•Abstract
Chronic hepatitis B is a common disease worldwide with significant morbidity and mortality. Early diagnosis is essential but
difficult, as most patients with chronic hepatitis B do not have specific symptoms until the symptoms of advanced disease
occur. The main goal of therapy is to prevent cirrhosis and hepatocellular carcinoma by suppressing hepatitis B virus (HBV)
DNA levels. The decision to treat and the choice of therapy require careful consideration of both patient and drug characteristics,
as stated in both an expert panel consensus recommendation and the American Association for the Study of Liver Diseases (AASLD)
treatment guidelines. Lamivudine, once the mainstay of oral antiviral treatment, has been supplanted by newer agents such as adefovir, entecavir, and telbivudine, which produce less drug resistance overall; these oral agents often require
long-term treatment. Pegylated interferon alfa-2a, which has a predefined treatment course but is often poorly tolerated,
is now the main option in interferon-based therapy, replacing interferon alfa-2b. The goal in the development of future therapies
is to improve effectiveness, lengthen the duration of response, and lessen resistance. (Formulary. 2007;42:429–438.)
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Hepatitis B virus (HBV) infection is a global public health problem that affects approximately 350 million people worldwide,
including 1.25 million people in the United States.1,2 All HBV genotypes (A–H) are found in the United States; genotypes A, B, and C are the most prevalent (35%, 22%, and 31%,
respectively).3 Active hepatitis, cirrhosis, and hepatocellular carcinoma develop in 15% to 40% of HBV carriers, leading to >1 million deaths
per year.4 The World Health Organization (WHO) now lists hepatitis B as the tenth-leading cause of death worldwide.5
Table1 Pharmacologic agents for the treatment of chronic hepatitis B
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HBV is transmitted through blood and bodily fluids.6 Vertical transmission from mother to neonate is the most common mode of transmission in highly endemic areas such as Asia,
Africa, and the Middle East. In the United States and other low-prevalence areas such as Australia, Western Europe, and much
of South America, the primary mode of transmission is horizontal transmission via unprotected sexual intercourse or intravenous
drug use with shared equipment.
The natural history of hepatitis B depends on the age of the patient at infection.7 Most children who acquire the virus perinatally do not clear the virus and develop chronic hepatitis B. Most of these children
experience an immune-tolerant phase in which the disease is present but clinically silent, resulting in normal alanine aminotransaminase
(ALT) levels until adulthood. Immunocompetent adults who acquire acute hepatitis B often clear the virus, except for 3% to
5% who develop chronic hepatitis B.7 The risk of developing chronic hepatitis B is elevated in immunocompromised patients.8
Chronic hepatitis B is often asymptomatic, but nonspecific symptoms of fatigue and anorexia/weight loss may be present. Extrahepatic
manifestations are less common and may include arthralgias, purpura, angioedema, and, rarely, vasculitis.9 Patients who develop cirrhosis may develop decompensated liver disease, which may present as jaundice, abdominal distention
from ascites, peripheral edema, renal insufficiency, easy bruising and bleeding, confusion, and gastrointestinal varices.
Because most patients with chronic hepatitis B do not have specific symptoms until the symptoms of advanced disease occur,
diagnosis is difficult; however, early diagnosis is essential to ensure favorable treatment outcomes. Diagnosis of chronic
hepatitis B is made when serum hepatitis B surface antigen (HBsAg) remains positive for >6 months and serum HBV DNA is present.10 Hepatitis B e antigen (HBeAg) is usually positive, but the absence of HBeAg does not preclude the diagnosis, as precore
and core promoter mutants suppress expression of HBeAg even as HBV replication occurs. ALT levels are often elevated but may
fluctuate over time.
In the setting of chronic hepatitis B, HBeAg may convert from positive to negative (HBeAg clearance), a process that is often
accompanied by the development of antibodies to HBeAg (HBeAg seroconversion), reduction in HBV DNA, and normalization of ALT
levels.1,11 These events may occur spontaneously or as a result of treatment and usually signal the onset of an inactive HBsAg carrier
state. Occasionally, HBeAg is cleared but HBV DNA and ALT levels are intermittently or persistently elevated, which implies
the development of precore or core promoter mutants and continued chronic active hepatitis B with HBV replication (HBeAg-negative
chronic hepatitis B).
Over time, chronic hepatitis B may lead to progressive liver fibrosis and cirrhosis or hepatocellular carcinoma, with resulting
morbidity and increased mortality.12 The HBV DNA levels and the presence of HBeAg are markers for HBV replication and active disease.
PHARMACOLOGIC TREATMENT AGENTS
The goals of anti-HBV therapy are 1) reduction of HBV DNA levels to as low as possible for as long as possible and 2) induction
of HBeAg clearance and HBeAg seroconversion to reduce the risk of fibrosis, cirrhosis, liver failure, hepatocellular carcinoma,
liver transplantation, and death.12 Suppression or clearance of HBV DNA is now considered the priority in treating hepatitis B, with HBeAg seroconversion as
a secondary goal. Other indicators of response include improvement in inflammation on liver histology and normalization of
ALT levels.
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Six drugs are currently approved by FDA for the treatment of chronic hepatitis B and are reviewed in Table 1 in chronological
order of approval.12–22 Interferon alfa-2b and pegylated interferon alfa-2a are injectable agents that have antiviral and immunomodulatory effects.
Lamivudine, adefovir, entecavir, and telbivudine are oral antiviral agents that are nucleoside or nucleotide analogues. Data from trials focusing on chronic hepatitis
B with complications of cirrhosis, liver failure, hepatocellular carcinoma, or liver transplantation are not included in this
review. Likewise, the treatment of chronic hepatitis B in special populations, such as patients with HIV co-infection, pregnant
patients, and pediatric patients, is beyond the scope of this review.
Older studies of these agents for the treatment of chronic hepatitis B used nonamplified laboratory assays to detect the presence
of HBV; the lower limit of HBV detection with these assays was 100,000 copies/mL. Newer, amplified polymerase chain reaction
(PCR)-based assays now can detect as few as 50 copies/mL.23 These newer techniques also allow better quantitation of HBV DNA reduction; as a result, trials now often report log10 reduction as a measure of therapeutic response. End points are usually reported at the 1-year mark for the purposes of FDA
approval and drug comparison, although the more established drugs have been studied for longer follow-up periods.
Most studies of these approved agents have enrolled patients with chronic hepatitis B who are HBeAg positive, but there is
a growing body of literature on patients with HBeAg-negative chronic hepatitis B. These patients have more advanced liver
disease and lower rates of spontaneous remission.24 Treatment end points for patients with HBeAg-negative chronic hepatitis B are more difficult to assess, as HBeAg status
cannot be monitored. Thus, it is difficult to determine an optimal treatment stopping point for these patients.
Interferon alfa-2b. Interferon alfa-2b was the first FDA-approved treatment for chronic hepatitis B. The glycoprotein has direct antiviral effects
and enhances immune response to viruses. The recommended dosage is 5 million units (MU)/d subcutaneously (SC) or intramuscularly
(IM) or 10 MU 3 times/wk SC or IM for ≥16 weeks in patients with HBeAg-positive chronic hepatitis B.20
Wong et al25 reviewed the efficacy of interferon alfa-2b in a meta-analysis of 15 randomized, controlled trials involving 837 patients
who were administered a 3- to 6-month treatment course of varying doses SC or IM and followed for 6 to 12 months after therapy.
At 12 months, HBV DNA was suppressed to <100,000 copies/mL in 37% of patients treated with interferon alfa-2b compared with
17% of those administered placebo. At follow-up, HBeAg clearance had occurred in 33% of patients treated with interferon alfa-2b
versus 12% of patients administered placebo, with subsequent HBeAg seroconversion in 18% of patients treated with interferon
alfa-2b. Seroconversion was well maintained in 80% to 90% of these patients during long-term follow-up of 4 to 8 years.26,27 During the treatment course or within 6 to 12 months of follow-up, actual elimination of HBsAg, representing a hepatitis
B "cure," occurred in 8% of patients treated with interferon alfa-2b and in 2% of patients administered placebo.25 Histologic improvement could not be compared between the 2 groups because of insufficient data.
In 4 randomized, controlled trials enrolling more than 150 patients with HBeAg-negative chronic hepatitis B, treatment with
3 to 5 MU of interferon alfa-2b administered SC or IM 3 times/wk resulted in HBV DNA suppression to <100,000 copies/mL in
40% to 90% of patients at the end of 6 to 12 months of treatment, but this result was counteracted by a high relapse rate,
leading to sustained response in only 24% of patients.10 Among those patients who achieved sustained viral response, approximately 30% eliminated HBsAg.
Interferon alfa-2b has been demonstrated to improve clinical outcomes in patients with chronic hepatitis B. Successful treatment with interferon alfa-2b manifests as
HBeAg clearance, reduced liver-specific complications, and reduced mortality.28 In a study by Lin et al,29 treatment with 4 to 6 MU/m2 of interferon alfa-2b administered IM reduced the incidence of hepatocellular carcinoma to 1.5% versus 12% in the untreated
group.
Unlike treatment with the more recently approved oral agents, treatment with interferon alfa-2b does not result in the development
of resistant HBV mutants. However, the frequency and severity of adverse effects, including flu-like symptoms (fever, chills,
myalgias, arthralgias, headache, and fatigue), anorexia/weight loss, depression, and bone marrow suppression may result in
poor tolerance to this agent.25 As a result, dose reduction is common, and in a study by Wong et al,30 5% of patients required early termination of therapy. Interferon alfa-2b is contraindicated in patients with decompensated
liver disease/ cirrhosis, autoimmune diseases, and severe depression or other psychiatric disorders.31 The labeling for interferon alfa-2b contains a boxed warning, which states that interferon alfa-2b may cause or aggravate
serious neuropsychiatric, autoimmune, ischemic, and infectious disorders.20 Patients receiving interferon alfa-2b therapy should be monitored periodically with clinical and laboratory evaluations.
If patients develop persistently severe or worsening signs and symptoms of these conditions, therapy with interferon alfa-2b
should be discontinued.
The ideal candidate for interferon alfa-2b therapy is a patient with elevated ALT levels and low HBV levels who has well-compensated
liver disease and sufficient physical and emotional reserve to deal with the possible adverse effects of the therapy. Patients
who have been treated with this drug have experienced documented improvement in morbidity and mortality, a significant advantage
of treatment.31 Additional considerations may include the desire to avoid drug resistance and a preference for shorter-term therapy. Predictors
of interferon alfa-2b response include low serum HBV levels (<200 pg/mL or <600x105 copies/ mL), elevated liver transaminases (ALT >100 IU/L), and HBV genotype A or B (vs C).32,33 Because pegylated interferon alfa-2a, the newer injectable agent, has prolonged therapeutic levels, increased efficacy,
and decreased administration frequency compared with interferon alfa-2b, therapy with this newer agent for 48 weeks is likely
to replace standard, 16-week interferon alfa-2b therapy in the treatment of chronic hepatitis B.12
Lamivudine. Lamivudine is a nucleoside analogue that blocks reverse transcriptase and inhibits viral DNA synthesis. The recommended dosage
is 100 mg/d orally for ≥1 year, as long-term therapy is necessary to prevent HBV recurrence.21 If HBeAg seroconversion occurs, treatment should be continued for ≥6 months after seroconversion to lower the relapse rate
after therapy discontinuation.34
In a randomized, double-blind, placebo-controlled trial of 143 patients by Dienstag et al,35 HBV DNA was suppressed to <100,000 copies/mL at 12 months in 44% (28/63) of patients treated with lamivudine 100 mg/d for
52 weeks compared with 16% (11/69) of patients administered placebo. HBeAg clearance occurred in 32% of lamivudine-treated
patients versus 11% of patients administered placebo, with subsequent HBeAg seroconversion in 17% of patients treated with
lamivudine. In a study by Guan et al,36 seroconversion was demonstrated to increase with time to 50% at 5 years with continuous treatment in an Asian population.
In an unblinded, observational study of 40 patients who experienced seroconversion with lamivudine therapy, seroconversion
was maintained in 77% of patients at 37 months after the cessation of therapy.37 In a study by Lai et al,38 histologic improvement was noted in 52% of lamivudine-treated patients, about twice the rate of improvement observed
in the placebo-treated patients.
For HBeAg-positive patients whose HBV DNA levels are ≥20,000 IU/mL, ALT levels should be measured.12 If ALT levels exceed the threshold, treatment with adefovir, entecavir, or pegylated interferon alfa-2a should be considered.
Lamivudine is not recommended as first-line therapy due to its high rate of resistance. For patients with high HBV DNA levels,
adefovir or entecavir is recommended as first-line therapy due to the diminished response of interferon-based therapy. For
patients with ALT levels below the threshold, treatment results in a lower rate of HBeAg clearance, but histologic improvement
may still occur. Therefore, a biopsy can be considered in patients aged >35 years, and treatment with adefovir, entecavir,
or pegylated interferon alfa-2a can be considered based on the result.
In a randomized, controlled trial of 125 patients with HBeAg-negative chronic hepatitis B and 2 open-label uncontrolled studies
of 40 patients with HBeAg-negative chronic hepatitis B, lamivudine treatment 100 to 150 mg/d for 52 weeks resulted in an HBV
DNA response rate of approximately 66% at 6 to 12 months, but this response rate had decreased to 40% at 30 months.39–41 Histologic improvement was noted in approximately 66% of lamivudine-treated patients at the end of treatment.
A significant disadvantage of treatment with lamivudine is the development of progressively increasing resistance with continued
treatment. The prevalence of lamivudine resistance via YMDD mutation, the most common resistance-inducing substitution in
HBV DNA polymerase, is 14% at 1 year and increases to 57% at 3 years.42 Development of resistance may result in significant clinical consequences, including elevations in ALT levels and increased
HBV replication, decompensated liver disease, and reversal of histologic improvement.43–45
Overall, lamivudine is well tolerated. In the study by Dienstag et al,35 common adverse effects during 1 year of treatment included fatigue/malaise, nausea/vomiting, and headache. Common laboratory
abnormalities included elevated lipase and creatinine kinase in 9% of treated patients; however, none of these adverse effects
was significantly different from the effects observed in the placebo group.35 Elevations of ALT levels to >500 IU/L were rare (3%) in both groups, but significantly more lamivudine-treated patients
had mild elevations of ALT levels (22%) than patients administered placebo (6%; P=.01). No patients in either group developed decompensated liver disease during treatment. The labeling for lamivudine includes
a boxed warning, which states that lactic acidosis and severe hepatomegaly with steatosis have been reported in patients treated
with nucleoside analogues, including some fatal cases.21 Additionally, the warning states that discontinuing lamivudine (or any other anti-hepatitis B treatment) may result in severe
acute exacerbations of hepatitis B.
Lamivudine is a well-established treatment with long-term efficacy and safety data available. Durability of response appears
to be lower than that observed with interferon alfa-2b-based therapies.1 The high prevalence of resistance and the associated potential clinical consequences favor the newer oral agents for routine use.12
Adefovir. Adefovir is a nucleotide analogue that inhibits both HBV reverse transcriptase and DNA polymerase activity. The recommended
dose of this agent is 10 mg/d orally for ≥48 weeks.18 The dose must be adjusted for patients with creatinine clearance <50 mL/min.10 The optimal duration of treatment is unclear, but data suggest that most patients may require long-term treatment, as high
relapse rates after adefovir discontinuation may occur in patients who have not undergone HBeAg seroconversion. Patients with
resistance to lamivudine may also require long-term treatment with adefovir.
In a double-blind, randomized, clinical trial by Marcellin et al46 of 515 patients with HBeAg-positive chronic hepatitis B, HBV DNA was suppressed to <400 copies/mL at 12 months in 21% of
patients treated with adefovir 10 or 30 mg/d compared with 0 patients administered placebo. Continuing treatment through 36 months extended suppression to 48% of patients
treated with adefovir.47 At 12 months, adefovir treatment had reduced HBV DNA levels by 3.52 log10 versus a reduction of 0.55 log10 in patients administered placebo.46 At 12 months, HBeAg clearance had occurred in 24% of adefovir-treated patients versus 11% of patients administered placebo;
at 36 months, HBeAg clearance had occurred in 53% of adefovir-treated patients.46,47 Subsequent HBeAg seroconversion had occurred in 12% of adefovir-treated patients at 12 months and 46% of adefovir-treated patients at 36 months. Seroconversion was well maintained in 91% of patients at 14
months after cessation of adefovir therapy.48 Histologic improvement was noted in 53% of adefovir-treated patients, approximately twice the rate of improvement observed
in patients treated with placebo.46
In patients with HBeAg-negative chronic hepatitis B, HBV DNA was suppressed to <400 copies/mL at 12 months in 51% (63/123)
of patients treated with adefovir 10 mg/d for 48 weeks versus 0 (0/61) patients treated with placebo.49 Treatment that was continued through 36 months resulted in suppression to <1,000 copies/mL in 79% of adefovir-treated patients.50 Histologic improvement was demonstrated in 64% of adefovir-treated patients versus 33% of untreated patients at 12 months,
with further improvement on continued therapy at 36 months.49,50
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In a randomized, controlled trial of 59 patients with lamivudine-resistant chronic hepatitis B who had compensated liver disease
and were undergoing lamivudine therapy, HBV DNA was suppressed to <1,000 copies/mL in 35% (7/20) of patients who had adefovir
10 mg/d added to their lamivudine 100 mg/d therapy and in 26% (5/19) of patients who were switched from lamivudine monotherapy
to adefovir monotherapy compared with 0 (0/20) patients who continued with lamivudine monotherapy.51 At 48 weeks, HBV DNA levels were reduced by approximately 4 log10 in both adefovir-treated groups. A similar median reduction in HBV DNA of 4.3 log10 was obtained in a larger controlled trial of 94 patients with lamivudine-resistant YMDD mutations who were randomized to
either adefovir plus lamivudine combination therapy or continued lamivudine monotherapy.52In a study by Hadziyannis et al,13 no adefovir-resistant mutants were detected after 1 year, but the prevalence of resistance with ongoing treatment in
patients with HBeAg-negative chronic hepatitis B was 3% after 2 years, 11% after 3 years, 18% after 4 years, and 29% after
5 years. Resistance led to elevated ALT levels and rebound in HBV DNA levels.50
Overall, adefovir is well tolerated at normal therapeutic doses. The most commonly reported adverse effects in clinical studies
were fatigue, headache, pharyngitis, and abdominal pain, but these effects were not significantly different from those observed
with placebo.50 Four of 185 patients (2%) in a long-term study required discontinuation of therapy because of abnormal liver tests without
decompensation or need for intervention (n=2); a skin disorder (n=1); or elevated creatinine levels, which subsequently normalized
(n=1). In the study by Marcellin et al,46 a higher dose of 30 mg/d resulted in significant nephrotoxicity; this dose is therefore no longer used. The labeling for
adefovir includes a boxed warning, which states that lactic acidosis and severe hepatomegaly with steatosis have been reported
in patients treated with nucleoside analogues, including some fatal cases.18
The most well-established role for adefovir is in the treatment of patients with lamivudine-resistant hepatitis B, but this
agent is also now being used in treatment-nave patients. The efficacy and tolerability of adefovir appear to be similar to
the efficacy and tolerability of lamivudine; adefovir, however, has an improved resistance profile.30 Adefovir should be used cautiously in patients at risk for nephrotoxicity, especially in those with cirrhosis.
Entecavir. Entecavir is a guanosine nucleoside analogue that inhibits HBV polymerase. The recommended dose is 0.5 mg/d in treatment-nave
patients and 1 mg/d in lamivudine-resistant patients.19 The dose should be adjusted in patients with renal impairment. The optimal duration of treatment is unknown, but similar
to the more established oral anti-HBV agents, long-term treatment of >48 weeks will likely be necessary.
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Entecavir was compared with lamivudine in a randomized clinical trial of 715 treatment-nave patients with HBeAg-positive
chronic hepatitis B.53 At 12 months, HBV DNA was suppressed to <300 copies/mL in 67% (236/354) of patients treated with entecavir 0.5 mg/d compared
with 36% (129/355) of those treated with lamivudine 100 mg/d. Entecavir reduced HBV DNA levels by 6.9 log10 compared with a reduction of 5.4 log10 in patients treated with lamivudine (P<.001). HBeAg clearance occurred in 22% of entecavir-treated patients, and subsequent HBeAg seroconversion occurred in 21%
of entecavir-treated patients, results similar to those observed in lamivudine-treated patients (20% and 18%, respectively).
Seroconversion was maintained in 82% of entecavir-treated patients at 6 months. Histologic improvement was noted in 72% of
the entecavir-treated patients compared with 62% of the lamivudine-treated patients.
In treatment-nave patients with HBeAg-negative chronic hepatitis B, HBV DNA was suppressed to <300 copies/mL at 12 months
in 90% of patients treated with entecavir 0.5 mg/d versus 61% of patients treated with lamivudine 100 mg/d.54 Entecavir reduced HBV DNA levels by 5 log10 compared with a reduction of 4.5 log10 in lamivudine-treated patients (P<.001). Histologic improvement was noted in 70% of the entecavir-treated patients compared with 61% of the lamivudine-treated
patients.
In a study of 286 patients with HBeAg-positive hepatitis B who were refractory to lamivudine therapy, a greater proportion
of patients achieved undetectable HBV DNA levels with entecavir 1 mg/d than with lamivudine 100 mg/d (19% vs 1%, respectively,
at 12 months).15 Furthermore, 55% of patients treated with entecavir 1 mg/d achieved histologic improvement compared with 28% of patients
treated with lamivudine 100 mg/d.
In the study by Lai et al,54 entecavir drug resistance was 0 for ≤2 years in treatment-nave patients but was 7% at 1 year and 9% at 2 years for patients
in whom lamivudine treatment had failed.
Adverse effects associated with entecavir treatment were not significantly different from those observed with lamivudine in
2 large studies involving 1,363 patients.53,54 The most common adverse events were headache, upper respiratory infection, gastrointestinal intolerance, and fatigue. Overall,
both drugs were well tolerated, and discontinuation because of entecavir-associated adverse effects was <1%. Long-term safety
has yet to be determined. The labeling for entecavir includes a boxed warning stating that lactic acidosis and severe hepatomegaly
with steatosis have been reported in patients treated with nucleoside analogues, including some fatal cases.19
In studies by Chang et al53 and Lai et al,54 entecavir compared favorably with lamivudine in terms of resistance rates at 12 months, and the 2 agents were both well
tolerated. Because entecavir is a newer oral agent, its long-term efficacy and safety are still being evaluated. Entecavir
has an important role in the treatment of lamivudine-resistant hepatitis B and is also now an option for treatment-nave patients.
Pegylated interferon alfa-2a. Pegylated interferon alfa-2a consists of interferon alfa-2b bound to polyethylene glycol, which reduces drug clearance and
results in a more sustained and consistent drug level. The recommended dose is 180 mcg/wk SC for 48 weeks.16
Pegylated interferon alfa-2a 180 mcg/wk monotherapy was compared with lamivudine 100 mg/d monotherapy and with pegylated interferon
alfa-2a plus lamivudine combination therapy in a randomized, partially blinded clinical trial of 814 patients with HBeAg-positive
chronic hepatitis B.55 Patients in the trial received treatment for 48 weeks. At 12 months, HBV DNA was suppressed to <400 copies/mL in 25% (68/271)
of patients treated with pegylated interferon alfa-2a monotherapy versus 40% (108/272) of patients treated with lamivudine
monotherapy. Pegylated interferon alfa-2a monotherapy reduced HBV DNA levels by 4.5 log10 compared with a reduction of 5.8 log10 observed with lamivudine monotherapy. HBeAg loss occurred in 30% of patients treated with pegylated interferon alfa-2a monotherapy
compared with 22% of patients treated with lamivudine monotherapy. Subsequent HBeAg seroconversion occurred in 27% of patients
treated with pegylated interferon alfa-2a monotherapy compared with 20% of patients treated with lamivudine monotherapy. Both
HBeAg clearance and seroconversion had increased slightly 6 months after the last dose of pegylated interferon alfa-2a monotherapy
(34% and 32%, respectively). At 72 weeks, histologic improvement was noted in 38% of the patients treated with pegylated interferon
alfa-2a monotherapy compared with 34% of the patients treated with lamivudine monotherapy. At 24 weeks after treatment, there
were no significant differences in HBV DNA suppression or normalization of ALT between the pegylated interferon alfa-2a monotherapy
arm and the pegylated interferon alfa-2a plus lamivudine combination arm.
In a double-blind, multicenter, controlled, 52-week study by Janssen et al,54 6,307 patients were randomized to receive pegylated interferon alfa-2a either as monotherapy or in combination with
lamivudine. At 26 weeks after treatment, the rates of HBV DNA suppression to <400 IU/mL, HBeAg seroconversion, and ALT normalization
did not differ between treatment groups.
Pegylated interferon alfa-2a has been demonstrated to be more effective than standard interferon alfa-2b therapy or lamivudine
monotherapy in other studies.57,58 In a phase 2, randomized trial of 194 patients with HBeAg-positive chronic hepatitis B, twice as many patients in the pegylated
interferon alfa-2a treatment group (either 90, 180, or 270 mcg/wk SC) than in the interferon alfa-2b group (4.5 MU 3 times/wk
SC) achieved HBV suppression, HBeAg clearance, and ALT normalization (24% vs 12%, respectively).57
In a randomized study of 537 patients with HBeAg-negative chronic hepatitis B, HBV was suppressed to undetectable levels 24
weeks after treatment completion in 20% of patients treated with pegylated interferon alfa-2a versus 7% of patients treated
with lamivudine for 48 weeks.58
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Pegylated interferon alfa-2a, like interferon alfa-2b, does not induce resistant mutants. The adverse effect profile, which
is essentially the same as the interferon alfa-2b adverse effect profile, includes flu-like symptoms, anorexia/weight loss,
depression, and bone marrow suppression. Contraindications, also similar to those observed with interferon alfa-2b, include
decompensated liver disease/ cirrhosis, autoimmune diseases, and severe depression or other psychiatric disorders. In 2 large
trials, the most common adverse events were fever, fatigue, myalgias, and headache.55,58 Dose modification was necessary in about 45% of patients, mostly because of laboratory abnormalities including ALT elevation,
neutropenia, and thrombocytopenia. Discontinuation of therapy occurred in 6% to 8% of patients in the pegylated interferon
alfa-2a monotherapy groups. The labeling for pegylated interferon alfa-2a includes a boxed warning, which states that this
agent may cause or aggravate serious neuropsychiatric, autoimmune, ischemic, and infectious disorders.16 Patients receiving therapy with pegylated interferon alfa-2a should be monitored periodically by clinical and laboratory
evaluations. If patients develop persistently severe or worsening signs and symptoms or these conditions, therapy with this
agent should be discontinued.
The ideal candidate for pegylated interferon alfa-2a therapy is a patient with elevated ALT levels (>100 IU/L) and low HBV
DNA levels (<200 pg/mL or <600x105 copies/mL) who has well-compensated liver disease and sufficient physical and emotional reserve to deal with the adverse
effects of therapy. Additional considerations may include a desire to avoid drug resistance and a preference for shorter-term
therapy.
Telbivudine. Telbivudine, a synthetic thymidine nucleoside analogue with activity against HBV DNA polymerase, was approved by FDA in October
2006 for the treatment of chronic hepatitis B in adult patients. The recommended dose is 600 mg/d orally; adjustment of the
dosing interval is recommended in patients with a creatinine clearance <50 mL/min. The exact optimal duration of treatment
is not well defined, but in clinical trials, treatment duration was up to 104 weeks, indicating that long-term therapy may
be warranted.17The 007 Globe trial, a phase 3 randomized clinical trial of 1,367 patients with chronic hepatitis B (including both HBeAg-positive
and HBeAg-negative patients), compared telbivudine 600 mg/d with lamivudine 100 mg/d for ≤104 weeks.17,59–62 At Week 52, HBV DNA levels in HBeAg-positive patients (n=921) were suppressed to <300 copies/mL in 60% of patients treated
with telbivudine compared with 40% of patients treated with lamivudine. HBeAg-positive patients treated with telbivudine also
achieved significantly greater HBV DNA reductions at 1 year compared with lamivudine patients (–6.45 log10 vs 5.54 log10). HBeAg seroconversion rates were similar between the telbivudine and lamivudine groups (23% and 22%, respectively). Histologic
improvement was noted in 69% of patients in the telbivudine group and in 60% of patients in the lamivudine group. In HBeAg-negative
patients (n=446), HBV DNA levels were suppressed to <300 copies/mL in 88% of patients (n=446) treated with telbivudine compared
with 71% of patients treated with lamivudine after 1 year of treatment. Patients treated with telbivudine achieved significantly
greater HBV DNA reductions at 1 year compared with lamivudine-treated patients (–5.53 log10 vs –4.40 log10, respectively). Histologic improvement was noted in 69% of patients in the telbivudine group and in 68% of patients in the
lamivudine group.
Lai et al63 performed a 1-year clinical trial of 104 HBeAg-positive patients randomized to lamivudine 100 mg/d monotherapy, telbivudine
400 or 600 mg/d monotherapy, or combination therapy consisting of lamivudine 100 mg/d plus telbivudine 400 or 600 mg/d. Combination
therapy offered no advantage over telbivudine monotherapy in virologic response (–6.01 log10 vs –5.99 log10, respectively), and HBeAg seroconversion with combination therapy was less common than with telbivudine monotherapy (15%
vs 31%, respectively). Likewise, the normalization of ALT levels was slightly less common with combination therapy than with
telbivudine monotherapy. Therefore, combination therapy with telbivudine plus lamivudine is not recommended.
Bzowej et al64 conducted a trial comparing telbivudine with adefovir for 52 weeks in patients with HBeAg-positive compensated hepatitis
B (N=135). After 24 weeks, patients being treated with adefovir were randomized to either continue with adefovir treatment
or to switch to telbivudine treatment. At Week 24, telbivudine-treated patients demonstrated a significantly greater mean
HBV DNA reduction (from baseline) than adefovir-treated patients (–6.30 vs –4.97 log10 copies/mL, respectively; P<.01). At 52 weeks, patients treated with telbivudine or those who switched to telbivudine compared with those who continued
with adefovir therapy had greater HBV DNA reductions, were more likely to reach HBV DNA levels <5 log10 copies/mL (91% and 87% vs 66%, respectively; P<.05), and had greater HBeAg loss (31% and 26% vs 21%, respectively; P value not reported).
Overall, telbivudine is well tolerated.17 The most commonly reported adverse drug reactions reported in clinical studies were upper respiratory tract infection, headache,
fatigue/malaise, abdominal pain, nasopharyngitis, elevated creatine phosphokinase levels, and influenza and influenza-like
symptoms; however, these effects were not directly attributable to telbivudine therapy and were not significantly different
from the effects reported by patients treated with lamivudine. The labeling for telbivudine includes a boxed warning regarding
the risk of lactic acidosis and severe hepatomegaly with steatosis, including reports of some fatalities, in patients taking
nucleoside analogues alone or in combination with antiretroviral agents.
TREATMENT RECOMMENDATIONS
Management of chronic hepatitis B has been largely shaped by 2 sets of treatment guidelines. One set of guidelines is an expert
panel consensus recommendation published in August 2006.12 It should be noted that telbivudine was not yet approved by FDA for the treatment of chronic hepatitis B at the time this
consensus recommendation was published. Another set of guidelines, issued by the American Association for the Study of Liver
Diseases (AASLD), was most recently updated in February 2007 and includes telbivudine in its recommendations.14
Expert panel consensus recommendation. According to the expert panel consensus recommendation, treatment of chronic hepatitis B should be based on a patient's HBeAg
status.12
HBeAg-positive patients.
If HBV DNA levels are <20,000 IU/mL (or <100,000 copies/mL), then patients are likely inactive HBsAg carriers and do not require treatment. However, HBV DNA and ALT
levels should continue to be monitored.12 If ALT levels exceed the threshold (30 IU/L for men or 19 IU/L for women), liver biopsy should be considered. For moderate
or severe inflammation seen on pathology, treatment should be considered.
The duration of oral antiviral treatment depends upon individual patient response.12 In a best-case scenario, HBeAg seroconversion occurs and HBV DNA levels decline until the HBV level is undetectable. Treatment
may be discontinued 6 to 12 months after the HBV DNA level becomes undetectable. If HBeAg seroconversion occurs and HBV DNA
levels are stable but not undetectable, patients should continue to receive treatment for an additional 6 months, at which
time maintenance of seroconversion should be confirmed and treatment discontinuation should be considered. If treatment is
stopped, serial labs (liver function tests and HBV DNA levels) should be monitored, and if relapse occurs, patients should
be re-treated. If HBeAg seroconversion does not occur, treatment should be continued indefinitely.
HBeAg-negative patients.
For patients with HBV DNA levels <2,000 IU/mL (or <10,000 copies/mL), clinical decision-making is identical to that employed for HBeAg-positive patients with low HBV DNA levels.12 If HBV DNA levels are >2,000 IU/mL, ALT levels should be determined. If ALT levels are higher than the threshold, treatment
with adefovir, entecavir, or pegylated interferon alfa-2a should be considered. Lamivudine is not recommended due to progressive
resistance over time and inferiority to entecavir in clinical trials. If ALT levels are lower than the threshold, then biopsy
should be considered or serial labs should be monitored.
Duration of treatment with adefovir and entecavir should be long term.12 Treatment is continued for ≥48 weeks; there are no recommendations for discontinuing treatment in this patient group. The
efficacy and safety of entecavir for >2 years are not yet established.
Lamivudine-resistant patients.
In patients with lamivudine resistance, adefovir should be added to lamivudine as combination therapy, as switching from
lamivudine to adefovir monotherapy may result in development of adefovir resistance.12 Switching to high-dose entecavir is also reasonable, but lamivudine should be discontinued to decrease the risk of entecavir
resistance.
AASLD guidelines. The AASLD guidelines state that the treatment of patients with chronic hepatitis B depends primarily on HBV DNA and ALT levels.12 The guidelines divide elevated ALT into 2 categories: 1 to 2 times the upper limit of normal and >2 times the upper limit
of normal. For patients with HBV DNA >20,000 IU/mL (regardless of HBeAg status), if ALT levels are >2 times the upper limit
of normal, then treatment is indicated. For HBeAg-positive patients with HBV DNA levels >20,000 IU/mL or for HBeAg-negative
patients with HBV DNA levels >2,000 IU/mL, if ALT levels are 1 to 2 times the upper limit of normal, then biopsy should be
considered if treatment is planned for moderate-severe inflammation or significant fibrosis. If ALT levels are normal, no
treatment is indicated. For the specific case of an HBeAg-positive patient with HBV DNA levels >20,000 IU/mL who does not
meet ALT criteria for treatment, the age criterion for consideration of biopsy is >40 years.
As noted earlier, telbivudine is included as a new treatment option in the AASLD guidelines update.14 Like lamivudine, telbivudine is not considered a first-line agent due to high rates of resistance. Standard interferon alfa-2b
is still considered a first-line therapy, but the guidelines note that pegylated interferon alfa-2a will likely soon replace
standard interferon alfa-2b. The guidelines make no mention of interferon-based therapy being less effective in the setting
of higher viral loads.
Overall, the 2006 expert panel consensus recommendation and the 2007 AASLD guidelines are similar, especially regarding the
selection of a first-line therapeutic agent. The application of the 2006 expert consensus guidelines would result in more
patients being treated. The reasoning behind this more aggressive approach is that a significant number of patients with normal
ALT levels may still have significant liver fibrosis and increased mortality from liver disease.12 The 2007 AASLD guidelines are more conservative, suggesting that liver biopsy and treatment decisions be based on a higher
ALT threshold (ie, lower ALT laboratory values) than the 2006 expert consensus recommendation. It remains to be seen which
recommendations will be more closely followed by US physicians.
FUTURE THERAPIES
The goal of more effective therapy with more durable response and less resistance drives the study and development of new
agents. Two agents are currently in phase 3 trials for the treatment of chronic hepatitis B.
Emtricitabine. Emtricitabine is a nucleoside analogue similar to lamivudine that has been studied in a phase 3 trial of 167 patients.65 HBV DNA was suppressed to <400 copies/mL in 56% of patients treated with emtricitabine 200 mg/d orally for 48 weeks compared
with 7% of patients administered placebo. Histologic improvement was noted in approximately 62% of emtricitabine-treated patients
compared with 25% of the placebo group at 48 weeks. However, there was no difference between the groups in HBeAg clearance or seroconversion.
Tenofovir. Tenofovir is an oral antiretroviral drug that is active against HBV at a dose of 300 mg/d. Small studies in lamivudine-resistant
patients have demonstrated HBV DNA suppression and reduction in HBV DNA levels.66
CONCLUSION
Chronic hepatitis B remains a common disease with significant morbidity and mortality worldwide. The development of sensitive
quantitative HBV assays has allowed better assessment of disease progression and therapeutic efficacy, so suppression of HBV
to even lower levels is now a primary goal of therapy. Drug selection remains a clinical challenge and must be tailored according
to the characteristics of drug and patient, as both the expert panel consensus recommendation and the AASLD guidelines state.
Oral nucleoside/nucleotide analogues and injectable interferon-based therapies are effective treatment options. Oral agents
are well tolerated, but patients often require extended therapy, which carries the potential for the subsequent development
of resistance. Adefovir and entecavir may be preferred over lamivudine due to reduced rates of resistance. Telbivudine therapy
may serve as an alternative agent for patients, especially in those with persistent viremia during lamivudine therapy. Pegylated
interferon alfa-2a is both more effective and easier to use than standard interferon alfa-2b, but the required duration of
therapy is longer. Adverse effects are more common with interferon-based therapies than with oral antiviral therapies. Investigational agents such as emtricitabine and
tenofovir are currently in phase 3 trials for the treatment of chronic hepatitis B; additional long-term trials for these
newer agents and for the agents already approved are warranted to help direct future care.
Dr Wong is a clinical consultant pharmacist, Clinical Pharmacy Services, Commonwealth Medicine at the University of Massachusetts
Medical School, Worcester. Dr Pomfret is a clinical consultant pharmacist, Clinical Pharmacy Services, Commonwealth Medicine at the University of Massachusetts
Medical School, and maintains an academic appointment as a clinical assistant professor at Northeastern University, School
of Pharmacy, Boston, Massachusetts.
Disclosure Information: The authors report no financial disclosures as related to products discussed in this article.
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