AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

The hepatitis B virus (HBV), discovered in 1966, infects more than 350 million people worldwide.¹ Hepatitis B can cause acute and chronic liver disease. The clinical presentation ranges from subclinical hepatitis to symptomatic hepatitis and, in rare instances, fulminant hepatitis. Long-term complications of hepatitis B include cirrhosis and hepatocellular carcinoma.² Perinatal or childhood infection is associated with few or no symptoms but has a high risk of becoming chronic. A limited number of medications can be used to effectively treat chronic hepatitis B; a safe and effective vaccine is available to prevent hepatitis B infection caused by HBV.³

Pathophysiology

HBV is a double-stranded DNA virus of the Hepadnaviridae family. HBV is a hepatotropic virus that replicates in the liver and causes hepatic dysfunction. HBV is transmitted by percutaneous or permucosal exposure to infectious body fluids, by sexual contact with an infected person, and by perinatal transmission from an infected mother to her infant. Persons with chronic HBV infection are predisposed to chronic liver disease and have a greater than 200-fold increased risk of hepatocellular carcinoma.

Fulminant hepatic failure occurs in approximately 0.1-0.5% of patients and is believed to be caused by massive immune-mediated lysis of infected hepatocytes. Various extrahepatic manifestations (eg, urticarial rashes, arthralgia, arthritis) are associated with acute clinical and subclinical HBV infection, as well as multiple immune-complex disorders such as Gianotti-Crosti syndrome (papular acrodermatitis), necrotizing vasculitis, and hypocomplementemic glomerulonephritis. HBV is associated with 20% of membranous nephropathy cases in children. Essential mixed cryoglobulinemia, pulmonary hemorrhage related to vasculitis, acute pericarditis, polyserositis, and Henoch-Schönlein purpura have been reported in association with HBV infection.

Frequency

United States

The Centers for Disease Control and Prevention report an estimated 150,000 new infections each year in the United States.⁴ More than 10,000 affected individuals require hospitalization, and 250 die of fulminant disease. In addition, 22,000 women with HBV infection give birth each year. The prevalence of chronic HBV infection in the United States is 0.35%. Although the reported incidence of acute hepatitis B increased by 37% from 1979-1985, the incidence has since 1986 declined to 1979 levels.

International

Infection with HBV is a serious health problem in many parts of the world. HBV infects more than 350 million people worldwide. Approximately 5% of the world's population has chronic HBV infection and it is the leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma worldwide. An estimated 500,000-1,000,000 persons die annually from HBV-related liver disease.

The distribution of hepatitis B infection widely varies throughout the world. In some regions, over 10% of the population is positive for hepatitis surface antigen (HB_sAg), which indicates active infection. Countries are classified as having low endemic rates (<2% of the population has the antibody to HB_sAg), intermediate endemic rates (2-8% positive for HB_sAg), or high endemic rates (>8% positive for HB_sAg).

In areas with high prevalence, such as southeast Asia, China, and Africa, more than half the population is infected at some time in their lives; approximately 10% are chronic carriers of the virus, which is the result of either neonatal transmission (vertical) or transmission from one individual to another (horizontal). Areas with low levels of endemicity include North America, Western Europe, and Australia, where only a minority of people come into contact with the virus (as a result of horizontal transmission among young adults).

The virus is present in all body fluids, except stool. Blood and body fluids are the primary vehicles of transmission; the virus may also spread by contact with body secretions, such as saliva, sweat, tears, breast milk, semen, and pathologic effusions. Most HBV infections in developed countries result from sexual activity, injection-drug use, or occupational exposure. Several well-characterized groups in the United States have an increased risk of infection, including those who use injection drugs, homosexual men, persons who have heterosexual contact with multiple partners, household contacts of persons with chronic infection, persons with hemophilia, patients on hemodialysis and the staff that tends to them, and persons with occupational exposure to blood and infectious body fluids.

Mortality/Morbidity

Of the 5000 persons in the United States who die each year from HBV-related conditions, 300 die from fulminant hepatitis, 3000-4000 die from cirrhosis, and 600-1000 die from primary hepatocellular carcinoma.

Race

The prevalence of HBV infection is higher among black populations than among white populations. According to the CDC, approximately 20% of new reported cases each year in the United States occur in African Americans.

Sex

Exacerbations of chronic HBV infection are observed more often in men than in women. Although the reason for this sex difference is not clear, the higher frequency of exacerbations in men may account, in part, for the higher incidence of HBV-related cirrhosis and hepatocellular carcinoma among men.

Age

Most acute HBV infections in the United States occur among young adults, although about one third of patients acquire chronic infections through perinatal and early childhood exposures. The prevalence increases with age. The age at infection primarily determines the rate of progression from acute infection to chronic infection, which is approximately 90% in the perinatal period, 20-50% in children aged 1-5 years, and less than 5% in adults.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The incubation period for hepatitis B virus (HBV) infection ranges from 6 weeks to 6 months, and the clinical manifestations depend on the age at infection, the level of HBV replication, and the host's immune status. Perinatally infected infants generally have no clinical signs or symptoms, and infection produces typical illness in only 5-15% of children aged 1-5 years. Older children and adults are symptomatic in 33-50% of infections.

Clinicopathologic syndromes

• Acute asymptomatic infection with recovery: Serologic evidence only
• Acute hepatitis with resolution: Anicteric or icteric
• Chronic hepatitis, with or without progression to cirrhosis
• Fulminant hepatitis with massive liver necrosis
• Coinfection with hepatitis D virus (hepatitis delta virus)

Physical

Acute hepatitis

Clinical signs and symptoms of acute HBV infection include anorexia, nausea, malaise, vomiting, arthralgias, myalgias, headache, photophobia, pharyngitis, cough, coryza, jaundice, dark urine, clay-colored or light stools, and abdominal pain.

Upon physical examination, with the onset of clinical jaundice, the liver becomes enlarged and tender, and the patient may have right upper quadrant pain and discomfort. Splenomegaly and cervical adenopathy are present in 10-20% of patients with acute hepatitis. A few spider angiomas may appear during the icteric phase and disappear during convalescence, although angiomas are rare.

Chronic hepatitis

Chronic hepatitis is symptomatic, and affected individuals have biochemical or serologic evidence of continuing or relapsing hepatic disease for longer than 6 months, with histologically documented liver inflammation. The clinical features vary. The common symptoms include fatigue, loss of appetite, and occasional bouts of mild jaundice.

Fulminant hepatitis occurs in 1-2% of persons with acute disease and has a case:fatality ratio of 63-93%. It may present as jaundice, encephalopathy, and fetor hepaticus. Life-threatening extrahepatic complications include coagulopathy, renal failure, adult respiratory distress syndrome, electrolyte and acid-base disturbances, and sepsis. Without liver transplantation, the overall mortality ranges from 25-90%.

Consider hepatitis D virus infection if a patient who is a carrier of chronic hepatitis B presents with recurrent acute hepatitis or sudden fulminant hepatitis.

Causes

Virology

HBV, a DNA virus in the Hepadnaviridae family, causes hepatitis B. The virus is responsible for 40% of hepatitis cases in the United States. Seven major genotypes of HBV are recognized, with different geographic distributions. The genotypes are thought to affect disease progression, but their role in response to treatment is not as clear as in hepatitis C. The genome of HBV is a partially double-stranded, circular DNA molecule of 3200 nucleotides that encodes the following:

• The precore/core region of a nucleocapsid core protein (hepatitis B core antigen [HB_cAg]) and a precore protein (hepatitis B e antigen [HB_eAg]: HB_cAg is retained in the infected hepatocyte; HB_eAg is secreted into blood and is essential for the establishment of persistent infection.
• Envelope glycoprotein (ie, HB_sAg), which may be produced and secreted into the blood in massive amounts: Blood HBsAg is immunogenic and can be visualized as spheres or tubules.
• A DNA polymerase with reverse transcriptase activity: Genomic replication takes place through an intermediate RNA known as pregenomic RNA. In this process, mutant viral genomes are frequently generated.
• HBV-X protein: This acts as a transcriptional transactivator for many viral and host genes through interaction with various transcription factors. HBV-X is required for viral infectivity and may have a role in the causation of hepatocellular carcinoma by regulating p53 degradation and expression.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Viral hepatitis shares certain clinical features with other viral diseases, such as Epstein Barr virus, herpes simplex, coxsackie viruses, and toxoplasmosis. These diseases elevate serum aminotransferase levels and, less commonly, serum bilirubin levels.

In addition, a complete drug history is particularly important because many drug and some anesthetic agents can produce a picture of acute hepatitis. Alcoholic hepatitis must also be considered in the differential. Acute hepatitis often is confused with acute cholecystitis, common duct stone, or ascending cholangitis.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are hallmarks of acute hepatitis. Values as high as 1000-2000 IU/L are typical, with ALT values higher than AST values. In patients with hepatitis, increases in bilirubin levels often lag behind increases in aminotransferase levels. The prothrombin time is the best indicator of prognosis. Alpha-fetoprotein levels as high as 8000 ng/mL may also be seen.
• Because the symptoms of acute hepatitis B virus (HBV) infection and the laboratory indicators of hepatocellular dysfunction are indistinguishable from those of other forms of viral hepatitis, definitive diagnosis depends on serologic testing for HBV infection. Serological findings are as follows:
• • HB_sAg appears before the onset of symptoms, peaks during overt disease, and then declines to undetectable levels in 3-6 months. Acute HBV infection is characterized by the presence of HB_sAg in the serum.
  • HB_eAg, HBV DNA, and DNA polymerase appear in the serum soon after HB_sAg, and all signify active viral replication. Measuring HBV DNA with quantitative DNA polymerase chain reaction (PCR) is ideal for monitoring disease progression and effect of treatment.
  • Immunoglobulin M (IgM) anti-HB_c becomes detectable in serum shortly before the onset of symptoms, concurrent with the onset of elevation of serum aminotransferases. Over months, the IgM antibody is replaced by immunoglobulin G (IgG) anti-HB_c.
  • Anti-HB_e is detectable shortly after the disappearance of HB_eAg, implying that the acute infection has peaked and the disease is on the wane.
  • IgG anti-HB_s does not rise until the acute disease is over and is usually not detectable for a few weeks to several months after the disappearance of HB_sAg. Anti-HB_s may persist for life, conferring protection; this is the basis for current vaccination strategies using noninfectious HB_sAg.
  • During convalescence, HB_sAg and HB_eAg are cleared, and IgG antibodies to HB_sAg, HB_cAg, and HB_eAg develop.
  • Hepatitis B surface antibody (HB_sAb) is a protective antibody that neutralizes the virus, although the coexistence of HB_sAg and HB_sAb has been reported in approximately 25% of individuals who are HB_sAg positive. HB_sAb, but not hepatitis B core antibody (HB_cAb), is detected in persons who have received the hepatitis B vaccine.
  • Total HB_cAb, including IgM and IgG, indicates exposure to the virus and viral replication. HB_cAb appears shortly after HB_sAg in acute disease and persists for life; therefore, HB_cAb is not a good marker for acute disease.
  • Detection of IgM HB_cAb is diagnostic of acute HBV infection. The carrier state is defined by the presence of HB_sAg in the serum for 6 months or longer after its initial detection.
  • The carrier state is defined by the presence of HB_sAg in serum for 6 months or longer after initial detection. The presence of HB_sAg alone does not necessarily indicate replication of complete virions, and patients may be asymptomatic and without liver damage.
  • In contrast, chronic replication of HBV virions is characterized by persistence of circulating HB_sAg, HB_eAg, and HBV DNA, usually with anti-HB_c and, occasionally, with anti-HB_s. In these patients, progressive liver damage may occur.
• The major clinical role of serum HBV DNA assays is the assessment of the candidacy of patients with chronic HBV infection for antiviral therapy and their response to it. Tests for HBV DNA in serum rarely help in identifying HBV as the cause of liver disease in patients who are HB_sAg-negative; knowledge of this fact is especially important in patients with fulminant hepatitis B in whom HB_sAg may have cleared by the time they seek care.

Procedures

• Patients with signs of chronic disease may require a liver biopsy to assess the extent of histologic involvement and response to therapeutic protocols.

Histologic Findings

Morphologic changes in acute and chronic viral hepatitis are shared among the hepatotropic viruses and can be mimicked by drug reactions. HBV infection may generate ground-glass hepatocytes, with a finely granular, eosinophilic cytoplasm depicted as spheres and tubules of HB_sAg using electron microscopy. Other HBV-infected hepatocytes may have sanded nuclei due to abundant HB_cAg; this finding indicates active viral replication.

With acute hepatitis, hepatocyte injury takes the form of diffuse swelling (balloon degeneration). Cholestasis is an inconstant finding. Two patterns of hepatocyte cell death are observed: cytolysis (cell rupture) and apoptosis (cell shrinkage). In severe cases, confluent necrosis of hepatocytes may lead to bridging necrosis. Inflammation is a prominent feature of acute hepatitis. Kupffer cells undergo hypertrophy and hyperplasia. Usually, the portal tracts are infiltrated with a mixture of inflammatory cells.

Histologic features of chronic hepatitis range from exceedingly mild to severe. In the mildest forms, significant inflammation is limited to the portal tracts. Liver architecture is usually well preserved, but smoldering hepatocyte necrosis throughout the lobule may occur in all forms of chronic hepatitis. Continued interface hepatitis and bridging necrosis are harbingers of progressive liver damage. Deposition of fibrous tissue is the hallmark of irreversible liver damage. Continued loss of hepatocytes and fibrosis results in cirrhosis, with fibrous septae and hepatocyte regenerative nodules. This pattern of cirrhosis is characterized by irregularly sized nodules separated by variable, but mostly broad, scars. Historically, this pattern of cirrhosis has been termed postnecrotic cirrhosis. The term postnecrotic cirrhosis has been applied to all forms of cirrhosis in which the liver shows large, irregular-sized nodules with broad scars, regardless of etiology.

Staging

In current practice, including a statement regarding the severity of inflammatory activity (grade) and fibrosis (stage) in the liver biopsy pathology report is recommended in patients with chronic hepatitis. Disease activity and histological response to treatment are usually defined based on a scoring system for the grade and stage of chronic hepatitis.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Until recently, no specific treatment has been available for persons with acute hepatitis B virus (HBV) infection. Supportive and symptomatic care used to be the mainstay of therapy for most patients. However, the recent advent of nucleoside analogues such as lamivudine and adefovir dipivoxil has had a major impact on treatment of chronic hepatitis B. Nucleoside analogues achieve viral suppression (as measured by loss of Hb_eAg and suppression of HBV DNA), and recombinant interferon alfa aims at immunomodulation.

New nucleosides that are not yet approved by the US Food and Drug Administration (FDA) for hepatitis B include tenofovir, emtricitabine, and clevudine (not approved in the United States for any indication as of January 2008). Entecavir is now approved and has the advantage of developing very little resistance and is effective against mutants resistant to lamivudine. Telbuvidine is an L-nucleoside with specific anti-HBV activity that was approved by the FDA in 2006. It seems to achieve significantly better viral suppression than lamivudine monotherapy, although resistance and cross-resistance is common. Combination therapy in the future may have additive or synergistic effects, reduction of adverse effects, and reduction of resistance with achievement of better viral suppression.

Surgical Care

• Liver transplantation for decompensated liver disease
• Surgical resection of hepatocellular carcinoma

Consultations

• Infectious disease specialists for placement in therapeutic protocols
• Gastroenterologist for biopsy assessment and therapy

Diet

A high-energy diet is desirable, and because many patients may have nausea late in the day, they best tolerate their major caloric intake in the morning. Intravenous feeding is necessary in the acute stage if the patient has persistent vomiting and cannot eat.

Activity

Although forced and prolonged bed rest is not essential for full recovery, many patients feel better with restricted physical activity.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Interferon alfa has been the mainstay of treatment for chronic hepatitis B since its introduction in the mid 1980s; however, only 30-40% of patients respond to this therapy. Lamivudine and the newer nucleoside analogues (ie, famciclovir, lobucavir, and adefovir dipivoxil) directly block the replication of hepatitis B virus (HBV); they are highly effective, bioavailable, and extremely well tolerated. To date, interferon alfa-2b, peginterferon alfa-2a, lamivudine, adefovir, entecavir, and telbivudine are FDA approved for hepatitis B. For more information, see Guidelines from the American Association for the Study of Liver Diseases (AASLD) for Chronic Hepatitis B.

Drug Category: Antiviral agents

Interferon may prevent the progression of acute hepatitis to the chronic stage and may promote more rapid resolution of viremia and normalization of serum aminotransferase levels. Several nucleoside analogues are active against HBV. The most widely used and studied is lamivudine, which has produced promising responses. However, relapse rates tend to be high after treatment is discontinued.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Most patients do not require hospital care. Patients with clinically severe illness may require hospitalization.
• A prolonged prothrombin time, low serum albumin level, hypoglycemia, and very high serum bilirubin values suggest severe hepatocellular disease; patients with these findings require prompt hospital admission.

Further Outpatient Care

• An HB_sAg-positive finding in an infant, which is rare, indicates failure of immunoprophylaxis, and the third vaccine dose is not necessary.
• Breastfeeding is acceptable and does not pose a risk of transmitting hepatitis B virus (HBV) to infants who have begun prophylaxis.
• Reserve routine screening using ultrasonography and alpha-fetoprotein determination for patients with severe chronic active hepatitis, cirrhosis, or both.⁵

Deterrence/Prevention

• Hepatitis B is one of the major diseases that can be prevented with vaccination. Two types of recombinant hepatitis B vaccines are licensed for use in the United States; both are effective and safe.
• Universal vaccination refers to the administration of HBV vaccine to all infants as a part of the routine childhood immunization schedule and to all children younger than 11 or 12 years who have not previously received a vaccine. Rapid (0-, 1-, and 2-mo) and standard (0-, 1-, 6-mo) schedules have identical efficacy.
• Passive immunization refers to the administration of preformed human or animal antibody, in the form of hepatitis B immunoglobulin (HBIG), to patients after or just before exposure.
• • The current recommendation for neonates of mothers who are HB_sAg positive is to administer HBIG 0.5 mL intramuscularly with the first dose of recombinant HBV vaccine within 12 hours of birth.
  • After immunization, serology should be tested for HB_sAg and anti-HB_s at age 9-18 months.
  • In infants of infected mothers, combined treatment with the vaccine and HBIG has 79-98% efficacy in preventing chronic HBV infection.
• Patients on dialysis and those who are immunocompromised need to be evaluated annually for hepatitis B; if the anti HB_sAb level is less than 10 mIU/mL, a booster dose is recommended. 
• Testing of hepatitis serology for immune response is recommended for high-risk groups such as homosexuals and bisexuals, patients on dialysis, sexual and household contacts of hepatitis B carriers and patients with human immunodeficiency virus (HIV) infection. 
• After 3 primary doses of the vaccine, if no serologic response with anti-HB_s of 10 mIU/ml is noted, reimmunization with a 3-dose series is recommended. If the response if still negative, they are unlikely to mount antibody with additional doses. 
• Twinrix is a combination of hepatitis B (Engerix-B, 20 mcg) and hepatitis A (Havrix, 720 ELU) vaccine approved for people aged 18 years or older in a 3-dose schedule administered at 0 months, 1 month, and 6 or more months later.
• For preterm infants who weigh less than 2000 g and are born to mothers with unknown HB_sAg status, 0.5 ml HBIG should be given within 12 hours. The birth dose should not be counted, and 3 additional doses are given according to recommendations.

Complications

• Fulminant hepatitis is the most feared complication of viral hepatitis. Fulminant hepatitis is observed primarily in hepatitis B (>50% of fulminant hepatitis cases) and in hepatitis D infection. Patients typically present with signs and symptoms of hepatic encephalopathy that may evolve to deep coma. Usually, the liver is small, and the prothrombin time is excessively prolonged.
• The most severe complications of chronic hepatitis B infection are cirrhosis and hepatocellular carcinoma.
• Rare complications of viral hepatitis are as follows:
• • Pancreatitis
  • Myocarditis
  • Atypical pneumonia
  • Aplastic anemia
  • Transverse myelitis
  • Peripheral neuropathy

Prognosis

• Among patients with acute hepatitis B, 90% have a favorable course and recover completely.
• Patients of advanced ages and those with serious underlying medical disorders, such as congestive heart failure, severe anemia, and diabetes mellitus, may have a prolonged course and are more likely to have severe hepatitis.
• The prothrombin time is the best indicator of the prognosis in patients with acute hepatitis.
• Although fatality rates for most cases of hepatitis B are low, patients ill enough to be hospitalized for acute hepatitis B have a 1% fatality rate.
• In patients with persistent infection, 10-30% develop chronic hepatitis. Of patients with chronic hepatitis, 20-50% of patients progress to cirrhosis, and approximately 10% of those who progress to cirrhosis may develop hepatocellular carcinoma.

Patient Education

• Educate patients who are HB_sAg carriers about safe-sex practices and universal vaccination benefits.
• For excellent patient education resources, visit eMedicine's Hepatitis Center and Children's Health Center. Also, see eMedicine's patient education articles Hepatitis B and Immunization Schedule, Children.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to screen a pregnant mother or a mother who presents in labor without having received prenatal care and whose hepatitis B status remains unknown could lead to physician liability because the baby may not have received optimal prophylaxis and is at risk for chronic hepatitis B.
• Failure of the physician to either notify an infected person identified with blood screening or other tests or provide appropriate counsel regarding transmission (eg, sexual contact, needle sharing) may lead to the exposure of additional people to hepatitis B.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Kane M. Global programme for control of hepatitis B infection. Vaccine. 1995;13 Suppl 1:S47-9. [Medline].
2. Izzo F, Cremona F, Ruffolo F, et al. Outcome of 67 patients with hepatocellular cancer detected during screening of 1125 patients with chronic hepatitis. Ann Surg. Apr 1998;227(4):513-8. [Medline].
3. Bhimma R, Coovadia HM, Adhikari M, Connolly CA. The impact of the hepatitis B virus vaccine on the incidence of hepatitis B virus-associated membranous nephropathy. Arch Pediatr Adolesc Med. Oct 2003;157(10):1025-30. [Medline].
4. McNabb SJ, Jajosky RA, Hall-Baker PA, et al. Summary of notifiable diseases --- United States, 2005. MMWR Morb Mortal Wkly Rep. Mar 30 2007;54(53):1-92. [Medline].
5. Rugge JB, Lochner J, Judkins D, Mendoza M. What is the best surveillance for hepatocellular carcinoma in chronic carriers of hepatitis B?. J Fam Pract. Feb 2006;55(2):155-6. [Medline].
6. APA. Hepatitis B. Red Book. Available at http://aapredbook.aappublications.org. Accessed January 15, 2008.
7. Chan HLY, Lok ASF. Hepatitis B in adults -- A clinical perspective. Clin Liver Dis. 1999;3(2):291-307.
8. Flink HJ, van Zonneveld M, Hansen BE, et al. Treatment with Peg-Interferon alpha-2b for HBeAg-Positive Chronic Hepatitis B: HBsAg Loss Is Associated with HBV Genotype. Am J Gastroenterol. Feb 2006;101(2):297-303. [Medline].
9. Khalili M, Perillo RP. Interferon therapy of hepatitis B. Clin Liver Dis. 1999;3(2):363-87.
10. Lai CL, Ratziu V, Yuen MF, Poynard T. Viral hepatitis B. Lancet. Dec 20 2003;362(9401):2089-94. [Medline].
11. Mahoney FJ, Long SS, Pickering LK. Hepatitis B virus. In: Principles and Practice of Pediatric Infectious Diseases. 1997:1194-202.
12. McMahon BJ. Selecting appropriate management strategies for chronic hepatitis B: who to treat. Am J Gastroenterol. Jan 2006;101(1 Suppl):S7-S12. [Medline].
13. Ng VL, Balistrera WF. Hepatitis B--Clinical perspectives in pediatrics. Clin Liver Dis. 1999;3(2):267-90.
14. Rosenberg PM, Dienstag JL. Therapy with nucleoside analogues for hepatitis B virus infection. Clin Liver Dis. 1999;3(2):349-361.

Article Last Updated: May 1, 2008