introduction eugene r. schiff, md
TRANSCRIPT
Introduction
Eugene R. Schiff, MD
Leonard Miller Professor of MedicineChief, Division of Hepatology
Director, Center for Liver DiseaseUniversity of Miami School of Medicine
Miami, Florida
When Do You Start Therapy?
HBV DNA >104-5 c/mL
ALT 1–2 x ULN
When Do You Start Therapy?
HBV DNA >104-5 c/mL
ALT 1–2 x ULN
What Are the First-Line Therapeutic Options?
Adefovir
Entecavir
Peginterferon
Lamivudine?
When Do You Start Therapy?
HBV DNA >104-5 c/mL
ALT 1–2 x ULN
What Are the First-Line Therapeutic Options?
Adefovir
Entecavir
Peginterferon
Lamivudine?
How Do You Manage Resistance,
Breakthrough, and Suboptimal Response?
Choice of drug
Monitor patient status
Switch or add-on therapy
Compliance
When Do You Start Therapy?
HBV DNA >104-5 c/mL
ALT 1–2 x ULN
What Are the First-Line Therapeutic Options?
Adefovir
Entecavir
Peginterferon
Lamivudine?
How Do You Manage Resistance,
Breakthrough, and Suboptimal Response?
Choice of drug
Monitor patient status
Switch or add-on therapy
Compliance
When Do You Stop Therapy?
HBeAg seroconversion?
HBV DNA <104-5 c/mL?
Normalization of ALT?
When Do You Initiate HBV Therapy?
Kris V. Kowdley, MD
Professor of MedicineSchool of Medicine
University of Washington Medical CenterSeattle, Washington
Natural Progression of HBV
Chronic Infection Cirrhosis Death
1. Torresi J, et al. Gastroenterology. 2000;118:S83. 2. Fattovich G, et al. Hepatology. 1995;21:77.3. Perrillo RP, et al. Hepatology. 2001;33:424.
5%–10%1
Liver Failure
30%1
23% in 5 y2
Liver Cancer (HCC)
Chronic HBV is the 6th leading indication of liver transplantation in the US3 (~5%)
Liver Transplantation
Acute flare
6% in 5 y2
UndetectableSerum
HBV DNA
HBeAg Lossor
Seroconversion
HBsAgClearance
Treatment Endpoints in Chronic Hepatitis B
TreatmentEndpoints
Decreased HAIand Fibrosis
Normal ALT
cccDNA Clearance
Objectives of Therapy
Decrease hepatic inflammation Decrease rate of progression to fibrosis Decrease incidence of long-term sequelae
(cirrhosis, end-stage liver disease, hepatocellular carcinoma)
Goals of Treatment in HBV
• Suppression of viral replication• Eradication of serum HBV DNA• HBeAg seroconversion• Liver histology improvement or
stabilization• HBsAg loss
Anti-HBV Treatment Guidelines
Type Year Author
AASLD (US) Evidence-based 2001; updated 2004
Lok ASF, et al1,2
NIH conference* (US)
Position paper 2000/2001 Lok ASF, et al3
US Algorithm* Position paper 2004 Keeffe EB, et al4
EASL (Europe) Evidence-based 2003 de Franchis R, et al5
APASL (Asia) Consensus statement
2003 Liaw YF, et al6
*New published reports coming out soon.
1. Lok ASF, et al. Hepatology. 2001;34:1225. 2. Lok ASF, et al. Hepatology. 2004;39:857. 3. Lok ASF, et al. Gastroenterology. 2001;120:1828. 4. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2004;2:87. 5. de Franchis R, et al. J Hepatol. 2003;39:S3. 6. Liaw YF, et al. J Gastroenterol Hepatol. 2003;18:239.
Accepted Criteria for Therapy
For patients without cirrhosis– HBV DNA >105 copies/mL1,2
– ALT >2 x ULN1,2
For patients with cirrhosis– ALT criteria not necessary1-3
– HBV DNA thresholds are variable1-3
1. Lok ASF, et al. Hepatology. 2004;39:857. 2. de Franchis, et al. J Hepatol. 2003;39:S3. 3. Liaw YF, et al. J Gastroenterol Hepatol. 2003;18:239.
HBV DNAHBeAg (copies/mL) ALT Management
+ >105 ≤2 x ULN Follow
+ >105 >2 x ULN Treat
– >105 >2 x ULN Treat
– – ≤2 x ULN Follow
+/– >105 Cirrhosis If compensated, treat;if decompensated*, refer
for liver transplant
+/– – Cirrhosis If compensated, observe;if decompensated*, refer
for liver transplant
Which Patients Should Be Treated?AASLD Guidelines1
1. Lok ASF, et al. Hepatology. 2004;39:857. 2. INTRON® A (interferon alfa-2b) Product Information. Kenllworth, NJ: Schering Corporation: 2004. 3. PEGASYS® (peginterferon alfa-2a) Product Information. Nutley, NJ: Hoffmann-La Roche Inc.: 2004.
*Do not use interferon or peginterferon if the patient has decompensated cirrhosis.2,3 Specific treatment recommendations are made elsewhere in this activity.
US Treatment Algorithm UpdateHBeAg+ Compensated Disease
• No treatment• Monitor every 6–12 mo
• Monitor every3–12 mo (immune tolerant)
• Consider biopsy, if age >35–40 y, and treat if significant disease
Treat
HBeAg Positive
ALT ElevatedALT Normal
HBV DNA≥105 c/mL
HBV DNA<105 c/mL
Courtesy of Emmet Keeffe, MD. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.
US Treatment Algorithm UpdateHBeAg– Compensated Disease
• No treatment• Monitor every 6–12 mo
• Monitor ALT, or• Consider biopsy, since
ALT often fluctuates, and treat if significant disease
• Long-term treatment required
• Treat• Long-term treatment
required
HBeAg Negative
ALT ElevatedALT Normal
HBV DNA≥104 c/mL
HBV DNA<104 c/mL
Courtesy of Emmet Keeffe, MD. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.
May Choose to Treat or Observe
Treat
HBV DNA(PCR)
HBV DNA<104 c/mL
HBV DNA≥104 c/mL
US Treatment Algorithm UpdateCompensated Cirrhosis
Courtesy of Emmet Keeffe, MD. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.
• Observe
• Wait list for transplant
• Treat• Wait list for transplant
HBV DNA Detectable by PCR?
No Yes
US Treatment Algorithm UpdateDecompensated Cirrhosis
Courtesy of Emmet Keeffe, MD. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.
Wang C, et al. Hepatology. 2005;42:573A.
Prevalence of Fibrosis Among Patients with Immunotolerance
14 immunotolerant individuals recruited– HBV DNA ≥106 copies/mL (median 5.1 x 107; range 4.5 x 103–
3.4 x 108)– 2 normal ALT measurements within 2 years prior to liver
biopsy (median 28 U/L; range 13–77 U/L)– Liver histology measured with Batts and Ludwig scoring
79% of individuals had fibrosis– Stage 1, 36%—Stage 2, 43%– No cirrhosis or septal fibrosis
Baseline mean ALT poorly correlated with liver biopsy stage– R2 coefficient = .08
Role of Liver Biopsy in Patients with Normal ALT and High Viral Load
190 individuals with HBV DNA >10,000 copies/mL– Persistently normal ALT*, n = 57
24% of individuals with persistently normal ALT levels had stage 2–4 fibrosis
Multiple Regression Analysis for Stage ≥2 Fibrosis
Parameter OR 95% CI P Value
ALT 1.778 1.235–2.558 .0020
Inflammation grade 6.790 4.010–11.500 <.0001
Age 1.053 1.027–1.080 <.0001
Alcohol intake 2.741 1.160–6.476 .0216
*Persistently normal ALT, 2 measurements 6 months apart.
Courtesy of M. Lai, MD.Lai M, et al. Hepatology. 2005;42:720A.
Clinical Significance of Viral Replication
Worsening Histology, Including Cirrhosis
HCC
Viral Replication
Elevated ALT
Baseline HBV DNA Level and Relative Risk of HCC
Multivariate-adjusted relative risk of HCC by cohort (N = 3653) entry serum HBV DNA level (94% of subjects with ALT <1 x ULN)
Adjusted for gender, age, smoking, alcohol consumption
0
7
<300 300–9.9x103 1.0–9.9x104 1.0–9.9x105 >105
Rel
ativ
e R
isk
1 1.1
2.3
6.66.1
HBV DNA (copies/mL)
654
32
1
Chen C-J, et al. JAMA. 2006;295:65.
Baseline HBV DNA Level and Cumulative Incidence of HCC
0
2
4
6
8
10
12
14
16
<300 300–<104 104–<105 105–<106 ≥106
N = 3653, 11-y follow-up
Cum
ulat
ive
Inci
denc
e of
HC
C
Chen C-J, et al. JAMA. 2006;295:65.
HBV DNA (copies/mL)
1.3 1.37
3.57
12.17
14.89
Baseline HBV DNA Level and Relative Risk of Cirrhosis
Iloeje UH, et al, Gastroenterology. 2006;130:678.
0
10
<300 300–9.9x103 1.0–9.9x104 1.0–9.9x105 >105
N = 3653, 11-y follow-up
Rel
ativ
e R
isk
1 1.42.5
5.9
9.8
Adjusted for gender, age, smoking, alcohol consumption
HBV DNA (copies/mL)
7654321
98
Effect of Lamivudine on Incidence of HCCTime of Diagnosis of HCC
Reprinted with permission, from Liaw YF, et al. N Engl J Med. 2004;351:1521. Copyright © 2004 Massachusetts Medical Society. All rights reserved.
Months
Lamivudine
Placebo
Dia
gnos
is o
f HC
C (
%)
0
10
60 12 18 24 30 36
P = .047
Effective Viral Suppression ReducesLevel of Inflammation on Biopsy
Mommeja-Marin H, et al. Serum HBV DNA as a marker of efficacy during therapy for chronic HBV infection: analysis and review of the literature. Hepatology. 2003;37:1309. Reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.
Review of 26 prospective studies (3428 patients)
Med
ian
Impr
ovem
ent i
n H
AI
HBV DNA Median log10 Decrease
r = 0.96P < .000003N = 3428
Post-treatment vs baseline
0
1
2
3
4
5
1 2 3 4 5-1-2
Goals of Treatment Are Changing!
1980s: Reduce severity of liver disease
Goals of Treatment Are Changing!
1980s: Reduce severity of liver disease
1990s: Reduce viral replication
Goals of Treatment Are Changing!
1980s: Reduce severity of liver disease
1990s: Reduce viral replication
2000s: Prevent cancer?
Initial Therapy:What Are the Therapeutic Options
and Considerations?
Robert G. Gish, MD
Medical DirectorLiver Transplant Program
California Pacific Medical CenterSan Francisco, California
Current FDA-Approved Anti-HBV Therapies
Interferon alfa-2b Lamivudine Peginterferon alfa-2a Adefovir Entecavir
Lamivudine
LamivudineConsiderations for Use
Short-term therapy– Chemotherapy– Immune suppressants– Pregnancy
Cost Lamivudine no longer a first-choice
therapy due to high rate of resistance1
1. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.
Peginterferon
PeginterferonConsiderations for Use
HBeAg+– Genotype A1,2
– ALT >80 IU/mL2
– HBV DNA <108 copies/mL2
– Compensated liver disease guidelines3-6
– Monoinfected– No psychiatric or medical contraindications
HBeAg-– No specific populations that benefit over others7
– Modest number of patients negative by PCR long-term7
Consider PEG IFN before nucleos(t)ide therapy due to defined treatment intervals and high HBeAg seroconversion rates
Should not be used in decompensated cirrhosis8
1. Janssen HL, et al. Lancet. 2005;365:123. 2. Lau G, et al. N Engl J Med. 2005;352:2682. 3. Liaw YF, et al. J Gastroenterol Hepatol. 2003;18:239. 4. De Franchis R, et al. J Hepatol. 2003;39:S3. 5. Lok AS, et al. Gastroenterology. 2001;120:1828. 6. Lok ASF, et al. Hepatology. 2004;39:957. 7. Marcellin P, et al. Hepatology. 2005;42:580A. 8. PEGASYS® (peginterferon alfa-2a) Product Information. Nutley, NJ: Hoffmann-La Roche Inc.: 2004.
32% 32%
27%
34%
19%22%
0
20
40
60
HBeAg Seroconversion HBV DNA <100,000 copies/mL
PEG IFN (n = 271)
PEG IFN + lamivudine (n = 271)
Peginterferon alfa-2a ± Lamivudine 24-Weeks Posttreatment, Overall
Patie
nts
(%)
With permission from Chow WC, et al. Hepatology. 2005;42:576A.
P < .001 P < .012
Lamivudine (n = 272)
52%
30% 31%
22%22%
29% 28%
18%20%
23%
18% 18%
0
20
40
60
A B C D
12/23 4/18 3/15 23/76 24/82 17/73 50/162 43/156 29/162 2/9 2/11 3/17
Patie
nts
with
H
BeA
g Se
roco
nver
sion
(%)
P = .002*
Genotype
P = .002*
*Mantel Haenszel Chi Square test stratified for the effect of HBV genotype
Peginterferon alfa-2a ± Lamivudine at 24-Weeks Posttreatment
HBeAg Seroconversion, by Genotype
With permission from Chow WC, et al. Hepatology. 2005;42:576A.
PEG IFN (n = 271)
PEG IFN + lamivudine (n = 271)
Lamivudine (n = 272)
Adefovir
5-Year Data Now Available
AdefovirConsiderations for Use
HBeAg+ and HBeAg- infection Continued use if 1-log reduction every 3 mo
and HBV PCR negative at 12–15 mo1,2
– If resistant to adefovir, switch to or add lamivudine, or switch to entecavir3
1. Locarnini S, et al. 40th EASL. April 13–17, 2005. Abstract 36. 2. Unpublished expert opinion. 3. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.
The Efficacy of Adefovir Dipivoxil is Sustained in HBeAg- Patients Over 5 Years
68%75%
71% 72%77%
67%
78%75%
0
20
40
60
80
100
Patie
nts
%
Serum HBV DNA < 1000 copies/mL
ALT Normalization
Treatment Duration (Weeks)
48 96 144 192 48 96 144 192
67%
240
69%
240
5-year cohort of patients
Hadziyannis S, et al. Management of Hepatitis B: 2006: NIH. April 6–8, 2006.
Long-Term Adefovir in HBeAg- InfectionProportion of Patients with Improved Ishak Fibrosis Scores
Over Time
8/24 (33%)
11/24 (46%)†
17/24 (71%)
P = .005*
*Cochran-Armitage exact test of trend over time for 5-y cohort. †LOCF (no improvement) n = 9 for 4-y cohort; n = 15 for 5-y.‡1 patient received concomitant lamivudine.
7/22 (32%)†
12/22 (55%)‡
5-y cohort 4-y cohort
0
10
20
30
40
50
60
70
80
0 1 2 3 4 5Years of Adefovir Treatment
Isha
k Fi
bros
is R
educ
ed ≥
1 P
oint
(%)
Hadziyannis S, et al. Hepatology. 2005;42:754A. Reprinted with permission.
Safety of Adefovir Dipivoxil Over 4–5 Years
Renal safety– No on-treatment hypophosphatemia– 4 patients (3%) had confirmed increases in creatinine ≥0.5
mg/dL Maximum value 1.5 mg/dL Maximum increase 0.8 mg/dL
Adverse events – 3 patients permanently discontinued adefovir due to an
adverse event– Serious adverse events occurred in 24 patients (19%)
None were related to adefovir 3 patients developed hepatocellular carcinoma
Hadziyannis S, et al. Hepatology. 2005;42:754A.
Entecavir
2-Year Data Now Available
EntecavirConsiderations for Use
Nucleoside-naive infection– HBeAg+– HBeAg-
Lamivudine-resistant infection Continued use if 1-log reduction every 3
months1,2
– If not, add tenofovir or adefovir
1. Locarnini S, et al. 40th EASL. April 13–17, 2005. Abstract 36. 2. Unpublished expert opinion.
Entecavir Phase 3 StudiesHistologic Endpoints – Primary
Efficacy Endpoint
Study 022*HBeAg+
Study 027*HBeAg–
Study 026†
LVD-Refractory
ETV 0.5 mg
(n = 314)
LVD100 mg
(n = 314)
ETV 0.5 mg
(n = 296)
LVD100 mg
(n =2 87)
ETV 1 mg
(n =1 24)
LVD100 mg
(n = 116)
Overall histologicimprovement
72% 62% 70% 61% 55% 28%
Fibrosis no worse 89% 82% 84% 79% 87% 70%
Necroinflammatory>2-point decrease
74% 64% 73% 64% 55% 32%
Ishak fibrosis scoreimprovement
39% 35% 36% 38% 34% 16%
Primary analysis: only patients with evaluable baseline biopsy included; missing/inadequate week-48 biopsy counted as failures. *Treatment for 52 weeks up to 96 weeks for partial responders. †Treatment for 48 weeks for up to 96 weeks for partial responders.
FDA. Entecavir briefing document. February 10, 2005.
ETV = entecavir; LVD = lamivudine.
Entecavir Phase 3 StudiesSelected Secondary Efficacy Endpoints
Study 022*HBeAg+
Study 027* HBeAg–
Study 026†
LVD-Refractory
ETV 0.5 mg
LVD100 mg
ETV 0.5 mg
LVD100 mg
ETV 1 mg
LVD100 mg
HBV DNA PCR <400 copies/mL 72% 42% 95% 77% 22% 1%
Log HBV DNA byPCR (meanchange frombaseline)
-7.0 -5.5 -5.2 -4.7 -5.1 -0.5
HBeAgseroconversion 21% 18% NA NA 8% 3%
ALT normalization (<1 x ULN) 69% 61% 78% 71% 65% 17%
FDA. Entecavir briefing document. February 10, 2005.ETV = entecavir; LVD = lamivudine.
*Treatment for 52 weeks up to 96 weeks for partial responders. †Treatment for 48 weeks for up to 96 weeks for partial responders.
Entecavir vs Lamivudine in HBeAg+ Infection* Virologic Response at Week 48 and
Through Week 96
*Nucleoside-naive infection.†EOD (end of dosing) is defined as the last observation on-treatment.
64%
40%
0
20
40
60
80
100
Entecavir
% H
BV
DN
A <
300
copi
es/m
L 156/243 66/164
LamivudineWeek 48 Week 48
81%
39%
197/243 64/164
EOD* EOD†
Gish RG, et al. Hepatology. 2005;42:267A.
Entecavir (n = 354)
Lamivudine (n = 355)
50
31%
26%
5%3%
110/354 92/355 18/354 10/3550
10
20
30
40
HBeAg Seroconversion HBsAg Loss
% P
atie
nts
Entecavir (n = 354)
Lamivudine (n = 355)
Gish RG, et al. Hepatology. 2005;42:267A.
*Nucleoside-naive infection.
Entecavir vs Lamivudine in HBeAg+ Infection* Serologic Response at Week 48 and
Through Week 96
All Treated HBeAg- Patients: Cumulative Confirmed HBV DNA Undetectable by PCR
Through Week 96
0102030405060708090
100
EntecavirLamivudine
ALT 1 x ULNHBV DNA < 300 copies/mL
89% 84%94%
77%
P < .0001
P < .05
With permission from Shouval D, et al. 41st EASL. April 26–30, 2006. Abstract 45.
Patie
nts
(%)
Tenofovir
A Medication in Evolution
TenofovirPotential Role
We need phase 3 trial results Coinfected patients Lamivudine-resistant infection (HIV negative)
– Yes, if the patient fails Adefovir
and Entecavir
Adefovir partial responder = incomplete responder– Yes, if fails entecavir
Telbivudine
Awaiting final results Robust viral suppression High HBeAg seroconversion Good safety profile 5%+? resistance: need all patients who are
DNA positive on treatment, screened for mutations
Summary of Three RecentInternational Meetings
HBV DNA quantification is emerging as the best single indicator of patient prognosis, including HCC1,2
Use the anti-HBV agent with the highest rate of HBV DNA suppression/negativity1
For HBeAg+ patients, also consider the rate of HBeAg seroconversion and durability of seroconversion (PEG IFN)3
Resistance is bad and has multiple implications1
Liver biopsy still has a role in selecting patients for treatment1
Long-term data are available on entecavir (2 years) and adefovir(5 years) in terms of safety and efficacy1,3
New data from China have shown equal efficacy for both adefovir and entecavir compared with data from licensing studies2
1. NIH - Management of Hepatitis B: 2006. 2. 2006 Shanghai-Hong Kong International Liver Congress: 2006. 3. 41st EASL: 2006.
Experts’ Approach to Managing Resistance, Breakthrough, and Suboptimal Response
Norah A. Terrault, MD, MPHAssistant Professor of Medicine
Department of Gastroenterology University of California, San Francisco
San Francisco, California
Definitions of Resistance
Genotypic resistance– Mutations in HBV genome that occur during therapy and confer drug
resistance Virologic breakthrough
– Rebound of serum HBV DNA levels by ≥1 log after prior decline– Follows development of genotypic resistance
Clinical breakthrough– Virologic breakthrough with increase in ALT levels, worsening
histology, or liver function Phenotypic resistance
– Decreased in vitro susceptibility to antiviral drugs associated with genotypic resistance
Dynamics of Drug Resistance
Pallier C, et al. J Virology. 2006;80:643. Reprinted with permission from American Society of Microbiology.
Lamivudine, 100 mg/day
HBV DNA
ALT
AST
HBV-
DNA
(IU/m
L)ALT/AST (IU/m
L)
Lamivudine-sensitive
Lamivudine-resistant
Real-time PCR cutoff
bDNA cutoff
109
106
103
500
400
300
200
100
M0 M2 M4 M6 M8 M10 M12 M14 M16 M18 M20 M22 M24 M26 M28 M30 M32 M34 M36
0%/100%
50
100%/0%
Lok AS, et al. Gastroenterology. 2003;125:1714.
Manifestations of Drug Resistance
Relapse of HBV DNA ALT elevation Decline in liver synthetic function Worsening of liver decompensation
– Can be acute presentation Liver-related death Need for liver transplantation
Viral mutations conferring resistance are less frequent& delayed in onset with adefovir and entecavir versus lamivudine
24%
2%
42%
11%
53%
70%
0
10
20
30
40
50
60
70
80
Year 1 Year 2 Year 3* Year 4*
Inci
denc
e of
Res
ista
nce
(%)
Lamivudine1
(YMDD)
Adefovir (N236T+A181V)2
0%
18%
Entecavir3
0%0%
1. Lai C-L, et al. Clin Infect Dis. 2003;36:687. 2. Locarnini S, et al. 40th EASL. April 13–17, 2005. Abstract 36. 3. Colonno R, et al. Hepatology. 2005;42:573A.
Note: Agents were not compared in head-to-head trial
Incidence of Resistance in Nucleos(t)ide-Naive Patients
*No 3- or 4-year resistance data available for entecavir
Predictors of Genotypic Resistance
Lamivudine– Baseline HBV DNA level1,2
– HBV DNA >103 IU/mL at 24 weeks3
– Male gender, higher HAI grade, higher BMI1 Adefovir
– HBV DNA >103 IU/mL at 48 weeks4
– Older age, genotype D, adefovir monotherapy (vs adefovir plus lamivudine)5
Entecavir?
1. Lai C-L, et al. Clin Infect Dis. 2003;36:687. 2. Zoulim F, et al. J Viral Hepatitis. 2006;13:278. 3. Yuen MF, et al. Hepatology. 2001;34:785. 4. Locarnini S, et al. 40th EASL. April 13–17, 2005. Abstract 36. 5. Fung SK, et al. J Hepatol. 2006;44:283.
8%13%
32%
64%
200 103 104 >104
HBV DNA Levels (c/mL) at 24 wk
Patie
nts
with
Res
ista
nce
(%)
4%
26%
67%
HBV DNA Levels (c/mL) at 48 wk
Patie
nts
with
Res
ista
nce
(%)
0
20
40
60
80
100
<103 103–106 >106
Lamivudine1 Adefovir2
1. Yuen et al. Hepatology. 2001;34:785. 2. Locarnini S, et al. 40th EASL. April 13–17, 2005. Abstract 36.
Risk of Resistance Predicted by HBV DNA Levels During Treatment
0
20
40
60
80
100
1. Lai CL, et al. N Engl J Med. 2006;354:1011. 2. Chang et al. N Engl J Med. 2006;354:1001. 3. Hadziyannis S, et al. N Engl J Med. 2003;348:800. 4. Marcellin P, et al. N Engl J Med. 2003;348:808.
*Only lamivudine and entecavir compared head-to-head
Changes in HBV DNA Levels During 48 Weeks of Treatment
Nucleos(t)ide-Naive Compensated HBV*
Lamivudine Entecavir Adefovir
Change HBV DNA baseline to wk 48
-4.5 HBeAg-1
-5.4 HBeAg+2
-5.0 HBeAg-1
-6.9 HBeAg+2
-3.91 HBeAg-3
-3.52 HBeAg+4
% with undetectable HBV DNA
72% HBeAg-1
36% HBeAg+2
90% HBeAg-1
67% HBeAg+2
51% HBeAg-3
21% HBeAg+4
Locarnini S, et al. Antiviral Therapy. 2004;9:679.
Methods to Prevent Resistance
Maximize antiviral activity – Select most effective regimen– Change if poor response
Maximize genetic barriers to resistance– Avoid sequential therapy– Choose drugs requiring multiple resistance
mutations Increase pharmacologic barriers
– Patient compliance– Drug doses appropriate for renal function
Summary of Strategies to Minimize Drug Resistance in Treatment-Naive HBV Infected
Patients First-line therapy = adefovir, entecavir, peginterferon Avoid lamivudine
– Limit to those with low-level virus and expected short-duration therapy
Monitor response and be prepared to modify (ie, add or change) if indicated– Fail to see progressive viral load decline– Persistence of HBV DNA (≥ 103 log IU/mL) at 6 months;
certainly at 12 months
Monitoring During Treatment
Assessment of initial response– Progressive decline in HBV DNA levels is the goal– Suboptimal response warrants change in antiviral strategy– Recommend following HBV DNA levels every 3 months
Detection of virologic breakthrough (resistance)– Recommend following HBV DNA levels every
3 months once suppressed– Confirm HBV DNA results (decisions should not be based
on single viral load result) – Make treatment change before clinical breakthrough
Response to Second-Line Therapy by Type of Resistance
Adapted from Lampertico P, et al. Hepatology. 2005;42:1414.
Virologic breakthrough (<6 log HBV DNA)
Virologic breakthrough (6–8 log HBV DNA)
Clinical breakthrough (> 8 log HBV DNA)
P < .0001
Patie
nts
with
Und
etec
tabl
e H
BV
DN
A
Patients still at risk
28 3 1 0 0 0 0 0 032 22 14 10 9 6 5 4 214 13 12 11 10 9 5 4 3
Months0 3 6 9 12 15 18 21 240
20
40
60
80
100
Management of Drug-Resistant HBV Disease
Add or change antivirals– If resistant to lamivudine
Change to adefovir or entecavir Add adefovir
– If resistant to adefovir Change to entecavir Add lamivudine
– If resistant to entecavir Change to adefovir
Conclusions
Resistance is a risk with all oral nucleos(t)ide antiviral agents– Highest with lamivudine– Known risk factors = baseline HBV DNA level and HBV DNA
level at 24 and 48 weeks of treatment Monitor for lack of HBV DNA suppression (≥103 IU/mL) and
virological breakthrough– Both scenarios require change of therapy
Treat when virologic breakthrough apparent; do not wait until clinical breakthrough occurs (ALT increase)
If using oral antivirals, combination therapy is better long-term strategy than sequential therapy
Ching-Lung Lai, MDProfessor of Medicine and Hepatology
Department of MedicineUniversity of Hong Kong
Queen Mary HospitalHong Kong, China
Duration of Therapy — How Long Do You Treat?
Effect of Timing of Infection
1. Lai CL, et al. Lancet. 2003;362:2089. 2. Hoofnagle JH, et al. Hepatology. 1987;7:758.
Asians, Africans, some Mediterraneans
Prolonged immune tolerance and immune clearance phases
Respond less well to immunomodulatory therapy
Disease continues to progress in a proportion of anti-HBe patients
Majority of Caucasian patients No immune tolerance phase Disease of relatively short
duration Respond better to
immunomodulatory therapy Disease nonprogressive after
HBeAg seroconversion, with HBV DNA levels undetectable by hybridization assays—“healthy carriers”2
Patients Infected During Early Childhood1
Patients Infected During Adolescence/Adulthood
“Healthy” Hepatitis B Carrier 19871-2
– HBeAg seroconversion to anti-HBe– HBV DNA not detectable by (relatively insensitive)
hybridization assays 20013
– HBeAg seroconversion Preceded by decrease in HBV DNA levels to
105 copies/mL (20,000 IU/mL) Followed by ALT normalization “Inactive” HBsAg carrier state
1. Hoofnagle JH, et al. Hepatology. 1987;7:758. 2. Di Bisceglie AM, et al. Gastroenterology. 1987;93:1236. 3. Lok AS, et al. Gastroenterology. 2001;120:1828.
Current Endpoints of Treatment
HBeAg+ – HBeAg seroconversion1
– HBeAg seroconversion, HBV DNA ≤105 copies/mL (20,000 IU/mL) and ALT normalization2
– HBeAg seroconversion +/- HBV DNA undetectable by PCR3
HBeAg– – HBV DNA undetectable by PCR plus ALT normalization1,3
1. Lok ASF, et al. Hepatol 2004;39:857. 2. de Franchis R, et al. J Hepatol. 2003:39:S3. 3. Liaw YF, et al. Liver Int. 2005;25:422.
Ultimate Aim of Treatment for Chronic Hepatitis B
To prevent/delay the development of complications of cirrhosis and hepatocellular carcinoma
HBeAg seroconversion, HBV DNA reduction, and ALT normalization are only means to achieve the ultimate aim
HBeAg Seroconversion to Anti-HBe
“Healthy” Hepatitis B Carrier
Probably true for some patients who acquirethe HBV infection at adolescence/adulthood, ie, Caucasian patients
Manno M, et al. Gastroenterology. 2004;127:756.
Risk of Cirrhosis/HCC for Northern Italian HBV Carriers
296 HBsAg carriers detected at blood donation– Mean follow-up 30 years– No increase in liver-related morbidity or mortality
compared with controls– 32.2% cleared HBsAg (1% per year)
Possible explanation for lack of increase in liver-related mortality– “Healthy” subjects with no co-morbidity– Normal ALT– Instruction to abstain from alcohol– Age of acquiring the HBV infection
Survival After HBeAg Seroconversion
Reprinted with permission, from Niederau C, et al. N Engl J Med. 1996;334:1422. Copyright © 1996 Massachusetts Medical Society. All rights reserved.
Prop
ortio
n of
Pa
tient
s Su
rviv
ing
IFNControl
103 IFN-treated vs 53 untreated patients followed for a mean of 50 months
Predominantly adult-acquired infection
53/103 patients receiving IFN achieved HBeAg seroconversion
7/53 control patients achieved HBeAg seroconversion
Clearance of HBeAg
No clearance of HBeAg
1.0
0.8
0.6
0.4
0.2
0.096847260483624120
Month
1. Lai CL, et al. Lancet. 2003;362:2089. 2. Laras A, et al. J Viral Hepat. 1998;5:241. 3. Chan HL, et al. Hepatology. 2000;31:763. 4. Yuen MF, et al. J Infect Dis. 2002;186:1335.
HBeAg Seroconversion and Precore/Core Promoter Mutations
HBeAg+– Disease progresses both histologically and clinically
after HBeAg seroconversion in patients who acquire the HBV infection at birth/early childhood, ie, Asians and some Mediterraneans1
HBeAg– – Mediterraneans >90% precore mutations2
– Asian 45%3–56.5%4 precore mutations 41%3–69.5%4 core promoter mutations
Liaw YF, et al. Hepatology. 1988;8:493.
Development of CirrhosisHBeAg Seroconversion to Anti-HBe
684 Taiwanese patients– HBV infection acquired in early childhood
Mean follow-up 35.3 months Development of cirrhosis
– HBeAg+ 6.9%; annual incidences 2.4%– Anti-HBe 4.0%; annual incidences 1.3%
(P = NS)
Cumulative Risk of Complications Among Asian Patients with Chronic HBV
Median Age of Study Population = 38 y
Yuen MF, et al. Gut. 2005;54:1610. Reprinted with permission from the BMJ Publishing Group.
Ris
k of
C
ompl
icat
ions
(%)
Follow-up (Months)
N = 3233
1801501209060300
15
12
9
6
3
0
Age and Anti-HBe Status at Time of Complications
Yuen MF, et al. Gut. 2005;54:1610.
Median Age (y) anti-HBe (%)
HBeAg seroconversion 35 -All complications 57.2 73.5Ascites 57.7 68.8SBP 60.0 76.7Varices 54.3 76.3Encephalopathy 58.5 65.0HCC 59.0 81.1
3233 Chinese patients Infection acquired in early childhood Mean follow-up 46.9 months
SBP = spontaneous bacterial peritonitis; HCC = hepatocellular carcinoma.
Progression of DiseaseHBeAg Seroconversion to Anti-HBe
In patients acquiring the disease at birth/early childhood, disease progresses after HBeAg seroconversion
Majority of complications occurs after HBeAg seroconversion
HBV DNA <105 copies/mL (20,000 IU/mL)
Chu CJ, et al. Hepatology. 2002;36:1408.
HBV DNA Levels Associated with HBeAg Clearance
165 Chinese patients– 51% patients HBV DNA >105 copies/mL (20,000
IU/mL) at HBeAg seroconversion– 45% HBeAg– patients with active disease
(ie, high ALT levels) and HBV DNA <105 copies/mL (20,000 IU/mL)
Conclusion: not possible to define cut-off HBV DNA value for HBeAg– patients with active and inactive disease
Yuan HJ, et al. J Viral Hepatitis. 2005;12:373.
79 Chinese with cirrhosis-related complications (158 controls)– 32.9% HBeAg+, 67.1% anti-HBe+– In anti-HBe+ patients with complications
37.7% HBV DNA <105 copies/mL (20,000 IU/mL) 24.5% HBV DNA <104 copies/mL (2000 IU/mL)
The most important factor associated with development of cirrhosis complications and HCC is HBV DNA level (which can become <104 copies/mL [2000 IU/mL] at the time of complications)
HBV DNA Levels and Cirrhosis-Related Complications
Chen CJ, et al. JAMA. 2006;295:65.
The Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer (REVEAL)–HBV
Study, Taiwan
Prospective, multicenter, observational cohort study 3851 HBsAg+ subjects with baseline HBV DNA levels
for HCC and cirrhosis analysis– 3653 seronegative for anti-HCV and included in
study
Persistent HBV Viral Load Elevation Is Associated with Greatest Risk of HCC
REVEAL Study
289 study participants, last follow-up serum samples not available
Cohort Entry Examination <104
104–105
104–105
104–105
105
105
105
Serum level of HBV DNA (copies/mL) Multivariate-Adjusted RR**
(95% CI) 1.0 (referent)1.6 (0.7–3.9)0.5 (0.1–3.6)3.5 (1.4–9.2)3.8 (1.7–8.4)
7.3 (3.5–15.3)10.1 (6.3–16.2)
Follow-Up Examination Not tested
<104
104–105
105
<104
104–105
105
*Adjustment for gender, age, cigarette smoking, and alcohol consumption
Chen CJ, et al. JAMA. 2006;295:65.
Disease Progression in Early Childhood-Acquired Infection
For patients acquiring the hepatitis B infection in early childhood, disease progression can occur when HBV DNA levels are <104 copies/mL (2000 IU/mL)
ALT Normalization
Men Women
AST (IU/L)20–29 2.5 3.330–39 8.0 18.2
ALT (IU/L)20–29 2.9 3.830–39 9.5 6.6
Conclusion: People with AST and ALT levels in the upper ranges of “normal” are at risk of liver disease/mortality
Kim HC, et al. BMJ. 2004;328:983.
ALT Levels and Liver-Related MortalityKorea Medical Insurance Corporation 94,533 men; 47,522 women 35–59 years of age
Relative Risk for Liver-Related Mortality compared with Serum Aminotransferase Levels at Baseline <20 IU/L
ALT and Hepatic Complications
Yuen MF, et al. Gut. 2005;54:1610. Reprinted with permission from the BMJ Publishing Group.
Months of Follow-Up
Ris
k of
C
ompl
icat
ions
(%)
ALT <0.5 X ULN
ALT 0.5–1 X ULN
ALT >2–6 X ULN
ALT >1–2 X ULN
ALT >6 X ULN
0
10
20
30
0 30 60 90 120 150 180
3233 Chinese CHB patients Stratified: ALT < 0.5 x ULN
ALT > 0.5–1 x ULN, ALT > 1–2 x ULNALT > 2–6 x ULN, ALT > 6 x ULN
ALT and Hepatic Complications
Risk for cirrhosis (including HCC) complications lowest when ALT < 0.5 x ULN
Risk significantly higher when ALT 0.5–1 x ULN Risk highest when ALT >1–2 x ULN
Yuen MF, et al. Gut. 2005;54:1610.
Treatment Endpoints and Infection Acquired at Birth/Early Childhood
In patients who acquire the HBV infection at birth/early childhood, disease progression continues– After HBeAg seroconversion (and HBsAg
seroclearance)– At HBV DNA levels <105 copies/mL (20,000
IU/mL)– At ALT levels >0.5–2 x ULN
Current treatment endpoints stop treatment with patients still at risk
Summary For patients acquiring the disease in adolescence/adulthood
– HBeAg seroconversion with HBV DNA levels at <105 copies/mL (20,000 IU/mL) and ALT normalization may be adequate endpoints
For patients acquiring the disease in early childhood– HBeAg seroconversion is not an adequate endpoint,
more a “way station” in the natural history of HBV infection– Ideal endpoints of treatment
HBV DNA permanently low (<104 copies/mL [2000 IU/mL] preferably undetectable by PCR)
ALT < 0.5 x ULN Clearance of cccDNA from the liver—not currently
feasible
Conclusion
Eugene R. Schiff, MD
Leonard Miller Professor of MedicineChief, Division of Hepatology
Director, Center for Liver DiseaseUniversity of Miami School of Medicine
Miami, Florida
When Do You Initiate HBV Therapy?
Parameters– HBV DNA levels >104-5 copies/mL– ALT levels >1–2 x ULN
Factors– HBeAg+ vs HBeAg–– Cirrhosis vs no cirrhosis– Compensated vs decompensated disease
Initial Therapy: What Are the Therapeutic Options and Considerations?
First-line therapy– Adefovir– Entecavir– Peginterferon alfa-2a
Lamivudine no longer considered first-line therapy due to high rate of resistance, except in specific settings
How Do You Manage Resistance, Breakthrough, and Suboptimal
Response?
Choose antivirals with a low likelihood of resistance
Monitor the response every 3 months to ensure viral suppression is achieved
If viral suppression is not achieved, change/add antiviral agent(s)
Reinforce the importance of adherence
How Long Do You Treat?
Traditional endpoints– HBeAg seroconversion– HBV DNA <105 copies/mL (20,000 IU/mL)– Normalization of ALT
These endpoints may be insufficient for patients with infection acquired at birth or early childhood
Potential ideal endpoints– HBV DNA undetectable– ALT within normal limits