2.  During his annual physical in Dec 2007, Mr. A, a 42 y old pilot, presented with elevated liver enzymes and positive antibodies to HCV.  He had no symptoms. BMI 27  His physical examination revealed no abnormalities and his liver was not enlarged.  His blood picture, renal profile, thyroid profile were within normal  His physical performed December 2006 was normal Case 1

3.  He was recently married.  He is frustrated  He will be subjected to another medical examination after 3 months.  He could not recall how, when or where he got the infection Mr. A’s Questions

4. ALT: 175 U/L HCV-PCR: 650, 000 IU/L Genotype 4 Mr. A’s labs

5. Mr. M’s questions:  Is treatment possible?  Is there a possibility of transmitting the infection to his wife?  What are the odds for having normal liver enzymes and negative HCV values after 3 months of therapy?  If treatment is considered will he be able to fly? When?

6. What to do at this time?  Request a liver biopsy  Do an ultrasound only  Request more investigations  Wait and see

7. A liver biopsy was performed revealing A2 and S1 based on the METAVIR scoring system

8.  Treat or not to treat?

9. Is this patient a good candidate for Peg-IFN + RBV therapy? Yes. He has a > 60% chance to achieve SVR Yes, but the likelihood of SVR is less than 30% No. He will not benefit from therapy.

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

11.  The patient was treated with PEG-IFN  2a plus RBV 1000 mg/day.  The patient was compliant  Treatment was well tolerated

12.  Weeks 4, 12 results W 4W 12 Alt24 U/L27 U/L HCV-PCRundetectable Hb12 g/dl12.4 RBCs4 M3,8 M WBCs4,200 cells/mm 3 3,700 cells/mm 3 Platelets172,000 cells/mm 3 163, 000 cells/mm 3  What is the significance of these results?

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

14. Terminology  RVR :Rapid virological response (4 weeks)  EVR :Early virological response (12 weeks) -Complete EVR : HCV RNA positive at Wk 4 but negative at Wk 12 - Partial EVR: HCV RNA positive at WK 4 and 12 but  2 log 10 IU/mL drop from baseline at Wk 12  SVR:Sustained virological response  NR :Non response; Transient virological response; relapse (20%) or breakthrough (10%)

15. Rapid Virological Response Genotype 1  216 patients  51 (24%) had RVR  SVR associated with RVR and lower HCV viral load (< 600,000 IU/ml)  RVR portends an 89% probability of SVR after 24 weeks of treatment Jensen DM et al, Hepatology 2006; 43(5):954-960

16. Rapid Virological Response Genotype 2 – 3 283 patients: RVR as a guide for 12w or 24w Shorter course as effective as 24w if patients are negative by week 4 Higher relapse rate (8.9 Vs. 3.6%) PEG-IFN alpha 2b (1.0 microg/Kg/week) Results consistent with a Norwegian trial Mangia A et al, NEJM 2005

17. Rapid Virological Response Genotype 4 318 patients: RVR, EVR as a guide for 24 w, 36 w or 48w Kamal et al, Hepatology, 2007 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

18. End of treatment and sustained virologic response rates Kamal et al, Hepatology. 2007 Dec;46(6):1732-40

19. RVR 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, Gastroenterology 2008

20. Main Findings 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

21. Distribution of Virologic Response Rates Retrospective analysis from 3 large trials (N = 1383) PegIFN alfa-2 + RBV RBV 800 mg/day for 24 wks in GT 2/3 RBV 1000-1200 mg/day for 48 wks in GT 1/4 Response, % GT 1 (n = 569) GT 2 (n = 395) GT 3 (n = 426) GT 4 (n = 24) RVR 16716038 cEVR 42242946 pEVR 20138 SVR49776879 Fried MW, et al. EASL 2008. Abstract 7.

22. SVR in Patients Who Achieved an RVR 90 282257 9 GT 1GT 2GT 3GT 4 100 86 88 Patients With an RVR Fried MW, et al. EASL 2008. Abstract 7. 0 20 40 60 80 100 SVR (%) n =

23. Kamal et al, Hepatology. 2007 Dec;46(6):1732-40  Rapid virologic response is 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.

24. RVR: Conclusions  Chronic Disease:  Genotype 1, 4: useful for 24 week strategies  Genotype 2 – 3: unclear the utility  HIV - HCV:  Encouraging marker

25. Predictive factors of Low SVR  Age ??  Gender ??  BMI 1,4  Fibrosis  Steatosis 1,4  HCV G 4 non a subtypes 4 ?? 44  Coinfections 6  No RVR or EVR  Higher AFP 5 1 Kamal et al, GUT; 2 Kamal et al, Hepatology 2007; 3 Kamal et al 2007; 4 Roulot et al 2006; 5 Gad et al, Liv Int 2008, 28 (8): 1112-1119; 6 Legrand-Abravane et al, J Med Virol 2005;77:66-69.

26. Case Presentation 2  Mr. N, an 49-year-old Egyptian American engineer living and working in the US since 12 years.  HCV (G4) accidentally detected since 8 years  He had received repeated blood transfusion 15 years before following a traffic accident.  He is diabetic on oral medications for diabetes mellitus.  He is obese. His BMI: 30

27. Previous therapy  He has been previously treated in 2004 with 48 weeks of PEG- IFN  -2b and ribavirin but relapsed.  He achieved an early virologic response (EVR).  At one point, his lab results showed anemia.  He had his ribavirin dosage repeatedly reduced until his anemia improved.  He was able to complete 48 weeks of treatment and achieved an ETR and SVR.  In 2007, HCV-RNA was detectable

28. Second presentation Dec. 2007  ALT: 70 U/L, AST: 60 U/L  Albumin: 3.9 g/dL  Blood picture: Hb: 13 gm%, Platelet count: 130,000, WBCs: 8,400.  Serum HCV RNA: 800 000 IU/mL  Genotype 4

29. He did not agree to repeat liver biopsy. Instead, testing with HCV Fibrosure was performed, yielding a fibrotic score of 0.73 (F3) and activity score of 0.61 (A3 inflammation).

30. What to do next?  Re-treat or not to re-treat?

31.  He was re-treated with PEG-IFN alpha 2a/RBV (1200)  Epoetin alfa was used during therapy  Week 12 HCV-PCR: 9000 IU/ml

32. What to Do? 1. Treat for 24 weeks 2. Treat for 36 weeks 3. Treat for 48 weeks 4. Stop the treatment 5. Other choices or suggestions

33. What about extending treatment?

34. Extending treatment: Ferenci et al, 2008 Patients with no RVR but EVR:  Group A : 48 W  Group B : 72 W Patients with no EVR:  Group C: 72 W Ferenci P, et al. Gastroenterol. 2008;135:451-458.

35. Extending treatment  Group A and B had similar SVR: 52% and 51%  Relapse rate lower in group B (19%) vs. 33% in group A  Complete EVR: SVR group A (71%) group B (78%)  Partial EVR: SVR group A (31%) group B (35%) Ferenci P, et al. Gastroenterol. 2008;135:451-458.

37.  Mr. H, a 21 y old man accidentally discovered elevated liver enzymes and positive antibodies to HCV during check-up.  His physical examination revealed no abnormalities and his liver was not enlarged.  His blood picture, renal profile, thyroid profile were within normal  He had no symptoms

38. History:  Depression since 5 years  Tri-cyclic antidepressant: 4 years  History of IDU for 3 years  Admitted to rehab for 6 months with withdrawal  Relapse after 3 months.  Readmitted to rehab and abstained for 1 year.

39. Lab:  ALT: 215 U/L  HCV-PCR: 850, 000 IU/L  Genotype 4

40. A liver biopsy was performed revealing A2 and S 0 based on the METAVIR scoring system

41.  Treat or not to treat?  Treat for how long?  What about his depression?  What about his addiction problem?

42. Case Study #4  38-year-old Greek man  Diagnosed with HIV since 2005  Doing well on HAART  He stopped using drugs (heroin).  He has recently separated from a partner of 3 years.

43. Case Study # 4 July 2007  ALT: 217 U/L  HCV-AB positive  HCV RNA: 1.2 M U/ml  Genotype 4  Liver biopsy: Grade 8, stage 2  CD4+: 520 What do you want to know?

44.  Transmission  Alcohol use  Depression/Antidepressants  Treatment Choices

45. HCV/HIV Coinfection  HIV accelerates Hep C liver disease (may cut time to cirrhosis in half!)  Hep C may impair immune reconstitution after HAART  HCC may occur at an earlier age with coinfection

46. HCV-G4/HIV Coinfection  Treatment of Chronic HCV-4 in HIV patients is less successful than treatment of chronic hepatitis C in HCV monoinfected individuals.  SVR rates:  IFN- monotherapy: 11.1%  IFN- plus ribavirin: 9.1%  PEG-IFN plus RBV: 22.7%  Legrand-Abravane et al, J Med Virol 2005;77:66-69.  SVR 15% Soriano et al, Antiviral Ther 2005;10:167-170..

47. HIV/HCV Treatment Predictors of success in achieving a sustained viral response:  CD4 count greater than 500  HIV RNA levels below 10,000 copies  No alcohol consumption

48. Treatment Decisions  Treat Hep. C first ? (if HIV stable, if CD4 count good)  Treat HIV first? (if immune compromised)

49. AIDS PEGASYS ® Ribavirin International CO-Infection Trial HIV/HCV Co-infection Study

50. 12% n = 285 20% n = 286 40% n = 289 Sustained Virologic Response* P = 0.0084 P  0.0001 * Defined as <50 IU/mL HCV RNA at week 72; ITT % Response 0% 10% 20% 30% 40% 50%60% IFN alfa-2a + RBV PEGASYS (40 kDa) + Placebo PEGASYS (40 kDa) + COPEGUS APRICOT

51.  Hepatitis C genotype 4 is no more a problem of Africa and the Middle East.  It’s now known that PEG/RBV gives reasonable results in chronic HCV-G4.  It’s now the time for refining the treatment. Conclusion

52.  Chronic HCV-G4 treatment in special populations, HCV/HIV and IDUs is still a challenge  Baseline viremia, early viral kinetics, treatment duration, and stage of liver disease are important factors that can be used to individualize therapy. Conclusion