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Treatment of Hepatitis B

Treating hepatitis B and C (in South Africa ) Dr Mark Sonderup Division of Hepatology and Department of Medicine University of Cape Town & Groote Schuur Hospital . Treatment of Hepatitis B. Evolution of HBV Therapy. Peginterferon alfa-2a. Entecavir. Tenofovir. Lamivudine.

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Treatment of Hepatitis B

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  1. Treating hepatitis B and C (in South Africa )Dr Mark Sonderup Division of Hepatology and Department of Medicine University of Cape Town & Groote Schuur Hospital

  2. Treatment of Hepatitis B

  3. Evolution of HBV Therapy Peginterferon alfa-2a Entecavir Tenofovir Lamivudine 1990 2006 1998 2002 2005 2008 Telbivudine Adefovir Interferon alfa-2b

  4. 4 Phases of Chronic HBV Infection Current Understanding of HBV Infection HBeAg Anti-HBeAg ALT activity HBV DNA Optimal treatment times Yim HJ, et al. Hepatology. 2006;43:S173-S181.

  5. REVEAL Study: Risk of HCC and Cirrhosis according to baseline HBV viral load HBV DNA, copies/mL HBV DNA, copies/mL 1.4 3.0 < 300300-999910,000-99,999100,000-999,999≥ 1 million < 300300-999910,000-99,999100,000-999,999≥ 1 million 1.2 2.5 1.0 2.0 0.8 Cirrhosis (% per Yr)[2] HCC (% per Yr)[1] 1.5 0.6 1.0 0.4 0.5 0.2 0 0 85 % HBeAgneg 1. Chen CJ, et al. JAMA. 2006;295:65-73. 2. Iloeje UH, et al. Gastroenterology. 2006;130:678-686.

  6. HCC Incidence in TDF Studies Lower Than Predicted by REACH-B Risk Model • Analysis of actual HCC incidence vs REACH-B predictions in 152 cirrhotic, 482 noncirrhoticpts treated with TDF for 8 yrs in studies 102 (HBeAg-) and 103 (HBeAg+) • Noncirrhotics: 8 observed cases vs 18 predicted over 7 yrs • Significant difference from Wk 240: 55% reduction in HCC • Cirrhotics: observed cases matched prediction over first 4 yrs; no observed cases in last 3 yrs • Combined analysis: 50% lower HCC incidence at Yr 7 Combined Analysis (Noncirrhotic and Cirrhotic) 30 PredictedObserved 25 20 15 Cumulative HCC Cases (n) SIR = 0.50*(95% CI: 0.294-0.837) 10 1st significantdifference 5 0 0 240 336 192 288 48 144 96 Wk *Statistically significant. Kim WR, et al. EASL 2013. Abstract 43.

  7. Treatment Criteria for Chronic Hepatitis BHBeAg pos and HBeAgneg Disease *Although ALT and HBV DNA are primary tests used to determine treatment candidacy, the levels of elevation that warrant consideration of treatment are not universally agreed upon. †Laboratory normal. ‡30 U/L for men and 19 U/L for women. **In patients older than 40 yrs of age, 2000 IU/mL should be considered as a cutoff for treatment. 1. EASL. J Hepatol. 2009;50:227-242. 2. Liaw YF, et al. Hepatol Int. 2008;3:263-283. 3. Lok ASF, McMahon BJ. Hepatology. 2009;50:661-662. Recommended HBV DNA and ALT levels ± Liver Biopsy

  8. NIH Guidelines: Indications for HBV Treatment Adapted from Sorrell MF, et al. Ann Intern Med. 2009;150:104-110.

  9. NIH Guidelines: Indications for HBV Treatment • Patients for Whom Therapy May Be Indicated • Active liver disease without advanced fibrosis or cirrhosis • - HBeAg pos or HBeAgneg chronic hepatitis B • Patients for Whom Immediate Therapy Is Not Routinely Indicated • Immune-tolerant phase (HBeAg pos, high serum HBV DNA levels, normal ALT or little activity on liver biopsy) • Inactive carrier or immune control phase (HBeAgneg, low or undetectable levels of serum HBV DNA, and persistently normal ALT) • Occult HBV infection (serum HBV DNA pos, IgG core pos, HBsAgneg) Adapted from Sorrell MF, et al. Ann Intern Med. 2009;150:104-110.

  10. Two Treatment strategies for CHB Interferon-based therapy • Dual Antiviral and immunomodulatory activity • Finite course of treatment • Aim for sustained off-treatment immune control ( HBsAg +, HBeAg - ) through dual mode of action Nucleos(t)ide analogue therapy • Antiviral activity • Long-term (potentially indefinite) treatment • Aim for on-treatmentviral suppression ( HBV DNA -) • Maintained through continuous antiviraltherapy • Suppression of replication to undetectable levels to avoid resistance

  11. HBeAg Positive Disease • End-points of treatment • Ideal end-point sAg loss  sAb • Durable eAg loss and seroconversion • Durable suppression of HBV DNA to low or undetectable

  12. HBeAg loss and seroconversion in HBeAg+ Patients after 1 Yr of Treatment -Not head-to-head trials; different patient populations and trial designs head trials; different patient populations and trial designs HBeAg Loss HBeAg Seroconversion 100 100 80 80 60 60 Outcome (%) 40 40 17-32 33 30 21 22 21 21 18 12-18 20 20 0 0 Peg-IFN Peg-IFN LAM ETV TDF LAM ADV ETV TDF Lok AS, et al. Hepatology. 2007;45:507-539. Lau GK, et al. N Engl J Med. 2005;352:2682-2695. Marcellin P, et al. N Engl J Med. 2003;348:808-816. Chang TT, et al. N Engl J Med. 2006;354:1001-1010. Lai CL, et al. N Engl J Med. 2007;357:2576-2588. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455. Janssen HL, et al. Lancet. 2005;365;123-129.

  13. Lowest HBsAg levels at week 12 are associated with highest rate of sustained immune control HBeAg positive patients treated with PEG-IFN-2a +/- lamivudine for 48 weeks 60 57% 51/90 50 40 32% HBeAg seroconversion6 months post-treatment (%) 30 72/223 20 16% 14/86 10 0 Low(<1500) Medium(1500–20,000) High(>20,000) HBsAg at week 12 (IU/mL) P<0.0001 for <1500 IU/mL vs higher levels Piratvisuth et al. APASL 2010

  14. HBeAg Negative Disease End-points of Treatment • Ideal end-point sAg loss  sAb • Durable suppression of HBV DNA to low or undetectable levels • NUC therapy long-term as relapse common after stopping treatment

  15. Virologic response in HBeAg- Patients (Undetectable* HBV DNA at Wk 48-52) Not head-to-head trials; different patient populations and trial designs 93 100 80 60-73 63 60 Patients With Undetectable HBV DNA (%) 40 20 0 LAM Peg-IFN TDF *By PCR based assay (LLD ~ 50 IU/mL) except for some LAM studies. Adapted from Lok AS, et al.Hepatology2007;45:507-539, Lok AS, et al.Hepatology 2009;50:661-662

  16. Undetectable HBV DNA Over Time in HBeAg-Negative Patients Not head-to-head trials; different patient populations and trial designs Extended Treatment With Nucleos(t)ide Analogues vsLimited Duration (1 Yr) Peginterferon Treatment 100 93 91 87 EntecavirTenofovirPeginterferon 80 63 60 Undetectable HBV DNA (%) 40 20 15 16 0 1 Yr 2 Yrs 3 Yrs *Single center study.

  17. HBsAg Loss Over Time in HBeAg Negative Patients Not head-to-head trials; different patient populations and trial designs On Extended Treatment With Nucleos(t)ide Analogues* vs Limited Duration (1 yr) Peginterferon Treatment 100 EntecavirTenofovirPeginterferon 80 60 Patients (%) 40 20 12 6 4 < 1 0 < 1 0 0 NA 0 1.0 Yr 1.5-2.0 Yrs 3.0-4.0 Yrs *With sustained undetectable HBV DNA. Lai CL, et al. N Engl J Med. 2006;354:1011-1020. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455. Marcellin P, et al. AASLD 2008. Abstract 146. Marcellin P, et al. APASL 2009. Abstract PE086. Shouval D, et al. J Hepatol. 2009;50:289-295. Marcellin P, et al. AASLD 2009. Abstract 481.

  18. HBsAg, more than HBV DNA, can distinguish between relapsers and responders to PEG-IFN in HBeAg Negative patients Sustained responders (N=12)* Relapsers (N=18)** Non-responders (N=18) 4 8 Treatment period Treatment period 7 3 6 5 HBsAg (log IU/mL) 2 4 HBV DNA (log copies/mL) 3 1 2 1 0 0 0 12 24 48 72 96 12 24 48 72 96 0 Time (weeks) Time (weeks) *HBV DNA undetectable by PCR 1 year post-treatment **HBV DNA undetectable at EOT but detected in following 24 weeks Moucari et al. Hepatology 2009

  19. To assess and Rx a patient with chronic HBV in 2013 you need the following as a minimum: ALT/AST TBr/albumin/INR HBeAg, eAb HBV viral load US liver Exclude HIV/HCV Access to TDF [LAM] IFN for selected patients

  20. Treatment of Hepatitis C

  21. Definitions : Virological Response Rapid virologicalresponse (RVR) • Undetectable HCV RNA 4 weeks after initiating treatment Complete early virological response (cEVR) • Undetectable HCV at 12 weeks of treatment Sustained virological response (SVR) • Undetectable HCV RNA levels at 24 weeks post-treatment Zeuzem et al. N Engl J Med. 2000.

  22. SVR = Viral Cure • Nearly 100% of patients who achieve SVR remain undetectable during long-term follow-up[1-4] 100[3] 100[4] 99[1] 99[2] 100 80 60 Patients With SVR (%) 40 20 0 3.9 yrs(mean) 3.4 yrs(median) 3.3 yrs(median) 5.4 yrs(median) Duration of Follow-up 1. Swain MG, et al. Gastroenterology. 2010;139:1593-1601. 2. Giannini EG, et al. Aliment Pharmacol Ther. 2010;31:502-508. 3. Maylin S, et al. Gastroenterology. 2008;135:821-829. 4. George SL, et al. Hepatology. 2009;49:729-738.

  23. Liver Failure Liver-Related Death Outcomes in advanced fibrosis with/without a SVR 50 50 5-yr occurrence SVR: 4.4% (CI: 0% to 12.9%)No SVR: 12.9% (CI: 7.7% to 18.0%)P = .024 5-yr occurrence SVR: 0%No SVR: 13.3% (CI: 8.4% to 18.2%)P = .001 (log likelihood) 40 40 30 30 Liver Failure (%) Liver-Related Death (%) 20 20 10 10 0 0 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 Year Year At risk 337 261 192 160 124 95 79 49 31 Events 0 5 11 16 20 24 25 28 30At 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 No SVR SVR Veldt BJ, et al. Ann Intern Med. 2007;147:677-684

  24. Evolution of hepatitis C therapy Discovery of HCV genome Treatment with IFN alfa for 24 or 48 weeks – 3x weekly dosing – Poor outcomes Addition of RBV to IFN alfa improved outcomes Peg-IFN mono – once-weekly dosing Peg-IFN αplus RBV becomes gold standard 1989 2011

  25. Results of HCV Rx : overall SVR rates 70 63 60 50 41 39 40 SVR (%) 30 20 13 6 10 0 IFN 24 wk 19981 IFN 48 wk 19981 IFN + RBV 19981,2 PEG-IFN 2000-20023,4,5 PEG-IFN + RBV 2001-20045,6,7 1. McHutchison et al. N Engl J Med. 1998. 2. Poynard et al. Lancet. 1998. 3. Zeuzem et al.N Engl J Med. 2000. 4. Lindsay et al. Hepatology. 2001. 5. Fried et al. N Engl J Med. 2002. 6. Manns et al. Lancet. 2001. 7. Hadziyannis et al. Ann Intern Med. 2004.

  26. PegIFN+ Ribavirin 80 70 76 60 50 40 46 30 20 10 0 Genotype 1 Genotype 2/3 Peginterferonα-2a + Ribavirin : SVR According to Genotype SVR (%) Fried et al. N Engl J Med. 2002.

  27. Predicting an SVR Viral kinetics : Response guided therapy

  28. Early virological response (EVR): HCV RNA ↓ ≥ 2 logs or Undetectable at Week 12 8 PegIFN/RBV 7 6 5 2 log decline 66% SVR HCV RNA (log10 IU/mL) 4 3 2 EVR Limit of detection 1 SVR 0 0 4 8 12 18 24 30 36 42 48 54 60 66 72 78 Weeks

  29. EVR is an essential predictor of achieving SVR: 12-week stopping rule EVR* SVR Yes 65% (n=253) 86% (n=390) Overall All patients (n=453) No NPV=97% 3% (n=2) 14% (n=63) Early virological response = >2 log10 drop in HCV RNA or undetectable at week 12 Ferenci P, et al.

  30. Rapid Virological response (RVR): HCV RNA Undetectable at week 4 8 PegIFN/RBV 7 6 5 2 log decline 90% SVR HCV RNA (log10 IU/mL) 4 3 RVR 2 Limit of detection 1 SVR 0 0 4 8 12 18 24 30 36 42 48 54 60 66 72 78 Weeks

  31. SVR in Patients Who Achieved an RVR Similar Across Genotypes 100% 88% 100 86% 86% 9 90 282 257 80 60 SVR (%) 40 20 n= 0 Geno 1 Geno 2 Geno 3 Geno 4 Patients With RVR RVR = HCV RNA negative (<50 IU/mL) at week 4; genotypes 1 and 4, patients were treated for 48 weeks; genotypes 2 and 3 patients were treated for 24 weeks

  32. HCV negative at week 4 and 12eRVR = Extended RVR

  33. IL28B

  34. 60 Mb IL28B gene IFN Lambda-3 gene 19q13.13 3 kb Single Nucleotide Polymorphism rs12979860 Chromosome 19 A Polymorphism on Chromosome 19 Predicts SVR Ge D, et al. Nature. 2009;461:399-401.

  35. 100 C/C 16 C/T 35 38 80 T/T 48 60 Percent 46 40 50 20 36 19 12 0 European African Hispanics IL28B rs12979860 polymorphism genotype frequency by population Americans Americans Ge D, et al. Nature. 2009;461:399-401.

  36. Response Rates by IL28B Polymorphism:GT 1 Treated With PegIFN/RBV 100 80 60 SVR (%) 40 20 n = 0 TT CT CC Ge D, et al. Nature. 2009;461:399-401.

  37. IL28B Genetic Variation and Viral Clearance with PEG/RBV The polymorphism on chromosome 19, rs12979860 (T/T, T/C, or C/C), was strongly associated with SVR in all patient groups. Ge D, et al. Nature. 2009;461:399-401

  38. IL28B Polymorphisms and Response to PegIFN/RBV by HCV Genotype Genotype 1 Genotype 2/3 Genotype 4 100 88 CC CT TT 85 79 78 80 60 50 45 SVR (%) 41 40 32 25 20 0 Stättermayer AF, et al. Clin Gastroenterol Hepatol. 2011;9:344-350.

  39. Predictive value of IL28B • CC IL-28B genotype is the strongest pre-Rx predictor of SVR • (OR 5.2; 95% CI, 4.1-6.7) Thompson et al., Gastroenterology 2010;139:120-9

  40. IL28B polymorphisms are not predictive in hepatitis C genotype 5 infected South African patients Mark W. Sonderup1, Wamda Abuelhassan2, C Wendy Spearman1 1. Department of Medicine and Division of Hepatology, Groote Schuur Hospital and University of Cape Town2. Department of Gastroenterology, Chris Hani-Baragwanath Academic Hospital, University of the Witwatersrand , Soweto, Johannesburg. 63rd Annual Meeting of the American Association for the Study of Liver Diseases, Boston, MA, USA November 9 - 13 2012

  41. Demographic data of treated patients

  42. Treatment outcomes % * lower level of detection of HCV is <15IU/ml # RVR = rapid virological response, cEVR = complete early virological response, SVR = sustained virological response and defined as undetectable HCV RNA at the end of a 24-week follow-up period

  43. RVR and IL28B polymorphism genotype

  44. SVR and IL28B polymorphism genotype

  45. Influence of ethnicity on achieving a SVR p = NS

  46. SUMMARY : SVR predictive factors 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. 4. Nguyen MH, et al. Am J Gastroenterol. 2008;103:1131-1135.

  47. The Evolution of HCV Therapy 1990-2000 2000-2011 The Empiric Phase The Refinement Phase • Viral kinetics • Optimal dosing • Special populations • Non-responders • Genomics Weisberg IS, Sigal SH, Jacobson IM. Current Hepatitis Reports. 2007;6:75-82.

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