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The present study describes the development and validation of a new stability indicating RP-HPLC method for simultaneous estimation of elbasvir and grazoprevir in bulk and pharmaceutical dosage form. The chromatographic separation was done by using reverse phase YMC column (4.6 x 250mm, 5µm).The mobile phase used was mixture of HPLC grade water acetonitrile (70:30V/V) at flow rate of 1ml/min in isocratic mode and detection was carried out using PDA detector at 244nm. The developed method showed a good linearity in the range of 100-500µg/mL for elbasvir and 200-1000 µg/mL for grazoprevir with regression co-efficient of 0.999 for both the drugs. The % recovery of drugs was found to be 100.1% for elbasvir and 100.38% for grazoprevir. The proposed stability indicating method was accurate, precise, robust, stable and specific. The developed method was validated in accordance with ICH guidelines. [ABSTRACT FROM AUTHOR]

Background and aim. Grazoprevir is an NS3/4A protease inhibitor (PI), while elbasvir is an NS5A inhibitor. We performed this meta-analysis to directly compare grazoprevir plus elbasvir and ribavirin regimen vs. grazoprevir and elbasvir without ribavirin in the treatment of hepatitis C virus genotype 1 infection and to precisely evaluate the efficacy of the latter regimen in cirrhotic, IL28 CC genotype patients and those coinfected with human immunodeficiency virus.Material and methods. A computer literature search of PubMed, Scopus, EBSCO, Embase, and Cochrane central was conducted. Studies were screened for eligibility. Sustained virologic response (SVR) rates were pooled using OpenMeta [Analyst] software for windows. A subgroup analysis was performed to stratify the treatment efficacy according to the different baseline characteristics of HCV patients.Results. Eight randomized controlled trials (n = 1,297 patients) were pooled in the final analysis. The overall SVR rate was 96.6% with 95% CI [95.5% to 98%]. For cirrhotic patients, the SVR rate was 95.7% with 95% CI [93.9% to 97.5%] and for non-cirrhotic patients, the SVR rate was 97% with 95% CI [95.9% to 98.4%]. Furthermore, the addition of ribavirin (RBV) to the treatment regimen did not significantly improve the SVR (RR 1.003, 95% CI [0.944 to 1.065]).The dual regimen was effective in patient populations with NS3 resistance-associated substitution (RAS). However, this regimen achieved lower SVR rates (< 90%) in patients with NS5A RAS.Conclusions. We conclude that the 12-week treatment regimen of the fixed dose combination of grazoprevir plus elbasvir achieved high SVR rates in patients with HCV genotype 1 infection. The addition of ribavirin to this regimen did not add a significant benefit.

Aim: The present study aimed to determine the real‐world efficacy and safety of the non‐structural protein (NS)5A inhibitor elbasvir (EBR) combined with the NS3/4A protease inhibitor grazoprevir (GZR) in patients with hepatitis C virus (HCV) genotype 1 (GT1) infection. Methods: This study retrospectively evaluated the rate of sustained virologic response at 12 weeks post‐treatment (SVR12) and the safety of EBR/GZR treatment in 159 men and 194 women with a median age of 72 years, and it assessed factors associated with the SVR12 rate. The attending physicians were responsible for selecting candidate patients for EBR/GZR in this retrospective study. Results: Treatment outcomes for EBR/GZR were good in direct‐acting antiviral (DAA)‐naïve patients, of whom 99.4% achieved SVR. Of 353 patients, 10 (2.9%) had treatment failure. Of these patients, eight previously underwent DAA therapy, and the remaining two had NS5A‐L31/Y93 double mutation. The SVR rate was 50% (8/16 patients) in patients who previously underwent DAA therapy, and 18.2% (2/11 patients) in patients with NS5A‐L31/Y93 double mutation. On multivariate logistic regression analysis, NS5A‐Y31/Y93 double mutation (odds ratio 356.3; 95% confidence interval, 23.91–16 940; P < 0.0001) was identified as an independent predictor of treatment failure. No serious adverse events were observed with EBR/GZR therapy. Conclusions: The SVR rate of EBR/GZR would have been 100% in patients without either a history of DAA therapy or double mutation. This combination of drugs could be safely given and is, thus, considered a highly useful first‐line treatment for DAA‐naïve patients with HCV. [ABSTRACT FROM AUTHOR]

Background: A 12-week grazoprevir/elbasvir regimen is highly effective against hepatitis C virus genotype 1 (HCV-1) infection. The efficacy of an 8-week regimen for treatment-naive HCV-1-infected patients with mild fibrosis has not been determined.Methods: Treatment-naive HCV-1b-infected patients with mild fibrosis were randomly assigned to receive 8 (n = 41) or 12 (n = 41) weeks of grazoprevir/elbasvir therapy. The primary end point was a sustained virologic response, defined as an HCV RNA level of < 12 IU/mL, at posttreatment week 12 (SVR12).Results: SVR12 was achieved by 87.8% of patients (36 of 41) in the 8-week arm and 100% (41 of 41) in the 8-week arm of the full-analysis population and by 90.0% (36 of 40) and 100% (41 of 41), respectively, in the per-protocol population (all P = .055). In the 8-week arm, a significantly lower SVR12 rate was observed among patients with a high HCV-1b load, defined as ≥1 500 000 IU/mL (79% vs 100%; P = .042), and among those with a baseline Y93H resistance-associated substitution (RAS) frequency of >15% in HCV nonstructural protein 5A (NS5A; 40.0% vs 97.1%; P = .004). Between-group analysis demonstrated that, among patient with a high HCV-1b load and a baseline Y93H RAS frequency of >15%, those in the 8-week arm had a substantially lower SVR12 rate than those in the 12-week arm (40.0% vs 100.0%). All 4 HCV-1b relapses had a Y93H RAS frequency of >99% at posttreatment week 12.Conclusions: Twelve weeks of grazoprevir/elbasvir therapy is highly effective for treatment-naive patients with mild fibrosis. A truncated, 8-week grazoprevir/elbasvir regimen might be applied for those with low viral loads or without a significant NS5A RAS frequency.Clinical Trials Registration: NCT03186365. [ABSTRACT FROM AUTHOR]

• Direct-acting antiviral agents (DAAs) has dramatically improved HCV treatment. • All combinations since 2014 achieved a cure rates over 95% with a good safety profile. • Pangenotypic regimens in 2017 allow treating patients regardless genotype and fibrosis. • New pangenotypic rescue regimen are available for DAAs-failure patients. The advent of oral direct-acting antiviral agents (DAAs) has dramatically improved the hepatitis C treatment landscape in the last 4 years, providing cure rates over 95% with shorter duration of treatment and a very good safety profile. This gave access to treatment to almost all Hepatitis C virus (HCV)-infected patients. The launch of two pangenotypic fixed-dose combinations (FDCs) in 2017 was a step forward in hepatitis C treatment, by slightly increasing efficacy and more importantly allowing the treatment of patients without HCV genotyping, and in some cases without fibrosis assessment. New triple regimens have solved the issue of retreatment of the few patients who present failure to DAAs therapy. In the present review we describe the current HCV landscape that allows almost all HCV-infected patients to be cured. [ABSTRACT FROM AUTHOR]

Abstract Direct-acting antivirals (DAA) have markedly improved the treatment of hepatitis C, with a series of DAA combinations available for treatment. A sensitive method by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed for the simultaneous quantification of seven commonly used DAAs, daclatasvir (DAC), elbasvir (ELB), grazoprevir (GZR), ledipasvir (LDV), simeprevir (SIM), sofosbuvir (SOF), velpatasvir (VEL) and the primary analyte of interest of SOF (GS-331007) in EDTA plasma. Adequate chromatographic separation with well-defined peaks for all eight analytes was achieved with an Acquity UPLC BEH C18 column (1.7 μm 2.1 × 50 mm). Runtime for the final assay was 12 min. Protein precipitation in the sample preparation and stable isotope- labelled internal standards resulted in a robust sensitive and rapid method. Method validation was performed in accordance with the "guideline on bioanalytical method validation" of the European Medicines Agency (EMA). No interferences from endogenous substances were observed and carry-over in the blank sample was <20% of the LLOQ of each analyte and <5% of the IS after injection of the HLOQ sample. Validation was established over the range of 10–5000 μg/L for DAC and SIM, 3.0–1500 μg/L for ELB and GZR, 7.5–1500 μg/L for LDV and VEL, 5.0–2500 μg/L for SOF and 25–5000 μg/L for GS-331007. Within-day accuracy values for all analytes, ranged from 94% to 109%, and precision expressed as residual standard deviation % (RSD) was <9.3%. Between-day accuracy ranged from 99 to 107% with a RSD of <5.3%. For the lower limit of quantification, the percent deviation from the nominal concentration and the relative standard deviation was <20%. The method has been applied successfully in clinical evaluation of patients treated with DAA and to describe the pharmacokinetics of DAAs in clinical studies. Highlights • Validated UPLC-MS/MS method for quantification of seven direct-acting antivirals • All drugs and one metabolite are simultaneously analysed. • Stable isotope labelled internal standards are used for all eight analytes. • The method is suitable for clinical care and research purposes. [ABSTRACT FROM AUTHOR]

Aim: Treatment with all‐oral direct‐acting antiviral agents (DAAs) elbasvir/grazoprevir (EBR/GZR) is associated with high sustained virologic response (SVR). The aim of this study was to evaluate the safety and treatment efficacy of EBR/GZR in hepatitis C virus (HCV)‐infected patients. Methods: This retrospective cohort study included 147 consecutive patients with chronic HCV genotype 1b infection who were treated with EBR (50 mg) plus GZR (100 mg) once daily for 12 weeks. The rates of SVR at 12 weeks after the end of treatment (SVR12) were evaluated based on patient baseline characteristics. Treatment efficacy was analyzed according to background chronic kidney disease (CKD), and retreatment efficacy in patients who failed to respond to previous DAAs. Results: The SVR12 was 94% (138 of 147 patients), based on intention‐to‐treat analysis. Rates of SVR12 were 97% (131 of 135) and 58% (7 of 12) in cases naïve to DAA treatment and failure to respond to prior DAAs, respectively. The SVR12 rates in patients with CKD stage 4–5 was 100% (8 of 8). All patients (4 of 4 patients) with stage 4–5 and advanced fibrosis (Fibrosis‐4 index ≥3.25) also achieved SVR12. Multivariate analysis that included the above variables identified pretreatment with other DAAs as an independent factor that was significantly and independently associated with non‐SVR12 (odds ratio, 97.5; P < 0.001). Relapsers of first DAAs, excluding the combination of ledipasvir and sofosbuvir, achieved SVR12. Characteristic novel non‐structural protein 5A substitutions were not detected after failure of retreatment with EBR/GZR. Conclusion: Treatment with EBR/GZR was highly efficacious with acceptable safety, even in patients with CKD stage 4–5. Retreatment of relapsers to prior DAAs, excluding ledipasvir and sofosbuvir, achieved SVR12. [ABSTRACT FROM AUTHOR]

Background: Elbasvir/grazoprevir is a once-daily fixed-dose combination therapy for the treatment of chronic HCV infection, including HCV/HIV coinfection.Objectives: To evaluate the pharmacokinetic interaction of elbasvir and grazoprevir with raltegravir or dolutegravir.Methods: Three open-label trials in healthy adult participants were conducted. In the raltegravir trials, participants received a single dose of raltegravir 400 mg, a single dose of elbasvir 50 mg or grazoprevir 200 mg, and raltegravir with either elbasvir or grazoprevir. In the dolutegravir trial, participants received a single dose of dolutegravir 50 mg alone or co-administered with once-daily elbasvir 50 mg and grazoprevir 200 mg.Results: The raltegravir AUC0-∞ geometric mean ratio (GMR) (90% CI) was 1.02 (0.81-1.27) with elbasvir and 1.43 (0.89-2.30) with grazoprevir. Dolutegravir AUC0-∞ GMR (90% CI) was 1.16 (1.00-1.34) with elbasvir and grazoprevir. The elbasvir AUC0-∞ GMR (90% CI) was 0.81 (0.57-1.17) with raltegravir and 0.98 (0.93-1.04) with dolutegravir. The grazoprevir AUC0-24 GMR (90% CI) was 0.89 (0.72-1.09) with raltegravir and 0.81 (0.67-0.97) with dolutegravir.Conclusions: Elbasvir or grazoprevir co-administered with raltegravir or dolutegravir resulted in no clinically meaningful drug-drug interactions and was generally well tolerated. These results support the assertion that no dose adjustments for elbasvir, grazoprevir, raltegravir or dolutegravir are needed for co-administration in HCV/HIV-coinfected people. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Pan-genotypic activity of voxilaprevir and glecaprevir in cell culture infectious HCV. • High fitness of engineered HCV genotype 1-6 protease position-80-variants. • Position-80-variants showed altered sensitivity to simeprevir but not to other PIs. • Q80K promoted accelerated HCV escape from PIs in long-term treatment. • Escape was mediated by rapid co-selection of additional resistance substitutions. Background & Aims Protease inhibitors (PIs) are of central importance in the treatment of patients with chronic hepatitis C virus (HCV) infection. HCV NS3 protease (NS3P) position 80 displays polymorphisms associated with resistance to the PI simeprevir for HCV genotype 1a. We investigated the effects of position-80-substitutions on fitness and PI-resistance for HCV genotypes 1-6, and analyzed evolutionary mechanisms underlying viral escape mediated by pre-existing Q80K. Methods The fitness of infectious NS3P recombinants of HCV genotypes 1-6, with engineered position-80-substitutions, was studied by comparison of viral spread kinetics in Huh-7.5 cells in culture. Median effective concentration (EC50) and fold resistance for PIs simeprevir, asunaprevir, paritaprevir, grazoprevir, glecaprevir and voxilaprevir were determined in short-term treatment assays. Viral escape was studied by long-term treatment of genotype 1a recombinants with simeprevir, grazoprevir, glecaprevir and voxilaprevir and of genotype 3a recombinants with glecaprevir and voxilaprevir, next generation sequencing, NS3P substitution linkage and haplotype analysis. Results Among tested PIs, only glecaprevir and voxilaprevir showed pan-genotypic activity against the original genotype 1-6 culture viruses. Variants with position-80-substitutions were all viable, but fitness depended on the specific substitution and the HCV isolate. Q80K conferred resistance to simeprevir across genotypes but had only minor effects on the activity of the remaining PIs. For genotype 1a, pre-existing Q80K mediated accelerated escape from simeprevir, grazoprevir and to a lesser extent glecaprevir, but not voxilaprevir. For genotype 3a, Q80K mediated accelerated escape from glecaprevir and voxilaprevir. Escape was mediated by rapid and genotype-, PI- and PI-concentration-dependent co-selection of clinically relevant resistance associated substitutions. Conclusions Position-80-substitutions had relatively low fitness cost and the potential to promote HCV escape from clinically relevant PIs in vitro , despite having a minor impact on results in classical short-term resistance assays. Lay summary Among all clinically relevant hepatitis C virus protease inhibitors, voxilaprevir and glecaprevir showed the highest and most uniform activity against cell culture infectious hepatitis C virus with genotype 1-6 proteases. Naturally occurring amino acid changes at protease position 80 had low fitness cost and influenced sensitivity to simeprevir, but not to other protease inhibitors in short-term treatment assays. Nevertheless, the pre-existing change Q80K had the potential to promote viral escape from protease inhibitors during long-term treatment by rapid co-selection of additional resistance changes, detected by next generation sequencing. [ABSTRACT FROM AUTHOR]

Background and Aim: This study aimed to evaluate the efficacy and safety of elbasvir/grazoprevir in genotype 1b chronic hepatitis C Japanese patients with chronic kidney disease (CKD), including those undergoing hemodialysis. Methods: This post hoc analysis of a multicenter, retrospective study included patients who had received elbasvir/grazoprevir. CKD was defined by an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2. The sustained virologic response (SVR) rate and frequency of treatment‐emergent adverse events were assessed in patients with CKD. Results: The study population comprised 155 men and 182 women. The median eGFR level at baseline was 69.6 mL/min/1.73 m2 (range, 3.0–128.5 mL/min/1.73 m2). Among the 337 patients, 109 (32.3%) had CKD: 72, 14, and 23 (including 20 hemodialysis) had CKD stages 3, 4, and 5, respectively. The SVR rates according to the baseline CKD stages were 98.1% (51/52) in stage 1, 98.3% (173/176) in stage 2, 93.9% (46/49) in stage 3a, 100% (23/23) in stage 3b, 100% (14/14) in stage 4, and 100% (23/23) in stage 5. All 20 patients undergoing hemodialysis achieved SVR. There was no significant decrease from baseline in the median eGFR level throughout the treatment period among the patients with CKD. The incidence of treatment‐emergent adverse events was 6.4% (7/109) among the patients with CKD and 9.7% (22/228) among the patients without CKD (not significant, P = 0.323). Conclusions: The present study demonstrated that elbasvir and grazoprevir are highly effective and safe for genotype 1b chronic hepatitis C Japanese patients with CKD, including those undergoing hemodialysis. [ABSTRACT FROM AUTHOR]

Background: The prevalence of hepatitis C virus (HCV) infection in hemodialysis patients is high and results in a poor prognosis. Thus, safer and more effective treatment regimens are required. In this prospective multicenter study, we investigated the efficacy and safety of the novel HCV-NS5A-inhibitor, elbasvir, and protease inhibitor, grazoprevir in Japanese hemodialysis patients with genotype 1b HCV infection.Methods: This study is registered at the UMIN Clinical Trials Registry as UMIN00002578. A total of 23 Japanese dialysis patients with genotype 1b HCV infection who were treated with elbasvir and grazoprevir between January 2017 and March 2018 and followed for more than 12 weeks after treatment completion were included. We evaluated the sustained virologic response at 12 weeks after treatment completion (SVR12) and safety during treatment.Results: Of the 23 patients, 7 had advanced liver fibrosis and 2 had a signature resistance-associated variant of NS5A (NS5A RAVs)-L31M/V or Y93H at baseline. All patients completed therapy, and 96.7% (22/23) of the patients achieved SVR12. All patients with advanced liver fibrosis and signature NS5A RAVs at baseline achieved SVR12 with a high safety profile. No patient experienced lethal or severe adverse events during therapy, and the most common adverse event was anemia. One patient, who was a non-responder to this therapy, had a history of failure with daclatasvir and asunaprevir therapies and had NS5A RAVs of A92K at baseline, but not signature NS5A RAVs.Conclusions: Grazoprevir and elbasvir combination is highly effective and safe for hemodialysis patients with genotype 1b HCV infection. [ABSTRACT FROM AUTHOR]

Background: The real-world virological efficacy and safety of an interferon (IFN)-free direct-acting antiviral (DAA) therapy with elbasvir (EBR) and grazoprevir (GZR) were evaluated in Japanese patients chronically infected with hepatitis C virus (HCV) genotype 1.Methods: The rate of sustained virologic response (SVR) and safety were analyzed in patients who started the EBR/GZR regimen between November 2016 and July 2017. SVR rates were compared based on patient baseline characteristics.Results: Overall, 371 of 381 patients (97.4%) achieved SVR. Multivariate analysis identified a history of failure to IFN-free DAA therapy and the presence of double resistance-associated substitutions (RASs) in HCV non-structural protein 5A (NS5A) as factors significantly associated with failure to EBR/GZR treatment. The SVR rates of patients with a history of IFN-free DAA therapy and those with double RASs were 55.6 and 63.6%, respectively. In all other subpopulations, the SVR rates were more than 90%. There were no severe adverse events associated with the treatment.Conclusions: The EBR/GZR regimen yielded high virological efficacy with acceptable safety. Patients with a history of failure to IFN-free DAA therapy or with double RASs in HCV-NS5A remained difficult to treat with this regimen. [ABSTRACT FROM AUTHOR]

Aim: Recently, elbasvir/grazoprevir combination therapy (EBR/GZR) was reported to have excellent antiviral effects for chronic genotype 1 hepatitis C virus (HCV) infection. However, it has not been recommended for patients with post‐liver transplant (LT) HCV re‐infections because of a lack of evidence for effectiveness and drug–drug interactions. Methods: We report the usage of EBR/GZR in five post‐LT HCV re‐infected patients with the kinetics of renal function and tacrolimus trough levels during and after therapy. Furthermore, to evaluate the antiviral effects, we examined the HCV kinetics during and after therapy and compared this with other interferon‐free therapy in post‐LT patients (n = 19). Results: All patients treated with EBR/GZR therapy obtained rapid virologic response and sustained at 12 weeks post‐treatment. There was no evidence of worsening estimated glomerular filtration rates. Three patients were given tacrolimus as immunosuppressive therapy and its trough levels were controllable with dosage adjustments. One patient developed grade 1 diarrhea 3 days after therapy induction. To evaluate the antiviral effects of EBR/GZR therapy for these patients, we compared them to the effects of daclatasvir/asunaprevir combination therapy (n = 8) and sofosbuvir/ledipasvir combination therapy (n = 11). The EBR/GZR combination was not inferior to other therapies in its early phase and late‐phase antiviral effects. Conclusions: Although further studies with a larger number of patients are required, we suggest that EBR/GZR therapy is an alternative therapy for patients with post‐LT genotype 1 HCV re‐infection. [ABSTRACT FROM AUTHOR]

Introduction: Most direct-acting antivirals (DAAs) and psychotropic drugs are metabolized by or induct/inhibit CYP enzymes and drug transporters. Although they are frequently coadministered, the drug-drug interactions (DDIs) have been little studied. Therefore, the aim of this review is to describe the interactions between the approved DAA or combination regimens and the main psychoactive substances, including legal and illegal drugs of abuse. Areas covered: We performed a literature search on PubMed database on drug interactions with the currently available antivirals for hepatitis C and a review of the information on pharmacokinetics, metabolism, and drug interactions from www.hep-druginteractions.org and from all the Summary of Product Characteristics (SmPC). This review covers the DDI between the DAA regimens approved, such as simeprevir and sofosbuvir, paritaprevir, glecaprevir, voxilaprevir, ombitasvir, ledipasvir, daclatasvir and sofosbuvir, elbasvir and grazoprevir, sofosbuvir and velpatasvir, glecaprevir/pibrentasvir, sofosbuvir and velpatasvir, and main psychotropic agents. Expert Commentary: DAA regimens based on sofosbuvir combination usually have less DDI than protease inhibitor-based regimens. Among protease inhibitors regimens, new combinations, such as glecaprevir/elbasvir and grazoprevir/elbasvir, seemed to have less DDI than the combination POrD (paritaprevir/ombitasvir/ritonavir/dasabuvir). However, the analysis of each interaction is theoretical and further interaction studies would be necessary to confirm actual effect. [ABSTRACT FROM AUTHOR]

Abstract: Background & Aims: The aim of this integrated analysis was to assess the efficacy of the once‐daily combination of elbasvir 50 mg and grazoprevir 100 mg, with and without ribavirin in HCV genotype 4 (GT4)‐infected participants enrolled in the Phase 2/3 clinical programme with elbasvir/grazoprevir. Methods: Treatment‐naïve and treatment‐experienced participants 18 years of age or older with chronic HCV GT4 infection and baseline HCV RNA ≥10 000 IU/mL were included in the analysis. The analysis population was the full analysis set (FAS; all participants who received at least 1 dose of study medication) and a total of 155 HCV GT4 participants were evaluated. The primary endpoint was sustained virologic response at week 12 (SVR12; HCV RNA less than the lower limit of quantitation at 12 weeks after the completion of study therapy). Results: Overall, among GT4‐infected participants treated with 12 or 16 weeks of elbasvir/grazoprevir ± ribavirin, the SVR12 efficacy rates were 96.4% (107/111) in treatment‐naïve participants and 88.6% (39/44) in treatment‐experienced participants. The SVR12 rates were 96.0% (97/101) in treatment‐naïve participants treated with 12 weeks of elbasvir/grazoprevir and 100% (8/8) in treatment‐experienced participants treated with 16 weeks of elbasvir/grazoprevir plus ribavirin. Efficacy was not impacted by GT4 subtype. Conclusions: The regimens of 12 weeks of elbasvir/grazoprevir without ribavirin, and 16 weeks of elbasvir/grazoprevir plus ribavirin, were efficacious in HCV GT4‐infected treatment‐naïve and treatment‐experienced participants respectively. Baseline NS5A resistance‐associated substitutions did not impact the efficacy of elbasvir/grazoprevir in GT4‐infected participants. [ABSTRACT FROM AUTHOR]

Summary: People with hepatitis C virus (HCV) infection other than genotype 1 represent a heterogeneous group. The aim of the phase 2 C‐SCAPE study was to evaluate elbasvir/grazoprevir (EBR/GZR), with or without ribavirin (RBV), in participants with HCV genotype 2, 4, 5 or 6 infection. This was a part randomised, open‐label, parallel‐group study (NCT01932762; PN047‐03) of treatment‐naive, noncirrhotic participants. Participants with HCV genotype 2 infection received GZR 100 mg + RBV ± EBR 50 mg for 12 weeks and those with genotype 4, 5 or 6 infection were randomized to receive EBR/GZR ± RBV for 12 weeks. The primary endpoint was sustained virological response 12 weeks after completion of treatment (SVR12; HCV RNA <25 IU/mL). Among participants with genotype 2 infection, SVR12 was achieved by 80% (24/30) of those receiving EBR/GZR + RBV and 73% (19/26) of those receiving GZR + RBV. SVR rates were high in participants with HCV genotype 4 infection receiving EBR/GZR with and without RBV (100% [10/10] and 90% [9/10]; respectively). In contrast, the addition of RBV to EBR/GZR appeared to increase SVR12 in participants with genotype 5 infection (EBR/GZR, 25%; EBR/GZR + RBV 100% [4/4]). In participants with genotype 6 infection, SVR12 was 75% (3/4) in both those receiving EBR/GZR and those receiving EBR/GZR + RBV. The safety profile was similar across treatment arms, with adverse events tending to occur more frequently among participants receiving RBV. In conclusion, these data support the inclusion of participants with genotype 4 or 6 infection in the EBR/GZR phase 3 studies. EBR/GZR ± RBV was unsatisfactory for participants with genotype 2 or 5 infection. [ABSTRACT FROM AUTHOR]

Abstract: Elbasvir (EBR)/grazoprevir (GZR) may be coadministered with immunosuppressant drugs in posttransplant people who are infected with hepatitis C virus. The aim of the present study was to assess the safety and pharmacokinetic interactions between EBR and GZR and single doses of cyclosporine, tacrolimus, mycophenolate mofetil (MMF), and prednisone. This was a 4‐part, open‐label study in 58 healthy volunteers. Participants received single doses of cyclosporine 400 mg, tacrolimus 2 mg, MMF 1 g, or prednisone 40 mg alone or in the presence of once‐daily EBR 50 mg/GZR 200 mg. Multiple oral doses of EBR + GZR had no significant effect on cyclosporine. However, in the presence of cyclosporine, the 24‐hour area under the concentration‐time curve of GZR was increased by approximately 15‐fold (geometric mean ratio [90%CI] 15.21 [12.83; 18.04]); the concentration of EBR was increased approximately 2‐fold in the presence of cyclosporine. Coadministration of EBR/GZR and tacrolimus did not affect the pharmacokinetics of EBR or GZR, but resulted in an increase in tacrolimus AUC (geometric mean ratio [90%CI] 1.43 [1.24; 1.64]). There were no clinically relevant interactions between EBR/GZR and either MMF or prednisone. Data from the present study indicate that EBR/GZR may be coadministered in people receiving tacrolimus, MMF, and prednisolone. EBR/GZR is contraindicated in people receiving cyclosporine because the significantly higher concentrations of GZR may increase the risk of transaminase elevations. [ABSTRACT FROM AUTHOR]

The first three UV spectrophotometric methods have been developed of simultaneous determination of two new FDA approved drugs namely; elbasvir and grazoprevir in their combined pharmaceutical dosage form. These methods include simultaneous equation, partial least squares with and without variable selection procedure (genetic algorithm). For simultaneous equation method, the absorbance values at 369 ( λ max of elbasvir) and 253 nm ( λ max of grazoprevir) have been selected for the formation of two simultaneous equations required for the mathematical processing and quantitative analysis of the studied drugs. Alternatively, the partial least squares with and without variable selection procedure (genetic algorithm) have been applied in the spectra analysis because the synchronous inclusion of many unreal wavelengths rather than by using a single or dual wavelength which greatly increases the precision and predictive ability of the methods. Successfully assay of the drugs in their pharmaceutical formulation has been done by the proposed methods. Statistically comparative analysis for the obtained results with the manufacturing methods has been performed. It is noteworthy to mention that there was no significant difference between the proposed methods and the manufacturing one with respect to the validation parameters. [ABSTRACT FROM AUTHOR]

Recent advances in our knowledge of hepatitis C virus (HCV) molecular biology have enabled improvements in the efficacy and tolerability of HCV treatment, and in this regard many direct-acting antiviral (DAA) agents have been developed. These drugs target specific stages in the HCV life cycle. Phase 3 clinical trials have demonstrated treatment success rates of 90% with these drugs and their combinations, while real world data indicate a rate of 80-90%. In this review, the use of DAA drugs in the treatment of chronic HCV infection is reviewed in detail. [ABSTRACT FROM AUTHOR]

Background and aim. Grazoprevir is an NS3/4A protease inhibitor (PI), while elbasvir is an NS5A inhibitor. We performed this meta-analysis to directly compare grazoprevir plus elbasvir and ribavirin regimen vs. grazoprevir and elbasvir without ribavirin in the treatment of hepatitis C virus genotype 1 infection and to precisely evaluate the efficacy of the latter regimen in cirrhotic, IL28 CC genotype patients and those coinfected with human immunodeficiency virus. Material and methods. A computer literature search of PubMed, Scopus, EBSCO, Embase, and Cochrane central was conducted. Studies were screened for eligibility. Sustained virologic response (SVR) rates were pooled using OpenMeta [Analyst] software for windows. A subgroup analysis was performed to stratify the treatment efficacy according to the different baseline characteristics of HCV patients. Results. Eight randomized controlled trials (n = 1,297 patients) were pooled in the final analysis. The overall SVR rate was 96.6% with 95% CI [95.5% to 98%]. For cirrhotic patients, the SVR rate was 95.7% with 95% CI [93.9% to 97.5%] and for non-cirrhotic patients, the SVR rate was 97% with 95% CI [95.9% to 98.4%]. Furthermore, the addition of ribavirin (RBV) to the treatment regimen did not significantly improve the SVR (RR 1.003, 95% CI [0.944 to 1.065]).The dual regimen was effective in patient populations with NS3 resistance-associated substitution (RAS). However, this regimen achieved lower SVR rates (< 90%) in patients with NS5A RAS. Conclusions. We conclude that the 12-week treatment regimen of the fixed dose combination of grazoprevir plus elbasvir achieved high SVR rates in patients with HCV genotype 1 infection. The addition of ribavirin to this regimen did not add a significant benefit. [ABSTRACT FROM AUTHOR]

Elbasvir ( EBR; HCV NS5A inhibitor) and grazoprevir ( GZR; HCV NS3/4A protease inhibitor) are approved as a fixed-dose combination to treat patients chronically infected with HCV genotypes 1 and 4. During the development programme and supported by in vitro potency, the efficacy of EBR+ GZR was assessed in HCV GT3-infected patients. This study's aim was to determine the efficacy and tolerability of 12 or 18 weeks of EBR+ GZR with ribavirin ( RBV) in treatment-naïve, noncirrhotic HCV GT3-infected patients. Randomized patients received open-label EBR (50 mg once daily) + GZR (100 mg once daily) + RBV. The primary efficacy objective was to evaluate the sustained virologic response rates 12 weeks after the end of all study therapy ( SVR12). SVR12 rates (95% confidence interval) were 45.0% (23.1, 68.5) and 57.1% (34.0, 78.2) after treatment with EBR+ GZR+ RBV for 12 weeks or 18 weeks, respectively. On-treatment virologic failure was observed in 41% (17 of 41) of patients. At virologic failure, resistance-associated substitutions ( RASs) with a >five-fold shift in potency occurred in the NS3 region in six (35%) patients and in the NS5A region in 16 (94%) patients. The most common RAS at virologic failure was Y93H in NS5A which was identified in 13 of 17 (76%) patients. The efficacy of EBR+ GZR+ RBV was suboptimal in HCV GT3-infected patients due to a high rate of on-treatment virologic failure and treatment-emergent RASs which demonstrates an inadequate barrier to the development of GT3 resistance. However, rapid viral clearance demonstrated the antiviral activity of EBR+ GZR+ RBV in GT3-infected patients.clinicaltrials.gov: NCT01717326. [ABSTRACT FROM AUTHOR]

Purpose. The chemistry, pharmacology, pharmacodynamics, pharmacokinetics, efficacy, safety, dosage, administration, and role of elbasvir-grazoprevir in the treatment of hepatitis C virus (HCV) infection are reviewed. Summary. Elbasvir-grazoprevir was recently approved by the Food and Drug Administration for the treatment of chronic HCV genotype 1 or 4 infections with or without ribavirin in patients with or without compensated cirrhosis. Elbasvir exhibits antiviral activity against HCV genotypes 1a, 1b, 2a, 3a, and 4a. Elbasvir-grazoprevir undergoes fecal excretion, does not require dosage adjustment in patients with renal impairment, and is contraindicated in moderate and severe hepatic impairment. In Phase II and III clinical trials, elbasvir-grazoprevir administered orally for 12 weeks was shown to achieve a high sustained virological response 12 weeks after the end of treatment. Elbasvir-grazoprevir is a once-daily, fixed-dose combination tablet that can be taken without regard to food. The adverse drug reactions most commonly reported include fatigue, headache, and nausea. Elbasvir-grazoprevir is indicated with ribavirin for treatment-naive and treatment-experienced patients with genotype 1a with baseline NS5A polymorphisms, for treatment-experienced patients with genotype 1b, and for treatment-experienced patients with genotype 4. Conclusion. Elbasvir-grazoprevir achieves a high cure rate in the treatment of patients with chronic HCV with a once-daily oral regimen and without serious adverse effects; however, it requires close monitoring of liver function values. It is an effective option for patients with HCV genotype 1a, 1b, or 4 with or without compensated cirrhosis and is a particularly attractive option in patients with chronic kidney disease receiving hemodialysis and in patients with HIV coinfection. [ABSTRACT FROM AUTHOR]

A New method was established for simultaneous estimation of Elbasvir and Grazoprevir by RP-HPLC method. The chromatographic conditions were successfully developed for the separation of Elbasvir and Grazoprevir by using Inertsil ODS column (4.6×250mm) 5μ, flow rate was 1ml/min, mobile phase ratio (40:60 v/v) Acetonitrile (CAN), phosphate buffer (KH2PO4) of pH 3 (pH adjusted with orthophosphoric acid), detection wavelength used by Waters HPLC Auto Sampler, Separation module 2695, UV detector 2489, Empower-software version-2. The retention times were found to be 2.841 mins and 4.337 mins. The % purity of Elbasvir and Grazoprevir were found to be 100.12 and 99.93 respectively. The present analytical method was validated according to ICH guidelines (ICH, Q2 (R1)). The linearity study of Elbasvir and Grazoprevir was found in the concentration range 100μg/ml-500μg/ml and 200μg/ml - 1000μg/ml and correlation coefficient (R²) be 0.999 and 0.999, % recovery was found to be 100.11 and 100.38, %RSD for repeatability 0.5 and 0.1, % RSD for intermediate precision was 0.6 and 0.2 respectively. The precision study was precision, robustness and repeatability. It is a convenient, simple and quick method for the determination of Elbasvir and Grazoprevir in its bulk and pharmaceutical dosage forms. [ABSTRACT FROM AUTHOR]