Transcript Optimal Management of HBV: A Partnership Between Primary

Optimal Management of HBV:
A Partnership Between
Primary Care and
Specialty Physicians
Primary Care
Specialist
Screening
Diagnostic testing
Identification of treatment candidates
Initiation of treatment
On-treatment monitoring
Long-term follow-up for
disease activation
HCC screening
Vaccination
Hepatitis B:
An Important Disease
for Primary Care and
Specialty Physicians
Why Is HBV Relevant in Primary Care?

High global impact
– High prevalence in specific risk groups
– Risk of death/cancer

Effective prevention

Effective treatment
– Improve liver disease outcomes
– Decrease progression to cirrhosis or HCC and improve
survival
Global Impact of HBV
A Significant Cause of Worldwide Morbidity
and Mortality







>2 billion have been infected1
4 million acute cases per year1
1 million deaths per year1
350 million chronic carriers1
– 25% of carriers die from chronic active hepatitis, cirrhosis,
or liver cancer1
– Nearly 75% of chronic carriers are Asian2
2nd most important carcinogen behind tobacco3
Causes 60%–80% of all primary liver cancer1
HBV is 100 times more contagious than HIV4
1. WHO. Hepatitis B. 2002. 2. Maynard JE, et al. In: Viral Hepatitis and Liver Disease. New York: Alan R. Liss, Inc. 1988.
3. CDC. Epidemiology & Prevention of Vaccine-Preventable Diseases. “The Pink Book.” 8th ed. 4. CDC. MMWR. 2001;50:
RR-11.
HBV
A Global Health Problem
Country
HBsAg+ (%)
China
5.3–122
South Korea
2.6–5.12
India
2.4–4.72
Taiwan
10–13.82
Viet Nam
5.7–102
Japan
4.4–133
Africa
5–192
Russia
1.4–82
Europe
0.3–122
HBsAg Prevalence (%)1
<8:
2–8:
<2:
High
Intermediate
Low
1. WHO. Hepatitis B. 2002. 2. Custer B. et al. J Clin Gastroenterol. 2004;38(10 suppl):S158. 3. WHO/WPRO data.
HBV Disease Progression
Liver
Cancer
(HCC)
Chronic
Infection
Cirrhosis
Liver
Transplantation
Liver
Failure
Torresi J, et al. Gastroenterology. 2000;118:S83. Fattovich G, et al. Hepatology. 1995;21:77.
Perrillo RP, et al. Hepatology. 2001;33:424.
Death
Burden of HBV Infection
in the United States
73,000
1,250,000
New Acute Infections
per Year1
Chronic Infections1
5000
3100
Deaths per
Year1
HCC per
Year2
230
Liver Transplants
per Year3
1. CDC. HBV Disease Burden. 2005. 2. El-Serag HB, et al. Arch Intern Med. 2000;160:3227. 3. UNOS/OPTN.
Poor Survival in
HBV-Related Cirrhosis
Patients Surviving (%)
100
80
Cirrhosis1
(n = 130)
60
55%
40
Decompensated Cirrhosis2
(n = 21)
20
14%
0
0
1
2
Years
3
4
5
1. Weissberg JI, et al. Ann Intern Med. 1984;101:613. 2. De Jongh FE, et al. Gastroenterology. 1992;103:1630.
HBV Is Preventable
Clinical-Epidemiologic
Correlations
Location
Age of
Infection
Mode of
Transmission
Low
N. America
W. Europe
Early
Adulthood
High
Sub-Sahara
Far East
Birth
Toddler
Endemicity
Chronicity
ESLD
Risk
HCC
Risk
Percutaneous
Sexual
Rare
Low
Low
Perinatal
Horizontal
Likely
High
High
HBV Vaccine
Indications



Routine vaccination of infants
– Regardless of mother’s HBsAg status
– With HBIG for HBsAg positive mothers
Catch-up vaccination of children and adolescents
Vaccination of adults with risk factors for infection
– High-risk sexual activity
– Illegal injection drug use
– Occupational exposure
– Hemodialysis patients
– Household contacts of infected persons
HBIG = hepatitis B immune globulin.
CDC. MMWR. 1991;40(RR-13):1.
Estimated Number of Cases
(Thousands)
US Incidence of Viral Hepatitis
Infection Over Time
Incidence of Hepatitis A, US
Incidence of Acute Hepatitis B, US
Incidence of Acute Hepatitis C, US
180
160
140
120
100
80
60
40
20
0
1990
1992
1991
1994
1993
1996
1995
1998
1997
Year
CDC. Disease burden from viral hepatitis A, B, and C in the United States. 2003.
2000
1999
2002
2001
2003
HBV Vaccination
Effect on HCC Incidence and Mortality*
Incidence
0.8
0.70
0.57
0.6
0.36
0.4
0.80
0.8
0.58
0.6
0.34
0.4
0.2
0.2
0
Mortality
1
Per 100,000 Children
(6–14 Years)
Per 100,000 Children
(6–14 Years)
1
1981–86
1986–90
1990–94
*Nationwide vaccination in Taiwan, implemented 7/84
Chang M-H, et al. N Engl J Med. 1997;336:1855.
0
1981–86
1986–90
1990–94
Screening for HBV
and Evaluating Infected
Patients
Who Should Be Screened?












Patients with abnormal ALT
Patients engaged in high-risk sexual behaviors
Injection drug users
Immigrants, refugees, or adoptees from areas of high endemicity
Immunocompromised patients
Dialysis patients
Recipients of organ/tissue transplants or blood transfusion
Household members or sexual partners of known HBV carriers
Occupational exposure (healthcare workers, police, EMTs)
Inmates in long-term correctional facilities or residents in institutions for the
developmentally disabled
Pregnant women
Individuals infected with HCV or HIV
Adapted from CDC. Epidemiology & Prevention of Vaccine-Preventable Diseases. “The Pink Book.” 8th ed, 2005.
Lok ASF, et al. Hepatology. 2001;34:1225.
Prevalence of HBV Serologic Markers in
Population Groups Who Should Be
Tested for HBV Infection
Prevalence of HBV Serologic Markers (%)
Population
HBsAg
Any Marker
Persons born in high endemic areas*
Men who have sex with men
Injection drug users
Dialysis patients
HIV infected patients
Pregnant females (USA)
Family/household and sexual contacts
13
6
7
3–10
8–11
0.4–1.5
3–6
70–85
35–80
60–80
20–80
89–90
30–60
*Africa; Southeast Asia, including China, Korea, Indonesia, and the Philippines; the Middle East,
except Israel; South and Western Pacific Islands; the interior Amazon River basin; and certain
parts of the Caribbean (Haiti and the Dominican Republic)
Lok ASF, et al. Hepatology. 2001;34:1225. Reprinted with permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc.
Screening Tests



HBsAg
– If positive, indicates infection
Anti-HBc
– If positive, indicates HBV exposure
Anti-HBs
– If positive, indicates immunity
History and Physical Evaluation

Risk factors for coinfection

Alcohol use

Family history of HBV infection and HCC

Physical findings of advanced disease
– Jaundice
– Abdominal swelling
– Upper GI bleeding
Lok ASF, et al. Hepatology. 2001;34:1225. Tsai NCS, et al. Semin Liver Dis. 2004;24(suppl 1):71.
Assessment of
Liver Disease Severity



Liver disease activity, biochemical
– ALT
– AST
Liver function/synthetic testing
– Albumin
– Bilirubin
– Prothrombin time (INR)
Ultrasonography: morphologic assessment
– Liver size, contour, and echogenicity
– Splenomegaly
Lok ASF, et al. Hepatology 2001;34:1225. Tsai NCS, et al. Semin Liver Dis. 2004;24(suppl 1):71.
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2004;2:87.
2nd-Phase Testing
in HBsAg+ Patients




Anti-HBc
– IgG: if positive, indicates HBV exposure
– IgM: if positive, indicates acute HBV
HBeAg
– If positive, indicates active HBV replication
– If negative
 If HBV DNA negative, suggests HBV replication is
suppressed
 If HBV DNA positive, most likely has precore mutation
Anti-HBe
HBV DNA quantification
– Quantitative level correlates with level of HBV replication
Further Testing
for HBsAg+ Patients

HCV antibody in at-risk individuals

HIV antibody or RNA quantification in
at-risk individuals

Consider screening for hepatitis delta virus (HDV)
if adult-acquired HBV
– Anti-HDV
– Delta antigen
– Delta RNA if any HDV testing is available
Hepatitis Delta Virus (HDV)
Clinical Scenario
Outcome
Acute HDV/acute HBV
 Risk of acute liver disease
Acute HDV/chronic HBV
 Risk of progressive liver
disease
Chronic HDV/chronic HBV
 Risk of cirrhosis and cancer
Who Are Treatment
Candidates?
Natural History of HBV Infection
Immune
Tolerance
>95%
Early
Childhood
HBeAgChronic
Hepatitis B
Cirrhosis
Courtesy of W. Ray Kim, MD
Chen DS, et al . J. Gastroenterol Hep. 1993:8(5):470.
Seeff L, et al. N Engl J Med. 1987;316(16):965.
Inactive
Carrier
Adulthood
<5%
HBeAg+
Chronic
Hepatitis B
Phases of Chronic HBV Infection
Immune
Tolerant
Phase
Inactive
HBsAg
Carrier
HBeAg
Positive
CHB
HBeAg
Negative
CHB*
HBsAg
+
+
+
+
HBeAg
+
–
+
–
Anti-HBe
–
+
–
+
Normal
Normal


HBV DNA
>105
copies/mL
>104
copies/mL
<105
copies/mL
>104†
copies/mL
Histology
Normal/Mild
Inactive
Active
Active
ALT
*Precore mutant
†Expert opinions vary as to this value
1IU = ~5 copies/mL
Lai CL, et al. Lancet. 2003:362:2089. Lok AS, et al. Gastroenterology. 2001;120:1828.
HBV Disease Progression
Liver
Cancer
(HCC)
5%–10%1
6% in 5 yr2
Chronic
Infection
30%1
Cirrhosis
Liver
Transplantation
Death
23% in 5 yr2
Acute Flare
Liver
Failure
Chronic HBV is the 6th leading
indication of liver transplantation
in the US3 ~5%
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.
HBeAg Negative Patients


HBeAg positive patients may develop
antibodies (anti-HBe)
When HBeAg is lost, 2 possible scenarios
– Inactive carrier (normal ALT, low or
negative HBV DNA level)
– Precore mutant chronic HBV (moderate
to high HBV DNA, elevated ALT)
Inactive Carriers



HBeAg negative, normal ALT, low/negative
HBV DNA
“Healthy carriers” = oxymoron
All patients who are HBsAg positive need
ongoing monitoring as part of management
– Monitor for increased ALT or HBV DNA
every 6 months
– Monitor for HCC in at-risk groups
Sherman M. Semin Liver Dis. 2005;25:143.
Precore Mutant (HBeAg Negative)
Chronic HBV

HBeAg negative, elevated ALT, moderate to high HBV DNA

Usually result of mutation in precore or basal core promoter
regions of HBV

Potentially more severe and progressive chronic disease

Longer, more aggressive (suppression of HBV DNA)
treatment needed

29% risk of adefovir resistance at 5 years of therapy1

Seen predominantly in genotypes B,C, and D
1. Borroto-Esoda K, et al. J Hepatol. 2006;44(Suppl 2):179.
HBV DNA and Prognosis
High viral load predicts
 Progression of liver disease1
 Cirrhosis1
 Cirrhosis-related complications2
 HCC1,3
– Independent of HBeAg, ALT,
and cirrhosis3
1. Chen G, et al. Abstract 996. Presented at: AASLD 2004. 2. Yuan JH, et al. J Viral Hepat. 2005;12:373.
3. Chen C-J, et al. JAMA. 2006;295:65.
Cumulative Incidence of HCC (%)
Baseline HBV DNA Level and
Cumulative Incidence of HCC
Entire Cohort
16
14
14.89
12.17
12
N = 3653, 13-year follow-up
10
8
6
3.57
4
1.3
2
0
<300
1IU = ~5 copies/mL
Chen C-J, et al. JAMA. 2006;295:65.
1.37
300–<104
104–<105
105–<106
HBV DNA (Copies/mL)
≥106
Baseline HBV DNA Level and Cumulative
Incidence of HCC
Cumulative Incidence of HCC (%)
Subgroup of Noncirrhotic HBeAg– Patients with Normal ALT
16
13.50
14
12
N = 2925
10
7.96
8
6
4
2
0
3.15
0.74
<300
Chen C-J, et al. JAMA. 2006;295:65.
0.89
300–<104
104–<105
105–<106
HBV DNA (Copies/mL)
≥106
Baseline HBV DNA Level and Relative
Risk of Cirrhosis
Relative Risk
Adjusted for gender, age, smoking, alcohol consumption
10
9
8
7
6
5
4
3
2
1
0
9.8
N = 3582, 11-year follow-up
5.9
2.5
1
<300
1.4
300–9.9x103
1.0–9.9x104
HBV DNA (Copies/mL)
Iloeje UH, et al, Gastroenterology. 2006;130:678.
1.0–9.9x105
>105
HBV DNA and Prognosis
Caveat
Low HBV DNA does not rule out risk

In HBeAg positive patients, HBV DNA
20,000 IU (<105 copies/mL) predicted better histology
– But 14.3% of patients with
HBV DNA 20,000 IU (<105 copies/mL) still had fibrosis1

In patients with cirrhosis, viral load was the best predictor of
complications
– But even with HBV DNA 20,000 IU (<104 copies/mL)
complications continued to develop2
1. Yuen MF, et al. Am J Gastroenterol. 2004;99:2031. 2. Yuan HJ, et al. J Viral Hepat. 2005;12:373.
Candidacy for anti-HBV Treatment
Principle
In general, a patient with chronic HBV is a treatment
candidate if there is evidence of

Liver disease (abnormal ALT) and

HBV replication (HBV DNA+)
When Do You Initiate
anti-HBV Therapy?


Parameters
– HBV DNA levels >104-5 copies/mL
– ALT levels >1–2 x ULN
Factors
– HBeAg positive vs HBeAg negative
– Cirrhosis vs no cirrhosis
– Compensated vs decompensated disease
Which Patients Should Be Treated?
AASLD Guidelines1
HBeAg
HBV DNA
(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
*Do not use interferon or peginterferon if the patient has decompensated cirrhosis.2,3 Specific treatment
recommendations are made elsewhere in this activity.
1. Lok ASF, et al. Hepatology. 2004;39:857. Reprinted with permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc.
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.
US Treatment Algorithm Update
HBeAg Positive Compensated Disease
HBeAg Positive
HBV DNA
<105 c/mL
HBV DNA
≥105 c/mL
ALT Normal


No treatment
Monitor every 6–12 mo


Courtesy of Emmet Keeffe, MD.
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.
Monitor every 3–12 mo
(immune tolerant)
Consider biopsy, if
age >35–40 y, and
treat if significant
disease
ALT Elevated
Treat
US Treatment Algorithm Update
HBeAg Negative Compensated Disease
HBeAg Negative
HBV DNA
<104 c/mL
HBV DNA
≥104 c/mL
ALT Normal


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
Courtesy of Emmet Keeffe, MD.
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.
ALT Elevated


Treat
Long-term
treatment
required
US Treatment Algorithm Update
Compensated Cirrhosis
HBV DNA
≥104 c/mL
HBV DNA
(PCR)
HBV DNA
<104 c/mL
May Choose to Treat or Observe
Treat
Courtesy of Emmet Keeffe, MD.
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.
US Treatment Algorithm Update
Decompensated Cirrhosis
HBV DNA
Detectable by PCR?
No


Observe
Wait list for transplant
Courtesy of Emmet Keeffe, MD.
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.
Yes


Treat
Wait list for transplant
Who May Not Need Referral
to a Specialist?
Noncirrhotic patients with persistently normal ALT
 Inactive carrier
– HBeAg negative
– DNA <104
– Persistently normal ALT
 Immune tolerant
– HBeAg positive
– Persistently normal ALT
Who Is Likely to Benefit
from Referral to a Specialist?
HBeAg positive chronic hepatitis B
– Abnormal ALT
– DNA >105
 HBeAg negative chronic hepatitis B
– Abnormal ALT
– HBV DNA may be variable
 Cirrhosis
– Regardless of HBeAg, DNA or ALT status

Management of Chronic HBV Infection
DNA
<2000 IU/mL
<10,0000 c/mL
DNA
>2000 IU/mL
>10,000 c/mL
ALT <17–25* U/L
ALT >17–25* U/L
Observe†
Biopsy‡
Biopsy
and treat if
active HBV
Treat:
eAg (+): >6 mo post Ag seroC
eAg (–): prolonged Rx
(at least 24 mo) beyond
NAT negative§ (Consider
biopsy or use noninvasive
testing to stage disease)
*Upper limits of normal for a person with normal BMI, 17 for women and 25 for men;
†Treat any patient with cirrhosis who is NAT positive, refer to specialist; ‡Rule out fatty liver and other causes of
CLD; §Consider 3–5 years. NAT = nucleic acid testing, such as PCR, bDNA or TMA.
Reprinted from Gish R. Clin Liver Dis. 2005;9:541, with permission from Elsevier.
Monitoring for Patients Not Considered
for Treatment


Check ALT every 3–6 months
– If ALT is persistently elevated,
reevaluate for treatment
HCC surveillance in relevant population
Lok ASF, et al. Hepatology. 2001;34:1225. Lok ASF, et al. Hepatology. 2004;39:857.
HCC Surveillance Is Recommended for
the Following Groups of Patients (Level III)
Hepatitis B Carriers
Nonhepatitis B Cirrhosis
Asian males ≥40 years
Asian females ≥50 years
All cirrhotic hepatitis B carriers
Family history of HCC
Africans over age 20
For noncirrhotic hepatitis B carriers not listed
above, the risk of HCC varies depending on
the severity of the underlying liver disease
and current and past hepatic inflammatory
activity. Patients with high HBV DNA
concentrations and those with ongoing
hepatic inflammatory activity remain at risk
for HCC.
Hepatitis C
Alcoholic cirrhosis
Genetic hemochromatosis
Primary biliary cirrhosis
Although the following groups have an
increased risk of HCC, no recommendations
for or against surveillance can be made
because a lack of data precludes an
assessment of whether surveillance would
be beneficial.
Alpha1-antitrypsin deficiency
Nonalcoholic steatohepatitis
Autoimmune hepatitis
Bruix J, Sherman M. Hepatology. 2005;42:1208. Reprinted with permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc.
Counseling of
HBV-Infected Patients




Limit use of alcohol1-3
Prevent transmission1,4
Screen and vaccinate sexual and
household contacts1,4
Vaccinate against hepatitis A1
1. Lok ASF, et al. Hepatology. 2001;34:1225. 2. Chevillotte G, et al. Gastroenterology. 1983;85:141.
3. Villa E, et al. Lancet. 1982;2:1243. 4. CDC. “The Pink Book.” 8th ed, 2005.
Treatment of
Hepatitis B
Primary Goal of anti-HBV Therapy
Preventing Cirrhosis, HCC, and Death
Durable Suppression
of HBV Replication
Treatment Goal
(Endpoints)

Remission of liver disease

Suppression of HBV

HBeAg positive HBV
– Seroconversion

HBeAg negative HBV
– Sustained suppression of HBV DNA
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
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.
Peginterferon

Pegylated recombinant interferon alfa protein/immune modulator

Subcutaneous injection, but less frequent than standard interferon

Dual immunomodulatory and antiviral mode of action

Defined, finite treatment interval

High rate of HBeAg seroconversion in wild-type infection

High rate of HBV DNA suppression in precore mutant variant

High rate of HBsAg seroconversion

No reports of resistance mutations

Significant adverse events
– Better than or similar to that when used to treat HCV infection
Peginterferon
Considerations for Use

HBeAg positive
–
Response in genotype A better than B = C, better than D1,2
–
ALT >80 IU/mL2
–
HBV DNA <108 copies/mL2
–
Compensated liver disease guidelines3-6
–
Monoinfected
–
No psychiatric or medical contraindications

HBeAg negative
–
No specific genotype populations that benefit over others7
–
Modest number of patients negative by PCR (20%) 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.
Lamivudine

First oral nucleoside approved for treatment of HBV

Cytidine nucleoside analog: inhibits 1st-strand DNA synthesis

Extensive database and publications
– Half of patients who are HBeAg positive undergo
seroconversion by 5 years1

Safety profile excellent except for resistance

Risk of resistance is high (70%) at 4 years of therapy2
– Associated with flares and decompensation
– No longer a first-choice therapy due to high rate of resistance3
1. Guan R, et al. J Gastroenterol Hepatol. 2001;16(suppl):A60. 2. Lai CL, et al. Clin Infect Dis. 2003;36:687. 3. Keeffe EB, et al.
Clin Gatroenterol Hepatol. 2006: In press.
Lamivudine in CHB
Incidence of YMDD Mutants Over Time—
Integrated Phase 3 Data
100
80
70%
53%
60
42%
40
24%
20
0
n = 426
n = 74
n = 58
n = 58
Year 1
Year 2
Year 3
Year 4
Lai C-L, et al. Clin Infect Dis. 2003;36:687.
Adefovir

Adenosine nucleotide analog

First oral medication and first nucleotide approved
by regulatory authorities for the treatment of HBV

Inhibits HBV DNA polymerase

Oral bioavailability not affected by food

No significant drug-drug interactions

Rare events of nephrotoxicity (overall risk – low)

Effective against lamivudine-resistant mutants

Long/indefinite duration
HEPSERA® Product Insert.
Safety of Adefovir Dipivoxil
Over 4–5 Years

Resistance is 29% at 5 years of use in HBeAg negative
patients1

Resistance is more likely if patients are lamivudine resistant
and switched to adefovir2

Renal safety
– Infrequent (3%) increases in creatinine ≥0.5 mg/dL

Maximum value 1.5 mg/dL

Maximum increase 0.8 mg/dL
1. Borroto-Esoda K, et al. J Hepatol. 2006;44(Suppl 2):179.
2. Lee YS, et al. Hepatology. 2006;43:1385.
3. Hadziyannis S, et al. J Hepatol. 2006;44(Suppl 2):283.
Entecavir




Oral deoxyguanine nucleoside analog
Inhibits priming of HBV DNA polymerase, reverse transcription of negative
DNA strand from pregenomic RNA, and synthesis of positive DNA strand
Superior efficacy to lamivudine1-3
Comparable safety profiles except fewer ALT flares compared with lamivudine13


ETV-associated resistance mutations were not observed in nucleoside-naive,
HBeAg positive, or negative studies4
ETV-associated resistance mutations with rebound were seen in 9%
of patients with previous lamivudine resistance during second year
of therapy4
ETV = entecavir.
1. Chang TT, et al. Hepatology. 2004;40:193A. 2. Sherman M, et al. Hepatology. 2004;40:664A. 3. Shouval D, et al.
Hepatology. 2004;40:728A. 4. Colonno RJ, et al. 56th AASLD. November 11–15, 2005. Poster 962.
Entecavir Phase 3 Studies
Histologic Endpoints–Primary Efficacy Endpoint
Study 022*
HBeAg+
Study 027*
HBeAg–
Study 026†
LVD-Refractory
ETV
0.5 mg
(n = 314)
LVD
100 mg
(n = 314)
ETV
0.5 mg
(n = 296)
LVD
100 mg
(n = 287)
ETV
1 mg
(n = 124)
LVD
100 mg
(n = 116)
Overall histologic
improvement
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 score
improvement
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. ETV = entecavir; LVD = lamivudine.
FDA. Entecavir briefing document. February 10, 2005.
Entecavir Phase 3 Studies
Selected Secondary Efficacy Endpoints
Study 022*
HBeAg+
Study 027*
HBeAg–
Study 026†
LVD-Refractory
ETV
0.5 mg
LVD
100 mg
ETV
0.5 mg
LVD
100 mg
ETV
1 mg
LVD
100 mg
72%
42%
95%
77%
22%
1%
-7.0
-5.5
-5.2
-4.7
-5.1
-0.5
HBeAg
seroconversion
21%
18%
NA
NA
8%
3%
ALT normalization
(<1 x ULN)
69%
61%
78%
71%
65%
17%
HBV DNA PCR
<400 copies/mL
Log HBV DNA by
PCR (mean
change from
baseline)
*Treatment for 52 weeks up to 96 weeks for partial responders. †Treatment for 48 weeks for up to 96 weeks
for partial responders. ETV = entecavir; LVD = lamivudine.
FDA. Entecavir briefing document. February 10, 2005.
Current FDA-Approved Nucleoside and
Nucleotide Treatment Options
(Not Head-to-Head Studies)
Resistance
E antigen seroconversion
Flares
Viral suppression
(log reduction)
DNA negativity
Availability of long-term data
AEs
Lam-R = lamivudine resistance
Slide Courtesy of Robert G. Gish, MD.
Lamivudine
~20%
Adefovir
~3%
~17%
Moderate
4.5–5.5
~12%
Low
3.5–5.5
Entecavir
~0% Naive;
9% Lam-R
~22%
Low
5.2–7
32%–78%
5 year
Rare
21%–51%
5 year
Rare
69%–91%
2 year
Rare
Results Following Suppression
of Viral Replication
Virologic
Response
Histologic
Improvement
Reduction in:
 HBV DNA
 cccDNA
Prevention of
Death,
Cirrhosis,
and HCC
Serologic
Response



HBeAg loss
HBeAg seroconversion
HBsAg loss and seroconversion
Biochemical and
Liver Synthetic
Test Improvement


ALT
Bilirubin, INR,
Albumin
Summary

HBV infection is a worldwide epidemiologic and clinical
challenge

Screening at-risk individuals identifies those with HBV
infection

Pretreatment evaluation includes history, physical exam,
and additional diagnostic testing

Candidates for anti-HBV treatment include patients with
active liver disease and high levels of HBV replication

Refer HBsAg positive patients for treatment with entecavir,
adefovir, or peginterferon