Cessation of Nucleos(t)ide Analogue Therapy in Non-Cirrhotic Hepatitis B Patients with Prior Severe Acute Exacerbation

Abstract

Chronic hepatitis B (CHB) with severe acute exacerbation (SAE) is an urgent problem requiring nucleos(t)ide analogue (NA) therapy. We aim to evaluate the clinical relapse (CR) risk after discontinuing NA in patients with prior SAE. Methods: In this retrospective cohort study, CHB patients who discontinued NA therapy were screened between October, 2003 and January, 2019. A total of 78 non-cirrhotic patients who had received NA therapy for CHB with SAE, i.e., bilirubin ≥ 2 mg/dL and/or prothrombin time prolongation ≥3 s, (SAE group) were matched 1:2 with 156 controls without SAE (non-SAE group) by means of propensity scores (age, gender, NA categories, NA therapy duration, and HBeAg status). Results: The 5-year cumulative incidences of severe CR, i.e., ALT > 10X ULN, (42.78%, 95%CI: 27.84–57.73% vs. 25.42%, 95%CI: 16.26–34.58%; p = 0.045) and SAE recurrence (25.91%, 95%CI: 10.91–40.91% vs. 1.04%, 95%CI: 0–3.07%; p < 0.001) were significantly higher in the SAE group. Prior SAE history (HR 1.79, 95%CI: 1.04–3.06) was an independent factor for severe CR. The 5-year cumulative incidence of HBsAg seroclearance was significantly higher in the SAE group than that in the non-SAE group (16.82%, 95%CI: 2.34–31.30% vs. 6.02%, 95%CI: 0–13.23%; p = 0.049). Conclusions: Even though it creates a greater chance of HBsAg seroclearance, NA therapy cessation may result in a high risk of severe CR in non-cirrhotic CHB patients with prior SAE.

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

“… [12] , [13] , [14] , [17] , [18] , [19] , 27 , [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] , [54] , [55] , [56] , [57] , [58] , [59] , [60] , [61] , [62] , [63] , [64] , [65] , [66] , [67] , [68] , [69] , [70] , [71] , [72] One of the studies involved two distinct cohorts, of which one consisted exclusively of individuals with prior severe acute exacerbation and the other consisted of patients who had never experienced such an event. 31 Therefore, 50 studies with 51 cohorts were included in the meta-research analysis. Results of the risk-of-bias assessment of the included studies are provided in Table S4 .…”

“…Data were pooled to generate risk estimates from 15 selected studies with 4,525 patients overall. 17 , 19 , 27 , 31 , 32 , 47 , 48 , 50 , 54 , 56 , 59 , 62 , 64 , 66 , 69 The analysis was further stratified by cirrhosis status: the non-cirrhotic subgroup analysis from 14 studies with 3,731 patients, 17 , 19 , 27 , 31 , 32 , 47 , 48 , 50 , 56 , 59 , 62 , 64 , 66 , 69 and the cirrhotic subgroup analysis from five studies with 744 patients. 17 , 19 , 27 , 56 , 62 The funnel plot did not detect a significant publication bias among the 15 studies ( Fig.…”

“…Regarding study design, most studies were primarily designed to analyze virological and/or biochemical relapses, and only ten studies prespecified safety outcomes with a clear definition. [17] , [18] , [19] , 27 , [30] , [31] , [32] , [33] , [34] , 69 Among these ten studies, only four included manifestations of hepatic insufficiency (such as jaundice, coagulopathy, or related clinical complications), instead of a certain serum alanine aminotransferase (ALT) level alone, in the outcome definition and had a sample size of >100 patients and a follow-up duration of >12 months. 17 , 18 , 27 , 69 The other six studies either relied on serum ALT levels alone to define the safety outcomes, 19 , 31 , 33 , 34 had a small (N = 46) sample size, 32 had a short (≤6 months) duration of follow-up, 30 , 34 or was exclusively composed of a special patient population (those with HBsAg <200 IU/ml 33 ) ( Table S8 ).…”

“…A total of 46 of 50 studies reported data on severe flares or hepatic decompensation, but heterogeneously defined them as hyperbilirubinemia (without or without concurrent coagulopathy), ascites, encephalopathy, and/or variceal bleeding, in addition to abrupt elevation of serum ALT. [12] , [14] , [17] , [18] , [19] , 27 , [30] , [31] , [32] , [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] , [54] , [55] , [56] , [57] , [58] , [59] , [61] , [62] , [63] , [64] , [65] , [66] , [67] , 69 , 70 , 72 The definition of hyperbilirubinemia was also heterogeneous and could be a level of serum bilirubin ≥2 mg/dl, >3 mg/dl, and >2.5x the upper limit of normal. Similarly, coagulopathy was heterogeneously defined by prolongation of prothrombin time (PT) >3 seconds or an international normalized ratio >1.5 ( Table S7 ).…”

“…In the analysis of the relationships between the reported safety outcomes and the characteristics of the studies, we excluded four cohorts that were comprised exclusively of special patient populations (3 cohorts of individuals with low HBsAg levels and one cohort of only individuals with prior severe acute exacerbation, 31 , 33 , 51 , 52 ) and included 44 cohorts reporting severe hepatitis flares or hepatic decompensation, [12] , [13] , [14] , [17] , [18] , [19] , 27 , [30] , [31] , [32] , [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] , [46] , [47] , [48] , [49] , [50] , [53] , [54] , [55] , [56] , [57] , [58] , [59] , [61] , [62] , [63] , [64] , [65] , [66] , [67] , 69 , 70 , 72 and 45 reporting hepatitis flare-related death or liver transplantation. [12] , [13] , [14] , 17 , 18 , 27 , [30] , [31] , [32] , …”