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Hepatitis B Resistance to Nucleos(t)ide Antiviral Medications

Hepatitis B Resistance to Nucleos(t)ide Antiviral Medications. ROBERT BROWN, MD Chief, Division of Abdominal Organ Transplantation Columbia University College of Physicians & Surgeons New York, New York. Learning Objectives (CME, CE, CPE).

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Hepatitis B Resistance to Nucleos(t)ide Antiviral Medications

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  1. Hepatitis B Resistance to Nucleos(t)ide Antiviral Medications ROBERT BROWN, MD Chief, Division of Abdominal Organ Transplantation Columbia University College of Physicians & Surgeons New York, New York

  2. Learning Objectives (CME, CE, CPE) At the completion of this educational activity, participants should be able to: Discuss the mechanism of action of anti-hepatitis B (HBV) therapeutics Relate the mechanisms of resistance to HBV therapies Discuss clinical trial results regarding preventing or treating HBV resistance to therapy Demonstrate an understanding of treatment guideline recommendations regarding adding or switching therapy due to development of resistance

  3. Implications ofResistance to HBV Therapies Loss of clinical benefits Loss of initial HBV DNA response with rebound ALT increase and eventual reversion of histologic improvement Progressive liver disease In patients with cirrhosis, decompensation Development of multidrug resistance Cross resistance New resistance mutations Transmission of resistant virus Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.

  4. HBV Virion, e-Antigen, and S Proteins HBsAg Pol Protein Spherical Particle~20 nm Diameter DNA HBeAg Core HBcAg Membrane VirusDane Particle40 nmDiameter Filamentous ParticleUp to 200 nm Long

  5. HBeAg HBV Virion HBsAg Golgi ER CCC DNA HBV mRNA

  6. HBeAg-Positive HBV Virion Half-Life HBeAg-Negative Virion Half-Life: 46 minutes (range: 4 to 224 minutes) Virion Half-Life: 150 seconds (range: 24 seconds to 13 minutes) Dandri M, et al. Hepatology. 2008;48:1079-1086.

  7. Rate of Generation ofHBV Mutants at Peak Infection n i *Computed as 3i() where n=3200 is the genome length, i is the number of base changes, and ( )is a binomial coefficient. n i High rate of mutations predisposes the virus to antiviral resistance. Whalley SA, et al. J Exp Med. 2001;193:847-854.

  8. Appearance of Resistance-Related Mutations Is Associated With Virologic Breakthrough HBV DNA log10 copies/mL Wild-Type Mutant Mixture Lee CZ, et al. World J Gastroenterol. 2006;12:5301-5305.

  9. Viral Persistence and Mechanism for Selection of Mutant HBV Strains cccDNA Half-Life Hepatocyte Half-Life Virus Spontaneous Errors in Viral Polymerase Viral Persistence Host Quasi-Species Antivirals Immune Response Selection of Resistant Strains Phenotypic Resistance Treatment Failure Fournier C, et al. Clin Liver Dis. 2007;11:869-892.

  10. Antiviral Resistance: Nomenclature Lok AS, et al. Hepatology. 2007;46:254-265.

  11. Antiviral Resistance: Nomenclature Lok AS, et al. Hepatology. 2007;46:254-265.

  12. Types of Virological Response On Treatment On Continuous Treatment Primary Non-Response Relapse (rebound) HBV DNA (Log10 IU/ml) Breakthrough LLOD LLOD 0 Sustained Response Maintained Response Months Months Slide courtesy of ASF Lok, MD.

  13. HBV Reverse Transcriptase Mutations Associated With Antiviral Resistance Terminalprotein Spacer Pol/RT RNaseH I(G) II(F) A B C D E rtV173L rtM204V/I/S Lamivudine rtL80V/I rtL180M Tenofovir DF Adefovir rtA181T/V* rtA181T/V rtN236T rtN236T* Entecavir rtL180M rtM204V/I Telbivudine rtL80V/I rtL180M rtM204I rtT184S/A/I/L rtS202G/C rtM250I/V 845 a.a. GVGLSPFLLA YMDD Allen MI, et al. Hepatology. 1998;27:1670-1677. Qi X, et al. 39th EASL. Berlin, 2004. Abstract 57. Schildgen O, et al. N Engl J Med. 2006;354:1807-1812. Telbivudine full prescribing information. Tenney DJ, et al. Antimicrob Agents Chemother. 2004;48:3498-3507. *Shown in vitro, but significance in vivo is unknown (not seen in any clinical trial for up to 2 years.

  14. Pre-Existing HBV ResistanceMutations Detected by Line-Probe Assay Resistance mutations seen in antiviral-naïve patients (N=146) Resistance determined by line probe assay and confirmed by direct sequencing Fung SK, et al. J Hepatol. 2008;48(suppl 2):S256. Abstract 688.

  15. 400 120 350 100 300 80 250 200 60 150 40 100 20 50 0 0 Infectivity By Mutational Pattern Replication in Presence of Lamivudine + Adefovir Replication Without Drug Villet S, et al. J Hepatol. 2008;48(suppl 2):S253. Abstract 681.

  16. Clinical Trial Data on Resistance

  17. Lamivudine Resistance

  18. Incidence ofLamivudine Resistance in Chronic HBV 67% Patients (%) 45% 38% 32% 1 3 4 2 Duration of Lamivudine Therapy (years) Dienstag JL, et al. N Engl J Med. 1999;341:1256-1263. Liaw YF, et al. Gastroenterology. 2000;119:172-180. Chang TT, et al. J Gastroenterol Hepatol. 2004;19:1276-1282.

  19. Lamivudine Resistance Accelerates Progression of Liver Disease 25 Placebo (n=215) 21% YMDDm (n=209) (49%) 20 Wild-type (n=221) 15 13% 10 5% 5 0 0 6 12 18 24 30 36 Time After Randomization (months) Patients With Disease Progression (%) Liaw YF, et al. N Engl J Med. 2004;351:1521-1531.

  20. Combination Adefovir + Lamivudine Is Superior to Adefovir Alone in Lamivudine Resistance Virologic Breakthrough* Adefovir Resistance† ADV mono ADV mono ADV+LAM ADV+LAM Patients With Virologic Breakthrough Patients with ADV-R 30% P<0.001 P<0.001 16% 6% 0.5% Months Patients still at risk 273 268 256 225 201 158 61 229 225 217 194 179 146 57 255 238 223 213 200 177 103 242 227 214 205 200 174 92 *>1 log rebound of HBV DNA compared to on-treatment nadir. †N236T or A181T-V in patients with virologic breakthrough. Lampertico P, et al. 57th AASLD. Boston, 2006. Abstract LB5.

  21. Entecavir for Patients With Lamivudine Resistance: 3-Year Results 65% 55% Patients (%) 7% 2% Normalized ALT HBV DNA <400 copies/mL HBeAgLoss HBeAgSeroconversion n=128 patients on long-term entecavir following lamivudine failure. Yao GB, et al. J Hepatol. 2008;48(suppl 2):S267. Abstract 715.

  22. Entecavir for LamivudineRefractory Patients: Patient Flow Randomized StudiesEntecavir 1.0 mg Responders1 Rollover StudyEntecavir 1.0 mg ETV-026:HBeAg+ Non-Responders1 Virologic Responders1 ETV-901 ETV-014:Dose Ranging Any ETV-015:Post-Transplant Any *Protocol-defined response criteria. Tenney DJ, et al. 18th APASL. Seoul, 2008. Abstract PL02.

  23. Lamivudine-Refractory Cohort (HBeAg+) Cumulative Probability of Entecavir Resistance Through 5 Years ETVr = LVDr (M204V + L180M) + T184, S202 and/or M250 substitutionsETVr + virologic Breakthrough (>1 log increase from nadir) 51% 46% 43% 41% 36% Cumulative Probability (%) 27% 15% 11% 6% 1% 3 (n=80) 4 (n=536) 1 (n=187) 5 (n=33) 2 (n=146) Year HBV DNA <300 copies/mL: 72/187 (39%), of whom 3 (4%) had subsequent genotypic entecavir resistance. *Protocol-defined response criteria. Tenney DJ, et al. 18th APASL. Seoul, 2008. Abstract PL02.

  24. Adefovir Resistance

  25. Adefovir Cumulative Probabilities of Virologic Outcomes and Resistance in HBeAg-Negative Patients Genotypic resistance* (n=29) Virologic rebound† (n=18) Clinical breakthrough‡ (n=13) Patients (%) 29% 18% 16% 13% 11% 11% 10% 8% 6% 3% 3% 2% 0% 0% 0% 3 5 1 2 4 Year *Genotypic resistance plus HBV DNA rebound. †Confirmed >1 log10 copies/mL increase in HBV DNA from nadir and/or having never achieved HBV DNA suppression <104 copies/mL. ‡Virologic rebound plus ALT elevations. Borroto-Esoda K, et al. 41st EASL. Vienna, 2006. Abstract 483.

  26. Adefovir: Resistance Incidence per Periodand Cumulative Risk From 5 Clinical Trials Per period Cumulative Resistance (%) 15% 8% 7% 5% 2% 2% 0% 97-144 (n=221) 0-48 (n=629) 49-96 (n=293) 145-192 (n=67) Weeks Combined analysis of 5 studies of adefovir monotherapy or combination therapy in patients with chronic HBV, with or without lamivudine resistance. Locarnini S, et al. 40th EASL. Paris, 2005. Abstract 36.

  27. Adefovir Resistance Uncommon Among Lamivudine-Resistant Patients Receiving Combination Adefovir + Lamivudine Monotherapy (n=125) Combination pre/post OLT (n=264) Combination in HIV-infected patients (n=35) Resistance (%) 29% 18% 11% 3% 0% 0% 0% 0% 0% 0% 0% 0% 3 5 1 2 4 Year Hadziyannis S, et al. 41st EASL. Vienna, 2006. Abstract 499. Lampertico P, et al. 41st EASL. Vienna, 2006. Abstract 116. Benhamou Y, et al. 15th IAC. Bangkok, 2006. Abstract WeOrA1329.

  28. Genotypic Resistance to Adefovir in Patients With Lamivudine-Resistant HBV Subjects were treated with combination adefovir + lamivudine. Lampertico P, et al. Gastroenterology. 2007;133:1445-1451.

  29. Adefovir Therapy: HBV DNA >103 Copies/mL at Week 48 Predicts Genotypic Mutations at 4 Years Undetectable HBV DNA (<103 copies/mL) Detectable HBV DNA (>103 copies/mL) 6% Genotypic Resistance 49% Genotypic Resistance 51% No Mutations 94% No Mutations Week 48 (n=89) Week 48 (n=35) Detectable HBV DNA (>103 copies/mL) at 48 weeks was the only significant predictor of resistance over 4 years (P=0.0003). Stepwise logistic regression analysis that included demographics, genotype, baseline fibrosis, and HBV DNA at week 48. Hadziyannis SJ, et al. Gastroenterology. 2006;131:1743-1751.

  30. * 12.5% Correlation of Viral Load With Response in Lamivudine-Resistant Subjects Receiving Adefovir Monotherapy Week 48 Resistance to Adefovir 20% 15% % Adefovir Resistance 10% 5% 2.9% 0% >6 log <6 log Baseline HBV DNA *P=0.05. Castel J, et al. J Hepatol. 2008;48(suppl 2):S255. Abstract 684.

  31. Add-On Adefovir + Lamivudine Prevents Emergence of Adefovir Resistance % HBV DNA <35 c/mL 1 2 4 5 3 Year n=63. No patient demonstrated rtN236T or rtA181V mutation at baseline or follow-up. Lampertico P, et al. J Hepatol. 2008;48(suppl 2):S259. Abstract 696.

  32. Entecavir Resistance

  33. Development ofResistance to Entecavir Combination of YMDD (M204V/I + L180M) and at least 1 entecavir substitution are required for virologic rebound due to resistance Primary entecavir substitutions (T184, S202, M250) can emerge on lamivudine therapy Primary entecavir mutations also seen in “wild-type” viral quasi-species Tenney DL, et al. Antimicrob Agent Chemother. 2004;48:3498-3507. Jardi R, et al. 57th AASLD. Boston, 2006. Abstract 966.

  34. Cumulative Resistance to Entecavir in Treatment-Naïve and Lamivudine-Resistant Populations Nucleos(t)ide naïve (n=664) Lamivudine resistant (n=50) Resistance (%) 39.5% 32% 14% 6% 0.4% 1.1% 0% 0.8% 3 1 2 4 Year Resistance associated with appearance of rtT184, rtS202 or rtT184 + rtS202 mutations. Colonno R, et al. 42nd EASL. Barcelona, 2007. Abstract 781.

  35. ETV 10000 1000 ETV EC50 (nM) 100 10 1 Baseline Rebound Phenotypic Sensitivity to Entecavirat the Time of Viral Rebound Entecavir at rebound No entecavir at rebound n=192, from all phase III clinical trials of entecavir. Tenney DJ, et al. Antimicrob Agents Chemother. 2007;51:902-911.

  36. Treatment of Entecavir ResistanceWith Adefovir + Lamivudine Reduction in HBV DNA from Baseline Week 24 Week 48 -2.47 ± 1.12 -2.88 ± 1.40 HBV DNA log10 Reduction n=10; lamivudine-refractory patients experiencing virologic breakthrough on entecavir. Yurdaydin C, et al. J Hepatol. 2008;48(suppl 2):S255. Abstract 685.

  37. Telbivudine Resistance

  38. GLOBE Study: Week 52 Telbivudine Resistance (as-treated analysis) HBV DNA >1000 Copies/mL >16 Weeks of Telbivudine Therapy 11.4% Resistance (%) 5.3% HBeAg Positive (n=430) HBeAg Negative (n=227) The rtM204I substitution was the most frequent mutation and was associated with virologic rebound (>1 log10 increase above nadir) in 34 of 46 patients. Telbivudine full prescribing information.

  39. Telbivudine Versus Lamivudine: Cumulative Resistance At Year 2 HBeAg Positive HBeAg Negative Telbivudine Lamivudine Telbivudine Lamivudine 35.0% 30.1% Cumulative Resistance (%) Cumulative Resistance (%) 21.9% 21.6% 17.8% 16.6% 8.6% 7.3% Per Protocol HBV DNA 1 Log Above Nadir Per Protocol HBV DNA 1 Log Above Nadir Per protocol resistance: rebound with HBV DNA >5 log10 copies/mL. P<0.001; less resistance for telbivudine in all pair-wise comparisons. Lai CL, et al. 57th AASLD. Boston, 2006. Abstract 91.

  40. Tenofovir DF Resistance

  41. Tenofovir DF Versus Adefovir as Monotherapyin Patients With Lamivudine Resistance -2.6 -2.8 -3.0 Change in HBV DNA (log10 copies/mL) -5.2* -5.4* -5.5* Tenofovir DF (n=35) Adefovir (n=18) 24 48 36 Week *P<0.001 versus adefovir. van Bömmel F, et al. Hepatology. 2004;40:1421-1425.

  42. Tenofovir DF Versus Adefovir Monotherapyin Lamivudine-Refractory Patients Single center study of patients with persistent lamivudine-resistant HBV Study arms Tenofovir DF (n=35) 72 to 130 weeks Adefovir (n=18) 60 to 80 weeks No evidence of tenofovir DF resistance at 48 weeks HBV DNA <105 Copies/mL 100% Patients (%) 44% Tenofovir DF Adefovir van Bömmel F, et al. Hepatology. 2004;40:1421-1425.

  43. Study 103 (HBeAg+):HBV DNA <400 Copes/mL (ITT) Open-Label Double-Blind TDF to TDF ADV to TDF 78% 76% 78% P<0.001 P=0.801 Patients (%) 13% 0 8 16 24 32 40 48 56 64 72 80 88 96 Weeks Includes 5 patients who had HBV DNA <400 copies/mL at week 96 on FTC/TDF. Heathcote EJ, et al. Hepatology. 2008;48(suppl):92A. Abstract 158.

  44. Study 102 (HBeAg-):HBV DNA <400 Copes/mL (ITT) Open-Label Double-Blind 93% 91% TDF to TDF ADV to TDF 89% P<0.001 P=0.166 63% Patients (%) 0 8 16 24 32 40 48 56 64 72 80 88 96 Weeks 18% of patients were lamivudine experienced and of these 93% and 96% of TDF to TDF and ADV to TDF patients had HBV DNA <400 copies/mL at week 96. Marcellin P, et al. Hepatology. 2008;48(suppl):88A. Abstract 146.

  45. Study 103 and 102:Virologic Analysis Plan • All patients • At baseline • Yearly if HBV DNA >400 copies/mL (> 69 IU/mL) • At discontinuation of tenofovir DF monotherapy if HBV DNA > 400 copies/mL • Any patient post baseline with • Conserved site changes in pol/RT • Virologic breakthrough* • Polymorphic site changes (>1 patient) *Confirmed 1 log10 increase in HBV DNA and/or confirmed HBV DNA >400 copies/mL after achieving HBV DBA <400 copies/mL. Snow-Lampart A, et al. Hepatology. 2008;48(suppl):745A. Abstract 977.

  46. Study 103 and 102:Resistance Surveillance at Week 96 Median duration of tenofovir DF monotherapy at time of discontinuation/addition of emtricitabine was 80 weeks. Snow-Lampart A, et al. Hepatology. 2008;48(suppl):745A. Abstract 977.

  47. Study 103 and 102: Patients Who Were Viremic or Had Virologic Breakthrough (week 72-96) HBV DNA >400 copies/mL Virologic Breakthrough HBeAg+ (n=12) HBeAg- (n=2) HBeAg+ (n=3) HBeAg- (n=4) 8 (67%) Patients (number) Patients (number) 3 (75%) 2 (17%) 2 (17%) 2 (67%) 1 (50%) 1 (50%) 1 (25%) 1 (33%) 0 (0%) 0 (0%) 0 (0%) No Change Polymorphic Conserved No Change Polymorphic Conserved Site Changes Site Changes Three HBeAg+ patients with HBV DNA >400 copies/mL were unable to be genotyped (PCR negative). Conserved site changes observed in one patient each at positions rtL101L/F and rtV173L + rtL180M + rtM204V. No two patients developed the same polymorphic site changes. Snow-Lampart A, et al. Hepatology. 2008;48(suppl):745A. Abstract 977.

  48. Study 103 (HBeAg+): Phenotypic Analysis of the Two Tenofovir DF-Treatment Patients Harboring Conserved Site Changes in HBV pol/RT *Clonal analysis of the baseline sample showed the presence of the LAM-Rmutations at a frequency of 6.5%. †Fold change: last on tenofovir DF EC50/ baseline EC50. Fold changes <2X are within the assay variability. Development of conserved site changes was not associated with phenotypic resistance to tenofovir DF. Snow-Lampart A, et al. Hepatology. 2008;48(suppl):745A. Abstract 977.

  49. Study 103 and 102: Phenotypic Analysis ofSeven Tenofovir DF-Treatment PatientsWith Virologic Breakthrough Study 103 (HBeAg+) Study 102 (HBeAg-) *Fold change: last on TDF EC50/ baseline EC50. Fold changes <2X are within the assay variability. Virologic breakthrough was not associated with phenotypic resistance to tenofovir DF. Snow-Lampart A, et al. Hepatology. 2008;48(suppl):745A. Abstract 977.

  50. Study 103 and 102:Resistance and Virologic Breakthrough No HBV pol/RT amino acid substitutions associated with resistance to tenofovir DF were detected through 96 weeks of tenofovir DF monotherapy Annual resistance surveillance on-going through year 8 (week 384) Virologic breakthrough was rare (study 103: 2.4%; study 102: 1.6%) Not associated with phenotypic resistance to tenofovir DF Majority of patients with virologic breakthrough had evidence of non-adherence Development of conserved site changes was rare and not associated with phenotypic resistance to tenofovir DF Snow-Lampart A, et al. Hepatology. 2008;48(suppl):745A. Abstract 977.

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