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Management of Resistance: Implications for Treatment Choices

Management of Resistance: Implications for Treatment Choices. Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis B, C and delta Virology Unit & INSERM U635 Department of Bacteriology and Virology Henri Mondor Hospital Universite Paris XII

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Management of Resistance: Implications for Treatment Choices

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  1. Management of Resistance:Implications for Treatment Choices Jean-Michel Pawlotsky, MD, PhD Director, French National Reference Center for Viral Hepatitis B, C and delta Virology Unit & INSERM U635 Department of Bacteriology and Virology Henri Mondor Hospital Universite Paris XII Créteil, France

  2. Primary Endpoints of HBV Therapy • Stop or slow the progression of liver disease in order to • Prevent cirrhosis • Prevent decompensation of cirrhosis • Prevent hepatocellular carcinoma

  3. HBV DNA as a Marker of Efficacy During Treatment of HBV • Literature analysis of 26 prospective studies • Investigation of the relationship between treatment-induced changes in HBV DNA, histology, other disease activity markers • Results • Statistically significant and consistent correlations between HBV DNA, histology, biochemical and serologic responses • HBV DNA had broader dynamic range than histology • Conclusion • Treatment-induced reduction in HBV DNA can be used to assess efficacy • Treatment goal should be profound and durable suppression of HBV DNA Mommeja-Marin H, et al. Hepatology. 2003;37:1309-1319.

  4. Endpoint of Therapy With HBV Oral Antiviral Drugs • Inhibition of HBV replication • As profound as possible • As sustained as possible ANTIVIRAL POTENCY NO RESISTANCE

  5. HBV Treatment Failureand Resistance

  6. Drug Discontinue Drug Sensitive Sensitive Sensitive Resistant Resistant Resistant Mechanisms of Resistance

  7. Drug Discontinue Drug Sensitive Sensitive Sensitive Resistant Resistant Resistant + Fit Mechanisms of Resistance

  8. Mechanisms of Resistance Drug Discontinue Drug Sensitive Sensitive Sensitive Resistant Resistant Resistant + Very Fit

  9. Terminalprotein Spacer Pol/RT RNaseH I(G) II(F) A B C D E HBV Resistance Mutations 845 a.a. GVGLSPFLLA YMDD rtV173L rtM204V/I/S LAM resistance rtL80V/I rtL180M ADV resistance rtA181T/V rtN236T rtl233V ? ETV resistance rtL180M rtM204V/I rtT184S/A/I/L rtS202G/C rtM250I/V LdT resistance rtL80V/I rtL180M rtM204I Allen MI, et al. Hepatology. 1998;27:1670-1677. Qi X, et al. J Hepatol. 2004;40(suppl 1):20-21. Tenney D, et al. Antimicrob Agents Chemother. 2004;48:3498-3507. Telbivudine product insert. Lai CL, et al. Gastroenterology. 2005;129:528-536. Schildgen O, et al. N Engl J Med. 2006;354:1807-1812.

  10. Incidence of HBV Resistance Lamivudine (nucleos[t]ide-naive patients) 100 80 71 65 55 60 Cumulative Incidence of Resistance (%) 46 40 23 20 0 1 2 3 4 5 Year Lai CL, et al. Clin Infect Dis. 2003;36:687-696.Lok AS, et al. Gastroenterology. 2003;125:1714-1722.

  11. 1 2 3 4 5 Year Incidence of HBV Resistance (cont’d) Adefovir (nucleos[t]ide-naive, HBeAg-negative patients); selection of resistance mutations with or without breakthrough 100 80 60 Cumulative Incidence of Resistance (%) 40 29 18 20 11 3 0 0 Borroto-Esoda K, et al. EASL 2006. Abstract 483.

  12. 1 2 3 4 5 Year Incidence of HBV Resistance Entecavir (genotypic resistance in HBeAg[+]/[-] nucleos(t)ide-naive patients) Entecavir (genotypic resistance in LAM-R patients) Entecavir (genotypic resistance plus viral rebound in LAM-R patients) 100 80 60 Cumulative Incidence of Outcome (%) 40 32 25 20 14 10 6 1.1 1 0.1 0.4 0 Colonno R, et al. AASLD 2006. Abstract 110.

  13. 100 80 60 Cumulative Incidence of Resistance (%) 40 20 0 1 2 3 4 5 Year Incidence of HBV Resistance Telbivudine Telbivudine (HBeAg-positive patients) Telbivudine (HBeAg-negative patients) 21.6 8.6 5.0 ? ? ? Lai CL, et al. Gastroenterology. 2005;129:528-536. Lai CL, et al. AASLD 2006. Abstract 91.

  14. Prevention ofHBV Resistance

  15. Prevention of Resistance • Experience from other therapies suggests that during prolonged antiviral therapy, resistance cannot be avoided indefinitely • Employment of appropriate therapeutic strategies can consistently delay the emergence of resistance

  16. Delaying Viral Resistance • Maximally reduce virus replication • Use highly potent antivirals

  17. Entecavir vs Lamivudine Entecavir Lamivudine LAM-R HBeAg+ Naive HBeAg+ Naive HBeAg- 0 -0.5 -2 Reduction in HBV DNA at Week 48 (log10 copies/mL) -4 -4.5 -5.0 -5.1 -5.4 -6 P < .0001 P < .0001 -6.9 -8 P < .0001 Chang T, et al. N Engl J Med. 2006;354:1001-1010. Lai C, et al. N Engl J Med. 2006;354:1011-1020. Colonno R, et al. AASLD 2006. Abstract 110. Sherman M, et al. Gastroenterology. 2006;130:2039-2049.

  18. Entecavir vs Lamivudine (cont’d) Entecavir Lamivudine 100 90 80 72 67 60 Undetectable HBV DNA at Week 48 (< 300 copies/mL) (%) 36 40 19 20 1 0 Naive HBeAg+ Naive HBeAg- LAM-R HBeAg+ Chang T, et al. N Engl J Med. 2006;354:1001-1010. Lai C, et al. N Engl J Med. 2006;354:1011-1020. Colonno R, et al. AASLD 2006. Abstract 110. Sherman M, et al. Gastroenterology. 2006;130:2039-2049.

  19. Entecavir vs Adefovir Week 12 Comparison ADV (n = 34) ETV (n = 35) 0 -1 -2 -3 Reduction in HBV DNA (log10 copies/mL) -4 - 4.42 -5 -6 - 6.23 -7 P < .0001 Wilber R, et al. NIH HBV 2006. Abstract 14.

  20. Telbivudine vsLamivudine:HBeAg-Positive Patients On-Treatment (N = 921) Posttreatment (n = 328) 0 -1 Lamivudine -2 Telbivudine -3 Mean Change in HBV DNA From Baseline(log10 copies/mL± SE) -4 -5 -5.2 -5.5 -6 -6.5 -6.6 -7 -8 Lai C, et al. HepDart 2005. Abstract 95.

  21. Telbivudine vs Lamivudine: HBeAg-Negative Patients On-Treatment (N = 446) Posttreatment (n = 135) 0 -1 -1 Lamivudine -2 -2 Telbivudine -3 -3 Mean Change in HBV DNA From Baseline(log10 copies/mL± SE) Mean Change in HBV DNA From Baseline(log10 copies/mL± SE) -4 -4 -5 -5 -4.4 -6 -6 -4.7 -5.2 -5.3 -7 -7 -8 -8 Lai C, et al. HepDart 2005. Abstract 95.

  22. Tenofovir vs Adefovir in LAM-R Patients Adefovir (n = 18) Tenofovir (n = 35) 0 1 HBV DNA < 400 copies/mL at Week 48 2 3 -2.8 log Week 48 Reduction in HBV DNA (log10 copies/mL) Adefovir: 44%Tenofovir: 100% 4 5 6 -5.5 log 7 P < .001 van Bommel F, et al. Hepatology. 2004;40:1421-1425.

  23. Delaying Viral Resistance • Maximally reduce virus replication • Use highly potent antivirals • Raise the “pharmacologic barrier” to viral escape • Reach high trough levels • Have a tissue distribution that permits no sanctuaries • Optimize patient adherence

  24. Delaying Viral Resistance • Maximally reduce virus replication • Use highly potent antivirals • Raise the “pharmacologic barrier” to viral escape • Reach high trough levels • Have a tissue distribution that permits no sanctuaries • Optimize patient adherence • Raise the “genetic barrier” to resistance • Combination therapies

  25. In Vitro Cross-resistance to Lamivudine Resistance Mutations Reduced susceptibility Resistant Dent J, et al. Hepatology. 2000;32:457A. Ono SK, et al. J Clin Invest. 2001;107:449-455. Delaney W, et al. Antiviral Res. 2001;50:A81. Fu L, et al. Antimicrob Agents Chemother. 2000;44:3402-3407. Delaney WE, et al. Antimicrob Agents Chemother. 2001;45:1705-1713. Delaney W, et al. EASL 2002. Abstract 181.

  26. In Vitro Cross-resistance to Lamivudine Resistance Mutations Reduced susceptibility Resistant Qi X, et al. EASL 2005. Abstract 75.

  27. In Vitro Cross-resistance to Adefovir Resistance Mutations Reduced susceptibility Resistant Qi X, et al. Gastroenterology. 2004;126(suppl 2):A-660. Abstract 3. Qi X, et al. EASL 2005. Abstract 536.

  28. Sensitive Resistant Mechanisms of HBV Resistance Drug Discontinue Drug Sensitive Sensitive Resistant Resistant

  29. Combination in Naive Patients Lamivudine + Adefovir Sensitive LAM-R ADV-R Sensitive LAM-R ADV-R LAM + ADV-R LAM + ADV-R

  30. Lamivudine + Adefovir:HBeAg-Positive, Naive Patients Lamivudine + adefovir Lamivudine + placebo 0 -1 -2 Week 52 Mean Change in HBV DNA From Baseline (log10 copies/mL) -3 -4 -5 -4.8 -5.2 -6 Sung J, et al. EASL 2003. Abstract 4313.

  31. Adefovir Resistance • All adefovir-resistant patients (22 reported to date) were on adefovir monotherapy • 20 from adefovir monotherapy trials • 2 from adefovir + lamivudine trials but had stopped lamivudine • No adefovir resistance observed to date when adefovir is added to ongoing lamivudine • No adefovir resistance observed to date in treatment-naive patients treated with adefovir + FTC or adefovir + lamivudine Locarnini S, et al. EASL 2005. Abstract 36.

  32. Summary • HBV resistance may be delayed for many years by • Using highly potent antiviral drugs with optimized pharmacologic profiles • Improving patients’ adherence to therapy • Using first-line combinations of drugs without cross-resistance

  33. Management ofHBV Resistance

  34. Management of HBV Resistance: Options • Continue current therapy • Switch to another drug • Add on another drug • Switch and add on

  35. Switch vsAdd-on in Lamivudine-Resistant Patients Lamivudine Stop Lamivudine Add Adefovir LAM-S ADV-S LAM-R ADV-S LAM-S LAM-S ADV-R LAM-S ADV-R LAM-S LAM-S LAM-R LAM-R LAM-R ADV-R

  36. Switch vsAdd-on in Lamivudine-Resistant Patients Continue Lamivudine Add Adefovir Lamivudine LAM-S LAM-S ADV-R LAM-S ADV-S LAM-R ADV-S LAM-S LAM-R ADV-R LAM-S ADV-R LAM-R LAM-R

  37. Add-on Adefovir in Lamivudine-Resistant Patients Adefovir resistance, presence of adefovir resistance mutations confirmed by molecular analysis in patients with virologic rebound; virologic rebound, > 1 log10 copies/mL increase in HBV DNA level. Lampertico P, et al. EASL 2006. Abstract 116.

  38. Practical Options • Lamivudine resistance • Switch to entecavir • Continue lamivudine and add adefovir • Switch to telbivudine and add adefovir • Switch to entecavir and add adefovir • Consider tenofovir instead of adefovir when approved • Consider tenofovir/FTC formulation when approved

  39. Practical Options (cont’d) • Adefovir resistance • Add lamivudine • Add telbivudine • Add entecavir • Switch to tenofovir when approved in combination with lamivudine, telbivudine, or entecavir • Switch to tenofovir/FTC when approved

  40. Practical Options (cont’d) • Entecavir resistance • Add adefovir • Add tenofovir when approved

  41. Summary • HBV resistance can be delayed • By using highly potent antivirals • By improving adherence • By using combination therapies • When resistance occurs • Consider add-on therapy rather than switching to second monotherapy • Consider using the most potent available antiviral combination

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