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Hepatitis C Update

Hepatitis C Update. Indications and Safety. Indications. Treatment indicated in adults with chronic HCV who have compensated liver disease. Patients with HCV and clinically stable cirrhosis, Child-Pugh class A. Patients with chronic HCV and clinically stable HIV disease.

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Hepatitis C Update

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  1. Hepatitis C Update

  2. Indications and Safety

  3. Indications • Treatment indicated in adults with chronic HCV who have compensated liver disease. • Patients with HCV and clinically stable cirrhosis, Child-Pugh class A. • Patients with chronic HCV and clinically stable HIV disease. • Patients with chronic HBV who have compensated liver disease and evidence of viral replication and liver inflammation.

  4. Safety • May cause or aggravate fatal or life threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Therapy should be withdrawn in patients with worsening signs or symptoms of these conditions. • Use of ribavirin may cause birth defects and/or death of the fetus. • Ribavirin causes hemolytic anemia. Severe anemia can cause worsening of cardiac disease • Ribavirin is genotoxic and mutagenic and should be considered a potential carcinogen.

  5. Contraindications • Autoimmune Hepatitis • Decompensated patients with cirrhosis • Neonates and infants • Hypersensitivity • Pregnant women and men whose female partners are pregnant (Category X) • Patients with hemoglobinopathies (sickle-cell anemia, thalassemia major)

  6. Common Side Effects • Depression • Insomnia • Irritability • Anxiety • Flu-like symptoms • Mood Alteration • Neutropenia • Anemia • Thrombocytopenia • Weight loss • Headache • Alopecia • Hyper- or hypothyroid • Myalgias

  7. Prevalence and Epidemiology

  8. HCV Disease Burden: US • Infectivity • Most chronic blood-borne viral infection • Approx. 3.2 million people are chronically infected • Liver Cirrhosis within 20-30 years • 10-20% will develop cirrhosis • 1.5% may develop hepatocellular carcinoma • Leading indication for liver transplant • Leading cause of death in patients with HIV

  9. Prevalence of HCV by Age and SexRate per 100,000

  10. Population at Risk for HCV • IVDU • HIV individuals • Patients with HBV • Recipients of blood transfusion or organ transplant before 1992 and blood products before 1987 • Persons who have ever been on hemodialysis • Children born to infected mothers • Individuals with unexplained ALT/AST elevations

  11. Populations at Risk (Cont’d) • Patients with multiple sex partners, MSM or history of sexually transmitted disease • Patients with tattoos and body piercings (particularly if done while incarcerated or homemade) • Healthcare workers with exposure to HCV contaminated blood and blood products

  12. Prevalence of HCV inRacial/Ethnic Populations

  13. Disease Progression and Impact

  14. Cirrhosis and Fibrosis Cirrhosis is a diffuse process characterized by fibrosis and conversion of the normal liver architecture into structurally abnormal nodules. Cirrhosis may be considered irreversible.

  15. Liver Histology Scoring Systems

  16. Progression of Fibrosis to Stage F4Based on Age of Infection • Infected at age <20, 25-30% chance of Stage 4 within 35-38 years. • Infected at age 21-30, 50% chance of Stage F4 within 50 years. • Infected at age 31-40, 85% chance of Stage F4 within 30 years. • Infected at age 41-50, 75% chance of Stage F4 within 20 years. • Regardless of age at infection, fibrosis starts progressing more rapidly after age 50

  17. Factors Associated with Advanced Fibrosis in HCV

  18. Other Impact of HCV • HCV is the leading indication for liver Transplant • Transplants have increased over the last decade • Rising Incidence of Liver and Bile Duct Carcinoma • Predominantly Asian

  19. Importance of Screening

  20. Reason for Lack of Treatment NHANES HCV Questionnaire • Unaware of diagnosis – 49% • Did not see a doctor – 9% • No treatment recommended – 24% • Patient refused – 6% • Treated – 12%

  21. Majority of Patients are Asymptomatic • However, symptoms differ from patient to patient and some may not have any symptoms for up to 20 years, yet their liver disease may be progressing • 80% of patients with HCV have no signs or symptoms

  22. Screening for HCV

  23. Importance of Early Treatment: Disease Progression • Without Advanced Fibrosis 60% • Bridging Fibrosis 51% • Cirrhosis 33%

  24. Who Should be Tested? • Illicit drug users • HIV-infected individuals • Patients with HBV • Recipients of blood transfusion or organ transplant before 1992 or clotting factors before 1987 • Persons on hemodialysis • Children born to infected mothers • Individuals with unexplained AST/ALT elevation

  25. Who should be tested (Cont’d) • Patients with multiple sex partners, MSM or history of sexually transmitted disease • Patients with tattoos and body piercings • Healthcare workers with exposure to HCV-contaminated blood and blood products • Baby Boomers (born between 1945 and 1965) • 5 x more likely to have HCV • 75% of infected people born between this time AASLD and CDC recommend that all patients with one or more risk factors be screened for Hepatitis C

  26. Prevalence of HCV in Different Risk Groups • HIGH (approx. 90%) HCV prevalence • Individuals with a history of IVDU • Individuals with hemophilia • MODERATE (approx. 10%) HCV prevalence • Recipients of drug transfusions prior to 1992 • LOW (approx. 1% to 5%) HCV prevalence • Individuals with needle stick exposure • Sexual partners of HCV-infected persons

  27. HCV Genotypes in the USA • HCV virus • RNA virus – high mutation rates • Evolved into different genotype • Genotypes 1-3 are the most common in the USA • Genotype 1 – 75% • Genotype 2 or 3 – 10% • Genotype 4-6 - 5% • Genotype and viral load do not impact disease progression • Predicts treatment response and may help determine treatment duration

  28. Normal ALT Does Not Mean “Healthy” • Up to 46% of HCV patients may have persistently normal ALT. Levels fluctuate over the course of infection • Despite persistently normal ALTs, >75% have some degree of liver damage • Portal Fibrosis – 26% • Bridging – 6% • Cirrhosis – 6 % There are no known factors that predict which patient will have disease progression

  29. Treatment of HCV Infection

  30. Goals of Therapy

  31. Clinical Significance of Sustained Virological Response (SVR) Definition: HCV RNA negative 24 weeks after end of treatment Most reliable endpoint for evaluation of therapy Liver histology may improve or stabilize with achievement of an SVR Preliminary results from ongoing study shows SVR is durable in >99% of patients

  32. Evolution of Treatment • 1991 • FDA approves interferon (Intron A) • 1996 FDA approves alpha interferon (Roferon) • 1997 • Consensus interferon (InterMune Infergen) Interferon is injected 3MU three times weekly SVR 29% Genotype 1, 62% Genotype 2,3

  33. Evolution Cont’d • 1998 FDA approves Rebetron with Intron A • SVR Genotype 1 -- 29% • SVR Genotype 2,3 -- 62% • 2001 PEG-Interferon (interferon alpha 2b) approved for use with Rebetol • SVR Genotype 1 -- 41% • SVR Genotype 2-6 -- 82%

  34. Evolution Cont’d • 2002 Pegasys approved Roche pegylated Interferon alpha 2a SVR alone G-1, 28% G2,3 56% SVR with Copegus (ribavirin) G-1 55-51% G-2,3 82%

  35. Evolution Cont’d • Direct acting antiviral agents (DAAs) approved • NS3/4A protease inhibitors • Telaprevir and Boceprevir licensed for use with pegylated interferon and ribavirin • Used with Genotype 1 only • Never used as monotherapy • SVR’s improved from 44% to 75% overall There are more than 20 new HCV treatment regimens undergoing Phase II or III trials at this time

  36. New Treatment for Genotype 1

  37. Telaprevir(Incivek)

  38. Indications • Used in combination with peginterferon and ribavirin • Genotype 1 only • Must not be administered as monotherapy • High proportion of previous null responders (especially with cirrhosis) did not achieve a SVR and had telaprevir resistance

  39. Safety • Contraindicated in women who are or may become pregnant or men who’s partners may be or become pregnant • Contraindicated when combined with drugs that are • highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious life-threatening events. • strongly induceaCYP3A and thus may lead to lower exposure and loss of efficacy of Incivek.

  40. Adverse Reaction • Adverse reactions to interferon and ribavirin apply to telaprevir combination treatment • Most common seen with an incidence >5% over controls were Rash 56% Fatigue 56% Pruritis 47% Nausea 39% Anemia 36% Diarrhea 26% Hemorrhoids 12% Anorectal outlet discomfort 11% Dysgeusia 10% Anal pruritis 6%

  41. SVR RatesNaïve or Retreatment

  42. Dosing

  43. Incivek is a 375 mg tablet • Recommended dose is 750 mg (two 375 mg tabs) orally 3 times per day 7-9 hours apart with food (30 GM fat) • Always administered with Interferon and Ribavirin • To prevent treatment failure, the dose must not be reduced or interrupted • If Incivek is discontinued to due adverse events or virologic failure, it must not be restarted

  44. Response Guided Therapy Response-Guided therapy is used to determine total treatment duration in treatment-naïve patients and prior relapsers. eRVR=undetectable HCV RNA at Weeks 4 and 12 Patients with eRVR can complete their total treatment duration in 24 weeks. Patients with detectable HCV RNA at these weeks will require treatment duration of 48 weeks Prior partial responders and null responders, treatment duration is 48 weeks.

  45. Futility Rules Patients with inadequate viral response are unlikely to achieve SVR. Futility rules are in place at key time points • If viral level >1000 IU/mL at Week 4 • Stop Incivek • Stop pegINF and Ribavirin • If viral level >1000 IU/mL at Week 12 • Incivek is complete • Stop pegINF and Ribavirin • If viral level detectable at all at Week 24 • Stop pegINF and Ribavirin

  46. Important Safety Information • Telaprevir is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh B or C, score >/= to 7 or patient with decompensated liver disease • Safety and efficacy of Incivek combination treatment has not been established in co-infected HCV/HIV or HCV/HBV patients, pediatric patients or in solid organ transplant patients

  47. Boceprevir(Victrelis)

  48. Indications • Must not be used as monotherapy • Treatment of HCV Genotype 1 only • Should only be used in combination with peg-INF and ribavirin • Efficacy not studied in patients who have previously been treated with a treatment regimen including boceprevir or other NS3/4A protease inhibitor

  49. Indications Cont’d • Not been studied in previous null responders (less than a 2 log RNA decline by Week 12 • Poorly INF responsive patients have a lower likelihood of achieving SVR and a higher rate of resistance

  50. Safety • Serious adverse events reported in 11% of patients compared to INF/RBV at 8% • 13% of patients discontinued due to side effects of triple therapy compared to 12% of patients on INF/RBV • Most common reason for dose reduction (RBV or INF) was anemia (26% vs 13%) • Drug/Drug interactions similar to telaprevir (CYP3A4/5 dependence)

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