Injecting drug use and hepatitis C virus infection independently increase biomarkers of inflammatory disease risk which are incompletely restored by curative direct-acting antiviral therapy

Anna C Hearps; Nikil Vootukuru; Salimeh Ebrahimnezhaddarzi; Brendan L Harney; Irene Boo; Long Nguyen; Damian Pavlyshyn; Paul M Dietze; Heidi E Drummer; Alexander J Thompson; Anthony Jaworowski; Margaret E Hellard; Rachel Sacks-Davis; Joseph S Doyle

doi:10.3389/fimmu.2024.1352440

Injecting drug use and hepatitis C virus infection independently increase biomarkers of inflammatory disease risk which are incompletely restored by curative direct-acting antiviral therapy

Front Immunol. 2024 Feb 14:15:1352440. doi: 10.3389/fimmu.2024.1352440. eCollection 2024.

Authors

Anna C Hearps^#^{1

2}, Nikil Vootukuru^#^{1

3}, Salimeh Ebrahimnezhaddarzi¹, Brendan L Harney^{1

2

4}, Irene Boo¹, Long Nguyen¹, Damian Pavlyshyn¹, Paul M Dietze^{1

5}, Heidi E Drummer^{1

6

7}, Alexander J Thompson⁸, Anthony Jaworowski^{1

2}, Margaret E Hellard^{1

2

4

6

9}, Rachel Sacks-Davis^{1

4

9}, Joseph S Doyle^{1

2}

Affiliations

¹ Disease Elimination Program, Burnet Institute, Melbourne, VIC, Australia.
² Department of Infectious Diseases, The Alfred and Monash University, Melbourne, VIC, Australia.
³ Department of Gastroenterology, Eastern Health and Monash University, Melbourne, VIC, Australia.
⁴ School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia.
⁵ National Drug Research Institute, Curtin University, Melbourne, VIC, Australia.
⁶ The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia.
⁷ Department of Microbiology, Monash University, Melbourne, VIC, Australia.
⁸ Department of Gastroenterology, St Vincent's Hospital and the University of Melbourne, Melbourne, VIC, Australia.
⁹ Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.

^# Contributed equally.

Abstract

Background: Hepatitis C virus (HCV) infections are more prevalent in people who inject drugs (PWID) who often experience additional health risks. HCV induces inflammation and immune alterations that contribute to hepatic and non-hepatic morbidities. It remains unclear whether curative direct acting antiviral (DAA) therapy completely reverses immune alterations in PWID.

Methods: Plasma biomarkers of immune activation associated with chronic disease risk were measured in HCV-seronegative (n=24) and HCV RNA+ (n=32) PWID at baseline and longitudinally after DAA therapy. Adjusted generalised estimating equations were used to assess longitudinal changes in biomarker levels. Comparisons between community controls (n=29) and HCV-seronegative PWID were made using adjusted multiple regression modelling.

Results: HCV-seronegative PWID exhibited significantly increased levels of inflammatory biomarkers including soluble (s) TNF-RII, IL-6, sCD14 and sCD163 and the diabetes index HbA1c as compared to community controls. CXCL10, sTNF-RII, vascular cell adhesion molecule-1 and lipopolysaccharide binding protein (LBP) were additionally elevated in PWID with viremic HCV infection as compared to HCV- PWID. Whilst curative DAA therapy reversed some biomarkers, others including LBP and sTNF-RII remained elevated 48 weeks after HCV cure.

Conclusion: Elevated levels of inflammatory and chronic disease biomarkers in PWID suggest an increased risk of chronic morbidities such as diabetes and cardiovascular disease. HCV infection in PWID poses an additional disease burden, amplified by the incomplete reversal of immune dysfunction following DAA therapy. These findings highlight the need for heightened clinical surveillance of PWID for chronic inflammatory diseases, particularly those with a history of HCV infection.

Keywords: biomarkers; direct-acting antivirals; hepatitis C virus; inflammation; people who inject drugs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents / therapeutic use
Biomarkers
Diabetes Mellitus* / drug therapy
Hepacivirus
Hepatitis C* / complications
Hepatitis C* / drug therapy
Hepatitis C, Chronic* / complications
Hepatitis C, Chronic* / drug therapy
Humans
Substance Abuse, Intravenous* / complications
Substance Abuse, Intravenous* / drug therapy
Substance Abuse, Intravenous* / epidemiology

Substances

Antiviral Agents
Biomarkers

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research as funded in part by an internal grant received from the Burnet Institute, Melbourne Australia.