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This study assessed the efficacy and safety of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) combined with dasabuvir (DSV) for treating hepatitis C genotype 4 (GT4) and genotype 1 (GT1) in patients with stage 4 or 5 chronic kidney disease (CKD). Among 88 patients, including treatment-naïve and Peginterferon/Ribavirin (RBV)-experienced, treated with OBV/PTV/r±RBV (dosed between 200 mg per week to daily) and additional DSV for GT1, 94.3% achieved sustained virologic response at 12 weeks (SVR12), demonstrating high efficacy. RBV was used at the discretion of the treating physician. The treatment was well-tolerated, with two non-treatment-related deaths reported. The findings suggest that a 12-week regimen of OBV/PTV/r±DSV is highly effective and safe for GT1 and GT4 patients with advanced CKD, regardless of baseline characteristics.

Aim: Utilizing the therapeutic potentials of previously approved medications against a new target or pharmacological response is known as drug repurposing. The health and scientific communities are under continual pressure to discover new compounds with antiviral potential due to the rising reports of viral resistance and the occurrence and re-emergence of viral outbreaks. The use of antiviral peptides has emerged as an intriguing option in this search. Here, this article includes the current United States Food and Drug Administration (FDA)-approved antiviral peptides that might be enforced for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and carried out docking study of the viral protease inhibitors. Methods: In silico techniques like molecular docking was carried out using Autodock Vina software. Results: The molecular docking studies of peptide-based antiviral agents against SARS-CoV-2 [Protein Data Bank (PDB) ID: 7P35] using docking software AutoDockTools 1.5.6. Among all the docked ligands, compound velpatasvir showed interaction with residues ILE213, GLN256, LEU141, GLN189, GLU166, HIS41, CYS145, and ASN142, and displayed the highest docking score of –8.2 kcal/mol. This medication could be a novel treatment lead or candidate for treating SARS-CoV-2. Conclusions: To conclude, a docking study of peptide based antiviral compounds for their binding mode in the catalytic domain of SARS-CoV-2 receptor is reported. On molecular docking, the compounds have showed remarkable binding affinity with the amino acids of receptor chain A. The compounds occupied the same binding cavity as the reference compound maintaining the interactions with conserved amino acid residues essential for significant inhibitory potential, especially for compound velpatasvir with binding score of –8.2 kcal/mol.

The immunosuppressive agents sirolimus and everolimus are sensitive CYP3A4 substrates with narrow therapeutic index. Ritonavir is a strong CYP3A inhibitor. A phase 1 study was conducted to evaluate the pharmacokinetics, safety, and tolerability of the co‐administration of sirolimus or everolimus with the ritonavir‐containing 3D regimen of the direct‐acting antiviral agents ombitasvir, ritonavir‐boosted paritaprevir, and dasabuvir in healthy subjects. This study had two independent arms, each with a two‐period, single‐sequence, crossover study design. A single dose of sirolimus 2 mg (N = 12) or everolimus 0.75 mg (N = 12) was administered in Period 1. In Period 2, multiple doses of the 3D regimen (ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily and dasabuvir 250 mg twice daily) were administered for 34 or 28 days, with a single dose of sirolimus 0.5 mg or everolimus 0.75 mg co‐administered on Day 15. Following co‐administration with the 3D regimen, the sirolimus dose‐normalized maximum observed blood concentration (Cmax) and area under the blood concentration–time curve from time zero to infinity (AUCinf) increased to 6.4‐fold and 38‐fold, respectively. Following co‐administration with the 3D regimen, the everolimus Cmax and AUCinf increased to 4.7‐fold and 27‐fold, respectively. Sirolimus and everolimus half‐lives increased from 96 to 249 h, and 42 to 118 h, respectively. There were no major safety or tolerability issues in this study. The ritonavir‐containing 3D regimen resulted in a significant increase in sirolimus or everolimus exposure, consistent with the known strong inhibitory effect of ritonavir on CYP3A requiring dose and/or frequency modification when co‐administered with each other. [ABSTRACT FROM AUTHOR]

Abstract The immunosuppressive agents sirolimus and everolimus are sensitive CYP3A4 substrates with narrow therapeutic index. Ritonavir is a strong CYP3A inhibitor. A phase 1 study was conducted to evaluate the pharmacokinetics, safety, and tolerability of the co‐administration of sirolimus or everolimus with the ritonavir‐containing 3D regimen of the direct‐acting antiviral agents ombitasvir, ritonavir‐boosted paritaprevir, and dasabuvir in healthy subjects. This study had two independent arms, each with a two‐period, single‐sequence, crossover study design. A single dose of sirolimus 2 mg (N = 12) or everolimus 0.75 mg (N = 12) was administered in Period 1. In Period 2, multiple doses of the 3D regimen (ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily and dasabuvir 250 mg twice daily) were administered for 34 or 28 days, with a single dose of sirolimus 0.5 mg or everolimus 0.75 mg co‐administered on Day 15. Following co‐administration with the 3D regimen, the sirolimus dose‐normalized maximum observed blood concentration (Cmax) and area under the blood concentration–time curve from time zero to infinity (AUCinf) increased to 6.4‐fold and 38‐fold, respectively. Following co‐administration with the 3D regimen, the everolimus Cmax and AUCinf increased to 4.7‐fold and 27‐fold, respectively. Sirolimus and everolimus half‐lives increased from 96 to 249 h, and 42 to 118 h, respectively. There were no major safety or tolerability issues in this study. The ritonavir‐containing 3D regimen resulted in a significant increase in sirolimus or everolimus exposure, consistent with the known strong inhibitory effect of ritonavir on CYP3A requiring dose and/or frequency modification when co‐administered with each other.

Abstract Background Prevalence of hepatitis C virus infection in patients with renal diseases is higher compared to the general population. FDA has approved ombitasvir/paritaprevir/ ritonavir for the treatment of patients with severe renal disease. This study aimed to evaluate the efficacy and safety of ombitasvir/paritaprevir/ritonavir with or without ribavirin in treatment of chronic hepatitis C Egyptian hemodialysis patients to compare it with the same treatment result in chronic hepatitis C Egyptian patients with normal renal functions. This case-control study was conducted on one hundred patients with confirmed diagnosis of HCV-positive infection at the Center of National Committee for Control of Viral Hepatitis [NCCVH] at Ain Shams University Hospital. Patients were divided into two groups: group I (control group) with 50 chronic hepatitis C virus patients with normal renal functions and group II (Case Group) with 50 chronic hepatitis C virus hemodialysis patients. Results 95.1% of prevalent hemodialysis patients achieved sustained virological response (SVR), while 100% of patients with normal kidney functions achieved sustained virological response. Most common side effects were hemoglobin drop, gastrointestinal disturbance, severe fatigue, and itching. Conclusion Ombitasvir, paritaprevir, and ritonavir are considered a safe and effective in treatment in HCV infection in patients on regular hemodialysis as in chronic hepatitis C virus infection patients with normal kidney functions.

Introduction and Aims: Treatment of hepatitis C virus (HCV) genotype 4 patient with fixed dose combination of ombitasvir‐paritaprevir‐ritonavir plus ribavirin (OBV/rPTV/RBV) has been proven efficacy and safety in many clinical trials. The current study reports the efficacy and safety of OBV/rPTV/RBV (for treatment‐naïve), and OBV/rPTV/RBV/sofosbuvir (SOF) (for treatment‐experienced), in chronic HCV genotype 4 patients in real life settings. Methods: Prospective cohort study including all adult chronic HCV genotype 4 patients who were scheduled to receive OBV/rPTV/RBV ± SOF for 12 or 24 weeks in New Cairo Viral Hepatitis Treatment Center. The primary efficacy endpoint was a virologic response at posttreatment week 12 (SVR12). Changes in hematological parameters, liver biochemical profile and fibrosis‐4 index (FIB‐4), as well as clinical and laboratory adverse events (AEs) across follow up visits (week 4, end of treatment [EOT], and SVR12), were recorded. Results: Our study included 325 patients (age; 47.63 ± 12.63 years, 55.38% [n = 180] men). Most of the included patients (89.85%, n = 292) were treatment naïve and only 7% (n = 23) had liver cirrhosis. Overall, SVR12 was attained by 98.44% (316 of 321) of the patients; 97.15% (307 of 316) of patients who received 12 weeks of OBV/rPTV/RBV ± SOF and 100% (9 of 9) of patients who received 24 weeks of OBV/rPTV/RBV as assessed by modified intention to treat analysis. There was a significant improvement of baseline alanine aminotransferase, aspartate aminotransferase, hemoglobin, FIB‐4 at SVR12 (P < 0.05). The most common reported AEs were anemia (n = 106), fatigue (n = 41) and elevated indirect bilirubin (n = 37). Conclusion: OBV/rPTV/RBV (±SOF) is a highly effective therapy for chronic HCV patients in real life settings. Highlight: Treatment of chronic HCV patients with ombitasvir‐paritaprevir‐ritonavir was highly effective in real life settings (cure rate 98.44%).We noticed significant improvement of baseline hepatic necroinflammatory markers, hemoglobin, FIB‐4 at SVR12 (p < 0.05).The most common reported treatment related adverse events were anemia, fatigue and indirect hyperbilirubinemia. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the efficacy and safety of ombitasvir (OMV), paritaprevir (PTV), ritonavir (r), ribavirin (RBV) (OMV/PTVr + RBV), ledipasvir (LDV) and sofosbuvir (SOF) therapies in genotype 4 (GT4) patients, and to determine if the rapid virological response (RVR) observed at 4th week of therapy has a role in predicting sustainability of the response at week 12 (SVR12) post-therapy. Methods: The investigation included 71 subjects with diagnosis of Hepatitis C (HCV) GT4. Some of the patients (40/71) were treated using combination of OMV (25 mg/day), PTV (150 mg/day), ritonavir (r) (100 mg/day), while the others (31/71) were treated using combination of LDV (90 mg/day) and SOF (400 mg/day). Body weight-based RBV was added to both treatment regimens, and the treatments given for a total of 84 days. Viral levels in the patients were evaluated after the 4th and 12th week of drug administration, and at 12 weeks post-administration. Results: The SVR12 responses of the patients on the basis of sub-groups, were 97.5 % for OMV/PTVr + RBV, 96.8 % for LDV/SOF + RBV (p = 0.6); 91.3 % for cirrhotic, 100 % for non-cirrhotic (p = 0.1); 100 % in untreated, and 95.5 % for treated (p = 0.33). While there were numerical differences, these were not statistically significant. The SVR12 response was 100 % in patients with RVR response, and 87.5 % for patients without RVR response (p < 0.05). When the patients’ aspartate transaminase (AST), alanine transaminase (ALT), platelet (PLT), albumin, creatinine, prothrombin time (PT) and fib4 values before and after treatment were compared, significant difference were observed for all variables (p < 0.01), except for PT (p = 0.3). there were no dangerous adverse events such as decompensation or death, aside from mild fatigue, with incidence of 19 %. Conclusion: RVR response after OMV/PTVr + RBV and LDV/SOF + RBV treatments show that the treatments can be used safely and effectively in patients with HCV genotype 4. Moreover, RVR might be a suitable determinant of SVR12 response. [ABSTRACT FROM AUTHOR]

This study assessed the efficacy and safety of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) combined with dasabuvir (DSV) for treating hepatitis C genotype 4 (GT4) and genotype 1 (GT1) in patients with stage 4 or 5 chronic kidney disease (CKD). Among 88 patients, including treatment-naïve and Peginterferon/Ribavirin (RBV)-experienced, treated with OBV/PTV/r±RBV (dosed between 200 mg per week to daily) and additional DSV for GT1, 94.3% achieved sustained virologic response at 12 weeks (SVR12), demonstrating high efficacy. RBV was used at the discretion of the treating physician. The treatment was well-tolerated, with two non-treatment-related deaths reported. The findings suggest that a 12-week regimen of OBV/PTV/r±DSV is highly effective and safe for GT1 and GT4 patients with advanced CKD, regardless of baseline characteristics., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Pharmacy and Bioallied Sciences.)

Antiviral therapeutics are highly effective countermeasures for the treatment of coronavirus disease 2019 (COVID-19). However, development of resistance to antivirals undermines their effectiveness. Combining multiple antivirals during patient treatment has the potential to overcome the evolutionary selective pressure towards antiviral resistance, as well as provide a more robust and efficacious treatment option. The current evidence for effective antiviral combinations to inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication is limited. Here, we demonstrate a combination of nirmatrelvir with ombitasvir, to jointly bring about potent inhibition of SARS-CoV-2 replication. We developed an in vitro 384- well plate cytopathic effect assay for the evaluation of antiviral combinations against Calu-3 cells infected with SARS-CoV-2 and found, that a combination of ombitasvir and nirmatrelvir was synergistic; thereby decreasing the nirmatrelvir IC 50 by approx. 16-fold. The increased potency of the nirmatrelvir-ombitasvir combination, over nirmatrelvir alone afforded a greater than 3 log 10 reduction in viral titre, which is sufficient to fully prevent the detection of progeny SARS-CoV-2 viral particles at 48 h post infection. The mechanism of this potentiated effect was shown to be, in-part, due to joint inhibition of the 3-chymotrypsin-like protease via a positive allosteric modulation mechanism. • We identified efficient combinations of antiviral compounds to inhibit SARS-CoV-2 replication. • Ombitasvir and nirmatrelvir combinations revealed synergistic interactions. • This potency, in part, is due to joint inhibition of the 3-chymotrypsin-like protease. [ABSTRACT FROM AUTHOR]

Introduction and aim. We assessed the characteristics of virological response to a combination treatment of ombitasvir, paritaprevir, and ritonavir in hepatitis C virus genotype 1-infected elderly Japanese patients.Material and Methods. This multicenter prospective study was conducted at six locations in Japan. Seventy patients with chronic hepatitis C virus genotype 1b infection were orally administered ombitasvir/paritaprevir/ritonavir once daily for 12 weeks. The primary endpoint was the proportion of elderly patients with sustained virological response (SVR) 12 weeks after the completion of treatment. Adverse events were also recorded to evaluate drug safety and tolerability during the trial period. SVR in elderly patients (age > 65; 94% [47 / 50]) was lower than that in younger patients (100% [20 / 20]).Results. No significant differences in SVR 12 weeks after the completion of treatment were observed between the age groups (P = 0.153). Adverse events were observed in 16 patients (23.3%). Multivariate analysis confirmed that the change or discontinuation of concomitant drugs owing to drug interactions was independent of risk factors for adverse events associated with this drug combination (P = 0.015; odds ratio, 15.9; 95% confidence interval, 1.79 - 148). Ombitasvir/paritaprevir/ritonavir combination treatment was highly effective in elderly patients.Conclusion. Tolerability should be monitored in older patients for whom concomitant medications are discontinued or changed because of drug interactions.

Background: The purpose of this study was to assess the antiviral efficacy and safety of the direct-acting antivirals (DAAs) in therapy of chronic hepatitis C virus (HCV) infection. Methods: This real-life multi-centric study was performed at the Clinic for Infectious Diseases, University Clinical Centre of the Republic of Srpska, Banja Luka and it included a total of 89 patients. All patients received the adequate doses of ombitasvir (OBV)/ paritaprevir (PTV)/ritonavir (RTV) + dasabuvir (DSV) plus ribavirin (RBV). RBV was given to all patients except to those with HCV sub-genotype 1b. DSV was not administered to patients infected with HCV genotype 4. For the majority of patients the treatment duration was 12 weeks. For ten patients with liver cirrhosis the duration of treatment was 24 weeks. Viraemia was assessed at three points in time: at baseline, 12 or 24 weeks after the beginning of treatment (end of treatment response - ETR), and 12 weeks after the end of treatment (sustained viral response - SVR). Results: Complete ETR after 12 weeks of treatment was achieved in 79 patients, while in 10 high-risk patients it was achieved after 24 weeks of treatment. Full SVR was recorded in 88 patients 12 weeks after the end of treatment. This therapy was well tolerated and mild adverse effects were recorded in only 10 patients. Conclusion: Treatment of patients with chronic HCV infection with OBV/PTV/ RTV+ DSV + RBV resulted in excellent antiviral activity and mild adverse events.

The ternary mixture under study is a recent hepatitis‐C antiviral medicine composed of three new directly acting antiviral drugs, namely, ombitasvir, paritaprevir, and ritonavir. They are co‐formulated as a single‐dose combined tablet dosage form. With more than 170 million infected patients worldwide, a large production scales of antivirals medicine is expected, and hence, new simple and fast methodologies are required to cover millions of analyses that are done routinely in the different pharmaceutical quality control and research laboratories. Ultraviolet spectrophotometry represents sensitive, fast, and cheap tool of analysis in all research and quality control laboratories that can cover the massive quality control of these regimens. However, the simultaneous determination of these three drugs using multivariate chemometric methods represents a high challenge as their spectra are strongly overlapping besides the large difference in their potency within the same tablet. In this research paper, four new different multivariate chemometric methods were developed for their simultaneous determination, namely, classical least square (CLS), principal component regression (PCR), partial least squares (PLS), and genetic algorithm‐partial least squares (GA‐PLS) techniques. The validated methods do not require extraction, separation, or derivatization steps. A comparative study was conducted among the four developed methods. All methods provided satisfactory results, whereas GA‐PLS showed better analytical performance as it had the lowest error with good higher correlation coefficient. The methods were applied in the simultaneous determination of the three drugs in pure form and in their combined tablet dosage form. The comparison confirmed agreement of the values obtained for all techniques. Ombitasvir, paritaprevir, and ritonavir are coformulated as a single‐dose combined tablet dosage form. In this research paper, four new different multivariate chemometric methods were developed for their simultaneous determination, namely, classical least square (CLS), principal component regression (PCR), partial least squares (PLS), and genetic algorithm‐partial least squares (GA‐PLS) techniques. The methods were applied in the simultaneous determination of the three drugs in pure form and in their combined tablet dosage form. [ABSTRACT FROM AUTHOR]

The current article describes the development of a systematic, science and risk-based stability-indicating LC-UV method for the routine analysis of Ombitasvir, Paritaprevir and Ritonavir in quality control laboratories from its bulk and formulated products. To mark the importance of QbD in the new era comparative results of this with other methods available from literature and validation data were presented. Quality by design approach was employed for optimization of method parameters like Organic phase, pH and Flow rate. The interaction effect of these parameters on the response variable theoretical plate number was evaluated through contour plots. Development of method was done using PHENOMENOX C18 (150 mm x 4.6 mm,5μm particle size) column in isocratic mode using Ammonium acetate buffer (pH adjusted to 6) and Acetonitrile (60:40%v/v) as mobile phase at a detection wavelength of 265nm and flow rate of 1.0 ml/min. The three-drug retention times were found to be 3.21 minutes for Ritonavir, 5.71 minutes for Ombitasvir, 6.41 minutes for Paritaprevir. The calibration plots linear regression analysis showed a good linear relationship with r²=0.999 for Ritonavir, r²=0.999 for Ombitasvir, r²=0.999 for Paritaprevir in the range of 12.5-75μg/ml, 3.125-18.75μg/ml,18.75-112.5μg/ml respectively. The HPLC method was applied for quantification of studied drugs in tablets; results agreed with label claim and were validated according to ICH guidelines. This is the first RP-HPLC method reported for the assay of three drugs in bulk and formulations by QbD approach. [ABSTRACT FROM AUTHOR]

Background & Aims: The 12-week regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir (OPrD) has shown high efficacy and tolerability in clinical trials for the treatment of chronic hepatitis C virus (HCV). The shorter 8-week regimen has been recently incorporated into clinical guidelines and on-label indications, but real-world evidence on its use is limited. Given this knowledge gap, the AMETHYST study aimed to evaluate the effectiveness of the 8- and 12-week regimens of OPrD in treatment-naive patients with HCV with mild to moderate liver fibrosis in Romanian clinical practice. Methods: This was a secondary data collection study analyzing data from a 1-year Patient Support Program in HCV in Romania. Patients received OPrD treatment for 8 or 12 weeks. The effectiveness endpoint was sustained virologic response 12 weeks post-treatment (SVR12). Results: A total of 1,835 treatment-naive patients with HCV with mild or moderate fibrosis were included in the study. Of these, 426 and 1,375 completed the 8-week and 12-week regimens, respectively. SVR12 was 98.1% in the 8-week treatment group and 98.7% in the 12-week treatment group. Conclusion: The study provides real-world evidence that 8-week and 12-week treatment regimens of OPrD are highly effective in treatment-naive patients with HCV with mild to moderate liver fibrosis. [ABSTRACT FROM AUTHOR]

Objective: Hepatitis C virus (HCV) infection is a global problem with personal, social and economic impacts. Approximately 85% of patients infected with HCV cannot achieve virus clearance. Cirrhosis, hepatocellular carcinoma and death may develop in patients with chronic infection.Until recently, treatments for chronic hepatitis C were difficult to use with many side effects, low treatment responses, and relapses. Direct-acting antivirals (DAAs) prevent HCV replication, and thir effectiveness is over 90%. In this study, we aimed to evaluate the achievement of these treatments. Methods: Fifty patients who would receive a DAA treatment regimen, i.e. sofosbuvir/ledipasvir (SOF/LDV) ± ribavirin (RBV) or paritaprevir/ritonavir/ombitasvir/dasabuvir (PrOD) ± RBV were included in the study. Laboratory values and HCV RNA results of all patients were evaluated before, at the 12th week and 24th week of treatment (at the 36th week for those who received 24 weeks of treatment), and aspartate aminotransferase (AST) to platelet ratio index (APRI), Fibrosis-4 (FIB-4), model for endstage liver disease (MELD) scores were calculated. Results: In 47 of 50 patients included in the study, who sustained viral response (SVR-12) could be evaluated at week 12, and HCV RNA was found negative in all patients evaluated. None of the patients had any side effects requiring discontinuation, and the most common side effect was weight gain.There was a significant decrease in AST and alanin aminotransferase (ALT) compared to their initial values.The calculated FIB-4 and APRI scores of the patients decreased significantly at the end of the treatment and in the SVR-12 period. Conclusions: DAAs used in the treatment of HCV infection provide a high rate of SVR without any significant side effects. [ABSTRACT FROM AUTHOR]

Background/Aims: Chronic hepatitis C (HCV) virus infection reactivates under immunosuppressive drugs and therefore has a negative impact on long-term survival of kidney transplant recipients. Treatment-induced clearance of hepatitis C virus (HCV) in kidney transplant candidates prevents virus reactivation after transplantation. Paritaprevir/Ritonavir/Ombitasvir with Dasabuvir (PrOD) represents a highly effective treatment regimen for HCV genotype 1 (GT1), also suitable for patients with end-stage renal disease (ESRD). Serious drug-drug interactions may represent a limiting factor of this regimen. The aim of this retrospective study was to evaluate safety, efficacy and drug-drug interactions management associated with PrOD treatment in the Czech real-world cohort. Methods: Emphasizing concomitant medication adjustment, we described the treatment course with PrOD regimen in 23 patients (4 with CKD4 and 19 on maintenance haemodialysis) infected with HCV GT1 (21 GT1b, 2 GT1a), 18 males and 5 females with an average age of 53.7 years. Six patients had compensated liver cirrhosis and 3 of them were liver transplant recipients. Results: All 23 patients completed the 12-week treatment and achieved sustained virological response 12 weeks after the treatment (SVR12 rate 100%). None of the patients presented with a significant decrease in haemoglobin level, white blood cell and platelet count during the treatment period. The most frequent adverse events were nausea, hypotension, diarrhoea, and hyperkalemia. Four patients presented with a serious adverse event unrelated to the antiviral drugs (salmonellosis, non-functional kidney graft rejection, early gastric cancer, renal cyst infection, initiation of haemodialysis). Concomitant medication had to be modified with the treatment initiation in 10 out of 23 (43.5%) patients (calcium channel blockers, ACE inhibitors, statins, diuretics, tacrolimus); four patients required further adjustment of antihypertensive drugs or tacrolimus dosage on-treatment. Conclusion: PrOD regimen demonstrated an excellent efficacy and good tolerability. Both prospective adjustment of concomitant medication and further on-treatment adjustment allowed for a safe treatment course.

What is known and objective: Direct‐acting antivirals (DAAs) have become the most widely used treatment of chronic hepatitis C infection. Comparative studies on DAAs regimens approved by the Egyptian Ministry of Health for easy‐to‐treat genotype 4 (G4) Egyptian patients are still deficient. In this prospective study, we compared the efficacy and cost of two DAA regimens that are used in the treatment of Egyptian chronic hepatitis C virus (HCV) G4. The cost‐saving regimen is determined. Methods: Eligible patients were randomized into 2 groups. Group 1 (Gp 1) received sofosbuvir plus daclatasvir, and group 2 (Gp 2) received ombitasvir, paritaprevir and ritonavir plus ribavirin (RBV) for 12 weeks. Data were collected and evaluated at baseline and at weeks 4, 8 and 12. Sustained virologic response 12 weeks after the end of treatment (SVR12) was evaluated. Cost‐minimization analysis (CMA) was performed. Results and discussion: Eligibility was achieved in 107 patients, Gp1 included 57 patients, and Gp 2 included 50 patients. Two patients dropped out from Gp 2 due to non‐compliance. All patients in the two groups showed negative HCV blood levels at the end of treatment. At the 24th week, 3 relapsers (5.2%) were detected in Gp1 and 2 relapsers (4.1%) were detected in Gp 2. SVR12 was 54/57 (94.7%) and 46/48 (95.8%) for Gp 1 and Gp 2, respectively. After the 12th week of treatment, a significant decrease in aspartate aminotransferase (AST), alanine aminotransferase (ALT) and haemoglobin levels were observed in both groups. Albumin levels declined in Gp 2 only. CMA showed higher cost in Gp 2 than Gp 1, although similar efficacy and safety. What is new and conclusion: The two DAA regimens showed high SVR12 and safety in Egyptian HCV G4 patients. Sofosbuvir plus daclatasvir is the cost‐saving regimen. [ABSTRACT FROM AUTHOR]

Background and Aim: Data regarding the efficacy and safety of paritaprevir/ritonavir, ombitasvir plus dasabuvir (PrOD) for East Asian non‐cirrhotic hepatitis C virus genotype 1b (HCV GT1b) patients receiving hemodialysis were limited. Methods: Forty‐six HCV GT1b non‐cirrhotic patients receiving hemodialysis who received PrOD for 12 weeks were prospectively enrolled in seven academic centers in Taiwan. The primary efficacy endpoint was sustained virologic response 12 weeks off‐therapy (SVR12). Patients' baseline characteristics, early virokinetics, and HCV resistance‐associated substitutions (RASs) potentially related to SVR12 were analyzed. The safety profiles were also assessed. Results: The SVR12 rate was 100% (46 of 46 patients). Patients' baseline characteristics, on‐treatment viral decline, and baseline HCV resistance‐associated substitutions did not affect SVR12. All patients tolerated treatment well. One patient with folliculitis temporarily discontinued treatment, and another two patients had serious adverse events (SAEs), which were considered not related to PrOD treatment. The common adverse events were pruritus (19.6%), fatigue (15.2%), and upper respiratory tract infection (6.5%). Twelve (19.6%) and one (2.2%) patients had hemoglobin levels < 10 and 8.5 g/dL, respectively, which were related to renal impairment. Five (10.9%) patients had on‐treatment total bilirubin level of 1.5–3.0 mg/dL, but none developed hepatic decompensation. The bilirubin levels peaked at week 1 of treatment and then declined with continuous treatment. Conclusion: Treatment with PrOD for 12 weeks is efficacious and well‐tolerated for East Asian non‐cirrhotic HCV GT1b patients receiving hemodialysis. [ABSTRACT FROM AUTHOR]

Background & Aims: The interferon‐free regimen paritaprevir/ritonavir, ombitasvir + dasabuvir (PTV/r/OBV/DSV) has shown high efficacy in patients with hepatitis C virus (HCV) genotype 1b infection when administered for 8 or 12 weeks, but data regarding the 8‐week treatment are scarce. The aim of our study was to assess the efficacy and safety of the 8‐week administration of PTV/r/OBV/DSV in a real‐world cohort. Methods: We performed a multicentre observational study from Spanish Hepa‐C database including patients receiving 8 weeks of PTV/r/OBV/DSV (October 2016‐November 2017). Those with advanced fibrosis, with non‐genotype 1b or who were treatment‐experienced were excluded. Results: A total of 211 patients were registered from 23 Spanish centres; eleven were excluded. At baseline, 42.5% (n = 85) were male, median (range) age was 57 (23‐86), ALT was 45 (11‐494) IU/mL, viral load was 6.1 (3.3‐8.2) log10 IU/mL, and 74.5% had mild liver fibrosis (F0‐F1) and 25.5% moderate fibrosis (F2). At the end of treatment (EOT), HCV viral load was undetectable in 100% (200/200). Seven patients relapsed after treatment discontinuation. Sustained virological response (SVR12) rates by intention‐to‐treat analysis were 96% (192/200). Regarding treatment safety, 2 patients developed ALT elevation >5x ULN, but there were no treatment discontinuations. One patient died 7 weeks after EOT. Conclusion: Treatment with PTV/r/OBV/DSV in genotype 1b‐infected treatment‐naive patients with mild‐moderate fibrosis shows excellent efficacy and safety in real life, similarly to clinical trials. Clinicaltrials.gov, number: NCT03122132. [ABSTRACT FROM AUTHOR]

Background: The present study aimed at evaluation of changes in estimated glomerular filtration rate (eGFR) among chronic Hepatitis C virus (HCV) patients with chronic kidney disease (CKD) Stages 3-5 who were treated with 12 weeks of ritonavir-boosted paritaprevir, ombitasvir plus ribavirin. Methods: Changes in renal functions were compared across follow up time points (baseline, SVR4, and SVR8). Data on on-treatment adverse events (AEs), serious AEs, laboratory abnormalities, treatment discontinuation were collected. Results: 171 patients were included (females 35%, mean age 53 years). 29 patients had liver cirrhosis. The most common etiologies of CKD were diabetes and/or hypertension (n = 67). All included patient reached the end of treatment (EOT) with no treatment discontinuations. The overall EOT response was 100%. 122/122 (100%) patients who reached 4 weeks post-treatment have achieved SVR4, and 80/80 (100%) have achieved SVR12. No reported SAEs. Ribavirin therapy was interrupted in 25% (43/171) of patients due to anemia; 16 patients required blood transfusions. The median eGFR improved from 33.5 (15) mL/min/1.73 m2 at baseline to 35 (36) mL/min/1.73 m2 at SVR8 (p = 0.0003). Conclusions: The use of ombitasvir, paritaprevir, and ritonavir for treatment of HCV-infected patients with advanced renal disease was safe and effective, moreover, it was associated with significantly improved eGFR. [ABSTRACT FROM AUTHOR]

Literature analysis of published data on mechanisms of infection, disease progression and treatment of chronic hepatitis C, associated with systemic cryoglobulinemic vasculitis and kidney involvement is presented. A clinical case of effective treatment of cryoglobulinemic vasculitis associated with HCV infection is described. Female with HCV infection genotype 1b with liver fibrosis 1 grade Metavir developed clinical picture of essential mixed cryoglobulinemia II type with monoclonal IgM/kappa production. Cryoglobulinemia was presented with skin hemorrhagic vasculitis, proliferative vasculitis of small liver vessels, kidney involvement with III type membranoproliferative glomerulonephritis. Treatment with Dasabuvir;Оmbitasvir+Paritaprevir+Ritonavir without immunosuppressive medications or steroids resulted in persistent virologic response by 12 weeks after administration and also dramatic reduction of cryoglobulimenia from 27% to 8%, suppression of detectable IgM/kappa production, diminished skin vasculitis, restoration of glomerular filtration rate, proteinuria and decrease in erythrocyteuria.

Trana Hussaini1,2 1Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada; 2Pharmaceutical Sciences, Vancouver General Hospital, Vancouver, BC, Canada Abstract: The treatment for chronic hepatitis C has been revolutionized with the development of direct-acting antiviral agents. Several regimens have been approved and are currently used in clinical practice, treating a wide range of patient populations infected with hepatitis C. The interferon-free combination of paritaprevir/ritonavir-ombitasvir and dasabuvir (PrOD or the three-drug [3D] regimen) with or without ribavirin is indicated for the treatment of chronic hepatitis C in both treatment-naïve and experienced patients infected with genotype 1, including those coinfected with HIV and patients post-liver transplantation. More recently, paritaprevir/ritonavir-ombitasvir (PrO, or 2D regimen) has been approved in hepatitis C virus patients infected with genotype 4. This review will summarize pharmacokinetic and clinical efficacy data for the 3D regimen in an attempt to help the clinicians delineate its place in the ever-increasing direct-acting antiviral armamentarium for the treatment of chronic hepatitis C. Keywords: hepatitis C, paritaprevir, ombitasvir, dasabuvir, 3D regimen

Hepatitis C virus (HCV) infection is one of the leading causes of end-stage liver disease and the main indication for liver transplantation (LT) in most countries. All patients who undergo LT with detectable serum HCV RNA experience graft reinfection progressing to cirrhosis within five years in 20% to 30% of them. Obtaining a sustained virological response (SVR) greatly improves overall and graft survival. Until 2011, standard antiviral therapy using PEGylated interferon (PEG-IFN) and ribavirin (RBV) was the only effective therapy, with an SVR rate around 30% in this setting. For patients infected with genotype 1, first generation NS3/4A protease inhibitors (PIs), boceprevir (BOC) or telaprevir (TVR), associated with PEG-IFN and RBV for 48 weeks have increased the SVR rates to 60% in non-transplant patients. However, tolerability and drug-drug interactions with calcineurin inhibitors (CNI) are both limiting factors of their use in the liver transplant setting. Over recent years, the efficacy of antiviral C therapy has improved dramatically using new direct-acting antiviral (DAA) agents without PEG-IFN and/or RBV, leading to SVR rates over 90% in non-transplant patients. Results available for transplant patients showed a better efficacy and tolerability and less drug-drug interactions than with first wave PIs. However, some infrequent cases of viral resistance have been reported using PIs or NS5A inhibitors pre- or post-LT that can lead to difficulties in the management of these patients.

A novel micellar electrokinetic capillary chromatographic (MEKC) method was developed for the simultaneous determination of ombitasvir (OMB), paritaprevir (PAR), ritonavir (RIT) and dasabuvir (DAS). The technique was based on the separation of all of the selected drugs in a deactivated fused silica capillary with a background electrolyte solution (BGE) composed of 25 mM phosphate buffer with 30 mM sodium dodecyl sulphate (SDS) (the pH of the aqueous phase was adjusted to 8) mixed with ethanol in a ratio of 65:35 (v/v). The capillary and sample temperature was maintained at 24 °C, and the detection was performed at 239 nm. The electrophoresis was performed by applying high voltage (30 kV) to the capillary. The strategy was completely approved according to ICH rules over the concentration range of 2.5 to 100 µg/mL for all of the drugs. The limits of detection were 0.16 µg/mL (PAR, DAS, and OMB) and 0.625 μg/mL (RIT), while the quantitation limits were 0.31 μg/mL (PAR, DAS, and OMB) and 1.250 μg/mL (RIT). The proposed MEKC method was successfully applied for the quantitation of the four drugs in tablets with high precision and accuracy. For the first time, these drugs were simultaneously determined by capillary electrophoresis. [ABSTRACT FROM AUTHOR]

Context. Hepatitis C and diabetes represent important health problems globally. The new-onset diabetes after transplantation is a particular entity that appears due to the use of immunosuppression among transplanted patients. Objective. We aim to describe the clinical and biological aspects of severe hyperglycemia in a kidney transplant recipient undergoing Interferon-free therapy for chronic hepatitis C, discussing the interference of different factors with the glucose metabolism. Design. The occurrence of diabetes in a patient with history of renal transplantation and Interferon-free treated hepatitis C was studied from both clinical and paraclinical points of view. Subjects and methods. When presenting to the hospital, extensive blood tests were performed on the patient, revealing significant hyperglycemia and an elevated level of blood tacrolimus. Creatinine clearance was calculated. ECG presented T-wave alterations. Intensive insulin protocol was applied, the case being managed in a multidisciplinary approach. Results. Blood glucose and tacrolimus were slowly normalized, under therapy. The antiviral treatment was continued, with the achievement of sustained virologic response. Conclusions. Diabetes mellitus can have many causes, hepatitis C and transplantation both having an impact on glucose metabolism. The association of the three entities should be carefully managed, due to its enhancing effect on morbidity and mortality. [ABSTRACT FROM AUTHOR]

Purpose: To analyse safety and efficacy of treatment based on ombitasvir/paritaprevir/ritonavir/dasabuvir plus ribavirin in the sub-group of GT1 patients older than 65 years.Methods: We collected data extracted from the ABACUS compassionate-use nationwide Italian programme, in patients with cirrhosis due to hepatitis C virus (HCV) Genotype-1 (GT1) or 4 and at high risk of decompensation. GT1-HCV-infected patients received once-daily ombitasvir/paritaprevir, with the pharmacokinetic enhancer ritonavir (25/150/100 mg) and twice-daily dasabuvir (250 mg) plus Ribavirin (RBV) (OBV/PTV/r + DSV + RBV) for 12 (GT1b) or 24 (GT1a) weeks. Endpoints were to evaluate safety and efficacy, the latter defined as HCV RNA negative 12 weeks after the end of treatment (SVR12).Results: Patients who suffered any adverse event (AE) were 74/240 (30.8%); 13/240 (5.4%) discontinued the treatment. A multivariate analysis found albumin < 3.5 g/dL (OR 2.04: 95% CI 1.0-4.2, p < 0.05) and hypertension (OR 4.6: 95% CI 2.3-9.2, p < 0.001) as variables independently associated with AE occurrence. The SVR12 was 95% (228/240). Multivariate analysis identified baseline bilirubin < 2 mg/dL (OR 4.9: 95% CI 1.17-20.71, p = 0.029) as the only variable independently associated with SVR12.Conclusion: Our findings suggest that OBV/PTV/r + DSV + RBV is safe and effective in real-life use in patients with compensated cirrhosis, HCV-GT1 infection, and age over 65. [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: Some individuals with hepatitis C virus infection treated with direct‐acting antivirals require ribavirin to maximize sustained virological response rates. We describe the clinical management of ribavirin dosing in hepatitis C virus‐infected patients receiving ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin. Methods: We performed a post hoc analysis of patients receiving ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin for 12 or 24 weeks in six phase 3 trials. Multivariate stepwise logistic regression models assessed predictors associated with ribavirin dose adjustments and with developing anaemia. Results: Of 1548 patients, 100 (6.5%) modified ribavirin dose due to haemoglobin declines, of which 99% achieved sustained virological response at 12 weeks post‐treatment. Median time to first ribavirin dose reduction was 37 days. Low baseline haemoglobin was significantly associated with an increased risk of requiring ribavirin dose modification (odds ratio: 0.618 [0.518, 0.738]; P < .001) and developing anaemia (odds ratio: 0.379 [0.243, 0.593]; P < .001). Conclusions: Ribavirin dose reductions were infrequent, occurred early in treatment, and did not impact sustained virological response at 12 weeks post‐treatment. Patients with low baseline haemoglobin should be monitored for on‐treatment anaemia. [ABSTRACT FROM AUTHOR]

Abstract: Background & Aims: Limited data have shown high efficacy of co‐formulated ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) in the treatment of hepatitis C virus (HCV) genotype (GT)‐4, and combined with dasabuvir (DSV) in GT1 patients, with chronic kidney disease (CKD) stages 4‐5 (<30 mL/min/1.73 m2). We assessed real‐world safety and efficacy of OBV/PTV/r ± DSV in GT1‐ and 4‐infected patients. Methods: In this observational cohort (n = 67), we enrolled stages 4‐5 CKD treatment‐naïve or Peginterferon/RBV‐experienced GT4‐infected patients (n = 32) treated for 12‐24 weeks with OBV/PTV/r ± RBV, and plus DSV in GT1 patients (n = 35, including 3 with GT1/4 co‐infection). RBV was dosed by physician discretion between 200 mg weekly and 200 mg daily. Primary endpoints were SVR12, calculated on intention‐to‐treat (ITT) basis, and occurrence of serious adverse events. Results: The mean age of the cohort was 45.7 ± 12.7 years, 50.7% were females, 20.9% had cirrhosis, 35.8% were treatment‐experienced and 97% were on haemodialysis. Three patients (F4) received 24‐week treatment, 2 with GT4, and 1 with GT1a; and 19.4% were treated without RBV, including 9 GT1, and 4 GT4. Overall, 65 (97.1%) patients achieved SVR12, including 100% of those with a post‐treatment follow‐up (modified ITT analysis). Of the two patients without SVR12, one died from sepsis‐related complications and the other from a myocardial infarction 2 weeks after completing therapy. Grades 3‐4 anaemia occurred in 8.9%. Conclusion: A 12‐week regimen of OBV/PTV/r ± DSV with or without RBV is highly effective with a favourable safety profile amongst GT4 and GT1 patients with CKD stages 4‐5. SVR12 rates were high regardless of patient characteristics. [ABSTRACT FROM AUTHOR]

Objective: To evaluate factors associated with increased serum cholesterol levels during interferon-free hepatitis C virus (HCV) therapy. Design: Prospective longitudinal study. Methods: HIV-infected patients who started and successfully completed interferon-free therapy for chronic HCV infection were included. Patients were treated using 2 different regimens, based on the clinician's opinion: sofosbuvir and ledipasvir (SOF/LDV), or paritaprevir coadministered with ombitasvir and dasabuvir (PrOD). Both total cholesterol and low-density lipoprotein cholesterol were evaluated at baseline, weeks 1, 2, 4, 8, end of treatment (EOT), weeks SVR4, SVR12, and SVR24. Results: The study population therefore comprised 85 patients reaching sustained virological response, 42 (49.4%) of whom were treated with SOF/LDV, and 43 (50.6%) with PrOD. Patients using SOF/LDV was showed a higher increase on both total cholesterol and low-density lipoprotein cholesterol during treatment period than those receiving PrOD. Analyzing the overall increase from baseline to weeks 1, 2, 4, 8, and EOT, choice of HCV regimen was associated with differential increases in total cholesterol during therapy. After EOT, no differences were found between SOF/LDV and PrOD with respect to total cholesterol. Conclusions: Our study suggests that the differential timing of the restoration of cholesterol metabolism in HIV/HCV genotype 1 coinfected patients achieving sustained virological response is not mediated by HCV clearance but depends on the drug combination used. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to clarify the effects and safety of ombitasvir/paritaprevir/ritonavir (OBT/PTV/r) therapy in genotype 1b chronic hepatitis C patients with non‐dialysis chronic kidney disease (CKD). Methods: This retrospective, multicenter study of 12‐week OBT/PTV/r therapy included genotype 1b patients with non‐dialysis CKD. Chronic kidney disease was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. Virologic responses and treatment‐emergent adverse events (TEAEs) in patients with CKD were compared with those in patients without CKD. Results: Two hundred and thirty‐five patients with a median age of 67 years (range, 27–89 years) were enrolled, consisting of 181 patients without CKD and 54 patients with CKD. Overall, the rates of rapid virologic response (RVR), end of treatment response (ETR), and sustained virologic response (SVR) were 78.7%, 98.7%, and 98.7%, respectively. Among the 181 non‐CKD patients, the rates were 77.3% (140/181), 98.9% (179/181), and 98.9% (179/181), respectively. Among the 54 CKD patients, the rates were 83.3% (45/54), 98.1% (53/54), and 98.1% (53/54), respectively. There were no significant differences in the virologic response rates between the two groups (P = 0.449 for RVR, 0.545 for ETR, and 0.545 for SVR). In the CKD group, the eGFR level did not significantly change throughout the treatment period. There was no significant difference in the incidence of TEAEs or treatment discontinuation due to TEAEs between the two groups. Conclusion: The present study showed that the effects and safety of OBV/PTV/r therapy in genotype 1b chronic hepatitis C patients with non‐dialysis CKD were not inferior to those in patients without CKD. [ABSTRACT FROM AUTHOR]

Background/Aims: Chronic hepatitis C (HCV) virus infection reactivates under immunosuppressive drugs and therefore has a negative impact on long-term survival of kidney transplant recipients. Treatment-induced clearance of hepatitis C virus (HCV) in kidney transplant candidates prevents virus reactivation after transplantation. Paritaprevir/Ritonavir/Ombitasvir with Dasabuvir (PrOD) represents a highly effective treatment regimen for HCV genotype 1 (GT1), also suitable for patients with end-stage renal disease (ESRD). Serious drug-drug interactions may represent a limiting factor of this regimen. The aim of this retrospective study was to evaluate safety, efficacy and drug-drug interactions management associated with PrOD treatment in the Czech real-world cohort. Methods: Emphasizing concomitant medication adjustment, we described the treatment course with PrOD regimen in 23 patients (4 with CKD4 and 19 on maintenance haemodialysis) infected with HCV GT1 (21 GT1b, 2 GT1a), 18 males and 5 females with an average age of 53.7 years. Six patients had compensated liver cirrhosis and 3 of them were liver transplant recipients. Results: All 23 patients completed the 12-week treatment and achieved sustained virological response 12 weeks after the treatment (SVR12 rate 100%). None of the patients presented with a significant decrease in haemoglobin level, white blood cell and platelet count during the treatment period. The most frequent adverse events were nausea, hypotension, diarrhoea, and hyperkalemia. Four patients presented with a serious adverse event unrelated to the antiviral drugs (salmonellosis, non-functional kidney graft rejection, early gastric cancer, renal cyst infection, initiation of haemodialysis). Concomitant medication had to be modified with the treatment initiation in 10 out of 23 (43.5%) patients (calcium channel blockers, ACE inhibitors, statins, diuretics, tacrolimus); four patients required further adjustment of antihypertensive drugs or tacrolimus dosage on-treatment. Conclusion: PrOD regimen demonstrated an excellent efficacy and good tolerability. Both prospective adjustment of concomitant medication and further on-treatment adjustment allowed for a safe treatment course. [ABSTRACT FROM AUTHOR]

Background: The current standard of care for patients with chronic hepatitis C virus (HCV) infection is a combination of direct-acting antiviral agents (DAAs). However, rare clinical trials have been reported on the combination regimen of sofosbuvir (SOF) with ombitasvir, paritaprevir, and ritonavir (OBV/PTV/r) plus ribavirin (RBV) for treated patients with HCV genotype 4 (GT4) infection.Aims: To clarify the retreatment efficacy and safety of the recent regimen, SOF with OBV/PTV/r + RBV, for chronic HCV GT4-experienced patients who failed treatment with DAA-based regimens.Methods: A total of 113 treatment-experienced patients were allocated for the completion of their treatment period. The enrolled patients were treated orally with SOF plus a fixed dose combination of OBV/PTV/r + RBV, which was administered orally based on the patients' tolerability. The primary end point was a sustained virological response (HCV RNA < 15 IU/mL), observed 12 weeks after the end of the treatment (SVR12).Results: Among all patients, the treatment-experienced patients with SOF plus OBV/PTV/r + RBV had a higher SVR12 rate (97%; 109/113). Further, SVR12 was achieved by 98% (81/83) of non-cirrhotic patients and 93% (28/30) of cirrhotic patients. Additionally, the most common adverse events reported included fatigue, headache, insomnia, nausea, and dyspnea.Conclusions: The recent multi-targeted regimen of SOF plus OBV/PTV/r + RBV was well tolerated and achieved excellent SVR rates among retreatment-experienced Egyptian patients with prior DAA treatments failure, thus providing an alternative regimen for the retreatment of difficult-to-cure HCV GT4 patients. [ABSTRACT FROM AUTHOR]

Abstract: Background & Aims: Drug–drug interactions (DDIs) with ombitasvir/paritaprevir/ritonavir with or without dasabuvir and with or without ribavirin (OBV/PTV/r ± DSV ± RBV) are common in clinical trials. Our aim was to analyze the prevalence and management of potential DDIs and adverse events (AEs) related to DDIs in patients with chronic hepatitis C (CHC) receiving OBV/PTV/r ± DSV ± RBV in clinical practice. Methods: 177 CHC patients started OBV/PTV/r ± DSV ± RBV in 4 Spanish hospitals and were screened for potential DDIs using the University of Liverpool database. Patients were classified according to the most serious potential DDIs at baseline and AEs during therapy. Results: At least one potential DDI was found in 110 (62.1%) patients: 100 (56.5%) had at least one manageable potential DDI and 10 (5.6%) at least one contraindicated. Patients with potential DDIs were receiving a higher number of concomitant drugs (4 vs. 2, P < 0.001). Routine medication was modified at baseline due to potential DDIs in 49 (27.7%) patients. During antiviral treatment, 67 (37.9%) patients presented at least one AE. In 9 (4.5%) patients, a DDI was suspected between OBV/PTV/r ± DSV ± RBV and the concomitant drug, requiring antiviral discontinuation in 4 patients. Conclusions: Potential DDIs are frequent with OBV/PTV/r ± DSV ± RBV, although a change in baseline medication is made in only one‐quarter of patients. More than half of potential DDIs were only followed, and only 5% of patients developed AEs in which the implication of DDIs could not be excluded. [ABSTRACT FROM AUTHOR]

Modification of a HCV NS5A inhibitor, ombitasvir, led to the identification of 10d with improved pan-genotype NS5A inhibition and better pharmacokinetic properties. The key structural changes to ombitasvir include bioisosteric replacement of carbon with silicon atom. Compared with ombitasvir, the activity of anti-HCV genotypes (GT 1 to 6) of 10d is increased to some extent, especially the inhibitory activity against genotype 3a and 6a is increased by more than seven times, and the dog's in vivo pharmacokinetics properties were also superior to ombitasvir. Further drug evaluation showed that 10d was similar to ombitasvir on plasma protein binding and liver distribution profiles, with no cytotoxicity and no inhibitory effect on both CYP 450 and hERG ligand binding. However, permeability assay results indicated that 10d was not the substrate of P-gp or BCRP transporter, which is different from that of ombitasvir. The results of a 14-day repeat-dose toxicity study identified no toxicity with 10d . Our findings in preclinical tests suggest that the silicon-containing compound 10d could be worthy of continued study as a potential drug candidate. [ABSTRACT FROM AUTHOR]

Background: The current international multicentre open-label, uncontrolled, real-world retrospective study aimed at evaluating the effectiveness and safety of ombitasvir / paritaprevir / ritonavir + dasabuvir - ribavirin (3D therapy) in treatment-naive and treatment-experienced hepatitis C virus (HCV) genotype 1-infected (GT1) patients. Methods: Adult patients with chronic HCV GT1 infection, scheduled for 3D therapy according to therapeutic guidelines, were eligible. Demographicandclinical datawerecollected retrospectively by reviewing individuals health records. The primary effectiveness endpoint was the sustained virological response at 12 weeks following the end of treatment (SVR12). Results: The participants in the current study consisted of 134 patients with HCV GT1 infection, including 10 liver transplant recipients. SVR12 was achieved in 120 (96.8%) non-transplant and all liver transplant patients (100%). Significant improvement in liver function tests were observed. Among 4 treatment failures, 2 patients were non-responders and 2 patients relapsed. OBV/PTV/r + DSV - RBV regimen was well tolerated in most patients with treatment discontinuation due to adverse events in 3 patients. The most frequent adverse events were asthenia (25.8%), fatigue (16.1%), skin pruritus (12.9%), and dyspepsia (11.3%). Conclusions: The current real-life study demonstrated the effectiveness and safety of OBV/PTV/r + DSV-RBV in patients with HCV GT1, including patients with cirrhosis, a liver transplant recipient and the one who failed previous antiviral therapies. [ABSTRACT FROM AUTHOR]

Treatment of HCV genotype (GT) 2-infected Japanese patients with paritaprevir (NS3/4A inhibitor boosted with ritonavir) and ombitasvir (NS5A inhibitor) without ribavirin for 12 weeks in the phase 2 study M12-536, and with ribavirin for 16 weeks in phase 3 study GIFT II resulted in SVR rates of 72.2% to 91.5%. Overall, 11 out of 125 patients with GT2a and 37 out of 79 patients with GT2b infection experienced virologic failure. The prevalence of baseline polymorphisms in NS3 and NS5A and their the impact on treatment outcome, as well as the development of viral resistance in GT2-infected patients experiencing virologic failure were evaluated by HCV NS3 and NS5A population and clonal sequence analyses. Baseline polymorphisms in NS3 that confer resistance to paritaprevir were rare in both GT2a- and GT2b-infected patients, while baseline polymorphisms in NS5A that confer resistance to ombitasvir were detected in 11.2% and 14.1% of the GT2a- and GT2b-infected patients, respectively. There was no significant impact of baseline polymorphisms on treatment outcome in Japanese patients. The most common treatment-emergent substitutions at the time of virologic failure occurred at amino acid positions 168 in NS3 and 28 in NS5A in both GT2a- and GT2b-infected patients. Although there was a higher rate of virologic failure in patients with GT2b infection, the resistance analyses presented in this report support the conclusion that testing for baseline resistance-associated polymorphisms is not warranted for HCV GT2-infected patients treated with a regimen of ombitasvir/paritaprevir/ritonavir + ribavirin for 16 weeks. [ABSTRACT FROM AUTHOR]

Introduction: We analyzed phase 3 trial data of ombitasvir/paritaprevir/ritonavir and dasabuvir (3D) ± ribavirin (RBV) in genotype 1 chronic hepatitis C patients to investigate the impact of 3D ± RBV on renal, cardiovascular and metabolic extrahepatic manifestations (EHMs), including persistency 52 weeks post treatment and differential impact by EHM disease severity. Methods: Estimated glomerular filtration rate (eGFR), fasting triglyceride and fasting glucose values from clinical trials were used to assess renal, cardiovascular and metabolic EHMs, respectively. Two placebo-controlled trials were used to study the effect of treatment, while the pooled sample of treated patients was used to study the persistency and differential effect of treatment by baseline EHM disease severity, as defined by baseline values of respective EHM biomarkers. Changes in EHM outcomes from baseline were assessed with mixed models adjusting for patient baseline demographic and clinical characteristics. Results: Treatment with 3D ± RBV resulted in statistically significant declines from baseline of triglycerides and glucose and no statistical change in eGFR. By 52 weeks post treatment patients with elevated triglycerides (−35.3 mg/dl), pre-diabetes (−4.4 mg/dl), diabetes (−34.2 mg/dl) and CKD stage 3 (+1.6 ml/min/1.73 m) at baseline experienced a statistically significant improvement in their respective EHM values. Patients with CKD stages 2, 4 and 5 experienced no statistically significant change in eGFR from baseline. Conclusion: Treatment with 3D ± RBV resulted in improvement or no worsening of cardiovascular, metabolic and renal EHM markers, especially in patients with severe EHMs at baseline, which persisted until 52 weeks post treatment. Funding: Abbvie Inc. [ABSTRACT FROM AUTHOR]