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What is New in HCV Genotype 4 ? Prof. Gamal Esmat

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.

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What is New in HCV Genotype 4 ? Prof. Gamal Esmat

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  1. What is New in HCV Genotype 4 ? Prof. GamalEsmat Endemic Medicine and Hepatology, Cairo University Director of Viral Hepatitis Treatment Centers,Egypt www.gamalesmat.com

  2. 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

  3. Epidemiological characteristics inpatients infected with HCV-4 • Retrospective study of 1532 HCV-4 infected patients Roulot et al, J Viral Hepat 2007; 14: 460

  4. Treatment of HCV Genotype 4 SVR to peg IFN Duration of Treatment Predictors of Response Future Therapy

  5. Response to interferon therapyIntention-to-treat analysis 100 IFN α-2b pegIFNα-2b 67 80 59 55 49 60 45 38 Patients (%) 40 20 0 24 weeks 48 weeks 72 weeks MTR ETR SVR Esmat et al, UEGW, 2003, Madrid

  6. Better SVR rates observed in patients with HCV-4a subtypes 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 (%) (4a) (4a,4d) (Multiple) n=242, p=<0.05 Roulot et al, J Viral Hepat 2007; 14: 460

  7. Efficacy of pegIFNα-2a + RBV in HCV-4 patients: German internet-based non-interventional study Patients (%) n=388, ITT=120 Zehnter et al, J Hepatol 2008; 48 (S2): S316, Abstract 842

  8. Sustained virologic response rates (SVR)in relation to HCV genotype 100 80 60 SVR (%) 40 20 0 HCV Type 1 Type 4 Type 3 Type 2

  9. HCV Genotype 4 SVR to Peg IFN Duration of Treatment Predictors of Response Future Therapy

  10. Check HCV-RNA at week 4 RVR No RVR Predicators of poor response * Check HCV-RNA at week 12 >2 Log decline Negative <2 Log decline NO YES Check HCV-RNA at week 24 Negative Positive 72 weeks therapy STOP 48 weeks therapy STOP 24 weeks therapy 48 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

  11. HCV Genotype 4 SVR to Peg IFN Duration of Treatment Predictors of Response Future Therapy

  12. 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)

  13. Effect of baseline viral load in HCV-4 patients Patients (%) Huepper et al, Hepatology 46 (4S): 389A, Abstract 336

  14. pegIFNα-2b (1.5 μg / kg / week) plus RBV (1,000 – 1,200 mg / day) for 48 weeks SVR rates and impact of fibrosis inpatients with HCV-4 SVR (%) Fibrosis score p=0.01 Roulot et al, J Viral Hepat 2007; 14: 460

  15. Predictors of treatmentfailure 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

  16. SVR (%) according to the Metavir fibrosis score and median AFP values Light grey: AFP  4.5 ng/ml Dark grey: AFP > 4.5 ng/ml

  17. 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

  18. 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

  19. HCV Genotype 4 SVR to pegIFN Duration of Treatment Predictors of Response Future Therapy

  20. HCV Genotype 4 (Future Therapy) New types of interferon New direct acting antiviral drugs

  21. HCV Genotype 4 New types of interferon

  22. Lambda interferon EASL 44- 2009 ,Copenhagen, Denmark 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.

  23. EMERGE Phase 2b EMERGE 2b Response Rates: * 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 IL-28B CC (favorable genotype) and non-CC (unfavorable genotype).

  24. 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.

  25. Y shaped Interferon Early virological response(Week 24) in the 3 treated groups (Ashour et al,AASLD 2011).

  26. Y shaped Interferon Haematological side effects in the treated groups(Ashour et al AASLD 2011).

  27. HCV Genotype 4 New types of interferon New direct acting antiviral drugs

  28. HCV Genotype 4 New direct acting antiviral drugs

  29. Hepatitis C Drug Development IFN & PEG IFN Ribavirin On Market Boceprevir Albumin-IFN alfa TMC 435350 Telaprevir Phase III Taribavirin KPE02001003 ME-3738 MK7009 R1728 Oglufanide HDV interferon TCM-700C ITMN 191 PF-868554 SCV-07 A-831 Thymalfasin Omega IFN SCY-635 Phase II Nitazoxanide PYN-17 Silibinin Controlled-release IFN Debio25 Medusa IFN BMS-790052 BIT225 ABT-333 IPH-1101 VCH-759 PHX1766 BMS-791325 IFN biopump DA-3021 ANA598 EGS21 GS9190 BI-201335 Phase I NIM811 Low-dose oral IFN Bavituximab EMZ702 IDX184 VCH-916 VX-813 BMS-650032 JTK-652 IFN beta-1a IL-29 CF102 MK-3281 VX-500 VBY-376 VCH-222 CYT 107 Many others, including immune stimulants and gene therapy Interferons Research/ Preclinical Ribavirins Protease inhibitors Polymerase inhibitors Note: Not a complete list of products in development. Information from public sources.Graphic courtesy of Dr. John McHutchison. Immunomodulators Others

  30. 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 .

  31. 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

  32. Other Drugs to improve SVR Vit D I.V Silibin Nitazoxanide

  33. 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

  34. Journal of Hepatology 2011 vol. 54 | S363

  35. 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.

  36. 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

  37. Gamal Esmat

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