bms-790052 and Viremia

Only a few prospective trials exist regarding the use of novel direct-acting antiviral agents (DAAs) in kidney transplant recipients (KTR) with chronic hepatitis C virus (HCV) infection.. This prospective single-center trial evaluated treatment with daclatasvir (DCV) and sofosbuvir (SOF) over 12 weeks in 16 adult chronic HCV infected KTR and eGFR > 30 ml/min/1.73m. Four of 16 study patients had previously failed interferon-based HCV treatment. Liver biopsy showed mostly moderate fibrosis score before therapy with DCV/SOF was initiated at a median of 10.3 years after transplantation. In total, 15 of 16 KTR achieved SVR12. One patient showed early viral relapse because of resistance-associated variants (RAVs) in the HCV NS5A region. Rescue treatment with SOF/velpatasvir/voxilaprevir resulted in SVR12. DAAs treatment led to significant improvement of liver metabolism and glucose tolerance accompanied with no therapy-associated major adverse events and excellent tolerability.. Our study demonstrates safety, efficacy and functional benefit of DCV/SOF treatment in KTR with chronic HCV infection. We provide data on rescue strategies for treatment failures due to present RAVs and amelioration of hepatic function and glucose tolerance.. Registry name: European Clinical Trials Register; Trial registry number (Eudra-CT): 2014-004551-32 , Registration date: Aug 28th 2015.

Topics: Adult; Aged; Aminoisobutyric Acids; Antiviral Agents; Biopsy, Needle; Calcineurin Inhibitors; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Glucose Intolerance; Hepacivirus; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Humans; Imidazoles; Kidney Failure, Chronic; Kidney Transplantation; Lactams, Macrocyclic; Leucine; Liver; Macrocyclic Compounds; Male; Middle Aged; Proline; Prospective Studies; Pyrrolidines; Quinoxalines; RNA, Viral; Salvage Therapy; Sofosbuvir; Sulfonamides; Treatment Outcome; Valine; Viral Load; Viral Nonstructural Proteins; Viremia

Topics: Carbamates; Drug Therapy, Combination; Hepatitis C, Chronic; Humans; Imidazoles; Liver Cirrhosis; Pyrrolidines; Sofosbuvir; Valine; Viremia

Combined daclatasvir (DCV)/asunaprevir (ASV) plus beclabuvir (BCV) treatment shows a high virological response for genotype 1b chronic hepatitis C patients. However, its efficacy for patients for whom previous direct-acting antiviral (DAA) therapy failed is not known. We analysed the efficacy of DCV/ASV/BCV treatment for HCV-infected mice and chronic hepatitis patients. Human hepatocyte chimaeric mice were injected with serum samples obtained from either a DAA-naïve patient or a DCV/ASV treatment failure and were then treated with DCV/ASV alone or in combination with BCV for 4 weeks. DCV/ASV treatment successfully eliminated the virus in DAA-naïve-patient HCV-infected mice. DCV/ASV treatment failure HCV-infected mice developed viral breakthrough during DCV/ASV treatment, with the emergence of NS5A-L31V/Y93H HCV resistance-associated variants (RAVs) being observed by direct sequencing. DCV/ASV/BCV treatment inhibited viral breakthrough in NS5A-L31V/Y93H-mutated HCV-infected mice, but HCV relapsed with the emergence of NS5B-P495S variants after the cessation of the treatment. The efficacy of the triple therapy was also analysed in HCV-infected patients; one DAA-naïve patient and four prior DAA treatment failures were treated with 12 weeks of DCV/ASV/BCV therapy. Sustained virological response was achieved in a DAA-naïve patient and one of the DCV/ASV treatment failures through DCV/ASV/BCV therapy; however, HCV relapse occurred in the other patients with prior DCV/ASV and/or sofosbuvir/ledipasvir treatment failures. DCV/ASV/BCV therapy seems to have limited efficacy for patients with NS5A RAVs for whom prior DAA treatment has failed.

Topics: Animals; Antiviral Agents; Benzazepines; Biomarkers; Carbamates; Drug Combinations; Drug Resistance, Viral; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; Humans; Imidazoles; Indoles; Isoquinolines; Mice; Protease Inhibitors; Pyrrolidines; Sulfonamides; Treatment Failure; Valine; Viral Nonstructural Proteins; Viremia

Recurrent hepatitis C infection after liver transplantation (LT) is associated with lower rates of graft and patient survival.. Here we describe the first use of daclatasvir, simeprevir, and ribavirin (RBV) as an all-oral triple regimen administered to 6 liver transplant recipients with recurrent hepatitis C, one with GT 1a and 5 with GT 1b. All patients were treated for 24 weeks. Trough levels of immunosuppression, laboratory measures, and potential adverse effects were closely monitored.. For all patients, viral load became undetectable between treatment weeks 4 and 12. One patient experienced a viral breakthrough at the 10th week of treatment; this was associated with the selection of resistance-associated variants (D168Y in NS3 and ΔP32 in NS5A). For the other 5 patients, end-of-treatment response and for 4 patients SVR24 was achieved. Viremia recurred in one patient 4 weeks after the end of treatment, which was again associated with the selection of resistance-associated variants (D168V in NS3 and ΔP32 in NS5A). Clinical measures of liver function improved substantially for all patients. Adverse events were few and limited to moderate anemia caused by RBV. Importantly, adjustments to the immunosuppressant dosage were not required.. The described regimen appears to be safe and effective for liver transplant patients and will be a promising treatment regimen for post-LT patients.

Topics: Antiviral Agents; Carbamates; Drug Resistance, Viral; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Immunosuppression Therapy; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Pyrrolidines; Recurrence; Ribavirin; Simeprevir; Valine; Viral Load; Viremia