Janin speaks on the dawn of a revolution for treating Hepatitis C. This was recorded at Bedside Critical Care Conference 4. Full postings can be found at www.intensivecarenetwork.com

1. Dawn of a revolution
P. Janin
RNSH – ICU
26.09.2013

2.  1965 - Blumberg & Alter
 1973 – Feinstone, Kapikian & Purcell
The hepatitis puzzle was still incomplete

4. ….
….

5.  Part of Flaviviridae family of viruses
 Associated with both human and animal disease
 3 genera: pestiviruses (cattle, pigs), flaviviruses (dengue,
yellow fever), hepaciviruses (HCV)
 In hepacivirus family
 6 major clades
 >100 different subtypes
 Countless quasispecies: mult. seen in each infected individual

7. Study of Infection, Replication and Release
Difficult:
 Lack of reliable culture system
 Does not integrate into host genome
 Low number of circulating virions

8. Structural genes Non-structural genes

9. Pathogenesis
Prevention
Therapy

10.  Complex, dynamic
distributions of non-identical
but related mutant RNA
genomes
 Encompasses a master
genome (dominant) and a
multitude of minor genomes

11. Escapes host immune surveillance ?
Establishes persistent infection ?

12. Exposure
(Acute Phase)
Resolved Chronic
CirrhosisStable
Liver Decompensation
Hepatocellular Carcinoma
5%-25% over 20-30 years
15-45%
55-85%
5%/yr decompensation
2-8%/yr HCC
75-95%
Primary Point
of Intervention
 Acute Hepatitis C
 Generally benign:
 No jaundice (80%). Usually asymptomatic.
 Can be severe, but liver failure rare
 15-40% will usually resolve.

13.  Only real threat of acute Hepatitis C is its ability to
reach chronic stages undetected and untreated.

14. 90%
5-10%
80-90%
70-85%
2% (coinfection)
90% (superinfection)
 Infants
 Adults
Normal
liver
Chronic
hepatitis
Cirrhosis

16.  3.2 million persons chronically infected (average age 55 years,
perhaps 40% have cirrhosis)
 8000-10.000 deaths each year (US)
 Majority unaware of infection: not clinically ill (only 25-30% have been
diagnosed, only 11% have been treated)

17.  221.000 people with chronic hepatitis C
 Leading reason for liver transplant
 Deaths have surpassed HIV
HIV HCV

20. Indirect
Serological assays
Direct
Virological assays
Commercial HCV Assays
Antibody assays
EIA-III
RIBA-III
HCV RNA detection
- Qualitative
- Quantitative
Molecular HCV genotyping
There is a seronegative window in which HCV RNA is the only
marker that permits the diagnosis of primary HCV infection and the
identification of potentially infectious patients that would be missed
by conventional antibody testing

21.  Genetic heterogeneity
 High rate of viral persistence
 Lack of solid immunity
 Poor definition of protection correlates
 Technical limitations in the study of HCV

22.  Viral eradication
 SVR = cure
 Arrest progression
of necrosis/fibrosis
 Reduce progression of
fibrosis/cirrhosis
 Prevent decompensation
 Prevent HCC
Primary objectives Secondary objectives
SVR: Sustained Virological Response

23.  SVR is defined as absence of HCV RNA in the serum
at the end of treatment and 6 months later
 Patients who achieve an SVR may be deemed
clinically cured of chronic HCV

24. ~1990’s mid-90’s ~2000-01

25. Peginterferon alfa-2a (40KD) Ribavirin
SC injection,
once weekly
By mouth,
twice daily
 Direct inhibition of HCV RNA-
dependent RNA polymerase ?
RNA mutagenesis ?
 Depletion of intracellular GTP
pools via IMPDH inhibition ?
 T-cell enhancement
 OAS: activates antiviral RNAses
 PKR: inactivates viral ptn
translation
 ADA: edits viral RNA

26. 30-40% 80%

27. RVR
RapidVirologic Response
HCV RNA negative at 4 weeks (< 50 IU/mL)
EVR
EarlyVirologic Response
HCV RNA negative or > 2 log10 drop at week 12.
cEVR (complete) or pEVR (partial)
SVR
Sustained Virologic
Response
HCV RNA negative 24 weeks after end of treatment
Relapse
HCV RNA negative at end of treatment but HCV RNA
positive after treatment stopped

29.  Previously, treatment recommendation was based on
the HCV genotype
 The early kinetics of HCV viremia (week 4) are
emerging as the most reliable predictive marker of
response
 Quantification of HCV viremia is essential for
tailoring the treatment schedule: Response Guided
Therapy

30.  Favorable
 Genotype 2 and 3
 HCV RNA < 400,000 IU/ml
 Mild fibrosis (F0-F2)
 Age < 40
 IL28B CC
 Adherence
 RVR and cEVR
 Unfavorable
 Genotype 1
 HCV RNA > 400,000 IU/ml
 Advanced fibrosis (F3-F4)
 Age > 40
 Steatosis, Insulin Resistance,
high BMI
 IL28B CT or TT
 Dose reduction > 60%
 Non-adherence

31. Side effects
 Flu-like symptoms
 Weight loss
 Depression
 Neutropenia
 Concentration/memory
disturbance
 Insomnia
 Thrombocytopenia

32. Side effects
 Haemolytic anaemia
 Significant teratogenicity
 Rash
 Fatigue
 Itching
 Sinusitis

37. Log(10)HCVRNAIU/ml
Days
8
6
4
2
14
Telaprevir
100
Peginterferon + Ribavirin
Telaprevir
+ Peg/RBV

38.  Are added to (do not replace) original therapy.
 Indications:
 treatment of chronic Hep C (genotype 1).
 with compensated liver disease, including cirrhosis.
 previously untreated or who have failed previous interferon
and ribavirin therapy.

39. Telaprevir (GT1)
(ADVANCE & REALIZE trials)
Boceprevir (GT1)
(SPRINT2 & RESPOND2)
%SVR

42. Mono infected
 GT 2,3: pegIFN + RBV x 24wk
 GT 4: x 48wk
 GT 1: pegIFN + RBV + DAA
 Variable duration based on response
(24, 36, or 48 wk)

43. Telaprevir
Time point HCV RNA Action
Week 4 or 12 > 1000 IU/mL Stop T/P/R
Week 24 Detectable Stop P/R
Boceprevir
Time point HCV RNA Action
Week 8 or 12 > 100 IU/mL Stop B/P/R
Week 24 Detectable Stop P/R

45. Telaprevir
DAA/P/R P/R
Pruritis 45-50% 28%
Nausea 40-43% 31%
Rash 56% 34%
Anemia 37-39% 19%
Diarrhea 28-32% 17%
Anorectal discomfort 11% 3%
Boceprevir
Anemia 50% 30%
Dysgeusia 35-43% 16%
Neutropenia 25% 19%
Nausea 46% 42%

48.  Wave 1 (2011-2014): add-on Rx
 1st generation PIs + SOC: naïve and experienced
 Wave 2 (2014-2016): the better mousetrap
 Substitution of 2nd generation PIs (better barrier to
resistance, tolerance), Nucs (better PK, tolerability)
 Substitution of better tolerated IFNs
 4 drug regimens for P/R/PI failures (quad therapy)
 Wave 3 (2015-2020): the holy grail
 Oral cocktails of DAAs, host cofactor inhibitors, RBV
 IFN-free regimen!

50.  Improved efficacy ?

51.  NEUTRINO study (Phase III registration trial)
 AE in >20%

52.  Strong barrier to resistance !

54.  For GT 1
 No anemia and no grade 3-4 AE

55.  For GT 2 and 3

56.  DCV (PI) + SOF (Nuc-PoI) in Boceprevir/PR failures.

59.  Genotype 1:
 PEG / RBV + Simeprevir (2nd gen PI)
 PEG / RBV + Sofosbuvir (PoI)
 Genotype 2, 3:
 RBV + Sofosbuvir
 Off label combination of available DAA classes
 Simeprevir + Sofosbuvir + RBV for GT1

60.  Emerging DAA therapy against 3 major viral proteins will
provide solutions for most patients with HCV.
 Strong potency
 Nonoverlapping resistance profile
 Enough genotypic / subgenotypic range
 High barriers compounds desirable for simplified regimens.
Can be matched by combinations of DAA classes.
 Novel host targets increasingly identified, including many
involved in Lipid metabolism. Inherently high barrier to
resistance.

61.  Thank you.
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