Epatite Cronica C

Definizione dei Prototipi Clinici

per la Personalizzazione

Terapeutica

Genotipo 4

Gloria Taliani

Sapienza Università

di Roma

• Genotype 4 HCV Virus

• Predictors of SVR

– IL28B, Insulin Resistance,

Steatosis, Viral Load, Fibrosis,

Schistosomiasis

• Antiviral Treatment

– IFN, Peg-IFN, New Drugs

• Cirrhosis, HCC, OLT

Genomic Heterogeneity of Hepatitis Viruses (A-E): Rolein Clinical Implications and Treatment

Zahid Hussain DOI: 10.5772/55231

Estimated HCV genotype distribution amongHCV-infected individuals in Europe

Esteban JI Hepatol 2008; 48: 148–162

Phylogenetic analysis and epidemiologicalprofiles of Geno-4

133 newly identified geno-4 patients in the Amstedam area

• Phylogenetic analysis revealedthree monophyletic clusters

• Each cluster is associated to a specific epidemiological profile– C1: Immigrants from Egypt (4a)

– C2: Individuals reporting IDU (4d)

– C3: HIV positive MSM (4d)

(Bruijne Jd et al, J Clin Microbiol 2009)

The virus

Different HCV genotype-4 clusters with

different subtype specificity, epidemiological

origin, risk factors, metabolic and biologic

characteristics, potential comorbidities and

sensitivity to IFN

• Genotype 4 HCV Virus

• Predictors of SVR

– IL28B, Insulin Resistance,

Steatosis, Viral Load, Fibrosis,

Schistosomiasis

• Antiviral Treatment

– IFN, Peg-IFN, New Drugs

• Cirrhosis, HCC, OLT

Predictors of Response to Treatment• Viral load (<800.000 IU/nl), quasispecies, subtype(Kamal SM et Al, Gut

2005; 54: 858–66. 6. Hasan F, et al. Am J Gastroenterol 2004; 99: 1733–7, Zekri AR et al. Virol J. 2007 Feb 14;4:16.)

• Age < 45 years(Papastergiou V et al. J Med Virol 2012; 84: 1217–23. Wirth S et al, J Hepatol2010; 52: 501–7)

• Fibrosis F3-F4 Metavir (Gad RR et al. Liver Int 2008; 28: 1112–9; De Nicola Hepatol 12;

55: 336-342; Abdel-Rahman M et al. Clin Res Hepatol Gastroenterol. 2013 Mar 26. S2210-7401

• Obesity (leptin), Steatosis(De Careaga BO et al Ann Hepatol 2006; 5: S24–8. EsmatG et al. Indian J Gastroenterol 2009; 28: 45–8)

• Insulin Resistance (adiponectine) (El-Shazly Y et al. Journal of Diabetology 2012; 2: 3. Khattab M et al. Am J Gastroenterol 2010; 105: 1970–7. Khattab M et al, Liver Int 2010; 30: 447–54)

• Coinfection with HIV, HBV, Schistosoma,H Pylori (Kamal Jhepatol 00; El-ZayadiA. Arab J Gastroenterol 2007; 8: 94–8. Elsharkawy A et al. J Hepatol 2012; 56(Suppl): S61. Esmat G et al. J Viral Hepat 2012; 19: 473–9)

• IL28B (Asselah T et al. J Hepatol 2012; 56: 527-32. De Nicola S et al. Hepatol 2012; 55:336-342.

Khairy M, et al Hepat Mon. 2013;13.Antaki N et al,JViral Hepat 2013; 20: 59–64. Derbala M et al. Virology 2013; 444: 292–300Ragheb M et al. Liver Int. in press)

El Ray A et al. Europ J Gastroenterol Hepatol2013; 25: 421-427;

El-Awadyet Al. Hepatol Monit 2012

Efficacy of therapy

Unfavourable predictors of antiviral efficacy alsopredictors of progression

SVR is the best predictor of non progression in Genotype 4 HCV infection(Alfaleh FZ et al. Liver Intern 13; 33: 871-83)

• Genotype 4 HCV Virus

• Predictors of SVR

– IL28B, Insulin Resistance,

Steatosis, Viral Load, Fibrosis,

Schistosomiasis

• Antiviral Treatment

– IFN, Peg-IFN, New Drugs

• Cirrhosis, HCC, OLT

Response of HCV Genotype-4 to Peg-IFN and ribavirin treatment according to etnicity

Country EVR ETR SVR

Peg-IFN Ribavirin 1000-12000 mg

Kuwait, Egypt, Saudi Arabia, Qatar, Syria

48 -78 % 47-77 % 32-69 %

Greece, Austria, France, Belgium

35-73 % NA 37-70 %

Thakeb Hepatol 03; DiagoAnn Intern Med 04; Hasan Am J Gastroenterol 04; Alfaleh Liver Intern 04; El Zayadi Am JGastroenterol 05; Kamal Gut 05; Kamal Hepatol 07; Ferenci Gastroenterol 08; Derbala J Viral Hepat 08; Martin

Carbonero J Viral Hepat 08; Moucari Gut 09; El MakhzanghyJMed Virol 09 ; Kamal Liver Int 09; Dahlan World JGastroenterol 09; Elefsiniotis Intervirology 09; VargheseHepatogaastroenterol 09; Rossignol Gastro 09; Khattab Am J

Gastroenterol 10; Khattab Liver Int 10; De Galocsy Acta Gastroenterol Belg 10; Al Ali Ann Hepatol 10; ElsharkawyA et al. J Hepatol 2012; Esmat G et al. J Viral Hepat 2012; Asselah T. J Hepatol 2012; De Nicola S. Hepatol 2012; 55:336-342.

Khairy M, et al Hepat Mon. 2013; Antaki N et al, JViral Hepat 2013; Derbala M et al. Virology 2013; Ragheb M et al. LiverInt. in press

Non-genotype 4 No SVR (n 14)

Genotype 4 No SVR group (n 29)

P = 0.022 by the Log-Rank (Mantel-Cox) test

Non-genotype 4 with SVR group (n 8)

Genotype 4 with SVR (n 24)

Alfaleh FZ et al. Liver Int. 2013: 33: 871–883

cumulative disease regression or stationarycourse in HCV genotype 4 versus non-4

PEG versus Standard IFN plus ribavirin in genotype 4

(Aljumah AA and Murad MH, Hepatol Res 2013)

• Five RCT, 386 patients• Quality of evidence moderate

due to HeterogeneityNo effect of Ribavirin dose

Management of Genotype 4Recommendations of an International Expert

Panel

Khattab MA et al. J Hepatol 2011; 54: 1250-62

Outcome by Virological Response at week 4 and 12 in Genotype 4 patients

Study N. Pts Week 4 Week 12

RVR N. (%) SVR N. (%) EVR N. (%) SVR N. (%)

Kamal et al Hepatology

2007

387 77 (19.8) 66 (85.7)* 275 (71.0)

170 (61.8)**

Ferenci et al Gastroenterol

2008

66 30 (19) 26 (86.6)* 28 (42.4)

13 (46.4)***

*Patients treated for 24 weeks ** Patients treated for 36-48 weeks*** Patients treated for 48-72weeks

(Kamal SM et al, Hepatol 07; 46: 1732; Ferenci P et al. Gastroenterol 08; 135: 451)

Start at week 8Start at week 12Start at week 20

Peg-IFN a-2b Therapy in Acute Hepatitis C: Impact of Onset According to Genotype

Kamal SM et al. Gastroenterology. 2006;130:632-638.

SVR

Delayed Therapy: Optimal Duration?

Kamal SM et al. Hepatology. 2006;43:923-931.Predictors of SVR

- neg HCV RNA at week 4

% RVR % SVR

Nitazoxanide Peg-IFN Riba 64 79

Nitazoxanide Peg-IFN 54 61

Peg-IFN Riba 38 50

Virological response rates in Geno-4 patientstreated with Nitazoxanide-Peg-IFN-Ribavirin

P= 0.023

Rossignol JF et Al Gastroenterology. 2009 Mar;136(3):856-62.

RVR cEVR SVR

Peg-IFN Riba 30/49* (61.2%) 35/50 (70%) 24/50 (48%)

Peg-IFN Riba Nitazoxanide

25/47* (53.2%) 36/50 (72%) 25/50 (50%)

Pvalue 0.44 0.82 0.84

* Missing results for one patient in group 1 and 3 patients in group 2

(Shehab HM et al, Liver International 2013)

Changes in the hepatitis C virus (HCV) RNA loadover 14 days treatment with Telaprevirfor each patient, by G4 HCV subtype and treatment group.

(BenhamouY et al, J Infect Dis 2013)

Telaprevir Telaprevir Peg-IFN RIBA Peg-IFN RIBA

SVR 5/8 SVR 4/8 SVR 5/8

Genotype 1, 4, 5, 6 Treatment-Naïve

SOFOSBUVIR+PEG-IFN+RBV x 12 WeeksNEUTRINO SVR12 by HCV Genotype

Pat

ien

ts w

ith H

CV

RN

A <

LL

OQ

(%

)

Overall GT 1 GT 4 GT 5,6

295/327 261/292 27/28 7/7

Lawitz E, et al. EASL 2013. Amsterdam, The Netherlands. Oral #1411Lawitz E, et al. N Engl J Med. 2013 May 16;368(20):1878-87

Error bars represent 95% confidence intervals

Genotype 4 Antiviral Treatment

Peg-IFN and ribavirin: mainstay. RGT

Predictors-oriented Treatment ??

Nitazoxanide, Telaprevir: efficacy ?, not approved

Sofosbuvir: great efficacy, cost (?), not yet approved

• Genotype 4 HCV Virus

• Predictors of SVR

– IL28B, Insulin Resistance,

Steatosis, Viral Load, Fibrosis,

Schistosomiasis

• Antiviral Treatment

– IFN, Peg-IFN, New Drugs

• Cirrhosis, HCC, OLT

HCV Genotype 4, Cirrhosis and Response to IFNAuthor Journal N. Pts % SVR Histology duration

KoshyA et al J Clin Gastroenterol 02 26 0 IFN14 Peg-IFN

F4 48

Hasan F et al Am J Gastroenterol 04 20 30 F3-F4 48

Derbala M et al J Viral Hepat 05 12 8.3 F4 38

Derbala M et al World J Gastroenterol 06 13 38.5 F3-F4 52

Males S et al Antiviral Ther 07 14 35.7 F4 48

Kamal SM et al Hepatol 07 27 0 F4 24-48

Roulot D et al J Viral Hepat 07 76 31.6 F3-F4 48

Ferenci P et al Gastroenterol 08 4 3/4 (75%) F3-F4 48

Gad RR et al Liver Int 08 78 37.2 F3-F4 48

El Makhzangy H et al

J Med Virol 09 33 45.5 F3-F4 48

Giannini EG et al J Intern Med 09 5 0 F4 Portal Hypert

48

Antaki N et al J Viral Hepat 13 82 ??? (63 tot) F3-F4 48

Asselah T et al J Hepatol 12 82 ??? (52 tot) F2-F3-F4 48

Abdo AA et al Hepatol intern 13 61 ??? (55.8 tot) F2-F3-F4 48

De Nicola S et al Hepatol 12 26 ??? (49 tot) S5-S6 48

Survival and Fibrosis progression after OLT 46 HCV patients (29 Genotype 4)

Survival analysis in genotype-4 patients (green) versus those with other genotypes (blue),

P=.297 by logrank test

(Mudawi H et Al Ann Saudi Med 2009)

Geno-4

Risk of fibrosis progression similar in genotype 4 and other genotypes p=0.99

The effect of genotype following

OLT iscontroversial

(Wali MH et al. Liver Transpl. 2003; 9:796–804. Gane E et al. N Engl J Med. 1996; 20: 773–779. Zekry A et al. LiverTranspl. 2003;9:339–347. Sugo H et al. Surg Today. 2003; 33: 421–425).

HCV RNA level at the time of biopsy : Predictorof advanced histological score

Cirrhosis: Lackof studies dedicatedto thispopulation

HCC: no systematic data

OLT: scantyinformation