Hepatitis B Virus

Authors: Stevan A. Gonzalez, M.D., M.S.


Hepatitis B virus (HBV) is an enveloped, partially double-stranded DNA virus of the Hepadnaviridae family (128). The infectious hepatitis B virion, known as the Dane particle, is approximately 42 nm in size and is composed of an outer lipid envelope containing viral glycoproteins as well as an inner nucleocapsid (Figure 1). The viral glycoproteins within the lipid envelope of the virion constitute the hepatitis B surface antigen (HBsAg). The nucleocapsid, composed of hepatitis B core antigen (HBcAg), encloses a copy of double-stranded circular HBV DNA and the HBV DNA polymerase.

The HBV life cycle begins with binding of the hepatitis B virion to hepatocytes through interactions between cell surface receptors and viral envelope proteins, including the HBsAg (Figure 2) (128). Binding of the HBV envelope proteins and cellular receptors is followed by entry of the hepatitis B virion into the hepatocyte through endocytosis and the nucleocapsid is subsequently released into the cytoplasm. The nucleocapsid is uncoated at the nuclear membrane and relaxed circular HBV DNA (rcDNA) is released into the nucleus. Within the hepatocyte nucleus, rcDNA is converted into a covalently closed circular double-stranded DNA (cccDNA) molecule. The conversion of rcDNA to cccDNA involves a process of DNA repair and covalent ligation of both strands of circular DNA (144192). The intranuclear HBV cccDNA serves as a template for ongoing transcription of viral RNA.

The double-stranded circular HBV DNA genome is approximately 3.2 kilobases (kb) in length and encodes four major RNA transcripts measuring 3.5 kb, 2.4 kb, 2.1 kb, and 0.7 kb. The largest (3.5 kb) transcript functions as both messenger RNA and as pre-genomic RNA. As transcription of the HBV cccDNA occurs within the hepatocyte nucleus, random integration of the HBV genome into the host chromosomes can also occur (16). Translation of viral RNA into the various HBV proteins involves four overlapping open reading frames (ORF): S (surface envelope), C (core), P (polymerase), and X (Figure 3). Both the S and C ORFs are characterized by in-frame initiation codons that facilitate the translation of different proteins within the RNA transcript (Figure 4). Thus, the C ORF encodes for the HBcAg and pre-core proteins, while the S ORF encodes for three different surface envelope proteins; large, middle, and small HBsAg. The pre-S domain of the large HBsAg protein appears to play a key role in binding of HBV to surface receptors on hepatocytes (110).  The pre-core protein ultimately undergoes proteolysis and becomes hepatitis B e antigen (HBeAg) in the endoplasmic reticulum. The HBeAg may have an immunoregulatory role that facilitates chronic infection within the host and is an important marker of viral replication (164). The P ORF encodes the HBV polymerase, an enzyme that plays several roles in the replication process including facilitation of DNA synthesis, reverse transcription, and degradation of pre-genomic RNA. The X ORF encodes the X protein (HBxAg), which is thought to be involved in several functions such as cell cycle regulation, signal transduction, transcriptional activation, and DNA repair (12). 

Assembly of the HBV nucleocapsid is initiated within the cytoplasm. Pre-genomic RNA enclosed within the nucleocapsid becomes a template for reverse transcription and synthesis of new HBV DNA. The conversion of pre-genomic RNA into viral rcDNA occurs via reverse transcription mediated by the HBV DNA polymerase. Further assembly of hepatitis B virions occurs at the endoplasmic reticulum. Mature virions are ultimately excreted through a process of budding and vesicular transport into the extracellular space. The HBV cccDNA molecule continues to exist as a viral minichromosome within the nucleus and is characterized by a high degree of stability, in which it can remain in the nucleus for the lifetime of the hepatocyte. Although levels of intrahepatic cccDNA can be suppressed with antiviral therapy, this form of HBV DNA appears to be resistant to eradication (48241).

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It is estimated that over 2 billion people have been exposed to HBV worldwide, while over 350 million people have chronic infection with HBV (2). The overall prevalence of chronic HBV infection appears to be declining in many parts of the world, likely due to increased immunization (178).  The prevalence of chronic HBV varies widely based on geography. As a result, certain populations in regions of Africa, Asia, and the Pacific disproportionately comprise the largest proportion of individuals with chronic infection (59). Up to 45% of the world’s population resides in these endemic areas where the rate of HBsAg seropositivity is over 8%. In hyperendemic areas of Asia and sub-Saharan Africa, as much as 20% of the population may have chronic infection (259). Other regions with high rates of HBsAg seropositivity include areas of South America, the Middle East, the Indian subcontinent, and Eastern Europe. In nonendemic regions such as North America and Western Europe, the distribution of chronic infection with HBV may reflect geographic immigration patterns of populations from endemic countries (108).  Eight genotypes of HBV have been identified (A through H) as well as several subgenotypes(113). HBV genotypes are defined by greater than 8% genomic divergence in nucleotide sequence, while subgenotypes are defined by greater than 4% divergence. The global distribution of genotypes varies by geography, such that A, F, G, and H occur most frequently in western countries while genotypes B, C, and E are most commonly encountered in Asia and Africa. Genotype D is most prevalent in the Mediterranean region (113201).

Risk Factors for Exposure

HBV is primarily transmitted through parenteral routes, mucosal contact, or perinatal exposure. In regions characterized by a very high prevalence of HBV in the general population such as Asia and sub-Saharan Africa, infection is most commonly acquired through vertical or horizontal transmission early in life (259). In developed countries, individuals at increased risk of exposure to HBV include injection drug users, persons with multiple sexual partners, incarcerated individuals, and dialysis patients (148168).  Most cases of acute infection with HBV are asymptomatic. The development of chronic infection following acute exposure varies by age. Approximately 5% of adults acutely exposed to HBV progress to chronic infection, while as many as 90% of newborns exposed through vertical transmission may develop chronic HBV (92). Acute infection can result in a fulminant clinical course; however this is rare and occurs in less than 1% of acute HBV cases (2). Risk factors for developing acute liver failure (ALF) in the setting of HBV infection include increased age at the time of exposure, co-infection with hepatitis D virus (HDV), and co-infection with hepatitis C virus (HCV) (190229).  Fulminant hepatitis B is associated with a high mortality of over 70% without liver transplantation (97176).  The proportion of ALF cases in adults resulting from acute HBV infection in developed countries appears to be in decline. Early reports described HBV as the cause of ALF in up to 50% of cases; however, numbers of cases have decreased significantly over the last two decades (97126205).  Recent data from one large prospective series from the United States from 1998 to 2007 reported HBV as the cause of ALF in 7% of cases (126).  Individuals who are inactive HBsAg carriers are also at risk of fulminant hepatitis from either reactivation in the setting of immunosuppressive therapy or other causes, as their risk of ALF in the setting of an acute hepatitis increases 9-fold, regardless of etiology (5354207).

Hepatitis B and Hepatocellular Carcinoma

Chronic infection with HBV is a major cause of hepatocellular carcinoma (HCC), a leading cause of cancer-related death (180).  The risk of HCC associated with HBV is significant and can exist in the absence of cirrhosis such that individuals with chronic infection have a 20-fold increase in risk of HCC (181).  At this time, chronic HBV infection is the most common risk factor for HCC worldwide, accounting for up to 54% of cases (181).  As a result, the distribution of HCC incidence throughout the world reflects the prevalence of HBV geographically (180).  The incidence of HCC is highest in hyperendemic regions where the majority of individuals acquire HBV infection through vertical or horizontal transmission early in life (23659).  Early acquisition of HBV infection is a risk factor for HCC-related mortality and may contribute to the increased risk of HCC observed within families, particularly in endemic areas (36161260).  First-degree relatives have over a 2-fold greater risk of HCC when one first-degree relative has HBV-associated HCC and a 5-fold greater risk when two first-degree relatives have HCC (260).  A prolonged duration of infection characterized by persistence of serum HBsAg (46270) and HBeAg (162253) following early exposure to HBV is a major contributor to this increase in risk. In those who have chronic HBV infection, additional risk factors for HCC have been identified including development of cirrhosis, elevated serum alanine aminotransferase (ALT) levels, increased age, male gender, Asian or African ethnicity, alcohol or tobacco abuse, and exposure to aflatoxin. Individuals co-infected with HDV, HCV, or human immunodeficiency virus (HIV) are also at increased risk. In light of the risk of HCC in those chronically infected with HBV, surveillance in the form of hepatic imaging with or without measurement of the serum tumor marker alpha-fetoprotein (AFP) at 6 to 12 month intervals is recommended for those considered to be at increased risk (Table 1) (2071107177).

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Chronic liver disease associated with hepatitis B is a major cause of morbidity and mortality worldwide, accounting for over 500,000 deaths annually (82). Efforts to prevent and treat chronic HBV infection may have a major impact on the global incidence of progressive liver disease, cirrhosis, and HCC. Several factors have been associated with progression of liver disease once chronic infection with HBV is established. Early exposure to HBV is a major risk factor, as up to 25% of individuals who develop chronic infection early in life will develop cirrhosis or HCC  (122). Additional risk factors for development of cirrhosis include elevated serum ALT levels, advanced age, and chronic heavy alcohol intake. Viral factors associated with disease progression include detectable serum HBeAg, increased serum HBV DNA levels, and infection with HBV genotype C (3956114142163).

Phases of Chronic Hepatitis B Infection

Once chronic infection is established within the host, the clinical course of HBV may fall into one of four phases: immune tolerance, immune clearance, inactive HBsAg carrier state, or reactivation (Table 2) (258).  Immune tolerance is most frequently associated with younger individuals who likely acquired HBV infection perinatally through vertical or horizontal transmission. This phase is characterized by very high serum HBV DNA levels, detectable HBeAg, normal serum ALT levels, and minimal histologic activity on liver biopsy. In contrast, the immune clearance phase is associated with elevated ALT levels and significant HBV-associated disease on liver biopsy. In this phase, HBeAg is detectable and HBV DNA levels are typically elevated. The inactive HBsAg carrier state is notable for persistently detectable serum HBsAg, yet normal ALT levels, low or undetectable HBV DNA, and typically minimal disease on liver biopsy. This phase is also associated with seroconversion of HBeAg, defined by loss of HBeAg and emergence of antibody to HBeAg (anti-HBe). Some individuals may transition into a HBV reactivation phase also known as HBeAg-negative chronic HBV infection. This phase is characterized by negative HBeAg, positive anti-HBe, persistently or intermittently elevated ALT levels, and significant disease on liver biopsy. In the reactivation phase, HBV DNA may be elevated but typically not as elevated as observed in HBeAg-positive infection. Individuals who are in the immune clearance phase (HBeAg-positive) and the reactivation phase (HBeAg-negative) may be candidates for antiviral therapy. Several groups have developed guidelines for selection of appropriate candidates in whom therapy should be considered (Table 3). Treatment of HBV infection is not indicated in the setting of immune tolerance or the inactive HBsAg carrier state; however these individuals should be monitored longitudinally as they may transition into a more active phase of infection.

Influence of Genotype and Mutations

As a result of a high rate of viral replication of approximately 1011 virions per day and lack of a proofreading mechanism in the HBV polymerase, HBV replication is associated with a very high rate of spontaneous mutations  (175). Within an infected host, HBV may exist in the form of multiple quasispecies in which viral strains will predominate as a consequence of endogenous and exogenous selection pressures, including replication fitness of specific viral mutants, host immunity, and antiviral therapy (50). Spontaneous mutations occur most frequently at the precore and core promoter regions (Figure 3). The frequencies of precore and core promoter mutations vary depending on HBV genotype. The most commonly encountered precore mutation (G1896A) is frequently associated with HBV genotype D infection and results in the formation of a stop codon within the precore region, leading to loss of production of the precore protein and HBeAg. In contrast, mutations occurring within the core promoter region are most commonly associated with genotype C infection, resulting in decreased production of HBeAg (50).  Core promoter mutations have been associated with an increased risk of HCC and may in part account for the increased prevalence of HCC observed in genotype C infection (92851106135138139221254267).  Mutations within the pre-S region also appear to occur more frequently in the setting of genotype C infection and are similarly associated with an increased risk of HCC (3599136140210231).  X promoter mutations and HBxAg have also been implicated in the development of HCC, although data are limited (12275). Mutations that arise during antiviral therapy may confer drug resistance leading to treatment failure. Strategies to minimize the potential for resistance are critical in maintaining optimal viral suppression and reducing the risk of disease progression as well as HCC.

Infection with specific HBV genotypes may have an impact on the clinical course of infection, development of advanced liver disease, and response to antiviral therapy. Genotype D has been reported with a higher prevalence in patients presenting with ALF associated with acute HBV infection (78229). Several studies in mostly Asian populations have reported an increased risk of HCC in patients infected with genotype C (2864105143248254262267) and possibly subgenotype Ce (29211).  In Alaska natives, a population known to have a very high prevalence of chronic HBV infection, genotype C infection was associated with a delayed onset of spontaneous HBeAg seroclearance and increased vertical transmission rates (142). Factors such as prolongation of the interval to immune clearance and an increased incidence of reactivation may contribute to the increased risk of cirrhosis and HCC associated with this population (56114142).  Genotype A has been associated with increased efficacy of interferon (IFN) alfa therapy with a higher potential of achieving clearance of HBeAg and HBsAg, while genotype C may be less IFN-responsive (204).  Genotype A has also been associated with higher efficacy in the setting of oral nucleotide therapy based on rates of HBeAg clearance and seroconversion with tenofovir therapy (90). 

Identifying Risk of Hepatocellular Carcinoma

In light of the increased risk among individuals with chronic HBV infection, elucidating viral factors that promote carcinogenesis and development of HCC are critical to identification of individuals who may be at particularly high risk, developing effective surveillance strategies, and selection of treatment candidates. Several prospective studies have established serum HBV DNA as a primary risk factor for HCC in patients with chronic HBV (29383940254).   The largest of these studies, the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV) study, prospectively investigated the association between serum HBV DNA levels and risk of HCC in a cohort of untreated HBsAg-positive patients in Taiwan(38).The study cohort included 3,653 mostly HBeAg-negative individuals who were followed over a mean of 11.4 years. The risk of HCC in this cohort increased in a linear relationship with serum HBV DNA levels, with the greatest risk observed at HBV DNA levels >104 copies/mL (Figure 4). The linear relationship between HBV DNA levels and risk of HCC occurred independently of cirrhosis, HBeAg positivity, or serum ALT levels. Although diminished, the risk of HCC also extends to individuals with low levels of HBV DNA, including inactive HBsAg carriers, who have an increased risk of HCC compared with HBsAg-negative controls (42). Other studies have noted that serologic markers of viral replication such as HBsAg(1037) and HBeAg (162253) are associated with an increased risk of HCC, in which the duration of antigenemia may contribute to this risk while spontaneous clearance of HBsAg may result in a reduction in risk (46270). The findings from the REVEAL-HBV study and others indicate that suppression of HBV with antiviral therapy plays a critical role in prevention of HCC. Prospective data involving patients with advanced liver disease have demonstrated significant reductions in the incidence of HCC with antiviral therapy (129). Additional analyses have also reported a lower incidence of HCC than predicted in patients receiving oral nucleoside or nucleotide analogue therapy vs. untreated patients over a long-term follow up, with reductions in HCC incidence by over 50% within a median of 4 years of therapy  (58208).

Extrahepatic Manifestations of Hepatitis B

Extrahepatic manifestations of HBV infection includes various forms of vasculitis, renal disease, and arthritis, typically associated with circulating immune complexes within the host (88). Polyarteritis nodosa as well as glomerulonephritis, including membranoproliferative, membranous, and mesangial proliferative variants, appear to be associated with immune complex deposition and may improve with antiviral therapy, although data are limited. Essential mixed cryoglobulinemia can also occur in association with HBV infection, initially presenting with purpura, recurrent arthritis, and weakness, but can then progress to advanced disease characterized by features of vasculitis, glomerulonephritis, and pulmonary involvement. Additional extrahepatic manifestations of HBV may include palpable purpura and generalized arthralgias, which can appear at the time of acute infection or once chronic infection is established.

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The diagnosis of HBV infection can be made with serological markers, while assessment of serum HBV DNA is instrumental in further differentiating between phases of chronic infection. Serological markers can also define prior infection with resolution or an individual who has undergone vaccination for HBV (Table 4). Serum HBsAg positivity or detection of serum HBV DNA defines the presence of HBV infection. In the setting of acute infection, both HBsAg and IgM antibodies to HBcAg may be positive; however assessment of HBV DNA is the most reliable test if ALF if present. Following the acute phase of infection, the host will develop IgG antibodies to HBcAg. In those who achieve spontaneous resolution with long-term immunity against HBV, antibodies directed against HBsAg (anti-HBs) will emerge coinciding with loss of HBsAg. In cases of chronic infection, HBsAg positivity will persist, defined by a positive serum HBsAg for greater than 6 months. Prior vaccination for HBV is characterized by the presence of anti-HBs, yet antibodies to HBcAg are absent.


In the setting of acute infection, development of a vigorous and multispecific cell-mediated response within the host directed towards HBV is critical in the achievement of spontaneous resolution. In contrast, a failure to develop an adequate adaptive immune response may result in persistence of viremia and subsequent development of chronic infection. Animal and human studies have demonstrated that HBV-specific CD8-positive cytotoxic T-cell immunity is essential in clearance of HBV-infected hepatocytes, while expression of pro-inflammatory cytokines such as IFN-γ play a major role in suppression of HBV replication. The host innate immune system may also contribute to achieving resolution of acute infection through activation of natural killer (NK), NKT cells, and Kupffer cells, resulting in further cytokine production and direct cytotoxicity mediated by these cell types.

The humoral immune response to HBV also plays a key role in establishing and maintaining immune control of acute infection as well as prevention of reactivation. The emergence of neutralizing antibodies directed towards HBcAg, HBeAg, and ultimately HBsAg indicate resolution of acute infection. These serologic markers also are important in monitoring long-term virologic response to therapy. Following recovery from acute infection, intranuclear HBV cccDNA can remain within hepatocytes. The persistence of host HBV-specific cell-mediated immunity as well as humoral immunity are essential to maintaining long-term immunologic control of HBV. Consequently, individuals with a history of recovery from HBV infection, particularly those who remain inactive HBsAg carriers, are at risk of HBV reactivation in the setting of immune suppression.

Acute Infection

Acute exposure to HBV is followed by an incubation phase characterized by a period of low viral replication and a subsequent progressive rise in viremia. Peak serum HBV DNA levels are reached at approximately 8 to 10 weeks following exposure, at which time up to 100% of hepatocytes can be infected with HBV (884216237). The host innate immunity may have an important role during the earliest phases of acute infection in which NK cell activity may coincide with peak viremia following initial exposure to HBV (237). A subsequent vigorous polyclonal, multi-specific CD8+ T cell-mediated response directed towards HBV core, envelope, and polymerase epitopes is required in establishing immune control of HBV, leading to spontaneous resolution (72152194237).  In particular, a clonal expansion of CD8+ T cells directed towards HBV core epitopes may be a key factor in achieving spontaneous clearance of HBV in the setting of acute infection (152237).

Chimpanzee studies have more precisely characterized the CD8+ T cell-mediated response during acute infection, which can be seen both in the liver and peripheral blood (216). Although a CD4+ T cell response can be observed during early phases of acute infection, a multispecific CD8+ cytotoxic response directed towards HBV envelope, core, and polymerase proteins appears to be critical in achieving viral clearance such that depletion of CD4+ T cells does not alter this response; however, depletion of CD8+ T cells will prolong HBV viremia until CD8+ subsets are restored (216). These events occur in concert with noncytolytic HBV suppression through increased intrahepatic expression of IFN-γ, TNF-α, and IFN-γ-induced genes (216243). This noncytolytic mechanism allows HBV to be cleared without destruction of infected hepatocytes and may be the primary means of eliminating virus in the acute setting (498384166189), possibly through disruption of HBV nucleocapsid assembly(244245). The host innate immune system may also have a contributing role in achieving viral clearance through activation of NK, NKT cells, and Kupffer cells, leading to increased cytokine production, cytotoxicity, and recruitment of adaptive immunity (6573237257).

Chronic Infection

Individuals with chronic infection consistently demonstrate very weak or absent polyclonal and multispecific CD8+ responses to the HBeAg, polymerase, core, or surface antigens in peripheral blood compared with those who achieve spontaneous resolution (72167182194).  However, some individuals with chronic infection maintain low level viremia and are found to have responsive peripheral and liver-infiltrating multispecific CD8+ T cells, more commonly directed towards HBV core epitopes (153238). In this setting, the observed CD8+ T cell reactivity appears to be narrowly focused and characterized by emergence of spontaneous mutations within epitopes that contribute to diminished T cell recognition of viral antigens, viral escape, and persistence of infection(13).  A pattern of ongoing cellular activation and CD8+ T cell cytotoxicity may occur within the liver in those with chronic infection which is largely ineffective in achieving control of HBV, resulting in a persistent state of inflammation, hepatocyte injury, progressive hepatic fibrosis, cirrhosis, and increased risk of hepatocellular carcinoma  (195).

Mechanisms of Persistence

In order to establish chronicity within the host and maintain persistence, HBV may have developed various mechanisms to effectively interfere with host immunity, diminish host recognition of the virus, and promote tolerance within the liver. In both human and chimpanzee studies, HBV appears to act as a stealth virus in which proinflammatory cytokine production is absent and NK cell activation is diminished following acute exposure, allowing early viral replication and immune tolerance (6586243).  In particular, the HBeAg may have a central role in promoting immune tolerance during HBV infection through various immunoregulatory mechanisms including inhibition of antibody production, reduction of HBeAg- and HBcAg-specific T cell responses through clonal deletion or anergy, and inhibition of toll-like receptor (TLR) expression and signaling (444547120145226).  Other viral particles may also have inhibitory effects on host immunity including HBsAg effects on TLR-mediated immunity, HBV polymerase and X protein inhibition of interferon regulatory factor (IRF) signaling, and X protein disruption of proteasome activity and downregulation of the mitochondrial antiviral signaling (MAVS) protein (94117225230234239251263). Spontaneous mutations could also play a major role in viral persistence. Mutations within cytotoxic T cell epitopes could result in viral escape through disruption of major histocompatibility complex (MHC) binding or T cell receptor peptide recognition as demonstrated in studies revealing that mutations within the HBV core region were associated with impaired viral peptide recognition, cytotoxic activity, and IFN-γ secretory responses (14).  Mutations occurring within the pre-core and core promoter regions can result in a loss or diminished expression of HBeAg. Longitudinal studies have suggested that pre-core mutations may occur under immunologic pressure at the time of HBeAg seroconversion, leading to disruption of HBeAg production (50). These events may coincide with core mutations within helper T cell epitopes, suggesting that this occurs as a result of immune pressure exerted by the host (27).  Ultimately, the potential for spontaneous alterations of the core protein epitope occurring under selection pressure could be another means of viral escape and persistence through limiting host cytotoxic T cell recognition of HBV.

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The development of new investigational antiviral agents continues to advance with a greater understanding of the HBV life cycle and the potential to specifically target critical steps involved in HBV replication (Figure 2). Various members of the Hepadnaviridae family, including the woodchuck hepatitis virus, duck hepatitis virus, and woolly monkey hepatitis B virus, have been utilized extensively as a platform to conduct in vitro and in vivo studies to further develop new antiviral agents targeted against HBV. The majority of research associated with antiviral drug development has focused on nucleoside and nucleotide analogues, which target HBV DNA synthesis and effectively inhibit viral replication. The nucleoside analogues lamivudine, entecavir, telbivudine, and emtricitabine as well as the nucleotide analogues adefovir and tenofovir have all demonstrated antiviral potency against HBV both in vitro and in vivo, resulting in the availability of these agents as treatment options in the management of HBV infection in humans. In contrast with the nucleoside and nucleotide analogues, many investigational agents in development have thus far been limited to in vitro and animal studies. Key stages of the HBV life cycle identified as potential targets for new antiviral therapies include encapsidation, virion assembly, and various phases of HBV replication.

Inhibition of Viral Entry

The large HBsAg envelope protein has been identified as playing an important role in facilitating attachment of the hepatitis B virion to the surface of hepatocytes and is required for viral entry. The large envelope protein mediates attachment of virions to cell surface heparan sulfate proteoglycans. The sodium taurocholate cotransporting polypeptide (NTCP), a cell surface hepatocyte protein involved in transport of bile salts, functions as a receptor for HBV in which binding of NTCP to the N-terminal pre-S1 domain of the large envelope protein subsequently allows viral entry (252). Studies defining these events have led to the development of pre-S-derived lipopeptides, such as Myrcludex B, which are capable of blocking NTCP-mediated viral entry. Myrcludex B successfully inhibits the spread of HBV within the liver in a mouse model and has been well tolerated in human studies, in which HBV replication is suppressed in a dose-dependent fashion (17227).  

Inhibition of Encapsidation

Encapsidation is a critical step in the HBV life cycle involving assembly of the HBV polymerase, pre-genomic RNA, and HBV core protein into the nucleocapsid. Following encapsidation, the pre-genomic RNA undergoes reverse transcription mediated by the HBV polymerase into new HBV DNA. Compounds known as heteroaryldihydropyrimidines (HAPs) bind to the HBV core protein, leading to dysfunctional polymer formation, degradation of core protein, and inhibition of proper nucleocapsid assembly (62209).  The inhibitory effects of HAPs on HBV have been demonstrated in HepG2.2.15 cells and in a transgenic mouse model  (62209236).  Studies involving the HAP compounds BAY 41-4109 and GLS4 have reported effective inhibition of HBV replication with GLS4 demonstrating a higher potency in vitro and in a mouse model as well as a lower potential for toxicities (19236249).  Peptide aptamers have also been reported to have an inhibitory effect on nucleocapsid formation through binding to the core protein (24220276).  Direct inhibition of encapsidation may also occur with another class of compounds known as phenylpropenamides, as reported in studies utilizing various transfected hepatoma cell lines (61109184).  The cellular inhibitor of apoptosis protein 2 (cIAP2) was found to have an inhibitory effect on HBV replication, primarily through targeting of the HBV polymerase leading to its degradation and inhibition of pre-genomic RNA encapsidation (235).The encapsidation inhibitor, NVR 3-778 has now emerged as a first-in-class agent that was well-tolerated in initial phase 1 trials and is now undergoing evaluation in patients with chronic HBV infection (77).  

Hepatitis B Virion Assembly

Assembly of HBV virions requires interaction between core and envelope proteins in the endoplasmic reticulum. Alpha-glucosidase inhibitors disrupt this interaction through inhibiting the glycosylation of HBV envelope proteins, affecting the proper folding and subsequent transport of these proteins as well as infectivity of hepatitis B virions as described in HepG2.2.15 cell lines and animal models using woodchuck hepatitis virus (15123). Peptide aptamers have also been reported to inhibit virion assembly through binding to the HBV core protein as described in vitro (66).

Disruption of Hepatitis B Replication

Novel gene therapies have emerged with the ability to target HBV replication by promoting breakdown and degradation of HBV RNA within hepatocytes. Antisense oligodeoxyribonucleic acids (ODNs) bind to complementary viral RNA, inhibit translation or reverse transcription, and ultimately lead to RNA degradation. ODNs have demonstrated efficacy against HBV in vitro using HepG2.2.15 cell lines as well in animal models of duck hepatitis virus (112198).  Short interfering RNAs (siRNAs) are short fragments of double-stranded RNA that can also inhibit mRNA transcription and lead to RNA breakdown. This occurs through a mechanism in which viral mRNA that is complementary to the siRNA is cleaved following introduction of siRNA into the cell. Inhibition of HBV replication through siRNAs has been demonstrated in HepG2.2.15 cells and in vivo through a mouse model (111161203).  Novel nucleic acid polymers have emerged with activity targeted against the HBsAg, exerting an inhibitory effect on HBsAg release. An HBsAg release inhibitor, REP 9AC demonstrated efficacy in a duck hepatitis virus model and has now undergone evaluation in patients with chronic HBV infection, leading to clearance of HBsAg in a significant proportion (5173174).   Additional HBsAg release inhibitors are now in development (265). Other targeted therapies against HBV include helioxanthin analogues, ribozymes, and immunomodulatory agents such as cytokines (Figure 2) (150259).

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Drugs of Choice

The primary goal of antiviral therapy in chronic HBV infection is the achievement of long-term virologic suppression for both HBeAg-positive and HBeAg-negative infection. Attaining this goal would provide the greatest potential to prevent disease progression, HCC, cirrhosis, and complications associated with end-stage liver disease (ESLD). At this time, five oral agents have been approved in the treatment of chronic HBV, including lamivudine, adefovir, entecavir, telbivudine, and tenofovir (Table 5). These oral agents are either nucleoside or nucleotide analogues, and are the most frequent form of therapy used for chronic HBV infection. As a class, the nucleoside and nucleotide analogues target the HBV polymerase and inhibit HBV DNA synthesis; although antiviral efficacy and the potential for drug resistance vary greatly among different agents. In light of their good tolerability, high potency, and high genetic barrier to resistance, entecavir and tenofovir are considered the preferred oral antiviral agents (363107133, 148).  An additional agent, IFN alfa, is administered in a subcutaneous form. In selected individuals, IFN alfa or the long-acting pegylated interferon (PegIFN) alfa may also be considered as a first-line agent.


Entecavir is a guanosine nucleoside analogue that inhibits HBV replication through several pathways including inhibition of base priming, HBV DNA polymerase reverse transcriptase activity, and HBV DNA synthesis. As a preferred agent, entecavir demonstrates a high potency in achieving viral suppression relative to other nucleoside or nucleotide analogues (Tables 6 and 7; Figure 6a and 6b). Entecavir is highly effective in suppressing HBV, as clearance of serum HBV DNA occurs in up to 67% and 90% of HBeAg-positive and HBeAg-negative patients, respectively, following one year of therapy (33118).  In patients with HBeAg-positive infection, HBeAg seroconversion has been reported in over 20% of patients at one year (33). In addition, entecavir therapy is associated with achievement of HBsAg loss within one year of therapy. Although HBsAg loss occurs in a minority of patients, achievement of this parameter within one year has not been reported in other antiviral agents other than tenofovir and PegIFN alfa. Long term follow up of HBeAg-positive patients undergoing entecavir therapy has demonstrated a continued increase in the proportion of patients who achieve viral clearance, with up to 94% with undetectable serum HBV DNA after five years of therapy (34). Entecavir has a high genetic barrier to resistance. The cumulative probability of genotypic resistance has been reported to occur in only 1.2% of patients following 6 years of therapy in nucleoside-naïve patients (Figure 7) (212). However, the potential for resistance to entecavir is significant in previously treated patients with lamivudine resistance. The presence of the rtM204V/I mutation conferring resistance to lamivudine is associated with development of entecavir resistance in up to one-half of patients following 5 years of therapy (213). Based on this observation, entecavir monotherapy is not recommended in patients with known genotypic resistance to lamivudine (81107).


Tenofovir disproxil fumarate is a prodrug of tenofovir, an acyclic nucleotide analogue that inhibits the HBV polymerase and promotes premature HBV DNA chain termination. Similar to entecavir, tenofovir has demonstrated a high potency in achieving viral suppression relative to other oral antiviral agents for treatment of HBV infection. Tenofovir therapy is associated with achievement of undetectable serum HBV DNA in 76% of HBeAg-positive and 93% of HBeAg-negative patients, respectively, after one year (Tables 6 and 7; Figure 6a and 6b) (155). As reported with entecavir, HBsAg loss has been observed within one year of tenofovir therapy. Three year follow-up data revealed that patients treated with tenofovir maintain viral clearance and among HBeAg-positive individuals, the cumulative probability of HBsAg loss is 8% (89). Tenofovir has a very high genetic barrier to resistance in which no cases of resistance have been identified following up to eight years of therapy (Figure 7) (158). Due to potential toxicity associated with tenofovir disproxil fumarate in those with compromised renal function, monitoring of serum creatinine may be indicated in individuals at risk and dose reductions are recommended in those with an estimated creatinine clearance less than 50 mL/min. Tenofovir alafenamide is a new prodrug of tenofovir currently undergoing evaluation in clinical trials associated with a reduction in systemic exposures and a much lower potential for toxicity, particularly in the setting of renal insufficiency (4).  Tenofovir is classified as pregnancy category B, in which animal studies have not demonstrated a risk to the developing fetus. Reviews of the Antiretroviral Pregnancy Registry database and several studies involving the use of tenofovir during pregnancy have reported an acceptable safety profile (232). Thus, tenofovir may be considered in the management of chronic HBV during pregnancy.

Interferon Alfa

Short-acting and long-acting forms of IFN alfa therapy are available as treatment for chronic HBV. Standard IFN alfa-2b, administered three times weekly, and PegIFN alfa-2a, administered once weekly, are currently approved in the treatment of chronic HBV in many countries. PegIFN alfa-2b has also demonstrated similar efficacy to PegIFN alfa-2a (101197).  Treatment of HBV infection with IFN alfa may have several advantages over oral agents while demonstrating comparable antiviral efficacy. The duration of IFN alfa therapy is fixed for both HBeAg-positive and –negative infections. In addition, IFN alfa has no known association with drug resistance. However, both IFN and PegIFN alfa have been associated with many side effects that could limit tolerability. A fixed duration of 48 weeks therapy with PegIFN alfa results in viral clearance at end of treatment in up to 25% and 63% of HBeAg-positive and HBeAg-negative patients, respectively (Tables 6 and 7; Figure 6a and 6b) (101121154197).  In HBeAg-positive infection, the rates of HBeAg loss and seroconversion at one year have been reported to be higher relative to oral nucleoside or nucleotide analogues (101121).  In addition, the potential for HBsAg loss exists following one year of therapy for both HBeAg-positive and –negative infection (101121154).  This is particularly notable in HBeAg-negative HBV, in which none of the oral agents have reported HBsAg loss within one year of therapy. Although data are limited, prolonged therapy with oral agents may result in similar rates of HBeAg seroconversion and HBsAg loss (34).  The virologic response to PegIFN is durable. In one long-term follow up of patients with HBeAg-positive infection who were treated with PegIFN alfa-2b for 32 weeks, over 75% who initially achieved HBeAg seroconversion at end of treatment maintained anti-HBe positivity after 5 years (247).  In addition, one-half of patients who did not demonstrate HBeAg seroconversion at the end of treatment eventually achieved this endpoint after 5 years of follow up. Caution should be used in patients with decompensated cirrhosis who receive IFN-based therapy due to risks of infection or a hepatitis flare; however, IFN is a safe option in those with well-compensated cirrhosis (22185).

Special Infections

Hepatitis D virus

Hepatitis D virus (HDV), also known as hepatitis Delta, is a defective virus limited to HBsAg carriers that requires the presence of HBsAg within the host for assembly of virions and infectivity. Co-infection of HDV and HBV occurs in up to 5% of all HBsAg carriers (68).  The primary mode of HDV transmission is through parenteral routes and injection drug use remains a dominant source of new infections (68109).  HDV infection is defined by the presence of the hepatitis D antigen (HDAg) and the diagnosis of chronic HDV can be made by assessment of serum HDAg and antibodies against HDAg (anti-HD). HDV infection may occur acutely with simultaneous HBV infection or in the form of superinfection with pre-existing chronic HBV, both of which can be associated with an increased risk of fulminant hepatitis. In comparison with HBV mono-infection, HBV-HDV co-infection is associated with a 2- to 3-fold greater risk of cirrhosis, HCC, clinical decompensation, and mortality (6870190).  Successful treatment of chronic HDV requires clearance of HBsAg. As a result, nucleoside and nucleotide analogues are not effective and therapy is generally limited to standard IFN or long-acting PegIFN (2685172272).  New therapies for HDV infection are emerging and currently in clinical trials, including the viral entry inhibitor Myrcludex B, which has activity against both HBV and HDV infections (17227).

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Underlying Diseases

Hepatitis B and HIV Co-infection

Approximately 10% of individuals infected with HIV are co-infected with HBV  (6). HIV and HBV have similar routes of transmission, a major factor accounting for the increased frequency of co-infection associated with these viruses. Additionally, prior infection with HIV is a risk factor for developing chronic HBV infection following acute exposure, as individuals with HIV have a six-fold increase in risk of chronicity associated with HBV (218).  Low CD4+ T cell counts in HIV infection may contribute to the development of chronic infection, decreased clearance of HBeAg, increased HBV DNA levels, and a higher prevalence of cirrhosis. Data also suggest that the risk of HCC associated with HBV-HIV co-infection increases with lowering of CD4+ T cell counts (57).  Consequently, HBV-HIV co-infection is associated with a higher liver-related mortality compared to those infected with HBV alone (217).

Management of HBV in the setting of HIV infection has become increasingly important in the era of highly active antiretroviral therapy (HAART), as liver disease associated with viral hepatitis has emerged as a major cause of morbidity and mortality while HIV infection has become more effectively controlled (102127).  Due to the frequency of co-infection, all individuals with HIV should be screened for HBV infection. A first approach in the management of individuals with HBV-HIV co-infection is to achieve control of HIV. Some nucleoside and nucleotide analogues used to treat HBV such as tenofovir, emtricitabine, and lamivudine are active against HIV, thus HBV infection can be treated simultaneously. Patients treated with lamivudine should be monitored carefully as the potential for lamivudine resistance may be greater in co-infected patients than in those infected with HBV alone (11).  Recent long-term data on tenofovir have noted a high proportion of co-infected patients achieving viral suppression within 5 years of therapy (60).  Guidelines have recommended use of a liver biopsy to assess for evidence of histologic disease in co-infected individuals with elevated HBV DNA levels and normal ALT levels, as they are still at risk of chronic liver disease and may be candidates for antiviral therapy (107).

Hepatitis B and hepatitis C Co-infection

Chronic infections with HBV and HCV may exist simultaneously within a host and can occur commonly through shared exposure routes, including injection drug use and blood transfusions. Although definitive epidemiological data are limited, as many as 10% of anti-HCV positive individuals are positive for HBsAg, although some estimates are much lower (115).  Likewise, it is estimated that up to 20% of HBsAg-positive individuals are positive for anti-HCV (52).  Co-infection can occur through simultaneous acute exposure to HBV and HCV, superinfection of HCV on pre-existing chronic HBV, or superinfection with HBV on pre-existing HCV.  In many cases one virus predominates with active replication, which is most commonly HCV. Patients with co-infection appear to be at greater risk of progressive fibrosis, advanced liver disease, HCC, and overall mortality (52115).  Although no guidelines exist for the management of HBV-HCV co-infection, a consideration is initiation of therapy with combination PegIFN and ribavirin, as both HBV and HCV are responsive to an IFN-based regimen. However, the emergence of direct-acting antiviral therapy for HCV has led to major changes in treatment options, including the availability of highly effective, all oral, IFN-free regimens. Direct-acting antivirals such as sofosbuvir, a nucleotide analogue targeting the HCV RNA-dependent RNA polymerase, and ledipasvir, an HCV replication complex inhibitor, are now widely used in the treatment of chronic HCV infection. Although sofosbuvir has no significant interaction with coadminstered tenofovir, ledipasvir may increase tenofovir concentrations and could increase the potential for tenofovir-associated toxicity (1).  Data assessing the role of HCV direct-acting antivirals or IFN in combination with a nucleoside or nucleotide analogue are limited, although this may be a consideration in patients with active HBV replication. Several prospective studies using IFN-based regimens have reported virologic response in both HBV and HCV (95137191224); however, patients should be monitored closely following completion of therapy as a significant proportion may experience a rebound in HBV DNA levels (191).  

Recipients of Chemotherapy, Immunosuppression, or Organ Transplants

Individuals who are inactive HBsAg carriers and undergo cancer chemotherapy or immunosuppressive therapy are at risk of acute reactivation of hepatitis B, which can present as fulminant hepatitis. As HBV persists as highly stable cccDNA within hepatocyte nuclei, reactivation can occur in virtually all patients infected with HBV, even in patients who experience spontaneous resolution of infection or successful antiviral therapy. The risk of HBV reactivation varies within an individual based on their HBV serologic status, type of immunosuppressive therapy, and potential disruption of immunologic control. The greatest risk of reactivation has been associated with the presence of detectable serum HBV DNA, HBeAg positivity, HBsAg positivity, and the use of systemic cancer chemotherapy, B cell depleting agents such as rituximab, or high dose steroids (93187).  Reactivation can occur in those who are HBsAg negative and has been described in association with biologic agents such as tumor necrosis factor (TNF) alpha inhibitors as well as in the setting of transarterial chemoembolization for hepatocellular carcinoma (100183).

The clinical presentation of HBV reactivation can vary widely, ranging from only mild elevations in serum aminotransferases to fulminant acute-on-chronic liver failure. Prophylactic antiviral therapy with an oral agent can reduce morbidity and mortality associated with reactivation and should be initiated prior to starting chemotherapy and extended beyond completion of the course for 6 to 12 months (Table 3) (151). In patients who present with acute-on-chronic liver failure as a result of acute reactivation of HBV infection, initiation of antiviral therapy may have an impact on survival, as suggested in a prospective randomized controlled trial in which patients with spontaneous reactivation who received tenofovir demonstrated a significant reduction in mortality compared with placebo (79).  A meta-analysis evaluating the role of oral nucleoside or nucleotide analogue therapy in acute-on-chronic liver failure attributed to HBV infection similarly noted reductions in mortality in patients receiving either lamivudine or entecavir (264).

The risk of HBV reactivation extends to HBsAg carriers who undergo solid organ transplantation requiring long-term immunosuppressive therapy. Organ transplantation from anti-HBc-positive, HBsAg-negative donors is associated with a small, but significant risk of transmission of HBV infection to the recipient. The risk of transmission may vary by organ type, with the greatest risk reported in liver transplant recipients (228).  HBV vaccination is recommended in all potential kidney transplant recipients. Post-transplant antiviral prophylaxis may be considered in recipients of anti-HBc-positive kidney transplants, although the need for this is uncertain (179).  In contrast, antiviral prophylaxis is recommended for recipients of anti-HBc-positive liver transplants, particularly in recipients who are both anti-HBs and anti-HBc negative. In liver transplant recipients of anti-HBc-positive organs, post-transplant oral nucleoside or nucleotide therapy should be initiated; however the inclusion of HBIG in this regimen does not appear to have an impact on the risk of transmission (200).

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Alternative Therapy


The first oral antiviral agent approved as a treatment for chronic HBV infection, lamivudine, is an L-nucleoside analogue that inhibits HBV DNA synthesis by promoting premature DNA chain termination. Although lamivudine has demonstrated potency against HBV, the potential for resistance is high. Consequently, lamivudine is no longer considered a preferred first-line agent in the treatment of chronic HBV infection. Rates of resistance have been reported in over 70% of patients within four years of therapy (Figure 7) (146). Lamivudine resistance most frequently involves the rtM204V/I mutation, which occurs within the YMDD locus of the HBV polymerase (80). In patients who fail lamivudine therapy or develop resistance, the addition of adefovir or conversion to tenofovir monotherapy can be effective in achieving viral suppression (Table 8) (193223).


Adefovir is an acyclic nucleotide analogue, similar to tenofovir. Results from clinical trials have demonstrated adefovir to have modest potency against HBV; however it has a low genetic barrier to resistance, in which nearly 30% of HBeAg-negative patients develop drug resistance within five years of initiating therapy (87). As in tenofovir, adefovir toxicity can occur in the setting of renal dysfunction and dose reductions are required with decreases in estimated creatinine clearance to below 50 mL/min.


Telbivudine is an L-nucleoside analogue, similar to lamivudine. Telbivudine has demonstrated relatively high antiviral potency, although it also has a low genetic barrier to resistance. Resistance to telbivudine has been reported to occur in up to 25% of patients at two years of therapy (119130) Telbivudine is classified as pregnancy category B and may be considered as an antiviral agent during pregnancy.


Emtricitabine is another L-nucleoside analogue with efficacy against HBV; however, it is not formally approved for the treatment of chronic HBV in most countries as either monotherapy or in combination with tenofovir. Emtricitabine appears to have substantial potency against HBV; however drug resistance is common, occurring in up to 13% within one year (134).

Combination Therapy

Combination therapy may have an important role in optimizing the potential for viral suppression in the setting of treatment failure or emergence of resistance (Table 8) (215). As increasingly potent oral antiviral agents with a high genetic barrier to resistance have become available, the potential need for combination therapy as a first-line approach may likely diminish. The results from a large prospective study evaluating the role of combination entecavir and tenofovir in HBeAg-positive and -negative treatment naïve patients revealed that entecavir alone was as effective as combination therapy (149).  Although a tenofovir monotherapy arm was not included for comparison, this study demonstrated that monotherapy is sufficient in the setting of highly potent therapy. In data restricted to the HBeAg-positive subset, a modest increase in achievement of viral suppression at 96 weeks was seen in those who received combination therapy and had a high baseline HBV DNA level of >108 IU/mL, although the impact of this finding on long-term endpoints is uncertain. In contrast with treatment naïve patients, a combination of highly potent agents with a high genetic barrier to resistance, such as entecavir and tenofovir, is effective in suppressing HBV even in the presence of multidrug resistance (188).  Although earlier studies involving combination lamivudine and PegIFN did not demonstrate improvements in virologic response in either HBeAg-positive or -negative patients (101,121154), a large randomized, controlled, open-label study reported higher rates of HBsAg loss associated with tenofovir plus PegIFN for 48 weeks compared with either tenofovir or PegIFN alone (157).


As a result of chronic HBV infection, approximately one in 3 to 4 individuals will progress to cirrhosis or HCC (55).  In those who are potential candidates, liver transplantation may be considered as a treatment option with a significant benefit in long-term survival. Prior to the availability of hepatitis B immunoglobulin (HBIG) or nucleoside and nucleotide analogues, liver transplantation for HBV was associated with up to an 80% allograft re-infection rate and 50% 2-year survival (206).  In contrast, current treatment strategies have improved survival rates to as high as 85% to 95% at 5 years (25).  An important consideration in the management of potential transplant candidates is achievement of viral suppression prior to transplantation. Following liver transplantation, a combination of an oral antiviral agent and HBIG are given with the goal of preventing allograft re-infection, which is achieved in over 90% of patients using this regimen (206).  Several strategies with an emphasis on minimizing HBIG have emerged, including HBIG dose reduction to improve cost efficacy and HBIG withdrawal; however further studies investigating the role of HBIG will be required to determine the most cost-effective option with the least potential for allograft re-infection, particularly in the context of potent oral antiviral therapy (76233).

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Selection of Treatment Candidates

Clinical and laboratory parameters used in assessing treatment candidacy in patients with chronic HBV include serum HBV DNA levels, serum ALT, and liver histology. Several groups have published guidelines with recommendations for the selection of potential treatment candidates and when to initiate therapy (Table 3) (3107133148).  Assessment of detectable HBV DNA in the presence of elevated ALT levels is a key factor in establishing treatment candidacy, particularly in light of emerging prospective data highlighting the association of elevated HBV DNA levels and risk of HCC and progressive chronic liver disease (2938394098254266268).  As the risk of disease progression has also been associated with low HBV DNA levels, particularly in those with HBeAg-negative infection, some guidelines recommend a lower threshold for initiation of therapy in this group (3107133).  Treatment is not indicated in those classified as inactive HBsAg carriers or in the setting of immune tolerance; however these individuals should be monitored longitudinally. Initiation of antiviral therapy with oral nucleoside or nucleotide analogues may be considered in the setting of fulminant hepatitis B infection; however data evaluating this are limited (116219).  One prospective study noted lamivudine therapy during severe acute HBV infection was associated with a more rapid decline in serum HBV DNA levels, although no clear benefit was noted in recovery from acute infection, serological markers, or biochemical parameters (116).  In the setting of HBV reactivation with acute-on-chronic liver failure, oral nucleoside or nucleotide analogue therapy can be beneficial (79264).

Antiviral therapy should be considered in those with cirrhosis, as treatment can have an impact on the development of complications related to ESLD as well as risk of HCC. In one seminal multicenter, randomized, placebo-controlled trial of lamivudine therapy in patients with advanced fibrosis or cirrhosis found that patients randomized to receive lamivudine had a lower incidence of HCC and slower progression of liver disease within 3 years of follow up (129).  Therefore, antiviral therapy with nucleoside or nucleotide analogues is recommended for all patients with decompensated cirrhosis and detectable serum HBV DNA. Additional studies involving treatment with other oral agents such as entecavir and tenofovir have reported antiviral efficacy, histologic improvement, and overall safety in this population, including those with hepatic decompensation (131132202).  Long-term data have now demonstrated significant histologic benefit in patients undergoing tenofovir therapy, including regression of fibrosis and cirrhosis(156). In the setting of compensated cirrhosis, a low threshold for initiation of therapy based on HBV DNA levels has been proposed by most groups (Table 3). The use of IFN alfa therapy is not recommended in patients with decompensated cirrhosis due to a significant risk of acute exacerbation of liver disease, characterized by high serum ALT levels further clinical decompensation, and risk of infection (91148185).

Antiviral therapy can be considered during pregnancy to prevent vertical transmission; however, administration of the HBV vaccine and HBIG to the newborn to achieve active immunization immediately after birth can avoid transmission of HBV. In early studies of combination vaccine and HBIG vs. placebo or no intervention, vertical transmission was avoided in over 95% of cases (124). If treatment is considered, tenofovir and telbivudine are both classified as pregnancy category B. Pregnant women who are positive for HBsAg can potentially experience a flare of hepatic disease before or after delivery and should be followed closely (169214). 

Monitoring Virologic Response and Management of Resistance

Monitoring serum HBV DNA levels during nucleoside or nucleotide analogue therapy is an important consideration in achieving optimal virologic response and minimizing the potential for developing antiviral drug resistance(107). During a course of therapy, the emergence of mutations conferring drug resistance can lead to persistent viremia with an increase in risk of progressive liver disease and HCC (7146).  The incidence of resistance varies among the nucleoside and nucleotide analogues (Figure 7) (87119130134146158213) and is influenced by an agent’s respective genetic barrier to resistance, defined by the probability of mutations occurring in response to the selective pressure exerted by the agent(107). Additional factors associated with the development of drug resistance include the presence of persistent viral replication despite therapy, the frequency of mutations, and the replication fitness of new mutations (144).  A treatment algorithm with on-treatment monitoring has been proposed with the goal of identifying individuals at risk of treatment failure or an inadequate virologic response associated with oral therapy. Primary treatment failure, defined by the inability to reduce HBV DNA by 1 log10 IU/mL from baseline, can be assessed at 12 weeks of therapy. HBV DNA levels at 24 weeks can be used to determine whether an individual has experienced a partial or inadequate virologic response, defined by levels of 60-2,000 IU/mL and >2,000 IU/mL, respectively (107). HBV DNA levels should be measured every 3 to 6 months thereafter for ongoing surveillance during therapy, with close follow up in partial responders to ensure continued viral suppression. An increase of ≥1 log10 IU/mL above the nadir HBV DNA level is considered virologic breakthrough and may indicate the development of resistance (147).  In the setting of primary treatment failure, an inadequate virologic response, or established antiviral resistance, the addition or conversion to an oral agent of another class with a higher potency should be considered (Table 8). This strategy will promote further viral suppression while avoiding potential cross-resistance, which is more likely to occur among antiviral agents within the same class (80107148193).  Adherence to therapy should be assessed in all patients who demonstrate an inadequate response.

Predictors of Response

Various host factors, viral factors, and on-treatment parameters have been identified as predictors of treatment response in the setting of oral antiviral therapy. Baseline characteristics such as elevated ALT levels (≥2x the upper limit of normal [ULN]) and low serum HBV DNA (< 9 log10 copies/mL) have been associated with viral clearance and HBeAg seroconversion in HBeAg-positive patients treated with telbivudine, while low body mass index (BMI) (< 22.5) is associated with viral clearance in both HBeAg-positive and HBeAg-negative infection (273).  After initiation of therapy, achievement of complete viral suppression at an early time point assessed through measurement of serum HBV DNA or quantitative HBsAg is also predictive of a successful response. Achievement of complete viral suppression within 24 weeks is predictive of HBV DNA clearance, decreased incidence of drug resistance, and increased HBeAg seroconversion (87269273).  In addition, a rapid decline in quantitative HBsAg levels is predictive of eventual HBsAG loss (250277).

Several baseline and on-treatment predictors have also been identified in association with a successful response to PegIFN therapy. In patients with HBeAg-positive infection, elevated ALT levels, low HBV DNA, and low quantitative HBeAg levels prior to initiation of therapy may be predictive of eventual HBeAg seroconversion (75186).  Likewise, in patients with HBeAg-negative infection, elevated ALT, low HBV DNA, younger age, and female gender are predictive of viral suppression after completion of therapy (18).  HBV genotype may also have an impact on virologic response to PegIFN, as genotypes A or B appear to be associated with a more favorable outcome, particularly in HBeAg-positive infection (236774101121).  During therapy, a significant decline in quantitative HBsAg levels indicated by a decline of 0.5 log10 IU/mL at 12 weeks, 1.0 log10 IU/mL at 24 weeks, or > 1.1 log10 IU/mL throughout the course of therapy have been reported to be predictive of achieving sustained viral suppression in HBeAg-negative patients (21165).  Ultimately, identifying baseline factors associated with a favorable virologic response may be more important in the selection of candidates for PegIFN therapy as tolerability is a concern in some patients.

Long-Term Endpoints of Therapy

In contrast with IFN-based therapy, in which the duration of therapy is well defined, assessing the endpoint of antiviral therapy with oral nucleoside or nucleotide analogues can be challenging. Serologic markers are instrumental in monitoring long-term virologic response to oral therapy, particularly in HBeAg-positive infection. HBeAg seroconversion, characterized by HBeAg loss and emergence of anti-HBe, can be used as an endpoint of therapy indicating a successful response. Following HBeAg seroconversion, discontinuation of therapy can be considered at 6 months after the appearance of anti-HBe (148), although a more conservative and common recommendation involves considering discontinuation after 12 months of both HBeAg seroconversion and HBV DNA negativity (3107133).   In contrast, oral antiviral therapy is frequently required over the long-term for those with HBeAg-negative infection. In both HBeAg-positive and –negative infection, discontinuation of treatment may be considered following HBsAg, although this is a rare occurrence (148). As complete eradication of HBV is not easily attainable due to persistence of intranuclear HBV cccDNA within the host, all patients in whom treatment is discontinued require long-term follow up as the risk of HBV reactivation can persist long after successful therapy.

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Hepatitis B infection is preventable with vaccination. The HBV vaccine may be administered as recombinant or plasma-derived HBsAg and is effective in preventing chronic HBV infection in over 95% of cases. Vaccination can provide long-term immunity for over 20 years based on data from longitudinal cohort studies (171). Two single-antigen vaccines are currently approved for HBV as well as one vaccine in combination with hepatitis A virus (Table 9) (160).  Overall, these vaccines are well tolerated in both children and in adults. In many countries in which a comprehensive immunization strategy has been initiated, the HBV vaccine is recommended in all routine infant vaccinations as well as unvaccinated individuals who are at risk of potential exposure to HBV including health care workers, travelers to HBV-endemic areas, household contacts of persons with chronic HBV infection, and organ transplant recipients (Table 10) (2). An additional group in whom vaccination is recommended includes patients with other underlying chronic liver diseases, as they may be at risk of a more fulminant course in the setting of superimposed acute HBV infection (160196). An adjunctive therapy to the HBV vaccine utilized during post-exposure prophylaxis or to prevent vertical transmission is HBIG, which can be given to individuals following a suspected exposure to HBV or to at-risk newborns immediately following delivery from HBsAg-positive mothers. Contraindications to receiving the vaccines include a history of previous severe allergic reaction or hypersensitivity to the vaccine or vaccine components. All HBV vaccines require a multiple dosing schedule, which is needed to ensure optimal immune protection against the virus. In immunocompromised individuals, assessment of quantitative anti-HBsAg may be required to ensure adequate dosing.


Decreasing the risk of transmission of HBV through immunization may be the most effective method of preventing HBV-associated disease including chronic hepatitis, cirrhosis, and HCC, particularly in high-risk populations (2). With the development of the HBV vaccine and its widespread use since 1982, HCC is regarded as the first major cancer that is preventable by the implementation of immunization programs. Through successful immunization strategies, the HBV vaccine is capable of preventing new HBV infections, subsequent chronic liver disease, and most cases of HCC on a global scale. Consequently the HBV vaccine may be considered as a primary prevention of liver cancer (2). In 1991, the World Health Organization (WHO) called for universal infant HBV immunizations, and by 2008, 177 countries had added the HBV vaccine to their immunization programs  (2).  However, the vaccine is not available in some endemic regions, particularly sub-Saharan Africa and the Indian subcontinent. In many countries where chronic HBV infection rates in children were as high as 8% to 15%, the rates of chronic infection have now been reduced to less than 1% through immunization programs (104).  In the US, the incidence of new infections with HBV has declined by over 80% since implementation of a large-scale immunization program in 1991 according to data from the National Notifiable Diseases Surveillance System of the Centers for Disease Control and Prevention (CDC) (199).  Likewise, large cohort studies involving young age groups in Taiwan have documented a significant decrease in the seroprevalence of HBsAg and decrease in the HBV carrier rate indicated by HBV core antibody seropositivity since the implementation of widespread immunization (41170). Recent estimates have noted a significant decline in overall HBV prevalence in many areas of the world, particularly in younger age groups, which appears be attributed to immunization programs (178).

A significant reduction in the incidence of HCC in some populations can be directly attributed to the HBV vaccine. One large study in Taiwan based on data from the Taiwan National Cancer Registry over a 13-year period found a significant decrease in HCC incidence and mortality in the years following the implementation of a national HBV immunization program in 1984 (30170171).  In another large cohort study from Korea, a trend towards a reduced relative risk of HCC was seen in vaccinated patients compared with unvaccinated patients after only 4 years of follow up (125).  Additional studies in Taiwan revealed that HCC incidence following implementation of the immunization program may be associated with vaccine failure or lack of hepatitis B immunoglobulin being given to infants with HBsAg-positive mothers (32).

Although these studies demonstrate the potential benefit of HBV vaccination in the prevention of HCC, some endemic areas are still at risk due to insufficient resources to support an immunization program (31). As the incidence of HCC increases with age, it is likely that the full positive impact of HBV immunization on the development of HCC will be seen in the years to come and in future generations.

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Individualized Surveillance for Hepatocellular Carcinoma

Identifying individuals with chronic HBV who are at increased risk of HCC is an important consideration in the development of an optimal HCC surveillance strategy. Early detection of HCC through surveillance has a major impact on long-term outcomes, including survival  (20274).  Although several organizations have provided guidelines for targeting specific HBV-infected patient groups who would benefit most from surveillance as a result of their increased risk of HCC, these guidelines are based primarily on clinical and demographic risk factors (Table 1), while well-established virologic risk factors such as HBV DNA level are not included (2071107177).  In light of these concerns, several predictive scoring systems have been published with the intent of enabling the clinician to estimate an individualized risk of HCC in a person with chronic HBV based on clinical, demographic, as well as virologic parameters (246255256271).   An individualized predictive score could then potentially guide strategies for HCC surveillance.

Predictive HCC risk scores based on two large single-center cohort studies from Hong Kong identified the presence of cirrhosis, core promoter mutations, male gender, and elevated serum HBV DNA levels as independent risk factors for HCC in individuals with chronic HBV (246271).  Other predictive scoring systems, including the use of nomograms as well as a risk score, have been developed from prospective data associated with the REVEAL-HBV cohort from Taiwan (255256).  The predictive nomograms include different risk variables, such that a different nomogram could be used depending on virologic data available to the clinician (256). A major limitation of the REACH-B systems is that the study cohort did not include patients with cirrhosis.

Although these studies have provided further evidence highlighting the importance of virologic parameters in assessment of HCC risk in patients with chronic HBV, validation of these scoring systems will be required to ensure that these findings are applicable to larger populations. Adoption of an individualized surveillance strategy could be cost effective as those considered low-risk may not require surveillance; however, a concern would be the potential exclusion of individuals who would benefit from surveillance. In contrast, those at higher risk may require earlier onset of surveillance with possibly more frequent follow up. Ultimately further studies will be required to elucidate factors that contribute to HCC risk and how an individualized assessment could guide optimal treatment and surveillance strategies in this population.

New Biomarkers for Detection of Hepatocellular Carcinoma

The most widely used tumor marker for HCC, alpha-fetoprotein (AFP), is limited in its ability to discriminate between individuals at high or low risk of HCC. As a result, alpha-fetoprotein has been excluded in some guidelines on HCC surveillance. Serum alpha-fetoprotein is characterized by a low sensitivity, in which over 45% of patients with HCC may have normal serum alpha-fetoprotein levels (69). Several alternative serum markers for HCC have been identified including a fucosylated isoform of alpha-fetoprotein reactive to Lens culinaris agglutinin, known as AFP-L3, and prothrombin induced by vitamin K absence II (PIVKA II), also known as des-γ-carboxyprothrombin (DCP). AFP-L3 has an increased sensitivity and specificity compared with alpha-fetoprotein; however, it can only be used in patients with elevated baseline AFP levels (222).  DCP is limited by low sensitivity, although its performance characteristics vary based on liver disease etiology and its sensitivity appears to be increased in chronic viral hepatitis, including HBV infection(159). Several additional markers have been identified as potential screening tools in the early detection of HCC including glypican-3 (GPC-3), osteopontin, golgi protein 73 (GP73), microRNA (miRNA), α-1-fucosidase, human telomerase reverse transcriptase, squamous cell carcinoma antigen, and transforming growth factor-β1. Efforts are ongoing to discover other potential biomarkers for HCC surveillance through genome-wide association studies, proteomic and metabolomic analysis, and glycomics. These techniques have identified novel genomic profiles, serum protein fragments, and alterations in N-glycosylation with differential expression in cases of HCC (4310341).  Ultimately an individualized approach based on clinical risk factors and a combination of genomic profiling with other biomarkers may provide the most accurate screening tool for discriminating individuals at increased risk of HCC.

Recognition of Hepatitis B Reactivation

Early recognition of individuals at risk of HBV reactivation in the setting of immunosuppression or cancer chemotherapy is critical to successful prevention and management of cases. Despite guidelines now in place recommending screening and pre-emptive antiviral therapy to prevent HBV reactivation (3133148240), reported screening rates among health care providers remains low. These findings have emerged while the utilization of immunosuppressive medications in the form of biologic agents and disease-modifying antirheumatic drugs (DMARDs) has increased, particularly in the treatment of various inflammatory disorders involving a diverse range of medical specialties including gastroenterology, dermatology, and rheumatology. Apart from cancer chemotherapy and conventional immunosuppression, DMARDs include azathioprine, methotrexate, cyclosporine, and biologic agents such as tumor necrosis factor (TNF) alpha inhibitors. Recent data have revealed that a very low proportion of health care providers who prescribe chemotherapy or immunosuppression routinely screen for underlying HBV infection. Two large retrospective reviews of screening practices in US cancer centers involving over 8,000 and 10,000 patients undergoing cancer chemotherapy, respectively, found only 16% to 17% of patients underwent screening to assess for the presence of serum HBsAg or anti-HBc (96242).  In one study, even when known risk factors for HBV infection were identified, less than 20% were screened (96).

In another study, almost 40% of patients who were screened and found to have HBV infection ultimately did not receive antiviral prophylaxis, leading to cases of reactivation (242).These findings highlight the need for increased awareness among healthcare providers involved in managing patients at risk of HBV reactivation, particularly in light of reactivation as a preventable event associated with a high potential for morbidity and mortality.

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Table 1: Guidelines for hepatocellular carcinoma surveillance in HBsAg carriers


Recommended surveillance population

AASLD, 2010 (20)

Africans and African Americans
Asian males >40 years old
Asian females >50 years old
Family history of HCC

U.S. Algorithm, 2008 (107)

Africans >20 years old
Asian males >40 years old
Asian females >50 years old
Asians >30 years old with presumed vertical or horizontal acquisition of HBV early in life
Family history of HCC
>40 years old with elevated ALT and/or HBV DNA level >2,000 IU/mL

WGO, 2010 (71)

African males >20 years old
Asian males >40 years old
Asian and African females >50 years old
Family history of HCC

APASL, 2010 (177)


Abbreviations: AASLD, American Association for the Study of Liver Diseases; ALT, alanine aminotransferase; APASL, Asia Pacific Association for the Study of the Liver; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; WGO, World Gastroenterology Association.

Table 2: Phases of chronic hepatitis B infection

Phase of infection Serum ALT HBeAg Anti-HBe Serum HBV DNA Liver Histology
Immune tolerance Normal Positive Negative Very high Minimal to no activity
Immune clearance (HBeAg-positive) Elevated Positive Negative Variable; high or fluctuating Significant activity
Inactive HBsAg carrier Normal Negative Positive Very low or undetectable Minimal to no activity
Reactivation (HBeAg-negative) Elevated, fluctuating Negative Positive Variable; lower than HBeAg-positive infection Significant activity

Abbreviations: ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; Anti-HBe, antibody against hepatitis B e antigen; HBV, hepatitis B virus.

Table 3:  Guidelines for initiation of antiviral therapy in chronic hepatitis B


EASL Guidelines (3)

APASL Guidelines (133)

AASLD Guidelines (148)

U.S. Algorithm (107)*


HBV DNA >2,000 IU/mL and ALT >ULN
• Consider liver biopsy if ALT >ULN or HBV DNA >2,000 IU/mL; initiate therapy if moderate to severe histologic disease

HBV DNA >20,000 IU/mL and ALT >2x ULN
• Obtain liver biopsy if age >40 and HBV DNA >20,000 IU/mL with ALT <2x ULN; initiate therapy if moderate to severe histologic disease

HBV DNA >20,000 IU/mL and ALT >2x ULN
• Observe 3 to 6 months; initiate therapy if no spontaneous HBeAg loss
• Consider liver biopsy if HBV DNA >20,000 IU/mL, ALT ≤2x ULN, and age >40 or family history of HCC
• Consider therapy if histologic disease and ALT ≤2x ULN

HBV DNA ≥20,000 IU/mL and ALT >ULN
• Consider liver biopsy if HBV DNA ≥20,000 IU/mL, normal ALT, and age >35; initiate therapy if histologic disease
• Consider therapy if known histologic disease, regardless of ALT


HBV DNA >2,000 IU/mL and ALT >ULN
• Consider liver biopsy if ALT >ULN or HBV DNA >2,000 IU/mL; initiate therapy if moderate to severe histologic disease

HBV DNA >2,000 IU/mL and ALT >2x ULN
• Obtain liver biopsy if age ≥40 and HBV DNA >2,000 IU/mL with ALT <2x ULN; initiate therapy if moderate to severe histologic disease

HBV DNA >20,000 IU/mL and ALT >2x ULN
• Consider liver biopsy if HBV DNA >2,000 IU/mL and ALT >ULN; initiate therapy if histologic disease

HBV DNA ≥2,000 IU/mL and ALT >ULN
• Consider liver biopsy if HBV DNA ≥2,000 IU/mL, normal ALT, and age >35
• Consider therapy if known histologic disease, regardless of ALT


Decompensated or compensated:  Any detectable HBV DNA

Decompensated: Any detectable HBV DNA
Compensated: HBV DNA >2,000 IU/mL

Decompensated:  Any detectable HBV DNA
Compensated:  HBV DNA >2,000 IU/mL
• Consider therapy if HBV DNA <2,000 IU/mL and ALT >ULN

Decompensated:  Any detectable HBV DNA
Compensated:  HBV DNA ≥2,000 IU/mL
• Consider therapy if HBV DNA <2,000 IU/mL, regardless of ALT

Immunosuppression or Chemotherapy

• Initiate oral antiviral therapy prior to onset of immunosuppression or chemotherapy, regardless of serum HBV DNA level; continue for 12 months following completion

HBsAg-negative, anti-HBc-positive
• consider initiation of oral antiviral therapy if receiving rituximab, combined regimens for hematologic malignancies, or bone marrow transplantation
• Monitor ALT and HBV DNA; initiate oral antiviral therapy if confirmed reactivation by HBV DNA positivity

HBsAg positive
• Initiate oral antiviral therapy prior to onset of immunosuppression or chemotherapy; continue for 6 months following completion

HBsAg-negative, anti-HBc-positive
• If receiving biologic agent, defer prophylaxis and maintain close monitoring of HBV DNA

• Initiate oral antiviral therapy at onset of immunosuppression or chemotherapy, regardless of serum HBV DNA level; continue for 6 months following completion; longer duration of therapy if HBV DNA >2,000 IU/mL

• Initiate oral antiviral therapy several weeks prior to onset of chemotherapy and continue for 6 months following completion; longer duration of therapy if HBV DNA ≥2,000 IU/mL

Adapted from European Association for the Study of the Liver (3), Liaw et al. (133), Lok and McMahon (148), and Keeffe et al. (107).

*ULN of ALT in the U.S. Algorithm defined by 30 IU/mL in men and 19 IU/mL in women.

Abbreviations:  AASLD, American Association for the Study of Liver Diseases; ALT, alanine aminotransferase; anti-HBc, antibody to hepatitis B core antigen; APASL, Asian Pacific Association for the Study of the Liver; EASL, European Association for the Study of the Liver; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; ULN, upper limit of normal

Table 4: Serologic assessment of hepatitis B infection.

  Serologic marker
  HBsAg Anti-HBs Anti-HBc (IgM) Total Anti-HBc
Acute infection + + +
Chronic infection + +
Resolved infection, immune + +
Previous vaccination, immune +
Unexposed, susceptible

Abbreviations: HBsAg, hepatitis B surface antigen; Anti-HBs, antibody against hepatitis B surface antigen; Anti-HBc, antibody against hepatitis B core antigen.

Table 5: Antiviral agents approved for treatment of chronic hepatitis B infection

Antiviral agent Drug class Dose Duration
Entecavir* Nucleoside analogue 0.5 mg daily Variable
Tenofovir* Nucleotide analogue 300 mg daily Variable
Lamivudine Nucleoside analogue 100 mg daily Variable
Adefovir Nucleotide analogue 10 mg daily Variable
Telbivudine Nucleoside analogue 600 mg daily Variable
Interferon alfa-2b Immune modulator 5 million IU daily or 10 million IU three times weekly 48 weeks
Pegylated interferon alfa* Immune modulator 1.5 mcg/kg weekly** (or) 180 mcg weekly*** 48 weeks

* Preferred agent

** Pegylated interferon alfa-2b is given at a dose of 1.5 mcg/kg weekly

*** Pegylated interferon alfa-2a is given at a dose of 180 mcg weekly

Table 6: Efficacy of antiviral therapy for HBeAg-positive chronic hepatitis B

Antiviral Agent HBV DNA negative HBeAg loss HBeAg seroconversion HBsAg loss
Entecavir* 67 22 21 2
Tenofovir* 76 22 21 3
Pegylated Interferon Alfa* 10-25 29-30 22-27 3-5
Lamivudine 36-44 17-32 16-21 0
Adefovir 13-21 24 12 0
Telbivudine 60 26 22-23 0
Emtricitabine 39 14 12 0

Data shown as percent patients based on achievement of virologic parameters at one year of therapy (63, 101, 121, 155)

*Preferred antiviral agents

Table 7: Efficacy of antiviral therapy for HBeAg-negative chronic hepatitis B

Antiviral Agent HBV DNA negative HBsAg loss
Entecavir* 90 0
Tenofovir* 93 0
Pegylated Interferon Alfa* 52-63 4
Lamivudine 60-73 0
Adefovir 51-64 0
Telbivudine 88 0
Emtricitabine 79 0

Data shown as percent patients based on achievement of virologic parameters at one year of therapy (63, 154, 155, 197)

*Preferred antiviral agents

Table 8:  Management of drug resistance associated with hepatitis B therapy

Antiviral drug resistance




Continue lamivudine and add adefovir or tenofovir
Switch to tenofovir or tenofovir/emtricitabine


Continue adefovir and add lamivudine or telbivudine
Switch to or add entecavir (only if no lamivudine resistance)
Switch to tenofovir or tenofovir/emtricitabine


Continue telbivudine and add adefovir or tenofovir
Switch to tenofovir/emtricitabine


Switch to or add adefovir or tenofovir
Switch to tenofovir/emtricitabine

Adapted from Lok and McMahon (148), and Keeffe et al.(107).

Table 9: Hepatitis B vaccines

Patient Group Recombivax HB Engerix-B Twinrix*** Pediarix****
Children 5mcg* 10mcg 10mcg
Adults (≥20 yrs) 10mcg 20mcg 20mcg
Immunocompromised or dialysis patients 40mcg 40mcg**

Adapted from Mast et al.(160) All hepatitis vaccines are administered as an intramuscular injection given in 3 doses at 0, 1, and 6 months, unless otherwise specified.

*Adolescents ages 10-15 yrs can receive an alternate regimen of 10mcg given in 2 doses at months 0 and 4-6.

**Dosing regimen of 40mcg given in 4 doses at months 0, 1, 2, and 6.

***Combined hepatitis A and hepatitis B vaccine. Approved for adults (>18 yrs). Alternate accelerated regimen involves 20mcg given in 4 doses at days 0, 7, 21 to 30, and at one year.

****Combined hepatitis B vaccine with diphtheria, tetanus, pertussis, and poliomyelitis vaccines; approved for ages 0-6 yrs given in 3 doses at 0, 2, and 4 months.

Table 10: Candidates for hepatitis B vaccination (2, 160)

Patient Group

All infants within 24 hours of birth
Health care workers
Individuals at risk of occupational exposure
Travellers to HBV endemic areas with high prevalence
Injection drug users
Men who have sex with men
Persons with multiple sex partners
Household and sexual contacts of persons with known chronic HBV infection
Incarcerated individuals
Dialysis patients
Solid organ transplant recipients
Persons with underlying chronic liver disease or HIV infection

Abbreviations: HBV, hepatitis B virus; HIV, human immunodeficiency virus


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Keeffe EB, et al. A Treatment Algorithm for the Management of Chronic Hepatitis B Virus Infection in the United States: 2008 Update. Clin Gastroenterol Hepatol. 2008;6:1315-1341.

Lok ASF, McMahon BJ. Chronic Hepatitis B: Update 2009. AASLD Practice Guidelines. Hepatology 2009:50;1-36.

Sorrell MF, et al. National Institutes of Health Consensus Development Conference Statement: Management of Hepatitis B. Ann Intern Med 2009;150(2):104-10.

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