1. Hepatitis C Game Changer
Jean-Marc Fix
Vice president - Research and Development

2. Agenda Epidemiology Portrait of a virus and etiology Transmission
Evaluation
Natural history
Treatment

3. The Silent Epidemic
A round 4-5 million infected people including 3+ million with active infection
Around 16,000 new cases a year
No big presence in the news
Leads to complication that will significantly tax health care systems if untreated or treated too late
E Chak Liver International 2011

4. Epidemiology

5. Epidemiology

6. Epidemiology

7. Reported number of acute hepatitis C cases United States, 2000–2012
Source: National Notifiable Diseases Surveillance System (NNDSS)

8. Incidence of acute hepatitis C, by age group — United States, 2000–2012
Source: National Notifiable Diseases Surveillance System (NNDSS)

9. Incidence of acute hepatitis C, by sex — United States, 2000–2012
Incidence rates of acute hepatitis C decreased dramatically for both males and females from and remained fairly constant from
Since 2010, rates for both males and females have increased and in 2012, rates among males and females were 0.7 and 0.5 cases per 100,000 population, respectively.
Source: National Notifiable Diseases Surveillance System (NNDSS)

10. Incidence of acute hepatitis C, by race/ethnicity — United States, 2000–2012
Rates for acute hepatitis C decreased for all racial/ethnic populations through 2003.
From , acute hepatitis C rates increased 86.2% among American Indians/Alaska natives, 36.2% among white, non-Hispanics, and 23.5% among Hispanics.
The 2012 acute hepatitis C rates for Asian/Pacific Islanders, black, non-Hispanics, Hispanics, white, non-Hispanic, and American Indian/Alaska Natives were 0.1, 0.2, 0.2, 0.6 and 2.0, respectively.
Source: National Notifiable Diseases Surveillance System (NNDSS)

11. Availability of information on risk exposures/behaviors associated with acute hepatitis C — United States, 2012
*Includes case reports indicating the presence of at least one of the following risks 6 weeks to 6 months prior to onset of acute, symptomatic hepatitis C: 1) using injection drugs; 2) having sexual contact with suspected/confirmed hepatitis C patient; 3) being a man who has sex with men; 4) having multiple sex partners concurrently; 5) having household contact with suspected/confirmed hepatitis C patient; 6) having had occupational exposure to blood; 7) being a hemodialysis patient; 8) having received a blood transfusion; 9) having sustained a percutaneous injury; and 10) having undergone surgery.
Source: National Notifiable Diseases Surveillance System (NNDSS)

12. Acute hepatitis C reports, by risk behavior† — United States, 2012
Number of cases
*A total of 1,778 case reports of hepatitis C were received in 2012.
† More than one risk behavior may be indicated on each case report.
§Risk data not reported.
¶A total of 955 hepatitis C cases were reported among males in 2012.
Source: National Notifiable Diseases Surveillance System (NNDSS)

13. Acute hepatitis C reports, by risk exposure† — United States, 2012
Number of cases
*A total of 1,778 case reports of hepatitis C were received in 2012.
†More than one risk exposure may be indicated on each case report.
§Risk data not reported.
Source: National Notifiable Diseases Surveillance System (NNDSS)

14. Global Prevalence
D Lavanchy Clin Micro and Infect :

15. Countries with very HIGH Prevalence
Egypt
Pakistan
Taiwan
Southern Italy
Most of Africa
Russia and former USSR

16. Evolution of Prevalence by Age
Hepatitis C Online HCV Epidemiology in the US retrieved 10/14

17. MORTALITY RATES COMPARISON
Hepatitis C Online HCV Epidemiology in the US retrieved 10/14

18. Forecasted Death
Hepatitis C Online HCV Epidemiology in the US retrieved 10/14

19. Agenda Epidemiology Portrait of a virus and etiology Transmission
Evaluation
Natural history
Treatment

20. Portrait of a virus and etiology
Born Dead circa 2030

21. Virus Characteristics
A flavivirus (same family as yellow fever)
Single stranded RNA 9600 nucleotide bases long
Finds its way to the liver
Each infected cell will produce around 50 virus

22. Hepatitis C Genetic Material
hypervariable
region
capsid
envelope
protein
protease/helicase
RNA-dependent
RNA polymerase
c22 5’
core E1 E2
NS2
NS3
33c
NS4
c-100
NS5 3’
Circa 1999

23. Hepatitis C Genetic Material
TKH Scheel & CM Rice Nature Medicine :837-49

24. Genotypes
There can be more than 25-30% variation in genome between Hep c viruses
11 “genotypes” identified so far (or is it 6?- 10 folds in 3, 7,8,9,11 in 6)
Adapted from P Simmonds Hepatology :

25. Genotypes
P Simmonds fig 1 Hepatology :

26. Genotypes Distribution
J Messina Hepatology :

27. Genotype Distribution
J Messina Hepatology :

28. Genotype Timeline in the US
N Zein Clin Microbiol Rev (2):

29. WHY Do Genotype Matter Impact on treatment
Impact on disease progression (1b harder to treat than 1a but is it true?)

30. Functional Portrait

31. Viral Penetration of Cell

32. Viral REPLICATION

33. Acute Infection Mostly through blood
70-80% have no or very mild symptoms- hence the “silent” part in “silent epidemic”
Symptoms appear 6-7 weeks after exposure
Fever, fatigue, loss of appetite, nausea, vomiting, abdominal pains, joint pain
Dark urine, clay colored stools, jaundice
Can be spread even if symptom less

34. Agenda Epidemiology Portrait of a virus and etiology Transmission
Evaluation
Natural history
Treatment

35. Multiple responses were possible
Transmission
Cause Identified
Number
Intravenous Drug Use
513
Multiple Sex Partners
187
Surgery 86
Needle Stick 52
Sex 18
Occupation 14
Household Contact 8
Dialysis 4
Total
1,778
Men having Sex with Men (out of 955 Men) 17
Multiple responses were possible
Source: National Notifiable Diseases Surveillance System (NNDSS)

36. Transmission
Hemodialysis: very low since 1997 although outbreaks have occurred, not uncommon before
Hemophilia: virtually nil since 1987, 6-10 thousand before
Household contact: very rare (don’t share your razor)
Immune Globulin-IV: outbreaks in 1993 and 1994
Non-injection drug use (pipes, tubes)
Organ/tissue transplants: very rare
Perinatal: 5-10% of babies of infected mothers
Tattoos (in unregulated environments)
Hepatitis C Online HCV Epidemiology in the US retrieved 10/14

37. MAIN Transmission Injection Drug Use
Sex, especially if multiple sex partners or men having sex with men
Receiving blood transfusion long ago(in the 1960s: 33%, since mid 90 very low 0.3%)
Hepatitis C Online HCV Epidemiology in the US retrieved 10/14

38. Detection Serology Virology
Enzyme Immuno Assay (EIA or ELISA) currently 3rd generation -97+% sensitive, 94%+ specific (1)
Detect antibodies to HCV (anti-HCV) (from 4 different areas)
Confirmatory test may be Recombinant ImmunBlot Assay (RIBA)
Past not too recent infection (7-8 weeks before positive)
Virology
Identify and now measures HCV-RNA
By polymerase chain reaction- amplification of the viral genetic material
Virus active in cell
(1) Ahrq.gov 2011 Screening for Hepatitis C Infection p32

39. Detection
N Zein Clin Microbiol Rev (2):

40. Interpretation of Test Results
EIA/ ELISA
HCV-RNA
Supplemental (RIBA)
Interpretation -
n/a
Not infected [JM: or too early] +
Not done
? Need confirmation
+/nd
Active infection
? Need repeat RNA or RIBA
Infected, need repeat RNA
Infected, need RNA
nd/-
False positive
R Kesli Arch Clin Microbio (4):1 doi /233

41. Liver Functions

42. Liver Functions

43. Evaluation Genotype: 1-6 (through PCR)
Interleukin 28: (gene mediating viral immune response)-has an impact on treatment “CC” mutation best, “TT” worst, “CT” in between
Profile: who is the applicant
Biopsy: how is the liver
Other non invasive
LFT: ALT and AST/ALT
J Vergniol Gastroenterology :
TJS Cross Journ Viral Hep 2009

44. INVASIVE TEST Gold (plated) standard: liver biopsy
Highly dependent on evaluator
Complications –
1. pain/anxiety/discomfort – 15-20%
2. hemorrhage – 0.5% (operator dependent?)
3. mortality – 0.01%
Small sample of the liver analyzed
J West Gastroenterology : JF Cadranel Hepatology :
L Seeff Clin Gastroenterol Hepatol (10):

45. Non Invasive tests
Fibroscan (transient elastography or liver stiffness measurement)
King’s score: [age x AST (in IU/L) x INR]/platelet counts (in x109/L)
PPV/NPV
Fibroscan
King’s score
Fibrosis (F3+)
78/49
53/75
Cirrhosis (F5+)
68/98
70/91
Fx is Ishak fibrosis score
INR= international normalized ratio prothrombin time in test/ normal PT
PPV positive predictive value true positive/all positive
NPV true negative/ all negative
TJS Cross J of Viral Hep 2009 (consecutive patients London, UK)

46. Non Invasive tests For cirhosis AUROC Sensitivity Specificity APRI
APRI score: AST and platelet count
FIB-4: as above + age and ALT
Fibro-test-Acti test:
Keeping in mind that from a univariate perspective AGE is the key driver
For cirhosis
AUROC
Sensitivity
Specificity
APRI
0.77
77%
94%
FIB-4
0.74
90%
92%
Fibro test
93%
70%
PPV= (sen x prev)/ [sen x prev+ (1-spec)x(1-prev)]
NPV= [spec x(1-prev)] / [(1-sen) x prev+ spec x (1-prev)]
L de Lucca Schiavon World J of Gastroenterology (11):
J Vergniol Gastroenterolgy :

47. Non Invasive vs. Invasive tests
For advanced fibrosis
Sensitivity
Specificity
Fibro Test
93%
70%
Fibroscan
96%
45%
Biopsy
67%
63%
ALT
79%
78%
For cirrhosis
Sensitivity
Specificity
Fibro Test
87%
41%
Fibroscan
93%
39%
Biopsy
95%
51%
ALT
78% 8%
AST/ALT>=1.0*
97%
T Poynard J Hepatol (3):
C Lackner Hepatology :

48. Natural history
health-fts.blogspot.com retrieved 10/14

49. Natural history the real story
N Zein Clin Microbiol Rev (2):

50. Natural History Modeling
HH Thein 2011 Estimating the Prognosis of Canadians Infected With the Hepatitis C Virus Through the Blood Supply, th revision

51. Factors affecting progression
Virus
Patient
External
Concentration??
Age at infection
Alcohol
Genotype/species?
Current age?
Smoking?
Age at diagnosis
Gender (M)
Environmental???
Race
Coinfection: HIV, HBV
Comorbidity: hemochromatosis, NASH, porphyria ct, iron overload?, liver steatosis, Diabetes M
Genetic: HLA II antigens
Adapted from Table 3, LB Seef Hepatology :S35-S46,
S Bruno Hep Med Evidence and Research :21-28

52. Predicted Histology by Age
Age grop
Mild Hep
Mod Hep
Cirrhosis
0-11
100% 0%
12-19
99% 1%
20-29
89%
11%
30-39
71%
22% 7%
40-49
50%
32%
18%
50-59
29%
43%
28%
60-69
54%
39%
70-79
80 & up
40%
60%
J Wong Am J of Pub Health :

53. Past Treatment

54. Was CURRENT TREATMENT Combination
Protease inhibitor (Incivek-telaprevir or Victrelis-boceprevir)
Interferon (Pegintron or Pegasys)
Ribavirin (Ribasphere)(nucleoside analog)

55. Current treatment
December 2013: FDA Approved Sovaldi (sofosbuvir) for Genotype 1-6
Combination of
sofosbuvir (Sovaldi) (for gen 1 to 6)
Ribavirin (Ribasphere) (for gen 1 to 6)
Pegylated interferon (for gen 1, 4, 5, 6)
For those who can’t receive interferon
Sovaldi+Olysio (simeprevir-protease inhibitor)+ribavirin (for gen 1)
Hot off the press: sofosbuvir+lepisdavir=Harvoni No interferon! (gen type 1)

56. Soon to be Current 99% cure rate for gen 1b

57. Future Treatment
EASL 44th Annual Meeting

58. Future TREATMENT TARGETS

59. Down the pike sofosbuvir (Sovaldi) telaprevir (Incivek) simeprevir
(Olysio)
boceprevir
(Victrelis)
APPROVED
asunaprevir
(Sunvepra)
daclatasvir
(Dazlinka)
SUBMITTED FOR APPROVAL
dasabuvir BI
BMS
faldaprevir
paritaprevir
ledipasvir
mericitabine
vaniprevir
ombitasvir
MK-8742
PHASE III
miravirsen
tegobuvir
GS-9451
sovaprevir
ACH-3102
ABT-072
TMC
MK-5172
GS-5816
IDX-719
GS-9669
filbuvir
danoprevir
VX-222
GSK
setrobuvir
VX-135
PHASE II
Nucleoside inhibitor
Protease inhibitor
Non nucleoside inhibitor
NS5 Inhibitor

60. Only half the Picture Treatment is great but…
From a health care impact, key missing link is timely detection (and prevention)
Right now 50% diagnosed, 35% referred to care, 10% start treatment, 5% cured.
Treatment is extremely expensive the $1,000 pill
Adapted from L Highleyman 2013 news from AASLD 2013

61. Natural history
health-fts.blogspot.com retrieved 10/14

62. Transition Rates Stage Transition Annual Rate RNA + to Fibrosis 1 5.7%
Fibrosis 1 to 2
14.5%
Fibrosis 2 to 3
15.0%
Fibrosis 3 to 4
12.0%
Fibrosis 4 to decompensation
6.5%
Fibrosis 4 to HCC
3.3%
HH Thein 2011 Estimating the Prognosis of Canadians Infected With the Hepatitis C Virus Through the Blood Supply, th revision

63. Transition Rates
After 25 years of infection on 185 patients (initially asymptomatic blood donors)
33% no fibrosis
52% stage 1 or 2 fibrosis
12% stage 3-4 bridging fibrosis
2% Cirrhosis
Seems lower than Thein
R Allison J Infect Dis :

64. Transition Rates Stage Transition Annual Rate Modifier
RNA + to Fibrosis 1
4.3%
75%
Fibrosis 1 to 2
5.8%
40%
Fibrosis 2 to 3
6.0%
Fibrosis 3 to 4 (cirrhosis)
4.8%
Fibrosis 4 to decompensation
6.5%
100%
Fibrosis 4 to HCC
3.3%
Fix model based on Thein to give Allison’s numbers

65. Fibrosis Progression 54% stable 14% fibrosis decreased
33% fibrosis increased
fibrosis score at first biopsy
fibrosis score at second biopsy 6 5 1 4 3 2 11 14
R Allison J Infect Dis :

66. Scoring Warning
METAVIR stage 4 and ISHAK (or ISHAK-KNODELL or HAI) stage 6= cirrhosis

67. How Does Hep C Kill You? All rates are annual rates Moderate chronic:
7.3% cirrhosis
0.1% HCC
Cirrhosis
2.5% ascites: 6.7% refractory ascites, 11% death
1.1% variceal hemorrhage:40% death Y1, 13% thereafter
0.4% hepatic encephalopathy: 68% death Y1, 40% thereafter
0.5% HCC: 86% death
Liver transplant: 21% y1 5.7% thereafter
J Wong AM J of Pub Health :

68. Mortality Insurance industry ALT>45 U/L => reflex to Hep C
9% ALT>45, 4-5% Hep C antibody positive (mostly from reflex testing)
0.6% positive (vs. 1-2% in adult US population)
Some are missed due to reflex scheme.
VF Dolan On the Risk (3):68-71

69. Mortality Age group Females Males 20-39 2.2 3.9 40-59 2.3 2.8 60-69
2.5
2.0
70+
1.6
1.8
Caveats:
Antibody positive HCV viral status unknown
Median of 7 years o follow-up
VF Dolan On the Risk (3):68-71

70. Mortality and ALT Level
D Winsemius eEnvoy July 2009 (Heritage Labs)

71. Viral Load and HCC All stages of fibrosis Advanced Fibrosis
For sustained virologic responders HCC risk is 24% of risk for non responders
US Subset (US vets) 31%
Advanced Fibrosis
For sustained virologic responders HCC risk is 23% of risk for non responders
US Subset (not same group as above) 18%
Observational meta-analysis…
RL Morgan Annals of Internal Med 158(5):

72. Questioning You know: you have EIA + HCV RNA +
Probably does not know status
If knows, what is treatment?
You suspect: EIA + or missing no other tests
Highly endemic area
Old IDU or blood transfusion

73. Questioning What does the liver “look” like?
LFT pattern - but don’t overestimate ALT level importance (unless very very high: x10 normal)
Best case:

74. Take Home Nuggets Transmission & risk factor Diagnosis Progression
Evaluation
Treatment revolution
Public health challenge