Guidelines hep c palestine may 2010

1. The First Congress of the Palestinian Society of Gastroenterology (20-22) May 2010
Recent guidelines/strategies in
chronic hepatitis C therapy
Antonio Ascione MD
Consultant Hepatologist
Center for liver diseases
Fatebenefratelli Hospital
Naples - ITALY

2. The overall prevalence, according to
the WHO, is around 3%
(range 1–10%).
Hepatitis C virus (HCV) infection is a
worldwide problem with at least 150–180
million of people chronically infected.

3. Outcomes of HCV Infection
100 acute HCV infections
20% recovery 80% persistent infections
20 patients 80 patients
Alcohol 30% stable, chronic, 40% variable 30% severe
HBV nonprogressive progression progressive hepatitis
HIV
Iron 24 patients 32 patients 24 patients
Steatosis
Antiviral therapy
56 patients
End-stage disease, HCC, Treatment Sustained
liver transplantation, failure (~40%) response (~60%)
death
13% LIVER RELATED 22 patients 34 patients
DEATHS IN 20 YRS

4. 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

5. Which Patients Should Be Treated ?
X
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

6. 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

7. Typical exclusion criteria in RCTs of therapy
in chronic hepatitis C
Age> 65 yrs Depression
Low hemoglobin (<12 g/dl) Psychiatric disease
Low WBC count (<3,000/mm3) Coronary artery dis
Neutropenia (<1,500/mm3) Cerebrovascular dis
Thrombocytopenia (< 100,000/ Neurologic illness
mm3) Seizure disorders
Decompensated liver disease Alcohol abuse
Bilirubin >2.0 mg/dL IV drug use
Albumin <3.5 g/dL Methadone treatment
Prothr time >2 sec prolonged Hemophilia
Creatinine >1.5 mg/dL Hemoglobinopathy
Alphafetoprotein >50 mg/dL Autoimmunity
HBsAg+ Thyroid diseases
Any other known liver disease Institutionalization

8. Schedules for Naive
Patients
PEG-IFN α2a 180 μg/week or
HCV - 1/4
Ribavirin 1000 (</=75 Kg) - 1.200 (>75 Kg) / d
x 48 weeks
TREATMENT MUST BE
PEG-IFN α2b 1.5 µg/Kg/wk
PERSONALIZED AND
Ribavirin 800/1400 according body weight
GUIDED BY THE
HCV - 2/3 RESPONSE TO THERAPY
PEGs same dosages, less ribavirin
x 24 weeks
DURATION: shorter ? Longer ?

9. FIRST OF ALL
Analyse carefully
THE PATIENT
And try and modify
negative factors

10. PATIENT DISEASE
THERAPY

11. 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

12. HIPPOCRATES
(Kos ~460 - Larissa~ 377 B.C.)
PRIMUM
NON
NOCERE
A fundamental medical precept: first do not harm

13. CONTRAINDICATIONS
PEG-IFN
Autoimmune liver diseases
IN decompensation in patients with cirrhosis
Hepatic
FEMALE UNDER THERAPY
Neonates and infants
CHECK MONTLY
Hypersensitivity
THE PREGNANCY TEST
PEG-IFN PLUS RIBAVIRIN
Pregnant women
Men whose partners are pregnant
Hemoglobinopathies (thalassemia)
Hypersensitivity

14. WARNINGS
PEGINTERFERON 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

15. Side effects
Nearly all patients experience one or more AE
Most common are: flu like syndrome, fatigue,
The patientarthralgias, insommia,
pyrexia, myalgia, headache,
should
know everything
anorexia, ansiety, depression, irritability,
psychiatric reactions
since the beginning
Other common symptoms are: anorexia, nausea,
vomiting, diarrea, pruritus, alopecia, injection site
reactions

16. 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.

17. 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 Group
HEPATOLOGY 2007;45:579-87.

18. Kaplan Meier curves of liver-related mortality
according to the achievement of SVR
1,0 SVR
,8
No SVR
p<0.001 by Log Rank test
,6
,4
,2
0,0
0 24 48 72 96 120 144 168
Patients at risk months
SVR 199 194 185 173 118 73 23

19. Kaplan Meier curves of HCC development
according to the achievement of SVR
1,0
Surveillance is
,8 mandatory for these
subjects
,6
p<0.001 by Log Rank test
,4
No SVR
,2
SVR
0,0
0 24 48 72 96 120 144 168
Patients at risk months
SVR 199 194 185 173 117 72 21

20. Survival
Sustained virological responders
p=0.02 log rank test
Survival probability (%)
Treatment failure
MONTHS
Picciotto FP et al, J Hepatol. 2007;46:459-65.

21. Effects of IFN Treatment on HRQOL
Baseline to 48-week mean changes
30
25 Virologic Responders (41) Virologic Non Responders (396)
20
15
10
5
0
Phys. Role-ph. Bodily Gen. Vitality Soc. Role emot. Mental
Funct. pain Health Funct. Health
(Multicenter Italian Study, 2004)

22. Histological Response Among
Sustained Virological Responders
100
83%
Histological Response (%)
79%
80
62 / 75
Patients With
19 / 24 P = 0.76
60
40
20
0
IFN α-2a PEG (40kDa) IFN α-2a
3 MIU 180 µg
J. Heathcote et al, NEJM, 2000

23. The effect of peginterferon α-2a on liver histology in chronic
hepatitis C: a meta analysis of individual patients data
Subgroup analysis of patients with cirrhosis (n=198)
66.1%
4 4
Before 3 24.2% 3 3 After
1 9.6 % 1 1
0 0% 0 0
SVR the only predictor for staging improvement
Cammà et al, Hepatology, 2004

24. Poynard et al ., Gastroenterology 2004

25. FULL REVERSAL
OF CIRRHOSIS
REMAINS:
A VIRTUAL REALITY
OF STATISTICAL ILLUSIONS
Valeer Desmet, J hepatol, 2005

26. Patterns of Virological Response
Baseline Treatment
Nonresponder
Breakthrough
HCV RNA
Partial
responder
Relapser
Detection limit Sustained
HCV RNA responder
(cure)
Undetectable
6 months
Time

27. Short term reponse of HCV-RNA to IFN
Direct
antiviral Immune
action Clearance
Null-responder
Serum HCV RNA
1st phase Flat partial responder
Slow partial responder
2nd phase
detection limit
0 1 2 3 7 14 21 28
Days Rapid virological responder
or SUPERESPONDERS

28. Patterns of Virological Response
Initial Response to
Post treatment observation
response treatment
HCV RNA
“Nonresponse”
Based on EVR
Complete EVR (cEVR)
RVR EVR LLD
Partial EVR (pEVR)
SVR
WEEKS 0 1 4 12 18 24 48
72
Modified from Pawlotsky JM, Hepatology vol. 32, #5, 2000

29. New Definitions of Response to
Treatment
Rapid Virologic
HCV RNA undetectable by Week 4
Response (RVR)
Early Virologic
≥ 2 log decline in HCV RNA by Week 12
Response (EVR)
End of Treatment
Undetectable HCV RNA at end of treatment
(EOT) Response
Partial Virologic ≥ 2 log decline in HCV RNA by Week 12, but HCV
Response RNA detectable at Week 24
Sustained
Virologic HCV RNA negativity 12-24 weeks after treatment end
Response (SVR)

31. Quantitative HCV-RNA (IU/mL) Tests
Dynamic Ranges of Assays
SuperQuant™
100 copies/mL 100 million copies/mL
ROCHE
COBAS
TaqMan™ 15 IU/mL 100 million IU/mL
HCV Test
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
Bayer bDNA 3.0 615 IU/mL 7.7 million IU/mL
Disclaimer: Information on this slide represents my opinions, not those of Roche

32. 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

37. STOPPING RULES TELL YOU
TO STOP TREATMENT IF AT
W12
HCV-RNA IS STILL POSITIVE

39. Why an RVR/EVR-guided Approach Makes Sense
● 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

40. HOW CAN WE OBTAIN
BETTER RESULTS?
• PAY ATTENTION TO THE BAD
FRIENDS
• ADHERENCE TO PRESCRIBED
THERAPY
• RIBAVIRIN ANEMIA AND
LEUKOPENIA
• TREAT SIDE EFFECTS!

41. BAD FRIENDS
• ALCOHOL
• OVERWEIGHT
• IRON
• STEATOSIS
• METABOLIC DISORDERS

42. ADHERENCE TO PRESCRIBED
THERAPY

43. Side efffects must be treated
Granulocyte-Col Stimulating Factor

44. How can we improve treatment
outcomes?
Identify and
Genotype is the most important
manage predictors
of poor response
baseline predictor of response
Use on-treatment 1. Response-guided therapy (RGT)
predictors of
2. Optimisation of ribavirin dosing
response and
optimise ribavirin
Treatment options for
New strategies
non-responders
Future strategies New molecules

45. Swain et al EASL Meeting, 2007,

46. 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).

47. Island of Procida (Napoli - ITALY)
CorricellaFisherman’s Port at sunrise
Materiale per Roma
Grazie

48. BACK UP SLIDES

49. 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-IFN
Thrombocytopenia caused by PEG-IFN

50. SYMPTOMS ASSOCIATED WITH:
• 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)

51. SIDE EFFECTS - 1
GENOTYPE 1/4 GENOTYPE 2/3
PEG-IFN PEG-IFN PEG-IFN PEG-IFN
ALPHA-2a PLUS ALPHA-2b PLUS ALPHA-2a PLUS ALPHA-2b PLUS TOTAL
RIBAVIRIN (N=93) RIBAVIRIN (N=93) RIBAVIRIN (N=67) RIBAVIRIN(N=67)
Number (%) Number (%) Number (%) Number (%) Number
(%)
DISCONTINUATION 3 (3.2) 13 (14) 1 (1.5) 9 (13.4) 26 (8.1)
Laboratory 0 5 (5.4) 0 0 5 (1.6)
abnormalities*
Adverse Events 3 (3.2) 8 (8.6) 1 (1.5) 9 (13.4) 21 (6.6)
DOSE 33 (35.5) 33 (35.5) 19 (28.4) 23 (34.3) 108
MODIFICATION ** (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

52. General Guidelines for RBV Dose Reduction
or Discontinuation
Laboratory Manufacturer Package Insert
values
Recommendations
Hemoglobin
No change in RBV dose if patient has minimal symptoms
< 11.0 but
> 10 g/dL In a symptomatic anemic patient, consider RBV dose reduction by
200 mg/day and/or starting an erythropoietic growth factor
Decrease RBV by 200 mg/day and/or consider starting an erythropoietic
< 10.0 but growth factor
> 8.5 g/dL 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.

53. Laboratory Values Manufacturer Package Insert Recommendations
LABORATORY MANUFACTURER PACKAGE INSERT
VALUES 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
PegIFN alfa-2a: reduce dose to 135 µg/wk and re-evaluate
< 0.75 x 109/L
PegIFN 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
PegIFN alfa-2a: reduce dose to 90 µg/wk and re-evaluate
< 50,000/mm3
PegIFN alfa-2b or cIFN: discontinue until resolution
< 25,000/mm3 PegIFN alfa-2a: discontinue until resolution

54. HOW TO MANAGE ANEMIA IN
CLINICAL PRACTICE ?
Full blood count at week 2
Hb >11 Hb <10
Check in 2 weeks
Reduce dose of
RBV
And check weekly
If Hb>10
follow up every 2 w Accurate evaluation of
the patient (age, heart
problems, SVR?

55. HOW TO MANAGE NEUTROPENIA
IN CLINICAL PRACTICE ?
Full blood count at week 2
Neutrophils >750 mm3 Neutrophils <750 mm3
Reduce dose and check
Check in 2 weekly
weeks
If N between 750 and If N still < 750 give
If N >750 follow-up 1000 Continue same dose for 2 w
every 2 weeks If N > 1000 go back With weekly check
If N >750 increase dose
to initial dose
and check weekly

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

57. 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)
Median Platelet Count, x 103/µL (Range)
Treatment Week Eltrombopag Eltrombopag Eltrombopag
Placebo
30 mg/day 50 mg/day 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)
 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
McHutchison JG, et al. N Engl J Med. 2007;357:2227-2236. clinicaloptions.com/hep

58. Maintaining Patients on HCV Treatment: Strategies for Successful Retreatment
Hematologic AEs Associated With HCV
Therapy
Anemia Neutropenia Thrombocytopenia
Definition  Hemoglobin < 12 g/dL  Absolute neutrophil count  Platelets < 75,000/mL
 > 3 g/dL decrease in Hb < 750 cells/mL
Etiology  RBV: hemolysis  Interferon: bone marrow  Interferon: bone marrow
 IFN: bone marrow suppression suppression
suppression
Monitor  Monitor labs closely first  Monitor labs closely first  Monitor platelet counts closely
weeks weeks during the first weeks
 Assess severity of symptoms  Assess severity of symptoms  Assess for gum bleeding,
bruising, nose bleeds
Dose Adjust  Adjust ribavirin dose  Adjust interferon dose  Adjust interferon dose
Consider  Epoetin alfa 40,000 units SC  Granulocyte colony-stimulating  Administration of oprelvekin is
Pharmacologic weekly or darbepoetin alfa 3 factor 300 µg SC TIW associated with edema in the
Intervention* µgKg SC every other week  Should not be given as lower extremities and cannot
primary therapy to prevent be recommended
pegIFN alfa dose reductions  Phase II studies of 75 mg/day
eltrombopag shows promise
*Off-label use.
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. clinicaloptions.com/hep

59. Maintaining Patients on HCV Treatment: Strategies for Successful Retreatment
Hematologic AEs Associated With HCV
Therapy
Anemia Neutropenia Thrombocytopenia
Definition  Hemoglobin < 12 g/dL  Absolute neutrophil count  Platelets < 75,000/mL
 > 3 g/dL decrease in Hb < 750 cells/mL
Etiology  RBV: hemolysis  Interferon: bone marrow  Interferon: bone marrow
 IFN: bone marrow suppression suppression
suppression
Monitor  Monitor labs closely first  Monitor labs closely first  Monitor platelet counts closely
weeks weeks during the first weeks
 Assess severity of symptoms  Assess severity of symptoms  Assess for gum bleeding,
bruising, nose bleeds
Dose Adjust  Adjust ribavirin dose  Adjust interferon dose  Adjust interferon dose
Consider  Epoetin alfa 40,000 units SC  Granulocyte colony-stimulating  Administration of oprelvekin is
Pharmacologic weekly or darbepoetin alfa 3 factor 300 µg SC TIW associated with edema in the
Intervention* µgKg SC every other week  Should not be given as lower extremities and cannot
primary therapy to prevent be recommended
pegIFN alfa dose reductions  Phase II studies of 75 mg/day
eltrombopag shows promise
*Off-label use.
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. clinicaloptions.com/hep

60. Virological Response: NEW definitions
Rapid virological response
HCV-RNA undetectable at week 4
SHORTER IFN/RIBA REGIMEN (?)
Early virological response
HCV-RNA undetectable at week 12
12 WEEKS RULE FOR STOPPING THERAPY

61. Quantitative HCV Tests
Dynamic Ranges of Assays
SuperQuant™
100 copies/mL 100 million copies/mL
ROCHE
COBAS
TaqMan™ 15 IU/mL 100 million IU/mL
HCV Test
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
Bayer bDNA 3.0 615 IU/mL 7.7 million IU/mL
HCV RNA IU/mL

62. Importance of Highly Sensitive HCV-RNA
Assays for IFN-treatment:
48 vs. 72 Weeks of Treatment
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

63. SUSTAINED VIROLOGICAL RESPONSE
** Manns * Fried * Hadzyiannis * DITTO
• ALL
NON RESPONDERS
54% 56% 63% 66%
~45%
• Gen 1 42% 46% 52% 60%
AF ALL TREATED
• G1 HVL 30% 41% 47%
PATIENTS
• >800.000 UI/ml
HVL 42% 53% 66%
*Pegasys 180 mcg + 1000-1200 mg x 48 weeks
**Pegintron 1.5 mcg/Kg + 800 mg x 48 weeks

64. Why does HCV treatment fail?
Host factors Virus
• Race ? • Genotype
• Age • Viral load
(patient/infection)
• Gender
• High estrogens
levels Reasons for
• Body weight treatment failure
• Fibrosis
• Siderosis
• Steatosis
• Diabetes
• Active drug abuse
• Concomitant Treatment
disease • Poor adherence to therapy
• COINFECTIONS • Discontinuation for side effects
• ALCOHOL • Use of a less than effective regimen (dose/duration)