A total of 761 patients were assessed (Fig. 1) and 404 patients were included in the analysis, after exclusion of 264 patients who were treated for < 6 months, 72 patients who were diagnosed with HCC within 6 months of NA initiation and/or other concomitant cancer(s) within 6 months before NA initiation, 11 patients who underwent organ transplantation, and 10 patients who died within 6 months of NA initiation. In addition, 17 patients had no imaging data since the initiation of NAs; thus excluded for the analysis of HCC incidence. The median follow-up time was 64.0 months [interquartile range (IQR) 30.5–84.3] and 49.1 months (IQR 37.7–62.2) for ETV and TDF, respectively.
The baseline characteristics are summarised in Table 1. A total of 55.9% of the patients were men (58.9% for the ETV vs. 53.6% for the TDF group; P = 0.31) and the mean age was 44.9 years (45.4 years for the ETV vs. 44.5 for the TDF group; P = 0.51). The median baseline values of laboratory parameters did not show a significant difference.
Hepatitis e antigen (HBeAg) positivity in the ETV group (67.4%) was significantly higher than that in the TDF group (57.1%; P = 0.038). Virological response at 1 year in the ETV group (68.4%) was significantly lower than that in the TDF group (79.4%; P = 0.018). Sustained virological suppression was defined as non-detection of HBV DNA after achieving virological response. The proportion of patients with sustained virological suppression in the TDF group (62.4%) was significantly higher than that in the ETV group (48.0%; P = 0.005). Biochemical12 and serological response at 1 year were comparable.
HCC developed in 24 patients; 18 and 6 in the ETV and TDF groups, respectively (Table 2). The cumulative incidence rate of HCC at 5 years in the ETV group [2.28 events per 100 person-years; 95% confidence interval (CI) 1.31‒3.63] was significantly higher than that in the TDF group (0.74 events per 100 person-years; 95% CI 0.29‒1.50; P = 0.014). Throughout the study period, 2.19 HCCs per 100 person-years (95% CI 1.33‒3.36) in the ETV group occurred vs. 0.71 HCCs per 100 person-years (0.28‒1.44) in the TDF group, with IRR of 3.07 (1.22‒7.74; P = 0.012) for ETV over TDF. The risk of HCC was 0.58%, 4.05%, and 8.67% for ETV-treated patients and 0.00%, 2.34%, and 2.80% for TDF-treated patients at 1, 3, and 5 years, respectively.
In contrast, death and transplantation was not significantly different (Table 2). The cumulative incidence rate of death and transplantation per 100 person-years (95% CI) was 0.45 (0.14‒1.05) and 0.23 (0.04‒0.70) for the ETV and TDF groups, respectively, with the IRR of 1.99 (0.37‒10.88; P = 0.42) for ETV over TDF. The risk of death and transplantation was 0.00%, 0.56%, and 1.11% for the ETV group and 0.00%, 0.89%, and 0.89% for the TDF group at 1, 3, and 5 years, respectively.
The univariate analysis revealed that TDF was associated with the lower incidence of HCC (HR, 0.31; 95% CI, 0.12‒0.79; P = 0.014; Supplemental Contents 2a and 3). However, for death and transplantation, TDF was not a predictive factor (HR, 0.53; 95% CI, 0.09‒2.98; P = 0.47; Supplemental Content 2b and 3).
Because of the low number of events, we proceeded to propensity score matching and inverse probability of treatment weighting rather than performing multivariate analyses.
Propensity score-matched cohort
Propensity score matching yielded 168 and 175 pairs of patients for the evaluation of HCC and death and transplantation, respectively (Supplemental Content 4). The risk of HCC in the TDF group was lower than that in the ETV group (Supplemental Content 5a; HR 0.27; 95% CI 0.08‒0.98; P = 0.046). However, the percentage of patients with sustained virological suppression remained significantly different after matching (44.8% in the ETV group vs. 57.8% in the TDF group; standardised mean difference [SMD], 0.26; Supplemental Content 4).
Death and transplantation did not differ (Supplemental Content 5b; HR, 1.00, 95% CI 0.06‒15.99; P > 0.99).
Inverse probability of treatment-weighted cohort
Supplemental Content 6 summarises the baseline characteristics of the patients after inverse probability of treatment weighting.
The risk of HCC in the TDF group was lower than that in the ETV group (HR 0.32; 95% CI 0.13‒0.80; P = 0.015), whereas patients treated with ETV or TDF had comparable outcomes in terms of death and transplantation (HR 0.49, 95% CI 0.08‒3.14; P = 0.45; Supplemental Content 7).
However, patients with sustained virological suppression (46.6% in the ETV group vs. 58.4% in the TDF group; SMD, 0.24) remained significantly imbalanced after weighting (Supplemental Content 6).
Effect of sustained virological suppression on clinical outcomes
Because a significant difference was observed in ‘sustained virological suppression’ between the two groups after matching and weighting, we assumed that sustained virological suppression can be a potential confounder that might have influenced the result. Therefore, sustained virological suppression was additionally included in the matching variables for propensity score matching. After matching, the proportion of patients with sustained virological suppression did not differ (44.8% in the ETV group vs. 52.8% in the TDF group; P = 0.18). In this matched cohort, the TDF group showed lower incidence of HCC (HR 0.36; 95% CI 0.12‒1.14; Fig. 2a); however, the statistical significance was not reached (P = 0.08). Both drugs showed a comparable risk of death and transplantation (Fig. 2b; HR 1.00; 95% CI 0.06‒15.99; P > 0.99).
Subsequently, the analyses excluding patients whose treatment regimen was changed during the study period showed that TDF was not significantly associated with lower incidence of HCC and death and transplantation in the matched cohort (Fig. 3).
Inverse probability of treatment weighting, additionally including the presence of sustained virological suppression, did not produce a balanced cohort (sustained virological suppression, 46.9% in the ETV group vs. 56.1% in the TDF group; P = 0.038); therefore reanalyses were not performed.
The baseline characteristics of cirrhotic patients (145 [35.9%]) before and after matching are shown in Supplemental Content 8.
HCC occurred in 16 and 5 patients in the ETV and the TDF groups, respectively. The HR of TDF was 0.30 (95% CI, 0.11‒0.84; P = 0.021) in the univariate analysis (Supplemental Content 9). Death and transplantation outcome did not differ (HR of TDF, 0.58; 95% CI, 0.10‒3.25; P = 0.53).
Figure 4 shows the incidence of primary outcomes according to the treatment regimen in the matched cohort. TDF-treated patients showed lower risk of HCC with marginal statistical significance (HR 0.36; 95% CI 0.12‒1.14; P = 0.08; Fig. 4a). The death and transplantation outcomes were comparable (HR, 1.00; 95% CI, 0.06‒15.99; P > 0.99; Fig. 4b).
A total of 52.2% of the ETV group (94 of 180 patients) and 29.5% of TDF group (66 of 224 patients) were treated ≥ 5 years. Among them, 3 patients developed HCC, and all were treated with ETV and were older than 50 years when ETV was initiated (Supplemental Content 10).
The incidence of HCC was not significantly associated with TDF treatment on the univariate analysis (HR 0.41; 95% CI 0.13‒1.35; P = 0.14; Supplemental Content 11). Death and transplantation was comparable (HR, 1.54; 95% CI, 0.14‒17.01; P = 0.72). After matching, the risk of HCC was marginally lower in the TDF group (HR 0.36; 95% CI 0.12‒1.14; P = 0.08; Fig. 4c). Death and transplantation (HR 1.00; 95% CI 0.06‒15.99; P > 0.99; Fig. 4d) did not differ between the two groups.