Clin Mol Hepatol > Volume 29(4); 2023 > Article |
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Guideline | Non-cirrhosis | Cirrhosis |
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International guidelines | ||
AASLD [9] | · Indefinite treatment duration (Quality and Certainty of Evidence: Low Strength of Recommendation: Conditional) | · Treatment discontinuation not recommended |
· May be considered in patients with HBsAg loss, but evidence insufficient | ||
APASL [10] | · HBsAg loss following either anti-HBsAb seroconversion or at least 12 months of a post-HBsAg clearance consolidation period (B1), or | · May be considered with a careful off-therapy monitoring plan (A1) |
· Treatment for ≥2 years with consolidation ≥1 year (B1) | ||
EASL [11] | · HBsAg loss, with or without anti-HBsAb seroconversion (Evidence level II-2, grade of recommendation 1), or | · Treatment discontinuation not recommended |
· May be considered after consolidation ≥3 years if close monitoring can be guaranteed (Evidence level II-2, grade of recommendation 2). | ||
WHO [24] | · Life-long therapy in general | · Treatment discontinuation not recommended |
· Discontinuation may be considered exceptionally in persons who can be followed carefully long term for reactivation and with persistently normal ALT levels and persistently undetectable HBV DNA levels | ||
· May be considered in persons who have evidence of persistent HBsAg loss and after completion of at least one additional year of treatment, regardless of prior HBeAg status. | ||
National guidelines | ||
Canada [25] | · HBsAg loss (moderate recommendation; class 2, level B) | · HBsAg loss or indefinite duration (moderate recommendation; class 2, level B) |
China [26] | · The therapy aims are “clinical cure” (i.e., functional cure) | |
· No recommended criteria for stopping treatment | ||
· No specific recommendations for patients with cirrhosis | ||
Japan [27] | · In general, it is necessary not to stop administration of the NAs | · Long-term treatment (Level 5, Grade B) |
· HBsAg loss (can be considered) | ||
· Treatment for ≥2 years without detectable HBV DNA or high relapse risk score according to serum HBcrAg and HBsAg levels | ||
Korea [28] | · HBsAg loss (A1). | · Long-term treatment (B1) |
· With reference to HBsAg level, cessation of NA therapy could be considered (B1). | ||
· HBcrAg and HBV RNA can be performed when considering cessation of NA therapy (B2) | ||
Sweden [29] | · HBsAg loss (B1) | · Long-term treatment (A1) |
· May be considered after long-standing treatment response but require close monitoring after termination(B2) | ||
Turkey [30] | · HBsAg loss | · Long-term treatment |
AASLD, American Association for the Study of the Liver; ALT, alanine aminotransferase; APASL, Asian Pacific Association for the Study of the Liver; anti-HBsAb, anti-hepatitis B s-antibody; DNA, deoxyribonucleic acid; EASL, European Association for the Study of the Liver; HBcrAg, hepatitis B core-related antigen; HBeAg, hepatitis B e-antigen; HBsAg, hepatitis B virus s-antigen; HBV, hepatitis B virus; NA, nucleos(t)ide analogue; RNA, ribonucleic acid; WHO, World Health Organization.
Cohort studies |
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Author (year) | Study type/Region | Number | Age |
Pretreatment status |
Criteria |
Severe adverse events |
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Cirrhosis | HBeAg(+) | Stopping NA | Resuming NA | Severe hepatitis flares or decompensation§ | Death or liver transplantation | Risk factors | ||||||
RETRACT-B Hirode et al. [33] (2023) | Prospective/International | 1,557 | 52.9† | 11.8% | 15.8% | As pre institution | As per institution | 20 (1.3%) | 4 (0.3%)∥ | · iCirrhosis | ||
Year | Incidence | 95%CI | · iPretreatment HBeAg(+) | |||||||||
1 | 1.0% | 0.6–1.6% | ||||||||||
2 | 1.4% | 0.9–2.2% | ||||||||||
3 | 1.6% | 1.1–2.5% | ||||||||||
4 | 1.8% | 1.1–3.0% | ||||||||||
5 | 1.8% | 1.1–2.0% | ||||||||||
Hsu et al. [34] (2022)* | EHR/Taiwan | 665 | 50.3‡ | 14.3% | 26.0% | Taiwan reimbursement | Taiwan reimbursement | 24 (3.6%) | 2 (0.3%) | · iCirrhosis | ||
i· Male | ||||||||||||
Liu et al. [35] (2022) | Prospective/Taiwan | 1,234 | 56.4† | 40.1% | 0% | APASL 2012 | Taiwan reimbursement | Hepatitis flares: 516 (41.8%) | 5 (0.4%) | · iCirrhosis · iPrior-treatment | ||
Decompensation: 13 (1.1%) | · iAge (cut-off: 55) · iGenotype B | |||||||||||
· iTDF (vs. ETV) | ||||||||||||
· iPretreatment viral load (cut-off: 6 log IU/mL) | ||||||||||||
· iPretreatment-HBsAg (cut-off: 3 log IU/mL) | ||||||||||||
· iEOT-HBsAg (≥500 vs. <100 log IU/mL) | ||||||||||||
PS: the predictors for hepatitis flares, not for decompensation | ||||||||||||
Hsu et al. [41] (2021) | EHR/Taiwan | 10,192 | 50.9† | 10.7% | n.a. | Taiwan reimbursement | Taiwan reimbursement | 132 (1.3%) | 51 (0.5%) | · iCirrhosis | ||
4 year: 1.8% (95% CI, 1.5–2.2%) | 4 years: 0.7% (95% CI, 0.5–1.9%) | · iMale | ||||||||||
· iAge (cutoff age, 50 years) | ||||||||||||
· iHistory of liver failure | ||||||||||||
Ma et al. [44] (2019) | Prospective and retrospective/Taiwan | 535 | 50.7† | 0% | 29.9% | APASL 2012 | Taiwan reimbursement | 7 (1.3%) | 1 (0.2%) | n.a. | ||
CREATE Sonneveld et al. [45] (2022) | Prospective and retrospective/International | 572 | 52.0‡ | n.a. | 16.6% | As per institution | As per institution | 2 (0.4%) | 0 (0%) | n.a. | ||
Wong et al. [46] (2020) | EHR/Hong Kong | 1,076 | 59.1† | 8.3% | 0% | n.a. | n.a. | 7 (0.7%) | n.a. | n.a. | ||
Meta-analysis study |
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Author (year) | Enrolled studies | Main finding | ||||||||||
Tseng et al. [43] (2022) | 50 articles reporting safety outcomes after NA cessation | · Heterogeneous design among studies (e.g., stopping rules, retreatment criteria, and definition of decompensation) | ||||||||||
15 studies (4,525 patients) pooled for risk estimate of overall population | · Serious adverse events not often reported in smaller studies with shorter follow up duration | |||||||||||
14 studies (3,731 patients) pooled for risk estimate of non-cirrhotic population | · Risk estimate (95% CI): | |||||||||||
5 studies (744 patients) pooled for risk estimate of cirrhotic population | Overall | Non-cirrhosis | Cirrhosis | |||||||||
Severe | 1.2% | 0.9% | 3.6% | |||||||||
flares/Decompensation | (0.7–2.1%) | (0.4–1.8%) | (1.8–7.3%) | |||||||||
Death/Liver | 0.4% | 0.3% | 1.0% | |||||||||
transplantation | (0.2–0.7%) | (0.1–0.7%) | (0.5–2.1%) |
For studies from similar institutions, we chose the most representative one such as the larger sample size or more detailed information about the adverse events.
APASL, Asian Pacific Association for the Study of the Liver; CI, confidence interval; EOT, end-of-treatment; EHR, electronic health record; ETV, entecavir; HBeAg, hepatitis B e-antigen; HBsAg, hepatitis B s-antigen; n.a., not available; NA, nucleo(s)tide analogue; TDF, tenofovir disoproxil fumarate.
∥ the number from another publication from RETRACT-B cohort. [48]
Author (year) | Race/Region/Setting | Number | Age (year) | Male (%) | Pre-treatment HBeAg (+) | ETV/TDF proportion | Cirrhosis | Stopping rule | Duration (month): Treatment/Consolidation/Follow-up | Event: Clinical relapse/HBsAg loss |
Performance of the SCALE-B |
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Clinical relapse | HBsAg loss | |||||||||||
Hsu et al. [62] (2019) | Asian/Taiwan/Prospective Multicenter | 135 | 49.5* | 80.7 | 31 (22.9%) | 100% | 0% | Treatment duration ≥3 years with undetectable HBV DNA and negative HBeAg on treatment cessation | 36.7*/25.2*/25.9* | 66 (48.9%)∥/8 (5.9%) | AUC**: | 3-year incidence** |
1Y: 0.87 (0.80–0.93) | High risk: 0 | |||||||||||
3Y: 0.87 (0.79–0.94) | Intermediate: 0 | |||||||||||
5Y: 0.90 (0.79–1.00) | Low risk: 27.1% (14.5–47.3%) | |||||||||||
5-year cumulative | ||||||||||||
incidence** | ||||||||||||
High risk: 86.2% (67.8–96.8%) | ||||||||||||
Intermediate: 61.6% (48.2–75.2%) | ||||||||||||
Low risk: 17.2% (7.5–36.9%) | ||||||||||||
CREATE Sonneveld et al. [45] (2022) | Mixed (Asian:79.9%)/ International/Prospective and retrospective | 572 | 52* | 68.2 | 16.6% | 77.8% | n.a. | Per institution | 73.8*/n.a./12§ | 92 (16.1%)‡/24 (4.2%) | Proportion at week 48§ | Proportion at week 48§ |
High risk: 31% | High risk: 1% | |||||||||||
Intermediate: 14% | Intermediat: 2% | |||||||||||
Low risk: 3% | Low risk: 11% | |||||||||||
Liao et al. [65] (2021) | Asian/China/Prospective Single center | 122 | 34* | 77.9 | 100% | 58.2% | 0% | APASL 2012 | 56.4*/30.0*/36.0* | 44 (36.1%)∥/12 (9.8%) | AUC** | Not mentioned |
1Y: 0.81 (0.73–0.89) | ||||||||||||
3Y: 0.74 (0.65–0.84) | ||||||||||||
5Y: 0.75 (0.65–0.85) | ||||||||||||
5-year cumulative | ||||||||||||
incidence** | ||||||||||||
High risk: 82.2% | ||||||||||||
Intermediat: 50.0% | ||||||||||||
Low risk:22.2% | ||||||||||||
Papatheodoridis et al. [66] (2020) | Caucasian/Greece/Prospective Multicenter | 57 | 60*,† | 64.9 | 0% | 100% | 0% | Treatment duration ≥4 years, ETV or TDF ≥2 years, and undetectable HBV DNA ≥3 years | n.a./63.6*/19.0* | 19 (33.3%)∥/12 (21.1%) | No association | Not mentioned |
Kaewdech et al. [91] (2022) | Asian/Thailand/Prospective Single center | 92 | 55.0* | 64.1 | 21.7% | 44.6% | 0% | APASL 2016 | 78.0*/n.a./35.5 | 31 (33.7%)/7 (7.6%) | AUC: | Proportion at week 96 |
2Y: 0.81 | High risk: 0% | |||||||||||
Intermediat: 2.4% | ||||||||||||
Low risk: 14.3% |
All the status are at the cessation of antiviral therapy unless otherwise specified.
ALT, alanine aminotransferase; APASL, Asian Pacific Association for the Study of the Liver; AUC, area under ROC curve; CI, confidence internal; DNA, deoxyribonucleic acid; EOT, end of treatment; ETV, entecavir; HBcrAg, hepatitis B core-related antigen; HBeAg, hepatitis B e-antigen; HBsAg, hepatitis B s-antigen; n.a., not available; NA, nucleos(t)ide analogue; RNA, ribonucleic acid; TDF, Tenofovir disoproxil fumarate.
Institution/Study, Site | Retreatment criteria |
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Criteria used in randomized controlled trials | |
FINITE study, [102] Multicenter in Germany | At least one of the criteria: |
· Increase of direct bilirubin by >1.5 mg/dL (>25 μmol/L) from baseline, and ALT >ULN | |
· Increase in PT ≥2.0 s (INR ≥0.5) prolonged from baseline with adequate vitamin K therapy, and ALT >ULN | |
· ALT >10X ULN with or without associated symptoms. | |
· ALT >2X ULN and ≤5X ULN persisting for ≥84 days (12 weeks), and HBV DNA >20,000 copies/mL (equivalent to 357 IU/mL) | |
· ALT >5X ULN and ≤10X ULN persisting for ≥28 days (4 weeks). | |
Stop-NUC study, [103] Multicenter in Germany | At least one of the criteria: |
· ALT >10X ULN | |
· 10X ULN ≥ALT>5X ULN for ≥28 days | |
· 5X ULN ≥ALT>2X ULN for ≥112 days and HBV DNA >2,000 IU/mL | |
Increase of total bilirubin by >1.5X ULN | |
Toronto-STOP study, [104] Toronto Centre for Liver Disease, Canada | At least one of the criteria: |
· HBeAg seroreversion | |
· HBV DNA >2,000 IU/mL and ALT >600 IU/mL at any visit | |
· HBV DNA >2,000 IU/mL and ALT >200 IU/mL (5X ULN) on two consecutive visits | |
· HBV DNA >2,000 IU/mL and ALT >200 IU/mL but <600 IU/mL for >6–8 weeks | |
· HBV DNA >20,000 IU/mL on two consecutive visits at least 4 weeks apart. | |
Criteria used in prospective observational study | |
Queen Mary Hospital64, Hong Kong | · Virological relapse: HBV DNA >2,000 IU/mL |
Australia multicenter study, [105] Australia | At least one of the criteria: |
· HBV DNA >2,000 IU/mL and serum ALT >5X ULN for ≥16 weeks or ALT >10X ULN for ≥8 weeks | |
· Clinical evidence of hepatic decompensation defined by INR ≥1.5 or bilirubin >2X ULN or ascites or hepatic encephalopathy Investigator discretion | |
DARING-B study, [106] Laiko General Hospital and Hippokration General Hospital, Greece | At least one of the criteria: |
· ALT >10X ULN | |
· ALT >5X ULN and total bilirubin >2 mg/dL at the same visit | |
· ALT >3X ULN and HBV DNA >100,000 IU/mL at the same visit | |
· ALT >ULN and HBV DNA >2,000 IU/mL on three sequential visits. | |
· According to patients’ and physicians’ decisions in case of virological relapse with HBV DNA >20,000 IU/mL | |
Nanfang Hospital, [65,107] China | Clinical relapse: HBV DNA >2,000 IU/mL and ALT >2X ULN |
Multiple centers in China [108] | |
Taiwan National Health Insurance, [71] Taiwan | ALT >2X ULN with 3 months apart and HBV DNA >2,000 IU/mL or total bilirubin >2 mg/dL, or prolongation of PT ≥3 seconds |
Study | Scale/Region | Primary outcome | Key inclusion criteria | Group | Age/Caucasian/Male/Fibroscan (kPa) | ETV or TDF (%)/Pre-Tx HBeAg (+)/HBsAg (log IU/mL)/NA duration (months) | Clinical relapse, number (%) | HBsAg loss, number (%) | Adverse events, number (%) |
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FINITE, Berg et al. [102] (2017) | Multicenter/Germany | HBsAg loss or seroconversion at week 144 | TDF ≥4 years | Stop: n=21 | 44.5†/18 (85.7%)/18 (85.7%)/6.1† | 21 (100%)/0 (0%)/4.4†/n.a. | At least 5 (23.8%)**,†† | 4 (19.0%) | Grade 3/4: 5 (23.8%) |
HBV DNA <400 copies/mL ≥3.5 years | |||||||||
Pre-Tx HBeAg(-) | |||||||||
No advanced fibrosis/cirrhosis (by histology or Fibroscan) | Continue: n=21 | 45.5†/19 (90.5%)/15 (71.4%)/5.0† | 21 (100%)/0 (0%)/4.6†/n.a. | 1 (4.8%)**,†† | 0 (0%) | Grade 3/4: 0 (0%) | |||
No history of decompensation | |||||||||
Stop-NUC*, van Bömmel et al. [103] (2020) | Multicenter/Germany | HBsAg loss at week 96 | NA ≥4 years | Stop: n=79 | 51.6†/62 (78.5%)/50 (63.3%)/5.7† | 71 (89.9%)/0 (0%)/3.5†/n.a. | 28 (35.4%)‡ | 10 (12.7%) | n.a. |
HBV DNA <1,000 IU/mL ≥4 years | |||||||||
Pre-Tx HBeAg(-) | |||||||||
Pre-Tx HBV DNA >2,000 IU/mL | |||||||||
No advanced fibrosis/cirrhosis (by histology of Fibroscan) | Continue: n=79 | 52.0†/68 (82.2%)/51 (64.6%)/5.7† | 72 (91.1%)/0 (0%)/3.6†/n.a. | 0 (0%)‡ | 0 (0%) | n.a. | |||
Toronto-STOP, Liem et al. [104] (2019) | Single center/Canada | HBV DNA <2,000 IU/mL at week 48 | NA ≥1 year | Stop: n=45 | 59†/2%/26 (57.8%)/4.9† | 45(100%)/27 (60.0%)/3.1†/72.0† | At least 10 (22.2%)§,∥ | 1 (0.2%)∥ | 22(48.9%): ALT >5X ULN |
Consolidation: | 1 (2.2%): bilirubin >66 μmol/L | ||||||||
Pre-Tx:HBeAg(+): 1 year and HBeAb(+) | |||||||||
Pre-Tx HBeAg(-): 3 years | Continue: n=22 | 50†/5%/14 (63.6%)/5.2† | 22 (100%)/13 (59.1%)/3.0†/61.2† | 0 (0.0%)§,∥ | 1 (0.5%)∥ | 0 (0.0%) | |||
No cirrhosis (defined by histology or Fibroscan) |
Jia-Horng Kao
https://orcid.org/0000-0002-2442-7952