bms-790052 and Inflammation

The achievement of virological response in the treatment of hepatitis C virus (HCV) can improve the extrahepatic manifestations. The present study aimed to investigate the effect of HCV eradication after sofosbuvir/daclatasvir (SOF/DCV) therapy on hematological and inflammatory biomarkers in type 2 diabetic patients infected with HCV genotype 4. Between October 2017 and August 2018, among 145 patients with HCV genotype 4, 30 patients were enrolled in the study based on the fact that they have type 2 diabetes. Enrolled HCV-diabetic patients were treated for 12 weeks with SOF/DCV regimen. Patients were screened by laboratory investigations before treatment (baseline values) and after HCV treatment (post-treatment values). Additionally, 30 healthy individuals were enrolled as a control group. Among the patient's cohort, the sustained virological response was achieved by 100% of the treated patients after 12 weeks of SOF/DCV therapy. Moreover, the levels of insulin resistance (HOMA-IR), nitric oxide, interleukin-1β, red cell distribution width, platelet distribution width, mean platelet volume were improved significantly (P < 0.001) in treated patients after successful viral clearance compared to baseline values. In addition, virological clearance exhibited positive correlations with interleukin-1β, nitric oxide, leukocytes count, red cell distribution width, and mean platelet volume. In conclusion, the data suggest the potential amelioration effect of HCV eradication after treatment with SOF/DCV regimen on the inflammatory status among HCV-diabetic patients which is reflected by the noticeable improvement of altered hematological indices and inflammatory biomarkers.

Topics: Adult; Antiviral Agents; Biomarkers; Carbamates; Diabetes Mellitus, Type 2; Female; Genotype; Glycated Hemoglobin; Hepacivirus; Hepatitis C; Humans; Imidazoles; Inflammation; Insulin Resistance; Interleukin-1beta; Male; Middle Aged; Pyrrolidines; Sofosbuvir; Sustained Virologic Response; Treatment Outcome; Valine

First, in patients receiving two different combinations of DAAs, we found that DAAs induced not only rapid viral clearance, but also a re-setting of antiviral immune responses in the peripheral blood. Specifically, we see a rapid decline in the expression of genes associated with chronic IFN stimulation (IFIT3, USP18, IFIT1) as well as a rapid decline in genes associated with inflammation (IL1β, CXCL10, CXCL11) in the peripheral blood that precedes the complete removal of virus from the blood. Interestingly, this rapid reversal of innate immune activation was not seen in patients who successfully clear chronic HCV infection using IFN-based therapy. Next, using a novel humanized mouse model (Fah-/-RAG2-/-IL2rgnull-FRG), we assessed the changes that occur in the hepatic tissue following DAA treatment. DAA-mediated rapid HCV clearance resulted in blunting of the expression of proinflammatory responses while functionally restoring the RIG-I/MAVS axis in the liver of humanized mice.. Collectively, our data demonstrate that the rapid viral clearance following treatment with DAAs results in the rebalancing of innate antiviral response in both the peripheral blood and the liver as well as enhanced antiviral signaling within previously infected hepatocytes.

Topics: Aged; Animals; Antiviral Agents; Benzazepines; Carbamates; Disease Models, Animal; Female; Gene Expression Regulation; Hepacivirus; Hepatitis C, Chronic; Hepatocytes; Humans; Imidazoles; Immunity, Innate; Indoles; Inflammation; Isoquinolines; Liver; Male; Mice; Middle Aged; Pyrrolidines; Sulfonamides; Valine