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Hepatitis B, Chronic

By Anna E. Rutherford, MD, MPH, Assistant Professor of Medicine; Clinical Director of Hepatology, Harvard Medical School; Brigham and Women’s Hospital

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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 mo 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 yr: 25 to 50%

  • Adults: About 5%

The CDC estimates that 850,000 to 2.2 million people in the US and about 240 million people worldwide have chronic hepatitis B infection.

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.

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.


  • 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 anti-HBc and negative IgM antibody to HBcAg (anti-HBc—see Table: Hepatitis B Serology*) and by measuring hepatitis B virus DNA (quantitative HBV-DNA).

Hepatitis B Serology*


Acute HBV Infection

Chronic HBV Infection

Prior HBV Infection






IgM anti-HBc


IgG anti-HBc












*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 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 function tests are needed if not previously done; they include serum ALT, AST, alkaline phosphatase, and bilirubin.

Other tests should be done to evaluate disease severity; they include serum albumin, platelet count, and 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 mo 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.)


  • 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

  • Elevated aminotransferase levels

  • Clinical or biopsy evidence of progressive disease

  • Both of the above

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.

Drug resistance is also a concern.

Seven antiviral drugs—entecavir, tenofovir, adefovir, interferon alfa (INF-alpha), pegylated INF-alpha (peginterferon-alpha), lamivudine, and telbivudine—are available (see Table: Comparison of Drugs Commonly Used to Treat Chronic Viral Hepatitis B).

Comparison of Drugs Commonly Used to Treat Chronic Viral Hepatitis B


(% of patients)


PEG IFN-alpha






Serum HBV-DNA becomes undetectable








Seroconversion from HBeAg to anti-Hbe occurs








ALT normalizes








Histologic improvement occurs








HBsAg becomes undetectable (at 1 yr)



< 1%





Resistance develops



At 1 yr: ~14–32%

At 5 yr: ~60–70%

At 1 yr: 0%

At 5 yr: 29%

At 1 yr: 0%

At 6 yr: 1.2%

At 1 yr: 5%

At 2 yr: 25%

After 6 yr: 0%

Anti-Hbe = antibody to HBeAg; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; INF-alpha = interferon alfa; PEG IFN-alpha = pegylated INF-alpha.

Adapted from Lok ASF, McMahon BJ: Chronic hepatitis B: Update 2009. American Association for the Study of Liver Diseases (AASLD) practice guidelines update. Hepatology 50: 661–699, 2009 and Terrault NA, Bzowej NH, Chang KM, et al: AASLD guidelines for treatment of chronic hepatitis B. Hepatology 63: 261–283, 2016.

First-line treatment is usually with

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

Oral antiviral drugs have few adverse effects and can be given to patients with decompensated liver disease. Combination therapy has not proved superior to monotherapy, but studies continue to examine their comparative usefulness.

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 po once/day; however, patients who have previously taken a nucleoside analog should take 1 mg po once/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. Dosage is 300 mg po once/day; dosing frequency may need to be reduced if creatinine clearance is reduced. Tenofovir alafenamide is a prodrug of tenofovir that can be used to treat chronic hepatitis B. Tenofovir alafenamide is similar in efficacy to tenofovir disoproxil but is safer in patients when creatinine clearance is reduced or when renal toxicity is a concern.

For adefovir, dosage is 10 mg po once/day.

Interferon alfa (IFN-alpha) can be used but is no longer considered first-line treatment. Dosage is 5 million IU sc once/day or 10 million IU sc 3 times/wk for 16 to 24 wk in patients with HBeAg-positive chronic HBV infection and for 12 to 24 mo in patients with HBeAg-negative chronic HBV infection. In about 40% of patients, this regimen eliminates HBV-DNA and causes seroconversion to anti-HBe; a successful response is usually presaged by a temporary increase in aminotransferase levels. The drug must be given by injection and is often poorly tolerated. The first 1 or 2 doses cause an influenza-like syndrome. Later, fatigue, malaise, depression, bone marrow suppression, and, rarely, bacterial infections or autoimmune disorders can occur.

Contraindications to INF-alpha include the following:

  • Advanced cirrhosis: In patients with cirrhosis, IFN-alpha can precipitate decompensation of cirrhosis.

  • Renal failure

  • Immunosuppression

  • Solid organ transplantation

  • Cytopenia

In a few patients, treatment must be stopped because of intolerable adverse effects. The drug should be given cautiously or not at all to patients with ongoing substance abuse or a major psychiatric disorder.

Pegylated IFN-alpha can be used instead of IFN-alpha. Dosage is usually 180 mcg by injection once/wk for 48 wk. Adverse effects are similar to those of IFN-alpha but may be less severe.

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 po once/day; it has few adverse effects.

Telbivudine is a newer 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 po once/day.

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

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 yr, and about 5% for adults).

  • The CDC estimates about 240 million people worldwide have chronic hepatitis B infection.

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

  • Antiviral drugs can improve liver function test results and liver histology and delay progression to cirrhosis but may need to be taken indefinitely; drug resistance is a concern.

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

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