Serious adverse events after cessation of nucleos(t)ide analogues in individuals with chronic hepatitis B: A systematic review and meta-analysis

Tseng, Cheng‐Hao; Chen, Tzu‐Haw; Wu, Jia‐Ling; Lee, Teng‐Yu; Borghi, John; Lin, Jaw–Town; Nguyen, Mindie H.; Hsu, Yao‐Chun

doi:10.1016/j.jhepr.2022.100617

Cited by 17 publications

(20 citation statements)

References 73 publications

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“…Liver decompensation after cessation of TAF therapy was 2.6% in our study. Compared with the previous study [ 18 ], our study had a higher liver decompensation rate. The reason was unclear, but the small population size may be the main cause.…”

Section: Discussioncontrasting

confidence: 67%

“…A systematic review and meta-analysis reported that severe hepatitis flares or decompensation occur in 1.21% of cases, and hepatitis flare-related death or liver transplantation occur in 0.37% of cases, with a mean follow-up duration of over 12 months [ 18 ]. However, this systematic review only included NUC therapies with entecavir and TDF.…”

Section: Discussionmentioning

confidence: 99%

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Chronic Hepatitis B Relapse Rates after Cessation of Tenofovir Alafenamide and Entecavir Therapy

Huang

Yang

et al. 2023

Biomedicines

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Chronic hepatitis B (CHB) relapse occurs after the cessation of nucleos(t)ide analogues (NUC) therapy due to the waning of viral suppression. Few studies have investigated the viral relapse rate and clinical relapse rate after tenofovir alafenamide (TAF) therapy. We compared the CHB relapse rate between TAF and entecavir therapy. We enrolled patients with chronic hepatitis B who underwent TAF or entecavir therapy. NUC therapy was terminated after HBeAg loss for 1 year in HBeAg-positive patients and after undetectable serum HBV DNA on three separate tests each >6 months apart in HBeAg-negative patients. After cessation of NUC therapy, we followed alanine aminotransferase (ALT) levels at 12, 24, and 48 weeks. Serum HBV DNA levels were checked if patients showed a two-fold elevation from the upper limit of normal ALT levels (41 IU/mL). Clinical relapse (CR) was defined as a two-fold elevation in ALT levels and HBV DNA levels > 2000 IU/mL. We then investigated the CR rate of HBV after cessation of TAF and entecavir therapy at 12, 24, and 48 weeks. Of the 117 patients enrolled, 78 were in the entecavir group and 39 were in the TAF group. At 12 weeks after cessation of NUC therapy, no patients had HBV CR in the entecavir group. However, three patients (CR cumulative rate 7.9%) had CR in the TAF group. At 24 weeks, the CR cumulative rate in the entecavir and TAF groups were 1.3% and 13.2%, respectively (p < 0.05). At 48 weeks, the CR cumulative rates were 9.2% and 24.2%, respectively (p = 0.055). Patients in the TAF group had a higher cumulative rate of CR than those in the entecavir group (log-rank p = 0.023). Furthermore, patients in the TAF group had earlier CR times than those in the entecavir group, especially in the first 24 weeks after cessation of therapies (p < 0.05). The cessation of TAF therapy had significantly earlier and higher CR rates than that of entecavir therapy. Close monitoring of liver function and HBV DNA levels may be necessary, especially within 24 weeks after cessation of TAF therapy.

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Section: Discussioncontrasting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Chronic Hepatitis B Relapse Rates after Cessation of Tenofovir Alafenamide and Entecavir Therapy

Huang

Yang

et al. 2023

Biomedicines

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“…42 This crucial gap in knowledge has recently been addressed by large cohort studies with more than 500 participants and also by pooled analyses of individual studies (Table 3). [33][34][35][43][44][45][46] In the Taiwanese population-based study by Hsu and colleagues, the cumulative incidence of severe flares with hepatic decompensation (defined by both hyperbilirubinemia and coagulopathy) was estimated at 1.8% (95% CI, 1.5-2.2%) at four years after treatment withdrawal. 41 After pooling fifteen studies with 4525 individual patients in a systematic review and meta-analysis of current literature updated to August 2022, Tseng and colleagues reported that 1.2% (95% CI, 0.70-2.1%) of patients would develop severe flares or hepatic decompensation (variably defined in respective studies) after stopping NA.…”

Section: Risk Estimation For Severe Withdrawal Flares With Hepatic De...mentioning

confidence: 99%

“…In those studies that included severe hepatitis flares or hepatic decompensation, one third (14 out of 46 reports) did not clearly define the safety events. 43 In fact, most of the previous studies focused on virological or clinical relapse and the observation could have been censored before occurrence of a more serious event. 32,42 Accordingly, we believe it is mandatory to include safety events as one of the study endpoints in every research that reports patient outcomes following NA cessation.…”

Section: Limitations In Current Knowledge and Perspectives For Future...mentioning

confidence: 99%

“…Moreover, existing studies were mostly retrospective and highly heterogeneous in various aspects, including compositions of patient populations, eligibility criteria for NA cessation, posttreatment monitoring, indications for retreatment, and measurements of outcomes. 32,43,87 For instance, the proportion of patients with cirrhosis and the criteria for retreatment varied greatly among studies. Without great caution, knowledge synthesis from the literature could be inaccurate and study findings would be erroneously extrapolated to patients who were not represented in the study.…”

Section: Limitations In Current Knowledge and Perspectives For Future...mentioning

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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Therapies against chronic hepatitis B infections: The times they are a-changin’, but the changing is slow!

Durantel

2023

Antiviral Research

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Serious adverse events after cessation of nucleos(t)ide analogues in individuals with chronic hepatitis B: A systematic review and meta-analysis

Cited by 17 publications

References 73 publications

Chronic Hepatitis B Relapse Rates after Cessation of Tenofovir Alafenamide and Entecavir Therapy

Chronic Hepatitis B Relapse Rates after Cessation of Tenofovir Alafenamide and Entecavir Therapy

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

Therapies against chronic hepatitis B infections: The times they are a-changin’, but the changing is slow!

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