Treatment of Chronic Hepatitis C:


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Treatment of Chronic Hepatitis C:

  1. 1. Treatment of Chronic Hepatitis C: Peginterferon and Ribavirin Sidney G. Smith, M.D.
  2. 2. Case <ul><li>43 yo WM presents to establish care at DHP-recently moved to this area </li></ul><ul><li>PMH of substance abuse (IVDU) and multiple traumas- ? Hx of hepatitis </li></ul><ul><li>Currently going to methadone clinic-denies current drug or alcohol use </li></ul><ul><li>Complains of palpitations and weight loss </li></ul><ul><li>AF/VSS with unremarkable PE--no stigmata of liver disease </li></ul>
  3. 3. Case (Cont)-Labs <ul><li>ALT 43 (ULN 36) </li></ul><ul><li>+Hepatitis C Antibody </li></ul><ul><li>- HIV antibody </li></ul><ul><li>-Hepatitis B core antibody and surface antigen </li></ul><ul><li>TSH 0.08 </li></ul><ul><li>Labs at next visit-- </li></ul><ul><ul><li>Hepatitis C genotype 1a </li></ul></ul><ul><ul><li>Viral load 2.2 million copies/ml </li></ul></ul>
  4. 4. Clinical question <ul><li>The patient inquires about Hepatitis C and is very concerned over his diagnosis. </li></ul><ul><li>What are the treatments? How effective are they? </li></ul>
  5. 5. HCV-Virology <ul><li>First identified in 1989 as primary cause of non-A/non-B Hepatitis </li></ul><ul><li>RNA Virus-family flaviviridae </li></ul><ul><li>Single RNA genome codes for a large polyprotein- cleaved into multiple proteins </li></ul><ul><li>RNA polymerase coded for and required for replication—Lacks “proofreading” capability </li></ul><ul><li>Rapid rate of virion production (trillions/d) and short serum half life (3-4 hours) </li></ul>
  6. 6. Virology (Cont) <ul><li>Six different genotypes (1-6) </li></ul><ul><ul><li>Large degree of variation between genotypes and even within same genotype </li></ul></ul><ul><ul><ul><li>Quasispecies (5-10%) variation </li></ul></ul></ul><ul><ul><ul><li>Subtype (15-30%) variation </li></ul></ul></ul><ul><ul><ul><li>Genotype (30-50%) variation </li></ul></ul></ul><ul><ul><li>Genotype does not affect progression but is important predictor of response to therapy </li></ul></ul>
  7. 7. Virology- Geographic variation
  8. 8. HCV-Epidemiology <ul><li>Viral Pandemic-170 million people infected worldwide </li></ul><ul><li>Prevalence varies worldwide—Egypt has highest prevalence (average 22%) </li></ul><ul><li>In U.S. is the most common chronic blood borne illness and most common reason for liver transplantation </li></ul>
  9. 9. Epidemiology (Cont)-U.S. <ul><li>Based on NHANES III data, 1. 8 % (3.9 million) of U.S. population has +HCV antibody </li></ul><ul><li>73.9% (2.7 million) of this group have +HCV RNA indicating chronic infection </li></ul><ul><li>Demographic Characteristics: Poverty, <12 yrs education, divorced/separated </li></ul><ul><li>Strongest independent risk factors: Illegal drug use and high risk sexual behavior </li></ul>
  10. 10. HCV-Risk Factors <ul><li>Hepatology 2002; 36(5): S93-S98. </li></ul>
  11. 11. HCV-Transmission <ul><li>Household transmission rare, but can occur (avoid sharing razors, toothbrush, any items with exposure to blood) </li></ul><ul><li>Role of tattooing controversial </li></ul><ul><li>No role for post-exposure immune globulin </li></ul>
  12. 12. HCV- Acute Clinical Manifestations <ul><li>Largely asymptomatic </li></ul><ul><li><20% become clinically jaundiced-when occurs assoc. with fatigue, lethargy, N/V, fevers, and RUQ pain </li></ul><ul><li>Symptoms occur around 7-8 weeks post exposure (range 2-12 weeks) </li></ul><ul><li>Fulminant hepatic failure rare but has been documented </li></ul><ul><li>75-80% progress to chronic HCV (defined as HCV RNA + for 6 months) </li></ul>
  13. 13. HCV-Course of Acute to Chronic <ul><li>Hepatology2002; 36(5):S21-S29 </li></ul>Symptoms
  14. 14. HCV-Chronic HCV Manifestations <ul><li>Chronic infection asymptomatic in large majority of patients </li></ul><ul><li>Symptoms when present include: </li></ul><ul><ul><li>Fatigue (most common) </li></ul></ul><ul><ul><li>RUQ pain </li></ul></ul><ul><ul><li>Nausea, anorexia, myalgias </li></ul></ul><ul><li>No association between symptoms and disease activity </li></ul><ul><li>Most patients have ALT in range of 1-2X ULN. 1/3 patients will have normal ALT. </li></ul>
  15. 15. HCV-Extrahepatic Manifestations <ul><li>Essential Mixed Cryoglobulinemia </li></ul><ul><li>Renal involvement (cryoglobulins, MPGN, membranous nephropathy) </li></ul><ul><li>Autoantibody formation (thyroid disease) </li></ul><ul><li>Dermatologic manifestations </li></ul><ul><li>? Association with DM, lymphoma, and gammopathies </li></ul>
  16. 16. Diagnosis of HCV <ul><li>Screening test is for HCV Antibody </li></ul><ul><ul><li>3 rd generation test now in use </li></ul></ul><ul><ul><li>>95% sensitive </li></ul></ul><ul><ul><li>Generally positive 7-10 weeks post infection </li></ul></ul><ul><ul><li>In low risk population (blood donors) false positives occur with greater freq. (Confirmatory testing required-RIBA or PCR) </li></ul></ul><ul><ul><li>False negatives more common in immunocompromised and in patients with cryoglobulinemia </li></ul></ul>
  17. 17. Diagnosis (Cont) <ul><li>PCR used to directly measure viral load (lower limit of detection <50 copies/ml) </li></ul><ul><ul><li>HCV RNA detectable 1-3 weeks post infection </li></ul></ul><ul><ul><li>Viral load helpful in predicting response to therapy </li></ul></ul><ul><ul><li>Useful as confirmatory test and in setting of Acute HCV infection </li></ul></ul><ul><ul><li>Used to follow response to treatment </li></ul></ul><ul><li>Genotype testing not required for diagnosis- helpful in determining response to therapy </li></ul><ul><li>Liver biopsy </li></ul>
  18. 18. HCV-Natural history <ul><li>Course of chronic HCV variable </li></ul><ul><ul><li>Markedly different outcomes in various studies as to % with ESLD/cirrhosis </li></ul></ul><ul><ul><li>In general, 20% will develop cirrhosis </li></ul></ul><ul><ul><ul><li>1/3 develop cirrhosis in <20 years (rapid fibrosis) </li></ul></ul></ul><ul><ul><ul><li>1/3 require 30 years or more to develop cirrhosis if ever (slow fibrosis) </li></ul></ul></ul><ul><ul><ul><li>Multiple factors affect rate of fibrosis/progression </li></ul></ul></ul>
  19. 19. HCV-Natural History (Cont) <ul><li>New England Journal of Medicine 2001; 345(1)41-52 </li></ul>
  20. 20. HCV-Natural history(Cont)
  21. 21. HCV-Treatment <ul><li>Rationale for treating vast majority of patients with chronic HCV is prevention of cirrhosis/ESLD </li></ul><ul><ul><li>Symptomatic improvement doubtful (especially fatigue—will get worse with treatment) </li></ul></ul>
  22. 22. HCV-Treatment/History <ul><li>Prior to discovery of HCV in 1989, interferon shown to be useful in treatment of Non-A/Non-B Hepatitis </li></ul><ul><li>Interferon Alpha approved by FDA in 1990 for treatment of chronic HCV </li></ul><ul><ul><li>Sustained Virological Response (defined as undetectable HCV RNA 24 weeks post therapy) rates very low with interferon monotherapy for 24 weeks (5-10%) </li></ul></ul><ul><ul><li>Extending treatment to 48 weeks improved SVR marginally (10-15%) </li></ul></ul><ul><li>Addition of Ribavirin to Interferon improved SVR to near 40% (1998) </li></ul><ul><li>Peginterferon monotherapy shows SVR 23-29% </li></ul>
  23. 23. HCV-Treatment (PEG) <ul><li>The role of pegylation </li></ul>
  24. 24. PEG-interferon alfa 0 5 10 15 20 25 30 0 8 24 48 72 96 120 144 168 Time (hours) Concentration (ng/mL) Multiple Dose (Week 48) 0 2 4 6 8 10 12 14 0 24 49 72 97 120 155 Time (hours) IFN tiw dosing Peginterferon  -2a Xu Z-X et al. Hepatology. 1998;28(4 pt 2):702A. IFN  qw dosing Concentration (U/mL)
  25. 25. HCV-Treatment (Contraindications) <ul><li>New England Journal of Medicine 2001; 345(1):41-52 </li></ul>
  26. 26. HCV-Treatment <ul><li>Two recent studies have focused on combination peginterferon/ribavirin for treatment of chronic HCV. </li></ul>
  27. 27. HCV-Treatment (Manns) <ul><li>Manns et al. Peginterferon alfa-2 b plus ribavirin compared with interferon alfa-2b for initial treatment of chronic HCV: a randomized trial. Lancet 2001. </li></ul><ul><li>Design: randomized trial carried out at 62 centers in Europe, Argentina, Canada, and U.S. </li></ul><ul><li>Primary endpoint: SVR (undetectable HCV RNA 24 weeks post therapy) </li></ul>
  28. 28. HCV Treatment (Manns) <ul><li>Patients: 1530 patients, 65% male, average age 43, 5-7% cirrhosis, 68%, genotype 1, 29-30% genotype 2 or 3 </li></ul>
  29. 29. HCV-Treatment (Manns) <ul><li>Exclusion Criteria: </li></ul><ul><ul><li>Decompensated cirrhosis </li></ul></ul><ul><ul><li>Elevated AFP </li></ul></ul><ul><ul><li>HIV </li></ul></ul><ul><ul><li>Other causes of liver disease </li></ul></ul><ul><ul><li>Preexisting Psych. disease </li></ul></ul><ul><li>Inclusion Criteria: </li></ul><ul><ul><li>No previous treatment </li></ul></ul><ul><ul><li>+ HCV RNA </li></ul></ul><ul><ul><li>Liver Bx within 1 year </li></ul></ul><ul><ul><li>Elevated ALT </li></ul></ul><ul><ul><li>Normal Renal Fx and CBC wnl </li></ul></ul>
  30. 30. HCV-Treatment (Manns) <ul><li>Treatment: 3 treatment arms </li></ul><ul><ul><li>511 Patients received 1.5mcg/kg/sq peg q week plus ribavirin 800 mg po QD x 48 weeks </li></ul></ul><ul><ul><li>514 Patients received 1.5mcg/kg/sq peg q week x 4 weeks, then 0.5mcg/kg/sq q week x 44 weeks plus ribavirin 1000mg/1200mg (weight based) po qd x 48 weeks </li></ul></ul><ul><ul><li>505 Patients received standard interferon 3 million units sq/tiw plus ribavirin 1000mg/1200mg (weight based) x 48 weeks </li></ul></ul>
  31. 31. HCV-Treatment (Manns) <ul><li>Results: </li></ul>
  32. 32. HCV-Treatment (Manns) <ul><li>Results by Ribavirin dose </li></ul>
  33. 33. HCV-Treatment (Manns) <ul><li>Adverse Events </li></ul><ul><ul><li>No new class of side effects </li></ul></ul><ul><ul><li>Flu symptoms higher in high dose PEG group </li></ul></ul><ul><ul><li>Neutropenia higher in high dose PEG group </li></ul></ul><ul><ul><li>Dose reduction higher in high dose PEG group </li></ul></ul><ul><ul><li>Discontinuation rate similar between groups </li></ul></ul>
  34. 34. HCV-Treatment (Manns) Conclusions: <ul><li>Overall SVR higher with high dose PEG (54% vs. 47%) </li></ul><ul><li>In genotype 1, high dose PEG achieves higher SVR than standard interferon (42% vs. 33%) </li></ul><ul><li>No difference in SVR between groups in those with genotype 2 or 3 </li></ul>
  35. 35. HCV-Treatment (Manns) <ul><li>Variables associated with increased SVR: </li></ul><ul><ul><li>Genotype other than 1 </li></ul></ul><ul><ul><li>Baseline viral load (<2 million copies) </li></ul></ul><ul><ul><li>Younger age </li></ul></ul><ul><ul><li>Absence of cirrhosis/bridging fibrosis </li></ul></ul><ul><ul><li>Weight based dosing of Ribavirin (>10.6 mg/kg) </li></ul></ul>
  36. 36. HCV-Treatment (Manns) Conclusions: <ul><li>Comparing high dose PEG vs. standard interferon </li></ul><ul><ul><li>Overall: ABI 7%, NNT 14 </li></ul></ul><ul><ul><li>Genotype 1: ABI 9%, NNT 11 </li></ul></ul>
  37. 37. HCV-Treatment (Fried) <ul><li>Fried et al. Peginterferon Alfa-2a Plus Ribavirin for Chronic HCV. NEJM 2002. </li></ul><ul><ul><li>Design: Randomized controlled trial conducted at 81 centers worldwide </li></ul></ul><ul><ul><li>Primary Endpoint: SVR, defined as – HCV RNA 24 weeks post therapy </li></ul></ul><ul><ul><li>Patients: 1121 patients, 71% male, average age 42, 84% white, 61-65% genotype 1, 12-15% with bridging fibrosis or cirrhosis </li></ul></ul>
  38. 38. HCV-Treatment (Fried) <ul><li>Inclusion Criteria: </li></ul><ul><ul><li>No previous treatment </li></ul></ul><ul><ul><li>Elevated ALT </li></ul></ul><ul><ul><li>Liver Bx </li></ul></ul><ul><ul><li>Positive HCV RNA </li></ul></ul><ul><li>Exclusion Criteria: </li></ul><ul><ul><li>Neutropenia (1,500) </li></ul></ul><ul><ul><li>Thrombocytopenia (<90,000) </li></ul></ul><ul><ul><li>Anemia (<12g F, <13g M) </li></ul></ul><ul><ul><li>HIV </li></ul></ul><ul><ul><li>Decomp. Liver Disease </li></ul></ul><ul><ul><li>Psych. Dz (poor control) </li></ul></ul><ul><ul><li>Alcohol/drug abuse within 1 year </li></ul></ul><ul><ul><li>Cr>1.5 x ULN </li></ul></ul>
  39. 39. HCV-Treatment (Fried) <ul><li>Treatment: 3 treatment arms </li></ul><ul><ul><li>Peginterferon Alfa-2a 180mcg sq/week plus ribavirin (weight based) 1000/1200mg po qd x 48 weeks </li></ul></ul><ul><ul><li>Peginterferon Alfa-2a 180 mcg sq/week plus placebo x 48 weeks </li></ul></ul><ul><ul><li>Interferon Alfa-2b 3 million units/sq tiw plus ribavirin (weight based) 1000/1200mg po qd x 48 weeks </li></ul></ul>
  40. 40. HCV-Treatment (Fried) <ul><li>Results: </li></ul>
  41. 41. HCV-Treatment (Fried)
  42. 42. HCV-Treatment (Fried) <ul><li>Adverse events: </li></ul><ul><ul><li>No new class of side effects with peginterferon </li></ul></ul><ul><ul><li>Similar number of patients withdrawn from each group (most due to depression) </li></ul></ul><ul><ul><li>Flu symptoms less common in peg groups </li></ul></ul><ul><ul><li>Neutropenia/ thrombocytopenia more common in peg groups </li></ul></ul>
  43. 43. HCV-Treatment (Fried) <ul><li>Conclusions: Peginterferon Alpha-2a/ribavirin for 48 weeks is superior to standard interferon/ribavirin, irrespective of genotype </li></ul><ul><ul><li>Higher SVR also noted in patients with high baseline viral load </li></ul></ul><ul><ul><li>If no response by week 12, chance of achieving SVR very low </li></ul></ul><ul><ul><li>Variables assoc. with higher SVR: </li></ul></ul><ul><ul><ul><li>Genotype other than 1 </li></ul></ul></ul><ul><ul><ul><li>Younger age (<40) </li></ul></ul></ul><ul><ul><ul><li>Weight <75kg </li></ul></ul></ul>
  44. 44. HCV Treatment- (Fried) <ul><li>Conclusions: comparing Peg/ribavirin vs. standard interferon/ribavirin </li></ul><ul><ul><li>Overall: ABI 12%, NNT 8 </li></ul></ul><ul><ul><li>Genotype 1: ABI 10%, NNT 10 </li></ul></ul><ul><ul><li>Genotype 2 or 3: ABI 15%, NNT 6 </li></ul></ul>
  45. 45. HCV-Treatment-Expense <ul><ul><ul><li>The Medical Letter 2003; 45: 19-20 </li></ul></ul></ul>
  46. 46. HCV-Treatment <ul><li>Improvements are being made in the treatment of HCV---BUT </li></ul><ul><ul><li>Can we apply these results to our patient population? </li></ul></ul>
  47. 47. HCV-Treatment <ul><li>Ytter et al. Surprisingly Small Effect of Antiviral Treatment in Patients with Hepatitis C. Annals of Internal Medicine 2002. </li></ul>
  48. 48. HCV-Treatment <ul><ul><ul><li>Design: Retrospective case series of consecutive patients referred to a liver clinic in Cleveland, Ohio. </li></ul></ul></ul><ul><ul><ul><li>Patients: 327 pts. with + ELISA for HCV </li></ul></ul></ul><ul><ul><ul><li>Objective: Measurement of treatment rates and reasons for non-treatment </li></ul></ul></ul><ul><ul><ul><li>Criteria for treatment: +HCV RNA and elevated ALT on two occasions over 6 months </li></ul></ul></ul><ul><ul><ul><li>Exclusion Criteria: Decompensated cirrhosis, other liver disease, alcohol or drug abuse, nonadherence (missing 2 visits), poorly controlled psych. disease or sz. d/o, autoimmune dz, symptomatic CAD, neutropenia (<1,500), thrombocytopenia (<75,000) </li></ul></ul></ul>
  49. 49. HCV-Treatment (Ytter) <ul><li>Conclusion: Many (if not most) patients are not candidates for treatment with the current interferon based regimens </li></ul>
  50. 50. HCV-Conclusions <ul><li>Treatments for chronic HCV have shown continual improvement over the last decade. </li></ul><ul><li>Peginterferon/Ribavirin is superior to standard interferon/Ribavirin and is now the standard of care </li></ul><ul><li>No direct comparison of the two peginterferons currently available has been done, but they appear to be equally effective </li></ul>
  51. 51. HCV-Conclusions <ul><li>The decision on who to treat is very difficult </li></ul><ul><ul><li>In theory everyone is candidate for treatment </li></ul></ul><ul><ul><li>Must be made on an individual basis </li></ul></ul><ul><ul><li>Patient preferences very important </li></ul></ul><ul><ul><li>Patients need to understand reasons for treatment and adverse effects of current regimen </li></ul></ul>
  52. 52. HCV-Conclusions <ul><li>In general, patients with genotype 2 or 3 should be offered treatment if no contraindications </li></ul><ul><li>Decision more difficult in patients with genotype 1, based on continued poor SVR </li></ul><ul><ul><li>Only reliable way to determine which pts. will benefit most from treatment is by histological evaluation </li></ul></ul><ul><ul><li>Liver bx results should be used to guide clinical decision making </li></ul></ul>
  53. 53. HCV-Back to the case <ul><li>The pt. was not felt to be a candidate for treatment </li></ul><ul><ul><li>Noncompliance (multiple “no-shows”) </li></ul></ul><ul><ul><li>Resumption of drug use </li></ul></ul><ul><ul><li>Autoimmune thyroid disease (initially) </li></ul></ul><ul><li>He was vaccinated against Hep A/B </li></ul><ul><li>Counseled regarding transmission of HCV </li></ul><ul><li>Urged to seek therapy for drug abuse AND abstain from alcohol </li></ul>
  54. 54. THANKS <ul><ul><li>Dr. Brandi Salomone </li></ul></ul><ul><ul><li>Dr. Jim Peacock </li></ul></ul><ul><ul><li>Dr. Joel Bruggen </li></ul></ul>