Patient characteristics

The median age was 68 years, and 52% of patients were male (Table 1). The distributions of patients with CP-A, CP-B and CP-C were 10% (20/206), 76% (156/206) and 15% (30/206), respectively, and the median MELD score was 11. Six patients had virological relapse, one had no-response, and two were missing HCV RNA data. Five patients died, and four were lost to follow-up before the SVR could be determined. The SVR rate was 91.3% (188/206) in intention-to-treat fashion.

Table 1 Patient characteristicsLT-free survival after SOF/VEL treatment

Among 206 patients, 26 patients died and two patients underwent LT during the median observation period of 28.1 months from the start of SOF/VEL treatment. The causes of death were liver failure in 13 patients, HCC in four patients, varix rupture, sepsis, heart failure, pancreatic cancer, cerebral infarction, gastric neuroendocrine carcinoma, and cancer of unknown primary in one patient each, and unknown causes in two patients. Two patients underwent LT due to liver failure without HCC. One was a 59-year-old female whose baseline CP score was 9. She achieved SVR, but her CP score deteriorated to 10 at 24 weeks after the EOT, and she underwent LT on day 298 after the start of treatment. The other was a 56-year-old male whose baseline CP score was 9. He achieved SVR, but his CP score deteriorated to 11 at 2 years after the EOT, and he underwent LT on day 833 after the start of treatment. The LT-free survival rates at 2 and 3 years were 90.0% and 83.2%, respectively (Fig. 1A). We compared survival rates according to baseline CP class by the Bonferroni method for multiple comparisons, and unadjusted p-values were shown. The 2 and 3-year LT-free survival rates were 95.0% and 95.0% for patients with CP-A, 91.2% and 83.2% for those with CP-B and 78.7% and 72.7% for those with CP-C, respectively, and there were no significant differences in LT-free survival rates (CP-A vs. CP-B; p = 0.678, CP-A vs. CP-C; p = 0.281, CP-B vs. CP-C; p = 0.191) (Fig. 1B).

Fig. 1

LT-free survival rates among all patients. A LT-free survival rates, B LT-free survival rates according to Child–Pugh class at baseline. Black solid line, patients with Child–Pugh class A; black dotted line, patients with Child–Pugh class B; grey solid line, patients with Child–Pugh class C. The log-rank test and Kaplan–Meier estimation were used to analyze the differences in LT-free survival rates. We compared survival rates according to CP class by the Bonferroni method for multiple comparisons, and unadjusted p-values were shown

Factors associated with LT-free survival among decompensated cirrhotic patients

We examined factors associated with LT-free survival by Cox proportional hazards model excluding nine patients who died or were lost to follow-up by 12 weeks after the EOT (Table 2). The characteristic of patients who died or were lost to follow-up by 12 weeks after the EOT are shown (Supplementary Table 1). In the LT-free survival analysis, 21 patients died and two patients underwent LT. In univariate analysis, the presence of ascites, HE, alanine aminotransferase (ALT) levels, creatinine levels, CP class at 12 weeks after the EOT and MELD score at 12 weeks after the EOT were significant factors. Multivariate analyses were conducted using two models that included either CP class (Model 1) or MELD score (Model 2). We excluded the factors of ascites and HE in the multivariate analysis using Model 1 and creatinine levels in the multivariate analysis using Model 2 since these factors were included in the formula for the CP score or MELD score. In Model 1, ALT levels (hazard ratio (HR): 0.976, 95% confidence interval (CI): 0.952–1.000, p = 0.046), creatinine levels (HR: 6.853, 95% CI: 1.964–23.912, p = 0.003) and CP-C at 12 weeks after the EOT (HR: 7.931, 95% CI: 2.441–25.773, p = 0.001) were significant factors for LT-free survival in multivariate analysis. In Model 2, the presence of HE (HR: 3.051, 95% CI: 1.098–8.474, p = 0.032) and MELD score at 12 weeks after the EOT (HR: 1.166, 95% CI: 1.042–1.306, p = 0.007) were significant factors for LT-free survival in multivariate analysis.

Table 2 Factors associated with LT-free survival after DAA treatmentLT-free survival rates according to baseline and posttreatment liver function

We examined LT-free survival rates according to CP class or MELD score excluding nine patients who died or were lost to follow-up by 12 weeks after the EOT (Fig. 2). We compared survival rates according to CP class by the Bonferroni method for multiple comparisons, and unadjusted p-values were shown. For baseline CP class, 2- and 3-year LT-free survival rates were 100% and 100% for patients with CP-A, 92.4% and 84.3% for those with CP-B and 84.8% and 78.3% for those with CP-C, respectively, and there were no significant differences in LT-free survival rates (CP-A vs. CP-B; p = 0.360, CP-A vs. CP-C; p = 0.246, CP-B vs. CP-C; p = 0.557) (Fig. 2A). Regarding CP class at 12 weeks after the EOT, the 2- and 3-year LT-free survival rates were 100% and 91.0% for patients with CP-A, 91.6% and 86.4% for those with CP-B and 60.4% and 51.8% for those with CP-C, respectively, and the survival rates of patients with CP-C were significantly lower than those of patients with CP-A or CP-B (CP-A vs. CP-B; p = 0.269, CP-A vs. CP-C; p < 0.001, CP-B vs. CP-C; p < 0.001) (Fig. 2B). Receiver operating characteristic analysis was used to determine the optimal cut-off value of the MELD score at 12 weeks after the EOT for predicting LT-free survival. The optimal cut-off value of the MELD score at 12 weeks after the EOT was 15 by the Youden index. For baseline MELD score, the 2-year LT-free survival rates were 93.3% and 92.3% for patients with MELD scores less than 15 and MELD scores of 15 or more, respectively, and there were no significant differences in LT-free survival rates (p = 0.493) (Fig. 2C). Regarding the MELD score at 12 weeks after the EOT, the 2-year LT-free survival rates were 95.2% and 69.6% for patients with MELD scores less than 15 and MELD scores of 15 or more, respectively, and the survival rates of patients with MELD scores of 15 or more were significantly lower than those of patients with MELD scores less than 15 (p < 0.001) (Fig. 2D).

Fig. 2

LT-free survival rates excluding nine patients who died or were lost to follow-up by 12 weeks after the EOT. A. LT-free survival rates according to Child–Pugh class at baseline. Black solid line, patients with Child–Pugh class A; black dotted line, patients with Child–Pugh class B; grey solid line, patients with Child–Pugh class C. B. LT-free survival rates according to Child–Pugh class at 12 weeks after the EOT. Black solid line, patients with Child–Pugh class A; black dotted line, patients with Child–Pugh class B; grey solid line, patients with Child–Pugh class C. C LT-free survival rates according to MELD score at baseline. Black line, patients with MELD scores less than 15; grey line, patients with MELD scores of 15 or more. D LT-free survival rates according to MELD score at 12 weeks after the EOT. Black line, patients with MELD scores less than 15; grey line, patients with MELD scores of 15 or more. The log-rank test and Kaplan–Meier estimation were used to analyze the differences in LT-free survival rates. We compared survival rates according to CP class by the Bonferroni method for multiple comparisons, and unadjusted p-values were shown. Abbreviations: EOT end of treatment; MELD score, model for end-stage liver disease score

Changes in liver function between baseline and 12 weeks after the EOT

We examined the changes in CP class or MELD score between baseline and 12 weeks after the EOT (Fig. 3). For CP class, we evaluated CP class both at baseline and 12 weeks after the EOT for 193 patients. Among 150 patients with baseline CP-B, 60 improved to CP-A, 83 remained in CP-B, and seven deteriorated to CP-C at 12 weeks after the EOT. Among 26 patients with baseline CP-C, one and 14 improved to CP-A and CP-B, respectively, and 11 remained in CP-C at 12 weeks after the EOT (Fig. 3A).

Fig. 3

Changes in liver function between baseline and 12 weeks after the EOT. A. Child–Pugh class. B. MELD score. Black solid line, improvement; grey solid line, stable; black dotted line, worsening. Abbreviations: EOT end of treatment; MELD score, model for end-stage liver disease score

For the MELD score, we evaluated the MELD score both at baseline and 12 weeks after the EOT for 177 patients. Among 16 patients with a baseline MELD score of 15 or more, 6 improved to a MELD score less than 15, and 10 maintained a MELD score of 15 or more at 12 weeks after the EOT (Fig. 3B).

Baseline factors associated with Child–Pugh class C at 12 weeks after the EOT among patients with Child–Pugh class B or C at baseline

Since no patients with CP-A at baseline deteriorated to CP-C at 12 weeks after the EOT, we examined baseline factors associated with CP class C at 12 weeks after the EOT among patients with CP-B or CP-C at baseline by a logistic regression model (Table 3). In the univariate analysis, the presence of HE, total bilirubin levels, the INR and albumin levels were significant factors. In the multivariate analysis, the presence of HE (HR: 4.200, 95% CI: 1.252–14.086, p = 0.020) and total bilirubin levels (HR: 1.786, 95% CI: 1.238–2.579, p = 0.002) were significant factors (Table 3).

Table 3 Baseline factors associated with Child–Pugh class C at 12 weeks after EOT among patients with Child–Pugh class B or C at baseline