Current management of chronic hepatitis B
Professor S. J. Hadziyannis, Department of Medicine and Hepatology, Henry Dunant Hospital, 107, Messogion Ave., 11526 Athens, Greece.
Chronic hepatitis B can be diagnosed in patients with increased aminotransferases, hepatitis B virus viraemia and necroinflammation with fibrosis on liver biopsy. Although, ideally, all patients with chronic hepatitis B should be treated, therapeutic intervention is currently recommended for cases with a relatively satisfactory likelihood of response and/or advanced disease. A realistic therapeutic approach aims to sustain hepatitis B e antigen (HBeAg) loss and hepatitis B e antibody (anti-HBe) seroconversion in HBeAg-positive chronic hepatitis B and to sustain biochemical and virological remission in HBeAg-negative chronic hepatitis B. Currently, three drugs are licensed for chronic hepatitis B: interferon-alpha, lamivudine and adefovir dipivoxil. In patients with HBeAg-positive chronic hepatitis B, all of these drugs achieve HBeAg loss (24–33%) and anti-HBe seroconversion (12–30%) rates significantly superior to those observed in untreated placebo controls. In patients with HBeAg-negative chronic hepatitis B, the sustained off-therapy response rate is 20–25% after a ≥ 12-month course of interferon-alpha and minimal (< 10%), if any, after a 12-month course of lamivudine or adefovir. Long-term lamivudine induces an initial response in 70–90% of patients, but only 30–40% of patients remain in remission after the third year due to progressively increasing viral resistance. Long-term adefovir achieves a response in approximately 70% of patients at 12 months, which is maintained at 24 months with rare (< 2%) drug resistance. Adefovir is also effective against lamivudine-resistant strains. Many other anti-viral agents, immunomodulatory approaches and combination therapies are currently being evaluated in chronic hepatitis B.
Introduction — rationale for therapeutic intervention in chronic hepatitis b
Chronic infection with hepatitis B virus (HBV) remains a significant public health problem world-wide, and is associated with increased morbidity and mortality.1, 2 Although the majority of the approximately 350 million people with chronic HBV infection may remain in an inactive phase associated with low viral replication and histological remission, a significant proportion will develop chronic hepatitis B, which is characterized by the presence of high HBV replication and chronic necroinflammation of the liver.1, 3 It is estimated that about 15–20% of patients with chronic hepatitis B develop cirrhosis within 5 years,4, 5 and only 55–85% of those with active HBV-related cirrhosis survive for more than 5 years.6–8 Moreover, although all patients with chronic HBV infection are at higher risk for hepatocellular carcinoma when compared with the general population, the risk becomes much higher when cirrhosis develops.9 Thus, it is estimated that over 250 000 patients world-wide die annually from HBV-related liver disease.10, 11
Chronic hepatitis B can be separated into two forms based on the presence of the hepatitis B e antigen (HBeAg) and antibody (anti-HBe).12, 13 HBeAg-positive chronic hepatitis B occurs during the early phases of chronic HBV infection and is characterized by extremely high HBV replication and persistently or intermittently increased aminotransferase levels.12 Depending on the mode of transmission of HBV, and perhaps the HBV genotype, HBeAg-positive chronic hepatitis B may occur almost immediately after the acute phase of HBV infection or develop after several years of HBeAg positivity, with immune tolerance to HBV characterized by high serum HBV-DNA levels, normal aminotransferases and minimal or no liver necroinflammation.12–14 Follow-up studies of patients with HBeAg-positive chronic hepatitis B have shown that approximately 5–15% per year may have a favourable outcome, with spontaneous clearance of HBeAg, the development of anti-HBe and transition to an inactive phase of the infection with little residual viral replication and minimal necroinflammation, also referred to as the ‘inactive chronic hepatitis B surface antigen (HBsAg) carrier state’.12, 14–16 However, the majority of such patients, if left untreated, maintain high HBV replication and severe liver necroinflammation, which is associated with worsening fibrosis, the development of cirrhosis and an increased risk of hepatocellular carcinoma.12, 14–17
HBeAg-negative chronic hepatitis B, also referred to as anti-HBe-positive chronic hepatitis B, represents a rather late phase in the course of chronic HBV infection.13, 18 It develops in a proportion of patients who lose HBeAg and seroconvert to anti-HBe, and appears to depend on the infecting HBV genotype and the selection of certain mutations in the genome of HBV.12–14, 18 Patients with HBeAg-negative chronic hepatitis B harbour replication-competent HBV variants that are unable to produce HBeAg due to mutations either at the pre-core (pre-core mutant chronic hepatitis B) or the basic core promoter region of the viral genome.13, 19 The disease is characterized by persistent or intermittent elevations in alanine aminotransferase activity and necroinflammation and fibrosis on liver histology that are linked aetiopathogenetically to the underlying HBV replication.18 Serum HBV-DNA levels are persistently or intermittently above 105 copies/mL, but they are usually lower than those detected in patients with HBeAg-positive chronic hepatitis B.12–14, 20 HBeAg-negative chronic hepatitis B represents a potentially severe and progressive form of chronic liver disease with very rare spontaneous remissions, frequent progression to cirrhosis and increased risk of the development of hepatocellular carcinoma.21–25
Given the poor rate of spontaneous remission and the increased risk of progression to cirrhosis and/or the development of hepatocellular carcinoma, it is obvious that effective therapeutic intervention is required in all patients with HBeAg-positive or HBeAg-negative chronic hepatitis B.
Initial evaluation — diagnosis of chronic hepatitis b in clinical practice
All patients with chronic HBV infection, defined in clinical practice by positive HBsAg for at least 6 months or by positive HBsAg and negative immunoglobulin M class antibody to hepatitis B core antigen, should be initially evaluated using a thorough history, physical examination and laboratory tests. In particular, risk factors for infection with hepatitis viruses (parenteral drug use, homosexuality, etc.), a family history of HBV infection and HBV-related liver cancer and alcohol use should be specifically sought. Laboratory tests should include full blood count, liver tests (alanine aminotransferase and aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl-transpeptidase, total protein, albumin), prothrombin time, HBeAg/anti-HBe and serum HBV-DNA levels. Patients should also be tested for possible co-infections with the hepatitis D and C viruses (antibody to hepatitis D virus, antibody to hepatitis C virus) and, perhaps, for those at risk, for antibody to human immunodeficiency virus.14 In areas of high (> 33%) prevalence of hepatitis A virus infection, all individuals with chronic HBV infection and undetectable antibody to hepatitis A virus should be vaccinated with two doses of hepatitis A vaccine 6–12 months apart.26 Moreover, they should be counselled that regular alcohol use should be minimal, if at all,27 and that they should take precautions in order to reduce the risk of transmission of HBV to others. In areas with vertical or horizontal transmission of HBV during early childhood, all first-degree relatives of any individual with chronic HBV infection should be also tested for markers of HBV infection.14
The diagnosis of HBeAg-positive chronic hepatitis B can be made in patients with chronic HBV infection who have positive HBeAg, serum HBV-DNA > 105 copies/mL, persistent or intermittent elevations in alanine aminotransferase activity and no evidence of decompensated cirrhosis (ascites, encephalopathy, variceal bleeding, jaundice).12, 14 Patients who fulfil the definition criteria for HBeAg-positive chronic hepatitis B may be followed up for 6 months with alanine aminotransferase/aspartate aminotransferase determinations and HBeAg/anti-HBe status for the possibility of spontaneous seroconversion from HBeAg to anti-HBe.12, 14
The diagnosis of HBeAg-negative chronic hepatitis B can be made in patients with chronic HBV infection and negative HBeAg/usually positive anti-HBe, persistent or intermittent elevations in alanine aminotransferase/aspartate aminotransferase activity, detectable serum HBV-DNA, active liver necroinflammation and no other concomitant or superimposed cause of liver disease or sign of decompensated cirrhosis.14, 20 Patients with HBeAg-negative chronic hepatitis B have an identical serological profile to inactive chronic HBV carriers and sometimes the differentiation between these two groups may not be straightforward. This is particularly true for patients with HBeAg-negative chronic hepatitis B and intermittent rather than continuous biochemical and virological activity with long-lasting intervening periods of remission.20 In studies with frequent assessments of alanine aminotransferase/aspartate aminotransferase and serum HBV-DNA levels, major fluctuations in viraemia and serum aminotransferase levels were observed in more than 40% of cases.28 It should also be noted that, although an arbitrary serum HBV-DNA level of 105 copies/mL has been suggested as a cut-off point for differentiation between patients with HBeAg-negative chronic hepatitis B and inactive carriers, several follow-up studies have shown that a significant proportion of patients with HBeAg-negative chronic hepatitis B may have serum HBV-DNA levels below 105 copies/mL at certain time points.29 According to our data, 20–30% of patients with histologically documented HBeAg-negative chronic hepatitis B first presented with normal alanine aminotransferase levels and low HBV-DNA values below the cut-off level of 105 copies/mL (and even 104 copies/mL), and were thus initially misclassified as inactive HBsAg carriers.29, 30 Currently, because of the high cost and the lack of an accurate and established cut-off level, very frequent assays of serum HBV-DNA cannot be recommended in clinical practice, and thus sequential alanine aminotransferase/aspartate aminotransferase determinations remain the basis for a safe differentiation between HBeAg-negative chronic hepatitis B and the inactive HBsAg carrier state.20 Alanine aminotransferase/aspartate aminotransferase determinations are also useful for the follow-up of inactive HBsAg carriers, as a percentage may eventually develop HBV reactivation and thus progress to the HBeAg-negative chronic hepatitis B phase.16, 18, 22
Indications for treatment in chronic hepatitis b
All patients who maintain positive HBeAg and elevated alanine aminotransferase/aspartate aminotransferase are candidates for treatment, given that the probability of response to any therapy increases with higher alanine aminotransferase/aspartate aminotransferase and lower serum HBV-DNA levels.12, 14, 31, 32 All patients with HBeAg-positive chronic hepatitis B and alanine aminotransferase or aspartate aminotransferase levels of greater than or equal to twice the upper limit of normal should be considered for liver biopsy and receive treatment (Table 1). Liver biopsy prior to the initiation of treatment is extremely useful, as it confirms the diagnosis of chronic hepatitis B (although it is not essential for diagnosis in clinical practice), provides important information on the prognosis and probability of response and helps in the planning of subsequent therapeutic decisions concerning patients who will not respond to treatment. In contrast with the previous sub-group, patients with HBeAg-positive chronic hepatitis B and alanine aminotransferase/aspartate aminotransferase levels of less than twice the upper limit of normal should not receive treatment, as their probability of response is very low (< 10%). These patients, as well as those with HBeAg-positive chronic HBV infection and normal alanine aminotransferase/aspartate aminotransferase levels (immune tolerance phase), should be closely monitored using alanine aminotransferase/aspartate aminotransferase determinations every 3 months, and should be considered for treatment if the alanine aminotransferase/aspartate aminotransferase levels increase to greater than or equal to twice the upper limit of normal12, 14 (Table 1). Treatment may also be recommended in a small proportion of patients with HBeAg-positive chronic hepatitis B and slight alanine aminotransferase/aspartate aminotransferase elevations who have severe histological lesions. Therefore, although liver biopsy is not included in the regular follow-up of such patients, it may be advised in cases with clinical evidence of underlying chronic liver disease.
Table 1. Current management recommendations for patients with chronic hepatitis B
|HBeAg-positive CHB||+||–||< 2 × ULN||High||No need for liver biopsy||Monitor ALT/AST every 3 months|
|+||–||≥ 2 × ULN||High||Moderate/severe CHB†||Therapeutic intervention|
|Inactive chronic HBV carrier||–||–/+||< ULN||Low||No need for liver biopsy||Monitor ALT/AST every 6 months|
|HBeAg-negative CHB||–||–/+||> ULN||High or low||Moderate/severe CHB†||Therapeutic intervention|
|–||–/+||> ULN||High or low||Minimal/mild CHB||Monitor ALT/AST every 3–6 months|
Similar to HBeAg-positive chronic hepatitis B, ideally, all patients with HBeAg-negative chronic hepatitis B should be treated, as they often run an indolent, progressive course, frequently terminating in cirrhosis, portal hypertension and liver decompensation if left untreated.33 However, patients with minimal or mild histological liver disease and usually minimal alanine aminotransferase elevations may run a non-deteriorating or very slow progressive course never reaching the cirrhotic stage. In view of the frequent interferon-alpha (IFN-α)-related side-effects and the need for very long-term maintenance therapy with nucleoside(nucleotide) analogues, often terminating in viral resistance and the relapse of chronic hepatitis B, it is reasonable not to recommend the initiation of therapy in such mild cases, at least at that time.12, 14 Thus, the severity of liver histological lesions is an important factor in the decision to treat (Table 1). Consequently, prior to the initiation of therapy, a liver biopsy should be performed in all patients with HBeAg-negative chronic hepatitis B.20 In patients with minimal or mild histological liver disease, frequent follow-up is mandatory, and treatment can be administered if the biochemical and liver disease profile deteriorates (Table 1).
Goals/End-Points Of Treatment In Chronic Hepatitis B
It is now becoming clear that complete viral eradication is not a realistic therapeutic end-point in either HBeAg-positive or HBeAg-negative chronic hepatitis B. Sensitive virological assays have documented that residual amounts of replicating HBV are detectable in many patients with sustained virological and biochemical responses, even in those who lose HBsAg and develop its antibody (anti-HBs).34–36 Thus, in HBeAg-positive chronic hepatitis B, sustained seroconversion of HBeAg to anti-HBe is considered to be the best therapeutic target.14 Indeed, HBeAg loss and seroconversion to anti-HBe have been shown to be associated with a decrease in serum HBV-DNA levels to non-detectability by the branched DNA assay (≤0.7 × 106 viral equivalents/mL), biochemical remission, HBsAg loss in some patients and eventually improved long-term outcome.34, 37 In HBeAg-negative chronic hepatitis B, however, loss of HBeAg and seroconversion to anti-HBe are not applicable, and sustained off-therapy biochemical and virological remission is considered to be the main therapeutic goal20, 38(Table 2). Recently, we have shown that, in patients with HBeAg-negative chronic hepatitis B, a sustained biochemical remission after therapy with IFN-α, usually accompanied by low residual viraemia levels and sometimes by HBsAg loss,39 is associated with a reduced risk of the development of liver decompensation and/or hepatocellular carcinoma and with improved survival.40
Table 2. Goals of therapy and definitions of response to therapy in chronic hepatitis B
|Goals of therapy||Ideal: HBV eradication (clearance HBsAg)|
|Realistic: Sustained suppression of HBV|
| HBeAg-positive CHB: sustained seroconversion of HBeAg to anti-HBe|
| HBeAg-negative CHB: sustained biochemical and virological response|
|Types of response||Biochemical: normalization of serum ALT/AST activity|
| HBeAg-positive CHB: loss of HBeAg (and development of anti-HBe) and decrease in serum HBV-DNA to low levels*|
| HBeAg-negative CHB: undetectable serum HBV-DNA by PCR assays (or perhaps decrease in serum HBV-DNA from initially high to low levels*)|
|Complete: Both biochemical and virological response as well as loss of serum HBsAg|
|Histological: Decrease in necroinflammatory activity by ≥ 2 points without worsening in fibrosis (compared with pre-treatment histological findings)|
|Time of assessment of response||On-therapy response: response during therapy|
|Initial response: response achieved at any time within the first 12 months of therapy|
|Maintained on-therapy response: response that persists throughout therapy|
|End-of-therapy response: response at the end of a defined course of therapy|
|Off-therapy or sustained response: maintenance of response for ≥ 12 months after discontinuation of therapy|
Definitions of response to treatment in chronic hepatitis b
In both HBeAg-positive and HBeAg-negative chronic hepatitis B, virological and biochemical responses can be evaluated during therapy (on-therapy responses) or after the discontinuation of therapy (off-therapy or sustained responses).14, 38 In particular, on-therapy responses may be subdivided into initial (achieved within the first few months of therapy), maintained (persisting throughout the course of therapy) and end-of-therapy (evaluated at the end of a course of therapy of defined duration) responses.38 Biochemical responses are defined by a decrease in alanine aminotransferase/aspartate aminotransferase levels to within the normal range, whereas virological responses, preferably evaluated by qualitative polymerase chain reaction assays, are arbitrarily considered to be achieved when serum HBV-DNA levels fall below 105 copies/mL.12, 14 In particular, in HBeAg-positive chronic hepatitis B, a virological response also requires the loss of HBeAg and seroconversion to anti-HBe. Although the serum HBV-DNA level of 105 copies/mL is currently used in many definitions of the virological response,12, 14 effective HBV suppression is probably achieved when serum HBV-DNA levels drop below 400 copies/mL or even 200 copies/mL, representing the cut-off levels of the Roche Monitor assay and most in-house real-time polymerase chain reaction assays.41, 42 Complete response is defined by both a biochemical and virological response accompanied by the loss of HBsAg.14 When virological and biochemical responses are maintained for several months, histological improvement can also be demonstrated, usually being defined as a reduction in the necroinflammatory (Histological Activity Index (HAI)/Knodell) score by two points or more without worsening of fibrosis.12, 14 Because on-therapy responses may not be maintained after the cessation of treatment, the efficacy of any drug or combination should be evaluated at the end and at ≥ 12 months after the cessation of therapy14, 20, 38 (Table 2).
Type of treatment for chronic hepatitis b
Currently, there are three drugs that are licensed for the treatment of both HBeAg-positive and HBeAg-negative chronic hepatitis B: IFN-α, lamivudine and adefovir dipivoxil. The latter has recently been approved for the treatment of chronic hepatitis B in both the USA and Europe (Table 3).
Table 3. Currently available agents for the treatment of chronic hepatitis B
|Side-effects||Frequent and potentially severe||Minimal||Minimal|
|Efficacy of courses of finite duration*||None||25%, 40%, > 50% |
at 1, 2 and 3 years
(< 2% at 2 years)
| In HBeAg-positive CHB|
| HBeAg loss||33% |
(controls: 6–11%)52, 53
| HBeAg seroconversion||18% |
(more than controls)14
(controls: 4–6%)52, 53
| In HBeAg-negative CHB|
| End-of-therapy response||46–54%39, 46||65–90%62||70–75%76|
| Sustained off-therapy response||22–30%39, 46||< 10–15%65, 66||Unknown|
|Efficacy of long-term therapy|
| In HBeAg-positive CHB|
| HBeAg seroconversion at 24 months||Unknown||27%61||21%†79|
| HBeAg seroconversion at 36 months||Unknown||33%†60||Unknown|
| HBeAg seroconversion at 48 months||Unknown||47%†57||Unknown|
| In HBeAg-negative CHB|
| On-therapy 24-month response||46%46||55–65%63, 64||71–73%†80|
| On-therapy 36-month response||Unknown||40–50%63, 64||Unknown|
| On-therapy 48-month response||Unknown||35–40%63, 64, 67||Unknown|
Interferon-alpha. IFN-α, an anti-viral and immunomodulatory agent, was the first effective therapeutic option in both HBeAg-positive and HBeAg-negative chronic hepatitis B.43 Many early controlled studies have shown that a 4–6-month course of IFN-α, at a dose of 5 MU daily or 10 MU thrice weekly, achieves HBeAg loss in approximately 33% of HBeAg-positive chronic hepatitis B patients, compared with 12% of controls, offering a benefit of 18% in the HBeAg seroconversion rate.31 Responses after IFN-α therapy are durable in the majority of patients, and even clearance of serum HBsAg may eventually develop in a proportion.34, 37, 44 Prolongation of IFN-α therapy to 32 weeks has been suggested to improve the efficacy of a 16-week course,45 but this has not been accepted universally, and a 16–24-week course of IFN-α, at a dose of 5 MU daily or 10 MU thrice weekly, remains the recommended dose regimen in this setting.12, 14
In HBeAg-negative chronic hepatitis B, early, relatively small, controlled and uncontrolled studies showed that IFN-α therapy for up to 6 months was associated with high (60–90%) end-of-therapy biochemical and virological response rates (evaluated by insensitive hybridization assays), but with very low sustained response rates due to frequent relapses after the cessation of therapy.38 Subsequently, longer courses of IFN-α were reported to improve the sustained response rates, reaching 20–25%. In a large cohort of 216 naive Greek patients, the sustained response rate was approximately 11% after 6 months and 22% after 12 months of IFN-α therapy. In this cohort, the response rate was not found to be affected by the IFN-α dose of 3 or 5 MU.39 In an Italian study, a 24-month course of IFN-α, at a dose of 6 MU thrice weekly, achieved sustained responses in 30% of 101 patients.46 Taken together, these findings indicate that IFN-α for at least 12 months at 3–6 MU thrice weekly appears to be the most appropriate IFN-α regimen for HBeAg-negative chronic hepatitis B.14, 38
Pegylated forms of IFN-α have almost replaced standard IFN-α in the treatment of chronic hepatitis C due to their superior efficacy (without increased toxicity) and easier applicability (once-weekly administration).47 Very recently, the efficacy of a 24-week course of pegylated IFN-α2a (180 µg weekly) has been reported to be superior to that of standard IFN-α (4.5 MU thrice weekly), even in HBeAg-positive chronic hepatitis B patients with a rather low likelihood of response.48 The results of ongoing, larger, randomized trials of pegylated IFN-α in both HBeAg-positive and HBeAg-negative chronic hepatitis B are expected soon.
The main advantage of IFN-α therapy is that a course of finite duration may achieve sustained off-therapy responses in a proportion of both HBeAg-positive and HBeAg-negative chronic hepatitis B patients. On the other hand, its main disadvantages are its frequent and potentially severe side-effects and high cost (Table 3). Patients treated with IFN-α should be closely monitored with monthly clinical examinations, full blood count and alanine aminotransferase/aspartate aminotransferase determinations. The most common adverse events include flu-like symptoms, fatigue, irritability, depression and bone marrow suppression.49 Approximately one-third of IFN-α-treated patients may require dose reduction and 5% may discontinue the drug prematurely due to adverse events.50
Lamivudine. Lamivudine (3TC or (–)-2′,3′-dideoxy-3′-thiacytidine), which was introduced for the treatment of chronic hepatitis B in the late 1990s, is a safe drug with rare and generally mild side-effects.51 A 12-month lamivudine course, at a daily dose of 100 mg, was found to achieve a loss of HBeAg in 17–32% of HBeAg-positive chronic hepatitis B patients, compared with 6–11% of controls, offering a benefit of 11–12% in the HBeAg seroconversion rate.52, 53 Similar to previous observations with IFN-α therapy,31, 32 the seroconversion of HBeAg to anti-HBe was more frequent in patients with high than low alanine aminotransferase levels.54 The percentage of responders who maintain HBeAg seroconversion after the cessation of lamivudine varies between studies. Maintenance of HBeAg seroconversion has been suggested to be associated with the extension of therapy after the development of anti-HBe seroconversion, the patients' origin and, perhaps, the duration of HBV infection. In particular, HBeAg seroconversion after the discontinuation of lamivudine has been reported to be maintained in 70–90% of patients from Western countries55, 56 and in 38–83% of patients from South-East Asia.57–59 Overall, the sustained HBeAg seroconversion rate after lamivudine seems to be slightly lower than that after IFN-α therapy.44 The prolongation of lamivudine therapy for more than 2 years may gradually increase the HBeAg seroconversion rate, as a 2-year course has been found to achieve seroconversion in 27%, a 3-year course in 33% and a 4-year course in 47% of cases.55, 57, 60, 61
In patients with HBeAg-negative chronic hepatitis B, a 12-month course of lamivudine at a daily dose of 100–150 mg has been shown to achieve initial biochemical and virological responses, even by sensitive polymerase chain reaction assays, in the majority (70–90%) of patients and end-of-therapy responses in about two-thirds of patients.62–64 Unfortunately, sustained off-therapy responses are rare; biochemical and virological relapses are observed in most patients after the cessation of a 12-month lamivudine course.65, 66 Given its excellent tolerability and safety profile, long-term treatment with lamivudine could be an acceptable maintenance therapy in patients with chronic hepatitis B. However, only one-third of patients with HBeAg-negative chronic hepatitis B may obtain long-term benefit from such an approach, because viral resistance develops in approximately two-thirds within the first 3 years of lamivudine monotherapy.63, 64, 67
The main advantages of lamivudine therapy are its excellent safety and tolerability profile and the relatively low cost, while its main disadvantage is the frequent emergence of viral resistance due to mutations within the YMDD motif in the major catalytic region C of the HBV polymerase gene (M552V/rtM204V or M552I/rtM204I), often accompanied by mutations within region B (L528M/rtL180M)19, 68, 69 (Table 3). Viral resistance is clinically expressed by the virological breakthrough phenomenon, defined as the reappearance of serum HBV-DNA after an initial clearance of viraemia despite the continuation of therapy, or, more rarely, as no virological response to therapy.68 Virological breakthroughs usually develop after the first 6 months of lamivudine monotherapy,70, 71 and their rate increases progressively thereafter with prolongation of therapy, ranging between 15% and 30% at 12 months and exceeding 50% after 3 years in both HBeAg-positive and HBeAg-negative chronic hepatitis B patients.57, 61, 63, 64, 72 Although several questions were initially raised about the clinical significance of viral resistance to lamivudine, it has now become clearer that the emergence of resistance has a negative impact on the efficacy of therapy in both HBeAg-positive and HBeAg-negative chronic hepatitis B patients. We have shown that virological breakthroughs in lamivudine-treated patients with HBeAg-negative chronic hepatitis B are almost invariably followed by increasing viraemia levels, culminating in biochemical breakthroughs,63, 64 which ultimately have an adverse effect on liver histology.64 This is of particular concern in patients with advanced liver disease. Moreover, in HBeAg-positive chronic hepatitis B patients, the emergence of YMDD mutant HBV strains has recently been shown to be associated with a lower likelihood of HBeAg loss and seroconversion and eventually with a negative impact on liver histology.73
Another disadvantage of lamivudine therapy, which refers only to HBeAg-negative chronic hepatitis B, is that no course of finite duration has been shown to achieve sustained off-therapy responses in a sizeable proportion of patients and the optimal duration of therapy is currently unknown.38 The course of HBeAg-negative chronic hepatitis B after the discontinuation of lamivudine, in patients who have remained in very prolonged complete on-therapy remission, is not known. Virological and biochemical relapses occurred in the majority of a series of Greek patients after the discontinuation of a 3-year course of effective lamivudine therapy (S. J. Hadziyannis, unpublished data, 2003).
Adefovir dipivoxil. Adefovir, a nucleotide analogue of adenosine, is a new anti-HBV agent that is administered orally as adefovir dipivoxil. The pro-drug adefovir dipivoxil is adefovir esterified with two pivalic acid molecules and has good oral availability.74 In two recently published, phase III, placebo-controlled trials, a 10 mg daily dose of adefovir dipivoxil was found to be very well tolerated and to have a safety profile similar to placebo,75, 76 whereas a higher daily dose of 30 mg was found to be associated with an increased risk of renal damage without a significant benefit in efficacy.75 Thus, the approved dose of adefovir dipivoxil for chronic hepatitis B is 10 mg daily, which can be safely administered, even in patients with hepatic or mild renal impairment. Dosing interval adjustments are recommended for patients with a creatinine clearance of < 50 mL/min and in those requiring haemodialysis.77
In HBeAg-positive chronic hepatitis B, a 12-month course of adefovir dipivoxil, at a daily dose of 10 mg, was found to achieve a loss of HBeAg in 24% of patients, compared with 11% of controls, offering a benefit of 6% in the HBeAg seroconversion rate.75 Similar to previous observations in HBeAg-positive chronic hepatitis B patients treated with IFN-α or lamivudine, higher baseline alanine aminotransferase levels were associated with an improved efficacy of adefovir dipivoxil therapy.78 Data on the efficacy of long-term adefovir dipivoxil therapy in HBeAg-positive chronic hepatitis B patients have recently been presented. In one phase II extension study, including 28 such patients, adefovir dipivoxil therapy maintained biochemical and virological remission at 2 years without significant toxicity and without any evidence of viral resistance.79 The extension of the large, phase III trial of adefovir dipivoxil in 85 patients with HBeAg-positive chronic hepatitis B75 showed that the HBeAg loss rate increased to 44% and the rate of anti-HBe development increased to 23% at 72 weeks of adefovir dipivoxil therapy (Gilead Sciences, data on file, 2003).
In HBeAg-negative chronic hepatitis B patients, adefovir dipivoxil was found to effectively suppress biochemical activity and HBV replication during the first 48 weeks of therapy.76 In particular, alanine aminotransferase levels normalized in 72% and 29% (P < 0.001) and serum HBV-DNA was undetectable by polymerase chain reaction in 51% and 0% (P < 0.001) of the 123 adefovir dipivoxil- and 61 placebo-treated patients, respectively. Median serum HBV-DNA levels decreased at 48 weeks compared with baseline by 3.9 log10 in the adefovir dipivoxil group and 1.35 log10 in the placebo group (P < 0.001). Moreover, at 48 weeks, histological improvement was observed in 64% of adefovir dipivoxil- and 33% of placebo-treated patients (P < 0.001).76 Whether a defined course of adefovir dipivoxil may achieve a sustained response after drug discontinuation in a sizeable proportion of HBeAg-negative chronic hepatitis B patients is currently unknown. However, the majority of on-therapy responders are expected to relapse soon after discontinuation of a 48-week course of adefovir dipivoxil therapy, and therefore long-term adefovir dipivoxil treatment will probably be needed in order to maintain on-therapy responses.68 Very recent data from a 96-week course of adefovir dipivoxil in HBeAg-negative chronic hepatitis B patients have shown that on-therapy biochemical and virological responses are maintained during the second year of therapy without significant toxicity80 and with rare development of viral resistance (2/124 or 1.6%).81 Resistance to adefovir dipivoxil appears to be associated with the selection of a novel asparagine to threonine mutation at residue rt236 in domain D of the HBV polymerase (rtN236T).81, 82
The main advantage of adefovir dipivoxil is the rare emergence of resistance, which makes the drug a favourable candidate for long-term maintenance therapy in chronic hepatitis B patients with advanced liver disease. On the other hand, its main disadvantages are its high cost and the absence of very long-term data on its efficacy and safety. Whether a long-term course of adefovir dipivoxil can achieve sustained off-therapy responses in a sizeable proportion of patients with HBeAg-negative chronic hepatitis B is still unknown38 (Table 3).
Patients with chronic hepatitis B, who fail to achieve a sustained response after a first course of IFN-α, can be re-treated with a second course of IFN-α, lamivudine or adefovir dipivoxil.83 In particular, re-treatment with IFN-α has been found to have a similar efficacy to that of an initial course of IFN-α in patients with HBeAg-positive and HBeAg-negative chronic hepatitis B.39, 84 Therefore, re-treatment with IFN-α can be recommended in chronic hepatitis B patients who fail a first course of IFN-α. In clinical practice, however, many patients are unwilling to be re-treated with IFN-α due to their experience of the efficacy and impact on the quality of life of the first course. This may be improved in the future with the use of pegylated forms of IFN-α. The efficacy of lamivudine or adefovir dipivoxil monotherapy is similar in both treatment-naive and previously IFN-α-treated patients with chronic hepatitis B, as shown in several trials.52, 53, 62, 75, 76
Patients who do not initially respond to lamivudine may be treated with IFN-α or adefovir dipivoxil or referred for treatment within clinical trials with other anti-viral agents.38 Patients who relapse after the discontinuation of lamivudine without having developed YMDD mutants may be re-treated with lamivudine,85 or even with a course of IFN-α or adefovir dipivoxil. In contrast, lamivudine re-treatment is ineffective in patients who develop YMDD mutant HBV strains during a previous course of lamivudine, as rapid re-emergence of the lamivudine-resistant strains will inevitably occur.72 There are no data for patients who do not respond to adefovir dipivoxil monotherapy, but lamivudine or IFN-α courses may be tried. In a very recent case report, a patient with resistance to adefovir dipivoxil responded to subsequent lamivudine therapy.82
Treatment of patients with resistance to lamivudine
The wide use of lamivudine in chronic hepatitis B during the last 5 years has resulted in a constant increase in patients with YMDD mutant HBV strains,68 whose therapeutic approach must be different from that of naive or IFN-α-treated patients. Adefovir dipivoxil is the only approved agent that has been shown to be effective in patients with resistance to lamivudine, whilst entecavir is a potential candidate in this setting.38, 86
In recent clinical trials, the addition of adefovir dipivoxil to lamivudine therapy has been shown to achieve a significant reduction in serum HBV-DNA levels and an improvement in liver function tests and Child–Pugh score in decompensated cirrhotics or transplant patients with resistance to lamivudine, irrespective of HBeAg status.87–90 Adefovir dipivoxil has also been found to have similar anti-viral efficacy against all types of lamivudine-resistant YMDD mutant HBV strains.91 Moreover, in a small randomized study in patients with HBeAg-positive chronic hepatitis B and resistance to lamivudine, adefovir dipivoxil monotherapy was reported to have the same efficacy as the combination of adefovir dipivoxil and lamivudine.92
Entecavir, a carboxylic analogue of guanosine, has potent and selective inhibitory activity on all HBV polymerase functions.93 Entecavir has been found to be effective against lamivudine-resistant YMDD mutant HBV strains.94 In a recent, large, randomized clinical trial, entecavir monotherapy was found to be safe and effective in chronic hepatitis B patients who had failed lamivudine.95, 96 In particular, 48 weeks of entecavir therapy, at a dose of 1.0 mg daily, resulted in the reduction of serum HBV-DNA levels by a mean of 5.1 log10, a lack of detectability of serum HBV-DNA by a sensitive polymerase chain reaction assay in 26% of treated patients and biochemical remission in 68% of treated patients.96 Entecavir monotherapy has also been shown to be effective in inducing virological and biochemical remission in HBV liver transplant patients with resistance to lamivudine.97
In addition to adefovir dipivoxil and entecavir, IFN-α has also been evaluated in the treatment of chronic hepatitis B with resistance to lamivudine.38 However, the efficacy of IFN-α therapy has not yet been evaluated in any well-designed study in this setting, and therefore no conclusion can de drawn.
Future therapeutic options for chronic hepatitis b
Although the development of lamivudine and, recently, adefovir dipivoxil has offered hepatologists new therapeutic options against HBV, the management of chronic hepatitis B still remains sub-optimal. IFN-α monotherapy may achieve sustained off-therapy responses in a proportion of both HBeAg-positive and HBeAg-negative chronic hepatitis B patients (approximately 30% and 20–25%, respectively), but eventually the great majority (70–80%) will not respond.12, 14, 38, 86 Both lamivudine and adefovir dipivoxil may achieve sustained off-therapy responses in a proportion of patients with HBeAg-positive chronic hepatitis B (< 20%). However, few, if any, patients with HBeAg-negative chronic hepatitis B (< 10%) achieve sustained off-therapy responses, even after long-term lamivudine or adefovir dipivoxil therapy.12, 14, 38, 86 Therefore, lamivudine and adefovir dipivoxil may be used as maintenance therapeutic options in an effort to maintain on-therapy remission and prevent worsening of fibrosis in patients with advanced liver disease. Thus, it is obvious that better therapeutic agents or approaches are needed in the management of chronic hepatitis B.
Several newer anti-viral drugs, mainly nucleoside analogues, and immunomodulatory agents are currently under evaluation for the treatment of chronic hepatitis B. Newer anti-viral agents, such as emtricitabine (the 5-fluorinated derivative of lamivudine), clevudine (a pyrimidine analogue) and l-nucleosides (natural nucleosides in a β-l-configuration), particularly l-deoxythymidine, have provided promising results in preliminary phase I/II trials.38, 86, 98 Initial data on the efficacy of immunomodulatory approaches, such as interleukin-2 or interleukin-12, IFN-γ and vaccine-based therapies, have been relatively disappointing.38
In addition to monotherapies with new anti-viral agents, which are unlikely to result in the clearance of HBV from infected hepatocytes or in sustained off-therapy responses,68 combinations of therapeutic agents are also under evaluation for the treatment of chronic hepatitis B.99 Promising results from the combination of IFN-α or, recently, pegylated IFN-α and lamivudine have been reported in some studies,100–102 but not in others,103, 104 and thus no definite conclusions can de drawn. Moreover, it has recently been reported that a 52-week course of lamivudine and adefovir dipivoxil combination therapy does not seem to be superior to a 52-week course of lamivudine monotherapy.105 All of these data suggest that the efficacy of combination therapies cannot be easily extrapolated from in vitro or small preliminary clinical studies, and must be documented in well-designed, large, clinical trials. However, even the most promising data show that the currently evaluated combination therapies may improve the sustained off-therapy response rates compared with the available monotherapies, but are not expected to be effective in the majority of chronic hepatitis B patients. Therefore, we appear to be at the dawn of a new era, in which long-term maintenance treatment with safe and well-tolerated anti-viral agents seems to be the most realistic therapeutic option for the majority of chronic hepatitis B patients.106