1. Efficacy, Resistance, and Durability Supported by an unrestricted educational grant from

2. clinicaloptions.com/hep HBV Providers’ Choice in Prime Time About These Slides  The full program accompanying these slides is available on the Clinical Care Options Hepatitis Web site: clinicaloptions.com/PRIME  Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options  We are grateful to Stephen Locarnini, MD, PhD, FRC (Path), and Nezam H. Afdhal, MD, FRCPI, for their assistance in developing these slides Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

3. clinicaloptions.com/hep HBV Providers’ Choice in Prime Time Patients for Whom Avoiding HBV Resistance Is Especially Important  Patients for whom risk of hepatitis flare is high if resistance develops –Advanced liver disease –Liver transplantation patients  HIV/HBV coinfection –ETV monotherapy not optimal with recent data on anti-HIV activity and genotypic resistance –Risk of resistance with any monotherapy in HIV/HBV coinfection  Established resistance to antiviral medication(s) –Transmission of resistant virus in the general population increases with drug usage

4. clinicaloptions.com/hep HBV Providers’ Choice in Prime Time Indications of Emergence of Drug- Resistant Virus  Increasing HBV DNA (≥ 1.0 log IU/mL)  Identification of known genotypic markers of drug resistance within viral polymerase –Primary resistance mutations (rtM204I) –Secondary resistance mutations (rtL180M with rtM204V) –Compensatory mutations (rtV173L)  Increasing serum ALT levels  Clinical deterioration Ono-Nita S, et al. J Clin Invest. 1999;103:1635-1640. Ono S, et al. J Clin Invest. 2001;107:449-455. Chin R, et al. Antimicrob Agents Chemother. 2001;45:2495-2501.

5. clinicaloptions.com/hep HBV Providers’ Choice in Prime Time Potential Consequences of Antiviral Drug Resistance in Chronic Hepatitis B OutcomeDescription VirologicReduced HBeAg seroconversion rates [1] Virologic breakthrough and rebound [2] BiochemicalBiochemical breakthrough [2] HistologicHistologic progression of disease [2,3] ClinicalHepatic flare and decompensation [4,5] Increased recurrence post liver transplantation [6] Public healthDevelopment of multidrug-resistant HBV population Transmission of drug-resistant HBV [7] Alteration in HBsAg potentially leading to vaccine failure [8] 1. Leung NW, et al. Hepatology. 2001;33:1527-1532. 2. Dienstag JL, et al. Gastroenterology. 2003;124:105-117. 3. Liaw YF, et al. N Engl J Med. 2004;351:1521-1531. 4. Yuen MF, et al. J Hepatol. 2003;39:850-855. 5. Nafa S, et al. Hepatology. 2000;32:1078-1088. 6. Mutimer D, et al. Gut. 2000;46:107-113. 7. Thibault V, et al. AIDS. 2002;16:131-133. 8. Torresi J, et al. Virology. 2002;293:305-313.

6. clinicaloptions.com/hep HBV Providers’ Choice in Prime Time Factors Contributing to Rapid Virus Evolution  Error-prone polymerases  Lack of proofreading mechanisms  Magnitude of replication –Large burden of infected cells –Generation time –Mutant fitness  Selective pressures –Drugs –Cellular and anatomic compartments –Immune responses Richman DD. Hepatology. 2000;32:866-867.

7. clinicaloptions.com/hep HBV Providers’ Choice in Prime Time 845 aa Terminal protein Spacer Pol/RT RNaseH ABCED YMDDF_V_LLAQ I(G)II(F) Allen MI, et al. Hepatology. 1998;27:1670-1677. Qi X, et al. EASL 2004. Abstract 57. Tenney D, et al. Antimicrob Agents Chemother. 2004;48:3498-3507. Telbivudine [package insert]. Locarnini S. IDRW 2006. Abstract P2. Qi X, et al. Antivir Ther. 2007;12:355-362. van Bommel F, et al. AASLD 2007. Abstract 960. rtM204V/I LAM resistance rtA18IT/V rtA181T/VrtN236T ADV/TDF resistance* rtM204V rtS202G/C/I rtM250I/V rtT184S/A/I/L/G/C/M ETV resistancertL180M rtM204ILdT resistance rtA181T/V 1 183 349 (rt1)692 (rt344) rtI169T *Based on in vitro data and therapy switch following emergence of genotypic ADV resistance. HBV Primary Resistance Mutations

8. clinicaloptions.com/hep HBV Providers’ Choice in Prime Time Prevention of HBV Drug Resistance Requires Addressing the Causes  The patient –Adherence  The prescribing care provider –Selecting an optimal regimen –Counseling the patient  The drugs –Potency –Genetic barrier to resistance –Tolerability –Pharmacokinetics Drugs Patient Care provider

9. clinicaloptions.com/hep HBV Providers’ Choice in Prime Time Genetic Barrier  The number of substitutions needed for primary antiviral drug resistance –LAM/LdT:rtM204I –ADV:rtN236T  Combination of low genetic barrier drugs: at least 2 mutations required  ETV: at least 3 mutations required: –rtL180M + rtM204V + one of –rtT184 or rtS202 or rtM250 change

10. clinicaloptions.com/hep HBV Providers’ Choice in Prime Time What Determines Rate of Resistance? Potency vs Genetic Barrier  Potency is only one part of the equation  LAM and LdT are potent with low genetic barrier and high rates of resistance  ETV and TDF are potent with high genetic barrier and low rates of resistance  ADV is less potent but with high genetic barrier and low rates of resistance  Genetic barrier is probably at least as important as potency

11. clinicaloptions.com/hep HBV Providers’ Choice in Prime Time Oral Therapy for Chronic Hepatitis B: 2008 Approximate Relative Antiviral Potency 2008 1998 2002 2005 2006 + ++ +++++++ ++++ ADV LdT ETV TDFLAM Genetic Barrier* 1 1 3 1 ? *Number of mutations needed for primary antiviral drug resistance.

12. clinicaloptions.com/hep HBV Providers’ Choice in Prime Time ? Year LAM ADV, HBeAg negative ETV LdT, all patients LdT, HBeAg positive LdT, HBeAg negative 0 23 55 71 65 46 12345 Patients (%) 80 40 60 20 100 0 3 11 19 30 <1 1.2 11 5 ? ? ? TDF ? ? ? 0 25 1.2 Cumulative Incidence of Resistance in Nucleos(t)ide-Naive Patients Not head-to-head trials; different patient populations and trial designs Lai CL, et al. Clin Infect Dis. 2003;36:687-696. Lok AS, et al. Gastroenterology. 2003;125:1714-1722. Adefovir [package insert]. Colonno R, et al. EASL 2007. Abstract 781. Lai CL, et al. Gastroenterology. 2005;129:528-536. Zeuzem S, et al. AASLD 2007. Abstract 994. Marcellin P, et al. AASLD 2007. Abstract LB2. Heathcote EJ, et al. AASLD 2007. Abstract LB6. Tenney DJ, et al. APASL 2008. Abstract PL02 Rates of Resistance With Oral Agents

13. clinicaloptions.com/hep HBV Providers’ Choice in Prime Time 40-44 21 67 60 76 LAMADVETVLdTTDF Adapted from Lok AS, et al. Hepatology. 2007;45:507-539. Heathcote EJ, et al. AASLD 2007. Abstract LB6. *By PCR based assay (LLD ~ 50 IU/mL) except for some LAM studies. Patients With Undetectable HBV DNA (%) Not head-to-head trials; different patient populations and trial designs Virologic Response in HBeAg+ Patients (Undetectable* HBV DNA at Wk 48-52) 100 80 60 40 20 0

14. clinicaloptions.com/hep HBV Providers’ Choice in Prime Time ~ 70 51 90 88 93 Adapted from Lok AS, et al. Hepatology 2007;45:507-539. Marcellin P, et al. AASLD 2007. Abstract LB2. Virologic Response in HBeAg- Patients (Undetectable* HBV DNA at Wk 48-52) Not head-to-head trials; different patient populations and trial designs Patients With Undetectable HBV DNA (%) 100 80 60 40 20 0 LAMADVETVLdTTDF *By PCR based assay (LLD ~ 50 IU/mL) except for some LAM studies.

15. clinicaloptions.com/hep HBV Providers’ Choice in Prime Time Antiviral Resistance Pathways in CHB PathwayMutationAssociated Resistance L-nucleosidertM204V/ILAM FTC LdT CLV Acyclic phosphonatertN236TADV TDF “Shared”rtA181T/VL-nucleosides and acyclic phosphonates (see above) Naive entecavir resistance rtL180M + rtM204V with one of rtT184, S202, or M250 ETV Multidrug resistanceComplex patterns, eg, rtA181T + rtN236T + rtM250L Multidrug Yuen L, et al. AASLD 2007. Abstract 949.

16. clinicaloptions.com/hep HBV Providers’ Choice in Prime Time Any Present Role for Combination Oral Therapy as Initial Treatment?  Conflicting results [1-5]  The newer, more potent antiviral agents have excellent resistance profiles  Studies to establish any advantage of combination therapy would require –Large number of patients –Long duration –Shorter-term endpoints than resistance  A potential role for combination therapy has been proposed for some patients in whom development of resistance may be particularly disastrous  If lower rates of resistance could be definitively shown, combination therapy might have a role in geographical areas where more potent agents are not available  Currently available drugs have excellent resistance profiles 1. Lai CL, et al. Gastroenterology. 2005;129:528-36. 2. Sung JJ, et al. J Hepatol. 2008;48:728-735. 3. Hui CK, et al. J Hepatol. 2008;48:714-720. 4. Berg T, et al. 2008 EASL. Abstract 76. 5. Hézode C, et al. Hepatitis B and C Virus Resistance Conference. Poster 24.

17. clinicaloptions.com/hep HBV Providers’ Choice in Prime Time Preventing Virologic Breakthrough With de Novo Combination Therapy Sung JJ, et al. J Hepatol. 2008;48:728-735. 0 20 40 60 80 100 Virologic Breakthrough* (%) 44 LAM LAM+ ADV 19 *Defined as > 1 log 10 IU/mL increase from on treatment nadir 2 Years

18. clinicaloptions.com/hep HBV Providers’ Choice in Prime Time Reasons for Concern About Sequential Monotherapy  Multidrug-resistant mutants can be found on the same viral genome after sequential monotherapy [1,2]  Poor virologic control with ETV can follow ADV resistance in LAM-pretreated patients [3]  Poor virologic control with ETV can follow limited response to ADV in LAM-nonresistant patients [4]  ETV resistance has been documented when rtL180M + rtM204V mutants preexist in treatment-naive patients in low concentrations [5]  Drug-resistant HBV has an altered viral envelope [6] 1. Yim HJ, et al. Hepatology. 2006:43:S173-S181. 2. Shaw T, et al. AASLD 2007. Abstract 986. 3. Schildgen O, et al. N Engl J Med. 2006;354:1807-1812. 4. Reijnders JG, et al. AASLD 2007. Abstract 951. 5. Colonno R, et al. Hepatology. 2006;44:1656- 1665. 6. Torresi J, et al. Virology. 2002;293:305-313.

19. clinicaloptions.com/hep HBV Providers’ Choice in Prime Time Cross-Resistance  Resistance associated mutations selected by drugs may diminish the antiviral activity of other drugs –This should be considered before any antiviral drug is prescribed  Cross-resistance tends to be more common for compounds sharing structural properties  Any change in therapy, typically combination or add-on strategies, should be made using drugs that lack cross- resistance with the failing agent

20. clinicaloptions.com/hep HBV Providers’ Choice in Prime Time A181V/T M250V L180M T184G/S S202I N236T M204V/I LAM* ADV/ TDF ETV LdT I169T Selection of LAM-resistant HBV Pol mutations affects future treatment options. Cross-Resistance Profiles

21. clinicaloptions.com/hep HBV Providers’ Choice in Prime Time Multidrug Resistance Shaw T, et al. EASL 2008. Abstract 699. MDR N236T L180M + A181T + M204V A181T + N236T + M250V A181T ? ADVLAMADV + LAMADV + ETV

22. clinicaloptions.com/hep HBV Providers’ Choice in Prime Time Public Health Significance of Drug- Resistant Strains Individual with chronic HBV treated with nucleos(t)ide analogues Selects for mutants that are not protected by vaccination Can infect naive (anti-HBs-) individuals Can infect hepatitis B–immunized (anti- HBs+) individuals

23. clinicaloptions.com/hep HBV Providers’ Choice in Prime Time Strategies to Limit Resistance  Use antiviral treatment only as needed  Use drugs with optimal antiviral potency  Use tolerable and convenient regimens to support adherence  LAM/LdT monotherapy not advisable as first-line therapy because of high incidence of resistance  Add additional antiviral agent if HBV DNA detectable (> 3 logs) after initial 12 months of monotherapy with ADV or ETV, or after 6 months with LAM or LdT Keeffe EB, et al. Clin Gastroenterol Hepatol. 2007;5:890-897.

24. clinicaloptions.com/hep HBV Providers’ Choice in Prime Time Strategies to Limit Resistance  Maximize genetic barriers to resistance –Choose drugs with a low incidence of resistance over time –Avoid sequential monotherapy and treatment interruptions –Consider first-line combination therapy  Anticipate the implications of resistance on the availability of future effective options Keeffe EB, et al. Clin Gastroenterol Hepatol. 2007;5:890-897.

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