Challenges in HCV Management

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Challenges in HCV Management

  1. 1. Prof Dr Nasir Khokhar MD FACP FACG Prof and Chief, Department of Medicine and Director, Division of Gastroenterology Shifa International Islamaabad Challenges in Management of HCV- Infected Patients
  2. 2. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Management of Special Populations of HCV-Infected Patients  Nonresponders  Patients with normal ALT levels  Children  Patients with HIV coinfection  Patients with renal disease  Patients with compensated and decompensated cirrhosis  Patients with solid organ transplantation  Acute infection  IV drug users  Patient with psychiatric illness  Black patients
  3. 3. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Non Responders
  4. 4. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update NR: IFN + RBV[1-6] Relapse: IFN + RBV[1,5,6] NR: IFN[1,3,5] 8% to 18% 40% to 50% 20% to 30% SVR(%)  Previous HCV RNA reduction predicts response  High relapse rate PegIFN + RBV for Previous IFN ± RBV Nonresponders/Relapsers 1. Jacobson IM, et al. Am J Gastroenterol. 2005;100:2453-2462. 2. Lawitz E, et al. DDW 2003. Abstract T1293. 3. Shiffman M, et al. Gastroenterology. 2004;126:1015-1023. 4. Gross JB, et al. AASLD 2005. Abstract 60. 5. Krawitt E, et al. J Hepatol. 2005;43:243-249. 6. Poynard T, et al. Gastroenterology. 2009;136:1618-1628. 100 90 70 50 30 10 0 80 60 40 20
  5. 5. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update 34 6 18 32 7 17 43 18 25 38 14 22 EPIC3: SVR by Previous Treatment and Response Poynard T, et al. Gastroenterol. 2009;136:1618-1628. 0 20 40 PegIFN alfa-2a + RBV (n = 375) All (N = 2293) SVR(%) 100 IFN/RBV (n = 1423) PegIFN alfa-2b + RBV (n = 488) All Previous nonresponders Previous relapsers Previous Regimen PegIFN alfa-2b 1.5 µg/kg/wk + Weight-Based RBV 800-1400 mg/day for 48 Wks Note: results from EPIC3 study led to expanded indication for nonresponders to nonpegylated interferon and RBV. 60 80
  6. 6. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Jensen D, et al. Ann Intern Med. 2009;150:528-540. Patients with chronic HCV infection not responsive to pegIFN alfa-2b/ RBV therapy PegIFN alfa-2a 180 µg/wk + RBV 1000/1200 mg/day (n = 317) Wk 48 Wk 96Wk 72 PegIFN alfa-2a 180 µg/wk + RBV 1000/1200 mg/day (n = 156) PegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg/day (n = 156) PegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg/day (n = 313) PegIFN alfa-2a 360 µg/wk + RBV 1000-1200 mg/day PegIFN alfa-2a 360 µg/wk + RBV 1000-1200 mg/day Wk 12 Follow-up Follow-up Follow-up Follow-up 2:1:1:2 randomization REPEAT: PegIFN alfa-2a Treatment of PegIFN alfa-2b Nonresponders
  7. 7. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update REPEAT: 72-Wk Treatment Duration Associated With Higher SVR Rate Jensen D, et al. Ann Intern Med. 2009;150:528-540. P = .006; OR: 1.8 (95% CI: 1.17-2.77) 7 14 9 16 0 100 SVR(%) 360/180 µg 72 Wks 360/180 µg 48 Wks 180 µg 72 Wks 180 µg 48 Wks 52/317 11/156 40 22/156 27/313n/N = 20 60 80
  8. 8. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update DIRECT Trial: Comparison of 2 Doses of cIFN + RBV in Previous Nonresponders Bacon B, et al. Hepatology. 2009;49:1838-1846. Copyright © 2009 . Reproduced with permission of John Wiley & Sons, Inc. cIFN + RBV SVR(%) P = .141 7 (17/245) 11 (26/242) 9 μg 15 μg 100 80 60 40 20 0  Highest rates of SVR in noncirrhotics with substantial previous HCV RNA reductions ITT Analysis
  9. 9. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update HALT-C: Final Results of Maintenance PegIFN alfa-2a in Nonresponders  No significant difference between arms in any primary outcome – 34.1% vs 33.8%; HR: 1.01 (95% CI: 0.81-1.26)  Low-dose pegIFN alfa-2a 90 µg/wk vs control group had – Greater reductions in HCV RNA and ALT (P < .0001) – Greater reductions in necroinflammation (P < .001)  No reduction or difference in fibrosis in either arm Di Bisceglie AM, et al. N Engl J Med. 2008;359:2429-2441. Study Arm Baseline Fibrosis Any Primary Outcome, % Death, % HCC, % CTP Score ≥ 7, % PegIFN alfa-2a 90 µg/wk (n = 517) 3/4 36.7 2.6 2.6 3.2 5/6 30.2 2.4 1.9 17.8 Control (n = 533) 3/4 35.5 0.6 1.6 3.2 5/6 31.2 2.7 4.6 14.6
  10. 10. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Ghany MG, et al. Hepatology. 2009;49:1335-1374. Nonresponders: Summary of Recommendations  PegIFN + RBV can be considered for nonresponders or relapsers to either standard IFN ± RBV or pegIFN monotherapy  PegIFN + RBV retreatment not recommended for patients without an SVR after previous full course of pegIFN + RBV  Maintenance therapy not recommended for patients with bridging fibrosis or cirrhosis who have failed a previous course of pegIFN + RBV
  11. 11. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update HCV with Normal ALT
  12. 12. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Updated Limits for Determining Normal ALT  ALT values differ by age, race, sex, and body mass index  Updated healthy ALT ranges determined from low-risk individuals[1] – Males: 30 IU/L – Females: 19 IU/L  Common definition for normal ALT – ALT < 40 IU/L on 2-3 occasions separated by ≥ 1 mo over period of 6 mos 1. Prati D, et al. Ann Intern Med. 2002;137:1-10.
  13. 13. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Persistently Normal ALT an Imperfect Marker of Liver Disease Severity  Significantly less liver fibrosis generally observed in patients with persistently normal ALT[1-2]  However, fibrosis and cirrhosis observed in patients with normal ALT[3] 0 20 40 60 80 100 No fibrosis Mild BridgingPortal Severity of Liver Disease Patients(%) Normal ALT (n = 58) Elevated ALT (n = 37) 23 19 39 19 26 24 6 16 Cirrhosis 6 22 1. Martinot-Peignoux M, et al. Hepatology. 2001;34:1000-1005. 2. Nutt AK, et al. Am J Med. 2000;109:62-64. 3. Shiffman ML, et al. J Infect Dis. 2000;182:1595-1601.
  14. 14. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Efficacy of PegIFN in HCV-Infected Patients With Normal ALT  Patients with ≥ 3 normal ALT measurements over 18 mos randomized to pegIFN alfa-2a 180 µg/wk + RBV 800 mg/day or no treatment 0 20 40 60 80 100 All Patients SVR(%) 24 wks of pegIFN + RBV (n = 212) 30 52 Zeuzem S, et al. Gastroenterol. 2004;127:1724-1732. Genotype 1 Genotypes 2 or 3 0 0 13 40 0 48 wks of pegIFN + RBV (n = 210) No treatment (n = 69) 72 78 P < .001 P < .001
  15. 15. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Normal ALT: Summary of Recommendations  Regardless of serum ALT levels, decision to initiate therapy with pegIFN + RBV should be individualized based on – Liver biopsy results – Potential for serious adverse effects – Likelihood of response – Presence of comorbid conditions  Treatment regimen for HCV-infected patients with normal ALT same as that for persons with elevated serum ALT Ghany MG, et al. Hepatology. 2009;49:1335-1374.
  16. 16. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update HCV in children
  17. 17. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update HCV Infection Among Children  23,048-42,296 children in United States chronically infected[1] – 7200 new cases/yr – Mother-to-child transmission most common mode of HCV transmission in US children  Children more likely to spontaneously clear HCV than adults[2]  Minimal progression of liver disease over 5- to 10-yr period[3] – However, since average child likely to be infected > 50 yrs, routine treatment may still be appropriate 1. Jhaveri R, et al. J Pediatr. 2006;148:353-358. 2. Guido M, et al. Gastroenterol. 1998;115:1525-1529. 3. Camarero C, et al. Eur J Pediatr .2008;167:219-224.
  18. 18. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update PegIFN alfa-2b + RBV Effective in Children and Adolescents  Open-label study of 62 children receiving pegIFN alfa-2b 1.5 µg/kg/wk + RBV 15 mg/kg/day for 48 wks  Dose modification of pegIFN due to adverse events in 31% of patients; discontinuation in 7% of patients Wirth S, et al. Hepatology. 2005;41:1013-1018. 0 20 40 60 80 100 Overall SVR(%) 59 Genotype 1 (n = 46) Genotypes 2 or 3 (n = 13) 48 100
  19. 19. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update  Routine anti-HCV testing not recommended at birth in children born to HCV-infected mothers due to high rate of positive antibody transfer from mother – HCV RNA testing may be considered at 1-2 mos if early diagnosis desired – Anti-HCV testing may be performed at ≥ 18 mos  Children aged 2-17 yrs should be considered appropriate candidates for treatment using same criteria as those used for adults – Appropriate treatment: pegIFN alfa-2b 1.5 µg/1.73 m2/wk + RBV 15 mg/kg/day Ghany MG, et al. Hepatology. 2009;49:1335-1374. Children: Summary of Recommendations
  20. 20. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update HCV HIV Co Infection
  21. 21. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Liver Disease a Leading Cause of Death in HIV-Infected Patients  D:A:D study (N = 23,441) – Median FU: 3.5 yrs  Baseline characteristics – Previous AIDS: 26.4% – HCV positive: 22.5% – Active HBV infection: 6.8% – Receiving antiretrovirals: 88.7%  Mortality over 3.5 yrs median FU – Total: 5.3% – Incidence: 1.62/100 patient-yrs – Median age: 44 yrs AIDS Liver-Related Diseases CVD N = 1246 Deaths(%) 31 15 11 Weber R, et al. Arch Intern Med. 2006;166:1632-1641. 0 20 40 80 100 10 30 60 70 50 90
  22. 22. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update PegIFN ± RBV vs Standard IFN in HIV/HCV-Coinfected Patients  868 HCV/HIV-coinfected patients randomized to standard IFN alfa-2a + RBV, pegIFN alfa-2a + placebo, or pegIFN alfa-2a + RBV for 48 wks 0 20 40 60 80 100 Overall SVR(%) 12 Baseline HCV RNA ≤ 800,000 IU/mL Baseline HCV RNA > 800,000 IU/mL PegIFN alfa-2a + placebo (n = 286) PegIFN alfa-2a + RBV (n = 289) IFN alfa-2a + RBV (n = 285) 20 40 22 34 61 7 15 33 P < .001 P < .001 Torriani F, et al. N Engl J Med. 2004;351:438-450. n = 82 79 79 203 206 208
  23. 23. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update 1. Torriani F, et al. N Engl J Med. 2004;351:438-450. 2. Chung R, et al. N Engl J Med. 2004;351:451-459. 3. Carrat F, et al. JAMA. 2004;292:2839-2848. 4. Laguno M, et al. AIDS. 2004;18:F27-F36. Efficacy of PegIFN + RBV in HCV/HIV-Coinfected Patients PegIFN alfa-2a + RBV 800[1] PegIFN alfa-2a + RBV 600-1000[2] PegIFN alfa-2b + RBV 800[3] Peg IFN alfa-2b + RBV 800-1200[4] 40 29 27 14 27 17 44 38 SVR(%) All patients GT1 patients 0 20 60 100 40 80
  24. 24. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Safety Considerations When Managing HCV/HIV-Coinfected Patients  RBV-related anemia more common in HCV/HIV-coinfected patients than in HCV-monoinfected patients[1] – Particularly common in patients also receiving the anti-HIV drug zidovudine[2]  RBV potentiates the toxic effects of the anti-HIV drug didanosine[3] – Can result in fatal lactic acidosis – Combination contraindicated 1. Moore RD. Clin Infect Dis. 1999;29:44-49. 2. Alvarez D, et al. J Viral Hepat. 2006;13:683-689. 3. Lafeuillade A, et al. Lancet. 2001;357:280-281.
  25. 25. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update HIV/HCV Coinfection: Summary of Recommendations  Anti-HCV testing should be performed in all HIV-infected persons  HCV should be treated in the coinfected patient if the risk of serious liver disease and likelihood of treatment response are judged to outweigh morbidity of therapy – Initial treatment of coinfected patients should be pegIFN + RBV for 48 wks at standard doses  Patients on zidovudine, and particularly those on didanosine, should be switch to an equivalent antiretroviral agent before beginning RBV therapy Ghany MG, et al. Hepatology. 2009;49:1335-1374.
  26. 26. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update HCV in Renal Disease
  27. 27. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update HCV Therapy in Patients With Kidney Disease  Kidney important for catabolism and filtration of both IFN and RBV – Reduced doses warranted  Standard IFN vs pegIFN for persons with kidney failure – Reduced excretion of pegIFN – Higher rate of adverse events with pegIFN vs standard IFN – Management of adverse events more difficult with pegIFN vs standard IFN Ghany MG, et al. Hepatology. 2009;49:1335-1374.
  28. 28. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update PegIFN Monotherapy Not Superior to Standard IFN Monotherapy in Dialysis Pts  78 hemodialysis patients treated with pegIFN alfa-2a 135 µg/wk[1] – SVR obtained in 14% of patients – Adverse events reported in 83% of patients (flu-like syndrome, mild to moderate thrombocytopenia, leukopenia, and anemia) – 32% of patients noncompliant  Randomized trial of 16 patients receiving pegIFN alfa-2b 1.0 or 0.5 µg/kg/wk discontinued due to adverse events and modifications[2] – 56% of patients in 1 µg/kg/wk group and 28% in 0.5 µg/kg/wk experienced serious adverse events requiring therapy discontinuation 1. Covic A, et al. J Nephrol 2006;19:794-801. 2. Russo MW, et al. Nephrol Dial Transplant. 2006;21:437-443.
  29. 29. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update IFN Monotherapy 3 MU TIW in Dialysis Patients Russo MW, et al. Am J Gastroenterol. 2003;98:1610-1615. 100 80 60 40 20 0 SVR(%) 20 27 21 20 19 56 58 68 33
  30. 30. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Patients With Renal Disease: Summary of Recommendations (I) Description GFR, mL/min*1.73 m2 Recommended Treatment Kidney damage with normal or increased GFR ≥ 90 Routine combination therapy Kidney damage with mildly decreased GFR 60-90 Moderately decreased GFR 30-59 PegIFN alfa-2b 1 µg/kg/wk or pegIFN alfa-2a 135 µg/wk + RBV 200-800 mg/day (starting with lowest dose and increasing if adverse effects manageable) Severely decreased GFR 15-29 Kidney failure < 15 Dialysis Standard IFN 3 mU 3x/wk or pegIFN alfa-2b 1 µg/kg/wk or pegIFN alfa-2a 135 µg/wk ± markedly reduced daily RBV dose* Ghany MG, et al. Hepatology. 2009;49:1335-1374. *Controversial.
  31. 31. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Patients With Renal Disease: Summary of Recommendations (II)  HCV treatment not recommended for patients who have undergone kidney transplantation, unless fibrosing cholestatic hepatitis develops  Patients with cryoglobulinemia, mild to moderate proteinuria, and slowly progressive kidney disease can be treated with standard IFN or reduced doses of pegIFN + RBV  Patients with cryoglobulinemia and marked proteinuria with evidence of progressive kidney disease or an acute flare of cryoglobulinemia can be treated with rituximab, cyclophosphamide + methylprednisolone, or plasma exchange followed by IFN-based treatment once the acute process has subsided Ghany MG, et al. Hepatology. 2009;49:1335-1374.
  32. 32. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Race
  33. 33. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update 1. Muir AJ, et al. N Engl J Med. 2004;350:2265-2271. 2. Conjeevaram H, et al. Gastroenterology. 2006;131:470-477. SVR(%) 0 20 40 60 80 100 PegIFN alfa-2b 1.5 µg/kg/wk + RBV 800-1000 mg/day[1] Non-Hispanic whites Blacks n = 52 19 P < .001 100100 52 28 P < .0001 SVR(%) 0 20 40 60 80 100 196205 PegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg/day[2] n = Lower SVR Rate in GT1 HCV–Infected Blacks Receiving PegIFN + RBV vs Whites
  34. 34. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update WIN-R Trial: Weight-Based RBV Dosing Superior to Flat Dosing in HCV GT1 Blacks  Randomized trial compared pegIFN alfa-2b 1.5 µg/kg/wk + either flat dosing of RBV (800 mg/day) or weight-based RBV (800-1400 mg) Jacobson IM, et al. Hepatology. 2007;46:982-990. P = .004 36/17430/188 50/174 HCVRNANegative(%) 16 10 21 29 0 20 40 60 80 100 End of Treatment SVR (Wk 24 Posttreatment) Flat dosing (n = 188) Weight-based dosing (n = 174) P = .006 10 30 50 70 90
  35. 35. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Black Patients: Summary of Recommendations  Blacks who are appropriate HCV treatment candidates should be treated with current optimal regimen of pegIFN + RBV  Blacks with baseline neutropenia (ANC < 1500/mm3) should receive HCV treatment Ghany MG, et al. Hepatology. 2009;49:1335-1374.
  36. 36. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update HCV Cirrhosis
  37. 37. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Observations in HCV-Infected Patients With Cirrhosis  Lower SVR rates in compensated cirrhotics vs patients without cirrhosis in registrational treatment trials[1-3] – 41% to 44% vs 57% to 63%, respectively  Treatment still strongly indicated in compensated cirrhotics – Serious adverse events common and should be closely monitored  Screening for varices and for HCC must be standard in cirrhotics – HCC risk declines but still exists after SVR in cirrhotics; must continue screening indefinitely  HCV recurrence after transplantation is almost universal  Treatment more difficult posttransplantation (more adverse events, lower SVR rates) 1. Manns MP, et al. Lancet. 2001;358:958-965. 2. Fried MW, et al. N Engl J Med. 2002;347:975-982. 3. Hadziyannis SJ, et al. Ann Intern Med. 2004;140:346-355.
  38. 38. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Low Accelerating Dose Regimen in Patients With Advanced Cirrhosis  124 patients with advanced cirrhosis treated with IFN + RBV or pegIFN + RBV – Treatment began with half doses of both IFN and RBV that were increased incrementally as tolerated  Frequent adverse events requiring dose reduction or discontinuation  Among patients HCV RNA negative before transplantation, 80% remained HCV RNA negative 6 mos later 19/3811/86 SVR(%) GT Non-1GT 1 0 40 80 100 13 50 Everson GT, et al. Hepatology. 2005;42:255-262. 60 20
  39. 39. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update HCV Therapy in Decompensated Cirrhotics Awaiting Liver Transplantation 1. Everson GT, et al. Hepatology. 2005;42:255-262. 2. Forns X, et al. J Hepatol. 2003;39:389-396. 3. Thomas RM, et al. Liver Transpl. 2003;9:905-915. 4. Crippin JS, et al. Liver Transpl. 2002;8:350-355. Patients(%) HCV Free Posttransplant* EVR 0 20 40 60 80 100 SVR Patients Receiving Transplant Everson[1] Forns[2] Thomas[3] Crippin[4] *Regardless of achieving SVR pretransplantation.
  40. 40. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Lessons of Low Acclerating Dose Regimen  SVR can be achieved in some well-selected patients with HCV and decompensated cirrhosis  If a patient achieves SVR before transplantation, posttransplantation recurrence of HCV is prevented  Risk of sepsis, hepatic failure, and death must be balanced against potential benefits  Risks usually outweigh benefits in Child’s C cirrhotics  Transplantation evaluation should be completed before treatment begins in case patient should decompensate further on treatment Ghany MG, et al. Hepatology. 2009;49:1335-1374.
  41. 41. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Cirrhosis: Summary of Recommendations  Compensated cirrhotics can be treated with standard regimen of pegIFN + RBV but require close monitoring for adverse events  Decompensated cirrhotics should be considered for liver transplantation  IFN-based therapy may be initiated at a lower dose in decompensated cirrhotics if – Treatment is administered by experienced clinician with vigilant monitoring – Preferably in patients already accepted as candidates for transplantation  Growth factors can be used for anemia and leukopenia to – Improve quality of life – May limit need for dose reductions in decompensated cirrhotics Ghany MG, et al. Hepatology. 2009;49:1335-1374.
  42. 42. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Liver Transplant Recipients
  43. 43. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update PegIFN + RBV Treatment for Recurrent HCV Post–Liver Transplantation 1. Mukherjee S. Transplant Proc. 2005;37:4403-4405. 2. Dumortier J, et al. J Hepatol. 2004;40:669-674. 3. Castells L, et al. J Hepatol. 2005;43:53-59. 4. Neumann U, et al. Transplantation. 2006;82:43-47. 5. Oton E, et al. Am J Transplant. 2006;6:2348-2355. 6. Sharma P, et al. Liver Transpl. 2007;13:1100-1108. Patients(%) 34 45 35 36 44 37 16 20 13 4 7 43 SVR Discontinued Mukherjee et al[1] Dumortier et al[2] Castells et al[3] Neuman et al[4] Oton et al[5] Sharma et al[6] 0 20 40 60 80 100
  44. 44. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Transplantation Recipients: Summary of Recommendations  Treatment of HCV-related liver disease following liver transplantation should be initiated with caution in appropriate candidates after demonstration of recurrent histologic disease – PegIFN ± RBV the preferred regimen when treating HCV post–liver transplantation  IFN-based therapies should not be used in recipients of heart, lung, and kidney grafts – Except for patients who develop fibrosing cholestatic hepatitis Ghany MG, et al. Hepatology. 2009;49:1335-1374.
  45. 45. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Acute Hepatitis C
  46. 46. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Spontaneous Clearance for Symptomatic Acute HCV High, Justifies Treatment Delay  60 patients with acute HCV (36 genotype 1) followed[1] – Spontaneous clearance in 52% of 51 symptomatic cases – No asymptomatic patient cleared virus spontaneously – SVR achieved in 81% of symptomatic patients without spontaneous clearance who were treated > 3 mos after symptom onset with IFN RBV  Recent study showed similar SVR rates in symptomatic adherent patients who delayed therapy for 12 wks vs those who received immediate treatment[2] 1. Gerlach JT, et al. Gastroenterol. 2003;125:80-88. 2. Deterding K, et al. EASL 2009. Abstract 1047.
  47. 47. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Very High Rate of SVR With IFN Monotherapy for Acute HCV  44 patients with acute HCV infection – 61% genotype 1 – 68% with icterus  Treated with IFN alfa-2b 5 MU/day x 4 wks, followed by IFN 3 MU TIW x 20 wks – Average time from infection to signs/symptoms: 54 days – Average time from infection to start of therapy: 89 days  43 of 44 (98%) had SVR Jaeckel E, et al. N Engl J Med. 2001;345:1452-1457.
  48. 48. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Randomized Trial of Treatment for Acute Hepatitis C at Variable Times After Onset  129 patients entered treatment for lack of spontaneous clearance within 8 wks of presentation – 37% genotype 1 – 41% genotype 4  Randomized to treatment at Wk 8, 12, or 20  Treatment with pegIFN alfa- 2b 1.5 µg/kg/wk x 12 wks Kamal SM, et al. Gastroenterol. 2006;130:632-638. Time of Treatment Initiation 43 4343 95* 92 76 SVR(%) n = *SVR rates significantly higher for genotype 1 patients who received treatment after 8 wks vs either 12 or 20 wks (P = .01 and P = .004, respectively). 0 20 40 60 80 100 8 wks 12 wks 20 wks
  49. 49. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Acute HCV Infection: Summary of Recommendations  Patients with acute HCV infection should be considered for IFN-based therapy  Treatment can be delayed 8-12 weeks after acute onset to allow for spontaneous resolution  Although standard IFN monotherapy effective in this population, pegIFN can be considered due to greater ease of administration  No definitive recommendation about optimal duration of treatment for acute hepatitis C; however, it is reasonable to treat for ≥ 12 weeks, and 24 weeks may be considered  Decision to use RBV made on a case-by-case basis Ghany MG, et al. Hepatology. 2009;49:1335-1374.
  50. 50. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Obesity and Steatosis
  51. 51. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Steatosis and HCV  2/3 of HCV patients have some steatosis  Steatosis is more common with obesity and genotype 3 infection  Increased steatosis may be associated with increased fibrosis progression, particularly in non-genotype 3 HCV  In genotype 3, the presence of steatosis correlates with viral replication Adinolfi L, et al. Hepatology. 2001;33:1358-1364. Hu K, et al. J Hepatol. 2004;40:147-154.
  52. 52. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update 4 3 2 1 0 Association of Hepatic Steatosis and Fibrosis Adinolfi L, et al. Hepatology. 2001;33:1358-1364. HepaticFibrosisScore Grade of Steatosis 0 1-2 3-4 P < .0001
  53. 53. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update BMI and Steatosis in Genotype 1 36 30 24 18 0 25 50 75 100 P < .001 BMI(kg/m2) Normal BMI Hepatocytes with Steatosis (%) Adinolfi L, et al. Hepatology. 2001;33:1358-1364.
  54. 54. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update HCV RNA & Steatosis in Genotype 3a 0 25 50 75 100 P < .001 SerumHCVRNA (Eq/mLx106) Hepatocytes with Steatosis (%) 24.0 16.0 8.0 0.2 Adinolfi L, et al. Hepatology. 2001;33:1358-1364.
  55. 55. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Steatosis and HCV Viral Factors:  Genotype 3  Steatosis correlated with intrahepatic viral replication  Eradication of HCV improves steatosis Host Factors:  Steatosis associated with obesity and insulin resistance  Associated with decreased response to IFN Other Factors:  Alcohol  Medications Steatosis > 50% of all HCV patients Negro F. Hepatology. 2002;36:1050-1052. Adinolfi L, et al. Hepatology. 2001;33:1358-1364.
  56. 56. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Decreased Response to Therapy in Obese CHC Patients with Coexistent Steatosis Harrison SA, et al. Hepatology. 2003;38(Suppl 1):626A. Overall Genotype 1 Genotype 2/3 0 10 20 30 40 50 60 70 80 90 SVR(%) HCV + > 33% steatosis HCV + < 33% steatosis P = .01 P = .19 P = .008 n = 39 n = 8 n = 15 n = 59 n = 101 n = 24
  57. 57. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Hyperinsulinemia Diminishes Antiviral Capacity of Interferon Impact of insulin level on interferon antiviral activity examined in HCV replicon system:  Interferon resulted in a rapid, sharp, stable decrease in HCV RNA  Interferon induced PKR and IRF-1 protein expression  Insulin prevented IFN-mediated HCV suppression: – Blocked the effects of key intra-hepatic proteins Sanyal AJ, et al. AASLD 2004. Abstract 39.
  58. 58. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Body Weight and HCV  BMI and steatosis are independent predictors of fibrosis progression  Weight loss may improve HCV disease progression in obese, steatotic individuals.  IFN response decreases with high body weight and is not necessarily overcome with higher IFN doses
  59. 59. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Drugs and Alcohol
  60. 60. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Drug Use and HCV  Methadone or buprenorphine use does not decrease interferon responsiveness  Continued IDU is a concern in treatment candidates: – Greater rate of depression – Risk of noncompliance – Should be an individualized decision Strader DB, et al. Hepatology. 2004;39:1147-1171.
  61. 61. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Alcohol and HCV  Increases the fibrosis progression rate  Increases HCV mortality rate  Threshold amount of alcohol necessary is unknown, but probably around 30-50 g/day  Alcohol may interfere with interferon responsiveness Poynard T, et al. Lancet. 1997;349:825-832. Oshnishi K, et al. Am J Gastroenterol. 1996;91:1374-1379. Sawada M, et al. Alcohol Alcohol Suppl. 1993;1B:85-90. Degos F. J Hepatol 1999;31 Suppl 1:113-118.
  62. 62. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Treatment of HCV in Methadone- Maintained Patients  71 patients on methadone treated with IFN + RBV  SVR rate higher in the 68% of patients who were adherent – 42% in adherent patients – 4% in nonadherent patients  Adherence in occasional drug users similar to abstinent patients  Predictors of nonadherence – Relapse to regular drug use (P = .03) – Preexisting psychiatric diagnosis (P = .04) Sylvestre DL, et al. Eur J Gastroenterol Hepatol. 2007;19:741-747.
  63. 63. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Impact of IV Drug Use on HCV Therapy: Swiss Hepatitis C Cohort Study Bruggmann P, et al. J Viral Hepat. 2008;15:747-752. 19/38 SVR(%) SVR (80:80:80) SVR (Overall) 0 20 60 100 60 65 80 40 69 76 Controls IVDUs  500 patients treated, most with pegIFN and RBV – 199 active IV drug users (30% GT1, 62% GT3) – 301 controls (47% GT1, 29% GT3)  IVDUs equally adherent vs controls – 66% vs 60% received ≥ 80% cumulative drug dose – 87% vs 86% received ≥ 80% treatment duration  Overall SVR: 63%
  64. 64. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Active Injection Drug Users: Summary of Recommendations  Treatment of HCV infection can be considered in persons who currently use illicit drugs or who are in a methadone maintenance program – Must be willing to undergo therapy and maintain close monitoring – Benefit must be judged to outweigh risks  Persons who use illicit drugs should receive continued support from drug abuse and psychiatric counseling services as an important adjunct to treatment Ghany MG, et al. Hepatology. 2009;49:1335-1374.
  65. 65. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update HCV in Psychiatric Patients
  66. 66. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update SVR and Dropout Rates Similar Between Psychiatric Patients and Controls  70 HCV-infected patients prospectively evaluated for response to HCV therapy based on presence of psychiatric disease or drug addiction – PegIFN alfa-2b + RBV administered for 24 wks (GT 2/3) or 48 wks (GT 1/4) Schaefer M, et al. Hepatology. 2007; 46:991-998. 0 20 40 60 80 100 SVR Dropout Psychiatric (n = 22) Methadone (n = 18) Former drug abuse (n = 13) Control (n = 17) 50 72 54 59 9 28 15 6 Patients(%)
  67. 67. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Approach to Managing Psychiatric Issues During HCV Treatment  Education, monitoring, and support – Information and psychoeducation before and during treatment – Monitoring of patients and past/current psychiatric issues – Assessment of current or previous substance abuse – Supportive psychotherapy and counseling – Management of sleep disturbances  Pharmaceutical strategies – Antidepressant treatment – Other treatments: antipsychotics, benzodiazepines (mood stabilizers, amphetamines, naltrexone, tryptophan, etc) – Antiviral therapy dose reduction, discontinuation if needed Schaefer M, et al. Curr Drug Abuse Rev. 2008;1:177-187.
  68. 68. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Patients With Psychiatric Illness: Summary of Recommendations  Patients with HCV infection and controlled mental and psychiatric disorders can be considered for treatment using currently approved regimens – Only with support of multidisciplinary team that should include psychiatric counseling services Ghany MG, et al. Hepatology. 2009;49:1335-1374.
  69. 69. Management of Other High-Risk Patients
  70. 70. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Seizure Disorders  Interferon may be associated with decreased seizure threshold leading to potential increased risk – Risk ~ 1 in 13,000 persons (no seizure history)  Uncontrolled seizure is absolute contraindication  Stable, controlled seizure disorder or remote seizure history may be considered for HCV treatment  Neurologic evaluation pretreatment may be indicated Shakil AO, et al. J Hepatology. 1996;24:48-51.
  71. 71. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Management of Hepatitis C in Patients With Coronary Artery Disease  Direct cardiac toxicity with interferon/ribavirin rare – Rare cases of cardiomyopathy  Ribavirin associated hemolytic anemia is primary concern – May precipitate cardiac ischemia  Assess cardiac risk in all persons prior to HCV treatment – Smoking, DM, HTN, family history, prior cardiac event – In persons at risk, consider exercise or pharmacologic stress test prior to treatment McHutchison JG, et al. Liver Int. 2006;26:389-398.
  72. 72. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Management of Hepatitis C in Patients With Coronary Artery Disease (cont’d)  Monitor hemoglobin closely in persons at increased risk for cardiac ischemia  Follow ribavirin dose reduction guidelines for this group  Consider hematopoietic growth factors to prevent severe anemia – Epoetin alfa 40,000 IU SC weekly – Darbepoetin alfa 200 µg SC every other week – Use before therapy?  Monotherapy is an option McHutchison JG, et al. Liver Int. 2006;26:389-398.
  73. 73. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update HCV and Hemophilia  HCV common among those receiving human-derived blood products before 1987  Increasing rates of liver disease among older men with bleeding disorders  Role of biopsy is controversial due to need for aggressive management peri-procedure – Biopsy can be performed safely – Noninvasive markers may be useful  HCV treatment is NOT contraindicated – No increased bleeding risk observed in trials 22 43 57 0 20 40 60 80 100 IFN IFN + RBV PegIFN + RBV Patients(%) SVR Rates Among HCV-Infected Hemophiliacs Posthouwer D, et al. Haemophilia. 2006;12:473-478. Maor Y, et al. Haemophilia. 2006;12:372-379. Manns MP, et al. Lancet. 2001;358:958-965. Fried MW, et al. N Engl J Med. 2002;347:975-982.
  74. 74. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Managements of Thalassemias and Hemoglobinopathies Thalassemia major/minor Sickle cell anemia RBV-associated hemolysis may increase blood transfusion requirements Management in HCV Limited data from case series suggest HCV treatment may be effective Key data Management in HCV Limited data from case series suggest HCV treatment may be effectiveKey data Avoid precipitation of crisis Butensky E, et al. Ann N Y Acad Sci. 2005;1054:290-299. Inati A, et al. Br J Haematol. 2005;130:644-646. Li CK, et al. Br J Haematol. 2002;117:755-758. Hassan M, et al. J Natl Med Assoc. 2003;95:872-874.
  75. 75. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Autoimmune Disease  Interferon may exacerbate underlying autoimmunity – Limited data on safety  Autoimmune hepatitis is a contraindication to interferon – However, patients who are ANA positive but do not fit the “typical” profile may have a positive ANA through complex HCV-immune interaction  Patients with RA, SLE or other conditions may be considered on a case-by-case basis only if disease is well controlled  Patients with sarcoid should not be treated due to risk of flare Yee HS, et al. Am J Gastroenterol. 2006;101:2360-2378.
  76. 76. Managing Difficult-to-Treat Patients at Low Risk for Complications
  77. 77. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Managing Older Patients With Hepatitis C Management considerations for HCV patients older than 70 yrs of age Consider treatment on a case-by-case basis Watch for excessive RBV-associated hemolysis Medical comorbidities Liver disease HCV genotype RBV is cleared by the kidneys and age-related reduction in CrCl leads to its accumulation Estimate GFR and consider lower dose RBV
  78. 78. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Management of HCV Infection in Blacks  Lower SVR rates not explained by differences in HCV genotype, viral load, liver disease, body weight, or adherence  Multiple studies under way to analyze the genetics of interferon responsiveness in this patient group  Although SVR rates are relatively low, individual patients may respond – Treat all black patients in whom the potential benefits of therapy outweigh the risks – Week 12 EVR rule applies: stop therapy if ≥ 2 log10 reduction in HCV RNA is not achieved
  79. 79. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Reduced Response Rates in Blacks vs Whites Black White 50 75 ETR SVR 20 58 19 52 VirologicResponse(%) 30 52 26 39 ETR SVR PegIFN Alfa-2a + RBV[2]PegIFN Alfa-2b + RBV[1] 1. Muir AJ, et al. N Engl J Med. 2004;350:2265-2271. 2. Jeffers L, et al. Hepatology. 2004;39:1702-1708. 25 0 50 75 25 0 VirologicResponse(%)
  80. 80. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Reduced Response Rates in Blacks vs Whites (cont’d) 46 40 28 13 32 74 70 52 6 25 0 20 40 60 80 100 Week 24 Week 48 SVR Virologic Breakthrough Relapse Black (n = 196) White (n = 205) Outcomes in Genotype 1 Patients Receiving Peginterferon alfa-2a + Ribavirin for up to 48 Weeks Patients(%) P < .0001 P < .0001 P < .0001 P < .05 P = NS Conjeevaram HS, et al. 2006;131:470-477.
  81. 81. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Management of Preexisting Neutropenia Key Data and Controversies HCV Management Strategies in Patients With Neutropenia  Typically seen in blacks and cirrhotics  Typically excluded from therapy – How low is too low?  Intratherapy declines expected – How low is too low? – Relative drop vs percentage drop – Is there a higher risk of infection?  Value of pretreatment GCSF not studied  Close attention to white blood cell counts/ANCs  Report any signs of infection/injury immediately  Judicious use of antibiotics  Use of GCSF  Discontinuation of therapy if SAE occurs such as pneumonia, urosepsis, or if hospitalization is required
  82. 82. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Management of HCV in Patients With Obesity Key Data HCV Management Strategies in Obese Patients  Epidemic in the US, common among persons with HCV infection  High BMI > 30 is associated with lower SVR rates  Insight into causes – Obesity is an active inflammatory state – Insulin resistance – Presence of steatosis – Increased fibrosis  Fixed dosing vs weight-based dosing – Can more interferon overcome impact of higher BMI?  Weight loss program BEFORE hepatitis C treatment – Diet, exercise, surgery  Insulin-sensitizing agents have been studied but remain experimental Bressler BL, et al. Hepatology. 2003;38:639-644. Brown RS Jr, et al. EASL 2006. Abstract 41. Hadziyannis SJ, et al. Ann Intern Med. 2004;140:346-355. Sanyal AJ, et al. Clin Gastroenterol Hepatol. 2004;2:1107-1115.
  83. 83. Impact of Treatment on Natural History of Hepatitis C
  84. 84. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Improvement in Fibrosis at Week 72 Following Start of HCV Therapy PatientsWithImprovementin Fibrosis≥1Stage(%) MeanFibrosisChange (MetavirStage) Everson GT, et al. Aliment Pharm Ther. 2008;27:542-551. Varied With Response to Treatment -1.2 -1.0 -0.8 -0.6 -0.4 -0.2 0 SVR Relapse NR 0 10 20 30 40 50 60 SVR Relapse NR 70 80 90 100
  85. 85. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update At risk 337 261 192 160 124 95 79 49 31 Events 0 5 11 16 20 24 25 28 30 At risk 142 76 48 35 25 14 8 6 5 Events 0 0 0 0 0 1 1 1 1 At risk 337 256 183 155 121 92 74 44 27 Events 0 8 21 24 27 29 31 35 35 At risk 142 76 48 35 25 14 8 6 5 Events 0 0 0 0 0 1 1 1 1 Posttreatment Outcomes in Patients With Advanced Fibrosis With/Without SVR Liver FailureLiver-Related Death Liver-RelatedDeath(%) Year 50 5-yr occurrence SVR: 4.4% (CI: 0% to 12.9%) No SVR: 12.9% (CI: 7.7% to 18.0%) P = .024 (log likelihood) Year 5-yr occurrence SVR: 0% No SVR: 13.3% (CI: 8.4% to 18.2%) P = .001 (log likelihood) 0 81 2 3 4 5 6 7 LiverFailure(%) 50 40 30 20 10 0 0 1 2 3 4 5 6 7 8 No SVR SVR 40 30 20 10 0 Veldt BJ, et al. Ann Intern Med. 2007;147:677-684. Reproduced with permission.
  86. 86. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Incidence of HCC in Patients With Advanced Fibrosis With/Without SVR SVRNo SVR At risk 337 259 188 153 117 90 71 43 30 Events 0 5 8 13 18 22 27 29 30 SVR At risk 142 76 48 35 24 14 8 6 5 Events 0 0 1 1 3 3 3 3 3 No SVR SVR Years 100 HCC(%) 80 60 40 20 0 80 1 2 3 4 5 6 7 5-yr occurrence SVR: 9.2% (95% CI: 0.0% to 19.6%) No SVR: 13.1% (95% CI: 7.6% to 18.6%) P = .192 (log likelihood) Veldt BJ, et al. Ann Intern Med. 2007;147:677-684. Reproduced with permission.
  87. 87. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Progression of HCV Liver Disease: Summary  Chronic HCV infection leads to cirrhosis and liver failure in a large number of persons – Clinical complications of advanced liver disease include portal hypertension, ascites, variceal bleeding, and HCC  Rates of progression dependent on modifiable and nonmodifiable factors  Effective treatment of chronic HCV infection can prevent fibrosis progression and reduce complications of HCV – Treatment outcomes impacted by baseline fibrosis and cirrhosis
  88. 88. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Conclusion  HCV infection is common among persons with comorbid medical and psychiatric conditions  Successful treatment is possible – Requires a team oriented approach – Experienced clinician in the management of chronic hepatitis C  Many other individuals could benefit from treatment – HIV, HBV – Cirrhosis, cryoglobulinemia – Prior relapsers and nonresponders
  89. 89. clinicaloptions.com/hepatitis AASLD Practice Guidelines: An Update Questions

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