George LAU

Hepatitis B e antigen positive patients: Why do I treat my patient with pegylated interferon? 2nd Hepatitis Paris conference George KK Lau, M.D. The University of Hong Kong

What do we want to achieve in treating HBeAg+ CHB patients? HBeAg seroconversion Disease remission ( ↓ HBV DNA; ↓ ALT) HBsAg loss/seroconversion Prevention of HCC and cirrhosis Increased survival Hoofnagle et al. Ann Intern Med 1981; Fattovich et al. Hepatology 1986; Di Bisceglie et al. Gastroenterology 1987; Niederau et al. NEJM 1996; Chu et al. Gastroenterology 2002; van Zonneveld et al. Hepatology 2004 HBeAg loss

Why is serological clearance of HBeAg  HBsAg important? HBsAgHBeAgALTRelative Risk normal1 (23/71,105 person-yr) elevated normal elevated normal elevated109 Yang et al., NEJM 2002 Study of HBV progression and HCC in 11,893 men in Taiwan

Registered treatment of chronic hepatitis B-2007 Immune therapy (finite) Conventional IFN-  Pegylated IFN-  2a Anti-viral (life-long) Lamivudine Adefovir dipivoxil Entecavir LdT Clevudine (Korea) Immune control, no antiviral drugs Continued need for antiviral drugs Aim for sustained remissionSuppression of viral replication ? Immune recovery

Peg-IFN  2aPeg-IFN  2b Cooksley 2003Lau 2005Janssen 2005Chan 2005 Comparator arm IFNLAM LAM+ pIFN LAM vs. pIFN + LAM Peginterferon-  trials on HBeAg positive CHB Hui et al Semin Liv Disease 2006

PEGASYS in CHB: Phase III Study Designs HBeAg-positive CHB – ITT population: n=814 Lamivudine 100 mg qd PEGASYS 180  g qw + lamivudine 100 mg qd PEGASYS 180  g qw + oral placebo qd week follow-up 72 Study weeks Randomised End of Treatment 48 weeks End of Follow-up 72 weeks Lau et al. NEJM 2005

HBV DNA Levels Over Time plus HBeAg Seroconversion at End of Follow-up 12 *all numbers shown are log 10 reduction from baseline On-treatmentFollow-up Mean HBV DNA (log 10 copies/mL) * -5.8* * % 27% 19% P=0.023 P<0.001 HBeAg Seroconversion Rates at End of Follow-up PEGASYS n=271 n=272 PEGASYS + LAM LAM Study week

HBV DNA Suppression in Patients Achieving HBeAg Seroconversion On-treatmentFollow-up Study week Mean HBV DNA (log 10 copies/mL) ,000 cp/mL patients with HBeAg seroconversion maintained DNA levels <10,000 cp/mL Fried et al. EASL 2005

Incidence of Hepatocellular Carcinoma (HCC) by HBV DNA Level Chen et al. JAMA 2006 Cumulative Incidence of HCC (%)* ≥ –10 5 <10 4 PCR negative Level of HBV DNA (cp/mL) *at the end of the 19 th year of follow-up 10 5 –10 6

% 38% 40% 69% 25% 10% 33% Chang NEJM 2006 Lau NEJM 2005 (%) Janssen Lancet 2005 ETVLAMPeg-2a + LAM LAMPeg-2aPeg-2b + LAM Peg-2b No DNA <400cp/ml HBeAg seroconversion at end of treatment (%) End of Treatment HBeAg seroconversion in Relation to Extent of HBV DNA Suppression

Serological clearance of HBsAg with current treatment ( ~ 1 yr) %Lam 1 ADV 2 LdT 3 ETV 4 Pegasys 5 Adoptive immune transfer 6 HBeAg181225*2132- HBsAg *HBeAg loss Spontaneous HBsAg clearance in Chinese %/yr 1 Lai et al NEJM 1998, 2 Marcellin et al NEJM 2003, 3 Poynard et al. J Hepatol 2004, 4 Chang et al. Hepatology 2004, 5 Lau et al. NEJM 2005, 6 Lau et al Gastroenterology 2002

Patients with HBeAg seroconversion (%) Lamivudine 1 1. Lok et al Gastroenterology 2004; 2. Marcellin et al AASLD 2004 Adefovir 2 Years 16% 17% 23% 28% 35% 12% NA NA = not available On-therapy Response to Long-term Nucleos(t)ide Analog Therapy in HBeAg-positive CHB 29% 43%

845 a.a. Terminal protein Pol/RTRNaseH ABCED YMDD V173L L180M M204I/V GVGLSPFLLA I(G)II(F) (rt1)(rt 344) Identified Mutations Associated with Drug Resistance LAM 1 / FTC 2 ETV * 4 T184A/G/I/S S202G/I M250V ADV 3 A181V N236T LdT 5 M204I * All ETV resistance require background YMDD mutations 1 Allen MI, et al. Hepatology 1998; 27: Gilead data on file 3 Qi X, et al. J Hepatol 2004, 40 (suppl 1): Tenney et al. AAC. 2004:48: Lai CL, et al. Hepatology 2003; 38: 262A 6 Soriano V et al, AASLD 2004 spacer

Duration of Lamivudine-Resistant Mutations (Years) % of Patients with Hepatitis Flare Not 4 detected Not 4 detected 3–5 x ULN n = 998 Long-Term Safety of Lamivudine in HBeAg Positive CHB Hepatitis Flares Hepatitis flares (ALT >3 x ULN) more frequent in patients with lamivudine resistance (P <.005) Hepatitis flares increased with duration of lamivudine resistance (P <.001) 5–10 x ULN >10 x ULN Lok ASF, et al. Gastroenterology. 2003;125:1714.

HBeAg Relapse Following Lamivudine and IFN  Cumulative % relapse of HBeAg seroconversion Time (weeks) after the end of therapy LAM IFN  van Nunen et al. Gut 2003 Cumulative rate of relapse in patients who had achieved HBeAg seroconversion by end of treatment 54% 32%

Adverse Events experienced in Chronic HBeAg+ patients PEGASYS ® + placebo (n=271) PEGASYS ® + lamivudine (n=271) lamivudine (n=272) At least 1 adverse event240 (89%) 152 (56%) Pyrexia133 (49%)148 (55%)12 (4%) Fatigue99 (37%) 36 (13%) Headache76 (28%)81 (30%)27 (10%) Myalgia70 (26%)77 (28%)8 (3%) Alopecia55 (20%)78 (29%)6 (2%) Injection site reaction30 (11%)15 (6%)0 (0%) Dizziness25 (9%)32 (12%)11 (4%) Urinary tract infections21 (8%)15 (6%)29 (11%) * AEs with an incidence of >10% in one treatment arm during treatment and up to 8 weeks post-therapy

Long-term Follow-up Study: 1-year Analysis * Lau et al. NEJM 2005; Marcellin et al. NEJM 2004 ** 1-year analysis of patients from initial study who completed 6-month follow-up Lamivudine 100 mg qd PEGASYS 180 μg qw mg lam qd PEGASYS 180 μg qw + placebo qd 48 weeks 12 months post-EOT (week 96) 5 years post-EOT ** Initial study* EOT (week 48) 6 months post EOT (week 72) Long-term study

40% 39% HBeAg Seroconversion: 40% of Asian Patients Achieved Sustained Responses 1 year Post-treatment 31% Patients achieving HBeAg seroconversion (%) n=238 n=58/150 n=60/150 Week 48Week 72Week 96 Time point Lau et al. Shanghai Hong Kong Liver Congress 2006 Initial study Entered long- term study  Over 80% of patients with responses 6 months post-treatment sustained these responses 1 year post-treatment (83%) Late responders Sustained responders

No HBeAg Seroconversion (n=67) HBV DNA Levels 1 Year Post-treatment According to Type of Response HBV DNA 1 year post-treatment (copies/ml) Sustained HBeAg Seroconversion (n=53) Late HBeAg Seroconversion (n=13)

StudyFU (yrs) Number of patientsComments IFNControl Niederau NEJM IFN induced serological clearance of HBeAg has improved clinical outcome Lin JVH IFN increase HBV clearance, reduces HCC, and prolongs survival Fattovich Hepatol IFN-induced disease remission associated with improved survival in HBeAg-positive patients with compensated cirrhosis Lin J Hepatol IFN-induced HBeAg seroconversion reduces liver cirrhosis and cancer Long-term follow-up on CHB patients with active hepatitis or advance fibrosis/cirrhosis Rx with IFN-based therapy Lau GK. J Hepatol 2007

Nucleos(t)ide analoguesImmunomodulatory Oral administrationSubcutaneous Potent HBV DNA suppressionLess potent HBV DNA suppression Not imunomodulatoryAntiviral and immunomodulatory Few side effectsFrequent side effects Risk of resistance developmentNo resistance HBsAg seroconversion rareHBsAg seroconversion more common Long-term therapy – potential for drug fatigue Finite therapy duration Pros and cons of available treatment options

Significant* Baseline Predictors of Response 24 Weeks Post-treatment Variable HBeAg-negative (combined response**) HBeAg-positive (HBeAg seroconversion) PEGASYS treatment (vs. lam) Age (young > old)  Gender (female > male)  Ethnicity  Bodyweight  Baseline ALT (high > low) Baseline HBV DNA (low > high) Baseline HBeAg (low > high) na Genotype  *P<0.05 by MV analysis; **ALT normalisation and HBV DNA <20,000 cp/mL Roche data on file

HBsAg-seroconversion by Genotype 1 Flink, Am J Gastroenterol 2006; 2 Hadziyannis, EASL 2005 PEG-IFN α-2b A n=47 5% 8% 0% B n=12 C n=21 D n= % Percentage of patients (%) HBV genotype PEG-IFN α-2a 2 22% A n=23 2% 0% B n=76 C n=162 D n=9 18 Percentage of patients (%) HBV genotype

Treatment Algorithm to Improve Clinical Outcomes 1st choice Aiming for sustained remission Using a treatment of finite duration eg pegylated or conventional IFN  Sustained remission yes no* 2nd choice Maintained remission Using a treatment of indefinite duration eg nucleos(t)ide analogues *or IFN  contraindicated / not tolerated Survival