Utilization of hepatitis B surface antigen-positive donors in liver transplantation for recipients with hepatocellular carcinoma: a retrospective and propensity score matching analysis

Patients enrollment

From January 2015 to April 2020, 338 patients were diagnosed with HCC and underwent deceased organ transplantations in our center. After excluded 11 combined or multi-organ transplantations, a total of 327 patients diagnosed with HCC and then underwent LT were retrospectively reviewed and enrolled in this study. Forty-eight HBsAg-positive donors and 279 HBsAg-negative donors were transplanted. The flow chart of this study is shown in Fig. 1.

PSM analysis

Because HBsAg-positive donor was not randomly assigned to patients with HCC, PSM was used to minimize patient selection bias and eliminate potential confounders (Badhiwala, Karmur & Wilson, 2021). Patients in the donor HBsAg-positive group were paired with those with HBsAg-negative donors at 1:1 ratio. Nearest-neighbor matching algorithm was adopted (caliper width = 0.01). Variables that may influence the clinical posttransplant outcome were included in the PSM model, which included the following variables (Pandyarajan, Govalan & Yang, 2021): donor gender (male or female) and age, donor type (DBD or DCD), body mass index (BMI), donor’s Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) and bilirubin, recipient gender (male or female) and age, pretransplant HBV-DNA (>100 or ≤ 100 copies /ml),pretransplant HBsAg(positive or negative), recipient BMI, Model for end-stage liver disease (MELD) score, Child-Pugh score, alpha feto-protein (AFP) level (≤400 or >400 ng/mL) , pretransplant treatment, TNM staging (I or II to III).

Post-transplant therapy and follow-up monitoring

The immunosuppressive regimen all patients received after LT was tacrolimus +mycophenolate mofetil. Basiliximab was used for immune induction with a dose of 20 mg by intravenous injection before abdominal closure and on posttransplant day 4. The target drug concentration of tacrolimus was 8 to 12 ng/ml in the first post-operative month and aimed at average of 5–7 ng/ml thereafter.

Antiviral prophylaxis and hepatitis B immunoglobulin therapy were given to the patients undergoing LT. Briefly, 5000 IU HBIG was given intravenously at the time of transplant during the anhepatic phase, followed by 2500 IU intravenous injection once in the first week and then weekly for the next 3 weeks, and 400 IU intramuscularly monthly. Antiviral treatment was with entecavir orally administrated daily.

Postoperative visits will be performed on postoperative day (POD) 1–7, POD 14 and each month post-transplantation. Biomedical values, complications, adverse events and medication administration records will be documented. Ultrasound doppler examination of vascular graft patency was performed was performed once every 2 days for 7 days. Serovirological test including HBsAg and HBVDNA was monitored at day 7, 14, 30 and then monthly. HBsAg more than 0.05 IU/ml was detectable and considered positive. HBV- DNA more than 1.0 × 10² copies/ml was detectable and considered positive. Diagnosis of tumor recurrence was based on imaging studies, clinical findings and laboratory tests and diagnosed according to Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2019 edition) in China (Qiu et al., 2020). The date of last follow-up or death was used for follow-up and Kaplan–Meier analysis, and the time to recurrence was calculated from the date of surgery to the date of recurrence or last follow-up.

Statistical analysis

All the statistical analyses of the data were performed using SPSS Version 26.0 (SPSS Inc., Chicago, IL, USA) and GraphPad Prism Version 9.0.1 (GrapPad, San Diego, CA, USA). Data are expressed as the mean ± standard deviation, median (range) or number (percentage). Categorical variables including gender, donor type, HBsAg positive or negative, HB-DNA positive or negative, tumor TNM staging were analyzed by chi-square tests, and continuous variables including age, value of AST, ALT and bilirubin, MELD score and Child-pugh score were analyzed by Fisher’s exact test. In addition, a Cox proportional hazards model was constructed for multivariate analysis. For survival analysis, OS and PFS were calculated by the Kaplan–Meier method with a log-rank test. A P value of less than 0.05 was considered significant.

Study population and patient characteristics

The baseline data of the two groups were shown in Table 1. Before PSM, significant differences of the recipients were noted in donor pretransplant bilirubin (21.48 ± 1.88 vs. 26.40 ± 1.54 umol/L, P = 0.045). Using PSM, we generated 44 matched pairs of patients. No significant difference was found between the HBsAg positive and negative donor groups in the comparison of all clinical characteristics (P > 0.05).

Post-PSM assessment of the perioperative outcomes of HBsAg-positive donors

The intratransplant and posttransplant data of two groups are presented in Table 2. No significant differences were found in anhepatic time(P = 0.345), cold ischemia time (P = 0.520) and operation duration( P = 0.129; Fig. 2A). In comparison of intratransplant transfusion, no significant differences were found in blood loss (P = 0.377), RBC transfusion (P = 0.989), FFP transfusion (P = 0.555) and platelet transfusion (P = 0.939), either (Fig. 2B). One patient suffered cardiac arrest and 5 patients suffered hypotension during operation (P = 0.315 and 0.645, respectively). After transplantation, the duration of mechanical ventilation and ICU stay were not significantly different between the two groups (P = 0.481 and 0.492, respectively).In addition, we observed that there was no difference when comparing the major early-stage complications between the two groups. No statistical significance was found in the incidence of abdominal bleeding (1 vs. 0, P = 0.315), HAT (0 vs. 4, P = 0.153), portal vein thrombosis (PVT, 0 vs. 1, P = 0.315), early allograft dysfunction (EAD, 16 vs. 21 P = 0.280) and primary nonfunction (2 vs. 0, P = 0.153). The 30-day mortality rate was 4.5% and 0 in the HBsAg-positive and HBsAg-negative allograft groups, respectively (P = 0.153). The result of HBV recurrence showed that HBsAg was detectable in three patients and HBV DNA was detectable in 1 patient in HBsAg-positive graft groups, respectively, without significant differences (P = 0.078 and 0.315, respectively).

Dynamic changes of postoperative liver function recovery between groups are presented in Fig. 3. Posttransplant monitoring results showed that ALT and AST dropped to normal level in day 4 after transplantation, however total bilirubin level remained high in 7 days after transplantation (Figs. 3A–3C). Maximum values of ALT, AST and TBIL within 7 days were not significantly higher in patients with HBsAg-positive liver grafts compared with those in HBsAg-negative liver grafts group (1224.75 ± 232.88 vs. 841.77 ± 103.48 IU/L, P = 0.138; 3281.00 ± 788.66 vs. 1888.48 ± 270.49 IU/L, P = 0.101; 126.60 ± 16.04 vs. 157.377 ± 18.00 umol/L, P = 0.205; Fig. 3E).

Survival and multivariant analysis between groups

During follow-up, tumor recurrence occurred in 18 of 44 (40.9%) and 12 of 44 (27.2%) patients in the donor HBsAg-positive and HBsAg-negative groups, respectively (Table 2). Based on Kaplan–Meier survival analysis, the 1-year and 3-year PFS rates were 65.9% and 18.1% in the donor HBsAg-positive group, respectively, compared with 90.9% and 70.4% in the donor HBsAg-negative group, respectively, and the differences were statistically significant (P = 0.0060; Fig. 4A). The 1-year survival rate and 3-year survival rate are 84.1% and 27.2%, respectively, in the HBsAg-positive liver graft groups, compared with 95.4% and 79.5%, respectively, in the HBsAg+ liver graft groups, and the differences were statistically significant ( P = 0.0039; Fig. 4B). In multivariate analysis, donor HBsAg-positivity was an independent risk factor for survival and incidence (P = 0.005 and 0.025, respectively, Table 3).