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Severe hepatitis B flare and liver failure: current assessment and management

Seng Gee Lim1,2,*orcid, Maria Buti3, Jordan J. Feld4, James Fung5, Adam J. Gehring4, K. Rajender Reddy6,*
Clinical and Molecular Hepatology 2026;32(3):1117-1134.
Published online: March 18, 2026

1Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore

2Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

3Liver Unit, Hospital General Universitari Valle Hebron, Barcelona, Spain

4Toronto Center for Liver Disease, Toronto General Hospital, University of Toronto, Toronto, ON, Canada

5Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR

6Department of Medicine, University of Pennsylvania, Philadelphia (K.R.R.), PA, USA

Corresponding author : Seng Gee Lim, Director of Hepatology, Division of Gastroenterology and Hepatology, National University Health System, 1E Lower Kent Ridge Road 119228, Singapore Tel: +65-67724369, Fax: +65-67724361, E-mail: mdclimsg@nus.edu.sg

Joint senior authors.


Editor: Hyung Joon Yim, Korea University, Korea

• Received: February 4, 2026   • Revised: March 11, 2026   • Accepted: March 11, 2026

Copyright © 2026 by The Korean Association for the Study of the Liver

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  • Hepatitis B flare is a common complication of chronic hepatitis B and is defined as an increase in HBV viral load associated with abnormal alanine aminotransferases (ALT), the consensus being an ALT level ≥5 times the upper limit of normal. The immunopathogenesis is related to induction of inflammatory cells and cytokines by the rise in HBV DNA. There are multiple causes of flares, and they carry the risk of progression to hepatic decompensation and acute-on-chronic liver failure (ACLF) with associated mortality, potentially requiring liver transplantation. Initial assessment should exclude other causes of liver dysfunction and determine severity and prognosis. General prognostic models of ACLF are useful but the COSSH-ACLF II score is specific to HBV. Early initiation of nucleos(t)ide analogues is crucial, even in severe HBV flares; it can reduce mortality by 73.6%. Once jaundice and coagulopathy occur, salvage by antivirals is challenging, and liver transplantation should be considered. However, many patients may not be suitable candidates for transplant or donor livers may not be available, as is common in Asia. Recently, there has been increasing evidence of the benefits of adjunctive therapies such as corticosteroids and plasma exchange, but there are associated risks and these approaches should be considered rescue therapies in severe HBV flares or ACLF. Liver transplant is the ultimate intervention when these other strategies fail. In summary, HBV flares are clinically serious events that can lead to hepatic decompensation, ACLF, and the need for a donor liver; however, strategies for rescue should be considered before liver transplantation.
  • Keywords: Alanine transaminase; Hepatitis B, chronic; Hepatitis B, chronic/therapy; Acute-on-chronic liver failure; Plasma exchange
One of the leading causes of liver damage from HBV is HBV flare [1], which describes a continuum of liver inflammation initiated by a rise in HBV DNA, and is dictated by the interaction between the virus and the host immune system (Fig. 1) [2]. HBV flares are typically asymptomatic,1 but severe HBV flares can lead to acute-on-chronic liver failure (ACLF) (25–50% of cases) and subsequent mortality if unresolved (Fig. 1) [3]. In China, HBV-ACLF accounts for 70% of ACLF [4], with short-term (28-day) mortality reaching 40–50% [5]. Recent developments and controversies regarding HBV flares and their treatment necessitate an update of the natural history, definition, pathogenesis, evaluation, and management of this condition, including adjunctive therapies in patients who progress to ACLF and may require liver transplantation. We used the best available evidence from meta-analyses and randomized controlled trials where available.
HBV flares can occur spontaneously as part of the natural history of chronic hepatitis B (CHB) or can be associated with precipitating events (Table 1). These events include initiation of antiviral therapy, stopping antiviral therapy, development of drug-resistant mutants, during or after immune suppressive therapy or chemotherapy, after immune restoration therapy, or after HCV therapy. While HBV flares have occurred in the setting of current antiviral therapy such as interferon and nucleoside analogues, the setting of novel therapeutics requires special consideration. These events have been seen in association with HBsAg reduction [6], and can be considered “therapeutic flares”, but need to be distinguished from drug-induced liver injury, the criteria for which have been established [7]. Newer anti-cancer therapies and immune-oncology therapies also carry the risk of HBV flares and have been recently reviewed [8].
The natural history of chronic HBV infection with regard to spontaneous HBV flares is complex and often dynamic, with the annual estimated frequency of spontaneous HBV flares to be around 13–60% in HBeAg positive patients and 6–33% in HBeAg negative patients [9]. Typically, in HBV flares, HBV DNA levels begin to decline at the peak of ALT elevation. HBeAg seroconversion occurs in up to 51% in those with ALT>5xULN [1]. Spontaneous HBV flares usually resolve, with only 20% persisting beyond 2 months in HbeAg-positive CHB, while those in HbeAg-negative patients tend to be persistent in about 30% [10]; clearance of HBsAg is rare.
It is unclear whether spontaneous HBV flares have different outcomes from HBV flares associated with stopping antiviral therapy. Patients who stop antiviral therapy in the context of a clinical study are typically more intensively monitored than patients with spontaneous HBV flares. The largest study of stopping NA was the RETRACT-B study [11] among 1,552 patients, where 11.9% were cirrhotic. Liver decompensation occurred in 4.3% of cirrhotic patients and 0.8% of non-cirrhotic patients. Of those who developed decompensation, 36.8% died. A study of 110 patients with severe HBV flares from Taiwan [12] found that 42% were spontaneous and 58% were related to stopping therapy, of which 5/110 (3.6%) developed decompensation. Multivariate analysis showed that only HBV DNA >16x108 copies/mL (equivalent to 2.8x108 IU/mL) was predictive of decompensation, and no differences in outcomes were found among those stopping therapy and those with spontaneous HBV flares.
In chronic infection, HBV-specific T cell frequency is barely detectable in functional assays [13,14] and requires magnetic enrichment for phenotypic analysis [15]. HBV-specific T cells display profound dysfunction, with inhibitory receptors and metabolic characteristics of exhaustion, reducing their overall function and ability to respond to infected hepatocytes [16,17]. The reduced function of HBV-specific T cells in chronic infection is distinctly different from functional CD8 T cells in acute infection, which drive liver damage through recognition of infected hepatocytes and initiation of an inflammatory cascade (Fig. 2).
Recent nucleoside analogue (NA) withdrawal studies have begun to yield insights into the predictable sequence of virological rebound and subsequent liver damage that occurs in HBV patients. Inflammatory cytokines show no, or modest, elevation upon HBV rebound in patients stopping NA [18,19]. These inflammatory markers only increase once ALT becomes elevated. The initial triggers are only detectable within the liver during HBV rebound, with preliminary reports pointing to an early type I IFN response [20]. Once this inflammatory cascade is set in motion, multiple lymphocyte populations likely contribute to antigen-independent tissue injury. Type I IFNs present during flares induce TNF-related apoptosis inducing ligand on CD56hi NK cells conferring the ability to kill hepatocytes in an antigenindependent manner (Fig. 2) [21,22]. CD8 T cells, and potentially NK cells, can express Fas ligand and cause antigenindependent liver damage [23] via bystander activation of inflammatory cytokines. This cytokine milieu likely determines the outcome of tissue damage, particularly with progressive immune activation that can then lead to ACLF (Fig. 2).
The outcomes of intrahepatic immune activation have, colloquially, been referred to as “good” and “bad” HBV flares. Good flares are “typically self-limiting, associated with a decrease in HBV DNA and tend to result in HBeAg loss/seroconversion and reduction in HBsAg levels but rarely HBsAg loss.” [1,9] Conversely, bad flares are protracted, associated with increased bilirubin and international normalized ratio (INR) and lead to progressive liver injury that may result in hepatic decompensation and/or death [1,9]. The terms “good” and “bad” can only be applied after the HBV flare is in progress and enough time has passed to measure changes in clinical parameters, hence proving a challenge for clinical management. Biomarkers to predict outcomes, are a major gap in our diagnostic arsenal. Again, NA withdrawal has presented the best opportunity to define immune biomarkers associated with HBV control, or “good” HBV flares. There is evidence that T cell immunity is positively associated with better outcomes after stopping therapy. Higher frequencies of HBV-specific T cells predicted better control of HBV rebound [24,25], and HBV envelope-specific CD4 T cells were associated with HBsAg loss in patients stopping therapy [26,27], but the role of T cells requires further validation before complex functional T cell assays can be used to predict outcomes [28]. Even if T cell responses don’t become a predictive factor for “good” versus “bad” flares, they may shed light on the underlying mechanisms leading to flares. There may be a difference between flares initiated by cytokines such type I IFNs (IFN-α/IFN-β) versus type II IFN (IFN-γ) which may also be useful but currently are only speculative in distinguishing the two pathways.
HBV reactivation refers to a re-appearance or increase in viral replication (Table 2). There are two scenarios for viral reactivation, the first in the setting of HbsAg-positive patients, and the second is the setting of HbsAg-negative patients with resolved HBV. Different thresholds for reactivation have been defined by different research groups (Table 2). For patients on antiviral therapy, reactivation may occur after stopping NA treatment. In this context, virological relapse is described by the European Association for Study of Liver (EASL) and Asia Pacific Association for Study of Liver (APASL) as HBV DNA ≥2,000 IU/mL after cessation of antiviral therapy.
Virological reactivation can occur spontaneously but is typically associated with precipitating factors (Table 1). Genetic variability and mutations have been implicated in reactivation; the most common mutations are G1896A in the preC/C region, the ntA1762T and ntG1764A mutations in the preC promoter region [29]. These mutations have also been implicated in ACLF [29]. Virological reactivation may be a result of loss of immune control leading to rapid increases in viral replication, but the mechanisms remain poorly understood.
Hepatitis B flare

HBV flare definition

While HBV reactivation describes HBV DNA changes, HBV flare refers to the development of abnormal ALT in association with these HBV DNA changes. HBV flares in the context of stopping NA therapy have also been called clinical relapse or biochemical relapse [30,31]. However, definitions differ widely in the literature, making it challenging to compare the frequency and severity of flares across studies.
Several thresholds for ALT elevation have been proposed, either as absolute values, fold-change from baseline, or a combination. APASL and American Association for Study of Liver Disease (AASLD) guidelines require an ALT>5× upper limit of normal (ULN) [30,32] while EASL has no threshold (Table 3). Defining the normal ALT is also problematic as some studies use ALT 40 U/L as ULN, while others use the laboratory normal range, and AASLD [32] uses the thresholds of 35 U/L for men and 25 U/L for women.

Severe HBV flares

An HBV flare can evolve into overt severe hepatitis and even liver decompensation. There is a lack of consensus definition of what constitutes a “severe hepatitis B flare”. Previous studies have defined severe hepatitis flares as HBV DNA ≥100,000 IU/mL and ALT≥10×ULN [33], ALT≥10×ULN alone [34], or ALT≥20×ULN [35], or ALT≥1,000 IU/mL or ALT≤1,000 IU/mL but bilirubin ≥3.5 mg/dL and/or INR≥1.5 (Table 3) [36].
In the current context, severity should not only describe the intensity of the flare in terms of ALT elevation, but also by its detrimental effects on liver function, and by the presence of hepatic decompensation and/or ACLF. Consequently, ALT>10×ULN or ALT>ULN with liver decompensation (APASL) [30] (bilirubin≥2.5×ULN and/or INR≥1.5) would be the most appropriate (Table 3). Severe or repeated acute flares progress to liver decompensation and subsequent ACLF in 25–50% [3].

Hepatic decompensation

Hepatic decompensation was not defined in AASLD [32] or EASL [31] guidelines but was defined in the APASL guidelines [30] based on raised serum bilirubin (>2.5×ULN) and prolonged prothrombin time (>3 s), or INR≥1.5 or occurrence of complications such as ascites and hepatic encephalopathy (Table 3). Other definitions include the occurrence of variceal bleeding [37], hepatorenal syndrome, and spontaneous bacterial peritonitis [37].
Hepatic decompensation classically occurs in the context of established cirrhosis with underlying portal hypertension. For these patients, a mild flare may be sufficient to cause acute decompensation due to underlying compromised pre-existing liver reserve, with worsening or development of the above symptoms. However, the majority of CHB patients with severe flares are non-cirrhotic and will not present with the classical complications of hepatic decompensation.

Acute-on-chronic liver failure

The development of ACLF is a serious event that carries a high risk of mortality. However, the definition of ACLF differs according to the EASL, AASLD, Chinese Group on the Study of Severe Hepatitis B (COSSH) and APASL guidelines (Supplementary Table 1). These definitions lead to different thresholds and criteria for diagnosing ACLF leading to the different populations included in studies, thus affect reports of 30-day mortality [38,39]. This complexity is further complicated by the fact that HBV-ACLF may differ from other causes of ACLF [39] such as alcohol [40] in terms of prognosis. Only the COSSH definition is specific for HBV.
Careful monitoring in the setting of HBV flares is critical, particularly for severe flares that may be asymptomatic. A proposed algorithm for management is suggested in Figure 3.
Establishing causation
Initially, it is critical to establish HBV as the cause, and evaluate precipitating factors, both HBV-related or unrelated (Table 1). Screening for other causes of acute hepatitis should be considered (Table 4), in the evaluation of a severe flare and/or ACLF.
Current HBV status as well as historical data (when available) for HBV DNA, HbeAg, and quantitative HBsAg should be evaluated promptly. In newly-diagnosed cases of HBV in the context of a severe flare, acute HBV needs to be distinguished from a chronic HBV flare. Acute HBV resolves, without treatment, with HBsAg loss in over 90% of immunocompetent adults, whereas a severe flare of chronic HBV may precipitate liver failure in the absence of treatment. A high anti-HBc IgM titer suggests acute infection, whereas a low titer still indicating positivity for anti-HBc IgM may be present in flares. Other factors to help exclude acute infection include exposure history, prior serological results, and a family history of HBV. Low HBV DNA levels at initial investigation may point to etiologies other than HBV as the cause for clinical presentation.
Establishing severity
In addition to ALT levels, assessment of liver function (bilirubin, INR and albumin) and renal function along with clinical evaluation for signs of liver failure (ascites, encephalopathy) are required. These can be used to calculate prognostic scores and determine management strategies. The presence of liver cirrhosis should be determined by imaging since noninvasive methods for evaluation may be unreliable during an acute flare with or without decompensation [41], however prior non-invasive methods of fibrosis assessments if available before the HBV flare could be used to determine the presence of cirrhosis. Finally, documentation of systemic inflammatory response syndrome (SIRS) is recommended as this affects the prognosis of severe flares [42]. SIRS diagnosis is based on any two of the following [43]: Temperature >38°C or <36°C, heart rate>90 beats/minute, respiratory rate>20 breaths/minute or partial pressure of CO2 <32 mmHg, leucocyte count >12,000 or <4,000/mL or >10% immature forms or bands.
For severe flares fulfilling the criteria for hepatic decompensation and ACLF, prognostic models can be used to predict mortality and the need for LT. This is complicated by definitions and prognostic models for ACLF. For most Asian countries, HBV flare is the leading cause in which direct liver injury is the predominant insult, in contrast to Western countries where infections and extra-hepatic organ failure are more common [44].
The three definitions of ACLF proposed by EASL-CLIF [45], AASLD-NASCSELD [46], and APASL [44] make creating a unified diagnosis of ACLF challenging (Supplementary Table 1). There is an evolving effort to unify the definition while also proposing criteria for defining organ failure [38,47]. The current existing differences in diagnostic criteria mean that the severity, prognosis, and outcomes of patients in ACLF are likely to be different based on the criteria used (Supplementary Table 1).
In addition, disease-specific prognostic models have also been derived from HBV-ACLF cohorts, as the prognosis may also be influenced by HBV-specific factors, such as viral load. The COSSH-ACLF II score was derived from 954 HBV-ACLF patients, identifying six predictive factors (INR, hepatic encephalopathy, neutrophil, total bilirubin, urea) to formulate a new model to predict 28- and 90-day mortality [48]. The performance of other HBV-specific ACLF scores also appear to outperform the generic ACLF score for HBV-ACLF patients, as summarized in Supplementary Table 2 [48-53].
With so many different ACLF predictive models available, navigating the current multitudes of scoring systems is a challenge. Each scoring system has been shown to outperform other scoring systems in individual cohorts, implying that both the definition of ACLF and scoring systems are inherently tied to their derivation cohort, and not specific to patients with severe HBV flares. For severe HBV flare patients with liver failure, extrahepatic organ failure is often a late and terminal complication. Those with liver failure may not fulfil the organ failure criteria used in defining and scoring ACLF [44] despite high mortality risk and requiring LT.
Given the complex interplay between the various factors, it is unlikely that any single model will achieve perfect accuracy. With the increasing advances in artificial intelligence, this technology may be used to identify novel parameters and models to better predict outcomes in HBV-ACLF in the future [44,54].
Severe hepatitis flares should be managed by a physician with expertise in the treatment of liver disease in connection with a center experienced in managing acute liver failure and with access to a liver transplant program. Despite highly potent antiviral therapy, patients with severe hepatitis flares may still succumb to ACLF. The decision to proceed to transplantation is often a difficult one, as some cases of severe hepatitis flare and liver decompensation and ACLF may reverse, thus avoiding an unnecessary liver transplant [55].
Patients with cirrhosis may decompensate even with a mild flare, and should be monitored closely to assess for clinical deterioration or hepatic decompensation [31,55,56]. Patients with raised bilirubin, prolonged prothrombin time, mental status changes or hepatic decompensation, should have immediate antiviral therapy, be considered for adjunctive rescue therapy and even LT (Fig. 3).
Initiation of NA is the first priority once a severe HBV flare has been identified (Fig. 3). NA have higher potency and a much better safety profile than interferon [30-32]. Among the three recommended antiviral agents— entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide—there are some minor differences. Dosage of both TDF and ETV must be adjusted to renal status to avoid adverse events, such as worsening of renal function and lactic acidosis seen in ETV-treated patients with decompensated cirrhosis and high Model for End-stage Liver Disease (MELD) scores [57]. In a severe flare, NA may improve survival, but not in all. Despite potent NA therapy, the time taken to reduce viral load is dependent on HBV DNA levels. In HBeAg positive patients with very high HBV DNA levels (>8.0 log10 IU/mL), TDF has shown potent antiviral activity, reducing HBV DNA levels >3.0 log10 IU/mL by week 4 of treatment [58], but development of liver decompensation may be too rapid for antivirals to take effect, particularly if HBV DNA is very high and liver dysfunction already present, which makes recovery from ACLF less likely.
In a randomized study of TDF versus placebo of 27 patients with severe CHB reactivation and ACLF [59], with a median baseline MELD of 25–27, TDF significantly reduced HBV-DNA levels, improved Child–Turcotte–Pugh and MELD scores, and reduced mortality, improving 3-month survival to 57% (8/14) from 15% (2/13) in those on placebo (P=0.03) (Table 5). Death was due to progressive liver failure leading to multiorgan failure. An independent predictor of survival was a >2 log reduction in HBV DNA levels at 2 weeks [59]. A meta-analysis of oral antiviral therapy for HBV ACLF showed mortality improvement from 77.3% to 44.8% [60], similar to the Garg et al. [59] randomized control trial (RCT). In a cohort study of 758 hospitalized patients with severe HBV flare (311 with ACLF and 447 without ACLF based on the APASL criteria) [61], the 8-week mortality was 5.5% in non-ACLF and 35.3% with ACLF. Patients were treated with lamivudine or ETV. A mutlivariate analysis of mortality at week 8 showed that age and MELD score were important but INR was the strongest predictor. Those with MELD <24.5 had an 8 weeks mortality of 17% while for those with MELD≥24.5 it was 57.45%.
Despite restarting antiviral therapy during HBV flares, some patients progress towards liver decompensation and liver failure. One patient who stopped NA during the REEF-1 clinical trial decompensated and needed a liver transplant despite close monitoring and restarting antiviral therapy [62]. In a case series, 11 CHB patients who ceased NA were referred for liver transplantation despite restarting antiviral therapy [63], demonstrating that by the time of severe ALT flare, not all patients may be able to be rescued with antiviral therapy alone.
The above collated data consistently inform us that mortality from HBV flares is related to liver function status at the initiation of antiviral therapy. With development of ACLF, mortality significantly increases and worsens as MELD score increases, particularly at >24.5. Consequently, recovery of patients with severe HBV flares with NA is dependent on liver reserve, particularly MELD score at antiviral therapy initiation.
Prevention of severe ALT flares may be a better strategy in situations of NA withdrawal. Recently a viral load threshold was proposed for restarting antiviral therapy after stopping NA; HBV DNA>10,000 IU/mL at week 6 after stopping therapy independently predicted post-treatment flares (ALT>5×ULN) [64], and such patients may benefit from early re-treatment1. In the REEF-2 study, HBV DNA ≥100,000 IU/mL predicted a severe ALT flare (defined as ALT ≥10xULN) in patients who stopped NA therapy, providing a criterion for restarting antiviral therapy before the onset of a severe flare [33].
Prevention of severe HBV flares requires patient education for compliance with antiviral therapy, particularly to avoid running out of medication, as well as regular monitoring with emphasis on the risk of decompensation and death. Patients should be advised that if they develop jaundice, lethargy, or abdominal discomfort, they should promptly seek medical attention.
Management of severe HBV flares and ACLF should be based on the first principle of controlling HBV replication, while considering adjunctive therapy based on the principles of (1) reducing severe inflammation and (2) enhancing regeneration of hepatocytes (Table 5).
Reducing severe inflammation

Corticosteroids

It seems counterintuitive to use corticosteroids to treat severe HBV flare/ACLF since these agents have been the cause of HBV flares [3]. The rationale of using them is to reduce severe inflammation and prevent catastrophic liver damage while HBV DNA is being suppressed by NA. A large multicenter trial [65] conducted at three centers in China randomized HBV flare patients with a mean MELD score of 23 to methylprednisolone (IV 1.5 mg/kg/day for 7 days), or standard medical care (SMC), all received NA therapy. The primary endpoint of 6 months mortality showed a statistically significant reduction from 42.5% to 32.4% (Table 5). A strong predictor of mortality was MELD>22.4 (AUROC 0.75) and patients who had advanced ACLF (ascites and/or encephalopathy) showed no survival advantage with steroid treatment. However, the incidence of hypoalbuminemia, fungal infection and ascites was higher in patients receiving corticosteroids. Supporting evidence for the use of steroids comes from a meta-analysis of corticosteroid therapy and SMC, with an OR of 0.23 for inpatient mortality in the steroid treated group compared to SMC [66]. Most studies of corticosteroid therapy come from China and seem to show a survival benefit in HBV-ACLF [67-70].
However, steroids do lead to increased risk of infections and may not be beneficial for all patients [71], particularly those with advanced ACLF. The presence of SIRS could potentially suggest systemic infection and such patients carry a high risk of mortality [66] with steroid therapy, hence such patients should not be candidates for steroid therapy. Consequently, the use of corticosteroids should be carefully considered.

Artificial liver support systems

Of the artificial liver support systems (ALSS), therapeutic plasma exchange (TPE) has been the most commonly studied for HBV-ACLF. The postulated mechanism by which treatment with TPE works in ACLF is by clearing inflammatory cytokines, damage-associated molecular patterns, and endotoxins, leading to improved monocyte phagocytic function and mitochondrial respiration, and increased anti-inflammatory cytokine IL-1 receptor antagonist, leading to a potential survival benefit [72]. In two recent meta-analyses [73,74], TPE was significantly associated with higher 30-day (risk reduction of 30–36%) and 90-day (risk reduction of 19–21%) survival in the meta-analyses [73,74].
For HBV-ACLF, using either TPE alone or in combination with other ALSS systems, a meta-analysis [75] showed a 28-day (survival rate 69%), 90-day (survival rate 53%) and 9-month (survival rate 51%) benefit. ALSS had a survival advantage in those with ACLF grade 1 (15% vs. 50% 3-month mortality in ALSS vs. SMC), but not in those with grade 2 (2 organ failures; MELD equivalent 25) or grade 3 (3 organ failures; MELD equivalent 32) [49].
Thus far, the overall data suggest that of the ALSS, TPE currently offers the best outcomes in terms of improvement in survival for HBV-ACLF patients. The APASL guidelines recommend TPE for ACLF patients as a bridging modality to liver transplant [76] and in many experienced transplant centers and regions where HBV infection remains endemic, TPE has become standard of care for HBV-ACLF patients, either as rescue therapy for ACLF or bridge to LT, as there are higher waiting times due to low organ donor rates in Asia. However, the downside of TPE is that it is labor intensive, and requires large volumes of replacement plasma, thereby precluding its widespread use. TPE is a relatively safe procedure with the main adverse event being skin rash [74] but requires that patients be hemodynamically stable.

N-acetylcysteine

N-acetylcysteine (NAC) has been the standard of care for paracetamol induced acute liver failure but has also been explored for non-paracetamol induced liver failure. The mechanism by which NAC works in acute liver failure is still debatable, other than reducing glutathione [77]. It is also proposed to attenuate hepatocyte apoptosis from oxidative stress, mitochondrial dysfunction and anti-inflammatory effects by inhibiting toll-like receptors and lowering cytokine levels [77]. In a Cochrane meta-analysis, the utility of NAC was inconclusive based on two RCTs due to risk of bias and imprecision [78]. Moreover, NAC has not been tested in severe HBV flares nor ACLF, consequently there is paucity of data on its utility.
Enhancing hepatocyte regeneration

Granulocyte colony stimulating factor

Granulocyte colony stimulating factor (G-CSF) not only acts on cells of neutrophilic lineage but also mobilizes hematopoietic stem and immune cells [79]. In animal models with liver damage, G-CSF has promoted liver repair by increasing migration of bone marrow precursors to the liver [80] and acting within the liver to facilitate hepatic restoration through oval cells [81]. A European RCT of patients with ACLF [82] and a meta-analysis of 4 RCTs [83] of ACLF failed to show any survival benefit. There have been two small RCTs in HBV ACLF [84,85] both showing a 3- and 6-month survival benefit. Overall, the safety of G-CSF seems to be similar to SMC in the RCTs, although 9.1% had to pause G-CSF due to high white cell counts. Its efficacy in HBV-ACLF is unclear.

Mesenchymal stem cell transplantation

Mesenchymal stem cells are multipotent cells that have the potential to differentiate into various types of cells, including hepatocytes [86]. Two meta-analyses were performed to assess mortality after mesenchymal stem cell transplantation (MSCT) in ACLF [87,88], but showed contrasting results despite using the same studies. Consequently, it remains inconclusive whether MSCT is beneficial for ACLF.
In summary, adjunctive therapies can be used in severe HBV flares and ACLF, but the choice of modality and the timing of intervention needs to be individualized. The utility of NAC, G-CSF and MSCT are less clear and should be considered as research strategies until there are more data.
The recognition of a severe flare, pre-ACLF or ACLF due to HBV flare is the time to initiate potent antiviral therapy. The presence of HBV DNA ≥6 log before or during an HBV flare or ALT ≥10×ULN is an indicator of possible progression to ACLF. These patients should be monitored closely for antiviral response of HBV DNA >2 log 2 weeks after starting therapy as a good prognostic marker for survival [59]. During this phase if ALT levels fail to decline sufficiently or there increasing bilirubin and/or INR, adjunctive therapies should be considered. Corticosteroids may be carefully considered provided the risk of sepsis and other infections is low. Antibiotic±anti-fungal treatment should be included if steroids are to be prescribed. The dose and duration of corticosteroid therapy have varied from study to study, but methylprednisolone 1.5 mg/kg (or equivalent) for 7 days was used in the RCT [65],. and this regimen should be considered if corticosteroids are to be initiated. In addition, steroids should be avoided for patients with MELD scores>22 and/or those with advanced ACLF (ascites and/or hepatic encephalopathy).
TPE should be considered for HBV-ACLF patients as a rescue therapy or a bridge to LT. Those with less advanced stages of ACLF appear to benefit most, whereas more advanced cases are likely to be futile, such as those with 2 or more organ failures [49,89]. TPE is best used before advanced ACLF as it showes little survival benefit in those with ACLF ≥2.
The choice of adjunctive therapies and timing of their introduction can vary widely, as severe HBV flares can progress rapidly. The decision to use such therapies needs to be balanced between benefit and safety in the light of LT prospects and should be assessed on a case-by-case basis. In particular, many HBV flare patients have presence of co-morbidities, malignancy, advanced age or lack of availability of a donor (particularly in Asia) may also preclude transplantation, consequently, adjunctive therapies may be life-saving.
For severe HBV flares with hepatic decompensation and/or ACLF, LT is often the only curative option. HBV-ACLF remains one of the most common indications for LT in many parts of Asia, with HBV-ACLF and HBV-HCC accounting for 66.7% of LTs in China [90], but it only accounts for 7% of ACLF cases in the U.S [91-93]. All patients with severe HBV flare and liver dysfunction or ACLF should undergo early assessment for LT [45,94].
The timing of liver transplantation is crucial as there is often a narrow window of opportunity before the development of multi-organ failure or cerebral edema preclude transplant [95], a so-called “golden window” of about 7–15 days [96]. Conversely, it is equally important to avoid unnecessary LT in those who may eventually recover.
Current guidelines recommend that those with grade II and III ACLF receive LT early [45,76]. An AARC score of 8 was proposed as a minimal score cut-off to ensure the benefit of early LT. Although HBV-specific scoring systems may predict short-term mortality, they do not give a clear recommendation or a cut-off for when LT should be performed.
Once the decision has been made for LT, prioritization for LT when donor organs are limited is still dependent on MELD score [56]. For severe HBV flares with ACLF where the predominant organ failure is liver-related, MELD score remains useful for both prognosis and prioritization (Supplementary Table 2). For HBV flare inpatients, MELD <18 had a 28-day mortality of 1.0% compared to 9.4% for MELD≥18, progression to ACLF in those with MELD ≥18 occurred in 26.6% within 28 days [97]. Using the day-to-day MELD score to account for the dynamic nature of severe HBV flares, MELD at any time point during admission could predict short term mortality (day 7, 14, 21, and 28) with an AUROC ranging from 0.871 to 0.909, which can help guide LT decisions when a graft becomes available [56]. To this end, the APASL ACLF recommends that organ allocation should still be based on prevailing scoring systems.
Hepatitis B flare is a serious and common complication of CHB, whether spontaneous in nature or precipitated by exogenous factors. In many patients, it resolves spontaneously but has the potential to progress to decompensation and ACLF. Evaluation requires not only assessment for precipitating factors, but also exclusion of other non-HBV causes masquerading as an HBV flare. Furthermore, clinical decompensation, laboratory parameters of reduced liver function, the presence of cirrhosis, and complications are important prognostic factors. A schematic diagram for suggested management can be viewed in Figure 3. Immediate initiation of oral antiviral therapy is needed as early intervention can lead to better outcomes, but with any evidence of raised bilirubin or prolonged INR, rescue measures should be considered, with discussion and preparation for LT. Adjunctive therapies that have shown a significant survival benefit in RCTs but are not widely utilized, however, should be considered when NA therapy fails to stop progression or when the patient already has pre-ACLF or ACLF, in order to manage this potentially fatal condition. This is particularly true for patients who have underlying cirrhosis or advanced fibrosis. These patients are more likely to require adjunctive therapies since LT is less likely for older patients, and for those with malignancy or significant co-morbidities that preclude transplantation or where a donor is not available. The choice of adjunctive therapies in individual patients relies on the preferences of the managing team and their experience as well as the availability of different therapeutic modalities. Such adjunctive therapies may be life-saving and should be used early before progression to advanced ACLF. The severity of the patient’s condition may dictate available options. Those with advanced ACLF are less likely to respond to adjunctive therapies. Ultimately, if there is progressive deterioration, LT will be necessary. Prognostic scoring systems should be used to prognosticate in a dynamic fashion the timing for transplant.

Authors’ contributions

Study concept, design: SGL, KRR. Search for relevant articles: all authors. Manuscript drafting: All authors contributed to relevant sections. Tables and figures: SGL, KRR, AJG, JF. Critical review and revision of manuscript: All authors. Approval of manuscript: All authors.

Acknowledgements

SGL was funded by NMRC grant NMRC/TCR/014- NUHS/2015, NMRC/CIRG/1351/2013, NMRC/CSASI/0016/2017, NMRC/CIRG/1479/2017 and NMRC/OFLCG-19May-0038.

Conflicts of Interest

Seng Gee Lim: Consulting/Advisory Board: Gilead Sciences, Abbott, Roche, GlaxoSmithKline, Aligos, Ausper-Bio, Sysmex. Speakers Bureau: Abbott, Sysmex GlaxoSmithKline, Gilead; Research funding: Abbott, Gilead Sciences, Sysmex, GlaxoSmithKline.

K. Rajender Reddy: Consulting /Advisory Board: Mallinckrodt, Spark Therapeutics, Novo Nordisk; Research funding (Paid to the University of Pennsylvania): Mallinckrodt, BMS, Exact Sciences, Pliant, Grifols, Sequana,Biovie, Intercept, HCC-TARGET, NASH-TARGET, Camurus AB. DSMB: Novartis, Astra Zeneca, Genkyotex.

Maria Buti: Consulting /Advisory Board: Gilead Sciences, Abbott, Roche, Janssen, GlaxoSmithKline, Arbutus, Assembly, Speakers Bureau: Gilead Sciences, Abbott, Glaxo-SmithKline.

Jordan Feld: Consulting /Advisory Board: Arbutus, Bluejay, Gilead, GSK, Janssen, Roche, Vir. Research funding: Altimmune, Eiger, Gilead, GSK, Janssen, Roche, Vir Biotechnology.

James Fung: None.

Adam Gehring: Consulting /Advisory Board: Assembly Biosciences, Bluejay Therapeutics, Gilead Sciences, GSK, Janssen Pharmaceuticals, Roche, Vir Biotech, Virion Therapeutics, VBI; Research Funding: GSK, Roche, Bluejay Therapeutics, Vir Biotechnology.

Supplementary material is available at Clinical and Molecular Hepatology website (http://www.e-cmh.org).

Supplementary Table 1.

Comparison of the different definitions of ACLF92
cmh-2026-0177-Supplementary-Table-1.pdf

Supplementary Table 2.

Different prognostic models for HBV-ACLF
cmh-2026-0177-Supplementary-Table-2.pdf
Figure 1.
Schematic diagram of progression of HBV reactivation to flare, and subsequent recovery, persistent hepatitis or ACLF. ACLF, acute on chronic liver failure; ALT, alanine aminotransferase; HBV, hepatitis B virus.
cmh-2026-0177f1.jpg
Figure 2.
Immunopathogenesis of acute versus chronic hepatitis B flare showing a schematic diagram of interplay of various immune cells, cytokines, chemokines and pathways. (I) Acute hepatitis. (A) HBV-specific CD8 T cells traffic to the liver, crawl along the endothelium with the help of platelets and recognize infected hepatocytes. (B) HBV-specific CD8 T cells kill infected hepatocytes and produce IFN-γ to initiate non-cytolytic clearance. (C) IFN-γ stimulates the production of chemokines that draw non-HBV-specific cells into the inflamed environment that react to bystander cytokines and kill hepatocytes in an antigen-independent manner. (II) Chronic hepatitis B flare. (A) An unknown trigger stimulates the production of type I IFN and T cell activating cytokines (IL-2, IL-12 and IL-15) that leads to bystander CXCR6+ CD8 T cell IFN-γ production. (B) IFN-γ stimulates the production of chemokines that draw non-HBV-specific cells into the inflamed environment. (C) infiltrating lymphocytes that react to bystander cytokines and kill hepatocytes in an antigen-independent manner through FasL and TRAIL.
cmh-2026-0177f2.jpg
Figure 3.
Proposed algorithm for assessment and management of HBV flare, showing evaluation, exclusion of other causes, initiation of nucleos(t)ide analogue therapy, adjunctive therapies and liver transplant consideration. HBV, hepatitis B virus; ALT, Alanine Transferase; AST, Aspartate Transferase; INR, international normalized ratio; ACLF, acute-on-chronic liver failure; ULN, upper limit of normal. *Total bilirubin. †Adjunctive therapies include corticosteroids and plasma exchange.
cmh-2026-0177f3.jpg
Table 1.
Causes of HBV flare and unique considerations
Table 1.
Possible cause Important points
At initiation or end of HBV treatment • IFN: Flares are more common with IFN [9]
• NA: Higher rates of HBeAg loss with flares [98]
• Therapy with novel agents: Capsid assembly modulators, nucleic acid polymers, small interfering RNA, anti-sense oligonucleotides, immune based therapies [99]
Stopping antiviral therapy • High rates of flares when stopping NA therapy [3]
• This may occur when patients are non-adherent, run out of medication, or stop on their own violation, or by their physician [100,101]
Drug resistant mutants during oral antiviral therapy • Particularly with lamivudine and adefovir, infrequently with entecavir [102]
During or after immunosuppressive/immunomodulatory therapy and after chemotherapy treatment • After chemotherapy, immune suppression novel immunetherapeutic agents [3,8]
• Organ103 or stem cell transplant [104]
After immune restoration • Late pregnancy/early post-partum period [105]
• Active retroviral therapy in HIV coinfected patients [106]
Spontaneous hepatitis B flare in patients with chronic HBV or cirrhosis • Occurs 13–60% in HBeAg positive patients and 6–33% in HBeAg negative patients [9]
HBV reactivation in the context of HCV therapy • High risk (24%) in HBsAg(+) patients but low risk (1.4%) in HBsAg(–) patients [107]

HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; IFN, interferon; NA, nucleoside analogues.

Table 2.
Definitions of HBV reactivation according to the liver societies
Table 2.
Reactivation AASLD [108] EASL [31] APASL [30]
Reactivation of CHB (HBsAg+) HBV DNA ≥10,000 IU/mL if the baseline HBV DNA level is unknown 100 fold increase in HBV DNA compared to baseline level HBV DNA ≥1,000 IU/mL in a patient with previously undetectable level 10-fold increase in HBV DNA levels from baseline ≥2 log increase from baseline levels or a new appearance of (HBV DNA to a level of ≥100 IU/mL) in a person with previously stable or undetectable levels, or detection of HBV DNA ≥20,000 IU/mL in a person with no baseline HBV DNA
Reactivation of resolved HBV (HBsAg–) HBV DNA detection or appearance of HBsAg (reverse seroconversion) HBV DNA detection (>100 IU/mL) or appearance of HBsAg (reverse seroconversion) HBV DNA detection or appearance of HBsAg (reverse seroconversion)

AASLD, American Association for Study of Liver Disease; APASL, Asia Pacific Association for Study of Liver; CHB, chronic hepatitis B; EASL, European Association for Study of Liver; HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen.

Table 3.
Definitions of HBV flare, severe HBV flare and liver decompensation
Table 3.
Flare & decompensation Reference
HBV flare ALT>5×ULN AASLD [108]
APASL [30]
Severe flare ALT>10×ULN Dongelmans et al. [34]
Liver decompensation Bilirubin ≥2.5×ULN and/or INR≥1.5 APASL [30]

AASLD, American Association for Study of Liver Disease; ALT, alanine aminotransferases; APASL, Asia Pacific Association for Study of Liver; HBV, hepatitis B virus; INR, international normalized ratio; ULN, upper limit of normal.

Table 4.
Evaluation of the patient with severe HBV flare
Table 4.
Assess for other viral hepatitis HAV, HCV, HDV, HEV
Assess for systemic viral infections CMV, EBV, HSV, VZV, Dengue, SARS-CoV-2
Consider other hepatic injury if appropriate Wilson disease, hemophagocytic lymphohistiocytosis, leptospirosis, malignant infiltration, Budd–Chiari syndrome, alpha-1 anti-trypsin deficiency, congestive liver disease, ischemic hepatitis, HELLP syndrome
Important conditions to exclude Drug induced liver injury, alcohol related liver injury, autoimmune hepatitis, MASH, biliary obstruction

CMV, cytomegalovirus; EBV, Epstein Barr virus; HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis delta virus; HELLP syndrome, hemolysis, elevated liver enzymes and low platelets syndrome; HEV, hepatitis E virus; HSV, herpes simplex virus; MASH, metabolic dysfunction-associated steatohepatitis; VZV, varicella zoster virus.

Table 5.
Therapies for rescue of patients with severe flares/ACLF including adjunctive therapies
Table 5.
Strategy Therapy used Efficacy
Controlling viral replication Nucleoside analogues RCT [59] showed 57% survival vs. 15% survival with baseline MELD 23–25. Meta-analysis showed 3-month mortality improved from 77.3% to 44.8% in HBV-ACLF treated with NA [60]
Reducing severe inflammation Corticosteroids RCT [65] showed 6month mortality reduction from 42.5% to 32.4% in baseline MELD 23
Artificial liver support system (plasma exchange) Meta-analysis [75] showed a OR 1.41 (95% CI 1.17–1.70) vs. standard medical care
N-acetylcysteine No data in ACLF
Enhancing hepatocyte regeneration Granulocyte colony stimulating factor (G-CSF) RCT [82] and meta-analysis [83] failed to show survival benefit
Mesenchymal stem cell transplantation Two meta-analysis [87,88] showed contrasting results, hence benefit inconclusive

ACLF, acute on chronic liver failure; G-CSF, granulocyte-colony stimulating factor; MELD, Model for End-stage Liver Disease; OR, odds ratio; RCT, randomized control trial.

AARC

APASL Asia Research Consortium

AASLD

American Association for Study of Liver Disease

ACLF

acute-on-chronic liver failure

ALSS

artificial liver support systems

ALT

alanine aminotransferases

APASL

Asia Pacific Association for Study of Liver

CHB

chronic hepatitis B

EASL

European Association for Study of Liver

ETV

entecavir

HBeAg

hepatitis B e antigen

HBsAg

hepatitis B surface antigen

HBV

hepatitis B virus

INR

international normalized ratio

MELD

Model for End-stage Liver Disease

NA

nucleoside analogue

RCT

randomized control trial

SIRS

systemic inflammatory response syndrome

SMC

standard medical care

TDF

tenofovir disoproxil fumarate

TPE

therapeutic plasma exchange

ULN

upper limit of normal
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Severe hepatitis B flare and liver failure: current assessment and management
Clin Mol Hepatol. 2026;32(3):1117-1134.   Published online March 18, 2026
DOI: https://doi.org/10.3350/cmh.2026.0177
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Severe hepatitis B flare and liver failure: current assessment and management
Clin Mol Hepatol. 2026;32(3):1117-1134.   Published online March 18, 2026
DOI: https://doi.org/10.3350/cmh.2026.0177
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Severe hepatitis B flare and liver failure: current assessment and management
Image Image Image
Figure 1. Schematic diagram of progression of HBV reactivation to flare, and subsequent recovery, persistent hepatitis or ACLF. ACLF, acute on chronic liver failure; ALT, alanine aminotransferase; HBV, hepatitis B virus.
Figure 2. Immunopathogenesis of acute versus chronic hepatitis B flare showing a schematic diagram of interplay of various immune cells, cytokines, chemokines and pathways. (I) Acute hepatitis. (A) HBV-specific CD8 T cells traffic to the liver, crawl along the endothelium with the help of platelets and recognize infected hepatocytes. (B) HBV-specific CD8 T cells kill infected hepatocytes and produce IFN-γ to initiate non-cytolytic clearance. (C) IFN-γ stimulates the production of chemokines that draw non-HBV-specific cells into the inflamed environment that react to bystander cytokines and kill hepatocytes in an antigen-independent manner. (II) Chronic hepatitis B flare. (A) An unknown trigger stimulates the production of type I IFN and T cell activating cytokines (IL-2, IL-12 and IL-15) that leads to bystander CXCR6+ CD8 T cell IFN-γ production. (B) IFN-γ stimulates the production of chemokines that draw non-HBV-specific cells into the inflamed environment. (C) infiltrating lymphocytes that react to bystander cytokines and kill hepatocytes in an antigen-independent manner through FasL and TRAIL.
Figure 3. Proposed algorithm for assessment and management of HBV flare, showing evaluation, exclusion of other causes, initiation of nucleos(t)ide analogue therapy, adjunctive therapies and liver transplant consideration. HBV, hepatitis B virus; ALT, Alanine Transferase; AST, Aspartate Transferase; INR, international normalized ratio; ACLF, acute-on-chronic liver failure; ULN, upper limit of normal. *Total bilirubin. †Adjunctive therapies include corticosteroids and plasma exchange.

Figure 1.

Figure 2.

Figure 3.

Severe hepatitis B flare and liver failure: current assessment and management
Possible cause Important points
At initiation or end of HBV treatment • IFN: Flares are more common with IFN [9]
• NA: Higher rates of HBeAg loss with flares [98]
• Therapy with novel agents: Capsid assembly modulators, nucleic acid polymers, small interfering RNA, anti-sense oligonucleotides, immune based therapies [99]
Stopping antiviral therapy • High rates of flares when stopping NA therapy [3]
• This may occur when patients are non-adherent, run out of medication, or stop on their own violation, or by their physician [100,101]
Drug resistant mutants during oral antiviral therapy • Particularly with lamivudine and adefovir, infrequently with entecavir [102]
During or after immunosuppressive/immunomodulatory therapy and after chemotherapy treatment • After chemotherapy, immune suppression novel immunetherapeutic agents [3,8]
• Organ103 or stem cell transplant [104]
After immune restoration • Late pregnancy/early post-partum period [105]
• Active retroviral therapy in HIV coinfected patients [106]
Spontaneous hepatitis B flare in patients with chronic HBV or cirrhosis • Occurs 13–60% in HBeAg positive patients and 6–33% in HBeAg negative patients [9]
HBV reactivation in the context of HCV therapy • High risk (24%) in HBsAg(+) patients but low risk (1.4%) in HBsAg(–) patients [107]
Reactivation AASLD [108] EASL [31] APASL [30]
Reactivation of CHB (HBsAg+) HBV DNA ≥10,000 IU/mL if the baseline HBV DNA level is unknown 100 fold increase in HBV DNA compared to baseline level HBV DNA ≥1,000 IU/mL in a patient with previously undetectable level 10-fold increase in HBV DNA levels from baseline ≥2 log increase from baseline levels or a new appearance of (HBV DNA to a level of ≥100 IU/mL) in a person with previously stable or undetectable levels, or detection of HBV DNA ≥20,000 IU/mL in a person with no baseline HBV DNA
Reactivation of resolved HBV (HBsAg–) HBV DNA detection or appearance of HBsAg (reverse seroconversion) HBV DNA detection (>100 IU/mL) or appearance of HBsAg (reverse seroconversion) HBV DNA detection or appearance of HBsAg (reverse seroconversion)
Flare & decompensation Reference
HBV flare ALT>5×ULN AASLD [108]
APASL [30]
Severe flare ALT>10×ULN Dongelmans et al. [34]
Liver decompensation Bilirubin ≥2.5×ULN and/or INR≥1.5 APASL [30]
Assess for other viral hepatitis HAV, HCV, HDV, HEV
Assess for systemic viral infections CMV, EBV, HSV, VZV, Dengue, SARS-CoV-2
Consider other hepatic injury if appropriate Wilson disease, hemophagocytic lymphohistiocytosis, leptospirosis, malignant infiltration, Budd–Chiari syndrome, alpha-1 anti-trypsin deficiency, congestive liver disease, ischemic hepatitis, HELLP syndrome
Important conditions to exclude Drug induced liver injury, alcohol related liver injury, autoimmune hepatitis, MASH, biliary obstruction
Strategy Therapy used Efficacy
Controlling viral replication Nucleoside analogues RCT [59] showed 57% survival vs. 15% survival with baseline MELD 23–25. Meta-analysis showed 3-month mortality improved from 77.3% to 44.8% in HBV-ACLF treated with NA [60]
Reducing severe inflammation Corticosteroids RCT [65] showed 6month mortality reduction from 42.5% to 32.4% in baseline MELD 23
Artificial liver support system (plasma exchange) Meta-analysis [75] showed a OR 1.41 (95% CI 1.17–1.70) vs. standard medical care
N-acetylcysteine No data in ACLF
Enhancing hepatocyte regeneration Granulocyte colony stimulating factor (G-CSF) RCT [82] and meta-analysis [83] failed to show survival benefit
Mesenchymal stem cell transplantation Two meta-analysis [87,88] showed contrasting results, hence benefit inconclusive
Table 1. Causes of HBV flare and unique considerations

HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; IFN, interferon; NA, nucleoside analogues.

Table 2. Definitions of HBV reactivation according to the liver societies

AASLD, American Association for Study of Liver Disease; APASL, Asia Pacific Association for Study of Liver; CHB, chronic hepatitis B; EASL, European Association for Study of Liver; HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen.

Table 3. Definitions of HBV flare, severe HBV flare and liver decompensation

AASLD, American Association for Study of Liver Disease; ALT, alanine aminotransferases; APASL, Asia Pacific Association for Study of Liver; HBV, hepatitis B virus; INR, international normalized ratio; ULN, upper limit of normal.

Table 4. Evaluation of the patient with severe HBV flare

CMV, cytomegalovirus; EBV, Epstein Barr virus; HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis delta virus; HELLP syndrome, hemolysis, elevated liver enzymes and low platelets syndrome; HEV, hepatitis E virus; HSV, herpes simplex virus; MASH, metabolic dysfunction-associated steatohepatitis; VZV, varicella zoster virus.

Table 5. Therapies for rescue of patients with severe flares/ACLF including adjunctive therapies

ACLF, acute on chronic liver failure; G-CSF, granulocyte-colony stimulating factor; MELD, Model for End-stage Liver Disease; OR, odds ratio; RCT, randomized control trial.

Table 1.

Table 2.

Table 3.

Table 4.

Table 5.

Clin Mol Hepatol : Clinical and Molecular Hepatology
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