Hepatitis B

Infectivity

HBV is transmitted efficiently by percutaneous and mucous membrane exposure to infectious body fluids. The virus is 50 to 100 times as infectious as HIV and 10 times as infectious as HCV. HBeAg seropositivity indicates a higher risk not only of transmission from mother to child, but also after needlestick exposure and in the setting of household contact. HBV DNA has been detected by sensitive techniques such as PCR methodology 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.¹⁰ Small amounts of HBV DNA have been demonstrated in peripheral mononuclear cells and liver tissue years after apparent resolution of chronic infection.^11,12 Extrahepatic localization of low levels of replicating virus explains the relatively high rate of HBV transmission from organ donors positive for antibody to hepatitis B core antigen (anti-HBc) (see later).¹³

Prevalence

Estimates of chronic HBV infection report a prevalence of 2.2 million persons in the United States.¹⁴ This number is approximately 1 million higher than formerly believed. The older figure of 1.25 million persons was an underestimate because of changing immigration patterns since the 1980s and an underrepresentation of certain minority groups in the National Health and Nutrition Examination Survey (NHANES) study. Nearly 15 million Asians live in the United States, and even a conservative estimate of the prevalence of HBV infection such as 5% would raise the overall number of HBV carriers in the United States by more than 750,000. Of all immigrants to the United States between 1974 and 1998, an estimated 60% were born in regions of intermediate or high HBV prevalence. This finding explains why more than 90% of chronic HBV infections in the United States are imported¹⁴ (Fig. 79-1).

In contrast to the growth of new cases of chronic hepatitis B, a decline in acute cases of hepatitis B since the 1990s has been the result 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.¹⁵ Health care workers have experienced a striking decline in HBV infection owing to high rates of vaccination.¹⁶

In the United States and much of the developed world, however, the highest incidence of acute cases continues to be in sexually active young adults.¹⁷ Since 1995, approximately 40% of cases of acute hepatitis B reported to the CDC were caused by intimate contact among heterosexuals. Fifteen percent to 20% were due to injecting drug use, and 12% occurred in men who have sex with men. No identifiable source of exposure was demonstrated in approximately 15% of cases.¹⁸ Cases of hepatitis B continue to result from hemodialysis, acupuncture, artificial insemination, and rarely, blood transfusion, but these cases account for a small contri­bution to the overall number of newly established acute infections.

Data from the CDC indicate that more than 95% of pregnant women in the United States are tested for HBsAg, and infant vaccine coverage levels are up to 93%. Despite these encouraging figures, however, the CDC also estimates that approximately 1000 new cases of hepatitis B in newborns each year are due to a missed birth dose or failure to complete the vaccine schedule.¹⁹

Several distinct trends in prevalence are noted when the results of the CDC-sponsored NHANES survey between 1988 and 1994 are compared with those obtained from 1999 to 2006. Although the prevalence of past and present infection was not different in the 2 groups as a whole, a significant decrease in the prevalence of infection was found in persons 6 to 19 and 20 to 49 years of age for the more recent time interval. Additionally, although the prevalence among foreign-born children continued to be higher than that among children born in the United States, it decreased by approximately 85%, most likely because of universal vaccination programs in the native countries of foreign-born children.²⁰ Little difference in prevalence was found in foreign-born and native adults 50 years of age and older.

Chronic Hepatitis B

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 predominately middle-aged or older male patients with acquisition of infection early in life ultimately die of liver-related causes. Outcomes are related to host (age, male gender, genetic background, immune status) and viral (serum HBV DNA level, HBV genotype, mutation patterns) factors. HCC is 4 times as likely to develop in males as in females.

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.²³ Cirrhosis is associated with decreased survival and an increased frequency of HCC. Prior to the advent of antiviral therapy, 5- and 20-year survival rates of 55% and 25%, respectively, were reported in patients with HBV-related cirrhosis, compared with 97% and 63%, respectively, for those with mild (noncirrhotic) disease.²⁴ In one study, an 84% 5-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 (see Chapters 74 and 92).²⁵ Multivariate analyses in several large cohort studies have identified age, ascites, hyperbilirubinemia, and renal dysfunction as correlating independently with survival in patients with HBV-related cirrhosis. Therefore, early hepatic decompensation is an indication for antiviral therapy as well as assessment for liver transplantation (see later).

Clearance of HBsAg from serum 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 improved long-term survival.²³ HBsAg clearance, however, is not an absolute safeguard against the future development of HCC in persons who have preexisting cirrhosis.²⁶

Viral Replication

Although HBV is a DNA virus, replication occurs through an RNA intermediate and requires an active viral reverse transcriptase/polymerase enzyme (Fig. 79-3). The mutation rate is higher for HBV than for other DNA viruses (an estimated 10¹³ to 10¹⁵ point mutations per day).²⁷ Complete HBV genomic sequencing has identified a large number of mutations within the HBV genome, many of which are silent or do not alter the amino acid sequence of encoded proteins. Because of genomic overlap, however, some of the silent mutations in 1 ORF (e.g., the polymerase gene) may result in an amino acid substitution in an overlapping ORF (surface gene), although with uncertain clinical implications.

HBV replication begins with encapsidation of the pregenomic RNA through complex interactions between host and viral proteins. HBV DNA polymerase reverse transcribes the pregenomic RNA into a negative-strand HBV DNA, which in turn serves as the template for positive-strand synthesis to form a partially double-stranded genome. Concurrent with HBV DNA synthesis, the nucleocapsid undergoes maturation and, through an incompletely understood mechanism, interacts with the S protein to initiate viral assembly in the endoplasmic reticulum. S protein is synthesized in the endoplasmic reticulum, where monomer aggregates that exclude host membrane proteins subsequently bud into the lumen as subviral particles. When formed, HBsAg undergoes glycosylation in the endoplasmic reticulum and the Golgi apparatus. Noninfectious subviral particles (spherical and filamentous forms of HBsAg) are secreted in great abundance when compared with mature virions. These subviral HBsAg particles exceed virions in number by a variable factor of 10² to 10⁵ and can accumulate up to concentrations of several hundred micrograms per milliliter of serum.²⁸

Genotypes

A genetic classification based on comparisons of complete genomes has demonstrated 10 genotypes (designated A through J) and numerous subtypes of HBV (Box 79-1).²⁹ These classifications are defined as a divergence in the entire HBV genomic sequence of 8% or more. 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.³⁰ 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. Genotypes I and J are the most recently discovered and have been observed in Vietnam and the Ryukyu Islands in Japan, respectively.²⁹

Clinical associations appear to exist with the various genotypes (see Box 79-1). The strongest clinical associations appear to be that (1) HBeAg seroconversion occurs earlier in patients with HBV genotype B than in those with genotype C, and (2) the response to therapy with interferon (IFN) is better with genotypes A and B than with C and D (see later).³¹ The viral genotype also has implications for the frequency of precore and core mutations (see later) and may have an effect on the frequency of HCC. There is no compelling evidence that genotypes affect the HBV DNA response to nucleoside analogs (see later).

The clinical associations with the various genotypes have not led to specific recommendations on routine testing because genotype classification does not generally lead to a difference in management. One exception to this rule, however, occurs when a patient is being considered for IFN therapy. In patients who are suitable candidates based on age and other factors (see later), genotype testing may have clinical value because genotypes A and B are associated with higher rates of a sustained virologic response and HBsAg clearance.³²

Mutations

The vast majority of mutations in the HBV genome that are identified by comparing nucleotide sequences with those of wild-type HBV are silent or do not alter the amino acid sequence in a particular ORF. Some mutations have potentially important disease associations, however, and are described below.

Serum 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. A serum ALT level within the normal laboratory reference range, however, has been shown to be an imperfect surrogate marker for lack of disease activity. Clinical laboratories base their range of normal values on donors without known liver disease, but this population may include obese persons, alcohol consumers, and diabetics, each of whom tends to expand the supposedly upper limit of normal. In fact, all-cause and liver-related mortality is increased when the serum ALT level exceeds 20 U/L in women and 30 U/L in men, and these values should be accepted as the upper limits of the normal range (see Chapter 73).⁶⁰ Studies in Asia and the United States have shown that as many as 20% to 30% of Asian HBV carriers with persistently normal serum ALT levels and serum HBV DNA levels over 2000 IU/mL (roughly equivalent to 10,000 copies/mL) have grade 2 or greater inflammation and stage 2 or greater fibrosis (on scales of 0 to 4) on a liver biopsy specimen.⁶¹ HBeAg-negative Asian HBV carriers with high-normal serum ALT levels by standard reference ranges tend to be older, have a greater frequency of serum HBV DNA levels in excess of 2000 IU/mL, and have a higher frequency of basal core promoter HBV mutations—all features that can be associated with adverse long-term outcomes.⁶² Therefore, liver biopsy or a noninvasive determination of hepatic fibrosis can be a useful tool to ensure that the severity of underlying liver disease is not underestimated in such persons (see Chapter 73).

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.^63,64 In the prospective REVEAL-HBV natural history cohort study, more than 3600 untreated HBsAg carriers from Taiwan were followed for more than 11 years. Of these, 60% were male, 40% were older than age 50, 85% were HBeAg negative, and 95% had normal serum ALT levels using standard reference ranges. 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 HBsAg carriers with undetectable serum HBV DNA by PCR assay.⁶⁴ 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 was highest (hazard ratio of 10) in persons with a serum HBV DNA level that was greater than 100,000 copies/mL and intermediate (hazard ratio of 3.8) in persons in whom the serum HBV DNA level decreased spontaneously from greater than 100,000 copies/mL at the time of enrollment to less than 10,000 copies/mL at the last point of follow-up. 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.

Some authorities recommend that Asian men 50 years of age or older with serum HBV DNA levels 100,000 copies/mL or greater receive long-term therapy with a nucleoside (or nucleotide) analog to prevent HCC, even if serum ALT values are normal.⁶⁵ Additional support for this recommendation can be found in a landmark study in which 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 the nucleoside analog lamivudine or placebo.⁶⁶ Disease progression and HCC occurred significantly more frequently in the group of patients randomized to placebo.

Chronic Hepatitis B

A history of acute or symptomatic hepatitis is often lacking in patients with chronic HBV infection. When symptoms are present, fatigue tends to predominate over other constitutional symptoms, such as poor appetite and malaise. Patients may remain asymptomatic even during periods of reactivated hepatitis. In other instances, particularly when superimposed on cirrhosis, reactivation of HBV infection may be associated with frank jaundice and signs of liver failure.

Physical examination may be normal, or hepatosplenomegaly may be found. In decompensated cirrhosis, spider telangiectasias, jaundice, ascites, and peripheral edema are common. During exacerbations of disease, serum ALT levels may be as high as 1000 U/L or more, and the clinical and laboratory picture is indistinguishable from that of acute hepatitis B, including the presence in serum of IgM anti-HBc in some cases. Progression to cirrhosis should be suspected whenever hypersplenism, hypoalbuminemia (in the absence of nephropathy), or prolongation of the prothrombin time is found. The serum AST level is typically higher than the serum ALT level in patients with advanced cirrhosis.

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 of 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. 79-5). 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 may also 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.⁷⁴ 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 nucleos(t)ide analog, the cytoplasmic core antigen staining often disappears, but nuclear core antigen staining due to persistence of the HBV cccDNA trancriptional template may remain.

Goals

The primary treatment goals for patients with chronic hepatitis B are to forestall progression of liver disease, prevent late complications (cirrhosis, liver failure, and HCC), and increase survival. All of these objectives are achievable with long-term suppression of viral replication with either IFN-α or nucleos(t)ide analogs. Unfortunately, less than 10% of patients with potentially treatable chronic hepatitis B are estimated to be given antiviral therapy. Missed opportunities for HBV screening and poor appreciation of the indications for treatment are the major impediments.^106,107

Cultural Barriers

More than two thirds of immigrant populations with chronic hepatitis B were born in areas of the world where hepatitis B is highly endemic. Many of these persons do not seek health care, and the possibility of hepatitis B is often not explored when they do.

Significant cultural barriers to the effective management of these patients exist. Appreciation of these barriers is critical because the potential impact on future health and financial resources needed to care for late complications of hepatitis B are immense. One of the greatest barriers to acceptance of antiviral therapy is the limited proficiency in English language skills that leads to isolation and may negatively influence government support to an individual or community. Asian immigrants, for example, often own small businesses or have jobs in which insurance is not provided, thus preventing them from having access to care. If they are able to obtain medical care, the health care provider often is not able to communicate with first-generation immigrants in their native tongues, further leading to distrust, confusion, and embarrassment. Cultural, religious, and stigmatizing beliefs may impede care. These barriers may be overcome, however, with sensitivity on the part of the care provider. Whenever possible, the provider should arrange for a translator or seek the assistance of someone who speaks the patient's native language.¹⁰⁸

Choice of Agent

In deciding on the appropriate type of therapy for a patient with chronic hepatitis B, the physician should consider the serum ALT level, serum HBV DNA level, and liver histology, if available, as well as the expense of treatment, potential for adverse events, age of the patient, and presence of other comorbid conditions (Table 79-4). Moreover, before starting antiviral therapy, the patient should be committed to having serial blood samples and assessments.

The latest generation of nucleos(t)ide analogs such as tenofovir and entecavir have a high genetic barrier to resistance and, therefore, can be used as monotherapy. Accordingly, these agents are generally preferred as first-line treatment when available (Table 79-5). In emerging nations, lamivudine and adefovir are often used as first-line therapy owing to financial constraints and limited availability of the newer oral agents.

IFN and nucleos(t)ide analogs each have advantages and disadvantages that should be considered when making a treatment decision (see Table 79-4). One major advantage of IFN is that treatment is limited to 1 year or less, and virologic responses tend to be quite durable, especially in patients with HBeAg-positive hepatitis B. The shorter time required for treatment may be an important factor for some patients.

Definitions of Response

Phase 3 drug registration trials for nucleos(t)ide analogs utilized predefined biochemical, virologic, and histologic end points to evaluate the response to treatment. Biochemical response required normalization of serum ALT levels, virologic response required a sustained disappearance of HBV DNA from serum for at least 6 months after treatment, and histologic response required a 2-point or greater improvement in the necroflammatory score without worsening fibrosis. HBeAg seroconversion to anti-HBe, rather than HBeAg disappearance alone, was used as an additional virologic end point to minimize the chance of virologic relapse.

Some of the large clinical trials of IFN used a virologic end point of HBeAg loss rather than HBeAg seroconversion, and the persistent detection of low levels of serum HBV DNA (<2000 IU/mL) was allowed in the definition of a sustained virologic response, because nondetectable HBV DNA occurs less frequently with IFN-based therapy than with nucleos(t)ide therapy. These less stringent requirements did not preclude a durable response to IFN in approximately 80% of HBeAg-positive patients when evaluated years later.¹⁰⁹ This durability has been hypothesized to be due to a continued immunoregulatory effect of IFN after treatment discontinuation. A sustained decline of serum HBV DNA levels to less than 2000 IU/mL was also included as a primary end point in many of the IFN trials in patients with HBeAg-negative hepatitis B. Long-term follow-up of these patients has indicated a higher rate of relapse when compared with HBeAg-positive patients, but sustained responses have been reported in 30% of the HBeAg-negative patients.

Irrespective of the type of antiviral therapy used, the best assurance that late relapses will not occur is provided by the disappearance of HBsAg, with or without seroconversion to anti-HBs; this occurrence comes closest to a clinical cure of hepatitis B. Unfortunately, this more stringent end point occurs uncommonly with IFN and is even more rarely achieved with nucleos(t)ide analog therapy despite the greater antiviral potency of the latter.

Nucleoside and Nucleotide Analogs

The vast majority of previously untreated (“treatment-naïve”) patients are treated with 1 or more nucleos(t)ide analogs rather than IFN. Between 70% and 85% of HBeAg-positive patients will become HBV DNA negative during the first year of treatment.¹¹⁰ The rate is as high as 85% to 95% after 2 years of therapy when drugs associated with a high genetic barrier to resistance are used. A small group of patients may still have HBV DNA detectable in serum after several years of therapy with high-genetic-barrier nucleos(t)ide analogs even though the clinical and biochemical response persists. The reason for the persistence of serum HBV DNA in these patients is not well understood, but the HBV DNA level is almost always below 2000 IU/mL, and drug-resistant mutants have not been demonstrated in this situation; most experts recommend continuing treatment with the same drug with a high genetic barrier to resistance.

The lack of side effects and excellent resistance profiles of the orally available antiviral agents are especially important properties because HBeAg seroconversion occurs slowly and often requires treatment for years or for an indefinite duration. Despite a rapid decline in serum HBV DNA levels on nucleos(t)ide analog therapy, only 20% to 25% of treated patients achieve HBeAg seroconversion after 1 year of treatment. The rate rises to 40% after 5 years of continuous treatment provided that the patient remains adherent and viral resistance does not occur.¹¹¹ Long-term or maintenance therapy is particularly likely to be necessary in patients with HBeAg-negative hepatitis B because relatively high rates of relapse have been demonstrated after drug withdrawal despite years of treatment during which HBV DNA has remained nondetectable.

From 15% to 20% of patients with HBeAg-positive hepatitis B have a virologic relapse, including reappearance of HBeAg as well as HBV DNA, within 1 year of treatment discontinuation. Continuation of nucleos(t)ide analog therapy for several months beyond the period when HBeAg seroconversion is first detected diminishes the chance of relapse.¹¹² Treatment for a minimum of 6 months after HBeAg seroconversion has been recommended by all the international liver societies. Even when this practice has been followed, however, some studies have reported relapse rates as high as 30% to 50% in Asian patients with HBeAg-positive chronic hepatitis B.¹¹³ The reasons for differences in relapse rates in various studies are not clear, but interstudy differences in HBV genotype and patient-related factors, such as the duration of infection, may be potential explanations.

Interferon

Both standard and pegylated forms of IFN-α are available. They have similar immunologic effects, but pegylated IFN has greater antiviral potency and is better tolerated.¹²³ Pegylated IFN is used more frequently worldwide. The FDA-approved duration of therapy is 48 weeks at a dose of 180 µg for both HBeAg-positive and HBeAg-negative chronic hepatitis B.

Predictors of response are the same for both types of IFN. Patients with baseline ALT values of at least 2 to 3 times the upper limit of normal, an HBV DNA level less than 10⁹IU/mL, and genotype A or B respond more frequently than patients without these features. Because ALT flares may occur during therapy, IFN is contraindicated in patients with even mildly decompensated cirrhosis and must be used with caution in patients with clinically stable cirrhosis.

Loss of HBsAg occurs in approximately 5% of HBeAg-positive patients within the first 6 months after completion of treatment.³¹ This rate compares with rates of disappearance of HBsAg in 5% of patients treated for 96 weeks with entecavir and 3% of those on tenofovir for 48 weeks.^124,125 Although these differences may seem minimal, sustained responses to IFN are often associated with incremental HBsAg loss during long-term follow up, a finding that has not been demonstrated for nucleos(t)ide analogs.^109,126 A 3-year follow-up study of patients who lost HBeAg and had sustained virologic response after a year of pegylated IFN-α demonstrated that initial responders with HBV genotypes A or B had the highest rates of durable virologic response (96% and 86%, respectively) and the highest rate of HBsAg clearance (58% and 14%, respectively).¹⁰⁹ By contrast, the same end points were achieved, respectively, in only 76% and 6% of initial responders with genotype D. Unlike nucleos(t)ide analogs, IFN use is not associated with drug resistance.

The more rapid decline in HBsAg concentration during IFN treatment of both HBeAg-positive and HBeAg-negative hepatitis B (see earlier) is thought to reflect immune-mediated elimination of HBV cccDNA (the genomic template for viral transcription). These differences in viral kinetics emphasize that the mechanisms of action of the 2 major classes of antiviral agents differ and provides a rationale for the use of combined IFN and nucleoside analog therapy.

Combination Interferon and Nucleos(t)ide Analog Therapy

From a conceptual standpoint, treatment with the combination of IFN and a nucleos(t)ide analog may prove to be more effective than either drug alone and may permit a shorter course of nucleos(t)ide analog therapy, thereby reducing the risk of viral resistance to low-genetic-barrier drugs. Three large multicenter studies evaluated responses to a combination of pegylated IFN and lamivudine compared with IFN alone. Although suppression of HBV DNA was greater in the combined-therapy arms, the response was not sustained after discontinuation of treatment.^31,127,128 Trials of pegylated IFN combined with entecavir or tenofovir are in progress, as are studies in which sequential therapy, starting with a nucleos(t)ide analog, is given.¹²⁹ It is hoped that IFN combined with a high-genetic-barrier nucleos(t)ide analog given for a longer interval than previously reported may be a more effective approach than prior treatment regimens.

Guidelines

Consensus guidelines for the treatment of hepatitis B have been published by the AASLD, Asian-Pacific Association for the Study of the Liver, and European Association for the Study of the Liver.^102,130,131 The recommendations made in the 3 sets of published guidelines have many similarities. In general, they recommend treatment of persons who have both biochemical evidence of liver injury and serum HBV DNA levels in excess of 20,000 IU/mL in HBeAg-positive patients and greater than 2000 IU/mL in HBeAg-negative patients.¹³² Nucleos(t)ide analog therapy is recommended specifically as first-line treatment in patients with decompensated cirrhosis. Emphasis also is given to the treatment of patients with serum ALT levels that are at least double the upper limit of normal, although some experts disagree with setting arbitrary serum ALT and HBV DNA thresholds.¹³² The guidelines indicate that treatment decisions ideally should be made in the context of moderately severe disease (stage 2 or greater fibrosis). Liver biopsy is no longer mandated in the AASLD guidelines but is encouraged whenever doubt about the extent of disease exists. Noninvasive assessment of fibrosis, such as US (e.g., transient) elastography and MR elastography, can be helpful in situations in which a liver biopsy is either not possible or contraindicated (see Chapters 73, 74, and 80).¹³³

The guidelines recommend continuing treatment for 6 to 12 months after HBeAg seroconversion to minimize the chance of virologic relapse. Defining the duration of treatment remains an even greater challenge in patients with HBeAg-negative hepatitis because of the absence of secure virologic end points. It is worth noting that although the published treatment guidelines are helpful in assessing the need for treatment, their reliance on grade A evidence (randomized controlled clinical trials) has led to the absence of definitive recommendations in special patient populations for which the data have been less stringently acquired.

HBV infection may still develop in 5% to 10% of appropriately immunized newborns of HBV-infected mothers and may occur when vaccination is delayed or incomplete (see later). Preliminary studies have shown that infected spermatozoa or maternal oocytes are associated with HBsAg-expressing embryos.¹³⁴ Threatened preterm labor, premature rupture of maternal membranes, and detection of HBV in the placenta have also been linked to intrapartum transmission.¹³⁵

There are only 2 reasons to treat HBsAg-positive pregnant women: to forestall disease progression in the mother or to prevent breakthrough infection in newborns of highly viremic mothers. Epidemiologic studies have shown that HBeAg-positive mothers with a serum HBV DNA level greater than 10⁶ or 10⁸ copies/mL present a significantly higher risk of maternal transmission to the neonate even when properly immunized at birth.^136,137 Several studies, most of which were neither prospective nor randomized and controlled in design, have shown that treatment of such highly viremic mothers in the third trimester reduces the rate of neonatal breakthrough infection.¹³⁷ Many experts have recommended administering antiviral therapy during the last trimester and even continuing it for a brief period after delivery to avoid postpregnancy flares of disease caused by recovery of immunologic function.¹³⁸

None of the current antiviral agents is licensed for use in pregnancy. Telbivudine and tenofovir are considered category B drugs by the FDA (defined as a lack of animal embryologic toxicity without studies in humans). 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 exists for lamivudine in HIV-infected mothers, and there is increasing data on tenofovir (category B) in the U.S. Antiretroviral Pregnancy Registry.¹³⁹ Of the more than 10,000 reported pregnancies in which the mother received an oral nucleos(t)ide analog, 95% had HIV infection, and less than 1% had HBV monoinfection. Nevertheless, 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.

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 during treatment, however, the risk of drug withdrawal and subsequent ALT flares must be balanced against the slight uncertainty of harmful effects to the fetus. Figure 79-6 shows a proposed algorithm for the treatment of HBsAg-pregnant mothers with a high level of viremia. Because lamivudine has an excellent safety record and the most extensive use during pregnancy, its use can been recommended for highly viremic mothers. The risk of developing drug-resistant HBV can be anticipated to be small because of the need for short-term treatment. Telbivudine has also been used successfully during pregnancy to prevent neonatal infection from highly viremic HBeAg-positive mothers and has an FDA status B classification.¹³⁷ Tenofovir is another reasonable choice not only because of its category B status, but also because it is more potent than lamivudine or telbivudine. IFN is contraindicated during pregnancy because of its antiproliferative effects. Breast-feeding is not contraindicated in infants of HBsAg-positive women. Mothers who remain on a nucleos(t)ide analog after delivery, however, are advised not to breast-feed because of a small amount of maternal transfer of drug to the newborn.¹⁴⁰

Hepatitis B Immune Globulin

HBIG is prepared from plasma that is known to contain high titers of anti-HBs. Numerous clinical trials have established the efficacy of HBIG in preventing HBV infection in high-risk persons, such as hemodialysis patients, sexual partners of patients with hepatitis B, and newborn infants of HBsAg-positive mothers within 12 hours of birth along with simultaneous vaccination. HBIG licensed in the United States has an anti-HBs titer of 1 : 100,000. In Europe, several preparations of HBIG with different concentrations and pharmacokinetic properties are available. HBIG is safe, although rare anaphylactic reactions can occur. Myalgias, rash, and arthralgias have also been reported and are believed to result from formation of antigen-antibody complexes.

Hepatitis B Vaccine

Currently marketed HBV vaccines make use of recombinant DNA technology by introducing the gene for HBsAg (S gene) into the genome of yeast. The 2 vaccines available in the United States are Recombivax HB (Merck, licensed in 1986) and Engerix-B (GlaxoSmithKline, licensed by SmithKline Beecham in 1989). No serious side effects of the HBV vaccine have been reported. Aluminum hydroxide is used as an adjuvant in both vaccines. Because thimerosal, a preservative used in the vaccines, contains mercury, thimerosal-free vaccines have become available, especially for use in infants. The HBV vaccine is administered intramuscularly in the deltoid muscle of adults and the anterolateral thigh of infants and neonates. Because the vaccines contain HBsAg only, anti-HBs is the sole antibody produced. Consequently, vaccinees who test positive for anti-HBc after vaccination should be considered to have either resolved infection or active infection depending on the results of reflex testing for HBsAg.

The vaccines typically achieve an anti-HBs titer greater than 100 mIU/mL. Antibody titers greater than 100 mIU/mL confer 100% protection against HBV infection, and a lower antibody titer (up to 10 mIU/mL) is seroprotective in most instances. Peak antibody titers and persistence of antibody levels vary among different persons. The titers drop steadily over the first 2 years after vaccination, sometimes to levels less than 10 mIU/mL. Two studies in different populations have demonstrated that anti-HBs titers decrease to nonprotective levels in at least 25% to 50% of recipients over a period of 5 to 10 years.¹⁵⁰

Although protective anti-HBs response rates after HBV vaccination occur in approximately 90% of patients, a number of factors can impede an adequate antibody response. Smoking; obesity; injection into the buttock; chronic liver disease; presence of HLA-DR3, DR7, and DQ2 alleles; absence of the HLA-A2 allele; and extremes of age may be associated with reduced immunogenicity. Such “hyporesponders” may benefit from a higher dose of vaccine. Response rates are also lower in immunocompromised patients, such as transplant recipients, patients receiving chemotherapy, and those with end-stage liver disease. Only 50% to 60% of patients on hemodialysis respond adequately to vaccination. Therefore, patients with chronic kidney disease should be vaccinated early in the course of their disease, before renal disease progresses, to ensure optimal response to vaccination. Five percent to 8% of HBV vaccine recipients do not achieve detectable anti-HBs levels (“nonresponders”).

Because HBV vaccination results in strong immunologic memory capable of preventing infection even in patients with low or undetectable antibody titers, recommendations do not call for a booster vaccine dose in immunocompetent adults and children. Booster doses are, however, recommended for patients undergoing hemodialysis, in whom anti-HBs titers should be tested annually and a booster dose given if the titer is lower than 10 mIU/mL.¹⁵¹ Data from a study in Taiwan demonstrated a surprisingly high rate of HBsAg positivity in adolescents who were vaccinated at birth, especially those born to HBeAg-positive mothers who did not receive HBIG or had less than 4 doses of vaccine. The suggestion was made that a booster dose may be needed at age 15 or older in such highly exposed individuals.¹⁵² Confirmation of this finding would have important implications.