Strategies for serum chemokine/cytokine assessment as biomarkers of therapeutic response in HCV patients as a prototype to monitor immunotherapy of infectious diseases

Abstract

In this study, strategies for serum biomarker assessment were developed for therapeutic monitoring of HCV patients. For this purpose, serum chemokine/cytokine levels were measured by cytometric-bead-array in HCV patients, categorized according to immunotherapy response as: non-responder/NR, relapser/REL and sustained-virologic-responder/SVR. The results demonstrated an overall increase of serum chemokine/cytokine levels in HCV patients. In general, therapeutic failure was associated with presence of a predominant baseline proinflammatory pattern with enhanced CCL5/RANTES, IFN-α, IFN-γ along with decreased IL-10 levels in NR and increased IL-6 and TNF in REL. SVR displayed lower baseline proinflammatory status with decreased CXCL8/IL-8, IL-12 and IL-17 levels. The inability to uphold IFN-α levels during immunotherapy was characteristic of NR. Serum chemokine/cytokine signatures further support the deleterious effect of proinflammatory baseline status and the critical role of increased/persistent IFN-α levels to guarantee the sustained virologic response. The prominent baseline proinflammatory milieu observed in NR and REL yielded a restricted biomarker network with small number of neighborhood connections, whereas SVR displayed a network with integrated cytokine connectivity. Noteworthy was that SVR presented a shift towards a proinflammatory pattern upon immunotherapy, assuming a pattern similar to that observed in NR and REL at baseline. Moreover, the immunotherapy guided REL towards a profile similar to SVR at baseline. Analysis of baseline-fold changes during treatment pointed out IFN-α and TNF as high-performance biomarkers to monitor immunotherapy outcome. This knowledge may contribute for novel insights into the treatment and control of the continuous public health threat posed by HCV infection worldwide.

Restoring Inflammatory Mediator Balance after Sofosbuvir-Induced Viral Clearance in Patients with Chronic Hepatitis C

“…In this study, IL-6 levels were not significantly altered after antiviral therapy. Confirming our results, IL-6 serum levels were not altered after DAA treatment in another Brazilian cohort with chronic hepatitis C patients [ 20 ]. Interestingly, another Brazilian study suggests that IL-6 and TNF polymorphisms might lead to a distinct range of proinflammatory cytokines [ 23 ].…”

“…On the other hand, the occurrence of downregulation of inflammatory and fibrotic biomarkers in association with HCV eradication after antiviral therapy is still unclear. Some authors demonstrated an increase in inflammatory mediators' serum levels after the end of IFN-based treatment [ 16 – 20 ]. Other studies reported decreased inflammatory biomarkers in plasma of chronic hepatitis C patients after IFN-free regimens including the newer DAA, although normalization was not reached [ 21 , 22 ].…”

Influence of hepatitis C virus eradication with direct‐acting antivirals on the gut microbiota in patients with cirrhosis

“…Our study also confirms that the production of inflammatory cytokines and chemokines is enhanced in patients with chronic HCV infection and is downregulated by viral eradication . Indeed, antiviral therapy significantly improved IL1‐ra, IL2, IL5, FGF‐basic, GM‐CSF, IFN‐gamma, CCL2, CCL3, CCL4, CCL11, CXCL10, PDGF‐BB, and TNF‐alpha plasma levels.…”

“…Indeed, this result may be affected by the relatively short follow-up period, as the evaluation of these parameters was performed 1 year after the end of the DAA treatment, and also by the fact that only patients with well-compen- Our study also confirms that the production of inflammatory cytokines and chemokines is enhanced in patients with chronic HCV infection and is downregulated by viral eradication. [28][29][30][31][32][33][34][35][36][37] Indeed, antiviral therapy significantly improved IL1-ra, IL2, IL5, FGF-basic, , faecal calprotectin) before and 1 y after the end of direct-acting antiviral (DAA) treatment. IL: interleukin; ra:receptor agonist; FGF: fibroblast growth factor; G-CSF: granulocyte colony-stimulating factor; GM-CSF: granulocytemacrophage colony-stimulating factor; IFN: interferon; CCL: C-C motif chemokine ligand; CXCL: C-X-C motif chemokine ligand; PDGF: plateletderived growth factor; TNF: tumour necrosis factor GM-CSF, IFN-gamma, CCL2, CCL3, CCL4, CCL11, CXCL10, PDGF-BB, and TNF-alpha plasma levels.…”

Interleukin-17A and B-cell activating factor in chronic hepatitis C patients with or without asymptomatic mixed cryoglobulinemia: effects of antiviral treatment and correlations with vitamin D

“…The study of Fathy et al described a normalizing immune response during treatment concerning IL-17A, in both responders and non-responders, but in a very small number of patients and over a short period of time [ 31 ], while Sousa et al described a non-significant downregulation in their non-responder group. Menezes et al reported that patients with SVR displayed lower IL-17 levels compared with non-responders [ 32 ].…”