Transcript Kamal2.pps

Case 1
 During his annual physical in Dec 2007, Mr. A, a 42 y old pilot,
presented with elevated liver enzymes and positive antibodies to
HCV.
 He had no symptoms. BMI 27
 His physical examination revealed no abnormalities and his liver
was not enlarged.
 His blood picture, renal profile, thyroid profile were within normal
 His physical performed December 2006 was normal
Mr. A’s Questions
 He was recently married.
 He is frustrated
 He will be subjected to another medical examination after
3 months.
 He could not recall how, when or where he got the
infection
Mr. A’s labs
• ALT: 175 U/L
• HCV-PCR: 650, 000 IU/L
• Genotype 4
Mr. M’s questions:

Is treatment possible?
 Is there a possibility of transmitting the infection
to his wife?
 What are the odds for having normal liver
enzymes and negative HCV values after 3
months of therapy?
 If treatment is considered will he be able to fly?
When?
What to do at this time?
 Request a liver biopsy
 Do an ultrasound only
 Request more investigations
 Wait and see
A liver biopsy was performed revealing
A2 and S1
based on the METAVIR scoring system
Treat or not to treat?
Is this patient a good candidate
for Peg-IFN + RBV therapy?
• Yes. He has a > 60% chance
to achieve SVR
• Yes, but the likelihood of SVR
is less than 30%
• No. He will not benefit from
therapy.
SVR Genotype 4
PEG-IFN alfa- + ribavirin
The patient was treated with PEG-IFN a 2a plus
RBV 1000 mg/day.
The patient was compliant
Treatment was well tolerated
Weeks 4, 12 results
W4
W 12
Alt
24 U/L
27 U/L
HCV-PCR
undetectable
undetectable
Hb
12 g/dl
12.4
RBCs
4M
3,8 M
WBCs
4,200 cells/mm3
3,700 cells/mm3
Platelets
172,000 cells/mm3
163, 000 cells/mm3
 What is the significance of these results?
What duration of PEG-IFN plus RBV is
recommended?
 24 weeks
 48 weeks
Terminology
 RVR :Rapid virological response (4 weeks)
 EVR :Early virological response (12 weeks)
-Complete EVR : HCV RNA positive at Wk 4 but
negative at Wk 12
- Partial EVR: HCV RNA positive at WK 4 and 12
but  2 log10 IU/mL drop from baseline at Wk 12
 SVR:Sustained virological response
 NR :Non response;
Transient virological response; relapse (20%) or
breakthrough (10%)
Rapid Virological Response
Genotype 1
 216 patients
 51 (24%) had RVR
 SVR associated with RVR and lower HCV viral load
(< 600,000 IU/ml)
 RVR portends an 89% probability of SVR after 24
weeks of treatment
Jensen DM et al, Hepatology 2006; 43(5):954-960
Rapid Virological Response
Genotype 2 – 3
 283 patients: RVR as a guide for 12w or 24w
 Shorter course as effective as 24w if patients are
negative by week 4
 Higher relapse rate (8.9 Vs. 3.6%)
 PEG-IFN alpha 2b (1.0 microg/Kg/week)
 Results consistent with a Norwegian trial
Mangia A et al, NEJM 2005
Rapid Virological Response
Genotype 4
 318 patients: RVR, EVR as a guide for 24 w, 36 w or 48w
358
patients
Adaptive
N=308
Fixed
N=50
RVR
N=69
24 w
cEVR
N=79
48 w
Kamal et al, Hepatology, 2007
36 w
pEVR
N=160
48 w
End of treatment and sustained
virologic response rates
100
90
86
86
EOT
SVR
76
75
70
65
56
58
50
25
0
Patients with
RVR
Patients with
complete EVR
Patients with
partial EVR
Fixed 48 weeks
Kamal et al, Hepatology. 2007 Dec;46(6):1732-40
RVR HCV Genotype 4
 66 patients with G4, Peg IFN α 2a and
RBV
 RVR: 45%
 26 (86.7%) of those achieved a SVR
 No relation: with degree of Fibrosis
with baseline viral load
with dose of RBV
Ferenci, Gastroenterology 2008
Main Findings
SVR in Patients Achieving RVR (%)
 In per-protocol analysis, 80.4% SVR rate in patients with RVR (115/143)
100
80
90.0
86.5
81.3
82.2
85.7
83.3
80.6
70.8
81.5 79.6
88.5
All
Genotype 1
Genotype 4
75.0 75.0 75.0
66.7
60
40
20
n/N = 61/74 52/64 9/10
0
37/45 25/31 12/14 17/24 12/18 5/6
≤ 400,000
400,000 > 800,000
800,000
By Baseline HCV RNA (IU/mL)
Ferenci P, et al. Gastroenterol. 2008;135:451-458.
97/119 74/93 23/26 18/24 15/20 3/4
F0-F2
F3-F4
By METAVIR Fibrosis Stage
Distribution of Virologic
Response Rates
 Retrospective analysis from 3 large trials (N = 1383)
 PegIFN alfa-2 + RBV
 RBV 800 mg/day for 24 wks in GT 2/3
 RBV 1000-1200 mg/day for 48 wks in GT 1/4
Response, %
RVR
cEVR
pEVR
SVR
GT 1
(n = 569)
16
42
20
49
Fried MW, et al. EASL 2008. Abstract 7.
GT 2
(n = 395)
71
24
1
77
GT 3
(n = 426)
60
29
3
68
GT 4
(n = 24)
38
46
8
79
SVR in Patients Who Achieved an RVR
100
100
88
86
86
90
282
257
SVR (%)
80
60
40
20
n=
0
GT 1
Fried MW, et al. EASL 2008. Abstract 7.
GT 2
GT 3
Patients With an RVR
9
GT 4
 Rapid virologic response is a clinically useful tool
for determining the duration of treatment in
chronic hepatitis C genotype 4.
 24 weeks therapy with peginterferon-alpha-2a
and ribavirin seems sufficient for patients with
chronic hepatitis C genotype 4 who have a rapid
virologic response.
Kamal et al, Hepatology. 2007 Dec;46(6):1732-40
RVR: Conclusions
 Chronic Disease:
 Genotype 1, 4: useful for 24 week strategies
 Genotype 2 – 3: unclear the utility
 HIV - HCV:
 Encouraging marker
Predictive factors of Low SVR
 Age ??
 Gender ??
 BMI 1,4
 Fibrosis
 Steatosis 1,4
 HCV G 4 non a subtypes4 ??
 Coinfections6
 No RVR or EVR
 Higher AFP5
1Kamal
44
et al, GUT; 2Kamal et al, Hepatology 2007; 3Kamal et al 2007; 4Roulot et al 2006; 5Gad et
al, Liv Int 2008, 28 (8): 1112-1119; 6Legrand-Abravane et al, J Med Virol 2005;77:66-69.
Case Presentation 2
 Mr. N, an 49-year-old Egyptian American engineer living
and working in the US since 12 years.
 HCV (G4) accidentally detected since 8 years
 He had received repeated blood transfusion 15 years
before following a traffic accident.
 He is diabetic on oral medications for diabetes mellitus.
 He is obese. His BMI: 30
Previous therapy
 He has been previously treated in 2004 with 48 weeks of PEG-
IFN a-2b and ribavirin but relapsed.
 He achieved an early virologic response (EVR).
 At one point, his lab results showed anemia.
 He had his ribavirin dosage repeatedly reduced until his anemia
improved.
 He was able to complete 48 weeks of treatment and achieved
an ETR and SVR.
 In 2007, HCV-RNA was detectable
Second presentation
Dec. 2007
 ALT: 70 U/L, AST: 60 U/L
 Albumin: 3.9 g/dL
 Blood picture: Hb: 13 gm%, Platelet count:
130,000, WBCs: 8,400.
 Serum HCV RNA: 800 000 IU/mL
 Genotype 4
He did not agree to repeat liver
biopsy. Instead, testing with HCV
Fibrosure was performed, yielding a
fibrotic score of 0.73 (F3) and activity
score of 0.61 (A3 inflammation).
What to do next?
Re-treat or not to re-treat?
He was re-treated with PEG-IFN alpha
2a/RBV (1200)
 Epoetin alfa was used during therapy
 Week 12 HCV-PCR: 9000 IU/ml
What to Do?
1.
2.
3.
4.
5.
Treat for 24 weeks
Treat for 36 weeks
Treat for 48 weeks
Stop the treatment
Other choices or suggestions
What about extending treatment?
Extending treatment: Ferenci et al, 2008
Patients with no RVR but EVR:
 Group A : 48 W
 Group B : 72 W
Patients with no EVR:
 Group C: 72 W
Ferenci P, et al. Gastroenterol. 2008;135:451-458.
Extending treatment
 Group A and B had similar SVR: 52% and
51%
 Relapse rate lower in group B (19%) vs.
33% in group A
 Complete EVR: SVR group A (71%) group
B (78%)
 Partial EVR: SVR group A (31%) group B
(35%)
Ferenci P, et al. Gastroenterol. 2008;135:451-458.
 Mr. H, a 21 y old man accidentally discovered elevated
liver enzymes and positive antibodies to HCV during
check-up.
 His physical examination revealed no abnormalities and
his liver was not enlarged.
 His blood picture, renal profile, thyroid profile were within
normal
 He had no symptoms
History:
 Depression since 5 years
 Tri-cyclic antidepressant: 4 years
 History of IDU for 3 years
 Admitted to rehab for 6 months with withdrawal
 Relapse after 3 months.
 Readmitted to rehab and abstained for 1 year.
Lab:

ALT: 215 U/L
 HCV-PCR:
 Genotype 4
850, 000 IU/L
A liver biopsy was performed revealing
A2 and S 0
based on the METAVIR scoring system
Treat or not to treat?
 Treat for how long?
 What about his
depression?
 What about his
addiction problem?
Case Study #4
 38-year-old Greek man
 Diagnosed with HIV since 2005
 Doing well on HAART
 He stopped using drugs (heroin).
 He has recently separated from a partner of 3
years.
Case Study # 4
July 2007
 ALT: 217 U/L
 HCV-AB positive
 HCV RNA: 1.2 M U/ml
 Genotype 4
 Liver biopsy: Grade 8, stage 2
 CD4+: 520
What do you want to know?
What do you want to know?
 Transmission
 Alcohol use
 Depression/Antidepressants
 Treatment Choices
HCV/HIV Coinfection
 HIV accelerates Hep C liver disease (may cut time
to cirrhosis in half!)
 Hep C may impair immune reconstitution after
HAART
 HCC may occur at an earlier age with coinfection
HCV-G4/HIV Coinfection
 Treatment of Chronic HCV-4 in HIV patients is less
successful than treatment of chronic hepatitis C in HCV
monoinfected individuals.
 SVR rates:
 IFN- monotherapy: 11.1%
 IFN- plus ribavirin: 9.1%
 PEG-IFN plus RBV: 22.7%
 Legrand-Abravane et al, J Med Virol 2005;77:66-69.
 SVR 15%
Soriano et al, Antiviral
Ther 2005;10:167-170.
.
HIV/HCV Treatment
Predictors of success in achieving a sustained viral
response:
 CD4 count greater than 500
 HIV RNA levels below 10,000 copies
 No alcohol consumption
Treatment Decisions
 Treat Hep. C first ? (if HIV stable, if CD4 count good)
 Treat HIV first? (if immune compromised)
HIV/HCV Co-infection Study
AIDS
PEGASYS®
Ribavirin
International
CO-Infection
Trial
Sustained Virologic Response*
60%
P 0.0001
P 0.0001
50%
% Response
40%
40%
P = 0.0084
30%
20%
20%
12%
10%
n = 285
n = 286
n = 289
IFN alfa-2a + RBV
PEGASYS
(40 kDa) + Placebo
PEGASYS
(40 kDa) + COPEGUS
0%
* Defined as <50 IU/mL HCV RNA at week 72; ITT
APRICOT
Conclusion
 Hepatitis C genotype 4 is no more a problem of Africa and
the Middle East .
 It’s now known that PEG/RBV gives reasonable results in
chronic HCV-G4.
 It’s now the time for refining the treatment.
Conclusion
Chronic HCV-G4 treatment in special populations, HCV/HIV
and IDUs is still a challenge
Baseline viremia, early viral kinetics, treatment duration,
and stage of liver disease are important factors that can be
used to individualize therapy.