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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