Precision stratification for hepatitis B functional cure: Biomarkers, machine learning and the combination-therapy era

Table 1 Selected therapeutic studies and their distinct endpoints

Study and design	Population and treatment background	Endpoint and assessment time	Results and denominator	Evidence maturity and interpretation
Imdusiran (AB-729-001)[8]. Phase 1a/b; randomized healthy part; open-label CHB parts	83 dosed: 18 healthy (12 active/6 placebo) and 65 CHB (22 single-dose/43 repeat-dose). Non-cirrhotic CHB; HBsAg ≥ 250 IU/mL; NA continued where prescribed	Primary: Safety. Healthy follow-up to day 29; CHB safety follow-up to 48 weeks, or 36 months in eligible NA discontinuers. Repeat dosing up to 48 weeks	No functional-cure n/N reported in the verified abstract. All 83 comprised the safety population	Early safety/antiviral study; total n includes healthy participants. Do not treat absence of a reported cure rate as zero efficacy
ARC-520/JNJ-3989 follow-up[9]. Prospective single-centre follow-up of earlier trials	53 siRNA + NA recipients (15 ARC-520/38 JNJ-3989) and 5 prior placebo recipients; 83% previously on NA; 34% HBeAg-positive	HBsAg seroclearance or HBsAg < 100 IU/mL at last follow-up (mean 52.5 months). Exact seroclearance threshold: NR; no off-all-treatment DNA composite verified	Seroclearance 1/53 (1.9%); HBsAg < 100 IU/mL 17/53 (32.1%); both 0/5 in placebo recipients	Long-term antigen durability with a small control group; not a demonstrated functional-cure comparison after withdrawal of all therapy
Xalnesiran ± immunomodulator (PIRANGA)[10]. Phase 2 randomized open-label adaptive platform	159 NA-suppressed CHB participants: Xalnesiran 100 mg (30), 200 mg (30), 200 mg + ruzotolimod (34), 200 mg + PegIFN (30), NA alone (35). NA stopping conditional	Primary: HBsAg < 0.05 IU/mL at 24 weeks after 48-week investigational treatment (week 72). HBV DNA not part of this primary endpoint	2/30 (7%), 1/30 (3%), 4/34 (12%), 7/30 (23%), and 0/35, respectively. Loss observed only with screening HBsAg < 1000 IU/mL	HBsAg loss is distinct from cure off all therapy. Small arms; exploratory baseline-HBsAg association does not establish a treatment-selection rule
JNJ-3989 ± bersacapavir (REEF-1)[11]. Phase 2b double-blind randomized trial	470 randomized across six NA-containing arms; treated/untreated and HBeAg-positive/negative strata. Reported efficacy uses modified ITT denominators	Primary: NA-stopping eligibility at week 48: HBsAg < 10 IU/mL, HBV DNA < LLOQ (20 IU/mL), HBeAg-negative and ALT < 3 × ULN	JNJ-3989 200 mg + NA: 18/94 (19%; 90%CI 13-27%); triple regimen: 8/94 (9%; 4%-15%); NA control: 1/45 (2%; 0%-10%)	Eligibility to stop NA is not functional cure. The 19% result did not involve bersacapavir; triple therapy contained JNJ-3989 100 mg
Elebsiran ± PegIFN[12]. Open-label phase 2; six cohorts	84 non-cirrhotic, NA-treated adults; entry HBsAg > 50 IU/mL and HBV DNA < 90 IU/mL. Cohort sizes 15/15/18/18/13/5; 12-48-week regimens	Primary: Safety. Secondary: HBsAg loss at any time and sustained through 24 weeks after investigational treatment. Exact HBsAg-loss threshold: NR; background NA continued	Any loss: 0/15, 1/15, 1/18, 5/18, 4/13, 0/5. Sustained loss: 0/15, 1/15, 0/18, 3/18, 2/13, 0/5 (6/84 overall)	Exploratory cohorts with unequal regimens; pooled 6/84 is not an estimate for one regimen and does not establish cure after stopping NA
Vebicorvir[14]. Randomized phase 2 placebo-controlled trial	73 non-cirrhotic NA-suppressed participants: 47 HBeAg-positive and 26 HBeAg-negative. Vebicorvir 300 mg daily or placebo added for 24 weeks	Primary: Change in HBsAg or HBeAg from baseline to week 24; continuous antigen endpoint, not an HBsAg/HBV DNA clearance composite	No between-group difference in antigen change; improved suppression of replication markers. Functional-cure n/N not reported in the verified abstract	Demonstrates antiviral activity without a demonstrated antigen-clearance advantage in this population; no inference about comparative cure efficacy
Elebsiran + BRII-179 ± interferon[15]. Phase 2a open-label randomized parallel-group study	90 CHB participants: Elebsiran alone (10), plus vaccine without interferon (41), or plus vaccine with interferon (39). Nine 4-weekly elebsiran doses	Virologic and immunologic follow-up to week 72. Sustained HBsAg loss and anti-HBs persistence evaluated; exact HBsAg-loss threshold: NR	No sustained HBsAg loss (0/90). Anti-HBs ≥ 100 IU/L persisted in approximately 40% for ≥ 32 weeks after combination treatment	Immunogenicity is not functional cure. The absence of sustained clearance in this regimen does not exclude a benefit from other vaccine-containing sequences
Bepirovirsen (B-Clear)[16]. Phase 2b randomized investigator-unblinded trial	457 ITT across four schedules: 227 on NA and 230 not on NA. For 300 mg weekly × 24 weeks: 68 on NA and 70 not on NA; background NA maintained	Primary: HBsAg < 0.05 IU/mL and HBV DNA < 20 IU/mL at every visit for 24 weeks after planned bepirovirsen end, without new antiviral rescue; week 48 for the 24-week regimen	300 mg × 24 weeks: 6/68 (9%) on NA and 7/70 (10%) not on NA	Original primary endpoint; separate from modified analyses allowing isolated blips. On-NA responses do not establish cure after stopping all therapy
Bepirovirsen (B-Well 1/2)[17]. Two replicate double-blind randomized phase 3 trials	1834 selected non-cirrhotic adults in the full analysis population on stable NA; entry HBsAg > 100 to 3000 IU/mL. Bepirovirsen 300 mg weekly or placebo for 24 weeks; eligible NA withdrawal at week 48	Primary: Functional cure at week 72, ≥ 24 weeks after all treatment stopped: HBsAg not detected (< 0.05 IU/mL) and HBV DNA < LLOQ (< 20 IU/mL or target not detected)	B-Well 1: 127/650 (20%) vs 0/328; B-Well 2: 106/570 (19%) vs 0/286	Replicated efficacy within an enriched population. HBsAg-based enrollment was not a randomized selection strategy; durability beyond current follow-up remains to be established
Bepirovirsen then PegIFN (B-Together)[19]. Phase 2b randomized open-label trial	108 ITT on stable NA throughout: 24-week (55) or 12-week (53) bepirovirsen, followed by up to 24-week PegIFN	Primary: HBsAg < 0.05 IU/mL and HBV DNA < 20 IU/mL at every visit for 24 weeks after planned PegIFN end, without new antiviral rescue; background NA continued	5/55 (9%) and 8/53 (15%), respectively; all responders had baseline HBsAg ≤ 3000 IU/mL	Proof of concept; no bepirovirsen-alone concurrent control. Cross-trial relapse comparisons do not prove the benefit of adding PegIFN
Selgantolimod[20]. Randomized phase 2 placebo-controlled trial	48 NA-suppressed participants (24 HBeAg-positive/24 negative): 39 active and 9 placebo. Weekly study drug for 24 weeks; NA continued through week 48	Primary: ≥ 1 log10 IU/mL HBsAg decline at week 24. Additional HBsAg loss through week 48; exact loss threshold: NR. No off-all-treatment composite	Primary endpoint 1/39 active; HBsAg loss 2/39 (5%) active vs 0/9 placebo through week 48	Small exploratory immunomodulator study; HBsAg loss on NA does not establish finite-treatment functional cure
NA withdrawal (STOP-NUC)[21]. Multicentre randomized stop-vs-continue trial	166 randomized; 158 analyzed, 79 per arm. HBeAg-negative; continuous long-term NA with HBV DNA < 172 IU/mL for ≥ 4 years	Primary: Sustained HBsAg loss to week 96. HBsAg assay LOD 0.05 IU/mL; HBV DNA assay LOD 10 IU/mL. Primary endpoint differs from the B-Well composite	8/79 (10.1%; 95%CI 4.8-19.5%) vs 0/79; P = 0.006. Baseline HBsAg < 1000 IU/mL subgroup: 7/25 (28%)	Selected withdrawal trial; 11/79 (13.9%) retreated. No cessation-related serious adverse events observed; small numbers do not exclude uncommon serious harm
Elebsiran + PegIFN (ENSURE)[13]. Partially randomized open-label phase 2 trial	55 randomized to PegIFN alone or plus elebsiran 200/100 mg; 31 previously vaccinated participants in a separate nonrandomized cohort. Non-cirrhotic, NA-suppressed; randomized entry HBsAg > 100 IU/mL to 3000 IU/mL	HBsAg < 0.05 IU/mL at end of 48-week treatment and 24 weeks later (week 72); HBV DNA assay LLOQ 10 IU/mL. NA continued until week 72; withdrawal assessed afterward	Week 72: 4/19 (21.1%) with 200 mg, 6/18 (33.3%) with 100 mg, 1/18 (5.6%) control. Prior-vaccine cohort: 8/19 anti-HBs responders vs 1/12 nonresponders	Randomized regimen comparison, but small samples and HBsAg enrichment. Prior-vaccine response is an exploratory association; endpoint does not establish cure off NA
OCTOPUS-1[22]. Open-label phase 2; randomized nivolumab schedules	37 virally suppressed adults; JNJ-3989 + NA with one (n = 18) or three (n = 19) nivolumab infusions. Background NA continued through week 72	Primary: HBsAg < 0.05 IU/mL at 24 weeks after the 24-week intervention (week 48); follow-up to week 72. HBV DNA LLOQ 20 IU/mL was a separate virological measure	Primary HBsAg loss: 0/18 and 0/19. One participant in the three-infusion arm achieved loss at 48-week follow-up	No internal arm without nivolumab; incremental benefit was assessed against an external REEF-1 cohort. No off-NA cure estimate. No serious or grade 3/4 adverse events; two transient asymptomatic hyperthyroidism cases
REEF-IT[23]. Open-label phase 2; regimen amended during study	54 untreated HBeAg-positive adults; JNJ-3989 + NA ± bersacapavir for 36-52 weeks, followed by 12-week PegIFN add-on. Most continued NA during follow-up; only one met NA-completion criteria	Primary: HBsAg < 0.05 IU/mL at 24 weeks after stopping all study treatment, without NA restart. Follow-up continued for 48 weeks. Assay threshold verified in NCT04439539	0/51 in the registered primary per-protocol set (54 enrolled). HBsAg loss at least once: 11/54 (20.4%); six maintained loss through follow-up week 48	On-treatment or transient antigen loss did not establish the off-all-treatment endpoint. Registry primary denominator is distinguished from the publication’s enrolled population. No deaths or serious adverse events; two stopped PegIFN
ALG-020572[24]. Double-blind, placebo-controlled phase 1	32 healthy participants (24 active/8 placebo); eight non-cirrhotic, HBeAg-negative, NA-suppressed CHB participants (6 active/2 placebo). CHB participants continued NA	Safety, pharmacokinetics and antiviral activity; planned up to seven 210-mg doses in CHB, with 12-week follow-up after the last dose. Trial stopped early for liver injury	ALT > 10 × ULN attributed to drug-induced liver injury in 4/6 active-treated CHB participants after 2-7 doses; one hospitalized. No functional-cure estimate	Three biopsies suggested drug-induced liver injury. All recovered without sequelae; development was terminated. Compound-specific serious toxicity must not be recast as a beneficial immune flare or generalized to all ASOs
Biomarker-guided NA withdrawal[25]. Multicentre randomized trial (2:1)	90 Asian patients in the modified ITT analysis: 60 stopped and 30 continued NA. HBsAg < 200 IU/mL, suppressed HBV DNA ≥ 12 months, and undetectable HBV RNA or HBcrAg; cirrhosis excluded	Published analysis: Cumulative HBsAg loss through 144 weeks. Qualitative HBsAg negativity; numerical loss threshold NR. Registry NCT04519359 lists a 72-week primary endpoint	Cumulative HBsAg loss 25.9% vs 4.2% (P = 0.013); raw event n/N NR. In the stop arm, 16/60 restarted NA; no serious adverse events were reported	Cumulative estimates are not raw proportions. Supports a selected withdrawal strategy, not isolated validation of RNA/HBcrAg added value or a broadly applicable safe-stopping rule

Evidence maturity is a narrative appraisal, not a formal certainty grade. Background NA continuation, eligibility and differing assessment intervals prevent direct cross-trial comparisons. HBsAg loss, antigen decline and NA-stopping eligibility are not interchangeable with functional cure after withdrawal of all treatment. NA: Nucleos(t)ide analogue; CHB: Chronic hepatitis B; HBeAg: Hepatitis B e antigen; HBsAg: Hepatitis B surface antigen; siRNA: Small interfering RNA; ASO: Antisense oligonucleotide; CAM: Capsid assembly modulator; PegIFN: Pegylated interferon; ALT: Alanine aminotransferase; ULN: Upper limit of normal; ITT: Intention to treat; LOD: Limit of detection; LLOQ: Lower limit of quantification; NR: Not retrievable in the sources checked for this revision, not evidence that the original report omitted the information.

Table 2 Selected prediction models by intended use and validation setting

Model/intended use	Population, events and prediction timing	Discrimination and validation	Calibration/overall accuracy	Development and missing data	Thresholds and limits for clinical use
GOLDEN[26]: Longitudinal discriminant analysis; HBsAg loss during NA therapy	China: Training 2835/61 events; geographic validation 3957/112 events; 173/6792 overall. qHBsAg every 6 months; loss < 0.05 IU/mL twice ≥ 6 months apart. Median follow-up 65.6 months; 5-year incidence 2.4%	AUROC: Training 0.981 (95%CI 0.974-0.987); validation 0.979 (0.974-0.983). Overall PPV 26.2%; mean prediction lead time 18.9 months among correctly predicted HBsAg-loss cases	Calibration plots for 5-year persistence of HBsAg in Supplementary Figure S5 of the original report[26]; slope/intercept not extracted	Nanfang Hospital training; 49 other centers validation; fivefold cross-validation. ≥ 2 qHBsAg samples ≥ 6 months apart required; explicit imputation strategy not located in examined main text	Score > 0.95 at any follow-up identified favorable trajectories; 5-year loss 17.0% training/29.1% validation. Dynamic outcome-proximal prediction differs from a baseline regimen-selection rule. Landmark evaluation is needed before treatment allocation; this audit does not establish leakage
Dong et al[36]: LightGBM; rapid on-treatment PegIFN response	Inactive HBeAg-negative Chinese patients, baseline HBsAg < 1000 IU/mL. Development n = 2882/541 events; training 2017, test 865; external 167/33 events. Baseline/week-12 inputs predict week-24 HBsAg < 0.05 IU/mL plus DNA < 20 IU/mL	AUROC training 0.902 (95%CI 0.881-0.923); internal test 0.891; external 0.917 (0.850-0.983). External precision 0.547, sensitivity 0.879, specificity 0.821	Brier score 0.091 and decision curves reported; Brier is overall predictive error, not a stand-alone calibration assessment. Calibration slope/intercept not located in examined text	70:30 stratified split; tenfold cross-validation; six selected predictors. Variables > 20% missing excluded; random-forest imputation; training-based normalization. Full nesting of preprocessing within resampling not established from report	Proposed probability < 0.3 PegIFN stopping rule; no prospective impact trial. Week-12 ALT/HBsAg ratio dominated SHAP. Week-24 response is not sustained off-treatment cure; patients already cleared by week 12 were not explicitly excluded. Model-choice discussion considers external performance, limiting a strictly untouched-test interpretation
SHAN/FLASH-N[38]: Baseline prediction of sustained HBsAg loss with PegIFN	Chinese HBeAg-negative patients: Derivation 202/94 events; overlapping advantaged subgroup 114/58. SHAN training/test 142/60; external 183, including 117 advantaged patients. Baseline predictors; HBsAg < 0.05 IU/mL sustained ≥ 24 weeks after cessation. External event counts not extracted	SHAN AUC training 0.908 (95%CI 0.860-0.955), test 0.949 (0.898-0.999), external 0.861 (0.805-0.916). FLASH-N AUC 0.920; bootstrap-corrected 0.889; external 0.800 (0.716-0.884)	Internal calibration plots and internal/external decision curves reported. External calibration plot or slope not identified in the examined body. Decision curves estimate net benefit; no impact trial	48 candidates; univariate screening, tenfold LASSO and stepwise logistic regression; bootstrap/Firth correction for FLASH-N. Key missing data, > 10 missing variables or absent follow-up excluded; MICE for remaining missingness. Full fold-wise nesting not established	SHAN uses ln(HBsAg+1), age, sex and neutrophil percentage; FLASH-N adds AFP/LDH. Retrospective, selected PegIFN recipients; 524/726 initially eligible patients excluded. No prospectively tested treatment-allocation threshold or comparative regimen selector
FC-48w[37]: Baseline Cox-derived score; HBsAg loss during PegIFN add-on	377 Chinese NA-suppressed, non-cirrhotic HBeAg-negative patients; development five centres 229/41 events, external five other centres 148/30. Baseline age, HBsAg and ALT; 48-week PegIFN plus NA. Off-treatment durability not established	AUC development 0.842 (95%CI 0.788-0.887); external 0.852 (0.785-0.905). Validation HBsAg loss: Low 2/73, intermediate 17/55, high 11/20	Calibration assessment not identified in examined main text. Risk-stratum separation does not establish calibration of individual probabilities	Univariate screening followed by forward stepwise Cox regression. 485 screened; 38 declined and 70 lost to follow-up excluded. Imputation strategy not identified in examined body. Most patients had HBsAg < 1500 IU/mL	Score = 0.008 × ALT (U/L) - 0.039 × age (years) - 0.002 × HBsAg (IU/mL). Derivation cutoffs -2.7/-1.3 target ≥ 90% sensitivity/≥ 85% specificity. Prognostic strata among PegIFN recipients; suggested treatment choices not prospectively tested against usual care or another regimen
REACH-B[44]: Cox-derived points score; HCC in untreated CHB	3584 untreated non-cirrhotic Taiwanese patients/131 HCC; external Hong Kong/Korea 1505/111 HCC. Baseline sex, age, ALT, HBeAg, HBV DNA; 3-year, 5-year, 10-year horizons	External AUROC 0.811 (95%CI 0.790-0.831), 0.796 (0.775-0.816), 0.769 (0.747-0.790) at 3/5/10 years. Later post-loss validation: 5-year AUC 0.64 (95%CI 0.52-0.75), n = 1200/23 HCC[47]	Predicted-vs-observed calibration plots, Figures 1 and 2. Correlations at 3/5/10 years 0.973/0.942/0.994; correlation alone is not equivalent to calibration slope/intercept	Independent hospital validation including 277 cirrhotic patients; separate non-cirrhotic analysis. Development median follow-up 12.0 years; validation mean 7.3 years. Missing-data strategy not located in examined main text	17-point score estimates continuous absolute risk; not developed as a post-HBsAg-loss surveillance stopping rule. Treatment and loss alter distributions/meaning of virological inputs
PAGE-B[45]: Cox-derived points score; HCC during ETV/TDF	Caucasian patients: Derivation 1325/51 HCC; external ninth-center validation 490/34 HCC. Age, sex, platelets at treatment initiation; 5-year horizon. Median follow-up 50 months overall	C-index derivation 0.82; bootstrap 0.81; external validation 0.82. Confidence intervals not provided in the examined main text. Later post-loss validation: 5-year AUC 0.62 (95%CI 0.49-0.75)[47]; cirrhosis comparative evaluation C-index 0.605 (0.568-0.644)[50]	Calibration plots for 5-year HCC-free probability in derivation and validation (Supplementary Figure 1A/B of the original report[45]); observed risk strata also assessed	Multiple imputation: 10 datasets, predictor selection in > 50%, Rubin pooling; 1000 bootstrap samples; geographic holdout	≤ 9, 10-17, ≥ 18: 5-year HCC 0%/3%/17% in derivation and 0%/4%/16% in validation. Developed during continuing antiviral treatment; a low score alone does not validate stopping surveillance after cure. Cohort overlaps the long-term PAGE-B report[2]
aMAP[46]: Cox-derived score; HCC across liver-disease etiologies	17374 participants; training 3688/95 HCC; nine validation cohorts 13686/536 HCC (sum of Table 1). Age, sex, albumin, bilirubin, platelets. Generally 5-year horizon; one cohort 3 years	Training C-index 0.82 (95%CI 0.77-0.86). CHB validation 0.82-0.87; e.g., European PAGE-B 0.82 (0.78-0.86). Cirrhotic subgroup values 0.61-0.83. Later post-loss validation: 5-year AUC 0.73 (95%CI 0.63-0.84)[47]; cirrhosis comparative evaluation C-index 0.603 (0.564-0.641)[50]	Observed-vs-predicted calibration plots for training and all validation cohorts (Figure 2); no slope/intercept extracted	Mixed treated HBV/HCV and non-viral cohorts. Available scores: 3662 training and 13324 validation; imputation method not located in examined main text	Cutoffs 50/60; validation NPV 99.3%-100% at 50, PPV 6.6%-15.7% at 60. Neither broad etiologic validation nor low observed incidence establishes a post-HBsAg-loss stopping threshold; no treatment-allocation role
PLAN-B[49]: Gradient boosting; HCC during NA treatment	Training 6051; external Korean 5817 and Caucasian PAGE-B 1640. Ten baseline parameters; HCC follow-up reported through 8 years. Event counts and complete input list not retrievable from primary sources examined	C-index training 0.79; external Korean 0.79, Caucasian 0.81. No significant advantage over modified PAGE-B in Caucasians (P = 0.42); confidence intervals not retrievable from sources examined. Later cirrhosis comparative evaluation C-index 0.638 (95%CI 0.600-0.675)[50]; independence from all original cohorts should not be assumed	Primary abstract explicitly reports a satisfactory calibration plot. Numerical calibration parameters not retrievable from sources examined	Independent geographic cohorts on ETV/TDF. Missing-data, tuning and internal-validation details not retrievable from primary sources examined	Minimal-risk group 11.2% Korean/8.8% Caucasian; < 0.5% HCC by 8 years. Not a post-seroclearance model. Ethnic labels do not establish viral genotype; between-cohort C-index comparisons do not measure calibration
PLAN-B-CURE[39]: Gradient boosting; composite liver-related outcomes after HBsAg loss	Training 944, internal validation 1102 (Korea), external 2741 (Hong Kong). Seven inputs: Age, sex, diabetes, alcohol, cirrhosis, albumin, platelets. Korean cohort: 123 composite events over median 55.2 months; 1.1%/person-year	Training C-index 0.82, AUROC 0.86, AUPRC 0.53. Primary abstract states replication in both validation cohorts; separate values/confidence intervals not retrievable from primary sources examined	Hosmer-Lemeshow P > 0.05 reported. Non-significance does not establish accurate individual risk estimates; slope/intercept not retrievable from sources examined	Six Korean centers plus Hong Kong database, seroclearance 2000-2022. Complete horizon-specific, event-split and missing-data methods not retrievable from primary sources examined	Outcome combines HCC, decompensation and liver-related death; not interchangeable with HCC risk. No verified threshold for withdrawing HCC surveillance. 123 events apply to Korea, not the total 4787. Full-text availability is an audit limitation, not evidence of deficient reporting
CAMP-B[48]: Cox-derived points score; HCC after HBsAg seroclearance	Korean development 3476/102 HCC, 24019 person-years; Hong Kong external validation 5255/85 HCC. Cirrhosis, age ≥ 50, male sex, platelets < 150000/mm3 after HBsAg loss; 5-year, 10-year, 15-year horizons	Development time-dependent AUC 0.782/0.817/0.825 at 5/10/15 years; external 0.785/0.771/0.796. AUC confidence intervals not retrievable from examined primary abstract	Calibration details not retrievable from examined primary abstract; publisher full text inaccessible. This is an access limitation, not proof of non-reporting	Retrospective development at two Korean hospitals with geographic external validation in Hong Kong. Multivariable Cox model. Missing-data and internal-validation details not retrievable from examined abstract	Points: Cirrhosis, 3; age ≥ 50 years, 2; male sex, 3; low platelets (< 150000/mm3), 1. External low/intermediate/high annual HCC incidence 0.07%/0.37%/0.90%; exact stratum cutoffs not extracted. Dedicated post-loss prediction does not establish safe surveillance withdrawal

Missing or unextracted fields describe the limits of accessible primary evidence, not proof of absent reporting. Models address different outcomes, time origins and populations and cannot be ranked directly. The later post-loss entries for REACH-B, PAGE-B and aMAP use the same 1200-patient cohort, not three independent cohorts. None supplies a validated integrated baseline regimen-allocation rule or a tested strategy for withdrawing indicated surveillance. PegIFN: Pegylated interferon; AFP: Alpha-fetoprotein; LDH: Lactate dehydrogenase; LASSO: Least absolute shrinkage and selection operator; MICE: Multiple imputation by chained equations. AUROC/AUC: Area under the receiver operating characteristic curve; AUPRC: Area under the precision-recall curve; PPV: Positive predictive value; NPV: Negative predictive value; HCC: Hepatocellular carcinoma; NA: Nucleos(t)ide analogue; ETV: Entecavir; TDF: Tenofovir disoproxil fumarate; qHBsAg: Quantitative hepatitis B surface antigen; ALT: Alanine aminotransferase; SHAP: Shapley additive explanations; HBsAg: Hepatitis B surface antigen; CHB: Chronic hepatitis B; HBeAg: Hepatitis B e antigen; HBV: Hepatitis B virus; HCV: Hepatitis C virus; C-index: Concordance index.