History of Injection Drug Use, HCV Linked to Persistent Immunological Changes After DAA Therapy

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Curative DAA therapy did not completely normalize immune activation and inflammatory biomarkers in individuals with a history of injection drug use and HCV infection.

Although direct-acting antiviral (DAA) therapy is highly effective for inducing sustained virological response (SVR) in individuals with hepatitis C virus (HCV), some immunological changes associated with infection may persist even after cure, including biomarkers relevant to the development of chronic morbidities.1

Findings from a recent study suggest these effects may be amplified among people who inject drugs (PWID), especially those with a history of HCV infection – even after curative DAA therapy, certain biomarkers remained altered and may increase the risk of chronic inflammatory diseases compared to patients without a history of injection drug use or HCV infection.1

The World Health Organization estimates around 11 million people inject drugs globally, accounting for an estimated 23-39% of new HCV infections. More than 95% of HCV cases can be resolved with a short-course oral, curative DAA treatment regimen, rendering the infection undetectable. However, less is known about the impact of DAAs on immunological changes caused by HCV infection.2,3

“To date there is limited information regarding the discrete effects of HCV and substance use-related risks on inflammatory pathways in PWID populations who are disproportionately affected by HCV,” wrote lead investigator Anna Hearps, PhD, senior research fellow and deputy director of the disease elimination program at Burnet Institute in Australia, and colleagues.1

Seeking to address this gap in research, investigators examined the independent effects of HCV infection and injection drug use on soluble inflammatory and immune activation biomarkers, further investigating whether these biomarkers normalized after curative DAA therapy. The retrospective cohort study enrolled volunteers from the general community with no history of injecting drug use or HCV infection, individuals with a history of injecting drug use but not HCV infection, and individuals with a history of injecting drug use and current HCV infection.1

Participants in the injection drug use groups were selected from 3 prospective cohort studies, all of which included individuals with a history of using injecting drugs recruited from Melbourne, Australia. PWID/HCV- participants (n = 24) had a history of injection drug use but not HCV infection, while PWID/HCV+ participants (n = 32) had a history of injection drug use as well as current HCV infection.1

Although all participants in the PWID/HCV- and PWID/HCV+ groups reported a history of injection drug use at baseline, more PWID/HCV+ participants reported use within the past month. Multivariable linear regression analysis revealed a lifetime history of injecting drug use was associated with significantly increased levels of multiple inflammatory biomarkers including sTNF-RII and IL-6 (both P <.001) and the myeloid cell activation markers sCD163 (P = .048) and sCD14 (P = .003).1

Upon further analysis, investigators noted individuals who had injected drugs within the previous month exhibited significantly greater levels of sTNF-RII, d-dimer, HbA1c (all P <.01), and sCD14 (P = .031). Additionally, viremic HCV infection was associated with elevated levels of the immune activation marker CXCL10 (P = .007), the inflammatory marker sTNF-RII (P = .002), the endothelial activation marker VCAM (P = .014), and the acute phase protein LBP (P = .005).1

However, investigators pointed out levels of other biomarkers including IL-6, sCD163, sCD14, and d-dimer were not significantly different in viremic PWID/HCV+ as compared with PWID/HCV-, despite being elevated in PWID/HCV- as compared with community controls.1

All participants in the PWID/HCV+ cohort initiated DAA therapy with sofosbuvir/velpatasvir and achieved SVR at the end of treatment. Investigators noted although DAA-mediated HCV cure appeared to reverse some elements of immune and endothelial activation induced by HCV viremia, certain biomarkers of inflammation (sTNF-RII) and LPS signaling/regulation (LBP) were not fully reversed. Despite DAA-mediated HCV elimination, sCD14 was increased by DAA therapy and remained elevated in PWID/HCV+.1

“These data add to a growing body of evidence that curative DAA therapy may not completely reverse immunological changes included by HCV infection, and biomarkers relevant to the development of chronic morbidities may remain elevated in some individuals,” investigators concluded.1 “This study also highlights the particular vulnerability of PWID with HCV to these effects given the overlapping impact of injecting drug use and related lifestyle factors on immunological changes relevant to the development of chronic inflammatory diseases.”


  1. Hearps AC, Vootukuru N, Ebrahimnezhaddarzi S, et al. 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;15:1352440. doi:10.3389/fimmu.2024.1352440
  2. World Health Organization. People who inject drugs. Global HIV, Hepatitis and STIs Programmes. Accessed March 7, 2024.
  3. World Health Organization. Hepatitis C. Newsroom. July 18, 2023. Accessed March 7, 2024.