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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
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HEPATITIS C
Dawn of a revolution
P. JaninRNSH – ICU26.09.2013
THE VIRUS
1965 - Blumberg & Alter
1973 – Feinstone, Kapikian & Purcell
The hepatitis puzzle was still incomplete
THE VIRUS
THE VIRUS
….
….
THE VIRUS
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
THE VIRUS
THE VIRUS
Study of Infection, Replication and Release Difficult:
Lack of reliable culture system Does not integrate into host genome Low number of circulating virions
THE VIRUS
Structural genes Non-structural genes
GENETIC VARIABILITY
Pathogenesis
Prevention
Therapy
THE VIRUS
Complex, dynamic distributions of non-identical but related mutant RNA genomes
Encompasses a master genome (dominant) and a multitude of minor genomes
Escapes host immune surveillance ?
Establishes persistent infection ?
GENETIC VARIABILITY
NATURAL HISTORY
Exposure(Acute Phase)
Resolved Chronic
CirrhosisStable
Liver DecompensationHepatocellular Carcinoma
5%-25% over 20-30 years
15-45%55-85%
5%/yr decompensation2-8%/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.
Only real threat of acute Hepatitis C is its ability to reach chronic stages undetected and untreated.
NATURAL HISTORY
THE DISEASE
90%
5-10%
80-90%
70-85%
2% (coinfection)
90% (superinfection)
Infants
Adults
Normal liver
Chronic hepatitis
Cirrhosis
LEADING CAUSE OF CHRONIC LIVER DISEASE
LEADING CAUSE OF CHRONIC LIVER DISEASE
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)
AUSTRALIA
221.000 people with chronic hepatitis C Leading reason for liver transplant Deaths have surpassed HIV
HIV HCV
DIAGNOSIS
IndirectSerological assays
DirectVirological assays
Commercial HCV Assays
Antibody assaysEIA-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
PREVENTION
Genetic heterogeneity High rate of viral persistence Lack of solid immunity Poor definition of protection correlates Technical limitations in the study of HCV
TREATMENT
Viral eradication SVR = cure
Arrest progressionof necrosis/fibrosis
Reduce progression of fibrosis/cirrhosis
Prevent decompensation
Prevent HCC
Primary objectives Secondary objectives
SVR: Sustained Virological Response
OBJECTIVE
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
TREATMENT
~1990’s mid-90’s ~2000-01
TREATMENT
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
RESULTS
30-40% 80%
RESPONSE
RVR Rapid Virologic Response
HCV RNA negative at 4 weeks (< 50 IU/mL)
EVREarly Virologic
Response
HCV RNA negative or > 2 log10 drop at week 12.cEVR (complete) or pEVR (partial)
SVRSustained Virologic Response
HCV RNA negative 24 weeks after end of treatment
RelapseHCV RNA negative at end of treatment but HCV RNA positive after treatment stopped
RESPONSE
TREATMENT
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
RESPONSE
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
INTERFERON
Side effects
Flu-like symptoms Weight loss Depression Neutropenia Concentration/memory disturbance
Insomnia Thrombocytopenia
RIBAVARINSide effects
Haemolytic anaemia Significant teratogenicity Rash Fatigue Itching Sinusitis
NEW DIRECTIONS
NEW DIRECTIONS
NS3-4A PROTEASE TARGET
RESISTANCE
Log(10) HC
V R
NA
IU/m
l
Days
8
6
4
2
14
Telaprevir
100
Peginterferon + RibavirinTelaprevir+ Peg/RBV
BOCEPREVIR & TELAPREVIR
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.
RESULTS
Telaprevir (GT1)(ADVANCE & REALIZE trials)
Boceprevir (GT1)(SPRINT2 & RESPOND2)
%SVR
BOCEPREVIR: RESPONSE GUIDED THERAPY
TELAPREVIR: RESPONSE GUIDED THERAPY
PROTOCOL
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)
STOPPING RULES
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
IMPORTANCE OF STOPPING RULES
SIDE EFFECTS
TelaprevirDAA/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%
BoceprevirAnemia 50% 30%
Dysgeusia 35-43% 16%
Neutropenia 25% 19%
Nausea 46% 42%
OTHER DAA: THE NEXT STEP
OTHER DAA: THE NEXT STEP
NEW WAVES OF HCV THERAPY
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!
2ND GENERATION PI: SIMEPREVIR
2ND GENERATION PI
Improved efficacy ?
NUC-POI (NS5B): SOFOSBUVIR
NEUTRINO study (Phase III registration trial) AE in >20%
Strong barrier to resistance !
NUC-POI (NS5B): SOFOSBUVIR
INTERFERON SPARING, ALL ORAL REGIMEN ?
INTERFERON SPARING, ALL ORAL REGIMEN ?
For GT 1
No anemia and no grade 3-4 AE
INTERFERON SPARING, ALL ORAL REGIMEN ?
For GT 2 and 3
INTERFERON SPARING, ALL ORAL REGIMEN ?
DCV (PI) + SOF (Nuc-PoI) in Boceprevir/PR failures.
PERSPECTIVES
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
THE NEXT 6-12 MONTHS
CONCLUSION
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.
Thank you.
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