Predicting 5-year Survival of Patients With Chronic HBV
Predicting 5-year Survival of Patients With Chronic HBV
A total of 650 patients were recruited (Figure 1). Among these patients, 23 (3.5%) were excluded for not interpretable LSM: liver stiffness failure (no valid shot) in eight patients (1.2%), less than 10 valid measurements in seven patients (1.1%), IQR/liver stiffness >0.30 in eight patients (1.2%). Moreover, eight patients (1.3%) had no FibroTest (two missing and six not applicable due to high ALT level). At least, 19 patients had no follow-up (3.1%). Therefore, 600 patients were evaluated. APRI and FIB4 were missing for 12 patients out of these 600 patients (platelet count or AST or ALT level missing).
(Enlarge Image)
Figure 1.
Chart-flow of the study population of patients chronically infected by HBV.
Median follow-up was 49.7 months (IQR 32.2–63.2). Clinical and biological characteristics of the patients are indicated in Table 1. A majority of them were men (64%), and mean age was 42.5 ± 15.2 years. Most of patients (56.5%) had normal ALT level (<40 IU/L in women, <50 IU/L in men). Only 13% of patients had ALT level >2 × ULN. Ninety-four patients (15.7%) had liver stiffness >9 kPa (cut-off value for severe fibrosis or cirrhosis in HBV patients with normal ALT level), 46 patients (7.7%) had FibroTest >0.74, 10 patients (1.7%) had APRI >2, and 27 patients (4.6%) had FIB-4 score >3.25. Liver biopsy was available in 214 patients (35.7%) and showed severe fibrosis or cirrhosis in 86 cases (40.2%). Median liver biopsy samples length was 22 mm.
As indicated in Table 2, liver stiffness and FibroTest had comparable diagnostic accuracy for the diagnosis of fibrosis stage, but higher accuracy in comparison with other biomarkers, when biopsy was taken as the reference.
At the beginning of the study, 11 patients (1.8%) had a hepatocellular carcinoma. At the end of follow-up, six of them were still alive. The overall number of death/transplantation was 29 (4.8%) of 600, 17 liver-related and 12 not liver-related deaths. Among these 29 patients, 25 patients were men, and 13 patients (44.8%) had LSM ≤9 kPa at inclusion. All transplanted patients received liver transplantation for HCC.
At inclusion, 209 patients (36.3%) were inactive carriers, 272 patients (47.4%) had chronic hepatitis with negative HBe antigen, and 94 patients (16.3%) had chronic hepatitis with positive HBe antigen. During follow-up, 452 patients (75.3%) did not receive any treatment for HBV infection.
Among the 94 patients with liver stiffness >9 kPa, 53 patients (56.4%) did not receive any treatment (six deaths in this group), and 41 patients received treatment (10 deaths in this group). Among the 506 patients with liver stiffness ≤9 kPa, 399 patients (78.8%) did not receive any treatment (eight deaths in this group), and 107 patients received treatment (five deaths in this group).
Details of the causes of deaths are given in Table 3. In the overall population (600 patients), the 5-year overall survival was 0.94 (95% CI 0.91–0.96), and the 5-year survival without liver-related death or transplantation was 0.96 (95% CI 0.94–0.98).
Only three deaths were observed in the 209 inactive carriers. All these deaths were unrelated to the liver (lung and pancreas cancers).
The survival probability of patients classified according to liver stiffness, FibroTest, APRI, FIB-4 and liver biopsy is detailed in Figure 2 and their specific association with survival in Table 4.
(Enlarge Image)
Figure 2.
Overall survival probability (Kaplan–Meier analysis) of 600 patients chronically infected by HBV according to: (A) liver stiffness (a: cut-off of 9 kPa; b: cut-off of 20 kPa), (B) Fibrotest (a: cut-off of 0.73; b: cut-off of 0.85), (C) blood tests (a: APRI; b: FIB-4) and (D) Liver biopsy.
For FibroTest and liver stiffness, two cut-offs were evaluated for predicting survival: 0.73 and 0.85 for Fibrotest, 9 and 20 kPa for liver stiffness, according to previous published results. As indicated in Figure 2A, B, overall survival was decreased according to liver stiffness and FibroTest values. The 5-year overall survival was 97.1% in patients with liver stiffness <9 kPa, and 61.5% in patients with liver stiffness >20 kPa, and 96.8% for FibroTest ≤0.73, and 49.2% in patients with FibroTest >0.85.
In univariate and multivariate analysis, FibroTest and liver stiffness had the higher prognostic values. The association persisted after adjustment on age, necro-inflammatory histological activity presumed by ActiTest, HBV-DNA and treatment.
When the prognostic performances were expressed using AUROC (Figure 3), there was high significance for Fibrotest 0.82 (95% CI 0.71–0.89), and liver stiffness 0.80 (0.70–0.87) without significant difference between these biomarkers.
(Enlarge Image)
Figure 3.
Prognostic values for overall survival of FibroTest and liver stiffness in 600 patients chronically infected by HBV. There was no significant difference between the two AUROCs: Fibrotest 0.82 (95%CI 0.71–0.89), and liver stiffness 0.80 (0.70–0.87) (P = 0.73).
Results
Characteristics of Patients
A total of 650 patients were recruited (Figure 1). Among these patients, 23 (3.5%) were excluded for not interpretable LSM: liver stiffness failure (no valid shot) in eight patients (1.2%), less than 10 valid measurements in seven patients (1.1%), IQR/liver stiffness >0.30 in eight patients (1.2%). Moreover, eight patients (1.3%) had no FibroTest (two missing and six not applicable due to high ALT level). At least, 19 patients had no follow-up (3.1%). Therefore, 600 patients were evaluated. APRI and FIB4 were missing for 12 patients out of these 600 patients (platelet count or AST or ALT level missing).
(Enlarge Image)
Figure 1.
Chart-flow of the study population of patients chronically infected by HBV.
Median follow-up was 49.7 months (IQR 32.2–63.2). Clinical and biological characteristics of the patients are indicated in Table 1. A majority of them were men (64%), and mean age was 42.5 ± 15.2 years. Most of patients (56.5%) had normal ALT level (<40 IU/L in women, <50 IU/L in men). Only 13% of patients had ALT level >2 × ULN. Ninety-four patients (15.7%) had liver stiffness >9 kPa (cut-off value for severe fibrosis or cirrhosis in HBV patients with normal ALT level), 46 patients (7.7%) had FibroTest >0.74, 10 patients (1.7%) had APRI >2, and 27 patients (4.6%) had FIB-4 score >3.25. Liver biopsy was available in 214 patients (35.7%) and showed severe fibrosis or cirrhosis in 86 cases (40.2%). Median liver biopsy samples length was 22 mm.
Accuracy of Biomarkers for the Diagnosis of Fibrosis Stage
As indicated in Table 2, liver stiffness and FibroTest had comparable diagnostic accuracy for the diagnosis of fibrosis stage, but higher accuracy in comparison with other biomarkers, when biopsy was taken as the reference.
Survival
At the beginning of the study, 11 patients (1.8%) had a hepatocellular carcinoma. At the end of follow-up, six of them were still alive. The overall number of death/transplantation was 29 (4.8%) of 600, 17 liver-related and 12 not liver-related deaths. Among these 29 patients, 25 patients were men, and 13 patients (44.8%) had LSM ≤9 kPa at inclusion. All transplanted patients received liver transplantation for HCC.
At inclusion, 209 patients (36.3%) were inactive carriers, 272 patients (47.4%) had chronic hepatitis with negative HBe antigen, and 94 patients (16.3%) had chronic hepatitis with positive HBe antigen. During follow-up, 452 patients (75.3%) did not receive any treatment for HBV infection.
Among the 94 patients with liver stiffness >9 kPa, 53 patients (56.4%) did not receive any treatment (six deaths in this group), and 41 patients received treatment (10 deaths in this group). Among the 506 patients with liver stiffness ≤9 kPa, 399 patients (78.8%) did not receive any treatment (eight deaths in this group), and 107 patients received treatment (five deaths in this group).
Details of the causes of deaths are given in Table 3. In the overall population (600 patients), the 5-year overall survival was 0.94 (95% CI 0.91–0.96), and the 5-year survival without liver-related death or transplantation was 0.96 (95% CI 0.94–0.98).
Only three deaths were observed in the 209 inactive carriers. All these deaths were unrelated to the liver (lung and pancreas cancers).
Prediction of Survival
The survival probability of patients classified according to liver stiffness, FibroTest, APRI, FIB-4 and liver biopsy is detailed in Figure 2 and their specific association with survival in Table 4.
(Enlarge Image)
Figure 2.
Overall survival probability (Kaplan–Meier analysis) of 600 patients chronically infected by HBV according to: (A) liver stiffness (a: cut-off of 9 kPa; b: cut-off of 20 kPa), (B) Fibrotest (a: cut-off of 0.73; b: cut-off of 0.85), (C) blood tests (a: APRI; b: FIB-4) and (D) Liver biopsy.
For FibroTest and liver stiffness, two cut-offs were evaluated for predicting survival: 0.73 and 0.85 for Fibrotest, 9 and 20 kPa for liver stiffness, according to previous published results. As indicated in Figure 2A, B, overall survival was decreased according to liver stiffness and FibroTest values. The 5-year overall survival was 97.1% in patients with liver stiffness <9 kPa, and 61.5% in patients with liver stiffness >20 kPa, and 96.8% for FibroTest ≤0.73, and 49.2% in patients with FibroTest >0.85.
In univariate and multivariate analysis, FibroTest and liver stiffness had the higher prognostic values. The association persisted after adjustment on age, necro-inflammatory histological activity presumed by ActiTest, HBV-DNA and treatment.
When the prognostic performances were expressed using AUROC (Figure 3), there was high significance for Fibrotest 0.82 (95% CI 0.71–0.89), and liver stiffness 0.80 (0.70–0.87) without significant difference between these biomarkers.
(Enlarge Image)
Figure 3.
Prognostic values for overall survival of FibroTest and liver stiffness in 600 patients chronically infected by HBV. There was no significant difference between the two AUROCs: Fibrotest 0.82 (95%CI 0.71–0.89), and liver stiffness 0.80 (0.70–0.87) (P = 0.73).
