks of therapy—the SVR rate was 97%. Although the numbers are small and no statistical analysis was performed, there is a trend suggesting that although the outcome with 12 weeks of therapy was excellent, the SVR rate was even better with 24 weeks of treatment.In my experience, patients typically are very reluctant to shorten HCV therapy if it compromises SVR rates, even if it is only a numerical decline and not a statistically significant difference. If the numerical decrease of 10% is confirmed in the final analysis of this study, I have doubts that this will be fully adopted in clinical practice.Paul Y. Kwo, MD:I agree with Dr. Zeuzem and think that clinicians may use these data not to recommend shorter durations of therapy from the outset, but rather to provide reassurance to patients with favorable characteristics, such as IL28B CC, who have marked difficulty in tolerating therapy, that truncating therapy at or after 12 weeks will not sacrifice a large percentage of their opportunity to achieve SVR. To that extent, I view these data as similar to those from the ADVANCE study, with 8 vs 12 weeks of telaprevir-based triple therapy: Although SVR rates were numerically lower with 8 weeks of therapy, they still were quite good.For more information on this study, review the CCO Capsule Summary at:Reference1. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:eRVRSVR4SVR12Relapse in 8% of patients in TVR12/PR12 arm vs 0% in T12/PR24 armSafety profile consistent with that observed in previous TVR studieseRVR: undetectable HCV RNA at Wks 4 and 12.Nelson DR, et al. EASL Abstract 881. Reproduced with permission.
21HCV RNA Undetectable (%) TARGET-C: TVR With Reduced RBV + Peg-IFN in HCV-Infected Hemodialysis PatientsTVR + PegIFN/RBV 200 mgWk 12Pts with GT 1 HCV;on hemodialysis(N = 36)PegIFN/RBV 400 mgTVR + PegIFN + PlaceboPlacebo + PegIFN/RBV 400 mgWk 24Wk 36Wk 48n = 12100PegIFN alfa-2a dosed at 135 µg/wkIncreased incidence of select AEs in TVR arms vs P/RAnemia (54% vs 33%)Neutropenia (50% vs 33%)Thrombocytopenia (37% vs 25%)Rash (42% vs 17%)Anorectal dysfunction (33% vs 0%)Dysgeusia (42% vs 17%)80676360HCV RNA Undetectable (%)5050AEs, adverse events; EOT, end of treatment; GT, genotype; HD, hemodialysis; HCV, hepatitis C virus; pegIFN/RBV, peginterferon/ribavirin; SOC, standard of care; SVR, sustained virologic response; TVR, telaprevir.David R. Nelson, MD:The last study, TARGET-C is a very small trial exploring the safety of using telaprevir with or without ribavirin in a hemodialysis population. It is a very interesting trial design, and I think the authors deserve a lot of credit for taking this approach. Patients were randomized to either 48 weeks of peginterferon/ribavirin plus a placebo (effectively the standard of care, although ribavirin is not approved in this population) or one of 2 different arms containing telaprevir and peginterferon, with or without ribavirin. The daily ribavirin dose was 200 mg when coadministered with telaprevir or 400 mg when it was used just with peginterferon. This study design is very similar to what clinicians who treat patients with renal failure or who are on dialysis actually do: introduce very low–dose ribavirin with interferon.Because of the very small numbers, the data must be interpreted with caution. Nevertheless, I think that this is a very revealing study. First, the coadministration of telaprevir with peginterferon/ribavirin increased the rates of adverse events including anemia, neutropenia, thrombocytopenia, rash, and anorectal symptoms. However, there was a clear efficacy advantage to telaprevir-based therapy, either with or without ribavirin, in this population.Telaprevir, as well as boceprevir, was approved only in combination with peginterferon/ribavirin, and the 3 drugs together are very efficacious if patients are able to get tolerate treatment, but this study also suggests that if patients cannot receive ribavirin, telaprevir plus peginterferon alone is still better than the previous standard of peginterferon/ribavirin.Stefan Zeuzem, MD:It was quite surprising to me that these patients tolerated 400 mg/day of ribavirin. Many nephrologists report that their patients are only tolerating 200 mg/day or low doses every second day. As such, these data are quite surprising, and I am not sure whether they are explained by more aggressive use of growth factor support or simply a different experience than that in other centers.A more general observation is that the protease inhibitors are hepatically metabolized and, therefore, do not need to be dose adapted in patients with renal insufficiency. However, we lack data on the other drug classes in this setting. Experience in hepatitis B has indicated that nucleos(t)ide hepatitis B virus polymerase inhibitors require very cautious dose adaptation in this population. Therefore, clinicians need to be aware that the experience using protease inhibitors in this population cannot simply be extrapolated to other DAA classes, especially the nucleos(t)ide HCV polymerase inhibitors.I agree with this important caution. Sofosbuvir is a nucleotide polymerase inhibitor that is not hepatically metabolized but rather is primarily eliminated through renal clearance. We need additional data on new agents in renally impaired patients before using these agents in this very special population.Paul Y. Kwo, MD:The investigators of this trial deserve enormous credit for treating a special population that clearly requires attention: the hemodialysis population. Hopefully, further investigations with this and additional agents will be undertaken, so that individuals on hemodialysis will have treatment options other than just peginterferon/ribavirin.40252520n/ N =8/ 126/ 123/ 127/ 126/ 123/ 12EOTSVRBasu P, et al. EASL Abstract 67.
23HCV-TARGET: TVR or BOC + P/R in a Diverse Patient Populations Interim analysis of longitudinal observational study of sequentially enrolled patients in academic and community medical centers in North AmericaPatient Disposition, n (%)DAA + P/R(N = 1919)Patients in current analysis1457Patients with cirrhosis550Still on treatment, < 16 wks139 (6)Still on treatment, > 16 wks664 (46)Completed full course319 (22)Patient DispositionDAA + P/R(N = 1457)Early discontinuation, n (%)335 (23)Lack of efficacy8Adverse event9Other reasons5Multiple reasons2BOC, boceprevir; DAA, direct-acting antiviral; HCV, hepatitis C virus; P/R, peginterferon/ribavirin; TVR, telaprevir.David R. Nelson, MD:This slide shows the first interim analysis from the HCV-TARGET database. This database encapsulates a large North American experience of DAA agents in a real-world population that includes both academic and community medical centers and very much complements the CUPIC data. Currently, there are approximately 2100 patients in the database; however, this interim analysis reported on the first 1457 patients, including a very large proportion of patients with cirrhosis.These data need to be interpreted carefully as they include on-treatment interim outcomes. However, the early results suggest that there was a virologic breakthrough rate of approximately 8% to 10%, and early discontinuation is occurring in approximately 1 in 4 patients, due to a variety of reasons including efficacy, adverse events, and lack or failure of stop rules.Fried MW, et al. EASL Abstract 818.
24HCV-TARGET: Baseline Characteristics Patient CharacteristicCirrhotic(n = 550)Noncirrhotic(n = 787)40-64 yrs of age, %8480Male, %6955White, %7870Genotype, %1a1bNot otherwise specified58192213Treatment naive, %4152Mean hemoglobin > 12 g/dL94Mean platelets, cells/mm3126,000203,000Mean total bilirubin, mg/dL (range)1.0 ( )0.63 ( )Mean albumin, g/dL (range)3.9 ( )4.2 ( )Mean Meld score (range)8 (6-22)N/APresence of varices, %331BOC, boceprevir; HCV, hepatitis C virus; N/A, not applicable; NOS, not otherwise specified; P/R, peginterferon + ribavirin; TVR, telaprevir.David R. Nelson, MD:Looking at the overall patient characteristics, the North American population is aging and is most likely to be infected with genotype 1a HCV. One concerning aspect of this database is that approximately 15% to 20% of patients with genotype 1 HCV are not further subtyped as 1a or 1b, and as we previously discussed, subtype-specific regimens and responses may be critical going forward. Consequently, at least in North America, clinicians need to be very specific about ordering an HCV genotype that provides them with the subtype as well.The database comprises approximately 50% treatment-naive and 50% treatment-experienced patients and is probably the largest cirrhotic database currently being followed. Patients with cirrhosis are carefully characterized by the presence or absence of portal hypertension and approximately one third of patients with cirrhosis has varices, with a range of model for end-stage liver disease scores that somewhat quantitate their degree of liver dysfunction.Fried MW, et al. EASL Abstract 818.
25HCV-TARGET: Virologic Response by Previous Treatment Category In interim analysis, on-treatment efficacy of telaprevir and boceprevir in real-world setting comparable to registration trialsTVR Wk 4 TVR Wk 12BOC Wk 8 BOC Wk 12100867878808073636160545448Undetectable HCV RNA (%)43444543BOC, boceprevir; HCV, hepatitis C virus; P/R, peginterferon/ribavirin; TVR, telaprevir.David R. Nelson, MD:This slide shows the interim on-treatment virologic response. Overall, there was very good on-treatment activity, similar to that seen in registration trials. The final SVR data are expected to be reported at the American Association for the Study of Liver Disease 2013 Liver Meeting.40252015n =40024710179133922825119742116149763732Treatment NaivePrevious RelapserPrevious Partial or Null ResponseUnknown ResponseFried MW, et al. EASL Abstract 818. Reproduced with permission.
26HCV-TARGET: Safety Assessment in Patients With Cirrhosis Event, %Cirrhotic(n = 550)Noncirrhotic(n = 787)SAE8Death, n21Early discontinuationDue to adverse eventDue to lack of efficacy264431213338Decompensation11Infection24Severe rash (grade 3/SCAR)Hemoglobin < 8.5 g/dL2014RBV dose reduction42EPO10Transfusion5BOC, boceprevir; EPO, erythropoietin; HCV, hepatitis C virus; P/R, peginterferon/ribavirin; RBV, ribavirin; SCAR, severe cutaneous adverse reaction; TVR, telaprevir.David R. Nelson, MD:I think the most important insights from the TARGET study, especially in relation to the CUPIC data that we just discussed, are the overall safety data comparing cirrhotic and noncirrhotic patients. Overall, there was an increased risk of adverse events, but the profile was somewhat different than the French experience.Deaths were relatively uncommon, occurring in only 2% of the cirrhotic population, but early discontinuation and adverse event rates were higher in the cirrhotic population. The key challenge was decompensation, which occurred in 11% of patients with cirrhosis. A multivariate analysis to assess potential predictive factors for decompensation is now under way and may shed some light on this issue. Infection was not significantly increased in the cirrhotic population, and severe rashes were fairly uncommon in North America and occurred at low level even in cirrhotics. Clearly, anemia had the biggest impact on treatment but was different from the CUPIC cohort: In the TARGET study, dose reduction was primarily used to manage anemia, limiting the development of anemia with hemoglobin levels < 8.5 g/dL—considered severe anemia—to only 20% of patients. Use of erythropoietin and transfusions was also less than that reported in the CUPIC database.This is an interesting database that is now also expanding to Europe and may help rapidly report real-world data as new drugs are approved.Paul Y. Kwo, MD:The TARGET study confirmed our own experience that clinicians using these triple-therapy regimens, particularly in patients with cirrhosis, are learning to accept lower hemoglobin levels because they are associated with better responses to therapy. Among patients who are responding to triple therapy, occasional transfusions are something that we now accept. Furthermore, it is also clear that ribavirin dose reduction does not result in lower SVR rates.Fried MW, et al. EASL Abstract 818.
27CUPIC Boceprevir and Telaprevir Treatment Regimens Peg-IFN α-2a + RBVTVR + Peg-IFN α-2a + RBVFollow-up48416128Weeks72SVR12BOC + Peg-IFN α-2b + RBVPeg-IFN + RBV36BOC: 800 mg/8h; Peg-IFNα-2b: 1.5 µg/kg/week; RBV: 800 to 1400 mg/dayTVR: 750 mg/8h; Peg-IFNα-2a: 180 µg/week; RBV: 1000 to 1200 mg/daySVR24Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, Abst. 60Hezode, C, et al. 63rd AASLD; Boston, MA; November 9-13, Abst. 51.
28CUPIC Baseline Demographics and Disease Characteristics Telaprevir N=295Boceprevir N=190Child-Pugh score A/B, n (%)*280 (95) / 6 (2)177 (93) /1 (1)MELD score, mean (range)8.1 (6-22)8.1 (6-28)Prothrombin time ratio, mean % (range)86 (27–100)87 (23–100)Serum albumin g/L, mean (range)40.0 (20.7–53.2)40.7 (27.0–50.3)Total bilirubin μmol/L, mean (range)15.5 (4.0–73.0)15.2 (4.0–78.0)Hgb level g/dL, mean (range)14.5 (9.0–19.7)14.8 (10.8–18.4)Neutrophils, mean (range) (109/mm3)3.3 ( )3.2 ( )Platelet count, mean (range) (103/mm3)151 (18–604)144 (34–346)Esophageal varices, n (%)51/145 (35.2)37/97 (38.1)* Missing data : 21Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, Abst. 60
29CUPIC Virological Response (ITT): SVR12 TELAPREVIRBOCEPREVIR10203040506070809010049%Patients with undetectable HCV RNA (Percentage)79%81%56%W4W8W12W24W48W60W1677 %68 %14629523423922720016511816%51%62%65%67%311909712412810857%7940%41%Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, Abst. 60
30CUPIC SVR12 According to HCV G1 Subtype Genotype1a1bUndeterminedgenotype 133/9875/1629/3334%46%27%P=0.004102030405060708090100SVR 12 (ITT ) (Percentage)TELAPREVIRGenotype1a1bUndeterminedgenotype 11020304050607080901006/16P=0.0331%51%37%49/9624/77BOCEPREVIRSVR 12 (ITT ) (Percentage)Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, Abst. 60
31CUPIC: SVR12 Safety Findings Patients, n(% patients with at least one event)Telaprevir n=295Boceprevir n=190Serious adverse events (SAEs)*535 in 160 patients (54.2%)321 in 97 patients(51.0%)Premature discontinuation /due to SAEs139 (47.1%) /63 (21.3%)80 (42.1%)/27 (14.2%)Death7 (2.4 %)3 (1.6%)Infection (Grade 3/4)27 (9.1 %)8 (4.2%)Hepatic decompensation(Grade ¾ )15 (5.1 %)9 (4.7%)Anemia (Grade ¾ : Hb < 8 g/dL)38 (12.9 %)19 (10%)Rash (grade 3/SCAR)16 (5.4 %)/ 2 (0.6 %)2 (1.0%)/EPO use / blood transfusion168 (57 %) /53 (18 %)119 (62.6%) /26 (13.7%)GCSF use8 (2.7 %)13 (6.8%)TPO use6 (2 %)Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, Abst. 60
32CUPIC Predictors of Death or Severe Complications PredictiveFactorsPlatelets count>100,000/mm3≤100,000/mm3Albumin 35 g/L3.4 %(10/298)4.3 %(3/69)Albumin <35 g/L7.1 %(2/28)44.1 %(15/34)Hezode, C, et al. 63rd AASLD; Boston, MA; November 9-13, Abst. 51.
33Meta-Analysis: Five Boceprevir Phase 3 Trials Vierling JM, et al. EASL Abstract 1430.A pooled analysis of 5 BOC phase III clinical trials in patients with HCV genotype 1 infectionCirrhosis defined as METAVIR F4 scoreCentral reading of all liver biopsiesStudyPatientsP/R,n (%)BOC/P/R 48 weeks,BOC P/RRGT,All,Cirrhotic Patients,SPRINT-2Previously untreated363 (33)366 (33)368 (34)1097 (100)53 (5)Anemia Management study—111 (16)576 (84)687 (100)60 (9)RESPOND-2Previous treatment failure80 (20)161 (40)162 (40)403 (100)49 (12)PEG2a67 (33)134 (67)201 (100)33 (16)PROVIDE134 (100)17 (13)Total510 (20)906 (36)1106 (44)2522 (100)212 (8)BOC = boceprevir; P/R = peginterferon and ribavirin; RGT = response-guided therapy
34Patient Characteristics Vierling JM, et al. EASL Abstract 1430.P/RBOC/P/RF0-2(n = 436)F3(n = 22)F4(n = 32)(n = 1638)(n = 107)(n = 180)Age, mean (SD), y49.5 (9.6)51.6 (10.2)54.7 (6.8)49.7 (9.4)52.7 (7.3)53.2 (6.7)Male, n (%)252 (58)20 (91)23 (72)860 (53)73 (68)112 (62)Viral loadLog10 Geometric Mean*6.546.226.496.476.39>800,000 IU/mL, n (%)372 (85)19 (86)20 (63)1371 (84)91 (85)144 (80)Genotype subtype, n (%)1a208 (48)10 (45)17 (53)811 (50)60 (56)92 (51)1b160 (37)11 (50)12 (38)622 (38)37 (35)65 (36)1 (other)68 (16)1 (5)3 (9)204 (12)10 (9)23 (13)Missing1 (<1)PlateletsMean (SD) × 109/L252.9 (69.3)188.5 (64.5)183.1 (73.4)249.8 (70.9)†198.4 (64.7)165.8 (57.4)<150 × 109 cells/L, n (%)26 (6)8 (36)10 (31)99 (6)27 (25)78 (43)Baseline haemoglobin (g/dL), mean (SD)14.7 (1.3)15.7 (1.3)15.2 (1.1)14.6 (1.3)15.1 (1.4)14.6 (1.2)Baseline serum albuminMean (range), g/L40.7 (32-49)40.1 (34-46)39.1 (34-44)40.9 (30-51)39.9 (30-49)38.8 (31-49)<35 g/dL, n (%)6 (<1)38 (2)5 (5)21 (12)BOC = boceprevir; PR = peginterferon and ribavirin*Baseline viral load is the geometric mean of all virology collections during screening and before the randomization date.†Baseline platelets for 1637 patients.
35Sustained Virologic Response Vierling JM, et al. EASL Abstract 1430.SVR rates were substantially higher with BOC/P/R compared with P/R alone, regardless of fibrosis scoreIn patients receiving BOC/P/R, SVR rates were similar in patients with bridging fibrosis (F3) and cirrhosis (F4)n=1638n=436n=107n=22n=180n=32*Treatment-naive patients and those with previous treatment failure combined.The analyses of the pooled studies were homogeneous for the SVR rates for F0-2 and F3 patients treated with BOC/P/R, and for F3 patients treated with P/R. Therefore, the fixed-effect estimates for the SVR rates were used for these patients. The analysis of the studies for the SVR rates was heterogeneous for F4 patients treated with BOC/P/R or P/R, and for F0-2 patients treated with P/R; therefore, the random-effect estimate for the SVR rate was used for these patientsBOC = boceprevir; CI = confidence interval; P/R = peginterferon and ribavirin; SVR = sustained virologic response.
36SVR According to TW4 Virologic Response Vierling JM, et al. EASL Abstract 1430.Regardless of METAVIR fibrosis score, SVR rates were higher in patients with ≥1 log10 decline in HCV RNA at TW4 than those with <1 log10 declineAmong patients with ≥1 log10 decline in HCV RNA, SVR rates with BOC/P/R were similar in patients with METAVIR F3 and F4 fibrosisSVR rate was 21% in cirrhotic patients receiving BOC/P/R with <1 log10 decline in HCV RNA at TW4895/1155168/41547/7010/3585/12810/48*Treatment-naive patients and those with previous treatment failure combined (total treatment duration = 8 weeks).CI = confidence interval; HCV = hepatitis C virus; SVR = sustained virologic response; TW = treatment week.
37SVR According to TW8 Virologic Response Vierling JM, et al. EASL Abstract 1430.SVR rates were high in all patients with undetectable HCV RNA at TW8, intermediate in those with >3 log10 decline at TW8, and low in those with <3 log10 decline at TW8, regardless of METAVIR fibrosis scoreFew F0-2 and no F3-4 patients with detectable HCV RNA and <3 log10 decline in HCV RNA at TW8 achieved SVR766/889293/54440/4716/4765/7328/795/780/50/17*Treatment-naive patients and those with previous treatment failure combined.BOC = boceprevir; CI = confidence interval; HCV = hepatitis C virus; PR = peginterferon plus ribavirin; SVR = sustained virologic response.
38Predictors of SVR in F3/F4 Patients Receiving BOC/PR Vierling JM, et al. EASL Abstract 1430.1234567810.57 (5.23 – 21.36); P<0.00012.64 (1.33 – 5.21); P=0.00532.23 (1.18 – 4.24); P=0.01412.55 (1.05 – 6.20); P=0.03831.76 (0.90 – 3.44); P=0.09711.08 (0.43 – 2.72); P=0.8636910Odds Ratio (95% CI)TW8: undetectable vs. detectable HCV-RNATW4: ≥1log decline vs.<1 log declineMale vs. femaleBaseline viral load≤800,000 IU/mLvs. >800,000 IU/mLG1b vs. G1aNon-black vs. blackCI = confidence interval; G = genotype; TW = treatment week.
39Vierling JM, et al. EASL 2013. Abstract 1430. SVR According to Treatment Duration in Patients with Undetectable HCV RNA at TW8 receiving BOC/PR*Vierling JM, et al. EASL Abstract 1430.279/306351/36758/1324/63/715/1816/1878/846/68/917/1838/39*Treatment-naive patients and those with previous treatment failure combined.BOC = boceprevir; CI = confidence interval; HCV = hepatitis C virus; PR = peginterferon plus ribavirin; SVR = sustained virologic response.
40Vierling JM, et al. EASL 2013. Abstract 1430. Significant Medical Events Patients with Potential Hepatic Decompensation or SepsisVierling JM, et al. EASL Abstract 1430.Patient ID(Study)Baseline DataEventTreatment regimen (weeks of treatment)OutcomeCirrhotic Patients016301(PROVIDE)Male, 64 yo; F4.History of ascitesPlatelets, 108KAlbumin, 3.7 g/LDecompensated cirrhosis with ascites and encephalopathy (confusion)BOC/P/R(TW6)Discontinued treatment; events resolved012072(RESPOND-2)Female, 51 yo; F4Platelets, 170KAlbumin, 3.5 g/LBleeding esophageal varices and portal hypertensionP/R(TW2)000603(PEG2a study)Male, 48 yo; F4Diabetic, IVDUPlatelets, 135KAlbumin, 3.8 g/LMulti-organ failure with total bilirubin peak 17.4 mg/dL(Staphylococcus pneumonia, resulting in multi-organ failure)(TW12)Died of multi-organ failureNon-Cirrhotic Patients000005Male, 52 yo; F2Platelets, 280KAlbumin, 4.2 g/LPossible urosepsis(negative blood and urine cultures)(TW3)Discontinued treatment; event resolved001868(SPRINT-2)Male, 58 yo; F2Platelets, 192KAscites(Hospitalized with severe epiglottitis and neutropenia; developed acute renal failure; treatment discontinued; ascites and oedema noted 12 days later)12 days after discontinuing BOC/P/R (TW12)Discontinued treatment for other AEs; ascites resolvedBOC = boceprevir; IVDU = intravenous drug user; P/R = peginterferon and ribavirin; TW = treatment week; yo = years old.
41Limitations of Current Regimens and Prospects for Future Regimens Must be eligible for pegIFN/ RBVHigh pill burden, TID dosing of PIs (at present); parenteral IFNMultiple adverse eventsSelection of resistance – associtaed variants with treatment failureOnly effective for genotype 1Risk of resistance with poor adherenceFutureIncreasingly IFN freeLower pill burden, daily dosing;Better toleratedLimited resistance-associated variantsPangenotypicHigher barrier to resistance with some classesGT, genotype; IFN, interferon; pegIFN, peginterferon; PI, protease inhibitor; RBV, ribavirin; TID, 3 times daily.
42Investigational Agents for HCV in 2013 InterferonsAntiviral agentsTherapeutic vaccinesHost targetmiRNA-122CyclophilinEntryReplication, polyprotein processing and/or assemblyCypAinhibitorsCyp, cyclophilin; HCV, hepatitis C virus.NS5B polymerase inhibitorsNS3/4A protease inhibitorsNS5A replication complex inhibitors
43Management of Chronic Hepatitis C in 2013 Regimens containing Peg-IFN are contraindicated for patients with cirrhosis who have all but one of the following:Compensated cirrhosisDecompensated cirrhosisAlbumin <3.5 mg/dL and Platelets <100,000 mm3ESRDHCC, hepatocellular carcinoma; SVR, sustained virologic response.