EASL Clinical Practice Guidelines

Methodology

These EASL CPGs represent an update of the last EASL HBV CPGs published in early 2009. They were developed by a CPG Panel of experts chosen by the EASL Governing Board, peer-reviewed by the experts of the 2009 HBV CPGs and approved by the EASL Governing Board. The CPGs have been based as far as possible on evidence from existing publications, and, if evidence was unavailable, on the experts' personal experience and opinion. Manuscripts and abstracts of important meetings published prior to September 2011 have been evaluated. The evidence and recommendations in these guidelines have been graded according to the Grading of Recommendations Assessment Development and Evaluation (GRADE) system. The strength of recommendations thus reflects the quality of underlying evidence. The principles of the GRADE system have been enunciated. The quality of the evidence in these CPGs has been classified in one of three levels: high (A), moderate (B) or low (C). The GRADE system offers two grades of recommendation: strong (1) or weak (2) (Table 1). The CPGs thus consider the quality of evidence: the higher the quality of evidence, the more likely a strong recommendation is warranted; the greater the variability in values and preferences, or the greater the uncertainty, the more likely a weaker recommendation is warranted [[32], [33], [34], [35], [36], [37]]. Grades are not provided for definitions. For practical reasons, months and not weeks were used in parts of the manuscript (e.g. 6 and 12 months instead of 24 and 48/52 weeks, respectively).


Table 1
Grading of evidence and recommendations (adapted from the GRADE system) [[32], [33], [34], [35], [36], [37]].

End points of therapy

Therapy must ensure a degree of virological suppression that will then lead to biochemical remission, histological improvement and prevention of complications. The ideal end point is HBsAg loss, which however is infrequently achievable with the currently available anti-HBV agents. A more realistic end point is the induction of sustained or maintained virological remission.

  1. In HBeAg-positive and HBeAg-negative patients, the ideal end point is sustained off-therapy HBsAg loss, with or even without seroconversion to anti-HBs. This is associated with a complete and definitive remission of the activity of CHB and an improved long-term outcome (A1).
  2. Induction of sustained off-therapy virological and biochemical response in HBeAg-negative patients (either HBeAg-positive cases at baseline with durable anti-HBe seroconversion or HBeAg-negative cases from baseline) is a satisfactory end point, because it has been shown to be associated with improved prognosis (A1).
  3. A maintained virological remission (undetectable HBV DNA by a sensitive PCR assay) under long-term antiviral therapy in HBeAg-positive patients who do not achieve anti-HBe seroconversion and in HBeAg-negative patients is the next most desirable end point (A1).

Definitions of response

Responses can be divided into biochemical, serological, virological and histological. All responses can be estimated at several time points during and after therapy. The definitions of virological responses vary according to the timing (on or after therapy) and type of therapy. Two different types of drugs can be used in the treatment of CHB: conventional or pegylated interferon alpha (IFN or PEG-IFN) and nucleoside/nucleotide analogues referred to collectively as NAs in this document.

Biochemical response is defined as normalisation of ALT levels. It can be evaluated at several time points on-therapy, at the end and after the end of therapy. Since ALT activity often fluctuates over time, a minimum follow-up of at least 1 year post-treatment with ALT determinations at least every 3 months is required to confirm sustained off-treatment biochemical response (B1). It should be noted that the rates of sustained off-treatment biochemical responses may sometimes be difficult to evaluate, as transient (usually ⩽3 months duration) ALT elevations before long-term biochemical remission may occur in some CHB patients within the first year after treatment discontinuation. In such cases, additional close ALT follow-up of at least 2 years after ALT elevation seems to be reasonable in order to confirm sustained off-therapy biochemical remission (C2).

Serological response for HBeAg applies only to patients with HBeAg-positive CHB and is defined as HBeAg loss and seroconversion to anti-HBe.

Serological response for HBsAg applies to all CHB patients and is defined as HBsAg loss and development of anti-HBs.

Virological responses on IFN/PEG-IFN therapy:

  • Primary non-response has not been well established.
  • Virological response is defined as an HBV DNA concentration of less than 2000 IU/ml. It is usually evaluated at 6 months and at the end of therapy as well as at 6 and 12 months after the end of therapy.
  • Sustained off-treatment virological response is defined as HBV DNA levels below 2000 IU/ml for at least 12 months after the end of therapy.

Virological responses on NA therapy:
  • Primary non-response is defined as less than 1 log10 IU/ml decrease in HBV DNA level from baseline at 3 months of therapy.
  • Virological response is defined as undetectable HBV DNA by a sensitive PCR assay. It is usually evaluated every 3–6 months during therapy depending on the severity of liver disease and the type of NA.
  • Partial virological response is defined as a decrease in HBV DNA of more than 1 log10 IU/ml but detectable HBV DNA after at least 6 months of therapy in compliant patients.
  • Virological breakthrough is defined as a confirmed increase in HBV DNA level of more than 1 log10 IU/ml compared to the nadir (lowest value) HBV DNA level on therapy; it may precede a biochemical breakthrough, characterised by an increase in ALT levels. The main causes of virological breakthrough on NA therapy are poor adherence to therapy and/or selection of drug-resistant HBV variants (resistance) (A1).
  • HBV resistance to NA(s) is characterised by selection of HBV variants with aminoacid substitutions that confer reduced susceptibility to the administered NA(s). Resistance may result in primary non-response or virological breakthrough on therapy (A1).
  • NA(s) discontinuation is not common practice to date. However, NA(s) may be discontinued in some patients. Sustained off-treatment virological response may be defined similarly to the definition used for IFN therapy, which requires HBV DNA values below 2000 IU/ml for at least 12 months after treatment discontinuation.
Histological response is defined as decrease in necroinflammatory activity (by ⩾2 points in HAI or Ishak's system) without worsening in fibrosis compared to pre-treatment histological findings.

Complete response is defined as sustained off-treatment virological response together with loss of HBsAg.

Indications for treatment

The indications for treatment are generally the same for both HBeAg-positive and HBeAg-negative CHB. This is based mainly on the combination of three criteria:

  • Serum HBV DNA levels.
  • Serum ALT levels.
  • Severity of liver disease.
Patients should be considered for treatment when they have HBV DNA levels above 2000 IU/ml, serum ALT levels above the upper limit of normal (ULN) and severity of liver disease assessed by liver biopsy (or non-invasive markers once validated in HBV-infected patients) showing moderate to severe active necroinflammation and/or at least moderate fibrosis using a standardised scoring system (A1). In patients who fulfil the above criteria for HBV DNA and histological severity of liver disease, treatment may be initiated even if ALT levels are normal (A1). Indications for treatment may also take into account age, health status, family history of HCC or cirrhosis and extrahepatic manifestations.The need for liver biopsy and treatment should be considered separately in the following subgroups of patients

  • Immunotolerant patients: HBeAg-positive patients under 30 years of age with persistently normal ALT levels and a high HBV DNA level, without any evidence of liver disease and without a family history of HCC or cirrhosis, do not require immediate liver biopsy or therapy. Follow-up at least every 3–6 months is mandatory (B1). Consider liver biopsy or even therapy in such patients over 30 years of age and/or with a family history of HCC or cirrhosis.
  • HBeAg-negative patients with persistently normal ALT levels (ALT determinations at least every 3 months for at least 1 year) and HBV DNA levels above 2000 but below 20,000 IU/ml, without any evidence of liver disease, do not require immediate liver biopsy or therapy (B1). Close follow-up with ALT determinations every 3 months and HBV DNA every 6–12 months for at least 3 years is mandatory (C1). After 3 years, they should be followed for life like all inactive chronic HBV carriers. Evaluation of the severity of fibrosis by a non-invasive method, such as Fibroscan, might be useful in such cases (C2).
  • Patients with obviously active CHB: HBeAg-positive and HBeAg-negative patients with ALT above 2 times ULN and serum HBV DNA above 20,000 IU/ml may start treatment even without a liver biopsy (B1). In such patients, liver biopsy may provide additional useful information, but it does not usually change the decision for treatment. A non-invasive method for the estimation of the extent of fibrosis and most importantly to confirm or rule out cirrhosis is extremely useful in patients who start treatment without liver biopsy (B1).
  • Patients with compensated cirrhosis and detectable HBV DNA must be considered for treatment even if ALT levels are normal (B1).
  • Patients with decompensated cirrhosis and detectable HBV DNA require urgent antiviral treatment with NA(s). Significant clinical improvement can be associated with control of viral replication [[60], [61], [62]]. However, antiviral therapy may not be sufficient to rescue some patients with very advanced liver disease who should be considered for liver transplantation at the same time (A1).