Hepatitis B Vaccines

Clinical Description

Infection with HBV causes a broad spectrum of liver disease, including subclinical (occult) infection, acute, clinically overt self-limited hepatitis, and fulminant hepatitis. Following acute infection, infected persons with HBV can develop persistent infection, which can lead to chronic liver disease (CLD) and death from cirrhosis or HCC or both. The age of acquisition of HBV infection is an important determining factor in the clinical expression of acute disease and the development of chronic infection. Genetic characteristics (i.e., genotype D of HBV), intake of hepatotoxic compounds such as excessive paracetamol doses or alcohol, and treatment with immunosuppressive agents (i.e., corticosteroids or checkpoint inhibitors) may lead to HBV reactivation, and contribute to outcome of infection and the relatively rare development of fulminant hepatitis B. Fewer than 10% of children younger than 5 years of age who become infected have initial clinical signs or symptoms of disease (i.e., acute hepatitis B), compared with 30–50% of older children and adults. The risk for developing chronic HBV infection varies inversely with age: approximately 90% of infants infected during the first year of life develop persistent infection, compared with 30% of children infected between ages 1 and 4 years and less than 5% of persons infected as adults ( Fig. 27.1 ). Persons with chronic diseases such as renal failure, HIV infection, and diabetes as well as immune suppressed subjects are at increased risk for developing chronic HBV infection, presumably as a result of enhanced viral replication and ineffective immune clearance. Globally, 2.7 million (7.6%) of the 38 million persons living with HIV infection are co-infected with HBV. Although HBV infection appears to have a minimal effect on the progression of HIV, the presence of HIV markedly increases the risk of developing HBV-associated liver cirrhosis and HCC.

Chronic Hepatitis B Virus Infection

Most of the disease burden associated with HBV infection occurs among persons with chronic infection. Persons who have persistence of HBsAg in serum for at least 6 months are classified as having chronic HBV infection (HBsAg carriers). Yet, occult, persistent HBV infection may also occur in the absence of detectable HBsAg in serum. HBV replication persists throughout the course of chronic HBV infection, and the natural history of chronic HBV infection is determined by the interaction between virus replication and host immune response. Additional factors that can contribute to progression include gender, alcohol consumption, and coinfection with other hepatotropic viruses (i.e., HDV or HCV).

Chronic HBV infection is a dynamic process that typically spans over several decades or longer. It is characterized by up to four phases ( Fig. 27.2 ), including a period of active viral replication without active liver disease (immune tolerance phase), a period of active viral replication and active liver disease (immune active phase), and a phase with low or absent viral replication and remission of active liver disease (inactive carrier state with chronic HBV infection). In addition, some patients with inactive chronic HBV infection may experience reactivation of HBV replication. HBV reactivation may develop spontaneously following treatment with immune suppressive agents or as a sequela of cessation of antiviral treatment. All four phases of chronic infection can occur in persons who acquire infection perinatally, whereas the latter three phases occur in persons who acquire infection as older children and adults.

The immune tolerant phase of perinatally acquired infections is characterized by high levels of virus replication, which correlates with hepatitis B e antigen (HBeAg) positivity and high levels of HBV DNA in serum. ^, However, these patients typically have no evidence of active liver disease, with normal ALT levels, no signs or symptoms of hepatitis, and minimal necroinflammatory activity on liver biopsy. ^, The absence of liver disease despite high levels of viral replication is attributable to immune tolerance. The initial phase of infection usually lasts 10–30 years. During this time, rates of spontaneous clearance of HBeAg from serum are less than 1% per year. ^{, ,} This low rate of HBeAg clearance accounts for the high prevalence of HBeAg among women of childbearing age in areas with high rates of perinatal HBV transmission.

The replicative-immune active phase is characterized by high levels of virus replication (see Fig. 27.2 ). These patients are usually HBeAg-positive, with high or fluctuating levels of HBV DNA in their serum. Evidence of active liver disease includes persistently or intermittently elevated ALT levels and necroinflammatory activity on liver biopsy. Development of fibrosis of the liver can lead to cirrhosis, which usually leads to an irreversible form of liver injury. Transition from this immune active phase of chronic HBV infection to the next, often inactive phase occurs with reduction in viral load and sometimes clearance of HBV DNA with HBeAg seroconversion. The rate of spontaneous clearance of HBeAg is approximately 10–20% per year, both in patients with perinatally acquired infections and in those who acquire infection at an older age. Most patients are asymptomatic during the immune-tolerant phase but conversion to HBeAg negativity can be accompanied by symptomatic exacerbations, with increased ALT levels. Hepatic decompensation might occur in approximately 2% of patients during these exacerbations, which can, in rare instances, lead to death from hepatic failure. In some patients with suboptimal immune response and abortive immune clearance, repeated exacerbations can occur, with intermittent clearance of HBV DNA from serum and transient loss of HBeAg. ^, Repeated episodes of necroinflammation might increase the risk for developing severe chronic liver disease and fibrosis. Ultimately, the outcome of chronic HBV infection depends primarily on the severity of liver disease at the time that HBeAg seroconversion occurs, and HBV replication is diminished.

The phase of inactive chronic HBV infection is characterized by low or absent levels of virus replication and remission of active liver disease (see Fig. 27.2 ). Patients are typically HBeAg-negative, have antibody to HBeAg (anti-HBe), and have low or undetectable levels of HBV DNA in serum. Most patients who clear HBeAg have normal ALT levels and resolution of necroinflammation on liver biopsy, indicating resolution of active liver disease. ^{, , , ,} However, a small percentage of these patients continue to have moderate levels of HBV replication, elevated ALT levels, and chronic inflammation on liver biopsy despite HBeAg seroconversion. ^, These patients may also have occult HBV infection with residual liver disease and can be misdiagnosed as having chronic liver disease of unknown etiology if they are HBsAg-negative. ^, Patients who clear HBeAg typically remain HBsAg positive for long periods, even in the absence of detectable HBV DNA. The annual rate of HBsAg clearance among patients with chronic HBV infection is approximately 0.5–2%. ^{, , ,} However, HBV DNA can be detected in up to 50% of these patients by polymerase chain reaction even after clearance of HBsAg.

HBV reactivation with enhanced viral replication might occur in HBeAg-negative as well as in HBeAg-positive persons with inactive chronic liver disease (i.e., following immunosuppression treatment) but may also evolve spontaneously. ^{, ,} Such reactivation may lead to significant liver injury but may also resolve spontaneously ( Fig. 27.3 ). In addition, some patients progress directly from HBeAg-positive chronic hepatitis to HBeAg-negative chronic hepatitis. In one study of Taiwanese patients followed for a median of 8.6 years after spontaneous HBeAg seroconversion, 67% had sustained remission, 4% had HBeAg reversion, and 24% had HBeAg-negative chronic hepatitis B.

Chronic HBV infection is an important cause of morbidity and mortality worldwide. For example, in cohort studies conducted in Taiwan, approximately 25% of persons who became chronically infected during childhood and 15% of those who became chronically infected at older ages died of HCC or cirrhosis. ^, In one population-based study, the incidence of decompensated cirrhosis among persons with chronic HBV infection was 0.5 per 1000 person-years. In studies of persons with chronic HBV infection referred to clinical centers, the incidence of cirrhosis is as high as 2–3% per year. ^, Risk factors for the development of cirrhosis in persons with chronic infection include older age, HBeAg positivity, heavy use of alcohol (>40 g/day), male sex and increased ALT levels.

Persons with chronic HBV infection are at high risk for developing HCC. ^, The annual risk of HCC is estimated to be less than 1% for chronically infected persons without cirrhosis and 2% to 3% for persons with cirrhosis. In a Taiwanese study, rates of HCC were approximately 100 times higher among men who were HBsAg-positive (495 per 100,000 per year) than among those who were HBsAg-negative (5 per 100,000 per year). ^, Most HCC cases occur in men, with an average male-to-female ratio of cases of 3.7 : 1. Other risk factors for HCC in persons with chronic HBV infection include high levels of virus replication, older age, family history of HCC, presence of cirrhosis, HBV genotype (C > B) (see “Virology” below), coinfection with hepatitis C virus (HCV), and increased alcohol intake. ^{, , ,} Although HCC is more common in persons with cirrhosis, approximately 30–50% of HBV-associated HCC cases occur in persons who do not have cirrhosis. Clearance of HBsAg might decrease the risk for HCC ; however, HCC can occur in persons who develop chronic HBV infection and then clear HBsAg. ^{, ,}

Virology

Hepatitis B virus, previously called the Dane particle, is a 42-nm DNA virus that belongs to the Hepadnaviridae family comprising five genera: Avihepadnavirus , Herpetohepadnavirus , Metahepadnavirus , Orthohepadnavirus , and Parahepadnavirus . The genus Avihepadnavirus comprises three species (Duck, heron, and parrot HBV) whose members infect birds. Members of the genus Herpetohepadnavirus infect reptiles and frogs, and members of both Metahepadnavirus and Parahepadnavirus infect fish. The genus Orthohepadnavirus comprises 12 species whose members infect mammals including the woodchuck ( Marmota monax ), the ground squirrel ( Spermophilus beecheyi ), the pig ( Sus scrofa ), the bat ( Miniopterus fuliginosus ), nonhuman primates (apes) such as orangutans, gibbons, gorillas, chimpanzees, and humans. The detection of endogenous avian hepadnavirus DNA integrated into the genomes of zebra finches has revealed a deep evolutionary origin of hepadnaviruses that was not previously recognized, dating back over 40 million years. ^, In comparison with human HBV, ape HBVs contain a 33-nucleotide deletion in the PreS1 gene with nucleotide similarities ranging from 84.1% to 92.6%. Human HBV is infectious to apes. ^, On the other hand, experiments showed that nonhuman HBVs (i.e., gibbon, orangutan, and bat HBVs) are able to infect human hepatocytes, thus capable of cross-species transmission. ^, Due to the ability of HBV to cross species barriers, reservoirs of infection in mammals may hamper attempts to eradicate HBV.

The outer lipoprotein envelope of HBV contains HBsAg, which is produced in excess amounts and circulates in the blood as 22-nm spherical and tubular particles ( Fig. 27.4 ). The inner nucleocapsid is a 28-nm icosahedral structure consisting of 180 copies of the HBV core protein (HBc), or hepatitis B core antigen (HBcAg), and it surrounds a single molecule of partially double-stranded DNA which is covalently linked to a DNA-dependent DNA polymerase ( Fig. 27.5 ).

The HBV genome is a small, circular, partially double-stranded DNA molecule (complete minus strand and partial plus strand) that is approximately 3200 nucleotides in length ( Fig. 27.6 ). The virus efficiently uses its genetic information to encode four groups of proteins and their regulatory elements by shifting the reading frames over the same genetic material. The pre-S/S gene has three separate open reading frames (ORFs) that encode three forms of HBsAg: the large (pre-S1), middle (pre-S2), and small (S) structural proteins of the virus envelope. The C gene has two ORFs (C and pre-C). The C ORF encodes the structural protein of the viral nucleocapsid (HBcAg), and the pre-C/C ORF encodes the nonstructural e protein, which is processed to produce soluble HBeAg. The X gene encodes the HBV X protein (HBx), a small transcriptional transactivator that influences the transcription of HBV genes by regulating the activity of transcriptional promoters. The P gene encodes a large polymerase protein that functions as both a reverse transcriptase for synthesis of the negative DNA strand from genomic RNA and an endogenous DNA polymerase for synthesis of the positive DNA strand using the negative strand as a template. Interestingly, P overlaps with all other coding regions, and mutations in the polymerase gene may also affect the overlapping S gene, with implications on viral infectivity, pathogenesis of liver disease, and resistance to treatments.

The HBV envelope contains a mixture of S, pre-S1, and pre-S2 HBsAg proteins in both glycosylated and nonglycosylated forms. These three proteins share the same carboxyterminus part but have different aminoterminal extensions. In particular, the S protein, which consists of 226 amino acids, is expressed in the largest quantities, and is coded for by the S genomic region alone. The pre-S2, containing an extra N-terminal extension of 55 amino acids, is coded for by pre-S2 and S regions. The pre-S1 protein, containing a further N-terminal of 108 or 119 amino acids—depending on the genotype—is coded for by the entire pre-S/S gene. Pre-S1 and pre-S2 proteins are also expressed individually in small quantities; these proteins contain several T- and B-cell epitopes. The pre-S1 protein appears to play an important role in the attachment of HBV to hepatocytes, essentially through the sodium taurocholate cotransporting polypeptide (NTCP) receptor, recently identified as an entry receptor of HBV and HDV. Notably, the S protein contains the major site for binding of neutralizing antibody, designated the a determinant. Two other major determinants of the S protein also have been described; one has either d or y specificity, and the other has w or r specificity, determined by mutually exclusive amino acid substitutions in positions 122 and 160 of the S region of HBV DNA. All combinations of these determinants have been found, resulting in four major subtypes— adw , adr , ayw , and ayr —and nine minor subtypes. Antibodies to the a determinant confer protection to all these serotypes, whereas antibodies to the subtype determinants do not. No apparent differences in infectivity or virulence of HBV have been attributed to HBsAg subtypes. However, these subtypes have a distinct geographic distribution worldwide and have been used in epidemiologic studies to identify patterns of virus transmission. The most common subtype among persons with chronic HBV infection in the United States is adw .

Based on a minimal divergence of 8% of the complete genome sequences derived from several HBV worldwide isolates, at least 10 genotypes labeled alphabetically from A to J and a number of subgenotypes—with a minimal genetic distance of 4%—have currently been identified, showing different geographic and ethnic distributions. ^, For example, genotypes A and D are prevalent in Europe, the United States, and Africa, whereas genotypes B and C are prevalent in Asia. Genotype D predominates in the Mediterranean Basin and in the near Middle East up to India. Genotype E is by far the dominant genotype in West Africa, whereas genotypes F and H have mostly been isolated in Amerindian populations in different countries in the Americas. Finally, genotype G has no specific endemic areas in the world and is usually detected in coinfection with other HBV genotypes, mostly genotype A. More recently two additional genotypes, named I and J, were isolated in Laotian and Japanese patients, ^, respectively. Emerging evidence suggests that HBV genotypes and subgenotypes may play a role in determining the severity of the liver disease and treatment outcomes of HBV infection.

Both the HBV core protein (HBcAg) and the e protein are translated from the C gene. HBV core protein is essential for multiple steps in viral replication cycle starting with transportation of the nucleocapsid to the nuclear pore complex, uncoating and release of partially double-stranded DNA into the nucleus, nucleocapsid formation, and packaging of pregenomic RNA (pgRNA). HBcAg is not detectable in serum by conventional techniques, but it can be detected immune-histologically in liver tissue in patients with acute or chronic HBV infection. The e protein is processed by the endoplasmic reticulum (ER), where it is cleaved and HBeAg is secreted. HBeAg is a soluble protein that is not part of the virus particle, but it can be detected in the serum of patients with acute hepatitis B and in persons with chronic HBV infection who have a high viral load. HBeAg is also expressed on the surface of hepatocytes and might be an important target for the immune defense mechanisms that lead to the destruction of hepatocytes.

Stages of Replication

HBV replication begins with attachment of the virus to the NCTP receptor on the hepatocyte surface ( Fig. 27.7 ). ^{, ,} The N-terminal 75 amino acid residues of the pre-S1 protein bear all the amino acids sequence required for receptor-binding function. This interaction allows viral entry into hepatocytes by endocytosis or fusion of the HBV envelope with the plasma membrane, followed by the release of HBV nucleocapsid into cytoplasm. Targeting HBV entry using entry inhibitors such as bulevirtide can inhibit attachment of HBV to NTCP. The nucleocapsid contains a partly double-stranded DNA genome in relaxed circular conformation (rcDNA). After uncoating in the cytoplasm, HBV core proteins on the shell of nucleocapsid binds importin-β and directs the transport of the nucleocapsid to the nuclear pore complex. The nucleocapsid disassembly occurs at the nuclear pore followed by translocation of HBV DNA into the nucleus. Once in the nucleus, the single-stranded gap in the viral genome is repaired by the host DNA repair machinery, and covalently closed circular DNA (cccDNA)—which is completely double stranded—is formed. The cccDNA serves as a template for transcription of the viral RNAs. Episomal HBV cccDNA persists in the hepatocyte as a stable mini chromosome organized by histone and nonhistone proteins. Several epigenetic regulations such as DNA methylation, histone acetylation, chromatin modifying enzymes, HBc, and HBx proteins appear to modulate cccDNA transcriptional activity.

In contrast to classic retroviruses such as HIV, integration of HBV DNA into the host genome is not necessary for viral messenger RNA (mRNA) synthesis or replication. However, integration of HBV DNA does occur during chronic infection, which might be an important factor for the development of HCC via genomic alterations. ^, Furthermore, HBV-DNA integration can serve as a template for HBsAg secretion. The cccDNA acts as the template for production of four mRNAs, each of which is expressed from its own promoter ¹⁵⁶ : (1) 0.7-kb mRNA transcript encodes for the X protein; (2) a 2.1-kb mRNA transcript encodes for pre-S2 and S proteins; (3) a 2.4-kb mRNA transcript encodes for pre-S1, pre-S2, and S proteins; and (4) a 3.5-kb mRNA encodes for HBcAg, HBeAg, and polymerase. These mRNA transcripts are transported into the cytoplasm, where translation yields the viral envelope, core, precore, and X proteins and the viral DNA polymerase. The 3.5-kb mRNA is also a pgRNA that serves as a template for HBV DNA synthesis. After the translation of viral proteins, encapsidation of the pgRNA into the nucleocapsid is the next step in the virus life cycle. HBV polymerase interacts with the epsilon structure at the 5´end of the pgRNA and, at the same time, core proteins interact with pgRNA and facilitate encapsidation. The encapsidated pgRNA within the nucleocapsid is retro-transcribed into negative-strand DNA by reverse transcription. The pgRNA is then degraded by the ribonuclease H (RNase H) activity of the polymerase. After the negative strand is synthesized, the polymerase starts to synthesize the positive DNA strand. However, the process is not completed, resulting in replicative intermediates consisting of full-length negative-strand DNA plus variable-length (20–80%) positive-strand DNA. Mature nucleocapsids, containing the newly synthesized partially double-stranded DNA with the polymerase bound to the 5´end of the negative strand DNA, are shuttled back to the nucleus to replenish the cccDNA pool or bud through the endoplasmic reticulum-Golgi intermediate compartment, where they acquire HBsAg/pre-S protein-containing envelopes. Virus particles are trafficked through the trans-Golgi to the hepatocyte surface via vesicular transport, from where they are released into the extracellular space. Due to the excess production of HBsAg, subviral noninfectious particles (SVPs) are also secreted in spherical and filamentous forms. SVPs outnumber infectious virus 10 ³ to 10 ⁶ to 1 and have diverse inhibitory effects on the innate and adaptive immune response. In addition, HBV pgRNA-containing nucleocapsids were also enveloped and secreted, thus became detectable in plasma of patients with chronic HBV infection. The recycling of nucleocapsids newly synthesized in the cytoplasm is the source of cccDNA without the need for reentry of the new virus leading to persistence of HBV in infected hepatocytes. Thus, inactivation or elimination of cccDNA is one of the potential novel strategies for eradication of HBV.

Because of this strategy of replication, HBV shows a greater mutability (at least 100 times) than other DNA viruses. Mutations and variations that occur naturally or following antiviral therapy play important roles in viral infectivity, pathogenesis of liver disease, vaccine efficacy, and resistance to antiviral therapies.

Pre-S/S Gene Mutants

Isolates with pre-S deletions are often found. There is evidence that a set of mutations (deletion in the pre-S region as well as precore and BCP mutations) are significantly associated with progressive liver disease and HCC. ^,

Mutations in the S gene can lead to conformational changes in the common a determinant (shared by all HBV genotypes and serotypes), which spans amino acids 124–147 within the major hydrophilic region (MHR) of HBsAg and is in a form of two major loops and one minor loop with cysteine-disulphide bonds, protruding from the outer surface of the virus. The second hydrophilic loop (amino acids 139–147 or 149) is the major target for neutralizing anti-HBs induced by natural infection or vaccination ( Fig. 27.8 ). Neutralizing (protective) antibodies produced by vaccination are targeted largely toward the conformational epitope of the a determinant, providing broad protection against all HBV genotypes and subtypes. Thus, alteration of residues within this region of the viral surface antigen can determine conformational changes that can allow replication of HBV in vaccinated persons.

The prototype of such mutants, the so-called G145R, which shows a point mutation from guanosine to adenosine at nt position 587, resulting in an amino acid substitution from glycine (G) to arginine (R) at position 145 in the a determinant of the surface antigen, was first observed in Italy some 25 years ago in infants born to HBsAg carrier mothers who developed breakthrough infections despite having received hepatitis B immunoglobulin (HBIG) and vaccine at birth. ^, Because the G145R substitution alters the projecting second loop of the a determinant, the neutralizing antibodies produced by vaccination are no longer able to recognize the mutated epitope. This mutant was infectious in experimentally infected chimpanzees. Besides the G145R, other S gene mutations (alone or in combination) across the entire a -determinant region (T116N, P120S/E, I/T126A/N/I/S, Q129H/R, M133L, K141E, P142S, D144A/E) that have been associated with escape from vaccine-induced immunity have been found worldwide. ^,

HBV infection with S gene mutant viruses has been reported to occur in anti-HBs antibody-positive infants born to HBV-infected mothers who received immunoprophylaxis, ^, in children who responded to vaccination, and in liver transplant recipients who received for prophylaxis of relapse of HBV infection. Concern has been expressed that these mutated viruses might allow replication of HBV in the presence of protective levels of anti-HBs (immunization escape mutants), negatively affecting the efficacy of vaccination. In addition, these mutants might not be detected by some commercially available HBsAg assays based on antibodies to the wild-type virus, posing a potential threat to the safety of blood supply (diagnostic escape mutants).

However, in population-based studies of infants born to HBsAg-positive mothers, S gene mutant viruses have not been found to be associated with a failure to prevent perinatal HBV transmission. In addition, preexposure vaccination of chimpanzees with currently licensed vaccines (not containing pre-S epitopes) conferred protection after intravenous challenge with the G145R HBV. At present, no evidence exists that S gene mutants have spread in immunized populations or that these mutants pose a public health threat to hepatitis B immunization programs. ^, Further studies and enhanced surveillance to detect the emergence of these mutants, as well as those resulting from the onset of resistance to antiviral therapy, are a high priority in monitoring the effectiveness of current immunization strategies.

Pathogenesis

HBV is primarily hepatotropic. However, although HBsAg has been detected in organs other than the liver, there is little evidence to indicate primary replication in sites other than hepatocytes. Upon viral entry, HBV is relatively inefficient at inducing the prototype innate cytokines such as IFN-α/β which is the characteristic of early responses to viral infections. However, HBV is a strong inducer of type III interferon (IFN-λ). This appears to be due to limited sensing combined with some active suppression of innate immunity. Importantly, most available experimental evidence suggests HBV is not directly cytopathic, and that liver damage is produced by the cellular immune response to viral proteins in infected hepatocytes. Extrahepatic manifestations that can appear during the prodromal phase of acute hepatitis B (e.g., arthritis, urticaria) and in patients with chronic infection (e.g., vasculitis, glomerulonephritis) appear to be mediated by immune complex formation.

Neonatal immune tolerance to viral antigens appears to play an important role in viral persistence in infants infected at birth. Defect of the HBV-specific T cell response, lower numbers of circulating and intrahepatic HBV-specific CD8+ and CD4+ T cells, as well as lower and restricted production of HBV-specific antibody has been demonstrated in chronic infection of HBV acquired at birth or perinatally. In an animal study, neonatally infected woodchucks that develop chronicity lack the IFN-γ and TNF-α surge and acute phase HBV-specific T-cell response, ^, which are present in those who are able to control infection. A study by Tian et al. showed that the qualitative and quantitative defects detected in HBV-specific CD8+ T cells in vertically infected neonatal mice were associated with inhibitory responses exerted by hepatic macrophages, leading to increased risk of vertical transmission and development of chronicity. Patients with acute hepatitis B whose infection has resolved have a vigorous T-cell response against multiple viral antigens, including the viral core, surface, and polymerase proteins. In contrast, persons who develop chronic infection have a weak or undetectable cellular immune response, suggesting to result from T-cell exhaustion by high antigen concentrations. The T-cell exhaustion promotes HBV-specific T-cell dysfunction and persistence of HBV.

Development of HCC in persons with chronic infection is apparently induced either directly by activating cellular oncogenes or inactivating tumor suppressor genes, or indirectly through chronic liver injury, inflammation, and the promotional effect of hepatocyte regeneration. In the bloodstream of chronically HBV-infected persons, intact virions are outnumbered by a 10 ³ - to 10 ⁶ -fold excess of SVPs consisting only of viral glycoproteins or HBsAg. Following infection, accumulation of large amounts of HBsAg in the endoplasmic reticulum activates the unfolded protein response (UPR) which leads to the formation of ground glass hepatocytes. The activation of UPR by HBsAg may sensitize hepatocytes to cell death and result in possible subsequent cellular changes leading to a premalignant phenotype. These effects appear to be driven by overproduction of PreS1, which leads to inhibition of SVP morphogenesis, accumulation of SVP filaments and inhibition of HBsAg secretion. Chronic elevation of cellular HBsAg is correlated with the onset of HCC, likely from chronic ER stress resulting in an oxidative DNA damage that induces mutagenesis and HCC. HBV-DNA integration in the DNA of hepatic cancerous cells occurs more commonly (86.4%) than in normal liver tissues (30.7%). This alteration in the host genome changes the tumor-suppressor gene expression, micro-RNAs and oncogenes and subsequently leads to the development of HCC. The role of micro-RNAs (miRNA) in the development of HCC has been recently investigated. Micro-RNAs regulate the gene expression by translational repression or degradation of mRNA of the target gene. The expression of miR-221 is upregulated in case of HCC and found to promote hepatocellular carcinogenesis. Various miRNAs including miR-106a, miR-18a/miR-18b, and miR-221 are involved in the development of HBV-mediated HCC. Hepatitis B virus X protein (HBx) represses miRNA-148a to enhance tumorigenesis in a mouse model of HCC. Long-term therapy with nucleos(t)ide analogs in patients with chronic HBV infection has selected reverse-transcriptase mutants in a substantial proportion of patients. Some mutations such as rtA181T/sW172* has been shown to enhance oncogenicity via altered host gene expressions, including MGST2 , HIF1A , and TGFbi. Although several mechanisms of HBV-mediated HCC have been reported, additional studies are needed to determine the HCC pathogenesis and HCC contributing factors which can lead to an innovative approach to prevent and treat HCC.

Diagnosis

Antigens and antibodies associated with HBV infection include HBsAg, anti-HBs, total (i.e., immunoglobulin [Ig] G and IgM) antibody to HBcAg (anti-HBc), HBeAg, and anti-HBe. At least one serologic marker is present during the different phases of HBV infection ( Table 27.1 ). Serologic assays are commercially available for all circulating markers except HBcAg, because no free HBcAg is secreted into the blood. However, HBcAg can be identified in liver tissue through immunohistologic assays. A newly reported HBV biomarker, Hepatitis B core-related antigen (HBcrAg), is a novel serum composite viral protein which showed correlation with intrahepatic covalently closed-circular DNA (cccHBV-DNA).

The presence of a confirmed circulating HBsAg may indicate current (or active) HBV infection but may also be the product of integrated HBV-DNA into the host genome. Currently, commercial assays are unable to distinguish between HBsAg produced by integrated HBV-DNA as compared to circulating HBsAg in plasma or serum. All HBsAg-positive persons should be considered infectious, yet infectivity is proportional to the magnitude of the viral load. In newly infected persons, HBsAg is the only conventional serologic viral marker detected during the first 3–5 weeks after infection ( Fig. 27.9 ). The average time from exposure to detection of HBsAg is 30 days (range: 6–60 days). ^, Highly sensitive single-sample nucleic acid tests can detect HBV DNA in the serum of an infected person 10–20 days before detection of HBsAg. Transient HBsAg positivity has been reported for up to 18 days after vaccination with standard hepatitis B vaccine dosages, ^, and for up to 28 days after vaccination with the increased dosages used for hemodialysis patients. This isolated HBsAg positivity is clinically insignificant and does not signify HBV infection.

Anti-HBc (mainly IgG) appears at the onset of symptoms or liver test abnormalities in acute HBV infection and frequently persists for life (see Fig. 27.9 ). Acute or recently acquired infection can be distinguished by the presence of the IgM class of anti-HBc, which is detected at the onset of acute hepatitis B and persists for up to 6 months if the disease resolves. In patients who develop chronic hepatitis B, IgM anti-HBc can persist at low levels during viral replication, although not always detectable by diagnostic assays used in different countries. Persons with exacerbation-reactivation of chronic HBV infection can test positive for IgM anti-HBc. Because the positive predictive value of testing for IgM anti-HBc is low in asymptomatic persons, testing for diagnosis of acute hepatitis B should be limited to persons with clinical evidence of acute hepatitis or an epidemiologic link to a case.

In persons who recover from acute HBV infection, HBsAg is cleared from the blood, usually within 3–4 months, and anti-HBs develops during convalescence ( Fig. 27.9 ). The presence of anti-HBs typically indicates immunity from HBV infection. Seroconversion from HBsAg to anti-HBs usually signifies either spontaneous resolution of HBV, treatment induced cure of HBV or “functional cure” following administration of antiviral treatment. Yet, detection of anti-HBs in serum does not guarantee complete resolution of intra-nuclear cccHBV-DNA. Furthermore, an unknown, but most likely small fraction of patients who recover clinically from acute HBV infection with anti-HBs seroconversion might still have low levels of viremia detectable by a sensitive HBV-DNA assay. In addition, anti-HBs can be detected after HBIG administration in liver-transplanted patients, irrespective of presence or absence of occult HBV in the graft. Persons who recover from “natural” infection are typically positive for both anti-HBs and anti-HBc, whereas persons who respond to hepatitis B vaccine develop only anti-HBs. In persons who become chronically infected, HBsAg and anti-HBc persist, typically for life. HBsAg becomes undetectable in approximately 0.5–2% of chronically infected persons yearly, and anti-HBs develops in most of these persons. ^{, ,}

In certain persons, the only HBV serologic marker detected in serum is isolated anti-HBc. Isolated anti-HBc can occur after HBV infection in persons who have recovered but whose anti-HBs levels have waned, or in chronically infected persons in whom anti-HBs failed to occur and in whom circulating HBsAg is not detectable by commercial serology. HBV DNA has been detected in the blood of fewer than 5% of persons with isolated anti-HBc in the absence of detectable HBsAg. ^, In such patients, occult HBV infection is manifested by the presence of low levels of HBV DNA in serum and intra-nuclear HBV cccDNA in hepatocytes. ^, Such persons with occult HBV are unlikely to be infectious except when they are treated with immunosuppressive agents or are the source for direct percutaneous exposure of susceptible recipients to substantial quantities of virus (e.g., through blood transfusion or after liver transplantation). ^, Typically, the frequency of isolated anti-HBc relates directly to the prevalence of HBV infection in the population. In populations with a high prevalence of HBV infection, isolated anti-HBc most likely indicates previous infection, with loss of anti-HBs. In these individuals, hidden immunity to HBV may be unmasked through a single HBV vaccine dose that leads to an anamnestic anti-HBs response.

For persons in populations with a low prevalence of HBV infection such as in Western Europe or the United States, anti-HBc “alone,” present in 10–20% of all individuals with HBV markers, and in 1–4% of the population, often represents a false-positive reaction. Most of these persons will have a primary anti-HBs response after a three-dose series of hepatitis B vaccine. ^, Infants who are born to HBsAg-positive mothers and who do not become infected might have detectable anti-HBc for up to 24 months after birth from passively transferred maternal antibody.

HBeAg can be detected in the serum of persons with acute or chronic HBV infection. The presence of HBeAg correlates with high levels of viral replication (i.e., HBV DNA levels of 10 ⁷ to 10 ⁹ IU/mL, indicating high infectivity). ^, Loss of HBeAg correlates with low levels (i.e., HBV DNA levels of <10 ⁵ IU/mL) of replicating virus, although some HBeAg-negative persons have HBV DNA levels up to 10 ⁸ –10 ⁹ IU/mL. A mutation in the precore region of the HBV genome has been found in HBeAg-negative persons with high HBV DNA levels. ^,

Treatment

Guidelines for antiviral treatment for HBV are available from the World Health Organization (2015 and 2020) and professional associations including the American Association for the Study of Liver Diseases (2018), the European Association for the Study of the Liver (2017), and the Asian Pacific Association for the Study of the Liver (2015). ^, No specific antiviral treatment is recommended for persons with acute hepatitis B, as approximately 95% of infected immunocompetent adults recover spontaneously with anti-HBs seroconversion. ^{, , ,}

Consequently, supportive care is the mainstay of therapy. Antiviral treatment can, however, be considered in patients with severe acute or fulminant hepatitis B. Antiviral therapy is effective for the treatment of certain patients with chronic HBV infection. The U.S. Food and Drug Administration (FDA) has approved at least six drugs for the treatment of chronic HBV infection. However, some of these drugs have been superseded by more effective and safer compounds with a high barrier to antiviral resistance. Drugs currently preferred for HBV treatment include Peg‐IFN‐α‐2a in adults and Peg IFN‐α‐2b for children, and the direct antiviral agents entecavir (ETV), tenofovir dipovoxil fumarate (TDF) and tenofovir alafenamide (TAF). TDF and TAF have the same metabolite and mechanism of action that inhibits HBV replication. Although considered safe, long duration therapy with TDF poses risk for renal tubular dysfunction and bone density loss. Compared to TDF, TAF is more stable in serum, can be given at a lower dose resulting in fewer adverse events from loss of bone mineral density and renal function. ^, Although the medications are typically given as monotherapy, ETV and TDF can be combined when the response to a single agent is incomplete or when resistance is suspected. ^, Pegylated interferon-α regimens are typically administered for 48 weeks. ETV or TDF/TAF regimens are given for at least 1 year after HBsAg seroconversion, indefinitely for other HBV infected patients eligible for treatment and lifelong for HBV infected persons with cirrhosis. With demonstrated safety, efficacy, and ease of administration of ETV and TDF/TAF, these agents have superseded pegylated interferon-α and the other antiviral regimens to become recommended as the primary therapies for chronic HBV infection.

For persons with chronic hepatitis B, the goal of treatment is increased survival and improved quality of life with the prevention of disease progression and development of HCC. The level of viral replication (HBV DNA) is the single most predictive indicator of disease progression and onset of HCC. Antiviral treatment is generally recommended for patients with an HBV DNA >2000 IU/mL, and elevated ALT and or evidence of fibrosis. All HBsAg+ patients with cirrhosis should receive HBV treatment. At least four clinical indicators can guide response and duration of therapy: (1) normalization of ALT levels; (biochemical response), (2) sustained clearance of markers of active HBV replication, including HBeAg seroconversion for HBeAg-positive patients and undetectable HBV DNA by polymerase chain reaction (PCR) for HBeAg-negative patients (virologic response); (3) improvement documented by liver biopsy (histologic response); and (4) sustained clearance of HBsAg (complete response). ^{, ,}

After six months following completion of pegylated interferon therapy, HBV DNA suppression and normalization of ALT was achieved for 30–42% and 34–52% of patients, respectively. For HBeAg positive and negative patients, long-term ETV or TDF therapy (>3 years) suppresses viral replication for 61–76% and 90–93%, respectively, and 68–81% and 76–88%, respectively, of patients have a return to normal values of ALT.

HBV therapy improves clinical outcomes for persons with chronic HBV infection. In a meta-analysis of data from 35 observational studies involving 59,201 patients with a mean follow‐up of 60 months, antiviral therapy versus no treatment was associated with a decreased risk of hepatocellular carcinoma (relative risk 0.50), all‐cause mortality (RR 0.6), and cirrhosis (RR = 0.6). Although current therapies improve survival and quality of life, the loss of HBsAg as evidence of complete cessation of viral replication is rare. Following treatment, a loss of HBsAg is observed for 8% of patients receiving 3 years of pegylated interferon therapy and 2% of patients receiving ETV or 3% receiving TDF/TAF for 1 year. Relapse can be associated with severe exacerbation of disease, which might cause hepatic decompensation and death.

A search is in progress for new strategies to achieve “functional cure” of chronic HBV infection, defined as sustained cessation of viral replication and HBsAg loss after a defined course of therapy. ^, A variety of compounds are under study to interfere with various stages of the HBV replicative cycle or to restore and strengthen the immune response to HBV infection ( Table 27.2 ). ^{, , ,} One new therapeutic class blocks entry of HBV into hepatocytes. These compounds also show promise in the treatment of HDV infection. In 2020, one entry inhibitor Bulevirtide (Myrcludex B ^TM ), was approved in the European Union (EU) for treatment of chronic HDV infection in HDV RNA positive adult patients with compensated liver disease.

Novel agents acting directly on HBV including core protein allosteric modulators or capsid assembly modulators interfere with packaging of HBV nucleic acids and reverse transcription. HBV small interfering RNAs degrade messenger RNA down regulating HBsAg production. Inhibitors of HBsAg block release from hepatocytes reducing HBsAg levels in blood and hepatocytes helping to restore immune function. Recombinant human monoclonal antibody binds to HBsAg inhibiting viral entry and with loss of HBsAg enhancing immune response to HBV infection. Several experimental inhibitors of cccDNA through disabling formation or enhancing destruction of HBV intended to lead to complete rather than functional cure for HBV are under investigation.

Enhancements of the host response to HBV infection can augment antiviral strategies. Molecules under study seek to restore or enhance the immune response to HBV leading to viral clearance. Immune modulators seek to overcome immune system “exhaustion” with restored HBV specific immune function. Stimulation of toll-like receptors (TLR) could increase detection of HBV nucleic acids signaling an innate immune response. Activation of TLR pathways suppress HBV replication and restore HBV specific immunity. ^, In human studies, an agonist to TLR‐7 taken with TDF did not result in clinically significant declines in HBsAg compared to TDF therapy alone.

Engineered T-cells could be transformed to specifically target HBV infected hepatocytes. Targeting programmed cell death protein (PD-1) and other immune system checkpoint inhibitors may also promote restoration of immune function. Based on a small number of clinical trials, licensed HBV vaccines do not appear to be efficacious for the treatment of chronic HBV. Experimental therapeutic vaccine(s) have been evaluated to stimulate HBV-specific immune control and reverse immune tolerance leading to suppression of HBV replication and cessation of HBsAg production. Therapeutic vaccines with several recombinant components (pre‐S1, pre‐S2 vaccines) elicit a humoral and cellular immune response.

To monitor the impact of therapy on viral replication and persistence of intra-nuclear HBV cccDNA, a variety of new serologic markers are under evaluation. Of these, hepatitis B core-related antigen (HBcrAg) is the serum biomarker significantly correlated with intrahepatic cccDNA activity, HBV replication and loss of HBeAg for HBeAg+ patients. HBcrAg can also be a predictive marker for development of HCC. ^,

HBV therapies also can prevent perinatal HBV infection. For newborns of HBsAg+ mothers receiving a timely HepB vaccine and HBIG at birth, the risk for perinatal HBV transmission is considerably reduced but remains significant for infants born to mothers with high viral loads of HBV. Studies of timely HepB birth dose and HBIG reveal the risk of breakthrough perinatal HBV infection is highest when the maternal HBV DNA is greater than 200,000 IU/mL. A meta-analysis of TDF prophylaxis (300 mg/day) for pregnant women in the third trimester of pregnancy plus a timely HepB birth dose and HBIG for their infants had a protective benefit with an odds ratio for transmission of 0.10 (95% CI: 0.03–0.35) with no significant findings of major adverse events for mothers or infants. ^, In 2018, the United States Advisory Committee on Immunization Practices (ACIP) and CDC recommended HBV DNA testing for all HBsAg+ pregnant women to guide clinical decisions for TDF prophylaxis particularly for women with HBV DNA >200,000 IU/mL. ^, In 2020, WHO also recommended HBV DNA testing for HBsAg+ women and TDF prophylaxis for women with HBV‐DNA level >200,000 IU/mL. In situations where HBV DNA testing is not available, HBeAg testing can be used. HBV prophylaxis is typically started after the 28th week of pregnancy and continued till birth or up to 3 months’ postpartum. ^, HBV infected women who meet eligibility criteria should continue treatment for their own health. Women who stop therapy should be monitored for reactivation of HBV infection and a “flare” of clinical disease for up to 6 months after treatment cessation.

Globally, the addition of maternal HBV DNA testing to guide TDF prophylaxis, is estimated to prevent an additional three million perinatal HBV infections with regional variations in the cost per DALY ranging from $890 to $7355. In the United States, the strategy of testing HBsAg-positive pregnant women for HBV DNA, followed by maternal antiviral prophylaxis for women with high HBV DNA, will cost an additional $3 million saving 2080 QALYs and preventing 324 chronic HBV infections; the ratio of $1583 per QALY saved is considered cost effective in the United States.

Burden

HBV infection is a highly prevalent around the globe, the frequency and burden of which varies by region and subpopulation. Approximately 30% of the world’s population (i.e., about 2 billion persons) have serologic evidence of HBV infection. Of these, an estimated 257 million persons have chronic (HBsAg+) HBV infection, representing a global prevalence of 3.5%. ^, In 2021, WHO estimates the prevalence of chronic HBV infection has increased to 296 million persons with an incidence of 1.5 million new chronic HBV infection annually.

The WHO Western Pacific and African regions have the highest HBsAg prevalence rates and largest number of HBsAg+ persons (∼115 [6.2%] million persons and 60 [6.1%] million persons, respectively). Countries with >6% of population positive for HBsAg are in the Western Pacific region and sub-Saharan Africa; certain indigenous populations in the Americas have high HBV prevalence. Countries of high endemicity can also be found in the Southeastern Asia Region (e.g., Myanmar). Countries with the largest population of HBsAg-positive persons include China (86–122 million), India (33–41 million), and Nigeria (20–21 million).

HBsAg prevalence among children less than 5 years of age is indicative of the effectiveness of HepB vaccination programs for newborns and infants. In 2018, global HBsAg prevalence fell below 1%, a 2020 target for the United Nations SDG and WHO Interim 2020 targets for HBV elimination. For this age population, HBsAg prevalence varies across WHO regions ranging from 2.5% in African region to 0.9% in the Western Pacific and 0.2% in the Americas. ^,

HBV causes significant morbidity and mortality worldwide. WHO recently estimated 820,000 (450,000–950,000) deaths were caused by HBV infection. For the year 2019, the Global Burden of Disease (GBD) study estimates HBV infection was the cause of 555,000 (487,000–630,000) deaths. The primary data sources and overall approach to estimation are substantially similar between WHO and GBD; both are based on vital registration for identifying deaths due to acute hepatitis, cirrhosis and liver cancer, and case-series data to determine the proportion to assign to HBV. However, WHO attributes all ICD-10 code C22.9 “Malignant neoplasm of liver, not specified as primary or secondary” to primary liver cancer, whereas GBD redistributes deaths coded as such to primary liver cancer as well as to cancers which metastasize to liver. The ranges of these respective estimates are statistically similar.

Based on GBD data, HBV accounted for 49% of all hepatitis related deaths and was the leading cause of deaths from primary liver cancer (39.5%) globally. Primary liver cancer, 70–90% caused by hepatocellular carcinoma, is the sixth most common cancer globally and the fourth leading cause of cancer-related death worldwide. The proportion of HCC attributed to HBV infection exceeds 50% in parts of the world where HBsAg prevalence is highest, Asia and Sub Saharan Africa. ^, Accordingly, HBV is the cause of most HCC in China (62%), Malaysia (57%), the Republic of Korea (54%), and Senegal (54%) and the leading cause in the Philippines (45%), Thailand (40%), Nigeria (39%), and India (35%).

Despite improvements in infant vaccination coverage, rates of HBV-related liver cancer remain high reflecting HBV infection in persons acquiring the virus during childhood (before the implementation of routine hepatitis B vaccination) and the decades-long latency period before development of HCC. The lifetime risk for HCC in a chronically infected person is approximately 10–25%, which is 15–20 times greater than that for persons without HBV infection. ^, In a study conducted in Taiwan, rates of HCC among men who were HBsAg-positive were approximately 100 times higher than rates among those who were HBsAg-negative (i.e., 495 vs 5 per 100,000 persons per year, respectively). ^,

Certain populations are disproportionately affected by HBV-related HCC. Among persons with chronic HBV infection, men have a two- to three-fold increased risk for HCC compared with women. The incidence of HCC in women chronically infected with HBV ranges from 120 to 178 cases per 100,000 persons, among men, incidence ranges from 340 to 804. The reasons for gender-related differences in HCC incidence remain unknown.

Other factors place certain persons with CHB at increased risk for developing HCC, including increasing age; HBeAg serostatus; increasing serum levels of HBV DNA and ALT; HBV genotype C; and concurrent infection with HCV, or HIV. ^{, ,} Cirrhosis is found in the majority of those who have HBV-related HCC (but not all patients with HCC will have had cirrhosis). ^, Behavioral factors that increase risk for HCC among persons infected with HBV include heavy alcohol consumption and aflatoxin ingestion. ^, Persons who achieve clearance of HBsAg (i.e., who have minimal or no viral replication) are at decreased risk for HCC. However, HCC can occur in persons who clear the virus. ^{, , , ,}

The median survival after diagnosis of HBV related HCC is 10.3 months in the United States. ^,

Routes of Transmission

Hepatitis B virus is transmitted by percutaneous (i.e., puncture through the skin) or mucosal (i.e., direct contact with mucous membranes) exposure to infectious blood or body fluids. All HBsAg-positive persons are potentially infectious, but those who are also HBeAg positive are more infectious because their blood contains high concentrations of HBV (typically 10 ⁷ –10 ⁹ virions/mL). Although HBsAg has been detected in multiple body fluids, only serum, saliva, semen, and vaginal fluid have been demonstrated to be infectious. HBV remains infectious for at least 7 days outside the body and can be found in very low concentrations on fomites, even in the absence of visible blood. Primary sources of HBV infection are perinatal exposure from infected mothers, nonsexual “horizontal” person-to-person contact, sexual contact, and percutaneous exposure to blood or infectious body fluids. HBV is not transmitted by air, food, or water.

Geographic Patterns of Transmission

In 2015, the global overall prevalence of HBV infection in the general population was 3.5%. However, the frequency and patterns of HBV transmission vary markedly in different parts of the world ( Fig. 27.10 ). HBsAg prevalence is greatest in the WHO regions of the Western Pacific including Pacific island nations (6.2%) and Africa (6.1%) followed by the Eastern Mediterranean (3.3%), South-East Asia (2.0%), Europe (1.6%) and the Americas (0.7%). Certain populations in areas of low endemicity (e.g., Australian Aborigines, New Zealand Maoris, and Alaskan Native Americans and indigenous peoples of the Amazon basin) also have elevated prevalence of HBV infection. Based on the survey data of chronic HBV infection, countries are categorized as having High (≥8%), Intermediate (2–7.9%) or Low (≤1.9%) endemicity for hepatitis B. Although less useful with improved routine HepB vaccination resulting in large differences in HBV prevalence among vaccinated and unvaccinated cohorts, the categorization of countries by HBsAg prevalence highlight differences in modes of transmission and priorities for HepB vaccination. In the absence of vaccination, the lifetime risk for HBV infection is greater than 60% in countries of high endemicity; rates of chronic liver disease and liver cancer also are very high in these areas. Most of HBV infections are acquired during the perinatal period and early childhood, when the risk for developing chronic HBV infection is greatest; acute hepatitis B is rarely detected because most infections in early childhood are asymptomatic. In the last several decades, many of these countries have successfully introduced hepatitis B vaccine into their routine childhood immunization schedule, resulting in lower HBV and HCC prevalences among vaccinated cohorts. However, the prevalence of chronic HBV infection remains high among older persons who did not receive hepatitis B vaccine earlier in life.

In 2002, China began routinely providing infants with a dose of vaccine at birth, followed by the complete hepatitis B vaccine series. As a result, from 1992 through 2006, HBsAg prevalence among children younger than 5 years of age declined from 9.7% to 1%. A follow-up survey conducted in 2014 revealed HBsAg prevalence declined further to 0.3% in this age group. From 1992 to 2014, the aging of vaccinated cohorts contributed to declines in HBsAg prevalence from 10.1% to 2.6% among persons 1–29 years of age. Despite these declines, HBsAg prevalence remains high among older unvaccinated populations.

In Thailand, HepB vaccination for newborns was introduced in two provinces in 1988 as part of the Expanded Program on Immunization (EPI) and extended to the whole country as universal immunization in 1992. A serologic survey conducted in 2014 showed that children and adolescents who were born after vaccine implementation had a HBsAg seroprevalence of 0.6% compared with HBsAg seroprevalence ranging between 3.7 and 6.0%, among adults 31 and 60 years of age; the carrier rate among children less than 5 years was 0.1%.

In areas of intermediate endemicity, the lifetime risk for HBV infection is 20–60%, and infections occur in all age groups. Acute hepatitis B is common in these areas because many infections occur in adolescents and adults. However, high rates of chronic HBV infection are maintained primarily because of infections occurring in infants and children. In these countries, infant Hep B immunization also is decreasing HBV infection. In 1991, Peru, a country of intermediate endemicity, launched a routine infant HepB vaccination in Albacan, a hyperendemic region followed in 2005, by the start of a national program. From 1991 to 2014, HBsAg prevalence among residents of Albacan decreased from 9.8% to 1.2%; in 2014 no persons <15 years of age were HBsAg+. ^,

Most HBV infections in areas of low endemicity occur in relatively well-defined adult risk populations. ^{, , ,} However, a high proportion of chronic HBV infections might occur because of perinatal and early childhood exposures. In Spain, a survey of adults aged 20–74 years found an HBsAg seroprevalence of 0.6% with nosocomial exposures and migration from other countries the predominant risks. The migration of persons from countries with high HBV endemicity account for more than a quarter of persons with chronic HBV infection in European Union and over 60% of chronic HBV infection in the United States.

The contribution of perinatal HBV transmission to the overall hepatitis B disease burden varies substantially in different geographic regions. In eastern and southeastern Asian countries and the Pacific Islands, 35–50% of HBsAg-positive women are also HBeAg-positive. ^, In these countries, approximately 3–5% of all infants develop chronic HBV infection after HBV infection during birth, and as many as 30–50% of all chronic infections among children result from perinatal transmission. In areas of high endemicity where the prevalence of HBeAg among pregnant women is low (i.e., Africa, South America, and the Middle East), perinatal HBV transmission contributes less to the pool of children with chronic infection than does postnatal early childhood horizontal transmission. Globally, with sustained improvements in infant immunization coverage, the proportion of HBV transmission attributed to perinatal HBV transmission is growing and expected to account for 50% of all new chronic HBV infections annually by 2030.

Risk Populations, Based on U.S. Data

In the United States, changes in the HBV incidence are the result policies for routine infant HepB immunization in 1992 and subsequent increases to >90% and >70% for infant and birth dose HepB vaccination coverage, respectively. Almost all cases of acute HBV are among adults who have not received HepB vaccination. In 2017, only 25.8% of adults ≥19 years of age had received three doses of hepatitis B vaccine. Among the 1183 adults in the United States with acute hepatitis B and with risks reported in 2019, the most common reported routes of HBV transmission were injection drug use (53%) and sexual contact (35%) including 7% of cases among MSM. In some states, HBV transmission attributed to injection-drug use is reversing the decades-long trend of declining HBV incidence.