Geographic Distribution and Sources of Exposure

The prevalence of hepatitis B varies markedly around the world. In highly endemic regions, such as Southeast Asia (excluding Japan), China, and much of Africa, 8% or more of the population are chronic HBV carriers, and the lifetime risk of infection ranges from 60% to 80%.² In these areas, perinatal transmission and horizontal spread among children are the major sources of infection. Approximately 60% of the world’s population reside in these areas where HBV is highly endemic.³ Regions of intermediate risk include parts of southern and eastern Europe, the Middle East, Japan, the Indian subcontinent, much of the former Soviet Union, and northern Africa. In intermediate-risk areas, the lifetime risk of infection is between 20% and 60%. Persons of all age groups are infected, but as in high-risk areas, most infections occur during infancy or early childhood. Regions of low prevalence are North America, western Europe, certain parts of South America, and Australia. In these areas, the lifetime risk of HBV infection is less than 20%, and transmission is primarily horizontal (i.e., between young adults). Sexual transmission is the main mode of transmission in Europe and North America, and injection drug use is a major contributor to new cases as well.⁴

Transmission of infection from an HBV carrier mother to her neonate accounts for the majority of new infections in the world today. Sixty to ninety percent of hepatitis B surface antigen (HBsAg)-positive mothers who are hepatitis B e antigen (HBeAg)-positive transmit the disease to their offspring, whereas mothers who are positive for antibody to HBeAg (anti-HBe) transmit the disease less frequently (15% to 20%) (see later discussion of diagnosis). Other less common sources of infection are household contact with an HBV carrier, hemodialysis, exposure to infected health care workers, tattooing, body piercing, artificial insemination, and receipt of blood products or organs. Since routine screening of the blood supply was implemented in the early 1970s, transfusion-associated hepatitis B has become rare in the United States. Hepatitis B can be transmitted by blood that tests negative for HBsAg but positive for antibody to hepatitis B core antigen (anti-HBc) because of low levels of circulating HBV DNA in such blood.⁵ HBsAg-negative blood that is positive for anti-HBc is excluded from the donor pool in the United States and many countries around the world. In 0% to 30% of persons who are seropositive for anti-HBc alone, HBV DNA is detectable in serum by polymerase chain reaction (PCR) testing.⁶

HBV is transmitted efficiently by percutaneous and mucous membrane exposure to infectious body fluids. The virus is 100 times as infectious as human immunodeficiency virus (HIV) and 10 times as infectious as hepatitis C virus (HCV). HBeAg seropositivity indicates a higher risk of transmission from mother to child, after needlestick exposure, and in the setting of household contact. HBV DNA has been detected by sensitive techniques such as PCR testing in most body fluids, except for stool that has not been contaminated with blood. Although HBV replicates primarily in hepatocytes, the presence of replicative intermediates and virally encoded proteins in other sites, such as the adrenal gland, testis, colon, nerve ganglia, and skin, suggests that a vast extrahepatic reservoir for infectious virus exists.⁷ Small amounts of HBV DNA have been demonstrated in peripheral mononuclear cells and liver tissue years after apparent resolution of chronic infection.^8,9 Extrahepatic localization of low levels of replicating virus explains the relatively high rate of transmission of infection from anti-HBc–positive organ donors.¹⁰

Rates of Infection in the United States

The incidence of hepatitis B has been declining in the United States over the past decade because of universal vaccination of newborns, adult vaccination programs for high risk persons, changes in sexual lifestyle, refinements in blood screening procedures, and the availability of virus-inactivated blood components.¹¹ Most striking has been the decrease among children and health care workers, groups with the highest rates of vaccination. Data from the Centers for Disease Control and Prevention (CDC) indicate that more than 95% of pregnant women in the United States are tested for HBsAg, and infant vaccine coverage levels are now equivalent to those of other vaccines in the childhood schedule. Nonetheless, an estimated 78,000 new HBV infections occurred in 2001, with the highest incidence rates among sexually active young adults (20 to 29 years old) and higher rates occurring among black and Hispanic persons than in white persons.¹² Since 1995, approximately 40% of cases of acute hepatitis B reported to the CDC were caused by intimate contact among heterosexuals, 15% to 20% were related to intravenous drug use, and 12% occurred in men who have sex with men. No identifiable source of exposure was demonstrated in approximately 15% of cases. Nearly one third of prison inmates have been infected with hepatitis B, and 2% are chronically infected.

According to the third National Health and Nutrition Examination Survey (1988 to 1994), one or more serologic markers of HBV infection were demonstrated in 4.9% of the U.S. population, and the prevalence of chronic infection was 0.2%.¹³ Traditional estimates based on the results of blood donation screening in the late 1970s also indicated a prevalence rate for chronic infection of 0.2% to 0.4% in the United States. Although traditional estimates are that the number of HBV carriers in the United States is between 1.25 and 1.5 million, this figure is likely to be a serious underestimate because of changing immigration patterns and underrepresentation of certain minority groups in field surveys. For example, 15 million Asians live in the United States, and even a conservative estimate that the prevalence in this group is 5% would raise the overall number of HBV carriers in the United States by more than 750,000.

Definitions

In common usage, the term HBV carrier has often been used to refer to persons persistently infected with HBV who have normal serum aminotransferase levels. (They are sometimes inappropriately referred to as “healthy” HBV carriers.) Because the nomenclature is potentially confusing, the proposal has been made that the carrier state be categorized as inactive or active. Inactive carriers are patients who have evidence of HBV replication on a PCR-based assay only (but not with a less sensitive non–PCR-based assay) and normal or only mildly elevated serum aminotransferase values (see later).¹⁴ Long-term follow-up of inactive carriers suggests that the majority of these patients do not have progressive liver disease and do not experience complications. Some of these patients, however, ultimately have one or more episodes of reactivated hepatitis in which the levels of viremia and serum aminotransferase activity increase. Also, some patients with the inactive carrier state may demonstrate HCC. Active carriers, on the other hand, have evidence of HBV replication on non–PCR-based assays for HBV DNA, intermittently or persistently elevated serum aminotransferase levels, and evidence of chronic hepatitis in a liver biopsy specimen.

Clinical Sequelae of Acute Hepatitis B Virus Infection

The age at which a person becomes infected with HBV is a principal determinant of the clinical outcome. HBV infection in adults with an intact immune system is likely to cause clinically apparent acute hepatitis B; only 1% to 5% of these persons become chronically infected.⁴ By contrast, as many as 95% of infected neonates become chronic HBV carriers because of immunologic tolerance to the virus.

In adults, fulminant liver failure caused by acute hepatitis B occurs in less than 1% of cases, but this group still accounts for 5% of all cases of acute liver failure and approximately 400 deaths annually in the United States.¹⁵ Rapid viral elimination may result in clearance of HBsAg from serum by the time of initial presentation. In these cases, the accurate diagnosis of fulminant hepatitis B may require testing with immunoglobulin (Ig) M antibody to hepatitis B core antigen (HBcAg) (IgM anti-HBc) (see later discussion of serologic markers of infection).¹⁶ The rate of spontaneous survival in acute liver failure caused by hepatitis B is only approximately 20%. Liver transplantation has resulted in survival rates of 50% to 60%. Recurrent disease in the allograft is now uncommon because of administration of hepatitis B immune globulin (HBIG) and potent orally administered antiviral agents (see later and Chapters 93 and 95).

Clinical Sequelae of Chronic Hepatitis B Virus Infection

Chronic hepatitis B develops in 2% to 5% of persons who acquire HBV infection in adulthood. Progressive liver disease (including cirrhosis and HCC) can be expected to develop in one quarter to one third of people who acquire infection in the first few years of life. An estimated 15% to 25% of patients ultimately die of liver-related causes, with the greatest risk in male HBV carriers.

The presence of active viral replication and long-standing necroinflammatory liver disease caused by HBV strongly influences the rate of progression to cirrhosis. The major determinant of survival is the severity of the liver disease when the patient first comes to medical attention.¹⁷ Cirrhosis is associated with decreased survival and an increased frequency of HCC. Five- and 20-year survival rates of 55% and 25%, respectively, have been reported in patients with cirrhosis at presentation, whereas rates of 97% and 63%, respectively, have been reported for those with mild (noncirrhotic) disease.¹⁸ Survival rates differ most dramatically between patients with compensated and decompensated cirrhosis. In one study, an 84% five-year survival rate was reported for patients with compensated HBV-related cirrhosis, compared with 14% for patients with cirrhosis complicated by ascites, jaundice, encephalopathy, or a history of variceal bleeding.¹⁹ Multivariate analyses in several large cohort studies have identified age, ascites, hyperbilirubinemia, and other features of advanced liver disease as correlating independently with survival in patients with HBV-related cirrhosis. Interferon-induced clearance of HBeAg (see later) has been associated with prolongation of survival without complications or the need for liver transplantation.²⁰

Clearance of HBsAg in patients with HBV-related cirrhosis has been associated with an excellent prognosis, including improvement in liver histology and function, a decreased chance of viral reactivation, and prolonged survival.¹⁷ Even HBsAg clearance, however, is not an absolute safeguard against the future development of HCC in persons who already have cirrhosis.²¹

Hepatitis B Virus Genotypes

A genetic classification based on comparisons of complete genomes has demonstrated eight genotypes of HBV, designated A through H (Table 78-1).²³ Several methods have been used for HBV genotyping, including a commercially available line probe assay. Genotypic differences are based on an intergroup divergence of 8% or more in the complete nucleotide sequence. Genotype A is the predominant genotype in northern Europe and the United States. Genotypes B and C are confined to populations in eastern Asia and the Far East, but changes in immigration patterns have resulted in an influx of Asian HBV carriers with these genotypes into the United States.²⁴ Genotype D is found worldwide but is especially prevalent in the Mediterranean area, Middle East, and south Asia. Genotype E is indigenous to western sub-Saharan areas, and genotype F prevails in Central America. Cases of genotype G have been reported in the United States and France. Genotype H has been described in Mexico.

Table 78-1 Hepatitis B Genotypes (A-H) and Their Possible Clinical Associations

Hepatitis B Surface Antigen Mutants

Mutations in the surface gene can result in changes in the antibody-binding domain. Accordingly, both virus neutralization by polyclonal antibody to HBsAg and testing for HBsAg by methods that depend on antibody binding can be affected. Large-scale vaccination programs in regions endemic for HBV have revealed a 2% to 3% frequency of vaccine escape mutants that result from alterations in the “a” determinant of the HBsAg protein, which is the major neutralizable epitope. The typical mutation results in the substitution of glycine for arginine at amino acid position 145; this substitution prevents binding of neutralizing antibodies (i.e., antibody to HBsAg [anti-HBs]). The clinical significance of these mutants for neonatal vaccination programs is highly controversial because the frequency of these variants among HBV-infected mothers whose infants respond to vaccination has been found to be similar to that of mothers whose infants do not respond. The “a” determinant mutants also are proposed to have clinical relevance after liver transplantation for hepatitis B. As many as 50% of patients in whom recurrent HBV infection develops despite the use of HBIG have been shown to have these escape mutants, and the rate at which the mutations are detected appears to correlate with the length of time over which HBIG is repeatedly administered.²⁶

Mutations in the Precore, Basal Core Promoter, and Core Genes

Mutations in the precore and basal core promoter regions of the HBV genome can influence the production of HBeAg. A precore mutation results in a stop codon at nucleotide 1896 that abolishes the synthesis of HBeAg,²⁷ whereas mutations in the basal core promoter at nucleotides 1762 and 1764 decrease HBeAg synthesis by approximately 70% while maintaining pregenomic RNA levels.²⁸ Both types of mutations have been observed in cases of severe or fulminant hepatitis, which has been attributed to the loss of the immune-tolerizing effects of HBeAg antigen (see later). The presence of core promoter mutations has been linked to a significantly increased risk of HCC.²⁹ Precore and basal core promoter mutants have been described in the same patients and are particularly common in Asian and European patients with chronic hepatitis B.³⁰ A large serosurvey of HBV carriers residing in the United States has found that precore and core promoter mutations are common (frequencies of 27% and 44%, respectively), depending on the ethnicity and places of birth of the patients. Both mutant forms of HBV were observed to occur far more commonly in HBeAg-negative patients (precore mutation in 38% of HBeAg-negative versus 9% of HBeAg-positive patients; core promoter mutation in 51% versus 36%).³¹ In addition to these mutations, upstream mutations in the core gene can influence immunologic responses to HBV. Core gene mutations have been shown to block recognition of HBV by cytotoxic T lymphocytes (CTLs), a key mode of viral clearance. Therefore, the mutations contribute to HBV immune escape and possibly influence the response to interferon.³² Core gene mutations within the immunodominant epitopes of the HBV nucleocapsid also can affect CD4⁺ T-cell reactivity.³³

In patients with perinatally acquired chronic hepatitis B, a prolonged immune tolerant phase with minimal to absent hepatic necroinflammatory activity is typically seen for the first 20 to 30 years of HBV infection. Sequencing studies have shown stable core gene sequences during this phase. Precore mutations are also uncommon during this phase. Core gene mutations become more common as patients pass from the immune tolerant phase, at which time a growing number of mutations are observed in the region of the core gene that includes many B- and T-cell epitopes. Both precore stop codon mutants and core gene mutants have been associated with a poor response to interferon therapy.

Hepatitis B Virus DNA Polymerase Mutants

The polymerase gene encodes a DNA polymerase enzyme needed for encapsidation of viral RNA into core particles, conversion of the pregenomic viral RNA into a negative strand of viral DNA (reverse transcription), and conversion of this first HBV DNA strand into a second DNA strand of positive polarity. In general, the HBV reverse transcriptase function of the polymerase gene is highly conserved because major mutations that impair the efficiency of viral replication lead to selection pressure against such variant forms. As indicated earlier, HBV has a high rate of replication (10¹¹ virions per day) and low replication fidelity, meaning that it has a propensity to mispair nucleotide bases when it reverse transcribes viral RNA to DNA. HBV DNA polymerase also lacks any proofreading activity, so it cannot repair its mistakes. Therefore, when a nucleotide base is misplaced, it remains in the growing viral DNA strand as a base mutation, and the new HBV DNA molecule has a different sequence from the original (wild-type) genome. The overall error rate of HBV DNA polymerase is estimated to be 1 per 10,000 nucleotides copied, which translates to the potential for 10 million base-pair errors per day in an infected person. All possible single-base mutations can be produced in a 24-hour period, although many such mutations will yield nonviable viruses.³⁴

Mutations in the sequence of HBV polymerase can lead to drug resistance to nucleoside analogs used to treat HBV infection because some HBV polymerase mutants have decreased susceptibility to these drugs and are selected during treatment. The mutations in the sequence of HBV DNA polymerase that confer drug resistance result in amino acid substitutions in the reverse transcriptase domain of the enzyme. The changes in the structure of the enzyme, in turn, are thought to sterically inhibit binding of the drugs to their active sites. The amino acids in the reverse transcriptase are numbered from 1 to 344, and an amino acid identity is given by the single letter amino acid code. By convention, substitutions in reverse transcriptase are designated by the wild-type amino acid, followed by the number of the amino acid, followed by the substituted amino acid. For example, for the nucleoside analog lamivudine (see later), two types of mutations occur at nucleotide position 204 of domain C (the catalytic site of the polymerase) that result in substitution of the amino acid methionine (M) for either isoleucine (I) or valine (V). These mutations are designated M204I and M204V, respectively, and are referred to collectively as YMDD mutants; the letters stand for the amino acids (Y = tyrosine, M = methionine, D = aspartate) in the C domain. The M204V mutation tends to occur in conjunction with a mutation in domain B that results in substitution of leucine (L) with methionine (L180M). The M204I mutation or the combined M204V-L180M mutations result in marked resistance to the effect of lamivudine (>10,000-fold reduction in susceptibility). After prolonged exposure to adefovir, drug resistant mutations in domains B and D are selected (A181V/T and N236T). Other nucleotide substitutions have been described that are instrumental for telbivudine and entecavir resistance (Fig. 78-3).

Figure 78-3. Common amino acid changes (top row) that result from nucleotide substitutions in the hepatitis B virus polymerase gene and confer drug resistance to oral antiviral agents (first column) used to treat hepatitis B (see text for description of nomenclature). Note that cross resistance exists among lamivudine, telbivudine, and entecavir, but entecavir requires the presence of one or more secondary substitutions at codons 184, 202, or 250 for clinically apparent drug resistance to appear. Note also that the potential for cross-resistance exists between adefovir and tenofovir, but the greater antiviral potency of tenofovir reduces the chances of resistance greatly. A, alanine; ADV, adefovir; ETV, entecavir; G, glycine; I, isoleucine; L, leucine; LAM, lamivudine; LdT, telbivudine; M, methionine; TDF, tenofovir; N, asparagine; S, serine; T, threonine; V, valine.

The inherent mutability of HBV indicates that single and even double polymerase mutants preexist as minor “quasispecies” even before treatment of HBV infection is begun. Because of the limitations in the sensitivities of current genotype assays, these mutants would not be detectable until they are selected and expanded under the pressure of drug treatment. Resistance to lamivudine is found in approximately 20% of patients after one year of treatment but in nearly 70% after five years (see Fig. 78-3).³⁵ Rates of resistance to adefovir, a nucleotide analog, are 0% at one year and 29% after five years.³⁶ The efficacy of both of these drugs against HBV is impaired by a single nucleotide substitution. The more mutations necessary for drug resistance (indicating a higher genetic barrier to resistance), the slower the emergence of and lower overall rate of resistance. For example, resistance to entecavir, another nucleoside analog, occurs in less than 1% of patients at five years because the preexistence of lamivudine-resistant mutations and one or more additional mutations in the viral polymerase gene are required for resistance.³⁷ Persistent infection with drug-resistant HBV ultimately is associated with progression of disease and blunting of hepatic histologic improvement with antiviral therapy.³⁸ Severe flares of hepatitis have also been reported after the emergence of drug-resistant mutants,³⁹ and acquisition of these mutants may lead to rapidly progressive liver disease after liver transplantation (Table 78-2).⁴⁰ Horizontal transmission of these mutants, which can complicate drug therapy in secondarily infected persons, is also possible.

Table 78-2 Hepatitis Flares in Patients with Chronic Hepatitis B

ALT, alanine aminotransferase; HIV, human immunodeficiency virus; HAART, highly active antiretroviral therapy; HBV, hepatitis B virus; YMDD, tyrosine-methionine-aspartate-aspartate.

* Has also been reported with adefovir and entecavir.

ALT as a Surrogate Marker for Disease Activity

The serum ALT level has been used conventionally as a measure of disease activity in patients with chronic hepatitis B. Use of the standard reference range (0 to 40 U/L), however, can be misleading for evaluating HBV-related disease activity. A serum ALT level within the normal range is an imperfect surrogate marker for the absence of disease activity because determination of standard reference ranges has not traditionally taken into account increased body mass index (BMI), diabetes mellitus, and other features, such as alcohol intake, that tend to inflate values in a “normal” reference population (see Chapter 73). An insurance record-based study in Korea that included more than 140,000 persons who were followed for eight years demonstrated that all-cause liver-related mortality is increased when the serum ALT level exceeds 20 U/L in women and 30 U/L in men.⁵² This finding is particularly relevant to the management of Asians with hepatitis B and viremia. Because these patients tend to have a small body mass, a normal serum ALT value according to the standard laboratory reference range may be misleading. Such patients often have been excluded from treatment and assumed to be immune tolerant (that is, without liver disease). Studies in Asia and the United States have shown that as many as 20% to 30% of HBV carriers with persistently normal serum ALT levels and serum HBV DNA levels >10⁴ copies/mL have stage 2 or greater (of 4) inflammation and stage 2 or greater (of 4) fibrosis on a liver biopsy specimen.⁵³ Moreover, Asian HBV carriers with high-normal serum ALT levels (>0.5 × upper limit of normal [ULN]) have been shown to have more fibrosis on liver biopsy specimens than do those with low-normal serum ALT levels (<0.5 × ULN) and often demonstrate higher serum ALT elevations on prolonged follow-up.^53–55 These data are consistent with the hypothesis that viremic HBV carriers who acquired HBV infection early in life and who have high-normal serum ALT levels may represent a subgroup of patients who have already entered the immune clearance phase and are not in the immune-tolerant phase. This occurrence should be suspected in particular in persons older than age 35 to 40 because immune tolerance often subsides after two to three decades of infection.⁵⁴ Liver biopsy can be a useful tool to distinguish persons in the immune clearance phase despite normal or near-normal ALT levels but with active liver disease from those in the immune tolerant phase and absence of active liver disease (see Fig. 78-4).

HBV DNA Level and Long-Term Complications

Population-based Asian cohort studies have established that the serum HBV DNA level is the single best predictor of future progression to cirrhosis and HCC in HBV-infected persons.^56,57 In a prospective cohort study, more than 3600 HBV carriers from Taiwan, of whom 60% were male, 70% were older than age 40, 85% were HBeAg negative, and 95% had normal serum ALT levels, were followed for a mean of 11 years. The calculated relative risks for cirrhosis and HCC were shown to correlate with the level of HBV DNA on entry into the study when compared with a reference population of HBV carriers in whom HBV DNA was undetectable in serum by a PCR assay.⁵⁷ Even serum HBV DNA levels as low as 10,000 copies/mL (equivalent to 2000 IU/mL) were associated with a higher relative risk of cirrhosis and HCC. The relative risk of HCC was highest in persons with a serum HBV DNA level of more than 1 million copies/mL and intermediate in those in whom follow-up serum samples indicated spontaneous reduction of the serum HBV DNA level from greater than 100,000 copies/mL to less than 10,000 copies/mL. These data can be interpreted to mean that both the duration and level of viremia are important risk factors for the development of HCC. The data also suggest that suppression of serum HBV DNA levels, whether spontaneously or as a result of antiviral therapy, lowers the risk of HCC. The serum HBV DNA level remained a significant predictor of cirrhosis and HCC even after adjustment for patient age, gender, serum ALT level, and HBeAg status. Other studies in Chinese HBV carriers have demonstrated that persons in whom liver decompensation and HCC develop often have modest serum ALT elevations that are frequently below the recommended threshold (2 × ULN) for antiviral treatment in current practice guidelines (see later).⁵⁸

On the basis of these data, some authorities have suggested that all persons who acquire HBV infection early in life and who are age 45 to 50 years or older and demonstrate serum HBV DNA levels of 100,000 or more copies/mL should receive long-term therapy with a nucleoside analog to prevent cirrhosis and HCC.^59,60 In a landmark study,⁶¹ more than 600 Asian patients with advanced fibrosis and a serum HBV DNA level greater than 100,000 copies/mL were randomized in a ratio of 2 : 1 to active treatment with lamivudine or placebo. Treatment was planned for 5 years, but the study was discontinued after a mean duration of only 32 months because disease progression and HCC occurred significantly more frequently in the group of patients randomized to placebo.⁶¹ Therapeutic benefit was independent of the serum ALT level at baseline. These data strongly suggest that continuing suppression of serum HBV DNA by antiviral therapy can alter the long-term outcome of active chronic hepatitis B.

Extrahepatic Manifestations

Extrahepatic syndromes seen in association with acute or chronic hepatitis B are important to recognize because they may occur without clinically apparent liver disease and can be mistaken for independent disease processes in other organ systems. The pathogenesis of these extrahepatic disorders has not been fully elucidated but likely involves an aberrant immunologic response to extrahepatic viral proteins.⁶⁷ Many of the extrahepatic manifestations (e.g., arthritis, dermatitis, glomerulonephritis, polyarteritis nodosa, cryoglobulinemia, papular acrodermatitis, and polymyalgia rheumatica) are observed in association with circulating immune complexes that activate serum complement. Antiviral therapy may be indicated for persistent symptoms.

Cryoglobulinemia

Type II cryoglobulins consist of a polyclonal IgG and monoclonal IgM, whereas type III cryoglobulins contain polyclonal IgG and rheumatoid factor. Type II and type III cryoglobulinemia have been associated with hepatitis B, but the association is uncommon. In a large patient cohort, the frequency of cryoglobulinemia was significantly higher in patients with chronic HCV infection (54%) than in patients with chronic HBV infection (15%) (see Chapter 79). Cryoglobulinemia may be associated with systemic vasculitis (purpura, arthralgias, peripheral neuropathy, and glomerulonephritis) but is often paucisymptomatic or asymptomatic. Interferon has been used successfully to treat symptomatic cryoglobulinemia in association with chronic hepatitis B. Experience with nucleoside analog therapy has not been reported.

Histopathologic Features

Chronic HBV infection is characterized by mononuclear cell infiltration in the portal tracts. Periportal inflammation often leads to the disruption of the limiting plate of hepatocytes (interface hepatitis), and inflammatory cells often can be seen at the interface between collagenous extensions from the portal tracts and liver parenchyma (referred to as active septa). During reactivated hepatitis B, lobular inflammation is more intense and reminiscent of that seen in acute viral hepatitis. Steatosis is not a feature of chronic hepatitis B, as it is in chronic hepatitis C.

The only histologic feature noted on routine light microscopy that is specific for chronic hepatitis B is the presence of ground-glass hepatocytes (Fig. 78-5). This morphologic finding results from accumulation of HBsAg particles (20 to 30 nm in diameter) in the dilated endoplasmic reticulum. Because of high levels of cysteine in HBsAg, ground-glass cells have a high affinity for certain dyes, such as orcein, Victoria blue, and aldehyde fuchsin. Ground-glass hepatocytes also may be seen in HBV carriers, in whom they may be detected in up to 5% of cells. When present in abundance, ground-glass hepatocytes often indicate active viral replication.⁷¹ Immunofluorescence and electron microscopic studies have shown HBcAg inside the hepatocyte nuclei of affected cells. During periods of intense hepatitis activity, cytoplasmic core antigen staining is generally observed. After successful treatment of HBV infection with a nucleoside analog, the cytoplasmic core antigen staining often disappears, but nuclear core antigen staining may remain, indicating persistence of the HBV cccDNA template.

Figure 78-5. A, Liver biopsy specimen showing ground-glass inclusions in hepatocytes. These inclusions represent large amounts of hepatitis B surface antigen (HBsAg) in the endoplasmic reticulum of infected hepatocytes (Hematoxylin and eosin, ×630.) B, Immunohistochemical stain for HBsAg. Note that the brownish inclusions correspond to the ground-glass inclusions seen in A (×630).

(Courtesy of Dr. Gist Farr, New Orleans, La.)

Spontaneous Flares

Spontaneous exacerbations of chronic hepatitis B often result from reactivated infection, and an increase in serum HBV DNA levels often precedes an increase in serum aminotransferase levels. Histologic evidence of acute lobular hepatitis superimposed on the changes of chronic viral hepatitis is frequently observed during these flares.⁷² IgM anti-HBc, a marker that is often diagnostic of acute viral hepatitis, may also appear in serum at this time.⁷³

The reasons for reactivated infection are unknown but likely relate to subtle changes in the immunologic control of viral replication. Reactivation seems to occur more commonly in persons who are infected with HIV.⁷⁴ In persons who acquire HBV infection early in life, flares become more common during adulthood, presumably because of a breakdown in immune tolerance to HBV.⁷⁵

Fatigue may be reported during flares of chronic hepatitis B, but in many instances, patients remain asymptomatic. Occasionally symptoms and signs of frank liver failure become apparent, particularly when the flare is superimposed on advanced chronic hepatitis B.

Most clinically recognizable flares occur in patients who are in the nonreplicative phase of HBV infection (i.e., initially testing positive for anti-HBe and negative for serum HBV DNA on a molecular hybridization assay). During such flares, serum HBV DNA levels increase, and HBeAg often reappears in serum (seroreversion). HBV DNA and HBeAg are often detectable in serum when the patient is first seen, but if the flare has been ongoing for several weeks or longer, the accompanying enhancement of the immune response may make it difficult to detect a rise in serum HBV DNA levels. Frequently, subsidence of these flares of hepatitis is accompanied by loss of HBV DNA and HBeAg in serum.

Flares also can occur in patients who are in the replicative phase of infection (i.e., already positive for HBV DNA and HBeAg in serum). In these instances, HBV replication intensifies, serum HBV DNA levels rise, and liver biochemical deterioration occurs, often without the subsequent loss of HBeAg. Multiple episodes of reactivation and remission have been shown to accelerate the progression of chronic hepatitis B and are particularly likely to occur in patients infected with the precore mutant form of chronic hepatitis B (see earlier).⁴⁷

Immunosuppressive Therapy-Induced Flares

Reactivation of HBV replication is a well-recognized complication in patients with chronic HBV infection who receive cytotoxic or immunosuppressive therapy.⁷⁶ Suppression of the normal immunologic responses to HBV leads to enhanced viral replication and is thought to result in widespread infection of hepatocytes by HBV. On discontinuation of immunosuppressive medications, such as cancer chemotherapy, antirejection drugs, and glucocorticoid therapy, immune competence is restored and infected hepatocytes are rapidly destroyed. The more potent the immunosuppression, the higher the level of viral replication and, thus, the greater the potential for serious clinical consequences of sudden withdrawal of the therapy and restoration of immunologic competence. Postmortem studies of liver tissue from patients with severe liver injury have documented sparse staining of viral antigens, suggesting that the patients were in an active state of immune clearance.⁷⁷

The vast majority of patients who experience immunosuppressive therapy–induced flares have been positive for HBsAg in serum before treatment, but some studies have described the reappearance of HBsAg in patients who were initially positive for anti-HBs, anti-HBc, or both.⁷⁸ Reactivated hepatitis in patients who are negative for HBsAg and positive for either anti-HBc or anti-HBs is explainable by the possible latency of HBV in liver and mononuclear cells and the large extrahepatic reservoir of HBV. Chemotherapy given to patients with cancer who are HBV carriers is associated with an increased risk of liver-related morbidity and mortality.⁷⁹

Reactivated hepatitis B also occurs in patients who are given immunosuppressive medications to prevent organ transplant rejection. The frequency of reactivated hepatitis appears to be particularly high in patients who undergo bone marrow transplantation because of extensive immunologic conditioning before transplantation and treatment of graft-versus-host disease.⁸⁰ Rarely, fibrosing cholestatic hepatitis, a rapidly progressive form of liver injury associated with inordinately high levels of HBsAg and HBcAg in liver tissue, may develop in such patients.⁸¹

Acute flares of hepatitis B resulting from cancer chemotherapy and other immunosuppressive drugs are often detected after substantial increases in serum aminotransferase levels have been noted. Initiation of antiviral treatment after detection of such biochemical abnormalities has little effect on reducing liver injury because much of the immunologic response to HBV and viral elimination has already occurred. Instead, the key to management lies in anticipating the occurrence of a flare, initiating antiviral treatment preemptively (e.g., 4 to 6 weeks before the start of chemotherapy), and continuing the treatment for 6 to 12 months after completion of chemotherapy.⁸²

Antiviral Therapy–Induced Flares

Antiviral treatment of chronic hepatitis B can be associated with flares of hepatitis in several circumstances. Flares may occur during interferon therapy, after withdrawal of nucleoside analogs or glucocorticoid therapy, and in association with lamivudine-resistant mutants (see also later discussion of treatment).

Interferons

Nucleoside and Nucleotide Analogs

Nucleoside analogs have excellent oral bioavailability, a good safety record, and antiviral efficacy comparable to that observed with interferon alfa-2b. These drugs have proved to be particularly useful in the management of patients with decompensated cirrhosis, in whom even small doses of interferon can lead to worsening liver failure and severe infections.

Nucleoside and nucleotide analogs replace natural nucleosides during the synthesis of the first or second strand (or both) of HBV DNA. They thus serve as competitive inhibitors of the viral reverse transcriptase and DNA polymerase. Because nucleos(t)ide analogs partially suppress viral replication, they have to be given for more than one year in most cases to achieve maximal efficacy. Unfortunately, drug resistance occurs with prolonged monotherapy. Figure 78-3 illustrates the common HBV nucleotide substitutions associated with drug resistance and the potential for cross resistance. Nucleos(t)ide analogs have several other limitations as well. With these agents, demonstrating the clearance of HBV cccDNA has been difficult, and in contrast to treatment with interferon, HBsAg clearance rarely occurs after one year of treatment with nucleoside analogs. These problems may result, in part, from the fact that these agents, unlike interferon, do not have a direct, enhancing effect on the immunologic response to HBV.⁷⁸ Also, as indicated earlier, postwithdrawal serum ALT flares have been seen in approximately 25% of cases after discontinuation of nucleoside analog therapy.

Viral Resistance to Nucleoside and Nucleotide Analogs

With the exception of tenofovir, all currently available nucleos(t)ide analogs have been associated with drug resistance when used as monotherapy. Genotypic resistance is the term that describes the finding of a nucleotide substitution in the HBV DNA polymerase gene that has been associated with clinical evidence of drug resistance. Such a mutation can be detected by a commercially available reverse hybridization assay (InnoLipa, Innogenetics, Belgium). The detection method can detect only known mutants and is limited by the ability to detect only the most common mutations. Furthermore, to be detectable, the drug-resistant mutant HBV has to constitute at least 10% of the viral population in an infected patient. Testing for drug-resistant HBV should be done prior to discontinuation of the drug because of the rapid re-emergence of wild-type HBV on discontinuation of the drug, at which point the mutant HBV can no longer be detected. Phenotypic resistance refers to the findings of an in vitro assay that uses a human liver cell line transfected with the relevant HBV DNA polymerase mutant. Various concentrations of test drug are added to the culture to assay for loss of susceptibility of the virus to the drug. This test is a research tool and is helpful in determining whether new genotypic changes cause clinically meaningful drug resistance.

Registration trials for nucleos(t)ide analogs have incorporated serial genotypic testing for drug-resistant HBV mutants. These studies have shown quite clearly that genotypic resistance to a nucleos(t)ide analog often occurs weeks to months before a virologic breakthrough (defined as greater than a 1-log₁₀ [10-fold] increase in serum HBV DNA levels above the previous nadir) (Fig. 78-6). Ultimately, if the patient is continued on the drug, virologic rebound (defined as an increase in serum HBV DNA levels to greater than 100,000 copies or 20,000 IU/mL) will occur and will be followed by elevation of the serum ALT level (see Fig. 78-6). Rescue therapy can modify this sequence of events if a second agent that lacks cross resistance to the original drug is used alone to replace the first drug or added to the first drug. many experts prefer to add another nucleos(t)ide analog that does not share the same resistance pattern rather than switch to an alternative monotherapy in this clinical situation.

Figure 78-6. Time course of events leading to clinically apparent drug resistance in patients treated for hepatitis B virus (HBV) infection. In this case, HBV DNA levels decline in serum during antiviral therapy. The levels may or may not become undetectable, and with continued selection pressure by the drug, compensatory mutations develop and improve the ability of the mutant to replicate. The drug-resistant HBV mutant expands within the viral quasispecies. Detection of genotypic resistance occurs weeks to months before virologic breakthrough (a rise in HBV DNA levels in serum), which in turn may precede biochemical breakthrough elevation of serum alanine aminotransferase (ALT) levels by weeks to months. Ultimately, if the patient continues to take the drug, virologic rebound (a marked rise in HBV DNA levels) and a further rise in serum ALT levels occur.

A patient treated with a nucleos(t)ide analog should be tested at periodic intervals to assess for virologic breakthrough.¹⁶⁸ Such testing enables assessment of suppression of viremia and permits detection of viral breakthrough as early during the course of treatment as possible. To do this, the serum HBV DNA level should be monitored at three-month intervals. Patients who do not have at least a 1-log₁₀ decline in the serum HBV DNA level after three months of treatment are considered to have primary treatment failure and should be given an alternative agent. The next key interval is at 24 weeks of treatment. In the GLOBE trial, the relative efficacies of lamivudine and telbivudine were compared, and persons who remained positive in serum for HBV DNA at 24 weeks of treatment with either drug were more likely to have a failed response and eventually developed resistance; the risk of a negative outcome to treatment was proportional to the level of detectable HBV DNA in serum at the 24-week point.¹⁵⁵ In clinical practice, patients often have a serum HBV DNA level of greater than 10,000 copies/mL at week 24 if their baseline level of viremia is high, even with very potent drugs. If such a patient is taking a nucleos(t)ide analog with a high genetic barrier to resistance (e.g., entecavir or tenofovir), continuing the drug is reasonable, with the expectation of an eventual response. By contrast, if such a patient is taking a nucleos(t)ide analog that is associated with either a high rate of resistance (e.g., lamivudine) or limited antiviral potency (e.g., adefovir), switching to an alternative drug is probably best.¹⁶⁹ Unless the choice of a particular nucleos(t)ide analog is restricted or the baseline serum HBV DNA level is relatively low (less than 10⁶ copies/mL), first-line therapy with a highly potent nucleos(t)ide analog such as entecavir or tenofovir is preferred because the rapidity of HBV DNA suppression associated with these agents makes it far less likely that drug-resistant mutants will emerge.

Whenever a virologic breakthrough occurs, the patient should be questioned about adherence to therapy. If poor adherence is not a factor, genotypic testing for resistance should be done, as described earlier. If drug resistance is confirmed, the treating clinician may prescribe an alternative nucleos(t)ide analog that lacks cross resistance to the first drug or add the new drug while continuing the first. Clinical experience has indicated, however, that adding a second drug may be preferred to switching to another single agent because sequential monotherapy can result in multidrug-resistant HBV.¹⁷⁰ When multidrug resistance occurs, combination therapy is not likely to be effective.

Combination Nucleoside or Nucleotide Analog Treatment

The combination of two or more nucleos(t)ide analogs may be more effective in the treatment of HBV infection than a single agent. In vitro data and studies in the woodchuck model of hepatitis B support a role for combination therapy of hepatitis B. Combination treatment is hoped to prevent or delay the emergence of drug resistance and lead to more rapid clinical stabilization. This outcome could be particularly important for patients with decompensated cirrhosis or those in urgent need of liver transplantation. Disadvantages of combination therapy are the added cost and the potential for greater toxicity. In addition, certain combinations could theoretically lead to multidrug resistance.

Somewhat surprisingly, the results of early clinical trials of combination therapy in previously untreated patients with HBeAg-positive chronic hepatitis B have shown that the combination of two nucleoside analogs (telbivudine and lamivudine) or the combination of a nucleoside analog and a nucleotide analog (lamivudine and adefovir) does not lead to greater viral inhibition during the first year of treatment than that seen with monotherapy.^154,171 The reasons for the lack of apparent additive effect in these studies remain unexplained. Possibly, nucleoside analogs such as telbivudine and lamivudine compete sterically for binding to the HBV DNA polymerase or compete for phosphorylation enzymes (kinases) required for drug activation. Another possible explanation is that a measurable increase in viral suppression may be difficult to demonstrate whenever a drug with substantially less antiviral activity is added to a more potent drug (for example, when lamivudine is added to telbivudine or when adefovir is added to lamivudine). A study in which the combination of lamivudine and adefovir was compared with lamivudine alone, each given for two years, clearly demonstrated a lower rate of lamivudine resistance in the combination therapy arm (15% vs. 43%, respectively).¹⁷¹ On the basis of these and similar observations and the clinical experience with combination reverse transcriptase inhibitors in HIV infection, some authorities have recommended combination therapy as a first-line approach to prevent drug resistance. With the newer nucleos(t)ide agents, however, resistance occurs so infrequently that combination therapy might be better reserved for patients with clinical and laboratory features that have been associated with drug resistance, such as a high level of viremia and high body mass index.¹⁶⁸

Combination Interferon and Nucleoside Analog Treatment

From a conceptual standpoint, treatment with the combination of interferon and a nucleoside analog might prove to be more effective than either drug alone because these agents have different mechanisms of action and might also permit a shorter course of nucleoside analog therapy, thereby reducing the risk of viral resistance. Three large multicenter studies evaluated these effects in patients given a combination of pegylated interferon and lamivudine. In one study, HBeAg-positive patients received peginterferon alfa-2b with either lamivudine or placebo for one year.¹²⁶ At the end of treatment, 44% of the patients who received combination therapy had lost HBeAg, whereas only 29% who received peginterferon alone had done so; however, response rates in the two groups were no longer significantly different 26 weeks after the end of treatment (35% and 36%, respectively). It is possible that the low dose of peginterferon used in this study (100 µg weekly for eight months followed by 50 µg weekly until the end of treatment) may have contributed to the relatively high relapse rates after remission. In the second study,¹²⁷ HBeAg-positive patients were treated with peginterferon alfa-2a, 180 µg weekly for 48 weeks, or combined therapy with lamivudine or with lamivudine monotherapy. Although the greatest degree of HBV DNA suppression was observed in the group that received combination therapy, the proportion of patients who underwent HBeAg seroconversion did not differ significantly between the two interferon-containing arms six months after completion of therapy. In the third study,¹²⁸ patients with HBeAg-negative chronic hepatitis B were treated with peginterferon alfa-2a in an identical design strategy to that of the HBeAg-positive trial. Again, viral suppression was greater in the combination therapy arm, but this advantage did not translate into a higher rate of sustained virologic response. An interesting finding from the three-arm studies that evaluated peginterferon alfa-2a was that the rate of lamivudine resistance was significantly lower with combination therapy than with lamivudine monotherapy. Taken together, these three studies provide proof of concept that pegylated interferon alpha and lamivudine have additive antiviral effects during treatment. Trials of combinations of pegylated interferon and entecavir or tenofovir given for more than one year are in progress.

Pregnant Women

Nucleos(t)ide analog therapy may be considered during pregnancy for two reasons: to protect the health of the mother and to prevent breakthrough HBV infection in HBV-vaccinated newborns. Several studies have shown that treatment of mothers who have high serum levels of HBV DNA during the last 4 to 12 weeks of pregnancy decreases the rate of HBV infection in newborns vaccinated at birth against HBV.^172,173 These studies have been small and generally have had problematic study designs or incomplete follow-up. Furthermore, breakthrough HBV infections develop in only 5% of newborns when the newborns are given a three-dose regimen of HBV vaccine and single dose of HBIG (see later). Therefore, antiviral treatment of the mother to prevent newborn HBV infection remains highly controversial and cannot be recommended at this time.

None of the current antiviral agents is licensed for use in pregnancy, and prominent warnings exist for the potential risk of harmful effects on the fetus. Telbivudine and tenofovir are considered category B drugs by the FDA (defined as a lack of animal embryologic toxicity without studies in humans). Extensive experience with tenofovir exists in HIV-HBV–coinfected mothers. Lamivudine is a category B drug in HIV-infected pregnant women but a category C drug in HBV-infected women (defined as embryotoxic or teratogenic in animals without study in humans). A large amount of safety data on lamivudine in HIV-infected mothers also exists.

Women who are of child-bearing age should be warned not to become pregnant while undergoing treatment with a nucleos(t)ide analog. If pregnancy occurs, the risk of drug withdrawal, including ALT flares, must be balanced against the uncertainity of harmful effects to the fetus. Because lamivudine has a long record of safety and has had the most extensive use during pregnancy in HIV-infected women, many hepatologists prefer to prescribe this agent whenever they feel compelled to treat the hepatitis B in a pregnant woman. Because defects in bone mineral density, including osteomalacia, have been described with tenofovir in HIV-infected patients, this drug seems to be a poor choice during pregnancy because of uncertainty about the effects on fetal bone maturation.

The degree of risk to the fetus from the use of nucleos(t)ide analogs that are licensed only for hepatitis B (adefovir, telbivudine, entecavir) is likely to be small. The Antiretroviral Pregnancy Registry in the United States has been tracking spontaneously reported maternal and fetal outcomes in women receiving oral nucleos(t)ide drugs since 1989. Of the nearly 10,000 reported pregnancies during which the mother had received an oral nucleos(t)ide analog, 95% had HIV infection, and less than 1% had HBV infection alone. Nonetheless, the overall frequency of birth defects in the infants of these women has not been shown to be significantly different from that reported in the general U.S. population. Interferon is contraindicated during pregnancy largely because of its antiproliferative effects. In the event of pregnancy, interferon should be discontinued. Breast feeding is not recommended during the first year of the infant’s life for mothers who are undergoing antiviral therapy.

Persons with Acute Hepatitis

Because of the high rate (>95%) of complete immunologic recovery from acute hepatitis B, definitive recommendations about the treatment of acute hepatitis B cannot be made. Some experts recommend nucleos(t)ide analog therapy when HBeAg remains detectable in serum for more than 10 to 12 weeks because of the high likelihood of evolution to the chronic HBV carrier state without treatment. A National Institutes of Health–sponsored clinical workshop on hepatitis B proposed that persons with acute viral hepatitis complicated by an increase in INR above 1.5 and deep jaundice persisting for more than four weeks should receive antiviral therapy.¹⁷⁴ Antiviral treatment of patients with fulminant hepatitis B is recommended in the AASLD guidelines because of the safety of nucleos(t)ide analog therapy and the need for liver transplantation in many of these patients.¹²⁰

Persons with Cirrhosis

Nucleos(t)ide analog therapy has been shown to be safe in patients with cirrhosis and has made a major difference in the care of patients with advanced liver disease. Interferon is contraindicated in patients with even mildly decompensated cirrhosis because immune-mediated flares of serum ALT levels may occur and may be associated with further clinical deterioration. Also, serious infections have been reported in treated patients.¹⁷⁵ Practice guidelines of the AASLD suggest that nucleos(t)ide analog therapy is preferred in all cases of HBV-related cirrhosis because of a greater chance of dose-limiting side effects and clinical worsening in the event of an ALT flare with interferon. Nevertheless, some studies have shown that patients with stable, well compensated cirrhosis can be treated safely and actually may have a higher rate of virologic response when compared with patients without cirrhosis.^176,177 Treatment of patients with HBV cirrhosis needs to be individualized, and all of those treated with interferon should be carefully monitored.

Persons with Human Immunodeficiency Virus–Hepatitis B Virus Coinfection

With improved control of HIV disease with HAART, liver disease has emerged as one of the leading causes of death in patients with HIV.¹⁷⁸ Antiviral therapy for hepatitis B should be considered for all HIV-HBV–coinfected patients with evidence of liver disease, irrespective of the CD4 count. In coinfected patients not requiring HAART, therapy for HBV should be based on agents with no HIV activity such as adefovir or pegylated interferon.¹⁷⁹ Entecavir treatment is associated with a decline in HIV RNA levels; thus, it also is not recommended for use in patients who are not receiving concomitant HIV treatment.¹⁸⁰ In patients with CD4 counts less than 350/mm³, the use of agents with dual anti-HIV and anti-HBV activity should be considered. Combination therapy with either emtricitabine and tenofovir or lamivudine and tenofovir should ideally be used to avoid or delay the development of antiviral resistance.

Persons with Hepatitis B Virus–Hepatitis C Virus Coinfection

When compared with monoinfected patients, HBV-HCV–coinfected patients tend to have more severe liver injury and a higher probability of cirrhosis.¹⁸¹ Limited data are available, however, to define the best approach to treatment in this group of patients. In most instances, one virus, often HCV, is dominant through the process of viral interference. The typical patient is positive for HCV RNA but negative for HBV DNA in serum. Close monitoring has been recommended before treatment is initiated, however, because some patients exhibit alternating viremia. In a prospective clinical trial of 19 patients with combined HBV-HCV infection, all were positive for HCV RNA, and only 5 were positive for HBV DNA prior to treatment. A high rate of sustained virologic response (74%) was observed after a 48-week course of pegylated interferon alpha and ribavirin (see Chapter 79), and two of the five HBV DNA-positive patients also had a virologic response. Unfortunately, HBV DNA became detectable again in four patients who were initially negative, suggesting that a risk exists that HBV may reactivate with eradication of HCV.¹⁸² The optimal therapy for patients who are positive in serum for both HBV DNA and HCV RNA is also unclear. In such instances, the author has had success in treating both infections simultaneously with a combination of a nucleos(t)ide analog, pegylated interferon alpha, and ribavirin.

Targeted High-Risk Groups

Table 78-6 lists the high-risk groups for whom HBV vaccination is recommended. Targeted vaccination has not achieved its objective in certain high-risk groups, such as injection drug users, but has achieved great success among health care workers and newborns. The CDC has extended its original recommendations for routine HBsAg screening to include persons born in countries in which the prevalence of hepatitis B exceeds 2%.¹⁹⁰ This new recommendation will facilitate identification of susceptible persons who are in need of vaccination and those in need of antiviral therapy.

Table 78-6 High-Risk Groups for Whom Hepatitis B Virus (HBV) Vaccination Should Be Considered

Vaccination Schedule

The doses of currently available HBV vaccines and recommendations for the schedules of administration are shown in Table 78-7. The typical vaccination schedule is zero, one, and six months. The first two doses have no effect on the final anti-HBs titer. The third dose acts as a booster to achieve a high anti-HBs titer. In immunocompromised patients and patients undergoing hemodialysis, four vaccine doses are recommended, with the fourth dose given to ensure the highest possible anti-HBs titer. If vaccination is interrupted, the second dose should be administered as soon as possible after the first.¹⁹⁰ If the third dose is not given on schedule, it should be given at least two months after the second dose.

Table 78-7 Recommended Dosing for the Currently Available Hepatitis B Vaccines*

* The standard schedule is 0, 1, and 6 months.

† Infants born to hepatitis B surface antigen-negative mothers.

‡ Special formulation (40 µg/mL).

§ Two 1.0-mL doses administered at one site in four-dose schedule (0, 1, 2, 6 months).

The HBV vaccine is currently administered to all children and infants as a part of the universal immunization program. Combination HBV vaccines with diphtheria-pertussis-tetanus (DPT) and Haemophilus influenzae type B (Hib) (DTPw-HB/Hib), the vaccines in current use for immunization of infants, do not reduce the immunogenicity of any of the components of HBV infection.¹⁹¹ Adolescents who have not been vaccinated in infancy or childhood should also be vaccinated.

Postexposure and Perinatal Prophylaxis

Table 78-8 summarizes recommendations for prevention of perinatal transmission of HBV. Table 78-9 lists recommendations for prophylaxis after exposure to a known HBsAg-positive source. Postexposure vaccination should be considered for any percutaneous, ocular, or mucous membrane exposure. The type of immunoprophylaxis is determined by the HBsAg status of the source and the vaccination-response status of the exposed person.

Table 78-9 Postexposure Prophylaxis of Hepatitis B if the Source Is HBsAg Positive

Anti-HBs, antibody to hepatitis B surface antigen; HBIG, hepatitis B immune globulin; HBsAg, hepatitis B surface antigen.

* Anti-HBs titer ≥10 mIU/mL.

† Anti-HBs titer <10 mIU/mL.

Bivalent Vaccine

A combined HAV and HBV vaccine has been licensed commercially (TWINRIX, GlaxoSmithKline, Research Triangle Park, NC) and has been shown to be highly immunogenic and protective against both infections (see Chapter 77). This vaccine offers ease of administration for persons at increased risk of both HAV and HBV infection (e.g., world travelers or men who have sex with men) and in patients with underlying chronic liver disease.¹⁹²

HBV Escape Mutants and Implications for Immunization

As described earlier, mutations in the HBV genome that encodes HBsAg can result in mutant HBV virus strains that can escape neutralization by anti-HBs. The mutation involves the “a” determinant and has shown decreased binding to monoclonal anti-a antibodies. Such mutants have been reported worldwide and are particularly common in areas endemic for HBV. These mutant viruses account for some instances in which the HBV vaccine has failed to prevent perinatal transmission. The frequency of this mutation is currently low, but in the future this HBV mutant could emerge as an important threat, in which case HBV vaccines may have to incorporate the mutant antigen to remain effective.