The new EASL guidelines for the management of chronic hepatitis B infection adapted for Swiss physicians

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FULL TEXT: http://www.smw.ch/docs/PdfContent/smw-12969.pdfThe new EASL

guidelines for the management of chronic hepatitis Binfection adapted for Swiss

physiciansFlorian Bihla, Mahnaz Alaeia, Francesco Negroa,ba Division of

Gastroenterology and Hepatology, University Hospital, Geneva, Switzerlandb

Division of Clinical Pathology, University Hospital, Geneva, SwitzerlandAll

authors declare that they have no conflict of interest in relation to this

manuscript.SummarySince the arrival of several new antivirals and due to the

growing molecular and clinical knowledge ofhepatitis B virus (HBV) infection,

therapy of hepatitis B has become complex. Clinical guidelines aim

atstreamlining medical attitudes: in this respect, the European Association for

the Study of the Liver (EASL) recentlyissued clinical practice guidelines for

the management of chronic hepatitis B. Guidelines made by internationalexperts

need however to be adapted to local health care systems. Here, we summarise the

EASL guidelines withsome minor modifications in order to be compatible with the

particular Swiss situation, while discussing in moredetail some aspects. Chronic

hepatitis B is a complex disease with several phases where host and viral

factorsinteract: the features of this continuous interplay need to be evaluated

when choosing the most appropriatetreatment. The EASL guidelines recommend, as

first-line agents, using the most potent antivirals available withthe optimal

resistance profile, in order to abate HBV DNA as rapidly and as sustainably as

possible. Once therapyhas been started, the infection evolves and resistant

viral strains may emerge. Rescue therapy needs to be startedearly with more

potent agents lacking cross-resistance.Key words: hepatitis B virus; antiviral

resistance; cirrhosisIntroductionOver the last decades several guidelines for

the treatment of chronic hepatitis due to the hepatitis B virus(HBV), or chronic

hepatitis B (CHB), have been issued by many organisations and expert panels

aimed at definingdiagnostic criteria and guiding decisions regarding the

management of CHB. These documents aim at streamliningthe current attitude in

dealing with HBV infection and disease, based on currently available evidence.

Theguideline-based approach to healthcare is relatively recent, its objectives

being to standardise medical care, toimprove its quality, reduce risks and

achieve the best balance between cost and medical effectiveness.

However,guidelines are often issued at international level and thus may need to

be adapted to local healthcare systems [1].In this review, we will summarise the

consensus statements and algorithms of the recently issued “EASL

clinicalpractice guidelines for the management of chronic HBV†[2] with some

adaptations due to the peculiar Swisscontext.HBV infection can cause chronic

liver infection and hepatitis and is a global public health problem.Worldwide,

about two billion people have been infected with HBV, of whom over 350 million

are currently,chronically infected, accounting for about 700000 deaths per year

[3]. In Switzerland, about 6.5% of thepopulation has been infected with HBV,

with an estimated 20000 cases presently suffering from CHB [4] Theannual

incidence of HBV-related hepatocellular carcinoma (HCC) is high, i.e. between 2

and 5%, once cirrhosis isestablished [5]. In addition, the global and the local

Swiss epidemiology of HBV is continually evolving, due topopulation migration,

essentially from high to low endemicity countries.When approaching HBV therapy,

one should consider that CHB is a dynamic infection with five major phases(table

1), each of them potentially lasting for years or even decades. The correct

appreciation of these phases isfundamental for the treatment of CHB.

Schematically, HBV infection proceeds from a HBeAg-positive phase to

aHBeAg-negative one. HBeAg-positive chronic HBV infection presents usually with

high levels of viral replicationand infectivity: liver disease can be mild or

nil, reflecting host immune tolerance. Then, spontaneousseroconversion from

HBeAg to anti-HBe may occur, usually accompanied by a hepatitis flare-up. This

ischaracertised by increased serum transaminases and inflammatory infiltrates of

liver lobules and decreasing viraemia levels, signalling the attempt of the

host immune response to eliminate HBV-infected hepatocytes. Ifefficacious, this

immune elimination may evolve towards a phase of inactive HBV carriage, with

stably normaltransaminases, no or minimal liver damage, and low to undetectable

HBV DNA. HBeAg seroconversion is acommonly accepted, surrogate end-point of

treatment outcome, since it is associated with improved prognosis.However,

evolution towards a distinct entity, namely HBeAg-negative chronic hepatitis B,

is also possible. This isassociated with mutations in the HBV genome, preventing

the virus from secreting HBeAg, and is characterised byfluctuating

transaminases, lower HBV DNA levels and sometimes progressive disease. The

choice of treatmentdiffers according to the phase of infection, and will be

discussed below. Recently, moreover, eight genotypes ofHBV have been identified

(A through H). Growing evidence shows that the natural history and treatment

responsemay differ depending on the infecting HBV genotype. In general, genotype

A is associated with better response tointerferon treatment, with higher HBeAg

seroconversion rates (47%) than genotype B (44%), genotype C (28%) orD (25%)

[7]. Also disease progression seems to vary according to genotypes, since it

appears to be slower ingenotype B than in C [8], whereas genotype C and certain

subtypes of B appear to be associated with a higher riskof developing cirrhosis

and HCC [9]. However, further data are warranted before HBV genotyping can

berecommended for clinical decision making.Indication for treatment: who needs

to be treated and why?Chronic infection with HBV does not necessarily mean

chronic liver disease. Thus, the accurate assessment ofthe appropriate markers

over an appropriate time period (at least two laboratory tests over 12 months)

isfundamental to establish a correct diagnosis and the indication for treatment.

Thus, prior to starting antiviraltherapy, the severity of liver disease should

be assessed, and any potential co-morbidity should be ruled out (table2). A

complex and still controversial issue is the role of the liver biopsy in CHB.

Liver biopsy is an invasiveprocedure primarily aimed at determining the degree

of inflammation and fibrosis. The EASL guidelinesrecommend performing a biopsy

either when ALT levels are abnormal or when serum HBV DNA levels are above2000

IU/ml. Moreover, a liver biopsy is not deemed necessary if treatment is

indicated regardless of liver histologyor in case of clinical evidence of

cirrhosis. However, it remains an open question, whether patients in the

“immunetolerant†phase (e.g. perinatally infected patients) should undergo

biopsy. Such patients present with no or onlymild necro-inflammation without

fibrosis [6]. Thus, a liver biopsy is unlikely to change the treatment decision

inpatients who might not be eligible for treatment anyway.Indication for therapy

is based on the combination of three criteria: 1) Serum HBV DNA levels; 2)

Serumaminotransferase levels and 3) Histological grade and stage (table 3).

Thus, treatment is indicated when serumALT levels are above the upper limit of

normal (ULN) and/or liver biopsy shows moderate to severe

necroinflammationand/or fibrosis (≥A2 and/or ≥F2 in the METAVIR score)

and/or HBV DNA is above 2000 IU/ml (or10,000 copies/ml), with the notable

exception of patients in the immune tolerant phase. Decision making cofactorsfor

therapy are the patient’s age and health status and whether the patient will

have continuous access to theanti-viral agents (problematic are patients without

stable residency or immigrants from developing countrieswithout legal

status).The objective of therapy is to suppress HBV replication in a sustained

manner to prevent progression towardscirrhosis and HCC. Thus, the main goal of

the therapy is HBV DNA reduction below the limit of detection (10 IU/ml). As

known from the HIV field, sustained viral abatement is necessary to avoid the

risk of antiviral resistance.However, the expected end-points of treatment

depend on the selected therapy (interferon versus nucleos(t)ideanalogues: NUCs)

and accordingly, three levels of therapy goals in CHB are obtainable: 1)

Complete anddefinitive remission of CHB characterised by HBsAg loss (± anti-HBs

seroconversion) 2) Seroconversion to anti-HBe in HBeAg positive CHB with loss of

HBeAg and 3) Sustained undetectable HBV DNA while on treatment.