Date post: | 25-Dec-2015 |
Category: |
Documents |
Upload: | georgiana-boyd |
View: | 216 times |
Download: | 1 times |
Eugene R. Schiff, MD, MACP, FRCP, MACG, AGAF
Program ChairLeonard Miller Professor of MedicineUniversity of Miami School of Medicine
Miami, Florida
Introduction and Program Overview
Program Overview• Chronic hepatitis B (HBV) infection is significantly under-
diagnosed 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 ObjectivesUpon 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 FacultyProgram Chair
Eugene R. Schiff, MD, MACP, FRCP, MACG, AGAFLeonard Miller Professor of MedicineDirector, Schiff Liver InstituteDirector, Center for Liver DiseasesDivision of HepatologyUniversity of Miami School of MedicineMiami, FL
Marion Peters, MD, FRACPProfessor of MedicineChief of Hepatology ResearchUniversity of California, San FranciscoSan Francisco, CA
Mark Sulkowski, MDAssociate Professor of MedicineMedical Director, Viral Hepatitis CenterJohns Hopkins University School of MedicineBaltimore, MD
Norah A. Terrault, MDAssociate Professor of MedicineDirector, Viral Hepatitis Research in Liver TransplantationDept of Medicine, Division of GastroenterologyUniversity of California, San FranciscoSan Francisco, CA
Tram T. Tran, MDAssistant Professor of MedicineGeffen UCLA School of MedicineDivision of GastroenterologyMedical Director of Liver TransplantComprehensive Transplant CenterCedars Sinai Medical CenterLos Angeles, CA
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, MDAssistant Professor of Medicine
Geffen School of Medicine at UCLA Medical Director of Liver TransplantComprehensive Transplant Center
Cedars-Sinai Medical CenterLos 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!
New CDC 2008 Guidelines recommend HBV screening in immigrants from endemic areas with hepatitis B prevalence of:
36%
24%
26%
14%
Audience Response Question
A. > 25%
B. >10%
C. >8%
D. >2%
Hepatitis B: Region/CountryRegion 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
*Per 100,000 population.
Males aged 0-19 yrMales aged 20-39 yrMales aged ≥40 yrFemales aged 0-19 yrFemales aged 20-39 yrFemales aged ≥40 yrTotal
Year
1996 1998 2000 20021994199219900
4
8
12
16
20
Inci
den
ce
Hepatitis B: Disease Progression
Acute Infection
Chronic Infection
Cirrhosis Death
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.
5%-10%
10%-30%
23% within 5 years
Liver Cancer (HCC)
Chronic HBV is the 6th leading cause of liver transplantation in the US
Liver Transplantation
Liver Failure (Decompensation)
2%-6%2%-6%
90% in perinatal30%-90% in children <5 years old5% in healthy adultsHigher in HIV, immunosuppressed
Asian-American Age-Adjusted Liver Cancer Rates (California, 2000-2002)
Incidence
Rat
e (p
er 1
00,0
00)
MaleFemale
23.3
7.6
54.3
15.8
33.7
8.1
McCracken M et al. CA Cancer J Clin. 2007;57:190-205.
Filipino Viet-namese
Korean Japanese WhiteChinese
16.8
5.4
15.9
9.36.8
2.5
Mortality
Rat
e (p
er 1
00,0
00)
MaleFemale
19.9
7.8
35.5
10.4
26.6
7.8
Filipino Viet-namese
Korean Japanese WhiteChinese
12.0
4.2
11.5
8.36.0
2.7
Approximately 3.7 million Asians in California. Cancer data from California Cancer Registry.
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!
This patient is most likely in which stage of CHB infection?
15%
21%
38%
8%
18%
Audience Response Question
A. Immune tolerant
B. Immunoactive/immune clearance
C. Inactive carrier
D. HBeAg CHB
E. 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 30105- 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.
0%
10%
20%
30%
40%
50%
60%
70%
PNALT ALT 1-1.5 ULN ALT >1.5 ULN
Per
cen
tag
e
Grade 0
Grade 1
Grade 2
Grade 3
34%
54%
78%
Lai M et al. J Hepatol. 2007;47(6):760-767.
Grade of Inflammation by ALT Group
PNALT, persistently normal ALT.
Stage of Fibrosis by ALT Group
18% 34%
62%
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.
Yuen MF et al. Gut 2005;54(11):1610-1614.
HBeAg Seroconversion to Anti-HBe
Median age (yr)
Percentage
anti-HBe
HBeAg seroconversion 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
• Development of cirrhosis complications and HCC
- 3233 Chinese patients
- Mean follow-up 46.9 months
50
40
30
20
10
0
HBeAg negativeHBeAg positive
Years
Per
cen
t
0 1 2 3 4 5
Incidence of Cirrhosis: HBeAg Status
Fattovich G et al. J Hepatol. 2008;48(2):335-352.
Taiwan and Korea Europe
50
40
30
20
10
0
HBeAg negativeHBeAg positive
Years
Per
cen
t
0 1 2 3 4 5
Cumulative Incidence of Hepatocellular Carcinoma (HCC)
Fattovich G et al. J Hepatol. 2008;48(2):335-352.
Taiwan, China, Singapore, Koreaand Japan Europe and USA
20
15
10
5
1
0
CirrhosisChronic hepatitisInactive carrier
Years
Per
cen
t
0 1 2 3 4 5
20
15
10
5
1
0
CirrhosisChronic hepatitisInactive carrier
Years
Per
cen
t
0 1 2 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!
Is it necessary to screen patients for HBV before anti-TNF therapy?
2%
3%
28%
68%
Audience Response Question
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 high- risk 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 anti-TNF 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 TreatWhen to Treat
Norah Terrault, MD, MPH
Associate Professor of MedicineDirector of Viral Hepatitis Research in
Liver TransplantationUniversity of California, San Francisco
San Francisco, California
Goals of Treatment
TIME
Loss of HBeAg
Loss of HBV DNA
Anti-HBe+ Loss ofHBsAg
Anti-HBs+Improvedsurvival
Improvedhistology
HBV is controlled not
eradicated
Decision to Treat: Balancing Benefits and Risks
Risk of Liver Complications
CostsSide Effects
Drug Resistance
Factors Associated With Disease Progression in Patients With CHB
Host Factors• >40 years of age
• Male
• Immune status
Virus Factors
• High serum HBV DNA concentrations
• 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
26/2034
Persistent Elevated HBV DNA and Cumulative Incidence of HCC
10.1
7.3
3.8
1
0
2
4
6
8
10
12
Chen CJ et al. JAMA. 2006;295(1):65-73.
< 104
Not Tested≥105
< 104 ≥105
≥105
≥105 → 104 - < 105
(1.7-8.4)
(3.5-15.3)
(6.3-16.2)
HBV DNA : Baseline Follow-up (copies/mL)
Ad
just
ed H
R f
or
HC
C
(95%
CI)
8/146 10/120 55/537
P = NS
P < .001
P < .001
P < .001
67% ≥40 yrs and 62% male
Case Presentation• A 37-year-old Asian woman is referred for HBsAg-
positive 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!
What do you recommend at this point?
45%
25%
4%
25%
Audience Response Question
A. Continue monitoring ALT every 3-6 months and treat if ALT increases to ≥2 X ULN
B. Obtain HBV genotype and treat if genotype A
C. Start treatment, regardless of HBV genotypeD. Obtain liver biopsy and treat if significant
inflammation or fibrosis
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
n=451
ALT<2 ULN With Revised ALT ULNs*
n=141
HBeAg(+) CHB
Necroinflammation ≥7
Fibrosis ≥465%
13%
68%
11%
HBeAg(-) CHB
Necroinflammation ≥7
Fibrosis ≥471%
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!
Based upon the AASLD Guidelines, which of the following HBeAg-positive profiles warrants treatment?
71%
3%
14%
12%
Audience Response Question
A. ALT 45, HBV DNA 50,000 IU/mL, no biopsy available
B. ALT 45, HBV DNA 500 million IU/mL, biopsy shows F0, G1-2 disease
C. ALT 18, HBV DNA 22 million IU/mL, no biopsy
D. ALT 45, HBV DNA 57,000 IU/mL, biopsy shows F2, G2-3 disease
HBeAg-Negative HBV Disease: Diagnostic Dilemmas
Active HBeAg-Negative Disease
Inactive Chronic HBV
Anti-HBe positive
HBV DNA >20,000 IU/mLHBV DNA <2000
IU or negative
ALT Elevated Normal
HistologySignificant
inflammation and fibrosis
Inactive hepatitis with variable
fibrosis
0
100
200
300
400
0
100
200
300
400
0
100
200
300
400
Biochemical patterns in 164 untreated patients after 23 months (range 12-36) monthly monitoring
00 1212 2424monthsmonths
With flares and normalizationWith flares and normalization
Without flaresWithout flares
With flares and without normalizationWith flares and without normalization
73 pts 73 pts (44.5%)(44.5%)
59 pts 59 pts (36.0%)(36.0%)
32 pts 32 pts (19.5%)(19.5%)
Asymptomatic flare-up:
90% of casesAALLTT
Flare-up yearlyfrequency:
once 57.1%twice 20%
< once 22.8%
Brunetto MR et al, J Hepatol 2002
Fluctuating Course of HBeAg-negative Chronic Hepatitis B
Let’s Vote!
Based upon the AASLD Guidelines, which of the following HBeAg-negative profiles warrants treatment now?
35%
21%
41%
3%
Audience Response Question
A. ALT 60, HBV DNA 500 IU/mL, no biopsy available
B. ALT 40, HBV DNA 8000 IU/mL, biopsy shows G2, F2, no steatosis
C. ALT 40, HBV DNA 200,000 IU/mL, biopsy shows G0-1, F0-1 fibrosis, G2 steatosis
D. ALT 20, HBV DNA 100 IU/ml, biopsy shows F4 (cirrhosis)
CHB Treatment Algorithm for Cirrhotic Patients
Keeffe EB et al. Clin Gastroenterol Hepatol. 2006;4(8):936-962.Lok AS, McMahon BJ. Hepatology. 2007;45(2):507-539.
Treatment Criteria Recommended Action
If HBV DNA ≥2000 IU/mL, any ALTOR
If HBV DNA <2000 IU/mL, elevated ALT Treat
If HBV DNA<2000 IU/mL and normal ALT Observe
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!
What do you recommend?
37%
28%
20%
16%
Audience Response Question
A. Defer treatment until after delivery of infant
B. Deferral of pregnancy to undergo treatment with peg-IFN for 24 weeks
C. Proceed with pregnancy but add lamivudine in last trimester for prevention of perinatal transmission
D. 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, MDAssociate Professor of Medicine
Divisions of Infectious Diseases and Gastroenterology/Hepatology
Johns Hopkins UniversityBaltimore, 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!
Which of the following evaluations may be helpful for guiding HBV treatment decisions?
57%
6%
24%
7%
6%
Audience Response Question
A. HBV genotype
B. Resistance testing
C. Liver biopsy
D. ALT level
E. 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 Unlabeled
• Interferon alfa- Interferon alfa-2b- Peginterferon alfa-2a
• Nucleoside analogues- Lamivudine*- Telbivudine- Entecavir
• Nucleotide analogues- Adefovir- Tenofovir DF*
• 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!
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?
6%
15%
53%
23%
3%
Audience Response Question
A. Male sexB. Genotype CC. Elevated ALTD. High HBV DNA levelE. Cirrhosis
Peg-IFN for Chronic Hepatitis B• 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
Peg-IFN
• Finite duration
• No resistance
• Higher rates of seroconversion
• Poor tolerance
• SQ injection
Let’s Vote!
Which of the following factors may influence the selection of nucleos(t)ide analogue therapy:
78%
7%
2%
12%
2%
Audience Response Question
A. Cost
B. Genetic barrier to resistance
C. Safety
D. Potency
E. 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
Approximate cost for 1 year
2500 6500 8700 6000 6000
Potency Moderate Modest High High High
Resistance High Moderate Low High Low
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
Heathcote J. EASL 2008. Abstract #1593
%
22
27
21
26
35
1 2
0
10
20
30
48 weeks 64 weeks
HBeAg loss HBeAbHBsAg loss 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*
73%
96%
Pro
po
rtio
n o
f p
atie
nts
(%
)
0
20
40
60
80
100
48 Weeks Long-term§
41/56‡ 55/57
Improvement in Ishak fibrosis score†
32%
88%
0
20
40
60
80
100
48 Weeks Long-term§
18/56‡ 50/57P
rop
ort
ion
of
pat
ien
ts (
%)
*≥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 weeksinadequate Week 48 biopsy; § Median time of long-term biopsy: 280 weeksLiaw Y-F et al. AASLD 2008; Poster #894
Clinical Outcomes by Treatment and Resistance Status
Wild Type (n=221)YMDDm (n=209) (49%)
Time After Randomization (Months)
0
5
10
15
20
25
0 6 12 18 24 30 36
% W
ith
Dis
ease
Pro
gre
ssio
n Placebo (n=215)
YMDDm
Placebo
5%
13%
21%
YF Liaw et al. N Engl J Med. 2004;351:1521-1531.
WT
Incomplete Suppression of Virus Replication Leads to Resistance
Fung SK & Lok ASF. Antivir Ther 2004; 9:1013–1026Locarnini S, et al. Antivir Ther 2004; 9:679–693
Drug Resistant Variant
• Incomplete Suppression- Inadequate Potency/Drug Levels- Inadequate Adherence- Pre-Existing Resistance Variants
Time
HB
V R
epli
cati
on
Treatment Initiated
DetectionLevel
Dominant Strain
Naturally Occurring Variants
Viral Suppression Reduces the Incidence of Resistance
Yuen M et al. Hepatology. 2001; 34(4):785-791.
P < .001 between groups
LAM in HBeAg-Positive Patients (Follow-up 29 months, n=159)
ADVin HBeAg-Negative Patients
(Follow-up 144 weeks, n=114)
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 TherapyCross-Resistance in Vitro
M204V
V173L
A181V/T
M250V
L180M
A184GS202I
N236T
M204I
LAMLAM
ADVADV
ETVETV
LdTLdT
FTCFTC
TDFTDF ? ?
HBV Resistance to Entecavir Affected by Previous Resistance to Lamivudine
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.
Year
Cu
mu
lati
ve In
cid
ence
(%
)
0
20
40
60
80
100
1 2 3 4 5
Entecavir (naive): genotypic resistance
Entecavir (lamivudine resistant): genotypic resistance
1.2
51
1.2
46
36
1.2
15
0.50.26
van Bömmel F, et al. 43rd EASL; 2008; Milan. Abstract 73.
TDF in Nucleos(t)ide-Experienced Patients: Undetectable* HBV DNA at Month 12
Virologic breakthrough not observed during follow-up period, independent of presence of ADV resistance at start of TDF
Un
det
ecta
ble
* H
BV
DN
A a
t M
on
th 1
2 (%
)
P =.001
P = NS P = NS
01020304050607080
10090
All Patients
HBeAgPositive
HBeAgNegative
Wild-Type HBV
YMDDMutations
ADV-R No ADV-R
8573
92100
92
30
90
n = 101 85 26 42 36 20 81
*HBV DNA < 400 copies/mL (< 69 IU/mL)
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, MDProfessor of Medicine
Chief of Hepatology ResearchUniversity 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!
How would you treat his HBV?
37%
22%
3%
23%
1%
5%
10%
Audience Response Question
A. Pegylated interferon (Peg-IFN) for 48 weeks
B. Lamivudine (LAM) 100 mg per day
C. Adefovir (ADV) 10 mg per day
D. Entecavir (ETV) 0.5 mg per day
E. Telbivudine (LdT) 600 mg
F. Tenofovir (TDF) 300 mg per day
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
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
LAM
Case Presentation: Laboratory Findings
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
LAM
Case Presentation: Laboratory Findings (cont’d)
Let’s Vote!
What has occurred?
8%
87%
5%
Audience Response Question
A. LAM nonresponse
B. LAM resistance
C. Noncompliance
12 n =
HBV DNA at Month 6 of LAM Predicts Later Risk of Resistance
HBeAg-Positive Patients (N = 159) Median Follow-up: 29.6 Months
Yuen ME et al. Hepatology. 2001;34:785-791.
Pat
ien
ts W
ith
Res
ista
nce
(%
)
813
32
64
0
20
40
60
80
100
≤ 2 ≤ 3 ≤ 4 > 4
Pat
ien
ts W
ith
Y
MD
D V
aria
nts
(%
)
HBV DNA at 6 Months (log10 copies/mL)
23 41 118
CaseCase 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!
How would you treat his HBV?
47%
8%
19%
15%
7%
3%
Audience Response Question
A. Switch to ADV 10 mg per day
B. Switch to ETV 0.5 mg per day
C. Switch to TDF 300 mg per day
D. Add ADV 10 mg per day
E. Add ETV 0.5 mg per day
F. Add TDF 300 mg per day
AddADV
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
LAM
Case Presentation: Laboratory Findings (cont’d)
AddADV
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
5-04 69 1.5 3.0 169 1,600,000,000
copies/mL
LAM
Case Presentation: Laboratory Findings (cont’d)
Let’s Vote!
What has occurred?
4%
4%
54%
28%
10%
Audience Response Question
A. ADV resistance
B. ADV primary nonresponse
C. ADV suboptimal response
D. Worsening liver failure
E. Noncompliance
Nonresponse, Suboptimal Response, and Virologic Breakthrough
Lok AS et al. Hepatology. 2007;45:507-539.
1 log
Ch
ang
e in
HB
V D
NA
(lo
g10
IU
/mL
)
0
-1.0
-2.0
-3.0
-4.0
1.0
Nadir
Virologic breakthrough
Antiviral Drug
Months
60 12 18
Primary nonresponse
Suboptimal response
HBV DNA at Week 48 of ADV Predicts Risk of Resistance at Week 144
Res
ista
nce
(%
)
1. Locarnini S et al. 40th EASL; 2005; Paris. Abstract 36.2. Hadziyannis SJ et al. Gastroenterology. 2006;131:1743-1751.
HBV DNA at Week 48 (log10copies/mL)
6
49
0
20
40
60
80
100
< 3 > 3
4
67
26
0
20
40
60
80
100
< 3 3-6 > 6
N = 114 Patients, Primarily HBeAg Negative1
N = 124 Patients, HBeAg
Negative2
Let’s Vote!
What would you do?
39%
34%
9%
17%
2%
Audience Response Question
A. Continue ADV
B. Add TDF 300 mg
C. Change to TDF and ADV
D. Change to TDF and LAM or emtricitabine (FTC)
E. Change to TDF and ETV
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
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 undetectable
<5 copies/mL
AddADV
LAM
Switch to TDF + LAM
Case Presentation: Laboratory Findings (cont’d)
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.
PEG-IFN alfa-2a +/- LAM for HBeAg+ CHB
*P<.05 vs lamivudine **P<.01 vs lamivudine***P<.001 vs lamivudine Lau GK et al. N Engl J Med 2005; 352(26):2682-2695.
Pat
ien
ts (
%)
Pat
ien
ts (
%)
Week 48 (End of therapy) Week 72 (24 weeks off-therapy)
ADV vs ADV + LAM for HBeAg-LAM-Resistant Patients• Multicenter cohort study; retrospective/prospective
‒ Mean follow-up: 33 months
Lampertico P et al. Gastroenterology. 2007;133(5):1445-1451. Lampertico P et al. 57th AASLD; 2006; Boston. Abstract LB5. CCO
P < .001
Undetectable HBV DNA* (%)
0 6 12 18 3630240
20
40
60
80
100
P = NS
ADV (n = 303)ADV + LAM (n = 285)
0
20
40
60
80
100
160
Year 3 Cumulative ADV Resistance
ADV(n = 303)
ADV + LAM(n = 285)Month
Pat
ien
ts (
%)
*< 1000 copies/mL.
ADV monotherapy (Study 438: naive patients)
ADV+ LAM (Studies 435 and 460i: LAM resistance*; Study 435: pre- and post-OLT; Study 460i: HIV/HBV)
ADV Resistance Not Observed With LAM Combination Therapy
*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.
Inci
den
ce o
f R
esis
tan
ce (
%)
0 0 3 0
11
0
19
30
0
20
40
60
Year 1 Year 2 Year 3 Year 4 Year 5
0
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
Adapted from Keeffe E et al. Clin Gastroenterol Hepatol. 2007;5:890-897.
Week 12 Assess for primary nonresponse
Week 24 Assess early predictors of efficacy
Complete responseHBV DNA negative by PCR
Partial responseHBV DNA
60 to < 2000 IU/mL
Inadequate responseHBV DNA ≥ 2000 IU/mL
ContinueMonitor 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
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.