bms-790052 and Kidney-Failure--Chronic

There is paucity of data using direct anti-viral agents (DAA) in patients on maintenance hemodialysis (MHD) infected with HCV-genotype 1 & 3. Aim of the study was to evaluate DAA therapy in patients infected with HCV-genotype 1 & 3 on MHD.. A prospective open label, parallel, non-randomized interventional trial was conducted in patients with Hepatitis-C on maintenance hemodialysis. Total of Sixty two (62) patients with hepatitis-C on maintenance hemodialysis were screened and 36 patients were enrolled and then equally allocated in 1:1 ratio to group 1 who received 400 mg daily sofosbuvir/ 60 mg daily daclatasvir and group 2 who received thrice a week 400 mg Sofosbuvir and daily 60 mg daclatasvir for 12 weeks. Patients with compensated cirrhosis received therapy for 24 weeks. Relevant data was obtained before, during and after therapy. HCV viral load was assessed at week 4, 8, at end of therapy and 12 weeks after treatment.. Eighteen (18) patients were allocated in each group. Three patients in group 1 withdrawn from the study after 2 weeks due to refusal to participate, while one withdrawn in group 2 due to development of adverse effect. Mean age of patients was 47.22 + 14.17 in group 1 and 53.89 + 14.11 in group 2. Genotype 3 was most common in group 1 patients, n = 12 (66.6%), and n = 11 (61.1%) in group 2. All patients in both groups achieved undetectable viral load at 12th week. As per intention to treat analysis overall 29/36 (80.55%) patients achieved SVR (group 1 = 15/18; group 2 = 14/18) and as per-protocol analysis overall 29/32 (90.62%) patients achieved SVR (group 1 = 15/15; group 2 = 14/17).. Direct acting antiviral therapy using sofosbuvir and declatsavir is highly effective and tolerable in patients with HCV genotype 1 & 3 undergoing maintenance hemodialysis, especially when given daily.. This trial is registered in WHO, International Clinical Trial Registry Platform, through Iranian Registry of Clinical Trials (IRCT) having IRCT ID: IRCT20170614034526N3, registered retrospectively on 2019-03-08.

Topics: Antiviral Agents; Carbamates; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Monitoring; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Kidney Failure, Chronic; Male; Middle Aged; Outcome and Process Assessment, Health Care; Prospective Studies; Pyrrolidines; Renal Dialysis; Sofosbuvir; Valine

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

Hepatitis C virus (HCV) infection is a major comorbidity in patients receiving hemodialysis. Interferon-based antiviral therapy to eradicate HCV is less effective in patients receiving hemodialysis than patients without renal dysfunction. Recently reported combination therapy with two oral direct-acting antiviral drugs, daclatasvir and asunaprevir, both of which are metabolized in the liver and excreted into the bile ducts, reportedly showed a high rate of HCV eradication. We evaluated the safety and efficacy of this therapy in patients receiving hemodialysis.. The safety and viral responses were compared among patients infected with HCV genotype 1, between 28 patients receiving hemodialysis, and propensity score-matched 56 patients without renal dysfunction.. The reduction in serum HCV RNA levels 1 day after the start of therapy was significantly larger (p = 0.0329) and the disappearance of serum HCV RNA occurred significantly earlier (p = 0.0017) in patients receiving hemodialysis than those without renal dysfunction. The rates of sustained virologic response, i.e., the eradication of HCV, were comparable between two groups; the rate of SVR12 was 100 % in patients receiving hemodialysis and 94.6 % in patients without renal dysfunction. No adverse constitutional events were observed in either of the groups. The elevation of serum alanine aminotransferase levels, a known adverse effect of these drugs, was observed in comparable rate of patients between the two groups.. The therapy with daclatasvir and asunaprevir has high antiviral efficacy in patients receiving hemodialysis with a comparable safety profile to patients without renal dysfunction.

Topics: Aged; Antiviral Agents; Carbamates; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Isoquinolines; Kidney Failure, Chronic; Male; Middle Aged; Pyrrolidines; Renal Dialysis; Sulfonamides; Treatment Outcome; Valine

Daclatasvir (DCV) is a pangenotypic inhibitor of the HCV NS5A replication complex approved in Japan and Europe for combination treatment of HCV. AI444-063 was an open-label, two-stage, adaptive study assessing DCV pharmacokinetics and safety in HCV-uninfected subjects with renal impairment.. Stage 1 included 12 subjects with end-stage renal disease (ESRD) on dialysis and 12 healthy controls (creatinine clearance [CLcr]≥90 ml/min, Cockcroft-Gault) matched by sex, age and weight. All participants received a single DCV 60-mg dose on day 1. DCV plasma levels were measured through day 4. Prespecified criteria for study expansion (ESRD versus control area under the curve extrapolated to infinite time [AUC∞] geometric mean ratio [GMR] upper 90% CI>1.5) were met; therefore, 12 subjects with moderate or severe renal impairment (estimated glomerular filtration rate, 30-59 and 15-29 ml/min/1.73m(2), respectively) were included in stage 2.. All 36 participants (30 male, mean age 54 years) completed the study. DCV AUC∞ was higher in ESRD subjects versus controls (GMR 1.264, 90% CI 0.989, 1.616). Compared with normal CLcr (90 ml/min), GMR and 90% CI for unbound DCV AUC∞ at CLcr 60, 30 and 15 ml/min were 1.18 (1.07, 1.30), 1.39 (1.14, 1.70) and 1.51 (1.18, 1.94), respectively. DCV was generally well tolerated in subjects with normal renal function, ESRD, or moderate or severe renal impairment.. Observed DCV exposure increases were within the normal range of variability and were not associated with an elevated risk of adverse events. DCV can be administered in subjects with renal impairment, including ESRD, without dose modification. ClinicalTrials.gov NCT01830205.

Topics: Antiviral Agents; Carbamates; Female; Glomerular Filtration Rate; Hepatitis C, Chronic; Humans; Imidazoles; Kidney Failure, Chronic; Male; Middle Aged; Pyrrolidines; Valine; Viral Nonstructural Proteins

Direct-acting antivirals (DAAs) play a key role in the eradication of hepatitis C virus (HCV) infection. However, limited data are available on DAA for treating HCV infection in hemodialysis (HD) patients. This study was to evaluate the pharmacokinetic characteristics and effectiveness of daclatasvir/sofosbuvir (DAC/SOF) and ledipasvir/SOF (LDV/SOF) in HD patients.. Seven patients were given SOF coadministered with DAC or LDV once daily for 12 weeks. The plasma concentrations of SOF007, DAC, and LDV were determined by high-performance liquid chromatography-electrospray ionization tandem mass spectrometry.. A sustained virologic response in week 12 (SVR12) was achieved in 6 (100%) patients, except for 1 patient dying due to severe cerebral hemorrhage not related to antiviral therapy. The extraction ratio of SOF007 was 66.67%, and the estimated HD clearance of SOF007 was 5.65 L/h.. The combination of SOF with either DAC or LDV is well tolerated and offers high SVR12 in HD patients.

Topics: Adult; Aged; Benzimidazoles; Carbamates; Clinical Trials as Topic; Drug Monitoring; Drug Therapy, Combination; Female; Fluorenes; Hepatitis C, Chronic; Humans; Imidazoles; Kidney Failure, Chronic; Male; Middle Aged; Pyrrolidines; Renal Dialysis; Sofosbuvir; Treatment Outcome; Valine

Hepatitis C virus (HCV) infection in patients undergoing haemodialysis is prevalent and aggressive. The treatment of chronic hepatitis C has been revolutionised by the advent of direct-acting antivirals (DAAs). However, the safety, efficacy, and tolerance of DAAs in the treatment of acute HCV infection in patients with end-stage renal disease who are on haemodialysis are unknown.. To evaluate the safety and efficacy of sofosbuvir plus daclatasvir in this specific, difficult-to-treat population.. We conducted a prospective and observational study of end-stage renal disease patients who were undergoing haemodialysis and were acutely infected with HCV. Patients received a half dose of sofosbuvir (200 mg) and a full dose of daclatasvir (60 mg) daily. The primary endpoint was the proportion of patients with sustained virological responses (SVRs); the other primary outcomes were safety and tolerability.. A half dose of sofosbuvir (200 mg once daily) plus a full dose of daclatasvir (60 mg once daily) were suitable for the treatment of acute HCV-infected patients who were undergoing end-stage renal disease and were on haemodialysis.

Topics: Acute Disease; Adult; Aged; Antiviral Agents; Carbamates; Drug Therapy, Combination; Female; Follow-Up Studies; Hepatitis C; Humans; Imidazoles; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Pyrrolidines; Renal Dialysis; Sofosbuvir; Sustained Virologic Response; Treatment Outcome; Valine; Young Adult

There is sparse data on the use of Sofosbuvir based directly acting antiviral (DAA) drug regimens in chronic hepatitis C (CHC) patients with chronic kidney disease (CKD) with estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m. Sixty-five CHC patients with CKD with eGFR less than 30 mL/min/1.73 m. Low-dose Sofosbuvir and full-dose Daclatasvir are safe and effective in treating CHC in patients with CKD with eGFR less than 30 mL/min/1.73 m

Topics: Adult; Antiviral Agents; Carbamates; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerular Filtration Rate; Hepatitis C, Chronic; Humans; Imidazoles; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Pyrrolidines; Severity of Illness Index; Sofosbuvir; Sustained Virologic Response; Treatment Outcome; Valine

The advent of direct-acting antiviral agents promises to change the management of hepatitis C in patients with end-stage renal disease, a patient group where the treatment of hepatitis C was historically challenging. We investigated the safety and efficacy of all-oral, interferon-free direct-acting antiviral agents for the treatment of hepatitis C in a 'real-world' group of patients with end-stage renal disease.. We performed a single-arm, multi-centre study in a cohort (n=30) of patients with advanced chronic kidney disease (mostly on dialysis) who underwent antiviral therapy with direct-acting antiviral agents. The primary end-point was sustained virologic response (serum hepatitis C virus RNA < 15 mIU/mL, 12 weeks after treatment ended). We collected data on on-treatment adverse events, serious adverse events and laboratory abnormalities.. In total, 23 (77%) and 7 (23%) patients underwent regular dialysis and had chronic kidney disease at pre-dialysis stage, respectively. Six regimens were adopted: elbasvir/grazoprevir ( n = 6), ledipasvir/sofosbuvir ± ribavirin ( n = 4), PrOD regimens ± ribavirin ( n = 10), simeprevir + daclatasvir ( n = 3), sofosbuvir + daclatasvir ± ribavirin ( n = 3), sofosbuvir + ribavirin ( n = 4). The SVR12 rate was 90% (95% confidence interval, 74%; 96%). A total of 27 (90%) patients achieved SVR12; there were three virologic failures - two were non-responders and one had a viral breakthrough while on therapy. Adverse events occurred in 53% (16/30) (95% confidence interval, 0.39; 0.73) of patients and were managed clinically without discontinuation of therapy or hospitalization. The most common adverse event was anaemia ( n = 12) that required blood transfusions in seven individuals; deterioration of kidney function occurred in one (14%).. All-oral, interferon-free therapy with direct-acting antiviral agents for chronic hepatitis C virus in advanced chronic kidney disease was effective and well tolerated in a 'real-life' clinical setting. Careful monitoring of haemoglobin and serum creatinine during therapy with direct-acting antiviral agents is suggested. Studies are under way to address whether sustained viral response translates into better survival in this population.

Topics: Aged; Antiviral Agents; Benzimidazoles; Carbamates; Cohort Studies; Drug Therapy, Combination; Female; Fluorenes; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Kidney Failure, Chronic; Male; Middle Aged; Pyrrolidines; Renal Dialysis; Retrospective Studies; Ribavirin; Simeprevir; Sofosbuvir; Sustained Virologic Response; Treatment Outcome; Uridine Monophosphate; Valine

The availability of direct acting antiviral agents (DAA) has transformed the treatment of hepatitis C virus (HCV) infection. The current study is a case series that reports the outcomes from a cohort of twenty-five HCV-infected ESRD patients who received a kidney from an anti-HCV-positive deceased organ donor followed by treatment with DAAs in the early post-transplant period. Time to transplantation and the efficacy of DAA therapy as measured by sustained viral response at 12 weeks were assessed. The median waiting time from original date of activation on the United Network Organ Sharing (UNOS) waiting list until transplantation was 427 days; however, the median time from entering the patient into UNet

Topics: Adult; Aged; Antiviral Agents; Benzimidazoles; Carbamates; Donor Selection; Drug Therapy, Combination; Female; Fluorenes; Follow-Up Studies; Hepatitis C, Chronic; Humans; Imidazoles; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Postoperative Care; Pyrrolidines; Retrospective Studies; Ribavirin; Simeprevir; Sofosbuvir; Tissue Donors; Treatment Outcome; Valine

Topics: Adult; Antiviral Agents; Carbamates; CD4 Lymphocyte Count; Coinfection; Drug Interactions; Hemophilia A; Hepatitis C, Chronic; HIV Infections; Humans; Imidazoles; Kidney Failure, Chronic; Male; Middle Aged; Pyrrolidines; RNA, Viral; Sofosbuvir; Treatment Outcome; Valine; Viral Load

Topics: Antiviral Agents; Carbamates; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Kidney Failure, Chronic; Liver Cirrhosis; Male; Middle Aged; Pyrrolidines; Renal Dialysis; Ribavirin; RNA, Viral; Sofosbuvir; Sustained Virologic Response; Valine; Viral Load