mk-8742 and Fatigue

Topics: Amides; Antiviral Agents; Benzofurans; Carbamates; Clinical Trials as Topic; Cyclopropanes; Drug Combinations; Fatigue; Hepatitis C; Humans; Imidazoles; Nausea; Quinoxalines; Sulfonamides

The PRIORITIZE trial (clinicaltrials.gov: NCT02786537) was the first comparative effectiveness study to directly compare ledipasvir/sofosbuvir (LDV/SOF) and elbasvir/grazoprevir (EBR/GZR) for the treatment of chronic hepatitis C virus (HCV). A secondary aim of this study was to compare LDV/SOF and EBR/GZR on sustainable changes in several HCV-associated symptoms and functional well-being in patients who achieved sustained virological response (SVR). PRIORITIZE, a randomized controlled trial conducted between 2016 and 2020, evaluated change in six PROMIS® symptom scores (fatigue, sleep disturbance, cognitive disturbance, nausea, diarrhoea, abdominal pain) and functional well-being using the disease-specific HCV-PRO instrument. Survey assessments were administered at baseline, early post-treatment (median = 6 months) and late post-treatment (median = 21 months). Constrained longitudinal linear mixed-effects models were used to evaluate within-treatment change and between-treatment differences. Data from 793 participants (average 55 years old, 57% male, 44% black, 17% with cirrhosis) were analysed. From baseline to early post-treatment, 5 out of 6 symptoms and functional well-being significantly improved (all p's < .05). In the LDV/SOF arm, mean changes ranged from -3.73 for nausea to -6.41 for fatigue and in the EBR/GZR, mean changes ranged from -2.19 for cognitive impairment to -4.67 for fatigue. Change of >3 points was consider clinically meaningful. Improvements in most symptoms slightly favoured LDV/SOF, although the magnitude of differences between the regimens were small. Both regimens demonstrated significant improvements in symptoms and functional well-being that were sustained during the late post-treatment phase. EBR/GZR and LDV/SOF regimens had clinically equivalent and durable improvements in HCV symptoms and functional well-being up to two years after SVR.

Topics: Amides; Antiviral Agents; Benzimidazoles; Benzofurans; Carbamates; Cyclopropanes; Drug Therapy, Combination; Fatigue; Female; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Imidazoles; Male; Middle Aged; Nausea; Quinoxalines; Sofosbuvir; Sulfonamides

Novel interferon- and ribavirin-free regimens are needed to treat hepatitis C virus (HCV) infection.. To evaluate the safety and efficacy of grazoprevir (NS3/4A protease inhibitor) and elbasvir (NS5A inhibitor) in treatment-naive patients.. Randomized, blinded, placebo-controlled trial. (ClinicalTrials.gov: NCT02105467).. 60 centers in the United States, Europe, Australia, Scandinavia, and Asia.. Cirrhotic and noncirrhotic treatment-naive adults with genotype 1, 4, or 6 infection.. Oral, once-daily, fixed-dose grazoprevir 100 mg/elbasvir 50 mg for 12 weeks, stratified by fibrosis and genotype. Patients were randomly assigned 3:1 to immediate or deferred therapy.. Proportion of patients in the immediate-treatment group achieving unquantifiable HCV RNA 12 weeks after treatment (SVR12); adverse events in both groups.. Among 421 participants, 194 (46%) were women, 157 (37%) were nonwhite, 382 (91%) had genotype 1 infection, and 92 (22%) had cirrhosis. Of 316 patients receiving immediate treatment, 299 of 316 (95% [95% CI, 92% to 97%]) achieved SVR12, including 144 of 157 (92% [CI, 86% to 96%]) with genotype 1a, 129 of 131 (99% [CI, 95% to 100%]) with genotype 1b, 18 of 18 (100% [CI, 82% to 100%]) with genotype 4, 8 of 10 (80% [CI, 44% to 98%]) with genotype 6, 68 of 70 (97% [CI, 90% to 100%]) with cirrhosis, and 231 of 246 (94% [CI, 90% to 97%]) without cirrhosis. Virologic failure occurred in 13 patients (4%), including 1 case of breakthrough infection and 12 relapses, and was associated with baseline NS5A polymorphisms and emergent NS3 or NS5A variants or both. Serious adverse events occurred in 9 (2.8%) and 3 (2.9%) patients in the active and placebo groups, respectively (difference <0.05 percentage point [CI, -5.4 to 3.1 percentage points]); none were considered drug related. The most common adverse events in the active group were headache (17%), fatigue (16%), and nausea (9%).. The study lacked an active-comparator control group and included relatively few genotype 4 and 6 infections.. Grazoprevir-elbasvir achieved high SVR12 rates in treatment-naive cirrhotic and noncirrhotic patients with genotype 1, 4, or 6 infection. This once-daily, all-oral, fixed-combination regimen represents a potent new therapeutic option for chronic HCV infection.. Merck & Co.

Topics: Administration, Oral; Adult; Aged; Amides; Antiviral Agents; Benzofurans; Carbamates; Cyclopropanes; Drug Administration Schedule; Drug Therapy, Combination; Fatigue; Female; Genotype; Headache; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Liver Cirrhosis; Male; Middle Aged; Nausea; Quinoxalines; Sulfonamides; Treatment Outcome; Viral Load; Young Adult

Hepatitis C virus (HCV) infection is known to affect long-term patient survivals. Elbasvir/grazoprevir (EBR/GZR) has shown a high cure rate in hemodialysis patients with HCV infection. However, the combination is rarely used in peritoneal dialysis patients. Herein, we report a case of successful treatment with EBR/GZR in a peritoneal dialysis patient with HCV genotype 1 b infection. A 54-year-old woman on peritoneal dialysis（PD）with HCV genotype 1 b infection had been received EBR (100 mg) and GZR (50 mg) once daily for 12 weeks. Hepatitis C virus RNA was undetectable 4 weeks after the treatment. She achieved a sustained virological response at 12 weeks after the end of treatment. Only fatigue was reported as side effect during the treatment. Thus, elbasvir/grazoprevir was effective and safe in this PD patient with HCV genotype 1 b infection.

Topics: Amides; Antiviral Agents; Benzofurans; Carbamates; Cyclopropanes; Drug Therapy, Combination; Fatigue; Female; Genotype; Hepacivirus; Hepatitis C; Humans; Imidazoles; Middle Aged; Peritoneal Dialysis; Quinoxalines; Sulfonamides; Sustained Virologic Response

In the Republic of Korea, an estimated 231,000 individuals have chronic hepatitis C virus (HCV) infection. The aim of the present analysis was to evaluate the safety and efficacy of elbasvir/grazoprevir (EBR/GZR) administered for 12 weeks in Korean patients who were enrolled in international clinical trial phase 3 studies.. This was a retrospective, integrated analysis of data from patients with HCV genotype (GT) 1b infection enrolled at Korean study sites in four EBR/GZR phase 3 clinical trials. Patients were treatment-naive or had previously failed interferon-based HCV therapy, and included those with human immunodeficiency virus coinfection or ChildPugh class A cirrhosis. All patients received EBR 50 mg/GZR 100 mg once daily for 12 weeks. The primary endpoint was sustained virologic response at 12 weeks after completion of therapy (SVR12, HCV RNA <15 IU/mL).. SVR12 was achieved by 73 of 74 (98.6%) patients. No patients had virologic failure and one discontinued from the study after withdrawing consent. SVR12 rates were uniformly high across all patient subgroups. A total of 16 patients had nonstructural protein 5A resistance-associated substitutions at baseline (16/73, 22%), all of whom achieved SVR12. Adverse events (AEs) reported in >5% of patients were fatigue (6.8%), upper respiratory tract infection (5.4%), headache (5.4%), and nausea (5.4%). Thirteen patients (17.6%) reported drug-related AEs, two serious AEs occurred, and two patients discontinued treatment owing to an AEs.. In this retrospective analysis, EBR/GZR administered for 12 weeks was well-tolerated and highly effective in Korean patients with HCV GT1b infection.

Topics: Adult; Aged; Amides; Antiviral Agents; Benzofurans; Carbamates; Clinical Trials, Phase III as Topic; Cyclopropanes; Drug Resistance, Viral; Fatigue; Female; Genotype; Hepacivirus; Hepatitis C; Humans; Imidazoles; Male; Middle Aged; Quinoxalines; Republic of Korea; Retrospective Studies; Sulfonamides; Sustained Virologic Response; Viral Nonstructural Proteins

Topics: Amides; Antiviral Agents; Asthenia; Benzofurans; Carbamates; Cyclopropanes; Drug Therapy, Combination; Fatigue; Female; Genotype; Headache; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Male; Middle Aged; Nausea; Quinoxalines; Randomized Controlled Trials as Topic; Ribavirin; RNA, Viral; Sulfonamides; Sustained Virologic Response; Viral Load