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

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.

Figure 1

Plasma biomarkers levels in community controls and PWID. Plasma biomarkers of inflammation and chronic disease risk were measured in HCV- community controls and PWID of a comparable age and sex. Annotations in blue text indicate association of each biomarker with relevant biological process. *, ** and *** indicate p value <0.05, 0.01 and 0.001 respectively as determined by multivariable linear regression analysis adjusted for age, sex and recent injecting drug use as described in Table 3 .

Figure 2

Impact of HCV infection and DAA therapy on biomarker levels in PWID. Model estimates of inflammatory biomarkers by HCV infection (pre-treatment timepoint), at end of DAA treatment and 48 weeks post-DAA therapy in HCV+ PWID with reference to HCV-uninfected PWID. Analysis was adjusted for sex, age and daily injecting drug use. Solid lines indicate parameters which were significantly different to HCV-uninfected PWID.

Figure 3

Plasma biomarker levels in PWID and HCV+ PWID pre and post DAA therapy. Inflammatory biomarkers were measured in PWID and PWID with chronic HCV infection prior to treatment (baseline; BL), and 12 weeks (12wk) or 48 weeks (48wk) after curative DAA therapy. Untransformed data are shown. CRP was not assessed at the 12 week timepoint whilst HbA1c was only assessed in HCV+ PWID 48 weeks after DAA therapy. Annotations in blue text indicate the association of each biomarker with relevant biological process. *, ** and *** indicate p value <0.05, 0.01 and 0.001, respectively as determined by multivariable linear regression (green asterisks, comparing to PWID to HCV+ PWID) or generalised estimating equation (red asterisks, comparing post-DAA to baseline in HCV+ PWID) analysis as described in Table 4 and Supplementary Table 2 , respectively. Note: similar statistical significance was obtained after removing two outlier datapoints from the CXCL10 analysis (data not shown).