Supportive care

High-calorie diet (often tolerated best in morning) Intravenous hydration and parenteral nutrition Avoidance of alcohol and drugs metabolized by the liver Avoidance of drugs that may produce adverse reactions (e.g., cholestasis) Bile-salt sequestrant resins, if severe pruritus Cholestyramine: up to 4 g PO 4 times daily

No role for glucocorticoids

Antiviral therapy
Nucleoside analogues In rare instances of severe acute hepatitis B, treatment with a nucleoside analogue has been successful.

Liver transplantation
Liver transplantation is indicated in the rare cases of Fulminant hepatic failure and Grade III or IV encephalopathy.

Prevention
Recommends screening certain high-risk groups and vaccinating those who are not already immune or infected
Pregnant women Persons born in hyperendemic areas Men who have sex with men Injection drugs users Patients on dialysis HIV-infected patients Family and household contacts of HBV-infected persons

Persons with HCV infection Person who require immunosuppressive or cytotoxic therapy

Vaccination
Recombinant hepatitis B vaccine Vaccine components and administration
2 available vaccines: 10 g IM or 20 g IM Half dose for children 40-g dose for patients receiving hemodialysis and immunocompromised adults Given at 0, 1, and 6 months Deltoid, not gluteal, injection

PREGNANCY IS NOT A CONTRAINDICATION.

Duration of protection
At least 5 years in ~8090% of immunocompetent vaccine recipients At least 10 years in ~6080% of immunocompetent vaccine recipients Booster vaccinations are indicated only for: Immunosuppressed individuals who no longer have detectable anti-HBs Immunocompetent persons who sustain percutaneous HBsAgpositive inoculations after losing detectable anti-HBs Dialysis patients whose anti-HBs antibody levels fall below 10 mIU/mL

Postexposure prophylaxis
Hepatitis B immune globulin: 0.06 mL/kg IM
1. Immediately after NEEDLESTICK, followed by a complete course of hepatitis B vaccine to begin within the first week Within 14 days of SEXUAL EXPOSURE followed by a complete course of hepatitis B vaccine to begin within the first week For PERINATAL EXPOSURE of infants born to an HBsAg-positive mother, a single 0.5-mL IM dose should be given immediately after birth in combination with a complete course of 3 injections of hepatitis B vaccine to be started within the first 12 hours of life.

2.

3.

Evaluation of Patients With Chronic HBV Infection

Initial evaluation
1. History and physical examination 2. Family history of liver disease, HCC 3. Laboratory tests to assess liver disease: complete blood counts with platelets, hepatic panel, and prothrombin time 4. Tests for HBV replication: HBeAg/anti-HBe, HBV DNA quantification 5. Ultrasound of liver and spleen 6. AFP

Lok AS, et al. Hepatology. 2007;45:507-539.

Evaluation of Patients With Chronic HBV Infection

Initial evaluation (contd)
7. Tests to rule out viral coinfections: HIV, HCV
HDV in persons from countries where HDV is common, any adult-acquired HBV, and in those with history of injection drug use

8. Tests to screen for HCC 9. Consider liver biopsy to grade and stage liver disease for patients who meet criteria for chronic hepatitis

Lok AS, et al. Hepatology. 2007;45:507-539.

Interpretation of Serologic Results

HBsAg
Negative Negative Negative Positive Positive Negative

Total Anti-HBc
Negative Positive Negative Positive Positive Positive

IgM Anti-HBc
---Negative Positive --

Anti-HBs
Negative Positive Positive Negative Negative Negative

Interpretation
Susceptible; offer vaccination Immune due to natural infection Immune due to hepatitis B vaccination Chronic HBV infection Acute HBV infection Unclear; could be any one of the following: 1. Resolved infection (most common) 2. False-positive anti-HBc; susceptible 3. Low-level chronic infection 4. Resolving acute infection

CDC. Hepatitis B FAQs for Health Professionals.

Chronic HBV Infection: Diagnostic Criteria

Disease Phase Chronic hepatitis B Diagnostic Criteria HBsAg+ > 6 mos Serum HBV DNA > 20,000 IU/mL (105 copies/mL), lower values 200020,000 IU/mL (104-105 copies/mL) often seen in HBeAg- disease Persistent or intermittent elevation in ALT/AST levels Liver biopsy showing chronic hepatitis with moderate or severe necroinflammation HBsAg+ > 6 mos HBeAg-, anti-HBe+ Serum HBV DNA < 2000 IU/mL Persistently normal ALT/AST levels Liver biopsy confirms absence of significant hepatitis Previous known history of acute or chronic hepatitis B or presence of anti-HBc +/- anti-HBs HBsAgUndetectable serum HBV DNA (very low levels may be detectable by sensitive PCR assays) Normal ALT levels

Inactive HBsAg carrier state

Resolved hepatitis B

Phases of Chronic HBV Infection

Immune Tolerance
Typical HBV DNA, IU/mL > 200,000 and often > 107-8

Immune Active/ HBeAg-Positive CHB

200,000 - 2 x 109

Nonreplicative (Inactive Carrier)

< 2000

HBeAg-Negative CHB
2000 - 2 x 107

HBeAg
ALT Other observations Treatment candidate?

Positive
Normal Liver biopsy typically normal or minimal findings No

Positive
Elevated or fluctuating Active inflammation on liver biopsy Yes

Negative
Normal HBsAg may become undetectable No

Negative
Elevated or fluctuating Active inflammation on liver biopsy

Yes

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

Phases of Chronic HBV Infection

Immune Tolerance Immune Clearance Low Replicative Phase Reactivation Phase

<

HBeAg+

><

HBeAg-/anti-HBe+ (precore/core promoter variants) > 2000 IU/mL < 2000 IU/mL

>

HBV DNA
2x 11 IU/mL 2 x 10 108 200,000 - 2 x 109 IU/mL

Phases of Chronic HBV Infection

Immune Tolerance Immune Clearance Low Replicative Phase Reactivation Phase

<

HBeAg+

><

HBeAg-/anti-HBe+ (precore/core promoter variants) > 2000 IU/mL < 2000 IU/mL

>

HBV DNA
2x 11 IU/mL 2 x 10 108 200,000 - 2 x 109 IU/mL

ALT

Phases of Chronic HBV Infection

Immune Tolerance Immune Clearance Low Replicative Phase Reactivation Phase

<

HBeAg+

><

HBeAg-/anti-HBe+ (precore/core promoter variants) > 2000 IU/mL < 2000 IU/mL

>

HBV DNA
2x 11 IU/mL 2 x 10 108 200,000 - 2 x 109 IU/mL

ALT

Normal/mild CH

Moderate/severe CH Cirrhosis

Normal/mild CH Inactive cirrhosis

Moderate/severe CH Cirrhosis

Phases of Chronic HBV Infection

Immune Tolerance Immune Clearance Low Replicative Phase Reactivation Phase

<

HBeAg+ HBV DNA 2x 11 IU/mL 2 x 10 108

><

HBeAg-/anti-HBe+ (precore/core promoter variants) > 2000 IU/mL < 2000 IU/mL

>

200,000 - 2 x 109 IU/mL

ALT

Normal/mild CH

Moderate/severe CH

Normal/mild CH

Moderate/severe CH

Cirrhosis HBeAg+ chronic hepatitis

Inactive cirrhosis Inactive-carrier state

Cirrhosis HBeAgchronic hepatitis

HBV Treatment Landscape in 2012

Peginterferon alfa-2a
Lamivudine 1990 Interferon alfa-2b 1998 2002 Entecavir 2005 2006 Telbivudine Tenofovir 2008

Adefovir

The First Branch Point in Choosing With What to Treat

Decision to treat

IFN (PegIFN alfa-2a)

Nucleos(t)ide analogues

Hepatitis
web study

When to Consider PegIFN

Favorable predictors of response

1. 2. 3. Low HBV DNA*( < 9 logs ) High ALT* Genotype A or B > C or D[3-5]

What is Pegylation?
Covalent attachment of polyethelene glycol to peptide Increases hydrodynamic size Prolonged circulation, delayed renal clearance.

Interferon is a protein naturally

produced in our bodies to fight viruses by boosting the immune system. The medication is a synthetic reproduction of the naturally produced Interferon. Whilst boosting

Hepatitis
web study

The Second Branch Point in Choosing With What to Treat

Nucleos(t)ide analogues

Lamivudine

Adefovir

Entecavir

Telbivudine

Tenofovir

Hepatitis
web study

Recommended Dosing of Anti-HBV Agents

Agent
Interferon alfa Peginterferon alfa2a Lamivudine Adefovir Entecavir Telbivudine Tenofovir

Route
SQ SQ PO PO PO PO PO

Recommended Dosing Adult

5 MU daily or 10 MU 3 x per wk 180 g/wk 100 mg QD* 10 mg QD* 0.5 mg QD (no previous LAM) 1.0 mg QD (if refr/resist to LAM)* 600 mg QD* 300 mg QD*

*Dose adjustment needed if eGFR < 50 mL/min. Persons coinfected with HIV should receive 150 mg BID. Should only be used in combination with other antiretrovirals. Lok AS, et al. Hepatology. 2009;50:661-662.

Agents used for Chronic HBV:

Medication Cautionary Note
CONTRAINDICATED in patients with: Uncontrolled major depression (especially with past suicide attempts) Autoimmune hepatitis or other autoimmune diseases Severe cardiovascular disease (e.g. uncontrolled hypertension, coronary artery disease, congestive heart failure) Decompensated cirrhosis or hepatocellular carcinoma Uncontrolled seizure disorder Not recommended for first-line anti-HBV therapy because of high resistance rates Caution in patients with baseline RENAL INSUFFICIENCY Taken on empty stomach (>2 hours before or after a meal); should not use without HIV therapy in HIV-HBV co-infected patients Creatine kinase elevation 8%, symptomatic myopathy rare

Interferon alfa-2b and Peginterferon alfa-2a

Lamivudine (3TC) Adefovir (ADV) Entecavir (ETV) Telbivudine (LdT)

Tenofovir (TDF)

Caution in patients with baseline RENAL INSUFFICIENCY

Hepatitis
web study

Factors Driving Selection of Initial Therapy

Nucleos(t)ide Analogues Peginterferon

Safety & tolerability Efficacy (potency) Barrier to resistance (durability) Safety & tolerability

Efficacy (potency)

Finite duration
Hepatitis
web study

PegIFN vs Nucleos(t)ide Analogues

PegIFN Pro Con

Nucleos(t)ide Analogues Pro Con

Finite course of therapy No resistance Higher rate of HBeAg loss in 1 yr Higher rate of HBsAg loss with short duration therapy*

SQ administration Frequent AEs Contraindicated in patients with cirrhosis, in pregnancy, with acute hepatitis B, and who are immunosuppressed

PO administration Infrequent AEs Safe for patients with decompensated disease

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. Hepatology. 2010;52:743-747. Buster EH, et al. Gastroenterology. 2008;135:459-467. Lange CM, et al. Hepatology. 2009;50:2001-2006.

Hepatitis
web study

Durability of HBeAg Seroconversion

Agent
Peginterferon[1] Lamivudine[1-4] Adefovir[5] Telbivudine[3] Entecavir[2]
*Median follow-up.

n
72 55 61 43 39 45 55 70

Posttreatment Time Point

24 wks 24 wks 24 wks 52 wks 40.7 mos* 150 wks* 52 wks 24 wks

Sustained HBeAg Seroconversion, %

82 58 72 93 77 91 86 77

1. Lau GKK, et al. N Engl J Med. 2005;352:2682-2695. 2. Gish RG, et al. Gastroenterology. 2007;133:14371444. 3. Poynard T, et al. EASL 2008. Abstract 706. 4. Dienstag JL, et al. Hepatology. 2003; 37:748-755. 5. Wu IC, et al. Clin Infect Dis. 2008;47:1305-1311. Hepatitis
web study

Goals of Therapy: 2 Distinct Patient Populations

HBeAg positive (wild type)

HBeAg loss seroconversion Suppression of HBV DNA ALT normalization

HBeAg negative (precore and core promoter mutants)

HBeAg seroconversion not an endpoint Suppression of HBV DNA ALT normalization

Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.

Hepatitis
web study

HBV Genotype Affects Hepatitis B Disease Progression and Outcomes

"HBV DNA levels decreased over time in patients infected with genotypes A, B or D," the study authors concluded.

"However, highly active genotype C or D infection often remained highly active, implying a risk for progressive liver damage."

Hepatitis
web study

AASLD CHB Guidelines: Treatment Candidacy for HBeAg-Positive Patients

HBsAg Positive HBeAg Positive

ALT < 1 x ULN HBV DNA < 20,000 IU/mL

Q 3-6 mos ALT Q 6-12 mos HBeAg

ALT 1-2 x ULN HBV DNA > 20,000 IU/mL

Q 3 mos ALT Q 6 mos HBeAg Consider biopsy if persistent or age > 40 Rx as needed

ALT > 2 x ULN HBV DNA > 20,000 IU/mL

Q 1-3 mos ALT, HBeAg Treat if persistent Liver bx optional Immediate Rx if jaundice or decompensated

Lok AS, McMahon BJ. Hepatology. 2009;50:661-662. Chronic Hepatitis B: Update 2009, Lok ASF, McMahon BJ, www.aasld.org. Copyright@2009. American Association for the Study of Liver Diseases, Reproduced with permission of the American Association for the Study of Liver Diseases.

AASLD CHB Guidelines: Treatment Candidacy for HBeAg-Negative Patients

HBsAg Positive HBeAg Negative

ALT < 1 x ULN HBV DNA < 2000 IU/mL Q 3 mos ALT x 3, then Q 6-12 mos if ALT still < 1 X ULN

ALT 1-2 x ULN HBV DNA 2000-20,000 IU/mL Q 3 mos ALT and HBV DNA Consider biopsy if persistent Rx as needed

ALT 2 x ULN HBV DNA 20,000 IU/mL Treat if persistent Liver biopsy optional

Lok AS, McMahon BJ. Hepatology. 2009;50:661-662. Chronic Hepatitis B: Update 2009, Lok ASF, McMahon BJ, www.aasld.org. Copyright@2009. American Association for the Study of Liver Diseases, Reproduced with permission of the American Association for the Study of Liver Diseases.

Can HBV Infection Be Cured?

HBV is controllable HBsAg seroconversion is the ultimate form of viral control

HBeAg Loss and Seroconversion in HBeAg+ Patients After 1 Yr of Treatment

Not head-to-head trials; different patient populations and trial designs
100 80 Outcome (%) 60 40 20 0 LAM ADV LdT 17-32 24

HBeAg Loss

100 80 60

HBeAg Seroconversion

26

30
21

40 20 22 12-18

23

21

22-27 21

NA
ETV TDF PegIFN

0 LAM ADV LdT ETV TDF

PegIFN

Lok AS, et al. Hepatology. 2007;45:507-539. Lau GK, et al. N Engl J Med. 2005;352:2682-2695. Marcellin P, et al. N Engl J Med. 2003;348:808-816. Chang TT, et al. N Engl J Med. 2006;354:1001-1010. Lai CL, et al. N Engl J Med. 2007;357:2576-2588. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455. Janssen HL, et al. Lancet. 2005;365;123-129.

Other Outcomes in HBeAg-Positive Patients After 1 Yr of Treatment

100

Not head-to-head trials; different patient populations and trial designs

~ 90 LAM ADV LdT ETV 50-80 38 TDF PegIFN

80 Outcome (%)

77 68 68 65 49-56 39

~ 80 72 74 69

60 48 40 41-75

53

20 NA NA 0 ALT Normalization Histologic Improvement Response Durability* 1 0 0 2 3.2 3 HBsAg Loss

*No/short duration consolidation treatment among LAM- and ETV-treated patients; most patients treated with ADV and LdT had consolidation.

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

Undetectable* HBV DNA After 1 Yr of Treatment

Not head-to-head trials; different patient populations and trial designs
Undetectable* HBV DNA (%) 100 80 60 40-44 40 20 0 LAM ADV LdT ETV TDF 13-21 25 20 0 LAM ADV LdT ETV 40 60

HBeAg Positive
76 67

100 80 60

HBeAg Negative
88 90 93 63

60-73
51-63

PegIFN

TDF PegIFN

*By PCR-based assay (LLD ~ 50 IU/mL) except for some LAM studies. Lok AS, et al. Hepatology. 2007;45:507-539. Lok AS, et al. Hepatology. 2009;50:661-662.

Cumulative Rates of Resistance With Oral Agents in Nucleos(t)ide-Naive Patients

Not head-to-head trials; different patient populations and trial designs Yr 1 Yr 2 Yr 3 Yr 4 Yr 5 Yr 6

Drug Generation

1st

LAM

24%

38%

49%

67%

70%

2nd 3rd

ADV LdT ETV TDF

0% 4% 0.2% 0%

3% 17% 0.5% 0%

11% 1.2% 0%

18% 1.2%

29%

1.2%

1.2%

EASL. J Hepatol. 2009;50:227-242. Tenny DJ, et al. EASL 2009. Abstract 20. Marcellin P, et al. AASLD 2009. Abstract 481. Heathcote E, et al. AASLD 2009. Abstract 483.

AASLD Guideline Preferred Agents

HBeAg-positive adults with indications for treatment: Treatment may be initiated with any of the 7 approved antiviral medications, but pegIFN-, tenofovir, or entecavir are preferred . HBeAg-negative adults with indications for treatment: Treatment may be initiated with any of the 7 approved antiviral medications but pegIFN-, tenofovir, or entecavir are preferred in view of the need for long-term treatment.

AASLD Guideline Recommendations for Duration of NA Treatment

Duration of nucleoside analogue treatment a. HBeAg-positive chronic hepatitis BTreatment should be continued until the patient has achieved HBeAg seroconversion and undetectable serum HBV DNA and completed at least 6 months of additional treatment after appearance of anti-HBe.

Close monitoring for relapse is needed after withdrawal of treatment.

b. HBeAg-negative chronic hepatitis BTreatment should be continued until the patient has achieved HBsAg clearance.

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

Definition of Response to Antiviral Therapy

Response
Primary nonresponse* Biochemical response

Definition
in serum HBV DNA by < 2 log10 IU/mL after 24 wks of therapy in serum ALT to within the normal range in serum HBV DNA to undetectable levels by PCR and loss of HBeAg in patients who were initially HBeAg positive in serum HBV DNA of 1 log10 IU/mL after discontinuation of treatment in 2 determinations > 4 wks apart in histology activity index by 2 points and no worsening of fibrosis score compared to pretreatment liver biopsy Fulfill criteria of biochemical and virologic response and HBsAg loss

Virologic response
Virologic relapse Histologic response Complete response

*Not applicable to interferon therapy.

Lok AS, et al. Hepatology. 2009;50:661-662. Chronic Hepatitis B: Update 2009, Lok ASF, McMahon BJ, www.aasld.org. Copyright@2009. American Association for the Study of Liver Diseases. Reproduced with permission of the American Association for the Study of Liver Diseases.

Medical management of HBV cirrhosis: Practice guidelines

Guideline recommendations

EASL1
Compensated cirrhosis Antiviral therapy if HBV DNA +, regardless of ALT

AASLD2
Antiviral therapy if ALT >2 x ULN or if HBV DNA >2,000 IU/mL

APASL4
Antiviral therapy with IFN (if no hepatitis flare) or NAs* if HBV DNA >2,000 IU/mL

Decompensated cirrhosis*

Immediate oral antiviral therapy *

1. EASL. J Hepatol 2009; 50:22742; 2. Lok & McMahon. Hepatology 2009; 50:136; 4. Liaw Y-F, et al. Hepatol Int 2008; 2:26383.

Management of Patients With Compensated Cirrhosis

Preferred therapies
ETV or TDF
NAs should be used; IFN can be associated with hepatitis flare

Treatment duration
Long-term treatment
Can discontinue in HBeAg-positive patients with confirmed HBeAg seroconversion and 6 mos consolidation therapy Can discontinue in HBeAg-negative patients with confirmed HBsAg clearance

Treatment discontinuation requires close monitoring for flare or relapse

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

Management of Patients With Decompensated Cirrhosis

Preferred therapies
(LAM or LdT) + (ADV or TDF); TDF or ETV monotherapy*
Treatment should be coordinated with transplantation center IFNs should not be used in decompensated cirrhosis

Treatment duration
Lifelong treatment recommended

*Clinical data documenting safety and efficacy of TDF or ETV monotherapy in decompensated cirrhosis are lacking.
Lok AS, et al. Hepatology. 2009;50:661-662.

HBV Transmission: When Does It Happen?

In utero (<10%)1
Associated with
Acute HBV in third trimester Maternal HBeAg and high HBV DNA History of threatened preterm labor HBV in the placenta

At the time of delivery1

HBeAg-positive mothers: 85% HBeAg-negative mothers: 31%

After birth
Breastfeeding not associated with transmission 2 May be related to scarification, other parenteral exposures

Gambarin-Gelwan Clinics Liv Disease 2007 2. Beasley Lancet 1975

HBV Treatment During Pregnancy:Telbivudine

From 20-32 wks antepartum HBsAg-positive pregnant women, HBV DNA > HBV DNA > 6 x 106 copies/mL

To 4 weeks postpartum

Telbivudine 600 mg/day (n = 95) No therapy (n= 95)

All infants received HBV vaccine series and HBIG (200 IU, single dose)

Infant Status at 28 Wks, % HBsAg+ (with or without HBV DNA)

TBV (n = 95) 2.11

No Rx (n = 92) 13.04

P Value .004

--Lower risk of postpartum ALT flare in telbivudine group (7.45% vs 18.48%; P = .025) --Postpartum ALT flare in 12.73% of telbivudine-treated patients after treatment discontinuation at Week 4 --No cases of severe hepatitis (ALT > 10 x upper limit of normal)
Han G AASLD 2010 Abstract 212.

Recent reports suggest that lamivudine therapy during the last trimester of pregnancy in pregnant HBsAg-positive women with high levels of viremia reduces the risk of intrauterine and perinatal transmission of HBV if given in addition to passive and active vaccination by HBIg and HBV vaccination.
Tenofovir or tenofovir with emtricitabine or entecavir could be considered. Although apparently safe, these protocols require further confirmation.

HDV co-infected patients

Active co-infection with HDV is confirmed by the presence of detectable HDV RNA, immuno-histochemical staining for HDV antigen, or IgM anti-HDV.

Interferon alpha (conventional or pegylated) is the only

drug effective on HDV replication