1. 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

2. 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

3. 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

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

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

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

7. 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

8. 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

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

10. 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

11. 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

12. 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)

13. 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)

14. 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

15. 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

16. 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

17. 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

18. 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)

19. 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 mg lamivudine
100 mg lamivudine qd 24 48 72
weeks
Marcellin, NEJM 2004

24. 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

25. 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

26. New Antiviral Agents
Adefovir
Entecavir
Clevudine
Telbivudine

27. 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

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

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

30. 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 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:

31. 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 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:

32. 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 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 and 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:

33. 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 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 log10 copies/mL with 12 weeks of treatment and 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:

34. 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 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:
Neumann A, et al. AASLD Abstract 186.

35. 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

36. 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

37. 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

38. 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)

39. 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)

40. 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)

41. 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 vs  (0.83, 3.09) 0.16
6 vs  (1.04, 3.47) 0.036
Child-Pugh score vs (1.62, 5.04) <0.001
(7, 8, 9) vs (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

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

43. Time to Disease Progression by YMDD status % with disease progression5 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)

44. Incidence of Fatalities by YMDD variant HBV status
Patient Group No Before Endpoint After Endpoint **
Lamivudine * (0.5%) 10 (2.3%)
• YMDDw (0.9%) 2 (0.9%)
• YMDDm (3.8%)
Placebo (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

45. 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.