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Clinicaloptions.com/hepatitis Seizing the Opportunity Management of Chronic Hepatitis C in 2013 John M. Vierling, M.D., F.A.C.P. Professor of Medicine.

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Presentation on theme: "Clinicaloptions.com/hepatitis Seizing the Opportunity Management of Chronic Hepatitis C in 2013 John M. Vierling, M.D., F.A.C.P. Professor of Medicine."— Presentation transcript:

1 clinicaloptions.com/hepatitis Seizing the Opportunity Management 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, Texas

2 clinicaloptions.com/hepatitis Seizing the Opportunity Management 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. A.True B.False

3 HCV Infection a Global Problem: 170 M Persons Hepatitis C Death Rates Per 100,000

4 clinicaloptions.com/hepatitis Seizing the Opportunity Chronic Hepatitis C: A Treatable Disease  HCV infection  Chronic in 70-85% and progressive in substantial proportion  Complications increasingly common [1,2]  Decompensated cirrhosis  Hepatic failure  HCC 3-7% per year in cirrhotics  Treatment resulting in SVR  Eradication of HCV infection (cure)  Results in histologic improvement and regression of fibrosis [3]  Reduces risk of hepatic failure and HCC  Improves survival [4,5] 1. Kanwal F, et al. Gastroenterology. 2011;140: Shaw JJ, et al. Expert Rev Gastroenterol Hepatol. 2011;5: Poynard T, et al. Gastroenterology. 2002;122: Craxi A, et al. Clin Liver Dis. 2005;9: Shiratori Y, et al. Ann Intern Med. 2005;142:

5 clinicaloptions.com/hepatitis Seizing the Opportunity Cirrhosis: Treat Before Decompensation! Fattovich G, et al. Gastroenterology. 1997;112: Compensated After first major complication Survival Probability 100 Patients (%) Mos Pts at Risk, n

6 clinicaloptions.com/hepatitis Seizing the Opportunity No SVR SVR 100 Patients With Liver Complications (%) Mos Liver-Related Complications Decrease Following SVR in Cirrhotic Patients Bruno S, et al. Hepatology. 2007;45: Pts at Risk, n

7 Compensated Cirrhosis: HVPG  10 mmHg is the strongest predictor of decompensation Ripoll et al (Timolol Study Group). Gastroenterology 2007; 133: Probability of decompensation (ascites, VH, HE) Probability of decompensation (ascites, VH, HE) Months Baseline HVPG ≥10mmHg Baseline HVPG <10mmHg Log rank test: p<0.01 HR 3.95 (2.29–6.83)

8 HCV Antiviral Therapy Decreases HVPG in Patients with Advanced Fibrosis or Cirrhosis with Portal Hypertension (n=20) Rincon et al. Am J Gastroenterol 2006;101:2269– /11 patients with HVPG12 mmHg 9/11 patients with HVPG ≥ 12 mmHg had a reduction >20% or to 20% or to <12 mmHg HVPG reduction superior in virological and biochemical responders at EOT * * Almost immediately after completing AVT

9  HVPG > 10%  HVPG  10% % Free of varices Months p=0.014 Groszmann, Garcia-Tsao, Bosch et al. N Engl J Med 2005, 353: Compensated Cirrhosis: Reduction in HVPG >10% at one-year prevents development of varices

10 clinicaloptions.com/hepatitis Use of Boceprevir and Telaprevir for the Treatment of Hepatitis C SVR is Meaningful Clinical Endpoint  SVR= endpoint of successful HCV treatment – Defined as undetectable serum HCV RNA levels 24 wks after end of treatment – Represents a cure  SVR associated with significant reductions of HCV-associated complications and mortality [1,2] 1.Morgan TR, et al. Hepatology. 2010;52: Backus L, et al AASLD. Abstract 213. SVR betterNo SVR better Genotype 1 Genotype 2 Genotype 3 P <.0001 P =.004 P <.0001 All-Cause Mortality HR (95% CI)

11 clinicaloptions.com/hepatitis Seizing the Opportunity Management of Chronic Hepatitis C in 2013 SVR after antiviral therapy for HCV infection: A.Represents a cure B.Reduces liver-related mortality C.Reduces all-cause mortality D.Needs to be better understood by Dr. Goss E.All of the above

12 clinicaloptions.com/hepatitis Seizing the Opportunity For HCV Genotype 2 or 3, PegIFN/RBV Current Standard of Care  Higher SVR rates than genotype 1  24 wks of therapy recommended [1,2]  Patients with RVR and low baseline HCV RNA can be treated for 16 wks  Relapse rates may be higher [2]  Future regimens may offer further improvements, such as  Shorter durations  All-oral therapy  Fewer adverse events 1. Ghany MG, et al. Hepatology. 2011;54: EASL. J Hepatol. 2011;55:

13 clinicaloptions.com/hepatitis Seizing the Opportunity Addition 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 therapy 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 SVR (%) Relapsers [3,4] Partial Responders [3,4] PegIFN + RBV Null Responders [4,5] BOC/TVR + pegIFN* + RBV Treatment Naive [1,2] *BOC was administered with pegIFN-α2b; TVR was administered with pegIFN-α2a in these trials.

14 clinicaloptions.com/hepatitis Seizing the Opportunity  TVR –Substrate of CYP3A –Inhibitor of CYP3A –Substrate and inhibitor of P-gp BOC and TVR Potential for Multiple Drug–Drug Interactions  BOC  Strong inhibitor of CYP3A4/5  Partly metabolized by CYP3A4/5  Potential inhibitor of and substrate for P-gp  Most 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)

15 clinicaloptions.com/hepatitis Seizing the Opportunity SPRINT-2: Influence of Baseline Patient and Virus Factors on SVR With BOC/PR 1. Poordad F, et al. N Engl J Med. 2011;364: Poordad F, et al. Gastroenterology. 2012;143: BOC + pegIFN-α2b/RBV RGT BOC + pegIFN-α2b/RBV 48 wks 93/ / b 1a Genotype [1] ≤ 800,000 > 800,000 HCV RNA (IU/mL) [1] F0-2 F3/F4 Fibrosis [1] 67 SVR (%) / 54 45/ / / 313 n/ N = / / / 34 22/ / / / 55 82/ / 44 CC CT TT IL28B [2]

16 clinicaloptions.com/hepatitis Seizing the Opportunity 1b 1a Genotype [1] < 800,000 ≥ 800,000 HCV RNA (IU/mL) [1] F0-2 F3/F4 Fibrosis [1] ADVANCE: Influence of Baseline Patient and Virus Factors on SVR With TVR Data from TVR12 + pegIFN-α2a/RBV arm only 1. Jacobson IM, et al. N Engl J Med. 2011;364: Jacobson IM, et al. EASL Abstract CC CT TT IL28B* [2] 152/ / SVR (%) / / 82 45/ / 290 n/ N = 45/ 50 48/ 68 16/ *IL28B testing was in whites only.

17 clinicaloptions.com/hepatitis Seizing the Opportunity Challenging Patients with Suboptimal Current Treatment Options  Cirrhosis (all genotypes)  Decompensated cirrhosis  Null responders  Pre-transplantation  Post-transplantation  Chronic Renal failure  Impaired renal function  Dialysis  Renal transplantation recipients  Injection-drug users  Methadone substitution  Thalassemics  Children  IFN contraindicated  IFN intolerant  Those with poor social support  Psychiatric comorbidities

18 HCV Antivirals New Studies Using Current Therapies

19 clinicaloptions.com/hepatitis HCV Phase III Studies and Approved Agents CONCISE: Telaprevir + P/R for Patients with HCV GT 1 and IL28B CC Interim analysis of ongoing, multicenter, randomized, active-controlled, exploratory phase IIIb study Treatment-naive patients or previous relapsers with GT 1 HCV, IL28B CC genotype, and no cirrhosis (N = 239) T12/PR24 Continue P/R alone (n = 52) 2:1 randomization* Wk 12 Wk 24 T12/PR12 Stop all treatment (n = 107) *Patients with RVR randomly assigned 2:1 to T12/PR12 or T12/PR24. Nelson DR, et al. EASL Abstract 881. Telaprevir + P/R

20 clinicaloptions.com/hepatitis HCV Phase III Studies and Approved Agents 0 CONCISE: Virologic Responses TVR12/PR12 vs. TVR12/PR24 after eRVR  Relapse in 8% of patients in TVR12/PR12 arm vs 0% in T12/PR24 arm  Safety profile consistent with that observed in previous TVR studies eRVR: undetectable HCV RNA at Wks 4 and 12. Nelson DR, et al. EASL Abstract 881. Reproduced with permission. n/N = 105/ / 52 93/ / 38 74/ 85 29/ Patients (%) eRVRSVR4SVR12 T12/PR12T12/PR24

21 clinicaloptions.com/hepatitis HCV Phase III Studies and Approved Agents TARGET-C: TVR With Reduced RBV + Peg-IFN in HCV-Infected Hemodialysis Patients  Increased incidence of select AEs in TVR arms vs P/R  Anemia (54% vs 33%)  Neutropenia (50% vs 33%)  Thrombocytopenia (37% vs 25%)  Rash (42% vs 17%)  Anorectal dysfunction (33% vs 0%)  Dysgeusia (42% vs 17%) Basu P, et al. EASL Abstract 67. n/ N = 8/ 12 6/ 12 3/ 12 7/ 12 6/ 12 3/ HCV RNA Undetectable (%) EOTSVR TVR + PegIFN/RBV 200 mg Wk 12 Pts with GT 1 HCV; on hemodialysis (N = 36) PegIFN/RBV 400 mg TVR + PegIFN + PlaceboPegIFN/RBV 400 mg Placebo + PegIFN/RBV 400 mg Wk 24 Wk 36 Wk 48 n = PegIFN alfa-2a dosed at 135 µg/wk

22 HCV Antiviral Therapy for Genotype 1 Cirrhotics

23 clinicaloptions.com/hepatitis HCV Phase III Studies and Approved Agents HCV-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 America Fried MW, et al. EASL Abstract 818. Patient Disposition, n (%)DAA + P/R (N = 1919) Patients in current analysis1457  Patients with cirrhosis550  Still 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 efficacy8  Adverse event9  Other reasons5  Multiple reasons2

24 clinicaloptions.com/hepatitis HCV Phase III Studies and Approved Agents HCV-TARGET: Baseline Characteristics Fried MW, et al. EASL Abstract 818. Patient CharacteristicCirrhotic (n = 550) Noncirrhotic (n = 787) yrs of age, %8480 Male, %6955 White, %7870 Genotype, %  1a  1b  Not otherwise specified Treatment naive, %4152 Mean hemoglobin > 12 g/dL9484 Mean platelets, cells/mm 3 126,000203,000 Mean 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/A Presence of varices, %331

25 clinicaloptions.com/hepatitis HCV Phase III Studies and Approved Agents HCV-TARGET: Virologic Response by Previous Treatment Category In interim analysis, on-treatment efficacy of telaprevir and boceprevir in real-world setting comparable to registration trials Fried MW, et al. EASL Abstract 818. Reproduced with permission. n = TVR Wk 4 TVR Wk 12 BOC Wk 8 BOC Wk 12 Treatment Naive Previous Relapser Previous Partial or Null Response Unknown Response Undetectable HCV RNA (%)

26 clinicaloptions.com/hepatitis HCV Phase III Studies and Approved Agents HCV-TARGET: Safety Assessment in Patients With Cirrhosis Fried MW, et al. EASL Abstract 818. Event, %Cirrhotic (n = 550) Noncirrhotic (n = 787) SAE88 Death, n21 Early discontinuation  Due to adverse event  Due to lack of efficacy Decompensation111 Infection2124 Severe rash (grade 3/SCAR)21 Hemoglobin < 8.5 g/dL2014 RBV dose reduction4231 EPO10 Transfusion115

27 CUPIC Boceprevir and Telaprevir Treatment Regimens Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, Abst. 60 Hezode, C, et al. 63rd AASLD; Boston, MA; November 9-13, Abst. 51. Peg-IFN α-2a + RBV TVR + Peg-IFN α-2a + RBV Follow-up Weeks 72 SVR12 BOC + Peg-IFN α-2b + RBVFollow-up Peg-IFN + RBV 36 BOC: 800 mg/8h; Peg-IFNα-2b: 1.5 µg/kg/week; RBV: 800 to 1400 mg/day TVR: 750 mg/8h; Peg-IFNα-2a: 180 µg/week; RBV: 1000 to 1200 mg/day SVR24

28 CUPIC Baseline Demographics and Disease Characteristics Characteristic Telaprevir N=295 Boceprevir N=190 Child-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) (10 9 /mm 3 )3.3 ( )3.2 ( ) Platelet count, mean (range) (10 3 /mm 3 ) 151 (18–604) 144 (34–346) Esophageal varices, n (%)51/145 (35.2)37/97 (38.1) Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, Abst. 60 * Missing data : 21

29 CUPIC Virological Response (ITT): SVR 12 Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, Abst. 60

30 CUPIC SVR 12 According to HCV G1 Subtype Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, Abst. 60 Genotype 1a Genotype 1b Undetermined genotype 1 33/9875/1629/33 34% 46% 27% P= SVR 12 (ITT ) (Percentage) TELAPREVIR Genotype 1a Genotype 1b Undetermined genotype /16 P= % 51% 37% 49/9624/77 BOCEPREVIR SVR 12 (ITT ) (Percentage)

31 CUPIC: SVR 12 Safety Findings Patients, n (% patients with at least one event)Telaprevir n=295Boceprevir n=190 Serious adverse events (SAEs)* 535 in 160 patients (54.2%) 321 in 97 patients (51.0%) Premature discontinuation / due to SAEs 139 (47.1%) / 63 (21.3%) 80 (42.1%)/ 27 (14.2%) Death 7 (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 transfusion 168 (57 %) / 53 (18 %) 119 (62.6%) / 26 (13.7%) GCSF use8 (2.7 %)13 (6.8%) TPO use6 (2 %)3 (1.6%) Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, Abst. 60

32 CUPIC Predictors of Death or Severe Complications Hezode, C, et al. 63rd AASLD; Boston, MA; November 9-13, Abst. 51. Predictive Factors Platelets count >100,000/mm 3 Platelets count ≤100,000/mm 3 Albumin  35 g/L 3.4 % (10/298) 4.3 % (3/69) Albumin <35 g/L 7.1 % (2/28) 44.1 % (15/34) 44.1 % (15/34)

33 Meta-Analysis: Five Boceprevir Phase 3 Trials A pooled analysis of 5 BOC phase III clinical trials in patients with HCV genotype 1 infection – Cirrhosis defined as METAVIR F4 score – Central reading of all liver biopsies BOC = boceprevir; P/R = peginterferon and ribavirin; RGT = response-guided therapy StudyPatients P/R, n (%) BOC/P/R 48 weeks, n (%) BOC P/R RGT, n (%) All, n (%) Cirrhotic Patients, n (%) SPRINT-2Previously untreated363 (33)366 (33)368 (34)1097 (100)53 (5) Anemia Management study Previously untreated—111 (16)576 (84)687 (100)60 (9) RESPOND-2 Previous treatment failure 80 (20)161 (40)162 (40)403 (100)49 (12) PEG2a Previous treatment failure 67 (33)134 (67)—201 (100)33 (16) PROVIDE Previous treatment failure —134 (100)— 17 (13) Total510 (20)906 (36)1106 (44)2522 (100)212 (8) Vierling JM, et al. EASL Abstract 1430.

34 Patient Characteristics P/RBOC/P/R F0-2 (n = 436) F3 (n = 22) F4 (n = 32) F0-2 (n = 1638) F3 (n = 107) F4 (n = 180) Age, mean (SD), y 49.5 (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 load Log 10 Geometric Mean * >800,000 IU/mL, n (%)372 (85)19 (86)20 (63)1371 (84)91 (85)144 (80) Genotype subtype, n (%) 1a 208 (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) Missing0001 (<1)00 Platelets Mean (SD) × 10 9 /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 × 10 9 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 albumin Mean (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)1 (5)3 (9)38 (2)5 (5)21 (12) *Baseline viral load is the geometric mean of all virology collections during screening and before the randomization date. †Baseline platelets for 1637 patients. BOC = boceprevir; PR = peginterferon and ribavirin Vierling JM, et al. EASL Abstract 1430.

35 Sustained Virologic Response SVR rates were substantially higher with BOC/P/R compared with P/R alone, regardless of fibrosis score In patients receiving BOC/P/R, SVR rates were similar in patients with bridging fibrosis (F3) and cirrhosis (F4) *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 patients BOC = boceprevir; CI = confidence interval; P/R = peginterferon and ribavirin; SVR = sustained virologic response. n=1638 n=436 n=107 n=22 n=180 n=32 Vierling JM, et al. EASL Abstract 1430.

36 SVR According to TW4 Virologic Response Regardless of METAVIR fibrosis score, SVR rates were higher in patients with ≥1 log 10 decline in HCV RNA at TW4 than those with <1 log 10 decline Among patients with ≥1 log 10 decline in HCV RNA, SVR rates with BOC/P/R were similar in patients with METAVIR F3 and F4 fibrosis SVR rate was 21% in cirrhotic patients receiving BOC/P/R with <1 log 10 decline in HCV RNA at TW4 *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. 895/ /415 47/70 10/35 85/128 10/48 Vierling JM, et al. EASL Abstract 1430.

37 SVR According to TW8 Virologic Response SVR rates were high in all patients with undetectable HCV RNA at TW8, intermediate in those with >3 log 10 decline at TW8, and low in those with <3 log 10 decline at TW8, regardless of METAVIR fibrosis score Few F0-2 and no F3-4 patients with detectable HCV RNA and <3 log 10 decline in HCV RNA at TW8 achieved SVR *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. 766/ / /47 16/47 65/7328/79 0/17 0/5 5/78 Vierling JM, et al. EASL Abstract 1430.

38 Predictors of SVR in F3/F4 Patients Receiving BOC/PR (5.23 – 21.36); P< (1.33 – 5.21); P= (1.18 – 4.24); P= (1.05 – 6.20); P= (0.90 – 3.44); P= (0.43 – 2.72); P= Odds Ratio (95% CI) TW8: undetectable vs. detectable HCV-RNA TW4: ≥1log decline vs. <1 log decline Male vs. female Baseline viral load ≤800,000 IU/mL vs. >800,000 IU/mL G1b vs. G1a Non-black vs. black CI = confidence interval; G = genotype; TW = treatment week. Vierling JM, et al. EASL Abstract 1430.

39 SVR According to Treatment Duration in Patients with Undetectable HCV RNA at TW8 receiving BOC/PR* *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. 58/132 4/6 279 /306 15/1878/846/68/916/183/7 351 /367 17/18 38/39 Vierling JM, et al. EASL Abstract 1430.

40 Significant Medical Events Patients with Potential Hepatic Decompensation or Sepsis Patient ID (Study) Baseline DataEvent Treatment regimen (weeks of treatment) Outcome Cirrhotic Patients (PROVIDE) Male, 64 yo; F4. History of ascites Platelets, 108K Albumin, 3.7 g/L Decompensated cirrhosis with ascites and encephalopathy (confusion) BOC/P/R (TW6) Discontinued treatment; events resolved (RESPOND-2) Female, 51 yo; F4 Platelets, 170K Albumin, 3.5 g/L Bleeding esophageal varices and portal hypertension P/R (TW2) Discontinued treatment; events resolved (PEG2a study) Male, 48 yo; F4 Diabetic, IVDU Platelets, 135K Albumin, 3.8 g/L Multi-organ failure with total bilirubin peak 17.4 mg/dL (Staphylococcus pneumonia, resulting in multi-organ failure) BOC/P/R (TW12) Died of multi-organ failure Non-Cirrhotic Patients (PEG2a study) Male, 52 yo; F2 Platelets, 280K Albumin, 4.2 g/L Possible urosepsis (negative blood and urine cultures) P/R (TW3) Discontinued treatment; event resolved (SPRINT-2) Male, 58 yo; F2 Platelets, 192K Albumin, 3.5 g/L Ascites (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 resolved BOC = boceprevir; IVDU = intravenous drug user; P/R = peginterferon and ribavirin; TW = treatment week; yo = years old. Vierling JM, et al. EASL Abstract 1430.

41 clinicaloptions.com/hepatitis Seizing the Opportunity Limitations of Current Regimens and Prospects for Future Regimens Current  Must be eligible for pegIFN/ RBV  High pill burden, TID dosing of PIs (at present); parenteral IFN  Multiple adverse events  Selection of resistance – associtaed variants with treatment failure  Only effective for genotype 1  Risk of resistance with poor adherence Future  Increasingly IFN free  Lower pill burden, daily dosing;  Better tolerated  Limited resistance-associated variants  Pangenotypic  Higher barrier to resistance with some classes

42 clinicaloptions.com/hepatitis Seizing the Opportunity Investigational Agents for HCV in 2013 Interferons Antiviral agents Therapeutic vaccines Host target Replication, polyprotein processing and/or assembly Entry NS5B polymerase inhibitors NS3/4A protease inhibitors NS5A replication complex inhibitors miRNA-122 Cyclophilin CypA inhibitors

43 clinicaloptions.com/hepatitis Seizing the Opportunity Management of Chronic Hepatitis C in 2013 Regimens containing Peg-IFN are contraindicated for patients with cirrhosis who have all but one of the following: A.Compensated cirrhosis B.Decompensated cirrhosis C.Albumin <3.5 mg/dL and Platelets <100,000 mm3 D.ESRD


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