Incidence of Hepatic Decompensation After Nucleos(t)ide Analog Withdrawal: Results From a Large, International, Multiethnic Cohort of Patients With Chronic Hepatitis B (RETRACT-B Study)

Abstract

on behalf of the RETRACT-B study group INTRODUCTION: Despite improvements in the management of chronic hepatitis B (CHB), risk of cirrhosis and hepatocellular carcinoma remains. While hepatitis B surface antigen loss is the optimal end point, safe discontinuation of nucleos(t)ide analog (NA) therapy is controversial because of the possibility of severe or fatal reactivation flares. METHODS:This is a multicenter cohort study of virally suppressed, end-of-therapy (EOT) hepatitis B e antigen (HBeAg)-negative CHB patients who stopped NA therapy (n 5 1,557). Survival analysis techniques were used to analyze off-therapy rates of hepatic decompensation and differences by patient characteristics. We also examined a subgroup of noncirrhotic patients with consolidation therapy of ‡12 months before cessation (n 5 1,289). Hepatic decompensation was considered related to therapy cessation if diagnosed off therapy or within 6 months of starting retreatment. RESULTS:Among the total cohort (11.8% diagnosed with cirrhosis, 84.2% start-of-therapy HBeAg-negative), 20 developed hepatic decompensation after NA cessation; 10 events were among the subgroup. The cumulative incidence of hepatic decompensation at 60 months off therapy among the total cohort and subgroup was 1.8% and 1.1%, respectively. The hepatic decompensation rate was higher among patients with cirrhosis (hazard ratio [HR] 5.08, P < 0.001) and start-of-therapy HBeAg-positive patients (HR 5.23, P < 0.001). This association between start-of-therapy HBeAg status and hepatic decompensation remained significant even among the subgroup (HR 10.5, P < 0.001). DISCUSSION:Patients with cirrhosis and start-of-therapy HBeAg-positive patients should be carefully assessed before stopping NAs to prevent hepatic decompensation. Frequent monitoring of viral and host kinetics after cessation is crucial to determine patient outcome.

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

“…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.…”

“…The international RETRACT-B consortium also found that the cumulative incidence of hepatic decompensation (defined as hyperbilirubinemia, coagulopathy, or clinical complications) was 1.8% at five years. 33 On the basis of these aforementioned studies, life-threatening flares were expected to occur in approximately 1-2% of HBV-infected patients who discontinued NA according to the stopping rules of earlier practice guidelines (mainly APASL) or local reimbursement policies. Notably, while the criteria of the APASL guidelines are the most stringent for treatment initiation, [9][10][11] they are comparatively more liberal than those of the EASL and AASLD guidelines for stopping NA therapy (Table 2).…”

“…54 The chance of HBsAg seroclearance was also significantly higher in Caucasian patients than in Asian patients although the incidence of ALT flares did not appear to differ by ethnicity. 33,48,75 This association might reflect differences in the geographic distribution of HBV genotypes, because the genotype was predominantly A or D in Caucasians, but B or C in Asians. 75,76 The mode of transmission, the age/duration of infection, or host genetic polymorphism should also be considered.…”

“…32 Knowledge about the safety of treatment cessation is indispensable to inform the practice of finite NA therapy, and data have been emerging to quantify the risk of severe withdrawal hepatitis flares and to identify the associated risk factors. [33][34][35] In this review with a special focus on patient safety, we summarized the data available to date and discussed the selection of patients suitable/unsuitable for NA cessation, patterns of off-therapy flares with implications for patient monitoring, and pragmatic considerations for the timing to resume antiviral therapy. We also stressed current knowledge gaps, pointed out pitfalls in existing literature, and provided our perspectives on future directions of research.…”

Getting to HBV cure: The promising paths forward

“…Whites were much more likely to lose HBsAg compared to Asians, and HBsAg <100 IU/ml predicted HBsAg loss with a high probability. [47] It should be noted that treatment discontinuation can also lead to detrimental outcomes in a minority of patients, given that cases of liver decompensation and death, even in patients without cirrhosis, have been reported. [46,48,49] Further studies using standardized criteria and definitions for NA withdrawal are required to identify the subset of patients likely to benefit from finite therapy.…”