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• W3007183243 abstract "Watch a video presentation of this article Hepatitis B virus (HBV) infection is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). The clinical course of HBV is diverse. The earlier age of HBV acquisition, the more likely for chronic infection to develop.1-3 The immune-tolerant (IT) phase is the first phase, and it is characterized by persistently normal alanine aminotransferase (ALT) levels, positive hepatitis B e-antigen (HBeAg), high viral replication rate (HBV-DNA > 106 to 107 IU/mL), and no or minimal liver injury.2 This phase is followed by the seroconversion of HBeAg in the majority of individuals to its antibody (anti-HBe), which indicates entry into the immune active (IA) phase, also called the immune clearance phase (Fig. 1).4 Copyright Theoretically, there are two options regarding the management of the IT phase of HBV: to treat all patients with HBV IT phase versus not to treat all patients with HBV IT phase. We show evidence that solidly supports the latter view. It is important to note that careful monitoring of host and viral markers is crucial to improving long-term outcome. It has been postulated that before birth, HBeAg acts as a “tolerogen viral protein” in the fetus, and thus HBV-specific T cells undergo deletion and/or hyporesponsiveness that may be partly caused by ineffective antigen processing.5 After years or decades, this tolerance by the innate immune system is broken, and the adaptive immune system begins to attack infected hepatocytes, causing liver injury. This indicates the start of the immune active phase where ALT levels increase and HBV-DNA levels decrease.5, 6 Infants born to HBeAg-negative hepatitis B surface antigen (HBsAg) carrier mothers generally acquire acute hepatitis, but not chronic infection, supporting the theory of HBeAg acting in an immune-regulatory role as a tolerogen.6 Further support to this theory is the lack of hepatitis flare on rebound viremia after stopping antiviral therapy, suggesting that the immune response to HBV in the IT phase is truly distinct.7, 8 However, some authors have challenged the concept of immune tolerance.9 Their studies depended on ex vivo measurements.10 Bertoletti et al.11 have noted that the main difference between the noninflammatory IT phase and the IA phase is the presence of an inflammatory milieu in the IA phase that drives nonspecific inflammation in response to HBV by T cells. Patients in the IT phase have minimal or no hepatic inflammation, suggesting a lack of immune recognition or tolerance to the virus.12 An early study in Chinese children in the IT phase showed that HBV DNA levels were highest in the youngest children. It was also demonstrated that although average ALT levels were similar at the first and last follow-up visits, mild transient elevations of ALT, sometimes accompanied by changes in HBV DNA, were noted during follow-up.13 A study from Hong Kong of paired liver biopsies showed little or no histological fibrosis on initial liver biopsy (median fibrosis Ishak stage 1) in 57 adult IT patients and a very low rate of progression over 5 years.14 A paired transient liver elastography study in HBeAg-positive patients found similarly low rates of fibrosis progression, 4.2% and 6.6% for the IT and IA phases, respectively, over 42 months.15 The “loss” of immune tolerance was noted to occur at a median age of 30.7 years.16, 17 Increasing age has been shown to predict adverse outcomes in HBeAg-positive patients18, 19 (Fig. 2).20 The American Association for the Study of Liver Diseases (AASLD) guidelines (2018)21 used age 40 years as the cutoff based on data from a study showing the risk for cirrhosis increased in patients who lost HBeAg before age 30 years (1.1%) and also at age 30 to 39 years (4.1%), which jumps to 28% in patients who lost HBeAg after age 40 years.22 By contrast, the EASL guidelines selected age 30 years as the cutoff.23 Although it is unclear which cutoff is more appropriate, there are more data to suggest that age 30 years is a crucial cutoff not necessarily to start treatment, but at least to initiate much closer monitoring of the IT group. Several studies have indicated a higher risk for liver cirrhosis if no therapeutic intervention is carried out in the IT phase (Table 1).24-28 On the surface, these findings are quite concerning. However, the important question is whether their studies had a true IT cohort at baseline and for the duration of the study.29 Treatment during the IT phase has not been recommended because of no liver injury or the presence of minimal liver disease and limited efficacy of interferon or nucleoside analogues (NAs) monotherapy.23, 30 Pegylated-interferon (PEG-IFN) and NAs inhibit HBV replication, but they do not eradicate HBV and rarely achieve the goal of HBsAg clearance.31 Chan et al.32 studied 126 adults with IT HBV who received tenofovir disoproxil fumarate with or without emtricitabine for 4 years. Only three (5%) patients cleared HBeAg and none cleared HBsAg. All patients had virological relapse when treatment was stopped. Rosenthal et al.33 found only a 3% response rate in IT children treated with PEG-IFN and entecavir. Viral relapse occurred in all patients when treatment was stopped and was not accompanied by ALT flares. In a recent study of IT Asian patients from 11 sites treated with PEG-IFN and entecavir for 40 weeks, only 4% cleared HBeAg. HBV DNA rebounded to baseline levels in all patients posttreatment.34 All major liver societies do not recommend treatment of IT phase but recommend close monitoring with ALT (at least every 6 months) and HBV-DNA measurements for most patients (Table 2).21, 23, 35, 36 The latest AASLD guidelines21 recommend against antiviral therapy for adults with IT HBV. The main rationale behind this is the lack of studies demonstrating that antiviral therapy is beneficial in reducing rates of HCC, cirrhosis, and liver-related death in patients with IT HBV; hence potential harm, including cost, antiviral drug side effects (metabolic bone disease, lactic acidosis, nephrotoxicity, and Fanconi syndrome), and development of resistance, outweighs its benefits. The following groups of patients with IT HBV should be considered for treatment21: (1) pregnant women with high viremia (>200,000 IU/mL), (2) infected health care workers, (3) immunocompromised patients or patients receiving immunosuppressive therapies, and (4) patients who have a family history of HCC. In the absence of curative therapies for HBV infection, the primary objective is the prevention of cirrhosis and HCC. Reasons to hold off on antiviral therapy in children and adults in IT phase include low rates of response, lack of robust data of established benefit in preventing HCC, and the cost/burden of long-term antiviral therapy.7, 37, 38" @default.
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• W3007183243 date "2020-01-01" @default.
• W3007183243 modified "2023-10-17" @default.
• W3007183243 title "CON: All Patients With Immune‐Tolerated Hepatitis B Virus Do Not Need to Be Treated" @default.
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• W3007183243 doi "https://doi.org/10.1002/cld.893" @default.
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