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

Material to Cover vs. Lecture Schedule

Liver Disease Southern 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!

Liver Disease Nevada 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.

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

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

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)

Revised Estimate of Infected Americans NHANES III NHANES III + Excluded Populations* HCV antibody positive 3.9 million 5.0 million HCV RNA positive 2.7 million 3.4 million *Populations excluded from NHANES included incarcerated, homeless, hospitalized, military, nursing home residents. Edlin BR. Hepatology 2005:42(suppl 1):213A.

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. .

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)

Sources of Infection for Persons With 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.

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

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

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

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

HCV: 20 Year Risks, Life Expectancy, and Quality Adjusted Life Expectancy Treated vs. Untreated HCV No Antiviral Treatment Peg-IFN Plus Wt-Based RBV 20-Year Risk (%) Compensated cirrhosis Decompensated cirrhosis Hepatocellular carcinoma Liver transplantation* Liver-related death 62 24 9.7 2.3 25 11 4.7 1.1 Life expectancy (years) 25.8 30.5 Quality Adjusted Life Expectancy (QALY) 22.8 27.7 *Only first transplantations included (no retransplantations). Siebert U et al. Gut. 2003;52:425-432. Siebert U et al. Gut. 2003;52:425-432.

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

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

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

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

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

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

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!

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

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+)

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

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

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

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

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

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

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

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

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