1. 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
HCC, hepatocellular carcinoma; SVR, sustained virologic response.

2. 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.
True
False
HCC, hepatocellular carcinoma; SVR, sustained virologic response.

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

4. 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]
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:

5. Cirrhosis: Treat Before Decompensation!
Survival Probability
Compensated
100
After first major complication 80 60
Patients (%) 40 20
HCV, hepatitis C virus. 12 24 36 48 60 72 84 96
108
120
Mos
384 65
342 21
288 11
236 7
165 4
126 4
79 3
52 3
39 2
25 1
Pts at Risk, n
Fattovich G, et al. Gastroenterology. 1997;112:

6. Patients With Liver Complications (%)
Liver-Related Complications Decrease Following SVR in Cirrhotic Patients
No SVR
100
SVR 80 60
Patients With Liver Complications (%) 40 20
SVR, sustained virologic response. 24 48 72 96
120
144
168
Mos
345 70
207 41
34 12
Pts at Risk, n
Bruno S, et al. Hepatology. 2007;45:

7. Probability of decompensation
Compensated Cirrhosis: HVPG  10 mmHg is the strongest predictor of decompensation
0.2
0.4
0.6
0.8
1.0
Probability of decompensation
(ascites, VH, HE) 80 20
100 40 60
Months
Baseline HVPG ≥10mmHg
Baseline HVPG <10mmHg
Log rank test: p<0.01
HR 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 mmHg
had a reduction >20% or to <12 mmHg
HVPG reduction superior in virological and biochemical responders at EOT *
* Almost immediately after completing AVT
Rincon et al. Am J Gastroenterol 2006;101:2269–2274.

9. Compensated Cirrhosis:
Reduction in HVPG >10% at one-year prevents development of varices 12 60 24 72
 HVPG > 10%
 HVPG  10%
% Free of varices
Months
100 80 40 20 36 48
p=0.014
Groszmann, Garcia-Tsao, Bosch et al. N Engl J Med 2005, 353:

10. 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]
SVR better
No SVR better
Genotype 1
P < .0001
Genotype 2
P = .004
Genotype 3
P < .0001
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
All-Cause Mortality HR (95% CI)
Morgan TR, et al. Hepatology. 2010;52:
2. Backus L, et al AASLD. Abstract 213.

11. Management of Chronic Hepatitis C in 2013
SVR after antiviral therapy for HCV infection:
Represents a cure
Reduces liver-related mortality
Reduces all-cause mortality
Needs to be better understood by Dr. Goss
All of the above
HCC, hepatocellular carcinoma; SVR, sustained virologic response.

12. 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
PegIFN, peginterferon; RBV, ribavirin; RVR, rapid virologic response.
1. Ghany MG, et al. Hepatology. 2011;54: EASL. J Hepatol. 2011;55:

13. 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
100
PegIFN + RBV
69-83 80
BOC/TVR + pegIFN* + RBV
63-75
40-59 60
SVR (%)
38-44
29-40 40
24-29
BOC, boceprevir; pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response; TVR, telaprevir. 20
7-15 5
Treatment 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.

14. BOC and TVR Potential for Multiple Drug–Drug Interactions
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)
TVR
Substrate of CYP3A
Inhibitor of CYP3A
Substrate and inhibitor of P-gp
BOC, boceprevir; P-gp, P-glycoprotein; PI, protease inhibitor; TVR, telaprevir.

15. SPRINT-2: Influence of Baseline Patient and Virus Factors on SVR With BOC/PR
BOC + pegIFN-α2b/RBV RGT
BOC + pegIFN-α2b/RBV 48 wks
93/ 133
89/ 134
100 50
1b a
Genotype[1] 70 66
≤ 800, > 800,000
HCV RNA (IU/mL)[1] 85 76
F F3/F4
Fibrosis[1] 67
SVR (%) 75 25
41/ 54
45/ 53
213/ 319
211/ 313
n/ N = 63 59 61 41 52
118/ 187
106/ 179
14/ 34
22/ 42
192/ 314
197/ 313
44/ 55
82/ 115
26/ 44
CC CT TT 80 71
IL28B[2]
BOC, 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:

16. ADVANCE: Influence of Baseline Patient and Virus Factors on SVR With TVR
Data from TVR12 + pegIFN-α2a/RBV arm only
100 90 79 78 78 74 73 71 71 75 62
SVR (%) 50 25
HCV, hepatitis C virus; pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response; TVR, telaprevir.
n/ N =
118/ 149
152/ 213
64/ 82
207/ 281
226/ 290
45/ 73
45/ 50
48/ 68
16/ 22
1b a
Genotype[1]
< 800,000 ≥ 800,000
HCV RNA (IU/mL)[1]
F F3/F4
Fibrosis[1]
CC CT TT
IL28B*[2]
*IL28B testing was in whites only.
1. Jacobson IM, et al. N Engl J Med. 2011;364: Jacobson IM, et al. EASL Abstract 1369.

17. 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
HCV, hepatitis C virus; IV, intravenous; PI, protease inhibitor.

18. HCV Antivirals New Studies Using Current Therapies

19. 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
Wk 12
Wk 24
T12/PR12
Stop all treatment
(n = 107)
Treatment-naive patients or previous relapsers with GT 1 HCV, IL28B CC genotype, and no cirrhosis
(N = 239)
Telaprevir +
P/R
2:1 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,[1] which showed that patients with the IL28B CC genotype had high SVR rates with telaprevir plus peginterferon/ribavirin for 12 weeks.
Reference
1. 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/PR24
Continue 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.

20. CONCISE: Virologic Responses TVR12/PR12 vs. TVR12/PR24 after eRVR
T12/PR12
T12/PR24 99 98
100 97
100 89 87 80 60
Patients (%) 40 20
105/ 106
51/ 52
93/ 104
38/ 38
74/ 85
29/ 30
n/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.[1]
For more information on this study, review the CCO Capsule Summary at:
Reference
1. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:
eRVR
SVR4
SVR12
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.

21. HCV RNA Undetectable (%)
TARGET-C: TVR With Reduced RBV + Peg-IFN in HCV-Infected Hemodialysis Patients
TVR + PegIFN/RBV 200 mg
Wk 12
Pts with GT 1 HCV;
on hemodialysis
(N = 36)
PegIFN/RBV 400 mg
TVR + PegIFN + Placebo
Placebo + PegIFN/RBV 400 mg
Wk 24
Wk 36
Wk 48
n = 12
100
PegIFN alfa-2a dosed at 135 µg/wk
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%) 80 67 63 60
HCV RNA Undetectable (%) 50 50
AEs, 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. 40 25 25 20
n/ N =
8/ 12
6/ 12
3/ 12
7/ 12
6/ 12
3/ 12
EOT
SVR
Basu P, et al. EASL Abstract 67.

22. HCV Antiviral Therapy for Genotype 1 Cirrhotics

23. 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
Patient Disposition, n (%)
DAA + P/R
(N = 1919)
Patients in current analysis
1457
Patients with cirrhosis
550
Still on treatment, < 16 wks
139 (6)
Still on treatment, > 16 wks
664 (46)
Completed full course
319 (22)
Patient Disposition
DAA + P/R
(N = 1457)
Early discontinuation, n (%)
335 (23)
Lack of efficacy 8
Adverse event 9
Other reasons 5
Multiple reasons 2
BOC, 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.

24. HCV-TARGET: Baseline Characteristics
Patient Characteristic
Cirrhotic
(n = 550)
Noncirrhotic
(n = 787)
40-64 yrs of age, % 84 80
Male, % 69 55
White, % 78 70
Genotype, % 1a 1b
Not otherwise specified 58 19 22 13
Treatment naive, % 41 52
Mean hemoglobin > 12 g/dL 94
Mean platelets, cells/mm3
126,000
203,000
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, % 33 1
BOC, 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.

25. 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
TVR Wk 4 TVR Wk 12
BOC Wk 8 BOC Wk 12
100 86 78 78 80 80 73 63 61 60 54 54 48
Undetectable HCV RNA (%) 43 44 45 43
BOC, 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. 40 25 20 15
n =
400
247
101 79
133 92 28 25
119 74 21 16
149 76 37 32
Treatment Naive
Previous Relapser
Previous Partial or Null Response
Unknown Response
Fried MW, et al. EASL Abstract 818. Reproduced with permission.

26. HCV-TARGET: Safety Assessment in Patients With Cirrhosis
Event, %
Cirrhotic
(n = 550)
Noncirrhotic
(n = 787)
SAE 8
Death, n 2 1
Early discontinuation
Due to adverse event
Due to lack of efficacy 26 44 31 21 33 38
Decompensation 11
Infection 24
Severe rash (grade 3/SCAR)
Hemoglobin < 8.5 g/dL 20 14
RBV dose reduction 42
EPO 10
Transfusion 5
BOC, 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.

27. CUPIC Boceprevir and Telaprevir Treatment Regimens
Peg-IFN α-2a + RBV
TVR + Peg-IFN α-2a + RBV
Follow-up 48 4 16 12 8
Weeks 72
SVR12
BOC + Peg-IFN α-2b + RBV
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
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.

28. CUPIC Baseline Demographics and Disease Characteristics
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) (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 : 21
Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, Abst. 60

29. CUPIC Virological Response (ITT): SVR12
TELAPREVIR
BOCEPREVIR 10 20 30 40 50 60 70 80 90
100
49%
Patients with undetectable HCV RNA (Percentage)
79%
81%
56% W4 W8
W12
W24
W48
W60
W16
77 %
68 %
146
295
234
239
227
200
165
118
16%
51%
62%
65%
67% 31
190 97
124
128
108
57% 79
40%
41%
Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, Abst. 60

30. CUPIC SVR12 According to HCV G1 Subtype
Genotype 1a 1b
Undetermined
genotype 1
33/98
75/162
9/33
34%
46%
27%
P=0.004 10 20 30 40 50 60 70 80 90
100
SVR 12 (ITT ) (Percentage)
TELAPREVIR
Genotype 1a 1b
Undetermined
genotype 1 10 20 30 40 50 60 70 80 90
100
6/16
P=0.03
31%
51%
37%
49/96
24/77
BOCEPREVIR
SVR 12 (ITT ) (Percentage)
Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, Abst. 60

31. CUPIC: SVR12 Safety Findings
Patients, n
(% patients with at least one event)
Telaprevir n=295
Boceprevir 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 use
8 (2.7 %)
13 (6.8%)
TPO use
6 (2 %)
Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, Abst. 60

32. CUPIC Predictors of Death or Severe Complications
Predictive
Factors
Platelets count
>100,000/mm3
≤100,000/mm3
Albumin 35 g/L
3.4 %
(10/298)
4.3 %
(3/69)
Albumin <35 g/L
7.1 %
(2/28)
44.1 %
(15/34)
Hezode, C, et al. 63rd AASLD; Boston, MA; November 9-13, Abst. 51.

33. Meta-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 infection
Cirrhosis defined as METAVIR F4 score
Central reading of all liver biopsies
Study
Patients
P/R,
n (%)
BOC/P/R 48 weeks,
BOC P/R
RGT,
All,
Cirrhotic Patients,
SPRINT-2
Previously untreated
363 (33)
366 (33)
368 (34)
1097 (100)
53 (5)
Anemia Management study —
111 (16)
576 (84)
687 (100)
60 (9)
RESPOND-2
Previous treatment failure
80 (20)
161 (40)
162 (40)
403 (100)
49 (12)
PEG2a
67 (33)
134 (67)
201 (100)
33 (16)
PROVIDE
134 (100)
17 (13)
Total
510 (20)
906 (36)
1106 (44)
2522 (100)
212 (8)
BOC = boceprevir; P/R = peginterferon and ribavirin; RGT = response-guided therapy

34. Patient Characteristics
Vierling JM, et al. EASL Abstract 1430.
P/R
BOC/P/R
F0-2
(n = 436) F3
(n = 22) F4
(n = 32)
(n = 1638)
(n = 107)
(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
Log10 Geometric Mean*
6.54
6.22
6.49
6.47
6.39
>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) 1b
160 (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)
Missing
1 (<1)
Platelets
Mean (SD) × 109/L
252.9 (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 albumin
Mean (range), g/L
40.7 (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.

35. Sustained 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 score
In patients receiving BOC/P/R, SVR rates were similar in patients with bridging fibrosis (F3) and cirrhosis (F4)
n=1638
n=436
n=107
n=22
n=180
n=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 patients
BOC = boceprevir; CI = confidence interval; P/R = peginterferon and ribavirin; SVR = sustained virologic response.

36. SVR 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 decline
Among patients with ≥1 log10 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 log10 decline in HCV RNA at TW4
895/
1155
168/415
47/70
10/35
85/128
10/48
*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.

37. SVR 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 score
Few F0-2 and no F3-4 patients with detectable HCV RNA and <3 log10 decline in HCV RNA at TW8 achieved SVR
766/
889
293/
544
40/47
16/47
65/73
28/79
5/78
0/5
0/17
*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.

38. Predictors of SVR in F3/F4 Patients Receiving BOC/PR
Vierling JM, et al. EASL Abstract 1430. 1 2 3 4 5 6 7 8
10.57 (5.23 – 21.36); P<0.0001
2.64 (1.33 – 5.21); P=0.0053
2.23 (1.18 – 4.24); P=0.0141
2.55 (1.05 – 6.20); P=0.0383
1.76 (0.90 – 3.44); P=0.0971
1.08 (0.43 – 2.72); P=0.8636 9 10
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.

39. Vierling 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
/306
351
/367
58/132
4/6
3/7
15/18
16/18
78/84
6/6
8/9
17/18
38/39
*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.

40. Vierling JM, et al. EASL 2013. Abstract 1430.
Significant Medical Events Patients with Potential Hepatic Decompensation or Sepsis
Vierling JM, et al. EASL Abstract 1430.
Patient ID
(Study)
Baseline Data
Event
Treatment regimen (weeks of treatment)
Outcome
Cirrhotic Patients
016301
(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
012072
(RESPOND-2)
Female, 51 yo; F4
Platelets, 170K
Albumin, 3.5 g/L
Bleeding esophageal varices and portal hypertension
P/R
(TW2)
000603
(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)
(TW12)
Died of multi-organ failure
Non-Cirrhotic Patients
000005
Male, 52 yo; F2
Platelets, 280K
Albumin, 4.2 g/L
Possible urosepsis
(negative blood and urine cultures)
(TW3)
Discontinued treatment; event resolved
001868
(SPRINT-2)
Male, 58 yo; F2
Platelets, 192K
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.

41. Limitations of Current Regimens and Prospects for Future Regimens
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
GT, genotype; IFN, interferon; pegIFN, peginterferon; PI, protease inhibitor; RBV, ribavirin; TID, 3 times daily.

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

43. 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:
Compensated cirrhosis
Decompensated cirrhosis
Albumin <3.5 mg/dL and Platelets <100,000 mm3
ESRD
HCC, hepatocellular carcinoma; SVR, sustained virologic response.