4 th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Anna S.F. Lok, MD Professor of Internal Medicine and Director of Clinical Hepatology University of Michigan, Ann Arbor Ann Arbor, Michigan Hepatitis B Virus Resistance: An Overview by a Clinician for a Clinical Audience

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Why Do Antiviral-Resistant HBV Mutants Arise?  High rate of virion production: virions per day  High rate of spontaneous mutations—lack of proofreading capacity of HBV reverse transcriptase: substitution/base/cycle  All possible single base changes can be produced each day  Antiviral resistant mutations may be present prior to therapy

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights What Causes Antiviral-Resistant HBV Mutants to Become Dominant? Antiviral Therapy S S S S S S S S S R R R R R RR  Survival of the fittest: selection of virus with survival advantage in the presence of antiviral therapy

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Factors Associated With Antiviral Resistance VIRUS DRUG HOST  Daily production  Replication fidelity  Preexistent mutations  Potency  Structure  Genetic barrier to resistance  Prior therapy  Compliance  Immune status  Pharmacogenetics  Body size

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Better Viral Suppression Reduces the Risk of Genotypic Resistance Yuen MF, et al. Hepatology. 2001;34: Locarnini S, et al. J Hepatol. 2005;42(suppl.2):17. LAM Resistance (median 29 mos) vs Week 24 HBV DNA ADV Resistance at Week 144 vs Week 48 HBV DNA % Resistance 8% 13% 32% 64% 4% 26% 67% Week 24 HBV DNA (log 10 c/mL) N = 159 HBeAg-positive patients < ND 3-6>6< ND> 4< 4< 3 Week 48 HBV DNA (log 10 c/mL) N = 114, primarily HBeAg-negative patients

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Genetic Barriers to Antiviral Resistance  No. of amino acid changes required to confer resistance  Decrease in susceptibility (increase in IC 50 ) caused by the mutations Nucleos(t)ide AnalogueMutationFold Decrease in Susceptibility LAM M204V/I> 1000 ADV A181V or N236T3-15 Entecavir 169 or or 250 M204V/I + 1 ETV-R M204V/I + 2 ETV-R ~ > 500 ETV-R, entecavir resistance mutation.

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Nomenclature for Antiviral Resistance  Virological breakthrough—consistent increase in serum HBV DNA by > 1 log above nadir while on treatment, after achieving initial response  Biochemical breakthrough—consistent increase in serum ALT while on treatment, after achieving initial response  Genotypic resistance—detection of HBV polymerase mutation(s) that has been shown to decrease susceptibility to treatment  Phenotypic resistance—in vitro confirmation that the mutation decreases susceptibility to treatment

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Manifestations of Antiviral Resistance HBV DNA (log 10 IU/mL) ALT (U/L) Biochemical breakthrough ULN Viral breakthrough Years Antiviral Treatment Hepatitis flare Viral rebound Genotypic resistance

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Indicators of Antiviral-Resistant HBV  Detection of antiviral resistant mutations  Viral breakthrough—> 1 log increase in serum HBV DNA  Viral rebound—serum HBV DNA exceeds pretreatment value or defined cutoff (eg, > 5 log)  Biochemical breakthrough—abnormal ALT  Hepatitis flares, hepatic decompensation

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Consequences of Antiviral-Resistant HBV  Loss of initial virologic, biochemical, and histologic response  Virologic and biochemical breakthrough  Hepatitis flares, hepatic decompensation, and death  Increased risk of HBV recurrence postliver transplant  Limit future treatment options  Transmission to treatment-naive persons → public health problem

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Selection of LAM-Resistant Mutations Limits Future Treatment Options L180M A181V/T T184G/S/A/C S202G M204V/1 N236T M250V LAM FTC LdT ADV ETV

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Multirug-Resistant HBV Responds Poorly to Combination Therapy Brunelle MN, et al. Hepatology. 2005;41: HBVLAM Fold Δ ADV Fold Δ LAM + ADV Fold Δ WT1.0 N236T L180M + M204V> L180M + M204V + N236T>

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights 5 samples with single drug resistant mutations 11 samples with MDR mutations Multidrug-Resistant HBV Mutants 15 samples from 6 patients Direct sequencing Clonal analysis215 clones Mutations to > 1 drug on the same genome in 183 clones Mutations to only 1 drug in 31 clones Wild-type HBV DNA in 1 clone Mutations to > 1 drug on the same genome in 5 clones Mutations to only 1 drug in 89 clones 94 clones Yim HJ, et al. Hepatology In press.

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Multidrug-Resistant HBV Mutants (cont’d)  Mutations to both therapies locate in same HBV genome in 85% clones analyzed  Progressive evolution from –All clones with LAM-R mutations → –Mixtures of clones with multidrug R mutations and clones with LAM-R mutations → –All clones with multidrug-resistant mutations  Combination therapy directed against mutants to each treatment may not be adequate in suppressing multidrug- resistant HBV

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Prevention of Antiviral-Resistant HBV  Judicious use of antiviral treatment—avoid futile/unnecessary treatment  Initiate treatment with combination therapy—what agents to combine?  Use potent agent that has high genetic barrier to resistance  Monitor viral response—switch therapy if response suboptimal  Avoid sequential monotherapy  Avoid cross-resistant drugs

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Management of Patients With Antiviral-Resistant HBV  Close monitoring for viral rebound, hepatitis flare, and decompensation  Strategies –Stop treatment and observe if patient did not warrant treatment initially (immune tolerant patient, inactive carriers) –Continue current treatment temporarily and observe if HBV DNA level is low, ALT is normal, and no cirrhosis or immune suppression –Implement rescue therapy immediately if viral rebound or hepatitis flare and in all patients with cirrhosis or immune suppression

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Rescue Therapy for Antiviral- Resistant HBV  Lamivudine-R –Add adefovir/tenofovir –Switch to emtricitabine + tenofovir or switch to entecavir (risk of subsequent entecavir-R)  Adefovir-R* –Add lamivudine or switch to emtricitabine + tenofovir –Switch to entecavir (if no prior LAM-R)  Entecavir-R* –Add or switch to adefovir or tenofovir  Multidrug R → ??? *Limited in vivo data

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights The Changing Face of Antiviral Therapy Robert P. Perrillo, MD Director, Academic Affairs Section of Gastroenterology and Hepatology Ochsner Clinic Foundation New Orleans, Louisiana

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights HBeAg Seroconversion vs Level of HBV DNA Suppression Lau GK, et al. N Engl J Med. 2005;352: On treatmentFollow-up Mean HBV DNA (log 10 copies/mL) * PEG-2a + placebo HBeAg seroconversion EOF = 32%* HBeAg seroconversion EOF = 27%* PEG-2a + LAM LAM HBeAg seroconversion EOF = 19% Weeks

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights On-Treatment ALT Maximums and HBeAg Seroconversion at Week 72 Piratvisuth T, et al. EASL Patients With HBeAg Seroconversion Rates in PEG/PLCPEG/LAMLAM ALT > 5 x bALT6/14 (43%)6/16/ (38%)3/12 (25%) > 10 x ULN20/48 (42%)12/35 (34%)3/31 (10%) > 5 - < 10 x ULN28/74 (38%)27/86 (31%)16/64 (25%) ≤ 5 x ULN39/149 (26%)35/150 (23%)33/177 (19%)

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights On-Treatment Flares (3 x BSL) With PEG-IFN α-2b According to Genotype Flink HJ, et al. Gut. 2005;54: A n = 19 Percent 33% 74% 43% B n = 7 C n = 11 D n = 26 P =.046 On-treatment flares A n = 19 18% 47% 28% 19% B n = 7 C n = 11 D n = 26 P =.05 Treatment response after flare 27% NB: Only host-induced flare and height of ALT during flare predicted response All HBsAg seroconverters had host-induced flare Percent

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights HBsAg Seroconversion: PEG-IFN in HBeAg(+) Patients According to Genotype 1. Flink HJ, et al. Am J Gastro. 2006;101: Hadziyannis S, et al. EASL PEG-IFN α-2b [1] A n = 90 3% 9% 2% B n = 23 C n = 39 D n = % Patients (%) PEG-IFN α-2a [2] A n = 23 2% 0% B n = 76 C n = 162 D n = % Patients (%) 21 24

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights 6-Month and 2-Year Posttreatment Responses in HBeAg-Negative CHB 1. Marcellin P, et al. N Engl J Med. 2004;351: Marcellin P, et al. EASL Months Posttreatment, % (n = 177) 2 Years Posttreatment, % (n = 116) ALT normal59 [1] 66 [2] HBV DNA < 20,000 copies/mL43 [1] 48 [2] HBV DNA < 400 copies19 [1] 23 [2] HBsAg loss4 [1] 9 [2]

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Tenofovir vs Adefovir in LAM- Resistant CHB van Bömmel F, et al. Hepatology. 2004;40: *P <.001 vs ADV Week 24Week 36Week Mean change in log 10 HBV DNA (PCR) Tenofovir 300 mg/day for weeks (n = 35) Adefovir 10 mg/day for weeks (n = 18) % HBV DNA < 400 copies/mL at Week 48  100% of tenofovir patients  44% of adefovir group -5.2* * * -2.8

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Virologic Response to Entecavir vs LAM: Week 48 vs 96 ParameterEntecavir, % (n = 354) LAM, % (n = 355) HBV DNA(-)  At Week 48*6736*  At Week HBeAg seroconversion  At Week  At Week Chang TT, et al. N Engl J Med. 2006;354:

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Entecavir vs Lamivudine in LAM-Refractory, HBeAg+ CHB Sherman M, et al. Hepatology. 2004;40: Patients (%) Histologic Improvement Composite Endpoint † * 55 * * -6 HBV DNA Mean Change From Baseline (log 10 copies/mL) Entecavir 1.0 mg QD (n = 141) LAM 100 mg QD (n = 145) ALT < 1.25 x ULN, HBV DNA < 0.7 MEq/mL † ALT < 1.25 x ULN, HBV DNA < 0.7 MEq/mL

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Combination LAM + ADV: Efficacy Outcomes at Week 104 *Defined as  1 log increase over lowest prior value on 2 or more successive visits (at least one value > 10 4 ) and same criteria at last visit † Roche, Cobas, LLOD 200 copies LAM + PLAC, % (n = 57) LAM + ADV, % (n = 54) HBeAg seroconversion2013 HBeAg loss2419 Sustained virologic breakthrough*4017 HBV DNA negative by PCR † 1426 ALT normalization4147

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Virologic Response at Week 52 to LdT, LAM, or Combination Therapy Lai, et al. Gastroenterology LdT + LAM LdTLAM % with HBeAg loss * 28 % 33% 17% % HBeAg sero 22% 31% 15% % Patients HBV DNA negative 32% 61%* 49% by PCR N *P <.05 compared to LAM

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Hepatitis B: Histology and Normal ALT in 452 Chinese Patients Yang et al. Chinese J Dig Dis. 2002;3:150. Patients (%) Grade 2 or MoreStage 2 or More Normal ALT, HBeAg positive Normal ALT, HBeAg negative Normal ALT, HBeAg negative Normal ALT, HBeAg positive

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Risk of Cirrhosis or HCC According to Baseline HBV DNA 1. Evans AA. AASLD Abstract Chen G. AASLD Abstract Chen G. EASL Abstract Iloeje UH, et al. Gastroenterology. 2006;130: Population Outcome VariableHBV DNARelative Risk 3754 Asian Americans [1] HCC< 10 5 > Chinese [2] Mild/mod CHB Cirrhosis/HCC , , Taiwanese [3] Cirrhosis≤10 3 vs 10 4 vs ≥ 10 5 E (-) 1.0, 1.9, 4.9 E (+) 2.6, 6.2, Taiwanese [4] Cirrhosis≥ 10 4 to < 10 5 ≥ 10 5 to < 10 6 ≥

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights New Drugs for the Treatment of Chronic Hepatitis B Patrick Marcellin, MD, PhD Professor of Medicine Service d’Hepatologie INSERM CRB3 Hôpital Beaujon University of Paris Clichy, France

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Emtricitabine Monotherapy in Chronic Hepatitis B  Emtricitabine is approved for treatment of HIV  FTCB 301: double-blind, placebo-controlled, phase III trial  248 patients randomized to receive: –Emtricitabine (200 mg/day) or placebo for 48 wks Shiffman M, et al. AASLD Abstract Week ResultsEmtricitabine, % (n = 167)Placebo, % (n = 81)P Value Histologic response <.001 Improvement in fibrosis <.009 Normal ALT <.001 Undetectable HBV DNA <.001 HBeAg seroconversion NS YMDD resistance12.6--

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Emtricitabine Plus Adefovir  Emtricitabine resistance limits its use as monotherapy –Combination therapy may resolve this issue  FTC-201: double-blind, placebo-controlled, phase II study –30 HBeAg-positive nucleoside-naive patients –Randomized to adefovir + emtricitabine or adefovir alone Lau G, et al. AASLD Abstract 245. Median Change in HBV DNA Adefovir, log 10 copies/mL (n = 14) Adefovir + Emtricitabine, log 10 copies/mL (n = 24) P Value Week Week

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights GLOBE: Year 1 Results of Telbivudine for Chronic Hepatitis B Lai C, et al. AASLD Abstract LB01. Summary of Year 1 Results With Telbivudine OutcomeHBeAg-Positive Patients, %HBeAg-Negative Patients, % LdT (n = 458) LAM (n = 463) LdT (n = 222) LAM (n = 224) Undetectable HBV DNA  Week 52  Week 76 75* 75* (n = 163) (n = 165) 88* 84* (n = 68) (n = 67) Virologic breakthrough by Week 483*102*9 Normalized ALT  Week 52  Week * (n = 163) (n = 165) (n = 68) (n = 67) Fibrosis decline by Week HBeAg seroconversion by Week 7641* (n = 100)26 (n = 93)N/A *P <.05 vs LAM  GLOBE trial: phase III international study (N = 1367)

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights GLOBE: Early HBV DNA Levels and Year 1 Outcomes With Telbivudine Lai C, et al. AASLD Abstract 92. Week 24 HBV DNA Levels, copies/mL Week 52 OutcomeUndetectable300 to < 3 log log 10 > 4 log 10 HBV DNA negative  HBeAg positive  HBeAg negative Normal ALT levels  HBeAg positive  HBeAg negative Virologic breakthrough  HBeAg positive  HBeAg negative HBeAg seroconversion  Year 1 outcomes linked to viral load at Weeks 12 and 24 –93% of individuals with HBV DNA > 3 log 10 copies/mL at Week 24 failed to seroconvert by Year 1

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights HBV DNA Undetectability at 1 Year by Genotype Thongsawat S, et al. EASL Abstract 110. HBeAg Positive BCOtherBC LdT LAM HBV DNA Undetectable (%) HBeAg Negative

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights 018 Trial: LdT vs ADV in HBeAg+ CHB Patients Results at 24 Weeks Chan HL, et al. EASL Abstract 52. Serum HBV DNA Mean Log ¹º Change From Baseline ± SE Weeks Adefovir (n = 89) Telbivudine (n = 44) PCR Negative at 6 Months Telbivudine: 38.6% Adefovir: 12.4% P < HBeAg Loss at 6 Months Telbivudine: 16% Adefovir: 10%

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Tenofovir vs Adefovir in LAM- Refractory Patients  Retrospective analysis: LAM-refractory patients switched to tenofovir 300 mg/day (n = 38) or adefovir 10 mg/day (n = 68)  More tenofovir patients with undetectable HBV DNA at M6  More patients receiving tenofovir exhibited HBeAg and HBsAg loss vs adefovir after up to 2 years van Bömmel F, et al. AASLD Abstract 184. Undetectable HBV DNA Tenofovir 300 mg/day, % (n = 38) Adefovir 10 mg/day, % (n = 68) Month Month Month Outcome Tenofovir 300 mg/day, % (n = 38) Adefovir 10 mg/day, % (n = 68) HBeAg loss4913 HBsAg loss196

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Tenofovir Use in Patients With Incomplete Response to Adefovir  Retrospective analysis (N = 20) of tenofovir in patients with chronic hepatitis B who had suboptimal response to adefovir –Lamivudine experienced prior to adefovir treatment –Mean change from baseline in HBV DNA -0.4 log 10 copies/mL (range: -4.2 to +3.4) during the adefovir treatment phase  At tenofovir initiation, the mean HBV DNA was 6.6 log 10 copies/mL –Mean changes from baseline in HBV DNA –- 3.2 log 10 copies/mL (range: -1.4 to -5.7) at 3 months –-3.8 log 10 copies/mL (range: -1.4 to -6.7) at 6 months –18 of 20 (90%) patients achieved HBV DNA < 400 copies/mL after a mean of 4 months (range: 1-9) –3 patients lost HBeAg after 3-5 months van Bömmel F, et al. AASLD Abstract 1000.

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights 12-Week Treatment With Clevudine Marcellin P, et al. AASLD Weeks Change From Baseline in Log 10 Serum HBV DNA Treatment period 10 mg 30 mg 50 mg

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Clevudine in HBeAg-Positive Patients  Multicenter, randomized, phase III trial –Patients received 24 weeks of clevudine 30 mg/day (n = 243) or placebo (n = 61) –Follow-up: 24 weeks Yoo BC, et al. AASLD Abstract 186. Outcome Clevudine 30 mg/day (n = 182) Placebo (n = 61) Change in HBV DNA, log 10 copies/mL  End of treatment  End of follow-up -5.10* -2.02* HBV DNA undetectable at treatment end, %590 Normalized ALT, %  End of treatment  End of follow-up 68* 61* HBeAg seroconversion at end of follow-up, %1012 *P <.0001 vs placebo

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Clevudine in HBeAg-Negative Patients  Multicenter, randomized, phase III trial –Patients received 24 weeks of clevudine 30 mg/day (n = 63) or placebo (n = 23) –Follow-up: 24 weeks Yoo BC, et al. AASLD Abstract 183. Outcome Clevudine 30 mg/day (n = 63) Placebo (n = 23) P Value Change in HBV DNA, log 10 copies/mL  End of treatment  End of follow-up <.0001 Undetectable HBV DNA, %  End of treatment  End of follow-up <.0001 Normal ALT, %  End of treatment  End of follow-up

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Pradefovir for Chronic Hepatitis B: Week 48 Analysis  Phase II randomized, open-label, multicenter trial of ADV-naive patients (N = 244) –Patients received adefovir 10 mg/day or pradefovir 5, 10, 20, or 30 mg/day for 48 weeks –Genotype C: 67% – Asian: 100% – HBeAg positive: 70% Lee KS, et al. EASL Abstract 741. Week 48 Outcome Pradefovir Adefovir (n = 50) 5 mg/day (n = 47) 10 mg/day (n = 49) 20 mg/day (n = 48) 30 mg/day (n = 48) HBV DNA < 400 copies/mL, % ALT normalized  HBeAg-positive patients, n  HBeAg-negative patients, n HBeAg seroconversion, %

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Pradefovir for Chronic Hepatitis B: Week 48 Analysis (cont’d) Lee KS, et al. EASL Abstract 741 Week Pradefovir 5 mg (n = 47) Mean (SE) Change in HBV DNA From Baseline (log 10 copies/mL) Adefovir 10 mg (n = 50) Pradefovir 10 mg (n = 49) Pradefovir 20 mg (n = 48) Pradefovir 30 mg (n = 48)

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Effect of Valtorcitabine on Serum HBV DNA Lim SG, et al. EASL Study Week Placebo 600 mg/day 900 mg/day 1200 mg/day Serum HBV DNA Mean Log 10 Reduction From Baseline

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights ANA380 (LB80380) in HBeAg-Positive Patients With LAM Resistance  Phase II, multicenter, dose- escalating study (N = 65)  HBeAg-positive Asian patients  5 dose escalation groups –ANA380 (30, 60, 90, 150, or 240 mg/day) + LAM for 4 weeks followed by 8 weeks ANA380 monotherapy Lai CL, et al. EASL (n = 13) 60 (n = 14) 90 (n = 14) 150 (n = 12) 240 (n = 12) Reduction in HBV DNA by Week 12 (log 10 copies/mL) ANA380 Dose

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Update on the Management of HBV Marc Ghany, MD Investigator, Liver Diseases Branch NIDDK, National Institutes of Health Bethesda, Maryland

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Goals of the 2006 NIH Workshop on the Management of CHB  Update definitions of response and endpoints of therapy using more sensitive PCR-based assays  Standardize the format in which clinical trials should be presented  Identify areas for future research

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Should HBV Genotyping Be Included in Initial Assessment? Yes HBV genotypes may correlate with  Rate of spontaneous HBeAg seroconversion  Severity of liver disease  Development of clinically important mutations  Response to treatment No  Many of the studies were retrospective, small and cross-sectional  Usually compared 2 major genotypes with each other A vs D, B vs C  Referral bias of studies conducted at tertiary care centers  Assays for genotyping not standardized

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Who Should Receive Treatment? HBsAg Positive HBeAg Inactive carrier/mild chronic hepatitis Monitor every 3-6 months Decompensated cirrhosis Consider antiviral therapy/ refer for OLT HBV DNA > 10 4 IU/mL; elevated ALT 3-6 months Pos Consider antiviral therapy Neg HBV DNA < 10 4 IU/mL; ALT normal 3-6 months Grey zone Consider Liver biopsy

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Should HBeAg(+) Patients With Normal ALT but High HBV DNA Receive Therapy? Yes  Older patient with higher risk for HCC  Patients with strong family history of HCC  Patients requiring cytoreductive chemotherapy  Patients in third trimester of pregnancy with high viral load No  Poor response to therapy  Risk of developing antiviral resistance

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Definitions of Response Virological  Full: decrease in HBV DNA to levels that are undetectable by sensitive PCR assay, eg, < 60 IU/mL  Partial: decrease in HBV DNA by at least 2 logs and to less than 20,000 IU/mL  Primary nonresponse: decrease in HBV DNA by < 2 logs Serological  HBeAg seroconversion: loss of HBeAg with gain of anti-HBe  HBsAg seroconversion: loss of HBsAg with gain of anti-HBs

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Definitions of Response Biochemical  Normalization of serum ALT level Histological  Decrease in hepatic necroinflammatory score by at least 2 points with no worsening in fibrosis score Complete response  Combined biochemical, virological, serological (loss of HBsAg), and histological

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Timing of Response On-treatment response  Initial response: response achieved at any time within the first 12 months of therapy  End-of-treatment response: response at the end of a defined course of therapy  Maintained response: response that persists while on therapy  Breakthrough: response that is lost while on therapy Off-treatment response  Sustained response: response that is maintained for ≥ 6 months after therapy is stopped  Relapse: response that is lost after therapy is stopped

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Interferon Therapy  Pros –Finite duration of therapy –Durable response –No resistance  Cons – Route of administration—injection –Frequent side effects –Cost

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Ideal Clinical Situation for IFN Therapy  High ALT (> 5 x ULN) and low HBV DNA level (< 200,000 IU/mL)  Younger patient  Black  Well-compensated cirrhosis  No contraindications to use of interferon  ? Genotype A or B

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Lamivudine  Pros –Oral –Negligible side effects –Excellent safety profile –Low cost  Cons –High rate of resistance and cross-resistance with other nucleoside analogues –Long/indefinite duration of therapy

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Ideal Clinical Situation for Lamivudine Use  Short duration of therapy –Prevention of disease flares/reactivation during chemotherapy –Protracted or severe acute hepatitis  Safety a concern –During pregnancy  Cost a concern –HBeAg-negative CHB in developing countries

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Adefovir  Pros –Route of administration: oral –Low rate of resistance –Effective against lamivudine resistant virus  Cons – Slow response and high rate of primary nonresponse – ? Renal toxicity with long-term use – Long/indefinite duration of therapy

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Ideal Clinical Situation for Adefovir Use  HBeAg-positive and HBeAg-negative chronic hepatitis B with low HBV DNA  Management of lamivudine-resistant chronic hepatitis B

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Entecavir  Pros –Route of administration: oral –Potent with low rate of resistance –Effective against LAM-R  Cons –Long-term safety unknown –Long/indefinite duration of therapy

clinicaloptions.com/hep 4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights Ideal Clinical Situation for Entecavir Use  HBeAg-positive or HBeAg-negative chronic hepatitis B with high viral load  Management of lamivudine resistance  Management of HIV/HBV coinfection in patients who do not require HAART