HBV is a partially double-stranded, partially single-stranded DNA virus (hepadnavirus type 1) that replicates via reverse transcription through an RNA intermediate. Although HBV is strongly hepatotropic, viral sequences, including HBV replicative intermediates, are present in extrahepatic tissues (lymph nodes, peripheral blood mononuclear cells); however, the vast bulk of—and the only pathophysiologically relevant—HBV replication is confined to the liver. The HBV genome contains four open reading frames that encode four major proteins: (1) the S gene, which codes for the envelope protein, hepatitis B surface antigen (HBsAg); (2) the C gene, which codes for the nucleocapsid proteins hepatitis B core antigen (HBcAg) and hepatitis B e antigen (HBeAg); (3) the P (or pol) gene, which codes for the DNA polymerase, which, in turn, catalyzes transcription and reverse transcription steps involved in viral replication; and (4) the X gene, which codes for the X protein, a protein of limited clinical relevance but which upregulates the transcription of host cellular and viral genes, including those of other viruses such as HIV.
The envelope protein of the virus, HBsAg, in serum is the primary marker of HBV infection. In the hepatocyte, HBsAg is expressed in the cytoplasm and can be recognized histologically by the presence of ground-glass hepatocytes. Eight HBV genotypes (A to H) have been identified; the prevalence of HBV genotype varies depending on geographic location. In the United States the prevalences of genotypes A, B, C, D, and others are 35%, 22%, 31%, 10%, and 2%, respectively. Recent data suggest that HBV genotypes may play an important role in progression of HBV-related liver disease as well as in response to interferon therapy. Similar associations have not been clarified definitively in patients treated with oral agents (nucleoside and nucleotide analogs); therefore, the testing of HBV genotype has not yet been adopted routinely as a prelude to antiviral therapy (see later discussion).
The C region has two initiation codons and therefore two gene transcripts (precore and core), the translation of which result in two protein products (HBeAg and HBcAg). HBcAg, the protein expressed on the 27-nm nucleocapsid core particles, is not secreted into serum but is localized predominantly to the hepatocyte nucleus and is expressed also in smaller quantities on the hepatocyte surface membrane. As such, HBcAg is the target of the host immune response to infection, playing an important role in the pathogenesis of HBV-induced liver damage. The other nucleocapsid protein, HBeAg, a low-molecular-weight nonparticulate protein, is encoded by the precore plus core region of the C gene, enters the secretory apparatus of the hepatocyte, and circulates in serum; the presence of HBeAg is indicative of active viral replication and correlates with increased infectivity and liver injury. The products of the same gene, HBcAg and HBeAg, have considerable amino acid homology and immune cross-reactivity at the T-cell level. Antibody to HBcAg (anti-HBc) appears at the onset of clinical hepatitis, shortly after the appearance of HBsAg, and may be the only marker detectable between the disappearance of HBsAg and the appearance of anti-HBs (less likely to be encountered now that the sensitivity of assays for HBsAg and anti-HBs are so high). During acute hepatitis B, anti-HBe appears as clinical symptoms, and aminotransferase levels are waning; its appearance marks a transition to lower viral replication, infectivity, and liver injury.
HBeAg-negative variants result from mutations in the precore region of the C gene, with failure of HBeAg synthesis (the serologic marker linked to active virus replication) yet with continued high-level viral replication and liver injury. "HBeAg-negative" mutant HBV has been associated with fulminant hepatitis (rarely) and chronic hepatitis (commonly).
Liver injury associated with HBV infection is the product of a combination of innate and adaptive immune responses, the latter of which are effected by cytotoxic T cells directed at liver membrane complexes of host histocompatibility antigens and HBcAg. The clinical outcome of HBV infection depends on the balance between viral activity and the host immune response, as reflected by the robustness of the CD8+ cytotoxic T-cell response and the release of antiviral T-cell cytokines; however, other than certain clinical features (eg, age, infection at birth, immunocompetence), what distinguishes those who recover from those who progress to chronic infection remains poorly defined. In perinatally acquired infection, immaturity of the neonatal immune system and the presence of HBV on hepatocytes shortly after birth combine to produce a level of immunologic tolerance to HBV that limits the adequacy of the host immune response to HBV. This state of immunologic tolerance can persist indefinitely. No robust cytotoxic T-cell response occurs against HBV, no clinical illness ensues, but chronic infection is almost invariable (>90%). In contrast, among young adults with acute hepatitis B, the cytotoxic T-cell response to HBV expressed on hepatocyte membranes is substantial and efficient, leading to an acute hepatitis illness and, typically, recovery; chronicity after clinically apparent acute hepatitis B in healthy, immunocompetent young adults occurs in fewer than 1% of cases.
Epidemiologically and clinically, chronic HBV infection is linked strongly to the development of hepatocellular carcinoma (HCC), which can occur in up to 50% of patients with HBV-induced cirrhosis following life-long infection acquired perinatally (see Chapter 49). The mechanism of viral oncogenesis has been studied extensively; viral integration into the host genome is required, but no consistent sites of integration have been identified (eg, adjacent to a host tumor promotor or suppressor gene). Cell turnover associated with chronic inflammation likely contributes to the pathogenesis of HCC, as do such cofactors such as alcohol use and environmental aflatoxin exposure.
Hepatitis B Virus Variants
Precore Mutants or HBeAg-Negative Chronic HBV
A precore nucleotide mutation or core-promoter mutation can lead to premature termination of the precore protein, preventing production of HBeAg. HBeAg-negative HBV is found more frequently in HBV genotypes other than genotype A, and its prevalence was concentrated initially in Mediterranean countries. Currently, HBeAg-negative chronic hepatitis B is the predominant form of chronic hepatitis B in Europe and represents a growing proportion (~40%) of chronic hepatitis B infections in the United States. Wild-type (HBeAg-positive) chronic hepatitis B is associated with higher levels of HBV replication (≥106 virions/mL) than HBeAg-negative chronic hepatitis B (≤105 virions/mL), whereas HBeAg-negative chronic hepatitis B is more likely to be associated with fluctuating levels of HBV DNA and aminotransferase activity. In addition, in HBeAg-negative chronic hepatitis B, patients treated with antiviral therapy (see later discussion) cannot experience treatment-induced HBeAg seroconversion, which, in HBeAg-positive chronic hepatitis B, can be used as a treatment end point. Therefore, the ideal duration of therapy remains undefined in HBeAg-negative chronic hepatitis B.
A mutation in the S gene has been reported in infants who are born to HBV-infected mothers but acquire HBV infection after vaccination and in liver transplant recipients who acquire breakthrough HBV reinfection despite treatment with hepatitis B immunoglobulin (HBIG). These mutations alter the antigenicity of the HBV envelope, evading neutralizing anti-HBs. Fortunately, the frequency of such mutations is limited.
Mutations in the polymerase gene are associated with resistance to HBV antiviral agents such as lamivudine, adefovir, and telbivudine (see later discussion).
The incubation period of acute hepatitis B is between 4 weeks and 6 months. Clinical symptoms are similar to those described earlier for acute hepatitis A (eg, fatigue, anorexia, jaundice), and aminotransferase elevations are the biochemical hallmark of illness. In 5–10% of patients with acute hepatitis B, a serum sickness-like syndrome with arthralgias, rash, angioedema, and, rarely, proteinuria and hematuria may develop in the prodromal phase. In children, hepatitis B may present rarely as anicteric hepatitis associated with a nonpruritic papular rash on the face, buttocks, and limbs (papular acrodermatitis of childhood).
Progression from acute to chronic hepatitis may be suggested by the persistence of anorexia, weight loss, and fatigue, although most patients with chronic hepatitis B are asymptomatic. Physical findings may include hepatomegaly and splenomegaly. Laboratory findings include persistence of HBsAg, detectable HBeAg in HBeAg-positive hepatitis, and elevations of aminotransferase, bilirubin, and globulin levels. Histologic features include the presence of portal inflammation, bridging or, in severe cases, multilobular hepatic necrosis, and the presence of fibrosis.
Many patients with chronic HBV infection are inactive carriers who have no symptoms, normal serum aminotransferase activity, low-level HBV DNA (≤103 virions/mL), circulating anti-HBe, and normal or near-normal liver histology.
Extrahepatic manifestations, when they occur, may include arthralgias, arthritis, Henoch-Schönlein purpura, generalized vasculitis (polyarteritis nodosa), glomerulonephritis, pleural effusions, pericarditis, and aplastic anemia (the latter not definitively linked to HBV infection, however). Uncommon complications of HBV infection include pancreatitis, myocarditis, atypical pneumonia, transverse myelitis, and peripheral neuropathy.
The diagnosis of HBV infection relies on the presence of HBsAg. Acute and chronic infections are distinguished by the presence of IgM versus IgG antibodies to HBcAg (anti-HBc). The presence of IgM anti-HBc indicates recent infection, generally within the previous 6 months. HBeAg appears early during acute hepatitis B, while viral replication is at peak levels, and in self-limited cases is replaced within 2–3 months by antibody to HBeAg (anti-HBe).
During chronic hepatitis B, in patients with wild-type HBV infection, the presence of HBeAg corresponds to a relatively highly replicative period, during which levels of HBV DNA exceed 106 virions/mL, infectivity is substantial, and liver injury is pronounced. Over time, this highly replicative phase gives way to a relatively low replicative phase, characterized by low-level HBV DNA (≤103 virions/mL) and negligible infectivity and liver injury. Patients in this phase are considered inactive carriers.
In patients with precore mutations (HBeAg-negative chronic hepatitis B), HBV DNA levels fluctuate between undetectable and approximately 105 virions/mL, and anti-HBe is detectable in serum. In chronic hepatitis B, anti-HBc is of the IgG class (except, rarely, during reactivation of chronic hepatitis B [eg, sero-reversion from anti-HBe-reactive back to HBeAg-reactive or during reactivation of clinically quiescent HBeAg-negative chronic hepatitis B], when IgM anti-HBc may reappear transiently). The presence of isolated anti-HBs is consistent with vaccine-induced immunity. Antibodies to both surface and core proteins (anti-HBs, anti-HBc, and anti-HBe) indicate prior HBV infection.
Interpretation of isolated IgG anti-HBc positivity is difficult and may represent ongoing, low-level HBV infection, prior HBV infection, or a false-positive test. Isolated anti-HBc with ongoing low-level HBV infection is more common in persons from high-prevalence areas, in persons with a history of injection drug use, and in patients with HIV infection.
In fulminant hepatitis B, intensive care in a specialized unit and early consideration for orthotopic liver transplantation likely reduces mortality. Only 25% of patients who have fulminant hepatitis B will survive without liver transplantation. Patients should be supported by maintaining fluid and electrolyte balance and cardiorespiratory function, controlling bleeding, treating prophylactically with broad-spectrum antibiotics, monitoring for cerebral edema, and managing other complications. Although antiviral treatment with interferon has not been shown to be of benefit in fulminant hepatitis B, treatment with oral nucleoside or nucleotide agents (described later) may be of benefit and would be recommended in most specialized treatment centers.
Corticosteroid therapy is not only ineffective but harmful, as demonstrated in clinical trials. Similarly, exchange transfusions, plasma perfusion, human cross-circulation, porcine liver cross-perfusion, and extracorporeal liver-assist devices have not been proven to be effective.
Orthotopic liver transplantation is being performed with increasing frequency, with excellent long-term results. Thus, patients should be supported maximally until spontaneous recovery or until prognostic factors indicate worsening outcome necessitating transplantation; the threshold for referring to a liver transplantation center should be very low. During and after transplantation, measures should be taken to prevent HBV infection of the graft (see later discussion).
The objectives of treatment for chronic hepatitis B are to suppress HBV replication and reduce liver injury. Among the end points of therapy are (1) profound reduction in circulating HBV DNA, preferably to levels undetectable by highly sensitive amplification assays; (2) in HBeAg-positive chronic hepatitis B, HBeAg seroconversion (loss of HBeAg and acquisition of anti-HBe); (3) normalization of ALT levels; (4) improvement in liver histology (reduction in the grade of necroinflammatory activity and limiting progression of, or even improving, the stage of fibrosis). Although not proven conclusively, data suggest that successful antiviral therapy has the potential to prevent or delay progression to cirrhosis, hepatic decompensation, and even HCC. Recommendations for patients with chronic hepatitis B who are candidates for treatment are summarized in Table 39–4; seven therapies are approved and currently available for treatment of chronic hepatitis B (Table 39–5).
Table 39–4. Recommendations for Treatment of Chronic Hepatitis B. ||Download (.pdf)
Table 39–4. Recommendations for Treatment of Chronic Hepatitis B.
|HBeAg||HBV DNA||ALT||Treatment Strategy|
|Positive||>20,000 IU/mL||≤2 × ULN|
Low efficacy of treatment
If ALT <ULN, observe
If ALT 1–2 × ULN:
• Consider biopsy for age >40 y, family history of HCC
• Treat if biopsy shows substantial inflammation or any fibrosis
|>20,000 IU/mL||>2 × ULN|
Treat with any of recommended agents
Of the oral antiviral agents, entecavir and tenofovir are favored over earlier-generation drugs with lower barriers to resistance; PEG IFN has supplanted standard IFN
Liver biopsy optional
|Negative||>20,000 IU/mL||>2 × ULN|
Treat with any of recommended agents
(Of the oral antiviral agents, entecavir and tenofovir are favored over earlier-generation drugs with lower barriers to resistance; PEG IFN has supplanted standard IFN)
Liver biopsy optional
|>2000 IU/mL||1–2 × ULN|
Treat if substantial inflammation or any fibrosis
Observe (inactive carrier)
Table 39–5. Approved Antiviral Therapy among Treatment-Naïve Patients with HBeAg-Positive Chronic Hepatitis B ||Download (.pdf)
Table 39–5. Approved Antiviral Therapy among Treatment-Naïve Patients with HBeAg-Positive Chronic Hepatitis B
|Resistance||None||None||∼14–32% year 1, ∼60–70% year 5||0% year 1, 29% year 5||0% year 1, 1.2% through year 5||5% year 1, 25% year 2||0% year 3, NA beyond year 3|
The first antiviral drug for hepatitis B, interferon-α2b (IFN-α), was approved by the U.S. Food and Drug Administration (FDA) in 1992. In patients with compensated chronic hepatitis B (including those with early cirrhosis), detectable HBeAg, and elevated aminotransferase activity, subcutaneous IFN-α injections of 10 million units three times per week or 5 million units daily for 16–24 weeks resulted in HBeAg loss in approximately 30% (along with suppression of HBV DNA to levels undetectable by relatively insensitive hybridization assays) and HBeAg seroconversion in approximately 18–20%. Patients with HBeAg-negative chronic hepatitis B should be treated for at least 12–24 months. In this early experience with interferon, almost 10% of HBeAg-reactive patients cleared HBsAg after their initial course of therapy; however, such high rates of HBsAg seroconversion have not been observed in more recent experiences. The strongest predictor of response to IFN-α in HBeAg-positive patients is a high pretreatment ALT level, but other factors favoring a response include a high histologic activity index, low HBV DNA level, and HBV genotypes A and B. Retreatment of nonresponders with a second course of IFN-α is unlikely to be of any clinical benefit.
In patients with HBeAg-negative hepatitis B, short courses of IFN-α are of little benefit and do not yield durable suppression of HBV DNA and ALT; in this patient group, long-term treatment (eg, 12–18 months) is preferable, but the durability of treatment effect is degraded over time to less than 20%, 5 years after therapy. Compensated cirrhotic patients respond as do patients with precirrhotic chronic hepatitis B; however, in decompensated cirrhosis, IFN-α may precipitate hepatic failure or be complicated by life-threatening infection or psychiatric effects and, therefore, is not recommended.
Side effects of interferon, which, in addition to the need for injection, are the major limitation to its use, include (1) flulike symptoms of fever, myalgias, fatigue, and headache; (2) marrow suppression (leukopenia, neutropenia, and thrombocytopenia); (3) anxiety, emotional lability, or depression; and (4) autoimmune disorders, primarily of the thyroid. IFN-α is accompanied by a flare in ALT in 30–40% of patients, and although flares are considered to be predictive of a favorable response, in patients with advanced or marginally compensated cirrhosis, an acute flare can precipitate decompensation.
Contraindications to IFN-α therapy include immune suppression or autoimmune disease, and severe, uncontrolled psychiatric disease or depression.
Before the availability of newer antiviral agents, IFN-α was considered a good therapeutic choice for patients with mild liver disease, low levels of HBV replication, and high serum aminotransferase levels. Some authorities recommend interferon-based therapy for young persons, based on the assumption that an approximately 30% chance of HBeAg loss with a time-confined course of therapy might be preferable for a young person to indefinite therapy with an oral agent (see later discussion). An equally compelling argument might be made to spare a young person the inconvenience and side effects of IFN-α therapy in favor of a side effect–free oral agent, which might require an extra half year to a year to achieve the same benefit as a course of IFN-α.
For all practical purposes, IFN-α as been supplanted by long-acting, once-weekly pegylated interferon for those favoring interferon therapy and by the several highly potent polymerase inhibitors for those who favor oral agents. What early studies of IFN-α have shown is that successful antiviral therapy can improve the natural history of chronic hepatitis B, improving survival and complication-free survival.
Pegylated Interferon Alfa (Peg IFN-α)
Pegylated interferons are produced by binding of a large, inert polyethylene glycol moiety to the interferon molecule, thus increasing the molecular weight of the compound, decreasing its renal clearance, altering its metabolic degradation, and increasing its half-life. Therefore, pegylated interferons can be administered by subcutaneous injection once weekly.
PEG IFN-α2a is the only pegylated interferon approved for the treatment of chronic hepatitis B in the United States. Clinical trials have demonstrated that the efficacy of PEG IFN-α2a is similar to or slightly better than that of standard IFN-α, in addition to its more convenient administration. For HBeAg-positive patients, the most definitive trial represented a comparison of 48 weeks of PEG IFN-α2a alone, versus lamivudine alone, versus combination therapy. During the 48 weeks of therapy, the level of HBV DNA suppression was highest in the combination-treatment arm, and HBeAg seroconversion occurred in a similar percentage of the three groups: 27%, 20%, and 24%, respectively. Twenty-four weeks after treatment was stopped, however, seroconversion was maintained in 32%, 19%, and 27% of the three groups, respectively, indicating that 48 weeks of PEG IFN-α2a monotherapy was superior to 48 weeks of lamivudine monotherapy as well as 48 weeks of combination therapy. In a study of HBeAg-negative patients, PEG IFN-α2a monotherapy was compared with lamivudine monotherapy versus combination therapy for 48 weeks; a sustained response, defined as suppression of HBV DNA to below 105 copies/mL or to undetectable by polymerase chain reaction (PCR) amplification (102 copies/mL) and a return to normal of ALT, was comparable in patients who received PEG IFN-α2a alone or in combination with lamivudine (100 mg), which were both better than lamivudine alone. In both HBeAg-reactive and HBeAg-negative studies, a small proportion of PEG IFN-α2a-treated study subjects experienced HBsAg seroconversion during (in the HBeAg-negative trial) or after (in the HBeAg-positive trial) therapy. Side effects and predictors of treatment response are similar to those of standard IFN-α therapy, but PEG IFN-α2a is better tolerated by most subjects.
Although some patients may choose a year of PEG IFN-α2a therapy, such therapy requires a year of weekly injections and clinically intense monitoring as well as willingness to accept interferon side effects. In these trials of PEG IFN-α2a, treatment was confined to a finite, 48-week period, which is typical of the way PEG IFN-α2a is used but not the way oral agents are used. Instead, oral agents, very well tolerated, are administered for longer periods (eg, until after HBeAg seroconversion or to maintain responsiveness in HBeAg-negative patients). In fact, the same HBeAg seroconversion rates achieved with 48 weeks of PEG IFN-α2a injection therapy occur when oral agent therapy is extended to 18–24 months. In addition, suppression of HBV DNA and ALT after interferon-based therapy in HBeAg-negative patients is lost gradually over time in the vast majority of patients. Therefore, the advantages of a year of PEG IFN-α2a therapy may be outweighed by the advantages of slightly longer treatment with substantially better tolerated oral agents. The recommended dose of PEG IFN-α2a is 180 mcg weekly for 48 weeks.
Lamivudine, an oral nucleoside analog that inhibits viral DNA synthesis by blocking reverse transcriptase and that is cleared renally, was approved by the FDA originally for the treatment of HIV (150 mg daily) in 1995 and then for the treatment of hepatitis B (100 mg daily) in 1998.
Several large, randomized controlled trials of HBeAg-positive patients treated for 1 year documented HBeAg seroconversion (with suppression of HBV DNA to undetectable levels as determined by insensitive hybridization assays) in 16–20% of treated patients (HBeAg loss in up to a third) compared with 4–6% spontaneous seroconversion in control subjects. Furthermore, loss of detectable HBV DNA occurs in the majority of patients, normalization of ALT in ≥50% of patients, and improvement in necroinflammatory histology scores in 49–56% of patients compared with 23–25% of control subjects. Recent studies in which lamivudine was the comparator arm for new oral nucleoside analogs, demonstrated that lamivudine suppresses HBV DNA by approximately 5.5 log10 copies/mL. Reductions in the progression of fibrosis and progression to cirrhosis have also been demonstrated. After HBeAg seroconversion, this serologic status is maintained in approximately 80% of patients as long as a period of consolidation therapy follows the seroconversion (at least 6 months in Western patients, longer in Asian patients). For patients who do not achieve HBeAg seroconversion during the first year of therapy, HBeAg seroconversion rates increase with extended courses of therapy, but the optimal duration of treatment with lamivudine, as with other oral agents, remains to be defined.
In HBeAg-negative patients, lamivudine suppresses HBV DNA by approximately 4.5 log10 copies/mL, suppresses HBV DNA to undetectable levels (as determined by sensitive amplification assays) in approximately 70%, and reduces ALT to normal in approximately 75%. When therapy is discontinued, however, generally, the therapeutic effect is lost as HBV DNA and ALT return to baseline levels. Therefore, almost all HBeAg-negative patients and the majority of HBeAg-positive patients require extension of therapy indefinitely beyond the first year.
Lamivudine is safe to use in patients with cirrhosis. Clinical trials have demonstrated that lamivudine therapy for several years can reverse cirrhosis and that, unlike interferon, this drug can be used in patients with hepatic decompensation, salvaging them from a further decline and leading to reversal of decompensation. In addition, a prospective trial of lamivudine versus placebo in compensated patients with advanced fibrosis and cirrhosis demonstrated the principle that such antiviral therapy can prevent the incidence over time of hepatic decompensation; in this important study, a trend was apparent in the prevention of, or delay in, the development of HCC.
Selection of lamivudine-resistant mutations is the main concern with lamivudine monotherapy. Genotypic resistance can be detected in 14–32% of patients after 1 year of lamivudine treatment and increases to 60–70% after 5 years of treatment. The most common mutation involves substitution of methionine for valine or isoleucine in the tyrosine-methionine-aspartate-aspartate (YMDD) motif of the HBV DNA polymerase. Factors associated with resistance include long duration of treatment, high pretreatment serum HBV DNA, and, most importantly, high levels of residual virus (>103–104 virions/mL) after initiation of treatment. Although in vitro the YMDD mutation actually decreases replication fitness of HBV, compensatory mutations restore the fitness of mutant HBV, and clinical benefit is lost eventually after lamivudine resistance emerges. Lamivudine resistance is usually detected by virologic breakthrough followed by biochemical breakthrough and, in some patients, can be associated with an acute exacerbation of hepatitis or, in marginally compensated cirrhotics, with hepatic decompensation.
Most patients with confirmed lamivudine resistance should receive rescue therapy with antiviral agents, such as adefovir or the now favored tenofovir, that are effective against lamivudine-resistant HBV mutants. When adefovir or tenofovir is used to treat patients with lamivudine resistance, the new drug should be added to lamivudine therapy; for example, switching to adefovir monotherapy renders the patient susceptible ultimately to adefovir resistance.
Because of the need for long lamivudine treatment courses in most patients, because of its low barrier to resistance, and because its efficacy is inferior to that of later-generation antivirals, lamivudine is no longer a first-line treatment for chronic HBV; now that more potent, less resistance-prone antiviral agents are available, lamivudine, despite its established safety, has been supplanted as an antiviral agent for hepatitis B.
Adefovir is a nucleotide analog of adenosine monophosphate that can inhibit both reverse transcriptase and DNA polymerase activity and is incorporated into HBV DNA, resulting in chain termination. Adefovir is effective in suppressing wild-type HBV as well as lamivudine-resistant HBV. The recommended dose for adults with normal renal function is 10 mg orally daily. Adefovir has been shown to produce a histologic response in 53% of HBeAg-positive patients versus 25% of placebo recipients after 48 weeks of therapy, HBeAg seroconversion in 12% of patients versus 6% of placebo recipients, a 3.5 log10 copies/mL decrease in HBV DNA in patients versus 0.6 log10 copies/mL in placebo recipients, and normalization of ALT levels in 48% of patients versus 16% of placebo recipients. Approximately 30% of patients with no prior nucleotide analog treatment have a primary nonresponse to adefovir (<2 log10 drop in HBV DNA after 6 months of treatment), and in approximately half of adefovir-treated patients, the antiviral response is slow. This suboptimal profile, which reduced the appeal of adefovir initially, led to its replacement by tenofovir (see below) when the newer agent became available.
In HBeAg-negative patients, suppression of HBV DNA, normalization of ALT, and histologic improvement occur as well, but the therapeutic effect is lost once the drug is stopped. Thus, as is the case for therapy with other oral agents, in HBeAg-negative patients, continued treatment is needed to maintain the antiviral response. In HBeAg-negative patients who have completed 5 years of adefovir treatment, HBV DNA was undetectable in 67% and ALT was normal in 69%.
Adefovir has been shown to be effective in liver allograft recipients and in HIV-HBV coinfected patients as well as in lamivudine-resistant HBV. Adefovir resistance occurs at a slower rate than with lamivudine treatment; the cumulative probabilities of genotypic resistance to adefovir at 1, 2, 3, 4, and 5 years have been reported to be 0%, 3%, 11%, 18%, and 29%, respectively, in HBeAg-negative patients (data in HBeAg-reactive patients are not available). As previously mentioned, in patients with lamivudine-resistant HBV, if adefovir is used, lamivudine should not be switched to adefovir; instead, adefovir should be added to lamivudine therapy.
Entecavir, a carbocyclic analog of 2′-deoxyguanosine, inhibits HBV replication at three steps: priming of the HBV polymerase, reverse transcription of the negative-strand HBV DNA from the pregenomic RNA, and synthesis of the positive-strand HBV DNA. Entecavir, which suppresses HBV DNA by almost 7 log10 copies/mL in HBeAg-positive patients (5.2 log10 copies/mL in HBeAg-negative patients), is more potent than lamivudine and adefovir and, although cross-resistance occurs between entecavir and other L-nucleosides, has such a low median effective concentration in vitro that in vivo levels of drug are sufficient to be effective against lamivudine-resistant HBV. Like other L-nucleosides, entecavir is effective against adefovir-resistant HBV mutants as well. The approved oral daily dose of entecavir is 0.5 mg for treatment-naïve patients but 1.0 mg for lamivudine-resistant patients.
In HBeAg-positive patients, after 48 weeks of treatment, when compared with lamivudine, entecavir had significantly higher rates of histologic (72% vs 62%), virologic (67% vs 36% undetectable HBV DNA by highly sensitive amplification assay), and biochemical (68% vs 60% with normal ALT) responses. Among HBeAg-positive patients who underwent HBeAg seroconversion during the first year (21%) and who stopped treatment at 48 weeks, 70% remained HBeAg negative. In HBeAg-negative patients, similar rates of histologic, virologic, and biochemical improvement have been seen; however, the majority of patients relapse if treatment is stopped after 1 year.
Entecavir has a very high barrier to resistance; in nucleoside-naïve patients, entecavir resistance has not been encountered during the first year of therapy and has emerged in 1.2% of patients through year 5. In lamivudine-resistant patients, however, entecavir resistance was observed in 7% of patients at 1 year, 16% of patients at 2 years, and 51% of patients after 5 years. Therefore, although entecavir is favored above other L-nucleosides for treatment of previously untreated patients, entecavir is not recommended and should not be used as replacement therapy for lamivudine-resistant hepatitis B, FDA approval for this indication notwithstanding.
Telbivudine is an L-nucleoside analog that was shown in clinical trials to be more potent than lamivudine in suppressing HBV replication. The approved dosage of telbivudine is 600 mg orally daily.
In HBeAg-positive patients, HBV DNA was undetectable in 60% of telbivudine recipients versus 40% of lamivudine recipients after 1 year and in 54% versus 8% after 2 years. Patients taking telbivudine also had significantly higher rates of normal ALT after 1 and 2 years of treatment compared with those taking lamivudine; however, as was true for entecavir, despite the substantially higher potency of telbivudine over lamivudine in suppressing HBV DNA, no difference was observed between telbivudine and lamivudine recipients in the rate of HBeAg seroconversion at the end of 1 and 2 years of treatment. In HBeAg-negative patients, telbivudine was superior to lamivudine in treatment measures by the same degree that entecavir exceeded lamivudine.
Unfortunately, telbivudine is associated with substantial resistance, and telbivudine-resistant mutations are cross-resistant with lamivudine. Like lamivudine, telbivudine selects for YMDD mutations, and genotypic resistance was observed in 5% and 25%% of HBeAg-positive patients after 1 and 2 years of therapy, respectively, and in 2.3% and 10.8% of HBeAg-negative patients after 1 and 2 years. Although one of the more (albeit not the most) potent HBV DNA inhibitors, telbivudine has a disappointing resistance profile and, therefore, does not have a role in monotherapy for HBV infection; it is not favored as first-line therapy.
Tenofovir Disoproxil Fumarate
Tenofovir is a nucleotide analogue, structurally similar to adefovir that was first approved for the treatment of HIV infection either alone or in combination with emtricitabine as a single pill. Tenofovir was approved for treatment of chronic hepatitis B in 2008. The approved oral dose of tenofovir for chronic hepatitis B treatment is 300 mg daily, although adjustments must be made for creatinine clearance <50 mL/min (as is true for other oral antiviral agents for hepatitis B).
In HBeAg-positive chronic hepatitis B, after 48 weeks of treatment, patients on tenofovir, when compared to patients treated with adefovir, had significantly higher rates of virologic (76% versus 13% undetectable HBV DNA), biochemical (74% versus 68% ALT normalization), and HBsAg loss (3% versus 0%), with similar rates of histologic response (74% versus 68%) and HBeAg seroconversion (21% versus 18%). In HBeAg-negative chronic hepatitis B, after 48 weeks of treatment, patients treated with tenofovir, when compared to those treated with adefovir, were more likely to experience suppression of HBV DNA to undetectable levels (93% versus 63%); however, biochemical and histologic reponses were similar in the two groups. Three percent of HBeAg-reactive patients treated with tenofovir for 1 year lost HBsAg; in HBeAg-negative patients, none lost HBsAg
Adefovir and tenofovir are cross-resistant. In the two principal phase-III clinical trials of tenofovir, 7 patients had virologic breakthrough during the first 2 year of treatment but had no detectable tenofovir-resistant mutations. In these large tenofovir trials, anyone who had persistent detection of serum HBV DNA at week 72 received additional treatment with emtricitabine; therefore data on resistance to tenofovir monotherapy beyond 72 weeks are limited; still, in the original cohorts followed after phase-III trials, resistance has not been encountered through year 3 of monitoring. Given its potency and limited resistance profile, the approval of tenofovir in 2008 provided a welcome, equally potent alternative to entecavir, particularly as first-line treatment of chronic hepatitis B in patients with lamivudine resistance. Currently, both entecavir and tenofovir are considered first-line oral treatments for chronic hepatitis B.
Other therapies currently being considered for approval for the treatment of HBV infection include emtricitabine (very similar to lamivudine in structure, potency/efficacy, and resistance profile) and combination therapies. A combination of emtricitabine and tenofovir, licensed for treatment of HIV infection, has the potential advantage of combination, non-cross-resistant L-nucleoside and nucleotide analog therapy. As patients begin to appear—in minuscule numbers to date—with mutations to both classes of these oral antiviral agents, interest in this combination and other combinations that can preempt the emergence of antiviral resistance will attract attention and be studied in clinical trials. To date, no advantage has been found for combinations of IFN-α or PEG IFN-α and oral agents.
Response rates to standard IFN-α are lower in patients with HBV-HIV coinfection. Lamivudine, emtricitabine (available currently only as a combination pill with tenofovir), and tenofovir are all nucleoside analogs with activity against both HIV and HBV; however, the rate of HBV resistance to lamivudine in HBV-HIV coinfected patients approaches 90% at 4 years. Given that antiretroviral regimens may include drugs with activity against HBV and that almost any oral regimen selected will include an agent with activity against HIV, clinicians should choose a combination antiviral regimen for HBV infection, regardless of whether or not HIV treatment is ongoing or planned. Entecavir was thought initially to have no anti-HIV activity and was considered a potential monotherapy for HBV-HIV coinfected patients not receiving HAART; however, eventually, entecavir was found to have modest activity against HIV, contraindicating its use (because of the potential for early emergence of HIV resistance) as monotherapy in patients with HIV-HBV coinfection who are not receiving HAART. To reiterate, then, in HBV-HIV coinfected patients combination antiviral therapy is the recommended choice for treating hepatitis B.
Refer to the later discussion of hepatitis D.
Limited information is available to guide treatment in this setting. Often, such patients have relatively nonreplicative chronic hepatitis B and need to be treated for hepatitis C. When both viruses need to be treated, PEG IFN-α (with ribavirin for hepatitis C) can be used to address both infections; alternatively, both diseases can be treated independently with PEG IFN-α plus ribavirin for hepatitis C and one of the oral agents for hepatitis B. Generally, antiviral therapy for hepatitis C in HCV-HBV coinfected patients yields sustained virologic responses similar to those achieved in patients being treated for HCV alone; however, suppression of HCV replication has been reported, rarely, to result in rebound replication of HBV.
Immunosuppressive, Cytotoxic, or Immunomodulatory Chemotherapy
Approximately 20–50% of patients with chronic hepatitis B, including inactive carriers, have been reported to have reactivation of HBV replication associated with immunosuppressive, cytotoxic (especially if the regimen includes high-dose corticosteroids), or immunomodulatory (anticytokine) chemotherapy. This event occurs primarily as chemotherapy is withdrawn and cytolytic immune responsiveness recovers. Subclinical as well as clinically severe, even fatal, reactivations can occur, reflected initially by increases in serum HBV DNA and ALT. Prophylactic antiviral therapy should be administered to such patients with chronic hepatitis B at the onset of chemotherapy and should be maintained for at least 6 months afterward; in fact, the duration of treatment is not known, and, in some cases, discontinuing therapy proves difficult. Most of the reported experience in this setting involves lamivudine, but entecavir, similar to lamivudine in its rapid onset of action and freedom from nephrotoxicity, has also been reported to be effective as preemptive therapy to prevent chemotherapy-associated reactivation of hepatitis B and represents an appealing alternative.
Liver transplantation is currently a successful therapy for end-stage chronic HBV-associated liver disease. Even with the 30% reduction in patients placed on the liver-transplantation waiting list in the decade following the introduction of oral antiviral therapy for hepatitis B, hepatitis B remains the seventh-most-common indication for liver transplantation in the United States, comprising about 4–5% of cases. Until the early 1990s, transplantation resulted in an 80% rate of reinfection in the absence of prophylaxis. The resulting hepatitis could be severe and was almost invariably chronic. The risk of reinfection was higher in patients with chronic liver disease versus fulminant disease and lower in those with HBV-HDV coinfection than in those with HBV infection alone. The introduction in 1993 of high-dose hepatitis B immunoglobulin (HBIG) perioperatively and postoperatively, combined with approval of lamivudine in 1998 for treatment of hepatitis B, has reduced graft infection rates to less than 5% in patients who receive both HBIG and a nucleoside analog posttransplantation. Given the need for long-term therapy and both the risk and consequences of lamivudine resistance in organ allograft recipients, newer drugs with higher barriers to resistance (eg, entecavir or tenofovir) and especially those with potent antiviral activity and limited nephrotoxicity (eg, entecavir) are favored first-line treatment to prevent recurrent HBV infection posttransplantation.
Disadvantages of prolonged HBIG use include cost, patient inconvenience, and intolerability. In some centers, switching from intravenous HBIG to intramuscular HBIG has been successful and associated with enhanced convenience and tolerability. No clear guideline exists for the duration of HBIG treatment post-transplantation; however, the risk of HBV reinfection was found to be negligible when HBIG was discontinued after 2 years and followed with continued use of a maintenance nucleoside or nucleotide analog treatment.
Patients who have undergone liver transplantation for HBV or HBV-HDV coinfection should have HBV DNA or HDV RNA, or both, followed every 3 months. Studies of combination nucleoside-nucleotide therapy after liver transplantation continue.
For neonates born to infected mothers and any person with a percutaneous or sexual exposure, HBIG is available and is helpful to achieve immediate high-level circulating anti-HBs (passive immunization). Simultaneously, active immunization with hepatitis B vaccine should be administered as well.
Ninety-five to 99% of healthy, immunocompetent young adult patients with clinically apparent acute HBV infection have a favorable course and recover completely. The case fatality rate is low (0.1%) but increases with age and associated comorbid systemic illnesses (eg, diabetes mellitus, congestive heart failure). The risk of chronicity is related to the age of acquisition (>90% in newborns, ~50% in young children, and 1–5% in immunocompetent adults). In addition, chronicity is more likely (>50%) in immunocompromised adults such as transplant-organ recipients, HIV-positive persons, and patients undergoing cytotoxic chemotherapy. Chronically infected patients may be inactive carriers or may have chronic hepatitis with or without cirrhosis.
Hepatitis B accounts for approximately half of all cases of fulminant viral hepatitis (see Chapter 38). The diagnosis is suggested by rising bilirubin, an increasing prothrombin time (INR), and signs of encephalopathy. Cerebral edema is common, and death usually results from a combination of brainstem compression, gastrointestinal bleeding, sepsis, respiratory failure, cardiovascular collapse, and renal failure. Survivors have complete biochemical and histologic recovery.
Patients with chronic hepatitis B, with or without HBeAg, who have highly replicative HBV infection are likely to experience the negative consequences of chronic infection, cirrhosis, hepatic decompensation, and HCC; indeed, patients with high-level HBV DNA are more likely to progress to cirrhosis and HCC than those with low-level HBV DNA, while relatively nonreplicative inactive carriers are less likely to progress to cirrhosis or to have HCC. In turn, patients with high-level HBV replication tend to progress histologically, and those with more advanced histologic stage have a worse prognosis. In one natural-history study, patients with cirrhosis had a 5-year survival of only 55% and a 15-year survival of only 40%.
Hepatitis B is a major risk factor for HCC. In HBV-endemic regions, HCC is the leading cause of cancer-related death. Cirrhosis is present in 70–80% of HBV-related HCC, and the chronic inflammation and regenerative cellular proliferation associated with cirrhosis may predispose to cellular transformation and malignancy. A proportion of patients with HBV-associated HCC, up to 20–30% in some series, do not have cirrhosis, contrasting with hepatitis C-associated HCC, almost all of which occurs in cirrhotic patients. In otherwise healthy, inactive hepatitis B carriers, the HCC incidence is 0.06–0.3% per year; in patients with chronic hepatitis, the annual incidence is 0.5–0.8%; and in those with cirrhosis, the rate of HCC is 1.5–6.6% per year. The cumulative risk of HCC almost doubles over 15 years in patients with high-level HBV DNA compared with those who have low-level HBV DNA. Furthermore, the risk of HCC is also significantly higher among men and older patients as well as in patients with a family history of HCC, a history of serologic reversion from anti-HBe to HBeAg, HBV genotype C, and coinfection with HCV. Population- and clinic-based screening programs that rely on serum α-fetoprotein (AFP) and liver imaging (primarily ultrasound) have led to identification of patients with small and potentially resectable tumors. Despite achieving earlier detection of HCC, however, such screening programs have not been shown to reduce mortality resulting from HCC (see Chapter 49). Furthermore, because of the nonspecificity of AFP elevations in chronic viral hepatitis, AFP screening is no longer recommended as part of HCC surveillance.
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