Journal of Hepatology
Volume 47, Issue 4 , Pages 588-597, October 2007

Best practice in the treatment of chronic hepatitis B: A summary of the European Viral Hepatitis Educational Initiative (EVHEI)☆☆☆

Department of Hepatology and Gastroenterology, St. Mary’s Hospital Campus, Imperial College, London, UK

published online 02 August 2007.

Associate Editor: R.P. Perrillo

Article Outline

Hepatitis B causes acute and chronic hepatitis, the latter resulting in cirrhosis and hepatocellular carcinoma. There are four phases of infection: during the phases of immune tolerance and immune control of the virus, no treatment is recommended but in the phases of immune clearance and immune escape, viraemia with biopsy evidence of significant fibrosis requires anti-viral therapy. The areas of agreement and disagreement between the various consensus statements are discussed. Health economic issues indicate that a trial of pegylated interferon should be offered in non-cirrhotic cases, particularly those that are HBe antigen positive, followed in those that do not establish a sustained viral response, by long term viral suppressive therapy with nucleoside analogues singly or in combination. The indications for treatment and methods of follow-up, as well as issues of viral resistance are discussed.

Keywords: Natural history of CHB, Immune tolerance, Immune clearance, Immune control and immune escape phases, Pegylated interferon and nucleoside therapies, Indications for treatment

 

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1. Phases of chronic hepatitis B infection and indications for therapy 

Chronic hepatitis B is defined as viraemia and hepatic inflammation continuing for more than 6 months following HBV infection. Most patients acquire the infection at birth or after a subclinical infection as an adult, so are unaware that they have been infected by the virus. The histological appearance may range from almost complete normality to various inflammatory states and cirrhosis, which may or may not show associated necro-inflammatory activity. The necro-inflammatory activity is graded (out of 18) and fibrosis expressed as a stage (out of 6) [1].

Chronic HBV infection generally passes through a series of stages, both virologically and clinically.

1.1. Virological classification 

‘HBe-positive virus’ infection is the form most commonly encountered in Northern Europe and North America where genotypes A and D are most common. The virus replicates and encodes infected liver cells to synthesize and secrete hepatitis B e antigen (HBeAg). As a result, HBeAg can be detected in the serum. As the infection continues, viral DNA can become integrated into the cellular DNA and after clearance of HBe antigen production of HBsAg can continue without viral replication.

‘HBe-negative virus’ infection has recently been recognized and is common with genotypes C and D. This is a variant form of HBV which can lead to productive viral infection without secretion of HBeAg. The HBe-negative virus is also known as the ‘pre-core mutant’, reflecting the mutation identified in the viral genome [2].

This form of the virus can emerge late in the course of infection in individuals initially infected with HBe-positive virus or can occur ab initio (particularly in patients from Mediterranean countries and the Far East).

1.2. Clinical classification 

In patients infected with HBe-positive virus, up to four stages of chronic infection (each of which may last for many years) may be described (Fig. 1).

  • View full-size image.
  • Fig. 1. 

    Stages of disease in patients infected with HBe-positive virus. Modification of Chu et al. [3]. Note: In Asian and Mediterranean patients the immune clearance phase may progress direct to the immune escape phase, with no period of immune control.

1.2.1. Immune tolerance phase 

Initially, particularly in those infected in utero or at birth, there may be high levels of viraemia (106–109 genomes per ml) without biochemical or histological evidence of hepatitis. During this phase therapy with interferon or nucleoside analogues is not indicated because therapy rarely induces HBe antigen clearance and control of viraemia is often incomplete resulting in selection of drug resistant variants.

1.2.2. Immune clearance phase 

Viraemia and HBe antigenaemia continue and there is increasing inflammatory necrosis of hepatocytes. HBV DNA is detectable at levels between 105 and 107 genomes per ml. As this phase continues the necroinflammatory process (hepatitis) may become sufficiently intense to result in clearance of HBeAg secreting infected hepatocytes and the development of anti-HBe. If the necroinflammation is prolonged, patients may develop cirrhosis. The phenomenon of loss of HBeAg and conversion to anti-HBe positivity is referred to as ‘HBe antigen/antibody seroconversion’. After this has occurred, there is a reduction of inflammation accompanied by histological change from active hepatitis to normal histology, or active cirrhosis to inactive cirrhosis. The spontaneous seroconversion rate is 5–10% per annum, although this varies between populations: HBe antigen clearance occurs most commonly with genotypes A and B.

Treatment during this phase with interferon or nucleoside analogues, usually for a finite period of 1 year, and then, in those that do not undergo ‘HBe antigen/antibody seroconversion’, prolonged maintenance viral suppressive therapy with nucleoside analogues, is indicated (see later).

1.2.3. Immune control phase (inactive HBs antigen carrier) 

This phase follows HBe antigen/antibody seroconversion; patients continue to produce HBsAg because of integrated sequences of viral DNA within host cell DNA but HBV replication is controlled by the cellular immune response at levels <105 genomes per ml. The liver may show normal histology, minimal hepatitis, or cirrhosis which is inactive, and the blood biochemistry may be normal.

Further treatment at this stage is not indicated in that it has no effect on clearance of HBs antigen. Despite the lack of HBeAg and HBV DNA present at only very low levels, the patient’s body fluids should still be considered infectious.

1.2.4. Immune escape phase (HBe negative viraemia/hepatitis) 

Further viraemia and hepatitis in the absence of HBe antigenaemia may follow, reflecting emergence (escape) of the HBe-negative (pre-core or core promoter mutant) strains of the virus from immune control. During this stage, transaminases become elevated and HBV DNA is detectable by PCR at concentrations of >105 genomes per ml, but HBeAg is not present in the serum. Continuing hepatitis in this phase may lead to cirrhosis. Treatment during this phase with interferon and then, in those that do not show sustained control of viraemia and resolution of hepatitis, maintenance viral suppressive therapy with nucleoside analogues, is indicated (see later).

In the second and fourth phases of the disease, when levels of viraemia are >105 genomes per ml, hepatitis may result in progressive fibrosis. Non-progressive disease, as exemplified by the inactive carrier state (immune control phase), is characterized by normal serum ALT, serum HBV DNA<104copies/ml. HBV DNA levels between 104 and 105copies/ml are an area of uncertainty.

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2. Who should be referred for specialist healthcare? 

Because of the difficulties in defining the various phases of CHB, most categories of chronic hepatitis B (viz. immune tolerance, immune clearance, immune control, and immune escape) should be referred for specialist healthcare.

For patients in the inactive carrier (immune control) phase, the disease course and long-term outcome are generally (although not invariably) benign [4], [5] and specialist referral is probably not necessary unless cirrhosis is present. These cases account for ∼60% of the chronic hepatitis B infections encountered in general practice. However because immune escape can occur at any time, albeit very infrequently, many argue that these individuals should be followed at yearly intervals with ALT testing for life.

All patients, regardless of HBeAg status, who exhibit elevated transaminase levels (i.e. the immune clearance and immune escape phases) are candidates for antiviral therapy and should be referred.

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3. Patient assessment following referral 

Assessment of the patient referred to the specialist from primary care comprises clinical assessment, laboratory examinations, imaging and liver histology. Clinical assessment consists of a detailed medical history, including family history of HBV infection and HCC common in families where the mother is infected and vertical transmission has occurred. Laboratory examinations involve serological tests of HBV infection (HBsAg, HBeAg/anti-HBe status and quantitative HBV DNA), liver function tests (serum ALT, AST, albumin, globulin, prothrombin and α-fetoprotein) and haematology. Serum HBV DNA levels should be determined using a sensitive and reliable technique with a linear sensitivity range from 102 to 1011copies(genomes/ml)(real-time PCR). It is important to consider HBV genotyping if considering interferon rather than nucleoside therapy: genotypes A and B have significantly better HBe antigen clearance rates than are seen in the other genotypes.

Imaging (upper abdomen ultrasound and Doppler examination) and liver histology are not required in all cases, but can provide important information. Liver histology is desirable: histology is useful not only for grading/staging liver disease, but also in excluding non-viral causes of liver damage. In several countries, therapy is only recommended if there is evidence on liver biopsy of fibrosis.

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4. Review and interpretation of the guidelines for management of HBV infection 

The decision as to whether to initiate treatment or to watch and wait is based upon a combined assessment of the patient’s medical history, laboratory tests (notably serum ALT), and level of ongoing viral replication (serum HBV DNA). To help guide healthcare providers in following evidence-based strategies to reduce the burden of HBV disease and improve patient outcomes, the major liver disease organizations have published consensus statements or treatment guidelines for the management of chronic hepatitis B, including the European Association for the Study of Liver Diseases (EASL Jury 2003), the Asian Pacific Association for the Study of the Liver [6], the American Gastroenterological Association Institute [7], the UK National Institute for Health and Clinical Excellence (NICE 2006) (http://www.nice.org), and the American Association for the Study of Liver Diseases [8]. The NICE guidelines differ from the other consensus documents in taking into consideration cost effectiveness, but have the drawback of under-estimating the impact of drug resistance because the evidence base is relatively short when assessing the clinical impact of viral drug resistance. The various guideline recommendations can be summarized for the different clinical subtypes of chronic hepatitis B.

4.1. HBeAg(+) chronic hepatitis B (non-cirrhotic) 

There is general agreement in the guidelines (Table 1) that when HBV DNA levels are ⩾105copies/ml and ALT levels are normal (immune tolerance phase) or mildly elevated (beginning of immune clearance phase), these patients should be monitored and treatment initiated only if the serum ALT level subsequently exceeds the 2×ULN threshold. Keeffe et al. [7] have pointed out that this is an arbitary definition and suggest that any elevation of ALT associated with viraemia should result in consideration of therapy. These guidelines point out that a substantial proportion of these patients are likely to have significant fibrosis and be candidates for treatment. A satisfactory compromise might be that these patients with viraemia and any ALT elevation should proceed to liver biopsy and if there is evidence of fibrosis, treatment should be offered.

Table 1. Summary of guideline recommendations for treatment of HBeAg(+) chronic hepatitis B (non-cirrhotic)
HBV DNAALTConsensus guideline
EASL 2003APASL 2005Keeffe et al. [7]NICE 2006AASLD 2007
⩾1×105copies/mlNormal or ⩽2×ULNNo treatment required. MonitorNo treatment required. Monitor every 3–6 monthsConsider liver biopsy or observe for elevated ALT. Treat with Peg-IFN, ADV or ETV if fibrosis presentNo treatment required. Consider treatment when ALT increasedMonitor. Consider biopsy, especially if age >40 years. Treat if biopsy shows moderate/severe inflammation or fibrosis
⩾1×105copies/ml>2×ULN Perform liver biopsy and treat if fibrosis is presentIFN as first-line treatment; LVD or ADV as second-lineIFN, Peg-IFN, LVD or ADV as first-line treatmentPeg-IFN, ETV or ADV as first-line treatmentPeg-IFN as first-line treatment; then maintenance LVD in IFN-non-responders. Add ADV if LDV resistantBiopsy optional. Treat if ALT persistently elevated. Peg-IFN, ADV or ETV preferred for first-line therapy
<1×105copies/mlNormal or ⩽2×ULN No treatment required

EASL, European Association for the Study of the Liver; APASL, Asian Pacific Association for Study of Liver; AASLD, American Association for Study of Liver Disease; NICE, UK National Institute of Clinical Excellence.

For patients with serum HBV DNA levels ⩾105copies/ml and serum ALT levels >2×ULN, some would argue that there are sufficient grounds to proceed to treatment without a confirmatory liver biopsy; others would argue that since treatment is likely to be long-term and incur an attendant risk of drug resistance, it should be limited to those patients with overt evidence of progressive liver disease (i.e. early fibrosis).

As regards choice of treatment, the various guidelines generally avoid recommending one particular drug, and instead leave the choice between the available licensed options (interferon, pegylated interferon, lamivudine, adefovir and entecavir) to the clinician’s discretion. In contrast, the NICE guidelines recommend initial use of pegylated-interferon as the most cost-effective treatment option in the HBeAg(+) patient. It is argued that since approximately one-third of these patients will clear HBeAg after 6 or 12 months of pegylated interferon therapy, this should be the preferred initial choice of treatment. The remaining two-thirds of patients, who fail to undergo HBe antigen/antibody conversion on pegylated-interferon, may be switched to long-term antiviral therapy (either lamivudine with add-on adefovir when resistance develops, or combination therapy). The NICE guidelines allow a number of treatment modifications that, although logical, are currently unsupported by evidence-based data. Thus, if lamivudine monotherapy fails to reduce the viral load to undetectable levels within the first 6 months, there is the option of adding adefovir immediately, before lamivudine resistance appears. For patients with pronounced viraemia (e.g. HBV DNA>107copies/ml) after the initial course of pegylated-interferon, there is the option of proceeding directly to combination nucleoside analogue therapy, which may be expected to reduce the risk of resistance. Possible future alternatives include the use of either entecavir or telbivudine instead of lamivudine, with add-on adefovir or tenovir, or ab initio use of combination entecavir or telbivudine plus adefovir or tenovir therapy. Future long-term studies will be required to establish the most clinically effective cost-effective therapy.

4.2. HBeAg(−) chronic hepatitis B (non-cirrhotic) 

Again there is a general consensus that treatment is not required for HBeAg(−) patients with serum HBV DNA levels <105copies/ml and normal (immune control phase) or minimally elevated ALT levels (late immune clearance phase) (Table 2).

Table 2. Summary of guideline recommendations for treatment of HBeAg(−) chronic hepatitis B (non-cirrhotic)
HBV DNAALTConsensus guideline
EASL 2003APASL 2005Keeffe et al. [7]NICE 2006AASLD 2007
⩾1×105copies/mlNormal or ⩽2×ULNNo treatment requiredNo treatment requiredConsider liver biopsy or observe for elevated ALT. Treat with Peg-IFN, ADV or ETV if fibrosis presentNo treatment requiredHBV DNA ⩾1×104copies/ml: Monitor and consider biopsy if ALT persistently elevated. Treat as required by biopsy findings
⩾1×105copies/ml>2×ULN. Perform liver biopsy and treat those with fibrosisIFN as first-line treatment; LVD or ADV as second-line. Long-term treatment requiredPeg-IFN, LVD or ADV preferred as first-line treatment; duration ⩾1 yearPeg-IFN, ADV or ETV as first-line treatment. Long-term treatment required with oral agentsPeg-IFN as first-line treatment, then maintenance LVD in IFN-non-responders. Add ADV if LDV resistantHBV DNA ⩾1×105copies/ml: Biopsy optional. Treat if ALT persistently elevated. Peg-IFN or ADV preferred as first-line treatment; duration ⩾1 year
<1×105copies/mlNormal or ⩽2×ULNNo treatment requiredNo treatment requiredNo treatment; monitor every 3 months on initial diagnosis and then every 6–12 monthsNo treatment requiredMonitor every 6–12 months

For those with higher levels of viraemia (HBV DNA⩾105copies/ml) and normal or minimally elevated ALT levels, there is agreement that treatment is probably not required. However, the problem posed by this latter group of patients (i.e. immune escape phase) is that a normal serum ALT, particularly if in the upper ‘normal range’, does not exclude the possibility of progressive liver disease: approximately 10–40% of patients with viral loads ⩾105copies/ml and serum ALT levels in the upper half of the normal range have stage 2 or higher fibrosis [9], [10]. Furthermore serum ALT may be intermittently elevated, and it is possible to have significant inflammatory liver disease, without persistent elevation of serum ALT. For this reason, the American Gastroenterological Association Institute guidelines recommend liver biopsy for this group of patients (i.e. those with viraemia but apparently normal ALT levels); alternatively, repeated 6-monthly serum ALT monitoring may be considered. The serum ALT levels at which patients are likely to show abnormal biopsy results are >30IU/ml in men and >19IU/ml in women.

All currently licensed anti-HBV drugs are considered appropriate for first-line treatment of HBeAg(−) patients, although the NICE guidelines are more specific in recommending the use of pegylated-interferon as initial therapy. It is argued that, since ∼20% of HBeAg(−) patients can be expected to achieve sustained viral suppression after 12 or more months of pegylated-interferon therapy, it is economically expedient to start treatment in this manner before committing the patient to long-term nucleoside analogue therapy. However, the rationale for this approach is questionable: there is substantial risk of relapse in each additional year of follow-up following interferon therapy in the HBeAg(−) patient, and hence the economic benefits of a strategy of universal interferon treatment followed by maintenance nucleoside analogue therapy in interferon non-responders are unclear. An alternative approach permitted under the NICE guidelines, which may be more appropriate for the HBeAg(−) patient, is to initiate treatment with a nucleoside analogue rather than pegylated-interferon. NICE recommend lamivudine with addition of adefovir should resistance occur, as the most cost effective approach. Other possible treatment options include entecavir (or, in future, telbivudine) with use of add-on adefovir or tenovir, if resistance to the primary drug develops. NICE are currently evaluating the cost effectiveness of these therapies against currently recommended lamivudine with add-on adefovir if resistance occurs.

For patients with viraemia (HBV DNA⩾105copies/ml) and elevated ALT (>2×ULN) (immune escape phase) – who will require long-term therapy once started and are therefore at increased risk of developing drug resistance – many clinicians would advocate biopsy and confine treatment to those with fibrosis, on the grounds that this latter group is likely to have progressive liver disease.

4.3. Chronic hepatitis B with cirrhosis 

With respect to the management of chronic hepatitis B with cirrhosis, the major difference between the various guidelines relates to the viral load required to trigger treatment (Table 3). In contrast to the various consensus documents, which suggest a viral load threshold of >105copies/ml for initiating treatment, the American Gastroenterological Association Institute guidelines argue that, since cirrhotic patients have reduced hepatic cell mass and are at risk of decompensation, any level of viraemia is disadvantageous and therefore the HBV DNA threshold for initiating treatment should be lowered (Table 4). However, there are to date no randomized controlled trials to substantiate this approach. Nucleoside analogue-induced viral suppression is preferable in these patients because an interferon-induced flare can precipitate hepatic decompensation; most of the consensus documents, including NICE, advise against the use of pegylated interferon if there is a risk of decompensation (which is applicable to all cirrhotic patients). Accordingly, for cirrhotic patients, and particularly those who are HBeAg(−), there is a much stronger rationale to start treatment with a nucleoside analogue rather than with interferon.

Table 3. Summary of guideline recommendations for treatment of chronic hepatitis B with cirrhosis
HBV DNAClinical statusConsensus guideline
EASL 2003APASL 2005Keeffe et al. [7]NICE 2006AASLD 2007
<1×105copies/mlCompensatedObserve. If decompensated, refer for transplantObserve. If decompensated, refer for transplantOption to treat if HBV DNA detectable; ADV or ETV preferredObserve. If decompensated, refer for transplantTreat if HBV DNA ⩾1×104copies/ml and ALT ⩽2×ULN, or (irrespective of HBV DNA) if ALT >2×ULN. ADV or ETV is preferred. If decompensated, treat with LVD and/or ADV and refer for transplant
⩾1×105copies/mlCompensatedIFN, LVD or ADV. If decompensated, treat with LVD or ADV and refer for transplantLVD or ADV. If decompensated, avoid Peg-IFN; refer for transplantADV or ETV as first-line treatment. Long-term treatment required, possibly with combination therapyLVD or ADV. If decompensated, avoid Peg-IFN; refer for transplant
Table 4. Guideline criteria for selecting HBV-infected patients for treatment
ParameterGuideline
EASL 2003, APASL 2005Keeffe et al. [7], AASLD 2007
HBeAg(+) patients without cirrhosis
Viral load>105copies/ml>105copies/ml
ALT and biopsy>2×ULN+fibrosis on biopsy>30IU/ml (men)
>19IU/ml (women)
+fibrosis on biopsy
HBeAg(−) patients without cirrhosis
Viral load>105copies/ml>104copies/ml
ALT and biopsy>2×ULN+fibrosis on biopsy>30IU/ml (men)
>19IU/ml (women)
+fibrosis on biopsy
Patients with compensated cirrhosis
Viral load>105copies/ml>104copies/mla
Patients with decompensated cirrhosis
TransplantationRefer for transplant
Viral load>105copies/ml: treatConsider treatment regardless of HBV DNA level

aIf viral load <104copies/ml, may choose to observe or treat.

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5. Monitoring the HBV-infected patient 

How should virological test results be used in selecting patients for anti-HBV treatment and assessing patient response?

5.1. Patient selection 

The use of serum HBV DNA levels as an indicator for treatment is complicated by the fact that intermediary levels (∼102–105copies/ml) can be present both in active HBeAg(+) and (−) disease and in the inactive carrier state. Serum HBV DNA levels >105copies/ml (in the case of HBeAg(+) patients) and >104copies/ml (HBeAg(−) patients) generally indicate the presence of active hepatitis and hence the need for treatment. Serum HBV DNA levels <102copies/ml are in most, if not all, cases indicative of the inactive carrier state. The intermediary level of 102–105copies/ml presents a real problem and there is considerable uncertainty as to how to use readings within this range to make treatment decisions. The problem is exemplified by the results of a study of the diagnostic and prognostic significance of HBV DNA levels in a homogeneous cohort of 597 HBeAg(−) patients chronically infected with HBV genotype D [11]. Clear demarcation in HBV DNA levels was evident between patients with chronic hepatitis (defined by ⩾1 abnormal ALT reading in the preceding 2 years) HBV DNA(>104IU/ml) and inactive carriers (<104IU/ml). However, among patients with chronic hepatitis, serum HBV DNA level (unlike serum ALT level) showed no significant correlation with histological activity; instead, there was substantial overlap in serum HBV DNA level between patients with Metavir A0–A1 and A2–A3 scores. Thus, while HBeAg(−) patients with genotype D-related HBV who show repeatedly normal serum ALT levels and HBV DNA levels <104copies/ml can be considered inactive carriers and unlikely to require treatment, for those with chronic hepatitis (i.e. a history of ALT elevation and HBV DNA levels >104copies/ml) a single HBV DNA determination is not a reliable indicator of histological disease activity or fibrosis. For these patients, the decision to treat must be based upon a specific assessment of liver disease severity by liver biopsy.

5.2. Monitoring the patient response 

In therapeutic terms, patients essentially fall into two main groups: those in whom a sustained response can be expected (predominantly patients with HBeAg(+) disease and elevated ALT) and those in whom it cannot (HBeAg(+) patients who have unfavourable prognostic factors (normal ALT) or have previously failed to achieve a sustained response on short-term therapy, and the vast majority of HBeAg(−) patients). The first group are candidates for short-term therapy with either pegylated-interferon or a nucleoside analogue, while the second group requires long-term (probably life-long) treatment with nucleoside analogues. There is strong support in certain Mediterranean countries (notably Italy and Greece) for extending short-term therapy to HBeAg(−) patients, although the argument for this is less convincing the longer the patients are followed.

Monitoring of response is relatively straightforward in those patients who are candidates for short-term therapy: therapeutic endpoints in HBeAg(+) patients are HBeAg and HBsAg seroconversion, whereas in HBeAg(−) patients they are sustained viral load reduction (albeit unlikely in the vast majority of such patients) and sustained normalization of serum ALT levels. For those patients who are candidates for long-term therapy, the goal of treatment is to achieve as profound and long-lasting inhibition of viral replication as possible, and monitoring is based upon regular HBV DNA assays. Monitoring at 6 months after starting therapy and every 3 months thereafter allows the identification of primary treatment failure or suboptimal response to therapy, and secondary treatment failure (defined as a ⩾1log increase in viral load above the nadir) due to drug resistance.

5.3. When can treatment be discontinued? 

In patients treated with interferon, who are expected to show a sustained treatment response, treatment is discontinued on completion of the designated 6- or 12-month course of therapy. In this setting, a finite course of therapy is of demonstrated benefit in clearing HBeAg and improving long-term survival in HBeAg(+) patients [12], [13]. In HBeAg-positive patients treated with nucleoside analogues, treatment can be stopped 6 months after HBe/antiHBe seroconversion.

Short-term therapy can also improve prognosis in HBeAg(−) disease: patients who achieve a sustained virological response after short-term pegylated-interferon therapy have lower rates of hepatic complications on long-term follow-up than non-sustained responders [13].

For those patients who are not expected to show a sustained response, the general rule is that nucleoside analogue therapy should be continued indefinitely [14], since viral replication will resume if treatment is interrupted. However, recent evidence suggests that sustained biochemical and virological remission can be maintained after discontinuation of successful long-term nucleoside analogue therapy [15]. It was found that two-thirds of HBeAg(−) patients maintained normal ALT levels and serum HBV DNA levels <5×104copies/ml for periods of 15–20 months when adefovir treatment was stopped after 4 or 5 years of continuous administration [15]. Further studies are needed to settle this issue.

5.4. Long-term prognosis: is disease regression feasible? 

Therapeutic endpoints employed in randomized clinical trials of chronic hepatitis B have altered over recent years, with the earlier emphasis on improvement in liver histology giving way to the current emphasis on reduction in viral load. In order to assess the effect of antiviral treatment on long-term prognosis we have to rely on late-stage endpoints such as decompensation, hepatocellular carcinoma and liver-related mortality, which will only be provided by large-scale post-marketing-surveillance studies.

The possibility of drug-induced disease regression can be assessed by examining the effects of anti-HBV treatments on rates of progression from chronic hepatitis to cirrhosis. Both pegylated interferon and the nucleoside analogues may significantly reduce necroinflammation and fibrosis, even during short-term therapy, as the result of active suppression of viral replication.

In HBeAg(+) disease, histological improvement (necroinflammation and fibrosis combined) occurs in ∼50% of patients after 12 months’ treatment with pegylated-interferon [16].

In HBeAg(−) disease, improvements in necroinflammation and fibrosis (⩾2-point reductions in HAI scores) are seen in ∼50% and 15% of patients, respectively, on follow-up (24-week) biopsy after 12 months’ treatment with pegylated interferon [17].

With respect to the nucleoside analogues, improvements in necroinflammation and fibrosis (⩾2-point reduction in total HAI score) and bridging fibrosis (⩾1-point reduction in HAI fibrosis score) are seen in ∼60% of HBeAg(+) patients on long-term (median 3.5 years) lamivudine therapy [18]. Similar response rates are obtained for regression of bridging fibrosis, with 44% of HBeAg(−) patients showing a ⩾2-point reduction in HAI fibrosis score after 3 years’ treatment with lamivudine [19]. Corresponding data for adefovir indicate that improvements in necroinflammation and fibrosis (⩾2-point reductions in HAI scores) occur in ∼70–80% and ∼40–50%, respectively, of HBeAg(+) and HBeAg(−) patients after 12 months’ treatment [20], [15]. The improvement in fibrosis is further consolidated on prolongation of adefovir therapy: the proportion of HBeAg(−) patients showing a ⩾1-point reduction in Ishak fibrosis score was reported to rise from 33% after 1 year to 71% after 5 years of continuous treatment, and 50% of patients showed regression of bridging fibrosis or cirrhosis [21]. For the newer nucleoside analogues, histological improvement (⩾2-point reduction in HAI necroinflammation score with no worsening of fibrosis) was reported in ∼70% of HBeAg(+) and HBeAg(−) patients after 12 months’ treatment with entecavir [22], [23] and telbivudine [24].

The beneficial effect of nucleoside analogues on necroinflammation is, however, blunted on discontinuation of treatment or emergence of YMDD variants [18]. In contrast, the improvement in fibrosis appears to be more stable, persisting after cessation of treatment. In the majority of patients, achievement of sustained viral suppression is associated with regression of fibrosis; it is unclear, however, whether complete cirrhosis regresses. Prevention of the late-stage endpoints of chronic hepatitis B (decompensation, hepatocellular carcinoma and HBV-related mortality) as the result of treatment-induced regression of early-stage disease (necroinflammation, fibrosis and cirrhosis) is highly likely, but this will only be demonstrated on long-term (⩾10-year) follow-up.

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6. Unresolved issues in the management of chronic hepatitis B 

6.1. How can treatment selection criteria be improved? 

More precise and stringent definition of treatment selection criteria – which patients need to be treated and how they can be identified – is needed. Appropriate patient selection is the key to rational and cost-effective treatment of chronic hepatitis B. There is a much greater likelihood of obtaining a sustained response and HBe/HBs antigen seroconversion in the patient with active liver disease than in the patient who presents in the immune tolerant phase of the disease. However, it is the healthy asymptomatic carrier who may have unrecognized underlying progressive liver disease who presents the greatest therapeutic challenge. At least one-third of HBV carriers have intermittent lobular hepatitis and these patients may present for annual monitoring with normal transaminase and undetectable HBV DNA levels. Identification of these patients requires more dynamic monitoring and more specific tests of liver function.

Another question is whether the decision to initiate treatment should be based on the presence of hepatic inflammatory activity alone, or whether evidence of fibrosis (usually an indicator of risk of disease progression) should also be required.

6.2. How should intermediary HBV DNA levels be interpreted? 

Intermediate HBV DNA levels (∼102–105copies/ml) do not currently provide the clinician with clear treatment guidance.

6.3. Do treatment objectives need to be reassessed? 

While achievement of undetectable HBV DNA levels facilitates HBeAg seroconversion, the ultimate goal of treatment is to achieve HBsAg seroconversion. Future trials in chronic hepatitis B should focus on HBsAg seroconversion, as well as the existing endpoints of control of viraemia and inflammatory liver disease, as a therapeutic endpoint and, in order to improve treatment efficacy (i.e. HBsAg seroconversion rate), clinical trials should assess combination nucleoside analogue plus immunomodulator (e.g. pegylated-interferon) therapy, since achievement of HBsAg seroconversion probably requires modulation of the immune response as well as suppression of viral replication.

Finally, long-term follow-up of patients attaining adequate control of viraemia and inflammatory liver disease with the various regimens needs to be undertaken to build on the existing observation that therapy with anti-virals also controls liver related mortality from decompensated liver disease and hepatocellular carcinoma [25].

6.4. Do clinical trials in chronic hepatitis B need to be re-focused? 

The objective for the patient receiving monotherapy with a nucleoside analogue should be achievement of undetectable HBV DNA (using a sensitive PCR assay) at either 24 or 48 weeks; once this is achieved, the patient can be maintained on monotherapy. For the patient who fails to achieve this goal within the specified time, it is unacceptable to persist with monotherapy, since this needlessly increases the risk of resistance; instead, switching to an alternative treatment or use of add-on therapy should be encouraged. Rather than conducting clinical trials in the entire patient population, there is a case for focusing on treatment-refractory patients – i.e. those patients who have failed to achieve the goal of undetectable HBV DNA after 24 or 48 weeks of nucleoside analogue monotherapy. With this in mind, decisions need to be reached regarding the most appropriate drug combinations to investigate in clinical trials; in particular, what is the optimal combination of first-line and rescue nucleoside analogue therapy? One obstacle is that the pharmaceutical industry is often reluctant to sponsor trials of combination therapies involving competitor drugs. Furthermore, clinical trials are required to determine the optimal strategy for minimizing the risk of drug resistance: should combination therapy be introduced sequentially after a predefined period of monotherapy or should it be used ab initio? Are there subgroups where each approach is appropriate?

6.5. Is continuous life-long nucleoside analogue therapy necessary? 

In light of recent evidence that HBeAg(−) patients can remain in clinical remission for appreciable periods (>1 year) after discontinuation of long-term adefovir therapy [26], the need for expensive life-long nucleoside analogue therapy may need to be reassessed. Rather than maintaining patients on treatment indefinitely, withdrawal and recommencement of therapy may be an option in appropriate cases.

6.6. How can chronic hepatitis B management be better coordinated? 

There is a need for clinicians, national health authorities and the pharmaceutical industry to act jointly and co-operatively to ensure that chronic hepatitis B treatment evolves in a rational manner and that the mistake of engendering multidrug-resistant HBV is avoided. Where several drugs are available, cost effectiveness evaluation is needed but must be based on data obtained on patients treated over several years.

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Acknowledgements 

The manuscript was developed by Howard Thomas (H.C.T.) in conjunction with International Medical Press. EVHEI is run by International Medical Press and is in receipt of educational grants from BMS and Valeant. The article is based on a paper presented at the meeting by H.C.T.

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References 

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☆ This article is based on the proceedings of the 2nd European Viral Hepatitis Educational Initiative (EVHEI) workshop held in Frankfurt, Germany, on 23–24 November 2006. The EVHEI faculty includes: Howard Thomas, MD (Chair), Ferrucio Bonino, MD, Graham Foster, MD, Stephanos Hadziyannis, MD, Michael Manns (Co-chair), MD, Patrick Marcellin, MD, Rafael Esteban-Mur, MD, Jean-Michel Pawlotsky, MD, Christian Trépo, MD, Ran Tur-Kaspa, MD, and Fabien Zoulim, MD.

☆☆ The author declares that the manuscript was developed by Howard C. Thomas (H.C.T.) in conjunction with International Medical Press. EVHEI is run by International Medical Press and is in receipt of educational grants from BMS and Valeant. The article is based on a paper presented at the meeting by H.C.T. The participants travel and accommodation were supported by the meeting’s sponsors. The author attends the International Advisory Boards of BMS, Genome Sciences, Roche, Gilead and Idenix/Novartis.

PII: S0168-8278(07)00413-8

doi:10.1016/j.jhep.2007.07.017

Journal of Hepatology
Volume 47, Issue 4 , Pages 588-597, October 2007

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