Evaluation & Management of Hepatitis C

1. Evaluation & Management of Hepatitis C Donald J. Hillebrand, MD. Division of GI-Hepatology Medical Director of Liver Transplantation Scripps Center for Organ & Cell Transplantation Southwest Viral Hepatitis Summit November 2008

2. Material to Cover vs. Lecture Schedule

3. Liver DiseaseSouthern California • Approximately 1 out of 7 liver disease related deaths in the U.S. occurs in California! • In 2003 there were 27,201 liver disease deaths in U.S.2 • In California alone there were 3,832 deaths that year (14.1% of U.S. deaths) • California • Triple the incidence of liver disease - 57 persons/100,000/yr • Nearly one-fourth of liver transplants performed in U.S. are performed in UNOS Region 5!

4. Liver DiseaseNevada • Mortality from cirrhosis/chronic liver disease significant in NV • US Mortality Rate = 9.0 / 100,000 AAR • NV Mortality Rate = 11.4 / 100,000 AAR • Total of 275 deaths in 2005 • c/w HIV total of 86 deaths & 3.6 / 100,000 rate Source: Table 29.CDC. National Vital Statistics Reports, Volume 56, Number 10, April 24, 2008.

5. Hmmmmm….. • *Total of 275 CLD deaths in 2005 (c/w 86 HIV deaths)

6. Evaluation & Management HCVOverview • Background information • Virus specifics including transmission • Evaluation • Candidates for therapy • Preparing for HCV Treatment • Standard of Care (SOC) Therapy • Future therapies

7. Hepatitis C Virus • Viral agent that infects liver cells • At least 3-4 million infected individuals in the U.S. • Most patients have not been diagnosed yet! • Serious disease (cirrhosis) in 30% • Approx 20% over first 20 years of disease • A leading cause of chronic liver disease in U.S. • Leading indication for liver transplantation • Accounts for 13,000-15,000 deaths annually (ing)

8. Revised Estimate of Infected Americans *Populations excluded from NHANES included incarcerated, homeless, hospitalized, military, nursing home residents. Edlin BR. Hepatology 2005:42(suppl 1):213A.

9. Estimated HCV Patient Status in the United States • 30% of CHC patients have been diagnosed • 41% of diagnosed CHC patients have been on treatment • 12% of CHC patients have been treated Undiagnosed CHC ~3.5M (70%) Diagnosed but Untreated CHC ~900K (18%) Diagnosed and Treated CHC ~600K (12%) Roche internal data, HCV Patient Research, April – May 2004, based on 3,762 screening interviews, HCV epidemiology statistics from the American Liver Foundation and Edlin BR. Hepatology 2005:42(suppl 1):213A. .

10. Hepatitis C • Transmission by blood and body fluids • Blood products transfusion prior to 1990 • Intravenous drug use • Nasal cocaine • Acupuncture, tattoos, body piercings, etc. • Incarceration (prison time) • Sexual contact • Vertical transmission (mother to newborn)

11. Sources of Infection for PersonsWith Hepatitis C Injection drug use 60% Sexual 15% Transfusion 10% (before screening) Occupational 4% Other * 1% Unknown 9% *Nosocomial; iatrogenic; Perinatal Adapted from Hepatitis Slide Kit http://www.cdc.gov/ncidod/diseases/hepatitis/slideset. Accessed 02/27/07.

12. Patient Evaluation Comprehensive panel (liver and kidney function) Cell counts (WBC, Hg, Platelets) HIV Hepatitis A and B status (vaccinate if non-immune) Iron studies Autoimmune markers Hepatitis C specific testing

13. Hepatitis C Testing • HCV Genotype (HCV “strain”) [GT 1-6] • Genotype 1 (vs non-type 1) • Most common • Not more aggressive • Less responsive to therapy • HCV RNA (HCV “viral load or level”) [IU/ml] • Not an indicator of severity of disease • Influences likelihood of responding to therapy • High viral level > 600,000 IU/ml

14. Liver Biopsy? • Advantages • Staging of liver disease • Disadvantages • Invasive procedure with risks • Alternatives • Platelet ratios • Serological tests of fibrosis (scarring) • Liver stiffness measurement

15. HCV Therapy Pegylated Interferon injections weekly AND Ribavirin pills (or liquid) twice daily

16. HCV: 20 Year Risks, Life Expectancy, and Quality Adjusted Life Expectancy Treated vs. Untreated HCV *Only first transplantations included (no retransplantations). Siebert U et al. Gut. 2003;52:425-432. Siebert U et al. Gut. 2003;52:425-432.

17. Ideal Treatment Situation • Well defined chronic HCV • Absence of other medical/psychiatric problems • Appropriate body weight • Obesity decreases response rate in addition to worsening liver disease • No alcohol use • Alcohol use decreases response rate in addition to worsening liver disease • Motivated/Educated patient

18. Keys to Successful Treatment • Motivated/Educated/Supported patient • Compliance is crucial! • Dialogue between patient and treatment team • Side effect management important to maintain compliance with drug dosing/duration • Adequate rest • Generous fluid intake

19. Treatment Monitoring • Medical examination(s) • Side effects discussed • Check for complications of treatment • Laboratory testing • CBC at 2 weeks • Comprehensive metabolic panel, CBC, and HCV RNA (viral level) monthly • TSH periodically

20. Treatment Side Effects • General Symptoms • Fatigue, malaise, muscle and joint aches • Insomnia, irritability, depression • Rash, diarrhea, nausea • Hypo/hyper-thyroidism • Cytopenias • Thrombocytopenia and leukopenia • Anemia

21. Treatment Aids Pharmacy/Pharmaceutical Support HCV Support Groups Nurse(s)/Nurse Practioner Physician

22. HCV RNA • The name of the game in HCV therapy is …. CLEARING VIRUS • Undetectable HCV RNA is endpoint that is critical!

23. Sustained Virological Response • Goal of HCV therapy! • Occurs in 50-55% of treated patients • Definition of SVR • Negative HCV RNA by sensitive testing method (50 IU/ml) 24 weeks after completion of therapy • Studies confirm that >99% will remain HCV RNA negative on subsequent follow up CURE!

24. SVR • Decrease in ALT levels (Biochemical response) • Decrease in mean histology activity index • Decrease in risk of primary liver cancer • Improvement in health-related quality of life

25. Responder/Relapser • ETR (End of Treatment Response) with no detectable HCV RNA at completion of treatment BUT relapse to detectable virus levels w/in 24 weeks of treatment end • Causes…. • Dose Modification(s)/Interruptions (RBV) • Delayed viral clearance (Week 12 HCV RNA+)

26. Nonresponder • Early stopping point • Week 12 HCV RNA level does not drop > 2 log • Anytime stopping point • Increasing HCV RNA levels (>1 log) after nadir • Late stopping point • Week 24 HCV RNA level still positive

27. Virological Responses to Interferon-Based Therapy PEG-IFN and RBV Non-Responsive Relapse HCV RNA (Log IU/mL) Undetectable SVR Weeks After Start of Therapy Adapted from Lindsay KL. Hepatology 2002;36:S114 - S120

28. New Trends in HCV Treatment • Treatment individualization critical • Individuals with RVR at Week #4 • Individuals with incomplete EVR at Week #12 • Individuals with NR at Week #12

29. Rapid Virological Response • Undetectable HCV RNA at Week # 4 = RVR • Genotype 1 individuals achieving ~91% SVR rate • Those with favorable predictors (low viral level) may be just as well served with 24 weeks (rather than 48) • Genotype 2&3 individuals achieving ~90% SVR rate • Shortening course from 24 weeks increases relapsers

30. Incomplete EVR • HCV RNA decreases > 2 log from baseline but remains detectable at Week #12 • Also called Slow to Respond-er • In those individuals that clear virus by Week #24 and complete therapy relapse is common resulting in 45% SVR rate • Data suggests that extending therapy to 72 weeks decreases relapsers and improves chance of SVR

31. Partial Response at Week #12 • HCV decreases > 1 log but less than 2 log = NR • Conversion to daily Consensus Interferon (Infergen) with continued ribavirin can result in some SVR • SVR rate ~10-20% • Difficult to tolerate due to side effects

32. Future Therapies • STAT-C Drugs • Specifically Targeted Antiviral Therapy for HCV • Polymerase Inhibitors • Protease Inhibitors (Phase III Studies in Progress) • Telaprevir (Vertex) • Boceprevir (Schering) • (Helicase Inhibitors) • Goals include  RVR,  Rx duration, and  SVR

33. “Far and away the best prize that life has to offer is the chance to work hard at work worth doing.” Theodore Rosevelt

34. Evaluation & Management HCVIn Conclusion…. Populations at risk Disease overview Evaluation Standard of Care (SOC) Therapy Future Therapies THE END! Questions?!