Treatment of HCV with direct-acting antivirals on reducing mortality related to extrahepatic manifestations: a large population-based study in British Columbia, Canada

Abstract

Background: HCV infection is associated with mortality due to extrahepatic manifestations (EHM). Sustained virologic response (SVR) following direct-acting antiviral (DAA) therapy has been linked to decreased all-cause and liver-related mortality. However, evidence regarding the impact of DAA on EHM-related deaths is lacking. This study aimed to assess the impact of DAA and SVR on EHM-related mortality.

Methods: The British Columbia Hepatitis Testers Cohort comprises ∼1.7 million people tested for HCV between 1990 and 2015 and is linked with administrative health data. Among individuals diagnosed with HCV by 12/31/2020, those who received at least one DAA treatment were matched to those who never received treatment by the year of their first HCV RNA positive date. We compared three groups: treated & SVR, treated & no-SVR, and untreated; and generated EHM mortality rates and incidence curves. To account for differences in baseline characteristics, we used inverse probability of treatment weights (IPTW). IPTW-weighted multivariable cause-specific Cox regression models were adjusted for competing risk and confounders.

Findings: Study population included 12,815 treated (12,287 SVR, 528 no-SVR) and 12,815 untreated individuals (median follow-up 3.4 years, IQR 2.9). The untreated group had the highest EHM mortality rate (30.9 per 1000 person-years [PY], 95% CI 29.2-32.8), followed by the treated & no-SVR group (21.2 per 1000 PY, 95% CI 14.9-30.1), while the treated & SVR group had the lowest EHM mortality rate (7.9 per 1000 PY, 95% CI 7.1-8.7). In the multivariable model, EHM mortality in the treated & SVR group was significantly decreased (adjusted cause-specific hazard ratio [acsHR] 0.20, 95% CI 0.18-0.23). The treated & SVR group had significant reductions in mortality related to each of the EHMs (78-84%).

Interpretation: Treatment of HCV with DAA was associated with significant reductions in EHM-related mortality. These findings emphasize the critical importance of timely diagnosis and treatment of HCV to prevent deaths associated with EHM, and have important implications for clinical practice and public health.

Funding: This work was supported by the BC Centre for Disease Control and the Canadian Institutes of Health Research (CIHR) [Grant # NHC-348216, PJT-156066, and PHE-337680]. DJ has received Doctoral Research Award (#201910DF1-435705-64343) from the Canadian Institutes of Health Research (CIHR) and Doctoral fellowship from the Canadian Network on Hepatitis C (CanHepC). CanHepC is funded by a joint initiative of the Canadian Institutes of Health Research (CIHR) (NHC-142832) and the Public Health Agency of Canada (PHAC).

Keywords: Direct-acting antivirals; Extrahepatic manifestations; HCV infection; Inverse probability of treatment weighting; Mortality; Population-based study.

Fig. 1

Study population flowchart. Abbreviations: DAA, direct-acting antivirals; EHM, extrahepatic manifestations; HCV, hepatitis C virus; SVR, sustained virologic response.

Fig. 2

The survival curves and cumulative incidence curves of extrahepatic mortality by treatment status. Abbreviations: EHM, extrahepatic manifestations; HCV, hepatitis C virus; SVR, sustained virologic response.

Fig. 3

Cumulative incidence of mortality related to each EHM by treatment status. (A) Deaths related to cardiovascular diseases. (B) Deaths related to cerebrovascular diseases. (C) Deaths related to chronic kidney diseases. (D) Deaths related to diabetes mellitus. (E) Deaths related to mood and anxiety disorders. (F) Deaths related to other mental health illnesses. Tables under figures show the number of individuals at risk and cumulative number of deaths related to each EHM at timepoints (Yrs 1–5). Abbreviations: EHM, extrahepatic manifestations; HCV, hepatitis C virus; SVR, sustained virologic response.