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Pacnejer AM, Negru MC, Arseniu AM, Trandafirescu C, Oancea C, Gligor FG, Morgovan C, Butuca A, Dehelean CA. Comparative Analysis of Neuropsychiatric Adverse Reactions Associated with Remdesivir and Nirmatrelvir/Ritonavir in COVID-19 Treatment: Insights from EudraVigilance Data. J Clin Med 2025; 14:1886. [PMID: 40142695 PMCID: PMC11942844 DOI: 10.3390/jcm14061886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Revised: 03/06/2025] [Accepted: 03/07/2025] [Indexed: 03/28/2025] Open
Abstract
Remdesivir (RDV) and nirmatrelvir/ritonavir (NMVr) are among the most widely used antivirals in the treatment of COVID-19, aiming to reduce disease severity and progression. Adverse neuropsychiatric effects, such as anxiety, sleep disturbances, and movement disorders, have emerged as significant concerns associated with these treatments. To better understand the safety profiles of RDV and NMVr, this study performs a pharmacovigilance analysis of individual case safety reports (ICSRs) from the EudraVigilance (EV) database. Objectives: This study evaluates the risk of neuropsychiatric adverse events associated with RDV and NMVr. Comparisons with other antiviral drugs, including darunavir, sofosbuvir, ribavirin, tenofovir, ritonavir, and sotrovimab, are also performed to develop a comprehensive understanding of the safety profiles. Methods: A retrospective analysis of ICSRs submitted to EV until 7 July 2024, with data extraction on 12 July 2024, was conducted. Demographic characteristics (age, sex, geographic region, and reporter type) and case severity were included in the descriptive analysis. Disproportionality analysis using reporting odds ratio (ROR) and 95% confidence intervals (CI) was performed to compare adverse drug reaction (ADRs) frequencies across 27 system organ classes (SOCs), with emphasis on "Nervous system disorders" and "Psychiatric disorders. Results: The total number of ICSRs was significantly higher for NMVr (n = 8078) compared to RDV (n = 3934). Nervous system disorders accounted for 3.07% of the total RDV reports and for 17.31% of NMVr reports, while psychiatric disorders represented 0.92% of the total ADRs reported for RDV (n = 60) and 3.61% for NMVr (n = 672). On the other hand, RDV showed a significantly lower frequency of reporting headache compared to NMVr (ROR: 0.1057; 95% CI: 0.0676-0.1653). Conclusions: NMVr presents a higher risk of neuropsychiatric ADRs than RDV, underscoring the need for enhanced monitoring, particularly in patients with preexisting central nervous system (CNS) conditions. These findings contribute to optimizing antiviral safety and informing clinical decision making.
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Affiliation(s)
- Aliteia-Maria Pacnejer
- Department of Toxicology, Drug Industry, Management and Legislation, Faculty of Pharmacy, “Victor Babeș” University of Medicine and Pharmacy, 2nd Eftimie Murgu Square, 300041 Timișoara, Romania; (A.-M.P.); (C.A.D.)
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (F.G.G.); (C.M.); (A.B.)
| | - Mihaela Cristina Negru
- Department of ENT, “Victor Babeș” University of Medicine and Pharmacy, Eftimie Murgu Square No. 2, 300041 Timișoara, Romania
| | - Anca Maria Arseniu
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (F.G.G.); (C.M.); (A.B.)
| | - Cristina Trandafirescu
- Discipline of Pharmaceutical Chemistry, Faculty of Pharmacy, “Victor Babeș” University of Medicine and Pharmacy, 2nd Eftimie Murgu Square, 300041 Timișoara, Romania;
| | - Cristian Oancea
- Department of Pulmonology, Center for Research and Innovation in Personalized Medicine of Respiratory Diseases, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timișoara, Romania;
| | - Felicia Gabriela Gligor
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (F.G.G.); (C.M.); (A.B.)
| | - Claudiu Morgovan
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (F.G.G.); (C.M.); (A.B.)
| | - Anca Butuca
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (F.G.G.); (C.M.); (A.B.)
| | - Cristina Adriana Dehelean
- Department of Toxicology, Drug Industry, Management and Legislation, Faculty of Pharmacy, “Victor Babeș” University of Medicine and Pharmacy, 2nd Eftimie Murgu Square, 300041 Timișoara, Romania; (A.-M.P.); (C.A.D.)
- Research Center for Pharmaco-Toxicological Evaluations, Faculty of Pharmacy, “Victor Babeș” University of Medicine and Pharmacy, Eftimie Murgu Square No. 2, 300041 Timișoara, Romania
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Gutiérrez-Rojas L, de la Gándara Martín JJ, García Buey L, Uriz Otano JI, Mena Á, Roncero C. Patients with severe mental illness and hepatitis C virus infection benefit from new pangenotypic direct-acting antivirals: Results of a literature review. GASTROENTEROLOGIA Y HEPATOLOGIA 2023; 46:382-396. [PMID: 35718017 DOI: 10.1016/j.gastrohep.2022.06.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 05/25/2022] [Accepted: 06/07/2022] [Indexed: 05/09/2023]
Abstract
INTRODUCTION Hepatitis C virus (HCV) infection is a global health problem that can results in cirrhosis, hepatocellular carcinoma and even death. HCV infection is 3-20-fold more prevalent among patients with versus without severe mental illness (SMI), such as major depressive disorder, personality disorder, bipolar disorder and schizophrenia. Treatment options for HCV were formerly based on pegylated interferon alpha, which is associated with neuropsychiatric adverse events, and this contributed to the exclusion of patients with SMI from HCV treatment, elimination programmes, and clinical trials. Moreover, the assumption of poor adherence, scant access to healthcare and the stigma and vulnerability of this population emerged as barriers and contributed to the low rates of treatment and efficacy. METHODS This paper reviews the literature published between December 2010 and December 2020 exploring the epidemiology of HCV in patients with SMI, and vice versa, the effect of HCV infection, barriers to the management of illness in these patients, and benefits of new therapeutic options with pangenotypic direct antiviral agents (DAAs). RESULTS The approval of DAAs has changed the paradigm of HCV infection treatment. DAAs have proven to be an equally efficacious and safe option that improves quality of life (QoL) in patients SMI. CONCLUSIONS Knowledge of the consequences of the HCV infection and the benefits of treatment with new pangenotypic DAAs among psychiatrists can increase screening, referral and treatment of HCV infection in patients with SMI.
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Affiliation(s)
| | | | - Luisa García Buey
- Gastroenterology Department, Liver Unit, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid, Madrid, Spain
| | - Juan I Uriz Otano
- Gastroenterology Department, Liver Unit, Complejo Hospitalario de Navarra, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain
| | - Álvaro Mena
- Infectious Diseases Unit, Internal Medicine Service, Clinical Virology Group, Instituto de Investigación Biomédica de A Coruña (INIBIC)-Complejo Hospitalario Universitario de A Coruña (CHUAC), Universidade da Coruña, Coruña, Spain
| | - Carlos Roncero
- Psychiatry Service, University of Salamanca Health Care Complex and Psychiatric Unit, School of Medicine, Institute of Biomedicine, University of Salamanca, Salamanca, Spain
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Pericot-Valverde I, Heo M, Niu J, Rennert L, Norton BL, Akiyama MJ, Arnsten J, Litwin AH. Relationship between depressive symptoms and adherence to direct-acting antivirals: Implications for Hepatitis C treatment among people who inject drugs on medications for opioid use disorder. Drug Alcohol Depend 2022; 234:109403. [PMID: 35306390 PMCID: PMC9278790 DOI: 10.1016/j.drugalcdep.2022.109403] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 02/16/2022] [Accepted: 03/08/2022] [Indexed: 11/16/2022]
Abstract
BACKGROUND Interferon-based regimens exacerbated depressive symptoms, which interfered with treating hepatitis C virus (HCV) among people who inject drugs (PWID). Direct-acting antivirals (DAA) are not associated with worsening depressive symptoms; however, the impact of depressive symptoms on adherence remains little known. We examined the association between depressive symptoms and adherence to DAA among HCV-infected PWID. A secondary aim was to identify the optimal cut-off for major depressive disorder for this population. METHODS Participants were 150 HCV-infected PWID on maintenance treatment enrolled in a randomized clinical trial testing three HCV care models. Severity of depressive symptoms were assessed using the Beck Depression Inventory-II (BDI-II) at baseline and every 4 weeks during treatment. Current major depressive disorder at baseline was diagnosed by the Mini-International Neuropsychiatric Interview. Adherence was measured during treatment (weeks 1-12) using electronic blister packs RESULTS: BDI-II scores ≥ 18 were identified as the optimal threshold for diagnosing major depressive disorder. Participants with BDI scores ≥ 18 at baseline had significantly lower adherence rates at weeks 1-4 of treatment compared to those with BDI scores < 18 (b = -0.23, 95% CI: 0.45-0.01, p = 0.044), but not in any other time intervals (weeks 5-8, b = -0.03, 95% CI: -0.32, 0.26, p = 0.825; weeks 9-12, b = -0.33, 95% CI -0.70, 0.02, p = 0.066). CONCLUSIONS Elevated depressive symptoms were associated with lower adherence to DAA only during the first 4 weeks of HCV treatment. Neither severe depressive symptoms nor major depressive disorder appears to be a barrier to DAA adherence among PWID.
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Affiliation(s)
- Irene Pericot-Valverde
- Prisma Health Addiction Research Center, Greenville, SC, USA; Clemson University School of Health Research, Clemson University, Clemson, SC, USA.
| | - Moonseong Heo
- Prisma Health Addiction Research Center, Greenville, SC, USA,Clemson University School of Health Research, Clemson University, Clemson, SC, USA,Department of Public Health Sciences, Clemson, SC, USA
| | - Jiajing Niu
- School of Mathematical and Statistical Sciences, Clemson University, Clemson, SC, USA
| | - Lior Rennert
- Clemson University School of Health Research, Clemson University, Clemson, SC, USA
| | - Brianna L. Norton
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Matthew J. Akiyama
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Julia Arnsten
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Alain H. Litwin
- Prisma Health Addiction Research Center, Greenville, SC, USA,Clemson University School of Health Research, Clemson University, Clemson, SC, USA,University of South Carolina School of Medicine, Department of Medicine, Greenville, SC, USA,Corresponding author: Alain H. Litwin, MD, MS, MPH, Department of Medicine, University of South Carolina School of Medicine, Greenville, SC, USA Department of Internal Medicine, Prisma Health, 605 Grove Road, Suite 205, Greenville, SC 29605, USA. 1-864-455-6658,
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Danilescu CM, Sandulescu DL, Pirlog MC, Streba CT, Rogoveanu I. Depressive and Anxious Symptoms in Hepatitis C Virus Infected Patients Receiving DAA-Based Therapy. Diagnostics (Basel) 2021; 11:2237. [PMID: 34943472 PMCID: PMC8700570 DOI: 10.3390/diagnostics11122237] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/26/2021] [Accepted: 11/27/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) represents the most important etiologic factor for advanced fibrosis/cirrhosis and hepatocellular carcinoma associated with a psychological dimension. Our study aims to assess, on a sample comprising of 90 HCV-infected subjects (96.67% F3-F4 METAVIR), the relationship between Direct-Acting Antiviral (DAA) therapies and the psychological effects of the liver disease, focused on the anxious and depressive symptoms. The comprehensive evaluation was done before starting the DAA treatment (BSL), after 12 weeks (End of Treatment-EOT), respectively after another 12 weeks (Sustained Viral Response-SVR). Presumable depressive and/or anxious symptoms were evaluated by Hospital Anxiety and Depression Scale (HADS). The reported depressive symptoms decreased from 21.11% (BSL) to 1.11% (SVR) (p < 0.00001), while the anxious ones dropped from 43.34% (BSL) to 4.44% (SVR) (p < 0.00001), without a clear evolutionary pattern. We identified no statistically significant interaction between comorbidities (anemia, CKD, obesity) over HADS scores evolution (p > 0.05), while the DAAs side-effects (fatigue, headache, pruritus) significantly influenced the anxious and depressive symptoms (p < 0.05). During and after the DAA-based therapy, patients with HCV infection presented a significantly reduced rate of the associated depressive and anxious relevant symptoms.
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Affiliation(s)
| | - Daniela Larisa Sandulescu
- Department of Gastroenterology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (D.L.S.); (I.R.)
| | - Mihail Cristian Pirlog
- Department of Medical Sociology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Costin Teodor Streba
- Department of Scientific Research Methodology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Ion Rogoveanu
- Department of Gastroenterology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (D.L.S.); (I.R.)
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Nevola R, Rinaldi L, Zeni L, Romano C, Marrone A, Galiero R, Pafundi PC, Acierno C, Vetrano E, Adinolfi LE. Changes in clinical scenarios, management, and perspectives of patients with chronic hepatitis C after viral clearance by direct-acting antivirals. Expert Rev Gastroenterol Hepatol 2021; 15:643-656. [PMID: 33445990 DOI: 10.1080/17474124.2021.1877136] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Hepatitis C virus (HCV) causes a systemic infection inducing hepatic and extrahepatic diseases. These latter involve cardiovascular system, kidney, brain, endocrine, glucose, and lipid metabolism, and the immune system. HCV infection is associated with an increased risk of morbidity and mortality for both hepatic and extrahepatic events. Direct-acting antivirals (DAA), introduced in the most recent years for HCV treatment, are effective in up to 99% of cases and have changed the clinical scenarios and management of these patients. AREAS COVERED The literature on the impact of HCV clearance by DAA on both hepatic and extrahepatic disease outcomes has been analyzed and discussed in this review in order to summarize the full therapeutic potential and its weaknesses. EXPERT OPINION Patients achieving HCV clearance have improved hepatic and extrahepatic diseases, quality of life and survival. They have lower incidence of cardiovascular disease, type 2 diabetes, kidney damage, and immuno-mediated manifestations. However, the improvements are related to the degree of pre-treatment organ damage. Therefore, a significant percentage of patients with advanced disease remains at risk of morbidity and mortality and must be monitored in the post-treatment. In addition, data emphasize the importance of starting treatment during the early stages of HCV infection.
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Affiliation(s)
- Riccardo Nevola
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Luca Rinaldi
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Letizia Zeni
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Ciro Romano
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Aldo Marrone
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Raffaele Galiero
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Pia Clara Pafundi
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Carlo Acierno
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Erica Vetrano
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Luigi Elio Adinolfi
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
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Pericot-Valverde I, Heo M, Niu J, Norton BL, Akiyama MJ, Agyemang L, Litwin AH. Declines in Depressive Symptoms Among People who Inject Drugs Treated With Direct-Acting Antivirals While on Opioid Agonist Therapy. Open Forum Infect Dis 2021; 7:ofaa380. [PMID: 33381611 PMCID: PMC7751182 DOI: 10.1093/ofid/ofaa380] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 08/25/2020] [Indexed: 11/29/2022] Open
Abstract
Background Hepatitis C virus (HCV) frequently co-occurs with symptoms of depression, which are aggravated on interferon-based regimens. However, it is unknown whether HCV treatment with direct-acting antivirals (DAAs) has effects on depressive symptoms among people who inject drugs (PWID). In this study, we examined changes in depressive symptoms during and after HCV treatment among PWID on opioid agonist therapies (OATs). Methods Participants were 141 PWID who achieved sustained viral response after on-site HCV treatment at 3 OAT programs. Depressive symptoms were assessed using the Beck Depression Inventory–II (BDI-II) at baseline, every 4 weeks during treatment, and 12 and 24 weeks after treatment completion. Current diagnosis of depression or other psychiatric diagnoses were obtained through chart review. Use of illicit drugs was measured by urine toxicology screening. Alcohol use was measured using the Addiction Severity Index–Lite. Results Of the 141 PWID infected with HCV, 24.1% had severe, 9.9% had moderate, 15.6% had mild, and 50.4% had minimal levels of depression as per BDI-II scores at baseline. HCV treatment was significantly associated with reductions in depressive symptoms that persisted long term, regardless of symptom severity (P < .001) or presence of depression (P ≤ .01) or other psychiatric diagnoses (P ≤ .01) at baseline. Concurrent drug use (P ≤ .001) or hazardous alcohol drinking (P ≤ .001) did not interfere with reductions in depressive symptoms. Conclusions Depressive symptoms are highly prevalent among HCV-infected PWID. HCV treatment was associated with sustained reductions in depressive symptoms. HCV therapy with DAAs may have important implications for PWID that go beyond HCV cure.
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Affiliation(s)
- Irene Pericot-Valverde
- Clemson University School of Health Research, Clemson, South Carolina, USA.,Department of Medicine, Prisma Health, Greenville, South Carolina, USA
| | - Moonseong Heo
- Department of Public Health Science, Health Sciences, Clemson University, Clemson, South Carolina, USA
| | - Jiajing Niu
- School of Mathematical and Statistical Sciences, Clemson University, Clemson, South Carolina, USA
| | | | | | | | - Alain H Litwin
- Clemson University School of Health Research, Clemson, South Carolina, USA.,Department of Medicine, Prisma Health, Greenville, South Carolina, USA.,Department of Medicine, University of South Carolina School of Medicine-Greenville, Greenville, South Carolina, USA
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Margusino-Framiñán L, Bobadilla-Pérez E, Cid-Silva P, Rodríguez-Sotelo A, Yáñez-Rubal JC, Mena-de-Cea Á, Suárez-López F, Prieto-Pérez A, Giménez-Arufe V, Delgado-Blanco M, Sanclaudio-Luhia AI, Martín-Herranz I, Castro-Iglesias Á. Effectiveness and safety of direct-acting antivirals in hepatitis C infected patients with mental disorders: Results in real clinical practice. J Med Virol 2020; 92:3488-3498. [PMID: 32181917 DOI: 10.1002/jmv.25772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 03/10/2020] [Indexed: 11/08/2022]
Abstract
The aim of this study is to analyze the effectiveness and safety of direct-acting antivirals (DAAs) in psychiatric patients with chronic hepatitis C (CHC). Secondary objectives included adherence and drug-drug interaction (DDIs) evaluations. Prospective observational comparative study carried out during 3 years. Psychiatric patients were included and mental illness classified by a psychiatric team based on clinical records. Main effectiveness and safety variables were sustained virologic response (SVR) at posttreatment week 12 (SVR12) and rate of on-treatment serious drug-related adverse events (AEs), respectively. A total of 242 psychiatric and 900 nonpsychiatric patients were included. SVR12 by intention-to-treat (ITT) analysis of psychiatric vs nonpsychiatric patients was 92.6% (95% confidence interval [CI], 89.1-96.1) vs 96.2% (95% CI, 94.9-97.5) (P = .02). SVR12 by modified-ITT analysis was 97.8% (95% CI, 95.0-99.3) vs 98.4% (95% CI, 97.5-99.3) (P = .74). 92.2% of psychiatric patients with mental disorders secondary to multiple drug use (MDSDU) and 93.0% of psychiatric patients without MDSDU vs 96.2% of nonpsychiatric patients reached SVR12 (P = .05 and P = .20, respectively). The percentage of adherent patients to DAAs did not show differences between cohorts (P = .08). 30.2% of psychiatric patients and 27.6% of nonpsychiatric patients presented clinically relevant DDIs (P = .47). 1.7% vs 0.8% of psychiatric vs nonpsychiatric patients developed serious AEs (P = .39); no serious psychiatric AEs were present. DAAs have shown a slightly lower effectiveness in psychiatric patients with CHC, as a result of loss of follow up, which justifies the need for integrated and multidisciplinary health care teams. DAAs safety, adherence, and DDIs, however, are similar to that of nonpsychiatric patients.
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Affiliation(s)
- Luis Margusino-Framiñán
- Pharmacy Service, Universitary Hospital of A Coruña, A Coruña, Spain
- Division of Clinical Virology, Biomedical Research Institute of A Coruña (INIBIC), Universitary Hospital of A Coruña, SERGAS, University of A Coruña (UDC), A Coruña, Spain
| | | | - Purificación Cid-Silva
- Pharmacy Service, Universitary Hospital of A Coruña, A Coruña, Spain
- Division of Clinical Virology, Biomedical Research Institute of A Coruña (INIBIC), Universitary Hospital of A Coruña, SERGAS, University of A Coruña (UDC), A Coruña, Spain
| | | | | | - Álvaro Mena-de-Cea
- Division of Clinical Virology, Biomedical Research Institute of A Coruña (INIBIC), Universitary Hospital of A Coruña, SERGAS, University of A Coruña (UDC), A Coruña, Spain
- Infectious Diseases Unit, Internal Medicine Service, Universitary Hospital of A Coruña, A Coruña, Spain
| | - Francisco Suárez-López
- Hepatology Unit, Digestive System Service, Universitary Hospital of A Coruña, A Coruña, Spain
| | | | | | - Manuel Delgado-Blanco
- Division of Clinical Virology, Biomedical Research Institute of A Coruña (INIBIC), Universitary Hospital of A Coruña, SERGAS, University of A Coruña (UDC), A Coruña, Spain
- Hepatology Unit, Digestive System Service, Universitary Hospital of A Coruña, A Coruña, Spain
| | | | | | - Ángeles Castro-Iglesias
- Division of Clinical Virology, Biomedical Research Institute of A Coruña (INIBIC), Universitary Hospital of A Coruña, SERGAS, University of A Coruña (UDC), A Coruña, Spain
- Infectious Diseases Unit, Internal Medicine Service, Universitary Hospital of A Coruña, A Coruña, Spain
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Neuroimaging Findings in Chronic Hepatitis C Virus Infection: Correlation with Neurocognitive and Neuropsychiatric Manifestations. Int J Mol Sci 2020; 21:ijms21072478. [PMID: 32252497 PMCID: PMC7177498 DOI: 10.3390/ijms21072478] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 03/26/2020] [Accepted: 03/31/2020] [Indexed: 01/18/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection is commonly associated with neurocognitive dysfunction, altered neuropsychological performance and neuropsychiatric symptoms. Quantifiable neuropsychological changes in sustained attention, working memory, executive function, verbal learning and recall are the hallmark of HCV-associated neurocognitive disorder (HCV-AND). This constellation is at variance with the neuropsychological complex that is seen in minimal hepatic encephalopathy, which is typified by an array of alterations in psychomotor speed, selective attention and visuo-constructive function. Noncognitive symptoms, including sleep disturbances, depression, anxiety and fatigue, which are less easily quantifiable, are frequently encountered and can dominate the clinical picture and the clinical course of patients with chronic HCV infection. More recently, an increased vulnerability to Parkinson’s disease among HCV-infected patients has also been reported. The degree to which neurocognitive and neuropsychiatric changes are due to HCV replication within brain tissues or HCV-triggered peripheral immune activation remain to be determined. Without absolute evidence that clearly exonerates or indicts HCV, our understanding of the so-called “HCV brain syndrome”, relies primarily on clinical and neuropsychological assessments, although other comorbidities and substance abuse may impact on neurocognitive function, thus confounding an appropriate recognition. In recent years, a number of functional and structural brain imaging studies have been of help in recognizing possible biological markers of HCV-AND, thus providing a rationale for guiding and justifying antiviral therapy in selected cases. Here, we review clinical, neuroradiological, and therapeutic responses to interferon-based and interferon-free regimens in HCV-related cognitive and neuropsychiatric disorder.
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Travaglini LE, Kreyenbuhl J, Graydon M, Brown CH, Goldberg R, Himelhoch S, Fang LJ, Slade E. Access to Direct-Acting Antiviral Treatment for Hepatitis C Virus Among Veterans With Serious Mental Illness. Psychiatr Serv 2020; 71:192-195. [PMID: 31615365 DOI: 10.1176/appi.ps.201900227] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
OBJECTIVE This study examined whether serious mental illness is associated with initiating and with completing sofosbuvir-based treatment for hepatitis C virus (HCV) among veterans who started treatment after the Veterans Health Administration (VHA) received expanded funding for HCV care. METHODS Administrative health care data from fiscal years 2016-2017 revealed 4,288 treatment-naïve patients with HCV, of whom 1,311 had initiated sofosbuvir-based treatment. Dependent variables were initiation and completion of ≥8 weeks of sofosbuvir treatment. Associations with serious mental illness were estimated with adjusted odds ratios from multivariable logistic regression analyses. RESULTS No statistically significant differences were found in the proportion of veterans with and veterans without serious mental illness who initiated (p=0.628) or completed ≥8 weeks (p=0.301) of sofosbuvir treatment. CONCLUSIONS Veterans with and without serious mental illness initiated and completed sofosbuvir treatment at similar rates. The VA should continue to provide equitable access to HCV treatments and support medication adherence.
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Affiliation(s)
- Letitia E Travaglini
- Veterans Affairs (VA) Capitol Healthcare Network (VISN 5) Mental Illness Research, Education and Clinical Center (MIRECC), Baltimore (Travaglini, Kreyenbuhl, Brown, Goldberg); Division of Psychiatric Services Research, Department of Psychiatry (Kreyenbuhl, Goldberg, Fang, Slade), and Department of Epidemiology and Public Health (Brown), University of Maryland School of Medicine, Baltimore; VA Maryland Health Care System, Baltimore (Graydon); Department of Psychiatry, University of Kentucky College of Medicine, Lexington (Himelhoch); Johns Hopkins University School of Nursing, Baltimore (Slade)
| | - Julie Kreyenbuhl
- Veterans Affairs (VA) Capitol Healthcare Network (VISN 5) Mental Illness Research, Education and Clinical Center (MIRECC), Baltimore (Travaglini, Kreyenbuhl, Brown, Goldberg); Division of Psychiatric Services Research, Department of Psychiatry (Kreyenbuhl, Goldberg, Fang, Slade), and Department of Epidemiology and Public Health (Brown), University of Maryland School of Medicine, Baltimore; VA Maryland Health Care System, Baltimore (Graydon); Department of Psychiatry, University of Kentucky College of Medicine, Lexington (Himelhoch); Johns Hopkins University School of Nursing, Baltimore (Slade)
| | - Meagan Graydon
- Veterans Affairs (VA) Capitol Healthcare Network (VISN 5) Mental Illness Research, Education and Clinical Center (MIRECC), Baltimore (Travaglini, Kreyenbuhl, Brown, Goldberg); Division of Psychiatric Services Research, Department of Psychiatry (Kreyenbuhl, Goldberg, Fang, Slade), and Department of Epidemiology and Public Health (Brown), University of Maryland School of Medicine, Baltimore; VA Maryland Health Care System, Baltimore (Graydon); Department of Psychiatry, University of Kentucky College of Medicine, Lexington (Himelhoch); Johns Hopkins University School of Nursing, Baltimore (Slade)
| | - Clayton H Brown
- Veterans Affairs (VA) Capitol Healthcare Network (VISN 5) Mental Illness Research, Education and Clinical Center (MIRECC), Baltimore (Travaglini, Kreyenbuhl, Brown, Goldberg); Division of Psychiatric Services Research, Department of Psychiatry (Kreyenbuhl, Goldberg, Fang, Slade), and Department of Epidemiology and Public Health (Brown), University of Maryland School of Medicine, Baltimore; VA Maryland Health Care System, Baltimore (Graydon); Department of Psychiatry, University of Kentucky College of Medicine, Lexington (Himelhoch); Johns Hopkins University School of Nursing, Baltimore (Slade)
| | - Richard Goldberg
- Veterans Affairs (VA) Capitol Healthcare Network (VISN 5) Mental Illness Research, Education and Clinical Center (MIRECC), Baltimore (Travaglini, Kreyenbuhl, Brown, Goldberg); Division of Psychiatric Services Research, Department of Psychiatry (Kreyenbuhl, Goldberg, Fang, Slade), and Department of Epidemiology and Public Health (Brown), University of Maryland School of Medicine, Baltimore; VA Maryland Health Care System, Baltimore (Graydon); Department of Psychiatry, University of Kentucky College of Medicine, Lexington (Himelhoch); Johns Hopkins University School of Nursing, Baltimore (Slade)
| | - Seth Himelhoch
- Veterans Affairs (VA) Capitol Healthcare Network (VISN 5) Mental Illness Research, Education and Clinical Center (MIRECC), Baltimore (Travaglini, Kreyenbuhl, Brown, Goldberg); Division of Psychiatric Services Research, Department of Psychiatry (Kreyenbuhl, Goldberg, Fang, Slade), and Department of Epidemiology and Public Health (Brown), University of Maryland School of Medicine, Baltimore; VA Maryland Health Care System, Baltimore (Graydon); Department of Psychiatry, University of Kentucky College of Medicine, Lexington (Himelhoch); Johns Hopkins University School of Nursing, Baltimore (Slade)
| | - Li Juan Fang
- Veterans Affairs (VA) Capitol Healthcare Network (VISN 5) Mental Illness Research, Education and Clinical Center (MIRECC), Baltimore (Travaglini, Kreyenbuhl, Brown, Goldberg); Division of Psychiatric Services Research, Department of Psychiatry (Kreyenbuhl, Goldberg, Fang, Slade), and Department of Epidemiology and Public Health (Brown), University of Maryland School of Medicine, Baltimore; VA Maryland Health Care System, Baltimore (Graydon); Department of Psychiatry, University of Kentucky College of Medicine, Lexington (Himelhoch); Johns Hopkins University School of Nursing, Baltimore (Slade)
| | - Eric Slade
- Veterans Affairs (VA) Capitol Healthcare Network (VISN 5) Mental Illness Research, Education and Clinical Center (MIRECC), Baltimore (Travaglini, Kreyenbuhl, Brown, Goldberg); Division of Psychiatric Services Research, Department of Psychiatry (Kreyenbuhl, Goldberg, Fang, Slade), and Department of Epidemiology and Public Health (Brown), University of Maryland School of Medicine, Baltimore; VA Maryland Health Care System, Baltimore (Graydon); Department of Psychiatry, University of Kentucky College of Medicine, Lexington (Himelhoch); Johns Hopkins University School of Nursing, Baltimore (Slade)
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10
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Nardelli S, Riggio O, Rosati D, Gioia S, Farcomeni A, Ridola L. Hepatitis C virus eradication with directly acting antivirals improves health-related quality of life and psychological symptoms. World J Gastroenterol 2019; 25:6928-6938. [PMID: 31908396 PMCID: PMC6938730 DOI: 10.3748/wjg.v25.i48.6928] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 12/13/2019] [Accepted: 12/22/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Alterations in health-related quality of life (HRQoL) and neuropsychological disorders were described in the hepatitis C virus (HCV) patients. Although several studies investigated the modifications of HRQoL after HCV eradication, no data exists on the modifications of neuropsychological symptoms. AIM To investigate the effect of directly acting antivirals (DAAs) treatment on HRQoL and neuropsychological symptoms. METHODS Thirty nine patients with HCV infection underwent a neuropsychological assessment, including Zung-Self Depression-Rating-Scale, Spielberg State-Trait Anxiety Inventory Y1-Y2 and the Toronto-Alexithymia Scale-20 items before and after DAAs treatment. HRQoL was detected by Short-Form-36 (SF-36). RESULTS All HRQoL domains, but role limitation physical and bodily pain, significantly improved after treatment. Interestingly, after DAAs treatment, all domains of HRQoL returned similar to those of controls. Each neuropsychological test significantly improved after HCV eradication. A significant correlation was observed among each psychological test and the summary components of SF-36. At multiple linear regression analysis including each psychological test as possible covariates, Zung-Self Depression Rating Scale (Zung-SDS) score was independently and significantly related to summary components of the SF-36 in the basal state and the difference between Zung-SDS score before and after treatment was the only variable significantly and independently related to the modification of HRQoL induced by the treatment. CONCLUSION Neuropsychological symptoms strongly influenced HRQoL in HCV patients and there was a significant improvement of neuropsychological tests and HRQoL after DAAs treatment.
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Affiliation(s)
- Silvia Nardelli
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
| | - Oliviero Riggio
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
| | - Davide Rosati
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
| | - Stefania Gioia
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
| | - Alessio Farcomeni
- Department of Economics & Finance, University of Rome “Tor Vergata”, Rome 00185, Italy
| | - Lorenzo Ridola
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
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11
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Back D, Belperio P, Bondin M, Negro F, Talal AH, Park C, Zhang Z, Pinsky B, Crown E, Mensa FJ, Marra F. Efficacy and safety of glecaprevir/pibrentasvir in patients with chronic HCV infection and psychiatric disorders: An integrated analysis. J Viral Hepat 2019; 26:951-960. [PMID: 30977945 PMCID: PMC6852431 DOI: 10.1111/jvh.13110] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 01/13/2019] [Accepted: 02/11/2019] [Indexed: 12/25/2022]
Abstract
Although direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) infection are highly efficacious and safe, treatment initiation is often limited in patients with neuropsychiatric disorders due to concerns over reduced treatment adherence and drug-drug interactions. Here, we report adherence, efficacy, safety and patient-reported outcomes (PROs) from an integrated analysis of registrational studies using the pangenotypic DAA regimen of glecaprevir and pibrentasvir (G/P). Patients with chronic HCV genotypes 1-6 infection with compensated liver disease (with or without cirrhosis) receiving G/P for 8, 12 or 16 weeks were included in this analysis. Patients were classified as having a psychiatric disorder based on medical history and/or co-medications. Primary analyses assessed treatment adherence, efficacy (sustained virologic response at post-treatment week 12; SVR12), safety and PROs. Among 2522 patients receiving G/P, 789 (31%) had a psychiatric disorder with the most common diagnoses being depression (64%; 506/789) and anxiety disorders (27%; 216/789). Treatment adherence was comparably high (>95%) in patients with and without psychiatric disorders. SVR12 rates were 97.3% (768/789; 95% CI = 96.2-98.5) and 97.5% (1689/1733; 95% CI = 96.7-98.2) in patients with and without psychiatric disorders, respectively. Among patients with psychiatric disorders, SVR12 rates remained >96% by individual psychiatric diagnoses and co-medication classes. Overall, most adverse events (AEs) were mild-to-moderate in severity with serious AEs and AEs leading to G/P discontinuation occurring at similarly low rates in both patient populations. In conclusion, G/P treatment was highly efficacious, well-tolerated and demonstrated high adherence rates in patients with chronic HCV infection and psychiatric disorders.
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Affiliation(s)
| | - Pamela Belperio
- U.S. Department of Veterans AffairsVA Palo Alto Healthcare SystemPalo AltoCalifornia
| | | | | | - Andrew H. Talal
- Jacobs School of Medicine and Biomedical SciencesUniversity of BuffaloBuffaloNew York
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12
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Gallach M, Vergara M, da Costa JP, Miquel M, Casas M, Sanchez-Delgado J, Dalmau B, Rudi N, Parra I, Monllor T, Sanchez-Lloansí M, Dosal A, Valero O, Calvet X. Impact of treatment with direct-acting antivirals on anxiety and depression in chronic hepatitis C. PLoS One 2018; 13:e0208112. [PMID: 30566421 PMCID: PMC6300319 DOI: 10.1371/journal.pone.0208112] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 11/12/2018] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND AND AIM Treatment of hepatitis C with direct-acting antiviral agents (DAA) has few side effects. Although pivotal studies suggested that DAA were safe in patients with psychiatric diseases who could not be treated with previous antiviral therapies, their effects on anxiety and depression have not yet been analysed in clinical practice. The aim of our study was to analyse anxiety and depression in the setting of DAA treatment in a clinical practice series. METHODS All patients starting DAA treatment between November 1, 2014 and October 31, 2015 were eligible. Patients completed the Hospital Anxiety and Depression scale at different times during treatment. The results were plotted on line graphs and evaluated using a linear regression model with repeated measures. RESULTS One hundred and forty-five patients were included (11% with major psychiatric disorders; 32% on psychiatric treatment). Sustained virologic response (SVR) was achieved in 97.3% of cases. Anxiety and depression measures did not differ between time points. No differences between patients on psychiatric treatment or with advanced fibrosis or cirrhosis were found at any time point analysed. CONCLUSION DAA treatment had no impact on anxiety or depression during or after chronic hepatitis C infection treatment, even in high-risk patients with major psychiatric disorders.
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Affiliation(s)
- Marta Gallach
- Hepatology unit, Digestive Disease Department, Parc Taulí Hospital Universitari, Institutd’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona; Sabadell, Spain
| | - Mercedes Vergara
- Hepatology unit, Digestive Disease Department, Parc Taulí Hospital Universitari, Institutd’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona; Sabadell, Spain
- CIBERehd, Instituto Carlos III, Madrid, Spain
| | - Joao Pedro da Costa
- Hepatology unit, Digestive Disease Department, Parc Taulí Hospital Universitari, Institutd’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona; Sabadell, Spain
| | - Mireia Miquel
- Hepatology unit, Digestive Disease Department, Parc Taulí Hospital Universitari, Institutd’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona; Sabadell, Spain
- CIBERehd, Instituto Carlos III, Madrid, Spain
| | - Meritxell Casas
- Hepatology unit, Digestive Disease Department, Parc Taulí Hospital Universitari, Institutd’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona; Sabadell, Spain
| | - Jordi Sanchez-Delgado
- Hepatology unit, Digestive Disease Department, Parc Taulí Hospital Universitari, Institutd’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona; Sabadell, Spain
- CIBERehd, Instituto Carlos III, Madrid, Spain
| | - Blai Dalmau
- Hepatology unit, Digestive Disease Department, Parc Taulí Hospital Universitari, Institutd’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona; Sabadell, Spain
- CIBERehd, Instituto Carlos III, Madrid, Spain
| | - Núria Rudi
- Pharmacy Department, Parc Taulí Hospital Universitari, Institutd’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain
| | - Isabel Parra
- Mental Health Department, Parc Taulí Hospital Universitari, Institutd’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain
| | - Teresa Monllor
- Nursing, Hepatology Day Hospital, ParcTaulí Hospital Universitari, Institutd’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain
| | - Meritxell Sanchez-Lloansí
- Nursing, Hepatology Day Hospital, ParcTaulí Hospital Universitari, Institutd’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain
| | - Angelina Dosal
- Nursing, Hepatology Day Hospital, ParcTaulí Hospital Universitari, Institutd’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain
| | - Oliver Valero
- Statistical services center, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Xavier Calvet
- Hepatology unit, Digestive Disease Department, Parc Taulí Hospital Universitari, Institutd’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona; Sabadell, Spain
- CIBERehd, Instituto Carlos III, Madrid, Spain
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13
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Hahn D, Stokes CS, Kaiser R, Meyer MR, Lammert F, Gruenhage F. Antidepressant effects of direct-acting antivirals against hepatitis C virus-Results from a pilot study. Eur J Clin Invest 2018; 48:e13024. [PMID: 30175442 DOI: 10.1111/eci.13024] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 07/30/2018] [Accepted: 08/29/2018] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIMS The new direct-acting antiviral agents (DAA) have revolutionized the treatment of patients with chronic hepatitis C virus (HCV) infection. This study investigates to which extent DAA affect fatigue and mood and, if so, whether this results from changes to tryptophan (TRP) metabolism, as reflected by two critical biosynthetic pathways, serotonin (SRT) generation from TRP and TRP degradation through kynurenines (KYN) via indoleamine 2,3-dioxygenase (IDO). METHODS This study assessed 24 patients with chronic HCV infection, before (T1), during (T2: at 4 weeks) and 12 weeks post-treatment with DAA (T3) with respect to viral load, fatigue and depressive symptoms (BDI-II questionnaire), physical activity (actigraph) and plasma serotonin-tryptophan metabolites (LC/MS). The KYN:TRP ratio reflected IDO activity. RESULTS All participants achieved sustained virological response (SVR12) with DAA treatment (79% sofosbuvir-based). Fatigue (scores at T1:0.83 ± 0.70, T2:0.48 ± 0.70, T3:0.30 ± 0.50; P = 0.023) and depressive symptoms (scores at T1:9.8 ± 10.2, T2:6.0 ± 7.3, T3:5.0 ± 7.6; P = 0.005) improved significantly on therapy, whereas no changes were noted in five untreated controls. TRP plasma concentrations markedly decreased (T1:306 ± 179 mg/L, T2:283 ± 84 mg/L), whereas 5-HTP levels increased (T1:0.08 ± 0.01 mg/L, T2:0.10 ± 0.06 mg/L). KYN concentrations (T1:2.4 ± 2.0 mg/L, T2:3.7 ± 1.4 mg/L, P = 0.003) increased significantly during treatment, as did IDO activity (T1:0.008 ± 0.006 mg/L, T2:0.014 ± 0.004 mg/L; P < 0.001). CONCLUSIONS In this study, DAA exert positive and persistent effects on both fatigue and mood in patients with chronic HCV infection. These extrahepatic benefits are, at least in part, related to the modulation of TRP metabolism. The robust elevation of KYN concentrations challenges the current paradigm of low KYN levels as prerequisite for mental health.
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Affiliation(s)
- Daphne Hahn
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Caroline S Stokes
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Ralf Kaiser
- Department of Medicine V, Saarland University Medical Center, Saarland University Homburg, Homburg, Germany
| | - Markus R Meyer
- Department of Experimental and Clinical Toxicology, Saarland University, Homburg, Germany
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Frank Gruenhage
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.,Department of Internal Medicine, RKN-Clinics, St. Elisabeth Hospital, Grevenbroich, Germany
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14
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Takeda K, Noguchi R, Namisaki T, Moriya K, Akahane T, Kitade M, Kawaratani H, Shimozato N, Kaji K, Takaya H, Sawada Y, Seki K, Fujinaga Y, Tsuji Y, Kubo T, Sato S, Saikawa S, Nakanishi K, Furukawa M, Kitagawa K, Ozutsumi T, Kaya D, Mitoro A, Mashitani T, Okura Y, Yamao J, Yoshiji H. Efficacy and tolerability of interferon-free regimen for patients with genotype-1 HCV infection. Exp Ther Med 2018; 16:2743-2750. [PMID: 30210615 PMCID: PMC6122593 DOI: 10.3892/etm.2018.6481] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 06/27/2018] [Indexed: 12/11/2022] Open
Abstract
Depression is a major reason for interferon (IFN) therapy cessation. IFN-free direct-acting antiviral (DAA) therapy for depression is not well-documented. Thus, four different IFN-free regimens were assessed in genotype-1 hepatitis C virus (HCV) patients with depression. Overall, 287 HCV genotype-1 patients who received combination therapies with IFN-free DAAs of daclatasvir/asunaprevir (DCV/ASV) (n=84), sofosbuvir/ledipasvir (SOF/LDV) (n=95), ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) (n=74), and elbasvir/grazoprevir (EBR/GZR) (n=34) were included. Treatment-induced depression as a complication of HCV therapy in IFN-free DAA regimens was assessed. The severity of depression was evaluated using the Beck Depression Inventory-II (BDI-II) questionnaire. It was demonstrated that all four DAA regimens achieved similar high efficacy in Japanese patients with HCV genotype-1 infection. Moreover, in seven patients with depression who received the 24-week DCV/ASV treatment regimen, the BDI-II scores significantly increased at week 4 as compared with pretreatment values; furthermore, they decreased below baseline at week 12 despite the rapid decline of serum HCV levels after the initiation of DCV/ASV therapy. The BDI-II scores gradually decreased during therapy in the remaining 77 DCV/ASV-treated patients without depression. The BDI-II scores showed a significant decrease from baseline to the end of treatment with 12-week regimens, including SOF/LDV and EBR/GZR. The 12-week DAA regimen of SOF/LDV and EBR/GZR can be safely used with high efficacy in patients with genotype-1 HCV infection, including those with depression.
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Affiliation(s)
- Kosuke Takeda
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Ryuichi Noguchi
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Tadashi Namisaki
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Kei Moriya
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Takemi Akahane
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Mitsuteru Kitade
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Hideto Kawaratani
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Naotaka Shimozato
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Kosuke Kaji
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Hiroaki Takaya
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Yasuhiko Sawada
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Kenichiro Seki
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Yukihisa Fujinaga
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Yuki Tsuji
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Takuya Kubo
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Shinya Sato
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Soichiro Saikawa
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Keisuke Nakanishi
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Masanori Furukawa
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Koh Kitagawa
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Takahiro Ozutsumi
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Daisuke Kaya
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Akira Mitoro
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Tsuyoshi Mashitani
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Yasushi Okura
- Department of Endoscopy, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Junichi Yamao
- Department of Endoscopy, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Hitoshi Yoshiji
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
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15
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Brown LV, Gaffney EA, Wagg J, Coles MC. Applications of mechanistic modelling to clinical and experimental immunology: an emerging technology to accelerate immunotherapeutic discovery and development. Clin Exp Immunol 2018; 193:284-292. [PMID: 30240512 PMCID: PMC6150250 DOI: 10.1111/cei.13182] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/31/2018] [Indexed: 12/15/2022] Open
Abstract
The application of in-silico modelling is beginning to emerge as a key methodology to advance our understanding of mechanisms of disease pathophysiology and related drug action, and in the design of experimental medicine and clinical studies. From this perspective, we will present a non-technical discussion of a small number of recent and historical applications of mathematical, statistical and computational modelling to clinical and experimental immunology. We focus specifically upon mechanistic questions relating to human viral infection, tumour growth and metastasis and T cell activation. These exemplar applications highlight the potential of this approach to impact upon human immunology informed by ever-expanding experimental, clinical and 'omics' data. Despite the capacity of mechanistic modelling to accelerate therapeutic discovery and development and to de-risk clinical trial design, it is not utilized widely across the field. We outline ongoing challenges facing the integration of mechanistic modelling with experimental and clinical immunology, and suggest how these may be overcome. Advances in key technologies, including multi-scale modelling, machine learning and the wealth of 'omics' data sets, coupled with advancements in computational capacity, are providing the basis for mechanistic modelling to impact on immunotherapeutic discovery and development during the next decade.
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Affiliation(s)
- L. V. Brown
- Wolfson Centre for Mathematical BiologyMathematical InstituteUniversity of OxfordOxfordUK
| | - E. A. Gaffney
- Wolfson Centre for Mathematical BiologyMathematical InstituteUniversity of OxfordOxfordUK
| | - J. Wagg
- Pharmaceutical Sciences, Clinical PharmacologyRoche Innovation CenterBaselSwitzerland
| | - M. C. Coles
- Kennedy Institute of RheumatologyUniversity of OxfordOxfordUK
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16
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Yeoh SW, Holmes ACN, Saling MM, Everall IP, Nicoll AJ. Depression, fatigue and neurocognitive deficits in chronic hepatitis C. Hepatol Int 2018; 12:294-304. [PMID: 29931590 DOI: 10.1007/s12072-018-9879-5] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Accepted: 06/05/2018] [Indexed: 12/11/2022]
Abstract
Patients with chronic hepatitis C virus (HCV) infection experience a range of symptoms including depression, fatigue and neurocognitive deficits, impairing quality of life. Depression, in particular, may be reactive to increased psychosocial stress, and the physical symptoms of advanced HCV or associated comorbidities. However, even patients at an early stage of HCV infection, with minimal hepatic inflammation or comorbidities, report more depressive symptoms and fatigue than the general population. Similarly, specific neurocognitive deficits occur in early stage HCV infection and are independent of the presence of depression or encephalopathy. Therefore, intracerebral neurobiological changes associated with HCV may potentially explain these symptoms. These changes may arise from infiltration of the brain by peripherally induced cytokines, as well as direct neuropathic effects of HCV viral particles penetrating the blood-brain barrier. These phenomena parallel those reported in human immunodeficiency virus (HIV) infection. HCV-associated intracerebral changes include upregulated inflammatory responses, altered neurotransmitter levels, hormonal dysregulation, and release of neurotoxic substances. These may subsequently lead to abnormal neuronal conduction and function in areas of the brain governing affective responses, emotional processing, motivation, attention and concentration. Although direct-acting antiviral medications lead to high rates of HCV clearance, intracerebral changes may not be subsequently reversed and symptoms of depression, fatigue and neurocognitive deficits may persist. There is an ongoing role for multidisciplinary care and pharmacotherapy to manage these symptoms in HCV patients. Furthermore, there may be opportunities for future therapies to specifically target and ameliorate HCV-associated intracerebral changes.
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Affiliation(s)
- Sern Wei Yeoh
- Department of Gastroenterology, Eastern Health, 3 West, Building B, 8 Arnold St, Box Hill, VIC, 3128, Australia.
| | - Alex C N Holmes
- Department of Psychiatry, University of Melbourne, Level 1 North, Main Block, Royal Melbourne Hospital, 300 Grattan St, Parkville, VIC, 3050, Australia
| | - Michael M Saling
- Melbourne School of Psychological Sciences, 12th Floor, Redmond Barry Building, Parkville Campus, University of Melbourne, Parkville, VIC, Australia, 3010.,Department of Clinical Neuropsychology, Austin Health, Heidelberg Repatriation Hospital, 300 Waterdale Rd, Ivanhoe, VIC, 3079, Australia.,Florey Institute for Neuroscience and Mental Health, 30 Royal Parade, Parkville, VIC, 3052, Australia
| | - Ian P Everall
- Department of Psychiatry, University of Melbourne, Level 1 North, Main Block, Royal Melbourne Hospital, 300 Grattan St, Parkville, VIC, 3050, Australia.,Institute of Psychiatry, Psychology and Neuroscience, Kings College London, 16 De Crespigny Park, London, SE5 8AF, UK.,South London and Maudsley NHS Foundation Trust, Bethlem Royal Hospital, Monks Orchard Road, Beckenham, BR3 3BX, UK
| | - Amanda J Nicoll
- Department of Gastroenterology, Eastern Health, 3 West, Building B, 8 Arnold St, Box Hill, VIC, 3128, Australia.,Department of Gastroenterology and Hepatology, Royal Melbourne Hospital, 300 Grattan St, Parkville, VIC, 3050, Australia
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Sundberg I, Lannergård A, Ramklint M, Cunningham JL. Direct-acting antiviral treatment in real world patients with hepatitis C not associated with psychiatric side effects: a prospective observational study. BMC Psychiatry 2018; 18:157. [PMID: 29843679 PMCID: PMC5975521 DOI: 10.1186/s12888-018-1735-6] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Accepted: 05/11/2018] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Treatment of Hepatitis C virus (HCV) infection has evolved from interferon (IFN)-based treatments to direct-acting antivirals (DAAs). Patients with HCV have an elevated psychiatric morbidity (including substance abuse) and patients with such comorbidity have often been excluded from treatment with IFN. To date, little is known about psychiatric adverse effects of DAA-based regimens. We therefore aimed to study the psychiatric side effects of new IFN-free treatment for HCV (including depressive symptoms and sleep) in real world patients also including those with a history of psychiatric diagnosis, substance abuse or drug dependence. METHODS Consecutive patients were monitored during treatment with three of the latest DAA agents (sofosbuvir, simeprevir and daclatasvir). Repeated expert psychiatric assessments from baseline to 12 weeks post-treatment were performed with the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) clinical version and the self-report versions of the Montgomery Åsberg Depression Rating Scale (MADRS-S) and the Pittsburgh Sleep Quality Index (PSQI). Friedman's test was performed to calculate differences in the MADRS-S and PSQI over time. In a post-hoc analysis Wilcoxon's test was used to compare baseline depressive symptoms with those at post-treatment. Spearman's rank correlation test was conducted in another post-hoc analysis to evaluate the correlation between symptoms of depression and HCV viral load at baseline. RESULTS At baseline, 15/17 patients (88%) had a history of any psychiatric diagnosis; 11 (65%) had a history of substance abuse or dependence; and 11 (65%) had previously been treated with IFN and six of those had experienced psychiatric side effects. There was no correlation between depressive symptoms and HCV viral load at baseline. Symptoms of depression did not increase during DAA treatment and were lower 12 weeks post-treatment compared with baseline: MADRS-S 10.7 vs. 8.3 (p = 0.01). This observation held when excluding patients taking antidepressant medication. Sleep quality did not significantly change during treatment. Adherence to treatment was estimated to 95% and sustained virological response was 88%. CONCLUSIONS Despite high psychiatric morbidity, including previous substance abuse, patients successfully completed DAA treatment without increasing depressive symptoms or sleep disturbance. Symptoms of depression were significantly reduced 12 weeks after DAA treatment.
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Affiliation(s)
- Isak Sundberg
- Department of Neuroscience, Psychiatry, Uppsala University Hospital, Entrance 10, Floor 3B, 751 85, Uppsala, Sweden.
| | - Anders Lannergård
- 0000 0001 2351 3333grid.412354.5Department of Medical Sciences, Section of Infectious Diseases, Uppsala University Hospital, Entrance 34, Floor 2, 751 85 Uppsala, Sweden
| | - Mia Ramklint
- 0000 0001 2351 3333grid.412354.5Department of Neuroscience, Psychiatry, Uppsala University Hospital, Entrance 10, Floor 3B, 751 85 Uppsala, Sweden
| | - Janet L. Cunningham
- 0000 0001 2351 3333grid.412354.5Department of Neuroscience, Psychiatry, Uppsala University Hospital, Entrance 10, Floor 3B, 751 85 Uppsala, Sweden
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He X, Hopkins L, Everett G, Carter WM, SchroppDyce C, Abusaada K, Hsu V. Safety and efficacy of ledipasvir/sofosbuvir on hepatitis C eradication in hepatitis C virus/human immunodeficiency virus co-infected patients. World J Hepatol 2017; 9:1190-1196. [PMID: 29109851 PMCID: PMC5666305 DOI: 10.4254/wjh.v9.i30.1190] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Revised: 07/14/2017] [Accepted: 09/04/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the safety and efficacy of ledipasvir/sofosbuvir on hepatitis C eradication in patients with hepatitis C virus (HCV)/human immunodeficiency virus (HIV) co-infection in an urban HIV clinic.
METHODS A retrospective cohort study of 40 subjects co-infected with HIV-1 and HCV treated with the fixed-dose combination of ledipasvir and sofosbuvir for 12 wk from 2014 to 2016. All patients included were receiving antiretroviral therapy (ART) with HIV RNA values of 100 copies/mL or fewer regardless of baseline HCV RNA level. The primary end point was a sustained virologic response of HCV at 12 wk (SVR12) after the end of therapy.
RESULTS Of the 40 patients enrolled, 55% were black, 22.5% had been previously treated for HCV, and 25% had cirrhosis. The patients were on a wide range of ART. Overall, 39 patients (97.5%) had a SVR 12 after the end of therapy, including rates of 97.1% in patients with HCV genotype 1a and 100% in those with HCV genotype 1b. One patient with HCV genotype 3a was included and achieved SVR12. Rates of SVR12 were similar regardless of previous treatment or the presence of compensated cirrhosis. Only 1 patient experienced relapse at week 12 following treatment and deep sequencing didn’t reveal any resistance associated mutation in the NS5A or NS5B region. Interestingly, 7 (17.5%) patients who were adherent to ART experienced HIV viral breakthrough which resolved after continuing the same ART regimen. Two (5%) patients experienced HIV-1 virologic rebound due to noncompliance with HIV therapy, which resolved after resuming the same ART regimen. No severe adverse events were observed and no patient discontinued treatment because of adverse events. The most common adverse events included headache (12.5%), fatigue (10%), and diarrhea (2.5%).
CONCLUSION This retrospective study demonstrated the high rates of SVR12 of ledipasvir/sofosbuvir on HCV eradication in patients co-infected with HCV and HIV, regardless of HCV baseline levels, HCV treatment history or cirrhosis condition. The oral combination of ledipasvir/sofosbuvir represents a safe and well tolerated HCV treatment option that does not require modification for many of the common HIV ART. Occasional HIV virologic rebound occurred but later resolved without the need to change ART.
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Affiliation(s)
- Xiaoping He
- the Internal Medicine Residency Program of Florida Hospital, Orlando, FL 32804, United States
| | - Lynne Hopkins
- Sunshine Care Center, Florida Department of Health in Orange County, Orlando, FL 32804, United States
| | - George Everett
- the Internal Medicine Residency Program of Florida Hospital, Orlando, FL 32804, United States
| | - Willie M Carter
- Sunshine Care Center, Florida Department of Health in Orange County, Orlando, FL 32804, United States
| | - Cynthia SchroppDyce
- Sunshine Care Center, Florida Department of Health in Orange County, Orlando, FL 32804, United States
| | - Khalid Abusaada
- the Internal Medicine Residency Program of Florida Hospital, Orlando, FL 32804, United States
| | - Vincent Hsu
- the Internal Medicine Residency Program of Florida Hospital, Orlando, FL 32804, United States
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The Effect of Psychosocial Factors on Success Rates of Hepatitis C Treatment. PSYCHOSOMATICS 2017; 58:624-632. [PMID: 28870488 DOI: 10.1016/j.psym.2017.07.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Revised: 07/10/2017] [Accepted: 07/11/2017] [Indexed: 12/18/2022]
Abstract
OBJECTIVE Our study was to determine which psychosocial factors interfere with patients reaching sustained virologic response (SVR), a marker for hepatitis C virus eradication. METHODS A retrospective chart review was performed between January 6, 2015 and February 24, 2016. The primary outcome was to assess which social and psychological factors may interfere with patients reaching SVR. SVR was defined as having an undetectable viral load 12 weeks after the completion of the treatment regimen. Bivariate analysis was followed by a multivariate logistic regression analysis to determine significant factors for SVR. Depression and generalized anxiety disorder were included. RESULTS A total of 204 patients completed treatment within the designated time frame and were included in the final analysis. Social or home support was associated with SVR (odds ratio = 7.0, p = 0.02). Cocaine use was also a significant factor predicting SVR. Historical cocaine use compared with active cocaine use during treatment was associated with an odds ratio of SVR of 39.3 (p = 0.04). Interestingly, historical cocaine use vs no history of cocaine use did not influence SVR. No history of depression or generalized anxiety disorder was associated with a higher rate of SVR (odds ratio = 10.4, p = 0.05). No depression/generalized anxiety disorder compared with untreated depression/generalized anxiety disorder was associated with a 13.1 times greater rate of SVR (p = 0.04). CONCLUSION It is important to recognize and address psychosocial factors related to mental illness and active cocaine addictions before hepatitis C virus treatment. Furthermore, patients without home or social support are at greater risk for failing treatment, thus strategies to provide support during treatment are necessary.
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