Impact of direct-acting antivirals on extrahepatic manifestations and ethnic disparities : insights from a large population-based cohort using linked health administrative data

Background: Direct-acting antivirals (DAAs) have demonstrated efficacy in reducing morbidity and mortality related to extrahepatic outcomes of chronic hepatitis C (HCV) infection. However, population-based evidence assessing the impact of DAA treatment on extrahepatic manifestations (EHMs) and their burden across ethnic groups remains limited. Objective: We evaluated the impact of DAA treatment on incident EHMs and EHM-related mortality risks, while also assessing ethnic disparities in EHMs among people diagnosed with HCV in British Columbia (BC). Methods: We used data from the BC Hepatitis Testers Cohort, including ~1.3 million people tested for or diagnosed with HCV between 1990 and 2015. To assess the impact of DAA treatment on EHMs, we created a 1:1 matched study population of individuals who were treated with DAAs and those who were never treated. We applied inverse probability of treatment weights and competing risk modelling to assess DAA treatment effects on incident EHMs and EHM-related mortality. Ethnic disparities in incident EHMs were examined across East Asians, South Asians, and Other ethnicities, further stratified by HCV treatment status (never treated, before treatment, after treatment, and spontaneously cleared). Results: Successful DAA treatment was associated with reduced risks of renal, cerebrovascular, cardiovascular and neurocognitive conditions (36-48%), but not type 2 diabetes. It also decreased EHM-related mortality risks by 78-84% for all EHMs. In BC, South and East Asians had higher EHM incidence rates compared to other ethnicities, especially among untreated individuals. Following treatment completion, these rates decreased in both Asian groups. Adjusted analyses showed that South Asians had the highest risk of renal diseases and type 2 diabetes, while East Asians had lower risks of cardiovascular diseases and neurocognitive disorders. HCV treatment mitigated ethnic disparities in EHMs, except for diabetes. Conclusions: DAA treatment can significantly reduce the risks of EHMs and EHM-related mortality, while mitigating most ethnic disparities in EHM incidence among Asian populations. These findings emphasize the importance of expanding strategies to diagnose and treat individuals living with HCV as early as possible to improve health outcomes and address ethnic disparities related to EHMs.