Hepatitis B 

Updated: Aug 01, 2018
Author: Nikolaos T Pyrsopoulos, MD, PhD, MBA, FACP, AGAF; Chief Editor: BS Anand, MD 

Overview

Practice Essentials

Hepatitis B infection is a worldwide healthcare problem, especially in developing areas. The hepatitis B virus (HBV) is commonly transmitted via body fluids such as blood, semen, and vaginal secretions.[1]

The hematoxylin and eosin (H&E) stain below depicts "ground-glass" cells seen in approximately 50-75% of livers affected by chronic HBV infection.

Under higher-power magnification, ground-glass cel Under higher-power magnification, ground-glass cells may be visible in chronic HBV infection. Ground-glass cells are present in 50% to 75% of livers with chronic HBV infection. Immunohistochemical staining is positive for HBsAg.

Signs and symptoms

The pathogenesis and clinical manifestations of hepatitis B are due to the interaction of the virus and the host immune system, which leads to liver injury and, potentially, cirrhosis and hepatocellular carcinoma. Patients can have either an acute symptomatic disease or an asymptomatic disease.

Icteric hepatitis is associated with a prodromal period, during which a serum sickness–like syndrome can occur. The symptomatology is more constitutional and includes the following:

  • Anorexia

  • Nausea

  • Vomiting

  • Low-grade fever

  • Myalgia

  • Fatigability

  • Disordered gustatory acuity and smell sensations (aversion to food and cigarettes)

  • Right upper quadrant and epigastric pain (intermittent, mild to moderate)

Patients with fulminant and subfulminant hepatitis may present with the following:

  • Hepatic encephalopathy

  • Somnolence

  • Disturbances in sleep pattern

  • Mental confusion

  • Coma

  • Ascites

  • Gastrointestinal bleeding

  • Coagulopathy

Patients with chronic hepatitis B infection can be immune tolerant or have an inactive chronic infection without any evidence of active disease, and they are also asymptomatic. Patients with chronic active hepatitis, especially during the replicative state, may have symptoms similar to those of acute hepatitis.

See Clinical Presentation for more detail.

Diagnosis

The physical examination findings in hepatitis B disease vary from minimal to impressive (in patients with hepatic decompensation), according to the stage of the disease.

Examination in patients with acute hepatitis may demonstrate the following:

  • Low-grade fever

  • Jaundice (10 days after appearance of constitutional symptomatology; lasts 1-3 mo)

  • Hepatomegaly (mildly enlarged, soft liver)

  • Splenomegaly (5-15%)

  • Palmar erythema (rarely)

  • Spider nevi (rarely)

Signs of chronic liver disease include the following:

  • Hepatomegaly

  • Splenomegaly

  • Muscle wasting

  • Palmar erythema

  • Spider angiomas

  • Vasculitis (rarely)

Patients with cirrhosis may have the following findings:

  • Ascites

  • Jaundice

  • History of variceal bleeding

  • Peripheral edema

  • Gynecomastia

  • Testicular atrophy

  • Abdominal collateral veins (caput medusa)

Laboratory studies

The following laboratory tests may be used to assess the various stages of hepatitis B disease:

  • Alanine aminotransferase and/or aspartate aminotransferase levels

  • Alkaline phosphatase levels

  • Gamma-glutamyl transpeptidase levels

  • Total and direct serum bilirubin levels

  • Albumin level

  • Hematologic and coagulation studies (eg, platelet count, complete blood count [CBC], international normalized ratio)

  • Ammonia levels

  • Erythrocyte sedimentation rate

  • Serologic tests

The serologic tests should include the following laboratory studies:

  • Hepatitis B surface antigen (HBsAg)

  • Hepatitis B e antigen (HBeAg)

  • Hepatitis B core antibody (anti-HBc) immunoglobulin M (IgM)

  • anti-HBc IgG

  • Hepatitis B e antibody (anti-HBe)

  • hepatitis B virus (HBV) deoxyribonucleic acid (DNA)

Imaging studies

The following radiologic studies may be used to evaluate patients with hepatitis B disease:

  • Abdominal ultrasonography

  • Abdominal computed tomography (CT) scanning

  • Abdominal magnetic resonance imaging (MRI)

Procedures

Liver biopsy, percutaneous or laparoscopic, is the standard procedure to assess the severity of disease in patients with features of chronic active liver disease (ie, abnormal aminotransferase levels and detectable levels of HBV DNA).

See Workup for more detail.

Management

The primary treatment goals for patients with hepatitis B infection are to prevent progression of the disease, particularly to cirrhosis, liver failure, or hepatocellular carcinoma (HCC).[2] Pegylated interferon alfa (PEG-IFN-a), entecavir, and tenofovir disoproxil fumarate are the first-line agents in the treatment of hepatitis B disease.

Pharmacotherapy

The following medications are used in the treatment of hepatitis B:

  • Nucleos(t)ide reverse transcriptase inhibitors (eg, tenofovir disoproxil fumarate, tenofovir alafenamide, lamivudine)

  • Hepatitis B/hepatitis C agents (eg, adefovir dipivoxil, entecavir, telbivudine, PEG-IFN-a 2a, interferon alfa-2b)

Dietary changes

For individuals with decompensated cirrhosis (prominent signs of portal hypertension or encephalopathy), the following dietary limitations are indicated:

  • A low-sodium diet (1.5 g/day)

  • High-protein diet (ie, white-meat protein [eg, chicken, turkey, fish])

  • Fluid restriction (1.5 L/day) in cases of hyponatremia

Liver transplantation

Orthotopic liver transplantation is the treatment of choice for patients with fulminant hepatic failure who do not recover and for patients with end-stage liver disease due to hepatitis B disease.

See Treatment and Medication for more detail.

Background

Hepatitis B is a worldwide healthcare problem, especially in developing areas. An estimated one third of the global population has been infected with the hepatitis B virus (HBV). Approximately 350-400 million people have lifelong chronic infection, and 0.5 % spontaneously seroconvert annually from having the hepatitis B surface antigen (HBsAg) to having the hepatitis B surface antibody (anti-HBs).[3] (See Pathophysiology, Etiology, and Epidemiology.)

Complications from hepatitis B include progression to hepatocellular carcinoma (HCC) and, rarely, cirrhosis. Glomerulonephritis and polyarteritis nodosa are seen, as well as various dermatologic, cardiopulmonary, joint, neurologic, hematologic, and gastrointestinal (GI) tract manifestations. (See Pathophysiology.)

Since the 1970s, considerable progress has also been made regarding the knowledge of the epidemiology, virology, natural history, and treatment of the hepatitis B virion, a hepatotropic virus particle (see the image below). In addition, ongoing vaccination programs have been successful in many countries in decreasing the prevalence of HBV disease (eg, Taiwan).[4] (See Etiology, Epidemiology, Workup, Treatment, and Medication.)

Hepatitis B virus (HBV) is a hepadnavirus, highly Hepatitis B virus (HBV) is a hepadnavirus, highly resistant to extremes of temperature and humidity, that invades the hepatocytes. The viral genome is a partially double-stranded, circular DNA linked to a DNA polymerase that is surrounded by an icosahedral nucleocapsid and then by a lipid envelope. Embedded within these layers are numerous antigens that are important in disease identification and progression. Within the nucleocapsid are the hepatitis B core antigen (HBcAg) and precore hepatitis B e antigen (HBeAg), and on the envelope is the hepatitis B surface antigen (HBsAg). Transmission electron micrograph (TEM) courtesy of Graham Colm and the Wikipedia, and licensed under the Creative Commons Attribution 3.0 Unported license.

HBV is transmitted hematogenously and sexually. The outcome of this infection is a complicated viral-host interaction that results in either an acute symptomatic disease or an asymptomatic disease. Patients clear HBV and develop anti-HBs; however, as long as the individual has antibody to hepatitis B core antigen (HBcAg), he or she is at risk for reactivation, because HBV infection remains an incurable disease, similar to Epstein-Barr virus (EBV), cytomegalovirus (CMV), and Herpes simplex virus (HSV) infections. Alternatively, the patient may develop a chronic infection state with positivity for HBsAg. Late consequences are cirrhosis and the development of HCC in 15-30% of individuals.[4, 5, 6, 7]

In immunocompetent adults, less than approximately 4% of HBV infections become chronic, whereas up to 90% of perinatally infected infants will have chronic disease.[8] Among children who acquire HBV infection between ages 1 and 5 years, 30-50% become chronically infected. According to the World Health Organization (WHO), by the end of 2010, the HBV vaccine had been routinely introduced in 179 countries, with a global coverage of 75%. Coverage in the Americas was at 89%; in Europe, 78%; in Africa, 76%; and in Southeast Asia, 52%.[9]

In Taiwan, which in 1984 launched a nationwide HBV vaccination program, the prevalence of HCC in children younger than 20 years has been reported to be 0.5% or less.[4]

Antiviral treatment may be effective in approximately 95% of the patients who are treated with first-line oral therapy, as defined by undetectable HBV DNA. For those who are treated with interferon, about 17% have persistent HBV DNA suppression. For selected candidates, liver transplantation currently seems to be the only viable treatment for the later stages of hepatitis B infection, with a posttransplantation viral control of greater than 90-95%. (See Treatment and Medication.)

See also Liver Disease in Pregnancy, Hepatitis A, Hepatitis C, Hepatitis D, and Hepatitis E.

Pathophysiology

Hepatitis B virus (HBV) is a hepadnavirus (see the following image), with the virion consisting of a 42-nm spherical, double-shelled particle composed of small spheres and rods and with an average width of 22 nm.[10, 11, 12, 13, 14] It is an exceedingly resistant virus, capable of withstanding extreme temperatures and humidity. HBV can survive when stored for 15 years at –20°C, for 24 months at –80°C, for 6 months at room temperature, and for 7 days at 44°C. Indeed, the approximately 400-year-old mummified remains of a child found on a mountain top in Korea had HBV in the liver that could be sequenced, and a viral genotype C was identified.[15]

Hepatitis B virus (HBV) is a hepadnavirus, highly Hepatitis B virus (HBV) is a hepadnavirus, highly resistant to extremes of temperature and humidity, that invades the hepatocytes. The viral genome is a partially double-stranded, circular DNA linked to a DNA polymerase that is surrounded by an icosahedral nucleocapsid and then by a lipid envelope. Embedded within these layers are numerous antigens that are important in disease identification and progression. Within the nucleocapsid are the hepatitis B core antigen (HBcAg) and precore hepatitis B e antigen (HBeAg), and on the envelope is the hepatitis B surface antigen (HBsAg). Transmission electron micrograph (TEM) courtesy of Graham Colm and the Wikipedia, and licensed under the Creative Commons Attribution 3.0 Unported license.

Viral genome

The viral genome of hepatitis B consists of a partially double-stranded, circular DNA molecule of 3.2 kilobase (kb) pairs that encodes the following 4 overlapping open reading frames:

  • S (the surface, or envelope, gene): Encodes the pre-S1, pre-S2, and S proteins

  • C (the core gene): Encodes the core nucleocapsid protein and the e antigen; an upstream region for the S (pre-S) and C (pre-C) genes has been found

  • X (the X gene): Encodes the X protein

  • P (the polymerase gene): Encodes a large protein promoting priming ribonucleic acid (RNA) ̶ dependent and DNA-dependent DNA polymerase and ribonuclease H (RNase H) activities

Surface gene

The S gene encodes the viral envelope. There are 5 mainly antigenic determinants: (1) a, common to all hepatitis B surface antigens (HBsAg), and (2-5) d, y, w, and r, which are epidemiologically important and identify the serotypes.

Core gene

The core antigen, HBcAg, is the protein that encloses the viral DNA. It can also be expressed on the surface of the hepatocytes, initiating a cellular immune response.

The e antigen, HBeAg, which is also produced from the region in and near the core gene, is a marker of active viral replication. It serves as an immune decoy and directly manipulates the immune system; it is thus involved in maintaining viral persistence. HBeAg can be detected in patients with circulating serum HBV DNA who have “wild type” infection. As the virus evolves over time under immune pressure, core promotor and precore mutations emerge, and HBeAg levels fall until the level is not measurable by standard assays.

Individuals who are infected with the wild type virus often have mixed infections, with core and precore mutants in up to 50% of individuals. They often relapse with HBeAg-negative disease after treatment.

X gene

The role of the X gene is to encode proteins that act as transcriptional transactivators that aid viral replication. Evidence strongly suggests that these transactivators may be involved in carcinogenesis.

Antibody production

The production of antibodies against HBsAg (anti-HBs) confers protective immunity and can be detected in patients who have recovered from HBV infection or in those who have been vaccinated.

Antibody to HBcAg (anti-HBc) is detected in almost every patient with previous exposure to HBV and indicates that there is a minute level of persistent virus, as demonstrated by the risk of reactivation in individuals who undergo immune suppression regardless of their anti-HBs status.

The immunoglobulin M (IgM) subtype of anti-HBc is indicative of acute infection or reactivation, whereas the IgG subtype is indicative of chronic infection. The activity of the disease cannot be understood using this marker alone, however.

Antibody to HBeAg may be suggestive of a nonreplicative state if there is undetectable HBV DNA or the emergence of the core/precore variants and of chronic HBV HBeAg-negative disease.

Variants of HBV

With the newest polymerase chain reaction (PCR) assay techniques, scientists are able to identify variations in the HBV genome (variants) as far back as 1995, even in patients who are positive for HBeAg. Mutations of various nucleotides such as the 1896, 1764, and 1768 (precore/core region) processing the production of the HBeAg have been identified (HBeAg-negative strain).[16]

The prevalence of the HBeAg-negative virus varies from one region to another. Estimates indicate that among patients with chronic HBV infection, 50-60% of those from Southern Europe, the Middle East, Asia, and Africa, as well as 10-30% of patients in the United States and Europe, have been infected with this strain.

Immune response

The pathogenesis and clinical manifestations of hepatitis B infection are due to the interaction of the virus and the host immune system. The immune system attacks HBV and causes liver injury, the result of an immunologic reaction when activated CD4+ and CD8+ lymphocytes recognize various HBV-derived peptides on the surface of the hepatocytes. Impaired immune reactions (eg, cytokine release, antibody production) or a relatively tolerant immune status result in chronic hepatitis. In particular, a restricted T-cell–mediated lymphocytic response occurs against the HBV-infected hepatocytes.[17, 18]

The final state of HBV disease is cirrhosis. With or without cirrhosis, however, patients with HBV infection are likely to develop hepatocellular carcinoma (HCC).[4, 5, 6] In the United States, the most common presentation of these patients with HCC is that they are of Asian origin and acquired HBV disease as newborns (vertical transmission).

Viral life cycle

The 5 stages that have been identified in the viral life cycle of hepatitis B infection are briefly discussed below. Different factors have been postulated to influence the development of these stages, including age, sex, immunosuppression, and coinfection with other viruses.

Stage 1: Immune tolerance

This stage, which lasts approximately 2-4 weeks in healthy adults, represents the incubation period. For newborns, the duration of this period is often decades. Active viral replication is known to continue despite little or no elevation in the aminotransferase levels and no symptoms of illness.

Stage 2: Immune active/immune clearance

In the immune active stage, also known as the immune clearance stage, an inflammatory reaction with a cytopathic effect occurs. HBeAg can be identified in the sera, and a decline in the levels of HBV DNA is seen in some patients who are clearing the infection. The duration of this stage for patients with acute infection is approximately 3-4 weeks (symptomatic period). For patients with chronic infection, 10 years or more may elapse before cirrhosis develops, immune clearance takes place, HCC develops, or the chronic HBeAg-negative variant emerges.

Stage 3: Inactive chronic infection

In the third stage, the inactive chronic infection stage, the host can target the infected hepatocytes and HBV. Viral replication is low or no longer measurable in the serum, and anti-HBe can be detected. Aminotransferase levels are within the reference range. It is most likely at this stage that an integration of the viral genome into the host's hepatocyte genome takes place. HBsAg still is present in the serum.

Stage 4: Chronic disease

The emergence of chronic HBeAg-negative disease can occur from the inactive chronic infection stage (stage 3) or directly from the immune active/clearance stage (stage 2).

Stage5: Recovery

In the fifth stage, the virus cannot be detected in the blood by DNA or HBsAg assays, and antibodies to various viral antigens have been produced. The image below depicts the serologic course of HBV infection.

Serologic course of hepatitis B virus (HBV) infect Serologic course of hepatitis B virus (HBV) infection. The flat bars show the duration of seropositivity in self-limited acute HBV infection. The pointed bars show that HBV DNA and e antigen (HBeAg) can become undetectable during chronic infection. Only immunoglobulin G (IgG) antibodies to the HBV core antigen (anti-HBc) are predictably detectable after resolution of acute hepatitis or during chronic infection. Antibody to hepatitis B surface antigen (anti-HBs) is generally detectable after resolution of acute HBV infection but may disappear with time. It is only rarely found in patients with chronic infection and does not indicate that immunologic recovery will occur or that the patient has a better prognosis. ALT = alanine transaminase. (Adapted from Liaw YF, Chu CM. Hepatitis B virus infection. Lancet. 2009;373(9663):582-92.)

Genotypes and disease progression

Ten different genotypes (A through J), representing a divergence of the viral DNA of about 8%, have been identified.[19] The prevalence of the genotypes varies in different countries. The progression of the disease seems to be more accelerated and the response to treatment with antiviral agents is less favorable for patients infected by genotype C, compared with those infected by genotype B. However, much of this can be explained by the presence of core and precore mutations found in multivariate analysis.[20, 21]

It has been confirmed that the risk of HCC is related to higher HBV DNA levels in the serum, when DNA is present for longer periods—with an even higher risk if there is an increasing level of hepatitis B viral load, the presence of genotype C, and the presence of mutations in the precore and basal core promoter regions.

Hepatocellular carcinoma

Even the presence of hepatitis B surface antibody (anti-HBs) in the absence of hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA is significantly related to an increased risk for HCC, although surveillance for HCC is not recommended in the affected group unless cirrhosis is present. In the United States, the estimated annual incidence of HCC in patients infected with hepatitis B is 818 cases per 100,000 persons. In Taiwan, the annual incidence of this malignancy in patients with hepatitis B and cirrhosis is 2.8%. Familial clustering of HCC has been described among families with hepatitis B in Africa, the Far East, and Alaska.

HBV and HCV coinfection

The prevalence of HCC among patients with HBV and hepatitis C virus (HCV) coinfection is higher than in those with a single infection. The rate of development of HCC per 100 person years of follow-up is 2% in patients with cirrhosis and HBV infection, 3.7% in patients with HCV infection, and 6.4% in patients with dual HBV and HCV infection. These findings point to a probable synergistic effect on the risk of HCC.

HBV and HDV coinfection

Individuals coinfected with hepatitis D (delta) virus (HDV) are thought to have a higher rate of HCC and cirrhosis, with the virus reportedly increasing the risk for HCC 3-fold and mortality rates 2-fold in patients with HBV cirrhosis.[22]

Worldwide, the prevalence of HDV coinfection among patients infected with HBV is 0-30%, with the highest prevalence in Mongolia, Southeast Turkey, and the Orinoco River in South America. The speculation that HDV may promote hepatocarcinogenesis in these patients has been investigated with varying results. The prevalence of anti-delta among patients with cirrhosis with and without HCC was not significantly different in one study, whereas most other investigations show the delta virus to be more aggressive, with higher rates of cirrhosis and cancer.[22, 23, 24]

Possible pathogenic mechanisms

The mechanism by which chronic hepatitis B infection predisposes to the development of HCC is not clear. Cirrhosis is a cardinal factor in carcinogenesis. Hepatocyte inflammation, necrosis, mitosis, and features of chronic hepatitis are major factors in nodular regeneration, fibrosis, and carcinoma. Liver cell dysplasia, defined as cellular enlargement, nuclear pleomorphism, and multinucleated cells affecting groups or whole nodules, may be an intermediate step. The high cell-proliferation rate increases the risk of HCC.

The fact that the facultative liver stem cells are capable of bipotent differentiation into hepatocytes or biliary epithelium, termed oval cells, may play an important role in the pathogenesis. These cells are small, with oval nuclei and scant pale cytoplasm.

Oval cells are prominent in actively regenerating nodules and in liver tissue surrounding the cancer. They appear to be the principal producers of alpha-fetoprotein (AFP). Although the cellular targets of carcinogenesis have not been identified, some evidence from experimental animal models suggests that oval cell proliferation is associated with an increased risk for the development of HCC.

Although cirrhosis is found in the majority of patients with HCC, it is not obligatory, because individuals with chronic infection may develop HCC even without the evidence of cirrhosis.

HBV has been speculated to have intrinsic hepatocarcinogenic activity, interacting with host DNA in different ways. After entering the hepatocyte, viral DNA is integrated within the genome. The site of integration is not constant but usually involves the terminal repeat sequences. Chromosomal deletions, translocations, rearrangements, inversions, or even duplications of normal DNA sequencing accompany integration.

Transactivation of the function of genes controlling transcriptional factors (ie, insulinlike growth factor II [IGF-2], transforming growth factor-alpha [TGF-a], TGF-beta, cyclin-a [a protein that controls cell division], epidermal growth factor-r [EGFR], retinoic acid receptor [RAR]), and oncogenes such as c-myc, fos, ras (activating the internal signal transduction cascade upregulating ras/mitogen–activated kinase, c-Jun N terminal kinase, nuclear factor–kB [NF-kB], Jak-1-STAT, src- dependent pathways) influence normal hepatocyte differentiation or cell cycle progression.

Furthermore, the integrated part of HBV controlling the production of the HBxAg (antigen for the X gene of HBV) is overexpressed. These observations suggest that the site of viral genomic integration into the host's DNA is not the only factor.

Most likely, the HBxAg produced by these sequences is the transactivating factor, because it has been found to bind to a variety of transcription factors such as CREB (cyclic adenosine monophosphate [cAMP]–response element-binding protein) and ATF-2 (activating transcription factor 2), which alters their DNA-binding specificity. Thus, the ability of the HBV pX protein to interact with cellular factors broadens the DNA-binding specificity of these regulatory proteins and provides a mechanism for pX to participate in transcriptional regulation. This shifts the pattern of host gene expression relevant to the development of HCC.

Additionally, HBxAg has been postulated to bind to the C-terminus and inactivate the product of the tumor suppressor gene TP53, as well as to do the following:

  • Sequester TP53 in the cytoplasm, resulting in the abrogation of TP53 -induced apoptosis (although controversy exists regarding this concept)

  • Reduce the ability for nucleotide excision repair by directly acting with proteins associated with DNA transcription and repair such as XPB and XPD

  • Reduce p21WAF1 expression, which is a cell cycle regulator

  • Bind to protein p55sen, which is involved in the cell fate during embryogenesis and is found in the liver of patients with hepatitis B, thus altering its function

The levels of tumor necrosis factor-alpha (TNF-a), a proinflammatory cytokine, are also upregulated. The transcriptional transactivation of nitric oxide (NO) synthetase II by pX and the elevated levels of TNF-a are responsible for the high levels of NO found in these patients. NO is a putative mutagen through several mechanisms of functional modifications of TP53, DNA oxidation, deamination, and formation of the carcinogenic N-nitroso compounds. A second transactivator is encoded in the pre-S/S region of the HBV genome, stimulating the expression of the human proto-oncogenes c-fos and c-myc; this upregulates the expression of TGF-a by transactivation.

Glomerulonephritis

The most common type of glomerulonephritis described in association with hepatitis B is membranous glomerulonephritis (MGN), found mainly in children. However, membranoproliferative glomerulonephritis (MPGN) and, even more rarely, immunoglobulin (Ig) A nephropathy, have also been identified.

The prevalence rate of glomerulonephritis among patients with chronic hepatitis B is not well known, although observations have been made in children that suggest a range of 11-56.2%. However, such a high prevalence is not recognized in the United States; this may be because of the differences in epidemiology of HBV, which may be predominantly perinatal in other geographic areas of the world (see Epidemiology).

A previous history of chronic liver disease is not present in the majority of patients with chronic hepatitis B at presentation, and most of them have no clinical or biochemical findings to suggest acute or chronic liver disease. However, liver biopsies often demonstrate features of chronic hepatitis. In addition, serologic markers of an HBV replicative state are often evident, and complement activation is suggested by low levels of C3 and C4.

Generally, the most prominent finding among affected children is MGN, primarily with capillary wall deposits of hepatitis B e antigen (HBeAg). In contrast, adults present with features of MPGN with mesangial and capillary wall deposits of HBsAg. A rare overlap between membranous nephropathy and IgA nephropathy has also been described.

Possible pathogenic mechanisms

The mechanism by which patients with chronic hepatitis B develop glomerulonephritis is not completely understood. One possible explanation is that HBV antigens (ie, HBsAg, HBeAg) act as triggering factors, eliciting immunoglobulins and thus forming immune complexes, which are dense, irregular deposits in the glomerular capillary basement membranes. HBV DNA has been identified by in situ hybridization in kidney specimens, distributed generally in the nucleus and cytoplasm of epithelial cells and mesangial cells of glomeruli and in the epithelial cells of renal tubules.

Polyarteritis nodosa

An association between hepatitis B and arteritis has been described when HBsAg is present in serum and in vascular lesions. Evidence for a cause-and-effect relationship is further supported by a high prevalence (36-69%) of HBsAg in patients with polyarteritis nodosa (PAN). This very serious complication presents early during the course of hepatitis B, and the incidence is high among certain populations, such as Alaskan Eskimos.

The pathogenesis of PAN is not clear. Circulating immune complexes containing HBsAg, immunoglobulins (IgG and IgM), and complement have been demonstrated by immunofluorescence in the walls of the affected vessels and may trigger the onset of PAN. However, whether these represent the primary etiology of the disease remains unclear.

The clinical manifestations of PAN include the following:

  • Cardiovascular (eg, hypertension [sometimes severe], pericarditis, heart failure)

  • Renal (eg, hematuria, proteinuria, renal insufficiency)

  • Gastrointestinal (GI) (eg, abdominal pain, mesenteric vasculitis)

  • Musculoskeletal (eg, arthralgias, arthritis)

  • Neurologic (eg, mononeuritis)

  • Dermatologic (eg, rashes)

Significant proteinuria (>1 g/day), renal insufficiency (serum creatinine >1.58 mg/dL), GI and central nervous system involvement, and cardiomyopathy are associated with increased mortality.

The course of PAN is independent of the severity and progression of the liver disease. Among patients with PAN, 20-45% die as a consequence of vasculitis in 5 years, despite treatment, with the mortality rate being similar whether patients are HBsAg seropositive or seronegative.

Etiology

Hepatitis B infection, caused by the hepatitis B virus (HBV), is commonly transmitted via body fluids such as blood, semen, and vaginal secretions.[1] Consequently, sexual contact, accidental needle sticks or sharing of needles, blood transfusions, and organ transplantation are routes for HBV infection. Infected mothers can also pass the infection to their newborns during the delivery period.[1]

Genetics of infection with hepatitis B

Several genes, many having to do with the host immune response, have been implicated in the susceptibility to chronic hepatitis B infection. The TNFSF9 gene encodes the CD137L protein, and its expression was found to be significantly higher in patients with chronic hepatitis B infection than in healthy controls. Its expression was also found to be higher in patients who had chronic hepatitis B with cirrhosis, in contrast to those without cirrhosis.[25]

Research done in West Africa, where 90% of the population is infected with hepatitis B, shows that certain human leukocyte antigen (HLA) class II haplotypes influence the likelihood of chronic infection. For reasons that are not completely clear, persons in the study who were heterozygous for the HLA-DRA and HLA-DQA1 genes were found to be less likely to develop a chronic infection.[26]

IFNGR1 gene

Several additional genes are associated with susceptibility to hepatitis B infection. The IFNGR1 gene is located at 6q23.3 and encodes the interferon gamma (IFN-γ) receptor 1, which has an important role in cell-to-cell communications and can be activated in response to infection, but it is not specific to hepatitis B.[27] Patients with significant dysfunction in this gene have a particular immune deficiency that leaves them extremely susceptible to mycobacterial infections.[27]

A more subtle change in the promoter region at location -56 in this gene has shown significant association with the natural history of hepatitis B infection. Individuals with the C allele at this location were found in a study to be more likely to clear the virus, whereas individuals with the T allele at this location were more likely to have persistent viral infection.[28]

IFNAR2 gene

The IFNAR2 gene is located at 21q22.1 and encodes the IFN-alpha, -beta, and -omega receptor 2. Although it presumably is like the previous gene, with multiple functions in the immune system, at the present time it is known only to be associated with susceptibility to hepatitis B.

A study looking at this gene found that a single nucleotide polymorphism, resulting in a phenylalanine-to-serine substitution at position 8, was associated with an increased risk for chronic hepatitis B infection.[29]

IL1OR2 gene

The same study also found that a polymorphism in the IL10R2 gene (or the CRFB4 gene), also located at 21q22.11, is associated with an increased risk of chronic hepatitis B infection. This particular polymorphism results in a lysine-to-glutamic acid substitution at position 47.[29]

Variations in vaccine response

It is also known that certain patients have different responses to the hepatitis B vaccine. One study found that 14% of patients who received the vaccine were low responders.[30] A greater-than-expected number of these patients were homozygotes for the HLA-B8, -SC01, and -DR3 haplotypes. It was hypothesized that because HLA II binds antigens, different haplotypes may alter the way in which vaccine peptides activate the immune system.[30]

Another study, which looked at 914 immune candidates in over 1600 patients who were given the HBV vaccine, found numerous single-nucleotide polymorphisms (SNPs) that were associated with inadequate levels of antibody response after vaccination,[31] with most found in the HLA genes.

However, one SNP was found in the 3 prime (3’) downstream region of the FOXP1 gene. This gene is a transcriptional repressor that plays a role in the differentiation of monocytes and the function of macrophages.[31]

Epidemiology

US statistics

An estimated 60,000 or less new cases of hepatitis B virus (HBV) infection occur annually in the United States, and about 2 million or more people have chronic infection.[32] The prevalence of the disease is higher among black individuals and persons of Hispanic or Asian origin.

HBV disease not only accounts for 5-10% of cases of chronic end-stage liver disease and 10-15% of cases of hepatocellular carcinoma (HCC) in the United States, it is also the dominant cause of cirrhosis and HCC worldwide.

HBV is blamed for at least 5000 US deaths annually. The prevalence is low in persons younger than 12 years born in the United States, with the subsequent increase being associated with the initiation of sexual contact (the major mode of transmission in adults, along with intravenous drug abuse [IVDA]). It is also associated with the occurrence of first intercourse at an early age. Additional risk factors, as identified in the National Health and Nutrition Examination Survey (NHANES) III, are as follows:

  • Non-Hispanic black ethnicity

  • Cocaine use

  • High number of sexual partners

  • Divorced or separated marital status

  • Foreign birth

  • Low educational level

Because of the implementation of routine vaccination of infants in 1992 and of adolescents in 1995, the prevalence of HBV infection is expected to decline further in individuals born in the United States.

International statistics

Globally, chronic HBV infection affects 350-400 million people,[33] with disease prevalence varying among geographic regions, from 1-20%. A higher rate exists, for example, among Alaskan Eskimos, Asian Pacific islanders, Australian aborigines, and populations from the Indian subcontinent, sub-Saharan Africa, and Central Asia. In some locations, such as Vietnam, the rate is as high as 30%. Such variation is related to differences in the mode of transmission, including iatrogenic transmission, and the patient's age at infection.

The lifetime risk of HBV infection is less than 20% in low prevalence areas (< 2%; generally, 0.1-2%),[8] and sexual transmission and percutaneous transmission during adulthood are the main modes through which it spreads. About 12% of HBV-infected individuals live in low-prevalence areas, which include the United States, Canada, western Europe, Australia, and New Zealand.[8]

Sexual and percutaneous transmission and transmission during delivery are the major transmission routes in areas of intermediate prevalence (rate of 3-5%). These regions include Eastern and Northern Europe, Japan, the Mediterranean basin, the Middle East, Latin and South America, and Central Asia. One study reported approximately 43% of HBV-infected individuals live in South Central and West Asia, Eastern Europe, Russia, and Central and South America, with a prevalence rate of 2-7% and a lifetime HBV risk of 20-60%.[8]

In areas of high prevalence (≥8%, generally 10-20%), the predominant mode of transmission is perinatal, and the disease is transmitted vertically during early childhood from the mother to the infant. Approximately 45% of individuals infected with HBV live in high-prevalence areas, with a lifetime infection risk of over 60%, as demonstrated by the presence of hepatitis B core antibodies (anti-HBc) to hepatitis B core antigen (HBcAg) in serum.[8] Such regions include China, Southeast Asia, Indonesia, sub-Saharan Africa, Pacific Islands, parts of the Middle East, and the Amazon Basin.

Vaccination programs implemented in highly endemic areas seem to have reduced the prevalence of HBV infection. In Taiwan, for example, HBV seroprevalence declined from 10% in 1984 (before vaccination programs) to less than 1% in 1994 after the implementation of vaccination programs, and the incidence of HCC declined from 0.52% to 0.13% during the same period.[4]

The 10 genotypes of HBV (A-J) also correspond to specific geographic distributions.[19] Genotype A is more frequently found in North America, northwestern Europe, India, and Africa, whereas genotypes B and C are endemic to Asia, and genotype D predominates in Eastern Europe and the Mediterranean. Type E is found in western Africa; type F, in South America; and type G, in France, Germany, Central America, Mexico, and the United States. Type H is prevalent in Central America;[8] type I, in Vietnam; and type J, in Japan.[19]

Race-, sex-, and age-related demographics

In the United States, blacks have a higher prevalence of HBV disease than do Hispanics or whites. In addition, more cases of chronic HBV disease occur in males than in females.

The earlier the disease is acquired, the greater the chance a patient has of developing chronic hepatitis B infection. Infants (mainly infected through vertical transmission) have a 90% chance, children have a 25-50% chance, adults have an approximately 5% chance, and elderly persons have an approximately 20-30% chance of developing chronic disease.

Prognosis

An estimated 1 million persons per year globally, including at least 5000 persons annually in the United States, die from chronic hepatitis B disease.[32]

Positive prognostic factors

Patients who have lost the hepatitis B e antigen (HBeAg) and in whom hepatitis B virus (HBV) DNA is undetectable have an improved clinical outcome, as characterized by the following:

  • Slower rate of disease progression

  • Prolonged survival without complications

  • Reduced rate of HCC and cirrhosis

  • Clinical and biochemical improvement after decompensation

Hepatocellular carcinoma

Chronic hepatitis B infection is the major contributor to the development of approximately 50% of cases of hepatocellular carcinoma (HCC) worldwide.[34] Studies indicate that the level of hepatitis B virus (HBV) DNA, which indicates viral replication, is a strong predictor for cirrhosis and HCC regardless of other viral factors.[34] Approximately 9% of patients in western Europe who have cirrhosis develop HCC due to hepatitis B infection at a mean follow-up of 73 months. The probability of HCC developing 5 years after the diagnosis of cirrhosis has been established at 6%, and the probability of decompensation is 23%.

Significant risk factors for carcinogenesis include the following:

  • Older age

  • Exposure to aflatoxins

  • Alcohol

  • Coinfection with HCV and HDV

  • Immune status

  • Genotype

  • Core and precore mutations

  • Cirrhosis

  • Thrombocytopenia

High serum viral load (ie, viral replication) that is persistently elevated over time is the most reliable indicator in predicting the development of HCC.[35]

Even the presence of hepatitis B core antibody (anti-HBc) in the absence of hepatitis B surface antigen (HBsAg) or HBV DNA is significantly related to an increased risk for HCC, although there are no recommendations for HCC surveillance in such cases unless cirrhosis is present.

The annual incidence of HCC reported in Taiwan in patients with hepatitis B infection and cirrhosis is 2.8%. The US estimates for the annual incidence of HCC in patients infected with HBV is 818 cases per 100,000 persons.

Distinct mutations associated with different HBV genotypes have been linked to an increased risk of developing HCC. Genotype C is closely associated with HCC; this appears to be related to a higher incidence of core and precore mutations in patients older than 50 years with cirrhosis and genotype C,[19] whereas genotype B is associated with HCC development in young, noncirrhotic patients and in postsurgical relapse.[35]

Mortality

Familial clustering of HCC has been described among families with hepatitis B infection in Africa, the Far East, and Alaska. The cumulative probability of survival is 84% at 5 years and 68% at 10 years.

Cox regression analysis has identified 6 variables that independently correlate with overall survival for individuals with cirrhosis or HCC. These include age, albumin level, platelet count, splenomegaly, bilirubin level, and positivity for hepatitis B e antigen (HBeAg) at the time of the hepatitis B diagnosis. Based on the contribution of each of these factors to the final model, a prognostic index has been constructed that allows calculation of the estimated survival probability.

Expression of inflammatory molecules in HBV-related HCC tissues is associated with poor prognosis.[35] Imbalance between intratumoral CD8* T cells and regulatory T cells or type 1 helper T cells (Th1), and type 2 helper T-cell (Th2) cytokines in peritumoral tissues can predict the prognosis of HBV-related HCC. These molecules are also important for developing active prevention and surveillance of HBV-infected patients.[35]

Glomerulonephritis

The prognosis of renal disease in hepatitis B is related to several factors, such as age and the response to therapy. Children with membranous glomerulonephritis (MGN) have a more favorable response than adults. White persons have a better response than Asian and black patients.

Approximately 30-60% of cases with MGN undergo spontaneous remission. However, the course of HBV-related membranous nephropathy in adults in areas in which the virus is endemic is not benign. Regardless of treatment, hepatitis B disease has a slow, but relentlessly progressive, clinical course in approximately one third of patients, resulting in progressive renal failure and necessitating maintenance dialysis therapy.

Patient Education

Patients with acute and chronic HBV infections should be advised that this is a blood-borne disease that can be transmitted during sexual intercourse or at the time of childbirth. Prophylaxis is strongly advised. Family members borne by the same parents should also be checked for HBV infection. The best preventative measurement is vaccination.[1]

For patient education information, see Hepatitis A; Hepatitis B; Hepatitis C; Cirrhosis; Liver Cancer; Immunization Schedule, Adults; and Immunization Schedule, Children.

 

Presentation

History

The spectrum of the symptomatology of hepatitis B disease varies from subclinical hepatitis to icteric hepatitis to fulminant, acute, and subacute hepatitis during the acute phase, and from an asymptomatic chronic infection state to chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) during the chronic phase.

Papular acrodermatitis, also recognized as Gianotti-Crosti syndrome, has been associated with hepatitis B, most commonly in children with acute infection.[36]

The following multisystem manifestations may occur in hepatitis B virus (HBV) infection:

  • Pleural effusion and hepatopulmonary and portopulmonary syndrome may occur in patients with cirrhosis

  • Diffuse intravascular coagulation may occur in patients with fulminant hepatitis

  • Myocarditis, pericarditis, and arrhythmia occur primarily in patients with fulminant hepatitis

  • Arthralgias and arthritic (serum sickness) subcutaneous nodules may also occur, but these are rare

  • Guillain-Barre syndrome, encephalitis, aseptic meningitis, and mononeuritis multiplex may occur in patients with acute hepatitis B

  • Pancreatitis may develop

  • Aplastic anemia is uncommon, and agranulocytosis is extremely uncommon

A variety of cutaneous manifestations have been recognized during the early course of viral hepatitis, including hives and a fleeting maculopapular rash. These various lesions are episodic, palpable, and, at times, pruritic. A discoloration of the skin can be identified after the resolution of the exanthem, particularly on the lower extremities. Women are more prone to developing cutaneous manifestations.

Acute phase

The incubation period is 1-6 months in the acute phase of hepatitis B infection. Anicteric hepatitis is the predominant form of expression for this disease. The majority of the patients are asymptomatic, but patients with anicteric hepatitis have a greater tendency to develop chronic hepatitis. Patients with symptomatology have the same symptoms as patients who develop icteric hepatitis.

Icteric hepatitis is associated with a prodromal period, during which a serum sickness –like syndrome can occur. The symptomatology is more constitutional and includes the following:

  • Anorexia

  • Nausea

  • Vomiting

  • Low-grade fever

  • Myalgia

  • Fatigability

  • Disordered gustatory acuity and smell sensations (aversion to food and cigarettes)

  • Right upper quadrant and epigastric pain (intermittent, mild to moderate)

Patients with fulminant and subfulminant hepatitis may present with the following:

  • Hepatic encephalopathy

  • Somnolence

  • Disturbances in sleep pattern

  • Mental confusion

  • Coma

  • Ascites

  • Gastrointestinal (GI) bleeding

  • Coagulopathy

Chronic phase

Patients with chronic hepatitis B disease can be immune tolerant or have an inactive chronic infection without any evidence of active disease; they are also asymptomatic.

Patients with chronic active hepatitis, especially during the replicative state, may complain of symptomatology such as the following:

  • Symptoms similar to those of acute hepatitis

  • Fatigue

  • Anorexia

  • Nausea

  • Mild upper quadrant pain or discomfort

If progressive liver disease is present, the following symptomatology may appear:

  • Hepatic decompensation

  • Hepatic encephalopathy

  • Somnolence

  • Disturbances in sleep pattern

  • Mental confusion

  • Coma

  • Ascites

  • GI bleeding

  • Coagulopathy

Physical Examination

The physical examination findings in hepatitis B disease vary from minimal to impressive (in patients with hepatic decompensation), according to the stage of disease.

Patients with acute hepatitis usually do not have any clinical findings, but the physical examination can reveal the following:

  • Low-grade fever

  • Jaundice (10 days after appearance of constitutional symptomatology, lasting for 1-3 mo)

  • Hepatomegaly (mildly enlarged, soft liver)

  • Splenomegaly (5-15%)

  • Palmar erythema (rarely)

  • Spider nevi (rarely)

The physical examination of patients with chronic hepatitis B virus (HBV) infection can reveal stigmata of chronic liver disease such as the following:

  • Hepatomegaly

  • Splenomegaly

  • Muscle wasting

  • Palmar erythema

  • Spider angioma

  • Vasculitis (rarely)

Patients with cirrhosis may have the following findings:

  • Ascites

  • Jaundice

  • History of variceal bleeding

  • Peripheral edema

  • Gynecomastia

  • Testicular atrophy

  • Abdominal collateral veins (caput medusa)

 

DDx

Diagnostic Considerations

When evaluating a patient with suspected hepatitis B virus (HBV) infection, also consider the other viral hepatitides and etiologies that can lead to cirrhosis and liver failure, such as drug hepatotoxicity. In addition, because a major mode of transmission of this disease is sexual, also consider the possibility of infection with human immunodeficiency virus (HIV) or other sexually transmitted diseases.

Differential Diagnoses

 

Workup

Approach Considerations

Please note that guidelines for the current diagnostic workup and management of hepatitis B virus (HBV) infection continue to evolve. Clinicians are advised to refer frequently to the most recent recommendations of the American Association for the Study of Liver Diseases (AASLD) at https://www.aasld.org/publications/practice-guidelines-0.

Laboratory evaluation of hepatitis B disease generally consists of liver enzyme tests, including levels of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase (GGT), as well as liver function tests (LFTs) that include total and direct serum bilirubin, albumin, and the measurement of the international normalized ratio (INR).[37] Hematologic and coagulation studies also include a platelet count and a complete blood count (CBC). Ammonia levels may be obtained, but the results often create diagnostic confusion in clinicians.[38]

Serologic tests for hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) immunoglobulin M (IgM) are required for the diagnosis of acute hepatitis B virus (HBV).[1, 39, 40]  HBsAg is positive in both acute and chronic HBV infection; however, the presence of IgM anti-HBc is diagnostic of acute or recently acquired infection.[39] Antibody to HBsAg (anti-HBs) is produced after a resolved infection and is the only HBV antibody marker present after vaccination. The presence of HBsAg and total anti-HBc, with a negative test for IgM anti-HBc, indicates chronic HBV infection; the absence of IgM anti-HBc or the persistence of HBsAg for 6 months indicates chronic HBV infection. The presence of anti-HBc alone might indicate acute, resolved, or chronic infection or a false-positive result.[39]

To evaluate the patient’s level of infectivity, quantification of hepatitis (HBV) DNA is essential, and the presence of hepatitis B e antigen (HBeAg) should be determined. Indeed, the best indication of active viral replication is the presence of HBV DNA in the serum. Hybridization or more sensitive polymerase chain reaction (PCR) assay techniques are used to detect the viral genome in the serum, as well as specific genotypes, mutants resistant to oral nucleoside and nucleotide analogues, and core and precore mutations.

A positive result suggests not only the likelihood of active hepatitis but also that the disease is much more infectious, as the virus is actively replicating.[40]

HBV DNA testing is also recommended when occult HBV is suspected (positive anti-HBc and negative antibody to HBsAg [anti-HBs] and HBsAg) or in cases in which all of the serologic tests are negative.[41]

American Association for the Study of Liver Diseases (AASLD) recommendations

The current AASLD recommendations for the initial evaluation of HBsAg-positive patients is summarized below.[37]

All patients

History and physical examination: Thoroughly evaluate for the following:

  • Alcohol, metabolic, and other risk factors for HBV infection
  • Patient's HBV vaccination status
  • Family history of HBV infection and hepatocellular carcinoma
  • The presence of symptoms/signs of cirrhosis

Routine laboratory studies

  • CBC, platelet count; INR
  • Levels of AST, ALT, total bilirubin, ALP, and albumin

Serologic/virologic studies

  • Hepatitis B e antigen (HBeAg)/anti-HBe
  • HBV DNA level
  • Anti-hepatitis A virus (anti-HAV) (to determine need for vaccination)

Imaging/staging studies 

  • Abdominal ultrasonography
  • Vibration-controlled transient elastography (eg, FibroScan) or a serum fibrosis marker panel (APRI [AST-to-platelet ratio index], FIB-4 [platelet count, ALT, AST, age], or FibroTest [gamma-2 macroglobulin, gamma-2 globulin, gamma globulin, apolipoprotein A1, gamma-GGT, total bilirubin])

Select patients

Routine laboratory studies: In the setting of elevated liver function test results, obtain tests to exclude other causes of chronic liver disease. Obtain levels of alpha-fetoprotein (AFP) and GGT.

Serologic/virologic studies

  • HBV genotyping
  • Tests for coinfection with hepatitis C virus (HCV), hepatitis D (delta) virus (HDV), and/or human immunodeficiency virus (HIV) in at-risk individuals aged 13-64 years who have not undergone one-time screening 

Screening

HBV

In June 2014, the US Preventive Services Task Force (USPSTF), which had previously recommended against screening asymptomatic persons for HBV infection, issued a recommendation in favor of screening of asymptomatic, nonpregnant adolescents and adults at high risk for HBV infection, including the following[42, 43, 44, 45] :

  • Those born in countries and regions where prevalence of HBV infection is at least 2%

  • Individuals born in the United States who were not vaccinated as infants and whose parents were born in regions with a high prevalence of HBV infection, such as sub-Saharan Africa and southeast and central Asia

  • HIV-positive individuals

  • Injection drug users

  • Men who have sex with men

  • Household contacts of individuals with HBV infection

Testing should be performed with a HBsAg test followed by a licensed, neutralizing confirmatory test for initially reactive screening results.[42, 43, 44, 45]

The United States currently screens foreign-born residents for HBV infection if their country of origin has an HBV prevalence of 2% or greater. According to a model developed by Eckman et al, although this threshold for screening is cost-effective, a broader screening program with a threshold of 1.3% or even 0.3% country-of-origin prevalence would be cost-effective as well, suggesting a reconsideration of the current policy.[46]

The following screening recommendations are from the 2018 AASLD guidance update[47] :

  • Perform screening with both hepatitis B surface antigen (HBsAg) and antibody to HBsAg (anti-HBs).
  • Individuals who should undergo screening include all those born in countries that have an HBsAg seroprevalence of 2% or greater, US-born persons in areas with high HBV endemicity (≥8%), pregnant women, those who require immunosuppression, and specific at-risk populations.
  • Vaccinate screened individuals who are negative for anti-HBs.
  • Although routine screening is not recommended for antibody to hepatitis B core antigen (anti-HBc) to assess for previous exposure, it is a valuable test in HIV patients; those about to receive hepatitis C or anticancer and other immunosuppressive treatment or renal dialysis; and in donated blood (or, organs, if feasible).

HCV

As previously mentioned, the prevalence of hepatocellular carcinoma (HCC) among patients with HBV and HCV coinfection is higher than in those with a single infection.

Some controversy exists regarding screening for HCV infections in adults. In August 2012, the Centers for Disease Control and Prevention (CDC) expanded their existing, risk-based testing guidelines to recommend a 1-time blood test for HCV infection in baby boomers—the generation born between 1945 and 1965, who account for approximately three fourths of all chronic HCV infections in the United States—without prior ascertainment of HCV risk (see Recommendations for the Identification of Chronic Hepatitis C Virus Infection Among Persons Born During 1945-1965.)[48]

The recommendations noted that 1-time HCV testing in baby boom population could identify nearly 808,600 additional people with chronic infection; thus, the CDC recommended that all individuals identified with HCV should be screened and/or managed for alcohol abuse, followed by referral to preventative and/or treatment services, as appropriate.[48]

However, in a systematic review for the US Preventive Services Task Force (USPSTF), Chou et al noted that despite the accuracy of screening tests in identifying asymptomatic adults with chronic HCV infection, screening strategies that target multiple risk factors can miss some of these patients.[49] They recommended further investigation to determine the effects of different HCV screening strategies on diagnostic yield and clinical outcomes.

Diagnostic Tests

Laboratory studies will be discussed according to the stage of the disease.

Acute hepatitis B disease

High levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), within a range of 1000-2000 IU/mL, is the hallmark of this stage of HBV disease, although values 100 times above the upper limit of normal (ULN) can be also be identified. Higher values are found in patients with icteric hepatitis. ALT levels are usually higher than AST levels.

Gamma-glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP) levels may be elevated, but they are usually not more than 3 times the ULN.

Albumin levels can be slightly low, and serum iron levels may be elevated as an acute phase reactant. In the preicteric period (ie, before the appearance of jaundice), leukopenia (ie, granulocytopenia) and lymphocytosis are the most common hematologic abnormalities and are accompanied by an increase in the erythrocyte sedimentation rate (ESR).

Anemia due to a shortened red blood cell survival period is an infrequent finding, although hemolysis may be noted. Thrombocytopenia is a rare finding. Patients with severe hepatitis experience a prolongation of the international normalized ratio (INR).

Several viral markers can be identified in the serum and the liver. Hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) (marker of infectivity) are the first markers that can be identified in the serum in acute disease. Hepatitis B core antibody (anti-HBc) immunoglobulin M (IgM) follows.

For patients who recover, seroconversion to hepatitis B surface antibody (anti-HBs) and hepatitis B e antibody (anti-HBe) is observed. The anti-HBc is of the IgG class. Patients with persistent HBsAg lasting more than 6 months are considered to have chronic hepatitis.

Inactive hepatitis B disease

The term “healthy carriers” is no longer used due to the fact that a person who is positive for HBsAg has a high risk of cirrhosis and hepatocellular carcinoma (HCC) and, therefore, cannot be defined as healthy. Such individuals have normal AST and ALT levels, with markers of infectivity, such as HBeAg, being negative and HBV DNA going undetected or being detected at very low levels (usually below 2,000 IU/ml). HBsAg, anti-HBc of IgG type, and anti-HBe are present in the serum. A minimum follow-up of these patients for 1 year with laboratory evaluation every 3 to 4 months is recommended.

Chronic active hepatitis B disease

Chronic active HBV disease is categorized into HBeAg-positive and HBeAg-negative disease.

Subtype “wild type” or HBeAg-positive disease

Patients have mild to moderate elevation of the aminotransferases (≤5 times the ULN). The ALT levels are usually higher than the AST levels. Extremely high levels of ALT can be observed during exacerbation or reactivation of the disease, and they can be accompanied by impaired synthetic function of the liver (ie, decreased albumin levels, increased bilirubin levels, and prolonged prothrombin time [PT]).

HBV DNA levels are high during this phase. HBsAg and anti-HBc of IgG or IgM type (in case of reactivation) are identified in the serum.

If the AST levels are higher than the ALT levels, the diagnosis of cirrhosis must be considered. Hyperglobulinemia is another finding, predominantly with an elevation of the IgG globulins. Tissue-nonspecific antibodies, such as anti–smooth muscle antibodies (ASMAs) (20-25%) or antinuclear antibodies (ANAs) (10-20%), can be identified. Tissue-specific antibodies, such as antibodies against the thyroid gland (10-20%), can also be found. Mildly elevated levels of rheumatoid factor (RF) are usually present, indicating the presence of cryoglobulins on further assessment.

Subtype chronic HBV HBeAg-negative disease

Note that although the HBeAg result is negative in this stage, HBeAg negativity can be associated with greater HBV DNA replication and more rapid disease progression in patients who carry mutations in either the precore or the basic core promoter region of the HBV genome.[41]

Cirrhosis

In the early stages of cirrhosis, findings of chronic viral hepatitis can be found. Later, as the disease progresses, low albumin levels, hyperbilirubinemia, prolonged PT, low platelet and white blood cell counts, and AST levels higher than ALT levels can be identified. Alkaline phosphatase (ALP) and GGT levels can be slightly elevated.

Radiologic Studies

Findings on imaging studies are briefly reviewed according to the disease stage.

Acute and chronic hepatitis B disease

Performing abdominal ultrasonography, computed tomography (CT) scanning, or magnetic resonance imaging (MRI) in patients with hepatitis B is important to help exclude biliary obstruction (see the following images). Nonspecific findings include increased echogenicity of the liver parenchyma.

Radiologic studies may be useful in all stages of Radiologic studies may be useful in all stages of hepatitis B infection. Ultrasonography, computed tomography (CT) scanning, or magnetic resonance imaging (MRI) may exclude biliary obstruction in acute infection. In chronic disease, ultrasonograms may show nonspecific increased echogenicity of the liver parenchyma. In patients with long-standing disease, CT imaging may be used to detect cirrhosis or hepatocellular carcinoma (as shown).
Long-standing cirrhosis leads to progressive repla Long-standing cirrhosis leads to progressive replacement of liver parenchyma with fibrotic tissue. Over time, the liver contracts and develops a lobulated contour. These changes are readily apparent on cross-sectional imaging. This contrast-enhanced computed tomography (CT) scan demonstrates extensive cirrhosis, as well as malignant hepatocellular lesions (arrow).

Cirrhosis

Imaging findings in cirrhosis include coarse echogenicity of the liver, with a nodular appearance, and findings compatible with portal hypertension (eg, varices, splenomegaly, ascites, pleural effusion [ie, hepatic hydrothorax]).

Neoplastic lesions can also be detected but may be very difficult to evaluate because they can be mistaken for regenerating nodules. In such cases, highly sophisticated techniques, such as MRI with superparamagnetic iron oxide (ferumoxides), should be considered. Ferumoxides (negative contrast material) are phagocytosed by the reticuloendothelial cells of the normal liver, producing predominant T2 imaging on MRI. Therefore, a marked decrease in the signal in the normal liver parenchyma occurs, effectively permitting the identification of tumors.

In a trial that compared ultrasonographic surveillance at 3- or 6-month intervals to detect hepatocellular carcinoma (HCC) in 1278 patients with cirrhosis due to hepatitis B virus (12.5%), hepatitis C virus (44.1%), or alcohol (39.2%), investigators reported that ultrasonographic surveillance at 3-month intervals detected more small focal lesions (≤10 mm) than at 6-month intervals; however, the shorter interval did not improve detection of small HCC.[50]

On December 17, 2014, the FDA gave marketing approval for the Hepatiq radiologic image processing system.[51, 52] The software application uses quantitative analysis of nuclear medicine liver-spleen images to determine the severity of the liver disease and to predict the clinical outcomes.[52] The developer notes that Hepatiq "automates the Quantitative Liver Spleen Scan (QLSS) that has been proven to be an accurate predictor of clinical outcomes in the recently concluded HALT-C [Hepatitis C Antiviral Long-term Treatment against Cirrhosis] trial."[52] The HALT-C trial was a multicenter, randomized controlled study that evaluated whether long-term interferon would suppress HCV, prevent progression to cirrhosis, prevent liver cancer, and reduce the need for liver transplantation.[53]

Liver Biopsy and Histologic Features

Liver biopsy, percutaneous or laparoscopic, is the standard means of assessing the severity of disease in patients with features of chronic active liver disease (ie, abnormal aminotransferase levels and detectable levels of hepatitis B virus [HBV] DNA).

Although liver biopsy is not indicated for patients with acute hepatitis B disease, the findings in the acute phase are predominantly lobular, with degenerative and regenerative hepatocellular changes, as well as accompanying inflammation. Necrosis may be predominantly centrilobular.

Acute vs chronic histologic findings

Acute hepatitis B

The hallmark of acute hepatitis B is liver cell death. Scattered within the lobule are small, individual clusters of dying hepatocytes in apoptosis. (When the nucleus is extruded, it is an eosinophilic, or Councilman, body). Many of the surviving hepatocytes show hydropic swelling known as ballooning degeneration. Lymphocytes diffusely infiltrate the lobule, with macrophages and neutrophils seen occasionally.

Chronic hepatitis B

The hallmark of chronic hepatitis B infection is lymphoid inflammation, mostly involving the portal tracts. However, occasional Councilman bodies are seen in the lobule. Hepatocytes that are distended with viral particles may acquire an unusual “ground-glass” appearance on the hematoxylin and eosin (H&E) stain (see the following image). Ground-glass cells are seen in approximately 50-75% of livers affected by chronic HBV infection, and they stain positive for hepatitis surface B antigen (HBsAg). Immunohistochemical staining of the specimen can help to identify the presence of HBsAg or hepatitis B core antigen (HBcAg) (ie, chronic infection).

Under higher-power magnification, ground-glass cel Under higher-power magnification, ground-glass cells may be visible in chronic HBV infection. Ground-glass cells are present in 50% to 75% of livers with chronic HBV infection. Immunohistochemical staining is positive for HBsAg.

As the severity of the histologic changes advance, interface hepatitis (piecemeal necrosis) appears, with erosion of the limiting plate by chronic inflammation from the portal side of the lobule. Over time, this ongoing type of inflammation may lead to increasing degrees of fibrosis that spreads out from that portal tract to connect with other nearby portal tracts (bridging fibrosis). When the fibrosis advances further in severity, regenerating nodules of hepatocytes appear; this constitutes cirrhosis (see the image below).

Liver biopsy with hematoxylin stain showing stage Liver biopsy with hematoxylin stain showing stage 4 fibrosis (ie, cirrhosis) in a patient with hepatitis B.

Staging

Liver damage is graded according to the inflammatory component and is described as follows:

  • Grade 0 – Portal inflammation only, no activity

  • Grade 1 – Minimal portal inflammation and patchy lymphocytic necrosis, with minimal lobular inflammation and spotty necrosis

  • Grade 2 – Mild portal inflammation and lymphocytic necrosis involving some or all portal tracts, with mild hepatocellular damage

  • Grade 3 – Moderate portal inflammation and lymphocytic necrosis involving all portal tracts, with noticeable lobular inflammation and hepatocellular change

  • Grade 4 – Severe portal inflammation and severe lymphocytic bridging necrosis, with severe lobular inflammation and prominent, diffuse hepatocellular damage

Liver damage staging (ie, fibrosis) is described as follows:

  • Stage 0 – No fibrosis

  • Stage 1 – Portal fibrosis

  • Stage 2 – Periportal fibrosis

  • Stage 3 – Septal, bridging fibrosis

  • Stage 4 – Cirrhosis

 

Treatment

Approach Considerations

Please note that guidelines for the current diagnostic workup and management of hepatitis B virus (HBV) infection continue to evolve. Clinicians are advised to refer frequently to the most recent recommendations of the American Association for the Study of Liver Diseases (AASLD) at https://www.aasld.org/publications/practice-guidelines-0.

The primary treatment goals for patients with hepatitis B (HBV) infection are to prevent progression of the disease, particularly to cirrhosis, liver failure, and hepatocellular carcinoma (HCC).[2, 37, 54] Risk factors for progression of chronic HBV include the following[2, 37, 54] :

  • Persistently elevated levels of HBV DNA and, in some patients, alanine aminotransferase (ALT), as well as the presence of core and precore mutations seen most commonly in HBV genotype C and D infections

  • Male sex

  • Older age

  • Family history of HCC

  • Alcohol use

  • Elevated alpha-fetoprotein (AFP)

  • Coinfection with hepatitis D (delta) virus (HDV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV)

A synergistic approach of suppressing viral load and boosting the patient’s immune response with immunotherapeutic interventions is needed for the best prognosis.[33] The prevention of HCC often includes the use of antiviral treatment using pegylated interferon (PEG-IFN) or nucleos(t)ide analogues.[34]

HBV infection can be self-limited or chronic.[39] No specific therapy is available for persons with acute hepatitis B; treatment is supportive.[39]

Therapy is currently recommended for patients with evidence of chronic active hepatitis B disease (ie, abnormal aminotransferase levels, positive HBV DNA findings, positive or negative hepatitis B e antigen [HBeAg]). Various algorithms have been proposed, such as that by the American Association for the Study of Liver Diseases (AASLD),[37, 55] the European Association for the Study of the Liver (EASL),[56] the Asian Pacific Association for the Study of the Liver (APASL),[57] the Canadian Association for the Study of the Liver (CASL),[58] the National Institute for Health and Clinical Excellence (NICE),[59] Kuo and Gish,[19] and Keeffe et al.[60]

National Institutes of Health recommendations

The National Institutes of Health (NIH) recommends nucleos(t)ide therapy for the treatment of patients with acute liver failure, as well as cirrhotic patients who are HBV DNA positive and those with clinical complications, cirrhosis or advanced fibrosis with positive serum HBV DNA, or reactivation of chronic HBV during or after chemotherapy or immunosuppression.[2] In addition, immunoglobulin and vaccination should be administered to newborns born to women positive for hepatitis B surface antigen (HBsAg).[2, 41, 61]

In general, for hepatitis B e antigen (HBeAg)-positive patients with evidence of chronic HBV disease, treatment is advised when the HBV DNA level is at or above 20,000 IU/mL (105 copies/mL) (or, per the EASL, >2,000 IU/mL[56] ) and when serum ALT is elevated for 3-6 months.[2, 37, 54]

For HBeAg-negative patients with chronic hepatitis B disease, treatment can be administered when the HBV DNA is at or above 2,000 IU/mL (104 copies/mL) and the serum ALT is elevated (ALT levels >20 U/L for females; 30 U/L for males) for 3-6 months.

In patients coinfected with HBV and HIV, initiate therapy against HBV and administer antiretroviral therapy (ART) as well.[41]

The NIH also indicates that immediate therapy is not routinely indicated for patients who have the following[2] :

  • Chronic hepatitis B with high levels of serum HBV DNA but normal serum ALT levels or little activity on liver biopsy (immune-tolerant phase)

  • Low levels of or no detectable serum HBV DNA and normal serum ALT levels (inactive chronically infected/low replicative phase)

  • Positive serum HBV DNA but not HBsAg (latent HBV infection), unless the patient is undergoing immunosuppression

World Health Organization (WHO) recommendations

The 2015 WHO guidelines for the prevention, care, and treatment of persons with chronic hepatitis B infection indicates treatment priority for individuals of all ages who have chronic hepatitis B infection and clinical evidence of compensated/decompensated cirrhosis (or cirrhosis based on APRI [aspartate aminotransferase (AST)-to-platelet ratio index] score >2 in adults), regardless of their levels of ALT or HBV DNA, or their HBeAg status.[54]  (Strong recommendation)

Treatment is recommended for adults with chronic hepatitis B infection without clinical evidence of cirrhosis (or based on APRI score ≤2 in adults), but who have all of the following features, and regardless of HBeAg status (strong recommendation)[54] :

  • Are older than 30 years (in particular)
  • Have persistently abnormal ALT levels
  • Have evidence of high-level HBV replication (HBV DNA >20,000 IU/mL). (If HBV DNA testing is unavailable, consider treatment based on persistently abnormal ALT levels alone, regardless of HBeAg status. [Conditional recommendation])

In individuals with HBV/human immunodeficiency virus (HIV) coinfection, the AASLD recommends initiating ART in (1) all those with evidence of severe chronic liver disease, regardless of CD4 count, as well as (2) those with a CD4 count of 500 cells/mm3 or below, regardless of their liver disease stage.[54] (Strong recommendation)

However, the AASLD does not recommend antiviral therapy, indicating it can be deferred, in individuals with all of the following, regardless of HBeAg status or age (strong recommendation)[54] :

  • No clinical evidence of cirrhosis (or based on APRI score ≤2 in adults)
  • Persistently normal ALT levels
  • Low levels of HBV DNA replication (HBV DNA < 2,000 IU/mL). (If HBV DNA testing is unavailable, treatment can be deferred in HBeAg-positive individuals aged 30 years or younger who have persistently abnormal ALT levels. (Conditional recommendation)]

American Association for the Study of Liver Diseases (AASLD) recommendations

The 2016 AASLD guidelines for the treatment of chronic hepatitis B[37]  as well as select recommendations from the 2018 AASLD guidance update on the prevention, diagnosis, and treatment of chronic hepatitis B[47]  are outlined below and in the Guidelines section.

Adults with immune-active chronic hepatitis B infection (ie, ALT >2 times the upper limit of normal [ULN] or significant histologic disease and HBeAg negative [HBV DNA >2,000 IU/mL] or HBeAg positive [HBV DNA >20,000 IU/mL]) (Strong recommendations)

Administer antiviral therapy to lower the risk of morbidity and mortality associated with chronic hepatitis B infection.

The recommended initial agent for adults is PEG-IFN, entecavir, or tenofovir. 

Adults with immune-tolerant chronic hepatitis B infection (ie, ULNs: ALT levels ≤30 U/L for men and ≤19 U/L for women)

Antiviral therapy is not recommended. (Strong recommendation)

The AASLD suggests obtaining ALT levels at least every 6 months to monitor for potential transition to immune-active or -inactive chronic hepatitis B. (Conditional recommendation)

For select patients older than 40 years, the AASLD suggests antiviral therapy in the setting of normal ALT levels, elevated HBV DNA (≥1,000,000 IU/mL), and significant necroinflammation or fibrosis on liver biopsy specimens. (Conditional recommendation)

Adults with HBeAg-positive immune-active chronic hepatitis B who seroconvert to anti-HBe on nucleos(t)ide analog (NA) therapy (Conditional recommendations)

After a period of treatment consolidation (treatment for ≥12 months in the setting of persistently normal ALT levels and undetectable serum HBV DNA), consider discontinuing NA therapy in noncirrhotic HBeAg-positive adults who seroconvert to anti-HBe while on NA treatment. If antiviral therapy is stopped, monitor the patient every 3 months for a minimum of 1 year for recurrent viremia, ALT flares, seroreversion, and clinical decompensation.

For cirrhotic HBeAg-positive adults who seroconvert to anti-HBe on NA therapy, the AASLD suggests indefinite antiviral therapy owing to the potential for clinical decompensation and death, unless a strong competing rationale for treatment discontinuation exists. If antiviral therapy is stopped, closely monitor these patients for recurrent viremia, ALT flares, seroreversion, and clinical decompensation.

Adults with HBeAg-negative immune-active chronic HBV infection

The AASLD suggests indefinite antiviral therapy for adults with HBeAg-negative immune-active chronic hepatitis B infection, unless there is a competing rationale for treatment discontinuation. (Conditional recommendation) If antiviral therapy is stopped, monitor the patient every 3 months for a minimum of 1 year for recurrent viremia, ALT flares, and clinical decompensation.

Antiviral therapy is not recommended for noncirrhotic individuals who are HBeAg negative and who have normal ALT activity and low-level viremia (< 2,000 U/mL; “inactive chronic hepatitis B”).

Children with chronic hepatitis B infection

For HBeAg-positive children aged 2 years up to 18 years who have both elevated ALT and detectable HBV DNA levels, the AASLD suggests antiviral therapy (IFN-alpha-2b: age ≥1 year; lamivudine, entecavir: age ≥2 year), with the goal of achieving sustained HBeAg seroconversion. (Conditional recommendation) If antiviral therapy is stopped, monitor the child every 3 months for a minimum of 1 year for recurrent viremia, ALT flares, and clinical decompensation.

Antiviral therapy is not recommended for HBeAg-positive children aged 2 years up to 18 years who have persistently normal ALT (conservative value: 30 U/L), regardless of the HBV DNA level. (Strong recommendation)

Individuals with HBV and HCV coinfection[47]

  • Test all HBsAg-positive patients for HCV infection with the anti-HCV test.
  • Those with HCV viremia should receive HCV therapy.
  • HBV treatment is based on levels of HBV DNA and ALT as indicated by the AASLD HBV guideline for monoinfected individuals.
  • HBsAg-positive individuals: At risk for HBV DNA and ALT flares with  HCV-DAA (direct-acting antiviral) therapy; monitor HBV DNA levels every 4-8 weeks during treatment and for 3 months posttreatment for individuals who do not meet the treatment criteria according to the AASLD HBV guidelines.
  • HBsAg-negative, anti-HBc-positive individuals with HCV: Low risk of reactivation with HCV-DAA therapy; monitor ALT levels at baseline, treatment completion, and during follow-up; reserve HBV DNA and HBsAg testing for individuals whose ALT levels rise or fail to normalize during treatment or posttreatment

Inpatient care

Patients with hepatitis B disease and fulminant hepatic failure should be hospitalized in the intensive care unit (ICU) and be considered as liver transplant candidates in the event that they do not recover. Any patient with acute HBV disease needs to be treated with first-line oral therapy, such as tenofovir disoproxil fumarate (TDF) or entecavir (ETV).

Patients with acute hepatitis should be monitored with blood tests in order to document biochemical improvement (see Workup).

Counseling

The recommendations below are from the 2018 AASLD guidance update.[47]

HBsAg-positive patients should receive counseling about the prevention of HBV transmission to others.

Healthcare workers and students who are HBsAg positive can continue with training or practice—unless their job requires they perform exposure-prone procedures. In such situations, these individuals should seek counseling/advice from their institutional expert review panel; they should not perform exposure-prone procedures if their serum HBV DNA level is above 1,000 IU/mL; and they can resume such procedures if their HBV DNA falls and is maintained below 1,000 IU/mL.

Aside from using universal precautions, special arrangements are not indicated for children with HBV in community setting (eg, daycare centers, schools, sports clubs, camps) unless they have a tendency to bite.

HBV-infected individuals are recommended to be abstinent or limit their alcohol use.

To prevent the concurrent development of fatty liver and metabolic syndrome, it is recommended that individuals with HBV optimize their body weight and treatment of metabolic complications (eg, control of diabetes and dyslipidemia).

Dietary limitations

Patients with acute or chronic hepatitis without cirrhosis have no dietary restrictions. For individuals with decompensated cirrhosis (signs of portal hypertension or encephalopathy), the following dietary limitations are indicated:

  • A low-sodium diet (1.5 g/day)

  • High-protein diet (ie, white-meat protein, such as chicken, turkey, or fish)

  • Fluid restriction (1.5 L/day) in cases of hyponatremia

Pharmacologic Management

Currently, pegylated interferon alfa (PEG-IFN-a), entecavir (ETV), and tenofovir disoproxil fumarate (TDF) are the first-line agents in the treatment of hepatitis B disease. These are the main treatment drugs approved globally for this disease, although ongoing trials are investigating new types of medications, such as tenofovir disoproxil in combination with emtricitabine (FTC). Encapsidation inhibitors, entry inhibitors, TLR7 agonists, and therapeutic vaccines are all in development.

In 2009, international phase III trials with clevudine (l-FMAU) for the treatment of chronic hepatitis B virus (HBV) infection were halted owing to a very high risk of myopathy.[62]

Lamivudine (3TC), telbivudine, and adefovir are of historical interest. These agents are currently considered second- or third-line therapy, or “nonpreferred” treatment.[63]

Approved antiviral therapies

The following are medications approved for the treatment of chronic hepatitis B in adult and/or pediatric patients (adjust all dosing in the setting of renal dysfunction).[37]

Preferred agents

  • Pegylated interferon (PEG-IFN)-alpha-2a (adults) or IFN-alpha-2b (children) – Adult dose 180 μg weekly; pediatric dose (age ≥1 year): 6 million IU/m 2 three times weekly
  • Entecavir – Adult dose: Daily 0.5 mg (lamivudine-/telbivudine-naive persons) or 1.0 mg (those with lamivudine/telbivudine experience or decompensated cirrhosis); pediatric dose (age ≥2 years): Weight-based to 10-30 kg; for children weighing more than 30 kg, use 0.5 mg daily
  • Tenofovir dipovoxil fumarate – Adult and pediatric (age ≥12 years) dose: 300 mg daily
  • Tenofovir alafenamide – Adult dose only: 25 mg daily; no pediatric dosing

Nonpreferred agents

  • Adefovir – Adult and pediatric dose (age ≥12 years): 10 mg daily
  • Lamivudine – Adult dose: 100 mg daily; pediatric dose (age ≥2 years): 3 mg/kg daily (maximum: 100 mg)
  • Telbivudine – Adult dose only: 600 mg daily; no pediatric dosing

World Health Organization (WHO) recommendations

First-line antiviral treatment (Strong recommendations)

All individuals aged 12 years or older who are eligible for antiviral therapy are recommended to receive therapy with tenofovir or entecavir, the nucleos(t)ide analogs (NAs) with a high barrier to drug resistance. Entecavir is recommended in children aged 2-11 years.

NAs with a low barrier to drug resistance (lamivudine, adefovir, or telbivudine) are not recommended owing to their potential for drug resistance.

In HBV/human immunodeficiency virus (HIV)-coinfected individuals aged 3 years or older, a fixed-dose combination of tenofovir/lamivudine (or emtricitabine)/efavirenz is the preferred option for initiation of ART.

Second-line antiviral treatment for managing treatment failure (Strong recommendation)

For individuals with confirmed or suspected antiviral resistance (ie, history of prior exposure or primary nonresponse) to lamivudine, entecavir, adefovir, or telbivudine, the WHO recommends switching to tenofovir.

Specific considerations

Special attention must be given to patients on liver transplantation lists. Initiation of treatment with entecavir or tenofovir is of cardinal importance before and after liver transplantation to achieve viral suppression and to prevent recurrence of the disease after the procedure. Combination therapy with ETV and TDF or, more rarely, TDF with FTC or 3TC can be considered if drug-resistant mutants are present or for patients with failing first-line therapy.

Caution must also be used with long-term and high-dose administration of adefovir or tenofovir therapy in patients with chronic HBV disease. In a National Institutes of Health (NIH) study, 15% of patients on adefovir or tenofovir for 2-9 years developed proximal renal tubular dysfunction, defined as de novo incidence of 3 of the following 5 features[64] :

  • Hypophosphatemia

  • Hypouricemia

  • Elevated serum creatinine level

  • Proteinuria

  • Glycosuria

Switching to other antiviral agents in the study allowed for partial reversal of the renal tubular dysfunction.[64]

ETV was associated with lactic acidosis in a study of 5 patients with liver failure who had Model for End-Stage Liver Disease (MELD) scores of greater than 20.[65]

In patients with HBV who are coinfected with human immunodeficiency virus (HIV), it may be possible to simplify treatment regimens with agents that have dual effectiveness against both viruses.[41] Hepatitis D (delta) virus (HDV) infection is best treated with PEG-IFN therapy.

Interferon alfa

Interferons are proteins that have antiviral, antiproliferative, and immunomodulatory effects. Published reports indicate that after IFN-a treatment with 5 million U/day or 10 million U 3 times per week subcutaneously (SC) for 4 months, HBV DNA levels and HBeAg become undetectable in 30-40% of patients.[66] In addition, 10% of patients seroconvert from hepatitis B surface antigen (HBsAg) to hepatitis B surface antibody (anti-HBs). Unfortunately, 5-10% of patients relapse after completion of treatment. A transient "flare," (ie, increased serum alanine aminotransferase [ALT] levels during the beginning of treatment) can be identified, and this represents the impact of the activated cytolytic T cells on the infected hepatocytes.

High levels of aminotransferases, a low viral load, and infection with the wild type virus are good prognostic factors for response to IFN-a treatment. However, Asian patients and patients with the precore mutant virus tend to not have a clinical response to IFN-a treatment.

Loss of HBsAg indicates resolution of the HBV infection, acute or chronic, but it is rare in chronic infection. A study by Tseng et al that followed Taiwanese patients with chronic hepatitis B infection who developed spontaneous HBeAg loss (seroconversion) showed that patients with low levels of HBsAg 1 year after their HBeAg seroconversion had a higher probability of loss of HBsAg.[67]

Glomerulonephritis

IFN-a therapy has been successful in treating HBV-related glomerulonephritis. A regimen of 5 million units of IFN-a subcutaneously (SC) daily for 4 months has achieved HBsAg seroconversion with improvement of glomerulonephritis. It has also been reported that IFN-a given at a dose of 3 million units 3 times per week led to an improvement of proteinuria only in patients with mesangial proliferative glomerulonephritis, not in those with membranoproliferative glomerulonephritis (MPGN).

Finally, a single case report described the resolution of this complication after liver transplantation. In addition to interferon, antiviral therapy with lamivudine (3TC) has not only been shown to significantly increase the incidences of proteinuria remission and of HBeAg seroconversion but also cause a decline in levels of HBV-DNA in adult patients with HBV-related glomerulonephritis relative to controls.[68]

Polyarteritis nodosa

Small and medium-sized arteries and arterioles are affected in polyarteritis nodosa (PAN). Although corticosteroids and immunosuppressive agents may be beneficial for treating vasculitis, they may potentially have a deleterious effect on the course of hepatitis B liver disease due to viral reactivation, particularly after the withdrawal of treatment.

The antiviral drug adenine arabinoside and IFN-a have been used in conjunction with plasmapheresis and a short course of corticosteroids, with promising results.

The combination of short-term corticosteroids accompanied by plasmapheresis and lamivudine, as used in one study, resulted in 100% clinical recovery and 66% seroconversion, although the number of patients in the trial was relatively small.[69]

Precautions

Special attention must be given to patients with HBV-decompensated cirrhosis (eg, ascites, encephalopathy) who are taking IFN-a, owing to the fact that, although they occasionally may have a treatment response, these individuals can also deteriorate further.

The adverse effects of IFN-a treatment can sometimes be severe, even devastating. Some patients cannot complete the treatment. A flulike syndrome, myelosuppression (eg, leukopenia, thrombocytopenia), nausea, diarrhea, fatigue, irritability, depression, thyroid dysfunction, and alopecia are among the adverse effects that may occur.

Pegylated IFN-a 2a

PEG-IFN-a 2a has an enhanced half-life relative to the standard INF-a. Pegylation lowers the rate of absorption following subcutaneous (SC) injection, reduces renal clearance, and decreases the immunogenicity of the interferon.

A 48-week regimen of PEG-IFN-a 2a may induce a 27% rate of HBeAg seroconversion and a 25% rate of loss of HBV DNA.[70] In a study by Lau et al involving a 48-week regimen, after 24 weeks of follow-up the HBeAg seroconversion rate with PEG-IFN-a 2a monotherapy was 32%, compared with 27% in those receiving combination therapy with 3TC and 19% in those receiving 3TC monotherapy.[70]

It appears that patients infected with HBV genotype A or B have a better response to IFN treatment than do patients infected with genotype C or D. This therapy also appears to be more appealing, especially for patients with increased ALT levels.

PEG-IFN-a 2a is also indicated for treatment of chronic hepatitis C, alone or in combination with ribavirin, in patients not previously treated with IFN-a, with compensated liver disease, or with HDV infection. At most, 17% of patients have durable suppression of the virus as defined by undetectable HBV DNA at 5 years posttreatment.[70, 71]

Telbivudine

Telbivudine, a cytosine nucleoside analogue, is a second-line agent (not preferred) used in HBV therapy.[19]  This drug is a potent inhibitor of HBV DNA polymerase. Although telbivudine appears to have slightly more potent antiviral activity than do adefovir and lamivudine, it is more expensive and plays a limited role in primary therapy.

HBeAg-positive patients

The results of the phase III GLOBE Trial that tested the administration of 600 mg of telbivudine versus 100 mg of 3TC over a 2-year period showed that in the HBeAg-positive population, therapeutic response (defined as HBV DNA < 10,000 copies/mL, with either ALT normalization or HBeAg loss) was 75% for the patients treated with telbivudine and 67% for the patients treated with 3TC.[72, 73]

Of the patients receiving telbivudine, 26% lost the e antigen, versus 23% of the patients receiving 3TC.[72, 73]  In addition, a 6.5-log reduction of the HBV DNA was noted for patients receiving telbivudine versus a 5.5-log reduction for patients receiving 3TC.

HBeAg-negative patients

In the HBeAg-negative patients in the phase III GLOBE Trial, the response rates at 1 year were 75% for the telbivudine group and 77% in the 3TC group, whereas 88% of the telbivudine-treated patients and 71% of the lamivudine-treated patients had undetectable HBV DNA. The HBV DNA log reduction was 5.2 (telbivudine group), compared with 4.4 (lamivudine group).[72, 73]

Regarding treatment resistance, a major issue in hepatitis B disease, the reported resistance rates at 1 year were 2.6% for patients on telbivudine and 8.2% for patients on lamivudine.[72, 73]

Entecavir

Entecavir is a first-line agent in the treatment of hepatitis B.[19] This drug is a potent guanosine analogue inhibitor of the viral polymerase with 1.2% resistance in patients who have no history of previous treatment with nucleos(t)ide analogues and almost 56% resistance in 3TC-resistant patients during a 6-year treatment period.[74]

Advantages of therapy with this agent include potent antiviral activity and a low drug resistance rate,[19] although entecavir has less of a role than other agents in the treatment of 3TC-resistant hepatitis B.

A retrospective study demonstrated that HBV DNA responses at 12 months can potentially be used to evaluate entecavir therapy in nucleos(t)ide analogue ̶ naïve, HBV-infected patients.[75] Investigators reported 3 independent predictors for maintenance of viral suppression among patients on entecavir treatment at 3 years—lower baseline HBV DNA, undetectable HBV DNA at month 12, and negative HBeAg—as well as for the probability of HBeAg-seroconversion and the risk of drug resistance.[75]

HBeAg-positive patients

With regard to the HBeAg-positive population, administration of 0.5 mg of entecavir in patients who were naïve to nucleoside analogues relative to patients who received 100 mg of 3TC for a duration of 48 weeks resulted in histologic improvement in 72% of the entecavir group compared with 62% of the 3TC group.[76] Undetectable serum HBV DNA levels were reported in 67% of entecavir-treated patients, compared with 36% of 3TC-treated patients.

In addition, normalized ALT levels were achieved in 68% of the entecavir group, versus 60% of the 3TC group.[76] The mean reduction in serum HBV DNA from baseline to week 48 was 6.9 log copies/mL (on a base-10 scale) in the entecavir-treated patients, relative to 5.4 log copies/mL in the 3TC-treated patients. HBeAg seroconversion occurred in 21% of patients treated with entecavir and in 18% of patients treated with 3TC.[76]

HBeAg-negative patients

In an HBeAg-negative population, administration of 0.5 mg of entecavir in patients who were naïve to nucleoside analogues compared with patients who received 100 mg of 3TC for a duration of 48 weeks resulted in histologic improvement in 71% of the entecavir group, versus 61% of the 3TC group.[74] Undetectable serum HBV DNA levels were found in 90% of the entecavir-treated patients, versus 72% of the 3TC-treated patients.

Normalized ALT levels were achieved in 78% of the entecavir group, compared with 71% of the 3TC group.[74] The mean reduction in serum HBV DNA levels from baseline to week 48 was 5.0 log copies/mL (on a base-10 scale) in the entecavir-treated patients, versus 4.5 log copies/mL in the 3TC-treated patients.[74]

Long-term (5- and 6-y) data

After up to 5 years (240 wk) of continuous entecavir therapy (1.0 mg qDay) for HBeAg-positive patients, 94% of patients had less than 300 copies/mL of HBV DNA, and 80% had normal ALT levels.[77] An additional 23% of patients achieved HBeAg seroconversion, and 1.4% lost HBsAg. Only 1 patient demonstrated treatment resistance with entecavir through 5 years.[77]

In another study, Schiff et al reported that long-term treatment with entecavir (about 6 y of cumulative therapy [range, 267-297 wk]) in nucleoside-naïve chronic hepatitis B patients with advanced fibrosis or cirrhosis resulted in durable virologic suppression, continued histologic improvement, and reversal of fibrosis/cirrhosis.[78] The patients received entecavir for at least 3 years and had evaluable biopsies at baseline and after long-term treatment.

Lamivudine

A nucleoside analogue, 3TC inhibits the viral polymerase. It appears to be effective in patients who do not have a treatment response to IFN-a (eg, patients infected by the precore mutant virus). However, its role in hepatitis B treatment is diminishing as alternate therapies become available[19] ; thus, this agent is a third-line therapy and not preferred.

Other agents, except for adefovir, are superior to 3TC in suppression of viral replication. Another disadvantage to this therapy includes its high rate of drug resistance.[19] Relative to other oral treatments, however, 3TC is lower in cost.

Therapy with 3TC has been associated with a 4-log reduction of the viral load.[63, 79, 80, 81] Treatment (100 mg/day) has also been associated with the following:

  • 16-18% seroconversion rate from HBeAg to anti-HBe

  • 30-33% rate of HBeAg loss

  • 40-50% normalization of the value of the aminotransferases

  • 1-2% HBsAg seroconversion rate

The HBeAg seroconversion rate has been shown to possibly increase to 27% after 2 years, 40% after 3 years, and 47% after 4 years of treatment in patients with a viral load of less than 104 pg/mL.

Histologic improvement (ie, reduction of the histologic activity index by >2 points) has been noticed in approximately 50% of patients taking 3TC. The adverse effects are negligible, although a transient elevation of aminotransferases can be noticed shortly after starting treatment.

Treatment with 3TC has also been shown to dramatically improve the condition of patients with decompensated disease due to HBV reactivation. Patients with HIV infection and fulminant hepatic failure due to active HBV infection may receive 3TC-only treatment.[41] Those with HIV/HBV coinfection who are eligible for antiretroviral therapy and have less severe hepatic injury should defer the antiretroviral treatment until resolution of the liver injury.[41]

Polyarteritis nodosa

As previously mentioned, the combination of short-term corticosteroids accompanied by plasmapheresis and lamivudine, as used in one study, resulted in 100% clinical recovery and 66% seroconversion in patients with HBV-associated PAN, although the number of patients in the trial was relatively small.[69]

HBV infection prophylaxis in HIV

In patients infected with HIV, antiretroviral therapy regimens containing 3TC or TDF may be prophylactic for HBV infection. A recent analysis examined stocked serum samples from 354 men with HIV who had not been vaccinated against hepatitis B and whose initial serum samples showed no signs of HBV.[82]

All of the patients in the study were men who had sex with men, a population in which hepatitis B infection in the presence of HIV is particularly common. An analysis of the final stocked samples from these patients found that sometime after their first serum samples were obtained, 43 (12%) of the 354 men had become infected with HBV.[82]

The investigators found that the rate of incident HBV infections was lower during periods when antiretroviral regimens using 3TC or TDF were used (0.669 incident infections in 100 person-years) than it was during periods when no antiretroviral therapy was used or when antiretroviral therapy employed neither 3TC or TDF (6.726 and 5.263 incident infections in 100 person-years, respectively).[82]

Complications

The emergence of viral variants is the major complication in hepatitis B disease.[83, 84] Approximately 15-30% of patients develop a mutation of the viral polymerase gene (the YMDD variants) after 12 months of treatment with 3TC; approximately 50% develop a mutation after 3 years of treatment with the drug, and as many as 70-100% develop a mutation with long-term therapy. However, continued treatment after the breakthrough with the variant type has been associated with lower HBV DNA levels, less aminotransferase activity, and histologic improvement. For these patients, discontinuation of treatment is accompanied by a reversion to a wild type of HBV and a flare of the disease.

Adefovir dipivoxil

Adefovir is another third-line agent (not preferred) that is indicated for the treatment of chronic hepatitis B disease with evidence of active viral replication, including patients with 3TC-resistant hepatitis B.[19] This agent is a nucleoside analogue, a potent inhibitor of the viral polymerase. The efficacy of adefovir dipivoxil has been tested in HBeAg-positive, HBeAg-negative, and 3TC-resistant patients with encouraging results.

The optimal dose seems to be 10 mg/day[85, 86] ; higher doses are nephrotoxic. The estimated rate of resistance to adefovir and the development of mutations (rtN236T and rtA181V) are approximately 4-6% after 3 years and approximately 30% after 5 years of treatment.[87, 88, 89, 90]

The results of 2 multicenter trials that used adefovir for 48 weeks noted that in HBeAg-positive patients who received 10 mg of adefovir daily, there was a median 3.52-log reduction of the viral load (HBV DNA) level.[85, 86] In 48% of the patients, normalized aminotransferase levels were reported, and histologic improvement was seen in 53% of the patients who received this regimen.[85] The HBeAg seroconversion rate was 12%.

Furthermore, of the HBeAg-negative population, 64% experienced histologic improvement after receiving 10 mg of adefovir for 48 weeks, and 72% had normalized aminotransferase levels.[85, 86] The serum HBV DNA level decreased in 51% of subjects. The outcomes were maintained if treatment was continued for 44 weeks, but the benefits were lost if treatment was discontinued at 44 weeks.[85, 86] The development rate for the resistant mutations rtN236T and rtA181V has been estimated to be around 6%.[86]

Tenofovir

Tenofovir may be used as the first-line therapy for treatment-naïve patients.[19] This agent is preferred as an additional therapy in patients with resistance to 3TC, telbivudine, or entecavir. Tenofovir provides more potent antiviral therapy than adefovir, and it can be used as a substitute in patients who do not have an adequate response to adefovir.

Tenofovir is a nucleotide analogue (adenosine monophosphate) reverse transcriptase and HBV polymerase inhibitor.

HBeAg-positive naïve patients

In a study that randomized patients to receive either tenofovir (300 mg once daily) or adefovir (10 mg once daily) for 48 weeks—with the adefovir-treated patients then switched to tenofovir—79% of the patients who received tenofovir were found to have a viral load below 400 copies/mL, whereas 76% of patients who received adefovir before switching to tenofovir were found to have a viral load below 400 copies/mL.[91]

In addition, 72% of patients in the adefovir arm who were found to have a viral load greater than 400 copies/mL achieved viral suppression after they were switched to tenofovir. For patients who achieved viral suppression on adefovir alone, the effect was maintained after they were switched to tenofovir.[91] Biochemical response was reported in 77% of patients in the tenofovir arm at week 72 and in 61% of those switching from adefovir to tenofovir.

With regard to seroconversion, 26% of patients who received tenofovir seroconverted at week 64, while in the adefovir arm, the observed seroconversion rate was reported as 21%.[91] It is noteworthy to mention that 5% of patients in the tenofovir arm experienced loss of the s antigen.

HBeAg-negative patients

In another report involving patients who were randomized to receive either tenofovir (300 mg once daily) or adefovir (10 mg once daily), with all eligible adefovir-treated patients being switched to tenofovir after 48 weeks, 91% of patients receiving tenofovir at 72 weeks of treatment were found to have a viral load below 400 copies/mL,[92] compared with 88% of patients in the adefovir-to-tenofovir arm. All of the adefovir-treated patients who had a viral load below 400 copies/mL at week 48 maintained a viral load below this level after switching to tenofovir.[92] Of the patients in the adefovir arm who did not achieve optimal viral response (that is, those with a viral load >400 copies/mL) by the time they switched to tenofovir, 94% had a viral load below 400 copies/mL by week 72.

Normal ALT levels at week 72 were observed in 79% of patients who initiated therapy with tenofovir and in 77% of patients who switched from adefovir to tenofovir.[92]

HBeAg-negative or -positive patients with chronic HBV

In 2 double-blind, phase III studies in which patients with HBeAg-negative or HBeAg-positive chronic hepatitis B were randomized to receive tenofovir (300 mg) or adefovir (10 mg) (ratio, 2:1) once daily for 48 weeks, Marcellin et al concluded that among patients with chronic hepatitis B, tenofovir at a daily dose of 300 mg had superior antiviral efficacy and a similar safety profile to adefovir at a daily dose of 10 mg through week 48.[93]

At week 48 in both studies, a significantly higher proportion of patients receiving tenofovir than those receiving adefovir had reached the primary end point (plasma HBV DNA level < 400 copies/mL [69 IU/mL]), and viral suppression occurred in more HBeAg-negative patients in the tenofovir group (93%) than in the adefovir group (63%), as well as in more HBeAg-positive patients receiving tenofovir (76%) than in those receiving adefovir (13%).[93]

Furthermore, significantly more HBeAg-positive patients in the tenofovir group (68%) not only had normalized ALT levels relative to those in the adefovir group (54%), but these individuals also had loss of HBsAg (3% tenofovir group vs 0% adefovir group).[93]

At the end of 48 weeks, none the patients had developed the amino acid substitutions within HBV DNA polymerase that are associated with phenotypic resistance to tenofovir or other drugs used to treat hepatitis B. Tenofovir produced a similar HBV DNA response in patients who had previously received lamivudine and in those who had not. The 2 treatments in both studies had similar safety profiles.[93]

5-Year data

Marcellin et al reported that patients who received tenofovir continuously for 240 weeks had sustained suppression of HBV DNA levels below 400 copies/mL (HBeAg-negative patients: 83%; HBeAg-positive patients: 65%).[59] Patients who were randomized to adefovir and then, at week 48, rolled over to tenofovir for the subsequent 192 weeks also maintained viral suppression (HBeAg-negative patients: 84%; HBeAg-positive patients: 66%).

Of the HBeAg-positive patients who received tenofovir through 240 weeks, 9% experienced s-antigen loss, and 7% seroconverted. The HBeAg loss rate was 46%, and the HBeAg seroconversion rate was 40%. No evidence of resistance to tenofovir emerged over the treatment period.[59]

In addition, 87% of the 348 patients who had paired biopsies at baseline and week 240 experienced an improvement in the overall liver histology, as measured by an improvement of a minimum of 2 points in the Knodell necroinflammatory score without worsening in the Knodell fibrosis score. Of the 96 patients who had cirrhosis (Ishak fibrosis score ≥5) at the start of therapy, 74% experienced regression of cirrhosis.[59]

HBV infection prophylaxis in HIV

As previously mentioned, in patients infected with HIV, antiretroviral therapy regimens containing 3TC or TDF may be prophylactic for HBV infection.

Surgical Intervention

Orthotopic liver transplantation (OLT) is the treatment of choice for patients with fulminant hepatic failure who do not recover and for patients with end-stage liver disease due to hepatitis B disease. The implementation of hepatitis B immunoglobulin (HBIG) during and after the OLT period, and of lamivudine (3TC) or adefovir in the pre- and post-OLT periods, dramatically reduces the recurrence rate of hepatitis B. The current standard is to use HBIG and tenofovir disoproxil fumarate (TDF) or entecavir (ETV). At some centers, HBIG is being stopped at approximately 12 months or sooner; at other centers, HBIG is no longer being used, with the focus on first-line therapy.

For more information, see the Medscape Drugs & Diseases articles Liver Transplants, Liver Transplantation, Transfusion Requirements in Liver Transplantation, and Imaging of Liver Transplantation Complications.

Hepatitis B and Pregnancy

The American College of Obstetricians and Gynecologists (ACOG) and the US Preventive Services Task Force (USPSTF) recommend routine prenatal screening for hepatitis B surface antigen (HBsAg) in all pregnant women—during every pregnancy—regardless of previous test results or vaccinations.[94, 95] Pregnant women at risk for hepatitis B infections should be specifically targeted for vaccination.[94] The risk of transmission of hepatitis B associated with amniocentesis is low.

For newborns born to mothers with chronic hepatitis B infection, administer combined immunoprophylaxis with hepatitis B immune globulin (HBIG) and hepatitis B vaccine within 12 hours of birth.[94, 95] Thereafter, these infants should follow the hepatitis B vaccine series as part of the recommended childhood immunization schedule.

Breastfeeding is not contraindicated in women chronically infected with hepatitis B if the infant receives HBIG passive prophylaxis and vaccine active prophylaxis.[94] Mothers with chronic hepatitis B infection are often treated in the third trimester if the serum hepatitis B virus (HBV) DNA level is greater than 106 -108 copies/mL, especially if she is positive for the hepatitis B e antigen (HBeAg).

The 2016 American Association for the Study of Liver Diseases (AASLD) has similar guidelines for the treatment of chronic hepatitis B in pregnant women.[37]  The AASLD suggests antiviral therapy to reduce the risk of perinatal HBV transmission in HBsAg-positive pregnant women with an HBV DNA level above 200,000 IU/mL. (Conditional recommendation) Infants of these mothers should receive immunoprophylaxis according to current World Health Organization and Centers for Disease Control and Prevention recommendations.

Therapy for pregnant women with immune-active hepatitis B should be based on the same recommendations as for their nonpregnant counterparts.

Antiviral therapy is not recommended to reduce the risk of perinatal HBV transmission in HBsAg-positive pregnant women whose HBV DNA level is at or below 200,000 IU/mL. (Strong recommendation)

Vaccination

Universal hepatitis B vaccination programs are ongoing in endemic areas, with encouraging results. The hepatitis B vaccine (HepB) consists of recombinant hepatitis B surface antigen (HBsAg) produced in yeast. A series of 3 injections may achieve HBsAg antibody (anti-HBs) levels greater than 10 million IU/mL in approximately 95% of vaccinated individuals. Vaccination with a single dose must be repeated every 5-10 years.

In a report that collected data from 2 studies assessing the 5- and 10-year persistence of anti-HBs and immune response to a hepatitis B virus (HBV) vaccine challenge in children and adolescents who had received the HBV 3-dose vaccine series in infancy, German investigators demonstrated that this routine practice induced long-term anti-HBs persistence for 10 years and immune memory against HBV—even with waning anti-HBs levels.[96]

2018 AASLD recommendations

The following recommendations are from the 2018 AASLD guidance update[47] :

  • Administer HBV vaccines as a 3-dose series at 0, 1, and 6 months (± hepatitis A vaccine). Alternatively, for adults, combination hepatitis A and B vaccine (Twinrix) uses a 4-dose regimen at 0, 7, 21-30 days, and 12 months. A 2-dose series for adults at 0 and 1 months (HEPLISAV-B) is also available.
  • Sexual partners and household contacts of HBV-infected individuals who are negative for HBsAg and anti-HBs should receive HBV vaccination.
  • At deliverly, infants born to HBV-infected mothers should receive hepatitis B immunoglobulin (HBIG) and HBV vaccine; thereafter, the recommended vaccination schedule should be completed. Postvaccination testing at age 9-15 months is recommended for infants with HBsAg-positive mothers.
  • Those who should be tested for their response to HBV vaccination 1-2 months after the last vaccine dose is received include healthcare workers, sexual partners of those with chronic HBV, patients on chronic hemodialysis, and immunocompromised patients (eg HIV patients).
  • Nonresponders to the initial vaccine series: Repeat the 3-dose vaccination series, with a double dose for immunocompromised individuals (eg, cirrhotic patients).
  • Vaccine responders: Annual follow-up testing is recommended for chronic hemodialysis patients.
  • Booster doses or revaccination: Not recommended except if anti-HBs levels remain below 10 mIU/mL after the initial vaccination of infants of HBsAg-positive mothers, in healthcare workers, hemodialysis patients, and immunocompromised patients.

Children

All newborns must be vaccinated against hepatitis B with a 3- or 4-dose series of HepB. For infants born to mothers with active hepatitis B, a passive-active approach (hepatitis B immunoglobulin [HBIG] and vaccination) is recommended.

Children and adolescents who have not been vaccinated as infants should receive a 3-dose series of HepB.

Adults

Vaccine options for adults include the following:

  • Heplisav-B (HepB-CpG), a yeast-derived vaccine prepared with a novel adjuvant, administered as a 2-dose series (0, 1 month) [97]  (FDA approved November 2017) [98, 99]  OR
  • Engerix B or Recombivax HB (HepB), administered as a 3-dose  series at 0, 1, and 6 months OR
  • Twinrx, combined hepatitis A and hepatitis B vaccine (HepA-HepB), at 0, 1, and 6 months

The following are Advisory Committee on Immunization Practices (ACIP) recommendations for immunizing adults at risk for hepatitis B infection[100] :

  • History of current or recent injection drug use, international travelers to countries with high or intermediate levels of endemic HBV infection (HBsAg prevalence ≥2%)
  • Chronic liver disease (including, but not limited to, hepatitis C infection, cirrhosis, fatty liver disease, alcoholic liver disease, autoimmune hepatitis, and an alanine aminotransferase [ALT] or aspartate aminotransferase [AST] level greater than twice the upper limit of normal)
  • Human immunodeficiency virus infection
  • At risk for infection through sexual exposure (eg, sex partners of HBsAg-positive persons, sexually active persons not in a long-term mutually monogamous relationship, persons seeking evaluation or treatment for a sexually transmitted infection, men who have sex with men)
  • At risk for infection by percutaneous or mucosal exposure to blood (eg, household contacts of HBsAg-positive persons, residents and staff of facilities for developmentally disabled persons, healthcare and public safety personnel with reasonably anticipated risk for exposure to blood or blood-contaminated body fluids, hemodialysis patients and predialysis, peritoneal dialysis, and home dialysis patients)
  • Persons with diabetes mellitus younger than 60 years and persons with diabetes mellitus aged at least 60 years at the discretion of the treating clinician [101]
  • Incarcerated persons
  • Other persons seeking protection from HBV infection (even without acknowledgment of a specific risk factor)

Low response rates and nonresponders

Low vaccination response rates have been associated with obesity, smoking, immunosuppression, and advanced age. Approximately 25-50% of persons who initially do not have a vaccine response will show a response to 1 additional vaccine dose, and 50-75% of individuals will have a response to a second 3-dose series.

It is recommended that testing for anti-HBs be obtained 4-12 weeks following vaccination.[41, 61] Revaccinate nonresponders, (HBsAb levels < 10 IU/L) with another series of 3-dose hepatitis B vaccine. Consider delaying revaccination for several months after initiation of antiretroviral therapy in patients with CD4 counts below 200 cells/mm3 or those with symptomatic HIV disease. The delay in these individuals is an attempt to maximize the antibody response to the vaccine.[41, 61]

Do not defer vaccination in pregnant patients or patients who are unlikely to achieve an increased CD4 count.[41, 61] Individuals at increased risk of severe complications due to HBV infection include those unlikely to achieve CD4 counts of 200 cells/mm3 or above after antiretroviral therapy (eg, HBV/hepatitis C virus [HCV] coinfection) and HIV-infected pregnant women.[41]

A combined hepatitis A virus (HAV)/HBV vaccine is licensed in many countries and offers the advantage of protection against both of these viruses at the same time. The vaccine seems to be safe, although some questions exist regarding neurologic complications.

Long-Term Monitoring

Individuals with inactive chronic infection with the hepatitis B virus (HBV) should have routine blood tests at least annually to check their aminotransferase levels. Patients with chronic active hepatitis should also undergo blood tests (ie, to evaluate aminotransferase levels, antigen-antibody HBV profile, viral load, and alpha-fetoprotein [AFP] levels). In rare cases, patients may be considered for liver biopsy.

Current guidelines recommend monitoring of HBV DNA and alanine aminotransferase (ALT) levels at least annually; however, a study conducted by Juday et al suggests that adherence falls below recommendations.[102] Expert opinion supports that following the recommended guidelines reduces the risk of disease progression.

Patients with cirrhosis must be monitored for hepatocellular carcinoma (HCC) by having their AFP levels checked every 6-12 months and undergoing surveillance with abdominal ultrasonography.[103]  Note, however, that AFP levels have been eliminated from the American Association for the Study of Liver Diseases (AASLD) guidelines.[37, 55]

Monitoring considerations

Physicians should keep the following in mind when managing a patient with hepatitis B:

  • Identify cases of fulminant hepatic failure, and list the patient as a candidate for liver transplantation

  • Monitor individuals with inactive chronic infection for probable disease reactivation

  • Inform the patients' spouse/sexual partners about the infectivity of hepatitis B and their need for screening, possible linkage to care, and possible need for vaccination

  • Monitor patients with cirrhosis and perform HCC surveillance studies (ie, liver ultrasonography) every 6-12 months

  • Place patients with cirrhosis on liver transplantation list when needed

  • Identify hepatitis D (delta) virus (HDV) superinfection in patients with HBV infection

  • Screen for human immunodeficiency virus (HIV) and/or hepatitis C virus (HCV) coinfection

  • Assess for hepatitis A virus (HAV) immunity; if the patient is not immune, provide immunization

Viral reactivation

Hepatitis B virus (HBV) may persist in the blood for decades after clinical recovery from acute hepatitis despite the presence of serum antibodies. Immunosuppressive conditions or drugs may allow dormant HBV to flare or reactivate. Additionally, genetic factors (eg, genetic mutations) may influence the risk for reactivation by affecting hepatitis B core antibody (anti-HBc) response.[104]

Close monitoring during and for several months after therapy with immunosuppressive drugs is appropriate. If reactivation of hepatitis B occurs, stopping the agent and initiating antiviral therapy may be warranted. Various national organizations including the AASLD and the National Institutes of Health (NIH) recommend the use of prophylactic antiviral therapy in inactive HBsAg carriers who are to undergo antineoplastic or immunosuppressive therapy.[2, 55, 104]

Medications that may increase the risk for hepatitis B reactivation include:

  • Anti-CD20 antibodies: Ofatumumab (Arzerra), rituximab (Rituxan)

  • Antineoplastic agents (including methotrexate)[105, 106]

  • Glucocorticoids, especially with abrupt discontinuation[107, 108]

  • Interleukin receptor antagonists: Ustekinumab (Stelara),[109] anakinra (Kineret), tocilizumab (Actemra)

  • Nucleoside and nucleotide therapy, due to immune reconstitution syndrome or discontinuation of antiviral therapy with anti-HBV properties

  • T-cell regulator: Abatacept (Orencia)[110]

  • Tumor necrosis factor (TNF) inhibitors: Infliximab (Remicade),[109] etanercept (Enbrel),[109] adalimumab (Humira),[109] certolizumab pegol (Cimzia), golimumab (Simponi, Simponi Aria)

 

Guidelines

2015 WHO Guidelines Summary

The 2015 World Health Organization (WHO) guidelines for the prevention, care, and treatment of persons with chronic hepatitis B infection[54] are presented below.

Noninvasive baseline and follow-up assessment of liver disease stage 

Conditional recommendation

In resource-limited settings, APRI (aspartate aminotransferase [AST]-to-platelet ratio index) is preferred to evaluate for liver fibrosis (APRI score >2 in adults).

Where resource availability and cost aren't major barriers, transient elastography (eg, FibroScan [measures tissue stiffness]) or FibroTest (5 biomarkers of liver fibrosis: gamma-2 macroglobulin, gamma-2 globulin, gamma globulin, apolipoprotein A1, gamma-glutamyl transpeptidase [GGT,] total bilirubin) may be preferred.

Who should or should not receive treatment for chronic hepatitis B

Individuals who should be treated 

Priority: Treat individuals of all ages who have chronic hepatitis B infection and clinical evidence of compensated/decompensated cirrhosis (or cirrhosis based on APRI score >2 in adults), regardless of their levels of alanine transaminase (ALT) or hepatitis B virus (HBV) DNA, or their hepatitis B e antigen (HBeAg) status. (Strong recommendation)

Recommended: Treat adults with chronic hepatitis B infection without clinical evidence of cirrhosis (or based on APRI score ≤2 in adults), but who have all of the following features, and regardless of HBeAg status (strong recommendation):

  • Are older than 30 years (in particular)
  • Have persistently abnormal ALT levels
  • Have evidence of high-level HBV replication (HBV DNA >20,000 IU/mL). (If HBV DNA testing is unavailable, consider treatment based on persistently normal ALT levels alone, regardless of HBeAg status. [Conditional recommendation])

In individuals with HBV/human immunodeficiency virus (HIV) coinfection, initiate antiretrovial therapy (ART) in (1) all those with evidence of severe chronic liver disease, regardless of CD4 count, as well as (2) those with a CD4 count of 500 cells/mm3 or below, regardless of their liver disease stage. (Strong recommendation)

Individuals who should not be treated but monitored

Antiviral therapy is not recommended and can be deferred in individuals with all of the following, regardless of HBeAg status or age (strong recommendation):

  • No clinical evidence of cirrhosis (or based on APRI score ≤2 in adults)
  • Persistently normal ALT levels
  • Low levels of HBV DNA replication (HBV DNA < 2,000 IU/mL). (If HBV DNA testing is unavailable, treatment can be deferred in HBeAg-positive individuals aged 30 years or younger who have persistently abnormal ALT levels. (Conditional recommendation)]

All individuals with chronic hepatitis B—particularly those who do not meet the treat/do-not-treat criteria above—require continued monitoring to determine if antiviral therapy may be indicated in the future for prevention of liver disease progression. Such persons include noncirrhotic individuals aged 30 years or younger:

  • With HBV DNA levels above 20,000 IU/mL  but persistently normal ALT levels
  • Who are HBeAg-negative, with HBV DNA levels that fluctuate between 2,000 and 20,000 IU/mL or with intermittently abnormal ALT levels (If HBV DNA testing is unavailable, continue to monitor noncirrhotic individuals aged 30 years or younger who have persistently abnormal ALT levels, regardless of their HBeAg status.)

Antiviral therapies

First-line antiviral treatment (Strong recommendations)

All individuals aged 12 years or older who are eligible for antiviral therapy are recommended to receive therapy with tenofovir or entecavir, the nucleos(t)ide analogs (NAs) with a high barrier to drug resistance. Entecavir is recommended in children aged 2-11 years.

NAs with a low barrier to drug resistance (lamivudine, adefovir, or telbivudine) are not recommended owing to their potential for drug resistance.

In HBV/HIV-coinfected individuals aged 3 years or older, a fixed-dose combination of tenofovir/lamivudine (or emtricitabine)/efavirenz is the preferred option for initiation of ART.

Second-line antiviral treatment for managing treatment failure (Strong recommendation)

For individuals with confirmed or suspected antiviral resistance (ie, history of prior exposure or primary nonresponse) to lamivudine, entecavir, adefovir, or telbivudine, the WHO recommends switching to tenofovir.

Treatment duration, cessation, and reinitiation

Lifelong NA therapy (Strong recommendation)

All individuals with cirrhosis based on clinical evidence (or APRI score >2 in adults) require lifelong NA therapy. Antiviral therapy in these individuals should not be discontinued owing to the potential for HBV reactivation.

Discontinuation of NA therapy (Conditional recommendation)

Individuals without clinical evidence of cirrhosis (or based on APRI score ≤2 in adults) who have all of the following features may be considered exceptionally for discontinuation of NAs:

  • Can be closely monitored for reactivation over the long term
  • Have evidence of HBeAg loss and seroconversion to anti-HBe (in those who were initially HBeAg positive), as well as after completion of at least one additional year of treatment
  • Have persistently normal ALT levels and persistently undetectable HBV DNA levels (where HBV DNA testing is available). (If HBV DNA testing is not available, consider discontinuation of NA therapy in those with evidence of persistent hepatitis B surface antigen [HBsAg] loss and after completion of at least one additional year of treatment, regardless of their previous HBeAg status). 

Retreatment (Strong recommendation)

Owing to the risk of relapse after discontinuation of NA therapy, the WHO recommends retreatment in the setting of consistent signs of reactivation (positive HBsAg or HBeAg, increasing ALT levels, or redetectable HBV DNA) (where HBV DNA testing is available).

Monitoring

Monitoring for disease progression and treatment response prior to, during, and posttreatment

The WHO recommends yearly monitoring at a minimum of the following (strong recommendation):

  • Levels of ALT (and AST level for APRI), HBsAg, HBeAg, and HBV DNA (where HBV DNA testing is available)
  • Liver fibrosis, in those without baseline cirrhosis, using noninvasive studies such as APRI score or FibroScan
  • Treatment adherence during therapy, at regular intervals and at each visit

More frequent monitoring may be indicated in certain individuals (Conditional recommendations)

Those who do not yet meet the criteria for antiviral therapy. Such individuals are those with intermittently abnormal ALT levels or HBV DNA levels that fluctuate between 2,000 IU/mL and 20,000 IU/mL (where HBV DNA testing is available), as well as HBV/HIV-coinfected persons.

Those receiving treatment or following treatment discontinuation. On-treatment monitoring is recommended at least every 3 months for the first year in/for the following:

  • Individuals with more advanced disease (compensated/decompensated cirrhosis)
  • Individuals coinfected with HBV/HIV
  • During the first year of treatment (to assess treatment response and adherence)
  • When treatment adherence is a concern
  • Individuals after treatment discontinuation

Monitoring for tenofovir and entecavir toxicity (Conditional recommendation)

Before initiating antiviral therapy, consider measuring all individuals' baseline renal function as well as evaluating their baseline risk for renal dysfunction.

Monitor renal function every year in individuals on long-term tenofovir or entecavir therapy; carefully monitor growth in children.

Monitoring for hepatocellular carcinoma (HCC)

Routinely obtain abdominal ultrasonography and alpha-fetoprotein (AFP) levels every 6 months for individuals who:

  • Are cirrhotic, regardless of their age or the presence of other risk factors (Strong recommendation)
  • Have a family history of HCC (Strong recommendation)
  • Are older than 40 years (younger age may be indicated based on the regional HCC incidence), do not have clinical evidence of cirrhosis (or based on APRI score ≤2), and have an HBV DNA level above 2,000 IU/mL (where HBV DNA testing is available) (Conditional recommendation)

Prevention

Infant and neonatal hepatitis B vaccination

It is recommended that all infants receive their first dose of hepatitis B vaccine as soon as possible after birth (≤24 hours preferred), followed by two or three doses. 

Prevention of mother-to-child HBV transmission using antiviral therapy 

HBV-monoinfected pregnant women should receive antiviral therapy as indicated for other adults, with tenofovir as the recommended NA. Currently, the WHO makes no recommendations for routine antiviral therapy for prevention of mother-to-child HBV transmission.

For HIV-infected pregnant and breastfeeding women (including those in the first trimester of pregnancy and women of childbearing age), the recommended first-line ART is a once-daily fixed-dose combination of tenofovir/lamivudine (or emtricitabine)/efavirenz (applicable to lifelong treatment as well as to ART initiated for prevention of mother-to-child HBV transmission and then stopped). (Strong recommendation)

2016 and 2018 AASLD Guidelines

Select recommendations from the 2016 American Association for the Study of Liver Diseases (AASLD) guidelines for the treatment of chronic hepatitis B[37]  as well as the 2018 AASLD guidance update on the prevention, diagnosis, and treatment of chronic hepatitis B[47] are outlined below.

Screening for hepatitis B infection

The following recommendations are from the 2018 AASLD guidance update[47] :

  • Perform screening with both hepatitis B surface antigen (HBsAg) and antibody to HBsAg (anti-HBs).
  • Individuals who should undergo screening include all those born in countries that have an HBsAg seroprevalence of 2% or greater, US-born persons in areas with high HBV endemicity (≥8%), pregnant women, those who require immunosuppression, and specific at-risk populations.
  • Vaccinate screened individuals who are negative for anti-HBs.
  • Although routine screening is not recommended for antibody to hepatitis B core antigen (anti-HBc) to assess for previous exposure, it is a valuable test in HIV patients; those about to receive hepatitis C or anticancer and other immunosuppressive treatment or renal dialysis; and in donated blood (or, organs, if feasible).

Recommendations for the initial evaluation of HBsAg-positive patients 

All patients

History and physical examination: Thoroughly evaluate for the following:

  • Alcohol, metabolic, and other risk factors for hepatitis B virus (HBV) infection
  • Patient's HBV vaccination status
  • Family history of HBV infection and hepatocellular carcinoma
  • The presence of symptoms/signs of cirrhosis

Routine laboratory studies

  • Complete blood cell (CBC) count, platelet count; international normalized ratio (INR)
  • Levels of aspartate transaminase (AST), alanine transaminase (ALT), total bilirubin, alkaline phosphatase (ALP), and albumin

Serologic/virologic studies

  • Hepatitis B e antigen (HBeAg)/anti-HBe
  • HBV DNA level
  • Anti-hepatitis A virus (anti-HAV) (to determine need for vaccination)

Imaging/staging studies 

  • Abdominal ultrasonography
  • Vibration-controlled transient elastography (eg, FibroScan) or a serum fibrosis marker panel (APRI [AST-to-platelet ratio index], FIB-4 [platelet count, ALT, AST, age], or FibroTest [gamma-2 macroglobulin, gamma-2 globulin, gamma globulin, apolipoprotein A1, gamma-glutamyl transpeptidase (GGT), total bilirubin])

Select patients

Routine laboratory studies: In the setting of elevated liver function test results, obtain tests to exclude other causes of chronic liver disease. Obtain levels of alpha-fetoprotein (AFP) and GGT.

Serologic/virologic studies

  • HBV genotyping
  • Tests for coinfection with hepatitis C virus (HCV), hepatitis D (delta) virus (HDV), and/or human immunodeficiency virus (HIV) in at-risk individuals aged 13-64 years who have not undergone one-time screening 

Counseling[47]

HBsAg-positive patients should receive counseling about the prevention of HBV transmission to others.

Healthcare workers and students who are HBsAg positive can continue with training or practice—unless their job requires they perform exposure-prone procedures. In such situations, these individuals should seek counseling/advice from their institutional expert review panel; they should not perform exposure-prone procedures if their serum HBV DNA level is above 1,000 IU/mL; and they can resume such procedures if their HBV DNA falls and is maintained below 1,000 IU/mL.

Aside from using universal precautions, special arrangements are not indicated for children with HBV in community setting (eg, daycare centers, schools, sports clubs, camps) unless they have a tendency to bite.

HBV-infected individuals are recommended to be abstinent or limit their alcohol use.

To prevent the concurrent development of fatty liver and metabolic syndrome, it is recommended that individuals with HBV optimize their body weight and treatment of metabolic complications (eg, control of diabetes and dyslipidemia).

Antiviral medications for adults and/or children

The aim of antiviral treatment is to lower the risk of associated liver-related complications of chronic HBV infection. Immunologic cure involves loss of hepatitis B surface antigen (HBsAg) and sustained suppression of HBV DNA. Virologic cure consists of viral eradication, including the covalently closed circular DNA (cccDNA form)—this type of cure is currently unattainable.

Antiviral therapy is indicated only for individuals with acute symptomatic hepatitis B and acute liver failure, or who have a protracted, severe disease course (total bilirubin >3 mg/dL or direct bilirubin >1.5 mg/dL; international normalize ratio [INR] >1.5; encephalopathy; or ascites).[47] Use the preferred agents (see below), and continue treatment until confirmation of HBsAg clearance or indefinitely in liver transplant recipients. Peg-IFN is contraindicated.[47] Individuals with chronic hepatitis B who fail to clear HBsAg after 6-12 months of treatment should receive ongoing management based on guidelines for chronic hepatitis B.

Drug regimens and monitoring

The following are medications approved for the treatment of chronic hepatitis B in pediatric and adult patients. Adjust all dosing in the setting of renal dysfunction.

 

Preferred drugs

Pegylated interferon (PEG-IFN)-alpha-2a (adults) or IFN-alpha-2b (children)

  • Adult dose: 180 μg weekly
  • Pediatric dose (age ≥1 year): 6 million IU/m 2 three times weekly
  • Pregnancy category: C
  • On-treatment monitoring: CBC count (monthly to every 3 months) and thyroid stimulating hormone level (every 3 months); evaluate for autoimmune, ischemic, neuropsychiatric, and infectious complications.

Entecavir

  • Adult dose: Daily 0.5 mg (lamivudine-naive persons) or 1.0 mg (those with lamivudine experience or decompensated cirrhosis)
  • Pediatric dose (age ≥2 years): Weight-based to 10-30 kg; for children weighing more than 30 kg, use 0.5 mg daily for lamivudine-naive children or 1.0 mg for those with lamivudine experience or decompensated cirrhosis
  • Pregnancy category: C
  • On-treatment monitoring: Obtain lactic acid levels if lactic acidosis is a concern; obtain HIV test before initiating treatment.

Tenofovir dipovoxil fumarate

  • Adult and pediatric (age ≥12 years) dose: 300 mg daily
  • Pregnancy category: B
  • On-treatment monitoring: Measure baseline creatinine clearance for those at risk for renal impairment, as well as at least annual levels of creatinine clearance, serum phosphate, urine glucose, and urine protein. Consider baseline and during-treatment bone density scans for those with a fracture history or at risk for osteopenia. Obtain lactic acid levels if lactic acidosis is a concern; obtain HIV test before initiating treatment.

Tenofovir alafenamide

  • Adult dose: 25 mg daily; no pediatric dosing
  • Pregnancy category: Insufficient human data
  • On-treatment monitoring: Obtain lactic acid levels if lactic acidosis is a concern; obtain HIV test before initiating treatment. Before initiation of, and during, therapy, measure serum creatinine, serum phosphorus, creatinine clearance, urine glucose, and urine protein levels in all patients as clinically appropriate.

 

Nonpreferred drugs

Adefovir

  • Adult and pediatric dose (age ≥12 years): 10 mg daily
  • Pregnancy category: C
  • On-treatment monitoring: Measure baseline creatinine clearance for those at risk for renal impairment, as well as at least annual levels of creatinine clearance, serum phosphate, urine glucose, and urine protein. Consider baseline and during-treatment bone density scans for those at risk for osteopenia or with a fracture history. Obtain lactic acid levels if lactic acidosis is a concern.

Lamivudine

  • Adult dose: 100 mg daily
  • Pediatric dose (age ≥2 years): 3 mg/kg daily (maximum: 100 mg)
  • Pregnancy category: C
  • On-treatment monitoring: Check amylase levels in symptomatic patients; obtain lactic acid levels if lactic acidosis is a concern; obtain HIV test before initiating treatment.

Telbivudine

  • Adult dose: 600 mg daily; no pediatric dosing 
  • Pregnancy category: B
  • On-treatment monitoring: Check creatine kinase levels in, and perform a clinical evaluation of, symptomatic patients; obtain lactic acid levels if lactic acidosis is a concern.

Treatment recommendations

Adults with immune-active chronic hepatitis B infection (ie, ALT >2 times the upper limit of normal [ULN] or significant histologic disease and HBeAg negative [HBV DNA >2,000 IU/mL] or HBeAg positive [HBV DNA >20,000 IU/mL]) (Strong recommendations)

Administer antiviral therapy to lower the risk of morbidity and mortality associated with chronic hepatitis B infection.

The recommended initial agents for adults are PEG-IFN, entecavir, or tenofovir. 

Adults with immune-tolerant chronic hepatitis B infection (ie, ULNs: ALT levels ≤30 U/L for men and ≤19 U/L for women)

Antiviral therapy is not recommended. (Strong recommendation)

The AASLD suggests obtaining ALT levels at least every 6 months to monitor for potential transition to immune-active or -inactive chronic hepatitis B. (Conditional recommendation)

For select patients older than 40 years, the AASLD suggests antiviral therapy in the setting of normal ALT levels, elevated HBV DNA (≥1,000,000 IU/mL), and significant necroinflammation or fibrosis on liver biopsy specimens. (Conditional recommendation)

Adults with HBeAg-positive immune-active chronic hepatitis B who seroconvert to anti-HBe on nucleos(t)ide analog (NA) therapy (Conditional recommendations)

After a period of treatment consolidation (treatment for ≥12 months in the setting of persistently normal ALT levels and undetectable serum HBV DNA), consider discontinuing NA therapy in noncirrhotic HBeAg-positive adults who seroconvert to anti-HBe while on NA treatment. If antiviral therapy is stopped, monitor the patient every 3 months for a minimum of 1 year for recurrent viremia, ALT flares, seroreversion, and clinical decompensation.

For cirrhotic HBeAg-positive adults who seroconvert to anti-HBe on NA therapy, the AASLD suggests indefinite antiviral therapy owing to the potential for clinical decompensation and death, unless a strong competing rationale for treatment discontinuation exists. If antiviral therapy is stopped, closely monitor these patients for recurrent viremia, ALT flares, seroreversion, and clinical decompensation.

Adults with HBeAg-negative immune-active chronic HBV infection

The AASLD suggests indefinite antiviral therapy for adults with HBeAg-negative immune-active chronic hepatitis B infection, unless there is a competing rationale for treatment discontinuation. (Conditional recommendation) If antiviral therapy is stopped, monitor the patient every 3 months for a minimum of 1 year for recurrent viremia, ALT flares, and clinical decompensation.

Antiviral therapy is not recommended for noncirrhotic individuals who are HBeAg negative and who have normal ALT activity and low-level viremia (< 2,000 U/mL; “inactive chronic hepatitis B”).

Patients with renal and bone disease on NA therapy

With regard to the potential long-term risks of renal and bone complications, the AASLD suggests no preference between entecavir and tenofovir. (Conditional recommendation)

Before initiating, and periodically during, treatment with tenofovir, evaluate patients' renal safety with levels of serum creatinine, phosphorus, urine glucose, and urine protein. If tenofovir is suspected of causing renal dysfunction and/or osteoporosis/osteomalacia, discontinue tenofovir and replace it with another NA, taking into account any previous drug resistance.

Adjust all NA dosing based on patients' renal function and creatinine clearance.

Patients with persistent low-level viremia on NA treatment (Conditional recommendations)

For patients with persistent low-level viremia (< 2,000 IU/mL) (plateau in the decline of HBV DNA and/or failure to achieve undetectable HBV DNA level after 96 weeks of therapy) on entecavir or tenofovir monotherapy, the AASLD suggests continuing monotherapy, regardless of ALT the level. 

For patients with virologic breakthrough on entecavir or tenofovir monotherapy (an increase in HBV DNA by >1 log compared to nadir or HBV DNA ≥100 IU/mL in those on NA therapy with previously undetectable levels [< 10 IU/mL]), either (1) switch to another antiviral monotherapy with a high barrier to resistance or (2) add a second antiviral drug that lacks cross-resistance.

To detect persistent viremia and virologic breakthrough, the AASLD suggests monitoring HBV DNA levels every 3 months until they are undetectable, followed by every 3-6 months thereafter. In addition, if NA therapy with a drug other than entecavir or tenofovir is used and virologic breakthrough occurs, switch to another antiviral monotherapy with a high genetic barrier to resistance or add a second antiviral with a complementary resistance profile.

Adults with cirrhosis and low-level viremia

In adults with compensated cirrhosis and low levels of viremia (< 2,000 IU/mL), regardless of ALT level, the AASLD suggests antiviral therapy (preferred: tenofovir, entecavir) to reduce the risk of decompensation. (Conditional recommendation).

Note the following:

  • If therapy is discontinued, closely monitor patients for a minimum of every 3 months for at least 1 year to detect early signs of viral rebound that may lead to decompensation.
  • In those not offered treatment, closely monitor every 3-6 months for an elevation in HBV DNA level and/or clinical decompensation; initiate treatment in these settings.
  • Patients with compensated cirrhosis and high HBV DNA levels (>2,000 U/mL) are treated according to the recommendations for HBeAg-positive and -negative immune-active chronic hepatitis B.

For HBsAg-positive adults with decompensated cirrhosis, the AASLD recommends indefinite antiviral therapy (preferred: entecavir, tenofovir) to reduce the risk of worsening liver-related complications, regardless of HBV DNA level, HBeAg status, or ALT level. (Strong recommendation) Also consider liver transplantation for eligible candidates.

Pregnant patients with chronic hepatitis B infection

The AASLD suggests antiviral therapy to reduce the risk of perinatal HBV transmission in HBsAg-positive pregnant women with an HBV DNA level above 200,000 IU/mL. (Conditional recommendation) Infants of these mothers should receive immunoprophylaxis according to current World Health Organization and Centers for Disease Control and Prevention recommendations.

Therapy for pregnant women with immune-active hepatitis B should be based on the same recommendations as for their nonpregnant counterparts.

Antiviral therapy is not recommended to reduce the risk of perinatal HBV transmission in HBsAg-positive pregnant women whose HBV DNA level is at or below 200,000 IU/mL. (Strong recommendation) 

Children with chronic hepatitis B infection

For HBeAg-positive children aged 2 years up to 18 years who have both elevated ALT and detectable HBV DNA levels, the AASLD suggests antiviral therapy (IFN-alpha-2b: age ≥1 year; lamivudine, entecavir: age ≥2 year), with the goal of achieving sustained HBeAg seroconversion. (Conditional recommendation) If antiviral therapy is stopped, monitor the child every 3 months for a minimum of 1 year for recurrent viremia, ALT flares, and clinical decompensation.

Antiviral therapy is not recommended for HBeAg-positive children aged 2 years up to 18 years who have persistently normal ALT (conservative value: 30 U/L), regardless of the HBV DNA level. (Strong recommendation)

Individuals with HBV and HCV coinfection[47]

  • Test all HBsAg-positive patients for HCV infection with the anti-HCV test.
  • Those with HCV viremia should receive HCV therapy.
  • HBV treatment is based on levels of HBV DNA and ALT as indicated by the AASLD HBV guideline for monoinfected individuals.
  • HBsAg-positive individuals: At risk for HBV DNA and ALT flares with  HCV-DAA (direct-acting antiviral) therapy; monitor HBV DNA levels every 4-8 weeks during treatment and for 3 months posttreatment for individuals who do not meet the treatment criteria according to the AASLD HBV guidelines.
  • HBsAg-negative, anti-HBc-positive individuals with HCV: Low risk of reactivation with HCV-DAA therapy; monitor ALT levels at baseline, treatment completion, and during follow-up; reserve HBV DNA and HBsAg testing for individuals whose ALT levels rise or fail to normalize during treatment or posttreatment

Vaccination

The following recommendations are from the 2018 AASLD guidance update[47] :

  • Administer HBV vaccines as a 3-dose series at 0, 1, and 6 months (± hepatitis A vaccine). Alternatively, for adults, combination hepatitis A and B vaccine (Twinrix) uses a 4-dose regimen at 0, 7, 21-30 days, and 12 months. A 2-dose series for adults at 0 and 1 months (HEPLISAV-B) is also available.
  • Sexual partners and household contacts of HBV-infected individuals who are negative for HBsAg and anti-HBs should receive HBV vaccination.
  • At deliverly, infants born to HBV-infected mothers should receive hepatitis B immunoglobulin (HBIG) and HBV vaccine; thereafter, the recommended vaccination schedule should be completed. Postvaccination testing at age 9-15 months is recommended for infants with HBsAg-positive mothers.
  • Those who should be tested for their response to HBV vaccination 1-2 months after the last vaccine dose is received include healthcare workers, sexual partners of those with chronic HBV, patients on chronic hemodialysis, and immunocompromised patients (eg HIV patients).
  • Nonresponders to the initial vaccine series: Repeat the 3-dose vaccination series, with a double dose for immunocompromised individuals (eg, cirrhotic patients).
  • Vaccine responders: Annual follow-up testing is recommended for chronic hemodialysis patients.
  • Booster doses or revaccination: Not recommended except if anti-HBs levels remain below 10 mIU/mL after the initial vaccination of infants of HBsAg-positive mothers, in healthcare workers, hemodialysis patients, and immunocompromised patients.

 

2017 and 2018 EASL Recommendations

In 2017, the European Association for the Study of the Liver (EASL) released updated guidelines for hepatitis B virus (HBV) infection[111]  and for HBV vaccination.[112, 113]  In 2018, the EASL released updates for the management of decompensated cirrhosis[114] and hepatocellular carcinoma (HCC).[115] Recommendations from these guidelines are outlined below.

HBV infection

All patients with e antigen (HBeAg)-positive or -negative chronic hepatitis B, defined by HBV DNA above 2,000 IU/mL, alanine aminotransferase (ALT) greater than the upper limit of normal (ULN), and/or at least moderate liver necroinflammation or fibrosis, should be treated.

Patients with compensated or decompensated cirrhosis need treatment with any detectable HBV DNA level and regardless of ALT levels.

Patients with HBV DNA >20,000 IU/ml and ALT greater than two times the ULN should start treatment regardless of the degree of fibrosis.

Patients with HBeAg-positive chronic HBV infection, defined by persistently normal ALT and high HBV DNA levels, may be treated if they are older than 30 years regardless of the severity of liver histologic lesions.

Patients with HBeAg-positive or HBeAg-negative chronic HBV infection and a family history of hepatocellular carcinoma (HCC) or cirrhosis and extrahepatic manifestations can be treated even if typical treatment indications are not fulfilled.

HBV vaccination

Clinicians should vaccinate against chronic HBV in all unvaccinated adults at risk for infection, including the following:

  • Adults at risk by sexual exposure (sex partners of hepatitis B surface antigen [HBsAg]-positive persons, sexually active persons who are not in a mutually monogamous relationship, persons seeking evaluation or treatment for a sexually transmitted infection, and men who have sex with men).

  • Adults at risk by percutaneous or mucosal exposure to blood (adults who are recent or current users of injection drugs; household contacts of HBsAg-positive persons; residents and staff of facilities for developmentally disabled persons; incarcerated, healthcare, and public safety workers at risk for exposure to blood or blood-contaminated body fluids).

  • Adults with chronic liver disease, including but not limited to hepatitis C virus infection, cirrhosis, fatty liver disease, alcoholic liver disease, autoimmune hepatitis, and an ALT or aspartate aminotransferase (AST) level greater than twice the upper limit of normal.

  • Adults with end-stage renal disease, including those receiving predialysis care, hemodialysis, peritoneal dialysis, and home dialysis.

  • Adults with human immunodeficiency virus (HIV) infection.

  • Pregnant women who are at risk for HBV infection during pregnancy (eg, having more than 1 sex partner during the previous 6 months, having been evaluated or treated for a sexually transmitted infection, recent or current injection drug use, or having an HBsAg-positive sex partner).

  • International travelers to regions with high or intermediate levels of endemic HBV infection.

  • Any adult seeking protection from HBV infection.

Clinicians should screen (HBsAg, antibody to hepatitis B core antigen [anti-HBc], and antibody to hepatitis B surface antigen [anti-HBs]) for HBV in high-risk persons, including persons born in countries with 2% or higher HBV prevalence, men who have sex with men, persons who inject drugs, HIV-positive persons, household and sexual contacts of HBV-infected persons, persons requiring immunosuppressive therapy, persons with end-stage renal disease (including hemodialysis patients), blood and tissue donors, persons infected with hepatitis C virus, persons with elevated ALT levels (≥19 IU/L for women and ≥30 IU/L for men), incarcerated persons, pregnant women, and infants born to HBV-infected mothers.

Clinicians should provide or refer all patients identified with HBV (HBsAg-positive) for posttest counseling and hepatitis B–directed care.

Cirrhosis

In patients with decompensated cirrhosis, the etiologic factor, should be removed, particularly alcohol consumption and hepatitis B or C virus infection, as this strategy is associated with decreased risk of decompensation and increased survival.

Strategies based on targeting abnormalities in the gut-liver axis by antibiotic administration (ie, rifaximin), improving the disturbed systemic circulatory function (ie, long-term albumin administration), decreasing the inflammatory state (ie, statins), and reducing portal hypertension (ie, beta blockers) have shown potential benefit to decrease cirrhosis progression in patients with decompensated cirrhosis.

A diagnostic paracentesis is recommended in all patients with new-onset grade 2 or 3 ascites, or in those hospitalized for worsening of ascites or any complication of cirrhosis.

Neutrophil count and culture of ascitic fluid culture (bedside inoculation blood culture bottles with 10 mL fluid each) should be performed to exclude bacterial peritonitis. A neutrophil count above 250 cells/µL is required to diagnose spontaneous bacterial peritonitis (SBP).

Ascitic total protein concentration should be performed to identify patients at higher risk of developing SBP.

The serum ascites albumin gradient (SAAG) should be calculated when the cause of ascites is not immediately evident, and/or when conditions other than cirrhosis are suspected.

Cytology should be performed to differentiate malignancy-related from non-malignant ascites.

Since the development of grade 2 or 3 ascites in patients with cirrhosis is associated with reduced survival, liver transplantation (LT) should be considered as a potential treatment option.

A moderate restriction of sodium intake (80–120 mmol/day, corresponding to 4.6–6.9 g of salt) is recommended in patients with moderate, uncomplicated ascites. This is generally equivalent to a no-added-salt diet with avoidance of pre-prepared meals. Adequate nutritional education of patients on how to manage dietary sodium is also recommended.

Diets with a very low sodium content (< 40 mmol/day) should be avoided, as they favor diuretic-induced complications and can endanger a patient’s nutritional status.

Patients with the first episode of grade 2 (moderate) ascites should receive an anti-mineralocorticoid drug alone, starting at 100 mg/day with stepwise increases every 72 hr (in 100 mg steps) to a maximum of 400 mg/day if there is no response to lower doses.

In patients who do not respond to anti-mineralocorticoids, as defined by a body weight reduction of less than 2 kg/wk, or in patients who develop hyperkalemia, furosemide should be added at an increasing stepwise dose from 40 mg/day to a maximum of 160 mg/day (in 40 mg steps).

Patients with long-standing or recurrent ascites should be treated with a combination of an anti-mineralocorticoid drug and furosemide, the dose of which should be increased sequentially according to the response.

Torasemide can be given in patients exhibiting a weak response to furosemide.

During diuretic therapy, a maximum weight loss of 0.5 kg/day in patients without edema and 1 kg/day in patients with edema is recommended.

Once ascites has largely resolved, the dose of diuretics should be reduced to the lowest effective dose.

In patients presenting with gastrointestinal (GI) hemorrhage, renal impairment, hepatic encephalopathy, hyponatremia, or alterations in serum potassium concentration, these abnormalities should be corrected before starting diuretic therapy. In these patients, cautious initiation of diuretic therapy and frequent clinical and biochemical assessments should be performed. Diuretic therapy is generally not recommended in patients with persistent overt hepatic encephalopathy.

Diuretics should be discontinued if severe hyponatremia (serum sodium concentration < 125 mmol/L), acute kidney injury (AKI), worsening hepatic encephalopathy, or incapacitating muscle cramps develop.

Furosemide should be stopped if severe hypokalemia occurs (< 3 mmol/L). Anti-mineralocorticoids should be stopped if severe hyperkalemia occurs (>6 mmol/L).

Albumin infusion or baclofen administration (10 mg/day, with a weekly increase of 10 mg/day up to 30 mg/day) is recommended in patients with muscle cramps.

Large volume paracentesis (LVP) is the first-line therapy in patients with large ascites (grade 3 ascites), which should be completely removed in a single session. LVP should be followed with plasma volume expansion to prevent postparacentesis circulatory dysfunction (PPCD).

In patients undergoing LVP greater than 5 L of ascites, plasma volume expansion should be performed by infusing albumin (8 g/L of ascites removed), as it is more effective than other plasma expanders, which are not recommended for this setting

In patients undergoing LVP less than 5 L of ascites, the risk of developing PPCD is low. However, it is generally agreed that these patients should still be treated with albumin because of concerns about use of alternative plasma expanders.

Nonsteroidal anti-inflammatory drugs should not be used in patients with ascites because of the high risk of developing further sodium retention, hyponatremia, and AKI.

Repeated LVP plus albumin (8 g/L of ascites removed) is recommended as first-line treatment for refractory ascites.

Diuretics should be discontinued in patients with refractory ascites who do not excrete >30 mmol/day of sodium under diuretic treatment.

Antibiotic prophylaxis is recommended in cirrhotic patients with acute GI bleeding because it reduces the incidence of infections and improves control of bleeding and survival. Treatment should be initiated on presentation of bleeding and continued for up to 7 days. Ceftriaxone (1 g/24 hr) is the first choice in patients with decompensated cirrhosis, those already on quinolone prophylaxis, and in hospital settings with high prevalence of quinolone-resistant bacterial infections. Oral quinolones (norfloxacin 400 mg bid) should be used in the remaining patients.

Hepatocellular carcinoma

Vaccination against hepatitis B reduces the risk of HCC and is recommended for all newborns and high-risk groups.

In patients with chronic hepatitis, antiviral therapies leading to maintained HBV suppression in chronic hepatitis B and sustained viral response in hepatitis C are recommended, since they have been shown to prevent progression to cirrhosis and HCC development.

Once cirrhosis is established, antiviral therapy is beneficial in preventing cirrhosis progression and decompensation. Furthermore, successful antiviral therapy reduces but does not eliminate the risk of HCC development. Antiviral therapies should follow the EASL guidelines for management of chronic hepatitis B and C infection.

Coffee consumption has been shown to decrease the risk of HCC in patients with chronic liver disease. In these patients, coffee consumption should be encouraged.

Diagnosis of HCC in cirrhotic patients should be based on noninvasive criteria and/or pathology.

In noncirrhotic patients, diagnosis of HCC should be confirmed by pathology.

Noninvasive criteria can only be applied to cirrhotic patients for nodule(s) ≥1 cm, in light of the high pretest probability and are based on imaging techniques obtained by multiphasic computed tomography (CT), dynamic contrast-enhanced magnetic resonance imaging (MRI), or contrast-enhanced ultrasound (CEUS). Diagnosis is based on the identification of the typical hallmarks of HCC, which differ according to imaging techniques or contrast agents (arterial phase hyperenhancement (APHE) with washout in the portal venous or delayed phases on CT and MRI using extracellular contrast agents or gadobenate dimeglumine, APHE with washout in the portal venous phase on MRI using gadoxetic acid, APHE with late-onset (>60 s) washout of mild intensity on CEUS).

Because of their higher sensitivity and the analysis of the whole liver, CT or MRI should be used first.

Fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan is not recommended for early diagnosis of HCC because of the high rate of false-negative cases.

In patients at high risk of developing HCC, nodule(s) less than 1 cm in diameter detected by ultrasound should be followed at ≤4-month intervals in the first year. If there is no increase in the size or number of nodules, surveillance could be returned to the usual 6-month interval thereafter.

In cirrhotic patients, diagnosis of HCC for nodules of ≥1 cm in diameter can be achieved with noninvasive criteria and/or biopsy-proven pathologic confirmation.

Repeated bioptic sampling is recommended in cases of inconclusive histologic or discordant findings, or in cases of growth or change in enhancement pattern identified during follow-up, but with imaging still not diagnostic for HCC.

Staging systems for clinical decision making in HCC should include tumor burden, liver function, and performance status.

Multiphasic contrast-enhanced CT or MRI is recommended for assessment of response after resection, locoregional, or systemic therapies.

Perioperative mortality of liver resection (LR) in cirrhotic patients should be less than 3%.

LR is recommended for single HCC of any size and in particular for tumors >2 cm, when hepatic function is preserved, and when sufficient remnant liver volume is maintained.

Tumor vascular invasion and extrahepatic metastases are an absolute contraindication for liver transplantation in HCC.

Thermal ablation with radiofrequency is the standard of care for patients with BCLC (Barcelona Clinic Liver Cancer) 0 and A tumors not suitable for surgery. Thermal ablation in single tumors 2 to 3 cm in size is an alternative to surgical resection based on technical factors (location of the tumor) and hepatic and extrahepatic patient conditions.

In patients with very early stage HCC (BCLC-0), radiofrequency ablation in favorable locations can be adopted as first-line therapy even in surgical patients.

Ethanol injection is an option in some cases where thermal ablation is not technically feasible, especially in tumors < 2 cm. 

Sorafenib is the standard first-line systemic therapy for HCC. It is indicated for patients with well-preserved liver function (Child-Pugh A) and with advanced tumors (BCLC–C) or earlier stage tumors progressing upon or unsuitable for locoregional therapies.

Lenvatinib has been shown to be non-inferior to sorafenib and is also recommended in first-line therapy for HCC given its approval. It is indicated for patients with well-preserved liver function (Child-Pugh A class), with good performance status, and with advanced tumors – BCLC-C without main portal vein invasion or tumors progressing upon or unsuitable for locoregional therapies.

Regorafenib is recommended as second-line treatment for patients tolerating and progressing on sorafenib and with well-preserved liver function (Child-Pugh A class) and good performance status. Recently, cabozantinib has shown survival benefits versus placebo in this setting.

 

Medication

Medication Summary

The goals of pharmacotherapy in patients with hepatitis B disease are to reduce the risk of progression of disease, prevent transmission to others, and decrease complications.

Currently, pegylated interferon alfa (PEG-IFN-a), entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) are the first-line agents in the treatment of hepatitis B disease. These are the main treatment drugs approved globally for this disease, although ongoing development and clinical trials are investigating new types of medications, such as encapsidation inhibitors, entry inhibitors, TLR7 agonists, and therapeutic vaccines.

The Centers for Disease Control and Prevention (CDC) recommends adults at risk for hepatitis B be immunized with hepatitis B vaccine. Hepatitis B vaccine is part of the standard immunization schedule for children.

Interferons

Class Summary

Interferons are naturally produced proteins with antiviral, antitumor, and immunomodulatory actions.

Peginterferon alfa 2a (Pegasys)

Peginterferon alfa-2a binds to cell surface receptors in a cascade of protein interactions, resulting in gene transcription. These stimulated genes inhibit viral replication in infected cells, cell proliferation, and immunomodulation. Peginterferon alfa-2a is indicated for adults with hepatitis B e antigen (HBeAg)–positive and HBeAg-negative chronic hepatitis B disease with compensated liver disease and evidence of viral replication and liver inflammation.

Peginterferon alfa-2a is also FDA approved for the treatment of chronic hepatitis C, alone or in combination with ribavirin, in patients not previously treated with interferon alfa, and with compensated liver disease.

Interferon alfa-2b (Intron A)

Interferon alfa-2b (Intron A)

Interferon alfa-2b is a protein product manufactured by recombinant DNA technology. Its mechanism of antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles.

The immunomodulatory effects of interferon alfa-2b include enhancement of cytolytic T-cell activity, stimulation of natural killer cell activity, amplification of human leukocyte antigen (HLA) class I protein on infected cells, and suppression of tumor cell proliferation. The direct antiviral activity of interferon alfa-2b activates viral ribonucleases and inhibits viral entry into cells and viral replication. A direct antifibrotic effect has been postulated.

Before initiation of therapy with interferon alfa-2b, perform tests to quantitate peripheral blood hemoglobin, platelets, granulocytes, hairy cells, and bone marrow hairy cells. Monitor the patient periodically (eg, monthly) during treatment to determine his/her response to therapy. If the patient's condition does not respond within 4 months, discontinue treatment.

If a response occurs, continue treatment until no further improvement is observed. Whether continued treatment is beneficial after that time remains unknown.

Antihepadnaviral, Reverse Transcriptase inhibitors

Class Summary

Antiviral agents interfere with viral replication and weaken or abolish viral activity.

Tenofovir disoproxil fumarate (Viread)

Tenofovir is a nucleotide analogue (adenosine monophosphate) reverse transcriptase and hepatitis B virus (HBV) polymerase inhibitor.

Tenofovir may be used as first-line therapy for treatment-naïve patients. It is preferred as additional therapy in patients with lamivudine, telbivudine, or entecavir resistance. This agent has more potent antiviral activity than adefovir and can be used as a substitute in patients who do not have an adequate response to adefovir.

Entecavir (Baraclude)

Entecavir is a guanosine nucleoside analogue with activity against hepatitis B virus (HBV) polymerase. This agent competes with the natural substrate deoxyguanosine triphosphate (dGTP) to inhibit HBV polymerase activity (ie, reverse transcriptase). Entecavir is less effective for lamivudine-refractory HBV infection. This drug is indicated for treatment of chronic HBV infection and is available as a tablet and as an oral solution (0.05 mg/mL; 0.5 mg = 10 mL).

Lamivudine (Epivir, Epivir-HBV)

Lamivudine is a thymidine analogue that blocks viral replication by competitive inhibition of viral reverse transcriptase. There is evidence that an indirect immunomodulatory effect can be observed.

Relative to other oral treatments, lamivudine is lower in cost. Other agents, however, except for adefovir, are superior to lamivudine in suppression of viral replication. Another disadvantage to this therapy includes its high rate of drug resistance. The role of lamivudine in hepatitis B treatment is diminishing as alternate therapies become available.

Adefovir dipivoxil (Hepsera)

Adefovir is used to treat chronic hepatitis B disease. This agent is a prodrug that is converted to the diphosphate salt. The active drug is classified as an antiviral nucleotide reverse transcriptase inhibitor. It inhibits hepatitis B virus (HBV) DNA polymerase (reverse transcriptase) by competing with the natural substrate deoxyadenosine triphosphate (dATP) and by causing DNA chain termination after its incorporation into viral DNA.

Telbivudine (Tyzeka)

Telbivudine is a nucleoside analogue approved by the US Food and Drug Administration (FDA) for chronic hepatitis B treatment. This drug inhibits hepatitis B viral DNA polymerase and is indicated for patients with evidence of ongoing hepatitis B viral replication and either persistently elevated aminotransferase activity or histologic evidence of active liver disease. Consider telbivudine for patients whose condition does not or is unlikely to respond to interferon or for patients who cannot tolerate interferon. Emergence of resistance is a major drawback of nucleoside analogue monotherapy.

Tenofovir AF (Vemlidy)

Tenofovir alafenamide (TAF) is a nucleotide reverse transcriptase inhibitor (NRTI) and a phosphonamidate prodrug of tenofovir. TAF, as a lipophilic cell-permeant compound, enters primary hepatocytes by passive diffusion and by the hepatic uptake transporters OATP1B1 and OATP1B3, and it is converted to tenofovir diphosphate. Tenofovir diphosphate inhibits HBV replication through incorporation into viral DNA by the HBV reverse transcriptase, which results in DNA chain-termination.

Compared with tenofovir disoproxil fumarate (TDF), TAF is a more targeted form of tenofovir that has demonstrated high antiviral efficacy at a dose that is 10 times lower than TDF, as well as an improved renal and bone safety profile.

It is indicated for the treatment of chronic HBV infection in adults with compensated liver disease.

Vaccines, Inactivated, Viral

Class Summary

Stimulates active immunity by developing antibodies to hepatitis B surface antigen (HBsAg).

Hepatitis b vaccine (Engerix B, Heplisav-B, Recombivax HB)

Hepatitis B vaccines are recommended by the CDC for at-risk adults who seek protection from HBV infection. Newborns should receive the vaccine within 24 hours of birth to HBsAg–negative mothers and within 12-h for HBsAg–positive mothers. Childhood catch-up and adolescent immunization schedules are also defined if a child did not receive the vaccine at birth. The vaccines are available as either a 3-dose regimen over 6 months (Engerix B, Recombivax HB) or a 2-dose regimen over 1 month (Heplisav-B is only for adults).

Hepatitis A/B vaccine (Twinrix)

Confers antibodies to HAV and HBV. It is indicated for active immunization against disease caused by hepatitis A virus and infection by all known subtypes of hepatitis B virus in adults aged 18 years or older.

 

Questions & Answers

Overview

What is hepatitis B (HBV) (Hep B)?

What is the pathogenesis of hepatitis B (HBV) (Hep B)?

What are the signs and symptoms of icteric hepatitis in patients with hepatitis B (HBV) (Hep B)?

What are the signs and symptoms of fulminant and subfulminant hepatitis in patients with hepatitis B (HBV) (Hep B)?

What is the clinical presentation of chronic hepatitis B (HBV) (Hep B) infection?

What are the physical findings suggestive of hepatitis B (HBV) (Hep B)?

What are the physical findings that suggest acute hepatitis B (HBV) (Hep B)?

What are the signs of chronic liver disease in patients with hepatitis B (HBV) (Hep B)?

What are the physical findings of cirrhosis in hepatitis B (HBV) (Hep B)?

Which lab tests may be used to assess the stages of hepatitis B (HBV) (Hep B)?

Which imaging studies are used to evaluate patients with hepatitis B (HBV) (Hep B) disease?

What procedure is performed to assess the severity of disease in patients with hepatitis B (HBV) (Hep B)?

What are the treatment goals for patients with hepatitis B (HBV) (Hep B) infection?

Which medications are used in the treatment of hepatitis B (HBV) (Hep B)?

What dietary limitations are indicated for patients with hepatitis B (HBV) (Hep B)?

What is the treatment of choice for fulminant hepatic failure and end-stage liver disease from hepatitis B (HBV) (Hep B) disease?

What is the global prevalence of hepatitis B (HBV) (Hep B)?

What are the possible complications of hepatitis B (HBV) (Hep B)?

What progress has been made in decreasing the prevalence of hepatitis B (HBV) (Hep B)?

How is hepatitis B (HBV) (Hep B) transmitted and what is the outcome of infection?

How common is chronic hepatitis B (HBV) (Hep B) in children and adults?

What is the efficacy of hepatitis B (HBV) (Hep B) vaccination in children?

What is the efficacy of antiviral treatment for hepatitis B (HBV) (Hep B)?

What is the pathophysiology of hepatitis B (HBV) (Hep B) infection?

What is encoded in the pathogenesis of hepatitis B (HBV) (Hep B) infection?

What is the role of S gene (surface gene) in the pathophysiology of hepatitis B (HBV) (Hep B) infection?

What is the role of the C gene (core gene) in the pathophysiology of hepatitis B (HBV) (Hep B) infection?

What is the role of the e antigen, (HBeAg) in the pathophysiology of hepatitis B (HBV) (Hep B) infection?

What is the role of the X gene in the pathophysiology of hepatitis B (HBV) (Hep B) infection?

What does the presence of antibodies against HBsAG (anti-HBs) indicate in the pathogenesis of hepatitis B (HBV) (Hep B) infection?

What does the presence of anti-HBc subtype IgM or IgG suggest in the pathogenesis of hepatitis B (HBV) (Hep B) infection?

What does the presence of antibodies to the e antigen (HBeAg) suggest in the pathogenesis of hepatitis B (HBV) (Hep B)?

How are hepatitis B (HBV) (Hep B) genome variants identified?

How does the global prevalence of the HBeAg-negative strain of hepatitis B (HBV) (Hep B) vary among regions?

What is the pathogenesis of hepatitis B (HBV) (Hep B) infection?

What is the final state of hepatitis B (HBV) (Hep B) disease?

What are the five stages in the life cycle of hepatitis B virus (HBV) (Hep B)?

What are the genotypes hepatitis B (HBV) (Hep B)?

Which factors increase the risk for hepatocellular carcinoma (HCC) in patients with hepatitis B (HBV) (Hep B)?

What is the prevalence of hepatocellular carcinoma (HCC) among patients with hepatitis B (HBV) (Hep B) and hepatitis C virus (HCV) coinfection?

What is the prevalence of hepatocellular carcinoma (HCC) among patients with hepatitis B (HBV) (Hep B) and hepatitis D (delta) virus (HDV) coinfection?

What is the role chronic hepatitis B (HBV) (Hep B) infection in the pathogenesis of hepatocellular carcinoma (HCC)?

What is the role of oval cells proliferation in the pathogenesis of hepatocellular carcinoma (HCC)?

Is cirrhosis suggestive of hepatocellular carcinoma (HCC) in patients with hepatitis B (HBV) (Hep B) infection?

What is the intrinsic hepatocarcinogenic activity in hepatitis B (HBV) (Hep B) infection?

What is the role of the HBxAg (antigen for the X gene of HBV) in the hepatocarcinogenic activity of hepatitis B (HBV) (Hep B) infection?

Which types of glomerulonephritis are caused by hepatitis B (HBV) (Hep B) infection?

What is the prevalence of glomerulonephritis among patients with chronic hepatitis B (HBV) (Hep B)?

What is the presentation of glomerulonephritis in patients with chronic hepatitis B (HBV) (Hep B)?

What is the pathogenesis of glomerulonephritis in patients with chronic hepatitis B (HBV) (Hep B)?

Can hepatitis B (HBV) (Hep B) cause arteritis?

What is the pathogenesis of polyarteritis nodosa (PAN) in patients with hepatitis B (HBV) (Hep B)?

What are the signs and symptoms of polyarteritis nodosa (PAN) in patients with hepatitis B (HBV) (Hep B)?

Which factors increase the risk of mortality from polyarteritis nodosa (PAN) in patients with hepatitis B (HBV) (Hep B)?

What is the prognosis of polyarteritis nodosa (PAN) in patients with hepatitis B (HBV) (Hep B)?

How is hepatitis B (HBV) (Hep B) transmitted?

Which genes increase the risk for developing chronic hepatitis B (HBV) (Hep B)?

What is the role of the IFNGR1 gene in hepatitis B (HBV) (Hep B) infection?

What is the role of the genes IFNAR2 and IL10R2 (CRFB4) in hepatitis B (HBV) (Hep B) infection?

Which genes may reduce hepatitis B (HBV) (Hep B) vaccine response?

What is the incidence of hepatitis B (HBV) (Hep B) in the US?

What are the risk factors for hepatitis B (HBV) (Hep B) infection in the US?

How has routine vaccination of infants for hepatitis B (HBV) (Hep B) infection affected the prevalence in the US?

What is the global prevalence of hepatitis B (HBV) (Hep B) infection?

How does the mode of transmission of hepatitis B (HBV) (Hep B) vary among global regions?

Which measures have reduced the global prevalence of hepatitis B (HBV) (Hep B)?

What is the geographic distribution of the 10 genotypes of hepatitis B (HBV) (Hep B)?

What are the race- and sex-related demographics of hepatitis B (HBV) (Hep B) disease?

How does the risk of developing chronic hepatitis B (HBV) (Hep B) vary among age groups?

How many deaths in the US are attributed to chronic hepatitis B (HBV) (Hep B) annually?

Which factors improve the prognosis in hepatitis B (HBV) (Hep B) infection?

Does chronic hepatitis B (HBV) (Hep B) increase the risk of hepatocellular carcinoma (HCC)?

What are risk factors for hepatocellular carcinoma (HCC) in patients with hepatitis B (HBV) (Hep B)?

What is the incidence of hepatocellular carcinoma (HCC) in patients with hepatitis B (HBV) (Hep B) infection and cirrhosis?

Which hepatitis B (HBV) (Hep B) mutations increase the risk of developing hepatocellular carcinoma (HCC)?

What are the mortality rates of hepatocellular carcinoma (HCC) among families with hepatitis B (HBV) (Hep B) infection?

What are variables that correlate with overall survival for individuals with cirrhosis or hepatocellular carcinoma (HCC) and hepatitis B (HBV) (Hep B) infection?

What is a poor prognostic factor for patients with hepatocellular carcinoma (HCC) and hepatitis B (HBV) (Hep B) infection?

What is the prognosis of renal disease in hepatitis B (HBV) (Hep B) related to?

How frequently does membranous glomerulonephritis (MGN) undergo spontaneous remission in patients with hepatitis B (HBV) (Hep B) infection?

What education should be given to patients with acute or chronic hepatitis B (HBV) (Hep B)?

Presentation

What is the spectrum of symptoms of hepatitis B (HBV) (Hep B) infection?

What are the multisystem manifestations of hepatitis B virus (HBV) (Hep B) infection?

What are the cutaneous symptoms of the early course hepatitis B (HBV) (Hep B) infection?

What is the incubation period in the acute phase of hepatitis B (HBV) (Hep B) infection?

What is icteric hepatitis?

What is the presentation of fulminant and subfulminant hepatitis B (HBV) (Hep B)?

What are the signs and symptoms of chronic hepatitis B (HBV) (Hep B)?

Which symptoms may be present in chronic hepatitis B (HBV) (Hep B) with progressive liver disease?

What is the variance in severity of physical findings in hepatitis B (HBV) (Hep B)?

Which physical findings suggest acute hepatitis B (HBV) (Hep B)?

Which physical findings suggest chronic hepatitis B (HBV) (Hep B)?

Which physical findings suggest cirrhosis and hepatitis B (HBV) (Hep B)?

DDX

Which conditions should be included in the differential diagnoses of hepatitis B virus (HBV) (Hep B) infection?

What are the differential diagnoses for Hepatitis B?

Workup

What is the role of lab testing in the workup of hepatitis B (HBV) (Hep B)?

How is severity determined in hepatitis B virus (HBV) (Hep B)?

How is a patient’s level of infectivity determined in hepatitis B (HBV) (Hep B) infection?

What is the role of DNA testing in the evaluation of hepatitis B (HBV) (Hep B)?

What are the AASLD recommendations for the initial evaluation of HBsAg-positive patients with hepatitis B (HBV) (Hep B)?

What are the AASLD recommendations for evaluation of hepatitis B (HBV) (Hep B) in HBsAg-positive patients with elevated LFTs?

What are the USPSTF recommendations for screening asymptomatic adolescents and adults at high risk for hepatitis B (HBV) (Hep B) infection?

When are foreign-born residents of the US screened for hepatitis B (HBV) (Hep B)?

Among which patients with hepatitis B (HBV) (Hep B) is hepatocellular carcinoma (HCC) more prevalent?

What are the CDC recommendations on screening for hepatitis C virus (HCV) infections in adults?

Which diagnostic test findings suggest acute hepatitis B (HBV) (Hep B)?

Which diagnostic findings are less common for acute hepatitis B (HBV) (Hep B) disease?

Which viral markers may be identified in the serum and the liver for acute hepatitis B (HBV) (Hep B)?

Which findings are diagnostic for chronic hepatitis B (HBV) (Hep B)?

Which diagnostic test findings are expected in patients with inactive hepatitis B (HBV) (Hep B) disease?

How is chronic hepatitis B (HBV) (Hep B) disease categorized?

What are diagnostic test findings of the HBeAg-positive subtype of chronic hepatitis B (HBV) (Hep B) disease?

What are the increased risks of HBeAg-negative of chronic hepatitis B (HBV) (Hep B)?

What are the expected diagnostic test findings for cirrhosis in patients with hepatitis B (HBV) (Hep B) infection?

What is the role of imaging studies in the diagnosis of hepatitis B (HBV) (Hep B) infection?

What are the likely imaging findings of cirrhosis in patients with hepatitis B (HBV) (Hep B) infection?

Is ultrasonographic surveillance for the detection of hepatocellular carcinoma (HCC) effective in patients with cirrhosis due to hepatitis B (HBV) (Hep B) infection?

What is the role of the Hepatiq radiologic image processing system in the evaluation for hepatitis B (HBV) (Hep B) infection?

What is the role of liver biopsy in the evaluation of hepatitis B (HBV) (Hep B) infection?

Which histologic findings suggest acute hepatitis B (HBV) (Hep B)?

Which histologic findings suggest chronic hepatitis B (HBV) (Hep B)?

How is liver damage graded in hepatitis B (HBV) (Hep B)?

How is liver damage staged in hepatitis B (HBV) (Hep B)?

Treatment

What are the WHO guidelines on treatment priorities for chronic hepatitis B (HBV) (Hep B) infection?

What are the risk factors for progression of hepatitis B (HBV) (Hep B) infection?

How is hepatocellular carcinoma (HCC) prevented in patients with hepatitis B (HBV) (Hep B) infection?

What is the treatment for acute hepatitis B (HBV) (Hep B) infection?

When is therapy indicated for the treatment of hepatitis B (HBV) (Hep B)?

What are the NIH recommendations for nucleos(t)ide therapy for hepatitis B (HBV) (Hep B) infection?

When is treatment recommended by the NIH for chronic hepatitis B (HBV) (Hep B)?

When is treatment recommended by the NIH for hepatitis B e antigen (HBeAg)-negative patients with chronic hepatitis B (HBV) (Hep B)?

What are the NIH recommendations for treatment of patients with hepatitis B (HBV) (Hep B) and HIV?

According to the NIH, when is therapy for hepatitis B (HBV) (Hep B) not routinely indicated?

When is treatment recommended by the WHO for chronic hepatitis B (HBV) (Hep B) infection?

What are the AASLD recommendations for treatment of individuals with hepatitis B (HBV) (Hep B) and HIV infection?

What are the AASLD guidelines for the treatment of chronic hepatitis B (HBV) (Hep B)?

What are the AASLD guidelines for the treatment of adults with HBeAg-negative immune-active chronic hepatitis B (HBV) (Hep B) infection?

What are the AASLD guidelines for the treatment of children with chronic hepatitis B (HBV) (Hep B) infection?

When is inpatient care indicated for patients with hepatitis B (HBV) (Hep B)?

What are the dietary restrictions for patients with hepatitis B (HBV) (Hep B)?

Which agents are used as first-line treatment for hepatitis B (HBV) (Hep B)?

Which medications are approved for the treatment of chronic hepatitis B (HBV) (Hep B)?

What is the first-line antiviral treatment for hepatitis B (HBV) (Hep B) in patients aged 12 years or older?

What is the first-line antiviral treatment for patients with hepatitis B (HBV) (Hep B) and HIV infection?

What is the second-line antiviral treatment for antiviral-resistant patients with hepatitis B (HBV) (Hep B)?

What are the special considerations of antiviral therapy in select patients with hepatitis B (HBV) (Hep B)?

What is a possible adverse effect of entecavir (ETV) in the treatment of hepatitis B (HBV) (Hep B)?

How are treatment regimens simplified in patients with hepatitis B (HBV) (Hep B) and HIV infection?

What is the efficacy of interferon alfa (IFN-a) treatment of hepatitis B (HBV) (Hep B)?

What are good prognostic factors for response to interferon alfa (IFN-a) treatment in patients with hepatitis B (HBV) (Hep B)?

Which findings indicate resolution of the hepatitis B (HBV) (Hep B) infection?

What is the efficacy of interferon alfa (IFN-a) therapy in treating hepatitis B (HBV) (Hep B)-related glomerulonephritis?

What are the effects of corticosteroids and immunosuppressive agents for treating vasculitis in patients with hepatitis B (HBV) (Hep B)?

Which antiviral drug has been used for the treatment of polyarteritis nodosa (PAN) in patients with hepatitis B (HBV) (Hep B)?

What are the adverse effects of interferon alfa (IFN-a) for the treatment of hepatitis B (HBV) (Hep B)?

What are the benefits of pegylated IFN-a 2a (PEG-IFN-a 2a) in the treatment of hepatitis B (HBV) (Hep B)?

What is the dosage regimen of pegylated IFN-a 2a (PEG-IFN-a 2a) for treatment of hepatitis B (HBV) (Hep B)?

Which patients with hepatitis B (HBV) (Hep B) have a better response to pegylated IFN-a 2a (PEG-IFN-a 2a)?

What is the role of telbivudine in the treatment of hepatitis B (HBV) (Hep B)?

Is telbivudine effective for the treatment of HBeAg-positive hepatitis B (HBV) (Hep B)?

Is telbivudine effective for the treatment of HBeAg-negative hepatitis B (HBV) (Hep B)?

What is the role of entecavir (ETV) in the treatment of hepatitis B (HBV) (Hep B)?

Is entecavir (ETV) effective for the treatment of HBeAg-positive hepatitis B (HBV) (Hep B)?

Is entecavir (ETV) effective for the treatment of HBeAg-negative hepatitis B (HBV) (Hep B)?

What is the efficacy of long-term treatment of hepatitis B (HBV) (Hep B) with entecavir (ETV) therapy?

What is the role of lamivudine (3TC) in the treatment of hepatitis B (HBV) (Hep B)?

What are the outcomes associated with lamivudine (3TC) in the treatment of hepatitis B (HBV) (Hep B)?

How is the HBeAg seroconversion rate affected after lamivudine (3TC) treatment for hepatitis B (HBV) (Hep B)?

What improvements have been seen in patients given lamivudine (3TC) for the treatment of hepatitis B (HBV) (Hep B)?

How is polyarteritis nodosa (PAN) treated in patients with hepatitis B (HBV) (Hep B) infection?

What therapy regimens may be prophylactic for hepatitis B (HBV) (Hep B) infection in patients with HIV infection?

How do viral variants complicate lamivudine (3TC) treatment of hepatitis B (HBV) (Hep B)?

When is adefovir indicated for the treatment of chronic hepatitis B (HBV) (Hep B)?

What is the optimal dose for adefovir for the treatment of hepatitis B (HBV) (Hep B)?

What is the efficacy of adefovir for the treatment of hepatitis B (HBV) (Hep B)?

When is tenofovir indicated for the treatment of hepatitis B (HBV) (Hep B)?

What is the efficacy of tenofovir for the treatment of HBeAg-positive hepatitis B (HBV) (Hep B)?

What is the efficacy of tenofovir for the treatment of HBeAg-negative hepatitis B (HBV) (Hep B)?

What is the efficacy of tenofovir for the treatment of chronic hepatitis B (HBV) (Hep B)?

Is tenofovir effective as the first-line therapy for hepatitis B (HBV) (Hep B)?

Which agents may provide prophylaxis against hepatitis B (HBV) (Hep B) infection?

What are the indications for surgical treatment of hepatitis B (HBV) (Hep B)?

What are the ACOG and the USPSTF recommendations for routine prenatal screening for hepatitis B (HBV) (Hep B)?

How are neonates of mothers with chronic hepatitis B (HBV) (Hep B) treated?

Is breastfeeding contraindicated in mothers with chronic hepatitis B (HBV) (Hep B)?

What are the guidelines for reducing the risk of perinatal hepatitis B (HBV) (Hep B) transmission?

What therapy should pregnant women with immune-active hepatitis B (HBV) (Hep B) receive?

When is antiviral therapy not recommended for pregnant women with hepatitis B (HBV) (Hep B)?

What does the hepatitis B (HBV) (Hep B) vaccine consist of?

How effective is the hepatitis B (HBV) (Hep B) 3-dose vaccine series when administered in infancy?

What are the recommendations for hepatitis B (HBV) (Hep B) vaccination in children?

What are the hepatitis B (HBV) (Hep B) vaccine options for adults?

What are the ACIP recommendations for immunizing adults at risk for hepatitis B (HBV) (Hep B) infection?

Which factors are associated with low hepatitis B (HBV) (Hep B) vaccination response rates?

Should nonresponders be revaccinated against hepatitis B (HBV) (Hep B)?

Should pregnant patients be vaccinated against hepatitis B (HBV) (Hep B)?

What is the advantage of a combined hepatitis A virus (HAV)/hepatitis B (HBV) (Hep B) vaccine?

What long-term monitoring is needed for individuals with inactive chronic hepatitis B virus (HBV) (Hep B)?

What are the guidelines for monitoring of hepatitis B (HBV) (Hep B) DNA and alanine aminotransferase (ALT) levels?

What long-term monitoring is needed for patients with hepatitis B (HBV) (Hep B) and cirrhosis?

What are the monitoring considerations for patients with hepatitis B (HBV) (Hep B)?

How long does hepatitis B (HBV) (Hep B) persist in the blood and what factors increase the risk of infection flare or reactivation?

What are the recommendations for prophylactic antiviral therapy in patients with hepatitis B (HBV) (Hep B)?

What medications may increase the risk for hepatitis B (HBV) (Hep B) reactivation?

Guidelines

What are the WHO guidelines for follow-up assessment of liver disease in hepatitis B (HBV) (Hep B)?

What are the WHO guidelines for treatment priority in chronic hepatitis B (HBV) (Hep B)?

What are the WHO guidelines for when hepatitis B (HBV) (Hep B) should be treated?

What are the WHO guidelines for when hepatitis B (HBV) (Hep B) should be monitored but not treated?

What are the WHO recommendations for first-line antiviral therapy in hepatitis B (HBV) (Hep B)?

What are the WHO recommendations for first-line antiviral therapy in patients with hepatitis B (HBV) (Hep B) and HIV infection?

What is the WHO recommendation for second-line antiviral therapy in antiviral-resistant hepatitis B (HBV) (Hep B)?

According to the WHO recommendations, which patients with hepatitis B (HBV) (Hep B) require lifelong nucleos(t)ide analog (NA) therapy?

According to the WHO recommendations, which patients may be considered for discontinuation of nucleos(t)ide analogs (NAs) for the treatment of hepatitis B (HBV) (Hep B)?

When is retreatment of nucleos(t)ide analog (NA) for hepatitis B (HBV) (Hep B) recommended by the WHO?

What are the WHO recommendations for monitoring for hepatitis B (HBV) (Hep B) progression?

According to the WHO, which individuals with hepatitis B (HBV) (Hep B) infection do not meet the criteria for antiviral therapy?

What is the WHO recommended monitoring for patients with hepatitis B (HBV) (Hep B) during treatment or following treatment discontinuation?

What is the WHO recommended monitoring of tenofovir and entecavir toxicity in patients with hepatitis B (HBV) (Hep B) infection?

What is the WHO recommendation for monitoring for hepatocellular carcinoma (HCC) and in which patients with hepatitis B (HBV) (Hep B) infection?

What is the WHO recommendation for infant and neonatal hepatitis B (HBV) (Hep B) vaccination?

What is the WHO recommendation for use of antiviral therapy to prevent vertical transmission of hepatitis B (HBV) (Hep B)?

What are the AASLD guidelines for the initial evaluation of hepatitis B surface antigen (HBsAg)-positive patients?

What is the goal of antiviral treatment for hepatitis B (HBV) (Hep B)?

What are the AASLD recommendations for medications for the treatment of chronic hepatitis B (HBV) (Hep B)?

What are the AASLD guidelines for treatment of adults with immune-active chronic hepatitis B (HBV) (Hep B) infection?

What are the AASLD guidelines for the treatment of adults with immune-tolerant chronic hepatitis B (HBV) (Hep B) infection?

What are the AASLD guidelines for the treatment of adults with HBeAg-positive immune-active chronic hepatitis B (HBV) (Hep B)?

What are the AASLD guidelines for the treatment of adults with HBeAg-negative immune-active chronic hepatitis B (HBV) (Hep B) infection?

What are the AASLD guidelines for monitoring renal disease in patients with hepatitis B (HBV) (Hep B)?

What are the AASLD guidelines for patients with poor response to antiviral treatment for hepatitis B (HBV) (Hep B)?

What are the AASLD guidelines for the treatment of cirrhosis and hepatitis B (HBV) (Hep B)?

What are the AASLD guidelines for the treatment of pregnant patients with chronic hepatitis B (HBV) (Hep B)?

What are the AASLD guidelines for the treatment of children with chronic hepatitis B (HBV) (Hep B)?

Medications

What are the goals of pharmacotherapy in the treatment of hepatitis B (HBV) (Hep B) disease?

Which first-line agents are used to treat hepatitis B (HBV) (Hep B)?

Which medications in the drug class Vaccines, Inactivated, Viral are used in the treatment of Hepatitis B?

Which medications in the drug class Antihepadnaviral, Reverse Transcriptase inhibitors are used in the treatment of Hepatitis B?

Which medications in the drug class Interferons are used in the treatment of Hepatitis B?