Neutrocyte-to-lymphocyte ratio predicts the presence of a replicative hepatitis C virus strand after therapy with direct-acting antivirals

Abstract

Residual HCV-RNA can persist in liver tissue and peripheral blood mononuclear cells (PBMCs) long after antiviral therapy of chronic hepatitis C in patients repeatedly negative for viral RNA in serum. This occult infection associates with impaired immune response and the risk of lymphoproliferative disorders or progressive liver disease. There are currently no monitoring strategies for patients after treatment. We investigated if serum inflammation markers and interferon lambda ( IFNL ) genotype can be predictors of the presence of HCV-RNA and the replicative HCV-RNA (−) strand in patients who reached sustained virological response after interferon-free therapy. Forty-two consecutive patients who remained HCV-RNA negative in serum 24 weeks after the end of treatment (EOT) and during the follow-up were enrolled. Total HCV-RNA and HCV-RNA (−) strand were detected using ultrasensitive RT-PCR in PBMCs collected 12–15 months after EOT. Polymorphisms within IFNL3 – IFNL4 region (rs12979860 and ss469415590) were genotyped with allele-specific PCR. Viral RNA was found in PBMCs from 31 (74%) patients, and of those 29 (69%) were also positive for HCV-RNA (−). Neither normalization of alanine aminotransferase nor IFNL genotype predicted the presence of residual HCV-RNA. A significantly higher neutrocyte-to-lymphocyte ratio (NLR) 24 weeks after the start of treatment predicted elimination of replicative HCV-RNA strand (OR 0.23; 95% CI 0.10–0.86; P = 0.019). Patients with no HCV-RNA (−) in PBMCs showed a greater increase in neutrocyte count between EOT and baseline ( P = 0.028). Lack of significant elevation of NLR after therapy with direct-acting antivirals could predict the presence of residual replicative HCV-RNA strand in PBMCs. Electronic supplementary material The online version of this article (10.1007/s10238-019-00561-y) contains supplementary material, which is available to authorized users.

Neutrophils in liver diseases: pathogenesis and therapeutic targets

“…17 In patients with HBV infection, C-X-C motif chemokine ligand 8 (CXCL8) produced by T cells is the major attractant for neutrophil influx into the liver, which increases the expression of triggering receptor expressed on myeloid cells 1 (TREM1) and aggravates the neutrophil-mediated immunopathology of the liver. 18 Meanwhile, the higher neutrophil-to-lymphocyte ratio (NLR) at the 24th week after the onset of interferon treatment predicted the elimination of the replicative HCV-RNA strand in the liver during the antiviral treatment of patients with chronic hepatitis C. 19 In a viral hepatitis model induced by lymphocytic choriomeningitis virus infection, deletion of neutrophils increased the viral load, aggravated the T-cell response, and increased liver injury, while IL-33 treatment contributed to reducing liver inflammation by promoting the aggregation and immunosuppressive phenotype transformation of neutrophils within the liver. 20 In acute murine viral hepatitis, increased infiltration of neutrophils into liver tissue is also exacerbated by endogenous IL-33 deficiency.…”

“… 17 In patients with HBV infection, C-X-C motif chemokine ligand 8 (CXCL8) produced by T cells is the major attractant for neutrophil influx into the liver, which increases the expression of triggering receptor expressed on myeloid cells 1 (TREM1) and aggravates the neutrophil-mediated immunopathology of the liver. 18 Meanwhile, the higher neutrophil-to-lymphocyte ratio (NLR) at the 24th week after the onset of interferon treatment predicted the elimination of the replicative HCV-RNA strand in the liver during the antiviral treatment of patients with chronic hepatitis C. 19 …”

Occult Infection with Hepatitis C Virus: Looking for Clear-Cut Boundaries and Methodological Consensus

“…Likewise, a complete viral clearance or occult HCV persistence after DAA seems to be determined by the patient's immune responsiveness at baseline and by the individual ability to induce a general inflammatory response after viral suppression by DAAs [51,52]. In our study, a significant and transient elevation of neutrocyte-to-lymphocyte ratio, a marker of systemic inflammation, which occurred during and shortly after DAA therapy, predicted elimination of the replicating residual HCV in PBMC at the follow up after SVR [53]. Additionally, patients without HCV-RNA (−) strand showed a greater increase in neutrocyte counts during therapy [53].…”

An increased pretreatment neutrophil-to-lymphocyte ratio predicts severe novel coronavirus-infected pneumonia

“…Lymphocytes, the main effector cells of the human immune response, are closely related to the immunity and defense of the body; accordingly, there is a negative correlation between the number of lymphocytes and the degree of in ammation (21,22). The NLR, the ratio of neutrophils to lymphocytes, is considered an important marker of the systemic in ammatory response, and more accurately re ects the balanced relationship between the severity of in ammatory reactions and the immune state (23,24). It is believed that the in ammatory cytokine storm may be related to the progression of the disease (25)(26)(27)(28).…”