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