Hepatitis B Guidelines

Updated: May 26, 2017
  • Author: Nikolaos T Pyrsopoulos, MD, PhD, MBA, FACP, AGAF; Chief Editor: BS Anand, MD  more...
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Guidelines

2015 WHO Guidelines Summary

The 2015 World Health Organization (WHO) guidelines for the prevention, care, and treatment of persons with chronic hepatitis B infection [53] are presented below.

Noninvasive baseline and follow-up assessment of liver disease stage 

Conditional recommendation

In resource-limited settings, APRI (aspartate aminotransferase [AST]-to-platelet ratio index) is preferred to evaluate for liver fibrosis (APRI score >2 in adults).

Where resource availability and cost aren't major barriers, transient elastography (eg, FibroScan [measures tissue stiffness]) or FibroTest (5 biomarkers of liver fibrosis: gamma-2 macroglobulin, gamma-2 globulin, gamma globulin, apolipoprotein A1, gamma-glutamyl transpeptidase [GGT,] total bilirubin) may be preferred.

Who should or should not receive treatment for chronic hepatitis B

Individuals who should be treated 

Priority: Treat individuals of all ages who have chronic hepatitis B infection and clinical evidence of compensated/decompensated cirrhosis (or cirrhosis based on APRI score >2 in adults), regardless of their levels of alanine transaminase (ALT) or hepatitis B virus (HBV) DNA, or their hepatitis B e antigen (HBeAg) status. (Strong recommendation)

Recommended: Treat adults with chronic hepatitis B infection without clinical evidence of cirrhosis (or based on APRI score ≤2 in adults), but who have all of the following features, and regardless of HBeAg status (strong recommendation):

  • Are older than 30 years (in particular)
  • Have persistently abnormal ALT levels
  • Have evidence of high-level HBV replication (HBV DNA >20,000 IU/mL). (If HBV DNA testing is unavailable, consider treatment based on persistently abnormal ALT levels alone, regardless of HBeAg status. [Conditional recommendation])

In individuals with HBV/human immunodeficiency virus (HIV) coinfection, initiate antiretrovial therapy (ART) in (1) all those with evidence of severe chronic liver disease, regardless of CD4 count, as well as (2) those with a CD4 count of 500 cells/mm3 or below, regardless of their liver disease stage. (Strong recommendation)

Individuals who should not be treated but monitored

Antiviral therapy is not recommended  and can be deferred in individuals with all of the following, regardless of HBeAg status or age (strong recommendation):

  • No clinical evidence of cirrhosis (or based on APRI score ≤2 in adults)
  • Persistently normal ALT levels
  • Low levels of HBV DNA replication (HBV DNA <2,000 IU/mL). (If HBV DNA testing is unavailable, treatment can be deferred in HBeAg-positive individuals aged 30 years or younger who have persistently abnormal ALT levels. (Conditional recommendation)]

All individuals with chronic hepatitis B—particularly those who do not meet the treat/do-not-treat criteria above—require continued monitoring to determine if antiviral therapy may be indicated in the future for prevention of liver disease progression. Such persons include noncirrhotic individuals aged 30 years or younger:

  • With HBV DNA levels above 20,000 IU/mL  but persistently normal ALT levels
  • Who are HBeAg-negative, with HBV DNA levels that fluctuate between 2,000 and 20,000 IU/mL or with intermittently abnormal ALT levels (If HBV DNA testing is unavailable, continue to monitor noncirrhotic individuals aged 30 years or younger who have persistently abnormal ALT levels, regardless of their HBeAg status.)

Antiviral therapies

First-line antiviral treatment (Strong recommendations)

All individuals aged 12 years or older who are eligible for antiviral therapy are recommended to receive therapy with tenofovir or entecavir, the nucleos(t)ide analogs (NAs) with a high barrier to drug resistance. Entecavir is recommended in children aged 2-11 years.

NAs with a low barrier to drug resistance (lamivudine, adefovir, or telbivudine) are not recommended owing to their potential for drug resistance.

In HBV/HIV-coinfected indviduals aged 3 years or older, a fixed-dose combination of tenofovir/lamivudine (or emtricitabine)/efavirenz is the preferred option for initiation of ART.

Second-line antiviral treatment for managing treatment failure (Strong recommendation)

For individuals with confirmed or suspected antiviral resistance (ie, history of prior exposure or primary nonresponse) to lamivudine, entecavir, adefovir, or telbivudine, the WHO recommends switching to tenofovir.

Treatment duration, cessation, and reinitiation

Lifelong NA therapy (Strong recommendation)

All individuals with cirrhosis based on clinical evidence (or APRI score >2 in adults) require lifelong NA therapy. Antiviral therapy in these individuals should not be discontinued owing to the potential for HBV reactivation.

Discontinuation of NA therapy (Conditional recommendation)

Individuals without clinical evidence of cirrhosis (or based on APRI score ≤2 in adults) who have all of the following features may be considered exceptionally for discontinuation of NAs:

  • Can be closely monitored for reactivation over the long term
  • Have evidence of HBeAg loss and seroconversion to anti-HBe (in those who were initially HBeAg positive), as well as after completion of at least one additional year of treatment
  • Have persistently normal ALT levels and persistently undetectable HBV DNA levels (where HBV DNA testing is available). (If HBV DNA testing is not available, consider discontinuation of NA therapy in those with evidence of persistent hepatitis B surface antigen [HBsAg] loss and after completion of at least one additional year of treatment, regardless of their previous HBeAg status). 

Retreatment (Strong recommendation)

Owing to the the risk of relapse after discontinuation of NA therapy, the WHO recommends retreatment in the setting of consistent signs of reactivation (positive HBsAg or HBeAg, increasing ALT levels, or redetectable HBV DNA) (where HBV DNA testing is available).

Monitoring

Monitoring for disease progression and treatment response prior to, during, and posttreatment

The WHO recommends yearly monitoring at a minimum of the following (strong recommendation):

  • Levels of ALT (and AST level for APRI), HBsAg, HBeAg, and HBV DNA (where HBV DNA testing is available)
  • Liver fibrosis, in those without baseline cirrhosis, using noninvasive studies such as APRI score or FibroScan
  • Treatment adherence during therapy, at regular intervals and at each visit

More frequent monitoring may be indicated in certain individuals (Conditional recommendations)

Those who do not yet meet the criteria for antiviral therapy. Such individuals are those with intermittently abnormal ALT levels or HBV DNA levels that fluctuate between 2,000 IU/mL and 20,000 IU/mL (where HBV DNA testing is available), as well as HBV/HIV-coinfected persons.

Those receiving treatment or following treatment discontinuation. On-treatment monitoring is recommended at least every 3 months for the first year in/for the following:

  • Individuals with more advanced disease (compensated/decompensated cirrhosis)
  • Individuals coinfected with HBV/HIV
  • During the first year of treatment (to assess treatment response and adherence)
  • When treatment adherence is a concern
  • Individuals after treatment discontinuation

Monitoring for tenofovir and entecavir toxicity (Conditional recommendation)

Before initiating antiviral therapy, consider measuring all individuals' baseline renal function as well as evaluating their baseline risk for renal dysfunction.

Monitor renal function every year in individuals on long-term tenofovir or entecavir therapy; carefully monitor growth in children.

Monitoring for hepatocellular carcinoma (HCC)

Routinely obtain abdominal ultrasonography and alpha-fetoprotein (AFP) levels every 6 months for individuals who:

  • Are cirrhotic, regardless of their age or the presence of other risk factors (Strong recommendation)
  • Have a family history of HCC (Strong recommendation)
  • Are older than 40 years (younger age may be indicated based on the regional HCC incidence), do not have clinical evidence of cirrhosis (or based on APRI score ≤2), and have an HBV DNA level above 2,000 IU/mL (where HBV DNA testing is available) (Conditional recommendation)

Prevention

Infant and neonatal hepatitis B vaccination

It is recommended that all infants receive their first dose of hepatitis B vaccine as soon as possible after birth (≤24 hours preferred), followed by two or three doses. 

Prevention of mother-to-child HBV transmission using antiviral therapy 

HBV-monoinfected pregnant women should receive antiviral therapy as indicated for other adults, with tenofovir as the recommended NA. Currently, the WHO makes no recommendations for routine antiviral therapy for prevention of mother-to-child HBV transmission.

For HIV-infected pregnant and breastfeeding women (including those in the first trimester of pregnancy and women of childbearing age), the recommended first-line ART is a once-daily fixed-dose combination of tenofovir/lamivudine (or emtricitabine)/efavirenz (applicable to lifelong treatment as well as to ART initiated for prevention of mother-to-child HBV transmission and then stopped). (Strong recommendation)

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2016 AASLD Guidelines

The 2016 American Association for the Study of Liver Diseases (AASLD) guidelines for the treatment of chronic hepatitis B [37]  are outlined below.

Recommendations for the initial evaluation of hepatits B surface antigen (HBsAg)-positive patients 

All patients

History and physical examination: Thoroughly evaluate for the following:

  • Alcohol, metabolic, and other risk factors for hepatitis B virus (HBV) infection
  • Patient's HBV vaccination status
  • Family history of HBV infection and hepatocellular carcinoma
  • The presence of symptoms/signs of cirrhosis

Routine laboratory studies

  • Complete blood cell (CBC) count, platelet count; international normalized ratio (INR)
  • Levels of aspartate transaminase (AST), alanine transaminase (ALT), total bilirubin, alkaline phosphatase (ALP), and albumin

Serologic/virologic studies

  • Hepatitis B e antigen (HBeAg)/anti-HBe
  • HBV DNA level
  • Anti-hepatitis A virus (anti-HAV) (to determine need for vaccination)

Imaging/staging studies 

  • Abdominal ultrasonography
  • Vibration-controlled transient elastography (eg, FibroScan) or a serum fibrosis marker panel (APRI [AST-to-platelet ratio index], FIB-4 [platelet count, ALT, AST, age], or FibroTest [gamma-2 macroglobulin, gamma-2 globulin, gamma globulin, apolipoprotein A1, gamma-glutamyl transpeptidase (GGT), total bilirubin])

Select patients

Routine laboratory studies: In the setting of elevated liver function test results, obtain tests to exclude other causes of chronic liver disease. Obtain levels of alpha-fetoprotein (AFP) and GGT.

Serologic/virologic studies

  • HBV genotyping
  • Tests for coinfection with hepatits C virus (HCV), hepatitis D (delta) virus (HDV), and/or human immunodeficiency virus (HIV) in at-risk individuals aged 13-64 years who have not undergone one-time screening 

Antiviral medications for adults and children

The aim of antiviral treatment is to lower the risk of associated liver-related complications of chronic HBV infection. Immunologic cure involves loss of hepatitis B surface antigen (HBsAg) and sustained suppression of HBV DNA. Virologic cure consists of viral eradication, including the covalently closed circular DNA (cccDNA form)—this type of cure is currently unattainable.

Drug regimens and monitoring

The following are medications approved for the treatment of chronic hepatitis B in pediatric and adult patients. Adjust all dosing in the setting of renal dysfunction.

Pegylated interferon (PEG-IFN)-2a (adults) or IFN-alpha-2b (children)

  • Adult dose: 180 μg weekly; pediatric dose (age ≥1 year): 6 million IU/m 2 three times weekly
  • Pregnancy category: C
  • On-treatment monitoring: CBC count (monthly to every 3 months) and thyroid stimulating hormone level (every 3 months); evaluate for autoimmune, ischemic, neuropsychiatric, and infectious complications

Lamivudine

  • Adult dose: 100 mg daily; pediatric dose (age ≥2 years): 3 mg/kg daily (maximum: 100 mg)
  • Pregnancy category: C
  • On-treatment monitoring: Check amylase levels in symptomatic patients; obtain lactic acid levels if lactic acidosis is a concern

Telbivudine

  • Adult dose: 600 mg daily; no pediatric dosing 
  • Pregnancy category: B
  • On-treatment monitoring: Check creatine kinase levels in, and perform a clinical evaluation of, symptomatic patients; obtain lactic acid levels if lactic acidosis is a concern

Entecavir

  • Adult dose: Daily 0.5 mg (lamivudine-/telbivudine-naive persons) or 1.0 mg (those with lamivudine/telbivudine experience or decompensated cirrhosis); pediatric dose (age ≥2 years): Weight-based to 10-30 kg; for children weighing more than 30 kg, use 0.5 mg daily
  • Pregnancy category: C
  • On-treatment monitoring: Obtain lactic acid levels if lactic acidosis is a concern

Adefovir

  • Adult and pediatric dose (age ≥12 years): 10 mg daily
  • Pregnancy category: C
  • On-treatment monitoring: Measure baseline creatinine clearance for those at risk for renal impairment, as well as at least annual levels of creatinine clearance, serum phosphate, urine glucose, and urine protein. Consider baseline and during-treatment bone density scans for those at risk for osteopenia or with a fracture history. Obtain lactic acid levels if lactic acidosis is a concern

Tenofovir

  • Adult and pediatric (age ≥12 years) dose: 300 mg daily
  • Pregnancy category: B
  • On-treatment monitoring: Measure baseline creatinine clearance for those at risk for renal impairment, as well as at least annual levels of creatinine clearance, serum phosphate, urine glucose, and urine protein. Consider baseline and during-treatment bone density scans for those at risk for osteopenia. Obtain lactic acid levels if lactic acidosis is a concern

Treatment recommendations

Adults with immune-active chronic hepatitis B infection (ie, ALT >2 times the upper limit of normal [ULN] or  significant histologic disease and HBeAg negative [HBV DNA >2,000 IU/mL] or HBeAg positive [HBV DNA >20,000 IU/mL]) (Strong recommendations)

Administer antiviral therapy to lower the risk of morbidity and mortality associated with chronic hepatitis B infection.

The recommended initial agent for adults is PEG-IFN, entecavir, or tenofovir. 

Adults with immune-tolerant chronic hepatitis B infection (ie, ULNs: ALT levels ≤30 U/L for men and ≤19 U/L for women)

Antiviral therapy is not recommended. (Strong recommendation)

The AASLD suggests obtaining ALT levels at least every 6 months to monitor for potential transition to immune-active or -inactive chronic hepatitis B. (Conditional recommendation)

For select patients older than 40 years, the AASLD suggests antiviral therapy in the setting of normal ALT levels, elevated HBV DNA (≥1,000,000 IU/mL), and significant necroinflammation or fibrosis on liver biopsy specimens. (Conditional recommendation)

Adults with HBeAg-positive immune-active chronic hepatitis B who seroconvert to anti-HBe on nucleos(t)ide analog (NA) therapy (Conditional recommendations)

After a period of treatment consolidation (treatment for ≥12 months in the setting of persistently normal ALT levels and undetectable serum HBV DNA), consider discontinuing NA therapy in noncirrhotic HBeAg-positive adults who seroconvert to anti-HBe while on NA treatment. If antiviral therapy is stopped, monitor the patient every 3 months for a minimum of 1 year for recurrent viremia, ALT flares, seroreversion, and clinical decompensation.

For cirrhotic HBeAg-positive adults who seroconvert to anti-HBe on NA therapy, the AASLD suggests indefinite antiviral therapy owing to the potential for clinical decompensation and death, unless a strong competing rationale for treatment discontinuation exists. If antiviral therapy is stopped, closely monitor these patients for recurrent viremia, ALT flares, seroreversion, and clinical decompensation.

Adults with HBeAg-negative immune-active chronic HBV infection

The AASLD suggests indefinite antiviral therapy for adults with HBeAg-negative immune-active chronic hepatitis B infection, unless there is a competing rationale for treatment discontinuation. (Conditional recommendation) If antiviral therapy is stopped, monitor the patient every 3 months for a minimum of 1 year for recurrent viremia, ALT flares, and clinical decompensation.

Antiviral therapy is not recommended for noncirrhotic individuals who are HBeAg negative and who have normal ALT activity and low-level viremia (<2,000 U/mL; “inactive chronic hepatitis B”).

Patients with renal and bone disease on NA therapy

With regard to the potential long-term risks of renal and bone complications, the AASLD suggests no preference between entecavir and tenofovir. (Conditional recommendation)

Before initiating, and periodically during, treatment with tenofovir, evaluate patients' renal safety with levels of serum creatinine, phosphorus, urine glucose, and urine protein. If tenofovir is suspected of causing renal dysfunction and/or osteoporosis/osteomalacia, discontinue tenofovir and replace it with another NA, taking into account any previous drug resistance.

Adjust all NA dosing based on patients' renal function and creatinine clearance.

Patients with persistent low-level viremia on NA treatment (Conditional recommendations)

For patients with persistent low-level viremia (<2,000 IU/mL) (plateau in the decline of HBV DNA and/or failure to achieve undetectable HBV DNA level after 96 weeks of therapy) on entecavir or tenofovir monotherapy, the AASLD suggests continuing monotherapy, regardless of ALT the level. 

For patients with virologic breakthrough on entecavir or tenofovir monotherapy (an increase in HBV DNA by >1 log compared to nadir or HBV DNA ≥100 IU/mL in those on NA therapy with previously undetectable levels [<10 IU/mL]), either (1) switch to another antiviral monotherapy with a high barrier to resistance or (2) add a second antiviral drug that lacks cross-resistance.

To detect persistent viremia and virologic breakthrough, the AASLD suggests monitoring HBV DNA levels every 3 months until they are undetectable, followed by every 3-6 months thereafter. In addition, if NA therapy with a drug other than entecavir or tenofovir is used and virologic breakthrough occurs, switch to another antiviral monotherapy with a high genetic barrier to resistance or add a second antiviral with a complementary resistance profile.

Adults with cirrhosis and low-level viremia

In adults with compensated cirrhosis and low levels of viremia (<2,000 IU/mL), regardless of ALT level, the AASLD suggests antiviral therapy (preferred: tenofovir, entecavir) to reduce the risk of decompensation. (Conditional recommendation).

Note the following:

  • If therapy is discontinued, closely monitor patients for a minimum of every 3 months for at least 1 year to detect early signs of viral rebound that may lead to decompensation.
  • In those not offered treatment, closely monitor every 3-6 months for an elevation in HBV DNA level and/or clinical decompensation; initiate treatment in these settings.
  • Patients with compensated cirrhosis and high HBV DNA levels (>2,000 U/mL) are treated according to the recommendations for HBeAg-positive and -negative immune-active chronic hepatitis B.

For HBsAg-positive adults with decompensated cirrhosis, the AASLD recommends indefinite antiviral therapy (preferred: entecavir, tenofovir) to reduce the risk of worsening liver-related complications, regardless of HBV DNA level, HBeAg status, or ALT level. (Strong recommendation) Also consider liver transplantation for eligible candidates.

Pregnant patients with chronic hepatitis B infection

The AASLD suggests antiviral therapy to reduce the risk of perinatal HBV transmission in HBsAg-positive pregnant women with an HBV DNA level above 200,000 IU/mL. (Conditional recommendation) Infants of these mothers should receive immunoprophylaxis according to current World Health Organization and Centers for Disease Control and Prevention recommendations.

Therapy for pregnant women with immune-active hepatitis B should be based on the same recommendations as for their nonpregnant counterparts.

Antiviral therapy is not recommended to reduce the risk of perinatal HBV transmission in HBsAg-positive pregnant women whose HBV DNA level is at or below 200,000 IU/mL. (Strong recommendation) 

Children with chronic hepatitis B infection

For HBeAg-positive children aged 2 years up to 18 years who have both elevated ALT and detectable HBV DNA levels, the AASLD suggests antiviral therapy (IFN-alpha-2b: age ≥1 year; lamivudine, entecavir: age ≥2 year), with the goal of achieving sustained HBeAg seroconversion. (Conditional recommendation) If antiviral therapy is stopped, monitor the child every 3 months for a minimum of 1 year for recurrent viremia, ALT flares, and clinical decompensation.

Antiviral therapy is not recommended for HBeAg-positive children aged 2 years up to 18 years who have persistently normal ALT (conservative value: 30 U/L), regardless of the HBV DNA level. (Strong recommendation)

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