RÉSUMÉ
Danoprevir is a potent and selective direct-acting antiviral agent that targets the protease activity of hepatitis C virus (HCV) NS3/4A. This agent results in a significant rapid decline in HCV RNA levels when it is used in monotherapy. The present study evaluated whether plasma concentrations of the inflammatory markers gamma interferon-inducible protein 10 (IP-10) and neopterin or the interferon-stimulated gene product 2'-5'-oligoadenylate synthetase (OAS-1) were correlated with the plasma HCV RNA concentration before or during 14-day danoprevir monotherapy. In contrast to pegylated interferon and ribavirin treatment, a higher baseline IP-10 concentration was positively correlated with a greater first-phase HCV RNA decline upon danoprevir administration. Changes in the IP-10 plasma concentration during danoprevir administration were also associated with categorical changes in HCV RNA concentration at days 7 and 14. The neopterin concentration appeared to be moderately decreased during danoprevir administration, although these changes were not statistically significant. However, changes in neopterin concentration showed a statistically significant correlation with changes in IP-10 concentration. Considerable variation in the OAS-1 concentration was observed before and during treatment, including in patients treated with placebo and/or patients with minimal virologic response. Overall, these results suggest that effective treatment with a direct-acting antiviral agent may reduce hepatic inflammation and that first-phase HCV RNA decline during treatment with an NS3/4A protease inhibitor is more robust in patients with high baseline IP-10 concentrations.
Sujet(s)
Antiviraux/usage thérapeutique , Hépatite C chronique/sang , Hépatite C chronique/traitement médicamenteux , Inflammation/sang , Inflammation/traitement médicamenteux , Lactames/usage thérapeutique , Sulfonamides/usage thérapeutique , 2',5'-Oligoadenylate synthetase/sang , Chimiokine CXCL10/sang , Cyclopropanes , Hépatite C chronique/génétique , Hépatite C chronique/immunologie , Humains , Inflammation/immunologie , Isoindoles , Lactames macrocycliques , Foie/effets des médicaments et des substances chimiques , Foie/métabolisme , Foie/virologie , Néoptérine/sang , Proline/analogues et dérivés , ARN viral/sangRÉSUMÉ
BACKGROUND AND AIM: Hepatocellular carcinoma (HCC) is a common complication in patients with chronic viral hepatitis. Detection of HCC at an early stage is critical for a favorable clinical outcome. The study aim was to: (i) compare the levels of des-gamma-carboxyprothrombin (DCP), alpha-fetoprotein (AFP) and AFP-L3 in HCC patients and in chronic viral hepatitis patients without HCC; (ii) define the level of each tumor marker with the best sensitivity and specificity for HCC diagnosis; and (iii) to correlate the levels of these markers with respect to size and tumor burden. METHODS: Two hundred and forty patients with either hepatitis B virus (HBV) or hepatitis C virus (HCV) infection were studied. These included 144 with HCC, 47 with chronic hepatitis (fibrosis stage I-III on liver biopsy) and 49 with cirrhosis. RESULTS: Levels of DCP, AFP and AFP L-3 were significantly higher in patients with HCC than in those without HCC (P < or = 0.0001). Receiver-operating curves (ROC) indicated that the cut-off value with the best sensitivity and specificity for each test was > or =84 mAU/mL for DCP, > or =25 ng/mL for AFP and > or =10% for AFP-L3. The sensitivity, specificity and positive predictive value (PPV) for DCP was 87%, 85% and 86.8%, for AFP 69%, 87% and 69.8%, and for AFP-L3 56%, 90% and 56.1%, respectively. DCP levels were below the ROC cut-off in all patients without HCC. In patients with single lesions, there was a direct correlation of DCP to tumor size. High levels of AFP correlated with diffuse type of HCC. All three markers were significantly elevated in the presence of metastatic HCC. No advantage was observed by combining two or three markers for HCC diagnosis. CONCLUSION: DCP had the highest sensitivity and PPV for HCC diagnosis, had a direct correlation with tumor size, and was not elevated in any patients without HCC. DCP should be used as the main serum test for HCC detection.
Sujet(s)
Marqueurs biologiques tumoraux/sang , Marqueurs biologiques/sang , Carcinome hépatocellulaire/sang , Hépatite B chronique/complications , Hépatite C chronique/complications , Cirrhose du foie/sang , Tumeurs du foie/sang , Précurseurs de protéines/sang , Alphafoetoprotéines/analyse , Adulte , Carcinome hépatocellulaire/anatomopathologie , Carcinome hépatocellulaire/virologie , Femelle , Hépatite B chronique/sang , Hépatite B chronique/anatomopathologie , Hépatite C chronique/sang , Hépatite C chronique/anatomopathologie , Humains , Cirrhose du foie/anatomopathologie , Cirrhose du foie/virologie , Tumeurs du foie/anatomopathologie , Tumeurs du foie/virologie , Mâle , Adulte d'âge moyen , Valeur prédictive des tests , Prothrombine , Courbe ROC , Sensibilité et spécificitéRÉSUMÉ
BACKGROUND & AIMS: Approximately half of hepatitis C virus (HCV)-infected patients do not respond to current interferon (IFN)-alpha combination therapy. To understand IFN-alpha resistance in vivo, we examined the dynamic responses to both type I and type II IFNs, human IFN (hIFN)-alpha, -gamma, and consensus IFN, in the chimpanzee model. METHODS: Naive and HCV-infected chimpanzees were treated with 3 forms of hIFNs in vivo. Quantitative real-time polymerase chain reaction was performed to evaluate the expression of IFN-stimulated genes (ISGs) in both peripheral blood mononuclear cells and liver to compare the responses to hIFN between naive and infected chimpanzees. The hepatic expression of IFN signaling components and inhibitory regulators including suppressor of cytokine signaling 3 (SOCS3) were assessed. SOCS3 expression was also evaluated in the liver of HCV-infected patients undergoing IFN treatment. RESULTS: The in vivo responses to all 3 hIFNs were much lower in the HCV-infected chimpanzees than those in the naive chimpanzees. This defect was particularly evident in the liver because induction of hepatic ISGs was barely detectable in the infected animals. Following IFN administration, the expression of SOCS3 was significantly up-regulated, possibly through induction of interleukin-6, in the liver of HCV-infected chimpanzees. HCV-infected humans also showed a differential pattern of hepatic SOCS3 expression in response to IFN that is associated with treatment response. CONCLUSIONS: Our data indicate a predominantly defective hepatic response to IFN in HCV-infected chimpanzees, which is probably mediated through the activation of SOCS3 and may explain the nonresponse of many HCV patients to IFN-based therapy.
Sujet(s)
Antiviraux/pharmacologie , Hépatite C chronique/traitement médicamenteux , Interférons/pharmacologie , Agranulocytes/effets des médicaments et des substances chimiques , Foie/effets des médicaments et des substances chimiques , Protéines SOCS/métabolisme , Animaux , Antiviraux/usage thérapeutique , Études cas-témoins , Cellules cultivées , Relation dose-effet des médicaments , Régulation de l'expression des gènes/effets des médicaments et des substances chimiques , Hepacivirus/génétique , Hépatite C chronique/métabolisme , Hépatite C chronique/virologie , Humains , Interféron de type I/pharmacologie , Interféron alpha-2 , Interféron alpha/pharmacologie , Interféron gamma/pharmacologie , Interférons/usage thérapeutique , Interleukine-6/métabolisme , Janus kinases/métabolisme , Agranulocytes/virologie , Foie/métabolisme , Foie/virologie , Pan troglodytes , Polyéthylène glycols/pharmacologie , ARN messager/métabolisme , ARN viral/sang , Protéines recombinantes , Facteurs de transcription STAT/métabolisme , Transduction du signal/effets des médicaments et des substances chimiques , Protéine-3 suppressive de la signalisation des cytokine , Facteurs temps , Échec thérapeutique , États-UnisRÉSUMÉ
Retinoic acid receptor-related orphan receptor-alpha (RORalpha) is a nuclear orphan receptor. Adenovirus-mediated overexpression of RORalpha1 and RORalpha4 suppressed tumor necrosis factor-alpha (TNF-alpha)-induced expression of vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) in human umbilical vein endothelial cells. Overexpression of RORalpha1 and RORalpha4 also suppressed TNF-alpha-stimulated translocation of p50 and p65 to the nucleus. In contrast, dominant-negative deletion mutants of RORalpha1 and RORalpha4 failed to suppress the induction of VCAM-1 and ICAM-1 and translocations of p50 and p65. These results suggest that RORalpha1 and RORalpha4 regulate the inflammatory responses via inhibition of the nuclear factor-kappaB signaling pathway in endothelial cells.