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Sanaa Kamal, M.D., Ph.D.
Professor
Ain Shams University, Cairo, Egypt
Clinical Challenges in the Management of Hepatitis C
Genotype 4
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HCV Genotype 4True 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?
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Worldwide Distribution of Genotypes
1 (1a)1 (1a) (1b)(1b)22
1b1b
1b1b1b1b1b1b2266
1 (1a)1 (1a)2233
55
331c1c
44
4490%90%
? 60%? 60%
60%60%
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
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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%)
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Chronic HCV Genotype 4
Could be your next patient!
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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
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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.
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TREAT??
Who, Why, How? What are the expectations?
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Treatment Evolution of HCV- Genotype 4 1992-Present
8%
15%
35% 35%
63%-70%
?%
0%
20%
40%
60%
80%
100%
% S
VR
IFN α-2b +placebo 24
weeks
IFN α-2b + placebo 48
weeks
IFN α-2b +ribavirin 48
weeks
Peg-IFN α-2b48 weeks
Peg-IFN α-2b+ ribavirin 48
weeks
Future Tx.Options
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SVR Genotype 4 PEG-IFN alfa- + ribavirin
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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
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The patient was treated with PEG-IFN 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?
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How long to treat chronic hepatitis C genotype 4?
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What duration of PEG-IFN plus RBV is recommended?
24 weeks
48 weeks
Others?
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Kamal S, et al, Gut 2005;54:858–866..
Sustained Virologic Response Rates PEG-IFN α-2b 1.5 µg/kg QW + ribavirin 1,000–1,200 mg/day
29%
65%67%
0%
20%
40%
60%
80%
100%
% p
atie
nts
SV
R
24 Weeks, n=95 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
* †
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Kamal S, et al, Gut 2005;54:858–866..
Sustained Virologic Response in Patients with EVR
* p= 0.002 for 36 vs. 24 weeks† p= 0.8 for 48 vs. 36 weeks‡ p= 0.001 for 48 vs. 24 weeks
* †, ‡
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Kamal S, et al, Gut 2005;54:858–866..
Sustained Virologic Response Rates in Patients with >2 million Copies/mL
0%
53%
65%
0%
20%
40%
60%
80%
100%
% p
ati
en
ts S
VR
24 Weeks 36 Weeks 48 Weeks
† p= 0.04 for 48 vs. 36 weeks
†
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Rapid Virological Response Genotype 4
RVR, EVR as a guide for 24 w, 36 w or 48w
48 w
Kamal et al, Hepatology. 2007 Dec;46(6):1732-40
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EOT and SVR rates in HCV-G4 patients with RVR & EVR
9086
6570
86
76
56 58
0
25
50
75
100
Patients withRVR
Patients withcomplete EVR
Patients withpartial EVR
Fixed 48 weeks
EOT SVR
Kamal et al, Hepatology. 2007 Dec;46(6):1732-40
% R
espo
nse
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21
Role of RVR in Determining Treatment Duration of Peginterferon /ribavirin in Chronic Hepatitis C Genotype 4
Total Total studystudy
population population ))
RVR RVR 26%26%
No SVRNo SVR 14%14%
SVRSVR86%86%
SVRSVR76%76%
cEVR cEVR 48%48%
No SVRNo SVR24%24%
End of follow upStart of study
Kamal et al, Hepatology. 2007 Dec;46(6):1732-40
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Kamal S, et al, Gut 2005;54:858–866..
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
Ferenci P, et al. Gastroenterol. 2008;135:451-458
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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)
Ferenci P, et al. Gastroenterol. 2008;135:451-458.
0
20
40
60
80
100
≤ 400,000 400,000 -800,000
> 800,000SV
R in
Pat
ien
ts A
chie
vin
g R
VR
(%
)
AllGenotype 1
F0-F2 F3-F4
By Baseline HCV RNA (IU/mL) By METAVIR Fibrosis Stage
Genotype 486.5 90.081.3 82.2 85.7
80.6
70.8
83.3
66.7
81.588.5
79.675.0 75.075.0
n/N = 61/74 52/64 9/10 37/45 25/31 12/14 17/24 12/18 5/6 97/119 74/93 23/26 18/24 3/415/20
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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?
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Does response differ between the PEG-IFN
preparations?
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Do response rates differ between PEG-IFN preparations?
% R
espo
nse
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Do patients respond similarly to therapy?
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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.
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Anything in the Horizon?
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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, placebo-controlled study of nitazoxanide treatment for 24 weeks in 50 patients with chronic hepatitis C genotype 4 wasconducted to evaluate safety with prolonged administration and to determine the antiviral efficacy of nitazoxanide monotherapy.
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Improved Virologic Response in Chronic Hepatitis C Genotype 4Patients Given Nitazoxanide, Peginterferon, and Ribavirin
Rossignol et al., Gastroenterology, 2009
+ *
Peg-IFN/RBV48 wk(n 40)
Peg-IFN/NTZ12 36 wk(n 28)
Peg-IFN/NTZRBV12 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.
-
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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
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HCV-G4/HIV Coinfection
Soriano et al, Antiviral Ther 2005;10:167-170..
Legrand-Abravane et al, J Med Virol 2005;77:66-69
Mart´ın- Carbonero et alJ Viral Hep, 2008
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26 published clinical trials on HCV-G4 therapy (PEG-IFN/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
What we have??
HCV-G4 Clinical trials
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Three trials on HCV-G4/HIV coinfected patients
Two trials on HCV-G4 heamophliacs
One trial on non-responders
One trial on extended therapy.
HCV-G4 Clinical trials
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Any Roadmap?
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Pre-treatment HCV-RNALiver biopsy
HCV Genotype 4 proposed therapy
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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.
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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 may know
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What we do not know
Non-responders
HCV-G4 Hemophiliacs
HCV/Schisto
HCV-G4Cirrhosis
HCV/HBV
Renal Disease
HCV-G4/HIV
DiabeticsNeuro-pshychiatric
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Thank you
Merci