Antonio Ascione MDConsultant HepatologistCenter for liver diseases

Fatebenefratelli HospitalNaples - ITALY

Recent guidelines/strategies  in chronic hepatitis  C therapy

The First Congress of the Palestinian Society of Gastroenterology (20-22) May 2010 The First Congress of the Palestinian Society of Gastroenterology (20-22) May 2010

Hepatitis C virus (HCV) infection is a worldwide problem with at least 150–180

million of people chronically infected.

The overall prevalence, according to the WHO, is around 3%

(range 1–10%).

20 patients

20% recovery

Outcomes of HCV Infection

100 acute HCV infections

80 patients

80% persistent infections

24 patients

30% stable, chronic, nonprogressive

34 patients22 patients

Antiviral therapy 56 patients

Sustained response (~60%)

End-stage disease, HCC,liver transplantation,

death

Treatment failure (~40%)

30% severe progressive hepatitis

40% variable progression

32 patients 24 patients

13% LIVER RELATED DEATHS IN 20 YRS

AlcoholHBVHIVIron

Steatosis

Development of therapies for HCV chronic hepatitis (SVR)

66%

Achille’s heel of guidelines:

• Fixed dose of the drugs

• Fixed lenght of treatment

• Characteristics of host response not taken into consideration

Which Patients Should Be Treated ?

HCV carriers older than 65y NO / YES

HCV carriers with normal ALT NO / YES

HCV carriers with abnormal ALT

• Mild histology NO / YES

Decision should depend on:- Age < 40-45 yrs- ALT profile > x 3 - 4 - Histologic activity

- HCV Genotype 2/3

• Moderate / severe YES

• Compensated cirrhosis YES / NO

• Decompensated cirrhosis NO

X

LONG-TERM OUTCOME AFTER ANTIVIRAL THERAPY OF DECOMPENSATED CIRRHOTIC PATIENTS WITH HEPATITIS C VIRUS INFECTION

IACOBELLIS Angelo, et al.Division of Gastroenterology and Digestive Endoscopy, “Casa Sollievo della Sofferenza” Hospital, IRCCS, S. Giovanni Rotondo

Results. Among 75 treated patients, 24 individuals (32%) achieved an SVR.

Conclusions. In cirrhotic patients secondary to HCV infection who have progressed to a stage of liver decompensation, attaining an SVR

after antiviral therapy has a substantial positive impact on the long-term prognosis.

LONG-TERM OUTCOME AFTER ANTIVIRAL THERAPY OF DECOMPENSATED CIRRHOTIC PATIENTS WITH HEPATITIS C VIRUS INFECTION

IACOBELLIS Angelo, et al.Division of Gastroenterology and Digestive Endoscopy, “Casa Sollievo della Sofferenza” Hospital, IRCCS, S. Giovanni Rotondo

Results. Among 75 treated patients, 24 individuals (32%) achieved an SVR.

Conclusions. In cirrhotic patients secondary to HCV infection who have progressed to a stage of liver decompensation, attaining an SVR

after antiviral therapy has a substantial positive impact on the long-term prognosis.

Accepted as oral presentation, MASL First meeting, Napoli (ITALY), June 13-15,2010

Typical exclusion criteria in RCTs of therapy in chronic hepatitis C

Age> 65 yrsLow hemoglobin (<12 g/dl)Low WBC count (<3,000/mm3)Neutropenia (<1,500/mm3)

Thrombocytopenia (< 100,000/mm3)Decompensated liver diseaseBilirubin >2.0 mg/dLAlbumin <3.5 g/dLProthr time >2 sec prolongedCreatinine >1.5 mg/dLAlphafetoprotein >50 mg/dLHBsAg+ Any other known liver disease

Age> 65 yrsLow hemoglobin (<12 g/dl)Low WBC count (<3,000/mm3)Neutropenia (<1,500/mm3)

Thrombocytopenia (< 100,000/mm3)Decompensated liver diseaseBilirubin >2.0 mg/dLAlbumin <3.5 g/dLProthr time >2 sec prolongedCreatinine >1.5 mg/dLAlphafetoprotein >50 mg/dLHBsAg+ Any other known liver disease

DepressionPsychiatric diseaseCoronary artery disCerebrovascular disNeurologic illnessSeizure disordersAlcohol abuseIV drug useMethadone treatmentHemophiliaHemoglobinopathyAutoimmunityThyroid diseasesInstitutionalization

DepressionPsychiatric diseaseCoronary artery disCerebrovascular disNeurologic illnessSeizure disordersAlcohol abuseIV drug useMethadone treatmentHemophiliaHemoglobinopathyAutoimmunityThyroid diseasesInstitutionalization

Schedules for Naive Patients

PEG-IFN α2a 180 μg/week or

Ribavirin 1000 (</=75 Kg) - 1.200 (>75 Kg) / d

PEG-IFN 2b 1.5 g/Kg/wk

Ribavirin 800/1400 according body weight

HCV - 1/4

HCV - 2/3

x 48 weeks

x 24 weeksPEGs same dosages, less ribavirin

DURATION: shorter ? Longer ?

TREATMENT MUST BE PERSONALIZED AND

GUIDED BY THE RESPONSE TO THERAPY

FIRST OF ALL

Analyse carefully

THE PATIENT

And try and modify negative factors

PATIENT

THERAPY

DISEASE

Which patient must be treated?

All those who show signs of progressive liver disease and have no contraindications to the treatment

(Consensus NIH, EASL, APASLD, AISF)All patients HCV-RNA positive should be

evaluated for therapy because of the natural history of HCV chronic infection

HIPPOCRATES (Kos ~460 - Larissa~ 377 B.C.)

PRIMUM NON

NOCEREA fundamental medical precept: first do not harm

CONTRAINDICATIONS

PEG-IFNAutoimmune liver diseasesHepatic decompensation in patients with cirrhosisNeonates and infantsHypersensitivity

PEG-IFN PLUS RIBAVIRINPregnant womenMen whose partners are pregnantHemoglobinopathies (thalassemia)Hypersensitivity

IN FEMALE UNDER THERAPY

CHECK MONTLY

THE PREGNANCY TEST

WARNINGSPEGINTERFERON CAN CAUSE

May cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Monitor closely with periodic clinical and laboratory evaluations and withdraw therapy in patients with persistently severe or worsening signs or symptoms of these conditions

RIBAVIRIN CAN CAUSE

Hemolytic anemia. The anemia associated with ribavirin therapy may result in a worsening of cardiac disease

Ribavirin is genotoxic and mutagenic and should be considered a potential carcinogen

Ribavirin may cause birth defects and/or death of the fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients

Ribavirin is not effective as monotherapy

Side effects

Nearly all patients experience one or more AE

Most common are: flu like syndrome, fatigue, pyrexia, myalgia, headache, arthralgias, insommia, anorexia, ansiety, depression, irritability, psychiatric reactions

Other common symptoms are: anorexia, nausea, vomiting, diarrea, pruritus, alopecia, injection site reactions

The patient should know everything

since the beginning

Goals of Therapy in HCV hepatitis

• Primary goal– Eradicate HCV infection SVR

• Secondary goals– Slow disease progression

– Improve histology

– Reduce risk of hepatocellular carcinoma

– Improve health-related quality of life

Lindsay et al. Hepatology. 2002;36:S114-S120.

Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study.

S. Bruno, T. Stroffolini, S. Bollani, A. Ascione, G. Mazzella, L. Benvegnù, A. Mangia, P Andreone, M. Persico, G. F. Gaeta, P. Almasio on behalf of the

AISF GroupHEPATOLOGY 2007;45:579-87.

168144120967248240

1,0

,8

,6

,4

,2

0,0

Kaplan Meier curves of liver-related mortality according to the achievement of SVR

p<0.001 by Log Rank test

No SVR

SVR

Patients at riskSVR 199 194 185 173 118 73 23 No SVR 1.015 944 870 747 528 332 74

months

Kaplan Meier curves of HCC development according to the achievement of SVR

months168144120967248240

1,0

,8

,6

,4

,2

0,0

SVR 199 194 185 173 117 72 21 No SVR 1.015 929 846 722 501 304 62

SVR

No SVR

p<0.001 by Log Rank test

Patients at risk

Surveillance is mandatory for these

subjects

Survival

Treatment failure

Sustained virological respondersS

urv

ival

pro

bab

ilit

y (%

)

MONTHS

p=0.02 log rank test

Picciotto FP et al, J Hepatol. 2007;46:459-65.

0

5

10

15

20

25

30

Phys.Funct.

Role-ph. Bodilypain

Gen.Health

Vitality Soc.Funct.

Role emot. MentalHealth

Virologic Responders (41) Virologic Non Responders (396)

Effects of IFN Treatment on HRQOLEffects of IFN Treatment on HRQOLBaseline to 48-week mean changesBaseline to 48-week mean changes

(Multicenter Italian Study, 2004)(Multicenter Italian Study, 2004)

Histological Response AmongSustained Virological Responders

0

20

40

60

80

100

Pa

tie

nts

Wit

h

His

tolo

gic

al R

esp

on

se (

%)

PEG (40kDa) IFN -2a 180 g

83%79%

IFN -2a3 MIU

P = 0.7619 / 24

62 / 75

J. Heathcote et al, NEJM, 2000

The effect of peginterferon -2a on liver histology in chronic hepatitis C: a meta analysis of individual patients data

Subgroup analysis of patients with cirrhosis (n=198)

0

1

3

4

0

1

3Before

0

1

3

4After

66.1%

24.2%

9.6 %

0 %

SVR the only predictor for staging improvement

Cammà et al, Hepatology, 2004

Poynard et al ., Gastroenterology 2004

FULL REVERSAL OF CIRRHOSIS

REMAINS:

A VIRTUAL REALITY

OF STATISTICAL ILLUSIONS

Valeer Desmet, J hepatol, 2005

Patterns of Virological Response

Sustainedresponder

(cure)

Nonresponder

Baseline Treatment

Time

Relapser

Partialresponder

HCV RNAUndetectable

HC

V R

NA

Breakthrough

Detection limit

6 months

Flat partial responder

Slow partial responder

Rapid virological responderor SUPERESPONDERS

Null-responder

Short term reponse of HCV-RNA to IFNShort term reponse of HCV-RNA to IFNS

erum

HC

V R

NA

0 1 2 3 7 14 21 28

detection limit

Days

1st phase

2nd phase

Direct antiviral

action

Immune Clearance

Patterns of Virological Response

RResponse toesponse tottreatmentreatment

Modified from Pawlotsky JM, Hepatology vol. 32, #5, 2000

HC

V R

NA

InitialInitialresponseresponse

““Nonresponse”Nonresponse”Based on EVRBased on EVR

WEEKS 0 1 4 12 18 24 48 72

RVR LLDEVR

Post treatment observationPost treatment observation

SVR

Complete EVR (cEVR)

Partial EVR (pEVR)

Rapid Virologic Response (RVR)

HCV RNA undetectable by Week 4

Early Virologic Response (EVR)

≥ 2 log decline in HCV RNA by Week 12

End of Treatment (EOT) Response

Undetectable HCV RNA at end of treatment

Partial Virologic Response

≥ 2 log decline in HCV RNA by Week 12, but HCV RNA detectable at Week 24

Sustained Virologic Response (SVR)

HCV RNA negativity 12-24 weeks after treatment end

New Definitions of Response to Treatment

Quantitative HCV-RNA (IU/mL) TestsDynamic Ranges of Assays

615 IU/mL 7.7 million IU/mLBayer bDNA 3.0

SuperQuant™100 copies/mL 100 million copies/mL

Roche COBAS AMPLICOR™ HCV MONITOR Test, v2.0 600 IU/mL 500 000 IU/mL

Roche AMPLICOR HCV MONITOR® Test, v2.0 600 IU/mL 850 000 IU/mL

ROCHE COBAS TaqMan™ HCV Test

15 IU/mL 100 million IU/mL

Disclaimer: Information on this slide represents my opinions, not those of Roche

RVR is an Important Predictor of SVR

• Methods

− Subanalysis of 3 phase III trials:

ACCELERATE, Fried, Hadziyannis− 1.383 patients treated for 24 (G2/3) or 48

(G1/4) weeks with Pegasys 180 mcg/wk plus ribavirin 800 mg/d (G2/3) or 1.000/1.2000 mg/d (G1/4)

Fried WW et al, presented at EASL 2008, April 23-27, 2008, Milan, Italy, Abstract #7

STOPPING RULES TELL YOU TO STOP TREATMENT IF AT

W12 HCV-RNA IS STILL POSITIVE

● Simplification of treatment in pts with a good prognostic profile (=RVR)

● Intensification of treatment in pts with a poor prognostic profile (non-RVR + EVR)

● Motivation of patients achieving early responses

Why an RVR/EVR-guided Approach Makes Sense

HOW CAN WE OBTAIN BETTER RESULTS?

• PAY ATTENTION TO THE BAD FRIENDS

• ADHERENCE TO PRESCRIBED THERAPY

• RIBAVIRIN ANEMIA AND LEUKOPENIA

• TREAT SIDE EFFECTS!

BAD FRIENDS

• ALCOHOL

• OVERWEIGHT

• IRON

• STEATOSIS

• METABOLIC DISORDERS

ADHERENCE TO PRESCRIBED THERAPY

Granulocyte-Col Stimulating Factor

Side efffects must be treated

How can we improve treatment outcomes?

Identify and manage predictors of poor response

Genotype is the most important baseline predictor of response

Use on-treatment predictors of response and

optimise ribavirin

New strategies

Future strategies

1. Response-guided therapy (RGT)2. Optimisation of ribavirin dosing

New molecules

Treatment options fornon-responders

Swain et al EASL Meeting, 2007,

CONCLUSIONS• Safety comes first! Check contraindications.• Follow carefully the patient for side effects: don’t

reduce/stop therapy too early: don’t run away. Compliance is crucial.

• Follow the on-treatment virological response in order to decide the duration of therapy

• RVR is highly predictive of success.• Use an appropriate test for HCV-RNA quantification.• Optimize the treatment with the drugs now available

(PEG+RIBA).

Materiale per Roma

Grazie

Island of Procida (Napoli - ITALY)

CorricellaFisherman’s Port at sunrise

BACK UP SLIDES

PEGINTERFERON PLUS RIBAVIRIN IS THE STANDARD OF CARE FOR

HCV CRHONIC INFECTION

Many side effects:Anemia caused by Ribavirin and PEG-IFN Neutropenia caused by PEG-IFNThrombocytopenia caused by PEG-IFN

• Anemia– Fatigue, impaired QoL, and reduced adherence– Can increase risk of myocardial ischemia, other

cardiovascular abnormalities• Higher risk in patients with chronic obstructive pulmonary disease

• Neutropenia– Can predispose to infection (very rare in

immunocompetent)

• Thrombocytopenia– Can predispose to bleeding (very rare)

SYMPTOMS ASSOCIATED WITH:

PEG-IFN ALPHA-2a PLUS

RIBAVIRIN (N=93)

PEG-IFN ALPHA-2b PLUS

RIBAVIRIN (N=93)

PEG-IFN ALPHA-2a PLUS

RIBAVIRIN (N=67)

PEG-IFN ALPHA-2b PLUS

RIBAVIRIN(N=67)

Number (%) Number (%) Number (%) Number (%) Number (%)

DISCONTINUATION 3 (3.2) 13 (14) 1 (1.5) 9 (13.4) 26 (8.1)

Laboratory abnormalities*

0 5 (5.4) 0 0 5 (1.6)

Adverse Events 3 (3.2) 8 (8.6) 1 (1.5) 9 (13.4) 21 (6.6)

DOSE MODIFICATION **

33 (35.5) 33 (35.5) 19 (28.4) 23 (34.3) 108 (33.7)

LABORATORY ABNORMALITIES*

Anemia 17 (18.3) 20 (21.5) 13 (19.4) 10 (14.9) 60 (18.7)

Neutropenia 3 (3.2) 3 (3.2) 1 (1.5) 1 (1.5) 8 (2.5)

Thrombocytopenia 4 (4.3) 3 (3.2) 3 (4.5) 3 (4.5) 13 (4.1)

NO ADVERSE EVENT 9 (9.7) 7 (7.5) 7 (10.4) 7 (10.4) 30 (9.4)

* Laboratory abnormalities included anemia, neutropenia, thrombocytopenia

** > 20% PEGINTERFERON or RIBAVIRIN dose modification

TOTAL

SIDE EFFECTS - 1GENOTYPE 1/4 GENOTYPE 2/3

Laboratory values

Manufacturer Package Insert Recommendations

Hemoglobin

< 11.0 but > 10 g/dL

No change in RBV dose if patient has minimal symptoms

In a symptomatic anemic patient, consider RBV dose reduction by 200 mg/day and/or starting an erythropoietic growth factor

< 10.0 but > 8.5 g/dL

Decrease RBV by 200 mg/day and/or consider starting an erythropoietic growth factor

Recheck hemoglobin levels at least every 2 wks or more frequently if indicated

< 8.5 g/dL Discontinue until resolution

In patients with stable underlying cardiac disease, reduce ribavirin by 200 mg/day if ≥ 2 g/dL drop in hemoglobin occurs over a 4-week period. If the hemoglobin level is < 12 g/dL after 4 weeks of dose reduction, discontinue RBV until resolution and reevaluation.

General Guidelines for RBV Dose Reduction or Discontinuation

Laboratory Values Manufacturer Package Insert Recommendations

White blood cell count

< 1.5 x 109/L PegIFN alfa-2b: reduce dose by 50% and re-evaluate

< 1.0 x 109/L PegIFN alfa-2b: discontinue until resolution

Absolute neutrophil count

< 0.75 x 109/LPegIFN alfa-2a: reduce dose to 135 µg/wk and re-evaluatePegIFN alfa-2b: reduce dose by 50% and re-evaluate

< 0.50 x 109/L PegIFN alfa or cIFN: discontinue until resolution

Platelet count

< 80,000/mm3 PegIFN alfa-2b: reduce dose by 50% and re-evaluate

< 50,000/mm3 PegIFN alfa-2a: reduce dose to 90 µg/wk and re-evaluatePegIFN alfa-2b or cIFN: discontinue until resolution

< 25,000/mm3 PegIFN alfa-2a: discontinue until resolution

LABORATORY VALUES

MANUFACTURER PACKAGE INSERT RECOMMENDATIONS

HOW TO MANAGE ANEMIA IN CLINICAL PRACTICE ?

Full blood count at week 2 Full blood count at week 2

Hb >11Hb >11

Check in 2 Check in 2 weeksweeks Reduce dose of Reduce dose of RBV RBV

And check weekly And check weekly

Accurate evaluation of Accurate evaluation of the patient (age, heart the patient (age, heart problems, SVR?problems, SVR?

Hb <10Hb <10

If Hb>10 If Hb>10 follow up every 2 wfollow up every 2 w

HOW TO MANAGE NEUTROPENIA IN CLINICAL PRACTICE ?

Full blood count at week 2 Full blood count at week 2

Neutrophils >750 mmNeutrophils >750 mm33

Check in 2 Check in 2 weeksweeks

If N >750 follow-upIf N >750 follow-up every 2 weeksevery 2 weeks

Neutrophils <750 mm3Neutrophils <750 mm3

Reduce dose and check Reduce dose and check weeklyweekly

If N between 750 and If N between 750 and 1000 Continue1000 Continue

If N > 1000 go back If N > 1000 go back to initial doseto initial dose

If N still < 750 give If N still < 750 give same dose for 2 w same dose for 2 w With weekly checkWith weekly check

If N >750 increase dose If N >750 increase dose and check weeklyand check weekly

Granulocyte colony-stimulating factor ( G-CSF): FILGRASTIM , LENOGRASTIM,PEGFILGRASTIM 300 µg SC TIW Cost: 183,26 EuroShould not be given as primary therapy to prevent pegIFN alfa dose reductions

clinicaloptions.com/hep

Maintaining Patients on HCV Treatment: Strategies for Successful Retreatment

Phase II Study: Eltrombopag Increased Platelet Counts at All Doses Evaluated Significantly more patients with HCV-associated

thrombocytopenia achieved ≥ 100,000 cells/μL at Week 4 by LOCF analysis in all eltrombopag dose groups compared with placebo (P .001)

Best responses with eltrombopag 75 mg/day

– 91% of this group able to initiate HCV therapy

– 65% of this group able to complete 12 weeks of therapy

Treatment Week

Median Platelet Count, x 103/µL (Range)

PlaceboEltrombopag

30 mg/dayEltrombopag

50 mg/dayEltrombopag

75 mg/day

Baseline, N = 74 55 (27-75) 59 (34-94) 52 (26-66) 54 (28-75)

Week 4 53 (34-74) 137 (40-528) 214 (47-499) 209 (78-527)

McHutchison JG, et al. N Engl J Med. 2007;357:2227-2236.

clinicaloptions.com/hep

Maintaining Patients on HCV Treatment: Strategies for Successful Retreatment

PEG-Intron [package insert]. Kenilworth, NJ: Schering Corp; March 2008. Pegasys [package insert]. Nutley, NJ: Roche Pharmaceuticals; January 2008. Soza A, et al. Hepatology. 2002;36:1273-1279. McHutchison JG, et al. N Engl J Med. 2007;357:2227-2236.

Hematologic AEs Associated With HCV Therapy

Anemia Neutropenia Thrombocytopenia

Definition Hemoglobin < 12 g/dL > 3 g/dL decrease in Hb

Absolute neutrophil count < 750 cells/mL

Platelets < 75,000/mL

Etiology RBV: hemolysis IFN: bone marrow

suppression

Interferon: bone marrow suppression

Interferon: bone marrow suppression

Monitor Monitor labs closely first weeks

Assess severity of symptoms

Monitor labs closely first weeks

Assess severity of symptoms

Monitor platelet counts closely during the first weeks

Assess for gum bleeding, bruising, nose bleeds

Dose Adjust Adjust ribavirin dose Adjust interferon dose Adjust interferon dose

Consider Pharmacologic Intervention*

Epoetin alfa 40,000 units SC weekly or darbepoetin alfa 3 µgKg SC every other week

Granulocyte colony-stimulating factor 300 µg SC TIW

Should not be given as primary therapy to prevent pegIFN alfa dose reductions

Administration of oprelvekin is associated with edema in the lower extremities and cannot be recommended

Phase II studies of 75 mg/day eltrombopag shows promise

*Off-label use.

clinicaloptions.com/hep

Maintaining Patients on HCV Treatment: Strategies for Successful Retreatment

PEG-Intron [package insert]. Kenilworth, NJ: Schering Corp; March 2008. Pegasys [package insert]. Nutley, NJ: Roche Pharmaceuticals; January 2008. Soza A, et al. Hepatology. 2002;36:1273-1279. McHutchison JG, et al. N Engl J Med. 2007;357:2227-2236.

Hematologic AEs Associated With HCV Therapy

Anemia Neutropenia Thrombocytopenia

Definition Hemoglobin < 12 g/dL > 3 g/dL decrease in Hb

Absolute neutrophil count < 750 cells/mL

Platelets < 75,000/mL

Etiology RBV: hemolysis IFN: bone marrow

suppression

Interferon: bone marrow suppression

Interferon: bone marrow suppression

Monitor Monitor labs closely first weeks

Assess severity of symptoms

Monitor labs closely first weeks

Assess severity of symptoms

Monitor platelet counts closely during the first weeks

Assess for gum bleeding, bruising, nose bleeds

Dose Adjust Adjust ribavirin dose Adjust interferon dose Adjust interferon dose

Consider Pharmacologic Intervention*

Epoetin alfa 40,000 units SC weekly or darbepoetin alfa 3 µgKg SC every other week

Granulocyte colony-stimulating factor 300 µg SC TIW

Should not be given as primary therapy to prevent pegIFN alfa dose reductions

Administration of oprelvekin is associated with edema in the lower extremities and cannot be recommended

Phase II studies of 75 mg/day eltrombopag shows promise

*Off-label use.

Virological Response: NEW definitions

Rapid virological responseHCV-RNA undetectable at week 4

Early virological response HCV-RNA undetectable at week 12

SHORTER IFN/RIBA REGIMEN (?)

12 WEEKS RULE FOR STOPPING THERAPY

Quantitative HCV TestsDynamic Ranges of Assays

HCV RNA IU/mL

615 IU/mL 7.7 million IU/mLBayer bDNA 3.0

SuperQuant™100 copies/mL 100 million copies/mL

Roche COBAS AMPLICOR™ HCV MONITOR Test, v2.0 600 IU/mL 500 000 IU/mL

Roche AMPLICOR HCV MONITOR® Test, v2.0 600 IU/mL 850 000 IU/mL

ROCHE COBAS TaqMan™ HCV Test

15 IU/mL 100 million IU/mL

W 12: < 2 log HCV RNA Reduction

W 24: 24% HCV RNA negative (< 50 IU/ml)

48 Weeks of Therapy 72 Weeks of Therapy

Relapse: 87% Relapse: 46%

Berg et al. Gastroenterology 2006

Importance of Highly Sensitive HCV-RNA Assays for IFN-treatment:

48 vs. 72 Weeks of Treatment

Importance of Highly Sensitive HCV-RNA Assays for IFN-treatment:

48 vs. 72 Weeks of Treatment

SUSTAINED VIROLOGICAL RESPONSE

** Manns * Fried * Hadzyiannis * DITTO

• ALL 54% 56% 63% 66%

• Gen 1 42% 46% 52% 60%

• G1 HVL 30% 41% 47%

• HVL 42% 53% 66%

*Pegasys 180 mcg + 1000-1200 mg x 48 weeks**Pegintron 1.5 mcg/Kg + 800 mg x 48 weeks

>800.000 UI/ml

NON RESPONDERS

~45%

AF ALL TREATED PATIENTS

Why does HCV treatment fail?

Host factors• Race ? • Age (patient/infection)• Gender• High estrogens levels• Body weight• Fibrosis• Siderosis• Steatosis• Diabetes• Active drug abuse• Concomitant

disease• COINFECTIONS• ALCOHOL

Treatment • Poor adherence to therapy• Discontinuation for side effects• Use of a less than effective regimen (dose/duration)

Virus• Genotype• Viral load

Reasons for treatment failure