Professor George KK Lau The University of Hong Kong Hong Kong SAR, China HBeAg-positive chronic hepatitis B: why do I treat my patients with pegylated interferon

Yang et al. NEJM Percent cumulative incidence Year HBsAg+, HBeAg+ HBsAg+, HBeAg – HBsAg –, HBeAg – Positivity for HBeAg is Associated with an Increased Risk of HCC – Taiwanese Data

Hsu. Hepatology Spontaneous HBeAg Seroconversion Confers Favorable Long-term Outcomes

Timing is important: earlier seroconversion is associated with reduced risk of cirrhosis Chu & Liaw 2007 Longitudinal study of 240 patients with normal ALT at baseline * Hazard ratio for progression to cirrhosis for each decade without HBeAg seroconversion Hazard ratio* = 3.4 (95% CI 1.4–8.2) < ≥50 Age of HBeAg seroconversion (years) % of patients with cirrhosis

IFN  -treated patients (n=233) Matched untreated controls (n=233) Cirrhosis 18% p = 0.041* 34% HCC 3% p = 0.011* 13% Survival 98% p = 0.003* 53% Lin et al. EASL 2005 and J Hepatol 2007 *p vs control Follow-up: mean 11 years (median 6.6 years; range: 1.1 to 16.5 years) Long-term Outcome of IFN  Treatment in HBeAg-positive CHB: 11-year Follow-up

Sung et al Aliment Pharmacol Ther 2008 Twelve studies (n = 2742) enrolling patients treated by IFN vs. control showed that the risk of HCC after treatment was reduced by 34% (RR: 0.66, 95% CI: 0.48–0.89). Meta-analysis: Effect of IFN treatment on HCC

Favourable long-term outcome following HBeAg seroconversion HBeAg seroconversion Disease remission HBsAg loss/seroconversion Prevention of HCC Increased survival Hoofnagle Ann Intern Med 1981; Fattovich Hepatology 1986;Di Bisceglie Gastroenterology 1987; Niederau NEJM 1996; Chu Gastroenterology 2002; van Zonneveld Hepatology 2004 HBeAg loss

Registered treatment of CHB-2009 Immune therapy (finite) Conventional IFN-  Pegylated IFN-  2a Anti-viral (life-long) Lamivudine Adefovir dipivoxil Entecavir Telbuvidine Clevudine (Korea) Tenofovir (EU and FDA) Sustained remission (~30-40%) = Maintained remission = Low viraemia ALT normalisation Immune control, no antiviral drugs Continued need for antiviral drugs

What are the response rates with longer-term treatment with NAs? LAM ADVETV LdT HBeAg response (%) Years of treatment PEGASYS off-treatment NAs on-treatment 24 wk 48 wk

Resistance Profiles of antiviral agents Genotypic resistance to adefovir 2 HBeAg(-) Year of treatment of resistance (%) Cumulative probability Genotypic resistance to lamivudine 1 HBeAg(+) Prevalence of resistance (%) Year of treatment 1. Lok AS, et al. Gastroenterology. 2003;125: Borroto-Esoda K. J Hepatol. 2006;44(suppl 2):S (Poster 483). 3. Standrigg DN, et al. J Hepatol. 2006;44(suppl 2):S191 (Poster 514). 4. Lai CL, et al. Hepatology. 2006;44(4 suppl 1):222A (Oral 91). 5. Colonno et al. J Hepatol 2007;46(suppl 1):S293 (oral 781). HBeAg(+) and (-) patients Nucleoside naive Lamivudine refractory Viral rebound with genotypic resistance to entecavir Year of treatment Cumulative Probability of Resistance (%) < Year of treatment Cumulative incidence of resistance (%) HBeAg(+)HBeAg(-) Viral rebound with genotypic resistance to telbivudine 3, <1 15

Peginterferon alfa-2b (12KD) 100  g qw* + oral placebo * PEG-IFN  -2b (12KD) dose reduced to 50  g qw after 32 weeks Janssen et al Lancet 2005 Peginterferon alfa-2b (12KD) 100  g qw*+ lamivudine 100 mg od Peginterferon alfa-2b (12KD) in HBeAg- positive CHB Patients with HBeAg-positive CHB were randomised using a 1:1 ratio ITT population: n= Study weeks 26 week follow-up End of Treatment (52 weeks) End of Follow-up (78 weeks) Off-label Product Use

HBeAg Loss 29% 35% Patients (%) End of Treatment (Week 52) End of Follow-up (Week 78) 44% P= % P=0.91 Peginterferon alfa-2b (12KD) + placebo Peginterferon alfa-2b (12KD) + lamivudine Janssen et al Lancet 2005 Relapse at wk 78 : 5/40 (13%) Vs 22/57 (39%), p=0.005 Janssen et al Gut 2007

Long-Term Follow-Up of Peginterferon and Lamivudine Combination Treatment in HBeAg-Positive CHB Chan LY Hepatology 2005

HBeAg Seroconversion* in Asian Patients (6 Months Post-treatment) 31% 19% Patients (%) PEGASYS + placebo PEGASYS + lamivudine Lamivudine 29% n=238 n=232 NS P=0.02 P=0.005 Overall population: HBeAg seroconversion 32% in PEGASYS monotherapy arm *HBeAg loss and presence of anti-HBe ABs

59/69 14/ Lau et al. N Engl J Med 2005; 2. Lau et al. EASL 2006 HBeAg Seroconversion Long-term Roll-over Study: 1 Year Analysis 173 patients from the PEGASYS mono therapy arm entered the long-term study (63% of original study): 69 responders and 103 non responders 86% of initial responders maintained response after 1 year % Patients (%) 87/ Initial study 1 24 weeks post-treatment Long-term study 2 48 weeks post-treatment 14% of initial non- responders developed a late response 6–12 months post-treatment 42% Overall response

HBsAg need to be cleared before the development of cirrhosis PopulationStatus at Clearance No. of cases Mean age (yr) Outcome Caucasian 1 Cirrhosis324422% Asian 2 Cirrhosis295417% No cirrhosis %* *only in those with HCV/HDV co-infection 1 Fattovich et al Am J Gastro 1998; 2 Liaw et al Gastroenterology 2002

Direct antiviralsInterferon-based Patient/physician preference Consider risk of drug resistance Length of treatment Side effects Immunocompetent Compensated liver disease Younger patients NA-failures/resistant Immunosuppressed Advanced liver disease IFN/PEG-IFN non-responders High ALT Low HBV DNA Liver lesions NA treatment should not be prescribed until the PATIENT understands that they CANNOT be stopped abruptly for any reason Who should be treated with what?

NAs Long-term maintenance (years) Risk of resistance, and cross-resistance – monitor closely Use in combination? Prescribe responsibly Optimising response in HBeAg-positive CHB through immune control PEGASYS Short-term, finite duration (48 wks) Long-term benefit in ~1/3 pts HBsAg seroconversion achievable No resistance Prior exposure to NAs not a barrier to tx For patients who do not respond or for whom IFN contraindicated we need to know how to use NAs appropriately !

Summary: 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 Lau GK, Marion P Hepatol Int 2008