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