Pibrentasvir Research Articles

Chemoprophylactic Assessment of Combined Intranasal SARS-CoV-2 Polymerase and Exonuclease Inhibition in Syrian Golden Hamsters.

Pibrentasvir (PIB) has been demonstrated to block exonuclease activity of the SARS-CoV-2 polymerase, protecting favipiravir (FVP) and remdesivir (RDV) from post-incorporation excision and eliciting antiviral synergy in vitro. The present study investigated the chemoprophylactic efficacy of PIB, FVP, RDV, FVP with PIB, or RDV with PIB dosed intranasally twice a day, using a Syrian golden hamster contact transmission model. Compared to the saline control, viral RNA levels were significantly lower in throat swabs in FVP (day 7), RDV (day 3, 5, 7), and RDV+PIB (day 3, 5) treatment groups. Similarly, findings were evident for nasal turbinate after PIB and RDV treatment, and lungs after PIB, FVP, and FVP+PIB treatment at day 7. Lung viral RNA levels after RDV and RDV+PIB treatment were only detectable in two animals per group, but the overall difference was not statistically significant. In situ examination of the lungs confirmed SARS-CoV-2 infection in all animals, except for one in each of the RDV and RDV+PIB treatment groups, which tested negative in all virus detection approaches. Overall, prevention of transmission was observed in most animals treated with RDV, while other agents reduced the viral load following contact transmission. No benefit of combining FVP or RDV with PIB was observed.

B-172 Development and Validation of an LC-MS/MS Assay for Quantification of Glecapravir/Pibrentasvir in Human Plasma

Abstract Background The global prevalence of chronic hepatitis C virus (HCV) infection is 58 million. Untreated chronic HCV infections can lead to serious health complications, including liver cirrhosis, damage, and disease. Direct acting antiviral (DAA) therapies for HCV infections are effective in the treatment and management of chronic infections. Glecapravir (GLE) and pibrentasvir (PIB) are DAAs that may be delivered alone or as a fixed-dose oral formulation to treat adolescent and adult patients with chronic HCV infections (genotypes 1–6) with or without cirrhosis. Here, we describe a liquid chromatographic-tandem mass spectrometric (LC-MS/MS) assay for the multiplexed quantification of GLE and PIB in human plasma, with future applications in clinical trials to evaluate the pharmacokinetics of intramuscularly delivered GLE/PIB. Methods Calibrators were prepared in human K2EDTA plasma at final concentrations ranging from 0.25 to 2000 ng/mL GLE and 0.25 to 1000 ng/mL PIB. Samples at the lower limit of quantification (LLOQ), low, mid, high, and dilution quality control (QC) levels were prepared at 0.25, 0.75, 800, 1800, and 20 000 ng/mL for GLE and 0.25, 0.75, 400, 800 ng/mL, and 10 000 ng/mL for PIB, respectively.Plasma samples containing GLE and PIB were combined with isotopically labeled internal standards and subjected to protein precipitation. Samples were evaporated to dryness, reconstituted in 50:50 mobile phase A (MPA, 0.1% formic acid in water): mobile phase B (MPB, 0.1% formic acid in 80:20 acetonitrile:water) and subjected to LC-MS/MS analysis.Chromatographic separation and analyte quantification occurred on an API 6500+ (Sciex, Foster City, CA) interfaced with an LC-30 (Shimadzu, Kyoto, Japan) operated in positive ionization and selective reaction monitoring modes. Chromatographic separation occurred using a Zorbax Eclipse C18 column under a gradient elution from MPA to MPB. Transitions monitored for analytes of interest were as follows: GLE (839.4 à 684.3 m/z), PIB (557.5 à 871.4 m/z), and their internal standards (GLE -IS 843.5 à 684.3 m/z; PIB-IS 561.5 à 629.3 m/z).The LC-MS/MS assay was validated in accordance with Food and Drug Administration Bioanalytical Method Validation Guidance for Industry recommendations. Results Inter-assay precision and accuracy ranged from 4.34% to 15.6% and −4.90% to 10.6% for GLE and 3.20% to 9.80% and −7.48% to −1.46% for PIB, respectively. GLE and PIB in plasma are stable following six freeze thaw cycles at <−70 °C, with a percent difference (%DIF) ≤±10.8% for GLE and ≤±12.4 for PIB. Additionally, GLE and PIB are stable at room temperature for up to 67 h and demonstrated re-injection stability at 4 °C for up to 101 h (GLE: %DIF ≤±4.1%; PIB %DIF: ≤±7.8%). Matrix effects were assessed quantitatively; negligible percent matrix effects were observed for PIB (106%) and PIB-IS (111%) across the measuring range of the assay. Significant ion suppression was observed for GLE (59.9%) and GLE-IS (63.9%); however, relative matrix effects were <5% between drug and internal standard and deemed acceptable. Other assay validation assessments in alternative matrices were also deemed acceptable. Conclusion An LC-MS/MS method for GLE and PIB quantification in plasma has been developed and validated and may be used in downstream applications to characterize DAA pharmacology for HCV treatment.

Pharmacokinetics, Tolerability, and Safety of Glecaprevir/Pibrentasvir Co-formulated Bilayer Tablet Following Repeated Administration in Healthy Chinese Adults.

Glecaprevir (GLE)/pibrentasvir (PIB) is an all-oral, interferon- and ribavirin-free, pan-genotypic fixed-dose combination regimen approved for the treatment of all major genotypes of hepatitis C virus (HCV) infection in many countries worldwide. To support clinical development in China, an open-label, single-center phase 1 study was conducted to evaluate the pharmacokinetics, safety, and tolerability of GLE/PIB in healthy Chinese adults in Mainland China. Eighteen participants received 3 tablets of coformulated GLE/PIB 100/40mg once daily (QD) for 7 days. Following GLE/PIB 300mg/120mg administration, GLE and PIB reached maximum concentration in 4-5 hours with a terminal elimination half-life of 5.9 and 25 hours, respectively. Both GLE and PIB reached steady state by day 5, with no-to-minimal accumulation (≤17% higher). GLE/PIB exposures in healthy Chinese participants were similar to historical observations across phase 1 studies in healthy Western participants. GLE/PIB was safe and well-tolerated, with most adverse events being mild. These pharmacokinetics and safety data, together with existing global efficacy and safety data in healthy and HCV-infected Western participants, support the use of GLE/PIB 300mg/120mg QD in adult Chinese patients with chronic HCV infection.

Development and validation of a liquid chromatographic-tandem mass spectrometric assay for the quantification of the direct acting antivirals glecaprevir and pibrentasvir in plasma

BackgroundDirect acting antiviral (DAA) therapies are effective in the treatment and management of chronic HCV infections. Glecaprevir (GLE) and pibrentasvir (PIB) are pangenotypic DAAs that are delivered alone or as a fixed-dose oral formulation to treat chronic HCV infections with or without cirrhosis. Sensitive and dynamic bioanalytical assays are needed to understand the pharmacology of GLE and PIB. MethodsDrug free K2EDTA plasma was spiked with GLE, PIB, and their internal standards. Drugs were extracted from plasma via protein precipitation, and subsequently quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The method was validated according to regulatory recommendations, and evaluated in remnant plasma samples from individuals prescribed GLE and PIB. ResultsThe analytical measuring ranges for GLE and PIB were 0.25–2000 ng/mL and 0.25–1000 ng/mL, respectively. The method showed acceptable accuracy and precision for both DAAs. GLE and PIB in plasma were stable following six freeze thaw cycles and at room temperature for up to 67 h. All analytes were stable in whole blood incubated at room temperature for 24 h, and at 40 °C and 100% humidity for 2 h. Negligible percent matrix effects were observed for PIB and PIB-IS across the measuring range of the assay. Significant ion suppression was observed for GLE, with an average matrix effects of 27.9%. However, relative matrix effects were < 6.3% between drug and internal standard, and deemed acceptable. Assay validation assessments in alternative matrices also met acceptance criteria. Both DAAs were successfully measured in remnant plasma samples from individuals administered GLE and PIB. ConclusionsAn LC-MS/MS method for GLE and PIB quantification in plasma has been developed and validated. The assay met acceptable performance criteria and may be used in downstream applications to characterize DAA pharmacology for HCV treatment.

Characterizing complex and competing drug-drug interactions between the antiviral regimen of glecaprevir and pibrentasvir with rifampin or carbamazepine.

The fixed-dose combination of the direct acting antivirals glecaprevir (GLE) and pibrentasvir (PIB) is an oral, once-daily treatment for all six major genotypes of chronic hepatitis C virus infection. A single and multiple-dose rifampin study (N=12) and a carbamazepine study (N=12) were conducted in healthy subjects to evaluate the effects of CYP3A/P-gp induction and OATP inhibition on the pharmacokinetics of GLE and PIB. In study 1, GLE 300 mg + PIB 120 mg was administered as a single dose either alone, after single and multiple daily doses of rifampin 600 mg, or 24 h after the last rifampin dose. In study 2, GLE 300 mg + PIB 120 mg was administered as a single dose either alone or after multiple doses of carbamazepine 200 mg. Relative to GLE + PIB alone, exposure of GLE was significantly increased by the first co-administered rifampin dose due to OATP inhibition, significantly decreased 24 h after the last rifampin dose due to CYP3A/P-gp induction, and slightly increased when co-administered with steady-state rifampin due to a combination of inhibition and induction forces. Exposure of PIB was not affected when co-administered with the first rifampin dose but was significantly decreased with steady-state rifampin co-administration, or 24 h after the last rifampin dose due to P-gp induction. Carbamazepine significantly decreased GLE and PIB exposure, mainly attributed to P-gp induction. The regimens tested were generally well-tolerated by the subjects and no new safety issues were identified.

The efficacy and tolerability of glecaprevir/pibrentasvir treatment in a real-world chronic hepatitis C patients cohort.

The aims of the present study were to evaluate the real-life efficacy and tolerability of glecaprevir (GLE)/pibrentasvir (PIB) in the treatment of patients with chronic hepatitis C (CHC). Between May 2019 and May 2022, 686 patients with CHC, treated with GLE/PIB combination from 21 participating centers in Turkiye, were enrolled in the study. All patients were Caucasian, and their median age was 56 years. At the start of GLE/PIB treatment, the median serum Hepatitis C virus RNA and serum alanine amino transaminase (ALT) levels were 6.74 log10 IU/mL and 47 U/L, respectively. Fifty-three percent of the patients were infected with genotype 1b, followed by genotype 3 (17%). Diabetes was the more common concomitant disease. The sustained virological response (SVR12) was 91.4% with intent-to-treat analysis and 98.5% with per protocol analysis. The SVR12 rates were statistically significant differences between the patients who were i.v. drug users and non-user (88.0% vs. 98.8%, p=0.025). From the baseline to SVR12, the serum ALT levels and Model for End-Stage Liver Disease score were significantly improved (p<0.001 and p=0.014, respectively). No severe adverse effect was observed. GLE/PIB is an effective and tolerable treatment in patients with CHC.

Unique Quality by Design Approach for Developing HPLC and LC-MS Method for Estimation of Process and Degradation Impurities in Pibrentasvir, Antiviral Agent for Hepatitis C.

Pibrentasvir (PIB) was approved for treating hepatitis C patients. A specific, accurate, linear, robust, and stability-indicating method was developed and validated for determining degradation impurities present in the PIB drug substance by studying the quality by design (QbD) principles. All identified degradation impurities were separated with the stationary phase HALO C18, 150 mm × 4.6 mm, 2.7 μm. Mobile phase A contains pH 2.5 phosphate buffer and acetonitrile in the ratio of (70:30, v/v), and mobile phase B contains water and acetonitrile in the ratio of (30:70, v/v), respectively. The chromatographic conditions were optimized, such as flow rate of 0.8 mL/min, UV detection at 252 nm, injection volume of 20 μL, and column temperature of 40 °C. The proposed method was validated per the current ICH Q2 (R1) guidelines. The recovery study and linearity ranges were established from limit of quantification (LOQ) to 300% optimal concentrations. The method validation results were between 98.6% and 106.2% for recovery, and linearity r 2 was more than 0.999 for all identified impurities. The method precision results achieved below 5% relative standard deviation (RSD). The forced degradation results demonstrated that the drug was sensitive to chemical stress conditions. During the stress study, degrading impurities were identified by the LC-MS technique and the mechanism pathway. A QbD-based experimental design (DoE) approach was used to establish the robustness of the method.

S3264 A Hepatitis C (HCV) Infection Treatment Dilemma

Introduction: HIV/HCV coinfection increases liver-related morbidity and mortality. This special population should be prioritized for treatment. Currently available direct-acting antivirals (DAAs) are safe and effective, but there are many drug interactions (DIs) to consider. Carbamazepine (CBZ) is contraindicated with all available DAAs. Patients that require treatment for HCV but cannot stop CBZ do not have a clear treatment option. Patients may be transitioned to newer antiepileptics that do not have the same contraindications, but some patients are unwilling or unable to change medications. Case Description/Methods: Patient is a 59-year-old man with well-controlled HIV on HAART, well-controlled trigeminal neuralgia on CBZ, anemia, and non-cirrhotic (FibroScan 12 kPa), treatment naïve, chronic HCV genotype 1a. Due to DIs between DAAs and CBZ, multiple attempts were made to discontinue CBZ but were unsuccessful. Neurosurgery offered surgical gamma knife management, but up to 40% of patients still require CBZ post-procedure. An initial plan for daclatasvir (DAC)-sofosbuvir (SOF)-ribavirin (RBV) was proposed, but DAC is no longer available in the US. Patient was followed conservatively but developed thrombocytopenia and progression of fibrosis (FibroScan 14.7kPa). Given worsening liver condition, shared decision-making was performed, and patient completed 16 weeks of Glecaprevir (GLE)/pibrentasvir (PIB) + SOF 400mg with 4 weeks of ezetimibe 10mg stopping when the viral load was undetectable. Patient was instructed to start the ezetimibe with the GLE/PIB + SOF but was hesitant to take it due to adverse reaction to statins in the past. At 4 weeks of treatment, HCV viral load was still detectable. Patient was re-educated on the purpose of the ezetimibe and reassured it was not a statin. He took it from week 4-8 of treatment. At week 8, HCV viral load was undetectable. Patient achieved SVR 12 and showed improvement of his FibroScan score to 9.6 kPa. Discussion: GLE/PIB is pangenotypic, has a high barrier to resistance, and has been proven safe and effective in combination with SOF + RBV in MAGELLAN 3 for 16 weeks duration. Patient has history of anemia, making RBV undesirable. Ezetimibe blocks the NPC1L receptor which potentially inhibits HCV entry into the hepatocyte. HCV relies on cell-to-cell transmission, so we chose to add ezetimibe 10mg daily until HCV not detected. There is a need for larger studies to determine the applicability of this case study to other patients.

Development and validation of a novel bioanalytical method for the simultaneous determination of glecaprevir and pibrentasvir in human plasma using reversed-phase high-performance liquid chromatography

Background and objective For the simultaneous determination of glecaprevir (GPR) and pibrentasvir (PTR) in human plasma, a novel, accurate, and selective reversed-phase high-performance liquid chromatography method was developed and validated.Materials and methods Owing to structural resemblance, bictegravir was selected as an internal standard. Anticoagulant used was K2-EDTA. The GPR-PTR was the first of its kind approved drug by FDA for the treatment of chronic hepatitis C. Precipitation technique with acetonitrile was employed for the extraction of analyte from human plasma. Kromasil C18 column (5 μ, 150×4.6 mm) with an isocratic mobile phase of 0.1% orthophosphoric acid buffer pH 4.3, adjusted with dilute hydrochloric acid: acetonitrile in the ratio of 70 : 30 v/v, was used for the resolution. At a flow rate of 1 ml/min, the mobile phase was pumped. Using a photodiode array detector, effluents were monitored at 250 nm.Results Over concentration ranges of 5–200 μg/ml and 6.650–266.000 μg/ml, the method was found to be linear for GPR and PTR, respectively, in human plasma, with the precision and accuracy ranging from 0.76 to 9.05% and 90.55 to 98.98% for GPR respectively, whereas for PTR ranged from 0.74 to 9.52% and 91.56 to 105.61%, respectively.Conclusion The stability of the analyte was evaluated in plasma under different stress conditions.

Successful treatment of Japanese hemophilia patient co-infected with HIV and HCV genotype 4a by glecaprevir/pibrentasvir therapy.

Although direct-acting antiviral (DAA)-based anti-hepatitis C virus (HCV) therapies are very effective for patients with genotypes 1 and 2, evidence of the efficacy of DAA-based therapy for the special population of patients with genotypes 3-6 is insufficient due to the relatively small number of these subjects in Japan. Human immunodeficiency virus (HIV)/HCV-co-infected patients are recommended to be treated as HCV-mono-infected patients by the latest version of the Japan Society of Hepatology guidelines. However, evidence of efficacy in patients with HIV/HCV genotype 3-6 co-infection is insufficient. Currently, HCV genotypes 3-6 can be treated with two DAA-based therapies, including glecaprevir (GLE)/pibrentasvir (PIB) therapy in Japan. We experienced a relatively rare case of a Japanese hemophilia patient co-infected with HIV/HCV genotype 4a. We evaluated resistance-associated substitutions (RASs) against GLE and PIB before GLE/PIB therapy and found that he had no RASs. He was treated with 12weeks of GLE/PIB therapy and achieved a sustained virologic response at post-treatment weeks 24. Although the treatment was well tolerated, the patient developed hyper-low-density lipoproteinemia that was probably associated with HCV elimination during the therapy. Additional studies are needed to confirm the efficacy and safety of GLE/PIB therapy for this special population in Japan.

Novel drug resistance-associated substitutions against pibrentasvir emerged in genotype 1b hepatitis C virus-infected human hepatocyte transplanted mice

Combination therapy with glecaprevir and pibrentasvir (PIB) has high efficacy for patients with hepatitis C virus (HCV) infection except among those who experienced NS5A-P32 deletion (del) mutation during prior DAA treatment failure. However, some patients fail to achieve SVR through combination treatment even in the absence of NS5A-P32del. We analyzed emergence of NS5A resistance-associated substitutions (RASs) against PIB using HCV-infected mice. Male human hepatocyte transplanted mice were infected with genotype 1b wild-type HCV. Mice were treated with PIB, resulting in a transient decrease in serum HCV RNA levels but followed by relapse during the treatment. Direct sequence analysis showed emergences of various mutations in the NS5A region, including L31V/P32del, L31F/P32del/Y93H, NS5A-P29del/Y85C, and NS5A-F37Y. PIB was less effective in mice with NS5A-F37Y mutations compared to mice with wild-type HCV. NS5A-F37Y showed 5.4-fold resistance to PIB relative to wild-type based on analysis using HCV subgenomic replicon systems. The present in vivo and in vitro studies identified NS5A-F37Y as a novel RAS against PIB and showed the possibility of emergence of various NS5A RASs including P29del, P32del and F37Y following PIB treatment. These mutations might emerge and lead to failure to respond to DAA therapies including PIB-based regimens in chronic hepatitis C patients.

Is an 8-week regimen of glecaprevir/pibrentasvir sufficient for all hepatitis C virus infected patients in the real-world experience?

The revolution of the antiviral treatment of hepatitis C virus (HCV) infection resulting in higher effectiveness came with the introduction of direct-acting antivirals with pangenotypic regimens as a final touch. Among them, the combination of glecaprevir (GLE) and pibrentasvir (PIB) provides the opportunity for shortening therapy to 8weeks in the majority of patients. Because of still insufficient evaluation of this regimen in the real-world experience, our study aimed to assess the efficacy and safety of 8-week GLE/PIB in chronic hepatitis C patients depending on liver fibrosis and genotype (GT). The analysis included patients who received GLE/PIB for 8weeks selected from the EpiTer-2 database, large retrospective national real-world study evaluating antiviral treatment in 12584 individuals in 22 Polish hepatology centers. A total of 1034 patients with female predominance (52%) were enrolled in the analysis. The majority of them were treatment naïve (94%), presented liver fibrosis (F) of F0-F3 (92%), with the most common GT1b, followed by GT3. The overall sustained virologic response after exclusion of nonvirologic failures was achieved in 95.8% and 98%, respectively (P=0.19). In multivariate logistic regression HCV GT-3 (beta=0.07, P=0.02) and HIV infection (beta=-0.14, P<0.001) were independent predictors of nonresponse. We demonstrated high effectiveness of 8-week GLE/PIB treatment in a non-GT3 population irrespective of liver fibrosis stage. Comparable efficacy was achieved in non-cirrhotic patients regardless of the genotype, including GT3 HCV.

Prodrug Strategies to Improve the Solubility of the HCV NS5A Inhibitor Pibrentasvir (ABT-530).

A research program to discover solubilizing prodrugs of the HCV NS5A inhibitor pibrentasvir (PIB) identified phosphomethyl analog 2 and trimethyl-lock (TML) prodrug 9. The prodrug moiety is attached to a benzimidazole nitrogen atom via an oxymethyl linkage to allow for rapid and complete release of the drug for absorption following phosphate removal by intestinal alkaline phosphatase. These prodrugs have good hydrolytic stability properties and improved solubility compared to PIB, both in aqueous buffer (pH 7) and FESSIF (pH 5). TML prodrug 9 provided superior in vivo performance, delivering high plasma concentrations of PIB in PK studies conducted in mice, dogs, and monkeys. The improved dissolution properties of these phosphate prodrugs provide them the potential to simplify drug dosage forms for PIB-containing HCV therapy.

A Thorough QT Study of the Combination Glecaprevir + Pibrentasvir on Cardiac Repolarization in Healthy Subjects

PurposeFixed-dose combination glecaprevir (GLE) 300 mg + pibrentasvir (PIB) 120 mg is an orally administered once daily antiviral regimen approved for the treatment of hepatitis C virus (HCV) infection. The objective of this study was to evaluate the potential for cardiac repolarization following GLE + PIB administration in healthy adults. MethodsThis placebo- and active-controlled, randomized, single-dose, 4-period, 4-sequence crossover study enrolled 48 healthy subjects. The doses of GLE 400 mg + PIB 120 mg were selected to provide exposures comparable to those with the doses that are therapeutic in the HCV-infected population, GLE 300 mg + PIB 120 mg. The doses of GLE 600 mg + PIB 240 mg were selected to provide supratherapeutic exposures without exceeding the exposures of the GLE + PIB maximal tolerated doses. Moxifloxacin 400 mg (active control/open label) was used for confirming the sensitivity of the ECG assay in detecting QTc prolongation. Time-matched plasma concentrations and triplicate ECGs were obtained on treatment days −1 and 1. The primary end point was time-matched, placebo-corrected, baseline-adjusted Fridericia-corrected QT interval (ΔΔQTcF). Pharmacokinetic–pharmacodynamic analyses characterized the relationship between GLE and PIB plasma concentrations and ΔΔQTcF using a linear regression model and linear mixed-effects model. Findings from categorical analyses of ECG-interval data were also summarized. Tolerability was evaluated through adverse-events monitoring, physical examination including vital sign measurements, ECGs, and laboratory tests. FindingsA total of 48 subjects (22 women [46%], 26 men [54%]), were enrolled in the study, and 47 subjects completed all 4 periods. None of the subjects had a change from baseline in QTcF interval of >30 msec or an absolute QTcF interval of >450 msec. Peak ΔΔQTcF values observed at 5 h postdose (Tmax) were 2.9 msec (upper 95% confidence limit, 4.9 msec) with the therapeutic dose and 3.1 msec (upper 95% confidence limit, 5.1 msec) with the supratherapeutic dose, with both upper 95% confidence limits well below the 10-msec threshold. Assay sensitivity was confirmed by peak ΔΔQTcF in the positive control (12.8 ms at 2 h postdose). No statistically significant GLE or PIB concentration-dependent effects on ΔΔQTcF were observed. Headache and skin irritation from ECG electrodes were the most commonly reported AEs. No clinically significant vital sign measurements, ECG findings, or laboratory measurements were observed. There were no patterns of T- and U-wave morphologic abnormalities. ImplicationsThe fixed-dose combination regimen of GLE/PIB does not prolong the QTc interval. ClinicalTrials.gov identifier.

Marked heterogeneity in the diagnosis of compensated cirrhosis of patients with chronic hepatitis C virus infection in a real-world setting: A large, multicenter study from Japan.

The presence of cirrhosis is an important factor for the management of patients with hepatitis C virus (HCV) infection and it determines the duration of treatment for HCV with the direct-acting antiviral (DAA) regimen of glecaprevir (GLE) and pibrentasvir (PIB), that is, 8 or 12weeks, if patients do not have a history of DAA failure. However, in real-world settings, determination of cirrhosis depends on the discretion of the attending hepatologists, and it is unclear whether compensated cirrhosis was homogenously diagnosed or not. In this study, we investigated the real-world diagnosis of cirrhosis by characterizing DAA-naïve patients who underwent a 12-week GLE/PIB regimen in whom cirrhosis was diagnosed, comparing their characteristics with those of patients who underwent an 8-week regimen in whom cirrhosis was absent. In a large, multicenter cohort study, we compared background characteristics and treatment outcomes among DAA-naïve patients who underwent an 8-week versus a 12-week GLE/PIB regimen. Among 977 patients enrolled, 296 (30.3%) were determined to have cirrhosis and underwent a 12-week regimen. Some patient characteristics largely overlapped between the two groups, including liver fibrosis indices. Sustained viral response rates were similar between groups after adjusting liver fibrosis index with propensity score matching. Although adequately diagnosed, the determination of cirrhosis varied widely among institutions or by hepatologists in real-world settings, and the severity of liver fibrosis overlapped significantly between patients in whom compensated cirrhosis was determined to be present and patients in whom cirrhosis was absent. Virologic efficacy was similar after adjusting for the degree of liver fibrosis.

Efficacy of Glecaprevir and Pibrentasvir in a Treatment-Experienced Population of HCV-Infected Patients

Glecaprevir plus pibrentasvir (G/P) is FDA-approved for the treatment of hepatitis C virus (HCV) infection in treatment-naive and treatment-experienced

Development of validated stability indicating RP-HPLC method for the estimation of glecaprevir and pibrentasvir in bulk and pharmaceutical dosage form

Simultaneous spectrophotometric determination of cefpodoxime proxetil and ofloxacin in tabletsPatel Sanket A, Patel Satish A

Efficacy of glecaprevir and pibrentasvir treatment for genotype 1b hepatitis C virus drug resistance-associated variants in humanized mice.

Combination therapy with glecaprevir (GLE) and pibrentasvir (PIB) has high efficacy for pan-genotypic hepatitis C virus (HCV)-infected patients. However, the efficacy for patients who acquired potent NS5A inhibitor resistance-associated variants (RAVs) as a result of failure to respond to previous direct-acting antiviral (DAA) therapies is unclear. We investigated the efficacy of GLE/PIB treatment for genotype 1b HCV strains containing RAVs using subgenomic replicon systems and human hepatocyte transplanted mice. Mice were injected with serum samples obtained from a DAA-naïve patient or daclatasvir plus asunaprevir (DCV/ASV) treatment failures including NS5A-L31M/Y93H, -P58S/A92K or -P32 deletion (P32del) RAVs, then treated with GLE/PIB. HCV was eliminated by GLE/PIB treatment in mice with wild-type and NS5A-L31M/Y93H but relapsed in mice with NS5A-P58S/A92K, followed by emergence of additional NS5A mutations after cessation of the treatment. In NS5A-P32del-infected mice, serum HCV RNA remained positive during the GLE/PIB treatment. NS5A-P58S/A92K showed 1.5-fold resistance to PIB relative to wild-type based on analysis using HCV subgenomic replicon systems. When mice were administered various proportions of HCV wild-type and P32del strains and treated with GLE/PIB, serum HCV RNA remained positive in mice with high frequencies of P32del. In these mice, the P32del was undetectable by deep sequencing before GLE/PIB treatment, but P32del strains relapsed after cessation of the GLE/PIB treatment. GLE/PIB is effective for wild-type and NS5A-L31M/Y93H HCV strains, but the effect seems to be low for P58S/A92K and NS5A-P32del RAVs. Although NS5A-P32del was not detected, the mutation may be present at low frequency in DCV/ASV treatment failures.

Upcoming direct acting antivirals for hepatitis C patients with a prior treatment failure.

Despite the high efficacy of direct acting antivirals (DAAs) not all patients successfully clear hepatitis C virus infection, in fact, approximately 1–3% fail to reach a sustained virological response 12 weeks after end of treatment. DAA failures are characterized by advanced liver disease, specific genotypes/subtypes and resistance associated substitutions to the DAA class they have been treated with. Current European Association for the Study of the Liver guidelines recommend three therapeutic options for such patients. The first is a 12 week course of sofosbuvir (SOF), velpatasvir (VEL) and voxilaprevir (VOX), which has shown to be effective in 90–99% of patients and was granted A1 level recommendation. The second option, reserved for patients who have predictors of failure consists in 12 weeks regimen with glecaprevir (GLE) and pibrentasvir (PIB), effective in 90–97%. Finally, although not supported by published data, for especially difficult to treat patients there should theoretically be a benefit in prolonged combinations of SOF+GLE/PIB or SOF/VEL/VOX±ribavirin. This review presents the latest evidence from both clinical trials and real-life on such therapeutic strategies.

Glecaprevir and pibrentasvir for Japanese patients with chronic hepatitis C genotype 1 or 2 infection: Results from a multicenter, real-world cohort study.

Glecaprevir (GLE) and pibrentasvir (PIB) are new direct-acting antiviral agents (DAAs) with pangenotypic inhibitors that respectively target the hepatitis C virus (HCV) NS3/4 protease and NS5A. The aim of this study was to evaluate the effectiveness and safety of combining GLE and PIB for patients with HCV genotype (GT) 1 or 2 infection in the clinical setting, including patients DAA-experienced or on hemodialysis. This multicenter, real-world, retrospective, cohort study consisted of 314 Japanese patients who were treated with GLE (300mg) and PIB (120mg) for a fixed 8- or 12-week duration. We evaluated the sustained virologic response rate 12weeks after the end of treatment (SVR12) and adverse events. Among the treated patients, 122 had GT1 and 192 GT2 infection. The overall SVR12 rates in the per-protocol populations were 99.2% (119/120) for GT1 and 98.9% (183/185) for GT2. High SVR12 rates were observed in almost all subgroups, including cirrhosis, receiving hemodialysis, or previous all-oral DAA groups treated with asunaprevir and daclatasvir (GT1b), ledipasvir/sofosbuvir (GT1), or sofosbuvir and ribavirin (GT2). Virological relapse occurred in only 1.0% (3/305) of the patients who completed treatment. The most common adverse events were pruritus and fatigue (>5% of patients). Serious adverse events were rare and discontinuation due to an adverse event was required for 1.6% of the patients. In this real-world cohort study, treatment with GLE/PIB achieved high SVR12 rates with a low rate of serious adverse events among patients with HCV GT1 or 2 infection.