Introduction - PowerPoint PPT Presentation

introduction n.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
Introduction PowerPoint Presentation
Download Presentation
Introduction

play fullscreen
1 / 95
Introduction
109 Views
Download Presentation
sanjiv
Download Presentation

Introduction

- - - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript

  1. Introduction Eugene R. Schiff, MD Chief, Division of Hepatology Director, Center for Liver Diseases University of Miami School of Medicine Miami, Florida

  2. Change… It’s Inevitable • Anticipate • Monitor • Adapt • Move • Be ready to do it again Johnson, S. Who Moved My Cheese? New York: G. P. Putnam’s Sons, 1998.

  3. The Handwriting on the WallThe Increasing Challenge of HCV Disease Burden HCV-related cirrhosis Hepatocellular carcinoma (HCC) End-stage liver disease

  4. Reality CheckAssessing the Present to Anticipate the Future • Parameters for success • Virologic • Histologic • Speed of response • Weeks, months • PEG IFN / RBV Future Present • Parameters for success • Sustained viral response • Speed of response • Days? • Synergistic combination of old and new? • PEG IFN / RBV plus STAT-C • Synergistic combination of STAT-Cs

  5. Finding Our Way in the MazeChanging Direction Toward More Effective Treatment Think more like virologists than hepatologists or gastroenterologists

  6. Let’s Talk What Are the Key Questions for the Future?

  7. The Handwriting on the Wall:The Increasing Challenge of HCV Disease Burden Hashem B. El-Serag, MD, MPHAssociate Professor of MedicineDepartment of MedicineMichael E. DeBakey VA Medical Center and Baylor College of MedicineHouston, Texas

  8. Age-Adjusted Incidence Rates for Hepatocellular Carcinoma (HCC) 3.5 3.3 3.1 3 2.7 2.5 2.3 2.0 2 1.8 Age-Adjusted Incidence Rate per 100,000 Person Years 1.6 1.4 1.4 1.5 1 0.5 0 76–78 79–81 82–84 85–87 88–90 91–93 94–96 97–99 2000–02 Year Analysis of SEER data, courtesy of Dr. H.B. El-Serag.

  9. Liver Cancer Has the Fastest Growing Death Rate in the United States Trends in US Cancer Mortality Rates All Other Cancers (Average) Corpus & Uterus, NOS Testis Lung & Bronchus (Female) Esophagus Thyroid Liver - 2 - 1 . 5 - 1 - 0 . 5 0 0 . 5 1 1 . 5 2 Annual Percent Change (1994–2003) National Cancer Institute. Seer Summary Figures and Tables. Available at: http://seer.cancer.gov/csr/1975_2003/results_merged/topic_graph_trends.pdf. Accessed on April 17, 2007.

  10. 9 8 7 6 5 4 3 2 1 0 Racial Incidence Rates for HCCIn the United States White Black Other (Asian) 8.4 8 7.9 7.2 7.2 6.6 6.3 6 5.2 5 Age-Adjusted Incidence Rate per 100,000 Person Years 4.6 3.9 3.7 3.4 2.9 2.6 2.5 2.5 2.5 2.3 1.9 1.7 1.4 1.3 1.1 1.1 1 76–78 79–81 82–84 85–87 88–90 91–93 94–96 97–99 2000–02 Year Analysis of SEER data, courtesy of Dr. H.B. El-Serag.

  11. 20 18 16 14 12 10 8 6 4 2 0 Temporal Trends in the Age Distribution of HCC 1982–84 1991–93 2000–02 Incidence Rate per 100,000 Patient Years 20–24 30–34 40–44 50–54 60–64 70–74 80–84 25–29 35–39 45–49 55–59 65–69 75–79 85+ Age (years) Analysis of SEER data, courtesy of Dr. H.B. El-Serag.

  12. HCV Cirrhosis and HCC Multiple smallfoci of HCC Graphic courtesy of Dr. H.B. El-Serag.

  13. Outlook for Thosewith Compensated Cirrhosis Study A1 Study B2 Study C3 Number 384 112 103 Follow-up (y) 5.0 4.5 3.3 Decompensation (%/y) 3.9 4.4 5.0 HCC (%/y) 1.4 2.3 3.3 5-year survival (%) 91 83 84 (at 4 y) 1. Fattovich G, et al. Gastroenterology. 1997;112:463. 2. Hu K, et al. Hepatology. 1999;29:1311. 3. Serfaty L, et al. Hepatology. 1998;27:1435.

  14. Clinical Complications and Mortality Developing in HCV Patients with Compensated Cirrhosis 214 HCV RNA-seropositive patients with Child-Pugh class A cirrhosis, no evidence of HCC at enrollment, and no history of previous clinical decompensation followed for 114 months Complication % Developing Ascites 23 Jaundice 17 Upper GI Bleeding 6 Encephalopathy 1 HCC 32 Death 35 Sangiovanni A, et al. Hepatology. 2006;43:1303.

  15. Risk Factors for HCC • Cirrhosis from any cause • HCV1,2 • HBV1,2 • Heavy alcohol consumption1,2 • Nonalcoholic fatty liver disease1 • HBV1,2 • Inherited metabolic diseases • Hemochromatosis1–3 • Alpha-1 antitrypsin deficiency3 • Glycogen storage disease4 • Porphyria cutanea tarda3 • Tyrosinemia3 • Autoimmune hepatitis2 1. Dorfman JD, et al. World J Gastroenterol. 2007;13:781. 2. El-Serag H, et al. Arch Intern Med. 2000;160:3227. 3. Montalto G, et al. Ann N Y Acad Sci. 2002;963:13. 4. Franco LM, et al. J Inherit Metab Dis. 2005;28:153.

  16. Risk Factors for HCC Among US Veterans 120 N = 823 cases with HCC N = 3459 controls 100 80 79 Adjusted Odds Ratio (95% CI) 60 40 20 19 17 15 9 0 HBV HCV ALD HCV + ALD HCV + HBV ALD = alcoholic liver disease El-Serag HB, et al. Am J Gastroenterol. 2001;96:2462. Graphic courtesy of Dr. H.B. El-Serag.

  17. Only HCV-related HCC Increased Among Veterans Between 1993 and 1998 • VA hospitals • HCV-related HCC accounted for 50% of increase • Overall, only one third of cases were HCV-related 20 15 Age-Adjusted Hospitalization Rate/100,000 10 5 * 0 1993–95 1996–98 Years ALD HBV Idiopathic HCV ALD = alcoholic liver disease El-Serag HB, et al. Arch Intern Med. 2000;160:3227. Graphic courtesy of Dr. H.B. El-Serag.

  18. Proportion of US-Born Patients with HCC Related to Viral Hepatitis 1993–95 (n = 143) 1996–98 (n = 216) 60 P = .5 50 40 P = .06 P = .01 Percent 30 20 10 0 HCV HBV None Viral Markers Reprinted from Hassan MM, et al. J Clin Gastroenterol. 2002;35:266, with permission.

  19. Viral Hepatitis in HCC in the United States1,2 47% 33% HCV Both HBV Neither (N = 691) 15% 5% • HBV most frequent in Asians • HCV most frequent in whites and blacks 1. Reprinted from El-Serag HB, et al. Gastroenterology. 2004;127:S27, with permission from Elsevier.2. Di Bisceglie AM, et al. Am J Gastroenterol. 2003;98:2060.

  20. Rate of Chronic HCV Infection in the United States Highest Among Young African-American Adults 7 African-American 6 5 Hispanic 4 Anti-HCV Positive (%) 3 2 Caucasian 1 0 6–11 12–19 20–29 30–39 40–49 50–59 60–69 ≥70 Age Group (y) CDC. MMWR. 1998;47:1-39.

  21. 1% (1%–3%/y) 15% (10%–30%/y) 25 years 90% (60%–95%/y) 100% HCV to HCC Pyramid HCC Cirrhosis Chronic Hepatitis HCV Infection Graphic courtesy of Dr. H.B. El-Serag.

  22. Efficacy of IFN +/- Ribavirin in Preventing HCV-HCC • Meta-analysis of 20 controlled trials (3 randomized controlled) • 4659 patients with HCV-cirrhosis • Decreased incidence of HCC in treated patients • 19/20 studies, significant difference in 13 studies • Pooled estimate of treatment effect • Risk difference: -12.2% (CI -8.4% to -16.1%, P < .00001) • Pooled risk difference for sustained biochemical responders: -19.1% (CI -13.1% to -25.2%, P < .00001) Craxi A, et al. Clin Liver Dis. 2005;9:329.

  23. HCC After IFN Therapy for HCV 30 25 20 No Response Cumulative Incidence of HCC (%) 15 10 Relapse 5 Sustained Response 0 0 1 2 3 4 5 6 7 Follow-up (y) Imai Y, et al. Ann Intern Med. 1998;129:94. Reprinted with permission.

  24. Efficacy of Peginterferon + Ribavirin in Achieving SVR 1. Manns M, et al. Lancet. 2001;358:958. 2. Fried M, et al. N Engl J Med. 2002;347:975. 3. Conjeevaram H, et al. Gastroenterology. 2006;131:470.

  25. Prevention and Treatment of HCC Community Effectiveness = Efficacy x Access x Correct Diagnosis x Recommendation x Acceptance x Adherence Clinical Trials Clinical Practice Reprinted from El-Serag HB. Gastroenterology. 2007;132:8, with permission from Elsevier.

  26. Efficacy and EffectivenessA Demonstration of the Multiplicative Effect of Factors Reprinted from El-Serag HB. Gastroenterology. 2007;132:8, with permission from Elsevier.

  27. Estimated Chronic HCV Patient Status in the US Veteran Population n = 52 Seropositive withno prior testing (14%) Seropositive and prior testing (86%) Unaware of diagnosis (46%) Aware of diagnosis (54%) Dominitz JA, et al. Hepatology. 2005;41:88.

  28. Eligibility and Acceptability of Anti-HCV Treatment • 4084 HCV+ patients in VA multi-center study 12/99–12/00 • Eligibility: 32% by standard criteria, 41% by treating physician • Predictors of noneligibility • Ongoing substance abuse OR 17.68 • Co-morbid medical disease OR 9.62 • Psychiatric disease OR 9.45 • Advanced liver disease OR 8.43 • Acceptability: 76% of eligible patients • Reasons for nonacceptance • Defer Rx until better therapies 50% • Concerns regarding side effects 22% • Treatment completion rates • ~50% (~8% of all patients) Bini E, et al. Am J Gastroenterol. 2005;100:1772.

  29. Prevention and Treatment of HCC Community Effectiveness = Efficacy x Access x Correct Diagnosis x Recommendation x Acceptance x Adherence Clinical Trials Clinical Practice Reprinted from El-Serag HB. Gastroenterology. 2007;132:8, with permission from Elsevier.

  30. HCC in the United StatesThe Handwriting on the Wall • A 2-fold increase in incidence during the past 2 decades • The greatest increase seen in • The latter half of the 1990s • White men between ages 45 and 65 • HCV is likely responsible for a large part of the increase • Current therapy is unlikely to reduce HCC incidence appreciably

  31. Reality Check:Assessing the Present to Anticipate the Future Nezam H. Afdhal, MDChief of HepatologyDirector, Liver CenterBeth Israel Deaconess Medical CenterBoston, Massachusetts

  32. Milestones in Anti-HCV Therapy 100 2002 1986 1998 2001 80 54–56 60 SVR (%) 42 39 34 40 16 20 6 0 IFN 6 mo IFN 12 mo IFN/RBV 6 mo IFN/RBV 12 mo PEG IFN 12 mo PEG IFN/RBV 12 mo Strader DB, et al. Hepatology. 2004;39:1147. Reprinted with permission ofWiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc.

  33. Interferon- Signal Transduction STAT 1/2 IFN IFN-stimulated genes Viral replication PKR 2′5′OAS STAT = Signal transducer and activator of transcription; PKR = RNA-dependent protein kinase; 2′5′ OAS = 2′5′-oligoadenylate synthetase. Katze MG, et al. Nature. 2002;2:675. Graphic courtesy of Dr. N. H. Afdhal.

  34. Constellation of Factors Affecting Anti-HCV Therapy ALT Extrahepatic features Family support • Genotype • Viral load • Race • Age • Fibrosis • Body weight • HIV coinfection Patient mind-set Duration of infection Cost Occupation Lifestyle issues Personal plans(marriage, pregnancy) Contraindications Inflammation on biopsy Graphic courtesy of Dr. I. Jacobson.

  35. Tailoring the Duration of Anti-HCV Therapy to the Individual Patient • New emphasis on rapidity of viral clearance as a key determinant of duration of therapy • Baseline viral load important in some patient groups

  36. Early Virologic Response (EVR)The Negative Predictor* EVR achieved† (HCV RNA negative or ≥ 2-log decrease at wk 12; n = 380/511) HCV RNA negative n = 308 (81%) HCV RNA positive n = 72 (19%) HCV neg at wk 24 n = 43 HCV pos at wk 24 n = 24 SVR n = 258 (84%) SVR n = 14 (33%) SVR n = 1 (4%) *Negative predictive value = 100%;positive predictive value = 72%. †PEG IFN -2b 1.5 µg/kg QW + RBV 800 mg/d Davis GL, et al. Hepatology. 2003;38:645.

  37. Rapid Virologic Response (RVR)The Positive Predictor* 100 91 PEG IFN -2a 180 mg + RBV 1000–1200 mg 80 72 60 60 48 Patients with SVR (%) 43 40 20 0 HCV RNA Status Week 4 Negative ≥2 log  <2 log ≥2 log  <2 log  Week 12 Negative Negative Negative ≥2 log ≥2 log  Week 24 Negative Negative Negative Negative Negative *Negative predictive value = 74%; positive predictive value = 75%. Ferenci P, et al. JHepatol. 2005;43:425, with permission from Elsevier.

  38. Critical ConceptRVR, SVR, and Relapse Less relapse Fast response More relapse Slow response What are the implications of this for duration of therapy? New studies provide some answers…

  39. RNA (+) week 4, genotype 3, high viral load Rapid response RNA (-) at week 4 Standard duration:24 weeks 12–16 weeks ≥24 weeks Tailoring the Duration of TherapyGenotypes 2 and 3 Genotypes 2, 3 HVL = high viral load. Graphic courtesy of Dr. N. H. Afdhal.

  40. Slow response: RNA (+) at week 12 RNA (-) at week 24 Standard duration: 12 months Low viral load (<600,000 IU/mL) Rapid response: RNA (-) at week 4 72 weeks? 24 weeks? Tailoring the Duration of TherapyHCV Genotype 1 Genotype 1 Graphic courtesy of Dr. N. H. Afdhal.

  41. Should Late Responders with Genotype 1 Be Treated Longer? 8 late responders PCR positive at wk 12 PCR negative at wk 24 72 wk treatmentPEG IFN 1.0 µg/kg QW/RBV 800 mg/d 7 sustained responders Buti M, et al. Hepatology. 2003;37:1226.

  42. 48 vs 72 Weeks of PEG IFN/RBV ~90% Genotype 1 Patients with detectable HCV RNA at week 4 P = .014 100 ETR SVR 80 61 60 52 % HCV RNA Negative 48% Relapse 13% Relapse 45 40 32 20 n=165 n=162 0 48 Weeks 72 Weeks PEG IFN -2a 180g/wk + RBV 800 mg/d ETR = end of treatment response. Sanchez-Tapias JM, et al. Hepatology. 2004;40:218A. Reprinted with permission ofWiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc.

  43. Prolonging Therapy May Decrease Relapse in Late Responders • N = 456, genotype 1 • PEG IFN -2a + RBV 800 mg/d 48 vs 72 wk • No effect on overall rate of SVR 81% 44% % Relapse Week 12 (+) 48 wk Week 12 (+) 72 wk Duration of Therapy (+) = HCV RNA positive. Berg T, et al. Hepatology. 2004;40:238A. Abstract 169.

  44. Rapidity of ResponseConclusions • Rapidity of viral clearance is a major predictor of relapse and sustained response • Implication that rapid responders have more rapid clearance of intracellular HCV • Rapidity of viral response can drive duration of therapy in several major patient groups • Rapidity of response should be critically evaluated as new therapies are developed

  45. PEG IFN/RBV in Genotype 1 African American and Caucasian American PatientsVirahep-C Study 100 PEG IFN -2a 180 µg QW + RBV 1000–1200 mg/d 80 52% 60 P < .0001 SVR (%) 40 28% 20 N=205 N=196 0 Caucasian American(n = 205) African American(n = 196) Conjeevaram H, et al. Gastroenterology. 2006;131:470.

  46. Racial Differences in Relapse and Breakthrough Virahep-C Study Conjeevaram H, et al. Gastroenterology. 2006;131:470.

  47. SVR Rates Across Individual Fibrosis StagesWIN-R Trial 4913 Patients Treated with PEG IFN (-2b 1.5 g/kg/d) + WBD (800–1400 mg/d) or FD (800 mg/d) RBV P < .0001 vs F4 P < .0005 vs F4 60 50 46% 44% 44% 44% 40 34% SVR (%) 30 20 n = 654 n = 1460 n = 1324 n = 975 n = 500 10 0 F0 F1 F2 F3 F4 Metavir Score WBD = weight-based dose; FD = fixed dose. Afdhal N, et al. DDW 2006. May 20-25, 2006. Abstract 655. Graphic courtesy of Dr. N. H. Afdhal.

  48. Propensity ScoreWIN-R Trial Caucasian female, age 22, F1 HCV-2 Fixed dosing Weight-based dosing 0.6 African-American male age 50, F3 HCV-1 0.4 SVR% 0.2 0 -2 -1.5 -1 -0.5 0 0.5 1 Propensity Score Jacobson WIN-R data abstract. Courtesy of Dr. I. Jacobson.

  49. Clinical Trials of PEG IFN + RBV in HIV/HCV Coinfection • APRICOT1 (n = 895) • 3 arms: IFN -2a/RBV vs PEG -2a vs PEG -2a/RBV for 48 wk • RBV 800/d • A50712 (n = 133) • 2 arms: IFN -2a/RBV vs PEG -2a/RBV for 48 wk • Escalating dose RBV • RIBAVIC3 (n = 412) • 2 arms: IFN -2b/RBV vs PEG -2b/RBV for 48 wk • RBV 800 g/d • > 30% F3 or F4, high rate of discontinuation • Barcelona4 (n = 95) • 2 arms: IFN -2a/RBV vs PEG IFN -2a/RBV for 24 or 48 wk • RBV 800–1200 g/d • Nongenotype 1 treated for 24 wk • 30% F3 or F4 1. Torriani FJ, et al. New Engl J Med. 2004;351:438. 2. Chung RT, et al. New Engl J Med. 2004;351:451. 3. Carrat F, et al. JAMA. 2004;292:2839. 4. Laguno M, et al. AIDS. 2004;18:F27.

  50. Response Rates with PEG IFN/RBV in HIV/HCV Coinfection 80 APRICOT1 70 73 A50712 60 RIBAVIC3 62 Barcelona4 50 53 Percent 40 44 38 30 29 20 17 10 14 0 Genotype 1 or 4 Nongenotype 1 1. Torriani FJ, et al. New Engl J Med. 2004;351:438. 2. Chung RT, et al. New Engl J Med. 2004;351:451. 3. Carrat F, et al. JAMA. 2004;292:2839. 4. Laguno M, et al. AIDS. 2004;18:F27. Graphic courtesy of Dr. N. H. Afdhal.