1. Sanaa Kamal, M.D., Ph.D. Professor Ain Shams University, Cairo, Egypt Clinical Challenges in the Management of Hepatitis C Genotype 4

2. HCV Genotype 4 True or False  HCV-G4 is of limited geographic distribution  HCV-G 4 is difficult to treat  All HCV-G4 infected individuals respond similarly to therapy  Therapy of chronic HCV G 4 has been optimized  Are new treatments on the horizon for HCV-G4?

4. Worldwide Distribution of Genotypes 1 (1a) (1b) (1b)2 1b 1b1b1b26 1 (1a) 23 5 31c 4 4 90% ? 60% 60%  HCV genotype 4 (G4) accounts for 20% of all global HCV infections  Hepatitis C genotype 4 has started to spread beyond it strongholds in Africa and the Middle East to Western countries

5. Epidemiology of Genotype 4 Country % of HCV-G 4 Subtypes Egypt 90%4a (55),4 (24), 4o (7), 4m (3),4l (3), 4n (2) Gabon97%4c (36%),4h (15), 4e (13),4 (13),4g(13),4f (5),4a (2.6) Central African Republic100%4 (66.7), 4k (33.3) Congo100%4 (30), 4c (30), 4k (24), 4r (14), 4a (5). Cameroon36%4f (22), 4 (5), 4t (5), 4k (5), 4e (1.4), 4o (1), 4p (1), Liberia100%4 (100) Uganda100%4 (66.7),4r (33.3) Tanzania50%4d Rwanda1004k (100) Sudan5%4, 4e, and 4c/4d Tunisia11%4k (5), 4a (3.6), 4 (2.6) Saudi Arabia60%4d (60), 4a (40) France 4-10%4d (2.3), 4a (2.2) Italy 8.3%4d (5.9), 4 (2.4) Spain 3-10%4c/4d (76.8%), 4 (11.5%), 4a (7.2%), 4e( 4.3%) Greece 13.2%4a (78%)

6. Chronic HCV Genotype 4 Could be your next patient!

7. Some Presentations  27-year-old Egyptian was diagnosed with chronic hepatitis C, genotype 4a. HCV-RNA 650,000 IU/mL  37-year-old Spanish woman with HIV on HAART since 2001. HIV-RNA < 50 copies/mL, CD4: 514 cells/mm 3. HCV was diagnosed 5 years ago. HCV-RNA 1.2 million IU/ml. Genotype 4d

8. Some Presentations  45-year-old former injection drug user pre-employment testing revealed elevated ALT level (135 U/L). HCV was confirmed. HCV-PCR: 1.2 million U/L. Genotype 4d  A 46-year-old Canadian working in Africa discovered upon her return from field work that she has was infected with HCV genotype 4c.

9. TREAT?? Who, Why, How? What are the expectations?

10. Treatment Evolution of HCV- Genotype 4 1992-Present

11. SVR Genotype 4 PEG-IFN alfa- + ribavirin

12. Case # 1  27-year-old Egyptian studying in France was diagnosed with chronic hepatitis C, genotype 4  Baseline labs: Hb 12.5 g/dL HCV-RNA 650,000 IU/mL ALT/AST 76/87 Bilirubin 1.2 mg/dL INR 1.2  Liver biopsy reveals grade 3, stage 1, steatosis

13.  The patient was treated with PEG-IFN  2a plus RBV 1000 mg/day.  The patient was compliant  Treatment was well tolerated  Weeks 4, 12: ALT within normal, HCV-PCR undetectable  How long to treat him?

14. How long to treat chronic hepatitis C genotype 4? Efficacy Safety Cost- effective ness

15. What duration of PEG-IFN plus RBV is recommended?  24 weeks  48 weeks  Others?

16. Kamal S, et al, Gut 2005;54:858–866.. Sustained Virologic Response Rates PEG-IFN α-2b 1.5 µg/kg QW + ribavirin 1,000–1,200 mg/day * p= 0.02 for 36 vs. 24 weeks † p= 0.5 for 48 vs. 36 weeks ‡ p= 0.01 for 48 vs. 24 weeks * †

17. Kamal S, et al, Gut 2005;54:858–866.. Sustained Virologic Response in Patients with EVR * p= 0.002 for 36 vs. 24 weeks † p= 0.8 for 48 vs. 36 weeks ‡ p= 0.001 for 48 vs. 24 weeks * †, ‡

18. Kamal S, et al, Gut 2005;54:858–866.. Sustained Virologic Response Rates in Patients with >2 million Copies/mL † p= 0.04 for 48 vs. 36 weeks †

19. Rapid Virological Response Genotype 4 RVR, EVR as a guide for 24 w, 36 w or 48w 358 patients Adaptive N=308 Fixed N=50 24 w RVR N=69 36 w cEVR N=79 48 w pEVR N=160 48 w Kamal et al, Hepatology. 2007 Dec;46(6):1732-40

20. EOT and SVR rates in HCV-G4 patients with RVR & EVR Kamal et al, Hepatology. 2007 Dec;46(6):1732-40 % Response

21. 21 Role of RVR in Determining Treatment Duration of Peginterferon /ribavirin in Chronic Hepatitis C Genotype 4 Total study population) RVR26% No SVR 14% 14% SVR86% SVR76% cEVR48% No SVR 24% End of follow up Start of study Kamal et al, Hepatology. 2007 Dec;46(6):1732-40

22. Kamal S, et al, Gut 2005;54:858–866.. RVR in HCV Genotype 4  66 patients with G4, Peg IFN α 2a and RBV  RVR: 45%  26 (86.7%) of those achieved a SVR  No relation: with degree of Fibrosis with baseline viral load with dose of RBV Ferenci P, et al. Gastroenterol. 2008;135:451-458

23. SVR rates in HCV-G4 patients with RVR & EVR Ferenci P, et al. Gastroenterol. 2008;135:451-458  In per-protocol analysis, 80.4% SVR rate in patients with RVR (115/143) Ferenci P, et al. Gastroenterol. 2008;135:451-458. 0 20 40 60 80 100 ≤ 400,000400,000 - 800,000 > 800,000 SVR in Patients Achieving RVR (%) All Genotype 1 F0-F2F3-F4 By Baseline HCV RNA (IU/mL) By METAVIR Fibrosis Stage Genotype 4 86.5 90.0 81.3 82.2 85.7 80.6 70.8 83.3 66.7 81.5 88.5 79.6 75.0 n/N =61/7452/649/1037/4525/3112/1417/2412/185/697/11974/9323/2618/243/415/20

24. Hepatology. 2007 Dec;46(6):1732-40  Rapid virologic response seems a clinically useful tool for determining the duration of treatment in chronic hepatitis C genotype 4.  24 weeks therapy with peginterferon-alpha-2a and ribavirin seems sufficient for patients with chronic hepatitis C genotype 4 who have a rapid virologic response. RVR in HCV Genotype 4

25. Back to the case  The patients completed 24 weeks successfully.  He achieved SVR  No viremia was detected a year and a half after completing therapy. Is HCV-G4 still hard to treat?

26. Does response differ between the PEG-IFN preparations?

27. Do response rates differ between PEG-IFN preparations? % Response

28. Do patients respond similarly to therapy?

29.  242 naïve French, Egyptian or (subsaharan) African patients received peginterferon plus ribavirin for 48 weeks.  HCV G4 with different subtypes  Liver fibrosis was significantly less severe in patients infected in France and Africa  An overall better response was observed in patients infected with the 4a subtype.  In multivariate analysis, two factors were associated independently with SVR: the Egyptian origin of transmission and the absence of severe fibrosis  Why was the response different? Roulot et al, J Viral Hepat. 2007 Jul;14(7):460-7.

30. Anything in the Horizon?

31. Improved Virologic Response in Chronic Hepatitis C Genotype 4 Patients Given Nitazoxanide, Peginterferon, and Ribavirin Rossignol et al., Gastroenterology, 2009 A phase II, randomized, double-blind, placebo- controlled study of nitazoxanide treatment for 24 weeks in 50 patients with chronic hepatitis C genotype 4 was conducted to evaluate safety with prolonged administration and to determine the antiviral efficacy of nitazoxanide monotherapy.

32. Improved Virologic Response in Chronic Hepatitis C Genotype 4 Patients Given Nitazoxanide, Peginterferon, and Ribavirin Rossignol et al., Gastroenterology, 2009 + * Peg-IFN/RBV 48 wk (n 40) Peg-IFN/NTZ 12 36 wk (n 28) Peg-IFN/NTZRBV 12 36 wk (n 28) RVR15 (38%)15 (54%)18 (64%)* cEVR28 (70%)19 (68%)24 (86%) EOT30 (75%)20 (71%)23 (82%) SVR20 (50%)17 (61%)22 (79%)# *P.048, compared with Peg-IFN/RBV. #P.023, compared with PegIFNRBV. -

33. Case #2  37-year-old Spanish woman with HIV for about 10 years on AZT/3TC, NVP  HIV-RNA < 50 copies/mL  CD4 444 cells/mm 3  HCV was diagnosed 5 years ago  HCV-RNA 1.2 million IU/ml  Genotype 4d  Liver biopsy done 6 months ago reveals grade 5, stage 2/4 fibrosis  She is asking about efficacy of treatment

34. HCV-G4/HIV Coinfection Soriano et al, Antiviral Ther 2005;10:167-170.. Legrand- Abravane et al, J Med Virol 2005;77:66- 69 Mart´ın- Carbonero et al J Viral Hep, 2008

35.  26 published clinical trials on HCV-G4 therapy (PEG- IFN/RBV therapy) with 1385 patients  12 registered ongoing trials  Five randomized clinical trials  Four trials on duration of therapy  Enrolled patients: Egyptians, Saudis, French, Spanish, Greek, Italian, Africans What we have?? HCV-G4 Clinical trials

36.  Three trials on HCV-G4/HIV coinfected patients  Two trials on HCV-G4 heamophliacs  One trial on non-responders  One trial on extended therapy. HCV-G4 Clinical trials

37. Any Roadmap?

38. Pre-treatment HCV-RNA Liver biopsy - Low viral load - Low histology scores No RVR Detectable HCV- RNA at week 4 Partial EVR > 2 log decline in HCV-RNA at week 12 48 weeks therapy Complete EVR Undetectable HCV RNA at week 12 36 weeks therapy - High viral load - High histology scores Super responder: RVR Undetectable HCV-RNA at week 4 24 weeks therapy HCV Genotype 4 proposed therapy

39. Predictors of Low SVR  Age??  Gender??  BMI 1,4  Fibrosis 6  Steatosis 1,6  HCV G 4 non a subtypes ?? 5  Coinfections 7  No RVR or EVR 1,2,3,4  Higher AFP?? 6 1 Kamal et al, GUT; 2 Kamal et al, Hepatology 2007; 3 Kamal et al 2007; 4 Ferenci et al, 2008; 5 Roulot et al 2006; 6 Gad et al, Liv Int 2008, 28 (8): 1112-1119; 7 Legrand-Abravane et al, J Med Virol 2005;77:66-69.

40.  Hepatitis C genotype 4 has started to spread beyond it strongholds in Africa and the Middle East to Western countries.  HCV-G4 might not be hard to treat in some infected patients  Recent clinical data have provided new insights on hepatitis C genotype 4 infections and have started to refine the treatment strategies.  Baseline viremia, early viral kinetics, treatment duration, and stage of liver disease each represent important considerations that can be used to individualize therapy.  These data can now be used as a platform for further research to define optimal treatment regimens to patients infected with genotype 4 HCV. What we may know

41. What we do not know Non-responders HCV-G4 Hemophiliacs HCV/Schisto HCV-G4CirrhosisHCV/HBV Renal Disease HCV-G4/HIV Diabetics Neuro-pshychiatric

42. Thank you Merci