BORDERNETwork Training on

Hepatitis C Dr. med. Wolfgang Güthoff / Alexander Leff ers, M.A.

www.bordernet.eu

www.aidshilfe-potsdam.de

This presentation arises from the BORDERNETwork project which has received funding from the European Union, in the framework of the Health Program, and co-funding of the Ministry of Environment, Health and Consumer Protection of the Federal State of Brandenburg. The sole responsibility of any use that may be made of the information lies with the authors (SPI, AIDS-Hilfe Potsdam e.V.)

Table of Contents

Epidemiology

Genotypes

Natural Course

Diagnostic

Therapy

Treatment

Overview: Epidemiology

WORLD:

• Estimated 170 – 180 Million individuals infected with HCV

• Estimated 100 - 130 Million individuals with chronic HCV

• Highest prevalence in Asia, Africa and Eastern Europa

EUROPE:

• Estimated 3 – 5 Million individuals with a chronic HCV infection

GERMANY:

• 400.000 – 500.000 persons with chronic HCV

• ~ yearly 7.000 – 8.000 with acute, new diagnosed HCV

infection

Global Hepatitis C Prevalence

> 10 %2,5 – 9,9 %

1 – 2,4 %0 – 0,9 %

Source: WHO 2003

Europe: Hepatitis C Prevalence

< 1 %1 – < 2 %2 – < 4 %> 8 % (Sicily) no recent data/ not included in reviewItaly: Northern Italy 2 - < 4% / Southern Italy 4 - < 8%

Source: adopted from ECDC: Hepatitis B and C in the EU neighbourhood, Stockholm 2010

HCV in Germany 2010

< 100 – 200 cases200 – 799 cases

800 – 1.200 cases

Source: SurvStat@RKI, 20.09.2011

Viral Hepatitis

Virus Transmission Clinical outcome

Hep. A RNA fecal-oral never chronic

Hep. B DNA parenteral 5-10% chronic

Hep. C RNA parenteral 50 - 80% chronic

Hep. D RNA parenteral as super infection 90% chronic

Hep. E RNA fecal-oral never chronic

Cause: RNA-Virus

Incubation period: 4 month

Transmission: parenteral

Natural course: > 50 - 80% chronic

Treatment of acute and chronic Hepatitis C is possible

But until now:No vaccination –

prophylaxis of exposure !!

Virus C-Hepatitis

Hepatitis C Virus Genome

Proteins encoded by the HCV genome

HCV RNA

Region encoding polyprotein precursor

5’ NTR 3’ NTR

C E1 E2 NS1 NS2 NS3 NS4A NS4B NS5A NS5B

Nonstructural proteinsStructural proteins

p70 p6 p27 p56/58p23gp70gp35p68p22

Nucleocapsid

Envelope glycoproteins

Transmebraneprotein

Cofactors

RNA polymerase

IFN-resistance protein

MetalloproteaseSerine proteaseRNA helicase

Hepatitis C virus (HCV): model structure and genome organisation. Expert Reviews in Molecular Medicine ©2003 Cambridge University Press

Hepatitis C - Genotypes

Distribution of HCV Genotypes 03/2003

Source: US Library of Medicine, National Institute of Health, Los Alamos National laboratory; URL: http://hcv.lanl.gov

Virus C – Hepatitis - Risk Situations

Parenteral transmission

Direct blood contact (professional

risk)

Hidden blood contact :

• Tattoo

• Piercing

• Needle sharing

Sexual intercourse

Vertical transmission

Decrease

of

infection

risk

Liver infected with Hepatitis C____________

Acute liver infection in 80 – 90 % without symptoms

Liver Cirrhosis

____________

1 out 3 chronic liver disease processes aggressive; 10 – 20 % of these cases developing a cirrhosis

Chronic liver disease____________

Development of chronic liver disease in 60 – 80%

Liver cancer

____________

Progress of the HCV

Source: Deutsche AIDS-Hilfe: virus hepatits 2011. Berlin 2011.

Natural Course of Chronic Hepatitis C

Acute Phase

15% resolved 85% chronic

5% per year

HCCHepatoCellular

Carcinoma

6% per year

ESLDEnd Stage Liver

Disease

20% Cirrhosis

progression during 20 years

Di Bisceglie et al. Hepatology; 2000; 31(4): 1014-1018

Factors That May Influence the Progression of HCV Infection

Virus:Viral loadHCV Genotype

Host:Age, Sex, RaceImmune ResponseDuration of Infection

Environment:Alcohol, DrugsHBV- and HCV co infectionsOther additional liver diseases

Alberti A, et al. J Hepatol. 1999;31(suppl 1):17-24.

Hepatitis C - Diagnostic possibilities

1. Blood Chemistry: Liver enzymes • ALAT (SGPT) • ASAT (SGOT) • Gamma GT

2. Serology: Detection of antibodies • anti-HCV (EIA, RIBA)

3. Viral Detection:• HCV qualitative (PCR)• HCH quantitative (PCR)• HCV genotype

(4.) Liver biopsy

I. Blood Chemistry - Diagnosis of HCV

Liver enzymes: ALAT (SGPT); ASAT (SGOT); Gamma GT

• in acute hepatitis higher levels

• in chronic hepatitis often mild or moderate elevations,

normal values are also possible

Other tests:

• Alkaline Phosphatase, Bilirubin

In progressive stages like Cirrhosis:

• Cholinesterase, Albumin;

• Prothrombin time

II. Serology of HCV - Detection of Antibodies

The HCV ELISA or EIA is a blood test that can detect HCV- antibodies. That means this person was infected with HCV at one time.

A positive anti HCV-Test could be:

• a status after acute Hepatitis C with recovery and without

chronic course

• acute Hepatitis C (but think about the diagnostic window in

the very early phase of an acute Virus C Hepatitis, in

this stage only HCVRNA is positive)

• chronic Hepatitis C

II. Serology - Detection of Antibodies

A negative anti-HCV test does not exclude HCV infection in

patients with suspected hepatitis c in following settings:

• acute HCV infection

• HIV infection

• patients with immunosuppression like e.g. chronic

haemodialysis

In immunosuppressed patients always an HIVRNA test should be

carried out if there is suspicion of hepatitis c infection independent

from the result of anti-HCV

Who should get an HCV –Test?

individuals who received blood, blood products or organs before

screening for HCV was implemented or where screening was not

yet widespread

current or former injecting drug users (even those who injected

drugs once many years ago)

patients on long-term haemodialysis

health-care workers

people living with HIV

individuals with abnormal liver tests or liver disease

infants born to infected mothers

Source: WHO June 2011

III. Viral Detection – Diagnosis of HCV

Viral Load: It measures the amount of HCV circulating in the blood in copies per millilitre or as a standard unit (International Units)

• Viral Load detection confirms the HCV replication

• Measurement is necessary predicting the medical response before starting treatment

• Analysis of the genotype choosing procedure of therapy

IV. Liver Biopsy for determination of Grading (inflammation) and Staging (Fibrosis)

There are three primary reasons for performing a liver biopsy:

• determination of the liver injury,

• grading and staging for the decision to initiate

therapy,

• with the diagnosis of advanced fibrosis or cirrhosis a

special surveillance for hepatocellular carcinoma

(HCC) and esophageal varices is necessary

Therapy of Chronic Hepatitis C

Pegylated Interferon alfa 2a or alfa 2b:

• 1 time per week subcutaneous

Ribavirin:

• daily 800 - 1200 mg, depending on HCV genotype and weight of the patient

Duration of therapy depends on HCV genotype, viral load,

viral kinetics!

HCV Therapy - Viral Kinetics

RVR - Rapid Viral Response • HCV-RNA is not detectable at week 4 (below 20 IU/ml)

cEVR - Complete Early Viral Response • HCV-RNA is not detectable at week 12 (below 20 IU/ml)

pEVR - Partial Early Viral Response• HCV-RNA reduction more than 2 Log at week 12

Nonresponder• HCV-RNA > 300 000 IU/ml at week 12• or < 2 Log decrease to week 12• or HCV-RNA is detectable at week 24

Relapse• HCV-RNA is detectable again 24 weeks after successful

therapy

Therapy in HCV-Infection Characteristics of Persons for Whom Therapy is widely accepted

Age 18 years or older, and HCV-RNA is detectable

Liver biopsy showing chronic hepatitis with fibrosis

Compensated liver disease

Acceptable haematological and biochemical indices

Willing to be treated and to adhere to treatment requirements

No contraindications

Ghany MG et al. AASLD Practice guidelines; Hepatology 2009

Standard therapy in HCV genotype 1/4

Treatment startHCV-RNA level

Week 4HCV-RNA-Determination

Week 12HCV-RNA-DeterminationHCV-RNA

< 15 IU/ml

Initial HCV-RNA< 800.000 IU/ml

HCV-RNA< 15 IU/ml

Week 24HCV-RNA positive

HCV-RNA decrease <2log or HCV-RNA >30.000 IU/ml

STOP TREATMENT

24 weeks of therapy

48 weeks of therapy

Z Gastroenterol 2010; 48:289–351.

Standard therapy in HCV genotype 2/3

Treatment startHCV-RNA level

Week 4HCV-RNA-Determination

Week 12HCV-RNA< 15 IU/ml

Initial HCV-RNA

< 800.000 IU/ml

HCV-RNApositive

Week 24

HCV-RNA decrease

<2log

STOP TREATMENT

16 weeks of therapy

48 weeks of therapy

HCV-RNA< 15 IU/ml

24 weeks of therapy

HCV-RNApositive

Z Gastroenterol 2010; 48:289–351.

Treatment of Hepatitis C - Protease Inhibitors

Very potent antiviral activity (HCV-RNA decline 3-5 Log within 3 - 7 days

Developed against HCV genotype 1

Very rapid emergence of viral resistance when applied as mono-therapy

Cross-resistance between different protease inhibitors

PI improve the SVR in patients with chronic hepatitis genotype 1

Treatment naïve patients:

SVR rates increases from 38 - 44% to 63 – 75%

Treatment experienced patients:

SVR rates increase from 17 – 21% to 59 – 66%

Approval Studies for Protease Inhibitors

Telaprevir:

First therapy: ADVANCE / ILLUMINATE

Re – Therapy: REALIZE

Boceprevir:

First therapy: SPRINT 2

Re – Therapy: RESPOND 2

ADVANCE: Study Design

Randomized, Double-Blind, Placebo-Controlled for TVR

eRVR = HCV RNA undetectable at week 4 and week 12

240 4a8 72Weeks 128 36

Follow-upSVR

Pbo + PR PR

TVR + PR

Follow-upSVR

eRVR- PR .

eRVR +Follow-up

SVR

PR

Follow-upSVR

TVR + PR

eRVR- PR .

Pbo +

PR

Follow-upSVReRVR +

PR

72 weeks

Follow-up

Follow-up

PR48 (control)

T12PR

T8PR

(T) TVR = Telaprevir 750 mg q8h; Pbo = Placebo; (P) Peg-IFN = Pegylated Interferon alfa-2a (40 kD) 180 µg/wk; (R) RBV = Ribavirian 1,000 or 1,200 mg/dayRoche Taqman® v2 LLOQ of 25 IU/mL

Stopping Rules of Triple Therapy Including Telaprevir

Time point Criteria for Stopping Action

Week 4 HCV RNA >1000 IU/mL Discontinue all treatment

Week 12 HCV RNA > 1000 IU/ml Discontinue all treatment

Week 24 HCV RNA detectable Discontinue all treatment

SPRINT 2: Boceprevir in HCV Mono-infected Patients

Sulkowski M, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 115.

BOCRGT(N=368) PR + Boceprevir

PRlead-in

BOC/PR48(N=366)

PR + BoceprevirPR

lead-in

Week 4 Week 48

PRlead-in

Week 28 Week 72

Control48 P/R(N=363)

PR lead-in

PR lead-in

PR lead-in

PR + Placebo

PR + Boceprevir

PR + Boceprevir

Follow-up

Follow-up

Follow-up

Follow-upPlacebo

TW 8-24 HCV RNA Undetectable

TW 8-24 HCV RNA Detectable

SPRINT 2: Boceprevir in HCV Mono-infected Patients

Peg-IFN + RBV4 wk

Placebo + Peg-IFN + RBV

BOC + Peg-IFN + RBV

BOC + Peg-IFN + RBV

No further treatment

Placebo + Peg-IFN + RBV

Yes

No

Undetectable weeks 8-28

Arm 1

Arm 2

Arm 3

0 4 8 28 48weeks

Peg-IFN + RBV4 wk

Peg-IFN + RBV4 wk

68%(53%)

40%(23%)

67%(42%)

SVR

Stopping Rules of Triple Therapy Including Boceprevir

Time point Criteria for Stopping Action

Week 12 HCVRNA > 100IU/ml Discontinue all treatment

Week 24 HCV RNA detectable Discontinue all treatment

Possible Side Effects of Hepatitis C Therapy

56 55

7466

38

(SVR-12)

Flu-like symptoms (fever, arthralgia, myalgia) Gastrointestinal disorders Weight loss Haematological and immunologic effects (anaemia, leucopoenia,

thrombocytopenia) Skin disorders (dry skin, rash – especially in connection with Telaprevir) Psychiatric side effects (fatigue, irritability, depressive episodes, dysgeusia

– especially in connection with Boceprevir) Disorders of the thyroids Cough and dyspnoea

Challenges in HCV - Therapy with PI

IVD - Patients

Patients with HIV Co-infections

Prevention of Resistance

Drug Interactions

Compliance

Goals of a HCV - Therapy

Main Goal of HCV Therapy: Eradication of the virus

Additional effects of successful therapy:

• Disease progression will be stopped

• Histological liver changes recover

• Risk of hepatocellular carcinoma decreases

• Normalized quality of life

• Prevent transmission of virus