HBV Reactivation Prediction Model in Allo-HSCT (HBV-post HSCT)

Multicenter prospective observational cohort

This is a multicenter, prospective, observational cohort study. Patients who are HBsAg-negative and anti-HBc-positive prior to allo-HSCT will be enrolled from multiple clinical centers and prospectively followed. Resolved HBV infection will be confirmed by two separate negative HBsAg tests and positive anti-HBc before initiation of conditioning. No investigational intervention is assigned; all participants receive routine clinical care per local practice. Baseline data include demographic characteristics, transplant-related variables (conditioning regimen, donor type, GVHD prophylaxis), recipient and donor HBV serological markers (anti-HBs titre, anti-HBc titre, HBeAg/anti-HBe, HBV DNA). Post-transplant complications (acute and chronic GVHD, CMV reactivation) and subsequent HBV reactivation (defined as reappearance of HBsAg and/or detectable HBV DNA ≥10 IU/mL) will be recorded. All patients will be followed for at least 36 months af

Altro: No Intervention: Observational Cohort

No study-specific intervention will be administered. Participants will receive standard clinical care after allo-HSCTaccording to institutional practice and treating physician discretion. This multicenter study will prospectively collect observational data on HBV reactivation and associated clinical outcomes in HBsAg-negative/anti-HBc-positive patients for at least 36 months post-transplant.

Hepatitis B Virus (HBV) Reactivation

HBV reactivation is defined according to the American Association for the Study of Liver Diseases (AASLD) 2018 guidance as the occurrence of any of the following events in patients who are HBsAg-negative/anti-HBc-positive at baseline:

Serological reactivation: Reappearance of hepatitis B surface antigen (HBsAg) from negative to positive (confirmed by two consecutive tests at least one week apart); OR Virological reactivation: Reappearance of detectable HBV DNA (≥10 IU/mL) in a patient who had undetectable HBV DNA at baseline; OR Virological flare: In patients with detectable HBV DNA at baseline, an increase in HBV DNA level of ≥10-fold (1 log₁₀ IU/mL) above baseline level, confirmed on two consecutive measurements within a 2-week period.

For patients receiving preemptive or prophylactic antiviral therapy, reactivation is defined as above, with the additional requirement that HBV DNA ≥10 IU/mL is confirmed on at least two consecutive measurements to exclude transient low-level dete

Time to HBV Reactivation

The time interval (in days) from the date of allogeneic hematopoietic stem cell transplantation (allo-HSCT) to the date of first occurrence of HBV reactivation. Patients without reactivation are censored at the date of last follow-up, death, or 36 months post-HSCT, whichever occurs first.

Hepatitis Due to HBV Reactivation

Hepatitis due to HBV reactivation is defined as the occurrence of all of the following criteria in a patient with documented HBV reactivation (as defined in the primary outcome):

Alanine aminotransferase (ALT) elevation >3 times the upper limit of normal (ULN) or >3 times baseline value if baseline was already elevated;

Exclusion of other causes of liver injury, including:

Acute or chronic graft-versus-host disease (GVHD) involving the liver (requires histologic confirmation or typical clinical presentation with other organ involvement);Drug-induced liver injury (DILI) - assessed by Roussel Uclaf Causality Assessment Method (RUCAM) score; Cytomegalovirus (CMV) or Epstein-Barr virus (EBV) hepatitis; Hepatic veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS); Iron overload; Sepsis or ischemic hepatopathy.

HBV-Related Mortality

Death directly attributable to HBV reactivation or its hepatic complications, including:

Death from hepatic failure as defined above; Death from cirrhosis-related complications (variceal hemorrhage, spontaneous bacterial peritonitis, hepatorenal syndrome) occurring after HBV reactivation; Death from hepatocellular carcinoma diagnosed after HBV reactivation (if no other etiology identified).

Deaths from other causes (relapse of underlying hematologic disease, infection, GVHD, etc.) will be considered competing events.

HBsAg Seroclearance After HBV Reactivation

In patients who experience HBV reactivation and receive antiviral treatment (entecavir, tenofovir, or other nucleos[t]ide analogues), HBsAg seroclearance is defined as:

Two consecutive negative HBsAg tests at least 4 weeks apart; and Confirmation by a third negative test at 12 weeks after the first negative test.

The proportion of patients achieving HBsAg seroclearance among those with HBV reactivation will be reported, along with the median time from reactivation to seroclearance.

Comparison of HBV Reactivation Incidence by Prophylaxis Status

The cumulative incidence of HBV reactivation will be compared between:

Patients receiving antiviral prophylaxis (entecavir, tenofovir, or lamivudine) started at or before conditioning; versus Patients not receiving antiviral prophylaxis.

The analysis will adjust for baseline differences using propensity score matching or multivariable regression. The types, doses, and durations of prophylaxis will be descriptively summarized.

Overall Survival (OS) and Non-Relapse Mortality (NRM)

Overall Survival: Time from allo-HSCT to death from any cause. Non-Relapse Mortality: Death from any cause other than relapse of the underlying hematologic malignancy. NRM will be estimated using cumulative incidence functions treating relapse as a competing risk.

These outcomes will be compared between patients with and without HBV reactivation.