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

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

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.

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

HBV Treatment Failure and Resistance

Mechanisms of Resistance Sensitive Resistant Drug Discontinue Drug

Mechanisms of Resistance Sensitive Resistant + Fit Resistant Drug Discontinue Drug

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

HBV Resistance Mutations Terminal protein Spacer Pol/RT RNaseH GVGLSPFLLA YMDD 845 a.a. I(G) II(F) A B C D E LAM resistance rtL80V/I rtV173L rtM204V/I/S 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.

Incidence of HBV Resistance Lamivudine (nucleos[t]ide-naive patients) 100 80 71 65 55 Cumulative Incidence of Resistance (%) 60 46 40 23 20 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.

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

Cumulative Incidence of Outcome (%) 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 Cumulative Incidence of Outcome (%) 60 40 32 25 20 14 10 6 0.1 1 0.4 1.1 Year 1 2 3 4 5 Colonno R, et al. AASLD 2006. Abstract 110.

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

Prevention of HBV Resistance

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

Delaying Viral Resistance Maximally reduce virus replication Use highly potent antivirals

Entecavir vs Lamivudine LAM-R HBeAg+ Naive HBeAg+ Naive HBeAg- -0.5 -2 Reduction in HBV DNA at Week 48 (log10 copies/mL) -4 -4.5 -5.0 -5.1 -6 -5.4 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.

Entecavir vs Lamivudine (cont’d) 100 90 80 72 67 60 Undetectable HBV DNA at Week 48 (< 300 copies/mL) (%) 40 36 19 20 1 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.

Reduction in HBV DNA (log10 copies/mL) Entecavir vs Adefovir Week 12 Comparison ADV (n = 34) ETV (n = 35) -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.

Telbivudine vs Lamivudine: HBeAg-Positive Patients On-Treatment (N = 921) Posttreatment (n = 328) -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.

Telbivudine vs Lamivudine: HBeAg-Negative Patients On-Treatment (N = 446) Posttreatment (n = 135) -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.

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

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

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

In Vitro Cross-resistance to Lamivudine Resistance Mutations Reduced susceptibility Resistant Fold-Change in Susceptibility Relative to Wild Type HBV HBV mutations 3TC L-FMAU L-Fd4C ETV FTC LdC LdT Wild type 1 L180M 5 3 11 12 9.4 M204I > 1000 570 NA 864 500 > 330 L180M + M204V 233 182 > 42 410 345 3TC, lamivudine; ETV, entecavir; FTC, emtricitabine; L-Fd4C, elvucitabine; Ldc, valtorcitabine; Ldt, telbivudine; L-FMAU, 1-(2-fluoro-5-methyl-beta, L-arabinofuranosyl) uracil); 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.

In Vitro Cross-resistance to Lamivudine Resistance Mutations Reduced susceptibility Resistant Fold-Change in EC50 From Wild Type Compound M204V + L180M M204V + L180M + V173L M204I M204I + L180M Tenofovir 0.8 1.8 2.1 0.7 Adefovir 1.1 Entecavir 37 164 471 38 Lamivudine > 700 > 1000 Qi X, et al. EASL 2005. Abstract 75.

In Vitro Cross-resistance to Adefovir Resistance Mutations Reduced susceptibility Resistant IC50 Fold Change N236T A181V Adefovir 7.30 4.20 Tenofovir 4.60 1.80 Entecavir 0.67 12.10 Lamivudine 2.10 14.10 Emtricitabine 2.60 Telbivudine (LdT) 2.40 > 24.00 Valtorcitabine (LdC) NA 87.00 Clevudine 4.90 > 164.00 Qi X, et al. Gastroenterology. 2004;126(suppl 2):A-660. Abstract 3. Qi X, et al. EASL 2005. Abstract 536.

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

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

Lamivudine + Adefovir: HBeAg-Positive, Naive Patients Lamivudine + placebo -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.

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.

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

Management of HBV Resistance

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

Switch vs Add-on in Lamivudine-Resistant Patients Stop Lamivudine Add Adefovir LAM-S ADV-S LAM-R ADV-S LAM-S ADV-R LAM-S LAM-S ADV-R LAM-S LAM-S LAM-R LAM-R LAM-R ADV-R

Switch vs Add-on in Lamivudine-Resistant Patients Continue Lamivudine Add Adefovir Lamivudine LAM-S ADV-R LAM-S LAM-S ADV-S LAM-R ADV-S LAM-S LAM-S ADV-R LAM-R ADV-R LAM-R LAM-R

Add-on Adefovir in Lamivudine-Resistant Patients Endpoints at Year 2 ADV Switch (n = 277) ADV + LAM (n = 294) P Value Virologic rebound, n (%) 41 (15) 11 (4) < .001 ADV genotypic resistance, n (%) 21 (8) 0 (0) 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.

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

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

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

Summary HBV resistance can be delayed When resistance occurs 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