Chronic Hepatitis B: Guidelines for Screening, Clinical Management - Whether to Follow or Treat, and How
NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 1
Chronic Hepatitis B: Guidelines for Screening,
Clinical Management, Whether to Follow or Treat,
and How 1
Emerging Challenges In Primary Care: 2015
Faculty • Christopher O'Brien, MD, AGAF, FRCMI
Professor of Clinical Medicine Center for Liver Diseases Medical Director, Liver and GI Transplantation Miami Transplant Institute University of Miami School of Medicine Miami, FL
• Eugene R. Schiff, MD, MACP, FRCP, MACG, AGAF, FAASLD Leonard Miller Professor of Medicine Dr. Nasser Ibrahim Al-Rashid Chair Director, Schiff Center for Liver Diseases Director, Hepatology Research Laboratory University of Miami Miller School of Medicine Miami, FL
• Elliot Wortzel, MD, FACG, FACP Gastroenterology Weston, FL
2
Disclosures • Christopher O'Brien, MD, AGAF, FRCMI conducts research
for and receives research grants from Gilead, BMS, Abbott (Abbvie), and Janssen.
• Eugene R. Schiff, MD, MACP, FRCP, MACG, AGAF, FAASLD is a consultant for Gilead and Merck. He serves on the scientific advisory boards of Bristol Myers Squibb, Gilead, Janssen Pharma, and Acorda; and he serves on the data monitoring boards of Bristol Myers Squibb, Salix, Pfizer, and Arrowhead. Dr. Schiff receives grant/research support from Abbott, Bristol Myers Squibb, Gilead, Merck, Orasure Technologies, Roche Molecular, Janssen Pharma, Discovery Life Sciences, Beckman Coulter, Siemens, MedMira, and Conatus.
• Elliot Wortzel, MD, FACG, FACP has no relationships to disclose.
3
Chronic Hepatitis B: Guidelines for Screening, Clinical Management - Whether to Follow or Treat, and How
NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 2
PRE-TEST QUESTIONS
4
Pre-test ARS Question 1
On a scale of 1 to 5, please rate how confident you would be treating a patient with Chronic Hepatitis B:
1. Not at all confident 2. Slightly confident 3. Moderately confident 4. Pretty much confident 5. Very confident
5
Case
• 47-yr-old woman, born in Viet Nam • No symptoms • Only medical problem: mild hypertension • Her husband and 2 sons, aged 20 and 25
yrs, have never been tested for HBV
6
Chronic Hepatitis B: Guidelines for Screening, Clinical Management - Whether to Follow or Treat, and How
NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 3
You decide to screen this patient for Hepatitis B. Which laboratory test confirms the diagnosis of chronic hepatitis B? 1. A positive hepatitis B surface antibody 2. A positive hepatitis B surface antigen and hepatitis B
core antibody IgM 3. A positive hepatitis B surface antigen of greater than six
months duration 4. A positive hepatitis B core antigen
7
Pre-test ARS Question 2
The Screening (and More) Results
• Hepatitis serologies – HBsAg positive, HBcAb positive, HBsAb
negative – HBeAg negative, anti-HBe positive
• CBC – WBC 4200 cells/mm3, Hb 13 g/dL, platelets
182,000 cells/mm3 • Liver Tests
– AST 12 IU/L, ALT 16 IU/L 8
Which of the following is not essential for determining further management of patients newly diagnosed with chronic hepatitis B?
1. Ask about family history2. Order a Fibroscan or an equivalent test3. Order an abdominal ultrasound4. Order a liver biopsy
9
Pre-test ARS Question 3
Chronic Hepatitis B: Guidelines for Screening, Clinical Management - Whether to Follow or Treat, and How
NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 4
Results
• Fibroscan shows no fibrosis
• Ultrasound of the abdomen is normal
• Family history is negative for liver cancer
• HBV DNA 145 IU/mL
10
Does the Patient Require Treatment or Only Medical Monitoring?
1. Treatment 2. Medical monitoring only with repeat labs every 6
months and abdominal ultrasound screening
11
Pre-test ARS Question 4
Family Member Screening for HBV • On screening of the family members for
HBV • Both sons have been vaccinated
– and are HBsAb (+) • Husband, however, is found to be
– HBsAg (+), HBcAb (+), HBsAb (-) – HBeAg (-) – HBV DNA 79,000 IU/mL – A Fibroscan shows moderate fibrosis – A screening abdominal US is negative 12
Chronic Hepatitis B: Guidelines for Screening, Clinical Management - Whether to Follow or Treat, and How
NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 5
What would be an appropriate treatment for the patient’s husband?
1. Tenofovir 300 mg oral daily 2. Ledipasvir 90 mg oral daily 3. Simeprevir 150 mg oral daily 4. Sofosbuvir 400 mg oral daily
13
Pre-test ARS Question 5
Learning Objectives • Identify patients who should be screened and
appropriate testing for those patients • Discuss evidence-based strategy for the overall
medical management of patients with chronic hepatitis B
• Determine which patients require medication for chronic hepatitis B and which should be monitored clinically
• Discuss the medications available for treating chronic hepatitis B and associated resistance issues 14
Geographic Prevalence of Chronic Hepatitis B May Be Impacted by Migration
• Identify patients who should be and appropriate testing for those patients
• Discuss evidence-based strategy for the overall medical management of patients with chronic hepatitis B
• Determine which patients require medication for chronic hepatitis B and which should be monitored clinically
• Discuss the medications available for treating chronic hepatitis B and associated resistance issues 15
Chronic Hepatitis B: Guidelines for Screening, Clinical Management - Whether to Follow or Treat, and How
NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 6
HBsAg Prevalence ≥8% - High 2-7% - Intermediate <2% - Low
Immigration numbers summed by continent from 1996-2002
~2 million Asians
~400,000 South Americans
~350,000 Africans
~930, 000 Europeans
Geographic Prevalence of Chronic Hepatitis B May Be Impacted by Migration
16
HBV: A Global Problem • HBV is 50-100 times more infectious than HIV
• 2 billion people worldwide have been infected with HBV
– ~ 350 million chronic carriers
• Leading cause of cirrhosis and hepatocellular carcinoma (HCC) worldwide
• 30% to 50% of HCC associated with HBV in the absence of cirrhosis
• Second only to tobacco in causing the most cancer deaths
17
Candidates for HBV Screening
• Persons born in high and intermediate endemic areas (≥ 2% prevalence)
• US-born children of immigrants from high endemic areas (≥ 8%; only if not vaccinated as infants in the US)
• Household and sexual contacts of HBV carriers
• Persons who have injected drugs
• Persons with multiple sexual partners or history of STDs
• Men who have sex with men • Inmates of correctional
facilities • Individuals with chronically
elevated ALT/AST • Individuals infected with HIV
or HCV • Patients undergoing dialysis • Patients undergoing
immunosuppressive therapy • All pregnant women • Infants born to HBV carrier
mothers
18
Chronic Hepatitis B: Guidelines for Screening, Clinical Management - Whether to Follow or Treat, and How
NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 7
Assess HBsAg
Positive
CHB*
Evaluate for treatment
Negative
Assess anti-HBs
Negative (no antibodies)
Positive (antibodies
present)
Vaccinate Immune to HBV
*Time from positive HBsAg test to diagnosis of CHB is 6 mos.
HBV Screening Algorithm
19
Outline • Identify patients who should be and appropriate
testing for those patients • Discuss evidence-based strategy for the overall
medical management of patients with chronic hepatitis B
• Determine which patients require medication for chronic hepatitis B and which should be monitored clinically
• Discuss the medications available for treating chronic hepatitis B and associated resistance issues 20
Childhood
Adulthood
Immune Tolerance
HBeAg-‐ CHB
HCC
<5%
>95%
Inac6ve carrier
HBeAg+ CHB
<15-30% of HCC associated with HBV occurs in the absence of cirrhosis or advanced fibrosis
Natural History of HBV Infection
21
Chronic Hepatitis B: Guidelines for Screening, Clinical Management - Whether to Follow or Treat, and How
NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 8
Assessment of Hepatic Fibrosis
• Is liver biopsy necessary for all HBV-infected patients before treatment? – Alternatives to biopsy
• Transient elastography (FibroScan) • Non-invasive assays (e.g., FibroTest, APRI, FIB-4)
– If a subset of patients should be biopsied, who are they?
• Important to identify patients with cirrhosis in order to define treatment duration 22
Cirrhosis
Normal
Cirrhosis Defined by Morphologic and Functional Changes of the Liver
23
Indirect Markers of Fibrosis
• FibroTest/FibroSure
– Alpha-2 globulin
– Alpha-2 macroglobulin
– Gamma globulin
– Apoliprotein A1
– GGT
24
• ActiTest
– Fibrotest +ALT
• Forns index
• APRI
• FIB-4
• AST/ALT ratio
• AST/ALT with plts
Chronic Hepatitis B: Guidelines for Screening, Clinical Management - Whether to Follow or Treat, and How
NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 9
Fibroscan
25
Fibroscan Propagation Speed Examples
4 kPa
36 kPa
High Speed
Low Speed
26
Role of Liver Biopsy • Needed less frequently
– Non-invasive tests improving – Less essential for decisions regarding timing of
treatment
• Worth considering if – Non-invasive tests conflicting and need info to
make treatment decision – Suspect second disease: e.g. NASH – Deferring treatment and concern for advanced
disease
27
Chronic Hepatitis B: Guidelines for Screening, Clinical Management - Whether to Follow or Treat, and How
NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 10
Medical Management of Cirrhosis
• Routine assessment for the presence of – Fluid retention (ascites) – Cognitive impairment (hepatic encephalopathy)
• Yearly endoscopy (as indicated) – Screening for varices
• Routine HCC screening – By ultrasound every 6 months
28
Hepatocellular Carcinoma Screening
• Screening with Ultrasound recommended at 6 month intervals in all individuals with cirrhosis
• HCC detected after the onset of symptoms has 0-10% survival at 5 years
• Early recognition may give a 5-year disease-free survival of greater than 50%
29
HCC Diagnostic Algorithm
Arterial hypervascularity AND venous or delayed
phase washout
Liver nodule
Repeat US at 3 months
Growing/changing character
Investigate according
to size
Other contrast Enhanced study (CT or MRI)
< 1 cm > 1 cm
CT or MRI with HCC tumor protocol
Arterial hypervascularity AND venous or delayed
phase washout Stable
Yes No
No
Biopsy
Yes
HCC
30
Chronic Hepatitis B: Guidelines for Screening, Clinical Management - Whether to Follow or Treat, and How
NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 11
Outline • Identify patients who should be and appropriate
testing for those patients • Discuss evidence-based strategy for the overall
medical management of patients with chronic hepatitis B
• Determine which patients require medication for chronic hepatitis B and which should be monitored clinically
• Discuss the medications available for treating chronic hepatitis B and associated resistance issues 31
Course of Chronic HBV Infection is Characterized by Remissions and Relapses
32
HBeAg-negative: • Low-level or no detectable replication • Inactive liver disease
HBeAg-negative: • Active viral replication • Active or inactive liver disease
HBeAg-positive: • Active viral replication • Active or inactive liver disease
HBV Patient Categories
33
Chronic Hepatitis B: Guidelines for Screening, Clinical Management - Whether to Follow or Treat, and How
NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 12
Information Needed to Determine HBV Treatment
• HBeAg status • ALT • HBV DNA level • Degree of liver fibrosis • Family history
34
Chronic Hepatitis B Disease Types
• HBeAg positive – Also known as “wild type” – Often, HBV DNA > 20,000 IU/mL
• HBeAg negative – Also known as “precore mutant” – HBV DNA variable
35
New Definition for Elevated ALT Levels
• Standard reference ranges for ALT vary – Men: 4-60 IU/L; women: 6-40 IU/L – Men: 0-55 IU/L; women: 0-40 IU/L
• Both AASLD and US treatment algorithms recommend lower ULN levels for ALT when making treatment-initiation decisions – 30 IU/L for men – 19 IU/L for women
36
Chronic Hepatitis B: Guidelines for Screening, Clinical Management - Whether to Follow or Treat, and How
NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 13
First-Line Therapy
Peginterferon alfa-2a PEGASYS® Roche Laboratories 2005
Entecavir
BARACLUDETM Bristol-Myers Squibb 2005
Tenofovir VIREAD® Gilead Sciences 2008
Second-Line Therapy
Adefovir dipivoxil HEPSERA™ Gilead Sciences 2002
Telbivudine TYZEKA™ Idenix and Novartis 2006
Third-Line Therapy
Lamivudine EPIVIR-HBV® GlaxoSmithKline 1998
FDA-Approved Therapies
37
Monitor if not cirrhotic every 6
months
Treat
HBeAg positive
HBsAg positive
2009 AASLD Guidelines: Treatment Candidacy for HBeAg-Positive Patients
ALT < 1 x ULN HBV DNA < 20,000 IU/mL
ALT 1-2 x ULN HBV DNA > 20,000 IU/mL
38
Treat q3 mos ALT x 3, then q6-12 mos if ALT still < 1 x ULN
HBeAg negative
ALT ≥ ULN HBV DNA ≥ 2,000 IU/mL
HBsAg positive
ALT < 1 x ULN HBV DNA < 2000 IU/mL
2009 AASLD Guidelines: Treatment Candidacy for HBeAg-Negative Patients
Lok AS, et al. Hepatology. 2009;50:661-662. 39
Chronic Hepatitis B: Guidelines for Screening, Clinical Management - Whether to Follow or Treat, and How
NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 14
Infant receives HBIG vaccine at birth
Previous child HBV (+)
Yes No
HBV DNA >108 – 109
copies/mL
HBV DNA<108 –109
copies/mL
HBV DNA >106
copies/mL
HBV DNA <106
copies/mL
Consider treatment with lamivudine, Tenofovir, or telbivudine at 32 weeks
Monitor
Algorithm for HBV Management During Pregnancy
• Prevention is more effective than treatment after HBV-related hepatitis is diagnosed
• Screen for HBV before start of immunosuppressive therapy
• Prophylactic antiviral therapy to high + moderate risk patients
Prevention of Reactivation During Immunosuppression
41
HBV Treatment in HBV/HIV Coinfected Patients
• HBV coinfection complicates disease course and management of HIV patients – HBV coinfection does not substantially affect
the course of HIV infection – HIV coinfection significantly alters the course
of HBV disease • All patients with active HBV infection should be treated
with ART containing emtricitabine/tenofovir DF – Entecavir may be useful in patients with active
replication despite tenofovir or in persons with contraindications to tenofovir in both infections 42
Chronic Hepatitis B: Guidelines for Screening, Clinical Management - Whether to Follow or Treat, and How
NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 15
Immunosuppressive Therapies Associated with HBV Reactivation
• Corticosteroids
• Anti-tumor necrosis factor
• Others: methotrexate, molecular target agents
• Cancer chemotherapy
• Rituximab – anti-CD20 monoclonal antibody
43
Outline • Identify patients who should be and appropriate
testing for those patients • Discuss evidence-based strategy for the overall
medical management of patients with chronic hepatitis B
• Determine which patients require medication for chronic hepatitis B and which should be monitored clinically
• Discuss the medications available for treating chronic hepatitis B and associated resistance issues 44
8
6
4
2
0 0 1 2 3
Years
Antiviral Treatment
HB
V D
NA
(Log
10 IU
/mL)
A
LT (I
U/m
L)
Genotypic Resistance
Virologic Breakthrough
Virologic Rebound
Hepatitis Flare
Biochemical Breakthrough
ULN
Manifestations of Antiviral Resistance
45
Chronic Hepatitis B: Guidelines for Screening, Clinical Management - Whether to Follow or Treat, and How
NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 16
HBV DNA Testing • Indicates chronic hepatitis when still positive 6 mos after
diagnosis of acute HBV infection – Can differentiate chronic, inactive carrier (< 2000 IU/mL) vs.
resolved HBV infection (undetectable) • HBV DNA level correlates with disease progression • Change in HBV DNA level used to monitor response to
therapy • Increasing HBV DNA level during antiviral therapy indicates
emergence of resistant variants
46
5-Yr Rates of Resistance With Oral Agents in Nucleos(t)ide-Naive Patients
70
29
17
1.2 0 0
20
40
60
80
100
Lamivudine Adefovir Telbivudine Entecavir Tenofovir
Cum
ulat
ive
Res
ista
nce
Rat
e (%
)
47
Selection of Entecavir vs Tenofovir: Either Is an Excellent Choice
21
2 < 1
21
3
0 0
5
10
15
20
25
HBeAg seroconversion
HBsAg loss
Entecavir Tenofovir
HBeAg Negative
HBsAg loss
HBeAg Positive
Res
pons
e at
Wk
48-5
2 (%
)
Parameter Entecavir Tenofovir Log HBV DNA ↓ at Wk 48-52
§ HBeAg positive 6.9 6.2
§ HBeAg negative 5.0 4.6
Genotypic resistance, %
§ NA naive 1.2 (Yr 5) 0 (Yr 3)
§ Lamivudine experienced 51 (Yr 5) NR
Pregnancy rating Class C Class B
AEs None Renal
toxicity; ↓ BMD
48
Chronic Hepatitis B: Guidelines for Screening, Clinical Management - Whether to Follow or Treat, and How
NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 17
Entecavir or Tenofovir Dosage and Administration
• Entecavir: oral administration – Patients naive to lamivudine therapy: 0.5 mg
QD – Patients who are refractory/resistant to
lamivudine: 1.0 mg QD – Dose adjustment needed if eGFR < 50 mL/
min • Tenofovir: oral administration
– 300 mg QD – Dose adjustment needed if eGFR < 50 mL/
min 49
Entecavir or Tenofovir Duration of Therapy
• Duration, based on clinical endpoints – HBeAg positive:
• Treat until HBV DNA undetectable and HBeAg seroconversion achieved;
• Continue for ≥ 6 mos after anti-HBe appearance • Close monitoring for relapse required after
treatment discontinuation – HBeAg negative:
• Continue treatment until HBsAg clearance
50
Case Presentation • 55 y.o. woman scheduled for treatment of rheumatoid
arthritis with Rituximab • P.E. positive for arthritic signs consistent with rheumatoid
arthritis • CBC and CMP WNL • Negative viral serologies for hepatitis A and C and HIV • Abdominal ultrasound without any significant
abnormalities • No family history of liver disease • No tobacco use; EtOH: 3-4 drinks/wk (wine)
51
Chronic Hepatitis B: Guidelines for Screening, Clinical Management - Whether to Follow or Treat, and How
NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 18
What Initial Testing Would You Recommend for This Patient?
1. Schedule a liver biopsy
2. Check her hepatitis B serologies
3. Observe, repeat labs every 6 months
4. Order an ultrasound of the abdomen
*ARS Question
52
Testing Results
• HBsAg (-), HBcAb (+), HBsAb (-)
• Liver tests are normal
• CBC is normal
53
Additional Testing • Blood fibrosis test shows no fibrosis and
the ultrasound of the abdomen is normal • HBV DNA 145 IU/mL
54
Chronic Hepatitis B: Guidelines for Screening, Clinical Management - Whether to Follow or Treat, and How
NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 19
Does Your Patient Require Treatment or Medical Management?
55
1. Refer to specialist to be seen
2. Ask the best approach from a friend
3. Start treatment
4. Observe, repeat labs every 6 months
*ARS Question
Which treatment would you recommend?
1. Sofosbuvir 400 mg oral daily
2. Entecavir 0.5 mg oral daily
3. Simeprevir 150 mg oral daily
4. Ledipasvir 90 mg oral daily
56
*ARS Question
POST-TEST QUESTIONS
57
Chronic Hepatitis B: Guidelines for Screening, Clinical Management - Whether to Follow or Treat, and How
NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 20
Case
• 47-yr-old woman, born in Viet Nam • No symptoms • Only medical problem: mild hypertension • Her husband and 2 sons, aged 20 and 25
yrs, have never been tested for HBV
58
You decide to screen this patient for Hepatitis B. Which laboratory test confirms the diagnosis of chronic hepatitis B? 1. A positive hepatitis B surface antibody 2. A positive hepatitis B surface antigen and hepatitis B
core antibody IgM 3. A positive hepatitis B surface antigen of greater than six
months duration 4. A positive hepatitis B core antigen
59
Post-test ARS Question 1
The Screening (and More) Results
• Hepatitis serologies – HBsAg positive, HBcAb positive, HBsAb
negative – HBeAg negative, anti-HBe positive
• CBC – WBC 4200 cells/mm3, Hb 13 g/dL, platelets
182,000 cells/mm3 • Liver Tests
– AST 12 IU/L, ALT 16 IU/L 60
Chronic Hepatitis B: Guidelines for Screening, Clinical Management - Whether to Follow or Treat, and How
NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 21
Which of the following is not essential for determining further management of patients newly diagnosed with chronic hepatitis B?
1. Ask about family history2. Order a Fibroscan or an equivalent test3. Order an abdominal ultrasound4. Order a liver biopsy
61
Post-test ARS Question 2
Results
• Fibroscan shows no fibrosis
• Ultrasound of the abdomen is normal
• Family history is negative for liver cancer
• HBV DNA 145 IU/mL
62
Does the Patient Require Treatment or Only Medical Monitoring?
1. Treatment 2. Medical monitoring only with repeat labs every 6
months and abdominal ultrasound screening
63
Post-test ARS Question 3
Chronic Hepatitis B: Guidelines for Screening, Clinical Management - Whether to Follow or Treat, and How
NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 22
Family Member Screening for HBV • On screening of the family members for
HBV • Both sons have been vaccinated
– and are HBsAb (+) • Husband, however, is found to be
– HBsAg (+), HBcAb (+), HBsAb (-) – HBeAg (-) – HBV DNA 79,000 IU/mL – A Fibroscan shows moderate fibrosis – A screening abdominal US is negative 64
What would be an appropriate treatment for the patient’s husband?
1. Tenofovir 300 mg oral daily 2. Ledipasvir 90 mg oral daily 3. Simeprevir 150 mg oral daily 4. Sofosbuvir 400 mg oral daily
65
Post-test ARS Question 4
Post-test ARS Question 5
On a scale of 1 to 5, please rate how confident you would be treating a patient with Chronic Hepatitis B:
1. Not at all confident 2. Slightly confident 3. Moderately confident 4. Pretty much confident 5. Very confident
66
Chronic Hepatitis B: Guidelines for Screening, Clinical Management - Whether to Follow or Treat, and How
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Post-test Question 6 Which of the statements below describes your approach to treating Chronic Hepatitis B?
1. I do not treat patients with Chronic Hepatitis B, nor do I plan to this year.
2. I did not treat patients with Chronic Hepatitis B, but as a result of attending this course I’m thinking of doing this now.
3. I do treat patients with Chronic Hepatitis B and this course helped me change my methods.
4. I do treat patients with Chronic Hepatitis B and this course confirmed that I don’t need to change my methods. 67