Dear Editor,

Despite advancements in chronic liver disease (CLD) management, CLD-related mortality has continued to increase in the United States (US) [1]. This upward trend in mortality is particularly concerning in the context of drug overdose from hepatitis C virus (HCV) [2]. The COVID-19 pandemic further complicates this landscape [3-5]. However, data regarding trends in CLD-related mortality within the setting of drug overdose during and after the COVID-19 pandemic remain limited. This study aims to provide updated insights into these trends by examining mortality from HCV and ALD in the context of drug overdose in the US from 2015 to 2023.

National death records for individuals aged 25 years and older from the National Vital Statistics System were examined using International Classification of Diseases, Tenth Revision (ICD-10) codes. CLD was identified using ICD-10 codes for HCV infection (B17.1, B18.2, B19.2) and ALD (K70) [6]. Drug overdose-related deaths among individuals with HCV or ALD were defined using ICD-10 codes X40– X44, X60–X64, X85, Y10–Y14, and T-codes 40.0–40.4 and 40.6 [7]. To determine age-standardized mortality, we divided deaths among individuals with CLD to the total US census population and calculated mortality per 100,000 persons by age group, adjusting to the 2010 US standard population’s age distribution. Trends in mortality and proportions were analyzed using the Joinpoint Regression Program to determine annual percentage change (APC) and average APC over the study period [8]. Because all National Vital Statistics System data are publicly available and de-identified, the study was not subject to institutional review board review and patient consent.

Between 2015 and 2023, there were 137,978 deaths from HCV and 283,916 deaths from ALD. Annual age-standardized mortality due to HCV without drug overdose de-creased with an annual rate of –8.2% (95% confidence interval [CI] –9.6% to –6.7%; Fig. 1A). The proportion of HCV-related mortality without drug overdose decreased by 0.4% annually (95% CI –0.4% to –0.3%). In line with the steady increase in age-standardized HCV-related deaths with drug overdose (APC 4.6%, 95% CI 2.1% to 7.1%; Fig. 1B), the proportion of HCV-related deaths with drug overdose significantly rose at an annual rate of 12.4% (95% CI 10.5% to 14.2%; Fig. 1C).

ALD-related mortality without drug overdose steadily increased (APC 4.1%, 95% CI 2.9% to 5.2%), with a sharp rise of 14.0% between 2018 and 2021 (Fig. 1A). Following the early COVID-19 pandemic, these rates declined steadily, with an APC of –6.5% (95% CI –11.1% to –2.0%). The proportion of ALD-related mortality with drug overdose increased annually by 1.9% (95% CI 0.6% to 2.7%) over the study period, with a sharp rise observed during the COVID-19 pandemic (APC 7.6%, 95% CI 1.5% to 11.6%; Fig. 1D).

Overall, HCV-related mortality significantly decreased, except for sub-populations affected by both drug overdose and HCV infection, which predominantly included younger non-Hispanic whites [2]. Therefore, increased screening is necessary to identify HCV-infected individuals, targeting not only baby boomers but also people who inject drugs (PWID). Despite the significant advances and therapeutic benefits achieved with direct-acting antivirals (DAA) alone, they cannot address the rising acute-care needs and mortality observed in HCV populations who use drugs [9]. DAA treatment initiation rates are generally lower in PWID than in the general population, although sustained virological response rates are comparable [10]. Those who continue to inject drugs are often ineligible for HCV treatment due to the risk of reinfection and poor adherence [11], Furthermore, access to HCV care and treatment also remains inade-quate [11]. In addition, rising drug-related overdose deaths observed among individuals with HCV-related CLD between 2015 and 2023 likely reflect the impacts of an increasingly toxic and unpredictable drug supply [12,13]. Over this period, the illicit drug market has evolved and is marked by the growing presence of high-potency synthetic opioids, such as fentanyl and its analogs, and unpredictable adulterants, which complicate overdose reversal and increase mortality risk [12,13]. Individuals with HCV may be particularly vulnerable, given the potential for altered drug metabolism and increased susceptibility. The escalating toxicity of the unregulated drug supply underscores the urgent need for expanded access to medications that reduce mortality in populations that use illicit opioids, harm reduction measures, and integrated care strategies that address both substance use and liver health in this high-risk population.

Given the substantial economic and population burden posed by ALD, there is an urgent need for public policies to alleviate this burden. The proportion of ALD-related mortality with drug overdose increased, with a sharp rise observed during the COVID-19 pandemic. Interruptions in service and interdiction efforts likely contributed to the rise in overdose deaths during the pandemic [14]. The study has limitations, including potential misclassification and underestimation in cause of death identification based on death certificates. However, since the method of reporting has remained consistent over time, these factors would not explain the observed temporal trends. In summary, while DAA agents have significantly reduced HCV-related mortality, continued vigilance and targeted public health interventions are needed to address the rising trends in overdose-related mortality and the increasing burden of ALDrelated mortality with drug overdose.