1. Viral Hepatitis Management in
2012
Paul Y Kwo, MD
Professor of Medicine
Medical Director, Liver Transplantation
Gastroenterology/Hepatology Division
Indiana University School of Medicine
975 W. Walnut, IB 327
Indianapolis, IN 46202-5121
phone 317-274-3090
fax 317-274-3106
pkwo@iupui.edu
2. Hepatitis B Virus
• Nucleic Acid: 3.2 kb DNA
• Classification: Hepadnaviridae
• Multiple serotypes and genotypes
42 nm A-H
• Enveloped
22 nm • In vitro model: primary
HBsAg
hepatocyte culture and
transfection of cloned HBV DNA
42 nm HBcAg • In vivo replication: in cytoplasm,
cccDNA in nucleus; hepatocyte
HBsAg
and other tissues, human and
HBV DNA
other primates
22 nm
3. Prevalence of HBV: Global Estimates
HBsAg
350 million With Chronic HBV Positive
(%)
Taiwan 10-13.8
Viet Nam 5.7-10
China 5.3-12
Africa 5-19
Philippines 5-16
Thailand 4.6-8
Japan 4.4-13
Indonesia 4.0
South Korea 2.6-5.1
HBsAg Prevalence
High (>8%)
India 2.4-4.7
Russia 1.4-8
Intermediate (2%-7%)
Low (<2%) United States 0.2-0.5
Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20.
Custer B, et al. J Clin Gastroenterol. 2004;38(10 suppl):S158-S168.
4. HBV Infection in the United States
• Revised HBV prevalence in the United States taking into
account recent estimates of foreign-born persons
• 847,145 to 2,243,757 persons with chronic HBV
• Average chronic HBV prevalence rate among
foreign-born persons living in the United States is
2.0% to 5.4%
Welch S, et al. Hepatology. 2008;48(suppl):687A-688A. Abstract 853.
5. HBV: How Do People Get
Infected?
• Hepatitis B is transmitted by contact with blood or body
fluids of an infected person
• The main ways of getting infected with HBV are:
• Perinatal (from mother to baby at birth)
• Child-to-child transmission
• Unsafe injections and transfusions
• Sexual contact
• HBV is 50 to 100 times more infectious than HIV
• Household contact is a documented risk factor
From http://www.who.int/vaccines/en/hepatitisb.shtml. Accessed 09/20/06.
American Journal of Epidemiology Vol. 132, No. 2: 220-232.
6. HBV - Epidemiology
Risk of Chronic Infection
100
80
60
%
Risk 40
20
0
Neonates Infants Children Adults
Age at Infection
7. Tests Used to Screen for HBV Infection
Test Significance
Viral antigens
HBsAg Acute or chronic infection; infectivity
HBeAg Acute or chronic infection; infectivity, wild type viral
infection
Viral antibodies
Anti-HBc Marker of exposure
Anti-HBe Low infectivity
Anti-HBs Marker of immunity
Molecular test
HBV DNA Acute or chronic infection; infectivity, risk of progression
to cirrhosis or cause
Lok AS, et al. Hepatology. 2007;45:507-539.
8. Typical Interpretation of
Serologic Test Results for HBV Infection
Serologic Marker Results
HBsAg Total IgM Anti-
Anti-HBc Anti-HBc HBs Interpretation
Never infected and no evidence of immunization
- - - -
Acute infection
+ + + -
Chronic infection
+ + - -
Recovered from past infection and immune
- + - +/-
Immune (immunization or natural)
- - - +
Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20.
9. Natural Course of Chronic HBV
Infection
HBeAg
Anti-HBe
HBV
DNA
ALT
Immune Immune Inactive Reactivation
Tolerance Clearance Carrier
10. Incidence of HCC (Hepatocellular cancer)
Increases with Increasing HBV DNA Baseline
Viral Level
20%
% cumulative incidence of HCC
14.9%
15%
12.2%
10%
5% 3.6%
1.3% 1.4%
0%
<300 >300 - 103> 103 - 104>104 - 106 ≥106
Baseline HBV DNA (copies/mL)
Chen JC, et al. JAMA. 2006;295:65-73.
11. HBV
Indications for HBV vaccination
• HBIG and HB vaccine to infants of HBsAg+
mothers
• Routine vaccination of infants and adolescents
• Catch-up vaccination of children
• Vaccination of adults at risk of infection
12. HBV Treatments 2012
Interferon or 5 oral agentsAdefovir
Interferon Lamivudine
Pegylated IFN Telbivudine Entecavir
Tenofovir
Pros • Finite duration of • Oral
• Oral
therapy
• Negligible side
• Effective against
• Durable response effects
lamivudine-resistant
post treatment
mutants
• Resistant mutants
• Resistant mutants not
not reported
reported at 1 year
Cons • Injection • Long / indefinite • Long / indefinite
duration of duration of therapy
• Frequent side therapy
effects • Long-term renal
• Resistant mutants toxicity unknown
• Higher with
lamivudine/telbivudine
13. Surrogate Clinical Markers for
Hepatitis B Outcomes
Liver histology Improves Serum HBV DNA declines
Prevention of
Death,
Cirrhosis,
and HCC
Seroconversion (loss of HBeAg, ALT normalization
production of anti-HBe)
15. Suggested Management of HBV
Infection During Pregnancy
HBsAg Positive
Yes
HBV DNA HBV DNA
>108 Copies/mL <108 Copies/mL **
Refer for consideration for
treatment with Lamivudine,
Tenofovir DF, or Telbivudine at
Week 32
Infant Receives
HBIG + HBV Vaccine at Birth
**May consider treatment if previous child HBV positive
Tran TT. Cleve Clin J Med. 2009;76(suppl 3):S25-9.
16. HBV Reactivation with
chemotherapy/immunosuppression
• HBV reactivation is common after immune suppression, can be clinically
severe, and result in death from acute liver failure or progressive liver
disease and cirrhosis
• Screen for HBsAg and anti-HBc in all patients undergoing cancer
chemotherapy, marked immunosuppressive treatment, or solid organ or
bone marrow transplantation
• Prophylaxis against HBV reactivation
• Chemotherapy
• Continue HBV prophylaxis for >6 months after stopping chemotherapy
• Prolonged immunosuppressive therapy
• Consider long-term HBV prophylaxis with an antiviral with a high genetic barrier to
resistance (tenofovir DF, entecavir)
Hoofnagle JH. Hepatology. 2009;49(5 suppl):S156-S165.
Hollinger FB, et al. J Viral Hepat. 2010;17:1-15.
17. Proposed Algorithm for Patients
Exposed to HBV Prior to Chemotherapy
Lubel JS, et al. J Gastroentrol Hepatol. 2010;25:865-871.
18. Bottom Line: When to Start Therapy:
1) Elevated HBV DNA Level
2) ALT Level above ULN
The Threshold and Guidelines for treating HBV are
falling and dynamic
19. Hepatitis C: A Global Health Problem
170-200 Million Carriers Worldwide
Far East Asia
Eastern 60 M
Western
Europe Europe
US 5M 10 M
3-4 M
South East Asia
Africa 30-35 M
Americas
12-15 M 30-40 M
Australia
0.2 M
World Health Organization, 1999.
20. Cirrhosis Due to HCV Expected to
Peak Over the Next Decade
25%
1,200,000 of patients with HCV currently
have cirrhosis
1,000,000
Number of Patients
800,000
600,000
37%
400,000 of patients with HCV are
projected to develop cirrhosis by
200,000 2020, peaking at 1 million
1990 2000 2010 2020 2030
Year
Adapted from Davis GL, et al. Gastroenterology. 2010;138:513-521.
21. HCV Is Nearly 4 Times as Prevalent as
HIV and HBV
4,000,000 ~2.7-3.9 M
3,000,000 Diagnosed
Undiagnosed
Infected
Number
Undiagnosed
Diagnosed
2,000,000
1.1 M
~0.8-1.4 M
1,000,000
0
HIV HBV HCV
HBV=hepatitis B virus.
HCV=hepatitis C virus.
HIV=human immunodeficiency virus.
Institute of Medicine. Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C. 2010.
Available at: http://books.nap.edu/openbook.php?record_id=12793&page=23. Accessed April 7, 2011.
22. Risk Factors for Acute Hepatitis C
United States, 1991-1995
Injection Drug Use 43.0%
Other
High Risk* 30.0%
*Other High Risk Unknown 1.0%
Household 3.0%
16% drug related
•11% previous drug use Occupational 4.0%
not within last 6 months
• 5% intranasal cocaine use Transfusion** 4.0%
4% history of STDs **None in 1995
1% prison
Sexual (Multiple Partners) 15.0%
9% lower socio-economic status (fewer years of education)
Alter MJ. Presented at the NIH Consensus Development Conference, March 24, 1997.
23. HCV Genotypes and Subtypes
Developed countries 2 Americas + Western Europe
South Africa
5
1
Middle East
North Africa
4
IVDU
Asia
3
Simmonds P, Journal of Hepatology, 1999 6
25. Why Do We Treat Chronic HCV?
1000
HCC
800 4+
ALT 3+
2+
ALT (U/L)
1+
600 Fibrosis Cirrhosis
Anti-HCV
400
HCV RNA
200
0
0 0.5 1 2 5 10 15 20 25 30 35 40 45 50
Years After Exposure
Hoofnagle JH. Hepatology 2002;36:S21-S29.
26. HCV Is “Curable”
Long-Term, Follow-Up Studies
IFN IFN alfa-2a IFN alfa-2b
Number of patients 997 492
Average follow-up 4.1 years 5.6 years
Undetectable HCV RNA 989 (99.2%) 487 (99.0%)
Relapse 9 5
Time of relapse 2 years (1.1-2.9) <2 years
McHutchison JG, et al. EASL. 2006. Abstract 744.
Swain MG, et al. J Hepatol. 2007;46(Suppl 1):S3. Abstract 1.
27. A Polymorphism on Chromosome 19 Predicts
SVR
60 Mb
IL28B gene IFN Lambda-3 gene
3 kb
19q13.13
Polymorphism rs12979860
Chromosome 19
Ge D, et al. Nature. 2009;461:399-401.
Chromosome 19 graphic courtesy of Oak Ridge National Laboratory. Available at:
http://www.ornl.gov/sci/techresources/meetings/ecr2/olsen.gif. Accessed on: October 21, 2009.
28. IL-28 CC allele is associated with SVR
Ge et al, Nature, 2009
29. 2 Protease Inhibitors Approved for
Genotype 1 HCV Infection
Protease Inhibitor Additional Regimen Considerations
Components
Boceprevir 800 mg TID PegIFN alfa Naive to previous therapy
(q7-9hrs)[1,2] + Previous treatment failure
weight-based RBV Compensated cirrhosis
RGT
Telaprevir 750 mg TID PegIFN alfa Naive to previous therapy
(q7-9hrs)[2,3] + Previous treatment failure
weight-based RBV Compensated cirrhosis
RGT
For patients with genotype 2/3 infection, HCV therapy
with pegIFN/RBV remains the standard of care
1. Boceprevir [package insert]. 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
3. Telaprevir [package insert]. 2011.
30. Clinical Pharmacology and Drug Interactions
• Boceprevir
• Strong inhibitor of CYP3A4/5
• Partly metabolized by CYP3A4/5
• Potential inhibitor of and substrate for P-gp
• Telaprevir
• Substrate of CYP3A
• Inhibitor of CYP3A
• Substrate of P-gp
• Must perform DDI survey or work with clinic pharmacology
• http://www.hep-druginteractions.org/
P-gp = p-glycoprotein
Boceprevir capsules [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2011.
Telaprevir tablets [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.
31. Telaprevir + PegIFN/RBV: Genotype 1
Treatment-Naive Patients
Dosage and Administration
• 750 mg (two 375-mg tablets) TID (every 7-9 hrs) with food (standard fat meal 20 g,)eg, ½ cup
nuts or 2 oz cheddar cheese)
• Must be administered with both pegIFN and RBV
• Telaprevir dose must not be reduced or interrupted
eRVR; stop at Wk 24/ f/u F/u
TVR + PegIFN + RBV PegIFN + RBV 24
No eRVR; PegIFN + RBV wks
0 4 12 24 48
Wks
Week 4 HCV RNA Week 12 HCV RNA Week 24 HCV RNA
Futility > 1000 IU/ml > 1000 IU/ml detectable
Treatment duration
• Patients with extended RVR (eRVR, undetectable* HCV RNA at Week 4 and 12) receive 24 wks
of therapy
• Patients without eRVR continue on pegIFN + RBV for a total of 48 wks
• Treatment-naive patients with compensated cirrhosis and eRVR may benefit from additional
Telaprevir package insert. pegIFN + RBV (ie, to Week 48)
36 wks of May 2011. *Assay should have a lower limit of HCV RNA quantification ≤ 25 IU/mL.
32. What can we tell our patients?
Significantly Higher SVR rates in Telaprevir-Treated Patients Compared to Peg
IFN/Ribavirin Alone
T12PR PR
100 P<0.0001
90
80
75
Percent of patients
70
60
50
44
40
with SVR
30
20
10
0
n/N = 271/363 158/361
SVR
Jacobson IM, et al. Hepatology 2010;52(Suppl 1):Abstract 211.
34. Telaprevir: Rash
• Patients treated with telaprevir
• Rash reported in 56% of subjects (vs 34% with PR48); 4% severe
• Typically eczematous, maculopapular, and papular-lichenoid
• In most subjects, the rash was mild-moderate
• Rash events resulted in discontinuation of TVR in 6% of subjects
• Occurred early, usually within first 4 weeks, but can occur at anytime
• < 1% Stevens Johnson Syndrome or DRESS
• Mechanism of rash remains unknown; however, pyrazinoic acid is a
major metabolite of TVR & may contribute to rash/pruritus
• Structural analog of niacin
• Improvement occurs after dosing completion or D/C; may take weeks
for complete resolution
Advisory Committee Briefing Document for NDA 201-917 Telaprevir 375 mg tablets. Silver Spring, MD; April 1, 2011.
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugs
AdvisoryCommittee/UCM252561.pdf. Accessed April 26, 2011.
Telaprevir tablets [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.
35. Stevens-Johnson Syndrome(SJS)/Drug
rash with eosinophilia and systemic
symptoms (DRESS)
• SJS: Fever, target lesions, mucosal
erosions/ulcerations
• Drug rash with eosinophilia and systemic
symptoms
• Rash, fever, facial edema, internal organ involvement
• ±eosinophilia
• Stop all medicines
• Urgent Dermatology referral
36. Gastrointestinal Side effects
• Nausea: Promethazine, ondansetron
• Telaprevir should be taken with 20 grams of fat to help
with absorption
• Perianal symptoms
• Anal Pruritus with telaprevir: antihistamines
• Topical therapies: Witch hazel topical,
hydrocortisone cream, mesalamine suppositories
• Diarrhea: loperamide, Bulk/fiber supplement
36
37. Telaprevir: Anemia
• Mechanism of anemia thought to be result of bone marrow
suppressive effect associated with telaprevir, not RBC
hemolysis
• Patients treated with telaprevir had
• A higher frequency of anemia, hemoglobin level
< 10 g/dL (36% vs 17%)
• A higher frequency of hemoglobin reductions to Grade 3 or higher
toxicity (7.0 to < 8.9 g/dL or any decrease
> 4.5 m/dL) levels (55% vs 25%)
• A higher frequency of hemoglobin level < 8.5 g/dL (14% vs 5%)
• More anemia-related SAEs (2.5% vs < 1%)
• A higher frequency of anemia-related discontinuations (4% vs < 1%)
Telaprevir tablets [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.
Advisory Committee Briefing Document for NDA 201-917 Telaprevir 375 mg tablets. Silver Spring, MD; April 1, 2011.
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugs
AdvisoryCommittee/UCM252561.pdf. Accessed April 26, 2011.
38. Boceprevir for genotype 1 naïve HCV
Milestones: Weeks 8, 12, 24
Week 4 Week 28 Week 48 Week 72
TW 8-24 HCV-RNA Undetectable*
Follow-up
PR PR + BOC (24 weeks)
lead-in Non-cirrhotic Week 36
PR+BOC
(32 weeks) PR Follow-up
Week 12 Week 24 TW 8 HCV-RNA Detectable/
TW 24 undetectable
PR PR + BOC (44) weeks for cirrhotic patients/
Follow-up
lead-in poorly responsive pts
Week 12 Futility Week 24 Futility
HCV > 100 IU/ml Detectable HCV RNA
*assay should have a lower limit of HCV-RNA quantification < 25 IU/mL, and limit of HCV-RNA
detection of approximately 10-15 IU/mL
39. SPRINT 2: SVR* and Relapse Rates
SVR
Relapse Rate
p <0.0001 p =0.004
p < 0.0001
100 100 p = 0.044
80 67 68 80
60 60 53
Percent
211 213
Percent
40 316 311
42
40 40
29
125 23 23 22
55
311
14 52
12 17
20 37 9 8 20 12
6
162 21 18 52 2 3
35
0 232 230
0 14 25
48 P/R BOC RGT BOC/PR48 48 P/R BOC RGT BOC/PR48
Non-Black Patients Black Patients
*SVR was defined as undetectable HCV RNA at the end of the follow-up period. The 12-week post-treatment HCV RNA level was used if the 24-week post-treatment
level was missing (as specified in the protocol). A sensitivity analysis was performed counting only patients with undetectable HCV RNA documented at 24 weeks
post-treatment and the SVR rates for Arms 1, 2 and 3 in Cohort 1 were 39%, 66% and 68%, respectively and in Cohort 2 were 21%, 42% and 51%, respectively.
40. SVR by Historical Response
Non-responders and Relapsers*
Arm 1: Arm 2: Arm 3:
48 P/R BOC RGT BOC/PR48
N = 80 N = 162 N = 161
Non-responder –
2/29 (6.9) 23/57 (40.4) 30/58 (51.7)
n/n (%)
Relapser
15/51 (29.4) 72/105 (68.6) 77/103 (74.8)
– n/n (%)
*Non-responders had a decrease in plasma HCV-RNA of at least 2-log10 by week
12 of prior therapy but with detectable HCV-RNA throughout the course of
therapy. Relapsers had undetectable HCV-RNA at end of prior therapy without
subsequent attainment of a sustained virologic response.
41. SVR and Relapse† Rates,
100 by Prior Treatment Response
90
80
68
% of Patients
70
60 56
50
40
40
30
20 14 15 17
10
19/47 53/78 5/9 3/22 9/62 1/6
0
SVR Relapse
Nulls Partials Relapsers
• SVR was also achieved in all 4 patients with ‘other’ prior non-response.
• Overall, 81 of 138 patients (59%) achieved SVR.
SVR rates if lead-in dropouts included: nulls 38% (19/50), partials 68% (53/78), relapsers 50% (5/10), overall 57% (81/142).
† denominator for relapse rate = patients with undetectable HCV RNA at EOT and not missing end of follow-up data.
41
42. Results – Primary and Key Efficacy
End Points
• End-of-treatment response, relapse, and SVR
were comparable between RBV DR and EPO
arms ∆ (95% CI)
–0.7% (– 8.6 , 7.2)*
Patients, %
203/249 205/251 178/249 178/251 19/196 19/197
CI, confidence interval; DR, dose reduction; EOT, end of treatment; EPO, erythropoietin; RBV, ribavirin;
SVR, sustained virologic response.
*The stratum-adjusted difference (EPO vs RBV DR) in SVR rates, adjusted for stratification factors and protocol cohort.
43. Anemia Management Recommendations
With TVR or BOC-based Therapy
• Monitoring: CBC pretreatment, every 2 weeks until treatment week 8,
then monthly
• Primary strategy: RBV dose reduction
• BOC—Hgb < 10 g/dL: decrease in dosage or
interruption of RBV is recommended
• TVR—If anemia occurs, use RBV dose reductions; if
inadequate, consider D/C TVR
• Hgb < 8.5 g/dL: discontinue all therapy
• If RBV is permanently D/C, BOC or TVR also must be D/C
• Do not reduce PI dose to manage anemia
• Once RBV dose reduction has been tried, erythropoietin can be
considered
Peginterferon alfa-2a Solution for Subcutaneous Injection [package insert]. South San Francisco, CA: Genentech, Inc.; 2011. Peginterferon
alfa-2b Injection, Powder for Solution for Subcutaneous Use [package insert]. Kenilworth, NJ: Schering Corporation; 2011.
Boceprevir capsules [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2011.
Telaprevir tablets [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.
44. Boceprevir Plus Peginterferon/Ribavirin for the
Treatment of HCV/HIV Co-Infected Patients: End of
Treatment (Week 48) Interim Results
J Mallolas1, S Pol2, A Rivero3, H Fainboim4, C Cooper5, J Slim6,
S Thompson7, J Wahl7,
W Greaves7, M Sulkowski8
1
Hospital Clinic-University of Barcelona, Barcelona, Spain; 2Universite Paris Descartes,
APHP, Hopital Cochin, Paris, France; 3University Hospital Reina Sofia, Córdoba, Spain,
4
Muñiz Hospital, Buenos Aires, Argentina; 5University of Ottawa, Ottawa, ON, Canada; 6Saint
Michael's Medical Center, Newark, NJ; 7Merck Sharp & Dohme, Whitehouse Station, NJ;
8
John Hopkins University School of Medicine, Baltimore, MD.
Abstract #366
International Liver Congress 2012
47 Annual Meeting of the European Association for the Study of the Liver
th
Barcelona, Spain
April 20, 2012
45. Virologic Response Over Time†
100 PR B/PR
80 73.4
Undetectable
% HCV RNA
65.6
59.4 60.7
60
42.2
40 32.4 29.4 26.5
23.5
20 14.7
8.8
4.7
3/34 3/64 5/34 27/64 8/34 38/64 11/34 47/64 10/34 42/64 9/34 37/61
0
4 8 12 24 EOT SVR12
Treatment Week
†
Three patients undetectable at FW4 have not yet reached FW12 and were not included
in SVR12 analysis. 45 45
46. Telaprevir in Combination with
Peginterferon Alfa-2a/Ribavirin in HCV/HIV
Co-infected Patients: SVR12 Interim
Analysis
Douglas T. Dieterich1, Vincent Soriano2, Kenneth E. Sherman3,
Pierre-Marie Girard4, Jurgen K. Rockstroh5, Joshua Henshaw6, Raymond
Rubin6, Mohammad Bsharat6, Nathalie Adda6, Mark S. Sulkowski7 On behalf
of the Study 110 Team
1Mount Sinai School of Medicine, New York, NY, United States, 2Hospital
Carlos III, Madrid, Spain, 3University of Cincinnati College of Medicine,
Cincinnati, OH, United States, 4Hopital St Antoine, Paris, France, 5University
of Bonn, Bonn, Germany, 6Vertex Pharmaceuticals Incorporated, Cambridge,
MA, United States, and 7Johns Hopkins University School of Medicine,
Baltimore, MD, United States.
46
49. DAAs - Key Characteristics
NS3 /4A Inhibitors (Protease inhbitorP I) NS5B Nucleos(t)ide Inhibitors (NI)
High potency Intermediate potency
Limited genotypic coverage Pan genotypic coverage
Low barrier to resistance High barrier to resistance
NS5A Inhibitors NS5B Non Nucleoside Inhibitors (NNI)
High potency Intermediate potency
Multi-genotypic coverage Limited genotypic coverage
Intermediate barrier to resistance Low barrier to resistance
49
50. BMS-790052 (NS5A inhibitor) + BMS-650032
(PI) ± PR in G1 null responders: phase IIa
study
BMS-790052 60 mg qd plus
BMS-650032 600 mg bid
no cirrhotics, N=21
responder to PR,
CHC, G1, null
BMS-790052 60 mg qd + BMS-650032 600
mg bid plus PR
0 Study weeks 24
Randomisation
Null response defined as <2 log10 decline in HCV RNA following
12 weeks of treatment with PR
Lok A, et al. EASL 2011, oral
51. Virologic Response before and after
treatment
100 100*
100
90
46 46
36 36
•Group A: 4(2/9 GT1a and 2/2 GT1b) patients achieved SVR12 and SVR24
•Group B; 10/10 achieved SVR12 and 9 had SVR24
•1 patient had HCVRNA<LLQ at post treatment week 24, and undetectable 35 d later
54. PROTON
PSI-7977 is a Potent and Specific Nucleotide
Analog Polymerase Inhibitor for HCV
PSI-7977
Antiviral activity (IC50 0.7-2.6 µM GT1b, GT3a,
GT4a) with broad HCV genotype coverage
Once-daily dosing
High barrier to resistance: To date, no virologic
breakthrough during 12+ weeks of PSI-7977 QD
Generally safe and well tolerated in clinical studies to date
Low potential for drug-drug interactions
55. Background
• GS-7977 (formerly PSI-7977) is a specific nucleotide analog
inhibitor of HCV NS5B
• Safe and well-tolerated in clinical studies
• Once-daily, with or without food
• Potent antiviral activity with broad HCV genotype coverage
with or without IFN in treatment-naïve patients
• ELECTRON genotype 2/3: 100% SVR1
• ELECTRON genotype 1: 100% RVR2
• PROTON genotype 1: 91% SVR3
• PROTON genotype 2/3: 94% SVR4
• High barrier to resistance
1
Gane E, et al. AASLD 2011; 2Gane E, et al. CROI; 3Lawitz E, et al. AASLD 2011; 4Lalezari J, et al. EASL 2011.
56. Atomic Study Design
Day 1 Wk Wk 24
12
Group A GS-7977 + PEG + GT 1
N = 52 RBV
Group B
GS-7977 + PEG + RBV GT 1, 4, 6
N = 125*
Group C GS-7977 + PEG + GS-7977 (n = 75)
GS-7977 + RBV (n = GT 1
N = 155† RBV
75)
♦ Patients with HCV genotype 1 were randomized 1:2:3 into 1 of 3 open-label arms
♦ Stratified by:
• IL28B genotype (CC vs non-CC)
• HCV RNA at screening (≤ vs >800,000 IU/mL)
♦ HCV RNA analyzed by TaqMan® HCV Test 2.0 (LOD: 15 IU/mL)
*Of the 125 patients enrolled in Arm B, 16 were genotype 4 or 6
†
5 of the 155 patients were not re-randomized at Week 12
57. 90% of Patients Achieved SVR12:
GS-7977 + PEG/RBV 12-Week Regimen
% Patients
7977+P/R 7977+P/R 7977+P/R
0
12 Wks 24 Wks 12+12 Wks
0 14 42 70 8 126 14
• 94% of patients in Arm A who reached follow up Week 12 were <LOD
66. M12-267 Study Design
12 Weeks (On Treatment) Follow Up
Period†
Treatment-naïve (N=11)
ABT-450/r 150/100 mg QD +
ABT-072 400 mg QD + RBV*
†
All subjects followed for 48 weeks after end of treatment
*Weight-based ribavirin 1000-1200mg/day
Registered with ClinicalTrials.gov as NCT01221298
72. A Randomized, Placebo-Controlled Trial of
Oral Silymarin (Milk Thistle) For Chronic
Hepatitis C: Final Results of the SYNCH
Multicenter Study
M.W. Fried, V.J. Navarro, N.H. Afdhal, S.H. Belle,
A.S. Wahed, R.L. Hawke, E.C. Doo, C.M. Meyers,
K.R. Reddy for the SYNCH Study Group
University of North Carolina, Thomas Jefferson
University, Beth Israel Deaconess Medical
Center, University of Pittsburgh, NIDDK, NIH,
NCCAM, NIH, University of Pennsylvania
This study was funded by NIH NCCAM and NIDDK
73. Silymarin for Hepatitis C
ITT Analysis of Primary Endpoints
Endpoint Placebo Silymarin Silymarin p-value
420 mg 700mg
(n=52) (n=50) (n=52)
ALT < 45 IU 1 (1.9%) 2 (4%) 2 (4%) 0.8
Serum ALT decline of 2 (3.8%) 1 (2%) 2 (3.8%) 0.8
at least 50% to < 65 IU
Either of the above 2 (3.8%) 2 (4%) 2 (3.8%) 1.0
74. Silymarin for Hepatitis C
Analysis of Secondary Endpoints
Endpoint* Placebo Silymarin Silymarin p-value
420 mg 700 mg
Change in ALT (IU/L) -4.3 -14.4 -11.3 0.75
Change in HCV RNA (log10 0.07 -0.03 0.04 0.54
IU)
Changes in Quality of Life
CESD score -0.26 -0.73 -0.41 (12.5)M8 0.97
SF36 (Physical) -0.69 -2.86 -0.27 0.18
SF36 (Mental) 0.24 0.35 -0.90 0.68
Chronic Liver Disease 0.12 -0.10 -0.03 0.26
Questionnaire (CLDQ)
* Data provided as mean values
75. Will Hepatitis C Therapy Parallel
Helicobacter pylori Therapy?
H pylori HCV
All Oral Therapy
Duration 12-24 weeks
Polymerase Inhibitor All Oral Therapy,
±
single tablet
Protease Inhibitor
±
NS5a
±
Cyclophylin Inhibitor
±
ribavirin
76. What I Tell Patients Regarding
Treatment of Hepatitis C
• HCV can be cured in 3/4ths of all cases
• Therapy is evolving: about ½ of all genotype 1 individuals
will can be treated with 6 months of therapy
• Genotype 2/3 still has SVR rates of >75% with peg
interferon/ribaviirn
• IL-28 CC genotype will identify those who can be treated
for shorter duration
• Silymarin …don’t bother
• Have a patient interested in a study?
• Email : pkwo@iupui.edu or you may call (317) 278-
4633 or email pasparks@iupui.edu
