Current Best Practice in Hepatitis B Management and Understanding Long-term Prospects for Cure

The hepatitis B virus (HBV) is a major cause of cirrhosis and hepatocellular carcinoma worldwide. Despite an effective vaccine, the prevalence of chronic infection remains high. Current therapy is effective at achieving on-treatment, but not off-treatment, viral suppression. Loss of hepatitis B surface antigen, the best surrogate marker of off-treatment viral suppression, is associated with improved clinical outcomes. Unfortunately, this end point is rarely achieved with current therapy because of their lack of effect on covalently closed circular DNA, the template of viral transcription and genome replication. Major advancements in our understanding of HBV virology along with better understanding of immunopathogenesis have led to the development of a multitude of novel therapeutic approaches with the prospect of achieving functional cure (hepatitis B surface antigen loss) and perhaps complete cure (clearance of covalently closed circular DNA and integrated HBV DNA). This review will cover current best practice for managing chronic HBV infection and emerging novel therapies for HBV infection and their prospect for cure. The hepatitis B virus (HBV) is a major cause of cirrhosis and hepatocellular carcinoma worldwide. Despite an effective vaccine, the prevalence of chronic infection remains high. Current therapy is effective at achieving on-treatment, but not off-treatment, viral suppression. Loss of hepatitis B surface antigen, the best surrogate marker of off-treatment viral suppression, is associated with improved clinical outcomes. Unfortunately, this end point is rarely achieved with current therapy because of their lack of effect on covalently closed circular DNA, the template of viral transcription and genome replication. Major advancements in our understanding of HBV virology along with better understanding of immunopathogenesis have led to the development of a multitude of novel therapeutic approaches with the prospect of achieving functional cure (hepatitis B surface antigen loss) and perhaps complete cure (clearance of covalently closed circular DNA and integrated HBV DNA). This review will cover current best practice for managing chronic HBV infection and emerging novel therapies for HBV infection and their prospect for cure. The hepatitis B virus (HBV) is a small hepatropic DNA virus that has been infecting humans for millennia. An ancestral strain was likely present in hunter-gatherers during the early Holocene period (approximately 20,000–12,000 years ago).1Kocher A. Papac L. Barquera R. et al.Ten millennia of hepatitis B virus evolution.Science. 2021; 374: 182-188Crossref PubMed Scopus (11) Google Scholar During human evolution, spread of HBV was likely facilitated by the establishment of agrarian societies in the Neolithic and Bronze Ages.2Locarnini S.A. Littlejohn M. Yuen L.K.W. Origins and evolution of the primate hepatitis B virus.Front Microbiol. 2021; 12653684Crossref PubMed Scopus (3) Google Scholar Currently, it is estimated that more than 2 billion persons have been exposed to HBV, of which 296 million (approximately 3.7% of the human population) have chronic infection.3Polaris Observatory CollaboratorsGlobal prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study.Lancet Gastroenterol Hepatol. 2018; 3: 383-403Abstract Full Text Full Text PDF PubMed Scopus (889) Google Scholar,4Schweitzer A. Horn J. Mikolajczyk R.T. et al.Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013.Lancet. 2015; 386: 1546-1555Abstract Full Text Full Text PDF PubMed Scopus (1760) Google Scholar Chronic HBV infection is responsible for approximately 820,000 deaths annually worldwide from complications of cirrhosis and hepatocellular carcinoma (HCC).5World Health Organization. Hepatitis B key facts. Available at: https://www.who.int/news-room/fact-sheets/detail/hepatitis-b. Accessed January 21, 2022.Google Scholar Despite the availability of an effective vaccine, approximately 1.5 million new infections occur annually. Nevertheless, the HBV vaccine has had a profound impact on the prevalence of chronic HBV infection and complication rate, particularly in high prevalence regions.6Chang M.H. Shau W.Y. Chen C.J. et al.Hepatitis B vaccination and hepatocellular carcinoma rates in boys and girls.JAMA. 2000; 284: 3040-3042Crossref PubMed Google Scholar,7Chang M.H. You S.L. Chen C.J. et al.Long-term effects of hepatitis B immunization of infants in preventing liver cancer.Gastroenterology. 2016; 151: 472-480.e471Abstract Full Text Full Text PDF PubMed Google Scholar Given the significant burden on global public health, the World Health Organization has set a goal of complete eradication of HBV by 2030, defined as a 65% reduction in mortality and a 90% reduction in incidence compared with the baseline levels obtained in 2015.8Cox A.L. El-Sayed M.H. Kao J.H. et al.Progress towards elimination goals for viral hepatitis.Nat Rev Gastroenterol Hepatol. 2020; 17: 533-542Crossref PubMed Scopus (63) Google Scholar Currently, only 12% of countries are on track to meet World Health Organization elimination targets.9CDA Foundation. Analysis.https://cdafound.org/polaris-public-faq/#sec13Date accessed: February 14, 2022Google Scholar The intact virion or Dane particle has an outer lipid envelope that surrounds a viral nucleocapsid containing the viral DNA and polymerase. The genome is partially double-stranded DNA with 4 overlapping open reading frames that encode for the following 7 viral proteins: polymerase; core; hepatitis B e antigen (HBeAg); large, middle, and small hepatitis B surface antigen (HBsAg); and X protein.10Tsukuda S. Watashi K. Hepatitis B virus biology and life cycle.Antiviral Res. 2020; 182104925Crossref PubMed Scopus (59) Google Scholar The viral life cycle is illustrated in Figure 1. During replication, double-stranded linear DNA forms are produced (approximately 5%–10%) that may integrate randomly into the host genome by using random sites of host cell DNA breaks.11Pollicino T. Caminiti G. HBV-integration studies in the clinic: role in the natural history of infection.Viruses. 2021; 13: 368Crossref PubMed Scopus (23) Google Scholar Apart from being a constant source of RNA and viral proteins, integration is also considered to be a contributor to the development of HCC. A substantial proportion of HBsAg may be derived from integrated HBV DNA, particularly among HBeAg-negative patients12Wooddell C.I. Yuen M.F. Chan H.L. et al.RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg.Sci Transl Med. 2017; 9eaan0241Crossref PubMed Scopus (259) Google Scholar (Figure 1), suggesting that HBsAg loss may ultimately require the elimination of integrated HBV DNA. The immune response contributes to both HBV clearance and liver injury. HBV does not readily activate the intracellular innate defense mechanisms including type I interferon (IFN) pathway.13Wieland S. Thimme R. Purcell R.H. et al.Genomic analysis of the host response to hepatitis B virus infection.Proc Natl Acad Sci U S A. 2004; 101: 6669-6674Crossref PubMed Scopus (550) Google Scholar,14Wieland S.F. Chisari F.V. Stealth and cunning: hepatitis B and hepatitis C viruses.J Virol. 2005; 79: 9369-9380Crossref PubMed Scopus (376) Google Scholar However, HBV replication is inhibited by pharmacological activation of type I/III IFNs and intracellular antiviral sensors, such as the Toll-like receptors (TLRs) and retinoid acid inducible gene-I (RIG-I)–like receptors, as well as exogenous IFN therapy.15Chang J. Guo J.T. Treatment of chronic hepatitis B with pattern recognition receptor agonists: current status and potential for a cure.Antiviral Res. 2015; 121: 152-159Crossref PubMed Scopus (31) Google Scholar HBV can also induce type III IFN through the interaction between the HBV pregenomic RNA and RIG-I16Sato S. Li K. Kameyama T. et al.The RNA sensor RIG-I dually functions as an innate sensor and direct antiviral factor for hepatitis B virus.Immunity. 2015; 42: 123-132Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar and with a biphasic IFN-stimulated gene induction in hepatocytes in vitro.17Shlomai A. Schwartz R.E. Ramanan V. et al.Modeling host interactions with hepatitis B virus using primary and induced pluripotent stem cell-derived hepatocellular systems.Proc Natl Acad Sci U S A. 2014; 111: 12193-12198Crossref PubMed Scopus (185) Google Scholar In addition, natural killer (NK) and NKT cells can be activated early in acutely HBV-infected patients.18Fisicaro P. Valdatta C. Boni C. et al.Early kinetics of innate and adaptive immune responses during hepatitis B virus infection.Gut. 2009; 58: 974-982Crossref PubMed Scopus (225) Google Scholar Thus, once HBV replication is established in hepatocytes, type III IFN and activation of NK and Kupffer cells may help to modulate viral replication and viral spread during the early stages of infection. As for the adaptive immune response, T cells play a key role in HBV clearance and liver disease pathogenesis, as shown in experimental animal models.19Guidotti L.G. Chisari F.V. Immunobiology and pathogenesis of viral hepatitis.Annu Rev Pathol. 2006; 1: 23-61Crossref PubMed Scopus (594) Google Scholar CD8 T cells directly recognize and kill (or cure) virus-infected hepatocytes that express viral epitopes on class I major histocompatibility complex, whereas CD4 T cells provide critical T-cell help and orchestrate the overall adaptive immune response. In acutely HBV-infected patients, spontaneous viral clearance and disease resolution are characterized by broadly specific and durable antiviral CD8 and CD4 T-cell responses, as well as HBsAg-specific neutralizing antibody response. Importantly, memory T-cell response to HBV can persist for decades after clinical resolution of acute HBV infection, maintained by trace amounts of virus in vivo20Rehermann B. Ferrari C. Pasquinelli C. et al.The hepatitis B virus persists for decades after patients' recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response.Nat Med. 1996; 2: 1104-1108Crossref PubMed Scopus (712) Google Scholar and likely mediating virus control—raising the possibility for their role in sustained virus control of HBV post therapy. Similarly, a critical role for B cells in HBV control is suggested by HBV reactivation by immunosuppressive regimens that deplete B cells.21Hwang J.P. Barbo A.G. Perrillo R.P. Hepatitis B reactivation during cancer chemotherapy: an international survey of the membership of the American Association for the Study of Liver Diseases.J Viral Hepat. 2015; 22: 346-352Crossref PubMed Scopus (40) Google Scholar,22Di Bisceglie A.M. Lok A.S. Martin P. et al.Recent US Food and Drug Administration warnings on hepatitis B reactivation with immune-suppressing and anticancer drugs: just the tip of the iceberg?.Hepatology. 2015; 61: 703-711Crossref PubMed Scopus (160) Google Scholar Evolution of acute HBV infection to chronic likely involves both host and viral factors,23Milich D. Liang T.J. Exploring the biological basis of hepatitis B e antigen in hepatitis B virus infection.Hepatology. 2003; 38: 1075-1086Crossref PubMed Scopus (316) Google Scholar,24Asabe S. Wieland S.F. Chattopadhyay P.K. et al.The size of the viral inoculum contributes to the outcome of hepatitis B virus infection.J Virol. 2009; 83: 9652-9662Crossref PubMed Scopus (227) Google Scholar although precise mechanisms are not well defined. Established chronic HBV infection is characterized by both HBV-specific and global T-cell25Ferrari C. Boni C. Rossi M. et al.T cell regulation in HBV-related chronic liver disease.J Hepatol. 2017; 66: 1096-1098Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,26Park J.J. Wong D.K. Wahed A.S. et al.Hepatitis B virus-specific and global T-cell dysfunction in chronic hepatitis B.Gastroenterology. 2016; 150: 684-695.e685Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar and B-cell dysfunction,27Salimzadeh L. Le Bert N. Dutertre C.A. et al.PD-1 blockade partially recovers dysfunctional virus-specific B cells in chronic hepatitis B infection.J Clin Invest. 2018; 128: 4573-4587Crossref PubMed Scopus (135) Google Scholar,28Burton A.R. Pallett L.J. McCoy L.E. et al.Circulating and intrahepatic antiviral B cells are defective in hepatitis B.J Clin Invest. 2018; 128: 4588-4603Crossref PubMed Scopus (145) Google Scholar due to prolonged exposure to viral antigens and inflammatory mediators, which leads to immune exhaustion with the induction of regulatory pathways and immune checkpoints, including regulatory T cells, PD-1,29Bengsch B. Martin B. Thimme R. Restoration of HBV-specific CD8+ T cell function by PD-1 blockade in inactive carrier patients is linked to T cell differentiation.J Hepatol. 2014; 61: 1212-1219Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar and CTLA-4,26 in addition to altered γδ T cells30Chang K.M. Traum D. Park J.J. et al.Distinct phenotype and function of circulating Vdelta1+ and Vdelta2+ gammadeltaT-cells in acute and chronic hepatitis B.PLoS Pathog. 2019; 15e1007715Crossref Scopus (18) Google Scholar and metabolic immune dysregulation through myeloid-derived suppressor cells and arginase31Fisicaro P. Barili V. Rossi M. et al.Pathogenetic mechanisms of T cell dysfunction in chronic HBV infection and related therapeutic approaches.Front Immunol. 2020; 11: 849Crossref PubMed Scopus (39) Google Scholar and antiviral T-cell elimination through activated NK cells and death pathways (eg, Bim).31Fisicaro P. Barili V. Rossi M. et al.Pathogenetic mechanisms of T cell dysfunction in chronic HBV infection and related therapeutic approaches.Front Immunol. 2020; 11: 849Crossref PubMed Scopus (39) Google Scholar,32Lopes A.R. Kellam P. Das A. et al.Bim-mediated deletion of antigen-specific CD8 T cells in patients unable to control HBV infection.J Clin Invest. 2008; 118: 1835-1845Crossref PubMed Scopus (173) Google Scholar Lacking adaptive immune control, nonspecific inflammatory infiltrates combining innate and adaptive immune cells accumulate in HBV-infected liver and promote hepatocellular injury and fibrosis without virus suppression.33Traum D. Wang Y.J. Schwarz K.B. et al.Highly multiplexed 2-dimensional imaging mass cytometry analysis of HBV-infected liver.JCI Insight. 2021; 6e146883Crossref PubMed Scopus (10) Google Scholar Thus, immune-mediated HBV therapy requires a fine balance between immune control of the virus and hepatocellular injury to avoid adverse clinical consequences. HBV vaccination has resulted in a significant reduction in both disease prevalence and complications of HBV, including HCC.6Chang M.H. Shau W.Y. Chen C.J. et al.Hepatitis B vaccination and hepatocellular carcinoma rates in boys and girls.JAMA. 2000; 284: 3040-3042Crossref PubMed Google Scholar,7Chang M.H. You S.L. Chen C.J. et al.Long-term effects of hepatitis B immunization of infants in preventing liver cancer.Gastroenterology. 2016; 151: 472-480.e471Abstract Full Text Full Text PDF PubMed Google Scholar In the United States, the Advisory Committee on Immunization Practices34Centers for Disease Control and Prevention. Hepatitis B vaccination: information for healthcare providers. Available at: https://www.cdc.gov/vaccines/vpd/hepb/hcp/index.html. Accessed February 18, 2022.Google Scholar recommends vaccination of all infants, children, adolescents, and adults through 59 years of age, as well as adults older than 60 years with risk factors. Additional information regarding available infant, child, adolescent, and adult vaccines; vaccinee schedules; and at-risk populations are provided in Supplementary Tables 1 and 2. The primary goal of therapy is to prevent cirrhosis, development of HCC, and liver-related mortality. However, these end points take decades to develop. Therefore, studies evaluating therapies for chronic HBV infection have relied on surrogate end points. These include undetectable HBV DNA using a sensitive polymerase chain reaction–based assay, normalization of serum alanine aminotransferase (ALT), loss of HBeAg, loss of HBsAg, and histologic improvement. HBsAg loss is considered the best end point because it is associated with durable suppression of HBV DNA and improvement in clinical outcomes, such as hepatic decompensation, hepatocellular carcinoma, and liver-related death.35Lok A.S. Zoulim F. Dusheiko G. et al.Hepatitis B cure: from discovery to regulatory approval.J Hepatol. 2017; 67: 847-861Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar,36Cornberg M, Lok AS, Terrault NA, et al. Guidance for design and endpoints of clinical trials in chronic hepatitis B - report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference [published online ahead of print November 12, 2019]. Hepatology https://doi.org/10.1002/hep.31030.Google Scholar However, as reported in 2 meta-analyses, the rate of spontaneous and treatment-related HBsAg loss is low, approximately 1% annually.37Yeo Y.H. Ho H.J. Yang H.I. et al.Factors associated with rates of HBsAg seroclearance in adults with chronic HBV infection: a systematic review and meta-analysis.Gastroenterology. 2019; 156: 635-646.e639Abstract Full Text Full Text PDF PubMed Google Scholar,38Zhou K. Contag C. Whitaker E. et al.Spontaneous loss of surface antigen among adults living with chronic hepatitis B virus infection: a systematic review and pooled meta-analyses.Lancet Gastroenterol Hepatol. 2019; 4: 227-238Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar Chronic hepatitis B (CHB) is a dynamic disease characterized by frequent fluctuations in disease activity. Historically, HBeAg status, HBV DNA, and ALT levels are used to assess disease activity. The 3 major liver societies, the American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver (EASL), and the Asian Pacific Association for the Study of the Liver (APASL) have provided guidance on indications for treatment (Table 1).39Terrault N.A. Lok A.S.F. McMahon B.J. et al.Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.Hepatology. 2018; 67: 1560-1599Crossref PubMed Scopus (1716) Google Scholar, 40European Association for the Study of the LiverEASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.J Hepatol. 2017; 67: 370-398Abstract Full Text Full Text PDF PubMed Scopus (2817) Google Scholar, 41Sarin S.K. Kumar M. Lau G.K. et al.Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update.Hepatol Int. 2016; 10: 1-98Crossref PubMed Scopus (1405) Google Scholar In addition, the World Health Organization has developed a more simplified approach to treatment for low- and middle-income countries that may lack access to viral load testing.42World Health Organization. Guidelines for the Prevention, Care and Treatment of Persons With Chronic Hepatitis B Infection. Published March 15, 2015http://apps.who.int/iris/bitstream/handle/10665/154590/9789241549059_eng.pdfGoogle Scholar All guidelines strongly agree that patients with decompensated liver disease, cirrhosis, and those with active disease (defined as those with elevated HBV DNA and ALT levels) should receive treatment. There are minor regional differences in the choice of HBV DNA level (eg, HBV DNA level of 20,000 IU/mL [AASLD and APASL] or 2000 IU/mL [EASL] in an HBeAg-positive patient) and ALT cutoffs (either twice the laboratory upper limit of normal [ULN] [APASL and EASL], above the ULN if moderate liver necroinflammation or fibrosis is present [EASL], or gender-specific ALT cutoffs –35 U/L for male patients and 25 U/L for female patients [AASLD]) to initiate therapy. Similarly, there is general agreement that patients whose disease is inactive (HBeAg-negative with low HBV DNA [<2000 IU/mL]) and with normal ALT levels can be safely observed without the need for treatment. There is some controversy on how patients with elevated HBV DNA but normal (≤1 × ULN) or mildly elevated ALT levels (>1 to <2 × ULN) should be managed. In these situations, obtaining additional evidence on disease severity, either through a liver biopsy or noninvasive assessment of fibrosis, is advised to assist in decision making. Among noninvasive tests, transient elastography43Singh S. Muir A.J. Dieterich D.T. et al.American Gastroenterological Association Institute technical review on the role of elastography in chronic liver diseases.Gastroenterology. 2017; 152: 1544-1577Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar or shear wave elastography44Herrmann E. de Ledinghen V. Cassinotto C. et al.Assessment of biopsy-proven liver fibrosis by two-dimensional shear wave elastography: an individual patient data-based meta-analysis.Hepatology. 2018; 67: 260-272Crossref PubMed Scopus (243) Google Scholar generally have higher diagnostic accuracy over serum biomarkers, such as APRI and FIB-4, and are therefore preferred for assessing fibrosis in the absence of a liver biopsy (Supplementary Tables 3 and 4). Noninvasive tests perform better at excluding than establishing advanced fibrosis/cirrhosis. In addition, other factors, such as age older than 40 years, family history of HCC, lengthy disease duration, HBsAg level ≥1000 IU/mL, and a patient’s willingness to receive treatment should be considered in the decision to recommend therapy.39Terrault N.A. Lok A.S.F. McMahon B.J. et al.Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.Hepatology. 2018; 67: 1560-1599Crossref PubMed Scopus (1716) Google Scholar, 40European Association for the Study of the LiverEASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.J Hepatol. 2017; 67: 370-398Abstract Full Text Full Text PDF PubMed Scopus (2817) Google Scholar, 41Sarin S.K. Kumar M. Lau G.K. et al.Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update.Hepatol Int. 2016; 10: 1-98Crossref PubMed Scopus (1405) Google Scholar,45Chen C.J. Yang H.I. Su J. et al.Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level.JAMA. 2006; 295: 65-73Crossref PubMed Scopus (2506) Google Scholar,46Chen C.F. Lee W.C. Yang H.I. et al.Changes in serum levels of HBV DNA and alanine aminotransferase determine risk for hepatocellular carcinoma.Gastroenterology. 2011; 141 (1248.e1241–e1242): 1240-1248Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar Other indications for treatment or prophylaxis are listed in Table 2.Table 1Indications for Treatment by Liver Society Guidelines and World Health OrganizationIndicationAASLDEASLAPASLWHOCirrhosis (any detectable HBV DNA)TreatTreatTreatTreatHBeAg-positive CHBTreat if:ALTaNormal ALT defined as ≤35 U/L and ≤25 U/L for men and women, respectively. ≥2 × ULN and HBV DNA> 20,000 IU/mLTreat if:HBV DNA > 2000 IU/mL, ALTbNormal ALT defined as less than or equal to the laboratory ULN (approximately 40 U/L). above ULN, and/or at least moderate liver necroinflammation or fibrosiscBased on histologic assessment of liver biopsy including moderate to severe inflammation by either Ishak activity score >3 or METAVIR activity score above A2. Fibrosis by Ishak score >3 or METAVIR >2, elastography (Fibroscan) >8 kPa.Treat if:HBV DNA > 20,000 IU/mL and ALTbNormal ALT defined as less than or equal to the laboratory ULN (approximately 40 U/L). >2 × ULN (if no concern of hepatic decompensation, observe)HBV DNA >20,000 IU/mL and ALT <2 ULN, treat if moderate to severe inflammation or fibrosiscBased on histologic assessment of liver biopsy including moderate to severe inflammation by either Ishak activity score >3 or METAVIR activity score above A2. Fibrosis by Ishak score >3 or METAVIR >2, elastography (Fibroscan) >8 kPa.HBV DNA <20,000 and any ALT treat if moderate to severe inflammation or fibrosiscBased on histologic assessment of liver biopsy including moderate to severe inflammation by either Ishak activity score >3 or METAVIR activity score above A2. Fibrosis by Ishak score >3 or METAVIR >2, elastography (Fibroscan) >8 kPa.Treat all adults older than 30 y if:HBV DNA >20,000 IU/mL and ALTbNormal ALT defined as less than or equal to the laboratory ULN (approximately 40 U/L). above ULN (tested 3 times during a 6–12-mo period)ALT above ULN and other causes of ALT elevation have been excluded (if HBV DNA testing unavailable)HBeAg negative CHBTreat if:ALT ≥2 × ULN and HBV DNA >2000 IU/mLTreat if:HBV DNA >2000 IU/mL, ALT above ULN and/or at least moderate liver necroinflammation or fibrosiscBased on histologic assessment of liver biopsy including moderate to severe inflammation by either Ishak activity score >3 or METAVIR activity score above A2. Fibrosis by Ishak score >3 or METAVIR >2, elastography (Fibroscan) >8 kPa.Treat if:HBV DNA >2000 IU/mL and ALT >2 × ULN (if no concern of hepatic decompensation, observe)HBV DNA >2000 IU/mL and ALT <2 × ULN, treat if moderate to severe inflammation or fibrosiscBased on histologic assessment of liver biopsy including moderate to severe inflammation by either Ishak activity score >3 or METAVIR activity score above A2. Fibrosis by Ishak score >3 or METAVIR >2, elastography (Fibroscan) >8 kPa.HBV DNA <2000 IU/mL treat if moderate to severe inflammation or fibrosiscBased on histologic assessment of liver biopsy including moderate to severe inflammation by either Ishak activity score >3 or METAVIR activity score above A2. Fibrosis by Ishak score >3 or METAVIR >2, elastography (Fibroscan) >8 kPa.CHB reactivationTreatTreatTreatTreatPregnant women with HBV DNA >200,000 IU/mL on third trimesterTreatTreatTreatdIf HBV DNA is >6–7 log IU/mL.Decision to treat should be based on regular treatment indications. No specific recommendation regarding prevention of vertical transmissionWHO, World Health Organization.a Normal ALT defined as ≤35 U/L and ≤25 U/L for men and women, respectively.b Normal ALT defined as less than or equal to the laboratory ULN (approximately 40 U/L).c Based on histologic assessment of liver biopsy including moderate to severe inflammation by either Ishak activity score >3 or METAVIR activity score above A2. Fibrosis by Ishak score >3 or METAVIR >2, elastography (Fibroscan) >8 kPa.d If HBV DNA is >6–7 log IU/mL. Open table in a new tab Table 2Indications for Treatment and ProphylaxisIndications for treatmentIndications for prophylaxis (prevention of HBV transmission/reactivation)Decompensated cirrhosisPost liver transplantationCompensated cirrhosis regardless of HBV DNA and ALT levelsPost liver transplantation from anti-HBc–positive donor to HBsAg-negative recipientHBV presenting with acute liver failureHBsAg-positive mother during the third trimester with HBV DNA >200,000 IU/mLHBeAg-positive immune active (HBV DNA >20,000 IU/mL and ALT >2 × ULN)HBsAg-positive patients receiving immunosuppression/chemotherapyHBeAg-negative immune active (HBV DNA >2000 IU/mL and ALT >2 × ULN)HBsAg-negative, anti-HBc–positive patients receiving immunosuppression/chemotherapy and at high risk for reactivationHBV/HDV co-infection with HBV DNA >2000 IU/mLHBV/HIV co-infectionHBV presenting with extrahepatic manifestationsHBsAg-positive health care worker with HBV DNA >2000 IU/mLHBc, hepatitis B core; HIV, human immunodeficiency virus. Open table in a new tab WHO, World Health Organization. HBc, hepatitis B core; HIV, human immunodeficiency virus. An alternate and more simplified approach to treatment being put forth by some experts, but not endorsed by any of the major liver society guidelines, is a “treat all” approach in which any HBsAg-positive individual with detectable viremia regardless of ALT level would receive treatment. In the case of HBeAg-positive patients with markedly elevated HBV DNA (>108 IU/mL) and normal ALT levels (immune-tolerant or HBeAg-positive chronic infection with no clear evidence of hepatocellular damage), the recommendation to treat is driven by a desire to limit the risk for HBV-specific T-cell depletion, DNA integrations that drive HCC risk, silent fibrosis progression, and risk of transmission. Indeed, this approach is supported by the REVEAL (Risk Evaluation of Viral Load Elevation and Associated Liver Disease) study,45Chen C.J. Yang H.I. Su J. et al.Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level.JAMA. 2006; 295: 65-73Crossref PubMed Scopus (2506) Google Scholar,47Iloeje U.H. Yang H.I. Su J. et al.Predicting cirrhosis risk based on the level of circulating hepatitis B viral load.Gastroenterology. 2006; 130: 678-686Abstract Full Text Full Text PDF PubMed Scopus (1307) Google Scholar which showed a relationship between elevated HBV DNA levels and subsequent development of cirrhosis and HCC, and a Korean study reporting that untreated immune-tolerant patients have a higher risk of HCC and death or transplantation than nucleos(t)ide analogue–treated immune-active phase.48Kim G.A. Lim Y.S. Han S. et al.High risk of hepatocellular carcinoma and death in patients with immune-tolerant-phase chronic hepatitis B.Gut. 2018; 67: 945-952Crossref PubMed Scopus (121) Google Scholar However, as data from the REVEAL study were obtained from an older, predominantly male, HBeAg-negative cohort, caution is advised in extrapolating to a younger HBeAg-positive cohort. Also, in the latter study from Korea, the HCC risk was lowest among patients with highest HBV DNA levels and normal ALT levels (true immune-tolerant patients). Notably in that study, the mean age of the immune-tolerant patients was 38 years, thus, many or most would have met the