EASL 2017 Clinical Practice Guidelines on the …

1 Clinical Practice Guidelines EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infectionq European Association for the Study of the Liver . Summary infection require specific focus. Future treatment strategies to achieve cure' of disease and new biomarkers are discussed. Hepatitis B virus (HBV) infection remains a global public health 2017 European Association for the Study of the Liver. Published problem with changing epidemiology due to several factors by Elsevier All rights reserved. including vaccination policies and migration. This Clinical Prac- tice Guideline presents updated recommendations for the opti- mal management of HBV infection.

2 Chronic HBV infection can be classified into five phases: (I) HBeAg-positive chronic infec- Introduction tion, (II) HBeAg-positive chronic hepatitis, (III) HBeAg-negative chronic infection, (IV) HBeAg-negative chronic hepatitis and (V) Infection with hepatitis B virus (HBV) remains an important glo- HBsAg-negative phase. All patients with chronic HBV infection bal public health problem with significant morbidity and mortal- are at increased risk of progression to cirrhosis and hepatocellular 3 New information on the pathogenesis and management of carcinoma (HCC), depending on host and viral factors. The main HBV infection has become available since the previous EASL Clin- goal of therapy is to improve survival and quality of life by pre- ical Practice Guidelines (CPGs) prepared in 2011 and published in venting disease progression, and consequently HCC development.

3 The objective of this manuscript is to update the recom- The induction of long-term suppression of HBV replication repre- mendations for the optimal management of HBV infection. In sents the main endpoint of current treatment strategies, while order to keep the manuscript and particularly the reference list HBsAg loss is an optimal endpoint. The typical indication for within a reasonable length, only references published after treatment requires HBV DNA [2,000 IU/ml, elevated ALT and/or 2012 have been considered, since the readers can find the older at least moderate histological lesions, while all cirrhotic patients supportive references in the 2012 EASL HBV The CPGs with detectable HBV DNA should be treated.]

4 Additional indica- do not fully address prevention including vaccination. In addi- tions include the prevention of mother to child transmission in tion, despite increasing knowledge, areas of uncertainty still exist pregnant women with high viremia and prevention of HBV reac- and therefore clinicians, patients and public health authorities tivation in patients requiring immunosuppression or chemother- must continue to make choices based on the evolving evidence. apy. The long-term administration of a potent nucleos(t)ide analogue with high barrier to resistance, , entecavir, tenofovir disoproxil or tenofovir alafenamide, represents the treatment of choice.

5 Pegylated interferon-alfa treatment can also be consid- Background ered in mild to moderate chronic hepatitis B patients. Combina- tion therapies are not generally recommended. All patients Epidemiology and public health burden should be monitored for risk of disease progression and HCC. Treated patients should be monitored for therapy response and Approximately 240 million people are chronic HBV surface anti- adherence. HCC remains the major concern for treated chronic gen (HBsAg) carriers, with a large regional variation of HBsAg- hepatitis B patients. Several subgroups of patients with HBV positive patients between low (\2%) and high ([8%) endemicity ,4 The prevalence is decreasing in several highly endemic countries due to improvements in the socioeconomic status, uni- versal vaccination programs and perhaps effective antiviral treat- Keywords: Hepatitis B; EASL Guidelines ; Treatment; Interferon; Entecavir; However, population movements and migration are Tenofovir; TAF; HBsAg; Hepatocellular carcinoma; HBV DNA; HBV reactivation.]

6 Currently changing the prevalence and incidence in several low Mother to child transmission. Received 23 March 2017 ; accepted 23 March 2017 . endemic countries in Europe ( , Italy, Germany), owing to the q Clinical Practice Guidelines panel: Chair: Pietro Lampertico; Panel members: higher HBsAg prevalence rates in migrants and refugees from Kosh Agarwal, Thomas Berg, Maria Buti, Harry Janssen, George Papatheodor- outside Europe compared with the indigenous ,7. idis, Fabien Zoulim; EASL Governing Board representative: Frank Tacke. Even with universal vaccination programs, it has been impossible Corresponding author. Address: European Association for the Study of the Liver to substantially prevent acute cases of HBV infection, especially (EASL), The EASL Building Home of Hepatology, 7 rue Daubin, CH 1203 Geneva, Switzerland.

7 Tel.: +41 (0) 22 807 03 60; fax: +41 (0) 22 328 07 24. in high risk ,9 The number of HBV related deaths E-mail address: due to liver cirrhosis and/or hepatocellular carcinoma (HCC). Journal of Hepatology 2017 vol. 67 j 370 398. JOURNAL OF HEPATOLOGY. increased between 1990 and 2013 by 33%, relating to [686,000 infection progresses through distinct disease phases that are cases in 2013 strongly associated with age. It has been observed that children and young adults with chronic HBV infection have an immune Virology and immunopathogenesis profile that is less compromised than that observed in older patients, challenging the concept of immune tolerance'.]

8 16 Several The viral life cycle studies showed that HBV persists with virus-specific and global T. Human HBV belongs to the Hepadnaviridae family of small, envel- cell dysfunction mediated by multiple regulatory mechanisms, oped, primarily hepatotropic DNA viruses. In the host, the virus but without distinct T cell based immune signatures for Clinical replicates and assembles exclusively in hepatocytes, and virions phenotypes (or Clinical phase of infection).16,17 Genome-wide are released non-cytopathically through the cellular secretory association studies recently identified the INTS10 gene at pathway. The viral genome shows an extremely compact organ- as a novel locus contributing to the susceptibility to per- isation.

9 The small ( kb), partially double-stranded, relaxed- sistent HBV infection among Chinese subjects, and being causa- circular (rc) DNA features 4 open reading frames encoding 7 pro- tive for HBV clearance by activation of IRF3 and then expression teins: HBeAg (HBV e antigen, secreted dimeric protein), HBcAg of anti-virus interferons hereby highlighting the role of innate (HBV core antigen, viral capsid protein), HBV Pol/RT (polymerase, immunity in viral reverse transcriptase activity), PreS1/PreS2/HBsAg (large, med- ium, and small surface envelope glycoproteins), and HBx (HBV Natural history and new nomenclature for the chronic states x antigen, regulator of transcription required for the initiation of infection).

10 11,12 Upon viral uptake into hepatocytes, the HBV Chronic HBV infection is a dynamic process reflecting the interac- nucleocapsid is transported to the nucleus to release the rcDNA tion between HBV replication and the host immune response and genome. In the nucleoplasm, the rcDNA is converted into a cova- not all patients with chronic HBV infection have chronic hepatitis lently closed circular DNA (cccDNA), which is wrapped by his- (CHB). The natural history of chronic HBV infection has been tones to form an episomal chromatinized structure. It then schematically divided into five phases, taking into account the serves as a transcription template for all viral transcripts that presence of HBeAg, HBV DNA levels, alanine aminotransferase are translated into the different viral Besides encoding (ALT) values and eventually the presence or absence of liver the capsid protein and the viral polymerase, the pregenomic RNA inflammation (Fig.)