Clinical Practice Guidelines

EASL clinical practice guidelines on the management of hepatitis B

infection

The guidelines were published in full in the August 2017 issue of the Journal of Hepatology
The full publication can be downloaded from the Clinical Practice Guidelines section of the EASL website
Please cite the published article as: European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol 2017;67:370–98

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These slides are intended for use as an educational resource and should not be used in isolation to make patient management decisions. All information included should be verified before treating patients or using any therapies described in these materials

Buti, Harry LA Janssen, George Papatheodoridis, Fabien Zoulim, Frank Tacke

(EASL Governing Board representative)

Reviewers
Maurizia Brunetto, Henry Chan, Markus Cornberg

Guideline panel

EASL CPG HBV. J Hepatol 2017;67:370–98

2008:336:924–6; EASL CPG HBV. J Hepatol 2017;67:370–98
Grading is adapted from the

GRADE system1

2017;67:370–98; 2. Schweitzer A, et al. Lancet 2015;386:1546–55; 3. Ott

JJ, et al. Vaccine 2012;30:2212–9; 4. GBD 2013 Mortality and Causes of Death Collaborators. Lancet 2015;385:117–71; 5. Coppola N, et al. Euro Surveill 2015;20:30009; 6. Hampel A, et al. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2016;59:578–83; 7. Chen C-L, et al. J Hepatol 2015;63:354–63.

Worldwide ≈250 million chronic HBsAg carriers2,3
686,000 deaths from HBV-related liver disease and HCC in 20134

2,000 and 20,000 IU/mL in some patients without signs of

chronic hepatitis; †Persisitently or intermittently, based on traditional ULN (~40 IU/L). ‡cccDNA can frequently be detected in the liver;
§Residual HCC risk only if cirrhosis has developed before HBsAg loss. EASL CPG HBV. J Hepatol 2017;67:370–98

The natural history of chronic HBV infection has been schematically divided into five phases

Chronic HBV
infection

Chronic hepatitis B

Hepatol 2017;67:847–61; 2. EASL CPG HBV. J Hepatol 2017;67:370–98

for treatment
Monitoring of patients currently not treated
Treatment strategies
Definition of response

to treatment
NA monotherapy
PegIFN monotherapy
Combination therapy
Patients with decompensated cirrhosis
Prevention of HBV recurrence after liver transplantation
Treatment in special patient groups

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of the chronic HBV infection;
†Achieved in most patients with long-term

suppression of HBV replication;
‡Indicates profound suppression of HBV replication and viral protein expression EASL CPG HBV. J Hepatol 2017;67:370–98

Goals
Improve survival and quality of life by preventing disease progression and HCC
Prevent mother-to-child transmission, hepatitis B reactivation, and prevent and treat HBV-associated extrahepatic manifestations

and/or at least moderate liver necroinflammation or fibrosis;
†Defined by persistently

normal ALT and high HBV DNA levels;
‡ Even if typical treatment indications are not fulfilled
EASL CPG HBV. J Hepatol 2017;67:370–98

Primarily based on the combination of 3 criteria
HBV DNA, serum ALT and severity of liver disease

2017;67:370–98
Patients with no current indication of antiviral therapy should be

monitored
Periodical assessments of serum ALT, HBV DNA and non-invasive markers for liver fibrosis

slide. EASL CPG HBV. J Hepatol 2017;67:370–98

features
*Stopping NAs after some years might be considered in selected

cases; †Psychiatric, neurological, endocrinological; ‡Uncertainties regarding kidney function, bone diseases for some NAs; §Decompensated disease, comorbidities etc.; ‖Dose adjustments in patients with eGFR <50 ml/min are required for all NAs except for TAF (no dose recommendation for TAF in patients with CrCl <15 ml/min who are not receiving haemodialysis); ¶Depending on baseline characteristics; **Slowly increases with treatment time in HBeAg-positive patients (a plateau in serological responses has been observed beyond treatment Year 4), usually very low in HBeAg-negative patients; ††So far no TDF or TAF resistance development has been detected EASL CPG HBV. J Hepatol 2017;67:370–98

traditional ULN (~40 IU/L);
†By ≥2 points in HAI or Ishak’s

system EASL CPG HBV. J Hepatol 2017;67:370–98

administration of a potent NA with a high barrier to

resistance is the treatment of choice
Regardless of severity of liver disease

with a high barrier to resistance*
*Evidence level I, grade of

recommendation 1; †Collation of currently available data – not from head-to-head studies;
‡No evidence of resistance has been shown after 8 years of TDF treatment
EASL CPG HBV. J Hepatol 2017;67:370–98

Cumulative incidence of HBV resistance to NAs in pivotal trials in NA-naïve patients with chronic hepatitis B†

preferred to ETV in patients with previous exposure to NAs;

†ETV dose needs to be adjusted if eGFR <50 ml/min; no dose adjustment of TAF is required in adults or adolescents (aged ≥12 years and ≥35 kg body weight) with estimated CrCl ≥15 ml/min or in patients with CrCl <15 ml/min who are receiving haemodialysis
EASL CPG HBV. J Hepatol 2017;67:370–98

In some circumstances ETV or TAF may be a more appropriate treatment choice than TDF

al. J Hepatol 2018;68:67281
Median change from baseline in eGFR over

96 weeks
TAF 25 mg (n=866) vs. TDF 300 mg (n=432)

TAF

TDF

TAF: -1.2

TDF: -4.8

p<0.001

al. J Hepatol 2018;68:67281
Median change from baseline in BMD over

96 weeks
TAF 25 mg (n=866) vs. TDF 300 mg (n=432)

TAF

TDF

Hip

Spine

TAF

TDF

p<0.001

p=0.80

should be performed every 3–4 months during the first year

and every 6 months thereafter. Serum HBV DNA should be determined every 3–4 months during the first year and every 6–12 months thereafter; †Including at least eGFR and serum phosphate levels. Frequency of renal monitoring can be every 3 months during the first year and every 6 months thereafter, if no deterioration. Closer renal monitoring is required in patients who develop CrCl <60 ml/min or serum phosphate levels <2 mg/dl; ‡Depending on previous LAM exposure
EASL CPG HBV. J Hepatol 2017;67:370–98

Periodical monitoring and long-term surveillance is required in patients treated with an NA with a high barrier to resistance

with NAs is usually required
HBV eradication is not usually achieved

recommendation 1; †Evidence level II-2, grade of recommendation 1;
‡Amino

acid substitution profiles. Level of susceptibility is given for each drug: S (sensitive), I (intermediate/reduced susceptibility), R (resistant); §In vitro data for tenofovir, in vivo data for TDF, no clinical data for TAF
EASL CPG HBV. J Hepatol 2017;67:370–98

Compliance with therapy should be checked in all cases of treatment failure*
Management of treatment failure should be based on cross-resistance data†

Cross-resistance data for the most frequent NA-resistant HBV variants:

recommendation 1; †Especially in patients with ADV-resistant mutations (rA181T/V and/or

rN236T) and high viral load, the response to TDF (TAF) can be protracted; ‡Not seen clinically so far; do genotyping and phenotyping in an expert laboratory to determine the cross-resistance profile; §The long-term safety of these combinations is unknown
EASL CPG HBV. J Hepatol 2017;67:370–98

Treatment should be adapted as soon as virological failure under NAs is confirmed*

disease should generally be considered for treatment with PegIFN

treated with PegIFN require ongoing monitoring during treatment and after

virological response

of recommendation 2; †Evidence level II-2, grade of recommendation 1
EASL

CPG HBV. J Hepatol 2017;67:370–98

not recommended

decompensated cirrhosis should be referred for liver transplantation and treated with

NAs as early as possible

2017;67:370–98
All patients who are candidates for liver transplantation should be treated

with NAs to achieve undetectable HBV DNA
Reduce the risk of graft infection

2017;67:370–98
HCV co-infection accelerates liver disease progression and increases the risk of

HCC in patients with chronic HBV infection
All patients with chronic HBV infection should be screened for HCV and other blood-borne viruses

J Hepatol 2017;67:370–98
The risk of fibrosis progression, cirrhosis and HCC

is greater in patients also infected with HDV or HIV

2017;67:370–98
Preventing the risk of acute or subacute liver failure is

the main treatment goal
Treating to improve quality of life and reducing risk of chronicity are also relevant treatment goals

may depend on severity of liver disease and timing of

a future pregnancy

HBV. J Hepatol 2017;67:370–98

HBV. J Hepatol 2017;67:370–98

Hepatol 2017;67:370–98
Some extrahepatic manifestations can be associated with HBV infection
Vasculitis,

skin manifestations (purpura), polyarteritis nodosa, arthralgias, peripheral neuropathy and glomerulonephritis
HBsAg-positive patients with extrahepatic manifestations and active HBV replication may respond to antiviral therapy
PegIFN can worsen some immune-mediated extrahepatic manifestations

biomarkers
cccDNA – limited by need for liver biopsy, will

be important in clinical trials
HBcrAg – composite biomarker, utility still under evaluation
HBV RNA – strong correlation with intrahepatic cccDNA, possible utility in predicting viral rebound after discontinuation of NAs
Future treatment options for HBV
Several novel direct-acting antivirals and immunotherapeutic agents are in preclinical and early clinical development
Combinations of antiviral and immune modulatory therapy, targeting multiple steps in the HBV lifecycle, will likely be needed to achieve an HBV ‘cure’
Future treatment options for HDV
Several candidates are under evaluation in clinical trials, mainly in combination with PegIFN and/or NAs
Whenever possible, enrolment in these clinical trials of new agents should be considered, either as a rescue of PegIFN or in treatment-naïve patients

J Hepatol 2016;64:S117–31

to start antiviral therapy in patients with HBeAg-positive chronic HBV infection
Stopping

rules for HBeAg-negative patients treated with an NA
Retreatment criteria after NA discontinuation
How to accelerate HBsAg decline in long-term NA-treated patients
Better baseline or on-treatment predictors of sustained response in patients treated with PegIFN
Definition of the residual risk of HCC in patients on long-term NA therapy and impact on surveillance
Requirement for new treatments with finite duration and high cure rates
Novel endpoints to define a cure of HBV infection
Biomarkers for the cure of infection and for the cure of liver disease