Evidence-based Treatment for Hepatitis B Infection Joseph Sung MD, PhD Center for Emerging Infectious Diseases Department of Medicine and Therapeutics The Chinese University of Hong Kong

HBV Infection 2 billion people in the world infected by HBV 350 million chronic carriers 75% are Asian 25-40% of them had cirrhosis or HCC 1.2 million death per year

Natural Course of HBV Infection Risk of HCC increased by 200 folds Beasley et al. Lancet 1981, Liaw et al. Liver 1989 Hepatitis Cirrhosis HCC 5-year survival 55% 40% of Asian men with CHB die of complications Weissberg et al. Ann Intern Med 1984, Beasley Lancet 1981 15-20% develop Cirrhosis in 5 years Liaw et al. Hepatology 1988, Fattovich et al Gut 1991

First line therapy Lamivudine is the most commonly used therapy What is the role of interferon and pegylated interferon?

Lamivudine for HBeAg+ CHB At one year Response Rate Asian Multi-center Trial on Lamivudine

Lamivudine for HBeAg+ CHB Cumulative Rate Asian Multi-center Trial on Lamivudine

Interferon for HBeAg+ CHB 15 RCT, 837 adults received IFN-a 5-10 MU 3x/week for 4-6 months Sustained Response Wong et al. Ann Intern Med 1993

Interferon for HBeAg- CHB 4 RCT, 86 adults received IFN-a 5-10 MU 3x/week for 4-6 months Sustained Response Alberti et al. Gastroenterol 2000

Treatment for HBV Infection Interferon-alpha 15-37% Lamivudine 16%, after 9-12m Combining IFN & Lamivudine?

Lamivudine plus Interferon-a Lamivudine for 8 week before combination with IFN Per-protocol Analysis P = 0.02 OR = 3.3 P =.07 Schalm et al. Gut 2000

Lamivudine plus Interferon-a Lamivudine for 8 week before combination with IFN Intention-to-treat Analysis P=0.12 OR=2.0 Schalm et al. Gut 2000

Current Treatment Guidelines for HBeAg positive CHB First Line Therapy: EASL = IFN1 APASL = IFN or lamivudine2* AASLD = IFN, lamivudine or adefovir3 Endpoint of treatment: HBeAg seroconversion3 1. EASL Consensus Statement J Hepatol 2003 (EASL Guidelines) 2. Liaw et al J Gastroenterol Hepatol 2003 (APASL Guidelines) 3. Lok and McMahon Hepatology 2004 (AASLD Guidelines)

Current Treatment Guidelines for HBeAg negative CHB Long-term therapy required (≥12 months) and optimal duration of therapy is unknown1–3 First Line Therapy: EASL = IFN1 APASL = IFN or lamivudine2* AASLD = IFN, lamivudine or adefovir3**  Lamivudine are not preferred due to need for long-term treatment 1. EASL Consensus Statement J Hepatol 2003 (EASL Guidelines) 2. Liaw et al J Gastroenterol Hepatol 2003 (APASL Guidelines) 3. Lok and McMahon Hepatology 2004 (AASLD Guidelines)

PIFN vs IFN: phase II Study 194 IFN-naive randomised EOT 48 weeks EOF 24 weeks 4.5 MIU IFN -2a tiw 90 µg PEG-IFN a-2a (40KD) qw 24 week follow-up 180 µg PEG-IFN a-2a (40KD) qw 270 µg PEG-IFN a-2a (40KD) qw 6 12 18 24 48 Study weeks Cooksley, J Viral Hepatitis 2003

Peginterferon alfa-2a Individual Responses at End of Follow-up 4.5 MIU IFN-2a tiw (n=51) 180 mg Peginterferon alfa-2a qw (n=46) HBeAg loss 25% 35% HBeAg seroconversion 33% HBV DNA suppression* 39% ALT normalisation Peginterferon alfa-2a: Individual Responses at End of Follow-up At 24 weeks after the end of treatment, Peginterferon alfa-2a acheived higher responses in all individual parameters compared with conventional IFN. Cooksley et al. J Viral Hepat 2003 Cooksley et al. J Viral Hepat 2003 * <500,000 copies/mL

Peginterferon alfa-2a Phase III Study HBeAg+ Patients with HBeAg-positive CHB were randomized using a 1:1:1 ratio ITT population: n=814 End of Treatment 48 weeks End of Follow-up 72 weeks Randomized Peginterferon alfa-2a 180 g qw + oral placebo qd Designed to compare the efficacy and safety of Peginterferon alfa-2a with/without lamivudine vs lamivudine alone in patients with HBeAg-positive chronic hepatitis B (CHB) This study represents the largest prospective study in HBeAg-positive CHB to date First and only study comparing a pegylated IFN with LAM monotherapy 24 week follow-up Peginterferon alfa-2a 180 g qw + lamivudine 100 mg qd lamivudine 100 mg qd 24 48 72 Study weeks

HBeAg seroconversion (%) HBeAg Seroconversion at End of Follow-up According to Baseline ALT Level Peginterferon alfa-2a + placebo Peginterferon alfa-2a + lamivudine 20 40 60 lamivudine 41% 37% HBeAg seroconversion (%) Patients with 30% 29% 28% 27% 20% 20% HBeAg Seroconversion at End of Follow-up According to Baseline ALT Level Because of poor response to conventional IFN, current treatment guidelines do not recommend treatment of patients with low ALT levels (<2 x ULN). However, patients with low baseline ALT levels responded as well to Peginterferon alfa-2a as those with moderate ALT levels. These results support the use of Peginterferon alfa-2a in patients with HBeAg-positive CHB and low baseline levels (<2 x ULN). Patients with very high baseline ALT (ie values > 5 x ULN) had the greatest chance of a response. Regardless of baseline ALT, treatment with Peginterferon alfa-2a resulted in higher HBeAg seroconversion rates than treatment with lamivudine. Lau et al. AASLD 2004 16% 27/92 19/93 19/96 36/121 30/111 20/129 24/58 25/67 13/47 2 x ULN 2–5 x ULN >5 x ULN ALT

HBeAg Seroconversion at End of Follow-up (Week 72) by Baseline HBV DNA Peginterferon alfa-2a + placebo Peginterferon alfa-2a + lamivudine lamivudine 53% 36% HBeAg seroconversion (%) Patients with 31% 28% 27% 21% HBeAg Seroconversion at End of Follow-up (Week 72) by Baseline HBV DNA By 24 weeks after the end of treatment, Peginterferon alfa-2a-treated patients with baseline HBV DNA levels <9 log10 copies/ml had a 53% chance of achieving HBeAg seroconversion. Treatment with Peginterferon alfa-2a ( lamivudine) resulted in higher rates of seroconversion than treatment with lamivudine alone, irrespective of baseline HBV DNA level. Cooksley et al. EASL 2005 18% 17% 10% 37/70 20/56 24/78 39/138 40/147 21/123 11/63 14/68 7/71 9.07 (1st Quartile) 9.07–10.26 >10.26 (4th Quartile) HBV DNA (log10 cp/mL)

Peginterferon alfa-2a Phase III Study HBeAg negative EOF 72 weeks EOT 48 weeks Randomised 180 μg PEG-IFN 2a + placebo 24 week follow-up 180 μg PEG-IFN 2a + 100 mg lamivudine 100 mg lamivudine qd 24 48 72 weeks Marcellin, NEJM 2004

Percentage of Patients with Normal ALT 6 and 12 Months After the End of Treatment 6 months after end of treatment (Initial Study ) 12 months after end of treatment (LT Study) 59% 59% 60% 52% 44% 43% Patients (%) n=177 n=99 n=179 n=98 n=181 n=65 Peginterferon a-2a + placebo Peginterferon a-2a + lamivudine lamivudine

Percentage of Patients with HBV DNA <20,000 cp/mL 6 and 12 Months After the End of Treatment 6 months after end of treatment (Initial Study ) 12 months after end of treatment (LT Study) 44% 43% 42% 41% 31% Patients (%) 29% n=177 n=97 n=179 n=97 n=181 n=65 Peginterferon a-2a + placebo Peginterferon a-2a + lamivudine lamivudine

New Antiviral Agents Adefovir Entecavir Clevudine Telbivudine

Adefovir dipivoxil Prodrug of adefovir Nucleotide analogue of adenosine monophosphate Phosphorylated intracellularly to adefovir diphosphate Chain terminator of HBV DNA N O P H 2

HBeAg+ (48 weeks, ITT) Marcellin et al N Engl J Med; 2003

Adverse events and discontinuations Marcellin et al 2003, Hadziyannis et al 2003

Entecavir vs Lamivudine in HBeAg positive patients ETV-022 trial (BEHoLD Study Group) Multinational, double-blind, phase 3 study 709 HBeAg(+) patients Randomized to entecavir (0.5 mg/day) or lamivudine (100 mg/day) Chang T, et al. AASLD 2004. Abstract 70. 48-wk Results Entecavir (n = 354) Lamivudine (n = 355) P Value Histologic improvement, % 72 62 .0085 Median change in HBV DNA from baseline, log10 copies/mL -6.98 -5.46 < .0001 HBV DNA < 0.7 mEq/mL, % 91 65 HBV DNA < 400 copies/mL, % 69 38 HBeAg seroconversion, % 21 18 NS Dr. Chang and colleagues evaluated the use of entecavir vs lamivudine in 709 HBeAg-positive chronic hepatitis B patients who were randomized to receive either entecavir (0.5 mg/day) or lamivudine (100 mg/day). Histologic improvement was noted in significantly more patients given entecavir compared with lamivudine (72% vs 62%). The median log reduction in HBV DNA was nearly 7 logs with entecavir, which was significantly higher than that observed with lamivudine, and HBV DNA suppression was significantly more likely to occur with entecavir. The HBeAg seroconversion rate was similar in the 2 treatment arms. For more information, please go online to: http://www.clinicaloptions.com/hep/conf/aasld2004/cs/70.asp

Entecavir vs Lamivudine in HBeAg negative patients ETV-027 trial Multinational, double-blind, phase 3 study 638 HBeAg(-) nucleoside-naive patients Randomized to entecavir (0.5 mg/day) or lamivudine (100 mg/day) Shouval D, et al. AASLD 2004. Abstract LB-07. 48-wk Results Entecavir (n = 325) Lamivudine (n = 313) P Value HBV DNA < 400 copies/mL, % 91 73 < .0001 HBV DNA < 200 copies/mL, % 89 70 ALT normalization, % 86 81 NS Histologic improvement, % (n = 296) 61 (n = 287) .014 Improved Ishak fibrosis score, % 36 38 Dr. Shouval and colleagues conducted a multinational, double-blind, phase 3 trial to evaluate the use of entecavir vs lamivudine in 638 patients with HBeAg-negative chronic hepatitis B. Patients were randomized to receive entecavir (0.5 mg/day) or lamivudine (100 mg/day) for 48 weeks. Histologic improvement occurred in 70% of patients treated with entecavir vs 61% of patients treated with lamivudine, and HBV DNA suppression was significantly better with entecavir vs lamivudine. However, the fibrosis score improvement and ALT normalization rates were similar between the 2 treatment arms. Overall, this study shows the superiority of entecavir over lamivudine in the treatment of HBeAg-negative chronic hepatitis B. For more information, please go online to: http://www.clinicaloptions.com/hep/conf/aasld2004/cs/LB-07.asp

Clevudine Use in Chronic HBV ALT normalization in most patients after 12 weeks ALT and virologic response maintained 24 weeks after treatment Clevudine is safe and well tolerated over 12 weeks of therapy Lee H-S, et al. AASLD 2004. Abstract 1130. CLV 50 mg (n = 24) CLV 30 mg Placebo (n = 33) Median change in HBV DNA at Wk 12, log10 copies/mL -4.45 -4.47 -0.12 ALT normalization, % Wk 12 55 53 7 Wk 36 63 71 12 HBeAg loss, % 16 19 20 Normalization of ALT levels was achieved in most patients after 12 weeks of therapy, and ALT and virologic responses were maintained 24 weeks after treatment. The median changes in HBV DNA at Week 12 were -4.45 and -4.47 log10 copies/mL for clevudine, 50 and 30 mg, respectively. HBeAg loss at Week 12 occurred in 16% of patients in both arms given clevudine. Overall, clevudine was shown to be safe and well tolerated during the 12-week course of therapy. For more information, please go online to: http://www.clinicaloptions.com/hep/conf/aasld2004/cs/1130.asp

Clevudine Use in Chronic HBV CLV (30 mg/day) for 24 wks vs 12 wks Greater antiviral activity against HBV No emergence of viral breakthrough Higher rates of ALT normalization Favorable safety profile Lee K, et al. AASLD 2004. Abstract 1138. 12 Wks of CLV Wk 24 of CLV Median change in HBV DNA from baseline, log10 copies/mL -4.21 -4.85 HBV DNA < 300 copies/mL, % 19.0 57.1 ALT normalization, % 47.6 66.7 HBeAg loss, % 10.0 23.8 Seroconversion, % 5.0 9.5 In this study, a 24-week course of clevudine (30 mg/day) was compared with a 12-week course of therapy. Overall, greater antiviral activity and higher rates of ALT normalization were achieved with longer therapy. The median change in HBV DNA was -4.21 log10 copies/mL with 12 weeks of treatment and -4.85 log10 copies/mL with 24 weeks of treatment, and more patients achieved HBV DNA levels below 300 copies/mL with longer therapy (57% vs 19%). The rates of ALT normalization, HBeAg loss, and HBeAg seroconversion were all higher after 24 weeks of treatment. No cases of viral breakthrough were reported, and clevudine had a favorable safety profile at 24 weeks. For more information, please go online to: http://www.clinicaloptions.com/hep/conf/aasld2004/cs/1138.asp

Telbivudine (LdT) Telbivudine is an L-nucleoside analogue (L-deoxythymidine) Potent and selective inhibitor of HBV replication Preferentially inhibits second strand HBV DNA synthesis in vitro Phase 1/2 dose-finding study 42 HBV-infected patients randomized to 25, 50, 100, 200, 400, or 800 mg/day of LdT or placebo LdT blocks HBV viral production at doses of 25-800 mg/day Biphasic HBV decline Effectiveness > 99% at doses ≥ 200 mg/day Time to relapse after stopping LdT longer with higher doses Telbivudine, also known as LdT, is a nucleoside analogue that is a potent and selective inhibitor of HBV replication that preferentially inhibits second-strand HBV DNA synthesis in vitro. Neumann and colleagues reported their findings from a phase 1/2, dose-finding study in which 42 patients with chronic hepatitis B were randomized to receive telbivudine in doses of 25, 50, 100, 200, 400, or 800 mg/day or placebo. Their results indicated that telbivudine blocks HBV viral production at all doses tested and that the HBV DNA decline was biphasic. The effectiveness of treatment was > 99% at telbivudine doses ≥ 200 mg/day. Interestingly, time to relapse after stopping telbivudine therapy was also longer with higher doses of telbivudine. This is valuable preliminary evidence that shows the effectiveness and safety of yet another nucleoside analogue. Further data are awaited. For more information, please go online to: http://www.clinicaloptions.com/hep/conf/aasld2004/cs/186.asp Neumann A, et al. AASLD 2004. Abstract 186.

Lamivudine for patients with chronic hepatitis B and advanced liver disease YF Liaw, JJY Sung, WC Chow et al on behalf of the CALM study group* Two abstracts have now been published based on this landmark study: Liaw YF, Sung JJY, Chow WC, Shue K, Keene O, Farrell G Lamivudine delays clinical progression and reduces incidence of liver cancer in patients with HBV-related cirrhosis: Results of a prospective placebo-controlled clinical trial J Gastroenterol Hepatol 2003;18(suppl):A104 Effects of lamivudine on disease progression and development of liver cancer in advanced chronic hepatitis B: a prospective placebo-controlled clinical trial Hepatology 2003;38(No.4,suppl1):262A-3A 41 sites from Taiwan, HK, China, Singapore, Thailand, Malaysia, Australia, NZ, Philippines

Study Design 2:1 e- Seroconversion FU off therapy Relapse Clinical endpoint Termination 2:1 Double- blind treatment One year open label lamivudine 67 (10%) 72 (11%) Drop-out n: 651 53 (8%) 460 (71%) off therapy 6m FU e- YMDDm adefovir 10mg YMDDw lamivudine Fallow-up for 24 months for Clinical endpoints

Study design and outcomes at the time of study termination (研究设计与结果) 中止治疗后随访 血清转换 复发 2:1 Double- blind treatment Seroconversion FU off therapy Relapse 67 (10%) 临床终点 One year open label lamivudine Clinical endpoint 双盲治疗 71 (11%) n = 651 终止 拉米夫定 一年 开放试验 This was a parallel group, centrally randomised, multicentre, double-blind, placebo-controlled study for up to 5 years. Patients were randomised 2:1 to receive lamivudine 100mg/day or placebo within 30 days after screening. During the double-blind phase, treatment was stopped for individual patients who reached a confirmed clinical endpoint. The investigators could also stop blinded treatment for patients who had achieved HBeAg seroconversion, and follow them up off-therapy. Patients who reached clinical endpoints or became HBV DNA positive again after stopping treatment due to HBeAg seroconversion were offered one-year open label treatment. When the trial was terminated according to the pre-defined stopping criteria, the patients were offered one year open label treatment. Patients could choose to continue with commercial lamivudine treatment during the 6-month follow-up after the open label treatment phase. The median treatment duration was 32.4 months (range 0-42 months, with 71% of patients having received study medication for at least 30 months) at the time the study was terminated. The shaded area in the slide depicts the scope of analysis of the treatment result of this study. Termination Lamivudine 拉米夫定(n=436) Placebo安慰剂 (n=215) 460 (71%) 脱落 Drop-out Primary endpoint analysis data set 分析主要终点数据 53 (8%) Exposure: Median 32.4 (0-42) months 研究中位时间 32.4 (0-42) 个月

Time to disease progression DB treatment and off-treatment follow-up 出现疾病进展的时间 双盲治疗以及終止治疗后随访 Percentage with disease progression 出现疾病进展 的比例 21% Placebo P=0.001 Kaplan-Meier estimates of patient proportions with disease progression after 3 years were 9% for lamivudine and 21% for placebo (ITT population). 9% Lamivudine Time to disease progression (months) 疾病进展的时间 (月) Placebo安慰剂 (n=215) Lamivudine 拉米夫定(n=436)

Time to Child-Pugh score increase Percentage with disease progression DB treatment and off-treatment follow-up Child-Pugh 评分升高的时间 双盲治疗以及終止治疗后随访 Percentage with disease progression 出现疾病进展 的比例 Placebo 10% Kaplan-Meier estimates of patient proportions with increase in Child-Pugh score after 3 years were 4% on lamivudine and 10% on placebo (ITT population). P=0.023 4% Lamivudine Time to disease progression (months) 疾病进展的时间 (月) Placebo安慰剂 (n=215) Lamivudine 拉米夫定(n=436)

Time to diagnosis of HCC Percentage with diagnosis DB treatment and off-treatment follow-up 诊断肝癌的时间 双盲治疗以及終止治疗后随访 Percentage with diagnosis 诊断肝癌的比例 10% Placebo Kaplan-Meier estimates of patient proportions developing HCC were 5% and 10% for lamivudine and placebo respectively. P=0.047 5% Lamivudine Time to diagnosis (months) 诊断时间（月） Excluding 5 cases in yr1: HR=0.47; P=0.052 Placebo安慰剂 (n=215) Lamivudine 拉米夫定(n=436)

Covariate modelling of time to disease progression* Variable in model Comparison Hazard ratio (95% CI) P Treatment group LAM vs PLB 0.42 (0.26, 0.68) <0.001 Sex Female vs Male 0.71 (0.35, 1.43) 0.34 Fibrosis staging score 5 vs  4 1.60 (0.83, 3.09) 0.16 6 vs  4 1.90 (1.04, 3.47) 0.036 Child-Pugh score 6 vs 5 2.85 (1.62, 5.04) <0.001 (7, 8, 9) vs 5 6.24 (3.36, 11.58) <0.001 Baseline ALT (/ULN) Per unit increase 0.91 (0.76, 1.08) 0.29 Age Per 10-year increase 1.41 (1.12, 1.77) 0.003 Baseline HBV DNA (log10) Per 10-fold increase 0.93 (0.75, 1.15) 0.50 Covariate modeling of time to disease progression showed that the factors to significantly impact the outcome, other than treatment, were baseline CP score, baseline Ishak fibrosis score. * using Cox’s proportional hazards model

Disease progression in patients with HBV Genotype B & C >95% either Genotype B or C

Time to Disease Progression by YMDD status % with disease progression 5 10 15 20 25 6 12 18 24 30 36 Placebo (n=215) 21% YMDDm (n=209) (49%) Wild Type (n=221) Placebo % with disease progression 13% YMDDm 5% Those with YMDD mutants were more likely to have disease progression than those without YMDD mutant, but had less endpoints than untreated controls WT Time after randomisation (months)

Incidence of Fatalities by YMDD variant HBV status Patient Group No Before Endpoint After Endpoint ** Lamivudine 430 2* (0.5%) 10 (2.3%) • YMDDw 221 2 (0.9%) 2 (0.9%) • YMDDm 209 0 8 (3.8%) Placebo 214 0 4 (1.9%) * 1 patient died of drowning following MI, 1 patient died of lymphoma recurrence ** 7 deaths occurred during off treatment FU and 7 during open label lamivudine

Conclusion Pegylated interferon alfa is more effective than lamivudine and standard interferon as a monotherapy Pegylated interferon alfa shows promising effects for HBeAg negative CHB Newer anti-virals (entecavir, LdT, clevudine) are more potent than lamivudine Long term viral suppression will halt the progression of liver disease.