PegIntron WCOG Bangkok

Report
Clinical Challenges in the
Management of Hepatitis C
Genotype 4
Sanaa Kamal, M.D., Ph.D.
Professor
Ain Shams University, Cairo,
Egypt
HCV Genotype 4
True or False
 HCV-G4 is of limited geographic
distribution
 HCV-G 4 is difficult to treat
 All HCV-G4 infected individuals
respond similarly to therapy
 Therapy of chronic HCV G 4 has
been optimized
 Are new treatments on the horizon
for HCV-G4?
Worldwide Distribution of Genotypes
1 (1a)
2
3
1 (1a)
(1b)
2
4
90%
60%
? 60%
1b
1b
1b
1b
2
6
4
3
1c
5
 HCV genotype 4 (G4) accounts for 20% of all global HCV infections
 Hepatitis C genotype 4 has started to spread beyond it
strongholds in Africa and the Middle East to Western countries
Epidemiology of Genotype 4
Country
% of HCV-G 4
Subtypes
Egypt
90%
4a (55),4 (24), 4o (7), 4m (3),4l (3), 4n (2)
Gabon
97%
4c (36%),4h (15), 4e (13),4 (13),4g(13),4f (5),4a (2.6)
Central African Republic
100%
4 (66.7), 4k (33.3)
Congo
100%
4 (30), 4c (30), 4k (24), 4r (14), 4a (5).
Cameroon
36%
4f (22), 4 (5), 4t (5), 4k (5), 4e (1.4), 4o (1), 4p (1),
Liberia
100%
4 (100)
Uganda
100%
4 (66.7),4r (33.3)
Tanzania
50%
4d
Rwanda
100
4k (100)
Sudan
5%
4, 4e, and 4c/4d
Tunisia
11%
4k (5), 4a (3.6), 4 (2.6)
Saudi Arabia
60%
4d (60), 4a (40)
France
4-10%
4d (2.3), 4a (2.2)
Italy
8.3%
4d (5.9), 4 (2.4)
Spain
3-10%
4c/4d (76.8%), 4 (11.5%), 4a (7.2%), 4e( 4.3%)
Greece
13.2%
4a (78%)
Chronic HCV Genotype 4
Could be your next patient!
Some Presentations
 27-year-old Egyptian was diagnosed with chronic hepatitis
C, genotype 4a. HCV-RNA 650,000 IU/mL
 37-year-old Spanish woman with HIV on HAART since
2001. HIV-RNA < 50 copies/mL, CD4: 514 cells/mm3. HCV
was diagnosed 5 years ago. HCV-RNA 1.2 million IU/ml.
Genotype 4d
Some Presentations
 45-year-old former injection drug user pre-employment
testing revealed elevated ALT level (135 U/L). HCV was
confirmed. HCV-PCR: 1.2 million U/L. Genotype 4d
 A 46-year-old Canadian working in Africa discovered upon
her return from field work that she has was infected with
HCV genotype 4c.
TREAT??
Who, Why, How?
What are the expectations?
Treatment Evolution of HCV- Genotype 4
1992-Present
100%
?%
% SVR
80%
63%-70%
60%
35%
35%
40%
15%
20%
0%
8%
IFN α-2b +
placebo 24
weeks
IFN α-2b +
placebo 48
weeks
IFN α-2b +
ribavirin 48
weeks
Peg-IFN α-2b
48 weeks
Peg-IFN α-2b
+ ribavirin 48
weeks
Future Tx.
Options
SVR Genotype 4
PEG-IFN alfa- + ribavirin
Case # 1
 27-year-old Egyptian studying in France was diagnosed
with chronic hepatitis C, genotype 4
 Baseline labs:
• Hb 12.5 g/dL
• HCV-RNA 650,000 IU/mL
• ALT/AST 76/87
• Bilirubin 1.2 mg/dL
• INR 1.2
 Liver biopsy reveals grade 3, stage 1, steatosis
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: ALT within normal, HCV-PCR
undetectable
 How long to treat him?
How long to treat chronic hepatitis C
genotype 4?
Efficacy
Safety
Costeffective
ness
What duration of PEG-IFN plus RBV is
recommended?
 24 weeks
 48 weeks
 Others?
Sustained Virologic Response Rates
PEG-IFN α-2b 1.5 µg/kg QW + ribavirin 1,000–1,200 mg/day
100%
% patients SVR
80%
65%
*
67%
†
60%
40%
29%
20%
0%
24 Weeks, n=95
Kamal S, et al, Gut 2005;54:858–866.
36 Weeks, n=96
48 Weeks, n=96
* p= 0.02 for 36 vs. 24 weeks
† p= 0.5 for 48 vs. 36 weeks
‡ p= 0.01 for 48 vs. 24 weeks
Sustained Virologic Response in Patients with
EVR
*
Kamal S, et al, Gut 2005;54:858–866.
†, ‡
* p= 0.002 for 36 vs. 24 weeks
† p= 0.8 for 48 vs. 36 weeks
‡ p= 0.001 for 48 vs. 24 weeks
Sustained Virologic Response Rates in
Patients with >2 million Copies/mL
100%
65%†
% patients SVR
80%
53%
60%
40%
20%
0%
0%
24 Weeks
36 Weeks
48 Weeks
† p= 0.04 for 48 vs. 36 weeks
Kamal S, et al, Gut 2005;54:858–866.
Rapid Virological Response
Genotype 4
RVR, EVR as a guide for 24 w, 36 w or 48w
358
patients
Adaptive
N=308
RVR
N=69
Fixed
N=50
Kamal et al, Hepatology. 2007 Dec;46(6):1732-40
24 w
cEVR
N=79
48 w
36 w
pEVR
N=160
48 w
EOT and SVR rates in HCV-G4 patients
with RVR & EVR
100
90
86
86
EOT
SVR
76
% Response
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
Role of RVR in Determining Treatment Duration of
Peginterferon /ribavirin in Chronic Hepatitis C Genotype 4
End of follow up
Start of study
No SVR
14%
RVR
26%
SVR
86%
Total study
population
)
SVR
76%
cEVR
48%
Kamal et al, Hepatology. 2007 Dec;46(6):1732-40
No SVR
24%
21
RVR in 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
Kamal
S, et P,
al, Gut
2005;54:858–866.
Ferenci
et al.
Gastroenterol.
2008;135:451-458
SVR rates in HCV-G4 patients with RVR & EVR
Ferenci P, et al. Gastroenterol. 2008;135:451-458
In per-protocol analysis, 80.4% SVR rate in patients with RVR (115/143)
SVR in Patients Achieving RVR (%)

100
90.0
86.5
80
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
≤ 400,000
5/6
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
F0-F2
18/24 15/20
3/4
F3-F4
By METAVIR Fibrosis Stage
Back to the case
The patients completed 24 weeks successfully.
He achieved SVR
No viremia was detected a year and a half after
completing therapy.
Is HCV-G4 still hard to treat?
Does response differ
between the PEG-IFN
preparations?
% Response
Do response rates differ between
PEG-IFN preparations?
Do patients respond similarly to
therapy?
242 naïve French, Egyptian or (subsaharan) African patients received
peginterferon plus ribavirin for 48 weeks.
HCV G4 with different subtypes
Liver fibrosis was significantly less severe in patients infected in France
and Africa
An overall better response was observed in patients infected with the
4a subtype.
In multivariate analysis, two factors were associated independently
with SVR: the Egyptian origin of transmission and the absence of
severe fibrosis
Why was the response different?
Roulot et al, J Viral Hepat. 2007 Jul;14(7):460-7.
Anything in the Horizon?
Improved Virologic Response in Chronic Hepatitis C
Genotype 4
Patients Given Nitazoxanide, Peginterferon, and Ribavirin
Rossignol et al., Gastroenterology, 2009
A phase II, randomized, double-blind, placebocontrolled study of nitazoxanide treatment for 24 weeks
in 50 patients with chronic hepatitis C genotype 4 was
conducted to evaluate safety with prolonged
administration and to determine the antiviral efficacy of
nitazoxanide monotherapy.
Improved Virologic Response in Chronic Hepatitis C Genotype 4
Patients Given Nitazoxanide, Peginterferon, and Ribavirin
Rossignol et al., Gastroenterology, 2009
Peg-IFN/RBV
48 wk
(n 40)
Peg-IFN/NTZ
12 36 wk
(n 28)
Peg-IFN/NTZRBV
12 36 wk
(n 28)
RVR
15 (38%)
+
15 (54%)
18 (64%)*
cEVR
28 (70%)
19 (68%)
24 (86%)
EOT
30 (75%)
20 (71%)
23 (82%)
SVR
20 (50%)
17 (61%)
22 (79%)#
*P .048, compared with Peg-IFN/RBV.
#P .023, compared with PegIFNRBV.
*
Case #2
 37-year-old Spanish woman with HIV for about 10 years
on AZT/3TC, NVP
 HIV-RNA < 50 copies/mL
 CD4 444 cells/mm3
 HCV was diagnosed 5 years ago
 HCV-RNA 1.2 million IU/ml
 Genotype 4d
 Liver biopsy done 6 months ago reveals grade 5, stage
2/4 fibrosis
 She is asking about efficacy of treatment
HCV-G4/HIV Coinfection
Soriano et al, Antiviral Ther 2005;10:167-170.
.
LegrandAbravane et
al, J Med
Virol
2005;77:6669
Mart´ın- Carbonero et al
J Viral Hep, 2008
What we have??
HCV-G4 Clinical trials
 26 published clinical trials on HCV-G4 therapy (PEGIFN/RBV therapy) with 1385 patients
 12 registered ongoing trials
 Five randomized clinical trials
 Four trials on duration of therapy
 Enrolled patients: Egyptians, Saudis, French,
Spanish, Greek, Italian, Africans
HCV-G4 Clinical trials
Three trials on HCV-G4/HIV coinfected patients
Two trials on HCV-G4 heamophliacs
One trial on non-responders
One trial on extended therapy.
Any Roadmap?
HCV Genotype 4
proposed therapy
Pre-treatment HCV-RNA
Liver biopsy
- Low viral load
- Low histology
scores
- High viral load
- High histology
scores
No RVR
Detectable HCVRNA at week 4
Partial EVR
Complete EVR
> 2 log decline in
HCV-RNA at week
12
Undetectable HCV
RNA at week 12
48 weeks
therapy
36 weeks
therapy
Super responder:
RVR
Undetectable
HCV-RNA at week 4
24 weeks
therapy
Predictors of Low SVR
Age??
 Gender??
 BMI 1,4
 Fibrosis 6
 Steatosis 1,6
 HCV G 4 non a subtypes ?? 5
 Coinfections7
 No RVR or EVR1,2,3,4
 Higher AFP??6
1Kamal
et al, GUT; 2Kamal et al, Hepatology 2007; 3Kamal et al 2007; 4Ferenci et al, 2008; 5Roulot et al
2006; 6Gad et al, Liv Int 2008, 28 (8): 1112-1119; 7Legrand-Abravane et al, J Med Virol 2005;77:66-69.
What we may know
 Hepatitis C genotype 4 has started to spread beyond it strongholds in
Africa and the Middle East to Western countries.
 HCV-G4 might not be hard to treat in some infected patients
 Recent clinical data have provided new insights on hepatitis C genotype
4 infections and have started to refine the treatment strategies.
Baseline viremia, early viral kinetics, treatment duration, and stage of
liver disease each represent important considerations that can be used to
individualize therapy.
These data can now be used as a platform for further research to define
optimal treatment regimens to patients infected with genotype 4 HCV.
What we do not know
Renal Disease
Non-responders
HCV-G4Cirrhosis
HCV-G4 Hemophiliacs
HCV-G4/HIV
HCV/Schisto
HCV/HBV
Neuro-pshychiatric
Diabetics
Thank you
Merci

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