Efficacy and safety of ombitasvir/paritaprevir/ritonavir-based therapy in HCV patients with chronic kidney disease.

BACKGROUND AND STUDY AIMS: Hepatitis C virus (HCV) prevalence inchronic kidney disease (CKD) patients is significantly higher than in the general population. This study evaluated the efficacy and safety of combined ombitasvir/paritaprevir/ritonavir-based therapy in HCV patients with renal impairment. PATIENTS AND METHODS: Our study included 829 patients with normal kidney functions (group 1) and 829 patients with CKD (group 2),which were subdivided into patients not requiring dialysis (group 2a) and those on hemodialysis (group2b). Patients received regimens of ombitasvir/paritaprevir/ritonavir with or without ribavirin or sofosbuvir/ombitasvir/paritaprevir/ritonavir with or without ribavirin for 12 weeks. Clinical and laboratory assessment was done before treatment, and patients were followed up for12 weeks after treatment. RESULTS: The sustained virological response (SVR) at week 12 was significantly higher in group 1 than in the other three groups/subgroups, being 94.2% vs 90.2%, 90%, and 90.7%, respectively. The regimen with the highest SVR was ombitasvir/paritaprevir/ritonavir with ribavirin. The most common adverse event was anemia, which was more common in group 2. CONCLUSION: Ombitasvir/paritaprevir/ritonavir-based therapy in chronic HCV patients with CKD is highly effective, with minimal side effects despite ribavirin-induced anemia.

Best therapy for the easiest to treat hepatitis C virus genotype 1b-infected patients.

BACKGROUND: The revolution in treatment of patients with chronic hepatitis C virus (HCV) infection dates back to the introduction of direct-acting antivirals (DAAs). The increase in efficacy was most pronounced in patients infected with genotype (GT) 1b, as this was the most poorly responsive population to treatment during the interferon era. AIM: To identify the most effective interferon-free therapy for GT1b-infected patients and to determine positive and negative predictors of virological response. METHODS: This real-world retrospective analysis included patients chronically infected with GT1b HCV whose data were obtained from the multicenter observational EpiTer-2 database. Treatment effectiveness was evaluated for each therapeutic regimen as the percentage of sustained virological responses (SVR). Assessment of the safety was based on the evaluation of the course of therapy, the occurrence of adverse events including serious ones, deaths during treatment and in the post 12-wk follow-up period. RESULTS: The studied population consisted of 11385 patients with a mean age of 53 ± 14.8 years and a female predominance (53.4%). The majority of them were treatment-naïve (74.6%) and patients with cirrhosis accounted for 24.3%. Of the DAA regimens used, 76.9% were GT-specific with ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin being the most used option (32.4%). A total of 10903 patients responded to treatment resulting in a 98.1% in the per-protocol analysis after excluding 273 patients without SVR data. The effectiveness of all regimens exceeded 90% and the highest SVR of 98.9% was achieved in patients treated with a combination of glecaprevir/pibrentasvir. Logistic regression analyses showed that the virologic response was independently associated with female sex [odds ratio (OR) = 1.67], absence of decompensated cirrhosis at baseline (OR = 2.42) and higher baseline platelets (OR = 1.004 per 1000/µL increase), while the presence of human immunodeficiency virus (HIV) coinfection significantly decreased the odds of response (OR = 0.39). About 95%-100% of patients completed therapy irrespective of the drug regimen. At least one adverse effect occurred in 10.9%-36.3% and most of them were mild. No treatment related deaths have been reported. CONCLUSION: We documented very high effectiveness and a good safety profile across all DAA regimens. Positive predictors of SVR were female sex, absence of decompensated cirrhosis at baseline and higher platelet count while HIV coinfection reduced the effectiveness.

Distribution of chronic hepatitis C genotype and evaluation of clinical factors affecting direct-acting antiviral treatment responses in the Western Black Sea Region, Turkey.

OBJECTIVE: Chronic Hepatitis C (CHC) is a substantial global public health issue with significant variation between countries because of the genotypic differences. A sustained viral response (SVR) is essential to reduce the complications associated with CHC and can be achieved in most patients via direct-acting antivirals (DAAs). The present study aimed at determining the genotype distribution in patients with CHC in our region and the SVR in DAA therapy patients. PATIENTS AND METHODS: The study was conducted retrospectively on 272 patients treated with DAA between September 2016 and 2021. Data including demographic and clinical characteristics of the patients (HCV RNA level, genotype, hepatitis B and HIV serology, cirrhosis and decompensation, presence of hepatocellular cancer, degree of hepatosteatosis, previous anti-HCV treatment experience, comorbidities) were recorded. The study's primary endpoint was to determine the SVR at week 24. RESULTS: Genotype 1 was the most common genotype (94.5%), with genotype 1b accounting for most patients (78%) among those. It was observed that the patients received Ombitasvir/Paritaprevir/Ritonavir/Dasabuvir (OPRD) (47%), Ledipasvir/sofosbuvir (LDS) (38%), and Glecaprevir/pibrentasvir (GCP) (15%) as DAA treatment. SVR was observed in 92% (223) of the 240 patients at the end of 24 weeks. SVR-24 was significantly higher in the patient group with serum HCV RNA level ≤ 852.533 (p=0.002), in the hypertensive group (p=0.018), and without the psychiatric disease group (p<0.001). CONCLUSIONS: A high rate of SVR-24 was achieved by DAAs in CHC patients, most of whom were genotype 1 in the Western Black Sea Region, Turkey. Also, high viral load, hypertension, and psychiatric disease affected SVR-24, and clinical factors, such as cirrhosis, cirrhosis complications, hepatosteatosis, and other comorbidities did not.

Safety and Efficacy of Direct-acting Antiviral Therapies for Chronic HCV Infection in Hemodialysis Patients.

BACKGROUND/AIM: The aim of this study was to determine the safety and efficacy of a direct-acting antiviral treatment, ombitasvir/paritaprevir/ritonavir and dasabuvir, without ribavirin, in a real-life setting. PATIENTS AND METHODS: We performed a prospective observational study including 108 patients undergoing hemodialysis for end-stage kidney disease, referred to our clinic for antiviral therapy for chronic hepatitis C virus infection. Patients received treatment with ombitasvir/paritaprevir/ritonavir and dasabuvir, for 12 weeks. Sustained virologic response (SVR) was defined as undetectable viremia at 12 weeks after the end of therapy. For safety analysis, we monitored serum levels of hemoglobin, albumin, total bilirubin, alanine-aminotransferase and aspartate- aminotransferase at the beginning and end of therapy, as well as at SVR. Verbal Numeric Rating Scale was used to assess the presence of nausea, headaches and fatigue. RESULTS: We noted a high prevalence of diabetic and hypertensive nephropathy as the underlying cause of chronic kidney disease. Most of the patients had F2 and F3 liver fibrosis (32.40% and 34.25%, respectively). The SVR rate was 96.2% (103/107 patients). We recorded an unrelated death after the completion of antiviral therapy. We found increased levels of nausea, headaches and fatigue at the end of therapy compared to at initiation, The presence and degree of symptoms did not correlate with the underlying cause of renal disease (p=0.72) nor with the degree of fibrosis (p=0.08). Minimal increases in transaminases and bilirubin were recorded at the end of treatment, with no statistical significance. CONCLUSION: Oral antiviral therapy with ombitasvir/paritaprevir/ritonavir and dasabuvir can be safely used in hemodialysis patients, with similar response rates compared to the general population.

A Real-World Study to Compare the Safety and Efficacy of Paritaprevir/Ombitasvir/Ritonavir and Dasabuvir, with or without Ribavirin, in 587 Patients with Chronic Hepatitis C at the Fundeni Clinical Institute, Bucharest, Romania.

BACKGROUND In the European Union, a tablet with fixed doses of ombitasvir, paritaprevir, and ritonavir combined with dasabuvir is an authorized treatment for patients with chronic hepatitis C virus (HCV) infection. Ribavirin is a broad-spectrum antiviral used in several treatment regimens for patients with HCV infection. This real-world study aimed to compare the safety and efficacy of ombitasvir, paritaprevir, and ritonavir combined with dasabuvir, with or without ribavirin, in 587 patients with chronic hepatitis C attending the Fundeni Clinical Institute, Bucharest, Romania. MATERIAL AND METHODS This is an observational prospective study including 315 patients with F4 degree of fibrosis and compensated cirrhosis, 185 patients with F3 fibrosis, and 83 patients with F2 fibrosis. Liver fibrosis was evaluated by liver biopsy or Fibromax. Efficacy was defined as undetectable HCV-RNA at 12 weeks after the end of treatment. In terms of safety, we monitored the development of adverse reactions, liver cytolysis, cholestasis, and hematologic disorders. RESULTS Of the 587 patients, 2 patients with B-cell lymphoma died during therapy. In total, 3/585 patients (0.51%) did not achieve sustained virologic response. Common adverse effects were nausea and asthenia (especially in patients with other medical treatments; P=0.03 and P=0.04, respectively) and anemia in patients who received ribavirin (P<0.01). None of the patients discontinued antiviral treatment. Patients with kidney transplant or end-stage kidney disease did not receive or discontinued ribavirin. CONCLUSIONS Ombitasvir, paritaprevir, and ritonavir combined with dasabuvir, with or without ribavirin had an efficacy rate of over 99% in HCV genotype 1b infection. We report no serious adverse reactions.

Glycemic Control in Patients Undergoing Treatment With Paritaprevir/Ombitasvir/Ritonavir and Dasabuvir for Chronic Hepatitis C Infection.

BACKGROUND/AIM: Patients with hepatitis C virus (HCV)-associated cirrhosis are more prone to developing type 2 diabetes mellitus than patients with any other etiology of cirrhosis. The main objective of this study was to evaluate the impact of all oral antiviral treatment with ritonavir-boosted paritaprevir/ombitasvir and dasabuvir (OBV/PTV/r + DSV) in patients with chronic genotype 1b HCV infection. PATIENTS AND METHODS: We retrospectively evaluated 806 patients who underwent antiviral therapy between December 2015 and July 2019. The laboratory data analyzed were liver function tests, kidney function tests, HCV viremia, fasting glucose levels, and glycosylated hemoglobin. RESULTS: Patients with impaired glucose metabolism were predominantly male and of older age compared to patients with normal glucose tolerance, and also had higher levels of transaminases. Proteinuria and higher creatinine levels were found in patients with impaired glucose metabolism. Overall, we found a 98.01% rate of sustained virologic response (SVR), with a non-significant difference between patients with normal and abnormal glucose metabolism. A statistically significant difference in SVR rates in patients with low degrees of fibrosis (F0-F2) versus those with advanced degrees of fibrosis (F3-F4) was found in both groups. Antiviral treatment resulted in significant decreases in fasting glucose levels and glycosylated hemoglobin levels in all patients with impaired glucose metabolism at SVR. CONCLUSION: Patients with pre-diabetes, as well as diabetic patients, achieved a better glycemic control after SVR obtained by ritonavir-boosted paritaprevir/ombitasvir and dasabuvir.

Combined Use of Calcium-channel Blockers With Ombitasvir/Paritaprevir/Ritonavir Exacerbates Peripheral Edema in Elderly Japanese Patients.

BACKGROUND/AIM: The antiviral agent ritonavir is a substrate for cytochrome P450 3A4 (CYP3A4); therefore, concomitant use of CYP3A4-metabolising drugs might cause adverse reactions to this drug. We investigated the plasma level of calcium channel blockers (CCBs) as CYP3A4 substrates and peripheral edema as a potential adverse drug reaction possibly caused by the anti-hepatitis C virus (HCV) regimen of ombitasvir/paritaprevir/ritonavir (OPR) and CCBs. PATIENTS AND METHODS: We enrolled Japanese patients prescribed OPR for HCV infection. Peripheral edema was graded according to the Common Terminology Criteria for Adverse Events ver. 4. Plasma samples were collected on days 0, 7, 14, 28, and 42 after antiviral treatment, at the trough level. RESULTS: Out of 52 patients, 64% experienced grade 1 or grade 2 peripheral edema, but not grade 3. Concomitant use of CCBs significantly increased the emergence of grade 2 edema (62%), compared with patients treated solely with OPR (48%). The use of OPR significantly increased the plasma concentration of amlodipine. CONCLUSION: Peripheral edema in patients treated with OPR and CCBs, although tolerable, should be closely monitored.

Failure on voxilaprevir, velpatasvir, sofosbuvir and efficacy of rescue therapy.

BACKGROUND & AIMS: There are limited data on patients with chronic HCV infection in whom combination voxilaprevir (VOX), velpatasvir (VEL), sofosbuvir (SOF) retreatment fails. Thus, we aimed to assess treatment failure and rescue treatment options in these patients. METHODS: Samples from 40 patients with HCV genotypes (GT) 1-4 in whom VOX/VEL/SOF retreatment failed were collected within the European Resistance Study Group. Population-based resistance analyses were conducted and clinical parameters and retreatment efficacies were evaluated retrospectively in 22 patients. RESULTS: Most VOX/VEL/SOF failure patients were infected with HCV GT3a (n = 18, 45%) or GT1a (n = 11, 28%) and had cirrhosis (n = 28, 70%). Previous treatments included an NS3-inhibitor (30%), an NS5A-inhibitor (100%) and SOF (85%). Baseline RAS data from a subgroup of patients before VOX/VEL/SOF retreatment (78%) showed few NS3 RASs apart from Q80K in GT1a (40%), typical NS5A RAS patterns in most patients (74%) and no S282T in NS5B. Sequencing after VOX/VEL/SOF failure was available in 98% of patients and showed only minor changes for NS3 and NS5A RASs. In 22 patients, rescue treatment was initiated with glecaprevir, pibrentasvir alone (n = 2) or with SOF±ribavirin (n = 15), VOX/VEL/SOF±ribavirin (n = 4) or VEL/SOF and ribavirin (n = 1) for 12 to 24 weeks. Sustained virologic response was achieved in 17/21 (81%) patients with a final treatment outcome. Of these, 2 GT3a-infected patients had virologic failure after rescue treatment with VEL/SOF or glecaprevir/pibrentasvir+SOF+ribavirin, and 2 patients with cirrhosis died during treatment or before reaching SVR12. CONCLUSIONS: VOX/VEL/SOF failure was mainly observed in HCV GT3- and GT1a-infected patients with cirrhosis and was not associated with specific RAS patterns within NS3, NS5A or NS5B target regions. Rescue treatment with multiple targeted therapies was effective in most patients. LAY SUMMARY: The advent of direct-acting antivirals has enabled the effective cure of chronic hepatitis C in most patients. However, treatment failure occurs in some patients, who are often retreated with a combination regimen called VOX/VEL/SOF, which is associated with very high rates of cure. However, VOX/VEL/SOF retreatment also fails in some patients. Herein, we analysed samples from patients in whom VOX/VEL/SOF retreatment failed and we assessed the efficacy of different rescue therapies, showing that rescue treatment is effective in most patients (81%).

Evaluation of the Immunosafety of Cucurbit[n]uril on Peripheral Blood Mononuclear Cells In Vitro.

Cucurbiturils (CB[n]s) are nanoscale macrocyclic compounds capable of encapsulating a molecule or part of a molecule by forming host-guest complexes. Integration of drugs with CB[n] is used for the following purposes: controlling clearance; protection of the drug from biodegradation; targeted delivery to specific organs, tissues, or cells; reduction of toxicity; and improving solubility. One of the major problems encountered in the application of new drug delivery systems is lack of knowledge of their biological properties. CB[n], unlike many other often toxic nanoparticles, has extremely low toxicity, even at high doses. However, many aspects of the biological actions of these nanoscale cavitands remain unclear, including the immunotropic properties. In this study, we investigated the immunotoxicity and immunomodulation properties of CB[n]. It was found that CB[7] and CB[6] did not decrease the viability of mononuclear cells at all tested concentrations from 0.1-1 mM. Overall, the results indicated an immunomodulatory effect of different concentrations of CB[n]. In the case of a longer cultivation time, CB[n] had an immunostimulating effect, which was indicated by an enhancement of the proliferative activity of cells and increased expression of HLA-DR on lymphocytes.

Ombitasvir/paritaprevir/ritonavir & dasabuvir ± ribavirin following protease inhibitors failure - a prospective multi-centre trial.

BACKGROUND: Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease and hepatocellular carcinoma. Treatment with first generation protease inhibitors (PI) + peg-interferon (pegIFN) and ribavirin (RBV) achieved sustained virologic response (SVR) rates of 65-75% but was associated with multiple side effects. The aim of this study was to evaluate safety and efficacy of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir (3D) ± RBV in HCV genotype 1 patients that failed previous treatment with first generation PIs. METHODS: An investigator-initiated, open-label, multi-centre clinical trial. HCV Genotype 1 patients who were previously null/partial responders or relapsers to telaprevir, boceprevir or simepravir+pegIFN/RBV and met eligibility criteria were included. 3D ± RBV were administrated for 12 or 24 weeks according to label. The primary outcome was antiviral response (SVR12); Secondary outcomes were patient reported outcomes, adverse events and resistance associated variants. RESULTS: Thirty-nine patients initiated treatment according to study protocol (59% men, age 54.0 ± 8.7 years, BMI 28.7 ± 4.5 kg/m2). Thirty-seven (94.9%) completed the study. Thirty-five patients had genotype 1b (9 cirrhotics) and 4 had genotype 1a (2 cirrhotics). Intention-to-treat SVR12 was 92.3% and per-protocol SVR12 was 97.3%. The rate of advanced fibrosis (FibroScan® score F3-4) declined from 46.2 to 25.7% (P = 0.045). Abnormal ALT levels declined from 84.6 to 8.6% (P < 0.001). Seven patients (17.9%) experienced serious adverse events (3 Psychiatric admissions, 1 pneumonia, 1 ankle fracture, 2 palpitations), and 12 patients (30.8%) experienced self-reported adverse events, mostly weakness. CONCLUSION: 3D ± RBV is safe and effective in achieving SVR among patients with HCV genotype 1 who failed previous first-generation PI treatment. TRIAL REGISTRATION: NCT02646111 (submitted to ClinicalTrials.gov, December 28, 2015).

Single dose escalation studies with inhaled POL6014, a potent novel selective reversible inhibitor of human neutrophil elastase, in healthy volunteers and subjects with cystic fibrosis.

BACKGROUND: POL6014 is a novel, orally inhaled neutrophil elastase (NE) inhibitor in development for cystic fibrosis (CF). METHODS: Two studies, one in healthy volunteers (HVs, doses 20 to 960 mg) and one in subjects with CF (doses 80 to 320 mg) were conducted to evaluate the safety, tolerability and pharmacokinetics (PK) of single ascending doses of inhaled POL6014 with a Pari eFlow® nebuliser. PK was evaluated over a period of 24 h. In addition, NE activity in CF sputum was measured. RESULTS: After single doses, POL6014 was safe and well tolerated up to 480 mg in HVs and at all doses in subjects with CF. POL6014 showed a dose-linear PK profile in both populations with Cmax between 0.2 and 2.5 µM in HVs and between 0.2 and 0.5 µM in subjects with CF. Tmax was reached at approximately 2-3 h. Mean POL6014 levels in CF sputum rapidly reached 1000 µM and were still above 10 µM at 24 h. >1-log reduction of active NE was observed at 3 h after dosing. CONCLUSION: Inhalation of POL6014 can safely lead to high concentrations within the lung and simultaneously low plasma concentrations, allowing for a clear inhibition of NE in the sputum of subjects with CF after single dosing. TRIAL REGISTRATION: European Medicines Agency EudraCT-Nr. 2015-001618-83 and 2016-000493-38.

Real-world evidence of the effectiveness of ombitasvir-paritaprevir/r ± dasabuvir ± ribavirin in patients monoinfected with chronic hepatitis C or coinfected with human immunodeficiency virus-1 in Spain.

AIM: We describe the effectiveness and safety of the interferon-free regimen ombitasvir/paritaprevir/ritonavir plus dasabuvir with or without ribavirin (OBV/PTV/r ± DSV ± RBV) in a nationwide representative sample of the hepatitis C virus (HCV) monoinfected and human immunodeficiency virus-1/hepatitis C virus (HIV/HCV) coinfected population in Spain. MATERIAL AND METHODS: Data were collected from patients infected with HCV genotypes 1 or 4, with or without HIV-1 coinfection, treated with OBV/PTV/r ± DSV ± RBV at 61 Spanish sites within the initial implementation year of the first government-driven "National HCV plan." Effectiveness was assessed by sustained virologic response at post-treatment week 12 (SVR12) and compared between monoinfected and coinfected patients using a non-inferiority margin of 5% and a 90% confidence interval (CI). Sociodemographic and clinical characteristics or patients and adverse events (AEs) were also recorded. RESULTS: Overall, 2,408 patients were included in the intention-to-treat analysis: 386 (16%) were patients with HIV/HCV. Patient selection reflected the real distribution of patients treated in each participating region in Spain. From the total population, 96.6% (95% CI, 95.8-97.3%) achieved SVR12. Noninferiority of SVR12 in coinfected patients was met, with a difference between monoinfected and coinfected patients of -2.2% (90% CI, -4.5% - 0.2%). Only genotype 4 was associated with non-response to OBV/PTV/r ± DSV ± RBV treatment (p<0.001) in the multivariate analysis. Overall, 286 patients (11.9%) presented AEs potentially related to OBV/PTV/r ± DSV, whereas 347 (29.0%) presented AEs potentially related to ribavirin and 61 (5.1%) interrupted ribavirin. CONCLUSIONS: Our results confirm that OBV/PTV/r ± DSV ± RBV is effective and generally well tolerated in a representative sample of the HCV monoinfected and HCV/HIV coinfected population in Spain within the experience of a national strategic plan to tackle HCV.

Chimeric peptidomimetic antibiotics against Gram-negative bacteria.

There is an urgent need for new antibiotics against Gram-negative pathogens that are resistant to carbapenem and third-generation cephalosporins, against which antibiotics of last resort have lost most of their efficacy. Here we describe a class of synthetic antibiotics inspired by scaffolds derived from natural products. These chimeric antibiotics contain a ß-hairpin peptide macrocycle linked to the macrocycle found in the polymyxin and colistin family of natural products. They are bactericidal and have a mechanism of action that involves binding to both lipopolysaccharide and the main component (BamA) of the ß-barrel folding complex (BAM) that is required for the folding and insertion of ß-barrel proteins into the outer membrane of Gram-negative bacteria. Extensively optimized derivatives show potent activity against multidrug-resistant pathogens, including all of the Gram-negative members of the ESKAPE pathogens1. These derivatives also show favourable drug properties and overcome colistin resistance, both in vitro and in vivo. The lead candidate is currently in preclinical toxicology studies that-if successful-will allow progress into clinical studies that have the potential to address life-threatening infections by the Gram-negative pathogens, and thus to resolve a considerable unmet medical need.

Real-life effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir in hepatitis C patients with previous DAA failure.

BACKGROUND & AIMS: Sofosbuvir/velpatasivr/voxilaprevir (SOF/VEL/VOX) is approved for retreatment of patients with HCV and a previous failure on direct-acting antivirals (DAAs), however real-life data are limited. The aim of this study was to assess the effectiveness and safety of SOF/VEL/VOX in a real-life setting. METHODS: All consecutive patients with HCV receiving SOF/VEL/VOX between May-October 2018 in 27 centers in Northern Italy were enrolled. Bridging fibrosis (F3) and cirrhosis (F4) were diagnosed by liver stiffness measurement: >10 and >13 kPa respectively. Sustained virological response (SVR) was defined as undetectable HCV-RNA 4 (SVR4) or 12 (SVR12) weeks after the end-of-treatment. RESULTS: A total of 179 patients were included: median age 57 (18-88) years, 74% males, median HCV-RNA 1,081,817 (482-25,590,000) IU/ml. Fibrosis stage was F0-F2 in 32%, F3 in 21%, F4 in 44%. HCV genotype was 1 in 58% (1b 33%, 1a 24%, 1nc 1%), 2 in 10%, 3 in 23% and 4 in 9%; 82% of patients carried resistance-associated substitutions in the NS3, NS5A or NS5B regions. Patients received SOF/VEL/VOX for 12 weeks, ribavirin was added in 22% of treatment schedules. Undetectable HCV-RNA was achieved by 74% of patients at week 4 and by 99% at week 12. Overall, 162/179 (91%) patients by intention to treat analysis and 162/169 (96%) by per protocol analysis achieved SVR12, respectively; treatment failures included 6 relapsers and 1 virological non-responder. Cirrhosis (p = 0.005) and hepatocellular carcinoma (p = 0.02) were the only predictors of treatment failure. Most frequent adverse events included fatigue (6%), hyperbilirubinemia (6%) and anemia (4%). CONCLUSIONS: SOF/VEL/VOX is an effective and safe retreatment for patients with HCV who have failed on a previous DAA course in a real-life setting. LAY SUMMARY: This is the largest European real-life study evaluating effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) in a large cohort of consecutive patients with hepatitis C virus infection and a prior direct-acting antiviral failure, who were treated within the NAVIGATORE Lombardia and Veneto Networks, in Italy. This study demonstrated excellent effectiveness (98% and 96% sustained virological response rates at week 4 and 12, respectively) and an optimal safety profile of SOF/VEL/VOX. Cirrhosis and hepatocellular carcinoma onset were the only features associated with treatment failure.

Treatment of hepatitis C infection among Egyptian hemodialysis patients: the dream becomes a reality.

BACKGROUND AND AIMS: New direct-acting antiviral drugs have become the corner-stone treatment for HCV infection: they show promising results with accepted side-effects and low dropout rates. One of the available regimens is paritaprevir/ombitasvir/ritonavir (PTV/OMV/RTV). Our aim was to study the efficacy and safety of this drug regimen among HCV-positive hemodialysis patients. METHODS: This prospective single-center study was performed in the Urology and Nephrology Center, Mansoura University, Egypt. Ninety-six maintenance hemodialysis patients were screened for HCV antibodies. Positive results were found in 46 patients (47.9%). HCV PCR was assessed in all HCV-antibody-positive patients; positive results were found positive for 38 (82%); all patients were HCV genotype 4. Four patients were excluded due to advanced liver cirrhosis, liver malignancy, or metastatic breast cancer. Thirty-four patients were prescribed PTV/OMV/RTV for 3 months to treat HCV. RESULTS: Mean age was 43.2 ± 11.9 years. Most patients were male (67.6%). There was a rapid response to treatment: HCV PCR became negative by 4 weeks after starting treatment. By 12 and 24 weeks post-DAA therapy, there was a sustained viral response (SVR 12, SVR 24) in 100% of patients with improved liver-enzyme levels. CONCLUSION: The PTV/OMV/RTV regimen was safe and effectively treated Egyptian HCV-positive genotype-4 hemodialysis patients.

Effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir in patients with chronic hepatitis C previously treated with DAAs.

BACKGROUND & AIMS: Around 5% of patients with chronic hepatitis C virus (HCV) infection treated with direct-acting antiviral (DAA) agents do not achieve sustained virological response (SVR). The currently approved retreatment regimen for prior DAA failure is a combination of sofosbuvir, velpatasvir, and voxilaprevir (SOF/VEL/VOX), although there is little data on its use in clinical practice. The aim of this study was to analyse the effectiveness and safety of SOF/VEL/VOX in the real-world setting. METHODS: This was a prospective multicentre study assessing the efficacy of retreatment with SOF/VEL/VOX in patients who had experienced a prior DAA treatment failure. The primary endpoint was SVR 12 weeks after the completion of treatment (SVR12). Data on safety and tolerability were also recorded. RESULTS: A total of 137 patients were included: 75% men, 35% with liver cirrhosis. Most were infected with HCV genotype (GT) 1 or 3. The most common prior DAA combinations were sofosbuvir plus an NS5A inhibitor or ombitasvir/paritaprevir/r+dasabuvir. A total of 136 (99%) patients achieved undetectable HCV RNA at the end of treatment. Overall SVR12 was 95% in the 135 patients reaching this point. SVR12 was lower in patients with cirrhosis (89%, p = 0.05) and those with GT3 infection (80%, p <0.001). Patients with GT3 infection and cirrhosis had the lowest SVR12 rate (69%). Of the patients who did not achieve SVR12, 1 was reinfected and 7 experienced treatment failure (6 GT3, 1 GT1a). The presence of resistance-associated substitutions did not impact SVR12. Adverse effects were mild and non-specific. CONCLUSION: Real-world data show that SOF/VEL/VOX is an effective, safe rescue therapy for patients with prior DAA treatment failure despite the presence of resistance-associated substitutions. However, patients with liver cirrhosis infected by GT3 remain the most-difficult-to-treat group. LAY SUMMARY: Treatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) for 12 weeks is the current recommendation for the 5% of patients infected with HCV who do not achieve eradication of the virus under treatment with direct-acting antivirals. In a Spanish cohort of 137 patients who failed a previous combination of direct-acting antivirals, a cure rate of 95% was achieved with SOF/VEL/VOX. Genotypic characteristics of the virus (genotype 3) and the presence of cirrhosis were factors that decreased the rate of cure. Treatment with SOF/VEL/VOX is an effective and safe rescue therapy due to its high efficacy and very good safety profile.

A pilot study of safety and efficacy of HCV retreatment with sofosbuvir/velpatasvir/voxilaprevir in patients with or without HIV (RESOLVE STUDY).

BACKGROUND & AIMS: Cure rates in response to retreatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) are high, but this regimen has not been studied in patients with a history of poor adherence or treatment interruption, nor in patients with HIV/HCV coinfection. Herein, we aimed to assess the safety and efficacy of this combination in patients with genotype 1 HCV infection who had relapsed following combination direct-acting antiviral (DAA) therapy, regardless of HIV infection or previous treatment course. METHODS: The RESOLVE study was a multicenter, open-label, phase IIb study investigating the safety, tolerability and efficacy of SOF/VEL/VOX in 77 patients with virologic rebound following combination DAA therapy. Efficacy was defined as HCV RNA below the lower limit of detection 12 weeks after the end of treatment (SVR12), while safety endpoints included the incidence of grade 3 and 4 adverse events (AEs) following treatment, and the proportion of patients who stopped treatment prematurely due to AEs. RESULTS: In an intent-to-treat analysis, 70/77 (90.9%, 95% CI 82.1-95.8%) patients achieved SVR12, including 14/17 (82.4%) HIV coinfected participants and 18/22 (81.8%) of those with previous non-completion of DAA therapy. In an analysis of all patients who completed 12 weeks of study medication, 70/71 patients (99%) achieved SVR12. One patient experienced a grade 3 AE, and 4 experienced a grade 4 AE, all unrelated to study participation. Reported AEs were similar in HIV-coinfected patients, and patients receiving dolutegravir-based antiretroviral treatment experienced no clinically significant increases in aminotransferases. CONCLUSION: Retreatment with 12 weeks of SOF/VEL/VOX was safe and effective in patients with relapsed HCV following initial combination DAA-based treatment. Treatment response was not affected by HIV coinfection or previous treatment course. LAY SUMMARY: Twelve weeks of the combination of direct-acting antivirals (SOF/VEL/VOX) was safe and effective in patients with relapsed hepatitis C virus infection who had previously received combination therapy with direct-acting antivirals. Treatment response was not diminished by HIV coinfection, or non-completion of previous direct-acting antiviral-based therapy.

Real-world safety and efficacy of paritaprevir/ritonavir/ombitasvir plus dasabuvir ± ribavirin in patients with hepatitis C virus genotype 1 and advanced hepatic fibrosis or compensated cirrhosis: a multicenter pooled analysis.

Paritaprevir/ritonavir, ombitasvir, and dasabuvir (PrOD) with or without ribavirin shows favorable results in hepatitis C virus genotype 1 (HCV-1) patients in terms of safety and efficacy, but real-world data remain limited for those with advanced hepatic fibrosis (fibrosis 3, F3) or compensated cirrhosis (F4). A total of 941 patients treated in four hospitals (the Keelung, the Linkuo, the Chiayi and the Kaohsiung Chang Gung Memorial Hospital) through a nationwide government-funded program in Taiwan were enrolled. Patients with HCV and advanced hepatic fibrosis or compensated cirrhosis received 12 weeks of PrOD in HCV-1b and 12 or 24 weeks of PrOD plus ribavirin therapy in HCV-1a without or with cirrhosis. Advanced hepatic fibrosis or compensated cirrhosis was confirmed by either ultrasonography, fibrosis index based on 4 factors (FIB-4) test, or transient elastography/acoustic radiation force impulse (ARFI). The safety and efficacy (sustained virologic response 12 weeks off therapy, SVR12) were evaluated. An SVR12 was achieved in 887 of 898 (98.8%) patients based on the per-protocol analysis (subjects receiving ≥1 dose of any study medication and HCV RNA data available at post-treatment week 12). Child-Pugh A6 (odds ratio: 0.168; 95% confidence interval (CI): 0.043-0.659, p = 0.011) was the only significant factor of poor SVR12. Fifty-four (5.7%) patients were withdrawn early from the treatment because of hepatic decompensation (n = 18, 1.9%) and other adverse reactions. Multivariate analyses identified old age (odds ratio: 1.062; 95% CI: 1.008-1.119, p = 0.024) and Child-Pugh A6 (odds ratio: 4.957; 95% CI: 1.691-14.528, p = 0.004) were significantly associated with hepatic decompensation. In conclusion, this large real-world cohort proved PrOD with or without ribavirin to be highly effective in chronic hepatitis C patients with advanced hepatic fibrosis or compensated cirrhosis. However, Child-Pugh A6 should be an exclusion criterion for first-line treatment in these patients.

Ritonavir-boosted paritaprevir, ombitasvir plus ribavirin could improve eGFR in patients with renal impairment and HCV: an Egyptian cohort.

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.