Background and aims: Flares are a well known phenomenon during antiviral treatment for chronic hepatitis B. Little is known about the effect of flares on response. We investigated the timing and characteristics of flares, in relation to treatment response (hepatitis B e antigen loss). Patients: A total of 266 patients, participating in a global randomised controlled study, were assigned to 52 weeks of 100 mg pegylated (Peg)-interferon a-2b weekly, combined with either daily lamivudine 100 mg or placebo. Results: Sixty seven patients (25%) exhibited 75 flares, with 38 (51%) flares in the combination therapy and 37 (49%) in the monotherapy groups. Overall, 30% of patients with and 38% of patients without a flare responded to therapy (p = 0.25). In 24 patients (36%) the flare was followed by a decrease in hepatitis B virus (HBV) DNA (host induced flare). In 25 (38%) patients the flare was preceded by an increase in HBV DNA (virus induced flare). In 17 (26%) patients the flare did not meet one of these criteria (indeterminate flare). Of patients with host induced flare, 58% responded whereas only 20% of patients with virus induced flares responded (p = 0.008). Hepatitis B surface antigen loss (n = 8) was exclusively seen in patients experiencing a host induced flare. Multivariate logistic analysis showed that host induced flares was an independent predictor of response (p = 0.043). Conclusion: Flares are not more common in responders than in non-responders to Peg-interferon a-2b therapy. Virus induced flares, which occur after an increase in HBV DNA level, and most probably are indicative for increased expression of viral antigens, did not lead to treatment response. In contrast, host induced flares which were followed by a HBV DNA decrease were highly associated with treatment response.
SummaryBackgroundStopping nucleos(t)ide analogues (NA) after hepatitis B e antigen (HBeAg) seroconversion is associated with high relapse rates in Asian patients, but data in Caucasian cohorts are scarce. Clinical course, outcomes and immunological aspects of chronic hepatitis B infections differ substantially between distinct ethnicities.AimThe aim of this study was to determine relapse rates, factors predicting relapse and clinical outcomes after nucleos(t)ide analogue cessation in a large, predominantly Caucasian cohort of chronic hepatitis B patients with nucleos(t)ide analogue‐induced HBeAg seroconversion.MethodsThis is a nationwide observational cohort study including HBeAg positive, mono‐infected chronic hepatitis B patients with nucleos(t)ide analogue‐induced HBeAg seroconversion from 18 centres in Belgium.ResultsA total of 98 patients with nucleo(s)tide analogue‐induced HBeAg seroconversion were included in the study. Of the 62 patients who stopped treatment after a median consolidation treatment of 8 months, 30 relapsed. Higher gamma‐glutamyl transferase levels at both treatment initiation (HR 1.004; P = 0.001 per unit increment) and HBeAg seroconversion (HR 1.006; P = 0.013 per unit increment) were associated with an increased risk of clinically significant relapse in a multivariate Cox regression model. Treatment cessation led to liver‐related death in 2 patients, of whom one showed a severe flare. Of the patients who continued treatment after HBeAg seroconversion, none relapsed or developed severe hepatic outcomes.ConclusionTreatment withdrawal in Caucasian chronic hepatitis B patients after nucleos(t)ide analogue‐induced HBeAg seroconversion results in viral relapses in more than half of patients with potential fatal outcomes. These real‐world data further lend support to preferentially continue NA treatment after HBeAg seroconversion until HBsAg loss.
K E Y W O R D S hepatitis B virus, treatment cessation, hepatitis B surface antigen, ethnicity, sustained virologic response, RRID:SCR_002865 1 | INTRODUC TI ON The hepatitis B virus (HBV) is a non-cytopathic DNA virus that infects hepatocytes and frequently causes a lifelong infection. As such, it accounts for up to 780 000 deaths annually. Nucleos(t)ide analogues (NA) efficiently suppress viral replication and substantially improve survival of chronic HBV patients. However, loss of the hepatitis B surface antigen (HBsAg) is rare in patients under NA treatment, often requiring years to decades. 1 Over the last years, the feasibility of stopping NA treatment prior to HBsAg loss has been extensively investigated in long-term virally suppressed hepatitis B e antigen (HBeAg)-negative hepatitis B patients. 2 Although viral relapse was found to be frequent, subsequent HBsAg loss has been reported in up to 39% of the patients. 3 This has been ascribed to beneficial alanine aminotransferase (ALT) flares with concomitantly restored HBV-specific T-cell responses. 4,5 However, in a recent, large cohort study of 691 HBeAg-negative hepatitis patients, sustained viral suppression rather than any type of relapse following treatment withdrawal was associated with HBsAg seroclearance. 6 Sustained off-treatment viral control is associated with high hepatitis B surface antigen seroclearance rates in Caucasian patients with nucleos(t)ide analogue-induced HBeAg seroconversion. J Viral Hepat. 2019;26:766-769. https://doi.
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