Product information and disease description Place of product in therapy Approaches to treatment Current treatment options and standard of care

Nucleos(t)ide analogue withdrawal

10 evidence topics · 7 sources

Recommendation against withdrawal before HBsAg loss: AASLD/IDSA 2025 guideline

“In adults with chronic hepatitis B, who are HBeAg-negative without cirrhosis, with sustained undetectable HBV DNA on nucleos(t)ide analogue therapy, AASLD suggests not withdrawing nucleos(t)ide analogue therapy until HBsAg loss.” (opens the source at this quote in a new tab)
“Strength of recommendation: Conditional” (opens the source at this quote in a new tab)
“Certainty of evidence: Very Low” (opens the source at this quote in a new tab)
“An alternate and preferable approach for HBeAg negative persons on NA treatment is to continue treatment until HBsAg loss is achieved and confirmed, after which treatment can be stopped.” (opens the source at this quote in a new tab)

Criteria, monitoring, and restart rules for persons who wish to stop: AASLD/IDSA 2025 guideline

“have a quantitative HBsAg level <100 IU/mL.” (opens the source at this quote in a new tab)
“Following withdrawal of treatment, serum ALT and HBV DNA should be monitored every 1-3 months for the initial 6 months, then every 3 months for the next 6 to 12 months. Thereafter, monitor at 3 to 6 month intervals depending on the ALT and HBV DNA values.” (opens the source at this quote in a new tab)
“an HBV DNA level ≥10,000 IU/mL (≥4 log IU/mL) regardless of ALT level, or” (opens the source at this quote in a new tab)
“ALT ≥5 x ULN regardless of HBV DNA or” (opens the source at this quote in a new tab)
“total bilirubin >2.5 mg/dL, or” (opens the source at this quote in a new tab)

Evidence summary behind the AASLD/IDSA 2025 recommendation

“The systematic review included 11 studies (4 RCTs and 7 observational studies) involving 1,957 individuals (948 in the discontinuation group and 1,009 in the continuation group).” (opens the source at this quote in a new tab)
“In the decision-making process, the committee considered that the majority of the evidence supporting the benefit of stopping therapy was derived from four small prospective RCTs in which the rates of HBsAg loss were modest, 10.6% over two years (versus 0% in those who remained on therapy, RR 12.65 (1.58 to 101.51) while the downsides, i.e. ALT flares 26.9% (RR 11.63 [0.15 to 891.61]) at two years and retreatment 23% (RR 0.24 [0.07-0.4]) at 1.5 years were substantial.” (opens the source at this quote in a new tab)
“Given the long-term safety of NA treatment and availability of low cost generics and reportedly higher rates of adverse complications including decompensation and death after NA discontinuation, from large cohort studies, the committee recommended against withdrawal of therapy until functional cure was achieved.” (opens the source at this quote in a new tab)

HBsAg loss and relapse after discontinuation: technical review supporting the AASLD/IDSA 2025 guideline

“PICO 3 analyses demonstrate that discontinuing antiviral therapy in persons who are HBeAg negative with undetectable HBV DNA increases HBsAg loss rates (OR: 12.65, 95% CI: 1.58–101.51) but carries moderate risks of virologic relapse (OR: 47.17, 95% CI: 2.79–797.35) and clinical flares.” (opens the source at this quote in a new tab)
“Discontinuation of therapy was associated with a higher risk of clinical flare, defined as ALT elevation>2× ULN if HBV DNA >2000 IU/mL.” (opens the source at this quote in a new tab)
“Clinical flare (5 y): Significantly higher with discontinuation (OR: 13.14, 95% CI: 1.09–158.85).” (opens the source at this quote in a new tab)
“The proportion requiring retreatment ranged from 13.9% to 100%, with a median interval between treatment discontinuation and restart of 12–42 weeks.” (opens the source at this quote in a new tab)
“Among the cohort studies, one cohort47 (62 individuals) with 3.5 years of follow-up reported a relapse rate of 22.6% (95% CI: 12.2%–33.0%), another cohort43 (325 individuals) with 5 years of follow-up reported a rate of 36.3% (95% CI: 31.1%–41.5%), and the last cohort44 (250 individuals) with 6 years of follow-up reported a rate of 56.4% (95% CI: 50.3%–62.5%).” (opens the source at this quote in a new tab)

Recommendations on stopping nucleos(t)ide analogues: EASL 2025 guideline

“Antiviral therapy with NAs should only be discontinued after consultation with a physician experienced in the treatment of hepatitis B and if close monitoring is guaranteed. HBsAg levels, HBeAg status, comorbidities, duration of HBV DNA suppression, stage of liver fibrosis in addition to patient understanding and preference should be taken into account (LoE 2, strong recommendation, strong consensus).” (opens the source at this quote in a new tab)
“Antiviral therapy with NAs should be stopped after confirmed HBsAg loss with or without anti-HBs seroconversion in the absence of coexisting risk factors (LoE 2, strong recommendation, consensus).” (opens the source at this quote in a new tab)
“In selected HBeAg-negative patients without advanced liver disease, NA therapy can be discontinued before HBsAg loss if HBV DNA has been undetectable for at least 3-4 years, HBsAg level is low (for values see comments below), and close monitoring is guaranteed after the end of therapy (LoE 1-2, weak recommendation, consensus).” (opens the source at this quote in a new tab)

HBsAg loss, relapse, and severe events after stopping: EASL 2025 evidence review

“In the prospective and randomised STOP-NUC study, the HBsAg loss rate 2 years after the end of therapy was 10% in all patients stopping NA treatment, and 28% in the subgroup of patients with an HBsAg level <1,000 IU/ml at the time of treatment discontinuation. No patient who continued NA therapy achieved HBsAg loss during this time.” (opens the source at this quote in a new tab)
“Of note, in multicentre studies in which Asians predominated and comprised up to 80% of the cohort, reported rates of functional cure were lower and generally did not exceed 10-15% at 5-6 years after discontinuation of NA therapy.” (opens the source at this quote in a new tab)
“A systematic review and meta-analysis assessed the risk of severe clinical events after discontinuing NA therapy, finding that 1.21% of patients experienced severe hepatitis flares or hepatic decompensation, with significantly higher risks in patients with cirrhosis (3.63%) and a 0.37% chance of flare-related death or liver transplantation.” (opens the source at this quote in a new tab)
“Frequent monitoring after NA discontinuation is essential, with assessments at least monthly for the first 6 months, followed by every 3 months for 12–24 months.” (opens the source at this quote in a new tab)
“Retreatment should be considered if HBV DNA exceeds 10,000 IU/ml, regardless of ALT levels, and initiated no later than when HBV DNA reaches ≥100,000 IU/ml to prevent severe liver injury.” (opens the source at this quote in a new tab)

Off-therapy outcomes in a multinational cohort: RETRACT-B

“Among 1552 patients with CHB, cumulative probability of HBsAg loss was 3.2% at 12 months and 13.0% at 48 months of follow-up.” (opens the source at this quote in a new tab)
“Virologic relapse occurred in 1207 patients, and cumulative probabilities increased from 47.8% (95% CI, 45.3%–50.3%) at 6 months to 68.9% (95% CI, 66.5%–71.2%) at 12 months and reached 83.4% (95% CI, 81.2%–85.5%) at 48 months of follow-up (Figure 2B).” (opens the source at this quote in a new tab)
“After NA cessation, 729 patients were retreated, and the cumulative probability of retreatment increased from 16.2% (95% CI, 14.4%-18.2%) at 6 months to 29.8% (95% CI, 27.5%–32.2%) at 12 months of follow-up and reached 54.7% (95% CI, 51.7%-57.7%) at 48 months (Figure 2F).” (opens the source at this quote in a new tab)
“There were 19 patients who developed hepatic decompensation after NA cessation (8/184 [4.3%] patients with cirrhosis vs 11/1368 [0.8%] patients without cirrhosis; P < .001) with an incidence rate of 0.48 per 1000 person-months.” (opens the source at this quote in a new tab)
“Death occurred in 7 (36.8%) of the 19 decompensated patients, of whom 6 died after starting retreatment.” (opens the source at this quote in a new tab)

Discontinuation considered only exceptionally: WHO 2024 guideline

“Antiviral therapy is lifelong. Discontinuation of nucleos(t)ide analogue therapy may be considered exceptionally for:” (opens the source at this quote in a new tab)
“Relapse is common after stopping therapy with nucleos(t)ide analogues.” (opens the source at this quote in a new tab)

Stopping after HBsAg loss: AASLD 2018 guidance

“Treatment discontinuation in persons with cirrhosis is not recommended owing to the potential for decompensation and death, although data are limited.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote
“Treatment discontinuation may be considered in persons who have demonstrated loss of HBsAg. However, there is currently insufficient evidence to definitively guide treatment decisions for such persons.” (opens the original PMC page at this quote in a new tab)View highlighted excerpt for this quote

Nucleos(t)ide analogue cessation after bepirovirsen: label criteria

“HIBSAGO must be stopped upon completion of 24 weeks of treatment, and patients must remain on their NrtI therapy for at least an additional 24 weeks. Following the 24 weeks of further NrtI treatment, stopping NrtI therapy can be considered in those patients who:” (opens the prescribing information at this quote)
“are hepatitis B e-antigen (HBeAg) negative,” (opens the prescribing information at this quote)
“have HBV DNA <LLOQ (lower limit of quantification, defined as <20 IU/mL), HBsAg not detectable (LOD = 0.05 IU/mL), and alanine aminotransferase (ALT) values ≤2x upper limit of normal (ULN), and” (opens the prescribing information at this quote)
“If NrtI therapy is stopped, frequent monitoring of HBsAg, HBV DNA, and hepatic function is recommended for at least one year following NrtI therapy cessation, with routine monitoring as clinically indicated afterwards” (opens the prescribing information at this quote)