Evidencebased Treatment for Hepatitis B Infection

1
Evidence-based Treatment forHepatitis 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
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 15-37
• Lamivudine 16, after 9-12m
• Combining IFN Lamivudine?

10
Lamivudine plus Interferon-aLamivudine for 8
week before combination with IFN
Per-protocol Analysis
Schalm et al. Gut 2000
11
Lamivudine plus Interferon-aLamivudine for 8
week before combination with IFN
Intention-to-treat Analysis
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 unknown13
• 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
EOF
48 weeks
194 IFN-naiverandomised
EOT
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
48
0
6
12
18
24
Study weeks
Cooksley, J Viral Hepatitis 2003
15
Peginterferon alfa-2aIndividual Responses at End
of Follow-up
Cooksley et al. J Viral Hepat 2003
lt500,000 copies/mL
16
Peginterferon alfa-2a Phase III Study HBeAg
Patients with HBeAg-positive CHB were randomized
using a 111 ratio ITT population n814
End of Treatment 48 weeks
End of Follow-up 72 weeks
Randomized
Peginterferon alfa-2a 180 ?g qw oral placebo qd
24 week follow-up
Peginterferon alfa-2a 180 ?g qw lamivudine 100
mg qd
lamivudine 100 mg qd
0
24
48
72
Study weeks
17
HBeAg Seroconversion at End of Follow-up
According to Baseline ALT Level
Peginterferon alfa-2a placebo
Peginterferon alfa-2a lamivudine
lamivudine
41
37
Patients with HBeAg seroconversion ()
30
29
28
27
20
20
16
19/96
36/121
30/111
20/129
24/58
25/67
13/47
27/92
19/93
25 x ULN
gt5 x ULN
?2 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
31
Patients with HBeAg seroconversion ()
28
27
21
18
17
10
24/78
39/138
40/147
21/123
11/63
14/68
7/71
37/70
20/56
9.0710.26
gt10.26 (4th Quartile)
?9.07 (1st 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 100 mg lamivudine
100 mg lamivudine qd
48
0
24
72
weeks
Marcellin, NEJM 2004
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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 ()
n177
n179
n181
n99
n98
n65
lamivudine
Peginterferon a-2a placebo
Peginterferon a-2a lamivudine
25
Percentage of Patients with HBV DNA lt20,000
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
29
Patients ()
n177
n179
n181
n97
n97
n65
Peginterferon a-2a placebo
Peginterferon a-2a lamivudine
lamivudine
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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

28
HBeAg (48 weeks, ITT)
Marcellin et al N Engl J Med 2003
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Adverse events and discontinuations
Marcellin et al 2003, Hadziyannis et al 2003
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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.
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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.
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 2004. Abstract 1130.
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 2004. Abstract 1138.
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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 gt 99 at doses 200 mg/day
• Time to relapse after stopping LdT longer with
  higher doses

Neumann A, et al. AASLD 2004. 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
41 sites from Taiwan, HK, China, Singapore,
Thailand, Malaysia, Australia, NZ, Philippines
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Study Design
37
Study design and outcomes at the time of study
termination (???????)
???????
????
??
21 Double- blind treatment
Seroconversion
FU off therapy
Relapse
67 (10)
One year open label lamivudine
????
Clinical endpoint
????
71 (11)
n 651
???? ?? ????
??
Termination
Lamivudine ????(n436) Placebo??? (n215)
460 (71)
??
Drop-out
Primary endpoint analysis data set ????????
53 (8)
Exposure Median 32.4 (0-42) months ?????? 32.4
(0-42) ??
38
Time to disease progression DB treatment and
off-treatment follow-up ????????? ?????????????
Percentage with disease progression
?????? ???
21
Placebo
P0.001
9
Lamivudine
Time to disease progression (months) ??????? (?)
Placebo??? (n215) Lamivudine ????(n436)
39
Time to Child-Pugh score increase DB treatment
and off-treatment follow-up Child-Pugh
??????? ?????????????
Percentage with disease progression
?????? ???
10
Placebo
P0.023
4
Lamivudine
Time to disease progression (months) ??????? (?)
Placebo??? (n215) Lamivudine ????(n436)
40
Time to diagnosis of HCC DB treatment and
off-treatment follow-up ??????? ?????????????
Percentage with diagnosis
???????
10
Placebo
P0.047
5
Lamivudine
Time to diagnosis (months) ????(?)
Excluding 5 cases in yr1 HR0.47 P0.052
Placebo??? (n215) Lamivudine ????(n436)
41
Covariate modelling oftime to disease
progression
Variable in model Comparison Hazard ratio (95
CI) P Treatment group LAM vs PLB 0.42
(0.26, 0.68) lt0.001 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) lt0.001 (7, 8, 9) vs 5 6.24
(3.36, 11.58) lt0.001 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
using Coxs proportional hazards model
42
Disease progression in patients with HBV Genotype
B C
gt95 either Genotype B or C
43
Time to Disease Progression by YMDD status
Placebo (n215)
21
YMDDm (n209) (49)
Wild Type (n221)
Placebo
with disease progression
13
YMDDm
5
WT
Time after randomisation (months)
44
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
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.