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1
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Li K, Lauschke VM, Zhou Y. Molecular docking to investigate HLA-associated idiosyncratic drug reactions. Drug Metab Rev 2025; 57:67-90. [PMID: 39811883 DOI: 10.1080/03602532.2025.2453521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Accepted: 01/09/2025] [Indexed: 01/16/2025]
Abstract
Idiosyncratic drug reactions (IDRs) pose severe threats to patient health. Unlike conventionally dose-dependent side effects, they are unpredictable and more frequently manifest as life-threatening conditions, such as severe cutaneous adverse reactions (SCARs) and drug-induced liver injury (DILI). Some HLA alleles, such as HLA-B*57:01, HLA-B*15:02, and HLA-B*58:01, are known risk factors for adverse reactions induced by multiple drugs. However, the structural basis underlying most HLA-associated adverse events remains poorly understood. This review summarizes the application of molecular docking to reveal the mechanisms of IDR-related HLA associations, covering studies using this technique to examine drug-HLA binding pockets and identify key binding residues. We provide a comprehensive overview of risk HLA alleles associated with IDRs, followed by a discussion of the utility and limitations of commonly used molecular docking tools in simulating complex molecular interactions within the HLA binding pocket. Through examples, including the binding of abacavir and flucloxacillin to HLA-B*57:01, carbamazepine to HLA-B*15:02, and allopurinol to HLA-B*58:01, we demonstrate how docking analyses can provide insights into the drug and HLA allele-specificity of adverse events. Furthermore, the use of molecular docking to screen drugs with unknown IDR liability is examined, targeting either multiple HLA variants or a single specific variant. Despite multiple challenges, molecular docking presents a promising toolkit for investigating drug-HLA interactions and understanding IDR mechanisms, with significant implications for preemptive HLA typing and safer drug development.
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Affiliation(s)
- Kejun Li
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Volker M Lauschke
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
- Center for Molecular Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden
- Margarete Fischer-Bosch Institute of Clinical Pharmacology (IKP), Stuttgart, Germany
- University of Tübingen, Tübingen, Germany
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yitian Zhou
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
- Center for Molecular Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden
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2
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Hasegawa A, Abe R. Stevens-Johnson syndrome and toxic epidermal necrolysis: Updates in pathophysiology and management. Chin Med J (Engl) 2024; 137:2294-2307. [PMID: 39238098 PMCID: PMC11441865 DOI: 10.1097/cm9.0000000000003250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Indexed: 09/07/2024] Open
Abstract
ABSTRACT Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening conditions characterized by extensive detachment of the epidermis and mucous membranes. These severe disorders carry a high mortality rate, and their pathogenesis remains largely unclear. Furthermore, optimal therapeutic strategies for SJS/TEN remain a subject of ongoing debate. Early diagnosis of SJS/TEN is challenging, and reliable biomarkers for diagnosis or severity prediction have not been firmly established. Certain drugs, such as carbamazepine and allopurinol, have shown a strong association with specific human leukocyte antigen (HLA) types. Recently, the potential benefits of HLA screening prior to administering these drugs to reduce the incidence of SJS/TEN have been explored. Epidermal cell death in SJS/TEN lesions is caused by extensive apoptosis, primarily through the Fas-Fas ligand (FasL) and perforin/granzyme pathways. Our findings suggest that necroptosis, a form of programmed necrosis, also contributes to epidermal cell death. Annexin A1, released from monocytes, interacts with the formyl peptide receptor 1 to induce necroptosis. Several biomarkers, such as CC chemokine ligand (CCL)-27, interleukin-15, galectin-7, receptor-interacting protein kinases 3 (RIP3), and lipocalin-2, have been identified for diagnostic and prognostic purposes in SJS/TEN. Supportive care is recommended for treating SJS/TEN, but the efficacy of various therapeutic options-including systemic corticosteroids, intravenous immunoglobulin, cyclosporine, and tumor necrosis factor-α antagonists-remains controversial. Recent studies have investigated the potential benefits of tumor necrosis factor-α antagonists. In this review, we discuss recent advances in the understanding and management of SJS/TEN.
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Affiliation(s)
- Akito Hasegawa
- Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
| | - Riichiro Abe
- Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
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Lungu GN, Diaconescu GI, Dumitrescu F, Docea OO, Mitrut R, Giubelan L, Zlatian O, Mitrut P. Liver Damage During Treatment with Reverse-Transcriptase Inhibitors in HIV Patients. CURRENT HEALTH SCIENCES JOURNAL 2024; 50:181-197. [PMID: 39371070 PMCID: PMC11447508 DOI: 10.12865/chsj.50.02.03] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 05/18/2024] [Indexed: 10/08/2024]
Abstract
The advent of highly active antiretroviral therapy (HAART) in 1996 has markedly enhanced the life expectancy of people living with HIV (PLWH), largely due to the effectiveness of reverse transcriptase inhibitors (RTIs). These drugs target the reverse transcriptase enzyme, crucial for the HIV virus to convert its RNA into DNA within host cells, effectively disrupting the viral replication process. This action reduces the patient's viral load, helping preserve immune function and prevent progression to AIDS. Consequently, the predominant causes of mortality among individuals living with HIV have transitioned from opportunistic infections and AIDS-related cancers to liver disease and cardiovascular complications. Liver damage in PLWH could arise from multiple sources including co-infections, chronic substance use, and notably, antiretroviral therapy itself, which can be hepatotoxic. This review highlights the risks of hepatic damage associated with nucleoside and non-nucleoside RTIs and underscores the variability in hepatotoxicity risks among different drugs. It emphasizes the necessity for regular monitoring of liver health in PLWH and adjusting antiretroviral regimens to minimize liver fibrosis risk. This risk is particularly pronounced in patients who associate the infection with hepatitis B or C virus, where the potential for hepatotoxicity significantly increases.
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Affiliation(s)
| | - Gheorghe Iulian Diaconescu
- Victor Babes" Infectious Diseases and Pneumophtisiology Clinical Hospital, Craiova, Romania
- VITAPLUS Clinic, 200345 Craiova, Romania
| | - Florentina Dumitrescu
- Victor Babes" Infectious Diseases and Pneumophtisiology Clinical Hospital, Craiova, Romania
- Department of Infectious Diseases, University of Medicine and Pharmacy of Craiova, Romania
| | - Oanca Oana Docea
- Department of Toxicology, University of Medicine and Pharmacy of Craiova, Romania
| | - Radu Mitrut
- Doctoral School, University of Medicine and Pharmacy of Craiova, Romania
| | - Lucian Giubelan
- Victor Babes" Infectious Diseases and Pneumophtisiology Clinical Hospital, Craiova, Romania
- Department of Infectious Diseases, University of Medicine and Pharmacy of Craiova, Romania
| | - Ovidiu Zlatian
- Microbiology Department, University of Medicine and Pharmacy of Craiova, Romania
- Medical Laboratory, County clinical emergency hospital of Craiova, Romania
| | - Paul Mitrut
- Division of Internal Medicine, University of Medicine and Pharmacy of Craiova, Romania
- Department of Internal Medicine II, County Clinical Emergency Hospital, Craiova, Romania
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Kazaoka A, Fujimori S, Yamada Y, Shirayanagi T, Gao Y, Kuwahara S, Sakamoto N, Susukida T, Aoki S, Ito K. HLA-B*57:01-dependent intracellular stress in keratinocytes triggers dermal hypersensitivity reactions to abacavir. PNAS NEXUS 2024; 3:pgae140. [PMID: 38628599 PMCID: PMC11018537 DOI: 10.1093/pnasnexus/pgae140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Accepted: 03/26/2024] [Indexed: 04/19/2024]
Abstract
Specific human leukocyte antigen (HLA) polymorphisms combined with certain drug administration strongly correlate with skin eruption. Abacavir hypersensitivity (AHS), which is strongly associated with HLA-B*57:01, is one of the most representative examples. Conventionally, HLA transmits immunological signals via interactions with T cell receptors on the cell surface. This study focused on HLA-mediated intracellular reactions in keratinocytes that might determine the onset of skin immunotoxicity by drug treatments. Abacavir exposure resulted in keratinocytes expressing HLA-B*57:01 exhibiting endoplasmic reticulum (ER) stress responses, such as immediate calcium release into the cytosol and enhanced HSP70 expression. In contrast, keratinocytes expressing HLA-B*57:03 (closely related to HLA-B*57:01) did not show these changes. This indicated that HLA-B*57:01 has a specific intracellular response to abacavir in keratinocytes in the absence of lymphocytes. Furthermore, abacavir exposure in HLA-B*57:01-expressing keratinocytes elevated the expression of cytokines/chemokines such as interferon-γ, interleukin-1β, and CCL27, and induced T lymphoblast migration. These effects were suppressed by ER stress relief using 4-phenylbutyrate (4-PB). HLA-B*57:01-transgenic mice also exhibited ER stress in epidermal areas following abacavir administration, and abacavir-induced skin toxicity was attenuated by the administration of 4-PB. Moreover, abacavir bound to HLA-B*57:01 within cells and its exposure led to HLA-B*57:01 protein aggregation and interaction with molecular chaperones in the ER of keratinocytes. Our results underscore the importance of HLA-mediated intracellular stress responses in understanding the onset of HLA-B*57:01-mediated AHS. We provide the possibility that the intracellular behavior of HLA is crucial for determining the onset of drug eruptions.
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Affiliation(s)
- Akira Kazaoka
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan
| | - Sota Fujimori
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan
| | - Yushiro Yamada
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan
| | - Tomohiro Shirayanagi
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan
| | - Yuying Gao
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan
| | - Saki Kuwahara
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan
| | - Naoki Sakamoto
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan
| | - Takeshi Susukida
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan
- Laboratory of Cancer Biology and Immunology, Section of Host Defences, Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan
| | - Shigeki Aoki
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan
| | - Kousei Ito
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan
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Guin D, Kukreti R. Drug hypersensitivity linked to genetic variations of human leukocyte antigen. Ther Drug Monit 2024:387-417. [DOI: 10.1016/b978-0-443-18649-3.00018-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Huang X, Hu B, Ye L, Li T, He L, Tan W, Yang G, Liu JP, Guo C. Pharmacogenomics and adverse effects of anti-infective drugs in children. Clin Exp Pharmacol Physiol 2024; 51:3-9. [PMID: 37840030 DOI: 10.1111/1440-1681.13830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 08/23/2023] [Accepted: 09/25/2023] [Indexed: 10/17/2023]
Abstract
Children, as a special group, have their own peculiarities in terms of individualized medication use compared to adults. Adverse drug reactions have been an important issue that needs to be addressed in the hope of safe medication use in children, and the occurrence of adverse drug reactions is partly due to genetic factors. Anti-infective drugs are widely used in children, and they have always been an important cause of the occurrence of adverse reactions in children. Pharmacogenomic technologies are becoming increasingly sophisticated, and there are now many guidelines describing the pharmacogenomics of anti-infective drugs. However, data from paediatric-based studies are scarce. This review provides a systematic review of the pharmacogenomics of anti-infective drugs recommended for gene-guided use in CPIC guidelines by exploring the relationship between pharmacogenetic frequencies and the incidence of adverse reactions, which will help inform future studies of individualized medication use in children.
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Affiliation(s)
- Xin Huang
- Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Biwen Hu
- Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Ling Ye
- Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Tong Li
- Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Li He
- Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Wei Tan
- Department of Neonatology, Maternal & Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Guoping Yang
- Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Jun-Ping Liu
- Institute of Aging Research, Hangzhou Normal University School of Medicine, Zhejiang, China
- Department of Immunology, Monash University Faculty of Medicine, Prahran, Victoria, Australia
| | - Chengxian Guo
- Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, China
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7
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Kalidasan V, Kunalan I, Rajasuriar R, Subbiah VK, Das KT. HLA-B*57:01 typing in a Malaysian cohort: implications of abacavir hypersensitivity in people living with HIV. Pharmacogenomics 2023; 24:761-769. [PMID: 37767641 DOI: 10.2217/pgs-2023-0136] [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] [Indexed: 09/29/2023] Open
Abstract
Background: Abacavir (ABC) in combination with other antiretroviral drugs, is used to treat people living with HIV (PLWH). However, it is linked to a fatal hypersensitivity reaction in susceptible individuals, and is strongly associated with the HLA-B*57:01 allele. Materials & methods: A total of 152 patients, 50 PLWH and 102 HIV-1 negative patients, were assessed for the HLA-B*57:01 allele through a sequence-specific primer PCR. Results: All PLWH tested negative for the HLA-B*57:01 allele, but two HIV-negative patients were found to have HLA-B*57, with one of them expressing the HLA-B*57:01 allele. Conclusion: Given the low prevalence of this risk allele in the population, testing for the presence of HLA-B*57:01 in PLWH may not provide significant benefit for the reported population.
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Affiliation(s)
- V Kalidasan
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, 13200, Kepala Batas, Penang, Malaysia
| | - Iswarya Kunalan
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, 13200, Kepala Batas, Penang, Malaysia
- School of Biological Sciences, Universiti Sains Malaysia, 11700, Gelugor, Penang, Malaysia
| | - Reena Rajasuriar
- Department of Medicine, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia
- Centre of Excellence Research in AIDS (CERiA), Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia
| | - Vijay Kumar Subbiah
- Biotechnology Research Institute, Universiti Malaysia Sabah, 88400, Kota Kinabalu, Sabah, Malaysia
| | - Kumitaa Theva Das
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, 13200, Kepala Batas, Penang, Malaysia
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8
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Bruno PM, Timms RT, Abdelfattah NS, Leng Y, Lelis FJN, Wesemann DR, Yu XG, Elledge SJ. High-throughput, targeted MHC class I immunopeptidomics using a functional genetics screening platform. Nat Biotechnol 2023; 41:980-992. [PMID: 36593401 PMCID: PMC10314971 DOI: 10.1038/s41587-022-01566-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 10/13/2022] [Indexed: 01/03/2023]
Abstract
Identification of CD8+ T cell epitopes is critical for the development of immunotherapeutics. Existing methods for major histocompatibility complex class I (MHC class I) ligand discovery are time intensive, specialized and unable to interrogate specific proteins on a large scale. Here, we present EpiScan, which uses surface MHC class I levels as a readout for whether a genetically encoded peptide is an MHC class I ligand. Predetermined starting pools composed of >100,000 peptides can be designed using oligonucleotide synthesis, permitting large-scale MHC class I screening. We exploit this programmability of EpiScan to uncover an unappreciated role for cysteine that increases the number of predicted ligands by 9-21%, reveal affinity hierarchies by analysis of biased anchor peptide libraries and screen viral proteomes for MHC class I ligands. Using these data, we generate and iteratively refine peptide binding predictions to create EpiScan Predictor. EpiScan Predictor performs comparably to other state-of-the-art MHC class I peptide binding prediction algorithms without suffering from underrepresentation of cysteine-containing peptides. Thus, targeted immunopeptidomics using EpiScan will accelerate CD8+ T cell epitope discovery toward the goal of individual-specific immunotherapeutics.
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Affiliation(s)
- Peter M Bruno
- Department of Genetics, Harvard Medical School and Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA
- Howard Hughes Medical Institute, Chevy Chase, MD, USA
| | - Richard T Timms
- Department of Genetics, Harvard Medical School and Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA
- Howard Hughes Medical Institute, Chevy Chase, MD, USA
- Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK
| | - Nouran S Abdelfattah
- Department of Genetics, Harvard Medical School and Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA
- Howard Hughes Medical Institute, Chevy Chase, MD, USA
| | - Yumei Leng
- Department of Genetics, Harvard Medical School and Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA
- Howard Hughes Medical Institute, Chevy Chase, MD, USA
| | - Felipe J N Lelis
- Department of Medicine, Division of Allergy and Immunology, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Duane R Wesemann
- Department of Medicine, Division of Allergy and Immunology, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Massachusetts Consortium on Pathogen Readiness, Boston, MA, USA
| | - Xu G Yu
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
- Infectious Disease Division, Brigham and Women's Hospital, Boston, MA, USA
| | - Stephen J Elledge
- Department of Genetics, Harvard Medical School and Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA.
- Howard Hughes Medical Institute, Chevy Chase, MD, USA.
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Huan X, Zhuo N, Lee HY, Ren EC. Allopurinol non-covalently facilitates binding of unconventional peptides to HLA-B*58:01. Sci Rep 2023; 13:9373. [PMID: 37296297 PMCID: PMC10256732 DOI: 10.1038/s41598-023-36293-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 05/31/2023] [Indexed: 06/12/2023] Open
Abstract
Allopurinol, widely used in gout treatment, is the most common cause of severe cutaneous adverse drug reactions. The risk of developing such life-threatening reactions is increased particularly for HLA-B*58:01 positive individuals. However the mechanism of action between allopurinol and HLA remains unknown. We demonstrate here that a Lamin A/C peptide KAGQVVTI which is unable to bind HLA-B*58:01 on its own, is enabled to form a stable peptide-HLA complex only in the presence of allopurinol. Crystal structure analysis reveal that allopurinol non-covalently facilitated KAGQVVTI to adopt an unusual binding conformation, whereby the C-terminal isoleucine does not engage as a PΩ that typically fit deeply in the binding F-pocket. A similar observation, though to a lesser degree was seen with oxypurinol. Presentation of unconventional peptides by HLA-B*58:01 aided by allopurinol contributes to our fundamental understanding of drug-HLA interactions. The binding of peptides from endogenously available proteins such as self-protein lamin A/C and viral protein EBNA3B suggest that aberrant loading of unconventional peptides in the presence of allopurinol or oxypurinol may be able to trigger anti-self reactions that can lead to Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).
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Affiliation(s)
- Xuelu Huan
- Singapore Immunology Network (SigN), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Singapore, 138648, Singapore
| | - Nicole Zhuo
- Singapore Immunology Network (SigN), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Singapore, 138648, Singapore
| | - Haur Yueh Lee
- Allergy Center and Department of Dermatology, Singapore General Hospital, Singapore, 169608, Singapore
| | - Ee Chee Ren
- Singapore Immunology Network (SigN), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Singapore, 138648, Singapore.
- Department of Microbiology & Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117545, Singapore.
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Tripathi S, Khatri P, Fatima Z, Pandey RP, Hameed S. A Landscape of CRISPR/Cas Technique for Emerging Viral Disease Diagnostics and Therapeutics: Progress and Prospects. Pathogens 2022; 12:56. [PMID: 36678404 PMCID: PMC9863163 DOI: 10.3390/pathogens12010056] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/22/2022] [Accepted: 12/25/2022] [Indexed: 12/31/2022] Open
Abstract
Viral diseases have emerged as a serious threat to humanity and as a leading cause of morbidity worldwide. Many viral diagnostic methods and antiviral therapies have been developed over time, but we are still a long way from treating certain infections caused by viruses. Acquired immunodeficiency syndrome (AIDS) is one of the challenges where current medical science advancements fall short. As a result, new diagnostic and treatment options are desperately needed. The CRISPR/Cas9 system has recently been proposed as a potential therapeutic approach for viral disease treatment. CRISPR/Cas9 is a specialised, effective, and adaptive gene-editing technique that can be used to modify, delete, or correct specific DNA sequences. It has evolved into an advanced, configurable nuclease-based single or multiple gene-editing tool with a wide range of applications. It is widely preferred simply because its operational procedures are simple, inexpensive, and extremely efficient. Exploration of infectious virus genomes is required for a comprehensive study of infectious viruses. Herein, we have discussed the historical timeline-based advancement of CRISPR, CRISPR/Cas9 as a gene-editing technology, the structure of CRISPR, and CRISPR as a diagnostic tool for studying emerging viral infections. Additionally, utilizing CRISPR/Cas9 technology to fight viral infections in plants, CRISPR-based diagnostics of viruses, pros, and cons, and bioethical issues of CRISPR/Cas9-based genomic modification are discussed.
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Affiliation(s)
- Shyam Tripathi
- Centre for Drug Design Discovery and Development (C4D), SRM University, Delhi-NCR, Rajiv Gandhi Education City, Sonepat 131029, India
| | - Purnima Khatri
- Centre for Drug Design Discovery and Development (C4D), SRM University, Delhi-NCR, Rajiv Gandhi Education City, Sonepat 131029, India
- Department of Microbiology, SRM University, Delhi-NCR, Rajiv Gandhi Education City, Sonepat 131029, India
| | - Zeeshan Fatima
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, Bisha 61922, Saudi Arabia
- Amity Institute of Biotechnology, Amity University Haryana, Gurugram 122413, India
| | - Ramendra Pati Pandey
- Centre for Drug Design Discovery and Development (C4D), SRM University, Delhi-NCR, Rajiv Gandhi Education City, Sonepat 131029, India
- Department of Microbiology, SRM University, Delhi-NCR, Rajiv Gandhi Education City, Sonepat 131029, India
| | - Saif Hameed
- Amity Institute of Biotechnology, Amity University Haryana, Gurugram 122413, India
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11
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Dashti M, Al-Matrouk A, Channanath A, Hebbar P, Al-Mulla F, Thanaraj TA. Distribution of HLA-B Alleles and Haplotypes in Qatari: Recommendation for Establishing Pharmacogenomic Markers Screening for Drug Hypersensitivity. Front Pharmacol 2022; 13:891838. [PMID: 36003520 PMCID: PMC9393242 DOI: 10.3389/fphar.2022.891838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 06/14/2022] [Indexed: 11/18/2022] Open
Abstract
Human leukocyte antigen (HLA) proteins are present at the cellular surface of antigen-presenting cells and play a crucial role in the adaptive immune response. Class I genes, specifically certain HLA-B alleles, are associated with adverse drug reactions (ADRs) and are used as pharmacogenetic markers. Although ADRs are a common causes of hospitalization and mortality, the data on the prevalence of HLA-B pharmacogenetics markers in Arab countries are scarce. In this study, we investigated the frequencies of major HLA-B pharmacogenomics markers in the Qatari population. Next-generation sequencing data from 1,098 Qatari individuals were employed for HLA-B typing using HLA-HD version 1.4.0 and IPD-IMGT/HLA database. In addition, HLA-B pharmacogenetics markers were obtained from the HLA Adverse Drug Reaction Database. In total, 469 major HLA-B pharmacogenetic markers were identified, with HLA-B*51:01 being the most frequent pharmacogenetic marker (26.67%) in the Qatari population. Moreover, HLA-B*51:01 is associated with phenytoin- and clindamycin-induced ADRs. The second most frequent pharmacogenetic marker was the HLA-B*58:01 allele (6.56%), which is associated with allopurinol-induced ADRs. The third most frequent pharmacogenetic marker was the HLA-B*44:03 allele, which is associated with phenytoin-induced ADRs. The establishment of a pharmacogenetics screening program in Qatar for cost effective interventions aimed at preventing drug-induced hypersensitivity can be aided by the highly prevalent HLA-B pharmacogenetic markers detected here.
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Affiliation(s)
- Mohammed Dashti
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Abdullah Al-Matrouk
- Narcotic and Psychotropic Department, Ministry of Interior, Farwaniya, Kuwait
| | - Arshad Channanath
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Prashantha Hebbar
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Fahd Al-Mulla
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City, Kuwait
- *Correspondence: Fahd Al-Mulla, ; Thangavel Alphonse Thanaraj,
| | - Thangavel Alphonse Thanaraj
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City, Kuwait
- *Correspondence: Fahd Al-Mulla, ; Thangavel Alphonse Thanaraj,
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12
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Sibiya T, Ghazi T, Chuturgoon A. The Potential of Spirulina platensis to Ameliorate the Adverse Effects of Highly Active Antiretroviral Therapy (HAART). Nutrients 2022; 14:nu14153076. [PMID: 35893930 PMCID: PMC9332774 DOI: 10.3390/nu14153076] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 05/31/2022] [Accepted: 06/03/2022] [Indexed: 12/04/2022] Open
Abstract
The human immunodeficiency virus (HIV) is one of the most prevalent diseases globally. It is estimated that 37.7 million people are infected with HIV globally, and 8.2 million persons are infected with the virus in South Africa. The highly active antiretroviral therapy (HAART) involves combining various types of antiretroviral drugs that are dependent on the infected person’s viral load. HAART helps regulate the viral load and prevents its associated symptoms from progressing into acquired immune deficiency syndrome (AIDS). Despite its success in prolonging HIV-infected patients’ lifespans, the use of HAART promotes metabolic syndrome (MetS) through an inflammatory pathway, excess production of reactive oxygen species (ROS), and mitochondrial dysfunction. Interestingly, Spirulina platensis (SP), a blue-green microalgae commonly used as a traditional food by Mexican and African people, has been demonstrated to mitigate MetS by regulating oxidative and inflammatory pathways. SP is also a potent antioxidant that has been shown to exhibit immunological, anticancer, anti-inflammatory, anti-aging, antidiabetic, antibacterial, and antiviral properties. This review is aimed at highlighting the biochemical mechanism of SP with a focus on studies linking SP to the inhibition of HIV, inflammation, and oxidative stress. Further, we propose SP as a potential supplement for HIV-infected persons on lifelong HAART.
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13
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Elzagallaai AA, Rieder MJ. Genetic markers of drug hypersensitivity in pediatrics: current state and promise. Expert Rev Clin Pharmacol 2022; 15:715-728. [DOI: 10.1080/17512433.2022.2100345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Affiliation(s)
- Abdelbaset A Elzagallaai
- Department of Paediatrics Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
- Department of Physiology and Pharmacology Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Michael J Rieder
- Department of Physiology and Pharmacology Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
- Robarts Research Institute, Western University, London, Ontario, Canada
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14
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Reizine N, O’Donnell PH. Modern developments in germline pharmacogenomics for oncology prescribing. CA Cancer J Clin 2022; 72:315-332. [PMID: 35302652 PMCID: PMC9262778 DOI: 10.3322/caac.21722] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 01/15/2022] [Accepted: 01/21/2022] [Indexed: 02/06/2023] Open
Abstract
The integration of genomic data into personalized treatment planning has revolutionized oncology care. Despite this, patients with cancer remain vulnerable to high rates of adverse drug events and medication inefficacy, affecting prognosis and quality of life. Pharmacogenomics is a field seeking to identify germline genetic variants that contribute to an individual's unique drug response. Although there is widespread integration of genomic information in oncology, somatic platforms, rather than germline biomarkers, have dominated the attention of cancer providers. Patients with cancer potentially stand to benefit from improved integration of both somatic and germline genomic information, especially because the latter may complement treatment planning by informing toxicity risk for drugs with treatment-limiting tolerabilities and narrow therapeutic indices. Although certain germline pharmacogenes, such as TPMT, UGT1A1, and DPYD, have been recognized for decades, recent attention has illuminated modern potential dosing implications for a whole new set of anticancer agents, including targeted therapies and antibody-drug conjugates, as well as the discovery of additional genetic variants and newly relevant pharmacogenes. Some of this information has risen to the level of directing clinical action, with US Food and Drug Administration label guidance and recommendations by international societies and governing bodies. This review is focused on key new pharmacogenomic evidence and oncology-specific dosing recommendations. Personalized oncology care through integrated pharmacogenomics represents a unique multidisciplinary collaboration between oncologists, laboratory science, bioinformatics, pharmacists, clinical pharmacologists, and genetic counselors, among others. The authors posit that expanded consideration of germline genetic information can further transform the safe and effective practice of oncology in 2022 and beyond.
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Affiliation(s)
- Natalie Reizine
- Division of Hematology and Oncology, Department of Medicine, The University of Illinois at Chicago
| | - Peter H. O’Donnell
- Section of Hematology/Oncology, Department of Medicine, Center for Personalized Therapeutics, and Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago
- Correspondence to: Dr. Peter H. O’Donnell, Section of Hematology/Oncology, Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, MC2115, Chicago, IL 60637, USA. ()
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15
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Shirayanagi T, Kazaoka A, Watanabe K, Qu L, Sakamoto N, Hoshino T, Ito K, Aoki S. Weak complex formation of adverse drug reaction-associated HLAB57, B58, and B15 molecules. Toxicol In Vitro 2022; 82:105383. [PMID: 35568130 DOI: 10.1016/j.tiv.2022.105383] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 05/04/2022] [Accepted: 05/09/2022] [Indexed: 10/18/2022]
Abstract
The combination of certain human leukocyte antigen (HLA) polymorphisms with administration of certain drugs shows a strong correlation with developing drug hypersensitivity. Examples of typical combinations are HLA-B*57:01 with abacavir and HLA-B*15:02 with carbamazepine. However, despite belonging to the same serotype, HLA-B*57:03 and HLA-B*15:01 are not associated with drug hypersensitivity. Recent studies have shown that several HLA polymorphisms are associated with multiple drugs rather than a single drug, all resulting in drug hypersensitivity. In this study, we compared the molecular structures and intracellular localization of HLA-B*57:01, HLA-B*58:01, and HLA-B*15:02, which pose risks for developing drug hypersensitivity, as well as HLA-B*57:03 and HLA-B*15:01 that do not present such risks. We found that HLA molecules posing risks have a low affinity for the subunit β2-microglobulin; notably, the weak hydrogen bond formed via Gln96 of the HLA molecule contributes to this behavior. We also clarified that these HLA molecules are easily accumulated in the endoplasmic reticulum, exhibiting a low expression on the cell surface. Considering that these hypersensitivity risk-associated HLA molecules form complexes with β2-microglobulin and peptides in the endoplasmic reticulum, we assumed that their low complex formation ability in the endoplasmic reticulum facilitates the interaction with multiple drugs.
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Affiliation(s)
- Tomohiro Shirayanagi
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-city, Chiba 260-8675, Japan
| | - Akira Kazaoka
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-city, Chiba 260-8675, Japan
| | - Kenji Watanabe
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-city, Chiba 260-8675, Japan
| | - Liang Qu
- Department of Physical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-city, Chiba 260-8675, Japan
| | - Naoki Sakamoto
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-city, Chiba 260-8675, Japan
| | - Tyuji Hoshino
- Department of Physical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-city, Chiba 260-8675, Japan
| | - Kousei Ito
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-city, Chiba 260-8675, Japan
| | - Shigeki Aoki
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-city, Chiba 260-8675, Japan.
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16
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Proteomic Profiling and T Cell Receptor Usage of Abacavir Susceptible Subjects. Biomedicines 2022; 10:biomedicines10030693. [PMID: 35327495 PMCID: PMC8945713 DOI: 10.3390/biomedicines10030693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 03/16/2022] [Accepted: 03/16/2022] [Indexed: 01/27/2023] Open
Abstract
Type B adverse drug reactions (ADRs) represent a significant threat as their occurrence arises unpredictable and despite proper application of the drug. The severe immune reaction Abacavir Hypersensitivity Syndrome (AHS) that arises in HIV+ patients treated with the antiretroviral drug Abacavir (ABC) strongly correlates to the presence of the human leukocyte antigen (HLA) genotype HLA-B*57:01 and discriminates HLA-B*57:01+ HIV+ patients from ABC treatment. However, not all HLA-B*57:01+ HIV+ patients are affected by AHS, implying the involvement of further patient-specific factors in the development of AHS. The establishment of a reliable assay to classify HLA-B*57:01 carriers as ABC sensitive or ABC tolerant allowed to investigate the T cell receptor (TCR) Vβ chain repertoire of effector cells and revealed Vβ6 and Vβ24 as potential public TCRs in ABC sensitive HLA-B*57:01 carriers. Furthermore, distinct effects of ABC on the cellular proteome of ABC sensitive and tolerant volunteers were observed and suggest enhanced activation and maturation of dentritic cells (DC) in ABC sensitive volunteers. Analysis of ABC-naïve cellular proteomes identified the T cell immune regulator 1 (TCIRG1) as a potential prognostic biomarker for ABC susceptibility and the involvement of significantly upregulated proteins, particularly in peptide processing, antigen presentation, interferon (IFN), and cytokine regulation.
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17
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Kuruvilla R, Scott K, Pirmohamed SM. Pharmacogenomics of Drug Hypersensitivity. Immunol Allergy Clin North Am 2022; 42:335-355. [DOI: 10.1016/j.iac.2022.01.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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18
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Unravelling the Proteomics of HLA-B*57:01+ Antigen Presenting Cells during Abacavir Medication. J Pers Med 2022; 12:jpm12010040. [PMID: 35055355 PMCID: PMC8781935 DOI: 10.3390/jpm12010040] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 12/21/2021] [Accepted: 12/30/2021] [Indexed: 12/19/2022] Open
Abstract
Type B adverse drug reactions (ADRs) are unpredictable based on the drug’s pharmacology and represent a key challenge in pharmacovigilance. For human leukocyte antigen (HLA)-mediated type B ADRs, it is assumed that the protein/small-molecule interaction alters the biophysical and mechanistic properties of the antigen presenting cells. Sophisticated methods enabled the molecular appreciation of HLA-mediated ADRs; in several instances, the drug molecule occupies part of the HLA peptide binding groove and modifies the recruited peptide repertoire thereby causing a strong T-cell-mediated immune response that is resolved upon withdrawal of medication. The severe ADR in HLA-B*57:01+ patients treated with the antiretroviral drug abacavir (ABC) in anti-HIV therapy is an example of HLA-drug-T cell cooperation. However, the long-term damages of the HLA-B*57:01-expressing immune cells following ABC treatment remain unexplained. Utilizing full proteome sequencing following ABC treatment of HLA-B*57:01+ cells, we demonstrate stringent proteomic alteration of the HLA/drug presenting cells. The proteomic content indisputably reflects the cellular condition; this knowledge directs towards individual pharmacovigilance for the development of personalized and safe medication.
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19
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The PD1 inhibitory pathway and mature dendritic cells contribute to abacavir hypersensitivity in human leukocyte antigen transgenic PD1 knockout mice. Toxicology 2021; 463:152971. [PMID: 34606953 DOI: 10.1016/j.tox.2021.152971] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 09/24/2021] [Accepted: 09/29/2021] [Indexed: 11/23/2022]
Abstract
Based on recent genome-wide association studies, abacavir-induced hypersensitivity is highly associated with human leukocyte antigen (HLA)-B*57:01 allele. However, the underlying mechanism of this occurrence is unclear. To investigate the underlying mechanism, we developed HLA-B*57:01 transgenic mice and found that application of abacavir could cause CD8 T cell activation with elevation in PD1 expression; however, severe skin hypersensitivity was not observed. To eliminate the immunosuppressive effect of PD1, HLA-B*57:01 transgenic/PD1 knockout (01Tg/PD1) mice were generated by mating HLA-B*57:01 transgenic mice and PD1 knockout mice. Thereafter, 01Tg/PD1 mice were treated with abacavir. Similar to the above results, severe skin hypersensitivity was not observed. Therefore, we treated 01Tg/PD1 mice with an anti-CD4 antibody to deplete CD4 T cells, followed by abacavir topically and orally. Severe abacavir-induced skin hypersensitivity was observed in 01Tg/PD1 mice after depletion of CD4 T cells, in addition to significant CD8 T cell activation and dendritic cell maturation. Taken together, we succeeded in reproducing severe skin hypersensitivity in a mouse model. And we found that through the combined depletion of PD1 and CD4 T cells, CD8 T cells could be activated and could proceed to clonal proliferation, which is promoted by mature dendritic cells, thereby eventually inducing severe skin hypersensitivity.
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20
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Regulation of the immune tolerance system determines the susceptibility to HLA-mediated abacavir-induced skin toxicity. Commun Biol 2021; 4:1137. [PMID: 34584206 PMCID: PMC8479119 DOI: 10.1038/s42003-021-02657-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 09/10/2021] [Indexed: 01/11/2023] Open
Abstract
Idiosyncratic drug toxicity (IDT) associated with specific human leukocyte antigen (HLA) allotype is a rare and unpredictable life-threatening adverse drug reaction for which prospective mechanistic studies in humans are difficult. Here, we show the importance of immune tolerance for IDT onset and determine whether it is susceptible to a common IDT, HLA-B*57:01-mediated abacavir (ABC)-induced hypersensitivity (AHS), using CD4+ T cell-depleted programmed death-1 receptor (PD-1)-deficient HLA-B*57:01 transgenic mice (B*57:01-Tg/PD-1−/−). Although AHS is not observed in B*57:01-Tg mice, ABC treatment increases the proportion of cytokine- and cytolytic granule-secreting effector memory CD8+ T cells in CD4+ T cell-depleted B*57:01-Tg/PD-1−/− mice, thereby inducing skin toxicity with CD8+ T cell infiltration, mimicking AHS. Our results demonstrate that individual differences in the immune tolerance system, including PD-1highCD8+ T cells and regulatory CD4+ T cells, may affect the susceptibility of humans to HLA-mediated IDT in humans. Using a transgenic mouse model that recapitulates abacavir hypersensitivity syndrome, an idiosyncratic adverse drug reaction, Susukida et al show that individual differences in the immune tolerance system affect the susceptibility to idiosyncratic drug toxicity.
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21
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Illing PT, van Hateren A, Darley R, Croft NP, Mifsud NA, King S, Kostenko L, Bharadwaj M, McCluskey J, Elliott T, Purcell AW. Kinetics of Abacavir-Induced Remodelling of the Major Histocompatibility Complex Class I Peptide Repertoire. Front Immunol 2021; 12:672737. [PMID: 34093574 PMCID: PMC8170132 DOI: 10.3389/fimmu.2021.672737] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 04/26/2021] [Indexed: 12/14/2022] Open
Abstract
Abacavir hypersensitivity syndrome can occur in individuals expressing the HLA-B*57:01 major histocompatibility complex class I allotype when utilising the drug abacavir as a part of their anti-retroviral regimen. The drug is known to bind within the HLA-B*57:01 antigen binding cleft, leading to the selection of novel self-peptide ligands, thus provoking life-threatening immune responses. However, the sub-cellular location of abacavir binding and the mechanics of altered peptide selection are not well understood. Here, we probed the impact of abacavir on the assembly of HLA-B*57:01 peptide complexes. We show that whilst abacavir had minimal impact on the maturation or average stability of HLA-B*57:01 molecules, abacavir was able to differentially enhance the formation, selectively decrease the dissociation, and alter tapasin loading dependency of certain HLA-B*57:01-peptide complexes. Our data reveals a spectrum of abacavir mediated effects on the immunopeptidome which reconciles the heterogeneous functional T cell data reported in the literature.
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Affiliation(s)
- Patricia T. Illing
- Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
| | - Andy van Hateren
- Institute for Life Sciences and Centre for Cancer Immunology, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Rachel Darley
- Institute for Life Sciences and Centre for Cancer Immunology, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Nathan P. Croft
- Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
| | - Nicole A. Mifsud
- Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
| | - Samuel King
- Institute for Life Sciences and Centre for Cancer Immunology, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Lyudmila Kostenko
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC, Australia
| | - Mandvi Bharadwaj
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC, Australia
| | - James McCluskey
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC, Australia
| | - Tim Elliott
- Institute for Life Sciences and Centre for Cancer Immunology, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
- Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Anthony W. Purcell
- Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
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22
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Russell LE, Zhou Y, Almousa AA, Sodhi JK, Nwabufo CK, Lauschke VM. Pharmacogenomics in the era of next generation sequencing - from byte to bedside. Drug Metab Rev 2021; 53:253-278. [PMID: 33820459 DOI: 10.1080/03602532.2021.1909613] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Pharmacogenetic research has resulted in the identification of a multitude of genetic variants that impact drug response or toxicity. These polymorphisms are mostly common and have been included as actionable information in the labels of numerous drugs. In addition to common variants, recent advances in Next Generation Sequencing (NGS) technologies have resulted in the identification of a plethora of rare and population-specific pharmacogenetic variations with unclear functional consequences that are not accessible by conventional forward genetics strategies. In this review, we discuss how comprehensive sequencing information can be translated into personalized pharmacogenomic advice in the age of NGS. Specifically, we provide an update of the functional impacts of rare pharmacogenetic variability and how this information can be leveraged to improve pharmacogenetic guidance. Furthermore, we critically discuss the current status of implementation of pharmacogenetic testing across drug development and layers of care. We identify major gaps and provide perspectives on how these can be minimized to optimize the utilization of NGS data for personalized clinical decision-support.
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Affiliation(s)
| | - Yitian Zhou
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Ahmed A Almousa
- Department of Pharmacy, London Health Sciences Center, Victoria Hospital, London, ON, Canada
| | - Jasleen K Sodhi
- Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California San Francisco, San Francisco, CA, USA.,Department of Drug Metabolism and Pharmacokinetics, Plexxikon, Inc., Berkeley, CA, USA
| | | | - Volker M Lauschke
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
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23
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Abacavir adverse reactions related with HLA-B*57: 01 haplotype in a large cohort of patients infected with HIV. Pharmacogenet Genomics 2021; 30:167-174. [PMID: 32453265 DOI: 10.1097/fpc.0000000000000409] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE Carriage of human leukocyte antigen (HLA)-B*57:01 allele increases the risk of abacavir hypersensitivity reaction. Therefore, since 2008 HIV treatment guidelines recommend HLA-B*57:01 screening before abacavir administration, greatly reducing hypersensitivity reaction rate. However, clinically suspected abacavir-related hypersensitivity reactions are described in allele non-carriers. Major aim of this study was to evaluate the relationship between HLA-B*57:01 pattern and abacavir-related hypersensitivity reaction, focusing on hypersensitivity reaction prevalence in allele non-carriers. METHODS We included all outpatients aged >18 years old with HIV infection and known HLA-B*57:01 pattern, followed at our Department from January 2000 until December 2017. Patients were divided according to HLA-B*57:01 pattern and first antiretroviral treatment prescribed (containing or not abacavir) as follows: HLA-B*57:01 allele carriers treated with abacavir and HLA-B*57:01 allele non-carriers treated with abacavir. We considered all adverse events reported during first abacavir administration, differentiating between confirmed hypersensitivity reactions and non-hypersensitivity reactions, according to abacavir hypersensitivity reaction definition included in the abacavir EU Summary of Product Characteristics and the US Prescribing Information. RESULTS A total of 3144 patients had a known HLA-B*57:01 pattern. About 5.4% of them showed allele polymorphism; Caucasian ethnicity was the most represented. In this cohort, 1801 patients were treated with a first abacavir-containing regimen (98.2% of them was represented by allele non-carriers). 191 out of 1801 patients discontinued abacavir because of toxicity/intolerance; among them 107 described adverse events fulfilled the criteria of confirmed abacavir hypersensitivity reaction (22/32 allele-positive patients and 85/1769 allele-negative patients). After having experienced a confirmed abacavir hypersensitivity reaction, abacavir was re-administered to eight HLA-B*57:01 negative patients. Seven of them re-experienced a syndrome consistent with hypersensitivity reaction, finally leading to drug discontinuation. Overall, no fatal reactions were described. CONCLUSION Not all abacavir-related side effects occur as a result of classic HLA-B*57:01-mediated hypersensitivity reaction, as they can develop irrespective of HLA-B*57:01 status. Clinical vigilance must be an essential part of the management of individuals starting abacavir, at any time during treatment. In a 'real-life' setting, clinical diagnosis of suspected abacavir hypersensitivity reaction in allele non-carriers remains crucial for further clinical decision making.
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24
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Adair K, Meng X, Naisbitt DJ. Drug hapten-specific T-cell activation: Current status and unanswered questions. Proteomics 2021; 21:e2000267. [PMID: 33651918 DOI: 10.1002/pmic.202000267] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 02/14/2021] [Accepted: 02/16/2021] [Indexed: 11/07/2022]
Abstract
Drug haptens are formed from the irreversible, covalent binding of drugs to nucleophilic moieties on proteins, which can warrant adverse reactions in the body including severe delayed-type, T-cell mediated, drug hypersensitivity reactions (DHRs). While three main pathways exist for the activation of T-cells in DHRs, namely the hapten model, the pharmacological interaction model and the altered peptide repertoire model, the exact antigenic determinants responsible have not yet been defined. In recent years, progress has been made using advanced mass spectrometry-based proteomic methods to identify protein carriers and characterise the structure of drug-haptenated proteins. Since genome-wide association studies discovered a link between human leukocyte antigens (HLA) and an individual's susceptibility to DHRs, much effort has been made to define the drug-associated HLA ligands driving T-cell activation, including the elution of natural HLA peptides from HLA molecules and the generation of HLA-binding peptides. In this review, we discuss our current methodology used to design and synthesise drug-modified HLA ligands to investigate their immunogenicity using T-cell models, and thus their implication in drug hypersensitivity.
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Affiliation(s)
- Kareena Adair
- Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK
| | - Xiaoli Meng
- Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK
| | - Dean J Naisbitt
- Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK
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25
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Doña I, Jurado-Escobar R, Pérez-Sánchez N, Laguna JJ, Bartra J, Testera-Montes A, de Santa María RS, Torres MJ, Cornejo-García JA. Genetic Variants Associated With Drug-Induced Hypersensitivity Reactions: towards Precision Medicine? CURRENT TREATMENT OPTIONS IN ALLERGY 2021. [DOI: 10.1007/s40521-020-00278-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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26
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Tong H, Phan NVT, Nguyen TT, Nguyen DV, Vo NS, Le L. Review on Databases and Bioinformatic Approaches on Pharmacogenomics of Adverse Drug Reactions. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2021; 14:61-75. [PMID: 33469342 PMCID: PMC7812041 DOI: 10.2147/pgpm.s290781] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 12/26/2020] [Indexed: 12/27/2022]
Abstract
Pharmacogenomics has been used effectively in studying adverse drug reactions by determining the person-specific genetic factors associated with individual response to a drug. Current approaches have revealed the significant importance of sequencing technologies and sequence analysis strategies for interpreting the contribution of genetic variation in developing adverse reactions. Advance in next generation sequencing and platform brings new opportunities in validating the genetic candidates in certain reactions, and could be used to develop the preemptive tests to predict the outcome of the variation in a personal response to a drug. With the highly accumulated available data recently, the in silico approach with data analysis and modeling plays as other important alternatives which significantly support the final decisions in the transformation from research to clinical applications such as diagnosis and treatments for various types of adverse responses.
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Affiliation(s)
- Hang Tong
- School of Biotechnology, International University, Ho Chi Minh City, Vietnam.,Vietnam National University, Ho Chi Minh City, Vietnam
| | - Nga V T Phan
- School of Biotechnology, International University, Ho Chi Minh City, Vietnam.,Vietnam National University, Ho Chi Minh City, Vietnam
| | - Thanh T Nguyen
- Department of Translational Biomedical Informatics, Vingroup Big Data Institute, Hanoi, Vietnam
| | - Dinh V Nguyen
- Department of Respiratory, Allergy and Clinical Immunology, Vinmec International Hospital, Hanoi, Vietnam.,College of Health Sciences, VinUniversity, Hanoi, Vietnam
| | - Nam S Vo
- Department of Translational Biomedical Informatics, Vingroup Big Data Institute, Hanoi, Vietnam
| | - Ly Le
- School of Biotechnology, International University, Ho Chi Minh City, Vietnam.,Vietnam National University, Ho Chi Minh City, Vietnam.,Department of Translational Biomedical Informatics, Vingroup Big Data Institute, Hanoi, Vietnam
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27
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Manson LEN, Swen JJ, Guchelaar HJ. Diagnostic Test Criteria for HLA Genotyping to Prevent Drug Hypersensitivity Reactions: A Systematic Review of Actionable HLA Recommendations in CPIC and DPWG Guidelines. Front Pharmacol 2020; 11:567048. [PMID: 33071783 PMCID: PMC7538700 DOI: 10.3389/fphar.2020.567048] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 08/25/2020] [Indexed: 12/19/2022] Open
Abstract
Introduction Certain HLA variants are associated with an increased risk of hypersensitivity reactions to specific drugs. Both the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) have issued actionable HLA gene - drug interaction guidelines but diagnostic test criteria remain largely unknown. We present an overview of the diagnostic test criteria of the actionable HLA - drug pairs. Methods A systematic literature search was conducted in PubMed, Embase, Web of Science and Cochrane Library. Original case-control and cohort studies were selected and sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and number needed to genotype (NNG) were calculated for the actionable HLA-drug pairs. Results In general, the HLA tests show high specificity and NPV for predicting hypersensitivity reactions. The sensitivity of HLA tests shows a wide range, from 0-33% for HLA-B*1502 testing to predict lamotrigine induced SJS/TEN up to 100% for HLA-B*5701 to predict immunologically confirmed abacavir hypersensitivity syndrome (ABC-HSR). PPV is low for all tests except for HLA-B*5701 and ABC-HSR which is approximately 50%. HLA-B*5701 to predict ABC-HSR shows the lowest NNG followed by HLA-B*5801 for allopurinol induced severe cutaneous adverse drug reactions and HLA-B*1502 for carbamazepine induced SJS/TEN. Discussion This is the first overview of diagnostic test criteria for actionable HLA-drug pairs. Studies researching HLA genes and hypersensitivity are scarce for some of the HLA-drug pairs in some populations and patient numbers in studies are small. Therefore, more research is necessary to calculate the diagnostic test criteria more accurately.
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Affiliation(s)
- Lisanne E N Manson
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, Netherlands.,Leiden Network for Personalized Therapeutics, Leiden, Netherlands
| | - Jesse J Swen
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, Netherlands.,Leiden Network for Personalized Therapeutics, Leiden, Netherlands
| | - Henk-Jan Guchelaar
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, Netherlands.,Leiden Network for Personalized Therapeutics, Leiden, Netherlands
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28
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Susukida T, Aoki S, Shirayanagi T, Yamada Y, Kuwahara S, Ito K. HLA transgenic mice: application in reproducing idiosyncratic drug toxicity. Drug Metab Rev 2020; 52:540-567. [PMID: 32847422 DOI: 10.1080/03602532.2020.1800725] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Various types of transgenic mice carrying either class I or II human leukocyte antigen (HLA) molecules are readily available, and reports describing their use in a variety of studies have been published for more than 30 years. Examples of their use include the discovery of HLA-specific antigens against viral infection as well as the reproduction of HLA-mediated autoimmune diseases for the development of therapeutic strategies. Recently, HLA transgenic mice have been used to reproduce HLA-mediated idiosyncratic drug toxicity (IDT), a rare and unpredictable adverse drug reaction that can result in death. For example, abacavir-induced IDT has successfully been reproduced in HLA-B*57:01 transgenic mice. Several reports using HLA transgenic mice for IDT have proven the utility of this concept for the evaluation of IDT using various HLA allele combinations and drugs. It has become apparent that such models may be a valuable tool to investigate the mechanisms underlying HLA-mediated IDT. This review summarizes the latest findings in the area of HLA transgenic mouse models and discusses the current challenges that must be overcome to maximize the potential of this unique animal model.
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Affiliation(s)
- Takeshi Susukida
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.,Laboratory of Cancer Biology and Immunology, Section of Host Defenses, Institute of Natural Medicine, University of Toyama, Toyama, Japan
| | - Shigeki Aoki
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Tomohiro Shirayanagi
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Yushiro Yamada
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Saki Kuwahara
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Kousei Ito
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
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29
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Pillaye JN, Marakalala MJ, Khumalo N, Spearman W, Ndlovu H. Mechanistic insights into antiretroviral drug-induced liver injury. Pharmacol Res Perspect 2020; 8:e00598. [PMID: 32643320 PMCID: PMC7344109 DOI: 10.1002/prp2.598] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 04/16/2020] [Indexed: 12/19/2022] Open
Abstract
All classes of antiretroviral therapy (ART) have been implicated to induce adverse drug reactions such drug-induced liver injury (DILI) and immune-mediated adverse reactions in Human Immunodeficiency Virus (HIV) infected individuals. Patients that develop adverse drug reactions tend to have prolonged stays in hospital and may require to change to alternative regimens if reactions persist upon rechallenge or if rechallenge is contraindicated due to severity of the adverse reaction. Diagnosis of DILI remains a huge obstacle that delays timely interventions, since it is still based largely on exclusion of other causes. There is an urgent need to develop robust diagnostic and predictive biomarkers that could be used alongside the available tools (biopsy, imaging, and serological tests for liver enzymes) to give a specific diagnosis of DILI. Crucial to this is also achieving consensus in the definition of DILI so that robust studies can be undertaken. Importantly, it is crucial that we gain deeper insights into the mechanism of DILI so that patients can receive appropriate management. In general, it has been demonstrated that the mechanism of ART-induced liver injury is driven by four main mechanisms: mitochondrial toxicity, metabolic host-mediated injury, immune reconstitution, and hypersensitivity reactions. The focus of this review is to discuss the type and phenotypes of DILI that are caused by the first line ART regimens. Furthermore, we will summarize recent studies that have elucidated the cellular and molecular mechanisms of DILI both in vivo and in vitro.
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Affiliation(s)
- Jamie N. Pillaye
- Division of Chemical and System BiologyDepartment of Integrative Biomedical SciencesFaculty of Health SciencesUniversity of Cape TownCape TownSouth Africa
| | - Mohlopheni J. Marakalala
- Africa Health Research InstituteDurbanKwaZulu NatalSouth Africa
- Division of Infection and ImmunityUniversity College LondonLondonUK
| | - Nonhlanhla Khumalo
- Hair and Skin Research LabDivision of DermatologyDepartment of MedicineGroote Schuur Hospital and University of Cape TownCape TownSouth Africa
| | - Wendy Spearman
- Division of HepatologyDepartment of MedicineGroote Schuur Hospital and University of Cape TownCape TownSouth Africa
| | - Hlumani Ndlovu
- Division of Chemical and System BiologyDepartment of Integrative Biomedical SciencesFaculty of Health SciencesUniversity of Cape TownCape TownSouth Africa
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30
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Zhou Y, Krebs K, Milani L, Lauschke VM. Global Frequencies of Clinically Important HLA Alleles and Their Implications For the Cost-Effectiveness of Preemptive Pharmacogenetic Testing. Clin Pharmacol Ther 2020; 109:160-174. [PMID: 32535895 DOI: 10.1002/cpt.1944] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 06/01/2020] [Indexed: 01/06/2023]
Abstract
Immune-mediated drug hypersensitivity reactions are an important source of iatrogenic morbidity and mortality. Human leukocyte antigen (HLA)-B*57:01, HLA-B*15:02, HLA-A*31:01, and HLA-B*58:01 constitute established risk factors and preemptive genotyping of these HLA alleles in patients prior to the initiation of abacavir, carbamazepine, and allopurinol-based therapies can prevent toxicity and improve patient outcomes. However, the cost-effectiveness of preemptive HLA testing has only been evaluated in the United States and few countries in Europe and Asia. In this study, we consolidated HLA genotypes from 3.5-6.4 million individuals across up to 74 countries and modeled the country-specific cost-effectiveness of genetic testing. We find major ethnogeographic differences in risk allele prevalence, which translated into pronounced differences in the number of patients needed to test to prevent one case of severe hypersensitivity reactions between countries and populations. At incremental cost-effectiveness ratio thresholds of $40,000, testing of HLA-B*57:01 in patients initiating abacavir was cost-effective in the majority of countries with potential exceptions of East Asia, Saudi Arabia, Ghana, and Zimbabwe. For carbamazepine, preemptive genotyping of HLA-B*15:02 is only cost-effective across most of East and South Asia, whereas HLA-A*31:01 testing is likely to be cost-effective globally. Testing of HLA-B*58:01 is more likely to be cost-effective throughout Africa and Asia compared with Europe and the Americas. We anticipate that this data set can serve as an important resource for clinicians and health economists to guide clinical decision making and inform public healthcare strategies.
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Affiliation(s)
- Yitian Zhou
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Kristi Krebs
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.,Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia
| | - Lili Milani
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Volker M Lauschke
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
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31
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Barquera R, Hernández-Zaragoza DI, Bravo-Acevedo A, Arrieta-Bolaños E, Clayton S, Acuña-Alonzo V, Martínez-Álvarez JC, López-Gil C, Adalid-Sáinz C, Vega-Martínez MDR, Escobedo-Ruíz A, Juárez-Cortés ED, Immel A, Pacheco-Ubaldo H, González-Medina L, Lona-Sánchez A, Lara-Riegos J, Sánchez-Fernández MGDJ, Díaz-López R, Guizar-López GU, Medina-Escobedo CE, Arrazola-García MA, Montiel-Hernández GD, Hernández-Hernández O, Ramos-de la Cruz FDR, Juárez-Nicolás F, Pantoja-Torres JA, Rodríguez-Munguía TJ, Juárez-Barreto V, Delgado-Aguirre H, Escutia-González AB, Goné-Vázquez I, Benítez-Arvizu G, Arellano-Prado FP, García-Arias VE, Rodríguez-López ME, Méndez-Mani P, García-Álvarez R, González-Martínez MDR, Aquino-Rubio G, Escareño-Montiel N, Vázquez-Castillo TV, Uribe-Duarte MG, Ruíz-Corral MDJ, Ortega-Yáñez A, Bernal-Felipe N, Gómez-Navarro B, Arriaga-Perea AJ, Martínez-Bezies V, Macías-Medrano RM, Aguilar-Campos JA, Solís-Martínez R, Serrano-Osuna R, Sandoval-Sandoval MJ, Jaramillo-Rodríguez Y, Salgado-Adame A, Juárez-de la Cruz F, Novelo-Garza B, Pavón-Vargas MDLÁ, Salgado-Galicia N, Bortolini MC, Gallo C, Bedoya G, Rothhammer F, González-José R, Ruiz-Linares A, Canizales-Quinteros S, Romero-Hidalgo S, Krause J, Zúñiga J, Yunis EJ, Bekker-Méndez C, Granados J. The immunogenetic diversity of the HLA system in Mexico correlates with underlying population genetic structure. Hum Immunol 2020; 81:461-474. [PMID: 32651014 DOI: 10.1016/j.humimm.2020.06.008] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 06/16/2020] [Accepted: 06/17/2020] [Indexed: 12/15/2022]
Abstract
We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) allele groups and alleles by PCR-SSP based typing in a total of 15,318 mixed ancestry Mexicans from all the states of the country divided into 78 sample sets, providing information regarding allelic and haplotypic frequencies and their linkage disequilibrium, as well as admixture estimates and genetic substructure. We identified the presence of 4268 unique HLA extended haplotypes across Mexico and find that the ten most frequent (HF > 1%) HLA haplotypes with significant linkage disequilibrium (Δ'≥0.1) in Mexico (accounting for 20% of the haplotypic diversity of the country) are of primarily Native American ancestry (A*02~B*39~DRB1*04~DQB1*03:02, A*02~B*35~DRB1*08~DQB1*04, A*68~B*39~DRB1*04~DQB1*03:02, A*02~B*35~DRB1*04~DQB1*03:02, A*24~B*39~DRB1*14~DQB1*03:01, A*24~B*35~DRB1*04~DQB1*03:02, A*24~B*39~DRB1*04~DQB1*03:02, A*02~B*40:02~DRB1*04~DQB1*03:02, A*68~B*35~DRB1*04~DQB1*03:02, A*02~B*15:01~DRB1*04~DQB1*03:02). Admixture estimates obtained by a maximum likelihood method using HLA-A/-B/-DRB1 as genetic estimators revealed that the main genetic components in Mexico as a whole are Native American (ranging from 37.8% in the northern part of the country to 81.5% in the southeastern region) and European (ranging from 11.5% in the southeast to 62.6% in northern Mexico). African admixture ranged from 0.0 to 12.7% not following any specific pattern. We were able to detect three major immunogenetic clusters correlating with genetic diversity and differential admixture within Mexico: North, Central and Southeast, which is in accordance with previous reports using genome-wide data. Our findings provide insights into the population immunogenetic substructure of the whole country and add to the knowledge of mixed ancestry Latin American population genetics, important for disease association studies, detection of demographic signatures on population variation and improved allocation of public health resources.
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Affiliation(s)
- Rodrigo Barquera
- Department of Archaeogenetics, Max Planck Institute for the Science of Human History (MPI-SHH), Jena, Germany; Molecular Genetics Laboratory, Escuela Nacional de Antropología e Historia (ENAH), Mexico City, Mexico.
| | - Diana Iraíz Hernández-Zaragoza
- Molecular Genetics Laboratory, Escuela Nacional de Antropología e Historia (ENAH), Mexico City, Mexico; Immunogenetics Unit, Técnicas Genéticas Aplicadas a la Clínica (TGAC), Mexico City, Mexico
| | - Alicia Bravo-Acevedo
- Blood Bank, UMAE Hospital de Gineco Obstetricia No. 4 "Luis Castelazo Ayala", Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico
| | | | - Stephen Clayton
- Department of Archaeogenetics, Max Planck Institute for the Science of Human History (MPI-SHH), Jena, Germany
| | - Víctor Acuña-Alonzo
- Molecular Genetics Laboratory, Escuela Nacional de Antropología e Historia (ENAH), Mexico City, Mexico
| | - Julio César Martínez-Álvarez
- HLA Laboratory, Central Blood Bank, Hospital de Especialidades, Unidad Médica de Alta Especialidad (UMAE), Centro Médico Nacional "Siglo XXI", Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico
| | - Concepción López-Gil
- Histocompatibility Laboratory, Unidad Médica de Alta Especialidad (UMAE) # 6, Instituto Mexicano del Seguro Social (IMSS), Puebla, Puebla, Mexico
| | - Carmen Adalid-Sáinz
- Laboratory of Histocompatibility, Unidad Médica de Alta Especialidad (UMAE) # 71, Instituto Mexicano del Seguro Social (IMSS), Torreón, Coahuila, Mexico
| | - María Del Rosario Vega-Martínez
- Molecular Biology and Histocompatibility Laboratory, Hospital Central Sur de Alta Especialidad, Petróleos Mexicanos (PEMEX), Mexico City, Mexico
| | - Araceli Escobedo-Ruíz
- Histocompatibility Laboratory, Hospital de Especialidades, Centro Médico Nacional de Occidente (CMNO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, Mexico
| | - Eva Dolores Juárez-Cortés
- Histocompatibility Laboratory, Central Blood Bank, Centro Médico Nacional "La Raza", Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico
| | - Alexander Immel
- Department of Archaeogenetics, Max Planck Institute for the Science of Human History (MPI-SHH), Jena, Germany; Institute of Clinical Molecular Biology (IKMB), Kiel University, University Hospital, Schleswig-Holstein, Germany
| | - Hanna Pacheco-Ubaldo
- Molecular Genetics Laboratory, Escuela Nacional de Antropología e Historia (ENAH), Mexico City, Mexico
| | - Liliana González-Medina
- Molecular Genetics Laboratory, Escuela Nacional de Antropología e Historia (ENAH), Mexico City, Mexico
| | - Abraham Lona-Sánchez
- Molecular Genetics Laboratory, Escuela Nacional de Antropología e Historia (ENAH), Mexico City, Mexico
| | - Julio Lara-Riegos
- Chemistry Faculty, Universidad Autónoma de Yucatán (UADY), Mérida, Yucatán, Mexico
| | - María Guadalupe de Jesús Sánchez-Fernández
- Department of Nephrology and Transplantation Unit, Centro Médico Nacional de Occidente (CMNO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, Mexico
| | - Rosario Díaz-López
- Molecular Biology Laboratory, Hospital Central Militar, Secretaría de la Defensa Nacional (SEDENA), Mexico City, Mexico
| | - Gregorio Ulises Guizar-López
- Molecular Biology Laboratory, Hospital Central Militar, Secretaría de la Defensa Nacional (SEDENA), Mexico City, Mexico
| | - Carolina Elizabeth Medina-Escobedo
- Unit of Research and Education in Health, Unidad Médica de Alta Especialidad (UMAE) # 10, Instituto Mexicano del Seguro Social (IMSS), Mérida, Yucatán, Mexico
| | - María Araceli Arrazola-García
- HLA Laboratory, Central Blood Bank, Hospital de Especialidades, Unidad Médica de Alta Especialidad (UMAE), Centro Médico Nacional "Siglo XXI", Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico
| | | | | | - Flor Del Rocío Ramos-de la Cruz
- Histocompatibility Laboratory, Unidad Médica de Alta Especialidad (UMAE) # 6, Instituto Mexicano del Seguro Social (IMSS), Puebla, Puebla, Mexico
| | | | - Jorge Arturo Pantoja-Torres
- Immunology Division, Unidad Médica de Alta Especialidad (UMAE) # 1, Instituto Mexicano del Seguro Social (IMSS), León, Guanajuato, Mexico
| | - Tirzo Jesús Rodríguez-Munguía
- Molecular Biology Laboratory, Hospital General "Norberto Treviño Zapata", Dirección de Servicios de Salud de Tamaulipas, Ciudad Victoria, Tamaulipas, Mexico
| | | | - Héctor Delgado-Aguirre
- Laboratory of Histocompatibility, Unidad Médica de Alta Especialidad (UMAE) # 71, Instituto Mexicano del Seguro Social (IMSS), Torreón, Coahuila, Mexico
| | | | - Isis Goné-Vázquez
- Histocompatibility Laboratory, Hospital de Especialidades, Centro Médico Nacional de Occidente (CMNO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, Mexico
| | - Gamaliel Benítez-Arvizu
- HLA Laboratory, Central Blood Bank, Hospital de Especialidades, Unidad Médica de Alta Especialidad (UMAE), Centro Médico Nacional "Siglo XXI", Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico
| | - Francia Paulina Arellano-Prado
- Pediatrics Hospital, Centro Médico Nacional de Occidente (CMNO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, Mexico
| | - Víctor Eduardo García-Arias
- Pediatrics Hospital, Centro Médico Nacional de Occidente (CMNO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, Mexico
| | - Marla Estefanía Rodríguez-López
- Pediatrics Hospital, Centro Médico Nacional de Occidente (CMNO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, Mexico
| | - Patricia Méndez-Mani
- Histocompatibility Laboratory, Unidad Médica de Alta Especialidad (UMAE) # 6, Instituto Mexicano del Seguro Social (IMSS), Puebla, Puebla, Mexico
| | - Raquel García-Álvarez
- Pharmacology Laboratory, Research Unit, Instituto Nacional de Pediatría (INP), Mexico City, Mexico
| | | | - Guadalupe Aquino-Rubio
- Molecular Biology Laboratory, Hospital General "Norberto Treviño Zapata", Dirección de Servicios de Salud de Tamaulipas, Ciudad Victoria, Tamaulipas, Mexico
| | - Néstor Escareño-Montiel
- Department of Transplantation, Unidad Médica de Alta Especialidad (UMAE) # 71, Instituto Mexicano del Seguro Social (IMSS), Torreón, Coahuila, Mexico
| | | | - María Guadalupe Uribe-Duarte
- Clinical Laboratory, Unidad Médica de Alta Especialidad (UMAE) # 2, Instituto Mexicano del Seguro Social (IMSS), Ciudad Obregón, Sonora, Mexico
| | - María de Jesús Ruíz-Corral
- Clinical Laboratory, Unidad Médica de Alta Especialidad (UMAE) # 2, Instituto Mexicano del Seguro Social (IMSS), Ciudad Obregón, Sonora, Mexico
| | - Andrea Ortega-Yáñez
- Department of Development Genetics and Molecular Physiology, Instituto de Biotecnología (IBT), Universidad Nacional Autónoma de México (UNAM), Cuernavaca, Morelos, Mexico
| | | | - Benjamín Gómez-Navarro
- Central Office of Nephrology, Centro Médico Nacional de Occidente (CMNO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, Mexico
| | - Agustín Jericó Arriaga-Perea
- Histocompatibility Laboratory, Central Blood Bank, Centro Médico Nacional "La Raza", Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico
| | | | - Rosa María Macías-Medrano
- Histocompatibility Laboratory, Central Blood Bank, Centro Médico Nacional "La Raza", Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico
| | - Jesús Abraham Aguilar-Campos
- Clinical Laboratory, Unidad Médica de Alta Especialidad (UMAE) # 2, Instituto Mexicano del Seguro Social (IMSS), Ciudad Obregón, Sonora, Mexico
| | - Raúl Solís-Martínez
- Department of Molecular Biology, Laboratorios Diagnóstica, Villahermosa, Tabasco, Mexico
| | - Ricardo Serrano-Osuna
- Clinical Laboratory, Unidad Médica de Alta Especialidad (UMAE) # 2, Instituto Mexicano del Seguro Social (IMSS), Ciudad Obregón, Sonora, Mexico
| | - Mario J Sandoval-Sandoval
- Central Office of Transplantation, Centro Médico Nacional de Occidente (CMNO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, Mexico; Health Research Division, Unidad Médica de Alta Especialidad (UMAE) # 71, Instituto Mexicano del Seguro Social (IMSS), Torreón, Coahuila, Mexico
| | - Yolanda Jaramillo-Rodríguez
- Direction of Health Education and Research, Unidad Médica de Alta Especialidad (UMAE) # 71, Instituto Mexicano del Seguro Social (IMSS), Torreón, Coahuila, Mexico
| | - Antonio Salgado-Adame
- Direction of Health Education and Research, Unidad Médica de Alta Especialidad (UMAE) # 71, Instituto Mexicano del Seguro Social (IMSS), Torreón, Coahuila, Mexico
| | - Federico Juárez-de la Cruz
- Department of Transplantation, Unidad Médica de Alta Especialidad (UMAE) # 71, Instituto Mexicano del Seguro Social (IMSS), Torreón, Coahuila, Mexico
| | - Bárbara Novelo-Garza
- Medical Infrastructure Planning Committee, Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico
| | - María de Los Ángeles Pavón-Vargas
- Histocompatibility Laboratory, Unidad Médica de Alta Especialidad (UMAE) # 6, Instituto Mexicano del Seguro Social (IMSS), Puebla, Puebla, Mexico
| | - Norma Salgado-Galicia
- Molecular Biology and Histocompatibility Laboratory, Hospital Central Sur de Alta Especialidad, Petróleos Mexicanos (PEMEX), Mexico City, Mexico
| | - Maria Cátira Bortolini
- Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Carla Gallo
- Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima, Peru
| | - Gabriel Bedoya
- Genética Molecular (GENMOL, Universidad de Antioquia, Medellín, Colombia
| | - Francisco Rothhammer
- Programa de Genética Humana, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile; Instituto de Alta Investigación, Universidad de Tarapacá, Arica, Chile
| | - Rolando González-José
- Instituto Patagónico de Ciencias Sociales y Humanas-Centro Nacional Patagónico, CONICET, Puerto Madryn, Argentina
| | - Andrés Ruiz-Linares
- Ministry of Education Key Laboratory of Contemporary Anthropology and Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai, China; Aix-Marseille Univ, CNRS, EFS, ADES, Marseille, France
| | - Samuel Canizales-Quinteros
- Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, Universidad Nacional Autónoma de México e Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | - Sandra Romero-Hidalgo
- Department of Computational Genomics, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico
| | - Johannes Krause
- Department of Archaeogenetics, Max Planck Institute for the Science of Human History (MPI-SHH), Jena, Germany
| | - Joaquín Zúñiga
- Laboratory of Immunobiology and Genetics, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, Mexico; Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City, Mexico
| | - Edmond J Yunis
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Carolina Bekker-Méndez
- Immunology and Infectology Research Unit, Infectology Hospital, Centro Médico Nacional "La Raza", Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico
| | - Julio Granados
- Department of Transplantation, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán" (INCMNSZ), Mexico City, Mexico.
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Hasegawa A, Abe R. Recent advances in managing and understanding Stevens-Johnson syndrome and toxic epidermal necrolysis. F1000Res 2020; 9. [PMID: 32595945 PMCID: PMC7308994 DOI: 10.12688/f1000research.24748.1] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/10/2020] [Indexed: 12/15/2022] Open
Abstract
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening diseases characterized by detachment of the epidermis and mucous membrane. SJS/TEN are considered to be on the same spectrum of diseases with different severities. They are classified by the percentage of skin detachment area. SJS/TEN can also cause several complications in the liver, kidneys, and respiratory tract. The pathogenesis of SJS/TEN is still unclear. Although it is difficult to diagnose early stage SJS/TEN, biomarkers for diagnosis or severity prediction have not been well established. Furthermore, optimal therapeutic options for SJS/TEN are still controversial. Several drugs, such as carbamazepine and allopurinol, are reported to have a strong relationship with a specific human leukocyte antigen (HLA) type. This relationship differs between different ethnicities. Recently, the usefulness of HLA screening before administering specific drugs to decrease the incidence of SJS/TEN has been investigated. Skin detachment in SJS/TEN skin lesions is caused by extensive epidermal cell death, which has been considered to be apoptosis via the Fas-FasL pathway or perforin/granzyme pathway. We reported that necroptosis, i.e. programmed necrosis, also contributes to epidermal cell death. Annexin A1, released from monocytes, and its interaction with the formyl peptide receptor 1 induce necroptosis. Several diagnostic or prognostic biomarkers for SJS/TEN have been reported, such as CCL-27, IL-15, galectin-7, and RIP3. Supportive care is recommended for the treatment of SJS/TEN. However, optimal therapeutic options such as systemic corticosteroids, intravenous immunoglobulin, cyclosporine, and TNF-α antagonists are still controversial. Recently, the beneficial effects of cyclosporine and TNF-α antagonists have been explored. In this review, we discuss recent advances in the pathophysiology and management of SJS/TEN.
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Affiliation(s)
- Akito Hasegawa
- Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Riichiro Abe
- Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
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Oussalah A, Yip V, Mayorga C, Blanca M, Barbaud A, Nakonechna A, Cernadas J, Gotua M, Brockow K, Caubet J, Bircher A, Atanaskovic‐Markovic M, Demoly P, Kase‐Tanno L, Terreehorst I, Laguna JJ, Romano A, Guéant J, Pirmohamed M. Genetic variants associated with T cell-mediated cutaneous adverse drug reactions: A PRISMA-compliant systematic review-An EAACI position paper. Allergy 2020; 75:1069-1098. [PMID: 31899808 DOI: 10.1111/all.14174] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 09/27/2019] [Accepted: 10/23/2019] [Indexed: 12/11/2022]
Abstract
Drug hypersensitivity reactions (DHRs) are associated with high global morbidity and mortality. Cutaneous T cell-mediated reactions classically occur more than 6 hours after drug administration and include life-threatening conditions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, and hypersensitivity syndrome. Over the last 20 years, significant advances have been made in our understanding of the pathogenesis of DHRs with the identification of human leukocyte antigens as predisposing factors. This has led to the development of pharmacogenetic screening tests, such as HLA-B*57:01 in abacavir therapy, which has successfully reduced the incidence of abacavir hypersensitivity reactions. We have completed a PRISMA-compliant systematic review to identify genetic associations that have been reported in DHRs. In total, 105 studies (5554 cases and 123 548 controls) have been included in the review reporting genetic associations with carbamazepine (n = 31), other aromatic antiepileptic drugs (n = 24), abacavir (n = 11), nevirapine (n = 14), trimethoprim-sulfamethoxazole (n = 11), dapsone (n = 4), allopurinol (n = 10), and other drugs (n = 5). The most commonly reported genetic variants associated with DHRs are located in human leukocyte antigen genes and genes involved in drug metabolism pathways. Increasing our understanding of genetic variants that contribute to DHRs will allow us to improve diagnosis, develop new treatments, and predict and prevent DHRs in the future.
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Affiliation(s)
- Abderrahim Oussalah
- INSERM UMR_S 1256 NGERE – Nutrition, Genetics, and Environmental Risk Exposure Faculty of Medicine of Nancy University of Lorraine Nancy France
- Department of Molecular Medicine Division of Biochemistry, Molecular Biology, and Nutrition University Hospital of Nancy Nancy France
| | - Vincent Yip
- Department of Molecular and Clinical Pharmacology MRC Centre for Drug Safety Science University of Liverpool Liverpool UK
- Royal Liverpool and Broadgreen University Hospital NHS Trust Liverpool UK
- The Wolfson Centre for Personalized Medicine Institute of Translational Medicine University of Liverpool Liverpool UK
| | - Cristobalina Mayorga
- Allergy Research Group Instituto de Investigación Biomédica de Málaga‐IBIMA‐ARADyAL Málaga Spain
- Allergy Unit Hospital Regional Universitario de Málaga‐ARADyAL Málaga Spain
| | - Miguel Blanca
- Allergy Research Group Instituto de Investigación Biomédica de Málaga‐IBIMA‐ARADyAL Málaga Spain
- Allergy Unit Hospital Regional Universitario de Málaga‐ARADyAL Málaga Spain
| | - Annick Barbaud
- Dermatology and Allergology Department Tenon Hospital (AP‐HP) Sorbonne Universities UPMC University Paris 06 Paris France
| | - Alla Nakonechna
- Allergy and Immunology Clinic Royal Liverpool and Broadgreen University Hospital Liverpool UK
| | - Josefina Cernadas
- Department of Allergy and Clinical Immunology Centro Hospitalar Universitário de Sâo João Porto Portugal
- Allergy Clinic Hospital Lusíadas Porto Portugal
| | - Maia Gotua
- Center for Allergy and Immunology Research Tbilisi Georgia
| | - Knut Brockow
- Klinik für Dermatologie und Allergologie am Biederstein Technische Universität München München Germany
| | | | - Andreas Bircher
- Dermatologie/Allergologie Universitätsspital Basel Basel Switzerland
| | - Marina Atanaskovic‐Markovic
- Medical Faculty Department of Allergology and Pulmonology University Children's Hospital University of Belgrade Belgrade Serbia
| | - Pascal Demoly
- Division of Allergy Department of Pulmonology Hôpital Arnaud de Villeneuve University Hospital of Montpellier Montpellier France
| | | | - Ingrid Terreehorst
- Academisch Medisch Centrum University of Amsterdam Amsterdam Netherlands
| | | | | | - Jean‐Louis Guéant
- INSERM UMR_S 1256 NGERE – Nutrition, Genetics, and Environmental Risk Exposure Faculty of Medicine of Nancy University of Lorraine Nancy France
- Department of Molecular Medicine Division of Biochemistry, Molecular Biology, and Nutrition University Hospital of Nancy Nancy France
| | - Munir Pirmohamed
- Department of Molecular and Clinical Pharmacology MRC Centre for Drug Safety Science University of Liverpool Liverpool UK
- Royal Liverpool and Broadgreen University Hospital NHS Trust Liverpool UK
- The Wolfson Centre for Personalized Medicine Institute of Translational Medicine University of Liverpool Liverpool UK
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Thomson PJ, Illing PT, Farrell J, Alhaidari M, Bell CC, Berry N, O’Neill PM, Purcell AW, Park KB, Naisbitt DJ. Modification of the cyclopropyl moiety of abacavir provides insight into the structure activity relationship between HLA-B*57:01 binding and T-cell activation. Allergy 2020; 75:636-647. [PMID: 31549414 DOI: 10.1111/all.14057] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 08/22/2019] [Indexed: 01/11/2023]
Abstract
BACKGROUND Abacavir is associated with hypersensitivity reactions in individuals positive for the HLA-B*57:01 allele. The drug binds within the peptide binding groove of HLA-B*57:01 altering peptides displayed on the cell surface. Presentation of these HLA-abacavir-peptide complexes to T-cells is hypothesized to trigger a CD8+ T-cell response underpinning the hypersensitivity. Thus, the aim of this study was to explore the relationship between the structure of abacavir with HLA-B*57:01 binding and the CD8+ T-cell activation. METHODS Seventeen abacavir analogues were synthesized and cytokine secretion from abacavir/abacavir analogue-responsive CD8+ T-cell clones was measured using IFN-γ ELIspot. In silico docking studies were undertaken to assess the predicted binding poses of the abacavir analogues within the HLA-B*57:01 peptide binding groove. In parallel, the effect of selected abacavir analogues on the repertoire of self-peptides presented by cellular HLA-B*57:01 was characterized using mass spectrometry. RESULTS Abacavir and ten analogues stimulated CD8+ T-cell IFN-γ release. Molecular docking of analogues that retained antiviral activity demonstrated a relationship between predicted HLA-B*57:01 binding orientations and the ability to induce a T-cell response. Analogues that stimulated T-cells displayed a perturbation of the natural peptides displayed by HLA-B*57:01. The antigen-specific CD8+ T-cell response was dependent on the enantiomeric form of abacavir at both cyclopropyl and cyclopentyl regions. CONCLUSION Alteration of the chemical constitution of abacavir generates analogues that retain a degree of pharmacological activity, but have variable ability to activate T-cells. Modelling and immunopeptidome analysis delineate how drug HLA-B*57:01 binding and peptide display by antigen presenting cells relate to the activation of CD8+ T-cells.
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Affiliation(s)
- Paul J. Thomson
- MRC Centre for Drug Safety Science Department of Molecular & Clinical Pharmacology University of Liverpool Liverpool UK
| | - Patricia T. Illing
- Infection and Immunity Program Department of Biochemistry and Molecular Biology Monash Biomedicine Discovery Institute Monash University Clayton Australia
| | - John Farrell
- MRC Centre for Drug Safety Science Department of Molecular & Clinical Pharmacology University of Liverpool Liverpool UK
| | - Mohammad Alhaidari
- MRC Centre for Drug Safety Science Department of Molecular & Clinical Pharmacology University of Liverpool Liverpool UK
| | - Catherine C. Bell
- MRC Centre for Drug Safety Science Department of Molecular & Clinical Pharmacology University of Liverpool Liverpool UK
| | - Neil Berry
- MRC Centre for Drug Safety Science Department of Molecular & Clinical Pharmacology University of Liverpool Liverpool UK
| | - Paul M. O’Neill
- MRC Centre for Drug Safety Science Department of Molecular & Clinical Pharmacology University of Liverpool Liverpool UK
| | - Anthony W. Purcell
- Infection and Immunity Program Department of Biochemistry and Molecular Biology Monash Biomedicine Discovery Institute Monash University Clayton Australia
| | - Kevin B. Park
- MRC Centre for Drug Safety Science Department of Molecular & Clinical Pharmacology University of Liverpool Liverpool UK
| | - Dean J. Naisbitt
- MRC Centre for Drug Safety Science Department of Molecular & Clinical Pharmacology University of Liverpool Liverpool UK
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Faridi RM, Patel S, Dharmani-Khan P, Gill J, Berka N, Khan FM. Comparison of abacavir-specific effector and proliferating functions of CD8 T cells in abacavir-treated HIV-1 patients. Microbiol Immunol 2020; 64:210-218. [PMID: 31876322 DOI: 10.1111/1348-0421.12769] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 11/28/2019] [Accepted: 12/16/2019] [Indexed: 01/12/2023]
Abstract
Susceptibility to abacavir hypersensitivity (ABH) in HIV-1-positive patients is strongly linked to the carriage of HLA-B*57:01 and the potential mechanism includes drug-specific activation of cytokine producing CD8 T cells exclusively in individuals carrying HLA-B*57:01. Here, we report a detailed characterization of abacavir-induced functional response of CD8 T cells in HLA-B*57:01pos individuals. Peripheral blood mononuclear cells (PBMNCs) from HLA-B*57:01pos ABHpos and HLA-B*57:01neg ABHneg individuals were stimulated with abacavir. Multicolor flow cytometry was performed to assess the cytokine (IFNγ) production and degranulation (CD107a expression) after 6-18 hr culture and to enumerate proliferating CD4/CD8 T cells by culturing carboxyfluorescein diacetate succinimidyl ester-loaded PBMNCs for 7 days. CD8 T cells from HLA-B*57:01pos ABHpos individuals were multifunctional: proliferating, IFNγ producing, degranulating (CD107apos ), and both degranulating and IFNγ producing (CD107apos IFNγpos ). Degranulating CD8 T cells in general and both degranulating and IFNγ producing CD8 T cells in particular dominated abacavir-specific immune response. All functional responses were partially blocked by addition of HLA-B*57:01-reactive Bw4 mAb, but not by non-HLA-B*57:01-reactive Bw6 mAb. In conclusion, the study demonstrates that abacavir-specific CD8 T-cell-restricted immune response in HLA-B*57:01pos ABHpos HIV-1 patients has multiple effector and proliferating functions, where the primary effector response appears to be the release of cytolytic granules. The findings have implications for immunotherapy of HLA-related drug hypersensitivities.
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Affiliation(s)
- Rehan M Faridi
- Department of Pathology and Laboratory Medicine, Cumming School of Medicine University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada.,Division of Hematopathology, Alberta Public Laboratories, 3535 Research Road NW, Calgary, Alberta, T2L 1Y1, Canada
| | - Stuti Patel
- Department of Pathology and Laboratory Medicine, Cumming School of Medicine University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada
| | - Poonam Dharmani-Khan
- Department of Pathology and Laboratory Medicine, Cumming School of Medicine University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada.,Division of Hematopathology, Alberta Public Laboratories, 3535 Research Road NW, Calgary, Alberta, T2L 1Y1, Canada
| | - John Gill
- Department of Pathology and Laboratory Medicine, Cumming School of Medicine University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada.,Department of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada.,Southern Alberta HIV Clinic, Sheldon M. Chumir Health Center, 1213 4 Street SW, Calgary, Alberta, T2R 0X7, Canada
| | - Noureddine Berka
- Department of Pathology and Laboratory Medicine, Cumming School of Medicine University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada.,Division of Hematopathology, Alberta Public Laboratories, 3535 Research Road NW, Calgary, Alberta, T2L 1Y1, Canada
| | - Faisal M Khan
- Department of Pathology and Laboratory Medicine, Cumming School of Medicine University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada.,Department of Paediatrics, Cumming School of Medicine, University of Calgary, 28 Oki Drive NW, Calgary, Alberta, T3B 6A8, Canada.,Division of Hematopathology, Alberta Public Laboratories, 3535 Research Road NW, Calgary, Alberta, T2L 1Y1, Canada
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Eriksen J, Carlander C, Albert J, Flamholc L, Gisslén M, Navér L, Svedhem V, Yilmaz A, Sönnerborg A. Antiretroviral treatment for HIV infection: Swedish recommendations 2019. Infect Dis (Lond) 2020; 52:295-329. [PMID: 31928282 DOI: 10.1080/23744235.2019.1707867] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The Swedish Reference Group for Antiviral Therapy (RAV) published recommendations for the treatment of HIV infection in this journal most recently in 2017. An expert group under the guidance of RAV here provides updated recommendations. The most important updates in the present guidelines are the following: (a) The risk of HIV transmission through condomless sex from individuals with fully suppressed HIV viral load is effectively zero. (b) Pre-exposure prophylaxis (PrEP) is recommended for groups with a high risk of HIV infection. (c) Since the last update, two new substances have been registered: bictegravir and doravirine. (d) Dual treatment may be an alternative in selected patients, using lamivudine + dolutegravir or lamivudine + boosted darunavir/atazanavir. As with previous publications, recommendations are evidence-graded in accordance with the Oxford Centre for Evidence Based Medicine. This document does not cover treatment of opportunistic infections and tumours.
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Affiliation(s)
- Jaran Eriksen
- Unit of Infectious Diseases/Venhälsan, Södersjukhuset, Stockholm, Sweden.,Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Christina Carlander
- Department of Infectious Diseases, Västmanland County Hospital, Västerås, Sweden.,Division of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Jan Albert
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.,Department of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden
| | - Leo Flamholc
- Department of Infectious Diseases, Skåne University Hospital, Malmö, Sweden
| | - Magnus Gisslén
- Department of Infectious Diseases, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Infectious Diseases, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Lars Navér
- Division of Paediatrics, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden.,Department of Paediatrics, Karolinska University Hospital, Stockholm, Sweden
| | - Veronica Svedhem
- Division of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.,Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Aylin Yilmaz
- Department of Infectious Diseases, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Anders Sönnerborg
- Division of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.,Department of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden.,Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden.,Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
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Rapid Detection of HLA-B*57:01-Expressing Cells Using a Label-Free Interdigitated Electrode Biosensor Platform for Prevention of Abacavir Hypersensitivity in HIV Treatment. SENSORS 2019; 19:s19163543. [PMID: 31416185 PMCID: PMC6719006 DOI: 10.3390/s19163543] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 07/30/2019] [Accepted: 08/11/2019] [Indexed: 12/19/2022]
Abstract
Pre-treatment screening of individuals for human leukocyte antigens (HLA) HLA-B*57:01 is recommended for the prevention of life-threatening hypersensitivity reactions to abacavir, a drug widely prescribed for HIV treatment. However, the implementation of screening in clinical practice is hindered by the slow turnaround time and high cost of conventional HLA genotyping methods. We have developed a biosensor platform using interdigitated electrode (IDE) functionalized with a monoclonal antibody to detect cells expressing HLA-B*57:01. This platform was evaluated using cell lines and peripheral blood mononuclear cells expressing different HLA-B alleles. The functionalized IDE sensor was able to specifically capture HLA-B*57:01 cells, resulting in a significant change in the impedance magnitude in 20 min. This IDE platform has the potential to be further developed to enable point-of-care HLA-B*57:01 screening.
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Alfirevic A, Pirmohamed M, Marinovic B, Harcourt‐Smith L, Jorgensen AL, Cooper TE, Cochrane Skin Group. Genetic testing for prevention of severe drug-induced skin rash. Cochrane Database Syst Rev 2019; 7:CD010891. [PMID: 31314143 PMCID: PMC6636675 DOI: 10.1002/14651858.cd010891.pub2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Drug-induced skin reactions present with a range of clinical symptoms, from mild maculopapular skin rashes to potentially fatal blistering skin rashes - such as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) - which may result in death. Milder reactions may be troublesome and lead to low drug compliance. The pathogenesis of these drug reactions is not yet fully understood; however, there is evidence that pretreatment genetic testing may help to predict and prevent these reactions in some cases. OBJECTIVES To assess the effects of prospective pharmacogenetic screening to reduce drug-associated skin reactions in a patient population. SEARCH METHODS We searched the following databases up to July 2018: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase and LILACS. We also searched five trials registers, and checked the reference lists of included studies and relevant reviews for further references to relevant randomised controlled trials (RCTs). SELECTION CRITERIA We included RCTs of participants who had prospective pharmacogenetic screening to determine genetic variants associated with hypersensitivity reactions, compared with those who did not have prospective pharmacogenetic screening. We included participants in any setting, who were of any age, gender, and ethnicity, who had been prescribed drugs known to cause delayed type hypersensitivity reactions. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. To assess studies for inclusion, two review authors independently screened all of the titles and abstracts of publications identified by the searches. Because there was only one included study, many of the planned data analyses were not applicable to the review. We used GRADE to assess the quality of the included study.The review's primary outcomes were the incidence of severe skin rashes with systemic symptoms (such as fever and multiple organ involvement), and long-term effects (such as scarring of eyelids or lung tissue). Secondary outcomes were hospitalisation for drug-induced skin reactions, blistering skin reactions (such as SJS, hypersensitivity (HSS) syndrome), and death. MAIN RESULTS One study, which was a randomised, double-blind, controlled, multicentre trial, fulfilled our inclusion criteria. The trial included 1956 adult participants (74% men, with a mean age of 42 years) across 265 centres (medical centres, hospitals, outpatient clinics) in 19 countries around the world who were infected with HIV-type 1 and who had not received abacavir previously. The participants, who had a clinical need for treatment with an antiretroviral-drug regimen containing abacavir, were randomly assigned to undergo prospective human leukocyte antigen (HLA) Class I, locus B, allele 57:01 (HLA-B*57:01) screening (prospective-screening group) before this treatment, or to undergo a standard-care approach of abacavir use without prospective HLA-B*57:01 screening (control group). Participants who tested positive for HLA-B*57:01 were not given abacavir; instead, they received antiretroviral therapy that did not include abacavir. The control group did have retrospective HLA-B*57:01 pharmacogenetic testing. The trial duration was six months. Each participant was observed for six weeks. Assessments were performed at the time of study entry, at baseline (day one of abacavir treatment), and at weeks one, two and six. This study was funded by the manufacturer of abacavir, GlaxoSmithKline.The study did not assess any of our primary outcomes, and it measured none of our secondary outcomes in isolation. However, it did assess an outcome of (characteristically severe) hypersensitivity reaction which included (but was not limited to) our secondary outcomes of HSS and SJS/TEN.The study demonstrated that prospective HLA-B*57:01 screening probably reduces the incidence of hypersensitivity reaction to abacavir. The incidence of clinically diagnosed HSS reaction to abacavir was lower in the screening arm (risk ratio (RR) 0.43, 95% confidence interval (CI) 0.28 to 0.67; 1650 participants; moderate-quality evidence), as was immunologically confirmed HSS reaction (RR 0.02, 95% 0.00 to 0.37; 1644 participants; moderate-quality evidence). A positive result from an epicutaneous patch test performed six to ten weeks after clinical diagnosis provided immunological confirmation.Overall, the study demonstrates a low risk of bias across five out of seven domains. There was a high risk of detection bias because hypersensitivity reactions were diagnosed by the principal investigator at the recruitment site without the use of predefined clinical criteria. Although there was also high risk of attrition bias due to excluding participants with incomplete follow-up from analyses, the authors did undertake a series of sensitivity analyses based on the intention-to-treat population, which demonstrated consistent results with the primary analysis. We rated the study quality as moderate-quality using GRADE criteria. AUTHORS' CONCLUSIONS Prospective screening for HLA-B*57:01 probably reduces severe hypersensitivity skin reactions to abacavir in patients positive for HIV-type 1. However, these results are only based on one study, which was at high risk of attrition and detection bias.Our primary outcomes (incidence of severe skin rashes with systemic symptoms, and long-term effects) were not assessed by the trial, and only one of the review's secondary outcomes was measured (hypersensitivity reaction); thus, we found no evidence relating to hospitalisation, death, or long-term conditions resulting from drug injury.We found no eligible evidence on genetic testing for severe drug-induced skin rash in relation to different drugs and classes of drugs. Further clinical trials based on other drugs, and in different patient populations, would be useful for advising policy changes for improving the prevention of adverse skin reactions to drug treatments.
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Affiliation(s)
- Ana Alfirevic
- Institute of Translational Medicine, University of LiverpoolDepartment of Molecular and Clinical PharmacologyCentre for Personalised Medicine, Block A: Waterhouse Building1‐5 Brownlow StreetLiverpoolUKL69 3GE
| | - Munir Pirmohamed
- Institute of Translational Medicine, University of LiverpoolDepartment of Molecular and Clinical PharmacologyCentre for Personalised Medicine, Block A: Waterhouse Building1‐5 Brownlow StreetLiverpoolUKL69 3GE
| | - Branka Marinovic
- University Hospital Centre Zagreb, School of Medicine, University of ZagrebDepartment of Dermatology and VenereologySalata 4ZagrebCroatia10000
| | - Linda Harcourt‐Smith
- The University of Nottinghamc/o Cochrane Skin GroupA103, King's Meadow CampusLenton LaneNottinghamUKNG7 2NR
| | - Andrea L Jorgensen
- University of LiverpoolCentre for Medical Statistics and Health EvaluationShelley's CottageBrownlow StreetLiverpoolUKL69 3 GS
| | - Tess E Cooper
- The Children's Hospital at WestmeadCochrane Kidney and Transplant, Centre for Kidney ResearchWestmeadNSWAustralia2145
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Hu K, Xiang Q, Wang Z, Mu GY, Zhang Z, Ma LY, Xie QF, Chen SQ, Zhou S, Zhang XD, Cui YM. Associations between human leukocyte antigen polymorphisms and hypersensitivity to antiretroviral therapy in patients with human immunodeficiency virus: a meta-analysis. BMC Infect Dis 2019; 19:583. [PMID: 31277607 PMCID: PMC6612203 DOI: 10.1186/s12879-019-4227-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 06/26/2019] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Human leukocyte antigen (HLA) alleles are implicated in drug-induced hypersensitivity, including by nevirapine and abacavir. The purpose of this meta-analysis was to evaluate the relationship between HLA polymorphisms and hypersensitivity to antiretroviral therapy in human immunodeficiency virus (HIV)-infected patients. METHODS We conducted a systematic search of PubMed, Embase, Web of Science, and the Cochrane Library for studies that evaluated the associations of HLA polymorphisms with antiretroviral therapy-induced hypersensitivity published in April 2019. The summary odds ratios (ORs) with 95% confidence intervals (CIs) were considered as estimates of the effect. RESULTS The meta-analysis included 17 studies that assessed a total of 4273 patients. First, carriers of HLA-A *24 were associated with an increased risk of hypersensitivity among patients with HIV who received antiretroviral therapy (OR: 12.12; P = 0.018). Second, five SNPs of HLA-B genotypes, including *18 (OR: 1.63; P = 0.028), *35 (OR: 2.31; P = 0.002), *39 (OR: 11.85; P = 0.040), *51 (OR: 1.66; P = 0.028), and *81 (OR: 8.11; P = 0.021), were associated with an increased risk of hypersensitivity. Conversely, carriers of HLA-B *15 were associated with a reduced risk of hypersensitivity (OR: 0.43; P < 0.001). Third, HLA-C *04 was associated with an increased risk of hypersensitivity (OR: 3.09; P < 0.001), whereas a lower risk for hypersensitivity was observed in patients who were carriers of HLA-C *02 (OR: 0.22; P = 0.030), *03 (OR: 0.53; P = 0.049), and *07 (OR: 0.61; P = 0.044). Finally, carriers of HLA-DRB1 *05 (OR: 0.18; P = 0.006) and *15 (OR: 0.23; P = 0.013) were associated with a reduced risk of hypersensitivity among patients receiving antiretroviral therapy. CONCLUSIONS The findings of this meta-analysis indicated patients carrying HLA-A *24, HLA-B *18, *35, *39, *51, *81, HLA-C *04 were associated with a higher risk of hypersensitivity. Conversely, subjects carrying HLA-B *15, HLA-C *02, *03, *07, HLA-DRB1 *05, *15 were associated with a reduced risk of hypersensitivity.
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Affiliation(s)
- Kun Hu
- Department of Pharmacy, Peking University First Hospital, 6# Dahongluochang Street, Xicheng District, Beijing, China
| | - Qian Xiang
- Department of Pharmacy, Peking University First Hospital, 6# Dahongluochang Street, Xicheng District, Beijing, China
| | - Zhe Wang
- Department of Pharmacy, Peking University First Hospital, 6# Dahongluochang Street, Xicheng District, Beijing, China.,Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmacy, Peking University Health Science Center, 38# Xueyuan Road, Haidian District, Beijing, China
| | - Guang-Yan Mu
- Department of Pharmacy, Peking University First Hospital, 6# Dahongluochang Street, Xicheng District, Beijing, China
| | - Zhuo Zhang
- Department of Pharmacy, Peking University First Hospital, 6# Dahongluochang Street, Xicheng District, Beijing, China
| | - Ling-Yue Ma
- Department of Pharmacy, Peking University First Hospital, 6# Dahongluochang Street, Xicheng District, Beijing, China
| | - Qiu-Fen Xie
- Department of Pharmacy, Peking University First Hospital, 6# Dahongluochang Street, Xicheng District, Beijing, China
| | - Shu-Qing Chen
- Department of Pharmacy, Peking University First Hospital, 6# Dahongluochang Street, Xicheng District, Beijing, China
| | - Shuang Zhou
- Department of Pharmacy, Peking University First Hospital, 6# Dahongluochang Street, Xicheng District, Beijing, China
| | - Xiao-Dan Zhang
- Department of Pharmacy, Peking University First Hospital, 6# Dahongluochang Street, Xicheng District, Beijing, China
| | - Yi-Min Cui
- Department of Pharmacy, Peking University First Hospital, 6# Dahongluochang Street, Xicheng District, Beijing, China.
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Konvinse KC, Trubiano JA, Pavlos R, James I, Shaffer CM, Bejan CA, Schutte RJ, Ostrov DA, Pilkinton MA, Rosenbach M, Zwerner JP, Williams KB, Bourke J, Martinez P, Rwandamuriye F, Chopra A, Watson M, Redwood AJ, White KD, Mallal SA, Phillips EJ. HLA-A*32:01 is strongly associated with vancomycin-induced drug reaction with eosinophilia and systemic symptoms. J Allergy Clin Immunol 2019; 144:183-192. [PMID: 30776417 PMCID: PMC6612297 DOI: 10.1016/j.jaci.2019.01.045] [Citation(s) in RCA: 125] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2018] [Revised: 01/17/2019] [Accepted: 01/23/2019] [Indexed: 01/11/2023]
Abstract
BACKGROUND Vancomycin is a prevalent cause of the severe hypersensitivity syndrome drug reaction with eosinophilia and systemic symptoms (DRESS), which leads to significant morbidity and mortality and commonly occurs in the setting of combination antibiotic therapy, affecting future treatment choices. Variations in HLA class I in particular have been associated with serious T cell-mediated adverse drug reactions, which has led to preventive screening strategies for some drugs. OBJECTIVE We sought to determine whether variation in the HLA region is associated with vancomycin-induced DRESS. METHODS Probable vancomycin-induced DRESS cases were matched 1:2 with tolerant control subjects based on sex, race, and age by using BioVU, Vanderbilt's deidentified electronic health record database. Associations between DRESS and carriage of HLA class I and II alleles were assessed by means of conditional logistic regression. An extended sample set from BioVU was used to conduct a time-to-event analysis of those exposed to vancomycin with and without the identified HLA risk allele. RESULTS Twenty-three subjects met the inclusion criteria for vancomycin-associated DRESS. Nineteen (82.6%) of 23 cases carried HLA-A*32:01 compared with 0 (0%) of 46 of the matched vancomycin-tolerant control subjects (P = 1 × 10-8) and 6.3% of the BioVU population (n = 54,249, P = 2 × 10-16). Time-to-event analysis of DRESS development during vancomycin treatment among the HLA-A*32:01-positive group indicated that 19.2% had DRESS and did so within 4 weeks. CONCLUSIONS HLA-A*32:01 is strongly associated with vancomycin-induced DRESS in a population of predominantly European ancestry. HLA-A*32:01 testing could improve antibiotic safety, help implicate vancomycin as the causal drug, and preserve future treatment options with coadministered antibiotics.
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Affiliation(s)
- Katherine C Konvinse
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA, 37232
| | - Jason A Trubiano
- Department of Infectious Diseases, Austin Health, Heidelberg, Victoria, AUS, 3084
- The National Centre for Infections in Cancer, Department of Infectious Diseases, Peter MacCallum Cancer Centre, Parkville, Victoria, AUS, 3000
- Department of Medicine, University of Melbourne, Parkville, Victoria, AUS, 3050
| | - Rebecca Pavlos
- Telethon Kids Institute, University of Western Australia, Nedlands, Western Australia, AUS, 6009
| | - Ian James
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, AUS, 6150
| | - Christian M Shaffer
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA, 37232
| | - Cosmin A Bejan
- Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA, 37232
| | - Ryan J Schutte
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida, USA, 32610
| | - David A Ostrov
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida, USA, 32610
| | - Mark A Pilkinton
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA, 37232
| | - Misha Rosenbach
- Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA, 19104
| | - Jeffrey P Zwerner
- Department of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee, USA, 37232
| | - Kristina B Williams
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA, 37232
| | - Jack Bourke
- Department of Clinical Immunology, Fiona Stanley Hospital, Murdoch, Western Australia, AUS, 6150
| | - Patricia Martinez
- Department of Clinical Immunology, Fiona Stanley Hospital, Murdoch, Western Australia, AUS, 6150
- Department of Clinical Immunology, Royal Perth Hospital, Perth, Western Australia, AUS, 6000
- Division of Pathology and Laboratory Medicine, School of Medicine, Faculty of Medicine, Dentistry and Health Sciences, University of Western Australia, Crawley, Western Australia, AUS, 6009
| | - Francois Rwandamuriye
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, AUS, 6150
| | - Abha Chopra
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, AUS, 6150
| | - Mark Watson
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, AUS, 6150
| | - Alec J Redwood
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, AUS, 6150
| | - Katie D White
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA, 37232
| | - Simon A Mallal
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA, 37232
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, AUS, 6150
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA, 37232
| | - Elizabeth J Phillips
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA, 37232
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, AUS, 6150
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA, 37232
- Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA, 37232
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Lauschke VM, Zhou Y, Ingelman-Sundberg M. Novel genetic and epigenetic factors of importance for inter-individual differences in drug disposition, response and toxicity. Pharmacol Ther 2019; 197:122-152. [PMID: 30677473 PMCID: PMC6527860 DOI: 10.1016/j.pharmthera.2019.01.002] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Individuals differ substantially in their response to pharmacological treatment. Personalized medicine aspires to embrace these inter-individual differences and customize therapy by taking a wealth of patient-specific data into account. Pharmacogenomic constitutes a cornerstone of personalized medicine that provides therapeutic guidance based on the genomic profile of a given patient. Pharmacogenomics already has applications in the clinics, particularly in oncology, whereas future development in this area is needed in order to establish pharmacogenomic biomarkers as useful clinical tools. In this review we present an updated overview of current and emerging pharmacogenomic biomarkers in different therapeutic areas and critically discuss their potential to transform clinical care. Furthermore, we discuss opportunities of technological, methodological and institutional advances to improve biomarker discovery. We also summarize recent progress in our understanding of epigenetic effects on drug disposition and response, including a discussion of the only few pharmacogenomic biomarkers implemented into routine care. We anticipate, in part due to exciting rapid developments in Next Generation Sequencing technologies, machine learning methods and national biobanks, that the field will make great advances in the upcoming years towards unlocking the full potential of genomic data.
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Affiliation(s)
- Volker M Lauschke
- Department of Physiology and Pharmacology, Section of Pharmacogenetics, Biomedicum 5B, Karolinska Institutet, SE-171 77 Stockholm, Sweden
| | - Yitian Zhou
- Department of Physiology and Pharmacology, Section of Pharmacogenetics, Biomedicum 5B, Karolinska Institutet, SE-171 77 Stockholm, Sweden
| | - Magnus Ingelman-Sundberg
- Department of Physiology and Pharmacology, Section of Pharmacogenetics, Biomedicum 5B, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
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Song B, Aoki S, Liu C, Susukida T, Ito K. An Animal Model of Abacavir-Induced HLA-Mediated Liver Injury. Toxicol Sci 2019; 162:713-723. [PMID: 29319822 DOI: 10.1093/toxsci/kfy001] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Genome-wide association studies indicate that several idiosyncratic adverse drug reactions are highly associated with specific human leukocyte antigen (HLA) alleles. For instance, abacavir, a human immunodeficiency virus reverse transcriptase inhibitor, induces multiorgan toxicity exclusively in patients carrying the HLA-B*57:01 allele. However, the underlying mechanism is unclear due to a lack of appropriate animal models. Previously, we developed HLA-B*57:01 transgenic mice and found that topical application of abacavir to the ears induced proliferation of CD8+ lymphocytes in local lymph nodes. Here, we attempted to reproduce abacavir-induced liver injury in these mice. However, oral administration of abacavir alone to HLA-B*57:01 transgenic mice did not increase levels of the liver injury marker alanine aminotransferase. Considering the importance of innate immune activation in mouse liver, we treated mice with CpG oligodeoxynucleotide, a toll-like receptor 9 agonist, plus abacavir. This resulted in a marked increase in alanine aminotransferase, pathological changes in liver, increased numbers of activated CD8+ T cells, and tissue infiltration by immune cells exclusively in HLA-B*57:01 transgenic mice. These results indicate that CpG oligodeoxynucleotide-induced inflammatory reactions and/or innate immune activation are necessary for abacavir-induced HLA-mediated liver injury characterized by infiltration of CD8+ T cells. Thus, we developed the first mouse model of HLA-mediated abacavir-induced idiosyncratic liver injury. Further investigation will show that the proposed HLA-mediated liver injury model can be applied to other combinations of drugs and HLA types, thereby improving drug development and contributing to the development of personalized medicine.
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Affiliation(s)
- Binbin Song
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba 260-8675, Japan
| | - Shigeki Aoki
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba 260-8675, Japan
| | - Cong Liu
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba 260-8675, Japan
| | - Takeshi Susukida
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba 260-8675, Japan
| | - Kousei Ito
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba 260-8675, Japan
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Abstract
Human immunodeficiency virus (HIV) has become a chronic disease with a near normal life span resulting in increased risk of organ failure. HIV organ transplantation is a proven and accepted intervention in appropriately selected cases. HIV-positive organ transplantation into HIV-positive recipients is in its nascent stages. Hepatitis C virus, high rates of organ rejection, and immune dysregulation are significant remaining barriers to overcome. This article provides an overview of the transplantation needs in the HIV population focusing on kidney and liver transplants.
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Affiliation(s)
- Alan J Taege
- Department of Infectious Disease, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
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Stainsby CM, Perger TM, Vannappagari V, Mounzer KC, Hsu RK, Henegar CE, Oyee J, Urbaityte R, Lane CE, Carter LM, Pakes GE, Shaefer MS. Abacavir Hypersensitivity Reaction Reporting Rates During a Decade of HLA-B*5701 Screening as a Risk-Mitigation Measure. Pharmacotherapy 2018; 39:40-54. [PMID: 30414209 PMCID: PMC6590466 DOI: 10.1002/phar.2196] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
INTRODUCTION Human leukocyte antigen (HLA)-B*5701 screening identifies patients at increased risk for abacavir (ABC) hypersensitivity reaction (HSR). Screening was adopted in GlaxoSmithKline and ViiV Healthcare clinical trials in 2007 and human immunodeficiency virus treatment guidelines in 2008. Company meta-analyses of trials pre-HLA-B*5701 screening reported HSR rates of 4-8%. We analyzed the effectiveness of HLA-B*5701 screening on reducing HSR rates using clinical trial, Observational Pharmaco-Epidemiology Research & Analysis (OPERA) cohort, and spontaneous reporting data. METHODS A meta-analysis examined 12 trials in 3063 HLA-B*5701-negative patients receiving an ABC-containing regimen from April 9, 2007, to September 22, 2015. Potential cases were identified using prespecified Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (drug hypersensitivity, hypersensitivity, anaphylactic reaction, anaphylaxis) and adjudicated against a Company ABC HSR case definition. Investigator-diagnosed cases were identified and rates were calculated. In the OPERA cohort, 9619 patients initiating their first ABC-containing regimen from January 1, 1999, to January 1, 2016, were identified. Patients were observed from regimen start until the earliest-following censoring event: ABC discontinuation, loss to follow-up, death, or study end (July 31, 2016). OPERA physicians evaluated events against OPERA definitions for definite/probable cases of ABC HSR; rates were calculated pre- and post-2008. The Company case definition was used to identify spontaneously reported cases for four marketed ABC-containing products; reporting rates were calculated using estimated exposure from sales data, through December 31, 2016. RESULTS Suspected ABC HSR rates were 1.3% or less in the meta-analysis. In the OPERA cohort, the rate was 0.4% among patients initiating ABC post-2008 versus 1.3% pre-2008 (p<0.0001). Spontaneous reporting rates were low post-2008 (54 to 22 cases per 100,000 patient-years exposure [PYE]) versus pre-2008 (618 to 55 cases per 100,000 PYE). CONCLUSIONS Clinically suspected ABC HSR rates were 1.3% or less in HLA-B*5701-negative patients. Recognizing their limitations, data from the OPERA cohort and spontaneous reporting indicate that HLA-B*5701 screening has reduced reporting rates of suspected HSR in clinical practice. Where screening for HLA-B*5701 is standard care, patients should be confirmed negative for this allele before starting ABC treatment.
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Affiliation(s)
- Chris M Stainsby
- Global Clinical Safety and Pharmacovigilance, GlaxoSmithKline, London, UK
| | | | - Vani Vannappagari
- Epidemiology and Real World Evidence, ViiV Healthcare, Research Triangle Park, North Carolina
| | - Karam C Mounzer
- Infectious Diseases, Philadelphia FIGHT, Philadelphia, Pennsylvania
| | - Ricky K Hsu
- Internal Medicine, AIDS Healthcare Foundation, New York, New York.,Internal Medicine, NYU Langone Medical Center, New York, New York
| | - Cassidy E Henegar
- Epidemiology and Real World Evidence, ViiV Healthcare, Research Triangle Park, North Carolina
| | - James Oyee
- Statistics, Programming and Data Strategy, GlaxoSmithKline, London, UK
| | | | - Charlotte E Lane
- Global Clinical Safety and Pharmacovigilance, GlaxoSmithKline, London, UK
| | - Lindsay M Carter
- Global Medical Sciences, ViiV Healthcare, Research Triangle Park, North Carolina
| | - Gary E Pakes
- Global Medical Sciences, ViiV Healthcare, Research Triangle Park, North Carolina
| | - Mark S Shaefer
- Global Medical Sciences, ViiV Healthcare, Research Triangle Park, North Carolina
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Gomez D, Power C, Fujiwara E. Neurocognitive Impairment and Associated Genetic Aspects in HIV Infection. Curr Top Behav Neurosci 2018; 50:41-76. [PMID: 30523615 DOI: 10.1007/7854_2018_69] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
HIV enters the central nervous system (CNS) early after infection. HIV-associated neurocognitive disorders (HAND) remain a serious complication of HIV infection despite available antiretroviral therapy (ART). Neurocognitive deficits observed in HAND are heterogeneous, suggesting a variability in individuals' susceptibility or resiliency to the detrimental CNS effects of HIV infection. This chapter reviews primary host genomic changes (immune-related genes, genes implicated in cognitive changes in primary neurodegenerative diseases), epigenetic mechanisms, and genetic interactions with ART implicated in HIV progression or HAND/neurocognitive complications of HIV. Limitations of the current findings include diversity of the HAND phenotype and limited replication of findings across cohorts. Strategies to improve the precision of future (epi)genetic studies of neurocognitive consequences of HIV infection are offered.
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Affiliation(s)
- Daniela Gomez
- Department of Psychiatry, University of Alberta, Edmonton, AB, Canada
| | - Christopher Power
- Departments of Psychiatry and Medicine, University of Alberta, Edmonton, AB, Canada
| | - Esther Fujiwara
- Department of Psychiatry, University of Alberta, Edmonton, AB, Canada.
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Genetic and nongenetic factors that may predispose individuals to allergic drug reactions. Curr Opin Allergy Clin Immunol 2018; 18:325-332. [DOI: 10.1097/aci.0000000000000459] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Cardone M, Garcia K, Tilahun ME, Boyd LF, Gebreyohannes S, Yano M, Roderiquez G, Akue AD, Juengst L, Mattson E, Ananthula S, Natarajan K, Puig M, Margulies DH, Norcross MA. A transgenic mouse model for HLA-B*57:01-linked abacavir drug tolerance and reactivity. J Clin Invest 2018; 128:2819-2832. [PMID: 29782330 DOI: 10.1172/jci99321] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Accepted: 03/20/2018] [Indexed: 01/11/2023] Open
Abstract
Adverse drug reactions (ADRs) are a major obstacle to drug development, and some of these, including hypersensitivity reactions to the HIV reverse transcriptase inhibitor abacavir (ABC), are associated with HLA alleles, particularly HLA-B*57:01. However, not all HLA-B*57:01+ patients develop ADRs, suggesting that in addition to the HLA genetic risk, other factors may influence the outcome of the response to the drug. To study HLA-linked ADRs in vivo, we generated HLA-B*57:01-Tg mice and show that, although ABC activated Tg mouse CD8+ T cells in vitro in a HLA-B*57:01-dependent manner, the drug was tolerated in vivo. In immunocompetent Tg animals, ABC induced CD8+ T cells with an anergy-like phenotype that did not lead to ADRs. In contrast, in vivo depletion of CD4+ T cells prior to ABC administration enhanced DC maturation to induce systemic ABC-reactive CD8+ T cells with an effector-like and skin-homing phenotype along with CD8+ infiltration and inflammation in drug-sensitized skin. B7 costimulatory molecule blockade prevented CD8+ T cell activation. These Tg mice provide a model for ABC tolerance and for the generation of HLA-B*57:01-restricted, ABC-reactive CD8+ T cells dependent on both HLA genetic risk and immunoregulatory host factors.
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Affiliation(s)
- Marco Cardone
- Laboratory of Immunology, Division of Biotechnology Review and Research III (DBRR III), Office of Biotechnology Products (OBP), Office of Pharmaceutical Quality (OPQ), Center for Drug Evaluation and Research (CDER), FDA, Silver Spring, Maryland, USA
| | - Karla Garcia
- Laboratory of Immunology, Division of Biotechnology Review and Research III (DBRR III), Office of Biotechnology Products (OBP), Office of Pharmaceutical Quality (OPQ), Center for Drug Evaluation and Research (CDER), FDA, Silver Spring, Maryland, USA
| | - Mulualem E Tilahun
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA
| | - Lisa F Boyd
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA
| | - Sintayehu Gebreyohannes
- Laboratory of Immunology, Division of Biotechnology Review and Research III (DBRR III), Office of Biotechnology Products (OBP), Office of Pharmaceutical Quality (OPQ), Center for Drug Evaluation and Research (CDER), FDA, Silver Spring, Maryland, USA
| | - Masahide Yano
- Laboratory of Immunology, Division of Biotechnology Review and Research III (DBRR III), Office of Biotechnology Products (OBP), Office of Pharmaceutical Quality (OPQ), Center for Drug Evaluation and Research (CDER), FDA, Silver Spring, Maryland, USA
| | - Gregory Roderiquez
- Laboratory of Immunology, Division of Biotechnology Review and Research III (DBRR III), Office of Biotechnology Products (OBP), Office of Pharmaceutical Quality (OPQ), Center for Drug Evaluation and Research (CDER), FDA, Silver Spring, Maryland, USA
| | - Adovi D Akue
- Division of Bacterial, Parasitic, and Allergenic Products (DBPAP), Office of Vaccines Research and Review (OVRR), Center for Biologics Evaluation and Research (CBER), US FDA, Silver Spring, Maryland, USA
| | - Leslie Juengst
- Laboratory of Immunology, Division of Biotechnology Review and Research III (DBRR III), Office of Biotechnology Products (OBP), Office of Pharmaceutical Quality (OPQ), Center for Drug Evaluation and Research (CDER), FDA, Silver Spring, Maryland, USA
| | - Elliot Mattson
- Laboratory of Immunology, Division of Biotechnology Review and Research III (DBRR III), Office of Biotechnology Products (OBP), Office of Pharmaceutical Quality (OPQ), Center for Drug Evaluation and Research (CDER), FDA, Silver Spring, Maryland, USA
| | - Suryatheja Ananthula
- Laboratory of Immunology, Division of Biotechnology Review and Research III (DBRR III), Office of Biotechnology Products (OBP), Office of Pharmaceutical Quality (OPQ), Center for Drug Evaluation and Research (CDER), FDA, Silver Spring, Maryland, USA
| | - Kannan Natarajan
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA
| | - Montserrat Puig
- Laboratory of Immunology, Division of Biotechnology Review and Research III (DBRR III), Office of Biotechnology Products (OBP), Office of Pharmaceutical Quality (OPQ), Center for Drug Evaluation and Research (CDER), FDA, Silver Spring, Maryland, USA
| | - David H Margulies
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA
| | - Michael A Norcross
- Laboratory of Immunology, Division of Biotechnology Review and Research III (DBRR III), Office of Biotechnology Products (OBP), Office of Pharmaceutical Quality (OPQ), Center for Drug Evaluation and Research (CDER), FDA, Silver Spring, Maryland, USA
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Van Den Driessche G, Fourches D. Adverse drug reactions triggered by the common HLA-B*57:01 variant: virtual screening of DrugBank using 3D molecular docking. J Cheminform 2018; 10:3. [PMID: 29383457 PMCID: PMC5790764 DOI: 10.1186/s13321-018-0257-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 01/17/2018] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Idiosyncratic adverse drug reactions have been linked to a drug's ability to bind with a human leukocyte antigen (HLA) protein. However, due to the thousands of HLA variants and limited structural data for drug-HLA complexes, predicting a specific drug-HLA combination represents a significant challenge. Recently, we investigated the binding mode of abacavir with the HLA-B*57:01 variant using molecular docking. Herein, we developed a new ensemble screening workflow involving three X-ray crystal derived docking procedures to screen the DrugBank database and identify potentially HLA-B*57:01 liable drugs. Then, we compared our workflow's performance with another model recently developed by Metushi et al., which proposed seven in silico HLA-B*57:01 actives, but were later found to be experimentally inactive. METHODS After curation, there were over 6000 approved and experimental drugs remaining in DrugBank for docking using Schrodinger's GLIDE SP and XP scoring functions. Docking was performed with our new consensus-like ensemble workflow, relying on three different X-ray crystals (3VRI, 3VRJ, and 3UPR) in presence and absence of co-binding peptides. The binding modes of HLA-B*57:01 hit compounds for all three peptides were further explored using 3D interaction fingerprints and hierarchical clustering. RESULTS The screening resulted in 22 hit compounds forecasted to bind HLA-B*57:01 in all docking conditions (SP and XP with and without peptides P1, P2, and P3). These 22 compounds afforded 2D-Tanimoto similarities being less than 0.6 when compared to the structure of native abacavir, whereas their 3D binding mode similarities varied in a broader range (0.2-0.8). Hierarchical clustering using a Ward Linkage revealed different clustering patterns for each co-binding peptide. When we docked Metushi et al.'s seven proposed hits using our workflow, our screening platform identified six out of seven as being inactive. Molecular dynamic simulations were used to explore the stability of abacavir and acyclovir in complex with peptide P3. CONCLUSIONS This study reports on the extensive docking of the DrugBank database and the 22 HLA-B*57:01 liable candidates we identified. Importantly, comparisons between this study and the one by Metushi et al. highlighted new critical and complementary knowledge for the development of future HLA-specific in silico models.
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Affiliation(s)
- George Van Den Driessche
- Department of Chemistry, Bioinformatics Research Center, North Carolina State University, Raleigh, NC, USA
| | - Denis Fourches
- Department of Chemistry, Bioinformatics Research Center, North Carolina State University, Raleigh, NC, USA.
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50
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Redwood AJ, Pavlos RK, White KD, Phillips EJ. HLAs: Key regulators of T-cell-mediated drug hypersensitivity. HLA 2018; 91:3-16. [PMID: 29171940 PMCID: PMC5743596 DOI: 10.1111/tan.13183] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 11/20/2017] [Indexed: 12/17/2022]
Abstract
Adverse drug reactions (ADR) can be broadly categorised as either on-target or off-target. On-target ADRs arise as a direct consequence of the pharmacological properties of the drug and are therefore predictable and dose-dependent. On-target ADRs comprise the majority (>80%) of ADRs, relate to the drug's interaction with its known pharmacological target and are a result of a complex interplay of genetic and ecologic factors. In contrast, off-target ADRs, including immune-mediated ADRs (IM-ADRs), are due to unintended pharmacological interactions such as inadvertent ligation of host cell receptors or non-pharmacological interactions mediated through an adaptive immune response. IM-ADRs can be classified according to the primary immune cell involved and include B-cell-mediated (Gell-Coombs type I-III reactions) and T-cell-mediated (Gell-Coombs type IV or delayed hypersensitivity) reactions. IM-ADRs mediated by T cells are associated with phenotypically distinct clinical diagnoses and can vary from a mild delayed rash to a life-threatening cutaneous, systemic or organ disease, such as Stephen Johnson syndrome/toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms and drug-induced liver disease. T-cell-mediated ADRs are strongly linked to the carriage of particular HLA risk alleles which are in the case of abacavir hypersensitivity and HLA-B*57:01 has led to translation into the clinic as a routine screening test. In this review, we will discuss the immunogenetics and pathogenesis of IM-ADRs and how HLA associations inform both pre-drug screening strategies and mechanistic understanding.
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Affiliation(s)
- Alec J. Redwood
- Institute for Immunology & Infectious Diseases, Murdoch University, Murdoch, Western Australia 6150
| | - Rebecca K. Pavlos
- Institute for Immunology & Infectious Diseases, Murdoch University, Murdoch, Western Australia 6150
| | - Katie D. White
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Elizabeth J. Phillips
- Institute for Immunology & Infectious Diseases, Murdoch University, Murdoch, Western Australia 6150
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Pharmacology, Vanderbilt University School of Medicine
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