The hepatitis B virus (HBV), discovered in 1966, infects more than 350 million people worldwide.[1] HBV 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]
The public health burden of HBV infection is almost entirely due to its long-term effects on liver function. Chronic HBV infection is a major cause of cirrhosis and hepatocellular carcinoma.
In addition to the human suffering that these diseases cause, the social and economic costs are large. More than $1 billion is spent each year for hepatitis B–related hospitalizations. The indirect costs of chronic HBV infection are harder to measure but include reduced physical and emotional quality of life, reduced economic productivity, long-term disability, and premature death.
See also Pediatric Hepatitis A, Pediatric Hepatitis C, and Viral Hepatitis.
HBV is a DNA virus in the Hepadnaviridae family. 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:
HBV is a double-stranded DNA virus of the Hepadnaviridae family. HBV is a hepatotropic virus that replicates in the liver and causes hepatic damage and 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.
The adaptive immune response is thought to be responsible for viral clearance and disease pathogenesis during HBV infection. The humoral antibody response contributes to the clearance of circulating virus particles and the prevention of viral spread within the host while the cellular immune response eliminates infected cells.
Persistent HBV infection is characterized by a weak immune response due to inefficient CD4+ T cell (helper T cell) priming early in the infection and subsequent development of a quantitatively and qualitatively ineffective CD8+ T (cytotoxic T cell) cell response.[4]
HBV is transmitted by percutaneous or permucosal exposure to infectious body fluids, by sexual contact with an infected person. It is also transmitted by perinatal transmission from an infected mother to her infant.
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.
Modes of transmission are the same as for the human immunodeficiency virus (HIV), but HBV is 50-100 times more infectious. Unlike HIV, HBV can survive outside the body for at least 7 days. During that time, the virus can still cause infection if it enters the body of a person who is not infected.
Common modes of transmission in developing countries are as follows:
In many developed countries (eg, those in Western Europe and North America), patterns of transmission are different from those mentioned above. Today, most infections in these countries are transmitted during young adulthood by sexual activity and injecting drug use. HBV is a major infectious occupational hazard of health workers.
HBV is not spread by contaminated food or water and cannot be spread casually in the workplace.
The incidence (rate of new cases) of acute HBV infection has decreased dramatically in the United States since the mid 1980s. Reported acute clinical cases declined from 8,064 in 2002 to 4,519 in 2007. Many HBV infections are either asymptomatic or never reported, however; consequently, the US Centers for Disease Control and Prevention (CDC) estimates that 43,000 new infections occurred in the US in 2007.[5]
The reduction in incidence can be attributed to the availability of an effective vaccine and widespread immunization of infants and high-risk populations. However, the number of people who have chronic HBV infection remains high because of the long duration of infection and influx of immigrants who have chronic infection. National surveys have estimated that more than 1 million US residents (that 0.3-0.5% of the population) have chronic infection, which contributes to an estimated 2,000-4,000 deaths each year. Of these persons, 47-70% were born outside the United States.
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.
A study by Schillie et al found that perinatal HBV infection occurred among 1% of infants, most of whom received recommended immunoprophylaxis. Infants at greatest risk of infection were those born to women who were younger, hepatitis B e-antigen positive, or who had a high viral load or those infants who received 6</ref>[7]
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. Each year, an estimated 500,000 people die of cirrhosis and hepatocellular carcinoma caused by chronic infection and an additional 40,000 people die of acute hepatitis B. An estimated 500,000-1,000,000 persons die annually from HBV-related liver disease.
The distribution of HBV infection widely varies throughout the world. In some regions, over 10% of the population is positive for hepatitis B surface antigen (HBsAg), which indicates active infection. Countries are classified as having low endemic rates (< 2% of the population has the antibody to HBsAg), intermediate endemic rates (2-8% positive for HBsAg), or high endemic rates (>8% positive for HBsAg).
Hepatitis B is endemic in China, Southeast Asia, and Africa. Most people in the region become infected with HBV during childhood. In these regions, 8-10% of the adult population is chronically infected, which is the result of either neonatal transmission (vertical) or transmission from one individual to another (horizontal). In the Middle East and Indian subcontinent, an estimated 2-5% of the general population is chronically infected. High rates of chronic infections are also found in the Amazon region of South America and the southern parts of eastern and central Europe. Less than 1% of the population in Western Europe and North America is chronically infected, mostly as a result of horizontal transmission among young adults.
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.
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.
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.
Among patients with acute hepatitis B, 90% have a favorable course and recover completely. Patients of advanced age 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.
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.
Approximately 2,000-4,000 persons in the United States die each year of HBV-related conditions. Most deaths are attributed to cirrhosis and primary hepatocellular carcinoma, and a smaller proportion of patients die of fulminant hepatitis. HBV-infected individuals are also at increased risk of death from nonliver causes such as non-Hodgkin lymphoma and circulatory diseases.
Educate patients who are HBsAg carriers about safe-sex practices and universal vaccination benefits.
For patient education information, see the Hepatitis Center and Children's Health Center, as well as Hepatitis B and Immunization Schedule, Children.
A thorough history should be taken. Special emphasis is placed on risk factors for coinfection, alcohol use, and family history of hepatitis B virus (HBV) infection and liver cancer.
The incubation period for HBV infection ranges from 6 weeks to 6 months. 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 include the following:
Following acute infection, the disease remains subclinical in 60-65% of patients; 20-25% develop acute hepatitis, 5-10% become carriers, and 4% develop chronic 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 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.
Rare complications of viral hepatitis are as follows:
All patients with chronic hepatitis B (HBV) infection should have laboratory tests to assess liver diseases (complete blood counts with platelets, hepatic panel, and prothrombin time), serologic markers of HBV replication, and tests for coinfection with HCV (anti HCV), HDV (anti HDV) in persons from countries where HDV infection is common and in those with history of injection drug use, or HIV (anti HIV) in those at risk. Test should be performed to screen for hepatocellular carcinoma–alpha fetoprotein (HCC-AFP) at baseline, and ultrasound should be performed in high-risk patients.
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 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.
HBV serologic testing can be confusing and requires multiple tests for antigens (Ag) and antibody (Ab) responses in order to accurately diagnose the stage of infection. See Hepatitis B Test.
HBV surface antigen (HBsAg) 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 HBsAg in the serum.
Hepatitis B e antigen HBeAg, HBV DNA, and DNA polymerase appear in the serum soon after HBsAg, 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-HBc 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-HBc. Detection of IgM HBcAb is diagnostic of acute HBV infection, but total HBcAb is not helpful since IgG antibodies to HBcAg may persist for life.
IgG anti-HBs 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 HBsAg. Anti-HBs may persist for life, conferring protection; this is the basis for current vaccination strategies using noninfectious HBsAg. Hepatitis B surface antibody (HBsAb), but not hepatitis B core antibody (HBcAb), is detected in persons who have received the hepatitis B vaccine. The coexistence of HBsAg and HBsAb has been reported in approximately 25% of individuals who are HBsAg positive.
The carrier state is defined by the presence of HBsAg in the serum for 6 months or longer after its initial detection.
The presence of HBsAg alone does not necessarily indicate replication of complete virions, and patients may be asymptomatic and without liver damage. Chronic replication of HBV virions is characterized by persistence of circulating HBsAg, HBeAg, and HBV DNA, usually with anti-HBc and, occasionally, with anti-HBs. In these patients, progressive liver damage may occur.
During convalescence, HBsAg and HBeAg are cleared, and IgG antibodies to HBsAg, HBcAg, and HBeAg develop.
Quantification of serum HBV DNA is a crucial component in the evaluation of patients with chronic HBV infection and in the assessment of the efficacy of antiviral treatment. Most HBV DNA assays used in clinical practice are based on polymerase chain reaction (PCR) amplification with lower limits of detection of 50-200 IU/mL (250-1,000 copies/mL) and a limited dynamic range, up to 4-5 log10 IU/mL.
Tests for HBV DNA in serum rarely help in identifying HBV as the cause of liver disease in patients who are HBsAg negative; knowledge of this fact is especially important in patients with fulminant hepatitis B, in whom HBsAg may have cleared by the time they seek care.
Patients with signs of chronic disease may require a liver biopsy to assess the extent of histologic involvement and response to therapeutic protocols. Liver biopsy is useful in patients who do not meet the clear-cut criteria for starting treatment. Liver biopsy helps to assess the degree of liver damage and rule out other causes of liver disease.
Decisions on liver biopsy should take into consideration age, the new suggested upper limits of normal for ALT, HBeAg status, HBV DNA levels, and other clinical features suggestive of chronic liver disease or portal hypertension. However, liver histology can improve significantly in patients who have sustained response to antiviral therapy or spontaneous HBeAg seroconversion. Liver histology also can worsen rapidly in patients who have recurrent exacerbations or reactivations of hepatitis.
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 HBsAg using electron microscopy. Other HBV-infected hepatocytes may have sanded nuclei due to abundant HBcAg; 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.
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.
From the time of initial diagnosis, optimal management of hepatitis B virus (HBV) infection requires a lifetime of routine monitoring, even when patients are asymptomatic. The aims of treatment of chronic hepatitis B are to achieve sustained suppression of HBV replication and remission of liver disease. The ultimate goal is to prevent cirrhosis, hepatic failure, and hepatocellular carcinoma (HCC). Children with HBV infection may not need treatment until well into their adolescent years or adulthood.
To date, no conclusive evidence from randomized controlled trials of anti-HBV therapy has demonstrated a beneficial impact on any of these primary clinical outcomes because cirrhosis, hepatocellular carcinoma, and death often do not occur for many years after infection with HBV and would therefore require long-term evaluation of therapy to demonstrate benefit. As a consequence, most published reports of anti-HBV therapy use changes in short-term virologic, biochemical, and histologic parameters to infer the likelihood of long-term benefit. Parameters used to assess treatment response include normalization of serum ALT, decrease in serum HBV DNA level, loss of HBeAg with or without detection of anti-HBe, and improvement in liver histology.
Currently, 7 agents have been approved by the US Food and Drug Administration (FDA) for use in the treatment of adults with chronic hepatitis B in the United States. In September 2012, tenofovir was FDA approved for children with chronic hepatitis B aged 12 years or older. These agents, categorized as either interferons (IFN-a2b and peginterferon-a2a) or nucleoside or nucleotide analogues (lamivudine, adefovir, entecavir, tenofovir, telbivudine), may be used as monotherapy or in combination. Interferon use has a defined, self-limited course; in contrast, therapy with nucleoside or nucleotide analogues can be long-term, often indefinite treatment.
Lamivudine is now considered first-line therapy, eclipsing interferon. Consider lamivudine in patients who fail or are unlikely to respond to interferon therapy or patients who cannot tolerate interferon.
Discontinue lamivudine only when repeated assays demonstrate HBeAg loss or seroconversion to HBeAb; the time for stopping treatment, however, is controversial. Results of a histologic study reported that lamivudine treatment for 3 y reduced necroinflammatory activity and reversed fibrosis (including cirrhosis) in most patients.
A study of adolescents with HBV infection treated with tenofovir showed excellent responses with improvements in viral load, liver enzyme levels and fewer adverse events compared to placebo.[8]
Surgical care for HBV infection includes liver transplantation for decompensated liver disease and surgical resection of hepatocellular carcinoma.
The American Association for the Study of Liver Diseases (AASLD) has published guidelines on the management of chronic hepatitis B.[9] The proceedings of the NIH 2008 Consensus Conference on Management of Chronic Hepatitis B were considered in the development of these guidelines.[10]
See also Pediatric Hepatitis A, Pediatric Hepatitis C, and Viral Hepatitis.
Most patients do not require hospital care, but 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.
Consultations may include the following:
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. Although forced and prolonged bed rest is not essential for full recovery from acute hepatitis, many patients feel better with restricted physical activity.
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- to 2-, 6-mo) schedules have identical efficacy.
The American Academy of Pediatrics recommends that the hepatitis B vaccine should be administered within the first 24 hours to all newborn infants with a birth weight of greater than or equal to 2000 g.[11]
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 HBV surface antigen (HBsAg) positive is to administer HBIG 0.5 mL intramuscularly with the first dose of recombinant HBV vaccine within 12 hours of birth.
After immunization of exposed infants, serology should be tested for HBsAg and anti-HBs at age 9-18 months. An HBsAg-positive finding in an exposed 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 HBV to infants who have begun prophylaxis.[12]
For preterm infants who weigh less than 2000 g and are born to mothers with unknown HBsAg status, 0.5 mL HBIG should be given within 12 hours. The birth dose of vaccine should not be counted, and 3 additional doses are given according to recommendations. 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 HBsAb 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-HBs of 10 mIU/mL is noted, reimmunization with a 3-dose series is recommended. If the response if still negative, the patient is unlikely to mount antibody with additional doses. Some experts recommended the second course be with the high-dose version of the vaccine typically used for dialysis patients.
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.
Some combination vaccines used in the routine vaccination schedule result in infants receiving 4 doses of HBV vaccine (eg, at 0, 2, 4, and 6 mo). This is considered acceptable.
A study by Bruce et al examined the hepatitis vaccine duration of protection in children and adults in a cohort of 1578 Alaska Native adults and children from 15 Alaska communities aged 6 months or older who received 3 doses of plasma-derived hepatitis B vaccine. The study estimated that ≥90% of participants had evidence of protection 30 years later and that booster doses are not needed based on anti-HBs level ≥10 mIU/mL at 30 years and an 88% booster dose response.[13, 14]
All persons with chronic hepatitis B who are not immune to hepatitis A should receive 2 doses of hepatitis A vaccine 6-18 months apart. Infants of HBsAg-positive women should receive hepatitis B immunoglobulin and hepatitis B vaccination within 12 hours of birth, a complete set of 3 vaccinations, and long-term follow-up.
Reserve routine screening using ultrasonography and alpha-fetoprotein determination for patients with severe chronic active hepatitis, cirrhosis, or both.[15]
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 approved for hepatitis B by the US Food and Drug Administration (FDA).
Clinical Context: Tenofovir is a nucleotide analogue (adenosine monophosphate) reverse-transcriptase and hepatitis B virus (HBV) polymerase inhibitor. It is approved to treat chronic hepatitis B infection in children aged 12 years or older who weigh at least 35 kg.
Clinical Context: Biologic interferons are proteins produced by host cells in response to viral infection. Three interferons have been identified, and each has antiviral and immunoregulatory actions: interferon-alfa is produced by B lymphocytes and monocytes; interferon-beta is produced by fibroblasts; and interferon-gamma is produced by T-helper and natural killer (NK) cells. Immunomodulatory effects of interferons are mediated by an increase in HLA class I antigen and FC receptor expression, an increased CD4/CD8 ratio, and activation of NK cell pathways.
Ideally, candidates for interferon therapy have evidence of ongoing viral replication (presence of hepatitis e antigen [HBeAg] or HBV DNA) for at least 6 months and either persistently increased serum aminotransferase activity or evidence of chronic hepatitis B infection on liver biopsy findings. Before recombinant interferon therapy, screening patients for at least 4-6 months to identify those who may be entering a period of spontaneous seroconversion to HBeAb is often beneficial.
Clinical variables associated with a favorable response to therapy are high pretherapy aminotransferase levels, low HBV DNA levels, and active disease at liver biopsy. Other, less useful, variables include female sex, acquisition of infection in adulthood, heterosexuality, HIV antibody negativity, and history of acute hepatitis.
Responses to interferon alfa-2b, is defined as a sustained loss of HBeAg and HBV DNA, with a normalization or near normalization of alanine aminotransferase (ALT) levels for at least 6 mo after therapy; this is observed in 25-40% of patients. Chinese children respond poorly to interferon therapy. Safety and effectiveness in patients aged 1-17 years have been established.
Clinical Context: Peginterferon alfa-2a binds to cell surface receptors in a cascade of protein interactions resulting in gene transcription. These stimulated genes modulate inhibit viral replication in infected cells, cell proliferation, and immunomodulation. This agent is indicated for adults with HBeAg-positive and HBeAg-negative chronic hepatitis B with compensated liver disease and evidence of viral replication and liver inflammation.
Clinical Context: Lamivudine inhibits HBV DNA polymerase. Its use should be considered in patients with ongoing HBV replication, elevated aminotransferase activity, and histologic evidence of liver injury. Lamivudine is now considered first-line therapy, eclipsing interferon. Consider lamivudine in patients who fail or are unlikely to respond to interferon therapy or patients who cannot tolerate interferon.
Discontinue lamivudine only when repeated assays demonstrate HBeAg loss or seroconversion to HBeAb; the time for stopping treatment, however, is controversial. Results of a histologic study reported that lamivudine treatment for 3 years reduced necroinflammatory activity and reversed fibrosis (including cirrhosis) in most patients.
Emergence of resistance is the major drawback of nucleoside analogue monotherapy (incidence of resistance rises from 15-32% in the first year to 67-69% by the fifth year of treatment). The proper management of viral breakthrough in patients treated with lamivudine is not yet defined. Continuation of lamivudine appears to be warranted in most cases because the resistant strains of HBV seem to be attenuated and are associated with only mild liver injury.
Combination therapy with 2-3 nucleoside analogues may delay or prevent emergence of viral resistance, but clinical trials are needed.
Lamivudine is safe and effective in children aged 2-17 y. Note that the available dosage forms differ between Epivir and Epivir-HBV (formula specific for hepatitis B virus). Epivir-HVB is available as a 100-mg tablet or oral solution (5 mg/mL), whereas Epivir contains 150 mg/tablet or 10 mg/mL in an oral solution.
Clinical Context: Adefovir is indicated for chronic hepatitis B. This agent is an acyclic analogue of deoxyadenosine monophosphate and inhibits amplification of circular DNA in HBV-infected hepatocytes. When given daily for 48 weeks, it has been associated with significant improvement of histologic results, higher rate of HbeAg seroconversion, reduction of HBV DNA by 3 logs, and higher normalization rate of ALT when compared with placebo. The chance of adefovir-resistance development is low; however, a new adefovir-resistant mutant has been detected in 1.6% of patients at 96 weeks follow-up.
Clinical Context: A guanosine nucleoside analogue with activity against HBV polymerase, entecavir competes with natural substrate deoxyguanosine triphosphate to inhibit HBV polymerase activity (ie, reverse transcriptase). It is less effective for lamivudine-refractory HBV infection. This agent is indicated for treatment of chronic hepatitis B infection. It as available in tablets and oral solution (0.05 mg/mL; 0.5 mg = 10 mL).
Clinical Context: Telbivudine is a nucleoside analogue approved by the FDA for chronic hepatitis B treatment. It inhibits hepatitis B viral DNA polymerase. It is indicated in patients with evidence of ongoing hepatitis B viral replication and either persistent elevated aminotransferase activity or histologic evidence of active liver disease. Consider its use in patients who did not or are unlikely to respond to interferon or for patients who cannot tolerate interferon. Emergence of resistance is major drawback of nucleoside analogue monotherapy.
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.
Clinical Context: This vaccine is used for immunization against infection caused by all known subtypes of hepatitis B virus.
Clinical Context: This combined hepatitis A–hepatitis B vaccine is used for active immunization of persons older than 18 years against disease caused by HAV and infection by all known subtypes of hepatitis B virus (HBV).
Hepatitis B vaccine is used for active immunization against disease caused by HBV.