emerging challenges in primary care:...

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



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



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


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




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


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



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


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





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



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




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



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



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



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








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



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



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



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



Immunosuppressive Therapies Associated with HBV Reactivation

•  Corticosteroids

•  Anti-tumor necrosis factor

•  Others: methotrexate, molecular target agents

•  Cancer chemotherapy

•  Rituximab – anti-CD20 monoclonal antibody

43






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



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



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



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



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



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



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


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




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



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



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

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