Sections

Hepatitis B

Guidelines

2016 and 2018 AASLD Guidelines

Select recommendations from the 2016 American Association for the Study of Liver Diseases (AASLD) guidelines for the treatment of chronic hepatitis B^[41]as well as the 2018 AASLD guidance update on the prevention, diagnosis, and treatment of chronic hepatitis B^[52]are outlined below.

Screening for hepatitis B infection

The following recommendations are from the 2018 AASLD guidance update^[52]:

Perform screening with both hepatitis B surface antigen (HBsAg) and antibody to HBsAg (anti-HBs).
Individuals who should undergo screening include all those born in countries that have an HBsAg seroprevalence of 2% or greater, US-born persons in areas with high HBV endemicity (≥8%), pregnant women, those who require immunosuppression, and specific at-risk populations.
Vaccinate screened individuals who are negative for anti-HBs.
Although routine screening is not recommended for antibody to hepatitis B core antigen (anti-HBc) to assess for previous exposure, it is a valuable test in HIV patients; those about to receive hepatitis C or anticancer and other immunosuppressive treatment or renal dialysis; and in donated blood (or, organs, if feasible).

Recommendations for the initial evaluation of 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 hepatitis 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

Counseling^[52]

HBsAg-positive patients should receive counseling about the prevention of HBV transmission to others.

Healthcare workers and students who are HBsAg positive can continue with training or practice—unless their job requires they perform exposure-prone procedures. In such situations, these individuals should seek counseling/advice from their institutional expert review panel; they should not perform exposure-prone procedures if their serum HBV DNA level is above 1,000 IU/mL; and they can resume such procedures if their HBV DNA falls and is maintained below 1,000 IU/mL.

Aside from using universal precautions, special arrangements are not indicated for children with HBV in community setting (eg, daycare centers, schools, sports clubs, camps) unless they have a tendency to bite.

HBV-infected individuals are recommended to be abstinent or limit their alcohol use.

To prevent the concurrent development of fatty liver and metabolic syndrome, it is recommended that individuals with HBV optimize their body weight and treatment of metabolic complications (eg, control of diabetes and dyslipidemia).

Antiviral medications for adults and/or 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.

Antiviral therapy is indicated only for individuals with acute symptomatic hepatitis B and acute liver failure, or who have a protracted, severe disease course (total bilirubin >3 mg/dL or direct bilirubin >1.5 mg/dL; international normalize ratio [INR] >1.5; encephalopathy; or ascites).^[52]Use the preferred agents (see below), and continue treatment until confirmation of HBsAg clearance or indefinitely in liver transplant recipients. Peg-IFN is contraindicated in those with acute hepatitis B.^[52]Individuals with chronic hepatitis B who fail to clear HBsAg after 6-12 months of treatment should receive ongoing management based on guidelines for chronic hepatitis B.

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.

Preferred drugs

Pegylated interferon (PEG-IFN)-alpha-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.

Entecavir

Adult dose: Daily 0.5 mg (lamivudine-naive persons) or 1.0 mg (those with lamivudine 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 for lamivudine-naive children or 1.0 mg for those with lamivudine experience or decompensated cirrhosis
Pregnancy category: C
On-treatment monitoring: Obtain lactic acid levels if lactic acidosis is a concern; obtain HIV test before initiating treatment.

Tenofovir dipovoxil fumarate

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 with a fracture history or at risk for osteopenia. Obtain lactic acid levels if lactic acidosis is a concern; obtain HIV test before initiating treatment.

Tenofovir alafenamide

Adult dose: 25 mg daily; no pediatric dosing
Pregnancy category: Insufficient human data
On-treatment monitoring: Obtain lactic acid levels if lactic acidosis is a concern; obtain HIV test before initiating treatment. Before initiation of, and during, therapy, measure serum creatinine, serum phosphorus, creatinine clearance, urine glucose, and urine protein levels in all patients as clinically appropriate.

Nonpreferred drugs

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.

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; obtain HIV test before initiating treatment.

Telbivudine (withdrawn from the US market in 2016 and the European Union market in 2020 but may still be available in other regions)

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.

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 agents for adults are 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 the ALT 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)

Individuals with HBV and HCV coinfection^[52]

Test all HBsAg-positive patients for HCV infection with the anti-HCV test.
Those with HCV viremia should receive HCV therapy.
HBV treatment is based on levels of HBV DNA and ALT as indicated by the AASLD HBV guideline for monoinfected individuals.
HBsAg-positive individuals: At risk for HBV DNA and ALT flares with HCV-DAA (direct-acting antiviral) therapy; monitor HBV DNA levels every 4-8 weeks during treatment and for 3 months posttreatment for individuals who do not meet the treatment criteria according to the AASLD HBV guidelines.
HBsAg-negative, anti-HBc-positive individuals with HCV: Low risk of reactivation with HCV-DAA therapy; monitor ALT levels at baseline, treatment completion, and during follow-up; reserve HBV DNA and HBsAg testing for individuals whose ALT levels rise or fail to normalize during treatment or posttreatment.

Vaccination

The following recommendations are from the 2018 AASLD guidance update^[52]:

Administer HBV vaccines as a 3-dose series at 0, 1, and 6 months (± hepatitis A vaccine). Alternatively, for adults, combination hepatitis A and B vaccine (Twinrix) uses a 4-dose regimen at 0, 7, 21-30 days, and 12 months. A 2-dose series for adults at 0 and 1 months (HEPLISAV-B) is also available.
Sexual partners and household contacts of HBV-infected individuals who are negative for HBsAg and anti-HBs should receive HBV vaccination.
At delivery, infants born to HBV-infected mothers should receive hepatitis B immunoglobulin (HBIG) and HBV vaccine; thereafter, the recommended vaccination schedule should be completed. Postvaccination testing at age 9-15 months is recommended for infants with HBsAg-positive mothers.
Those who should be tested for their response to HBV vaccination 1-2 months after the last vaccine dose is received include healthcare workers, sexual partners of those with chronic HBV, patients on chronic hemodialysis, and immunocompromised patients (eg HIV patients).
Nonresponders to the initial vaccine series: Repeat the 3-dose vaccination series, with a double dose for immunocompromised individuals (eg, cirrhotic patients).
Vaccine responders: Annual follow-up testing is recommended for chronic hemodialysis patients.
Booster doses or revaccination: Not recommended except if anti-HBs levels remain below 10 mIU/mL after the initial vaccination of infants of HBsAg-positive mothers, in healthcare workers, hemodialysis patients, and immunocompromised patients.

2017 and 2018 EASL Recommendations

In 2017, the European Association for the Study of the Liver (EASL) released updated guidelines for hepatitis B virus (HBV) infection^[122]and for HBV vaccination.^{[123, 124]}In 2018, the EASL released updates for the management of decompensated cirrhosis^[125]and hepatocellular carcinoma (HCC).^[126]Recommendations from these guidelines are outlined below.

HBV infection

All patients with e antigen (HBeAg)-positive or -negative chronic hepatitis B, defined by HBV DNA above 2,000 IU/mL, alanine aminotransferase (ALT) greater than the upper limit of normal (ULN), and/or at least moderate liver necroinflammation or fibrosis, should be treated.

Patients with compensated or decompensated cirrhosis need treatment with any detectable HBV DNA level and regardless of ALT levels.

Patients with HBV DNA >20,000 IU/ml and ALT greater than two times the ULN should start treatment regardless of the degree of fibrosis.

Patients with HBeAg-positive chronic HBV infection, defined by persistently normal ALT and high HBV DNA levels, may be treated if they are older than 30 years regardless of the severity of liver histologic lesions.

Patients with HBeAg-positive or HBeAg-negative chronic HBV infection and a family history of hepatocellular carcinoma (HCC) or cirrhosis and extrahepatic manifestations can be treated even if typical treatment indications are not fulfilled.

HBV vaccination

Clinicians should vaccinate against chronic HBV in all unvaccinated adults at risk for infection, including the following:

Adults at risk by sexual exposure (sex partners of hepatitis B surface antigen [HBsAg]-positive persons, sexually active persons who are not in a mutually monogamous relationship, persons seeking evaluation or treatment for a sexually transmitted infection, and men who have sex with men).
Adults at risk by percutaneous or mucosal exposure to blood (adults who are recent or current users of injection drugs; household contacts of HBsAg-positive persons; residents and staff of facilities for developmentally disabled persons; incarcerated, healthcare, and public safety workers at risk for exposure to blood or blood-contaminated body fluids).
Adults with chronic liver disease, including but not limited to hepatitis C virus infection, cirrhosis, fatty liver disease, alcoholic liver disease, autoimmune hepatitis, and an ALT or aspartate aminotransferase (AST) level greater than twice the upper limit of normal.
Adults with end-stage renal disease, including those receiving predialysis care, hemodialysis, peritoneal dialysis, and home dialysis.
Adults with human immunodeficiency virus (HIV) infection.
Pregnant women who are at risk for HBV infection during pregnancy (eg, having more than 1 sex partner during the previous 6 months, having been evaluated or treated for a sexually transmitted infection, recent or current injection drug use, or having an HBsAg-positive sex partner).
International travelers to regions with high or intermediate levels of endemic HBV infection.
Any adult seeking protection from HBV infection.

Clinicians should screen (HBsAg, antibody to hepatitis B core antigen [anti-HBc], and antibody to hepatitis B surface antigen [anti-HBs]) for HBV in high-risk persons, including persons born in countries with 2% or higher HBV prevalence, men who have sex with men, persons who inject drugs, HIV-positive persons, household and sexual contacts of HBV-infected persons, persons requiring immunosuppressive therapy, persons with end-stage renal disease (including hemodialysis patients), blood and tissue donors, persons infected with hepatitis C virus, persons with elevated ALT levels (≥19 IU/L for women and ≥30 IU/L for men), incarcerated persons, pregnant women, and infants born to HBV-infected mothers.

Clinicians should provide or refer all patients identified with HBV (HBsAg-positive) for posttest counseling and hepatitis B–directed care.

Cirrhosis

In patients with decompensated cirrhosis, the etiologic factor, should be removed, particularly alcohol consumption and hepatitis B or C virus infection, as this strategy is associated with decreased risk of decompensation and increased survival.

Strategies based on targeting abnormalities in the gut-liver axis by antibiotic administration (ie, rifaximin), improving the disturbed systemic circulatory function (ie, long-term albumin administration), decreasing the inflammatory state (ie, statins), and reducing portal hypertension (ie, beta blockers) have shown potential benefit to decrease cirrhosis progression in patients with decompensated cirrhosis.

A diagnostic paracentesis is recommended in all patients with new-onset grade 2 or 3 ascites, or in those hospitalized for worsening of ascites or any complication of cirrhosis.

Neutrophil count and culture of ascitic fluid (bedside inoculation blood culture bottles with 10 mL fluid each) should be performed to exclude bacterial peritonitis. A neutrophil count above 250 cells/µL is required to diagnose spontaneous bacterial peritonitis (SBP).

Ascitic total protein concentration should be performed to identify patients at higher risk of developing SBP.

The serum ascites albumin gradient (SAAG) should be calculated when the cause of ascites is not immediately evident, and/or when conditions other than cirrhosis are suspected.

Cytology should be performed to differentiate malignancy-related from non-malignant ascites.

Since the development of grade 2 or 3 ascites in patients with cirrhosis is associated with reduced survival, liver transplantation (LT) should be considered as a potential treatment option.

A moderate restriction of sodium intake (80–120 mmol/day, corresponding to 4.6–6.9 g of salt) is recommended in patients with moderate, uncomplicated ascites. This is generally equivalent to a no-added-salt diet with avoidance of pre-prepared meals. Adequate nutritional education of patients on how to manage dietary sodium is also recommended.

Diets with a very low sodium content (< 40 mmol/day) should be avoided, as they favor diuretic-induced complications and can endanger a patient’s nutritional status.

Patients with the first episode of grade 2 (moderate) ascites should receive an anti-mineralocorticoid drug alone, starting at 100 mg/day with stepwise increases every 72 hr (in 100 mg steps) to a maximum of 400 mg/day if there is no response to lower doses.

In patients who do not respond to anti-mineralocorticoids, as defined by a body weight reduction of less than 2 kg/wk, or in patients who develop hyperkalemia, furosemide should be added at an increasing stepwise dose from 40 mg/day to a maximum of 160 mg/day (in 40 mg steps).

Patients with long-standing or recurrent ascites should be treated with a combination of an anti-mineralocorticoid drug and furosemide, the dose of which should be increased sequentially according to the response.

Torasemide can be given in patients exhibiting a weak response to furosemide.

During diuretic therapy, a maximum weight loss of 0.5 kg/day in patients without edema and 1 kg/day in patients with edema is recommended.

Once ascites has largely resolved, the dose of diuretics should be reduced to the lowest effective dose.

In patients presenting with gastrointestinal (GI) hemorrhage, renal impairment, hepatic encephalopathy, hyponatremia, or alterations in serum potassium concentration, these abnormalities should be corrected before starting diuretic therapy. In these patients, cautious initiation of diuretic therapy and frequent clinical and biochemical assessments should be performed. Diuretic therapy is generally not recommended in patients with persistent overt hepatic encephalopathy.

Diuretics should be discontinued if severe hyponatremia (serum sodium concentration < 125 mmol/L), acute kidney injury (AKI), worsening hepatic encephalopathy, or incapacitating muscle cramps develop.

Furosemide should be stopped if severe hypokalemia occurs (< 3 mmol/L). Anti-mineralocorticoids should be stopped if severe hyperkalemia occurs (>6 mmol/L).

Albumin infusion or baclofen administration (10 mg/day, with a weekly increase of 10 mg/day up to 30 mg/day) is recommended in patients with muscle cramps.

Large volume paracentesis (LVP) is the first-line therapy in patients with large ascites (grade 3 ascites), which should be completely removed in a single session. LVP should be followed with plasma volume expansion to prevent postparacentesis circulatory dysfunction (PPCD).

In patients undergoing LVP greater than 5 L of ascites, plasma volume expansion should be performed by infusing albumin (8 g/L of ascites removed), as it is more effective than other plasma expanders, which are not recommended for this setting

In patients undergoing LVP less than 5 L of ascites, the risk of developing PPCD is low. However, it is generally agreed that these patients should still be treated with albumin because of concerns about use of alternative plasma expanders.

Nonsteroidal anti-inflammatory drugs should not be used in patients with ascites because of the high risk of developing further sodium retention, hyponatremia, and AKI.

Repeated LVP plus albumin (8 g/L of ascites removed) is recommended as first-line treatment for refractory ascites.

Diuretics should be discontinued in patients with refractory ascites who do not excrete >30 mmol/day of sodium under diuretic treatment.

Antibiotic prophylaxis is recommended in cirrhotic patients with acute GI bleeding because it reduces the incidence of infections and improves control of bleeding and survival. Treatment should be initiated on presentation of bleeding and continued for up to 7 days. Ceftriaxone (1 g/24 hr) is the first choice in patients with decompensated cirrhosis, those already on quinolone prophylaxis, and in hospital settings with high prevalence of quinolone-resistant bacterial infections. Oral quinolones (norfloxacin 400 mg bid) should be used in the remaining patients.

Hepatocellular carcinoma

Vaccination against hepatitis B reduces the risk of HCC and is recommended for all newborns and high-risk groups.

In patients with chronic hepatitis, antiviral therapies leading to maintained HBV suppression in chronic hepatitis B and sustained viral response in hepatitis C are recommended, since they have been shown to prevent progression to cirrhosis and HCC development.

Once cirrhosis is established, antiviral therapy is beneficial in preventing cirrhosis progression and decompensation. Furthermore, successful antiviral therapy reduces but does not eliminate the risk of HCC development. Antiviral therapies should follow the EASL guidelines for management of chronic hepatitis B and C infection.

Coffee consumption has been shown to decrease the risk of HCC in patients with chronic liver disease. In these patients, coffee consumption should be encouraged.

Diagnosis of HCC in cirrhotic patients should be based on noninvasive criteria and/or pathology.

In noncirrhotic patients, diagnosis of HCC should be confirmed by pathology.

Noninvasive criteria can only be applied to cirrhotic patients for nodule(s) ≥1 cm, in light of the high pretest probability and are based on imaging techniques obtained by multiphasic computed tomography (CT), dynamic contrast-enhanced magnetic resonance imaging (MRI), or contrast-enhanced ultrasound (CEUS). Diagnosis is based on the identification of the typical hallmarks of HCC, which differ according to imaging techniques or contrast agents (arterial phase hyperenhancement (APHE) with washout in the portal venous or delayed phases on CT and MRI using extracellular contrast agents or gadobenate dimeglumine, APHE with washout in the portal venous phase on MRI using gadoxetic acid, APHE with late-onset (>60 s) washout of mild intensity on CEUS).

Because of their higher sensitivity and the analysis of the whole liver, CT or MRI should be used first.

Fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan is not recommended for early diagnosis of HCC because of the high rate of false-negative cases.

In patients at high risk of developing HCC, nodule(s) less than 1 cm in diameter detected by ultrasound should be followed at ≤4-month intervals in the first year. If there is no increase in the size or number of nodules, surveillance could be returned to the usual 6-month interval thereafter.

In cirrhotic patients, diagnosis of HCC for nodules of ≥1 cm in diameter can be achieved with noninvasive criteria and/or biopsy-proven pathologic confirmation.

Repeated bioptic sampling is recommended in cases of inconclusive histologic or discordant findings, or in cases of growth or change in enhancement pattern identified during follow-up, but with imaging still not diagnostic for HCC.

Staging systems for clinical decision making in HCC should include tumor burden, liver function, and performance status.

Multiphasic contrast-enhanced CT or MRI is recommended for assessment of response after resection, locoregional, or systemic therapies.

Perioperative mortality of liver resection (LR) in cirrhotic patients should be less than 3%.

LR is recommended for a single HCC lesion of any size and in particular for tumors >2 cm, when hepatic function is preserved, and when sufficient remnant liver volume is maintained.

Tumor vascular invasion and extrahepatic metastases are an absolute contraindication for liver transplantation in HCC.

Thermal ablation with radiofrequency is the standard of care for patients with BCLC (Barcelona Clinic Liver Cancer) 0 and A tumors not suitable for surgery. Thermal ablation in single tumors 2 to 3 cm in size is an alternative to surgical resection based on technical factors (location of the tumor) and hepatic and extrahepatic patient conditions.

In patients with very early stage HCC (BCLC-0), radiofrequency ablation in favorable locations can be adopted as first-line therapy even in surgical patients.

Ethanol injection is an option in some cases where thermal ablation is not technically feasible, especially in tumors < 2 cm.

Combination atezolizumab and bevacizumab is first-line systemic therapy for HCC. For patients with contraindications to this regimen or with progression of disease on this regimen, alternative first-line/second-line therapy with sorafenib or lenvatinib can be offered. Sorafenib was previously the standard first-line systemic therapy for HCC. It is indicated for patients with well-preserved liver function (Child-Pugh A) and with advanced tumors (BCLC–C) or earlier stage tumors progressing upon or unsuitable for locoregional therapies.

Lenvatinib has been shown to be non-inferior to sorafenib. It is indicated for patients with well-preserved liver function (Child-Pugh A class), with good performance status, and with advanced tumors – BCLC-C without main portal vein invasion or tumors progressing upon or unsuitable for locoregional therapies.

Following first-line therapy with either sorafenib or lenvatinib or in patients who did not have access to atezolizumab-bevacizumab, second-line therapy with regorafenib, cabozantinib, nivolumab (with or without ipilimumab), or pembrolizumab can be offered.^[127]

2015 and 2020 WHO Guidelines Summary

The 2015 World Health Organization (WHO) guidelines for the prevention, care, and treatment of persons with chronic hepatitis B infection^[59]and the 2020 WHO guidelines on antiviral prophylaxis in pregnancy^[101]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 normal 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 individuals 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 ofNA 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 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 to complete the primary series.

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

All pregnant women should undergo testing at least once for HIV, syphilis, and HBsAg (especially when there is a ≥2% seroprevalence in the general population) and as early as possible in the pregnancy.

To prevent maternal-fetal HBV transmission, HBsAg-positive gravida who have an HBV DNA ≥5.3 log₁₀ IU/mL (≥200,000 IU/mL) are recommended to receive tenofovir prophylaxis beginning the 28th week of pregnancy until at least birth.^[101]This is in addition to the three-dose hepatitis B vaccination in all infants, including a timely birth dose. (Conditional recommendation)

When antenatal HBV DNA testing is not available, HBeAg testing can be used as an alternative study to determine eligibility for tenofovir prophylaxis to prevent mother-to-child transmission of HBV.^[101](Conditional recommendation)

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 the prevention of mother-to-child HBV transmission and then stopped). (Strong recommendation)

Medication

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Media Gallery

Hepatitis B. Under higher-power magnification, ground-glass cells may be visible in chronic hepatitis B virus (HBV) infection. Ground-glass cells are present in 50% to 75% of livers with chronic HBV infection. Immunohistochemical staining is positive for hepatitis B surface antigen (HBsAg.)
Hepatitis B. Liver biopsy with hematoxylin stain showing stage 4 fibrosis (ie, cirrhosis) in a patient with hepatitis B.
Hepatitis B. Hepatitis B virus (HBV) is a hepadnavirus, highly resistant to extremes of temperature and humidity, that invades the hepatocytes. The viral genome is a partially double-stranded, circular DNA linked to a DNA polymerase that is surrounded by an icosahedral nucleocapsid and then by a lipid envelope. Embedded within these layers are numerous antigens that are important in disease identification and progression. Within the nucleocapsid are the hepatitis B core antigen (HBcAg) and precore hepatitis B e antigen (HBeAg), and on the envelope is the hepatitis B surface antigen (HBsAg). Transmission electron micrograph (TEM) from Graham Colm and Wikipedia, licensed under the Creative Commons Attribution 3.0 Unported license.
Hepatitis B. Serologic course of hepatitis B virus (HBV) infection. The flat bars show the duration of seropositivity in self-limited acute HBV infection. The pointed bars show that HBV DNA and e antigen (HBeAg) can become undetectable during chronic infection. Only immunoglobulin G (IgG) antibodies to the HBV core antigen (anti-HBc) are predictably detectable after resolution of acute hepatitis or during chronic infection. Antibody to hepatitis B surface antigen (anti-HBs) is generally detectable after resolution of acute HBV infection but may disappear with time. It is only rarely found in patients with chronic infection and does not indicate that immunologic recovery will occur or that the patient has a better prognosis. ALT = alanine transaminase. (Adapted from Liaw YF, Chu CM. Hepatitis B virus infection. Lancet. 2009;373(9663):582-92.)
Hepatitis B. Radiologic studies may be useful in all stages of hepatitis B infection. Ultrasonography, computed tomography (CT) scanning, or magnetic resonance imaging (MRI) may exclude biliary obstruction in acute infection. In chronic disease, ultrasonograms may show nonspecific increased echogenicity of the liver parenchyma. In patients with long-standing disease, CT imaging may be used to detect cirrhosis or hepatocellular carcinoma (as shown).
Hepatitis B. Long-standing cirrhosis leads to progressive replacement of liver parenchyma with fibrotic tissue. Over time, the liver contracts and develops a lobulated contour. These changes are readily apparent on cross-sectional imaging. This contrast-enhanced computed tomography (CT) scan demonstrates extensive cirrhosis, as well as malignant hepatocellular lesions (arrow).
Hepatitis B. Liver biopsy with hematoxylin stain showing stage 4 fibrosis (ie, cirrhosis) in a patient with hepatitis B.

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Author

Nikolaos T Pyrsopoulos, MD, PhD, MBA, FACP, AGAF, FAASLD, FRCP(Edin) Professor and Chief, Division of Gastroenterology and Hepatology, Professor of Physiology, Pharmacology, and Neuroscience, Medical Director of Liver Transplantation, Rutgers New Jersey Medical School

Nikolaos T Pyrsopoulos, MD, PhD, MBA, FACP, AGAF, FAASLD, FRCP(Edin) is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Liver Foundation, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Transplantation, International Liver Transplantation Society, Transplantation Society

Disclosure: Received research grant from: GRIFOLS. BAYER, DURECT, INTERCEPT, BEIGENE, BMS.

Coauthor(s)

Ranya Selim, MD Gastroenterologist/Transplant Hepatologist

Ranya Selim, MD is a member of the following medical societies: American College of Gastroenterology

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

BS Anand, MD Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

BS Anand, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Acknowledgements

George Y Wu, MD, PhD Professor, Department of Medicine, Director, Hepatology Section, Herman Lopata Chair in Hepatitis Research, University of Connecticut School of Medicine

George Y Wu, MD, PhD is a member of the following medical societies: American Association for the Study of Liver Diseases, American Gastroenterological Association, American Medical Association, American Society for Clinical Investigation, and Association of American Physicians

Disclosure: Springer Consulting fee Consulting; Gilead Consulting fee Review panel membership; Gilead Honoraria Speaking and teaching; Bristol-Myers Squibb Honoraria Speaking and teaching; Springer Royalty Review panel membership

Hepatitis B Guidelines