ledipasvir and Fatigue

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

New potent direct-acting antiviral (DAA) regimens against hepatitis C virus have been approved in recent years. However, information about the rate of adverse events (AEs) across different DAA regimens is limited. We aimed to evaluate differences in AEs and treatment efficacy in patients with chronic hepatitis C (CHC), genotype (GT) 1 or 3, randomized to two different treatment arms, correspondingly.. We randomly assigned 96 patients in a 1 : 1 ratio, to treatment for 12 weeks with either paritaprevir/ombitasvir/ritonavir/dasabuvir/ribavirin (RBV) or ledipasvir/sofosbuvir (SOF)/RBV if infected with GT1 (72 patients) or to daclatasvir/SOF/RBV for 12 weeks or SOF/RBV for 24 weeks, if infected with GT3 (24 patients). Data on AEs were collected throughout the entire study period.. A total of 70 (97%) patients with CHC with GT1 and 20 (83%) patients with GT3 achieved cure. The GT3 treatment arm was prematurely terminated, owing to change in national treatment guidelines. Thus, only AEs for GT1 patients are described. AEs occurred in 70 (97%) GT1 patients, and most common AEs were anemia (n=56/78%), fatigue (n=53/74%), and headache (n=33/46%). No difference was observed in relation to treatment group (P=1.0), anemia (P=1.0), or liver cirrhosis (P=0.53). In seven (11%) patients, AEs assessed by the investigator to be possibly related to the DAA regimen were still present 12 weeks after treatment.. We found no difference in AEs possibly related to the DAA regimen in patients with CHC, but surprisingly, AEs possibly related to the DAA regimen persisted in a significant number of patients after treatment. This finding can be of importance for clinicians in relation to patient information concerning AEs possibly related to DAA treatment.

Topics: 2-Naphthylamine; Adult; Anemia; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Cyclopropanes; Drug Therapy, Combination; Fatigue; Female; Fluorenes; Genotype; Headache; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sofosbuvir; Sulfonamides; Treatment Outcome; Uracil; Valine; Viral Load

Patients with chronic hepatitis C virus (HCV) genotype 2 have high rates of response to treatment with sofosbuvir and ribavirin. However, ribavirin is associated with hemolytic events and is poorly tolerated by some patients. We evaluated the effectiveness of sofosbuvir and ledipasvir in treatment-naïve and treatment-experienced patients with HCV genotype 2, comparing 12 versus 8 weeks of treatment.. This Phase 2, open-label study included 2 cohorts in New Zealand. The first received a fixed-dose combination tablet of ledipasvir-sofosbuvir (90/400 mg) once daily for 12 weeks. If this cohort had a 90% rate of sustained virologic response (SVR) 4 weeks after treatment, a second cohort receiving 8 weeks of ledipasvir-sofosbuvir was to be enrolled. The primary endpoint in both cohorts was the percentage of patients with HCV RNA <15 IU/mL 12 weeks after therapy (SVR12).. SVR12 rates were 96% (25/26; 95% CI, 80%-100%) for 12 weeks and 74% (20/27; 95% CI, 54%-89%) for 8 weeks of ledipasvir-sofosbuvir. The single patient receiving 12 weeks of ledipasvir-sofosbuvir who did not reach SVR12 did not complete treatment because of withdrawing consent after receiving 1 dose of study drug. Six of the 7 patients who did not reach SVR12 after 8 weeks of treatment experienced virologic relapse after stopping therapy. The most common adverse events were headache (26% of patients), fatigue (21%), and nausea (17%). No patients discontinued treatment because of an adverse event.. For treatment-naïve and -experienced patients, ledipasvir-sofosbuvir for 12 weeks is highly effective for the treatment of HCV genotype 2 (ClinicalTrials.gov: NCT02202980).

Topics: Antiviral Agents; Benzimidazoles; Drug Combinations; Fatigue; Female; Fluorenes; Genotype; Headache; Hepacivirus; Hepatitis C, Chronic; Humans; Male; Middle Aged; Nausea; Sofosbuvir; Sustained Virologic Response

A fixed-dose combination of ledipasvir and sofosbuvir (LDV/SOF) has been approved for treatment of HCV patients. We assessed the effect of LDV/SOF on patient-reported outcomes (PROs) in HIV-HCV-co-infected patients. Patient-reported outcomes data from HIV-HCV-co-infected patients who were treated with LDV/SOF for 12 weeks were collected as a part of a clinical trial (ION-4). Historical controls were HIV-HCV-co-infected patients treated with SOF and ribavirin (RBV) in PHOTON-1. We included 335 HIV-HCV-co-infected patients (SVR-12 in HCV genotype 1 was 96%) who received LDV/SOF, while 223 patients (SVR-12 in HCV genotype 1 was 76.3%) received SOF/RBV. During treatment, patients receiving LDV/SOF showed improvement in all of their PRO scores (+6.0% in activity/energy of CLDQ-HCV, +5.0% in fatigue score of FACIT-F, +6.8% in physical component of SF-36; all P < 0.0001) while those receiving SOF+RBV showed moderate decline in some of their PRO scores (-4.8% in physical functioning of SF-36, -4.4% in fatigue score of FACIT-F, both P < 0.001). Patients who achieved sustained virologic response with LDV/SOF also showed improvement of PROs (average +5.1%) while those treated with SOF/RBV showed less or no improvement (average +1.4%). In a multivariate analysis, in addition to depression and fatigue, receiving SOF+RBV (vs LDV/SOF) was independently associated with more PRO impairment during treatment (beta -6.1 to -12.1%, P < 0.001). Hence, HIV-HCV patients treated with LDV/SOF show significant improvement of their health-related quality of life and other patient-reported outcomes during treatment and after treatment cessation.

Topics: Adult; Antiviral Agents; Benzimidazoles; Efficiency; Fatigue; Female; Fluorenes; Hepatitis C, Chronic; HIV Infections; Humans; Male; Middle Aged; Patient Satisfaction; Sofosbuvir; Treatment Outcome

We evaluated an all-oral regimen comprising the nucleotide polymerase inhibitor sofosbuvir (SOF) with the NS5A inhibitor ledipasvir (LDV) or the NS5B non-nucleoside inhibitor GS-9669 in patients with genotype 1 hepatitis C virus (HCV) infection.. A total of 113 patients were enrolled. Sofosbuvir (400 mg once daily) and LDV (90 mg once daily) plus ribavirin (RBV) were given for 12 weeks to treatment-naïve (TN) patients (n = 25) and those who did not respond to previous therapy (prior null responders, n = 9). Sofosbuvir and GS-9669 (500 mg once daily) plus RBV were given for 12 weeks to TN patients (n = 25) and prior null responders (n = 10). Additionally, prior null responders with cirrhosis were randomly assigned to groups given a fixed-dose combination of SOF and LDV, with RBV (n = 9) or without RBV (n = 10). Finally, a group of TN patients received SOF, LDV, and RBV for 6 weeks (n = 25). The primary efficacy end point was sustained virologic response 12 weeks after therapy (SVR12).. SVR12 was achieved by 25 of 25 (100%) TN patients receiving SOF, LDV, and RBV and 23 of 25 (92%) of those receiving SOF, GS-9669, and RBV. Of TN patients receiving 6 weeks of SOF, LDV, and RBV, 17 of 25 (68%) achieved SVR12. All noncirrhotic prior null responders receiving 12 weeks of SOF along with another direct-acting antiviral agent plus RBV achieved SVR12-9 of 9 (100%) of those receiving SOF, LDV, and RBV and 10 of 10 (100%) of those receiving SOF, GS-9669, and RBV. Among cirrhotic prior null responders, SVR12 was achieved by 9 (100%) of those receiving SOF, LDV, and RBV and 7 (70%) of those receiving SOF and LDVD without RBV. The most common reported adverse events were headache, fatigue, and nausea.. The combination of SOF and a second direct-acting antiviral agent is highly effective in TN patients with HCV genotype 1 infection and in patients that did not respond to previous treatment. ClinicalTrials.gov ID NCT01260350.

Topics: Adult; Aged; Antiviral Agents; Benzimidazoles; Drug Therapy, Combination; Enzyme Inhibitors; Fatigue; Female; Fluorenes; Furans; Genotype; Headache; Hepacivirus; Hepatitis C; Humans; Incidence; Male; Middle Aged; Nausea; Sofosbuvir; Thiophenes; Treatment Outcome; Uridine Monophosphate; Viral Nonstructural Proteins

Fatigue is a disturbing symptom of chronic hepatitis C virus (HCV) infection. We assessed the effects of sustained virologic response 12 weeks after the end of therapy (SVR12) on fatigue.. We performed a retrospective analysis of 100 patients with chronic HCV infection who achieved an SVR12 after treatment with ledipasvir and sofosbuvir, with or without ribavirin. Data were collected on fatigue-related patient-reported outcomes (PROs) and assessed by using the Functional Assessment of Cancer Therapy-Fatigue scoring system and the Vitality subscale of Short Form 36. We measured levels of cytokines and growth factors in frozen serum samples collected at baseline, week 12 of treatment, and 4 weeks after treatment. Central fatigue and peripheral or muscle fatigue (PF) were determined by using items from PROs. Serum levels of cytokines, growth factors, serotonin, alanine aminotransferase, and aspartate aminotransferase were measured by using the Bio-Plex, enzyme-linked immunosorbent, and enzymatic assays.. Compared with baseline, 4 weeks after the end of treatment, all fatigue-associated PROs improved significantly. Baseline PROs correlated inversely with serum level of interferon-γ; level of platelet-derived growth factor correlated with PF, central fatigue, and total fatigue score. Only PF correlated with serum level of serotonin. At baseline, high PF scores correlated with high serum levels of serotonin and low levels of interleukin-10 and tumor necrosis factor-α. In multivariate analysis, serum level of interleukin-8 was associated with greater fatigue (P < .02). Reductions in levels of chemokine (C-C motif) ligand 2 (also called monocyte chemotactic protein 1) were associated with fatigue after treatment (P = .0165).. In an analysis of data from patients with chronic HCV infection participating in a clinical trial of ledipasvir and sofosbuvir, SVR12 was associated with reduced fatigue, compared with baseline. High baseline serum levels of interferon-γ were associated with fatigue. Reductions in levels of chemokine (C-C motif) ligand 2 were associated with persistent fatigue after SVR12. Central and peripheral fatigue each associated with different biomarkers, suggesting different pathogenic pathways.

Topics: Adult; Aged; Antiviral Agents; Benzimidazoles; Biomarkers; Blood Chemical Analysis; Cytokines; Enzyme-Linked Immunosorbent Assay; Fatigue; Female; Fluorenes; Hepatitis C, Chronic; Humans; Male; Middle Aged; Retrospective Studies; Ribavirin; Sofosbuvir; Treatment Outcome

Topics: Aged; Aged, 80 and over; Antiviral Agents; Benzimidazoles; Carbamates; Drug Therapy, Combination; Fatigue; Female; Fluorenes; Hepatitis C, Chronic; Humans; Imidazoles; Male; Pruritus; Pyrrolidines; Recurrence; Simeprevir; Sleep Initiation and Maintenance Disorders; Sofosbuvir; Sustained Virologic Response; Treatment Outcome; Valine

Health-related quality of life (HRQoL) is impaired in HIV/HCV-coinfected patients (HIV/HCV) and further decreased by interferon (IFN)-based therapies. We aimed to investigate the impact of IFN- and ribavirin (RBV)-free therapies on HRQoL and fatigue.Thirty-three HIV/HCV-coinfected patients who underwent HCV therapy with sofosbuvir in combination with daclatasvir or ledipasvir were retrospectively studied and compared to 17 patients who received boceprevir (BOC)/PEGIFN/RBV. HRQoL (mental [MCS] and physical [PCS] component score) and fatigue were assessed using the SF-36 (Short Form 36 Health Survey) and the FSS (Fatigue Severity Scale), respectively. HRQoL/fatigue was evaluated at baseline (BL), midway, and 12 weeks after the end of treatment (FU).At BL, both domains of HRQoL as well as the severity of fatigue were significantly impaired in HIV/HCV, when compared to a healthy population. Already during treatment, IFN/RBV-free therapy improved physical health (PCS: 41.4 ± 9.7 vs. 47.0 ± 11.2; P < 0.01) and reduced fatigue (37.8 ± 14.0 vs. 31.9 ± 15.2; P = 0.01), whereas we observed a substantial worsening of both factors in patients treated with BOC/PEGIFN/RBV. Since these improvements were maintained, patients treated with IFN/RBV-free therapy reported an improvement in physical health (PCS: 41.4 ± 9.7 vs. 45.8 ± 12.7; P < 0.01) and fatigue (37.8 ± 14.0 vs. 30.9 ± 14.8; P = 0.04) at FU. While AIDS-patients had a higher severity of fatigue at BL and showed a reduction of fatigue (42.5 ± 14.0 vs. 31.6 ± 15.7; P = 0.01), mental health only improved in patients without AIDS (MCS: 35.7 ± 5.3 vs.40.7 ± 6.4; P = 0.04). HIV/HCV with severe fatigue at BL (>median BL-FSS) showed most pronounced improvements in severity of fatigue (49.7 ± 7.0 vs. 32.0 ± 16.7; P < 0.01).In contrast to IFN-based regimens, highly effective and well-tolerated IFN-/RBV-free regimens improve HRQoL (especially physical health) and fatigue already during treatment. All patients with HIV/HCV coinfection should be considered for HCV treatment; however, patients with severe fatigue should be prioritized.

Topics: Antiviral Agents; Austria; Benzimidazoles; Carbamates; Coinfection; Fatigue; Female; Fluorenes; Hepatitis C, Chronic; HIV Infections; Humans; Imidazoles; Male; Middle Aged; Pyrrolidines; Quality of Life; Retrospective Studies; Severity of Illness Index; Sofosbuvir; Treatment Outcome; Valine