Discontinuation of nucleot(s)ide analogue therapy in HBeAg-negative chronic hepatitis B: a meta-analysis

Abstract

Background and aimsSustained virological suppression and hepatitis B surface antigen (HBsAg) loss have been described after nucleot(s)ide analogue (NA) discontinuation for patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). We performed a meta-analysis of the clinical outcomes after NA discontinuation for HBeAg-negative CHB.MethodsStudies involving NA cessation in HBeAg-negative CHB individuals with a median follow-up of ≥12 months were included. Participants were HBeAg-negative at the time of NA initiation. Random effects meta-analyses were performed for the following clinical outcomes: (1) virological relapse (VR) at 6 and 12 months; (2) clinical relapse (CR) at 6 and 12 months and (3) HBsAg loss. Effect of other variables was estimated using subgroup analysis and meta-regression. Studies including patients stopping entecavir (ETV) and/or tenofovir disoproxil fumarate (TDF) were considered separately to studies including patients stopping older generation NA.ResultsN=37 studies met inclusion criteria. Cumulative incidence of VR and CR after stopping ETV/TDF was 44% and 17% at 6 months and 63% and 35% at 12 months. Similar relapse rates were observed after stopping older NAs. Among patients stopping ETV/TDF, TDF cessation was associated with increased CR rates at 6 months versus ETV. There was an association between follow-up ≥4 years and HBsAg loss rates when stopping older NAs. Hepatic decompensation and hepatocellular carcinoma were rare but occurred more frequently in studies including cirrhotic individuals.ConclusionVR is common after NA discontinuation, however, CR was only seen in one-third of patients at 12 months. Stopping NA therapy can be followed by HBsAg clearance, and rates are higher with longer follow-up.

Finite nucleos(t)ide analogue therapy in hepatitis B e antigen‐negative chronic hepatitis B: From an “option” to an “active recommendation”

“…After the pivotal report of a high HBsAg loss rate by Hadziyannis et al, 19 several small European studies and large Asian studies have confirmed that HBsAg loss rate is increasing after cessation of Nuc in HBV suppressed patients, especially in Caucasian patients and studies with off-Nuc follow-up >4 years. 23 In particular, a randomized control trial in 21 versus 21 patients showed a 3-year off-TDF HBsAg loss rate of 19% versus 0% (p = 0.022) in those who continued TDF therapy, 24 and a large study involving 691 ETV/TDF-treated patients showed a 6-year off-Nuc HBsAg loss rate of 36% in those with sustained HBV DNA <2,000 IU/ml and 19% in un-retreated clinical relapsers. 25 It was documented that the increase in the incidence of HBsAg loss became more evident after 4-year off-Nuc therapy and was higher in Caucasian than Asian patients.…”

“…25 It was documented that the increase in the incidence of HBsAg loss became more evident after 4-year off-Nuc therapy and was higher in Caucasian than Asian patients. 23 The much increased incidences of HBsAg loss in Asian patients with HBeAg-negative patients off-Nuc therapy as compared with those on indefinite longterm Nuc therapy are shown in Table 1. [25][26][27][28][29][30][31] It has been proposed that immune restoration during Nuc therapy and/or HBV reactivation elicited immune response may facilitate further HBsAg decline toward HBsAg loss.…”

“…In particular, a randomized control trial in 21 versus 21 patients showed a 3‐year off‐TDF HBsAg loss rate of 19% versus 0% ( p = 0.022) in those who continued TDF therapy, 24 and a large study involving 691 ETV/TDF‐treated patients showed a 6‐year off‐Nuc HBsAg loss rate of 36% in those with sustained HBV DNA <2,000 IU/ml and 19% in un‐retreated clinical relapsers 25 . It was documented that the increase in the incidence of HBsAg loss became more evident after 4‐year off‐Nuc therapy and was higher in Caucasian than Asian patients 23 . The much increased incidences of HBsAg loss in Asian patients with HBeAg‐negative patients off‐Nuc therapy as compared with those on indefinite long‐term Nuc therapy are shown in Table 1 25–31 .…”

KASL clinical practice guidelines for management of chronic hepatitis B

“…When HBV DNA is not detectable over a long term, and virological response is well maintained, the HBsAg loss rate increases even after cessation of therapy in patients with HBeAg-negative CHB. Therefore, cessation of therapy could be considered in these patients with long-term undetectable HBV DNA [ 244 - 246 , 250 ]. The lower is the HBV DNA level, the better is the clinical status; however, when the HBV DNA level is 60–2,000 IU/mL, the risk of cirrhosis and HCC is similar to that of patients with undetectable HBV DNA [ 68 , 70 ].…”

“…Evidence for HBV DNA level as a surrogate indicator in these patients is lacking. Also, in practice, most patients with undetectable HBV DNA relapsed after cessation of NA therapy [ 194 , 244 - 246 ]. Hence, undetectable HBV DNA cannot be the sole indicator determining treatment cessation.…”