RESUMEN
The interaction of lipoproteins with hepatitis C virus (HCV) has pathogenic and therapeutic implications. Our aim was to evaluate changes in the apolipoprotein profile of patients with chronic hepatitis C during and after successful cure with ledipasvir and sofosbuvir (LDV/SOF) with and without ribavirin (RBV). One hundred HCV genotype 1 patients who had achieved SVR-12 after treatment with 12 weeks of LDV/SOF ± RBV were selected from the ION-1 clinical trial. Frozen serum samples from baseline, end of treatment and week 4 of follow-up were used to assay apolipoproteins (apoAI, apoAII, apoB, apoCII, apoCIII, apoE) using the Multiplex platform to assess for changes in the apolipoprotein levels. At the end of treatment compared to baseline, a significant reduction in apoAII levels (-14.97 ± 63.44 µg/mL, P = 0.0067) and apoE levels (-4.38 ± 12.19 µg/mL, P < 0.001) was noted. These declines from baseline in apoAII (-16.59 ±66.15 µg/mL, P = 0.0075) and apoE (-2.66 ± 12.64 µg/mL, P = 0.015) persisted at 4 weeks of post-treatment follow-up. In multivariate analysis, treatment with LDV/SOF + RBV was independently associated with reduction in apoE (beta = 5.31 µg/mL, P = 0.002) (compared to RBV-free LDV/SOF) (P < 0.05). In contrast, apoCII levels overall increased from baseline to end of treatment (+2.74 ±11.76 µg/mL, P = 0.03) and persisted at 4 weeks of follow-up (+4.46 ± 12.81 µg/mL from baseline, P = 0.0005). Subgroup analysis revealed an increase in apoCII during treatment only in patients receiving LDV/SOF without RBV (+5.52 ± 11.92 µg/mL, P = 0.0007) but not in patients receiving LDV/SOF + RBV (P = 0.638). Treatment with LDV/SOF ± RBV is associated with a persistent reduction in the apolipoprotein AII and E after achieving cure. These data suggest that treatment with LDV/SOF ± RBV may be associated with alterations in serum apolipoproteins which could potentially impact viral eradication.
Asunto(s)
Antivirales/uso terapéutico , Apolipoproteínas/sangre , Bencimidazoles/uso terapéutico , Fluorenos/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Sofosbuvir/uso terapéutico , Quimioterapia Combinada , Femenino , Hepacivirus/efectos de los fármacos , Hepacivirus/metabolismo , Hepatitis C Crónica/virología , Humanos , Masculino , Persona de Mediana Edad , Ribavirina/uso terapéuticoRESUMEN
Interferon (IFN)-α treatment for infectious diseases and cancer is associated with significant depressive symptoms that can limit therapeutic efficacy. Multiple mechanisms have been implicated in IFN-α-induced depression including immune, neuroendocrine and neurotransmitter pathways. To further explore mechanisms of IFN-α-induced depression and establish associated genetic risk factors, single nucleotide polymorphisms in genes encoding proteins previously implicated in IFN-α-induced depression were explored in two self-reported ethnic groups, Caucasians (n=800) and African Americans (n=232), participating in a clinical trial on the impact of three pegylated IFN-α treatment regimens on sustained viral response in patients with chronic hepatitis C. Before treatment, all subjects were free of psychotropic medications and had a score ≤20 on the Center for Epidemiologic Studies Depression Scale (CES-D), which was used to assess depressive symptom severity throughout the study. In Caucasians, a polymorphism (rs9657182) in the promoter region of the gene encoding indoleamine-2,3-dioxygenase (IDO1) was found to be associated with moderate or severe IFN-α-induced depressive symptoms (CES-D>20) at 12 weeks of IFN-α treatment (P=0.0012, P<0.05 corrected). Similar results were obtained for treatment weeks 24, 36 and 48. In subjects homozygous for the risk allele (CC, n=150), the odds ratio for developing moderate or severe depressive symptoms at treatment week 12 was 2.91 (confidence interval: 1.48-5.73) compared with TT homozygotes (n=270). rs9657182 did not predict depression in African Americans, who exhibited a markedly lower frequency of the risk allele at this locus. The findings in Caucasians further support the notion that IDO has an important role in cytokine-induced behavioral changes.
Asunto(s)
Depresión/genética , Predisposición Genética a la Enfermedad/genética , Predisposición Genética a la Enfermedad/psicología , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Interferón-alfa/efectos adversos , Polietilenglicoles/efectos adversos , Adulto , Negro o Afroamericano/genética , Negro o Afroamericano/psicología , Alelos , Antivirales/efectos adversos , Depresión/complicaciones , Depresión/psicología , Femenino , Genotipo , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/psicología , Humanos , Interferón alfa-2 , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Regiones Promotoras Genéticas/genética , Escalas de Valoración Psiquiátrica , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto/psicología , Proteínas Recombinantes/efectos adversos , Población Blanca/genética , Población Blanca/psicologíaRESUMEN
Endoscopic sphincterotomy is the treatment of first choice for stones that remain in the bile duct after cholecystectomy. There is a small group of patients in whom this technique is not successful; many of these patients carry a high risk for surgery because of their age or associated medical conditions. A variety of non-surgical techniques is available; however, none is well established. We have used an in-vitro model to show that human gallstones are fragmented readily by shock-wave lithotripsy. Two elderly frail patients with difficult bile-duct stones have been treated successfully by extracorporeal shock-wave lithotripsy. The bile ducts were cleared of stones and the patients suffered no adverse effects. Extracorporeal shock-wave lithotripsy is a new and promising alternative to the current non-surgical techniques for the management of bile-duct stones.