Best Primary Care Practices
for Hepatitis B Infection:
Focus on Therapeutic Strategies
Larry Culpepper, MD, MPH
Professor of Family Medicine
Department Family Medicine
Boston University School of Medicine
Learning Objectives
1. Increase the rate at which family
physicians screen at-risk patients for
hepatitis B infection
2. Provide accurate patient education and
counseling to HBsAg-positive patients
3. Devise or refer for ongoing monitoring,
follow-up, and determination of
treatment candidacy
Why Care About Hepatitis B Virus
(HBV) Infection?
HBV infection is:
A public health problem
Prevalent
Underdiagnosed and undertreated
Associated with signifcant morbidity and
mortality
Family physicians are well positioned to
reach at-risk communities
HBV is a Public Health Problem
Institute of Medicine (IOM)
Hepatitis and Liver Cancer:
A National Strategy for Prevention
and Control of Hepatitis B and C1
US Department of Heath and Human
Services (HHS)
Combating The Silent Epidemic of
Viral Hepatitis: Action Plan for the
Prevention, Care & Treatment of
Viral Hepatitis2
1. Institute of Medicine Committee on the Prevention and Control of Viral Hepatitis
Infections. 2011. www.iom.edu/viralhepatitis
2. US Department of Heath and Human Services. 2011.
www.hhs.gov/ash/.../hepatitis/actionplan_viralhepatitis2011.pdf
IOM Report: Key Findings
Inadequate disease surveillance systems
At-risk unaware
Poor access
preventive services
testing
social support
medical management services
Chronically infected do not know they are infected
Many health-care providers do not
screen for risk factors
know how to manage infected people
Institute of Medicine Committee on the Prevention and Control of Viral Hepatitis
Infections. 2011. www.iom.edu/viralhepatitis
HBV Infection is Prevalent
2 billion infected
>400 million have chronic infection
United States
In 2009, estimated 38,000 newly infected
~1.4 million persons have chronic infection
Minority properly diagnosed (~500,000)
Only half are receiving care (~250,000)
~50,000 receiving antiviral treatment
WHO. 2012. http://www.who.int/mediacentre/factsheets/fs204/ en/index.html
CDC Division of Viral Hepatitis. 2012. http://www.cdc.gov/hepatitis/hbv/hbvfaq.htm
Cohen C, et al. J Viral Hepat. 2011;18(6):377-383. PMID: 21143343.
HBV Morbidity and Mortality
50-100 x more infectious than HIV
Chronic HBV develops in 90% infected as infants
and 1-10% infected as adults
Chronic infection can lead to cirrhosis, liver
failure, and cancer (usually over 20-30+ years)
Premature death in 15-25% of chronically
infected
A leading cause of cirrhosis and hepatocellular
carcinoma (HCC)
620,000 each year worldwide die from HBV
related disease
CDC Division of Viral Hepatitis. 2012. http://www.cdc.gov/hepatitis/hbv/hbvfaq.htm
Family Physicians Positioned to
Reach At-Risk Communities
1° and 2°
prevention
Long-term
Follow-up
HBV Risk Assessment
Screening
Serology Results
Interpretation
Screening: Use the CDC Guideline
CDC. 2008.
http://www.cdc.gov/hepatitis/HBV/PDFs/ChronicHepBTe
Persons at High Risk are
Candidates for HBV Screening
Persons born in regions of high and intermediate
HBV endemicity (HBsAg prevalence (≥2%)
US born persons not vaccinated as infants
whose parents were born in regions with high
HBV endemicity (≥8%)
Household and sexual contacts of HBV carriers
Persons who have injected drugs
Persons with multiple sexual partners or history
of STDs
Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20. PMID: 18802412.
Persons at High Risk are
Candidates for HBV Screening
All pregnant women
Infants born to HBV carrier mothers
Individuals with chronically elevated ALT/AST
Patients undergoing immunosuppressive therapy
Individuals infected with HIV or HCV
Men who have sex with men
Inmates of correctional facilities
Patients undergoing hemodialysis
Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20. PMID: 18802412.
HBV Screening Recommendations
by Risk Group
Persons born in high and
intermediate endemic areas
Test for HBsAg, regardless
of vaccination status
US born persons not vaccinated
as infants in the US whose
Test for HBsAg regardless
parents were born in regions
of maternal HBsAg status
with high HBV endemicity
Pregnant women
Infants born to HBV carrier
mothers
Test for HBsAg during each
pregnancy
Test for HBsAg and antiHBs 1–2 mos after 3 doses
of HBV vaccine
Centers for Disease Control and Prevention. 2008.
http://www.cdc.gov/hepatitis/HBV/PDFs/ChronicHepBTestingFlwUp.pdf
HBV Screening Recommendations
by Risk Group
Household, needle-sharing, or sex
contacts of persons known to be
HBsAg positive
Injection-drug users
Men who have sex with men
HIV-positive persons
Test for HBsAg, as well
as anti-HBc or antiHBs to identify
susceptible persons
Persons needing immunoTest for all markers of
suppressive therapy
HBV infection (HBsAg,
Patients undergoing hemodialysis anti-HBc, and anti-HBs)
Individuals with elevated ALT/AST
Test for HBsAg
of unknown etiolog
Centers for Disease Control and Prevention. 2008.
http://www.cdc.gov/hepatitis/HBV/PDFs/ChronicHepBTestingFlwUp.pdf
Chronic HBV
Centers for Disease Control and Prevention. 2008.
http://www.cdc.gov/hepatitis/HBV/PDFs/ChronicHepBTestingFlwUp.pdf
HBV Infection: Possible Outcomes
Acute HBV infection
3-5% adult-acquired
95% infant-acquired
Chronic HBV infection
Chronic Hepatitis
12-25% in 5 yrs
6-15% in 5 yrs
Hepatocellular
carcinoma (HCC)
Death
Cirrhosis
20-23% in 5 yrs
Liver failure
Liver
transplant
Death
Acute HBV Infection with Recovery
Typical Serologic Course
Symptoms
HBeAg
anti-HBe
Total anti-HBc
Titre
HBsAg
0 4
anti-HBs
IgM anti-HBc
8 12 16 20 24 28 32 36
Weeks after Exposure
52
100
Acute HBV Infection with Progression to
Chronic Infection: Typical Serologic Course
Acute
(6 months)
Chronic
HBeAg
(Years)
Anti-HBe
HBsAg
Total anti-HBc
IgM antiHBc
0
4
8 12 16 20 24 28 32 36
Weeks after Exposure
52
Years
HBV Serologic Markers
Marker
HBsAg
Anti-HBs
HBeAg
Anti-HBe
Anti-HBc
Interpretation
Chronic hepatitis B when > 6 mos
Immunity
Active viral replication and high infectivity
Recovery phase or reactivation phase
Past and possibly current infection
HBeAg and Anti-Hbe
NOT used for screening
Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20. PMID: 18802412.
Pattern
HBsAg
anti-HBc
anti-HBs
HBsAg
anti-HBc
anti-HBs
HBsAg
anti-HBc
anti-HBs
HBsAg
anti-HBc
IgM anti-HBc
anti-HBs
HBsAg
anti-HBc
IgM anti-HBc
anti-HBs
HBsAg
anti-HBc
anti-HBs
−
−
−
−
+
+
−
−
+
+
+
+
−
+
+
−
−
−
+
−
Interpretation
Susceptible
Immune due to natural infection
Immune due to HB vaccination
Acutely infected
Chronically infected
1. Resolved infection (most common)
2. False-positive anti-HBc, thus susceptible
3. “Low level” chronic infection
4. Resolving acute infection
CDC Division of Viral Hepatitis. 2012. http://www.cdc.gov/hepatitis/hbv/hbvfaq.htm
Serologic Results
Guide Next Steps
Counseling of HBV
Susceptible Patients
Counsel patients on
Modes of transmission
Found in semen, saliva, vaginal
mucus, and tears
Not found in urine, sweat, or stool
Prevention strategies
Condoms
Avoid IV drug use
HBV Vaccination is Highly Effective
80% Decline in Incidence Since Universal
Infant Vaccination Begun in 1991
Incidence
(Cases per 100,000
population)
14
12
10
8
6
4
2
0
1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006
Year
Wasley A, et al. MMWR Surveill Summ. 2008;57(SS-2):1-24.
Further Test Patients
Who Are HBsAg Positive
Assess for liver
disease
CBC
Hepatic panel
INR
Assess HBV
replication
HBeAg
anti-HBe
HBV DNA
Lok AS, et al. Hepatology.
2009;50(3):661-662. PMID:
19714720.
Rule out HCV and HIV
anti-HCV
anti-HDV*
anti-HIV
Screen for HCC
Ultrasound preferred (AFP as
alternative)
Consider liver biopsy to
grade & stage liver disease
* In persons from countries where
HDV infection is common and in those
with history of injection drug use
Surveillance for Hepatocellular
Carcinoma in Chronic HBV
Cost effective at annual incidence
• Without cirrhosis: >0.2%
• With cirrhosis: 1.5-2%
Age Related
Asian men ≥ age of 40
Asian women ≥ age 50
Caucasians with viral
load ≥ 20,000 IU and
active inflammation
Men ≥ age 40
Women ≥ age 50
At Time of Diagnosis
Africans and North
American Blacks
Patients with a family
history of HCC
Patients with cirrhosis
• No Surveillance: Caucasians with low HBV
titers and not cirrhosis
Surveillance Techniques for
HCC in Chronic HBV
Ultrasound sensitivity
94% overall
63% for early HCC
Ultrasound surveillance interval
6 months
Based on tumor growth rate, not
degree of risk
Alpha-fetoprotein (AFP) no data on
which to base use – not recommended
Bruix J, Sherman M, American Association for the Study of Liver Diseases.
Management of hepatocellular carcinoma: an update. Hepatology 2011; 53:1020
Making the Decision to
Treat or Refer
Consider referral to a specialist
For HBV-infected patients who are
Coinfected with HIV or HCV
Pregnant
At an advanced stage of disease
And when you are concerned about
Antiviral resistance
How best to manage a patient
Treatment
Goals and Benefits
of Hepatitis B Treatment
Prevent long-term outcomes
(cirrhosis, liver transplantation,
HCC, death) by durable
suppression of HBV DNA
Primary endpoint
Sustained decrease in serum HBV
DNA level to undetectable
Secondary endpoints
Decrease or normalize serum ALT
Improve liver histology
Induce HBeAg loss or seroconversion
in HBeAg-positive disease
Induce HBsAg loss or seroconversion
Lok AS, et al. Hepatology. 2009;50(3):661-662. PMID: 19714720.
Treatment
often long
term or
lifelong,
particularly
in HBeAgnegative
patients
Management: HBsAg+ and HBeAg+
ALT < 1 x ULN
HBV DNA < 20,000
IU/mL
ALT 1-2 x ULN
HBV DNA > 20,000
IU/mL
ALT > 2 x ULN
HBV DNA > 20,000
IU/mL
q3-6 mos ALT
q6-12 mos
HBeAg
q3 mos ALT
q6 mos HBeAg
Consider biopsy if
persistent or older
than 40 yrs of age
Treat as needed
q1-3 mos ALT,
HBeAg
Treat if persistent
Liver biopsy optional
Immediate rx if
jaundice or
decompensated
Lok AS, et al. Hepatology. 2009;50(3):661-662. PMID: 19714720.
Management: HBsAg+ and HBeAg-
ALT < 1 x ULN
HBV DNA < 2000
IU/mL
ALT 1-2 x ULN
HBV DNA 2000-20,000
IU/mL
ALT ≥ 2 x ULN
HBV DNA ≥ 20,000
IU/mL
q3 mos ALT x 3,
then q6-12 mos if
ALT still < 1 x ULN
q3 mos ALT and
HBV DNA
Consider biopsy if
persistent
Treat as needed
Treat if persistent
Liver biopsy
optional
Lok AS, et al. Hepatology. 2009;50(3):661-662. PMID: 19714720.
Other Guidelines
European Association For The Study Of The Liver
(EASL) guidelines1
Asian-Pacific consensus statement on the
management of chronic hepatitis B: a 2008 update2
Indications for therapy in HBV3
US treatment algorithm for chronic HBV in the US 4
Management of chronic HBV in Asian Americans5
1.
2.
3.
4.
5.
EASL. B. J Hepatol. 2009;50(2):227-242. PMID: 19054588.
Liaw YF, et al. Hepatol Int. 2008;2(3):263-283. PMID: 19669255.
Degertekin B, Lok AS. Hepatology. 2009;49(5 Suppl):S129-137. PMID: 19399799
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4(8):936-962. PMID: 16844425.
Tong MJ, et al.. Dig Dis Sci. 2011;56(11):3143-3162. PMID: 21935699.
Mr. Huỳnh
● 38-yo Asian-American man in for CPE
● emigrated from Vietnam at age 7
● Routine preventive care labs normal
● Agreed to HBV testing
HBsAg
Anti-HBs
Anti-HBc
+
-
+
Chronic HBV infection
Mr. Huỳnh: Lab Evaluation
Assess
Liver
function
HBV
replication
HCV & HIV
HCC
Using
Mr. Huỳnh
CBC & platelets
LFTs
INR
Normal
Normal
Normal
HBV DNA
HBeAg/anti-HBe
anti-HCV
<2000 IU/mL
Negative
Negative
anti-HIV
Ultrasound
Negative
Negative
Lok AS, et al. Hepatology. 2009;50(3):661-662. PMID: 19714720
4 Phases of Chronic HBV Infection
HBeAg
Anti-HBe
Mr. Huỳnh
HBV DNA
ALT
Phase
Liver
Immune
Tolerant
Minimal
inflammation
and fibrosis
Immune Clearance
Chronic active
inflammation
Inactive
Carrier State
Mild hepatitis
and minimal
fibrosis
Reactivation
Active
inflammation
Optimal treatment times
Treatment Candidacy for
HBeAg-Positive Patients
AASLD Guidelines
ALT
HBV DNA
APPROACH
< 1 x ULN
1-2 x ULN
> 2 x ULN
and
and
and
< 20,000 IU/mL
> 20,000 IU/mL
> 20,000 IU/mL
Monitor
Q3-6 mos ALT
Q6-12 mos
HBeAg
Monitor
Q3 mos ALT
Q6 mos HBeAg
MONITOR
Q1-3 mos ALT
and HBeAg
and treat if
elevations persist
Consider biopsy
if persistent or
aged > 40 yrs
and Treat as
needed
Lok AS, et al. Hepatology. 2009;50(3):661-662. PMID: 19714720.
TREAT
immediately if
jaundice or
decompensated
Treatment Candidacy for
HBeAg-Negative Patients
AASLD Guidelines
ALT
HBV DNA
< 1 x ULN
1-2 x ULN
≥ 2 x ULN
and
and
2000-20,000
IU/mL
and
< 2000 IU/mL
Monitor
APPROACH Q3 mos ALT x
3, then Q6-12
mos if ALT still
< 1 X ULN
Lok AS, et al. Hepatology.
2009;50(3):661-662. PMID: 19714720.
Monitor
Q3 mos ALT
and HBV DNA
Consider
biopsy
if persistent
and treat as
needed
≥ 20,000 IU/mL
Treat if
elevations
persist
Mr. Huỳnh
Family Follow-up
● Wife tested  not immune
● They used condoms until she completed
vaccine series
● Following that, they started trying to conceive
● Healthy boy 2 years later  HBV vaccines
and was immune
● Sister was tested and was positive
● Sees a doctor regularly now
● Thankful her brother asked her to get tested
● Mr. Huynh has inactive disease for the next 10
years
Mr. Huỳnh
10 Years Later
● Presents to his family physician with symptoms
of morning stiffness in feet and ankles and
ankle pain
● Diagnosed with rheumatoid arthritis
● Began therapy with methotrexate
● Monitored for HBV Reactivation Q 3 months
● HBV DNA <2,000 IU/mL at start of therapy
● 4,500 IU/mL within three months
HBV Reactivation: Loss of HBV
immune control in a patient with
inactive HBV infection
● Abrupt reappearance or increase in viral
replication
● Rise in HBV DNA
● Return of HBeAg in some
● Subsequent liver damage
● Increase in ALT
● May progress to liver failure and death, even
with antiviral therapy
Hoofnagle JH. Hepatology. 2009;49(5 suppl):S156-S165.
Chronic HBV Infection
Reactivation
HBeAg
Anti-HBe
HBV DNA
ALT
Phase
Liver
Immune
Tolerant
Minimal
inflammation
and fibrosis
Immune Clearance
Chronic active
inflammation
Inactive
Carrier State
Mild hepatitis
and minimal
fibrosis
Reactivation
Active
inflammation
Optimal treatment times
HBV Reactivation:
Risk Factors
● Malignancy
● Solid tumors (e.g., breast cancer): 20% to
41% of HBsAg positive have flair
● Lymphoma: 40% to 58% of HBsAg positive
have flair
● Chemotherapy
● Related to potency of immunosuppression
● HBV DNA > 3 × 105 copies/mL
● Elevated if HBeAg positive
● Male
Yeo W, et al. Hepatology. 2006;43:209-220.
Agents Reported to Cause
HBV Reactivation
Corticosteroids
•Prednsone
•Budesonide
Anti-TNF
•Infliximab
•Adalimumab
•Etanercept
Antimetabolite
Purine
Analogues
Other
•Methotrexate
•Azathioprine
•6-MP
•Cyclosporine
Roche B, et al. Liver Int. 2011;31(suppl 1):104-110.
•Rituximab
HBV Therapy:
Therapeutic Goals
● Primary goal
● Prevention of long-term negative clinical
outcomes (e.g., cirrhosis, HCC, death)
achievable by durable suppression of HBV
DNA to low or undetectable levels
● Secondary goals
● Decrease or normalize serum ALT
● Seroconversion from HBeAg+ to HBeAg● Seroconversion from HBsAg+ to HBeAgs
Lok AS, et al. Hepatology. 2009;50(3):661-662. PMID: 19714720.
HBV Chronic HBV Therapy:
FDA-Approved Agents
● Entecavir, peginterferon alfa-2a, and tenofovir
recommended as first-line therapy
● Rapid onset of action
● Low rate of drug resistance with prolonged use
● Favorable safety profiles
● Adefovir, interferon alfa-2b, lamivudine, and
telbivudine also approved
Lok AS, et al. Hepatology. 2009;50(3):661-662. PMID: 19714720.
Overview of First-Line
Therapies
Entecavir/Tenof
ovir
Parenteral
Oral
Significant
Minimal
Short
Long
Yes (TF in
Contraindicated
pregnancy)
Interferon
Administration
Side-effects
Duration of therapy
Use in decompensated
patients or pregnancy
HBV DNA suppression
(HBeAg negative, 1 yr)
HBeAg seroconversion 1 yr
HBsAg loss (3-5 yrs)
Drug resistance
63%
90-93%
27%
8-11%
None
21%
0-10%
0-1.2%
Scaglione SJ, Lok AS. Gastroenterology. 2012;142(6):1360-1368. PMID: 22537444.
HBV DNA and HCC
REVEAL: long-term follow-up (mean 11.4 yrs) cohort study to
determine risk of cirrhosis and HCC among untreated HBsAg+
14
N = 3653 Taiwanese patients
Cumulative
Incidence of
HCC (%)
12
Baseline HBV DNA Level, copies/mL
≥ 1 million
10
100,000-999,999
8
10,000-99,999
6
300-9999
4
< 300
2
0
0
1
2
3
4
Chen CJ, et al. JAMA. 2006;295:65-73.
5
6
7
8
9
Years of Follow-up
10
11
12
13
Summary
Family physicians well positioned to:
Recognize risk factors
Screen if indicated
Immunize
Diagnose
Assess disease stage, need for therapy
Manage treatment
Surveil for reactivation if immune status
compromised
Monitor disease progression and for
hepatocellular carcinoma