RESUMEN
Real-world studies are relevant to complement clinical trials on novel antiviral therapies against chronic hepatitis C; however, clinical practice data are currently limited. This study investigated effectiveness and safety of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r)±dasabuvir (DSV)±ribavirin (RBV) for treatment of HCV genotype (GT) 1 and GT4 infection in a large real-world cohort. The German Hepatitis C Registry is an observational cohort study prospectively collecting clinical practice data on direct-acting antiviral therapies. Patients with GT1/4 infection treated with OBV/PTV/r±DSV±RBV were analysed. Effectiveness was assessed by sustained virologic response in 558 patients who reached post-treatment week 12 (SVR12). Safety is reported in 1017 patients who initiated treatment. Of the patients, 892 (88%) had GT1 and 125 (12%) had GT4 infection. Prior treatment experience and cirrhosis were reported in 598 (59%) and 228 (22%) patients, respectively. Overall, SVR12 (mITT) was 96% (486/505) in GT1- and 100% (53/53) in GT4 patients. SVR12 rates were high across subgroups including patients with cirrhosis (95%, 123/129), patients with moderate to severe renal impairment (100%, 34/34), and subgroups excluded from registrational trials like patients ≥70 years (96%, 64/67) and failures to prior protease inhibitor treatment (96%, 46/48). Adverse events (AEs) and serious AEs were reported in 52% (525/1017) and 2% (21/1017) of patients, respectively, and led to treatment discontinuation in 1.5% (15/1017) of patients. OBV/PTV/r±DSV±RBV was effective and generally well tolerated for treatment of HCV infection in clinical practice.
Asunto(s)
Anilidas/administración & dosificación , Carbamatos/administración & dosificación , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/virología , Compuestos Macrocíclicos/administración & dosificación , Ritonavir/administración & dosificación , Sulfonamidas/administración & dosificación , Uracilo/análogos & derivados , 2-Naftilamina , Adulto , Anciano , Anilidas/efectos adversos , Carbamatos/efectos adversos , Estudios de Cohortes , Ciclopropanos , Quimioterapia Combinada , Femenino , Genotipo , Alemania , Hepacivirus/genética , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/diagnóstico , Humanos , Lactamas Macrocíclicas , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/etiología , Compuestos Macrocíclicos/efectos adversos , Masculino , Persona de Mediana Edad , Prolina/análogos & derivados , Ritonavir/efectos adversos , Índice de Severidad de la Enfermedad , Sulfonamidas/efectos adversos , Resultado del Tratamiento , Uracilo/administración & dosificación , Uracilo/efectos adversos , Valina , Carga ViralRESUMEN
The mode of action of ribavirin is not completely understood. Ribavirin monotherapy has a measurable antiviral effect, which shows great variability. It might lead to an earlier steady state of plasma concentration and therefore enhance the effect of following combination treatment. The aim of this study was to evaluate the antiviral effect of ribavirin priming and its influence on sustained virologic response after combination treatment in a group of patients with different hepatitis C virus (HCV) types with or without prior treatment experience. Retrospective analysis of 75 patients (37 treatment naïve, 20 prior relapse, 16 prior nonresponse, genotype 1 present in 60 patients) from five centres who received ribavirin priming as part of an individual strategy in order to improve treatment outcome. All patients received ribavirin monotherapy with a mean dose of 14.5 mg kg-1 body weight for a mean of 28 days. After ribavirin priming, dual combination treatment with pegylated interferon alfa and ribavirin was started. The mean HCV RNA decline after ribavirin priming was 0.6 log10 IU mL-1 (P<.001). The initial viral decline depended on HCV type and previous treatment status being highest among prior relapsers (0.8 log10 IU mL-1 ; P=.002) and HCV type 2/3 (1.2 log10 IU mL-1 ; P=.05) and lowest among those with prior nonresponse (0.3 log10 IU mL-1 , P=.01). IFNL4 (formerly IL28B) genotype for rs12979860 and IFNL3 genotype rs8099917 did not influence the initial viral decline. The study demonstrates a significant variability in the viral dynamics and antiviral efficacy of ribavirin monotherapy, which is mainly influenced by prior treatment status. The fact that the lowest response pattern was observed in prior nonresponder patients to pegylated interferon alfa plus ribavirin combination therapy can be taken as a hint that not only the individual interferon, but also the ribavirin sensitivity contributes significantly to the nonresponsive state.
Asunto(s)
Antivirales/administración & dosificación , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/virología , Ribavirina/administración & dosificación , Carga Viral , Adulto , Anciano , Quimioterapia Combinada/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Respuesta Virológica Sostenida , Resultado del TratamientoRESUMEN
Incomplete suppression of hepatitis C virus (HCV) replication with persistence of minimal viremia (partial virologic response) leading to treatment failure can be observed in a significant proportion of HCV type 1-infected patients during antiviral therapy. Recently, high-dose intravenous silibinin has demonstrated strong antiviral activity against HCV. We were therefore interested in whether patients with partial virologic response can be rescued by the on-treatment addition of a short-term course of high-dose intravenous silibinin infusions. Twenty patients who failed to achieve a complete virologic response to different interferon-based regimens qualified for the rescue strategy and received 1400 mg/day silibinin infusions on two consecutive days. Complete viral suppression (below the limit of detection <6 IU/mL, TMA assay) could be induced in 13 of 20 patients within the first week after the short-term silibinin infusion, and all but one of them also remained HCV RNA negative during the subsequent follow-up period on continued peginterferon plus ribavirin treatment. In the remaining seven patients, no complete suppression could be achieved although four showed a significant HCV RNA reduction in response to silibinin. Silibinin infusions were generally well tolerated, and activation of abdominal peristalsis with nausea, diarrhoea and vomiting were the most prominent side effects. Of the twelve patients who exhibited a durable response to peginterferon and ribavirin treatment, three achieved an SVR, two achieved a week 12 SVR and four suffered a viral relapse. Three patients could not complete the assigned antiviral treatment with peginterferon alpha and ribavirin for nonvirological reasons. Short-term administration of high-dose intravenous silibinin might be an interesting approach to rescue patients with ongoing minimal residual viremia while on interferon-based therapy. These preliminary findings may stimulate further studies to evaluate more refined therapeutic strategies.
Asunto(s)
Antioxidantes/administración & dosificación , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/tratamiento farmacológico , Silimarina/administración & dosificación , Adulto , Anciano , Antioxidantes/efectos adversos , Antivirales/administración & dosificación , Quimioterapia Combinada/métodos , Femenino , Humanos , Infusiones Intravenosas , Interferón-alfa/administración & dosificación , Masculino , Persona de Mediana Edad , Ribavirina/administración & dosificación , Silibina , Silimarina/efectos adversos , Resultado del Tratamiento , Viremia/tratamiento farmacológicoRESUMEN
Hepatitis B virus-infected patients frequently have viral particles with DNA derived from differently spliced RNA. Which factors influence the synthesis of these splice variants is unclear. We analysed the type of splice variants produced from different genotypes and determined whether they are secreted as efficiently as wild-type virus. We demonstrate production of a single splice variant from genotypes D, C, and E as dominant species in two hepatoma cell lines. The type of minor splice variants synthesised varied between genotypes but was identical in both hepatoma cell lines. A novel splice variant with a deletion in the core gene was identified for genotype D. Viral DNA from intracellular compared with extracellular viral particles was spliced approximately five times more often than wild-type-sized genomes. A variable amount of the major splice variant was also identified in sera from patients infected with genotypes A, D, and C. These data indicate genotype A-, C-, D-, and E- as well as hepatoma cell line-independent synthesis of a dominant single splice variant and argue for a biological function of the corresponding splice sites. This study clearly demonstrates the intracellular accumulation of viral particles containing spliced genomes and offers a tool for the investigation of underlying mechanisms.