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Hepatitis B, Chronic

By

Sonal Kumar

, MD, MPH, Weill Cornell Medical College

Last full review/revision Oct 2019| Content last modified Oct 2019
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Topic Resources

Hepatitis B is a common cause of chronic hepatitis. Patients may be asymptomatic or have nonspecific manifestations such as fatigue and malaise. Without treatment, cirrhosis often develops; risk of hepatocellular carcinoma is increased. Antiviral drugs may help, but liver transplantation may become necessary.

Hepatitis lasting > 6 months is generally defined as chronic hepatitis, although this duration is arbitrary.

Acute hepatitis B becomes chronic in about 5 to 10% of patients overall. However, the younger the age when acute infection occurs, the higher the risk of developing chronic infection:

  • For infants: 90%

  • For children aged 1 to 5 years: 25 to 50%

  • For adults: About 5%

The Centers for Disease Control and Prevention (CDC) estimates that 850,000 to 2.2 million people in the US (1) and about 257 million people worldwide have chronic hepatitis B (2).

Without treatment, chronic hepatitis B can resolve (uncommon), progress rapidly, or progress slowly to cirrhosis over decades. Resolution often begins with a transient increase in disease severity and results in seroconversion from hepatitis B e antigen (HBeAg) to antibody to hepatitis B e antigen (anti-HBe). Coinfection with hepatitis D virus (HDV) causes the most severe form of chronic HBV infection; without treatment, cirrhosis develops in up to 70% of patients. Chronic HBV infection increases the risk of hepatocellular carcinoma.

General references

  • 1. CDC: Hepatitis B Questions and Answers for Health Professionals. Accessed 9/4/19.

  • 2. World Health Organization: Hepatitis B. Accessed 9/4/19.

Symptoms and Signs

Symptoms of chronic hepatitis B vary depending on the degree of underlying liver damage.

Many patients, particularly children, are asymptomatic. However, malaise, anorexia, and fatigue are common, sometimes with low-grade fever and nonspecific upper abdominal discomfort. Jaundice is usually absent.

Often, the first findings are

A few patients with chronic hepatitis develop manifestations of cholestasis (eg, jaundice, pruritus, pale stools, steatorrhea).

Extrahepatic manifestations may include polyarteritis nodosa and glomerular disease.

Diagnosis

  • Serologic testing

  • Liver biopsy

The diagnosis of chronic hepatitis B is suspected in patients with any of the following:

  • Suggestive symptoms and signs

  • Incidentally noted elevations in aminotransferase levels

  • Previously diagnosed acute hepatitis

Diagnosis is confirmed by finding positive hepatitis B surface antigen (HBsAg) and IgG antibody to hepatitis B core (IgG anti-HBc) and negative IgM anti-HBcAg (see table Hepatitis B Serology) and by measuring hepatitis B virus DNA (quantitative HBV-DNA).

Table
icon

Hepatitis B Serology*

Marker

Acute HBV Infection

Chronic HBV Infection

Prior HBV Infection†

HBsAg

+

+

Anti-HBs

+

IgM anti-HBc

+

IgG anti-HBc

+

±

HBeAg

±

±

Anti-HBe

±

±

HBV-DNA

+

+

* Antibody to hepatitis D virus (anti-HDV) levels should be measured if serologic tests confirm HBV and infection is severe.

† Patients have had HBV infection and recovered.

‡ Anti-HBs is also seen as the sole serologic marker after HBV vaccination.

Anti-HBc = antibody to hepatitis B core; anti-HBe = antibody to HBeAg; anti-HBs = antibody to HBsAg; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus.

If chronic hepatitis B is confirmed, testing for hepatitis B e antigen (HBeAg) and antibody to hepatitis B e antigen (anti-HBe) is usually done to help determine the prognosis and to guide antiviral therapy. If serologically confirmed HBV infection is severe, antibody to hepatitis D virus (anti-HDV) is measured.

Quantitative HBV-DNA tests (viral load) are also used before and during treatment to assess response.

Biopsy is typically done to evaluate the extent of liver damage and to exclude other causes of liver disease. Liver biopsy is most useful in cases that do not meet clear-cut guidelines for treatment (see also the American Association for the Study of Liver Disease's practice guideline Diagnosis and Management of Autoimmune Hepatitis.).

Other tests

Liver tests are needed if not previously done; they include serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and bilirubin.

Other tests should be done to evaluate liver function; they include serum albumin, platelet count, and prothrombin time/international normalized ratio (PT/INR).

Patients should also be tested for HIV and hepatitis C infection because transmission of these infections is similar.

If symptoms or signs of cryoglobulinemia develop during chronic hepatitis, cryoglobulin levels and rheumatoid factor should be measured; high levels of rheumatoid factor and low levels of complement suggest cryoglobulinemia.

Screening for complications

Patients with chronic HBV infection should be screened every 6 months for hepatocellular carcinoma with ultrasonography and serum alpha-fetoprotein measurement, although the cost-effectiveness of this practice, particularly alpha-fetoprotein measurement, is debated. (See also the Cochrane review abstract on Alpha-fetoprotein and/or liver ultrasonography for liver cancer screening in patients with chronic hepatitis B.)

Treatment

  • Antiviral drugs

  • Sometimes liver transplantation

(See also the American Association for the Study of Liver Disease’s Practice Guidelines for the Treatment of Chronic Hepatitis B.)

Antiviral treatment is indicated for patients with chronic hepatitis B and one or more of the following:

  • Elevated aminotransferase levels

  • Elevated HBV viral load

  • Clinical or biopsy evidence of progressive disease

The goal is to eliminate HBV-DNA (1). Treatment can occasionally cause loss of hepatitis B e antigen (HBeAg), or, even more rarely, loss of hepatitis B surface antigen (HBsAg). However, the majority of patients treated for chronic hepatitis B must be treated indefinitely; thus, treatment may be very expensive.

Stopping treatment prematurely can lead to relapse, which may be severe. However, treatment may be stopped if one of the following occurs:

  • HBeAg converts to antibody to HBeAg (anti-HBe).

  • Tests for HBsAg become negative.

Multiple antiviral drugs are active against hepatitis B, but only four are currently recommended: entecavir, tenofovir disoproxil fumarate, tenofovir alafenamide, and pegylated interferon-alfa (peginterferon alfa): Adefovir, interferon alfa, lamivudine, and telbivudine have been used but are no longer recommended as first-line treatment because of increased risk of adverse effects and development of drug resistance.

First-line treatment is usually with one of the following:

  • An oral antiviral drug, such as entecavir (a nucleoside analog) or tenofovir (a nucleotide analog)

  • Pegylated interferon alfa

Oral antiviral drugs have few adverse effects and can be given to patients with decompensated liver disease. Lactic acidosis is a potential side effect, and lactic acid levels should be checked if there is clinical concern. Combination therapy has not proved superior to monotherapy, but studies continue to examine their comparative usefulness. Patients should be tested for HIV before treatment is initiated.

If HBsAg becomes undetectable and HBeAg seroconversion occurs in patients with HBeAg-positive chronic HBV infection, these patients may be able to stop antiviral drugs. Patients with HBeAg-negative chronic HBV infection almost always need to take antiviral drugs indefinitely to maintain viral suppression; they have already developed antibodies to HBeAg, and thus the only specific criterion for stopping HBV treatment would be HBsAg that becomes undetectable.

Entecavir has a high antiviral potency, and resistance to it is uncommon; it is considered a first-line treatment for HBV infection. Entecavir is effective against adefovir-resistant strains. Dosage is 0.5 mg orally once a day; however, patients who have previously taken a nucleoside analog should take 1 mg orally once a day. Dose reduction is required in patients with renal insufficiency. Serious adverse effects appear to be uncommon, although safety in pregnancy has not been established.

Tenofovir has replaced adefovir (an older nucleotide analog) as a first-line treatment. Tenofovir is the most potent oral antiviral for hepatitis B; resistance to it is minimal. It has few adverse effects. There are two forms of tenofovir:

  • Tenofovir disoproxil fumarate (TDF)

  • Tenofovir alafenamide (TAF), which is newer

Dosage for TDF is 300 mg orally once a day; dosing frequency may need to be reduced if creatinine clearance is reduced. Potential side effects include nephropathy, Fanconi syndrome, and osteomalacia. If patients are at risk of renal impairment, creatinine clearance, serum phosphate, and urine glucose and protein should be checked at least annually. Bone density studies at baseline and during treatment should be considered if patients have a history of fracture or risk factors for osteopenia.

Dosage for TAF is 25 mg orally once a day; no dose adjustments are necessary if creatinine clearance is reduced. TDF and TAF are similar in efficacy, but TAF is safer in patients when renal toxicity or bone density is a concern. Serum creatinine and phosphorus, creatinine clearance, and urine glucose and protein should be checked before initiating and during therapy.

Pegylated interferon alfa can be used instead of interferon alfa. Dosage for pegylated interferon alfa is usually 180 mcg by injection once a week for 48 weeks. Adverse effects are similar to those of interferon alfa but may be less severe. More than 40% of patients treated with pegylated interferon alfa report fatigue, fever, myalgia, and headache. Other potential side effects include mood disturbances, cytopenia, and autoimmune disorders.

Contraindications to pegylated interferon alfa include the following:

  • Decompensated liver disease

  • Autoimmune hepatitis

  • Renal failure

  • Immunosuppression

  • Solid organ transplantation

  • Cytopenia

The following tests should be used to monitor patients treated with pegylated interferon alfa:

  • Complete blood count (monthly to every 3 months)

  • Thyroid-stimulating hormone (every 3 months)

  • Clinical monitoring for autoimmune, ischemic, neuropsychiatric, and infectious complications

  • Lactic acid levels if there is clinical concern

  • Test for HIV before initiating treatment

Nonpreferred antiviral therapies (adefovir, lamivudine, telbivudine, interferon alfa) may be considered if the above drugs are unavailable.

Adefovir is a nucleotide analog. Dosage is 10 mg orally once a day. It is not a preferred first-line treatment because renal failure and lactic acidosis are risks.

Lamivudine (a nucleoside analog) is no longer considered first-line treatment for HBV infection because risk of resistance is higher and efficacy is lower than those of newer antiviral drugs. Dosage is 100 mg orally once a day; it has few adverse effects.

Telbivudine is a nucleoside analog that has greater efficacy and potency than lamivudine but also has a high rate of resistance; it is not considered first-line treatment. Dosage is 600 mg orally once a day.

Interferon alfa can be used but is no longer considered first-line treatment and has generally been replaced by pegylated interferon alfa.

Liver transplantation should be considered for end-stage liver disease caused by HBV. In patients with HBV infection, the long-term use of first-line oral antivirals and peritransplantation use of hepatitis B immune globulin (HBIG) has improved outcomes after liver transplantation. Survival is equal to or better than that after transplantation for other indications, and recurrences of hepatitis B are minimized.

Treatment reference

  • 1. Terrault NA, Lok ASF, McMahon BJ, et al: Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 67 (4):1560-1599, 2018. doi: 10.1002/hep.29800.

Key Points

  • Acute hepatitis B becomes chronic in about 5 to 10% of patients overall; risk is highest at a young age (90% for infants, 25 to 50% for children aged 1 to 5 years, and about 5% for adults).

  • The CDC estimates that about 257 million people worldwide have chronic hepatitis B infection.

  • Symptoms vary depending on the degree of underlying liver damage.

  • Antiviral drugs can improve liver test results and liver histology and delay progression to cirrhosis but may need to be taken indefinitely; drug resistance has become less of a concern with newer drugs.

  • Liver transplantation may be required in patients with decompensated cirrhosis due to hepatitis B.

More Information

Drugs Mentioned In This Article

Drug Name Select Trade
Gammagard S/D
TYZEKA
EPIVIR
VIREAD
BARACLUDE
HEPSERA
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