The Role of Off-Therapy Viral Kinetics in the Timing and Severity of Flares in Hepatitis B e Antigen–Negative Patients

Liu, Yen-Chun; Jeng, Wen–Juei; Peng, Chien‐Wei; Chien, Rong‐Nan; Liaw, Yun–Fan

doi:10.1016/j.cgh.2022.08.021

Cited by 10 publications

(18 citation statements)

References 19 publications

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“…A recent retrospective study reported that a much steeper HBV DNA upsurge was associated with the risk of severe flares although the association appeared to interact with the NA regimen. 96 Serum level of HBsAg may markedly change following NA withdrawal in contrast to the typically unfluctuating state during continuous treatment. The time-varying HBsAg level in posttreatment follow-up can be useful to stratify the risk of subsequent relapses.…”

Section: Dynamic Risk Prediction In the Follow-up Of Na Stoppersmentioning

confidence: 99%

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Safety considerations for withdrawal of nucleos(t)ide analogues in patients with chronic hepatitis B: First, do no harm

Hsu¹,

Tseng²,

Kao³

2023

Clin Mol Hepatol

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Nucleos(t)ide analogues (NA) are widely used to treat hepatitis B virus (HBV) infection, but they cannot eradicate the virus and treatment duration can be lifelong if the endpoint is set at seroclearance of the hepatitis B surface antigen (HBsAg). As an alternative strategy, finite NA therapy without the prerequisite of HBsAg seroclearance has been proposed to allow treatment cessation in patients with sustained undetectable HBV viremia for two to three years. However, reactivation of viral replication almost always follows NA withdrawal. Whereas HBV reactivation might facilitate HBsAg seroclearance in some, it could lead to serious acute flare-ups in a certain proportion of patients. Occurrence and consequences of NA withdrawal flares are complicated with various factors involving the virus, host, and treatment. Accurate risk prediction for severe flares following NA cessation is essential to ensure patient safety. The risks of life-threatening flares in patients who discontinued NA according to the stopping rules of current guidelines or local reimbursement policies have recently been quantitatively estimated in large-scale studies, which also provided empirical evidence to help identify vulnerable patients at risk of devastating outcomes. Moreover, risk predictors were further explored and validated to hopefully aid in patient selection and management. In this narrative review with a focus on patient safety, we summarize and discuss current literature on the incidence of severe flares following NA cessation, risk stratification 4 for candidate selection, rules of posttreatment monitoring, and indications for treatment resumption. We also share our thoughts on the limitations of existing knowledge and suggestions for future research.

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Section: Dynamic Risk Prediction In the Follow-up Of Na Stoppersmentioning

confidence: 99%

“…Withholding retreatment may not be necessary, because a fierce rebound of viremia often forecasts clinical flares that eventually require antiviral therapy. [94][95][96]…”

Section: Dilemma Over the Timing Of Treatment Resumptionmentioning

confidence: 99%

Safety considerations for withdrawal of nucleos(t)ide analogues in patients with chronic hepatitis B: First, do no harm

Hsu¹,

Tseng²,

Kao³

2023

Clin Mol Hepatol

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“…However, the criteria to reinitiate NUCs are contentious without a consensus 7 . Based on findings from both the current study and previous ones, 33–35 treatment resumption is recommended in cases of severe virological relapse with a high viral load, without the need to wait for clinical flares to occur.…”

Section: Discussionmentioning

confidence: 85%

Severe hepatitis B flares with hepatic decompensation after withdrawal of nucleos(t)ide analogues: A population‐based cohort study

Hsu

Lin

Lee

et al. 2023

Aliment Pharmacol Ther

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Background: Finite nucleos(t)ide analogue (NUC) therapy has been proposed as an alternative treatment strategy for chronic hepatitis B (CHB). Aim:To quantify the incidence of severe hepatitis flares following NUC cessation in everyday clinical practice.Methods: This population-based cohort study enrolled 10,192 patients (male 71.7%, median age 50.9 years, cirrhosis 10.7%) who had received first-line NUCs for at least 1 year before discontinuing treatment. The primary outcome was severe flare with hepatic decompensation. We used competing risk analyses to assess event incidences and associated risk factors.Results: During a median follow-up of 2.2 years, 132 patients developed severe flares with hepatic decompensation, yielding a 4-year cumulative incidence of 1.8% (95% confidence interval [CI], 1.5%-2.2%). Significant risk factors were cirrhosis (adjusted sub-distributional hazard ratio [aSHR], 2.74; 95% CI, 1.82-4.12), manifestations of

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“…Until recently, ALT is the focus of post-treatment safety monitoring and criteria for resuming treatment, but data from studies of NA withdrawal and new therapies have shown that a marked increase in HBV DNA levels often precede ALT flares and might be a safer trigger for reinitiating treatment. 36 , 99 …”

Section: Strategies Toward Hbv Curementioning

confidence: 99%

What will it take to cure hepatitis B?

Jeng

Lok

2023

Hepatology Communications

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The current treatment of chronic HBV infection, pegylated interferon-α (pegIFNα) and nucleos(t)ide analog (NA), can suppress HBV replication, reverse liver inflammation and fibrosis and reduce the risks of cirrhosis, HCC, and HBV-related deaths, but relapse is common when the treatment is stopped before HBsAg loss. There have been major efforts to develop a cure for HBV, defined as sustained HBsAg loss after a finite course of therapy. This requires the suppression of HBV replication and viral protein production and the restoration of immune response to HBV. Direct-acting antivirals targeting virus entry, capsid assembly, viral protein production and secretion are in clinical trials. Immune modulatory therapies to stimulate adaptive or innate immunity and/or to remove immune blockade are being tested. NAs are included in most and pegIFNα in some regimens. Despite the combination of 2 or more therapies, HBsAg loss remains rare in part because HbsAg can be derived not only from the covalently closed circular DNA but also from the integrated HBV DNA. Achievement of a functional HBV cure will require therapies to eliminate or silence covalently closed circular DNA and integrated HBV DNA. In addition, assays to differentiate the source of circulating HBsAg and to determine HBV immune recovery, as well as standardization and improvement of assays for HBV RNA and hepatitis B core-related antigen, surrogate markers for covalently closed circular DNA transcription, are needed to accurately assess response and to target treatments according to patient/disease characteristics. Platform trials will allow the comparison of multiple combinations and channel patients with different characteristics to the treatment that is most likely to succeed. Safety is paramount, given the excellent safety profile of NA therapy.

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The Role of Off-Therapy Viral Kinetics in the Timing and Severity of Flares in Hepatitis B e Antigen–Negative Patients

Cited by 10 publications

References 19 publications

Safety considerations for withdrawal of nucleos(t)ide analogues in patients with chronic hepatitis B: First, do no harm

Safety considerations for withdrawal of nucleos(t)ide analogues in patients with chronic hepatitis B: First, do no harm

Severe hepatitis B flares with hepatic decompensation after withdrawal of nucleos(t)ide analogues: A population‐based cohort study

What will it take to cure hepatitis B?

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