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What is New in HCV Genotype 4 ?
Prof. Gamal Esmat
Endemic Medicine and Hepatology, Cairo University
Director of Viral Hepatitis Treatment Centers,Egypt
www.gamalesmat.com
Genotype 4
• Genotype 4 predominates throughout the Middle East
and parts of Africa, often in association with a high
population prevalence as in Egypt
• More than 90% of Egyptian HCV isolates belong to
genotype 4
• Phylogenetic analysis of the complete genomic
sequence of genotype 4 revealed a closer relationship
between genotype 4 and genotype 1 than with other
genotypes
Habib et al, Hepatology 2001; 33: 248-253
Angelico et al, J Hepatol 1997; 26: 236-43
Epidemiological characteristics in
patients infected with HCV-4
• Retrospective study of 1532 HCV-4 infected patients
n
HCV-4 subtype
Predominant route of
infection
France
1056
4a, 4d
Intravenous drug abuse
Egypt
227
4a
Parenteral treatment of
schistosomiasis
sub-Saharan
Africa
249
More than 7
different subtypes
None found
Country
Roulot et al, J Viral Hepat 2007; 14: 460
Treatment of HCV Genotype 4
SVR to peg IFN
Duration of Treatment
Predictors of Response
Future Therapy
Response to interferon therapy
Intention-to-treat analysis
IFN α-2b
100
67
80
Patients (%)
pegIFNα-2b
55
60
59
49
38
45
40
20
0
24 weeks
48 weeks
72 weeks
MTR
ETR
SVR
Esmat et al, UEGW, 2003, Madrid
Epidemiological characteristics and response to
pegIFN plus RBV in patients with HCV-4
pegIFNα-2b (1.5 mg / kg / week) plus RBV
(1000 – 1200 mg / day) for 48 weeks
SVR (%)
100
54.9
40.3
0
(4a)
32.4
(4a,4d)
Egypt
France
(Multiple)
Africa
n=242, p=<0.05
• Better SVR rates observed in patients with HCV-4a subtypes
Roulot et al, J Viral Hepat 2007; 14: 460
Efficacy of pegIFNα-2a + RBV in HCV-4 patients:
German internet-based non-interventional study
Patients (%)
100
50.8
45.3
0
EOT
SVR
n=388, ITT=120
Zehnter et al, J Hepatol 2008; 48 (S2): S316, Abstract 842
Sustained virologic response rates (SVR)
in relation to HCV genotype
100
SVR (%)
80
60
40
20
0
HCV
Type 1
Type 4
Type 3
Type 2
HCV Genotype 4
SVR to Peg IFN
Duration of Treatment
Predictors of Response
Future Therapy
Check HCV-RNA
at week 4
RVR
No RVR
Predicators of poor response *
Check HCV-RNA at week 12
NO
YES
>2 Log
decline
Negative
<2 Log
decline
Check HCV-RNA
at week 24
Negative
24 weeks
48 weeks
therapy
therapy
72 weeks
therapy
Positive
STOP
48 weeks
therapy
STOP
* High basal viral load (≥800,000)/ Advanced degree of fibrosis (≥F3,4)/ High degree of basal insulin resistance (HOMA-IR ≥2) . Khattab et al. J. Hepatology 2011
HCV Genotype 4
SVR to Peg IFN
Duration of Treatment
Predictors of Response
Future Therapy
PREDICTORS OF RESPONCE
Viral Factors:(Genotype,, Viral load, Quaise species)
Drug Factors : (Type of INF , Dose, Duration)
Patient Factors:
Age, Sex, Ethnicity, IL 28 b
Infections (HIV,HBV, Schistosomiasis)
Metabolic ( D.M, Weight, BMI,IR)
Liver histopathology (Cirrhosis ,Steatosis, Iron)
Effect of baseline viral load in HCV-4
patients
100
HCV RNA at baseline <600,000, IU/ML (n=24)
HCV RNA at baseline ≥600,000, IU/ML (n=21)
Patients (%)
67
48
38
21
14
13
0
SVR
Relapse
Non-responder
Huepper et al, Hepatology 46 (4S): 389A, Abstract 336
SVR rates and impact of fibrosis in
patients with HCV-4
100
SVR (%)
65
46.4
46.6
36
21.2
27.3
Egyptian
French
African
0
F0 - F1 - F2
p=0.01
F3 - F4
Fibrosis score
• pegIFNα-2b (1.5 μg / kg / week) plus RBV (1,000 – 1,200 mg / day) for 48
weeks
Roulot et al, J Viral Hepat 2007; 14: 460
Predictors of treatment failure in HCV 4
• In univariate analysis:
– Weight > 80 kg
– METAVIR score  F3
– Steatosis
– AFP levels > median value
• In multivariate analysis:
– AFP levels only
Males et al, Antiviral Therapy ,2007,12:797
SVR (%) according to the Metavir
fibrosis score and median AFP values
100
90
81
75
80
Light grey:
AFP  4.5 ng/ml
70
60
50
43
39
40
30
20
10
0
F1 or F2
F3 or F4
Dark grey:
AFP > 4.5 ng/ml
Serum alpha-fetoprotein predicts treatment outcome
in HCV patients regardless of genotype
.
Abdoul H, Mallet V, Pol S, Fontanet A.
They examined the association between AFP level and SVR in
93 chronic hepatitis C patients. The SVR rate was much
higher among patients with serum AFP levels below rather
than above the median value (5.7 ng/ml) (58.7% and 19.2%,
respectively; P<0.0001).
They concluded that AFP should be added to the list of
factors predictive of treatment response in chronic HCV.
Plo S One,2008
IL28B polymorphism is associated with
SVR in HCV genotype 4 patients.
The data showed a better treatment
response rate of the C allele of the IL28B
gene (p=0.0008). The response rates were
81.8%, 46.5%, and 29.4% for genotype CC,
CT, and TT, respectively. No significant
relationship was found between the
polymorphism and the severity of the
disease.
Asselah et al,J.Hepat,2011
HCV Genotype 4
SVR to pegIFN
Duration of Treatment
Predictors of Response
Future Therapy
HCV Genotype 4 (Future Therapy)
New types of interferon
New direct acting antiviral drugs
HCV Genotype 4
New types of interferon
Lambda interferon
 PEG-interferon-λ1a (PEG-IFN-λ/PEG-rIL-29) is a Type III
interferon that binds to a unique receptor with a
more limited distribution than the Type I interferon
receptor. The IFN-λ receptor, compared to theIFN-α
receptor, is expressed only on epithelial-derived cells,
including hepatocytes.
EASL 44- 2009 ,Copenhagen, Denmark
EMERGE Phase 2b
EMERGE 2b Response Rates:
Alfa
G1,4
(95% CI)
Lambda
240 μg
180 μg
120 μg
cEVR
39.7%
(28.5,48.0)
56.3%*
(46.2,66.1)
55.9%*
(45.7,65.7)
55%*
(44.7,65.0)
cEVR-CC
66.7%
(41.0,86.7)
82.4%
(56.6,96.2)
81.8%
(59.7,94.8)
73.7%
(48.8,90.9)
cEVR-CT/TT
26.3%
(15.5,39.7)
50%
(33.8,66.2)
42.1%
(26.3,59.2)
45.7%
(30.9,61.0)
RVR
5.8%
(202,12.2)
16.5%*
(9.9,25.1)
14.7%*
(8.5,23.1)
6%*
(2.2,12.6)
* Statistically significant (p-value < 0.05, not adjusted for multiple comparisons)
In an exploratory analysis, when the response rates were analyzed with
respect to host genotype, treatment with Lambda using all three doses,
compared to treatment with Alfa, led to better response rates for both the IL28B CC (favorable genotype) and non-CC (unfavorable genotype).
Y shaped Interferon
Structure of Y-shaped pegylated interferon α-2a
Modified by 40KD, Y-shaped branched PEG
Modification site with high potency
 This novel interferon molecule was recently evaluated
in 90 chronic HCV 4 infected Egyptian naive patients.
Y shaped Interferon
PCR W 24
Group 1
(7 days)
Group 2
(10days)
Group3
(14days)
Patients No.
Negative
25
25
23
73
5
5
7
30
30
30
90
83.3%
88%
76.7%
NS
Positive
Total no of
patients
Percentage
17
Early virological response(Week 24) in the 3 treated groups
(Ashour et al,AASLD 2011).
Y shaped Interferon
Group1
(7days)
Group 2
(10days)
Group3
(14days)
Haemoglobin
below 10gm/dl
6(23%)
7(24%)
3(11%)
P=0.39
Neutrophils
below 750/ml
3(11.1%)
5(16.7%)
1(3.6%)
P=0.27
Platelet below
75000
2(7.7%)
1(3.3%)
3(10.7%)
P=0.55
Haematological side effects in the treated groups(Ashour et al AASLD 2011).
HCV Genotype 4
New types of interferon
New direct acting antiviral drugs
HCV Genotype 4
New direct acting antiviral drugs
Hepatitis C Drug Development
Phase III
Ribavirin
IFN & PEG IFN
On Market
Boceprevir
Albumin-IFN alfa
TMC 435350
Telaprevir
Taribavirin
R1728
MK7009
HDV interferon
KPE02001003
ME-3738
Oglufanide
TCM-700C
ITMN 191
Phase II
Controlled-release
IFN
Medusa IFN
Phase I
EMZ702
IPH-1101
Silibinin
BIT225
BMS-791325
Low-dose
oral IFN
BI-201335
ANA598
GS9190
EGS21
NIM811
VCH-916
BMS-650032
IDX184
IFN beta-1a
VBY-376
Research/
Preclinical
ABT-333
PYN-17
SCY-635
DA-3021
VX-813
IL-29
Debio25
VCH-759
A-831
Thymalfasin
Nitazoxanide
BMS-790052
PHX1766
IFN biopump
SCV-07
PF-868554
Omega IFN
VX-500
VCH-222
Many others, including
immune stimulants and
gene therapy
Note: Not a complete list of products in development.
Information from public sources.
Graphic courtesy of Dr. John McHutchison.
MK-3281
Bavituximab
JTK-652
CF102
CYT 107
Interferons
Ribavirins
Protease inhibitors
Polymerase inhibitors
Immunomodulators
Others
Protease inhibitors
 Most of these new antiviral drugs have only been
developed and investigated for genotype-1 HCV
 The first two HCV protease inhibitors (telaprevir
and boceprevir) were recently approved for
genotype-1 HCV, in some countries.
 With genotypes 1 and 2 being most susceptible and
genotypes 4 and 5 most resistant .
NS5A Inhibitors
 The HCV nonstructural protein 5A (NS5A) is a
multifunctional protein that is expressed in basally
phosphorylated (p56) and hyperphosphorylated
(p58) forms. NS5A phosphorylation has been shown
to play a role in regulating numerous aspects of HCV
replication. Classes of compounds that inhibit HCV
RNA replication by targeting NS5A were recently
discovered
Other Drugs to improve SVR
Vit D
I.V Silibin
Nitazoxanide
NTZ increases phosphorylation of protein kinase activated by
RNA (PKR) and induces eukaryotic initiation factor 2-alpha
(eIF2a), which ultimately inhibits translation of viral RNA
Journal of Hepatology 2011 vol. 54 | S363
Summary
 Epidemiological trials show that HCV-4 has spread
beyond Africa and the Middle East to Western
countries
 Recent clinical data provides new insights into HCV-4
infection and treatment strategies
 Baseline viremia, early viral kinetics, AFP and stage of
liver disease are important to individualize therapy.
Conclusion
 HCV-4 seems to have SVR (60%), in between genotype
1 and genotypes 2 & 3
 24 weeks of therapy may be successful in RVR
patients who clear the virus at week 4
 Future Therapy
New IFN
DAAs
Others