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1
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Zhang Y, Hao H, Li H, Duan Q, Zheng X, Feng Y, Yang K, Shen S. Cellular Metabolomics Reveals Differences in the Scope of Liver Protection Between Ammonium-Based Glycyrrhizinate and Magnesium Isoglycyrrhizinate. Metabolites 2025; 15:263. [PMID: 40278392 DOI: 10.3390/metabo15040263] [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: 01/05/2025] [Revised: 03/14/2025] [Accepted: 04/01/2025] [Indexed: 04/26/2025] Open
Abstract
Background: Despite the well-established liver-protective efficacy of monoammonium glycyrrhizinate (MONO), diammonium glycyrrhizinate (DIAM), and magnesium isoglycyrrhizinate (MAGN), which has been translated into clinical practice, their clinical differentiation remains elusive owing to their structural similarities and overlapping therapeutic effects. Methods: The present study delves into the pharmacokinetics, cellular-level liver-protective potencies, and underlying mechanisms of action of these three compounds through a comprehensive analysis. Results: The findings reveal that both DIAM and MAGN exhibit superior bioavailability and hepatoprotective profiles compared to MONO. Notably, an investigation of the metabolic pathways mediating liver protection in normal human liver cells (LO2), utilizing an ultra-performance liquid chromatography-time of flight tandem mass spectrometry (UPLC-TOF-MS/MSe) platform, demonstrated that MAGN augments antioxidant components, thereby favoring its application in drug-induced liver injury (DILI). Conversely, DIAM appears to be a more suitable candidate for addressing non-alcoholic fatty liver disease (NAFLD) and viral hepatitis. Conclusion: This study contributes novel perspectives on the mechanisms of action and potential clinical utilities of DIAM and MAGN in liver disease prevention and management.
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Affiliation(s)
- Yihua Zhang
- Key Laboratory of Analytical Science and Technology of Hebei Province, College of Chemistry and Materials Science, Hebei University, Baoding 071002, China
- NDMA Key Laboratory for Quality Control and Evaluation of Generic Drug, Hebei Institute for Drug and Medical Device Control, Shijiazhuang 050200, China
| | - Han Hao
- School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China
| | - Hui Li
- NDMA Key Laboratory for Quality Control and Evaluation of Generic Drug, Hebei Institute for Drug and Medical Device Control, Shijiazhuang 050200, China
| | - Qiong Duan
- NDMA Key Laboratory for Quality Control and Evaluation of Generic Drug, Hebei Institute for Drug and Medical Device Control, Shijiazhuang 050200, China
| | - Xiaoming Zheng
- NDMA Key Laboratory for Quality Control and Evaluation of Generic Drug, Hebei Institute for Drug and Medical Device Control, Shijiazhuang 050200, China
| | - Yan Feng
- NDMA Key Laboratory for Quality Control and Evaluation of Generic Drug, Hebei Institute for Drug and Medical Device Control, Shijiazhuang 050200, China
| | - Kun Yang
- School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China
| | - Shigang Shen
- Key Laboratory of Analytical Science and Technology of Hebei Province, College of Chemistry and Materials Science, Hebei University, Baoding 071002, China
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Alaofi AL, Shahid M, Raish M, Ansari MA, Syed R, Kalam MA. Identification of Doxorubicin as Repurposing Inhibitory Drug for MERS-CoV PLpro. Molecules 2022; 27:7553. [PMID: 36364379 PMCID: PMC9654812 DOI: 10.3390/molecules27217553] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 10/26/2022] [Accepted: 10/30/2022] [Indexed: 07/29/2023] Open
Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV), belonging to the betacoronavirus genus can cause severe respiratory illnesses, accompanied by pneumonia, multiorgan failure, and ultimately death. CoVs have the ability to transgress species barriers and spread swiftly into new host species, with human-to-human transmission causing epidemic diseases. Despite the severe public health threat of MERS-CoV, there are currently no vaccines or drugs available for its treatment. MERS-CoV papain-like protease (PLpro) is a key enzyme that plays an important role in its replication. In the present study, we evaluated the inhibitory activities of doxorubicin (DOX) against the recombinant MERS-CoV PLpro by employing protease inhibition assays. Hydrolysis of fluorogenic peptide from the Z-RLRGG-AMC-peptide bond in the presence of DOX showed an IC50 value of 1.67 μM at 30 min. Subsequently, we confirmed the interaction between DOX and MERS-CoV PLpro by thermal shift assay (TSA), and DOX increased ΔTm by ~20 °C, clearly indicating a coherent interaction between the MERS-CoV PL protease and DOX. The binding site of DOX on MERS-CoV PLpro was assessed using docking techniques and molecular dynamic (MD) simulations. DOX bound to the thumb region of the catalytic domain of the MERS-CoV PLpro. MD simulation results showed flexible BL2 loops, as well as other potential residues, such as R231, R233, and G276 of MERS-CoV PLpro. Development of drug repurposing is a remarkable opportunity to quickly examine the efficacy of different aspects of treating various diseases. Protease inhibitors have been found to be effective against MERS-CoV to date, and numerous candidates are currently undergoing clinical trials to prove this. Our effort follows a in similar direction.
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Affiliation(s)
- Ahmed L. Alaofi
- Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
- College of Pharmacy Building 23, Pharmaceutics Department, King Saud University, Ground Floor, Office AA 79, P.O. Box 2457, Riyadh 11451, Saudi Arabia
| | - Mudassar Shahid
- Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
| | - Mohammad Raish
- Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
| | - Mushtaq Ahmad Ansari
- Department of Phamacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
| | - Rabbani Syed
- Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
| | - Mohd Abul Kalam
- Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
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Radhakrishnan A, Kuppusamy G, Ponnusankar S, Mutalik S. Towards next-generation personalization of tacrolimus treatment: a review on advanced diagnostic and therapeutic approaches. Pharmacogenomics 2021; 22:1151-1175. [PMID: 34719935 DOI: 10.2217/pgs-2021-0008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
The benefit of personalized medicine is that it allows the customization of drug therapy - maximizing efficacy while avoiding side effects. Genetic polymorphisms are one of the major contributors to interindividual variability. Currently, the only gold standard for applying personalized medicine is dose titration. Because of technological advancements, converting genotypic data into an optimum dose has become easier than in earlier years. However, for many medications, determining a personalized dose may be difficult, leading to a trial-and-error method. On the other hand, the technologically oriented pharmaceutical industry has a plethora of smart drug delivery methods that are underutilized in customized medicine. This article elaborates the genetic polymorphisms of tacrolimus as case study, and extensively covers the diagnostic and therapeutic technologies which aid in the delivery of personalized tacrolimus treatment for better clinical outcomes, thereby providing a new strategy for implementing personalized medicine.
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Affiliation(s)
- Arun Radhakrishnan
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamilnadu, India
| | - Gowthamarajan Kuppusamy
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamilnadu, India
| | - Sivasankaran Ponnusankar
- Department of Pharmacy Practice, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamilnadu, India
| | - Srinivas Mutalik
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Karnataka, India
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4
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Sodhi JK, Liu S, Benet LZ. Intestinal Efflux Transporters P-gp and BCRP Are Not Clinically Relevant in Apixaban Disposition. Pharm Res 2020; 37:208. [PMID: 32996065 DOI: 10.1007/s11095-020-02927-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 09/10/2020] [Indexed: 02/06/2023]
Abstract
PURPOSE The involvement of the intestinally expressed xenobiotic transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) have been implicated in apixaban disposition based on in vitro studies. Recommendations against co-administration of apixaban with inhibitors of these efflux transporters can be found throughout the literature as well as in the apixaban FDA label. However, the clinical relevance of such findings is questionable due to the high permeability and high solubility characteristics of apixaban. METHODS Using recently published methodologies to discern metabolic- from transporter- mediated drug-drug interactions, a critical evaluation of all published apixaban drug-drug interaction studies was conducted to investigate the purported clinical significance of efflux transporters in apixaban disposition. RESULTS Rational examination of these clinical studies using basic pharmacokinetic theory does not support the clinical significance of intestinal efflux transporters in apixaban disposition. Further, there is little evidence that efflux transporters are clinically significant determinants of systemic clearance. CONCLUSIONS Inhibition or induction of intestinal CYP3A4 can account for exposure changes of apixaban in all clinically significant drug-drug interactions, and lack of intestinal CYP3A4 inhibition can explain all studies with no exposure changes, regardless of the potential for these perpetrators to inhibit intestinal or systemic efflux transporters.
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Affiliation(s)
- Jasleen K Sodhi
- Department of Bioengineering and Therapeutic Sciences Schools of Pharmacy and Medicine, University of California San Francisco, 513 Parnassus Ave Rm HSE 1164, UCSF Box 0912, San Francisco, California, 94143, USA
| | - Shuaibing Liu
- Department of Bioengineering and Therapeutic Sciences Schools of Pharmacy and Medicine, University of California San Francisco, 513 Parnassus Ave Rm HSE 1164, UCSF Box 0912, San Francisco, California, 94143, USA.,Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Leslie Z Benet
- Department of Bioengineering and Therapeutic Sciences Schools of Pharmacy and Medicine, University of California San Francisco, 513 Parnassus Ave Rm HSE 1164, UCSF Box 0912, San Francisco, California, 94143, USA.
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5
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Grabarek BO, Wcisło-Dziadecka D, Garncarczyk A, Michalska-Bańkowska A. BMI changes and concentration of selected morphological and biochemical indices during cyclosporin A therapy. Dermatol Ther 2019; 32:e13124. [PMID: 31628762 DOI: 10.1111/dth.13124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Revised: 10/11/2019] [Accepted: 10/16/2019] [Indexed: 11/29/2022]
Affiliation(s)
- Beniamin Oskar Grabarek
- Katowice School of Technology, The University of Science and Art, Katowice, Poland.,Center of Oncology, M. Sklodowska-Curie Memorial Institute, Cracow Branch, Poland.,Department of Molecular Biology, School of Pharmaceutical Sciences Sosnowiec, Medical University of Silesia, Katowice, Poland
| | - Dominika Wcisło-Dziadecka
- Department of Cosmetology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Poland
| | - Agnieszka Garncarczyk
- Department of Cosmetology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Poland
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Huppertz A, Ott C, Bruckner T, Foerster KI, Burhenne J, Weiss J, Zorn M, Haefeli WE, Czock D. Prolonged‐Release Tacrolimus Is Less Susceptible to Interaction With the StrongCYP3A Inhibitor Voriconazole in Healthy Volunteers. Clin Pharmacol Ther 2019; 106:1290-1298. [DOI: 10.1002/cpt.1529] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2019] [Accepted: 05/10/2019] [Indexed: 01/28/2023]
Affiliation(s)
- Andrea Huppertz
- Department of Clinical Pharmacology and PharmacoepidemiologyUniversity of Heidelberg Heidelberg Germany
| | - Christian Ott
- Department of Clinical Pharmacology and PharmacoepidemiologyUniversity of Heidelberg Heidelberg Germany
| | - Thomas Bruckner
- Department of Medical Biometry and InformaticsUniversity of Heidelberg Heidelberg Germany
| | - Kathrin I. Foerster
- Department of Clinical Pharmacology and PharmacoepidemiologyUniversity of Heidelberg Heidelberg Germany
| | - Jürgen Burhenne
- Department of Clinical Pharmacology and PharmacoepidemiologyUniversity of Heidelberg Heidelberg Germany
| | - Johanna Weiss
- Department of Clinical Pharmacology and PharmacoepidemiologyUniversity of Heidelberg Heidelberg Germany
| | - Markus Zorn
- Central LaboratoryUniversity Hospital Heidelberg Heidelberg Germany
| | - Walter E. Haefeli
- Department of Clinical Pharmacology and PharmacoepidemiologyUniversity of Heidelberg Heidelberg Germany
| | - David Czock
- Department of Clinical Pharmacology and PharmacoepidemiologyUniversity of Heidelberg Heidelberg Germany
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Liu J, Ma B, Cao W, Li M, Bramer WM, Peppelenbosch MP, Pan Q. Direct-acting antiviral agents for liver transplant recipients with recurrent genotype 1 hepatitis C virus infection: Systematic review and meta-analysis. Transpl Infect Dis 2019; 21:e13047. [PMID: 30615227 PMCID: PMC6850617 DOI: 10.1111/tid.13047] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 12/18/2018] [Accepted: 12/23/2018] [Indexed: 12/15/2022]
Abstract
Background Comprehensive evaluation of safety and efficacy of different combinations of direct‐acting antivirals (DAAs) in liver transplant recipients with genotype 1 (GT1) hepatitis C virus (HCV) recurrence remains limited. Therefore, we performed this systematic review and meta‐analysis in order to evaluate the clinical outcome of DAA treatment in liver transplant patients with HCV GT1 recurrence. Methods Studies were included if they contained information of 12 weeks sustained virologic response (SVR12) after DAA treatment completion as well as treatment related complications for liver transplant recipients with GT1 HCV recurrence. Results We identified 16 studies comprising 885 patients. The overall pooled estimate proportion of SVR12 was 93% (95% confidence interval (CI): 0.89, 0.96), with moderate heterogeneity observed (τ2 = 0.01, P < 0.01, I2=75%). High tolerability was observed in liver transplant recipients reflected by serious adverse events (sAEs) with pooled estimate proportion of 4% (95% CI: 0.01, 0.07; τ2 = 0.02, P < 0.01, I2 = 81%). For subgroup analysis, a total of five different DAA regimens were applied for treating these patients. Sofosbuvir/Ledipasvir (SOF/LDV) led the highest pooled estimate SVR12 proportion, followed by Paritaprevir/Ritonavir/Ombitasivir/Dasabuvir (PrOD), Daclatasvir (DCV)/Simeprevir (SMV) ± Ribavirin (RBV), and SOF/SMV ± RBV, Asunaprevir (ASV)/DCV. There was a tendency for favoring a higher pooled SVR12 proportion in patients with METAVIR Stage F0‐F2 of 97% (95% CI: 0.93, 0.99) compared to 85% (95% CI: 0.79, 0.90) for stage F3‐F4 (P < 0.01). There was no significant difference between LT recipients treated with or without RBV (P = 0.23). Conclusions Direct‐acting antiviral treatment is highly effective and well‐tolerated in liver transplant recipients with recurrent GT1 HCV infection.
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Affiliation(s)
- Jiaye Liu
- Biomedical Research Center, Northwest Minzu University, Lanzhou, China.,Erasmus MC Cancer Institute, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Buyun Ma
- Erasmus MC Cancer Institute, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Wanlu Cao
- Erasmus MC Cancer Institute, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Meng Li
- Erasmus MC Cancer Institute, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Wichor M Bramer
- Department of Medical Library, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Maikel P Peppelenbosch
- Erasmus MC Cancer Institute, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Qiuwei Pan
- Biomedical Research Center, Northwest Minzu University, Lanzhou, China.,Erasmus MC Cancer Institute, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
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8
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Tod M, Goutelle S, Bleyzac N, Bourguignon L. A Generic Model for Quantitative Prediction of Interactions Mediated by Efflux Transporters and Cytochromes: Application to P-Glycoprotein and Cytochrome 3A4. Clin Pharmacokinet 2018; 58:503-523. [DOI: 10.1007/s40262-018-0711-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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9
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Huang F, Voelk C, Trampisch M, Rowland L, Schultz A, Sabo JP. Pharmacokinetic Interaction between Faldaprevir and Cyclosporine or Tacrolimus in Healthy Volunteers: A Prospective, Open-Label, Fixed-Sequence, Crossover Study. Basic Clin Pharmacol Toxicol 2018; 123:84-93. [PMID: 29427400 DOI: 10.1111/bcpt.12980] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2017] [Accepted: 01/31/2018] [Indexed: 12/14/2022]
Abstract
Faldaprevir (FDV) is a potent, orally administered inhibitor of hepatitis C virus. In this single-centre, open-label, fixed-sequence, crossover study of 32 healthy adult male and female volunteers, subjects received either a single dose of cyclosporine (CsA) 50 mg (N = 16) or tacrolimus (TAC) 0.5 mg (N = 16), followed by a washout of at least 14 days. Each subject then received a loading dose of FDV 240 mg followed by 120 mg FDV once daily for 6 days. FDV 120 mg was then co-administered with an additional single dose of CsA (50 mg) or TAC (0.5 mg), followed by an additional 6 days of FDV 120 mg once daily. Intensive blood sampling was performed to assess the PK interaction potential. Assessment of relative BA indicated that exposure to CsA co-administered with FDV was similar to CsA alone. However, the AUCτ,ss and Cmax,ss of FDV were increased by 23% and 41%, respectively, when FDV was co-administered with CsA. Exposure to TAC was slightly increased (AUC0-∞ increased by 27%, no change in Cmax ) when TAC was co-administered with FDV. In contrast, exposure to FDV co-administered with TAC was similar to FDV alone. No unexpected safety findings arose from the trial. The limitations of the study (use of single, low dose of TAC and CsA, and only healthy volunteers in the trial) are discussed.
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Affiliation(s)
- Fenglei Huang
- Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA
| | - Claudia Voelk
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | | | - Lois Rowland
- Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA
| | - Armin Schultz
- CRS Clinical Research Services Mannheim GmbH, Mannheim, Germany
| | - John P Sabo
- Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA
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10
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Xia Y, Zhou H, Zhu F, Zhang W, Wu C, Lu L. Diagnosis and treatment of pulmonary cavity after liver transplantation. ANNALS OF TRANSLATIONAL MEDICINE 2017; 5:301. [PMID: 28856141 DOI: 10.21037/atm.2017.05.14] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Although the outcomes have improved in the current era, pulmonary infection remains a significant post-transplant complication in liver transplant (LT) recipients. Pulmonary infection with cavity formation often leads to higher mortality rates after LT. We wished to investigate the diagnosis and treatment of pulmonary cavity (PC) formation after LT. METHODS We evaluated (retrospectively) five cases of PC formation, shown on CT scans of the chest after LT, by analyzing imaging features, diagnosis, treatment, liver function, and the concentration changes and efficacy of immunosuppressants. RESULTS According to the results from the CT scan, serum Aspergillus galactomannan (GM) assay, the purified protein derivative (PPD) skin test, and the sputum smears and blood culture, three cases were diagnosed with Aspergillus infection, and the other two cases were diagnosed with Mycobacterium tuberculosis infection. Liver function and FK506 concentration were monitored during treatment. Antibiotics used for treatment of Aspergillus and Mycobacterium tuberculosis infections affected liver function and FK506 concentration. However, after adjustment of drug doses, antibiotic treatment was tolerated in all patients. Four cases were cured, but 1 patient died of Aspergillus infection. CONCLUSIONS Distinguishing between Aspergillus infection and Mycobacterium tuberculosis infection for PCs after liver transplantation (LT) using a CT scan is difficult. The diagnosis can be confirmed using clinical characteristics, sputum culture, GM assay, PPD, and sputum smears. Early diagnosis and treatment could lead to a better prognosis.
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Affiliation(s)
- Yongxiang Xia
- Department of Liver Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.,Key Laboratory of Living Donor Liver Transplantation, National Health and Family Planning Commission, Nanjing 210029, China
| | - Haoming Zhou
- Department of Liver Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.,Key Laboratory of Living Donor Liver Transplantation, National Health and Family Planning Commission, Nanjing 210029, China
| | - Feipeng Zhu
- Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Wei Zhang
- Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Chen Wu
- Department of Liver Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.,Key Laboratory of Living Donor Liver Transplantation, National Health and Family Planning Commission, Nanjing 210029, China
| | - Ling Lu
- Department of Liver Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.,Key Laboratory of Living Donor Liver Transplantation, National Health and Family Planning Commission, Nanjing 210029, China
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12
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Miuma S, Ichikawa T, Miyaaki H, Haraguchi M, Tamada Y, Shibata H, Taura N, Soyama A, Hidaka M, Takatsuki M, Eguchi S, Nakao K. Efficacy and Tolerability of Pegylated Interferon and Ribavirin in Combination with Simeprevir to Treat Hepatitis C Virus Infections After Living Donor Liver Transplantation. J Interferon Cytokine Res 2016; 36:358-66. [DOI: 10.1089/jir.2015.0147] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Affiliation(s)
- Satoshi Miuma
- Department of Gastroenterology, Hepatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Tatsuki Ichikawa
- Department of Gastroenterology, Hepatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
- Department of Gastroenterology, Nagasaki Harbor Medical Center City Hospital, Nagasaki, Japan
| | - Hisamitsu Miyaaki
- Department of Gastroenterology, Hepatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Masafumi Haraguchi
- Department of Gastroenterology, Hepatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Yoko Tamada
- Department of Gastroenterology, Hepatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Hidetaka Shibata
- Department of Gastroenterology, Hepatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Naota Taura
- Department of Gastroenterology, Hepatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Akihiko Soyama
- Department of Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Masaaki Hidaka
- Department of Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Mitsuhisa Takatsuki
- Department of Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Susumu Eguchi
- Department of Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Kazuhiko Nakao
- Department of Gastroenterology, Hepatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
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Hohmann N, Haefeli WE, Mikus G. CYP3A activity: towards dose adaptation to the individual. Expert Opin Drug Metab Toxicol 2016; 12:479-97. [PMID: 26950050 DOI: 10.1517/17425255.2016.1163337] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Co-medication, gene polymorphisms and co-morbidity are main causes for high variability in expression and function of the CYP3A isoenzymes. Pharmacokinetic variability is a major source of interindividual variability of drug effect and response of CYP3A substrates. While CYP3A genotyping is of limited use, direct testing of enzyme function ('phenotyping') may be more promising to achieve individualized dosing of CYP3A substrates. AREAS COVERED We will discuss available phenotyping strategies for CYP3A isoenzymes and causes of intra- and interindividual variability of CYP3A. The impact of phenotyping on the dose selection and pharmacokinetics of CYP3A substrates (docetaxel, irinotecan, tyrosine kinase inhibitors, ciclosporin, tacrolimus) are reviewed. Pubmed searches were conducted during March-November 2015 to retrieve articles related to CYP3A enzyme, phenotyping, drug interactions with CYP3A probe substrates, and phenotyping-guided dosing algorithms. EXPERT OPINION While ample data is available on the choice appropriate phenotyping drugs (midazolam, alfentanil, aplrazolam, buspirone, triazolam), less clinical trial data is available concerning strategies to usefully guide dosing in the clinical practice. Implementation into the clinical routine necessitates further research to identify (1) an easy-to-use and cheap test for CYP3A activity that (2) adequately predicts drug exposure to (3) allow a sound decision on dose adaptation and hence (4) improve clinical outcome and/or reduce the intensity or frequency of adverse drug effects.
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Affiliation(s)
- Nicolas Hohmann
- a Department of Clinical Pharmacology and Pharmacoepidemiology , University Hospital Heidelberg , Heidelberg , Germany
| | - Walter E Haefeli
- a Department of Clinical Pharmacology and Pharmacoepidemiology , University Hospital Heidelberg , Heidelberg , Germany
| | - Gerd Mikus
- a Department of Clinical Pharmacology and Pharmacoepidemiology , University Hospital Heidelberg , Heidelberg , Germany
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Vanhove T, Annaert P, Kuypers DRJ. Clinical determinants of calcineurin inhibitor disposition: a mechanistic review. Drug Metab Rev 2016; 48:88-112. [DOI: 10.3109/03602532.2016.1151037] [Citation(s) in RCA: 95] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Khalilieh S, Feng HP, Hulskotte EGJ, Wenning LA, Butterton JR. Clinical pharmacology profile of boceprevir, a hepatitis C virus NS3 protease inhibitor: focus on drug-drug interactions. Clin Pharmacokinet 2016; 54:599-614. [PMID: 25787025 DOI: 10.1007/s40262-015-0260-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Boceprevir is a potent, orally administered ketoamide inhibitor that targets the active site of the hepatitis C virus (HCV) non-structural (NS) 3 protease. The addition of boceprevir to peginterferon plus ribavirin resulted in higher rates of sustained virologic response (SVR) than for peginterferon plus ribavirin alone in phase III studies in both previously treated and untreated patients with HCV infection. Because boceprevir is metabolized by metabolic routes common to many other drugs, and is an inhibitor of cytochrome P450 (CYP) 3A4/5, there is a high potential for drug-drug interactions when boceprevir is administered with other therapies, particularly when treating patients with chronic HCV infection who are often receiving other medications concomitantly. Boceprevir is no longer widely used in the US or EU due to the introduction of second-generation treatments for HCV infection. However, in many other geographic regions, first-generation protease inhibitors such as boceprevir continue to form an important treatment option for patients with HCV infection. This review summarizes the interactions between boceprevir and other therapeutic agents commonly used in this patient population, indicating dose adjustment requirements where needed. Most drug interactions do not affect boceprevir plasma concentrations to a clinically meaningful extent, and thus efficacy is likely to be maintained when boceprevir is coadministered with the majority of other therapeutics. Overall, the drug-drug interaction profile of boceprevir suggests that this agent is suitable for use in a wide range of HCV-infected patients receiving concomitant therapies.
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Affiliation(s)
- Sauzanne Khalilieh
- Department of Clinical Pharmacology, Merck & Co., 1 Merck Drive, Kenilworth, NJ, 08889, USA
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Fung J. Era of direct acting antivirals in chronic hepatitis C: Who will benefit? World J Hepatol 2015; 7:2543-2550. [PMID: 26523206 PMCID: PMC4621468 DOI: 10.4254/wjh.v7.i24.2543] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Revised: 09/07/2015] [Accepted: 10/13/2015] [Indexed: 02/06/2023] Open
Abstract
In the era of highly effective direct acting antiviral (DAA) drugs for the treatment of chronic hepatitis C (CHC) infection, where eradication is almost ensured with minimal side effects, all hepatitis C carriers should benefit theoretically. In the real world setting however, only a small proportion will benefit at this time point due to the multiple barriers to accessing therapy. Given that universal treatment is unlikely, treatment with DAAs will likely be restricted to those with the highest health benefits, and for those who can afford the high expense of a treatment course. Those with the highest unmet needs include those who have failed previous interferon-based therapy or who are interferon-ineligible with evidence of active disease, those with advance liver disease, and those with recurrence of hepatitis C after liver transplantation. In the future, the focus should be on increasing access to treatment for those infected with CHC.
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Coilly A, Dumortier J, Botta-Fridlund D, Latournerie M, Leroy V, Pageaux GP, Agostini H, Giostra E, Moreno C, Roche B, Antonini TM, Guillaud O, Lebray P, Radenne S, Saouli AC, Calmus Y, Alric L, Debette-Gratien M, De Ledinghen V, Durand F, Duvoux C, Samuel D, Duclos-Vallée JC. Multicenter Experience with Boceprevir or Telaprevir to Treat Hepatitis C Recurrence after Liver Transplantation: When Present Becomes Past, What Lessons for Future? PLoS One 2015; 10:e0138091. [PMID: 26394142 PMCID: PMC4578772 DOI: 10.1371/journal.pone.0138091] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Accepted: 08/25/2015] [Indexed: 12/20/2022] Open
Abstract
Background and aims First generation protease inhibitors (PI) with peg-interferon (PEG-IFN) and ribavirin (RBV) have been the only therapy available for hepatitis C virus (HCV) genotype 1 infection in most countries for 3 years. We have investigated the efficacy and tolerance of this triple therapy in transplanted patients experiencing a recurrence of HCV infection on the liver graft. Patients This cohort study enrolled 81 liver transplant patients (Male: 76%, mean age: 55.8±9.7 years) with severe HCV recurrence (F3 or F4: n = 34 (42%), treatment experienced: n = 44 (54%)), treated with boceprevir (n = 36; 44%) or telaprevir (n = 45; 56%). We assessed the percentages of patients with sustained virological responses 24 weeks after therapy (SVR24), and safety. Results The SVR24 rate was 47% (telaprevir: 42%; boceprevir: 53%, P = ns). At baseline, a normal bilirubin level (p = 0.0145) and albumin level >35g/L (p = 0.0372) and an initial RBV dosage of ≥800 mg/day (p = 0.0033) predicted SVR24. During treatment, achieving an early virological response after 12 weeks was the strongest independent factor to predict SVR24 (p<0.0001). A premature discontinuation of anti-HCV therapy due to a serious adverse event (SAE) was observed in 22 patients (27%). Hematological toxicity, infections and deaths were observed in 95%, 28% and 7% of patients, respectively. A history of post-LT antiviral therapy and thrombocytopenia (<50G/L) during treatment were both independent predictors of the occurrence of infections or SAE (p = 0.0169 and p = 0.011). Conclusions The use of first generation PI after liver transplantation enabled an SVR24 rate of 47% in genotype 1 patients, but induced a high rate of SAE. The identification of predictive factors for a response to treatment, and the occurrence of SAE, have enabled us to establish limits for the use of this anti-HCV therapy in the transplant setting.
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Affiliation(s)
- Audrey Coilly
- AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Villejuif, F-94800, France, Université Paris-Sud, UMR-S 785, Villejuif, F-94800, France, Inserm, Unité 785, Villejuif, F-94800, France, Hepatinov, Villejuif, F-94800, France
| | - Jérôme Dumortier
- Department of Digestive Diseases, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon, France
| | - Danielle Botta-Fridlund
- Assistance Publique—Hôpitaux de Marseille, Centre Hospitalo-Universitaire Conception, Service d'Hépato-Gastro-Entérologie, Marseille, France
| | | | - Vincent Leroy
- Service d’hépato-gastro-entérologie, hôpital A.-Michallon, 38700, La Tronche, France
| | - Georges-Philippe Pageaux
- Fédération médico-chirurgicale des maladies de l’appareil digestif, hôpital Saint-Eloi, 34295, Montpellier, France
| | - Hélène Agostini
- AP-HP, Hôpital Bicêtre, Unité de recherche clinique Paris-Sud, Kremlin-Bicêtre, France
| | - Emiliano Giostra
- Department of Gastroenterology and Hepatology, Geneva University Hospital, Rue Gabrielle-Perret-Gentil 4, 1211, Geneva, 14, Switzerland
| | - Christophe Moreno
- Liver unit, Department of Gastroenterology, Hepatopancreatology and Digestive oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
| | - Bruno Roche
- AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Villejuif, F-94800, France, Université Paris-Sud, UMR-S 785, Villejuif, F-94800, France, Inserm, Unité 785, Villejuif, F-94800, France, Hepatinov, Villejuif, F-94800, France
| | - Teresa Maria Antonini
- AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Villejuif, F-94800, France, Université Paris-Sud, UMR-S 785, Villejuif, F-94800, France, Inserm, Unité 785, Villejuif, F-94800, France, Hepatinov, Villejuif, F-94800, France
| | - Olivier Guillaud
- Department of Digestive Diseases, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon, France
| | - Pascal Lebray
- Assistance Publique Hôpitaux de Paris (AP-HP), Groupe Hospitalier Pitié-Salpêtrière, Paris, France
| | - Sylvie Radenne
- Service d’hépatologie, HCL, hôpital de la Croix-Rousse, 69205, Lyon, France
| | - Anne-Catherine Saouli
- Hepato-Bilio-Pancreatic Surgery and Liver Transplantation Center, Université de Strasbourg, Strasbourg, France
| | - Yvon Calmus
- Department of Hepatobiliary and Liver Transplantation Surgery, Hopital Saint Antoine, Assistance publique-Hopitaux de Paris, 184 rue du Faubourg Saint-Antoine, 75012, Paris Cedex, France
| | - Laurent Alric
- Internal medecine-Digestive department UMR 152 IRD Toulouse 3 University, Toulouse, France
| | - Maryline Debette-Gratien
- Service d'Hépato-gastroentérologie, CHU de Limoges, 2 avenue Martin-Luther-King, 87042, Limoges, France, Inserm UMR 1092, Faculté de médecine de Limoges, Université de Limoges, Limoges, France
| | | | - François Durand
- Service d’hépatologie, hôpital Beaujon, AP–HP, 92118, Clichy, France
| | - Christophe Duvoux
- Service d’hépatologie, hôpital Henri-Mondor, AP–HP, 94000, Créteil, France
| | - Didier Samuel
- AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Villejuif, F-94800, France, Université Paris-Sud, UMR-S 785, Villejuif, F-94800, France, Inserm, Unité 785, Villejuif, F-94800, France, Hepatinov, Villejuif, F-94800, France
| | - Jean-Charles Duclos-Vallée
- AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Villejuif, F-94800, France, Université Paris-Sud, UMR-S 785, Villejuif, F-94800, France, Inserm, Unité 785, Villejuif, F-94800, France, Hepatinov, Villejuif, F-94800, France
- * E-mail:
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Aguilera V. Hepatitis C virus recurrence after liver transplantation: how to treat and when. Transplant Proc 2015; 46:3100-3. [PMID: 25420834 DOI: 10.1016/j.transproceed.2014.09.177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Chronic hepatitis C (CHC) is an important cause of cirrhosis and hepatocellular carcinoma and a common indication of liver transplantation (LT). Recurrence of hepatitis C occurs universally after LT with an accelerated course of the natural history of CHC in the graft. Treatment of hepatitis C before transplantation is the most effective strategy because it prevents graft reinfection, but applicability is low with pegylated interferon regimens. Treatment after LT is the strategy more frequently used. A sustained viral response (SVR) is achieved by one-third of those treated with dual therapy and is associated with better outcomes after LT. Triple therapy with protease inhibitors after LT has efficacy to 60%-70% of SVR but is associated with higher rates of secondary effects and drug-drug interactions that require an intensified and frequent monitoring of calcineurin inhibitors during treatment. In the near future, interferon-free regimens with new oral antiviral drugs will likely prevent viral reinfection before or after LT, and shorter treatment regimens and less toxicity are expected.
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Affiliation(s)
- V Aguilera
- Hospital Universitari i Politècnic la Fe, Valenza, Valencia, Spain Valencia, Spain.
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Torres HA, Chong PP, De Lima M, Friedman MS, Giralt S, Hammond SP, Kiel PJ, Masur H, McDonald GB, Wingard JR, Gambarin-Gelwan M. Hepatitis C Virus Infection among Hematopoietic Cell Transplant Donors and Recipients: American Society for Blood and Marrow Transplantation Task Force Recommendations. Biol Blood Marrow Transplant 2015; 21:1870-82. [PMID: 26256943 DOI: 10.1016/j.bbmt.2015.07.033] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Accepted: 07/31/2015] [Indexed: 02/08/2023]
Affiliation(s)
- Harrys A Torres
- The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Pearlie P Chong
- University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Marcos De Lima
- University Hospitals Case Medical Center and University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, Ohio
| | | | - Sergio Giralt
- Memorial Sloan Kettering Cancer Center, New York, New York
| | - Sarah P Hammond
- Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Patrick J Kiel
- Indiana University Simon Cancer Center, Indianapolis, Indiana
| | - Henry Masur
- National Institutes of Health Clinical Center, Bethesda, Maryland
| | - George B McDonald
- University of Washington and Fred Hutchinson Cancer Research Center, Seattle, Washington
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20
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Verna EC, Saxena V, Burton JR, O'Leary JG, Dodge JL, Stravitz RT, Levitsky J, Trotter JF, Everson GT, Brown RS, Terrault NA. Telaprevir- and Boceprevir-based Triple Therapy for Hepatitis C in Liver Transplant Recipients With Advanced Recurrent Disease: A Multicenter Study. Transplantation 2015; 99:1644-51. [PMID: 25715116 PMCID: PMC4818984 DOI: 10.1097/tp.0000000000000629] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND Antiviral treatment with sustained virologic response (SVR) improves survival in liver transplant (LT) recipients, and is especially relevant to patients with advanced recurrent hepatitis C virus (HCV). We assessed the safety and efficacy of protease inhibitor-based triple therapy in patients with recurrent advanced fibrosis and cholestatic hepatitis. METHODS The LT recipients with genotype 1 HCV and advanced fibrosis (F3-4/4) or cholestatic hepatitis treated with telaprevir- or boceprevir-based triple therapy at 6 centers (CRUSH-C consortium) were retrospectively assessed. The primary endpoints were SVR at 12 weeks (SVR12) and safety. RESULTS Forty-five patients with advanced fibrosis and 9 with cholestatic hepatitis (74% men, 57% genotype 1a, 63% previous nonresponders) were included. SVR12 occurred in 51% with advanced fibrosis and 44% with cholestatic hepatitis. Extended rapid virologic response was highly predictive of SVR12. Hispanic ethnicity (odds ratio, 0.16; P = 0.03), previous null/partial response (0.24; P = 0.02), IL28B genotype CC (7.0; P = 0.02), albumin (3.87; P = 0.03), platelet count (1.01; P = 0.02), and steroid use (0.21; P = 0.03) were associated with SVR12. Six (11%) patients died, and hepatic decompensation occurred in 22% with advanced fibrosis and 33% with cholestatic hepatitis. Albumin (0.02; P = 0.001), encephalopathy (12.0; P = 0.04) and Hispanic ethnicity (odds ratio, 6.17; P = 0.01) were associated with death or decompensation. CONCLUSIONS For LT recipients with recurrent advanced HCV and at greatest need of cure, protease inhibitor-based triple therapy achieved approximately 50% SVR12. However, there is significant risk of serious adverse events, arguing for earlier intervention. The availability of treatments with better efficacy and safety is of particular importance for posttransplant patients with advanced disease.
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Affiliation(s)
- Elizabeth C Verna
- 1 Center for Liver Disease and Transplantation, Division of Digestive and Liver Diseases, Columbia University, New York, NY. 2 Division of Gastroenterology and Hepatology, University of California, San Francisco, CA. 3 Division of Gastroenterology and Hepatology, University of Colorado, Denver, Aurora, CO. 4 Division of Hepatology and Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX. 5 Section of Hepatology and Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, VA. 6 Department of Gastroenterology and Hepatology, Northwestern University, Chicago, IL
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Mitchell O, Gurakar A. Management of Hepatitis C Post-liver Transplantation: a Comprehensive Review. J Clin Transl Hepatol 2015; 3:140-8. [PMID: 26357641 PMCID: PMC4548349 DOI: 10.14218/jcth.2015.00005] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Revised: 03/19/2015] [Accepted: 03/22/2015] [Indexed: 02/07/2023] Open
Abstract
Infection with hepatitis C virus (HCV) is a common cause of chronic liver disease, and HCV-related cirrhosis and hepatocellular carcinoma are the leading causes for liver transplantation in the Western world. Recurrent infection of the transplanted liver allograft is universal in patients with detectable HCV viremia at the time of transplant and can cause a spectrum of disease, ranging from asymptomatic chronic infection to an aggressive fibrosing cholestatic hepatitis. Recurrent HCV is more aggressive in the post-transplant population and is a leading cause of allograft loss, morbidity, and mortality. Historically, treatment of recurrent HCV has been limited by low rates of treatment success and high side effect profiles. Over the past few years, promising new therapies have emerged for the treatment of HCV that have high rates of sustained virological response without the need for interferon based regimens. In addition to being highly effective, these treatments have higher rates of adherence and a lower side effect profile. The purpose of this review is to summarize current therapies in recurrent HCV infection, to review the recent advances in therapy, and to highlight areas of ongoing research.
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Affiliation(s)
- Oscar Mitchell
- Department of Transplant Hepatology, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ahmet Gurakar
- Department of Transplant Hepatology, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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22
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Lim KBL, Sima HR, Fiel MI, Khaitova V, Doucette JT, Chernyiak M, Ahmad J, Bach N, Chang C, Grewal P, Kim-Schluger L, Liu L, Odin J, Perumalswami P, Florman SS, Schiano TD. Utility of the low-accelerating-dose regimen in 182 liver recipients with recurrent hepatitis C virus. World J Gastroenterol 2015; 21:6236-45. [PMID: 26034358 PMCID: PMC4445100 DOI: 10.3748/wjg.v21.i20.6236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2014] [Revised: 02/09/2015] [Accepted: 03/12/2015] [Indexed: 02/06/2023] Open
Abstract
AIM To describe our experience using a low-accelerating-dose regimen (LADR) with pegylated interferon alpha-2a and ribavirin in treatment of hepatitis C virus (HCV) recurrence. METHODS From 2003, a protocolized LADR strategy was employed to treat liver transplant (LT) recipients with recurrent HCV at our institution. Medical records of 182 adult patients with recurrent HCV treated with LADR between 1/2003 and 1/2011 were reviewed. Histopathology from all post-LT liver biopsies were reviewed in a blinded fashion. Paired recipient and donor IL28B status were assessed. A novel technique was employed to ascertain recipient and donor IL28B (rs12979860) Gt data using DNA extracted from archival FFPE tissue from explanted native livers and donor gallbladders respectively. The primary endpoint was SVR; secondary endpoints examined include (1) patient and graft survival; (2) effect of anti-viral therapy on liver histology (fibrosis and inflammation); (3) incidence of on-treatment development of ACR, CDR, or PCH; (4) association of recipient and donor IL28B genotype with SVR; and (5) incidence of anti-viral therapy-associated adverse events (anemia, leukopenia, thrombocytopenia, depression) and hepatic decompensation. RESULTS The overall SVR rate was 38% (29% Gt1, 67% Gt2, 86% Gt3 and 58% Gt4). HCV Gt (P < 0.0001), donor age (P = 0.003), cytomegalovirus mismatch (P = 0.001), baseline serum bilirubin (P = 0.002), and baseline viral load (P = 0.04) were independent predictors for SVR. SVR rates were significantly higher in the recipient-CC/donor-non CC pairs (P = 0.007). Neither baseline fibrosis nor change in fibrosis stage after anti-viral therapy were associated with SVR. Fibrosis progressed in 72% of patients despite SVR. Median graft survival was 91 mo. Five-year patient survival was superior in patients who achieved SVR (97% vs 82%, P = 0.001). Pre-treatment ALP ≥ 150 U/L (P = 0.01), total bilirubin ≥ 1.5 mg/dL (P = 0.001) and creatinine ≥ 2 mg/dL (P = 0.001) were independently associated with patient survival. Only 13% of patients achieving SVR died during the follow-up period. Treatment discontinuation and treatment-related mortality occurred in 35% and 2.2% of patients, respectively. EPO, G-CSF and blood transfusion were needed in 89%, 40% and 23% of patients, respectively. Overall hospitalization rate for treatment-related serious adverse events was 21%. Forty-six (25%) of the patients were deceased; among those who died, 25 (54%) were due to liver-related complications, and 4 deaths (9%) occurred while receiving therapy (2 patients experienced hepatic decompensation and 2 sepsis). CONCLUSION LADR strategy remains relevant in managing post-LT recurrent HCV where access to DAAs is limited. SVR is associated with improved survival, but fibrosis progression still occurs.
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Filipec Kanizaj T, Kunac N. Hepatitis C: New challenges in liver transplantation. World J Gastroenterol 2015; 21:5768-77. [PMID: 26019441 PMCID: PMC4438011 DOI: 10.3748/wjg.v21.i19.5768] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Revised: 02/28/2015] [Accepted: 04/17/2015] [Indexed: 02/06/2023] Open
Abstract
In an era of great achievements in liver transplantation, hepatitis C viral infection (HCV) remains an unsolved problem. As a leading indication for liver transplantation in Western countries, HCV poses a significant burden both before and after transplantation. Post-transplant disease recurrence occurs in nearly all patients with detectable pretransplant viremia, compromising the lifesaving significance of transplantation. Many factors involving the donor, recipient and virus have been evaluated throughout the literature, although few have been fully elucidated and implemented in actual clinical practice. Antiviral therapy has been recognized as a cornerstone of HCV infection control; however, experience and success are diminished following transplantation in a challenging cohort of patients with liver cirrhosis. Current therapeutic protocols surpass those used previously, both in sustained viral response and side-effect profile. In this article we review the most relevant and contemporary scientific evidence regarding hepatitis C infection and liver transplantation, with special attention dedicated to novel, more efficient and safer antiviral regimens.
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24
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Stock PG, Terrault NA. Human immunodeficiency virus and liver transplantation: Hepatitis C is the last hurdle. Hepatology 2015; 61:1747-54. [PMID: 25292153 DOI: 10.1002/hep.27553] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2014] [Accepted: 09/11/2014] [Indexed: 01/16/2023]
Affiliation(s)
- Peter G Stock
- Departments of Surgery and Medicine, University of California San Francisco, San Francisco, CA
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Price JC, Terrault NA. Treatment of hepatitis C in liver transplant patients: interferon out, direct antiviral combos in. Liver Transpl 2015; 21:423-34. [PMID: 25604355 DOI: 10.1002/lt.24080] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Revised: 11/20/2014] [Accepted: 01/11/2015] [Indexed: 12/14/2022]
Abstract
Although chronic infection with hepatitis C virus (HCV) is the leading indication for liver transplantation in the United States, graft and patient survival rates are reduced because of HCV recurrence after transplant. Interferon-based antiviral treatment administered either before or after transplant to prevent or treat HCV recurrence, respectively, is limited because of poor tolerability and low efficacy. However, the treatment of HCV in the transplant setting is changing considerably with the availability of newer direct-acting antivirals and interferon-free regimens. This article will review the experience to date with treating HCV in the setting of cirrhosis and liver transplantation and will discuss the unique challenges encountered when this population is being treated.
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Affiliation(s)
- Jennifer C Price
- Department of Medicine, University of California San Francisco, San Francisco, CA
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Herzer K, Gerken G. Hepatitis C virus reinfection after liver transplant: New chances and new challenges in the era of direct-acting antiviral agents. World J Hepatol 2015; 7:532-538. [PMID: 25848476 PMCID: PMC4381175 DOI: 10.4254/wjh.v7.i3.532] [Citation(s) in RCA: 3] [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: 08/29/2014] [Revised: 10/21/2014] [Accepted: 12/17/2014] [Indexed: 02/06/2023] Open
Abstract
The first interferon-free regimens have been approved for the treatment of patients with chronic hepatitis C virus (HCV). In the liver transplant (LT) setting, these regimens are expected to have an important effect, because graft loss due to HCV recurrence is a serious problem after LT. The response to the hitherto conventional treatment with pegylated interferon and ribavirin is poor. The significantly better response rates achieved with boceprevir-based and telaprevir-based triple therapy have led to better graft and patient survival rates, but severe drug interactions with immunosuppressants limit the feasibility of this therapy for LT patients. With the approval of sofosbuvir in January 2014, of simeprevir in May 2014, and of daclatasvir in August 2014, three antiviral agents are now available and promise to be applicable without relevant adverse effects or negative interactions with immunosuppressants. Thus, 2014 marks the beginning of a new era of treatment options for HCV recurrence after LT. Although safety and efficacy studies of several interferon-free regimens for patients with HCV recurrence after LT have achieved good preliminary results, reports of clinical experiences with LT patients are scarce. The lack of randomized studies, the small number of enrolled and carefully selected patients, and the heterogeneity of these studies make the results questionable. Real-life experiences are eagerly awaited so that clinicians can estimate the usefulness and the pitfalls of these new regimens. Additionally, the high costs of these agents may limit their accessibility for many patients. The aim of this review is to summarize the current experience with and the expectations of the new direct-acting antiviral agents for LT patients.
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Pharmacokinetic interaction between HCV protease inhibitor boceprevir and methadone or buprenorphine in subjects on stable maintenance therapy. Eur J Clin Pharmacol 2015; 71:303-11. [PMID: 25666027 DOI: 10.1007/s00228-014-1789-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Accepted: 12/01/2014] [Indexed: 02/06/2023]
Abstract
PURPOSE Intravenous opioid use is a common route of hepatitis C virus (HCV) infection; consequently, the prevalence of HCV is high among patients on methadone or buprenorphine/naloxone. The authors evaluated the pharmacokinetic interaction of boceprevir with methadone or buprenorphine/naloxone in patients on stable maintenance therapy. METHODS This was a two-center, open-label, fixed-sequence study in 21 adult volunteers on stable maintenance therapy. Oral methadone (20-150 mg once daily) or sublingual buprenorphine/naloxone (8/2-24/6 mg once daily) was administered alone or in combination with boceprevir (800 mg every 8 h) on days 2-7. Pharmacokinetic sampling occurred before and up to 24 h after the dose on days 1 and 7. RESULTS Coadministration of boceprevir reduced the area under the concentration-time curve during a dosing interval τ (AUC τ ) and maximum observed plasma (or serum) concentration (C max) of R-methadone (geometric mean ratios (GMRs) [90 % confidence intervals (CIs)], 0.85 [0.74, 0.96] and 0.90 [0.71, 1.13]) and S-methadone (GMRs [90 % CIs], 0.78 [0.66, 0.93] and 0.83 [0.64, 1.09]). Boceprevir increased the AUC τ and C max of buprenorphine (GMRs [90 % CIs], 1.19 [0.91, 1.58] and 1.18 [0.93, 1.50]) and naloxone (GMRs [90 % CIs], 1.33 [0.90, 1.93] and 1.09 [0.79, 1.51]). Boceprevir exposure upon methadone or buprenorphine/naloxone coadministration was not clinically different from historical controls and there was no evidence of opioid withdrawal or excess. CONCLUSIONS There was no clinically meaningful impact of boceprevir on methadone or buprenorphine pharmacokinetics, suggesting that methadone/buprenorphine dose adjustments are not required upon coadministration with boceprevir. Individual patients may differ in their clinical experience and clinicians should maintain vigilance when coadministering these medications.
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Dutkowski P, Linecker M, DeOliveira ML, Müllhaupt B, Clavien PA. Challenges to liver transplantation and strategies to improve outcomes. Gastroenterology 2015; 148:307-23. [PMID: 25224524 DOI: 10.1053/j.gastro.2014.08.045] [Citation(s) in RCA: 191] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Revised: 08/29/2014] [Accepted: 08/29/2014] [Indexed: 02/07/2023]
Abstract
Liver transplantation (LT) is a highly successful treatment for many patients with nonmalignant and malignant liver diseases. However, there is a worldwide shortage of available organs; many patients deteriorate or die while on waiting lists. We review the important clinical challenges to LT and the best use of the scarce organs. We focus on changes in indications for LT and discuss scoring systems to best match donors with recipients and optimize outcomes, particularly for the sickest patients. We also cover controversial guidelines for the use of LT in patients with hepatocellular carcinoma and cholangiocarcinoma. Strategies to increase the number of functional donor organs involve techniques to perfuse the organs before implantation. Partial LT (living donor and split liver transplantation) techniques might help to overcome organ shortages, and we discuss small-for-size syndrome. Many new developments could increase the success of this procedure, which is already one of the major achievements in medicine during the second part of the 20th century.
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Affiliation(s)
- Philipp Dutkowski
- Swiss HPB and Transplantation Center, Departments of Surgery and Medicine, University Hospital Zurich, Zurich, Switzerland
| | - Michael Linecker
- Swiss HPB and Transplantation Center, Departments of Surgery and Medicine, University Hospital Zurich, Zurich, Switzerland
| | - Michelle L DeOliveira
- Swiss HPB and Transplantation Center, Departments of Surgery and Medicine, University Hospital Zurich, Zurich, Switzerland
| | - Beat Müllhaupt
- Swiss HPB and Transplantation Center, Departments of Surgery and Medicine, University Hospital Zurich, Zurich, Switzerland
| | - Pierre-Alain Clavien
- Swiss HPB and Transplantation Center, Departments of Surgery and Medicine, University Hospital Zurich, Zurich, Switzerland.
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Saab S, Manne V, Bau S, Reynolds JA, Allen R, Goldstein L, Durazo F, El-Kabany M, Han S, Busuttil RW. Boceprevir in liver transplant recipients. Liver Int 2015; 35:192-7. [PMID: 24673728 DOI: 10.1111/liv.12548] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2014] [Accepted: 03/18/2014] [Indexed: 02/13/2023]
Abstract
BACKGROUND There has been increasing interest in using protease inhibitors with pegylated interferon and ribavirin to treat recurrent hepatitis C (HCV) disease in liver transplant recipients. METHODS We retrospectively evaluated the safety and efficacy in liver transplant recipients treated for recurrent hepatitis C genotype 1 with the combination of peginterferon, ribavirin and boceprevir. RESULTS Twenty liver transplant recipients were treated for recurrent hepatitis C. Baseline alanine aminotransferase, total bilirubin and HCV RNA values (± SD) were 67.5 (±50.9) mg/dl, 1.78 (±1.99) U/L, and 16 955 510 (±21 620 675) IU/ml. Anaemia was a common adverse event requiring epoetin in 16 of 20 recipients and ribavirin dose reductions in 17 of 20 recipients. One-third of recipients required a blood transfusion. Filgrastim was used in 11 of 20 patients (55%) and eltrombopag in two of 20 recipients (10%) over the course of treatment. Serum creatinine level increased significantly from a baseline value of 1.33 mg/dl to 1.59 mg/dl at week 20 of boceprevir (P < 0.005). The overall sustained viral response (SVR) was 50%. Of the 14 patients who had a viral load less than 1000 IU/ml at week 4 of boceprevir, the SVR was 71%. The SVR was 83% of the 11 patients who had undetectable viral levels at week 4 of boceprevir. CONCLUSIONS Antiviral therapy utilizing boceprevir in liver transplant recipients requires close monitoring. Anaemia and neutropenia were common requiring growth factors in most recipients. On-treatment viral responses appear promising but long-term data are needed.
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Affiliation(s)
- Sammy Saab
- Departments of Medicine, The University of California, Los Angeles, CA, USA; Departments of Surgery, The University of California, Los Angeles, CA, USA
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30
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Farnik H, Zimmermann T, Herrmann E, Bechstein WO, Kronenberger B, Galle PR, Labocha S, Ferreiros N, Geisslinger G, Zeuzem S, Sarrazin C, Welker MW. Telaprevir drug monitoring during antiviral therapy of hepatitis C graft infection after liver transplantation. Liver Int 2015; 35:176-83. [PMID: 24649882 DOI: 10.1111/liv.12532] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Accepted: 03/13/2014] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Recurrence of hepatitis C virus (HCV) infection after orthotopical liver transplantation (OLT) is common and associated with reduced graft and patient survival. The protease inhibitor telaprevir may enhance virological response rates in patients after OLT in combination with pegylated interferon-alfa and ribavirin. Pharmacokinetic studies have shown significant drug-drug interactions between telaprevir and immunosuppression (IS), but telaprevir pharmacokinetics in OLT patients with IS are unknown. Aim of the present study was to analyse telaprevir plasma concentrations in patients with HCV genotype 1 infection after OLT in comparison to patients without OLT and IS. METHODS Five patients with HCV genotype 1 infection after OLT and 37 HCV genotype 1-infected patients patients without prior OLT were treated with telaprevir 2250 mg daily, ribavirin 1000/1200 mg daily and pegylated interferon-alfa-2a 180 μg once weekly (triple therapy). Telaprevir plasma concentrations were analysed by liquid chromatography-electrospray-ionization-tandem mass spectrometry. HCV RNA was assessed by automatized reverse-transcription polymerase chain-reaction. RESULTS Median (range) telaprevir plasma concentrations of TW 4, 8 and 12 were 3970 (1980-4430) ng/ml and 2520 (1870-8730) ng/ml in patients after OLT and ciclosporin- or tacrolimus-based IS, respectively, as compared to 2790 (1870-3140) in non-OLT patients (P = 0.3). In one patient with tacrolimus-based IS, telaprevir dose had to be adjusted to achieve virological response. Telaprevir plasma concentrations were steady at treatment weeks 4, 8 and 12 in patients with and without IS. CONCLUSIONS Telaprevir drug monitoring may be necessary in patients with tacrolimus-based IS in patients with HCV graft infection after OLT.
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Affiliation(s)
- Harald Farnik
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, Frankfurt, 60590, Germany
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Cheng KW, Cheng SC, Chen WY, Lin MH, Chuang SJ, Cheng IH, Sun CY, Chou CY. Thiopurine analogs and mycophenolic acid synergistically inhibit the papain-like protease of Middle East respiratory syndrome coronavirus. Antiviral Res 2014; 115:9-16. [PMID: 25542975 PMCID: PMC7113672 DOI: 10.1016/j.antiviral.2014.12.011] [Citation(s) in RCA: 141] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Revised: 12/08/2014] [Accepted: 12/12/2014] [Indexed: 01/08/2023]
Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) is a new highly pathogenic human coronaviruses that emerged in Jeddah and Saudi Arabia and has quickly spread to other countries in Middle East, Europe and North Africa since 2012. Up to 17 December 2014, it has infected at least 938 people with a fatality rate of about 36% globally. This has resulted in an urgent need to identify antiviral drugs that are active against MERS-CoV. The papain-like protease (PL(pro)) of MERS-CoV represents an important antiviral target as it is not only essential for viral maturation, but also antagonizes interferon stimulation of the host via its deubiquitination activity. Here, we report the discovery that two SARS-CoV PL(pro) inhibitors, 6-mercaptopurine (6MP) and 6-thioguanine (6TG), as well as the immunosuppressive drug mycophenolic acid, are able to inhibit MERS-CoV PL(pro). Their inhibition mechanisms and mutually binding synergistic effect were also investigated. Our results identify for the first time three inhibitors targeting MERS-CoV PL(pro) and these can now be used as lead compounds for further antiviral drug development.
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Affiliation(s)
- Kai-Wen Cheng
- Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan
| | - Shu-Chun Cheng
- Department of Nephrology, Chang-Gung Memorial Hospital, Keelung 204, Taiwan
| | - Wei-Yi Chen
- Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan
| | - Min-Han Lin
- Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan
| | - Shang-Ju Chuang
- Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan
| | - I-Hsin Cheng
- Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan
| | - Chiao-Yin Sun
- Department of Nephrology, Chang-Gung Memorial Hospital, Keelung 204, Taiwan.
| | - Chi-Yuan Chou
- Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan.
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Lens S, Mariño Z, Forns X. Efficacy of new direct acting antivirals in transplant recipients and patients with advanced disease. Dig Liver Dis 2014; 46 Suppl 5:S197-205. [PMID: 25458782 DOI: 10.1016/j.dld.2014.10.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Accepted: 10/06/2014] [Indexed: 12/11/2022]
Abstract
The development of new direct acting antivirals constitutes a clinical revolution in the field of hepatitis C therapy and, most probably, in the history of Hepatology. Difficult-to-treat patients, such as cirrhotics or patients in the peri-transplant setting, will clearly benefit from these therapies, particularly from interferon-free all-oral combinations. However, despite the substantial improvement of the hepatitis C drug market, access to these therapies will likely be different around the world due to economic restrictions. This review aims to clarify the current stage of different antiviral strategies (with or without interferon) in these difficult populations by analysing specific efficacy and safety results in patients with cirrhosis, patients on the waiting list for liver transplantation and recipients with hepatitis C recurrence after liver transplantation. Hitherto, some important challenges still remain unanswered in these patients and will need to be assessed in clinical practice, such as the evaluation of safety and efficacy in advanced cirrhotic patients with portal hypertension, the impact (if any) of viral clearance on clinical outcomes in patients with decompensated liver disease, the role of ribavirin in all-oral combinations, the relevance of the development of multi-drug viral resistant strains and the drug-drug interaction profiles of these drugs, especially after liver transplantation.
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Affiliation(s)
- Sabela Lens
- Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, University of Barcelona, Barcelona, Spain
| | - Zoe Mariño
- Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, University of Barcelona, Barcelona, Spain
| | - Xavier Forns
- Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, University of Barcelona, Barcelona, Spain.
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Ajala OS, Jukov A, Ma CM. Hepatitis C virus inhibitory hydrolysable tannins from the fruits of Terminalia chebula. Fitoterapia 2014; 99:117-23. [DOI: 10.1016/j.fitote.2014.09.014] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Revised: 09/16/2014] [Accepted: 09/17/2014] [Indexed: 12/25/2022]
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Jiménez-Pérez M, González-Grande R, Rando-Muñoz FJ. Management of recurrent hepatitis C virus after liver transplantation. World J Gastroenterol 2014; 20:16409-16417. [PMID: 25469009 PMCID: PMC4248184 DOI: 10.3748/wjg.v20.i44.16409] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Revised: 08/27/2014] [Accepted: 10/14/2014] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection is the leading cause of death from liver disease and the leading indication for liver transplantation (LT) in the United States and Western Europe. LT represents the best therapeutic alternative for patients with advanced chronic liver disease caused by HCV or those who develop hepatocarcinoma. Reinfection by HCV of the graft is universal and occurs in 95% of transplant patients. This reinfection can compromise graft function and patient survival. In a few cases, the histological recurrence is minimal and non-progressive; however, in most patients it follows a more rapid course than in immunocompetent persons, and frequently evolves into cirrhosis with graft loss. In fact, the five-year and ten-year survival of patients transplanted because of HCV are 75% and 68%, respectively, compared with 85% and 78% in patients transplanted for other reasons. There is also a pattern of recurrence that is very severe, but rare (< 10%), called fibrosing cholestatic hepatitis, which often involves rapid graft loss. Patients who present a negative HCV viremia after antiviral treatment have better survival. Many studies published over recent years have shown that antiviral treatment of post-transplant HCV hepatitis carried out during the late phase is the best option for improving the prognosis of these patients. Until 2011, PEGylated interferon plus ribavirin was the standard of care, resulting in a sustained virological response in around 30% of recipients. The addition of protease inhibitors, such as boceprevir or telaprevir, to the standard of care, or the use of other direct-acting antiviral drugs may involve therapeutic changes in the context of HCV recurrence. This may result a better prognosis for these patients, particularly those with severe recurrence or factors predicting rapid progression of fibrosis. However, the use of these agents in LT still requires clarification in terms of safety and efficacy.
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MESH Headings
- Antiviral Agents/adverse effects
- Antiviral Agents/therapeutic use
- Carcinoma, Hepatocellular/diagnosis
- Carcinoma, Hepatocellular/mortality
- Carcinoma, Hepatocellular/surgery
- Carcinoma, Hepatocellular/virology
- Drug Therapy, Combination
- End Stage Liver Disease/diagnosis
- End Stage Liver Disease/mortality
- End Stage Liver Disease/surgery
- End Stage Liver Disease/virology
- Hepatitis C, Chronic/complications
- Hepatitis C, Chronic/diagnosis
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/immunology
- Hepatitis C, Chronic/mortality
- Humans
- Immunocompromised Host
- Immunosuppressive Agents/adverse effects
- Liver Neoplasms/diagnosis
- Liver Neoplasms/mortality
- Liver Neoplasms/surgery
- Liver Neoplasms/virology
- Liver Transplantation/adverse effects
- Liver Transplantation/mortality
- Recurrence
- Risk Factors
- Time Factors
- Treatment Outcome
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Gambato M, Lens S, Navasa M, Forns X. Treatment options in patients with decompensated cirrhosis, pre- and post-transplantation. J Hepatol 2014; 61:S120-31. [PMID: 25443340 DOI: 10.1016/j.jhep.2014.07.020] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2014] [Revised: 07/03/2014] [Accepted: 07/11/2014] [Indexed: 12/21/2022]
Abstract
Interferon-based treatments have a poor safety profile and limited efficacy in patients with advanced liver disease and in patients with hepatitis C (HCV) recurrence after liver transplantation (LT). Despite the recent approval of the first interferon-free regimen, which will be followed by several other interferon-free combinations in 2014 and 2015, data in patients with advanced cirrhosis and hepatitis C after LT are still limited. One study has already proven the concept that graft HCV infection can be prevented in a significant proportion of patients by treating them with sofosbuvir and ribavirin while awaiting LT. Two interferon-free regimens have also demonstrated a high efficacy in patients with hepatitis C recurrence after transplantation. Before these treatment strategies can be implemented in clinical practice, a few issues need to be addressed: (1) safety and efficacy of new antivirals in patients with decompensated cirrhosis, (2) the impact of viral clearance on liver function, (3) the potential consequences of virological failure (and the selection of multi-drug resistant HCV strains) in patients with decompensated cirrhosis or with severe hepatitis C recurrence after LT, and (4) drug-drug interactions (DDI) profiles. Finally, in the transplant setting it is also relevant to learn which strategy is most cost-effective in minimizing the negative impact of hepatitis C: preventing graft infection by treating patients before transplantation or treating hepatitis C recurrence after LT.
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Affiliation(s)
- Martina Gambato
- Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, University of Barcelona, Spain
| | - Sabela Lens
- Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, University of Barcelona, Spain
| | - Miquel Navasa
- Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, University of Barcelona, Spain
| | - Xavier Forns
- Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, University of Barcelona, Spain.
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36
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Delaborde L, Logerot S, Fonrose X. [Drug-drug interaction with telaprevir or boceprevir in liver transplant patients: about four cases]. Therapie 2014; 69:491-7. [PMID: 25320939 DOI: 10.2515/therapie/2014201] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Accepted: 07/28/2014] [Indexed: 01/12/2023]
Abstract
Boceprevir and telaprevir are both direct-acting antivirals indicated, as part of combination therapy for the management of chronic hepatitis C virus (HCV) genotype 1 infection. Transplanted patients treated with anticalcineurines (tacrolimus and cyclosporine) are confronted with major risks of interactions. Indeed, these antiviral are strong inhibitors of the enzyme cytochrome 3A4/A5, responsible for the metabolisme of ciclosprine and tacrolimus. The literature gives evidence of the dangerousness of this drug-drug interaction. We report four clinical cases illustrating the dosage adaptations at liver transplant patients and treated by telaprevir or boceprevir. To protect the immunosuppressive efficiency, a multidisciplinary care and narrow monitoring of the interaction between immunosuppressing agents and protease inhibitors were necessary.
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Affiliation(s)
- Lucie Delaborde
- Département de pharmacie, Centre hospitalier universitaire de Grenoble, La Tronche, France
| | - Sophie Logerot
- Centre régional de pharmacovigilance, Centre hospitalier universitaire de Grenoble, La Tronche, France
| | - Xavier Fonrose
- Laboratoire de pharmacologie-toxicologie, Centre hospitalier universitaire de Grenoble, La Tronche France
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Kakati B, Seetharam A. Hepatitis C Recurrence after Orthotopic Liver Transplantation: Mechanisms and Management. J Clin Transl Hepatol 2014; 2:189-96. [PMID: 26355427 PMCID: PMC4521242 DOI: 10.14218/jcth.2014.00016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Revised: 06/06/2014] [Accepted: 07/07/2014] [Indexed: 12/04/2022] Open
Abstract
Chronic Hepatitis C (HCV) infection is the leading indication for orthotopic liver transplantation and recurrence is nearly universal. Chronic HCV infection is frequently established through evasion of the innate immune system. Priming of adaptive immune responses modulate the severity and rate of fibrosis progression. Those with demonstrable viremia entering the transplant period uniformly suffer recurrence post-transplant. Progression to cirrhosis is accelerated post-transplant secondary to systemic immunosuppression. In addition, a number of factors, including donor, host, and viral characteristics, influence severity and rate of fibrosis progression. Interferon-based therapy, the previous standard of care, in those with advanced cirrhosis or post-transplant has been limited by a number of issues. These include a relative lack of efficacy and poor tolerability with higher incidence of infection and anemia. Recently, approval of direct acting antivirals have ushered in a new era in HCV therapeutics and have applicability in these special populations. Their use immediately prior to or post-transplant is expected to improve both morbidity and mortality.
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Affiliation(s)
- Bobby Kakati
- Banner Transplant and Advanced Liver Disease Center, Phoenix, AZ, USA
| | - Anil Seetharam
- Banner Transplant and Advanced Liver Disease Center, Phoenix, AZ, USA
- University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA
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38
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Faisal N, Yoshida EM, Bilodeau M, Wong P, Ma M, Burak KW, Al-Judaibi B, Renner EL, Lilly LB. Protease inhibitor-based triple therapy is highly effective for hepatitis C recurrence after liver transplant: a multicenter experience. Ann Hepatol 2014. [DOI: 10.1016/s1665-2681(19)31252-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/15/2023]
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Burton JR, O'Leary JG, Verna EC, Saxena V, Dodge JL, Stravitz RT, Levitsky J, Trotter JF, Everson GT, Brown RS, Terrault NA. A US multicenter study of hepatitis C treatment of liver transplant recipients with protease-inhibitor triple therapy. J Hepatol 2014; 61:508-14. [PMID: 24801415 PMCID: PMC4394742 DOI: 10.1016/j.jhep.2014.04.037] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2014] [Revised: 04/21/2014] [Accepted: 04/24/2014] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS NS3/4A protease inhibitors, boceprevir or telaprevir, combined with peginterferon and ribavirin was the standard treatment for HCV genotype 1 and remains the only available direct antiviral drug based therapy in some countries. Efficacy and safety data in liver transplant recipients are limited. METHODS This was a retrospective cohort study of 81 patients with genotype 1 HCV treated with boceprevir (10%) or telaprevir (90%) plus peginterferon and ribavirin at 6 US transplant centers (53% stage 3-4/4 fibrosis, 57% treatment experienced). The primary end point was undetectable HCV RNA 12 weeks after treatment completion (SVR12). RESULTS The intent-to-treat SVR12 rate was 63% (51/81). Patients with an extended rapid virologic response, (undetectable HCV RNA at 4 and 12 weeks after starting boceprevir or telaprevir), had a higher rate of SVR12 than all other patients (85% vs. 15%, p<0.001). Adverse effects were common; 21% of patients experienced hemoglobin <8g/dl and 57% required blood transfusions during the first 16 weeks. Twenty seven percent were hospitalized and 9% died; all were liver-related. CONCLUSIONS The addition of boceprevir or telaprevir to peginterferon and ribavirin yields SVR12 of 63% in liver transplant recipients with genotype 1 recurrent HCV, despite a high prevalence of advanced fibrosis and prior non-response to peginterferon and ribavirin. Rapid virologic response predicted a high likelihood of SVR. Despite a doubling of SVR rates, poor tolerability and high rates of adverse events were frequent and pose barriers to its widespread application.
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Affiliation(s)
- James R Burton
- University of Colorado, Denver, Aurora, CO, United States
| | | | | | - Varun Saxena
- University of California at San Francisco, San Francisco, CA, United States
| | - Jennifer L Dodge
- University of California at San Francisco, San Francisco, CA, United States
| | | | | | | | | | | | - Norah A Terrault
- University of California at San Francisco, San Francisco, CA, United States.
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40
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Verna EC. Hepatitis viruses and liver transplantation: evolving trends in antiviral management. Clin Liver Dis 2014; 18:575-601. [PMID: 25017077 DOI: 10.1016/j.cld.2014.05.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Viral hepatitis is both a leading indication for liver transplant (LT) and an important cause of posttransplant graft loss and mortality. Treatment and prevention of hepatitis B virus in LT recipients, with the observed corresponding improvement in post-LT outcomes, is among the great success stories in transplantation. By comparison, treatment of hepatitis C virus with safe and effective regimens is only just becoming a reality. Chronic hepatitis E virus infection in LT recipients represents a newly described phenomenon that can also lead to graft loss; early diagnosis and treatment may be key in the management of these patients.
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Affiliation(s)
- Elizabeth C Verna
- Division of Digestive and Liver Diseases, Center for Liver Disease and Transplantation, Columbia University College of Physicians and Surgeons, 622 West 168th Street, New York, NY 10032, USA.
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41
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Dall’Agata M, Gramenzi A, Biselli M, Bernardi M. Hepatitis C virus reinfection after liver transplantation: Is there a role for direct antiviral agents? World J Gastroenterol 2014; 20:9253-9260. [PMID: 25071318 PMCID: PMC4110555 DOI: 10.3748/wjg.v20.i28.9253] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Revised: 03/27/2014] [Accepted: 06/05/2014] [Indexed: 02/06/2023] Open
Abstract
Recurrence of hepatitis C virus (HCV) infection following liver transplantation (LT) is almost universal and can accelerate graft cirrhosis in up to 30% of patients. The development of effective strategies to treat or prevent HCV recurrence after LT remains a major challenge, considering the shortage of donor organs and the accelerated progression of HCV in LT recipients. Standard antiviral therapy with pegylated-interferon plus ribavirin is the current treatment of choice for HCV LT recipients, even though the combination is not as effective as it is in immunocompetent patients. A sustained virological response in the setting of LT improves patient and graft survival, but this is only achieved in 30%-45% of patients and the treatment is poorly tolerated. To improve the efficacy of pre- and post-transplant antiviral therapy, a new class of potent direct-acting antiviral agents (DAAs) has been developed. The aim of this review is to summarize the use of DAAs in LT HCV patients. PubMed, Cochrane Library, MEDLINE, EMBASE, Web of Science and clinical trial databases were searched for this purpose. To date, only three clinical studies on the topic have been published and most of the available data are in abstract form. Although a moderately successful early virological response has been reported, DAA treatment regimens were associated with severe toxicity mitigating their potential usefulness. Moreover, the ongoing nature of data, the lack of randomized studies, the small number of enrolled patients and the heterogeneity of these studies make the results largely anecdotal and questionable. In conclusion, large well-designed clinical studies on DAAs in HCV LT patients are required before these drugs can be recommended after transplantation.
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Gambato M, Lens S, Fernández-Carrillo C, Alfaro I, Forns X. Viral hepatitis and liver transplantation: pathogenesis, prevention and therapy of recurrent disease. Dig Dis 2014; 32:538-44. [PMID: 25034286 DOI: 10.1159/000360831] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Cirrhosis secondary to hepatitis C virus infection is the leading cause of liver transplantation in most countries. Hepatitis C has an accelerated course after transplantation, and for this reason graft and patient survival are decreased in comparison with other indications of liver transplantation. The development of direct-acting antivirals has been a major step in the management of hepatitis C and in a few years from now the infection will be eradicated with the combination of oral drugs with a good safety profile. This will likely allow prevention of hepatitis C recurrence in most cases. Meanwhile, management of hepatitis C virus infection still relies on the combination of interferon, ribavirin and the first-generation protease inhibitors telaprevir and boceprevir.
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Affiliation(s)
- Martina Gambato
- Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, Barcelona, Spain
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[Experience in the management of immunosuppressant treatment with hepatitis C virus protease inhibitors]. GASTROENTEROLOGIA Y HEPATOLOGIA 2014; 37:558-63. [PMID: 24951300 DOI: 10.1016/j.gastrohep.2014.05.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Revised: 04/16/2014] [Accepted: 05/05/2014] [Indexed: 11/20/2022]
Abstract
INTRODUCTION Antiviral drugs for the treatment of hepatitis C virus (HCV) infections have a large number of interactions. The aim of this study was to describe the interactions of telaprevir, boceprevir and sofosbuvir with immunosuppressive drugs in liver transplant recipients. METHODS A retrospective observational study was performed in liver transplant patients with HCV infection who started treatment with telaprevir, boceprevir or sofosbuvir. Dose, regimens and plasma levels of tacrolimus, cyclosporine and sirolimus before and after antiviral treatment initiation were collected. Average variations in dose, dosing interval and immunosuppressive plasma levels after the start of treatment were calculated. RESULTS Thirty-five patients were included. In patients treated with telaprevir (n = 18), the cyclosporine dose was reduced by an average of 59.1% (SD = 14.6%), yielding an average reduction of 14.6% (18.8%) in plasma levels. The dose of tacrolimus was reduced by 34.3% (31.7%), increasing the dosing interval by a mean of 73.4 (38.2) hours. After this variation, tacrolimus levels were increased by an average of 59.7% (89.6%). In patients treated with boceprevir (n = 4), tacrolimus started with a reduction of 18.1% (9.8%) of the initial dose and an average increase in the dosing interval of 12.0 (16.9) hours, showing a mean reduction in plasma levels of 37.7% (21.8%). Sofosbuvir therapy (n = 13) showed no significant variations in immunosuppressive drug levels. CONCLUSIONS The interaction of telaprevir and boceprevir with immunosuppressive drugs requires a substantial dose reduction at the beginning of treatment and close monitoring of plasma levels.
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Bunchorntavakul C, Reddy KR. Management of Hepatitis C Before and After Liver Transplantation in the Era of Rapidly Evolving Therapeutic Advances. J Clin Transl Hepatol 2014; 2:124-33. [PMID: 26357623 PMCID: PMC4521260 DOI: 10.14218/jcth.2014.00002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2014] [Revised: 02/13/2014] [Accepted: 02/20/2014] [Indexed: 12/14/2022] Open
Abstract
Management of hepatitis C (HCV) in liver transplantation (LT) population presents unique challenges. Suboptimal graft survival in HCV+ LT recipients is attributable to universal HCV recurrence following LT. Although eradication of HCV prior to LT is ideal for the prevention of HCV recurrence it is often limited by adverse events, particularly in patients with advanced cirrhosis. Antiviral therapy in LT candidates needs careful monitoring, and prophylaxis with HCV antibodies is ineffective. Early antiviral therapy after LT has been investigated, but no clear benefit has been demonstrated. Protocol liver biopsy is generally recommended in HCV+ LT recipients, and antiviral therapy can be considered in those with severe/progressive HCV recurrence. Sustained virological response (SVR) can be achieved in approximately 30% of LT recipients with pegylated interferon/ribavirin (PEG-IFN/RBV) with survival benefit, but adverse effects are common. Favorable patient characteristics for response to therapy include non-1 genotype, previously untreated, low baseline HCV-RNA, and donor IL28B genotype CC. Direct acting antiviral (DAA)-based triple therapy is associated with higher rates of SVR, but with similar or slightly higher rates of side effects, and immunosuppressive regimens need to be closely monitored and adjusted during the treatment period. Notably, the safety and efficacy of HCV treatment are very likely to improve with newer generation DAA. The benefit of immunosuppressive strategy on the natural history HCV recurrence has not been well elucidated. Based upon available evidence, cyclosporine A (CSA), mycophenolate mofetil (MMF), and sirolimus appear to have a neutral or small beneficial impact on HCV recurrence. Donor interleukin 28 B (IL28B) polymorphisms appear to impact the course and treatment outcomes in recurrent HCV. Retransplantation should be considered for patients with reasonable survival probability.
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Affiliation(s)
- Chalermrat Bunchorntavakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Rajavithi Hospital, College of Medicine, Rangsit University, Bangkok, Thailand
| | - K. Rajender Reddy
- Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA, USA
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Talavera Pons S, Lamblin G, Boyer A, Sautou V, Abergel A. Drug interactions and protease inhibitors used in the treatment of hepatitis C: how to manage? Eur J Clin Pharmacol 2014; 70:775-89. [PMID: 24817413 DOI: 10.1007/s00228-014-1679-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2013] [Accepted: 04/01/2014] [Indexed: 11/30/2022]
Abstract
PURPOSE The first-generation protease inhibitors (PI) boceprevir and telaprevir combined with pegylated interferon have revolutionized the treatment of type-1 hepatitis C by increasing the rates of sustained virologic response. However, they induce drug interactions, and their clinical relevance is difficult to predict. This review compiles available data on drug-drug interactions (DDI) based on their pharmacokinetic and pharmacodynamic properties with the aim of assisting clinicians in managing DDI METHODS: PubMed, drug interaction databases and hepatology and infectious disease conference abstracts were systematically searched using the key search terms "interaction", "hepatitis C", "telaprevir" and "boceprevir". All known interactions were compiled and reclassified according to their pharmacokinetic and pharmacodynamic mechanisms. The state of knowledge of interaction mechanisms are reported and a therapeutic approach is proposed. RESULTS Boceprevir and telaprevir are both substrates and potent inhibitors of cytochrome P450 3A4 and the drug transporter P-glycoprotein. They induce overdosage but can sometimes decrease the effect of other drugs by inducing other cytochromes. Overdosage or low dosage mainly affects drugs with a narrow therapeutic range, such as immunosuppressants or antiretrovirals. The distribution and elimination of PI are unaffected by interactions. In terms of pharmacodynamic interactions, PI can trigger drug-induced QT interval prolongation, which means that clinicians should manage such risk factors as potassium/magnesium levels or avoid other QT-prolonging drugs. CONCLUSIONS Management of hepatitis C therapy is complex. The key to interpreting DDI data is a solid understanding of the pharmacokinetic and pharmacodynamic profiles of the drugs involved. Their ability to inhibit cytochrome P450 3A4 and prolong the QT interval can have significant clinical consequences. This review provides a practical guide to the safe and effective management of therapy with boceprevir and telaprevir.
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Affiliation(s)
- Sarah Talavera Pons
- Department of Pharmacy, Clermont-Ferrand University Hospital, Clermont-Ferrand, France,
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Méndez-Sánchez N, Ridruejo E, Alves de Mattos A, Chávez-Tapia NC, Zapata R, Paraná R, Mastai R, Strauss E, Guevara-Casallas LG, Daruich J, Gadano A, Parise ER, Uribe M, Aguilar-Olivos NE, Dagher L, Ferraz-Neto BH, Valdés-Sánchez M, Sánchez-Avila JF. Latin American Association for the Study of the Liver (LAASL) clinical practice guidelines: management of hepatocellular carcinoma. Ann Hepatol 2014; 13 Suppl 1:S4-S40. [PMID: 24998696 DOI: 10.1016/s1665-2681(19)30920-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2025]
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third most common cause of cancer death, and accounts for 5.6% of all cancers. Nearly 82% of the approximately 550,000 liver cancer deaths each year occur in Asia. In some regions, cancer-related death from HCC is second only to lung cancer. The incidence and mortality of HCC are increasing in America countries as a result of an ageing cohort infected with chronic hepatitis C, and are expected to continue to rise as a consequence of the obesity epidemic. Clinical care and survival for patients with HCC has advanced considerably during the last two decades, thanks to improvements in patient stratification, an enhanced understanding of the pathophysiology of the disease, and because of developments in diagnostic procedures and the introduction of novel therapies and strategies in prevention. Nevertheless, HCC remains the third most common cause of cancer-related deaths worldwide. These LAASL recommendations on treatment of hepatocellular carcinoma are intended to assist physicians and other healthcare providers, as well as patients and other interested individuals, in the clinical decision-making process by describing the optimal management of patients with liver cancer.
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Affiliation(s)
| | - Ezequiel Ridruejo
- Hepatology Section, Department of Medicine. Centro de Educación Médica e Investigaciones Clínicas Norberto Quirno "CEMIC". Ciudad Autónoma de Buenos Aires, Argentina; Hepatology and Liver Transplant Unit. Hospital Universitario Austral, Pilar, Argentina
| | | | | | - Rodrigo Zapata
- Hepatology and Liver Transplantation Unit. University of Chile School of Medicine, German Clinic. Santiago, Chile
| | - Raymundo Paraná
- Associate Professor of School of Medicine - Federal University of Bahia Head of the Gastro-Hepatologist Unit of the University Bahia University Hospital
| | - Ricardo Mastai
- Transplantation Unit. German Hospital.Buenos Aires, Argentina
| | - Edna Strauss
- Clinical hepatologist of Hospital do Coraçao - São Paulo - Brazil. Professor of the Post Graduate Course in the Department of Pathology at the School of Medicine, University of São Paulo
| | | | - Jorge Daruich
- Hepatology Department, Clinical Hospital San Martín. University of Buenos Aires Buenos Aires, Argentina
| | - Adrian Gadano
- Section of Hepatology, Italian Hospital of Buenos Aires. Buenos Aires, Argentina
| | - Edison Roberto Parise
- Professor Associado da Disciplina de Gastroenterologia da Universidade Federal de São Paulo, Presidente Eleito da Sociedade Brasileira de Hepatologia
| | - Misael Uribe
- Digestive Diseases and Obesity Clinic, Medica Sur Clinic Foundation. México City, Mexico
| | - Nancy E Aguilar-Olivos
- Digestive Diseases and Obesity Clinic, Medica Sur Clinic Foundation. México City, Mexico
| | - Lucy Dagher
- Consultant Hepatologist. Metropolitan Policlinic- Caracas- Venezuela
| | - Ben-Hur Ferraz-Neto
- Director of Liver Institute - Beneficencia Portuguesa de São Paulo. Chief of Liver Transplantation Team
| | - Martha Valdés-Sánchez
- Department of Pediatric Oncology National Medical Center "Siglo XXI". Mexico City, Mexico
| | - Juan F Sánchez-Avila
- Hepatology and Liver Transplantation Department National Institute of Nutrition and Medical Sciences "Salvador Zubirán" Mexico City, Mexico
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Lens S, Alfaro I. Perspectivas futuras del tratamiento de la hepatitis C, ¿sin interferón y sin ribavirina? GASTROENTEROLOGIA Y HEPATOLOGIA 2014; 37:311-21. [DOI: 10.1016/j.gastrohep.2014.01.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Revised: 01/22/2014] [Accepted: 01/29/2014] [Indexed: 12/18/2022]
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Tischer S, Fontana RJ. Drug-drug interactions with oral anti-HCV agents and idiosyncratic hepatotoxicity in the liver transplant setting. J Hepatol 2014; 60:872-84. [PMID: 24280292 PMCID: PMC4784678 DOI: 10.1016/j.jhep.2013.11.013] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Revised: 11/14/2013] [Accepted: 11/17/2013] [Indexed: 02/06/2023]
Abstract
Studies of boceprevir and telaprevir based antiviral therapy in liver transplant (LT) recipients with hepatitis C genotype 1 infection have demonstrated dramatic increases in tacrolimus, cyclosporine, and mTOR inhibitor exposure. In addition to empiric dose reductions, daily monitoring of immunosuppressant blood levels is required when initiating as well as discontinuing the protease inhibitors to maximize patient safety. Although improved suppression of HCV replication is anticipated, 20 to 40% of treated subjects have required early treatment discontinuation due to various adverse events including anemia (100%), infection (30%), nephrotoxicity (20%) and rejection (5 to 10%). Simeprevir and faldaprevir will likely have improved efficacy and safety profiles but potential drug interactions with other OATP1B1 substrates and unconjugated hyperbilirubinemia are expected. In contrast, sofosbuvir and daclatasvir based antiviral therapy are not expected to lead to clinically significant drug-drug interactions in LT recipients but confirmatory studies are needed. Liver transplant recipients may also be at increased risk of developing drug induced liver injury (DILI). Establishing a diagnosis of DILI in the transplant setting is very difficult with the variable latency, laboratory features and histopathological manifestations of hepatotoxicity associated with a given drug, the need to exclude competing causes of allograft injury, and the lack of an objective and verifiable confirmatory test. Nonetheless, a heightened awareness of the possibility of DILI is warranted in light of the large number of medications used in LT recipients and the potential adverse impact that DILI may have on patient outcomes.
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Affiliation(s)
- Sarah Tischer
- Department of Pharmacy Services, University of Michigan Medical Center, Ann Arbor, MI 48109, United States
| | - Robert J Fontana
- Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109, United States.
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Mauss S, Klinker H. Drug-drug interactions in the treatment of HCV among people who inject drugs. Clin Infect Dis 2014; 57 Suppl 2:S125-8. [PMID: 23884060 DOI: 10.1093/cid/cit299] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Boceprevir and telaprevir are inhibitors and substrates of the cytochrome P450 3A4 family. With the use of these HCV protease inhibitors as part of standard therapy for chronic hepatitis C genotype 1 infection, drug-drug interactions with multiple medications being inductors, inhibitors, or substrates of cytochrome P450 3A4 can be expected. Due to the complexity of these interactions, predicting the expected magnitude and sometimes even the direction of the effect has proven to be difficult. Pharmacokinetic studies should be carried out to evaluate drugs with clinical relevance and possible interactions. This review focuses on the data available regarding drugs that are frequently used in the setting of addiction or used by patients with addiction. In addition to highlighting relevant drug-drug interactions, alternative drugs that can be safely used are suggested.
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Affiliation(s)
- Stefan Mauss
- Center for HIV and Hepatogastroenterology, Düsseldorf, Germany.
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Coilly A, Roche B, Duclos-Vallée JC, Samuel D. Management of HCV transplant patients with triple therapy. Liver Int 2014; 34 Suppl 1:46-52. [PMID: 24373078 DOI: 10.1111/liv.12406] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
Hepatitis C virus (HCV) infection is one of the leading causes of end-stage liver disease and the main indication for liver transplantation (LT) in most countries. All patients who undergo LT with detectable serum HCV RNA experience graft reinfection. Between 20 and 30% of patients have developed cirrhosis at 5 years post-LT. The outcome of transplant patients with cirrhosis on the graft is severe, with a rate of decompensation at 1 year of approximately 40%. To date, retransplantation is the only option in patients with decompensated liver disease. Until 2011, standard antiviral therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV), was the only effective therapy. Obtaining a sustained virological response (SVR) in patients with LT greatly improves overall and graft survival but this only occurs in 30% of transplanted patients. Direct acting antivirals (DAAs) such as protease inhibitors (PI), polymerase or other non-structural proteins inhibitors represent a new era in HCV associated liver disease. Although their use in the field of LT will certainly be essential there are some limitations because of safety and tolerance. One limitation is the potential interaction with calcineurin inhibitors. We describe the results of triple therapy with boceprevir (BOC) or telaprevir (TVR) for efficacy and safety and comment on future therapeutic strategies in liver transplant recipients.
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Affiliation(s)
- Audrey Coilly
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif, France; Univ Paris-Sud, UMR-S 785, Villejuif, France; Inserm, Unité 785, Villejuif, France; Hepatinov, Villejuif, France
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