what is new in hcv genotype 4 ? prof. gamal esmat endemic medicine and hepatology, cairo university...
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What is New in HCV Genotype 4 ?
Prof. Gamal EsmatEndemic Medicine and Hepatology, Cairo UniversityDirector of Viral Hepatitis Treatment Centers,Egypt
www.gamalesmat.com
Genotype 4Genotype 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 inEpidemiological characteristics inpatients infected with HCV-4patients infected with HCV-4
• Retrospective study of 1532 HCV-4 infected patients
Country n HCV-4 subtypePredominant route of
infection
France 1056 4a, 4d Intravenous drug abuse
Egypt 227 4aParenteral treatment of
schistosomiasis
sub-Saharan Africa
249More than 7
different subtypesNone found
Roulot et al, J Viral Hepat 2007; 14: 460
Treatment of HCV Genotype 4Treatment of HCV Genotype 4
SVR to peg IFN
Duration of Treatment
Predictors of Response
Future Therapy
Response to interferon therapyResponse to interferon therapyIntention-to-treat analysisIntention-to-treat analysis
Esmat et al, UEGW, 2003, Madrid
38
4955
45
5967
0
20
40
60
80
100
24 weeks 48 weeks 72 weeks
IFN α-2b pegIFNα-2b
MTR ETR SVR
Pat
ient
s (%
)
54.9
40.332.4
0
100
Egypt France Africa
Epidemiological characteristics and response to Epidemiological characteristics and response to pegIFN plus RBV in patients with HCV-4pegIFN plus RBV in patients with HCV-4
• Better SVR rates observed in patients with HCV-4a subtypes
n=242, p=<0.05
pegIFNα-2b (1.5 mg / kg / week) plus RBV (1000 – 1200 mg / day) for 48 weeks
(4a) (4a,4d) (Multiple)
Roulot et al, J Viral Hepat 2007; 14: 460
SV
R (
%)
Efficacy of pegIFNEfficacy of pegIFNαα-2a + RBV in HCV-4 patients: -2a + RBV in HCV-4 patients: German internet-based non-interventional studyGerman internet-based non-interventional study
45.350.8
0
100
EOT SVR
n=388, ITT=120
Zehnter et al, J Hepatol 2008; 48 (S2): S316, Abstract 842
Pat
ient
s (%
)
Sustained virologic response rates (SVR)Sustained virologic response rates (SVR)in relation to HCV genotypein relation to HCV genotype
Type 1 Type 4 Type 3 Type 2HCV0
20
40
60
80
100
SV
R (
%)
HCV Genotype 4HCV Genotype 4
SVR to Peg IFN
Duration of Treatment
Predictors of Response
Future Therapy
Check HCV-RNA
at week 4
No RVRRVR
Check HCV-RNA at week 12
<2 Logdecline
Negative
<2 Logdecline
Check HCV-RNA
at week 24
Positive
Negative
STOP72
weekstherapy
48 weeks
therapySTOP
Predicators of poor response*
YESNO
48 weeks
therapy
24 weeks
therapy* 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 4HCV Genotype 4
SVR to Peg IFN
Duration of Treatment
Predictors of Response
Future Therapy
PREDICTORS OF RESPONCEPREDICTORS 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 Effect of baseline viral load in HCV-4 patientspatients
67
2113
48
14
38
0
100
SVR Relapse Non-responder
HCV RNA at baseline <600,000, IU/ML (n=24)HCV RNA at baseline ≥600,000, IU/ML (n=21)
Huepper et al, Hepatology 46 (4S): 389A, Abstract 336
Pat
ient
s (%
)
SVR rates and impact of fibrosis inSVR rates and impact of fibrosis inpatients with HCV-4patients with HCV-4
65
46.646.4
21.2
3627.3
0
100
F0 - F1 - F2 F3 - F4
Egyptian
French
African
• pegIFNα-2b (1.5 μg / kg / week) plus RBV (1,000 – 1,200 mg / day) for 48 weeks
p=0.01Fibrosis score
Roulot et al, J Viral Hepat 2007; 14: 460
SV
R
(%)
Predictors of treatment failure in HCV 4Predictors 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 SVR (%) according to the Metavir fibrosis score and median AFP valuesfibrosis score and median AFP values
4339
7581
0
10
20
30
40
50
60
70
80
90
100
F1 or F2 F3 or F4
Light grey: AFP 4.5 ng/ml
Dark grey: AFP > 4.5 ng/ml
Serum alpha-fetoprotein predicts treatment outcome Serum alpha-fetoprotein predicts treatment outcome in HCV patients regardless of genotypein HCV patients regardless of genotype..Abdoul H, , Mallet V, , Pol S, , Fontanet A..
They examined the association between AFP level and SVR in They examined the association between AFP level and SVR in 93 chronic hepatitis C patients. The SVR rate was much 93 chronic hepatitis C patients. The SVR rate was much higher among patients with serum AFP levels below rather higher among patients with serum AFP levels below rather than above the median value (5.7 ng/ml) (than above the median value (5.7 ng/ml) (58.7%58.7% and and 19.219.2%, %, respectively; P<0.0001).respectively; P<0.0001).They concluded that AFP should be added to the list of They concluded that AFP should be added to the list of factors predictive of treatment response in chronic HCV.factors predictive of treatment response in chronic HCV.
Plo S One,2008 Plo S One,2008
IL28B polymorphism is associated with IL28B polymorphism is associated with SVR in HCV genotype 4 patients.SVR in HCV genotype 4 patients.
The data showed a better treatment The data showed a better treatment response rate of the C allele of the IL28B response rate of the C allele of the IL28B gene (p=0.0008). The response rates were gene (p=0.0008). The response rates were 81.8%81.8%, , 46.5%46.5%, and , and 29.4%29.4% for genotype for genotype CCCC, , CTCT, and , and TTTT, respectively. No significant , respectively. No significant relationship was found between the relationship was found between the polymorphism and the severity of the polymorphism and the severity of the disease.disease. Asselah et al,J.Hepat,2011Asselah et al,J.Hepat,2011
HCV Genotype 4HCV 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
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.
Lambda interferon
EASL 44- 2009 ,Copenhagen, Denmark
Alfa Lambda
240 μg 180 μg 120 μg
G1,4(95% CI)
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)
EMERGE Phase 2bEMERGE 2b Response Rates:
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 IL-28B CC (favorable genotype) and non-CC (unfavorable genotype).
* Statistically significant (p-value < 0.05, not adjusted for multiple comparisons)
This novel interferon molecule was recently evaluated in 90 chronic HCV 4 infected Egyptian naive patients.
Y shaped Interferon
Structure of Y-shaped pegylated interferon α-2aModified by 40KD, Y-shaped branched PEG
Modification site with high potency
Y shaped Interferon
PCR W 24 Group 1 (7 days)
Group 2 (10days)
Group3 (14days)
Patients No.
Negative 25 25 23 73
Positive 5 5 7 17
Total no of patients
30 30 30 90
Percentage
83.3% 88% 76.7% NS
Early virological response(Week 24) in the 3 treated groups (Ashour et al,AASLD 2011).
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
Y shaped Interferon
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
MK7009
Hepatitis C Drug Development
Phase IIPhase II
On MarketOn Market
Phase IIIPhase III
Phase IPhase I
Research/ Research/ PreclinicalPreclinical
Thymalfasin
Albumin-IFN alfa
IFN & PEG IFN
Many others, includingimmune stimulants and
gene therapy
Ribavirin
Taribavirin
Medusa IFN
A-831
Telaprevir
Debio25
Omega IFN
Boceprevir
R1728
TMC 435350
Note: Not a complete list of products in development. Information from public sources.Graphic courtesy of Dr. John McHutchison.
Silibinin
BI-201335 GS9190
BMS-650032
Interferons
Ribavirins
Immunomodulators
Protease inhibitors
Polymerase inhibitors
BMS-790052
ITMN 191
VBY-376
Others
MK-3281
ANA598
VCH-759
JTK-652
BIT225
BMS-791325
Controlled-release IFN
Low-dose oral IFN
IFN biopump DA-3021
IL-29
ME-3738
SCV-07
Oglufanide
IPH-1101
CYT 107
EGS21
SCY-635
KPE02001003
TCM-700C
PYN-17Nitazoxanide
VX-500
ABT-333PHX1766
IDX184EMZ702
HDV interferon
NIM811Bavituximab
CF102
VX-813
VCH-222
IFN beta-1a
PF-868554
VCH-916
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 .
Protease 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
NS5A Inhibitors
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
Gamal Esmat