Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + Download Section PDF Listen ++ For further information, see CMDT Part 16-06: Chronic Viral Hepatitis + Key Features Download Section PDF Listen +++ +++ Essentials of Diagnosis ++ Chronic inflammatory reaction of the liver of more than 3–6 months' duration Repeated detection of hepatitis B surface antigen (HBsAg) in serum, often with elevated serum aminotransferase levels +++ General Considerations ++ Early in the course, hepatitis Be antigen (HBeAg) and hepatitis B virus (HBV) DNA are present in serum Indicative of active viral replication and necroinflammatory activity in the liver These persons are at risk for progression to cirrhosis and for hepatocellular carcinoma Low-level IgM anti-HBc is also present in about 70% Clinical and biochemical improvement may coincide with Disappearance of HBeAg and HBV DNA from serum Appearance of anti-HBe Integration of the HBV genome into the host genome in infected hepatocytes If cirrhosis has not yet developed, such persons are at a lower risk for cirrhosis and hepatocellular carcinoma Chronic hepatitis is characterized on the basis of The etiology The grade of portal, periportal, and lobular inflammation (minimal, mild, moderate, or severe) The stage of fibrosis (none, mild, moderate, severe, cirrhosis) Five phases of chronic HBV infection are recognized Immune tolerant phase Immune active (or immune clearance) phase Inactive HBsAg carrier state Reactivated chronic hepatitis B phase HBsAg-negative phase +++ Demographics ++ Chronic hepatitis B afflicts 248 million people worldwide and 2.2 million (predominantly males) in the United States + Clinical Findings Download Section PDF Listen +++ +++ Symptoms and Signs ++ Clinically indistinguishable from chronic hepatitis due to other causes Immune active phase (HBeAg-positive chronic hepatitis B) HBeAg and HBV DNA are present in serum, indicative of active viral replication Serum aminotransferase levels are normal, with little necroinflammation in the liver This phase is common in infants and young children whose immature immune system fails to mount an immune response to HBV Inactive HBsAg carrier state (HBeAg-negative chronic HBV infection) Patients have entered this phase when biochemical improvement follows immune clearance and cirrhosis has not yet developed Patients in this phase are at a low risk for cirrhosis and hepatocellular carcinoma Patients with persistently normal serum aminotransferase levels infrequently have histologically significant liver disease Reactivated chronic hepatitis B phase (HBeAg-negative chronic hepatitis B) Risk factors for reactivation include Male sex and HBV genotype C Advanced age Alcohol use Cigarette smoking Coinfection with HCV or HDV In patients with either HBeAg-positive or HBeAg-negative chronic hepatitis B, the risk of cirrhosis and of hepatocellular carcinoma correlates with the serum HBV DNA level HIV coinfection is also associated with an increased frequency of cirrhosis when the CD4 count is low Occasional patients (only 1% of treated and untreated patients per year) reach the HBsAg-negative phase, in which Anti-HBe may remain Serum ALT levels are normal HBV DNA is undetectable in serum but remains present in the liver In some cases, anti-HBs appears in serum +++ Differential Diagnosis ++ Hepatitis C and D (delta) Autoimmune hepatitis Alpha-1-antiprotease deficiency Drug-induced chronic hepatitis Wilson disease + Diagnosis Download Section PDF Listen +++ +++ Laboratory Tests ++ Immune tolerant phase HBeAg and HBV DNA are present in serum, indicative of active viral replication When HBV infection is acquired in infancy or early childhood, serum aminotransferase levels often are normal and little necroinflammation is present in the liver Immune active phase Aminotransferase levels are elevated Inactive HBsAg carrier state Disappearance of HBeAg and reduced HBV DNA levels (< 105 copies/mL, or < 20,000 international units/mL) in serum, appearance of anti-HBe, and integration of the HBV genome into the host genome in infected hepatocytes Reactivated chronic hepatitis B phase May result from infection by a pre-core mutant of HBV or spontaneous mutation of the pre-core or core promoter region of the HBV genome during the course of chronic hepatitis caused by wild-type HBV There is a rise in serum HBV DNA levels and possible progression to cirrhosis (at a rate of 8–10% per year), particularly when additional mutations in the core gene of HBV are present Elevated serum bilirubin level, low albumin level, and prolonged prothrombin time reflect advanced disease (severe inflammation or cirrhosis, or both) Table 16–5 +++ Diagnostic Procedures ++ Liver biopsy may be indicated for diagnosis, staging, and predicting response to therapy + Treatment Download Section PDF Listen +++ +++ Medications ++ Patients with active viral replication (HBeAg and HBV DNA [≥ 105 copies/mL, or ≥ 20,000 international units/mL] in serum; elevated serum aminotransferase levels) may be treated with a nucleoside or nucleotide analog or pegylated interferon Entecavir Dosage: 0.5 mg orally daily for patients not resistant to lamivudine and 1 mg orally daily for patients who are already resistant to lamivudine Entecavir resistance is rare unless a patient is already resistant to lamivudine Suppression of HBV DNA in serum occurs in nearly all treated patients, and histologic improvement is observed in 70% of patients Has been reported to cause lactic acidosis when used in patients with decompensated cirrhosis Tenofovir disoproxil fumarate (TDF) Dosage: 300 mg orally daily Equally effective against HBV and is used as a first-line agent or when resistance to a nucleoside analog has developed Has a low rate of resistance when used as initial therapy Long-term use may lead to an elevated serum creatinine level and reduced serum phosphate level (Fanconi-like syndrome) that is reversible with discontinuation of the drug Classified as pregnancy category B; treatment is recommended starting in the third trimester when mother's serum HBV DNA level is > 200,000 international units/mL to reduce levels at time of delivery Tenofovir alafenamide (TAF) Dosage: 25 mg orally daily May be associated with a lower rate of renal and bone toxicity than tenofovir disoproxil fumarate Lamivudine Dosage: 100 mg orally daily No longer considered first-line therapy in the United States but may be used in countries in which its relative low cost is a deciding factor By the end of 1 year, however, 15–30% of responders experience a relapse (and occasionally frank decompensation) The rate of resistance reaches 70% by 5 years of therapy Classified as pregnancy category C; safe to use in pregnant women with HIV; starting treatment in third trimester when serum HBV DNA level is > 200,000 international units/mL is recommended to reduce levels at time of delivery Adefovir dipivoxil Dosage: 10 mg orally once daily for at least 1 year Has activity against wild-type and lamivudine-resistant HBV but is the least potent of the oral antiviral agents for HBV Adding the drug may be effective in patients who have become resistant to lamivudine A small number of patients achieve sustained suppression of HBV replication Resistance occurs in up to 29% of patients treated for 5 years Patients with underlying kidney dysfunction are at risk for nephrotoxicity Telbivudine Dosage: 600 mg orally daily More potent than either lamivudine or adefovir but like them associated with resistance, especially in patients who are resistant to lamivudine Elevated creatine kinase levels are common Classified as pregnancy category B; treatment is recommended starting in the third trimester when mother's serum HBV DNA level is > 200,000 international units/mL to reduce levels at time of delivery Peginterferon alfa-2a Dosage: 180 mcg subcutaneously once weekly for 48 weeks Leads to sustained normalization of serum aminotransferase levels, disappearance of HBeAg and HBV DNA from serum, appearance of anti-HBe, and improved survival in up to 40% of treated patients Response is most likely in patients with a low baseline HBV DNA level and high aminotransferase levels and is more likely in those infected with HBV genotype A than with other genotypes (especially genotype D) and who have certain favorable polymorphisms of the IL28B gene Most complete responders eventually clear HBsAg and develop anti-HBs in serum, and are thus cured Relapses are uncommon in complete responders who seroconvert from HBeAg to anti-HBe Patients with HBeAg-negative chronic hepatitis B have a response rate of 60% after 48 weeks of therapy but the response may not be durable Response to interferon is poor in patients with HIV coinfection +++ Therapeutic Procedures ++ Activity is modified according to symptoms; bed rest is not necessary The diet should be well balanced, without limitations other than sodium or protein restriction if dictated by fluid overload or encephalopathy + Outcome Download Section PDF Listen +++ +++ Complications ++ Cirrhosis Hepatocellular carcinoma Extrahepatic: polyarteritis nodosa, membranous glomerulonephritis +++ Prognosis ++ Sequelae of chronic hepatitis B include Cirrhosis Liver failure Hepatocellular carcinoma The 5-year mortality rate 0–2% in those without cirrhosis 14–20% in those with compensated cirrhosis 70–86% following decompensation The risk of cirrhosis and hepatocellular carcinoma correlates with serum HBV DNA levels, and a focus of therapy is to suppress HBV DNA levels below 300 copies/mL (60 international units/mL) There is some evidence that HBV genotype C is associated with a higher risk of cirrhosis and hepatocellular carcinoma than other genotypes Antiviral treatment Improves the prognosis in responders Prevents (or leads to regression of) cirrhosis Decreases the frequency of liver-related complications (although the risk of hepatocellular carcinoma does not become as low as that in inactive HBV carriers and hepatocellular carcinoma may even occur after clearance of HBsAg) A risk score (PAGE-B) based on a patient's age, gender, and platelet count has been reported to predict the 5-year risk of hepatocellular carcinoma in white patients receiving entecavir or tenofovir +++ Prevention ++ Strict isolation of patients is not necessary Thorough hand washing by anyone who may contact contaminated utensils, bedding, or clothing is essential Screening of donated blood for HBsAg and anti-HBc has reduced the risk of transfusion-associated hepatitis markedly Pregnant women should be tested for HBsAg Persons with HBV should practice safer sex Vaccinate those with chronic hepatitis B against HAV (after prescreening for prior immunity) +++ When to Refer ++ For liver biopsy For antiviral therapy +++ When to Admit ++ Hepatic encephalopathy INR > 1.6 + References Download Section PDF Listen +++ + +Backus LI et al. Impact of sustained virologic response with direct-acting antiviral treatment on mortality in patients with advanced liver disease. Hepatology. 2019 Feb;69(2):487–97. [PubMed: 28749564] + +Hou J et al. Management algorithm for interrupting mother-to-child transmission of hepatitis B virus. Clin Gastroenterol Hepatol. 2019 Sep;17(10):1929–36. [PubMed: 30312789] + +Seto WK et al. Chronic hepatitis B virus infection. Lancet. 2018 Nov 24;392(10161):2313–24. [PubMed: 30496122] + +Tang LSY et al. Chronic hepatitis B infection: a review. JAMA. 2018 May 1;319(17):1802–13. [PubMed: 29715359] + +Terrault NA et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018 Apr;67(4):1560–99. [PubMed: 29405329] + +Thomas DL. Global elimination of chronic hepatitis. N Engl J Med. 2019 May 23;380(21):2041–50. [PubMed: 31116920] + +Yeo YH et al. Factors associated with rates of HBsAg seroclearance in adults with chronic HBV infection: a systematic review and meta-analysis. Gastroenterology. 2019 Feb;156(3):635–46. [PubMed: 30342034]