Mortality in patients with successfully treated hepatitis C in the interferon-free antiviral era: a population-based cohort study

patient characteristics

A total of 21,790 people successfully treated for HCV were included in the analysis: 11,942 (56.3%) from British Columbia, 7,691 (33.6%) from Scotland, and 2,157 (10.2%) from England (Fig. 1). The majority of people on successful HCV treatment did not have cirrhosis, 74% in Scotland and 84% in British Columbia (Figure 1). Patients with cirrhosis and end-stage liver disease were successfully treated for HCV earlier and were significantly older than patients without cirrhosis (Figs. S1-S2). Notably, people in Scotland who were successfully treated for HCV were more than 10 years younger than people in British Columbia. For example, the average age of patients without cirrhosis in Scotland was 44.4 years, compared with 56.1 years in British Columbia (Table 1). Men outnumbered women (65-75%) in all cohorts and disease severity groups. The proportion of patients hospitalized for alcohol abuse before successful treatment for HCV increases significantly with disease severity. Two-fifths to one-half of the participants had previously been hospitalized for substance abuse (table 1 and fig. S3).

Follow-up and observed mortality

The total follow-up time of the cohort was 53,370 person-years. At the individual patient level, the average follow-up time per patient was 2.2 years (British Columbia), 2.5 years (Scotland), and 3.9 years (England). A total of 1,572 deaths were observed. The leading causes of death were drug-related death (n=383, 24.4%), liver failure (n=286, 18.2%), liver cancer (n=250, 15.9%) and extrahepatic cancer (n=181, 11.5%) ; Table S14).

mortality rate—The crude mortality rates (deaths per 1,000 person-years) were 31.43 (95% confidence interval 29.32 to 33.66), 22.73 (20.71 to 24.95), and 39.58 (35.41 to 44.25) in British Columbia, Scotland, and England, respectively (Figure 2) . Mortality increases significantly with increasing severity of liver disease. For example, in Scotland, the crude mortality rates for patients without cirrhosis, compensated cirrhosis, and end-stage liver disease were 16.10 (14.13 to 18.35), 35.25 (30.24 to 41.10), and 63.56 (48.68 to 82.98), respectively. ..

Standardized mortality rates are more comparable between England, Scotland and British Columbia than equivalent crude mortality rates (Figure 2). However, even after standardization, key differences remain. In particular, the mortality rate among patients with end-stage liver disease was much higher in British Columbia (118.2 deaths per 1,000 person-years) than in Scotland (64.8) and England (68.4). This difference persisted in sensitivity analyzes excluding patients with cured liver cancer (Figs. S4–S5).

Figures S6-S11 show cause-specific mortality. Among people without cirrhosis, mortality from drug abuse is much higher than from other causes of death (7.0–9.3 deaths per 1000 person-years; fig. S6). In patients with compensated cirrhosis, drug-related mortality was comparable to that in patients without cirrhosis, but liver cancer deaths (5.5–7.2 deaths per 1000 person-years) and liver failure (4.1–7.5) were more prominent (fig. S7) . In contrast, among patients with end-stage liver disease, the incidence of liver failure (22.4-45.6) and liver cancer mortality (20.3-31.1) far exceeded other causes of death (Fig. S8).

Death rate relative to total population—Mortality rates were significantly higher than in the general population in all cohorts and disease stage groups (Figure 3). In Scotland, all-cause mortality in all patients was 4.5 times higher than in the general population, with 442 observed deaths and 98 expected deaths (standardized mortality rate 4.53, 95% confidence interval 4.10 to 5.00; P< 0.001). In British Columbia, the mortality rate was 3.9 times higher, with 821 actual deaths and 209 expected deaths (3.94, 3.68 to 4.21; P<0.001). In England, the total number of deaths observed (309) was five times the expected number (62; 5.02, 4.45 to 5.66; P<0.001); as the cohort did not include people without cirrhosis, this estimate cannot be directly compared with the UK Estimates for Columbia and Scotland are compared. Standardized mortality rates increased significantly with liver disease severity; for example, from 2.96 (2.71 to 3.23; P<0.001) in British Columbia patients without cirrhosis to 13.61 (11.94 to 15.49; British Columbia patients with end-stage liver disease; P<0.001; Figure 3).

Figures S12-S14 outline the causes of specific standardized mortality rates. For patients without cirrhosis, the leading cause of excess mortality was drug-related deaths, accounting for 74% and 44% of all excess deaths in Scotland and British Columbia, respectively. In contrast, for patients with cirrhosis, the two main drivers are liver cancer and liver failure. Together, these causes account for 80% of excess deaths (Figure 4). After adjusting for regional deprivation in Scotland, standardized mortality rates fell but remained significantly higher compared with the total population. For example, the standardized mortality rate for all patients in Scotland was 3.35 (95% confidence interval 3.04 to 3.68; P<0.001) when adjusting for poverty, age, sex and year; was 4.53 (4.10 to 5.00; P<0.001). Adjusted separately for age, sex, and year (Fig. S15).

Factors associated with mortality and standardized mortality rates—Across all disease stages and settings, older age was consistently associated with higher mortality in multivariable regression (Table 2 and Table S15). For example, among people without cirrhosis in Scotland, a 10-year increase in age was associated with a 30% increase in all-cause mortality (mortality ratio 1.30, 95% confidence interval 1.14 to 1.49; P<0.001). Hospital admission for alcohol and drug abuse before hepatitis C is cured is also associated with higher mortality. In general, patients who were recently admitted experienced larger increases compared with patients who were not recently admitted. For example, among people from British Columbia without cirrhosis, the mortality rate for patients who had recently been admitted to the hospital for substance abuse was almost threefold compared with patients who had not been previously admitted (mortality ratio 2.90, 95% confidence The range is 2.17 to 3.88; P<0.001)), while non-recent admissions increase 2.2 times (2.17, 1.67 to 2.83; P<0.001). Higher Charlson comorbidity index was also associated with higher mortality. These associations were nonlinear in some subgroups (Fig. S16).

In addition to all-cause mortality, we also modeled all-cause standardized mortality (Tables S16-S17). In general, the association of each covariate with standardized mortality reflects its association with mortality. However, a notable exception was older age, which was associated with lower standardized mortality rates but higher mortality rates. For example, among Scottish patients with compensated cirrhosis, a 10-year increase in age was associated with a 43% reduction in standardized mortality (0.57, 95% confidence interval 0.50 to 0.66; P<0.001), but was also associated with a 25% reduction in standardized mortality. Mortality was increased (rate ratio 1.25, 95% confidence interval 1.07 to 1.47; P=0.006).