Robert PERRILLO

2 nd Paris Hepatitis Conference Why Do I Treat my HBeAg Negative Chronic Hepatitis B Patients with Pegylated Interferon

They say that to have hepatitis B is to have it forever… But perhaps they were just talking about the duration of treatment needed for nucleoside analogs

Proper Patient Selection Remains Key Age < 60, otherwise healthyAny age adult Baseline HBV DNA < 10 9 copies/mL Baseline HBV DNA > copies/mL Baseline ALT at least 2-3 x ULNBaseline ALT > 5 x ULN Genotype A or B preferentiallyAny genotype Non-cirrhoticCirrhosis, w/wo decompensation Chemotherapy Perrillo, Hepatology, 2006 Pegylated Interferon Nucleoside Analog

Finite treatment Diminished infectivity Durability Potential for long term benefit Drug cost /cost of care Indirect costs Tolerability Convenience Need for monitoring Many Factors Go Into a Treatment Decision Perrillo, Hepatology, 2006

Problems Confronting Clinician with HBeAg-Negative Hepatitis B Becoming the most common form of CHB in world today High rate of relapse to conventional strategies Patients tend to be older with severe disease ….affects tolerability to IFN Little known about predictors of sustained virologic response to IFN

IFN alfa Lam Lam ADV ADV ECV ECV Peg IFN Antiviral activity /+++ + Resistance None25 –68% at 1-5 yrs % at 1-5 yrs < 1% to yr 2 None EOT Resp. At 12 mo46-54%65-85% 70-75% 84% 36% SVR22-30%<10-15% 8% NA 36% On Rx Response at 24 Mos 46% 52-65% 71-73% NA NA After Hadziyannis and Papatheodoridis, Semin Liver Disease, 2006 Comparative Experience with Current Drugs in HBeAg (-) CHB

Problems Confronting Clinician with HBeAg Negative Hepatitis B Becoming most common form of CHB in world today High rate of relapse to conventional strategies Patients tend to be older with severe disease Little known about predictors of sustained virologic response to IFN

216 Naïve Patients 3 MU tiw x mos or 3 MU tiw x mos 51 retreated Relapse : 1.6 x more likely with short course Sustained remission 3.5 times more likely if biochemica/virologic response by mo 4

ALT-0 Univariate Multivariate P = P = Hazard Ratio Factors Associated with Relapse After 12 Months of Standard IFN (63 Patients) Baltayiannis Aliment Pharmacol Ther, 2006 HBV DNA < 10,000 copies at treatment mo 6 prior ETOH > 60 gm/d age gender alcohol ALT-0 HBV DNA grade stage

Virologic relapse Fung, 2004 Months to Relapse 50 Chinese patients treated with LAM 37 treated for 2 yrs 27 neg. by PCR for ≥ 9 mos meet criteria for treatment withdrawal Prolonged PCR Negativity Does not Allay Concerns About Relapse Clinical relapse

Worldwide Distribution of HBV Genotypes Genotype A Genotype B Genotype C Genotype D Genotype E Genotype F Genotype G 1 Westland, Gastroenterology 2003; 2 Chu, Gastroenterology 2003 Asia 1 Europe 1 USA 2 Mediterranean 1 42% 46% 9% 83% 14% 35% 40% 15% 22% 35% 31% 10%

Response to PEG-IFN α-2a by Genotype HBsAg-seroconversion in HBeAg neg patients (EOF in 177 patients) Hadziyannis, EASL A n=11 3% 18% 2% 0% B n=43 C n=63 D n=55 Percentage of patients (%)

Predicting Response* to Peg IFN 2a, Lam or Both for HBeAg (-) CHB: 24 Week Post Treatment /10 1/8 19/43 9/41 19/49 Genotype A Genotype B 31/63 36/69 15/57 Genotype C 9/55 20/54 7/63 Genotype D Peg IFN alfa-2a Peg IFN + Lamivudine Lamivudine * ALT normal and HBV DNA < 20,000 copies Bonino, in press, GUT 3/11 44% 22% 16% 37%

4.5 – 15% of all IFN  treated patients 36–45% of sustained responders at 5 – 7 years Anti-HBs-positive: > 90% of those who clear HBsAg Conventional IFN  : HBsAg Clearance in HBeAg-negative CHB Manesis EK, et al. Gastroenterology. 2001;121: Lampertico P, et al. Hepatology. 2003;37:

Retreated During median fu of 7 yrs, HBsAg loss in 18 of 57 SVRs (32%) vs 1% NRs One IFN Course Retreat 11% 25% 36% Yrs From Start of Rx Cumulative HBsAg Loss In SVRs Naive Retreated 5% 69% Cumulative Rate of HBsAg Loss in SVRs

HBsAg Levels with IFN Alfa and Lamivudine in HBeAg (-) CHB 315 sera from 44 patients analyzed for HBsAg/ HBV DNA HBsAg quantitated at multiple time points No correlation between BSL HBsAg and HBV DNA HBsAg decreased in both treatment groups - Sharp drop in most IFN treated patients; continued drop after treatment if SVR - More gradual slope for LAM: EPTU for HBsAg is median of 18 yrs of treatment Manensis, EASL, 2005

HBsAg ng/mL BaselineTreatment Week 12 Week 12 Treatment Treatment Week 60 Week 60 Follow up Week 12 Week 12 Follow up Week 24 Resp 1* 6,515 6,515 7, Resp 2 >7692 >7692 > Resp 3 1,619 1, Resp 4 >7,692 >7, NR 1 NR 1 1,212 1,056 NA 1,910 1,473 NR 2 6,881 >7,692 6,088 6,823 5,219 NR NA 189 NR 4 5,019 6,030 7,584 6,161 7,715 Measuring HBsAg in HBeAg (-) CHB: with Extension of Peg IFN Alfa -2a Perrillo, 2006 * Response = PCR negative at FU week 24

Why Is HBsAg Clearance So Important?

Qualitative Differences Between HBsAg Loss and HBeAg Seroconversion Durability of virologic response Lower levels of genomic template (cccDNA ) Better long-term prognosis –Less Liver cancer –Lower rate of progression to cirrhosis Less chance of viral reactivation –Spontaneous –Immune suppression related

PEG IFN alfa-2a in HBeAg (-) CHB Two Years Post-treatment Follow-up * Marcellin et al. NEJM 2004 Lamivudine 100 mg qd PEGASYS 180 μg qw mg lam qd PEGASYS 180 μg qw + placebo qd 48 weeks 2 years post-EOT 5 years post-EOT Initial study* EOT (week 48) 6 months post EOT (week 72) Long-term study PEGASYS 180 μg + placebo (n = 116) PEGASYS 180 qw + lam qd (n = 114)

Six Month and 2 Year Post-treatment Responses in HBeAg (-) CHB 6 MO POST TRT (n = 177 ) 2 YR POST TRT (n = 116) ALT Normal 59% 1 32% 2 HBV DNA < 20,000 copies/mL 43% 1 49% 2 HBV DNA < 400 copies 19% 1 16% 2 HBsAg loss 4% 1 9% 2 1 Marcellin, NEJM, 2004; 2 Marcellin, AASLD, 2006

Other Considerations

Cost-effectiveness of IFN  -Based Therapies IFN  more cost effective over long-term than lamivudine or adefovir in HBeAg-negative CHB 1 PEG-IFN  2a offers life expectancy benefits over lamivudine at a favorable cost-effectiveness ratio in patients with HBeAg-positive or HBeAg- negative CHB 2,3 1. Kanwal F, et al. Ann Intern Med. 2005;142: Sullivan SD, et al. APASL Abstract DL Veenstra, et al. APASL Abstract 132.

Peg Interferon Alfa-2b Plus Adefovir: Effect on cccDNA and HBsAg Reduction Serum HBV < 100 copies Hepatocyte total HBV DNA reduction Hepatocyte cccDNA reduction Serum HBsAg reduction HBsAg seroconversion 13/24 (54%) log -2.4 log log 4/24 (17%) Wursthorn, Hepatology, 2006

HBeAg Negative Chronic Hepatitis B: Rationale for Pegylated IFN First Lasting responses to finite therapy avoids long term treatment with nucleoside analogs Predictors of response are becoming better identified HBsAg concentration decreases during therapy and decline in level may be predictive of response and length of therapy needed

Rationale for Pegylated IFN First (cont) HBsAg loss occurs in SVRs and this increases as a function of time Genotype D patients tend not to respond to Peg IFN given alone but this group may possibly benefit from combination therapy (??) Patients can be treated subsequently with nucleoside analogs without increased risk for drug failure should Peg IFN fail to achieve benefit

C’est fini