Hepatitis B Cronica Candidatos A TX 2012

Candidacy and Guidelines for HBV Therapy
This program is supported by educational grants from
A Mentorship Program Linking Primary Care Providers With Expert HBV Faculty
clinicaloptions.com/hepatitis
About These Slides

Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent
These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com)
Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.
Faculty
Program Director
Danny Chu, MD
Clinical Instructor Albert Einstein School of Medicine New York, New York
Chul S. Hyun, MD, PhD

Clinical Assistant Professor Division of Gastroenterology and Hepatology Weill Cornell Medical College Attending Physician Division of Gastroenterology and Hepatology NewYork Presbyterian Hospital New York, New York
Charles G. Phan, MD, AGAF

Assistant Professor of Surgery Department of Surgery Baylor College of Medicine Houston, Texas
Faculty Disclosures
Danny Chu, MD, has disclosed that he has received consulting fees and fees for non-CME/CE services from Bristol-Myers Squibb and Gilead Sciences.
Chul S. Hyun, MD, PhD, has no significant financial relationships to disclose. Charles G. Phan, MD, AGAF, has disclosed that he has received consulting fees from Bristol-Myers Squibb, Gilead Sciences, and Merck and fees for non-CME/CE services from Bristol-Myers Squibb, Gilead Sciences, Merck, Otsuka, and Procter & Gamble.
Overview of Current Presentation

Scope of the Problem
Assessing Patients for Treatment Candidacy: To Treat or Not to Treat Case Discussion Selecting Optimal First-line Therapy
Scope of the Problem
HBV: A Global Problem

2 billion people worldwide have been infected with HBV[1]
~ 350 million chronic carriers[2] Leading cause of cirrhosis and HCC worldwide[2] Causes 80% of all HCC in Asian Americans[3] 30% to 50% of HCC associated with HBV in the absence of cirrhosis[4] Second only to tobacco in causing the most cancer deaths[5] HBV is 50-100 times more infectious than HIV[1]
1. World Health Organization. HBV fact sheet. 2. Conjeevaram HS, et al. J Hepatology. 2003;38(suppl 1):s90-s103. 3. Stanford Asian Liver Center. For hepatitis B and liver cancer patients. 4. Bosch FX, et al. Clin Liver Dis. 2005;9:191-211. 5. World Health Organization. Global alert and response: hepatitis BIntroduction.
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
Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20. Lok AS, et al. Hepatology. 2009;50:661-662.
HBV Screening Algorithm

Assess HBsAg
Positive
Negative
CHB*
Assess anti-HBs
Negative (no antibodies)
Positive (antibodies present)
Evaluate for treatment
Vaccinate
Immune to HBV
*Time from positive HBsAg test to diagnosis of CHB is 6 mos. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.
Assessing Patients for Treatment Candidacy: To Treat or Not to Treat?
When to Start HBV Treatment?
Benefits
Likelihood of Patients age and Adverse outcome preference without treatment Costs Long-lasting response
Risks
Adverse effects Drug resistance
Likelihood of adverse outcome without treatment

Activity and stage of liver disease at presentation Risk of cirrhosis/HCC in the next 10-20 yrs
Likelihood of long-term benefit with treatment
Natural History of HBV Infection

Childhood
> 95%
Immune tolerance
Adulthood
< 5%
HBeAg+ CHB
HBeAg- CHB
5-Yr Incidence Rates Cirrhosis: 8% to 38% of chronically infected patients HCC: 10% to 17% of patients with cirrhosis
Inactive carrier
Cirrhosis
Chen DS, et al. J Gastroenterol Hepatol. 1993;8:470-475. Seeff L, et al. N Engl J Med. 1987;316:965-970. Fattovich G, et al. J Hepatol. 2008;48:335-352.
4 Phases of Chronic HBV Infection

Current Understanding of HBV Infection HBeAg Anti-HBe
ALT activity HBV DNA
Phase
Immune Tolerant
Immune Clearance
Inactive Carrier State
Reactivation
Liver
Minimal inflammation and fibrosis
Chronic active inflammation
Mild hepatitis and minimal fibrosis
Active inflammation
Optimal treatment times

Yim HJ, et al. Natural history of chronic hepatitis B virus infection: what we knew in 1981 and what we know in 2005. Hepatology. 2006;43:S173-S181. Copyright 19992012 John Wiley & Sons, Inc. All Rights Reserved.
Goals and Benefits of Hepatitis B Treatment

Prevention of long-term negative clinical outcomes (eg, 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
Treatment is often long term or lifelong, particularly in HBeAg-negative patients
What Information Is Needed to Determine HBV Treatment Candidacy?

HBeAg ALT HBV DNA Liver histology Family history?
Chronic Hepatitis B Disease Types

HBeAg positive
Also known as wild type Antibody to HBeAg negative
HBV DNA > 20,000 IU/mL (> 105 copies/mL)
HBeAg negative
Also known as precore mutant
Antibody to HBeAg positive

HBV DNA > 2000 IU/mL (> 104 copies/mL)
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2004;2:87-106. Chu CJ, et al. Gastroenterology. 2003;125:444-451.
What Is an Elevated ALT Level?

Reference ranges for ALT vary between 2 most widely used commercial laboratories
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
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. Prati D, et al. Ann Intern Med. 2002;137:1-10. Lok AS, et al. Hepatology. 2009;50:661-662.
Histology
Liver biopsy
Establishes disease baseline before initiation of therapy Helps to exclude other causes of liver disease
More sensitive and accurate than ALT

May be considered in patients who meet criteria for chronic hepatitis Limitations
Invasive procedure Sampling error Interobserver variability
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)
Change in HBV DNA level used to monitor response to therapy

Increasing HBV DNA level during antiviral therapy indicates emergence of resistant variants HBV DNA level correlates with disease progression HBV DNA levels reported as IU/mL (standard) or copies/mL
For conversion: 1 IU/mL = ~ 5 copies/mL
Adapted from Keeffe EB, et al. Clin Gastroenterol Hepatol. 2004;2:87-106.
Determining Treatment Candidacy for Chronic Hepatitis B: Guidelines

Guidelines HBeAg Positive HBV DNA, IU/mL AASLD 2009[1] EASL 2009[2] APASL 2008[3] NIH Consensus Conference 2009[4] > 20,000 > 2000 20,000 > 20,000 ALT HBeAg Negative HBV DNA, IU/mL 20,000 > 2000 2000 20,000 ALT
> 2 x ULN or positive biopsy*

> ULN > 2 x ULN > 2 x ULN or positive biopsy*
2 x ULN or positive biopsy*

> ULN > 2 x ULN 2 x ULN or positive biopsy*
*Moderate/severe inflammation or significant fibrosis.
Expert guidelines also published with recommendations specific for HBV management in US[5] and more recently for Asian Americans[6]
Some key differences between these guidelines
1. Lok AS, et al. Hepatology. 2009;50:661-662. 2. EASL. J Hepatol. 2009;50:227-242. 3. Liaw YF, et al. Hepatol Int. 2008;3:263-283. 4. Degerekin B, et al. Hepatology. 2009;S129-S137. 5. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. 6. Tong MJ, et al. Dig Dis Sci. 2011;56:3143-3162.
2009 AASLD Guidelines: Treatment Candidacy for HBeAg-Positive Patients

HBsAg positive
HBeAg positive
ALT < 1 x ULN HBV DNA < 20,000 IU/mL q3-6 mos ALT q6-12 mos HBeAg
ALT 1-2 x ULN HBV DNA > 20,000 IU/mL q3 mos ALT q6 mos HBeAg Consider biopsy if persistent or older than 40 yrs of age Treat as needed
ALT > 2 x ULN HBV DNA > 20,000 IU/mL q1-3 mos ALT, HBeAg Treat if persistent Liver biopsy optional Immediate treatment if jaundice or decompensated
Lok AS, et al. Hepatology. 2009;50:661-662.
2009 AASLD Guidelines: Treatment Candidacy for HBeAg-Negative Patients

HBsAg positive
HBeAg negative
ALT < 1 x ULN HBV DNA < 2000 IU/mL q3 mos ALT x 3, then q6-12 mos if ALT still < 1 x ULN
ALT 1-2 x ULN HBV DNA 2000-20,000 IU/mL q3 mos ALT and HBV DNA Consider biopsy if persistent Treat as needed
ALT 2 x ULN HBV DNA 20,000 IU/mL Treat if persistent Liver biopsy optional
Who Should Be Treated?

Not a question of who to treat, but when: treat now or monitor and treat later when indicated
All HBV carriers are potential treatment candidates A patient who is not a treatment candidate now can be a treatment candidate in the future
Changes in HBV replication status and/or activity/stage of liver disease
Availability of new or improved treatments
What Challenges Might You Face in Determining Treatment Candidacy?

Busy practice
Dealing with patients other health concerns (ie, the primary reason they were in your office) Dealing with patient resistance Knowing the right tests to order Knowing how to interpret test results
When Should You Seek the Advice of an HBV Expert Before Initiating Therapy?
Seek advice in the following situations
Treatment-experienced patients Patients with advanced disease stage, especially decompensated cirrhosis Concern for antiviral resistance Patients with HIV or HCV coinfection Pregnant women Any time you have concerns about how best to manage a patient
Case Discussion
Case 1: Patient History

47-yr-old woman, born in Korea, came to the US at 35 yrs of age, recently found to be HBsAg positive during life insurance checkup
No previous history of jaundice or acute hepatitis
No symptoms
Only medical problem: mild hypertension Family history
No known history of hepatitis B or liver cancer Husband and 2 sons aged 20 and 25 yrs not yet tested for HBV
Case 1: Current Presentation

Exam: normal, no jaundice or hepatosplenomegaly
Labs
Hb 14 g/dL, WBC 5200 cells/mm3, platelets 142,000 cells/mm3 AST 11 IU/L, ALT 12 IU/L Alb 4.4 g/dL, alk phos 105 IU/L, T bil 0.8 mg/dL AFP 4.3 ng/mL HBsAg positive, HBeAg negative, anti-HBe positive
HBV DNA 110 IU/mL
Ultrasound
Liver normal size and texture with no mass, borderline splenomegaly
For Discussion: What Would You Recommend for This Patient?

A. Start treatment now
B. Order liver biopsy; start treatment if cirrhosis confirmed C. Observe, repeat labs q3 mos, start treatment if ALT/HBV DNA increase D. Reassure and discharge patient
Inactive Carrier State vs HBeAg-Negative Chronic Hepatitis B

Inactive carrier state
HBeAg negative Persistently normal ALT Serum HBV DNA persistently undetectable or < 2000 IU/mL
Serial follow-up necessary to differentiate inactive carriers from patients with HBeAg-negative chronic hepatitis B and intermittently normal ALT
Case 1: Follow-up
Repeat labs
Time Point Mo 3 Platelet Count, cells/mm3 154,000 AST, IU/L 25 ALT, IU/L 29 HBV DNA, IU/mL 45
Mo 6
Mo 9
148,000
137,000
35
42
41
59
1180
7375
For Discussion: What Would You Recommend for This Patient at This Time?
A. Start treatment
B. Liver biopsy C. Continue to observe
Case 1: Management Decisions

Liver biopsy performed
Mild inflammation, bridging fibrosis
Oral antiviral therapy started
Case 1: Recommended Monitoring for This Patient During Oral Antiviral Therapy
Serum HBV DNA: q3-6 mos
Liver panel, platelets: q3 mos HBsAg: q12 mos (after HBV DNA undetectable)
Virologic breakthrough: check medication compliance before drug resistance
Case 2: Patient History

40-yr-old Filipino male
ALT 28 IU/L HBsAg positive, HBeAg positive
Serum HBV DNA 60,000,000 IU/mL

Negative viral serologies for hepatitis A and C and HIV Abdominal ultrasound without any significant abnormalities
Previous medical history noncontributory

No family history of liver disease No tobacco use; EtOH: 3-4 drinks/wk (wine)
Case 2: Further Workup

6 mos later, ALT level increased to 34 IU/L and patient agreed to a liver biopsy
Liver biopsy showed grade 1 inflammation and stage 1 fibrosis
The patient continued to be monitored q6 mos

2 yrs later, ALT level was 92 IU/L and HBV DNA (PCR) level was 48,000,000 IU/mL
HBV serology repeated

HBeAg positive, anti-HBe antibody negative
For Discussion: How Would You Classify His Chronic Hepatitis B Infection?
A. Chronic carrier
B. Immune clearance C. Immune tolerance
D. Reactivation
For Discussion: Should We Start Therapy in This Patient?

A. Yes
B. No
Selecting Optimal First-line Therapy
HBV Treatment Landscape in 2011

Peginterferon alfa-2a
Lamivudine 1990 Interferon alfa-2b 1998 2002 Entecavir 2005 2006 Telbivudine Tenofovir 2008
Adefovir
Current Guideline Recommendations for First-line Therapy

Peginterferon alfa-2a
Exceptions: pregnancy, chemotherapy prophylaxis, decompensated cirrhosis, acute infection
Entecavir Tenofovir
EASL. J Hepatol. 2009;50:227-242. Liaw YF, et al. Hepatol Int. 2008;2:263-283. Lok AS, et al. Hepatology. 2009;50:661-662.
5-Yr Rates of Resistance With Oral Agents in Nucleos(t)ide-Naive Patients

Cumulative Resistance Rate (%)
100 80 60
70
40
20 0
29 17 1.2 0
Lamivudine[1] Adefovir[1] Telbivudine*[1] Entecavir[1] Tenofovir[2] *Telbivudine rate determined at Yr 2.

1. EASL. J Hepatol. 2009;50:227-242. 2. Marcellin P, et al. AASLD 2011. Abstract 1375.
Selection of Entecavir vs Tenofovir: Either Is an Excellent Choice for Most Patients

25 Response at Wk 48-52 (%) 21 21 20 Entecavir Tenofovir Parameter Log HBV DNA at Wk 48-52 HBeAg positive HBeAg negative Genotypic resistance, % NA naive Lamivudine experienced 2 0 HBeAg seroconversion 3 <1 0 HBsAg loss HBeAg Negative Pregnancy rating AEs 1.2 (Yr 5) 51 (Yr 5) Class C None 0 (Yr 3) NR Class B 6.9 5.0 6.2 4.6 Entecavir Tenofovir
15
10
HBsAg loss
Renal toxicity; BMD
HBeAg Positive
Lok AS. Hepatology. 2010;52:743-747.
How to Use 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
How to Use Entecavir or Tenofovir

Duration, based on clinical endpoints
HBeAg positive: continue treatment 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
Monitoring of Patients Receiving Nucleos(t)ide Analogue Therapy

Time Point q12 wks q12-24 wks q24 wks q6-12 mos Monitoring
Liver panel Serum creatinine (if receiving TDF or ADV)

HBV DNA levels HBeAg/anti-HBe (if initially HBeAg positive) HBsAg in HBeAg-negative patients with persistently undetectable HBV DNA
Clinical Scenarios of Concern

8
HBV DNA (log10 IU/mL) ALT (U/L) Virologic rebound Virologic breakthrough 4 Hepatitis flare
Biochemical breakthrough
2 ULN
0
-1 0 1 Yrs 2 3
Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50:661-662. Copyright 19992012 John Wiley & Sons, Inc. All Rights Reserved.
PegIFN vs Nucleos(t)ide Analogues

PegIFN Pro Finite course of therapy No resistance Higher rate of HBeAg loss in 1 yr Higher rate of HBsAg loss with short duration therapy* Con SQ administration Frequent AEs Contraindicated in patients with cirrhosis, in pregnancy, with acute hepatitis B, and who are immunosuppressed Nucleos(t)ide Analogues Pro PO administration Infrequent AEs Safe at all stages of disease, including decompensated cirrhosis Safe in immunocompromised populations Selected drugs probably safe in pregnancy Con Need for longterm or indefinite therapy Potential for drug resistance
*Particularly for HBeAg-positive patients with genotype A infection. Recent case report of lactic acidosis in severe liver failure. Lok AS, et al. Hepatology. 2007;45:507-539. Lok AS, et al. Hepatology. 2009;50:661-662. Lok AS. Hepatology. 2010;52:743-747. Buster EH, et al. Gastroenterology. 2008;135:459-467. Lange CM, et al. Hepatology. 2009;50:2001-2006.
When to Consider PegIFN

Favorable predictors of response[1,2]
Low HBV DNA* High ALT*
Specific patient demographics[1,2]

Generally young people
Young women wanting pregnancy in near future
Genotype A or B > C or D[3-5]

Not advanced disease
Absence of comorbidities
Patient preference[1,2]
Concomitant HCV infection

*Also predictive of response to nucleos(t)ide analogues.
1. Lok AS, et al. Hepatology. 2009;50:661-662. 2. Lok AS. Hepatology. 2010;52:743-747. 3. Janssen HL, et al, Lancet. 2005;365;123-129. 4. Lau GK, et al. N Engl J Med. 2005;352:2682-2695. 5. Flink HJ, et al. Am J Gastroenterol. 2006;101:297-303.
How to Use PegIFN alfa-2a

Dosage/administration
180 g/wk by SQ injection
Duration of therapy
48 wks
Treatment endpoints: how to determine success or failure

Finite duration therapy; not based on specific endpoints
Virologic response to therapy defined as decrease in serum HBV DNA to undetectable levels by PCR at end of treatment and loss of HBeAg in patients who were initially HBeAg positive
Potential Barriers to HBV Treatments

Patient resistance or cultural beliefs about treatment
Potential adverse effects (particularly interferon) Challenges with long-term therapy
Understanding endpoints and monitoring strategies

Lack of symptoms Lack of ability to cure disease with current regimens in most patients Adherence
Go Online for More CCO Coverage of HBV Infection

Interactive Virtual Presentations review and consider challenging patient cases with guidance from expert faculty members Text-Based Modules plus downloadable PowerPoint slides

Hepatitis B Cronica Candidatos A TX 2012

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Hepatitis B Cronica Candidatos A TX 2012

Uploaded by

Copyright:

Available Formats

Candidacy and Guidelines for HBV Therapy

This program is supported by educational grants from

About These Slides

Chul S. Hyun, MD, PhD

Charles G. Phan, MD, AGAF

Overview of Current Presentation

Scope of the Problem

HBV: A Global Problem

Candidates for HBV Screening

All pregnant women

HBV Screening Algorithm

Negative (no antibodies)

Positive (antibodies present)

Evaluate for treatment

Assessing Patients for Treatment Candidacy: To Treat or Not to Treat?

When to Start HBV Treatment?

Likelihood of adverse outcome without treatment

Likelihood of long-term benefit with treatment

Natural History of HBV Infection

4 Phases of Chronic HBV Infection

Inactive Carrier State

Minimal inflammation and fibrosis

Chronic active inflammation

Mild hepatitis and minimal fibrosis

Optimal treatment times

Goals and Benefits of Hepatitis B Treatment

Induce HBeAg loss or seroconversion in HBeAg-positive disease

Treatment is often long term or lifelong, particularly in HBeAg-negative patients

What Information Is Needed to Determine HBV Treatment Candidacy?

Chronic Hepatitis B Disease Types

HBV DNA > 20,000 IU/mL (> 105 copies/mL)

Antibody to HBeAg positive

What Is an Elevated ALT Level?

More sensitive and accurate than ALT

HBV DNA Testing

Change in HBV DNA level used to monitor response to therapy

Determining Treatment Candidacy for Chronic Hepatitis B: Guidelines

> 2 x ULN or positive biopsy*

2 x ULN or positive biopsy*

*Moderate/severe inflammation or significant fibrosis.

2009 AASLD Guidelines: Treatment Candidacy for HBeAg-Positive Patients

Lok AS, et al. Hepatology. 2009;50:661-662.

2009 AASLD Guidelines: Treatment Candidacy for HBeAg-Negative Patients

Lok AS, et al. Hepatology. 2009;50:661-662.

Who Should Be Treated?

Availability of new or improved treatments

What Challenges Might You Face in Determining Treatment Candidacy?

Case 1: Patient History

Case 1: Current Presentation

HBV DNA 110 IU/mL

For Discussion: What Would You Recommend for This Patient?

Inactive Carrier State vs HBeAg-Negative Chronic Hepatitis B

Case 1: Management Decisions

Oral antiviral therapy started

Virologic breakthrough: check medication compliance before drug resistance

Case 2: Patient History

Serum HBV DNA 60,000,000 IU/mL

Previous medical history noncontributory

Case 2: Further Workup

The patient continued to be monitored q6 mos

HBV serology repeated

For Discussion: Should We Start Therapy in This Patient?

Lamivudine[1] Adefovir[1] Telbivudine[1] Entecavir[1] Tenofovir[2] Telbivudine rate determined at Yr 2.