Transcript Natural History of Compensated Cirrhosis in Patients with

Introduction and Program Overview
Eugene R. Schiff, MD, MACP,
FRCP, MACG, AGAF
Program Chair
Leonard Miller Professor of Medicine
University of Miami School of Medicine
Miami, Florida
Program Overview
• Chronic hepatitis B (HBV) infection is significantly underdiagnosed and under-treated in the US
• Much new data has emerged, increasing our knowledge
of the natural history of this disease and its treatment
• Effective new anti-HBV agents and novel treatment
approaches for long-term management are now in use
• Interactive case presentations will help us review the
latest developments in the understanding and treatment
of the disease
Educational Objectives
Upon completion of this activity, participants should be able to:
• DESCRIBE the epidemiology and natural history of hepatitis B virus
(HBV) infection
• IMPLEMENT an activity of screening, vaccination, and diagnosis of
HBV within their clinical practices
• EVALUATE the risks and benefits of available agents for treating
chronic HBV infection
• EVALUATE current data on the potential use of combination therapy
for patients with chronic HBV infection
Agenda
• The Hepatitis B Virus: A Silent Killer
• Whom to Treat/When to Treat
• Treatment Options for Chronic
HBV Infection
• Combination Therapy: Controversies
and Uncertainties
Program Faculty
Program Chair
Eugene R. Schiff, MD, MACP, FRCP, MACG, AGAF
Leonard Miller Professor of Medicine
Director, Schiff Liver Institute
Director, Center for Liver Diseases
Division of Hepatology
University of Miami School of Medicine
Miami, FL
Norah A. Terrault, MD
Associate Professor of Medicine
Director,
Viral Hepatitis Research in Liver Transplantation
Dept of Medicine, Division of Gastroenterology
University of California, San Francisco
San Francisco, CA
Marion Peters, MD, FRACP
Professor of Medicine
Chief of Hepatology Research
University of California, San Francisco
San Francisco, CA
Tram T. Tran, MD
Assistant Professor of Medicine
Geffen UCLA School of Medicine
Division of Gastroenterology
Medical Director of Liver Transplant
Comprehensive Transplant Center
Cedars Sinai Medical Center
Los Angeles, CA
Mark Sulkowski, MD
Associate Professor of Medicine
Medical Director, Viral Hepatitis Center
Johns Hopkins University School of Medicine
Baltimore, MD
Audience Participation
• Audience Response System
 Used to pose a series of questions during the meeting
 At slide prompts, key in your answers on the keypads
 Please return your keypad at the end of the program
• Questions?
 Question cards
• Please jot down your questions, and staff will pick them up
during the course of the meeting
 Microphones
Accreditation Statement
• This activity has been planned and implemented through
the joint sponsorship of the University of Kentucky
College of Medicine and HealthmattersCME
• The University of Kentucky College of Medicine
designates this educational activity for a maximum of 2.0
AMA PRA Category 1 Credits™
How to Obtain CME Credit
• Complete this activity in its entirety
• After the activity, go to
www.cecentral.com/getcredit
• Enter activity code MLN09103
• Log in or register for a free account
• Complete activity evaluation and
get credit
• A printable certificate will be issued
Disclosure Statements
Program faculty have disclosed their relevant
financial relationships with commercial interests
that produce health care goods and/or services
consumed by, or used on patients.
Written disclosures can be found within your folder.
The Hepatitis B Virus:
A Silent Killer
Tram T. Tran, MD
Assistant Professor of Medicine
Geffen School of Medicine at UCLA
Medical Director of Liver Transplant
Comprehensive Transplant Center
Cedars-Sinai Medical Center
Los Angeles, California
Case Presentation
• A 44-year-old Russian man who immigrated
to the United States in 1989 is seeing you for
abnormal transaminase levels.
- ROS: occasional flares of diarrhea and
abdominal pain, currently asymptomatic
- PMH: Crohn’s disease; previously vaccinated for
hepatitis B virus
- Social: 1-2 drinks per week, works construction
- Family Hx: Mother d. cirrhosis; was “drinker”
- Meds: 5-aminosalicylic acid (5-ASA)
- PE: normal
Let’s Vote!
Audience Response Question
New CDC 2008 Guidelines recommend HBV
screening in immigrants from endemic areas with
hepatitis B prevalence of:
14%
A. > 25%
26%
B. >10%
24%
C. >8%
36%
D. >2%
Hepatitis B: Region/Country
Region
Countries
Africa
All countries
Asia
All countries
Australia & South Pacific
All countries except Australia and New Zealand
Middle East
All countries except Cyprus and Israel
Eastern Europe
All countries except Hungary
Western Europe
Malta, Spain, and indigenous populations of
Greenland
North America
Alaska and indigenous populations of northern
Canada
Mexico and Central
America
Guatemala and Honduras
South America
Ecuador, Guyana, Suriname, Venezuela, Amazonian
areas
Caribbean
Antigua, Dominica, Granada, Haiti, Jamaica, St Kitts
and Nevis, St Lucia, Turks and Caicos
CDC.MMWR 2008
Incidence* of Acute Hepatitis B, by Age Group,
Sex, and Year – United States, 1990-2002
20
Males aged 0-19 yr
Males aged 20-39 yr
Males aged ≥40 yr
Females aged 0-19 yr
Females aged 20-39 yr
Females aged ≥40 yr
Total
Incidence
16
12
8
4
0
1990
1992
1994
1996
Year
*Per 100,000 population.
1998
2000
2002
Hepatitis B: Disease Progression
Liver Cancer
(HCC)
5%-10%
2%-6%
Acute
Infection
Chronic
Infection
90% in perinatal
30%-90% in children <5 years old
5% in healthy adults
Higher in HIV, immunosuppressed
Cirrhosis
Liver
Transplantation
Death
10%-30%
Liver Failure
(Decompensation)
23% within 5 years
Chronic HBV is the
6th leading cause of
liver transplantation
in the US
Torresi J et al. Gastroenterology. 2000;118(2 Suppl 1):S83-S103. Fattovich G et al. Hepatology. 1995;21(1):77-82.
Moyer LA et al. Am J Prev Med. 1994;10(Suppl):45-55. Perrillo RP et al. Hepatology. 2001;32(2):424-432.
Asian-American Age-Adjusted Liver
Cancer Rates (California, 2000-2002)
Incidence
Male
Female
54.3
Rate (per 100,000)
Rate (per 100,000)
Male
Female
Mortality
33.7
23.3
16.8
15.8
15.9
9.3 8.1
7.6
5.4
35.5
26.6
19.9
12.0
Filipino
Vietnamese
Korean
Japanese
11.5
8.3 7.8
7.8
6.8
4.2
2.5
Chinese
10.4
White
Chinese
Filipino
2.7
Vietnamese
Korean
Approximately 3.7 million Asians in California. Cancer data from California Cancer Registry.
McCracken M et al. CA Cancer J Clin. 2007;57:190-205.
6.0
Japanese
White
Case Presentation:
Laboratory Findings
•
•
•
•
•
•
•
•
CBC: WBC 5.5, Hgb 12.5, Plt 288
AST 39 IU/L, ALT 35 IU/L
Bilirubin 1.0 mg/dL, INR 1.1, albumin 3.7 g/dL
HBsAg: positive
HBeAg: negative
Anti-HBe: positive
HBV DNA 1800 IU/mL
HCV, HIV, HDV negative
Let’s Vote!
Audience Response Question
This patient is most likely in which stage of
CHB infection?
18%
8%
38%
21%
15%
A.
B.
C.
D.
E.
Immune tolerant
Immunoactive/immune clearance
Inactive carrier
HBeAg CHB
Can’t tell
Phases of HBV Infection
Yim JY, Lok AS-F. Hepatology. 2006;43:S173-S181.
Case Presentation (cont’d)
• Serial follow-up of his liver tests reveals
- ALT fluctuation 30105
- HBV DNA 1800 IU/mL 7600 IU/mL
ALT and Histology
• 192 patients (Boston)
• HBV DNA > 10,000 copies/mL
• Liver biopsy data
• Stratified by ALT
- Persistently normal (< 40 IU/L), n=59
- 1-1.5 x ULN, n=26
- >1.5 x ULN, n=107
Lai M et al. J Hepatol. 2007;47(6):760-767.
Grade of Inflammation by ALT Group
78%
70%
Percentage
Grade 0
54%
60%
Grade 1
50%
40%
34%
Grade 2
Grade 3
30%
20%
10%
0%
PNALT
ALT 1-1.5 ULN
PNALT, persistently normal ALT.
Lai M et al. J Hepatol. 2007;47(6):760-767.
ALT >1.5 ULN
Stage of Fibrosis by ALT Group
62%
18%
34%
Case Presentation (cont’d)
• Liver biopsy is performed:
- Grade 2-3 inflammation
- Stage 2 fibrosis
HBeAg Seroconversion
• 298 patients with documented HBeAg seroconversion
- 116 treatment induced, 182 spontaneous
• Reactivation in 71 patients (39%)
- Older age, male gender, and higher ALT at seroconversion
were risks for reactivation (all P <.006)
- No difference between interferon, adefovir, lamivudine
treatment
• Treatment-induced seroconversion less durable than
spontaneous
- Remission of ALT shorter (14 vs 22 months, P=.037)
- More likely to have HBeAg reactivation at 48 months
(38% vs 25%, P=.048)
Lim G et al. 58th AASLD; 2007; Boston. Poster 937.
HBeAg Seroconversion to Anti-HBe
• Development of cirrhosis complications and HCC
- 3233 Chinese patients
- Mean follow-up 46.9 months
Median age (yr)
Percentage
anti-HBe
35
-
All complications
57.2
73.5
Ascites
57.7
68.8
Spontaneous bacterial peritonitis
60.0
76.7
Varices
54.3
76.3
Encephalopathy
58.5
65.0
Hepatocellular carcinoma
59.0
81.1
HBeAg seroconversion
Yuen MF et al. Gut 2005;54(11):1610-1614.
Incidence of Cirrhosis:
HBeAg Status
Taiwan and Korea
Europe
50
50
HBeAg negative
HBeAg positive
40
30
Percent
Percent
40
20
30
20
10
10
0
0
0
1
2
3
HBeAg negative
HBeAg positive
4
Years
Fattovich G et al. J Hepatol. 2008;48(2):335-352.
5
0
1
2
Years
3
4
5
Cumulative Incidence of
Hepatocellular Carcinoma (HCC)
Taiwan, China, Singapore, Korea
and Japan
Europe and USA
20
20
Cirrhosis
Chronic hepatitis
Inactive carrier
15
10
Percent
Percent
15
5
10
5
1
1
0
0
0
1
2
3
Cirrhosis
Chronic hepatitis
Inactive carrier
4
Years
Fattovich G et al. J Hepatol. 2008;48(2):335-352.
5
0
1
2
Years
3
4
5
AASLD Guidelines:
Periodic Screening for HCC
• At-risk hepatitis B carriers
-
Asian males >40 years of age
Asian females >50 years of age
All cirrhotic hepatitis B carriers
Family history of hepatocellular carcinoma
Africans >20 years of age
Those with high HBV DNA levels and those with
ongoing hepatic inflammatory activity remain at risk
for hepatocellular carcinoma
• Liver ultrasound every 6 to 12 months
Bruix J et al. Hepatology. 2007;42:1208-1236.
Case Presentation (cont’d)
• Patient’s Crohn’s disease flares; consideration is
made for steroids and possibly anti-tumor
necrosis factor (TNF) therapy
Let’s Vote!
Audience Response Question
Is it necessary to screen patients for HBV
before anti-TNF therapy?
68%
28%
3%
2%
A. Yes, screen all patients
B. Yes, but only those with risk factors for
HBV
C. No, just monitor
D. No, never
Screening: New CDC Guidelines
• CDC Guidelines 2006
- Persons born endemic
areas >8% prevalence
- Pregnant women, infants
- Sexual, household
contacts of HBV+
- HIV
- Needlestick/assault
- Hemodialysis patients
- Blood donors
• CDC Guidelines 2008
- Persons born endemic
areas >2% prevalence
- US-born children of
immigrants from highrisk areas
- Injection drug users
- MSM
- Immunosuppressive Rx
• GI, rheumatologic,
oncologic, tx
- ALT/AST elevation
Centers for Disease Control; MMWR Sept 19 2008
Case Presentation (cont’d)
• Patient started on antiviral therapy prior to antiTNF treatment
• HBV DNA becomes undetectable
• ALT remains persistently normal
Summary
• HBV burden is significant, some groups
disproportionately affected
• New CDC guidelines have broadened screening
recommendations
• Disease progression may be independent of
biochemical and serological markers
Whom to Treat
When to Treat
Norah Terrault, MD, MPH
Associate Professor of Medicine
Director of Viral Hepatitis Research in
Liver Transplantation
University of California, San Francisco
San Francisco, California
Goals of Treatment
Improved
histology
Anti-HBe+
Anti-HBs+
Improved
survival
Loss of
HBsAg
Loss of
HBeAg
Loss of
HBV DNA
HBV is
controlled not
eradicated
TIME
Decision to Treat:
Balancing Benefits and Risks
Risk of Liver
Complications
Costs
Side Effects
Drug Resistance
Factors Associated With Disease
Progression in Patients With CHB
Host Factors
Virus Factors
• >40 years of age
• High serum HBV
DNA
concentrations
• Male
• Immune status
• Prolonged time to
HBeAg
seroconversion
• Development of
HBeAg(-) chronic
hepatitis
• Core promoter
HBV variant
• Genotype C
Yim HJ, Lok ASF. Hepatology. 2006;43:S173-S181.
Environmental
Factors
• Concurrent
infection (HCV,
HDV, HIV)
• Alcohol
consumption
• Diabetes mellitus
• Obesity
Persistent Elevated HBV DNA and
Cumulative Incidence of HCC
P < .001
Adjusted HR for HCC
(95% CI)
12
67% ≥40 yrs and 62% male
10.1
(6.3-16.2)
10
P < .001
7.3
8
(3.5-15.3)
P < .001
6
3.8
(1.7-8.4)
4
P = NS
2
0
1
26/2034
< 104
HBV DNA : Baseline
Follow-up (copies/mL) Not Tested
Chen CJ et al. JAMA. 2006;295(1):65-73.
8/146
≥105
< 104
10/120
≥105 →
104 - < 105
55/537
≥105
≥105
Case Presentation
• A 37-year-old Asian woman is referred for HBsAgpositive status. Discovered when mother was diagnosed
with HCC at age 65
• Asymptomatic, recently married, husband vaccinated,
no children
• No medications other than oral contraceptives
• Initial lab results:
- HBeAg+, HBV DNA 2.5 million IU/mL
- ALT 30 IU/L, AST 27 IU/L, total bilirubin 0.6 mg/dL,
albumin 4.0, g/dL, INR 1.0, platelets 300K
Case Presentation (cont’d)
• Ultrasound findings:
- Normal-appearing liver with normal echotexture,
no splenomegaly or collaterals
• Repeat labs:
- 3 months: ALT 35 IU/L
- 6 months: ALT 31 IU/L, HBV DNA 1.3 million
IU/mL
Let’s Vote!
Audience Response Question
What do you recommend at this point?
A.
Continue monitoring ALT every 3-6 months and treat
if ALT increases to ≥2 X ULN
4%
B.
Obtain HBV genotype and treat if genotype A
25%
C.
D.
Start treatment, regardless of HBV genotype
Obtain liver biopsy and treat if significant
inflammation or fibrosis
25%
45%
Recommendations: Whom to Treat
AASLD Guidelines 2007
• Treatment indicated for ‘active’ disease:
- ALT ≥2 ULN
- HBV DNA ≥20,000 IU/mL
Or if
- ALT 1-2 ULN and ≥age 40, consider biopsy and
treat if significant fibrosis or necroinflammation
is present
Recommendations: Whom to Treat:
NIH 2008 HBV Consensus Statement
Treatment Indicated
• Fulminant and
decompensated
disease
• Cirrhosis with elevated
HBV DNA
• Chemotherapy or other
IMS therapy
• (Liver transplantation)
Treatment May be
Indicated
• Immune active phase
• Reactivation phase
Treatment Not Indicated
• Immune tolerant
• Immune inactive
• Latent HBV
NIH Consensus Development Conference: Management of Hepatitis B. Draft Statement.
October 22, 2008 5:50 PM; http://consensus.nih.gov/2008/hepB
Recommendations: Whom to Treat
AASLD Guidelines 2007
• HBV DNA ≥20,000 IU/mL
• ALT ≥2 ULN
• If ALT 1-2 ULN and ≥age
40, consider biopsy and
treat if significant fibrosis
or necroinflammation
EASL Guidelines 2009
• HBV DNA ≥ 2,000 IU/mL
• ALT ≥ ULN
“Gray Areas”
• ALT cutoff
- New “normal” ULN for ALT
- Is ≥2 ULN appropriate?
• Biopsy criteria
- Significant? ≥G2 or G3,
≥F2?
• HBV viral load
- Differs for HBeAg negative
vs positive CHB?
Patients With CHB With Significant Liver Disease
(ALT<2 ULN and HBV DNA >105 copies/mL)
ALT<2 ULN With
Laboratory Cutoff
ALT<2 ULN With Revised
ALT ULNs*
n=451
n=141
HBeAg(+) CHB
Necroinflammation ≥7
Fibrosis ≥4
65%
13%
68%
11%
HBeAg(-) CHB
Necroinflammation ≥7
Fibrosis ≥4
71%
8%
75%
17%
* <30 IU/L males, <19 IU/L females
Terrault NA et al. Digestive Disease Week; 2007; Washington, DC.
Chronic HBV Infection and Normal
ALT: Summary of Recent Literature
If focus on fibrosis:
• Range 8% to 47% of patients have stage 2
fibrosis or greater
• Normal ALT levels often  on follow-up
• Factors associated with higher fibrosis
- Age >35 yr
- Male gender
- Level of ALT
Yang LM et al. Chinese J Dig Dis. 2002;3:150-153.
Tsang PSY et al. Clin Gastroenterol Hepatol. 2008;6:569-574.
Kumar J et al. Gastroenterology. 2008;134:1376-1384.
Wang C et al. Hepatology. 2005;42:573A.
Lai M et al. Hepatology. 2005;42:720A.
Terrault NA et al. Gastroenterology. 2007;132:A72. [#94]
Let’s Vote!
Audience Response Question
Based upon the AASLD Guidelines, which of
the following HBeAg-positive profiles warrants
treatment?
A. ALT 45, HBV DNA 50,000 IU/mL, no biopsy
available
B. ALT 45, HBV DNA 500 million IU/mL, biopsy
14%
shows F0, G1-2 disease
C. ALT 18, HBV DNA 22 million IU/mL, no
3%
biopsy
D. ALT 45, HBV DNA 57,000 IU/mL, biopsy
71%
shows F2, G2-3 disease
12%
HBeAg-Negative HBV Disease:
Diagnostic Dilemmas
Anti-HBe positive
HBV DNA
ALT
Histology
Active HBeAgNegative Disease
Inactive Chronic
HBV


>20,000 IU/mL
HBV DNA <2000
IU or negative
Elevated
Normal
Significant
inflammation and
fibrosis
Inactive hepatitis
with variable
fibrosis
Fluctuating Course of HBeAgnegative Chronic Hepatitis B
400
With flares
300
73 pts
(44.5%)
and normalization
200
Asymptomatic
flare-up:
90% of cases
100
0
A
L
T
400
Without flares
300
59 pts
(36.0%)
200
100
Flare-up yearly
frequency:
once 57.1%
twice 20%
< once 22.8%
0
400
With flares and
without normalization
300
200
32 pts
(19.5%)
100
0
0
12
months
24
Brunetto MR et al, J Hepatol 2002
Biochemical patterns in 164 untreated patients after 23 months (range 12-36) monthly monitoring
Let’s Vote!
Audience Response Question
Based upon the AASLD Guidelines, which of the
following HBeAg-negative profiles warrants
treatment now?
3%
41%
21%
35%
A.
B.
C.
D.
ALT 60, HBV DNA 500 IU/mL, no biopsy available
ALT 40, HBV DNA 8000 IU/mL, biopsy shows G2,
F2, no steatosis
ALT 40, HBV DNA 200,000 IU/mL, biopsy shows
G0-1, F0-1 fibrosis, G2 steatosis
ALT 20, HBV DNA 100 IU/ml, biopsy shows F4
(cirrhosis)
CHB Treatment Algorithm for
Cirrhotic Patients
Treatment Criteria
Recommended
Action
If HBV DNA ≥2000 IU/mL, any ALT
OR
If HBV DNA <2000 IU/mL, elevated ALT
Treat
If HBV DNA<2000 IU/mL and normal ALT
Observe
Keeffe EB et al. Clin Gastroenterol Hepatol. 2006;4(8):936-962.
Lok AS, McMahon BJ. Hepatology. 2007;45(2):507-539.
Considerations in Applying
Treatment Guidelines
• HBV viral load
- HBeAg-negative: if 2000-20,000 IU/mL, may
benefit from additional testing to determine disease
severity
• ALT cutoff
- Use “normal” ULN for ALT
- Lack of ALT elevation does not exclude significant
disease, though advance fibrosis infrequent
• Cirrhosis
- Levels of HBV DNA differ, any ALT
Case Presentation (cont’d)
• You perform a liver biopsy, which shows grade 2
necroinflammation and stage 2 fibrosis
• Additional laboratory testing:
- HBV genotype B
• Patient informs you that she and her husband
would like to start a family within the year
Let’s Vote!
Audience Response Question
What do you recommend?
16% A.
20%
B.
28% C.
37% D.
Defer treatment until after delivery of infant
Deferral of pregnancy to undergo treatment with
peg-IFN for 24 weeks
Proceed with pregnancy but add lamivudine in last
trimester for prevention of perinatal transmission
Start treatment now with tenofovir
HBV Treatment and Pregnancy
• If can defer, this is often best strategy
• If treating in pregnancy:
- Lamivudine is treatment of choice, if limited duration
 Pregnancy category C drug with long safety record in
HIV+ women
- Tenofovir and telbivudine
 Pregnancy category B drugs
 Tenofovir has accumulating safety record in HIV+ women
- Risk-benefit needs to be individualized
- Antiviral therapy in last trimester may reduce perinatal
transmission if mother has high HBV DNA
(>107-8 IU/mL)
van Zonneveld et al. J Viral Hepat. 2003(4);10:294-297.
Hepatitis B Treatment: Summary
• Chronic HBV is dynamic disease
- Regular monitoring needed to determine timing of
treatment and other interventions
• Primary determinants of treatment
initiation are
- HBV DNA level ≥20,000 IU/mL
- ALT level ≥2 ULN
- ± Histological severity of disease
• Assessment of histology most helpful in
borderline ALT and HBV DNA cases
• Cirrhotics: lower thresholds to treat
Treatment Options for
Chronic Hepatitis B
Infection
Mark Sulkowski, MD
Associate Professor of Medicine
Divisions of Infectious Diseases and
Gastroenterology/Hepatology
Johns Hopkins University
Baltimore, Maryland
Case Presentation
• A 58-year-old man from Malaysia is referred
for evaluation
– No comorbid conditions
– He reports that his mother died of liver cancer
– He was initially diagnosed ~ 1999 and treated for
about 3 months with “a pill”
• Evaluation
–
–
–
–
–
AFP = 9 ng/mL
HBeAg +
ALT = 64 (< 40 U/L)
HBV DNA = 28.8 million IU/mL
Liver CT scan = “normal”
Let’s Vote!
Audience Response Question
Which of the following evaluations may be
helpful for guiding HBV treatment decisions?
6%
7%
24%
6%
57%
A.
B.
C.
D.
E.
HBV genotype
Resistance testing
Liver biopsy
ALT level
All of the above
Case Presentation (cont’d)
• Liver biopsy was performed
– Chronic portal inflammation with mild focal
lobular hepatitis
– Portal and septate fibrosis with ill-defined focal
parenchymal nodularity
• HBV genotype C
• PCR amplification and DNA sequencing reveal
polymorphism at position 204 (M → V)
Goal of Anti-HBV Therapy
• Improve QOL and survival by preventing
progression to cirrhosis, end-stage liver disease,
hepatocellular carcinoma and death
• Mechanisms to achieve this goal
– Immune control of HBV replication:
seroconversion
– Antiviral control of HBV replication: long term
suppression
• Eradication is not possible, due to cccDNA
EASL Clinical Practice Guidelines. J Hepatol. 50(2009),doi:10.1016/j.jhep.2008.10.001.
Recommended First-Line HBV
Treatment: Peg-IFN, ETV, TDF
Approved for HBV
• Interferon alfa
•
•
- Interferon alfa-2b
- Peginterferon alfa-2a
Nucleoside analogues
- Lamivudine*
- Telbivudine
- Entecavir
Nucleotide analogues
- Adefovir
- Tenofovir DF*
Unlabeled
• Emtricitabine*
• Combination therapy
- PegIFN + nucleos(t)ide
analogue
- Nucleoside + nucleotide
analogue*
*Approved by the FDA for treatment of HIV infection
First-line agents in guidelines: Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008 Aug 23. [Epub ahead of
print]; EASL Clinical Practice Guidelines. J Hepatol. 50(2009),doi:10.1016/j.jhep.2008.10.001.
Let’s Vote!
Audience Response Question
A 55-year-old man
-
Genotype C
HBV DNA = 28.8 million IU/mL
ALT = 54
Histologic evidence of cirrhosis
Which of the following characteristics is/are associated with
a favorable response to interferon?
3%
23%
53%
15%
6%
A.
B.
C.
D.
E.
Male sex
Genotype C
Elevated ALT
High HBV DNA level
Cirrhosis
Peg-IFN for Chronic Hepatitis B
Peg-IFN
• Finite duration
• No resistance
• Higher rates of
seroconversion
• Poor tolerance
• SQ injection
• High ALT activity1,2,3
• Low baseline serum HBV
DNA concentration4
• Genotype A or B5,6
• Absence of comorbidities
• No cirrhosis
• No decompensated liver
disease
1. Piratvisuth T, et al. Hepatology. 2004;40:656A. Abstract 1137.
2. Flink HJ, et al. Gut. 2005;54(11):1604-1609.
3. LauGKK et al. 56th AASLD;2005; San Francisco. Abstract 66086.
4. Fried MW, et al. Hepatology. 2005;42:268A. Abstract 182.
5. FlinkHJ, et al. Am J Gastroenterol. 2006;101(2):297-303.
6. Hadziyannis SJ, et al. J Hepatol. 2005;42(suppl 2):178. Abstract 49
Let’s Vote!
Audience Response Question
Which of the following factors may influence the
selection of nucleos(t)ide analogue therapy:
2%
12%
2%
7%
78%
A.
B.
C.
D.
E.
Cost
Genetic barrier to resistance
Safety
Potency
All of the above
Antiviral Agents: Safety, Tolerability,
Cost, and Risk:Benefit
LAM
ADV
Entecavir
Telbivudine
Tenofovir
Dosing
QD
QD
QD
QD
QD
Tolerability
Well
tolerated
Well
tolerated;
Watch
serum Cr
Well
tolerated
Well
tolerated;
Watch CPK
Well
tolerated;
Watch
serum Cr
Pregnancy
C
C
C
B
B
6500
8700
6000
6000
Approximate
2500
cost for 1 year
Potency
Moderate Modest
High
High
High
Resistance
High
Low
High
Low
Moderate
Dienstag JL. N Engl J Med. 2008;35(14):1486-500.
HBeAg-Postive Chronic HBV: HBV DNA
Suppression and HBe Seroconversion at 1 Year
EASL Clinical Practice Guidelines. J Hepatol. 50(2009),doi:10.1016/j.jhep.2008.10.001; Dienstag JL. N Engl J Med. 2008;359(14):1486-1500.
Higher Rates of Seroconversion
With Longer Viral Suppression
30
27
22
26
21
%
20
10
3
5
2
1
0
48 weeks
HBeAg loss
HBsAg loss
Heathcote J. EASL 2008. Abstract #1593
64 weeks
HBeAb
HBsAb
HBeAg-Negative Chronic HBV: HBV DNA
Suppression and ALT Normalization at 1 Year
EASL Clinical Practice Guidelines. J Hepatol. 50(2009),doi:10.1016/j.jhep.2008.10.001; Dienstag JL.. N Engl J Med. 2008;35(14):1486-1500.
Histologic improvement with long-term HBV
DNA suppression with ETV
Histologic Improvement*
96%
100
Proportion of patients (%)
Proportion of patients (%)
100
80
Improvement in Ishak fibrosis score†
73%
60
40
20
41/56‡
55/57
48 Weeks
Long-term§
0
88%
80
60
40
32%
20
18/56‡
50/57
0
48 Weeks Long-term§
*≥2-point decrease in Knodell necroinflammatory score and no worsening of Knodell fibrosis score compared with baseline
† ≥1-point decreasepatient had an inadequate Week 48 biopsy; ‡One § Median time of long-term biopsy: 280 weeks
inadequate Week 48 biopsy; § Median time of long-term biopsy: 280 weeks
Liaw Y-F et al. AASLD 2008; Poster #894
% With Disease Progression
Clinical Outcomes by Treatment and
Resistance Status
25
Placebo (n=215)
YMDDm (n=209) (49%)
Wild Type (n=221)
20
Placebo
21%
YMDDm
13%
WT
5%
15
10
5
0
0
6
12
18
24
Time After Randomization (Months)
YF Liaw et al. N Engl J Med. 2004;351:1521-1531.
30
36
Incomplete Suppression of Virus
Replication Leads to Resistance
Dominant Strain
Treatment
Initiated
Naturally Occurring Variants
HBV Replication
Drug Resistant Variant
• Incomplete Suppression
- Inadequate Potency/Drug Levels
- Inadequate Adherence
- Pre-Existing Resistance Variants
Time
Detection
Level
Fung SK & Lok ASF. Antivir Ther 2004; 9:1013–1026
Locarnini S, et al. Antivir Ther 2004; 9:679–693
Viral Suppression Reduces the
Incidence of Resistance
LAM
in HBeAg-Positive Patients
ADV
in HBeAg-Negative Patients
(Follow-up 29 months, n=159)
(Follow-up 144 weeks, n=114)
P < .001 between groups
Yuen M et al. Hepatology. 2001; 34(4):785-791.
Locarnini S et al. J. Hepatology . 2005;42(Suppl 2):17.
Monitoring for Treatment Failure With
Nucleos(t)ide Analogue Therapy
• Primary nonresponse
– Less than 1-log10 drop at week 12
• Partial virological response (detectable)
– Week 24: LAM, LdT, ADV
– Week 48: TDF, ETV
• Virological breakthrough
– Rise in serum HBV DNA (≥ 1.0 log10 IU/mL)
above nadir
Cumulative Incidence of
HBV Resistance
EASL Clinical Practice Guidelines. J Hepatol. 50(2009),doi:10.1016/j.jhep.2008.10.001; Dienstag JL. N Engl J Med. 2008;35(14):1486-1500
HBV Antiviral Therapy
Cross-Resistance in Vitro
LAM
ETV
LdT
FTC
ADV
TDF
?
?
HBV Resistance to Entecavir Affected by
Previous Resistance to Lamivudine
Cumulative Incidence (%)
100
Entecavir (naive): genotypic resistance
Entecavir (lamivudine resistant): genotypic resistance
80
60
51
46
40
36
20
15
6
0
0.2
1
0.5
2
1.2
3
Year
1.2
4
Colonno RJ, et al. 42nd EASL;2007;Barcelona. Abstract 781; Lai CL, et al. Clin Infect Dis. 2003;36:687-696;
Lok AS, et al. Gastroenterology. 2003;125:1714-1722; Tenney DJ, et al. 18th APASL; 2008:Seoul.. Abstract PL02.
1.2
5
TDF in Nucleos(t)ide-Experienced Patients:
Undetectable* HBV DNA at Month 12
P = NS
Undetectable* HBV DNA
at Month 12 (%)
P = NS
100
90
80
70
60
50
40
30
20
10
0
100
92
85
P =.001
92
90
73
30
All
Patients
n = 101
HBeAg
Positive
85
HBeAg
Negative
26
Wild-Type
YMDD
HBV
Mutations
42
36
ADV-R
No ADV-R
20
81
Virologic breakthrough not observed during follow-up period, independent of presence of
ADV resistance at start of TDF
*HBV DNA < 400 copies/mL (< 69 IU/mL)
van Bömmel F, et al. 43rd EASL; 2008; Milan. Abstract 73.
Case Presentation (cont’d)
• Patient initiates treatment with TDF 300 mg/day
– HBV DNA
• 3 months: 120,000 IU/mL
• 6 months: 785 IU/mL
• 12 months: < 22 IU/mL
• Serum Cr stable
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2007;5:890-897.
HBV Therapy
• HBV replication is closely linked to the lifetime risk of
disease outcomes (HCC, ESLD)
• New treatment paradigm = long-term control of HBV
replication:
– ↓ hepatic inflammation and fibrosis
– ↓ risk of hepatic decompensation and/or HCC
• First-line therapy – high potency/low resistance
–
–
–
–
Peg-IFN
Tenofovir
Entecavir
Combination antiviral therapy?
Combination Therapy
for Treatment of
Chronic HBV Infection
Marion Peters, MD
Professor of Medicine
Chief of Hepatology Research
University of California, San Francisco
San Francisco, California
Case Presentation
• A 45-year-old man was admitted with fatigue,
malaise, and abdominal swelling in June 2003
• He was born in Greece, came to United States
at age 14
• His brother had a liver transplant for HBV
in 1998
• Examination reveals jaundice, ascites, no
muscle wasting, spider nevi
Case Presentation: HBV Laboratory
• Bilirubin 3.7, AST 129, ALT 106, albumin 2.4, PT
1.7, ammonia 51, creatinine 0.9
• MELD (model for end-stage liver disease) score, 19
• HBsAg and HBeAg positive
• HBV DNA 1.7 billion copies per mL
• AFP 741 µg/L
• Paracentesis WCC 183, albumin <1
Let’s Vote!
Audience Response Question
How would you treat his HBV?
10%
A. Pegylated interferon (Peg-IFN) for 48 weeks
5%
B. Lamivudine (LAM) 100 mg per day
1%
C. Adefovir (ADV) 10 mg per day
23%
D. Entecavir (ETV) 0.5 mg per day
3%
E. Telbivudine (LdT) 600 mg
22%
F. Tenofovir (TDF) 300 mg per day
37%
G. Combination LAM + TDF
Case Presentation: Treatment
• June 2003 started LAM 100 mg daily
- Well tolerated
- Patient has improvement in well-being
• Listed for liver transplantation
• Ultrasound: cirrhotic liver, no masses
• CT, quadruple phase: no masses
Case Presentation:
Laboratory Findings
LAM
Date
AST
Bili
Albumin
AFP
HBV DNA
6-03
160
3.7
2.5
741
1,700,000,000
11- 03
59
0.9
3.1
14
2,000,000
copies/mL
Case Presentation:
Laboratory Findings (cont’d)
LAM
Date
AST
Bili
Albumin
AFP
HBV DNA
6-03
160
3.7
2.5
741
1,700,000,000
11- 03
59
0.9
3.1
14
2,000,000
2-04
74
1.3
2.9
193
2,500,000,000
copies/mL
Let’s Vote!
Audience Response Question
What has occurred?
5%
A. LAM nonresponse
87%
B. LAM resistance
8%
C. Noncompliance
HBeAg-Positive Patients (N = 159)
Median Follow-up: 29.6 Months
100
Patients With
YMDD Variants (%)
Patients With Resistance (%)
HBV DNA at Month 6 of LAM
Predicts Later Risk of Resistance
80
64
60
40
20
32
8
13
12
23
41
118
0 n=
≤2
≤3
≤4
>4
HBV DNA at 6 Months (log10 copies/mL)
Yuen ME et al. Hepatology. 2001;34:785-791.
Case Presentation: HBV Status
• HBV genotype A, HBeAg positive
• Polymerase mutations
- L180M, +M204V
- No precore mutations detected
- No ADV mutations detected
• HIV negative
• Hepatitis D virus negative
Let’s Vote!
Audience Response Question
How would you treat his HBV?
3%
A. Switch to ADV 10 mg per day
7%
B. Switch to ETV 0.5 mg per day
15%
C. Switch to TDF 300 mg per day
19%
D. Add ADV 10 mg per day
8%
E. Add ETV 0.5 mg per day
47%
F. Add TDF 300 mg per day
Case Presentation:
Laboratory Findings (cont’d)
LAM
Add
ADV
Date
AST
Bili
Albumin
AFP
6-03
160
3.7
2.5
741
1,700,000,000
11- 03
59
0.9
3.1
14
2,000,000
2-04
74
1.3
2.9
193
2,500,000,000
HBV DNA
copies/mL
Case Presentation:
Laboratory Findings (cont’d)
LAM
Add
ADV
Date
AST
Bili
Albumin
AFP
6-03
160
3.7
2.5
741
1,700,000,000
11- 03
59
0.9
3.1
14
2,000,000
2-04
74
1.3
2.9
193
2,500,000,000
5-04
69
1.5
3.0
169
1,600,000,000
HBV DNA
copies/mL
Let’s Vote!
Audience Response Question
What has occurred?
10%
A. ADV resistance
28%
B. ADV primary nonresponse
54%
C. ADV suboptimal response
4%
D. Worsening liver failure
4%
E. Noncompliance
Nonresponse, Suboptimal Response, and
Virologic Breakthrough
Change in HBV DNA
(log10 IU/mL)
1.0
Antiviral Drug
Primary
nonresponse
0
Virologic
breakthrough
-1.0
Suboptimal
response
-2.0
-3.0
Nadir
-4.0
0
6
12
Months
Lok AS et al. Hepatology. 2007;45:507-539.
1 log
18
HBV DNA at Week 48 of ADV Predicts
Risk of Resistance at Week 144
N = 114 Patients,
Primarily HBeAg Negative1
Resistance (%)
100
100
N = 124
Patients, HBeAg
Negative2
80
80
67
60
60
40
40
49
26
20
20
6
4
0
0
<3
3-6
>6
<3
HBV DNA at Week 48 (log10copies/mL)
1. Locarnini S et al. 40th EASL; 2005; Paris. Abstract 36.
2. Hadziyannis SJ et al. Gastroenterology. 2006;131:1743-1751.
>3
Let’s Vote!
Audience Response Question
What would you do?
2%
A. Continue ADV
17%
B. Add TDF 300 mg
9%
C. Change to TDF and ADV
34%
D. Change to TDF and LAM or emtricitabine (FTC)
39%
E. Change to TDF and ETV
Case Presentation:
Laboratory Findings (cont’d)
Date
AST
Bili
LAM
6-03
160
3.7
2.5
741
1,700,000,000
Add
ADV
11- 03
59
0.9
3.1
14
2,000,000
2-04
74
1.3
2.9
193
2,500,000,000
5-04
69
1.5
3.0
169
1,600,000,000
8-04
68
1.8
3.4
42
78,000,000
11-04
67
1.0
3.7
16.2
97,000
5-06
52
1.1
4.0
8
2,590
5-07
28
1.0
4.4
2.9
Switch 
to TDF +
LAM
Albumin AFP
HBV DNA
undetectable
<5 copies/mL
Why Consider Combination
Therapy?
• Sequential monotherapy with nucleos(t)ide analogs has
led to HBV resistance
• There may be special populations in whom combination
is recommended:
- Cirrhotics in whom development of resistance may have
irreversible severe consequences
- HIV/HBV coinfected
• Changing to another nucloes(t)ide after failure increases
chance of poor or nonresponse and of resistance to next
drug, eg, ETV
• Multidrug-resistant mutants described after sequential
monotherapy1,2
• Resistance has been low with combination therapy
1. Yim HJ et al. Hepatology. 2006:43:S173-181.
2. Shaw T et al. 58th AASLD; 2007; Boston. Abstract 986.
Combination Therapy
• Peg-IFN and LAM showed more HBV DNA
suppression while patients on therapy but
suppression lost after end of therapy; no
increased HBeAg seroconversion
• ADV and LAM/FTC: less resistance but no
increase in efficacy
Lampertico P et al. Gastroenterology. 2007;133(5):1445-1451.
Patients (%)
Patients (%)
PEG-IFN alfa-2a +/- LAM for HBeAg+ CHB
Week 48 (End of therapy)
*P<.05 vs lamivudine
**P<.01 vs lamivudine
***P<.001 vs lamivudine
Week 72 (24 weeks off-therapy)
Lau GK et al. N Engl J Med 2005; 352(26):2682-2695.
ADV vs ADV + LAM for HBeAgLAM-Resistant Patients
• Multicenter cohort study; retrospective/prospective
‒ Mean follow-up: 33 months
Undetectable HBV DNA* (%)
ADV + LAM (n = 285)
ADV (n = 303)
100
Patients (%)
Year 3 Cumulative ADV
Resistance
100
80
80
60
60
P = NS
40
40
20
20
0
0
0
6
12
18
Month
*< 1000 copies/mL.
24
30
36
P < .001
16
0
ADV
(n = 303)
ADV + LAM
(n = 285)
Lampertico P et al. Gastroenterology. 2007;133(5):1445-1451. Lampertico P et al. 57th AASLD; 2006; Boston.
Abstract LB5. CCO
ADV Resistance Not Observed With
LAM Combination Therapy
Incidence of Resistance (%)
ADV monotherapy (Study 438: naive patients)
60
ADV+ LAM
(Studies 435 and 460i: LAM resistance*;
Study 435: pre- and post-OLT;
Study 460i: HIV/HBV)
40
30
20
19
11
0
0
0
Year 1
3
0
0
Year 2
Year 3
0
Year 4
Year 5
*Two patients enrolled in Study 435 initially received combination therapy with adefovir + lamivudine and
subsequently selected adefovir resistance mutation N236T. However, they had switched to adefovir
monotherapy at a time when adefovir resistance mutation was detected.
Lee YS,et al. Hepatology. 2006;43:1385-1391. Lampertico P et al. 57th AASLD; 2006; Boston.
Abstract LB5. Schiff E et al. Liver Transpl. 2007;13:349-360. Hepsera [package insert].
Managing Responses in the
Treatment of CHB
Week 12
Assess for primary nonresponse
Week 24
Assess early predictors of efficacy
Complete response
HBV DNA negative by PCR
Partial response
HBV DNA
60 to < 2000 IU/mL
Inadequate response
HBV DNA ≥ 2000 IU/mL
Continue
Monitor every 6 months
Add another drug without
cross-resistance or continue
Monitor every 3 months
Add/switch to
more potent drug
Monitor every 3 months
Adapted from Keeffe E et al. Clin Gastroenterol Hepatol. 2007;5:890-897.
Combination Therapy
• Combination therapy has reduced the
emergence of resistance
• This may lead to better long-term outcomes
• At present no FDA-approved indication for use
of combination therapy in patients with chronic
HBV infection and no synergy in HBV DNA
decline noted
• Use in cirrhotic patients especially those with
preexisting YMDD mutations and in HIV HBV
patients appears warranted
Jacobson IM. J Hepatol. 2008;48:687-691; CDC Guidelines for HIV patients. 2008.