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## Complete Summary

#### GUIDELINE TITLE

\(1\) Chronic hepatitis B. (2) Corrections to AASLD guidelines on
chronic hepatitis B.

#### BIBLIOGRAPHIC SOURCE(S)

Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2007
Feb;45(2):507-39. \[275 references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17256718)

Lok AS, McMahon BJ. Corrections to AASLD guidelines on chronic hepatitis
B. Hepatology 2007 Jun;45(6):1347. \[1 reference\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17476694)

#### GUIDELINE STATUS

This is the current release of this guideline.

This guideline updates a previous version: Lok AS, McMahon BJ. Chronic
hepatitis B. Alexandria (VA): American Association for the Study of
Liver Diseases; 2004. 25 p.

### \*\* REGULATORY ALERT \*\*

#### FDA WARNING/REGULATORY ALERT

**Note from the National Guideline Clearinghouse**: This guideline
references drugs for which important revised regulatory information has
been released:

-   [August 16, 2007, Baraclude
    (Entecavir)](http://www.fda.gov/medwatch/safety/2007/safety07.htm#Baraclude):
    Revisions to the prescribing information for Baraclude to indicate
    that the drug is not recommended for HIV/hepatitis B virus (HBV)
    co-infected patients who are not also receiving highly active
    antiretroviral therapy (HAART) due to the potential for the
    development of HIV resistance.

### COMPLETE SUMMARY CONTENT

 \*\* REGULATORY ALERT \*\*\
 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 CONTRAINDICATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

Chronic hepatitis B

#### GUIDELINE CATEGORY

Counseling\
Diagnosis\
Evaluation\
Management\
Prevention\
Screening\
Treatment

#### CLINICAL SPECIALTY

Family Practice\
Gastroenterology\
Infectious Diseases\
Internal Medicine\
Obstetrics and Gynecology\
Pediatrics\
Preventive Medicine

#### INTENDED USERS

Advanced Practice Nurses\
Health Care Providers\
Nurses\
Physician Assistants\
Physicians

#### GUIDELINE OBJECTIVE(S)

To assist physicians and other health care providers in the recognition,
diagnosis, and management of patients chronically infected with the
hepatitis B virus (HBV)

#### TARGET POPULATION

-   Individuals at risk for hepatitis B virus (HBV) infection

-   Individuals with chronic HBV infection

**Note**: Management of hepatitis B in patients waiting for liver
transplantation and prevention of recurrent hepatitis B post-liver
transplant have been covered in a recent review article and will not be
discussed in these guidelines.

#### INTERVENTIONS AND PRACTICES CONSIDERED

**Screening, Counseling, Prevention**

1.  Screening for hepatitis B virus (HBV) in high-risk groups and
    vaccination, if negative

2.  Counseling of carriers of HBV regarding prevention of transmission

3.  Testing of sexual and household contacts of carriers for HBV and
    vaccination, if negative

4.  Treatment of newborns of HBV-infected mothers with hepatitis B
    immune globulin (HBIG) and hepatitis B vaccine at delivery

5.  Periodic testing of persons at risk for HBV infection for response
    to vaccination

6.  Abstinence or limited use of alcohol in HBV carriers

7.  Hepatitis B vaccination for persons who are positive only for
    hepatitis B core antibody (anti-HBc) and who are from a low endemic
    areas with no risk factors for HBV

8.  Antiviral prophylaxis of hepatitis B carriers who receive
    immunosuppressive or cytotoxic therapy

**Evaluation/Management**

1.  History and physical examination and family history of HBV infection
    and liver cancer

2.  Laboratory tests including assessment of liver disease; tests for
    HBV replication; tests to rule out coinfection with hepatitis C
    virus (HCV), hepatitis D virus (HDV), and human immunodeficiency
    virus (HIV) in those at risk; tests to screen for hepatocellular
    carcinoma (HCC) (alpha-fetoprotein \[AFP\] at baseline and, in high
    risk patients, ultrasound)

3.  Vaccination for hepatitis A

4.  HBV DNA assay

5.  Liver biopsy

6.  Evaluation for treatment of patients who have chronic HBV infection

7.  Follow-up of patients not considered for treatment, including
    monitoring of alanine aminotransferase (ALT) and HBV DNA levels and
    screening tests for hepatocellular carcinoma in patients at high
    risk

**Treatment**

1.  Treatment of chronic HBV

    -   Pegylated (peg) interferon (IFN)-alpha

    -   IFN-alpha

    -   Lamivudine

    -   Adefovir

    -   Entecavir

    -   Telbivudine

2.  Treatment of drug-resistant HBV

3.  Treatment of patients with HBV/HIV

4.  Prophylactic antiviral therapy for HBV carriers at the onset of
    chemotherapy or immunosuppressive therapy

5.  Treatment of symptomatic acute HBV

6.  Treatment monitoring and discontinuation or adjustment of treatment
    as indicated

#### MAJOR OUTCOMES CONSIDERED

-   Sensitivity, specificity, and diagnostic accuracy of screening tests

-   Efficacy of treatment

-   Adverse events

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Searches of Electronic Databases

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

A formal review and analysis of published literature on hepatitis B
(Medline search up to February 2006 and meeting abstracts in 2003--2005)
was performed. In addition, the proceedings of the 2000 and 2006
National Institutes of Health conferences on the \"Management of
Hepatitis B\", the European Association for the Study of the Liver
(EASL) 2002 International Consensus Conference on Hepatitis B and the
Asian-Pacific Consensus Statement on the Management of Chronic Hepatitis
B: a 2005 Update, were considered in the development of these
guidelines.

#### NUMBER OF SOURCE DOCUMENTS

Not stated

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Weighting According to a Rating Scheme (Scheme Given)

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

**Grade I**: Randomized controlled trials

**Grade II-1**: Controlled trials without randomization

**Grade II-2**: Cohort or case-control analytic studies

**Grade II-3**: Multiple time series, dramatic uncontrolled experiments

**Grade III**: Opinions of respected authorities, descriptive
epidemiology

#### METHODS USED TO ANALYZE THE EVIDENCE

Review of Published Meta-Analyses\
Systematic Review

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

Not stated

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Not stated

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

Not applicable

#### COST ANALYSIS

A formal cost analysis was not performed and published cost analyses
were not reviewed.

#### METHOD OF GUIDELINE VALIDATION

Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

This guideline was produced in collaboration with the Practice
Guidelines Committee of the American Association for the Study of Liver
Diseases. This committee provided extensive peer review of the
manuscript. The guideline was approved by the American Association for
the Study of Liver Diseases.

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

**Note from the National Guideline Clearinghouse (NGC) and the American
Association for the Study of Liver Diseases (AASLD)**: This guideline
was originally published in 2001 and was updated most recently in
February of 2007. Subsequently, a correction to the update was published
in June 2007. The following recommendations reflect the complete updated
guidelines.

Recommendations are followed by quality of evidence ratings (Grades I,
II-1, II-2, II-3, III), which are defined at the end of the \"Major
Recommendations\" field.

**[Screening High Risk Populations to Identify Hepatitis B Virus (HBV)
Infected Persons]{.underline}**

**Recommendations for Persons Who Should Be Tested for HBV Infection**

1.  The following groups should be tested for HBV infection: persons
    born in hyperendemic areas (see Table below), men who have sex with
    men, persons who have ever used injecting drugs, dialysis patients,
    human immunodeficiency virus (HIV)-infected individuals, pregnant
    women, and family members, household members, and sexual contacts of
    HBV-infected persons. Testing for hepatitis B surface antigen
    (HBsAg) and hepatitis B surface antibody (anti-HBs) should be
    performed, and seronegative persons should be vaccinated. **(Grade
    I)**

**Table. Groups at High Risk for HBV Infection Who Should be Screened**

+-----------------------------------------------------------------------+
| Individuals born in areas of high^2^ and intermediate prevalence      |
| rates^3^ for HBV including immigrants and adopted children^1,4^       |
|                                                                       |
| -   Asia; all countries (except Sri Lanka)                            |
|                                                                       |
| -   Africa; all countries                                             |
|                                                                       |
| -   South Pacific Islands; all countries and territories (except      |
|     nonindigenous populations of New Zealand and Australia)           |
|                                                                       |
| -   Middle East: all countries (except Cyprus)                        |
|                                                                       |
| -   Western Europe: Greece, Italy, Malta, Portugal, and Spain         |
|                                                                       |
| -   Eastern Europe: all countries (except Hungary)                    |
|                                                                       |
| -   The Arctic: indigenous populations                                |
|                                                                       |
| -   South America: Argentina, Bolivia, Brazil, Ecuador, Guyana,       |
|     Suriname, Venezuela, and Amazon region of Colombia and Peru       |
|                                                                       |
| -   Central America: Belize, Guatemala, Honduras, and Panama          |
|                                                                       |
| -   Caribbean: Antigua and Barbuda, Dominica, Dominican Republic,     |
|     Grenada, Haiti, Jamaica, Puerto Rico, St. Kitts and Nevis, St.    |
|     Lucia, St. Vincent and Grenadines, Trinidad and Tobago, and Turks |
|     and Caico                                                         |
+-----------------------------------------------------------------------+
| Other high-risk groups recommended for screening                      |
|                                                                       |
| -   Household and sexual contacts of HBsAg-positive persons^4^        |
|                                                                       |
| -   Persons who have ever injected drugs^4^                           |
|                                                                       |
| -   Persons with multiple sexual partners or history of sexually      |
|     transmitted disease^4^                                            |
|                                                                       |
| -   Men who have sex with men^4^                                      |
|                                                                       |
| -   Inmates of correctional facilities^4^                             |
|                                                                       |
| -   Individuals with chronically elevated alanine aminotransferase    |
|     (ALT) or aspartate aminotransferase (AST)^4^                      |
|                                                                       |
| -   Individuals infected with hepatitis C virus (HCV) or HIV^4^       |
|                                                                       |
| -   Patients undergoing renal dialysis^4^                             |
|                                                                       |
| -   All pregnant women                                                |
+-----------------------------------------------------------------------+

^1^ If HBsAG-positive persons are found in the first generation,
subsequent generations should be tested.\
^2^ HBsAg prevalence \>8%\
^3^ HBsAg prevalence 2 to 7%\
^4^ Those who are seronegative should receive hepatitis B vaccine.

**[Counseling and Prevention of Hepatitis B]{.underline}**

**Recommendations for Counseling and Prevention of Transmission of
Hepatitis B from Individuals with Chronic HBV Infection**

2.  Carriers should be counseled regarding prevention of transmission of
    HBV (see the Table below). **(Grade III)**

**Table. Recommendations for Infected Persons Regarding Prevention of
Transmission of HBV to Others**

+-----------------------------------------------------------------------+
| Persons who are HBsAg-positive should                                 |
|                                                                       |
| -   Have sexual contacts vaccinated                                   |
|                                                                       |
| -   Use barrier protection during sexual intercourse if partner not   |
|     vaccinated or naturally immune                                    |
|                                                                       |
| -   Not share toothbrushes or razors                                  |
|                                                                       |
| -   Cover open cuts and scratches                                     |
|                                                                       |
| -   Clean blood spills with detergent or bleach                       |
|                                                                       |
| -   Not donate blood, organs, or sperms                               |
|                                                                       |
| Children and adults who are HBsAg-positive:                           |
|                                                                       |
| -   Can participate in all activities including contact sports        |
|                                                                       |
| -   Should not be excluded from daycare or school participation and   |
|     should not be isolated from other children                        |
|                                                                       |
| -   Can share food, utensils, or kiss others                          |
+-----------------------------------------------------------------------+

3.  Sexual and household contacts of carriers who are negative for HBV
    seromarkers should receive hepatitis B vaccination. **(Grade III)**

4.  Newborns of HBV-infected mothers should receive hepatitis B immune
    globulin (HBIG) and hepatitis B vaccine at delivery and complete the
    recommended vaccination series. **(Grade I)**

5.  Persons who remain at risk for HBV infection such as infants of
    HBsAg-positive mothers, health care workers, dialysis patients, and
    sexual partners of carriers should be tested for response to
    vaccination. **(Grade III)**

    -   Postvaccination testing should be performed at 9 to 15 months of
        age in infants of carrier mothers and 1 to 2 months after the
        last dose in other persons. **(Grade III)**

    -   Follow-up testing of vaccine responders is recommended annually
        for chronic hemodialysis patients. **(Grade III)**

6.  Abstinence or only limited use of alcohol is recommended in
    hepatitis B carriers. **(Grade III)**

7.  Persons who are positive only for hepatitis B core antibody
    (anti-HBc) and who are from a low endemic area with no risk factors
    for HBV should be given the full series of hepatitis B vaccine.
    **(Grade II-2)**

**[Evaluation and Management of Patients with Chronic HBV
Infection]{.underline}**

**Recommendations for Initial Evaluation of Persons with Chronic HBV
Infection**

8.  Initial evaluation of persons newly diagnosed with chronic HBV
    infection should include history, physical examination, and
    laboratory testing as outlined in the Table below. **(Grade III)**

**Table. Evaluation of Patients with Chronic HBV Infection**

+-----------------------------------------------------------------------+
| *Initial Evaluation*                                                  |
|                                                                       |
| 1.  History and physical examination                                  |
|                                                                       |
| 2.  Family history of liver disease, hepatocellular carcinoma (HCC)   |
|                                                                       |
| 3.  Laboratory tests to assess liver disease---complete blood counts  |
|     with platelets, hepatic panel and prothrombin time                |
|                                                                       |
| 4.  Tests for HBV replication---hepatitis B e antigen                 |
|     (HBeAg)/antibody to hepatitis B e antigen (anti-HBe), HBV DNA     |
|                                                                       |
| 5.  Tests to rule out viral coinfections---antibody to hepatitis C    |
|     virus (anti-HCV), antibody to hepatitis D virus (anti-HDV) (in    |
|     persons from countries where HDV infection is common and in those |
|     with history of injection drug use), and anti-HIV in those at     |
|     risk                                                              |
|                                                                       |
| 6.  Tests to screen for HCC-alpha fetoprotein (AFP) at baseline and,  |
|     in high risk patients, ultrasound                                 |
|                                                                       |
| 7.  Consider liver biopsy to grade and stage liver disease---for      |
|     patients who meet criteria for chronic hepatitis                  |
+-----------------------------------------------------------------------+

9.  All persons with chronic hepatitis B not immune to hepatitis A
    should receive 2 doses of hepatitis A vaccine 6 to 18 months apart.
    **(Grade II-3)**

**Recommendations for Monitoring Patients with Chronic HBV Infection
(See Figure 1 in the original guideline document.)**

10. HBeAg-positive and HBeAg-negative patients who meet criteria for
    chronic hepatitis B (see Table below) should be evaluated for
    treatment. **(Grade I)**

**Table. Diagnostic Criteria of HBV Infection**

+-----------------------------------------------------------------------+
| *Chronic Hepatitis B*                                                 |
|                                                                       |
| 1.  HBsAg+ \>6 months                                                 |
|                                                                       |
| 2.  Serum HBV DNA \>20,000 IU/mL (10^5^ copies/mL), lower values      |
|     2,000 to 20,000 IU/mL (10^4^ to 10^5^ copies/mL) are often seen   |
|     in HBeAg-negative chronic hepatitis B                             |
|                                                                       |
| 3.  Persistent or intermittent elevation in ALT/AST levels            |
|                                                                       |
| 4.  Liver biopsy showing chronic hepatitis with moderate or severe    |
|     necroinflammation                                                 |
|                                                                       |
| *Inactive HBsAg Carrier State*                                        |
|                                                                       |
| 1.  HBsAg+ \>6 months                                                 |
|                                                                       |
| 2.  HBeAg-, anti-HBe+                                                 |
|                                                                       |
| 3.  Serum HBV DNA \<2,000 IU/mL                                       |
|                                                                       |
| 4.  Persistently normal ALT/AST levels                                |
|                                                                       |
| 5.  Liver biopsy confirms absence of significant hepatitis            |
|                                                                       |
| *Resolved Hepatitis B*                                                |
|                                                                       |
| 1.  Previous known history of acute or chronic hepatitis B or the     |
|     presence of anti-HBc [+]{.underline} anti-HBs                     |
|                                                                       |
| 2.  HBsAg-                                                            |
|                                                                       |
| 3.  Undetectable serum HBV DNA^\*^                                    |
|                                                                       |
| 4.  Normal ALT levels                                                 |
+-----------------------------------------------------------------------+

\*Very low levels may be detectable using sensitive polymerase chain
reaction (PCR) assays

11. HBeAg-positive patients:

    -   HBeAg-positive patients with persistently normal ALT should be
        tested for ALT at 3- to 6-month intervals. ALT along with HBV
        DNA should be tested more often when ALT levels become elevated.
        HBeAg status should be checked every 6 to 12 months. **(Grade
        III)**

    -   Patients who remain HBeAg positive with HBV DNA levels \>20,000
        IU/mL after a 3- to 6-month period of elevated ALT levels
        between 1 to 2 times the upper limit of normal (ULN), or who
        remain HBeAg positive with HBV DNA levels \>20,000 IU/mL and are
        \>40 years old, should be considered for liver biopsy, and
        treatment should be considered if biopsy shows moderate/severe
        inflammation or significant fibrosis. **(Grade III)** Patients
        who remain HBeAg positive with HBV DNA levels \>20,000 IU/mL
        after a 3- to 6-month period of elevated ALT levels \>2 x ULN
        should be considered for treatment. **(Grade III)**.

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12. HBeAg-negative patients:

    -   HBeAg-negative patients with normal ALT and HBV DNA \<2,000
        IU/mL should be tested for ALT every 3 months during the first
        year to verify that they are truly in the \"inactive carrier
        state\" and then every 6 to 12 months. **(Grade III)**

    -   Tests for HBV DNA and more frequent monitoring should be
        performed if ALT or AST increases above the normal limit.
        **(Grade III)**

**Recommendations for HCC Screening**

13. HBV carriers at high risk for HCC such as Asian men over 40 years
    and Asian women over 50 years of age, persons with cirrhosis,
    persons with a family history of HCC, Africans over 20 years of age,
    and any carrier over 40 years with persistent or intermittent ALT
    elevation and/or high HBV DNA level \>2,000 IU/mL should be screened
    with ultrasound (US) examination every 6-12 months. **(Grade II-2)**

14. For HBV carriers at high risk for HCC who are living in areas where
    US is not readily available, periodic screening with AFP should be
    considered. (**Grade II-2)**

**[Treatment of Chronic Hepatitis B]{.underline}**

**Recommendations on Whom to Treat and with What Antiviral Agent (see
Table 12 in the original guideline document.)**

15. Patients with HBeAg-positive chronic hepatitis B

    a.  *ALT greater than 2 times normal or moderate/severe hepatitis on
        biopsy, and HBV DNA \>20,000 IU/mL.* These patients should be
        considered for treatment. **(Grade I)**

        -   Treatment should be delayed for 3 to 6 months in persons
            with compensated liver disease to determine if spontaneous
            HBeAg seroconversion occurs. **(Grade II-2)**

        -   Patients with icteric ALT flares should be promptly treated.
            **(Grade III)**

        -   Treatment may be initiated with any of the 6 approved
            antiviral medications, but pegylated (peg) interferon
            (IFN)-alpha, adefovir, or entecavir are preferred. **(Grade
            I)**

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    b.  *ALT persistently normal or minimally elevated (\<2 times
        normal).* These patients generally should not be initiated on
        treatment. **(Grade I)**

        -   Liver biopsy may be considered in patients with fluctuating
            or minimally elevated ALT levels especially in those above
            40 years of age. **(Grade II-3)**

        -   Treatment may be initiated if there is moderate or severe
            necroinflammation or significant fibrosis on liver biopsy.
            **(Grade I)**

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    c.  *Children with elevated ALT greater than 2 times normal.* These
        patients should be considered for treatment if ALT levels remain
        elevated at this level for longer than 6 months. **(Grade I)**

        -   Treatment may be initiated with IFN-alpha or lamivudine.
            **(Grade I)**

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16. Patients with HBeAg-negative chronic hepatitis B (serum HBV DNA
    \>20,000 IU/mL and elevated ALT \>2 times normal) should be
    considered for treatment. **(Grade I)**

    -   Liver biopsy may be considered for HBeAg-negative patients with
        lower HBV DNA levels (2,000 to 20,000 IU/mL) and borderline
        normal or minimally elevated ALT levels. **(Grade II-2)**

    -   Treatment may be initiated if there is moderate/severe
        inflammation or significant fibrosis on biopsy. **(Grade I)**

    -   Treatment may be initiated with any of the 6 approved antiviral
        medications but pegIFN-alpha, adefovir, or entecavir are
        preferred in view of the need for long-term treatment. (**Grade
        I for pegIFN-alpha, adefovir, entecavir, and telbivudine and
        Grade II-1 for IFN-alpha and lamivudine)**

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17. Patients who failed to respond to prior IFN-alpha (standard or
    pegylated) therapy may be retreated with nucleoside analogues (NA)
    if they fulfill the criteria listed above. **(Grade I)**

18. Patients who failed to achieve primary response as evidenced by \<2
    log decrease in serum HBV DNA level after at least 6 months of NA
    therapy should be switched to an alternative treatment. **(Grade
    III)**

19. Patients who develop breakthrough infection while receiving NA
    therapy (see Table below)

    -   Compliance should be ascertained, and treatment resumed in
        patients who have had long lapses in medications. **(Grade
        III)**

    -   A confirmatory test for antiviral-resistant mutation should be
        performed if possible to differentiate primary non-response from
        breakthrough infection and to determine if there is evidence of
        multi-drug resistance (in patients who have been exposed to more
        than one NA treatment). **(Grade III)**

    -   All patients with virologic breakthrough should be considered
        for rescue therapy. **(Grade II-2)**

    -   For patients in whom there was no clear indication for hepatitis
        B treatment and who continue to have compensated liver disease,
        withdrawal of therapy may be considered but these patients need
        to be closely monitored and treatment reinitiated if they
        experience severe hepatitis flares. **(Grade III)**

**Table. Management of Anti-Viral Resistant HBV**

+---------------+------------------------------------------------------+
| *Prevention*  |                                                      |
|               |                                                      |
| -   Avoid     |                                                      |
|               |                                                      |
|   unnecessary |                                                      |
|     treatment |                                                      |
|               |                                                      |
| -   Initiate  |                                                      |
|     treatment |                                                      |
|     with      |                                                      |
|     potent    |                                                      |
|     antiviral |                                                      |
|     that has  |                                                      |
|     low rate  |                                                      |
|     of drug   |                                                      |
|               |                                                      |
|    resistance |                                                      |
|     or with   |                                                      |
|               |                                                      |
|   combination |                                                      |
|     therapy   |                                                      |
|               |                                                      |
| -   Switch to |                                                      |
|               |                                                      |
|   alternative |                                                      |
|     therapy   |                                                      |
|     in        |                                                      |
|     patients  |                                                      |
|     with      |                                                      |
|     primary   |                                                      |
|               |                                                      |
|  non-response |                                                      |
|               |                                                      |
| *Monitoring*  |                                                      |
|               |                                                      |
| -   Test for  |                                                      |
|     serum HBV |                                                      |
|     DNA (PCR  |                                                      |
|     assay)    |                                                      |
|     every 3   |                                                      |
|     to 6      |                                                      |
|     months    |                                                      |
|     during    |                                                      |
|     treatment |                                                      |
|               |                                                      |
| -   Check for |                                                      |
|               |                                                      |
|    medication |                                                      |
|               |                                                      |
|    compliance |                                                      |
|     in        |                                                      |
|     patients  |                                                      |
|     with      |                                                      |
|     virologic |                                                      |
|               |                                                      |
|  breakthrough |                                                      |
|               |                                                      |
| -   Confirm   |                                                      |
|     antiviral |                                                      |
|               |                                                      |
|    resistance |                                                      |
|     with      |                                                      |
|     genotypic |                                                      |
|     testing   |                                                      |
+---------------+------------------------------------------------------+
| *Treatment*   |                                                      |
+---------------+------------------------------------------------------+
| Lamivudi      | Add adefovir or tenofovir\                           |
| ne-resistance | \                                                    |
|               | Stop lamivudine, switch to Truvada^1,3^\             |
|               | \                                                    |
|               | Stop lamivudine, switch to entecavir (preexisting    |
|               | lamivudine-resistant mutation predisposes to         |
|               | entecavir resistance)^2^                             |
+---------------+------------------------------------------------------+
| Adefov        | Add lamivudine^2^\                                   |
| ir-resistance | \                                                    |
|               | Stop adefovir, switch to Truvada^1,3^\               |
|               | \                                                    |
|               | Switch to or add entecavir^2,3^                      |
+---------------+------------------------------------------------------+
| Entecav       | Switch to or add adefovir or tenofovir^3^            |
| ir-resistance |                                                      |
+---------------+------------------------------------------------------+
| Telbivudine-  | Add adefovir or tenofovir\                           |
| resistance^4^ | \                                                    |
|               | Stop telbivudine, switch to Truvada\                 |
|               | \                                                    |
|               | Stop telbivudine, switch to entecavir (preexisting   |
|               | telbivudine-resistant mutation predisposes to        |
|               | entecavir resistance)                                |
+---------------+------------------------------------------------------+

^1^ Truvada = combination pill with emtricitabine 200 mg and tenofovir
300 mg\
^2^ Durability of viral suppression unknown, especially in patient with
prior lamivudine resistance\
^3^ In HIV coinfected persons; scanty in vivo data in non-HIV infected
persons\
^4^ Clinical data not available

20. Treatment of patients with lamivudine (or telbivudine)-resistant HBV

    a.  If adefovir is used, lamivudine (or telbivudine) should be
        continued indefinitely to decrease the risk of hepatitis flares
        during the transition period and to reduce the risk of
        subsequent adefovir resistance. **(Grade II-3 for
        lamivudine-resistant HBV and Grade III for telbivudine-resistant
        HBV)**

    b.  If entecavir is used, lamivudine or telbivudine should be
        stopped as continued presence of lamivudine (or
        telbivudine)-resistant mutations will increase the risk of
        entecavir resistance. **(Grade II-3 for lamivudine-resistant HBV
        and Grade III for telbivudine-resistant HBV)**

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21. Treatment of patients with adefovir-resistant HBV

    a.  In patients with no prior exposure to other NA, lamivudine or
        entacavir may be added. **(Grade III)**

    b.  In patients with prior lamivudine resistance in whom lamivudine
        had been stopped when treatment was switched to adefovir,
        lamivudine may be added but the durability of response is
        unknown and reemergence of lamivudine-resistant mutations has
        been reported. **(Grade II-2)**

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22. Treatment of patients with entecavir-resistant HBV

    a.  Adefovir can be used as it has been shown to have activity
        against entecavir-resistant HBV in in vitro studies, but
        clinical data are lacking. **(Grade II-3)**

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23. Patients with compensated cirrhosis---Treatment should be considered
    for patients with ALT \>2 times normal, and for patients with normal
    or minimally elevated ALT if serum HBV DNA levels are high (\>2,000
    IU/mL). **(Grade II-2)**

    a.  Patients with compensated cirrhosis are best treated with NAs
        because of the risk of hepatic decompensation associated with
        IFN-alpha-related flares of hepatitis. In view of the need for
        long-term therapy, adefovir or entecavir is preferred. **(Grade
        II-3)**

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24. Patients with decompensated cirrhosis---Treatment should be promptly
    initiated with a NA that can produce rapid viral suppression with
    low risk of drug resistance. **(Grade II-1)**

    a.  Lamivudine or adefovir may be used as initial treatment
        preferably in combination to reduce the risk of drug resistance
        and to achieve rapid virus suppression. **(Grade II-2)**
        Telbivudine may be substituted for lamivudine but clinical data
        documenting its safety and efficacy in patients with
        decompensated cirrhosis are lacking.

    b.  Entecavir would be an appropriate treatment in this setting but
        clinical data documenting its safety and efficacy in patients
        with decompensated cirrhosis are lacking. **(Grade III)**

    c.  Treatment should be coordinated with a transplant center.
        **(Grade III)**

    d.  IFN-alpha/pegIFN-alpha should not be used in patients with
        decompensated cirrhosis. **(II-3)**

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25. In patients with inactive HBsAg carrier state antiviral treatment is
    not indicated, but these patients should be monitored (see
    Recommendation 12). **(Grade II-2)**

*Dose Regimens*

26. IFN-alpha and pegIFN-alpha are administered as subcutaneous
    injections.

    a.  The recommended dose of standard IFN-alpha for adults is 5 MU
        daily or 10 MU thrice weekly. The recommended dose of
        pegIFN-alpha2a is 180 mcg weekly. **(Grade I)**

    b.  The recommended IFN-alpha dose for children is 6 MU/m^2^ thrice
        weekly with a maximum of 10 MU. **(Grade I)** PegIFN-alpha has
        not been approved for treatment of chronic hepatitis B in
        children.

    c.  The recommended treatment duration for HBeAg-positive chronic
        hepatitis B is 16 weeks for standard IFN-alpha and 48 weeks for
        pegIFN-alpha. **(Grade I)**

    d.  The recommended treatment duration for HBeAg-negative chronic
        hepatitis B is 48 weeks for both standard and peg-IFN-alpha
        **(Grade II-3)**

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27. Lamivudine is administered orally.

    a.  The recommended lamivudine dose for adults with normal renal
        function and no HIV coinfection is 100 mg daily **(Grade I)**.
        Dose adjustment is needed for patients with estimated glomerular
        filtration rate \<50 mL/min (see Table 10a in the original
        guideline document). **(Grade I)**

    b.  The recommended lamivudine dose for children is 3 mg/kg/day with
        a maximum of 100 mg/day. **(Grade I)**

    c.  The recommended dose of lamivudine for persons co-infected with
        HIV is 150 mg twice daily. Lamivudine should only be used in
        combination with other antiretroviral medications. **(Grade I)**

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28. Adefovir is administered orally.

    a.  The recommended adefovir dose for adults with normal renal
        function is 10 mg daily. **(Grade I)** Dose adjustment is needed
        for patients with estimated glomerular filtration rate \<50
        mL/min (see Table 10b in the original guideline document).

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29. Entecavir is administered orally.

    a.  The recommended entecavir dose for adults with normal renal
        function is 0.5 mg daily for patients with no prior lamivudine
        treatment, and 1.0 mg daily for patients who are
        refractory/resistant to lamivudine. **(Grade I)**

    b.  Dose adjustment is needed for patients with estimated glomerular
        filtration rate \<50 mL/min (see Table 10c in the original
        guideline document).

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30. Telbivudine is administered orally.

    a.  The recommended dose for adults with normal renal function is
        600 mg daily. **(Grade I)** Dose adjustment is needed for
        patients with estimated glomerular filtration rate \<50 mL/min
        (see Table 10d in the addendum to the original guideline
        document).

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31. Duration of nucleoside analogue treatment

    a.  HBeAg-positive chronic hepatitis B---Treatment should be
        continued until the patient has achieved HBeAg seroconversion
        and completed at least 6 months of additional treatment after
        appearance of anti-HBe. **(Grade I)**

        -   Close monitoring for relapse is needed after withdrawal of
            treatment. **(Grade I)**

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    ```
    b.  HBeAg-negative chronic hepatitis B---Treatment should be
        continued until the patient has achieved HBsAg clearance.
        **(Grade I)**

    c.  Compensated cirrhosis---These patients should receive long-term
        treatment. However, treatment may be stopped in HBeAg-positive
        patients if they have confirmed HBeAg seroconversion and have
        completed at least 6 months of consolidation therapy and in
        HBeAg-negative patients if they have confirmed HBsAg clearance.
        **(Grade II-3)**

        -   Close monitoring for viral relapse and hepatitis flare is
            mandatory if treatment is stopped. **(Grade II-3)**

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    d.  Decompensated cirrhosis and recurrent hepatitis B post-liver
        transplantation - Life-long treatment is recommended. **(Grade
        II-3)**

**[Special Populations]{.underline}**

**Recommendations for Treatment of Patients with HBV/HIV Coinfection**

32. Patients who meet criteria for chronic hepatitis B should be
    treated. **(Grade III)**

    -   Liver biopsy should be considered in patients with fluctuating
        or mildly elevated ALT (1 to 2 x normal). **(Grade II-3)**

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33. Patients who are not on highly active anti-retroviral therapy
    (HAART) and are not anticipated to require HAART in the near future
    should be treated with an antiviral therapy that does not target
    HIV, such as pegIFN-alpha, adefovir, or entecavir. Caution should be
    exercised if entecavir is used in this setting. Although telbivudine
    does not target HIV, it should not be used in this circumstance.
    **(Grade II-3)**

34. Patients in whom treatment for both HBV and HIV is planned should
    receive therapies that are effective against both viruses:
    lamivudine plus tenofovir or emtricitabine plus tenofovir are
    preferred. **(Grade II-3)**

35. Patients who are already on effective HAART that does not include a
    drug active against HBV may be treated with pegIFN alpha, adefovir,
    or entecavir. **(Grade II-3)**

36. In patients with lamivudine resistance, tenofovir or adefovir should
    be added. **(Grade III)**

37. When HAART regimens are altered, drugs that are effective against
    HBV should not be discontinued without substituting another drug
    that has activity against HBV, unless the patient has achieved HBeAg
    seroconversion and has completed an adequate course of consolidation
    treatment. **(Grade II-3)**

**[Antiviral Prophylaxis of Hepatitis B Carriers Who Receive
Immunosuppressive or Cytotoxic Chemotherapy]{.underline}**

**Recommendations for Treatment of Hepatitis B carriers Who Require
Immunosuppressive or Cytotoxic Therapy**

38. HBsAg testing should be performed in patients who are at high risk
    of HBV infection (see recommendation number 1), prior to initiation
    of chemotherapy or immunosuppressive therapy. **(Grade II-3)**

39. Prophylactic antiviral therapy is recommended for HBV carriers at
    the onset of cancer chemotherapy or of a finite course of
    immunosuppressive therapy.

    a.  Patients with baseline HBV DNA \<2,000 IU/mL level should
        continue treatment for 6 months after completion of chemotherapy
        or immunosuppressive therapy. **(Grade III)**

    b.  Patients with high baseline HBV DNA (\>2,000 IU/mL) level should
        continue treatment until they reach treatment endpoints as in
        immunocompetent patients. **(Grade III)**

    c.  Lamivudine or telbivudine can be used if the anticipated
        duration of treatment is short ([\<]{.underline}12 months).
        **(Grade I for lamivudine and Grade III for telbivudine)**

    d.  Adefovir or entecavir is preferred if longer duration of
        treatment is anticipated. Entecavir has more rapid onset of
        action than adefovir and may be more appropriate in this
        setting. **(Grade III)**

    e.  IFN-alpha should be avoided in view of the bone marrow
        suppressive effect. **(Grade II-3)**

**Recommendations for Treatment of Patients with Acute Symptomatic
Hepatitis B**

40. Treatment is only indicated for patients with fulminant hepatitis B
    and those with protracted, severe acute hepatitis B. **(Grade III)**

41. Lamivudine, telbivudine, or entecavir is preferred. **(Grade II-3)**

    a.  Treatment should be continued until HBsAg clearance is confirmed
        or indefinitely in those who undergo liver transplantation.
        **(Grade II-1)**

    b.  IFN-alpha is contraindicated. **(Grade III)**

**[Definitions]{.underline}**:

**Quality of Evidence**

**Grade I**: Randomized controlled trials

**Grade II-1**: Controlled trials without randomization

**Grade II-2**: Cohort or case-control analytic studies

**Grade II-3**: Multiple time series, dramatic uncontrolled experiments

**Grade III**: Opinions of respected authorities, descriptive
epidemiology

#### CLINICAL ALGORITHM(S)

Algorithms are provided in the original guideline document for follow-up
of hepatitis B virus (HBV) carriers who are hepatitis B e antigen
(HBeAg)-positive and HBeAg-negative.

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

The type of evidence is specifically stated for selected recommendations
(see the \"Major Recommendations\" field).

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

-   Effective screening for hepatitis B virus (HBV)

-   Prevention of transmission of HBV

-   Effective treatment of HBV, including suppression of HBV
    replication, increased hepatitis B e antigen (HBeAg) seroconversion,
    decreased HBeAg reversion, and decreased HBV relapse

-   Effective treatment of relapsed HBV

-   Decreased development and progression of HBV-related liver disease

-   Improved overall survival and survival free of hepatic
    decompensation

#### POTENTIAL HARMS

**Standard or Pegylated (peg) Interferon-alpha (IFN)**

-   The most common side effect is an initial influenza-like illness:
    fever, chills, headache, malaise and myalgia. Other common side
    effects include fatigue, anorexia, weight loss, and mild increase in
    hair loss.

-   IFN-alpha has myelosuppressive effects but significant neutropenia
    (\<1000/mm^3^) or thrombocytopenia (\<50,000/mm^3^) are uncommon
    except in patients who have decreased cell counts prior to
    treatment.

-   IFN-alpha treatment is accompanied by flare in alanine
    aminotransferase (ALT) in 30 to 40% of patients. Hepatitis flares
    are considered to be an indicator of a favorable response but they
    can lead to hepatic decompensation, especially in patients with
    underlying cirrhosis.

-   The most troublesome side effect of IFN-alpha is emotional lability:
    anxiety, irritability, depression, and suicidal tendency.

-   IFN-alpha has been reported to induce the development of a variety
    of autoantibodies. In most instances, this is not accompanied by
    clinical illness. However, both hyper- and hypothyroidism that
    require treatment have been reported.

-   Rarely, retinal changes and impaired vision have been reported.

**Lamivudine**

Various adverse events including a mild (2- to 3-fold) increase in ALT
level have been reported in patients receiving lamivudine, but these
events occurred in the same frequency among the controls.

**Adefovir**

Nephrotoxicity has been reported in 3% of patients with compensated
liver disease after 4 to 5 years of continued adefovir therapy, and in
12% of transplant recipients and 28% of patients with decompensated
cirrhosis during the first year of therapy.

**Entecavir**

Similar safety profile as lamivudine

**Telbivudine**

Safety profile comparable to lamivudine

### CONTRAINDICATIONS

#### CONTRAINDICATIONS

-   Interferon (IFN)-alpha is contraindicated in patients with
    symptomatic acute hepatitis B because of the risks of worsening
    hepatitis and the frequent side effects.

-   IFN-alpha/pegylated (peg)IFN-alpha should not be used in patients
    with decompensated cirrhosis.

-   Telbivudine should not be used in hepatitis B virus (HBV)/human
    immunodeficiency virus (HIV) coinfected patients.

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

These recommendations suggest preferred approaches to the diagnostic,
therapeutic and preventive aspects of care. They are intended to be
flexible.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

An implementation strategy was not provided.

#### IMPLEMENTATION TOOLS

Clinical Algorithm\
Personal Digital Assistant (PDA) Downloads

For information about
[availability](#identifying-information-and-availability), see the
\"Availability of Companion Documents\" and \"Patient Resources\" fields
below.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Living with Illness\
Staying Healthy

#### IOM DOMAIN

Effectiveness\
Patient-centeredness

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2007
Feb;45(2):507-39. \[275 references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17256718)

Lok AS, McMahon BJ. Corrections to AASLD guidelines on chronic hepatitis
B. Hepatology 2007 Jun;45(6):1347. \[1 reference\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17476694)

#### ADAPTATION

Not applicable: The guideline was not adapted from another source.

#### DATE RELEASED

2001 Dec (revised 2007 Feb; addendum released 2007 Jun)

#### GUIDELINE DEVELOPER(S)

American Association for the Study of Liver Diseases - Private Nonprofit
Research Organization

#### SOURCE(S) OF FUNDING

American Association for the Study of Liver Diseases

#### GUIDELINE COMMITTEE

Practice Guidelines Committee

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

*Primary Authors*: Anna S. F. Lok, Division of Gastroenterology,
University of Michigan Medical Center, Ann Arbor, MI; Brian J. McMahon,
Liver Disease and Hepatitis Program, Alaska Native Medical Center and
Arctic Investigations Program, Centers for Disease Control, Anchorage,
AK

*Committee Members*: Margaret C. Shuhart, MD, MS (*Chair*); Andres
Cardenas, MD, MMSc;  Stanley M. Cohen, MD; Timothy J. Davern, MD; Steven
L. Flamm, MD; Steven-Huy B. Han, MD; Charles D. Howell, MD; David R.
Nelson, MD; K. Rajender Reddy, MD; Bruce A. Runyon, MD; John B. Wong,
MD; Nizar N. Zein, MD

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

Dr. McMahon\'s spouse owns stock in GlaxoSmith-Kline. Dr. Lok is a
consultant for, received grants, and is on the Scientific Advisory Board
of, Bristol-Myers Squibb, GlaxoSmithKline, Idenix, Roche, Gilead, and
Innogenetics. She is also on the Scientific Advisory Board of
Pharmasset. Dr. Lok received grants from Schering-Plough. Please refer
to [www.aasld.org](http://www.aasld.org/) for disclosures by Practice
Guidelines Committee members.

#### ENDORSER(S)

Infectious Diseases Society of America - Medical Specialty Society

#### GUIDELINE STATUS

This is the current release of this guideline.

This guideline updates a previous version: Lok AS, McMahon BJ. Chronic
hepatitis B. Alexandria (VA): American Association for the Study of
Liver Diseases; 2004. 25 p.

#### GUIDELINE AVAILABILITY

Electronic copies: Available in Portable Document Format (PDF) from the
[American Association for the Study of Liver Diseases Web
site](https://www.aasld.org/eweb/docs/chronichep_B.pdf).

Print copies: Available from the American Association for the Study of
Liver Diseases, 1729 King Street, Suite 200; Alexandria, VA 22314;
Phone: 703-299-9766; Web site: [www.aasld.org](http://www.aasld.org/);
e-mail: <aasld@aasld.org>.

#### AVAILABILITY OF COMPANION DOCUMENTS

This guideline is available as a Personal Digital Assistant (PDA)
download via the APPRISOR™ Document Viewer from
[www.apprisor.com](http://www.apprisor.com/).

#### PATIENT RESOURCES

None available

#### NGC STATUS

This NGC summary was completed by ECRI on May 9, 2003. The information
was verified by the guideline developer as of June 12, 2003. The summary
was updated by ECRI on July 27, 2004. The updated information was
verified by the guideline developer as of August 25, 2004. This NGC
summary was updated by ECRI Institute on June 12, 2007. The updated
information was verified by the guideline developer on August 22, 2007.

#### COPYRIGHT STATEMENT

This NGC summary is based on the original guideline, which is subject to
the American Association for the Study of Liver Diseases\' copyright
restrictions.

### DISCLAIMER

#### NGC DISCLAIMER

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Date Modified: 11/3/2008