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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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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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Zhou XY, Li CX, Zhang JB, Tan JT, -Yang X, Albarmaqi RA, Li YY, Kuang YQ. Association of Human Leukocyte Antigen Alleles and Hypersensitivity of Efavirenz/Nevirapine in HIV-Infected Chinese Patients. AIDS Res Hum Retroviruses 2022; 38:884-889. [PMID: 36226442 DOI: 10.1089/aid.2022.0027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
To examine the association between human leukocyte antigen (HLA) and nevirapine (NVP)- and efavirenz (EFV)-induced cutaneous adverse reactions in human immunodeficiency virus (HIV) patients, we conducted a case-control study at our center consisting of 96 patients. Patients were further assigned based on the occurrence of cutaneous adverse events and the drugs involved. All patients were subjected to next generation sequencing (NGS)-based screening with focus on HLA phenotype, including the presence of HLA-B, HLA-C, and HLA-DRB1. Our data indicated that the HLA-C*01:02:01 allele presence was observed in 47.4% (18/38) of patients in the EFV-hypersensitivity group compared with 18.9% (7/30) in the control group [odds ratio (OR) = 5.837; 95% confidence interval (CI) = 1.727-19.722, p = .005]. In contrast, the occurrence of HLA-DRB1*08:03 was found to be significantly lower in the EFV-hypersensitivity group (4/38, 10.5%) compared with the corresponding control group (12/37, 32.4%) (OR = 0.148; 95% CI = 0.035-0.625, p = .009). In addition, the HLA-DRB1*04:05:01 antigen was expressed more frequently in the NVP-hypersensitivity group (23.8%, 5/21) compared with the control group (10.8%, 4/37) (OR = 7; 95% CI = 1.265-38.793, p = .026). Our data not only revealed a significant association between HLA-C*01:02:01 and EFV-induced cutaneous adverse reactions but may also shed light on defining the treatment for Chinese HIV patients.
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Affiliation(s)
- Xiao-Yan Zhou
- Department of Dermatology, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Chong-Xi Li
- Department of HIV/AIDS, Third People's Hospital of Kunming City, Kunming, China
| | - Jian-Bo Zhang
- Department of Dermatology, Second People's Hospital of Dali City, Dali, China
| | - Jun-Ting Tan
- Department of Dermatology, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Xi -Yang
- Department of Dermatology, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Rowida A Albarmaqi
- Department of Dermatology, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Yu-Ye Li
- Department of Dermatology, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Yi-Qun Kuang
- NHC Key Laboratory of Drug Addiction Medicine, First Affiliated Hospital of Kunming Medical University, Kunming Medical University, Kunming, China.,Scientific Research Laboratory Center, First Affiliated Hospital of Kunming Medical University, Kunming, China
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Biswas M, Sawajan N, Rungrotmongkol T, Sanachai K, Ershadian M, Sukasem C. Pharmacogenetics and Precision Medicine Approaches for the Improvement of COVID-19 Therapies. Front Pharmacol 2022; 13:835136. [PMID: 35250581 PMCID: PMC8894812 DOI: 10.3389/fphar.2022.835136] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 01/24/2022] [Indexed: 01/18/2023] Open
Abstract
Many drugs are being administered to tackle coronavirus disease 2019 (COVID-19) pandemic situations without establishing clinical effectiveness or tailoring safety. A repurposing strategy might be more effective and successful if pharmacogenetic interventions are being considered in future clinical studies/trials. Although it is very unlikely that there are almost no pharmacogenetic data for COVID-19 drugs, however, from inferring the pharmacokinetic (PK)/pharmacodynamic(PD) properties and some pharmacogenetic evidence in other diseases/clinical conditions, it is highly likely that pharmacogenetic associations are also feasible in at least some COVID-19 drugs. We strongly mandate to undertake a pharmacogenetic assessment for at least these drug-gene pairs (atazanavir-UGT1A1, ABCB1, SLCO1B1, APOA5; efavirenz-CYP2B6; nevirapine-HLA, CYP2B6, ABCB1; lopinavir-SLCO1B3, ABCC2; ribavirin-SLC28A2; tocilizumab-FCGR3A; ivermectin-ABCB1; oseltamivir-CES1, ABCB1; clopidogrel-CYP2C19, ABCB1, warfarin-CYP2C9, VKORC1; non-steroidal anti-inflammatory drugs (NSAIDs)-CYP2C9) in COVID-19 patients for advancing precision medicine. Molecular docking and computational studies are promising to achieve new therapeutics against SARS-CoV-2 infection. The current situation in the discovery of anti-SARS-CoV-2 agents at four important targets from in silico studies has been described and summarized in this review. Although natural occurring compounds from different herbs against SARS-CoV-2 infection are favorable, however, accurate experimental investigation of these compounds is warranted to provide insightful information. Moreover, clinical considerations of drug-drug interactions (DDIs) and drug-herb interactions (DHIs) of the existing repurposed drugs along with pharmacogenetic (e.g., efavirenz and CYP2B6) and herbogenetic (e.g., andrographolide and CYP2C9) interventions, collectively called multifactorial drug-gene interactions (DGIs), may further accelerate the development of precision COVID-19 therapies in the real-world clinical settings.
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Affiliation(s)
- Mohitosh Biswas
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
- Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand
- Department of Pharmacy, University of Rajshahi, Rajshahi, Bangladesh
| | - Nares Sawajan
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
- Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand
- Department of Pathology, School of Medicine, Mae Fah Luang University, Chiang Rai, Thailand
| | - Thanyada Rungrotmongkol
- Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
- Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok, Thailand
| | - Kamonpan Sanachai
- Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
| | - Maliheh Ershadian
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
- Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand
| | - Chonlaphat Sukasem
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
- Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand
- Pharmacogenomics and Precision Medicine, The Preventive Genomics and Family Check-up Services Center, Bumrungrad International Hospital, Bangkok, Thailand
- MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
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The Immunogenetics of Cutaneous Drug Reactions. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1367:411-431. [PMID: 35286706 DOI: 10.1007/978-3-030-92616-8_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Singh M, Pawar M, Bhargava S, Gupta P, Adhicari P. A novel association of efavirenz induced severe cutaneous adverse reactions with HLA- DRB1*03:01: A case-control study from North-East India. Dermatol Ther 2021; 34:e14760. [PMID: 33421254 DOI: 10.1111/dth.14760] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 12/27/2020] [Indexed: 11/27/2022]
Abstract
HIV-infected patients have a higher risk of developing cutaneous reactions to drugs than the general population. Severe cutaneous adverse reactions (SCARs) are not uncommon in patients taking antiretroviral therapy (HAART]. To evaluate HLA class I and II allele frequencies in HIV patients on HAART who develop SCARs due to nevirapine (NVP] or efavirenz (EFZ] containing regime and compare this genotype composition with HAART tolerant patients and healthy organ donors. A case-control study for 4 years was conducted with four subsets of patients hailing from north-east India:Cohort 1- HIV seropositive patients who developed SCARs due to EFZ (n = 8];Cohort 2 - HIV seropositive patients who developed SCARs due to NVP (n = 15]; Cohort 3 -HIV seropositive NVP/EFZ-tolerant patients (n = 18]; Cohort 4 - Healthy HIV seronegative organ donors (n = 169].Cohort 3 & 4 acted as control-group. These patients were genotyped for the HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1, and HLA-DPB1 by a sequence-based HLA typing method. HLA-DRB1*03:01 allele revealed a significant association with EFZ regimen-induced SCARs in 62.5% patients compared with only 5.56% observed in HAART-tolerant patients and 4.14% in healthy organ. HLA-B*3505was found to be significantly associated with NVP induced SCARs. We found significant novel association of HLA-DRB1*03:01 with EFZ induced SCARs in North-East Indian HIV patients. Thus, HLA-DRB*03:01 may be useful as a genetic marker to avoid EFZ induced serious cutaneous rashes. The molecular HLA characterization of these alleles may provide a novel insight into the immunological basis of the antiretroviral drug reactions.
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Affiliation(s)
- Mehak Singh
- Department of Dermatology, LN Medical college and JK hospital, Bhopal, India
| | - Manoj Pawar
- Department of Dermatology, Varun Arjun Medical College, Shahajahanpur, U.P., India
| | - Shashank Bhargava
- Department of Dermatology, R. D. Gardi Medical College, Ujjain, India
| | - Prakhar Gupta
- Department of General Medicine, LN Medical College and JK hospital, Bhopal, India
| | - Pankaj Adhicari
- Department of Dermatology, Gauhati Medical College and Hospital, Guwahati, India
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Pharmacogenomics and COVID-19: clinical implications of human genome interactions with repurposed drugs. THE PHARMACOGENOMICS JOURNAL 2021; 21:275-284. [PMID: 33542445 PMCID: PMC7859465 DOI: 10.1038/s41397-021-00209-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Revised: 12/07/2020] [Accepted: 01/15/2021] [Indexed: 02/07/2023]
Abstract
The outbreak of Coronavirus disease 2019 (COVID-19) has evolved into an emergent global pandemic. Many drugs without established efficacy are being used to treat COVID-19 patients either as an offlabel/compassionate use or as a clinical trial. Although drug repurposing is an attractive approach with reduced time and cost, there is a need to make predictions on success before the start of therapy. For the optimum use of these repurposed drugs, many factors should be considered such as drug–gene or dug–drug interactions, drug toxicity, and patient co-morbidity. There is limited data on the pharmacogenomics of these agents and this may constitute an obstacle for successful COVID-19 therapy. This article reviewed the available human genome interactions with some promising repurposed drugs for COVID-19 management. These drugs include chloroquine (CQ), hydroxychloroquine (HCQ), azithromycin, lopinavir/ritonavir (LPV/r), atazanavir (ATV), favipiravir (FVP), nevirapine (NVP), efavirenz (EFV), oseltamivir, remdesivir, anakinra, tocilizumab (TCZ), eculizumab, heme oxygenase 1 (HO-1) regulators, renin–angiotensin–aldosterone system (RAAS) inhibitors, ivermectin, and nitazoxanide. Drug-gene variant pairs that may alter the therapeutic outcomes in COVID-19 patients are presented. The major drug variant pairs that associated with variations in clinical efficacy include CQ/HCQ (CYP2C8, CYP2D6, ACE2, and HO-1); azithromycin (ABCB1); LPV/r (SLCO1B1, ABCB1, ABCC2 and CYP3A); NVP (ABCC10); oseltamivir (CES1 and ABCB1); remdesivir (CYP2C8, CYP2D6, CYP3A4, and OATP1B1); anakinra (IL-1a); and TCZ (IL6R and FCGR3A). The major drug variant pairs that associated with variations in adverse effects include CQ/HCQ (G6PD; hemolysis and ABCA4; retinopathy), ATV (MDR1 and UGT1A1*28; hyperbilirubinemia; and APOA5; dyslipidemia), NVP (HLA-DRB1*01, HLA-B*3505 and CYP2B6; skin rash and MDR1; hepatotoxicity), and EFV (CYP2B6; depression and suicidal tendencies).
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Sanabria-Cabrera J, Medina-Cáliz I, Stankevičiūtė S, Rodríguez-Nicolás A, Almarza-Torres M, Lucena MI, Andrade RJ. Drug-Induced liver Injury Associated with Severe Cutaneous Hypersensitivity Reactions: A Complex Entity in Need of a Multidisciplinary Approach. Curr Pharm Des 2020; 25:3855-3871. [PMID: 31696806 DOI: 10.2174/1381612825666191107161912] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 11/06/2019] [Indexed: 12/12/2022]
Abstract
Idiosyncratic drug-induced liver injury (DILI) occasionally occurs in the setting of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). This strengthens the proposed immunologic mechanism associated with this adverse reaction. DRESS exhibits the most common association with DILI. SCARs have a wide spectrum of heterogeneous clinical presentations and severity, and genetic predisposition has been identified. In the context of SCARs, DILI present a different clinical picture, ranging from mild injury to acute liver failure. Elucidating the role of DILI in the clinical presentation and outcome of SCARs represents a challenge due to limited information from published studies and the lack of consensus on definitions. The cholestatic and mixed pattern of liver damage typically predominates in the case of DILI associated with SCARs, which is different from DILI without SCARs where hepatocellular is the most common injury pattern. Only a few drugs have been associated with both DILI and SCARs. Is this article, the criteria used for DILI recognition among SCARS have been revised and discussed, along with the drugs most commonly involved in these syndromes as well as the outcome, prognostic factors and the need for a multidisciplinary approach to improve the management of DILI in the context of SCARs.
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Affiliation(s)
- Judith Sanabria-Cabrera
- Servicio de Farmacologia Clinica, Instituto de Investigacion Biomedica de Malaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Malaga, Malaga, Spain.,UCICEC IBIMA, Plataforma SCReN (Spanish Clinical Research Network), Madrid, Spain
| | - Inmaculada Medina-Cáliz
- Servicio de Farmacologia Clinica, Instituto de Investigacion Biomedica de Malaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Malaga, Malaga, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | | | | | - Marina Almarza-Torres
- Servicio de Farmacologia Clinica, Instituto de Investigacion Biomedica de Malaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Malaga, Malaga, Spain
| | - M Isabel Lucena
- Servicio de Farmacologia Clinica, Instituto de Investigacion Biomedica de Malaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Malaga, Malaga, Spain.,UCICEC IBIMA, Plataforma SCReN (Spanish Clinical Research Network), Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Raúl J Andrade
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.,Servicio de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain
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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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Immunogenicity assessment of fungal l-asparaginases: an in silico approach. SN APPLIED SCIENCES 2020. [DOI: 10.1007/s42452-020-2021-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
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11
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Alfirevic A, Pirmohamed M, Marinovic B, Harcourt‐Smith L, Jorgensen AL, Cooper TE. 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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12
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Devarbhavi H, Raj S. Drug-induced liver injury with skin reactions: Drugs and host risk factors, clinical phenotypes and prognosis. Liver Int 2019; 39:802-811. [PMID: 30515930 DOI: 10.1111/liv.14004] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 10/30/2018] [Accepted: 11/07/2018] [Indexed: 02/13/2023]
Abstract
While dermatologic manifestations of adverse drug reactions are frequent, drug-induced liver injury is rare. Numerous drugs are implicated in either Drug-Induced Liver Injury or Drug-Induced Skin Injury. However, concomitant Drug-Induced Liver Injury and Drug-Induced Skin Injury are uncommon, not well characterized and appear to be caused by a limited number of drugs. These are often associated with immuno-allergic or hypersensitivity features such as fever, skin rash, blisters or peeling of skin, eosinophilia, lymphadenopathy and mucositis. Liver injury can range from asymptomatic elevation of liver biochemical tests to severe hepatitis and acute liver failure needing liver transplantation. Severe cutaneous adverse reaction, particularly drug reaction with eosinophilia and systemic symptoms is commonly associated with internal organ involvement, the liver being the most frequently involved in approximately 90% of the cases. In Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis, abnormalities in liver biochemistry tests are common but severe liver disease is rare. There is a strong association of Human Leukocyte Antigen genotype with both drug reaction with eosinophilia and systemic symptoms and Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis. It is likely that the delayed immune-mediated reaction triggering skin reaction is also responsible for hepatitis. Drug-specific lymphocytes are found in the organs involved and also in circulating blood, which along with the cytokines and chemokines play a role in pathogenesis. Anti-epileptic drugs, allopurinol, sulfonamides, antibiotics and nevirapine are the top five causes of concomitant liver and skin injury. This review will focus on drug and host factors causing concomitant Drug-Induced Skin Injury and Drug-Induced Liver Injury and discuss the characteristics of liver involvement in patients with severe cutaneous adverse reaction.
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Affiliation(s)
- Harshad Devarbhavi
- Department of Gastroenterology and Hepatology, St. John's Medical College Hospital, Bangalore, India
| | - Sujata Raj
- Department of Dermatology, St. John's Medical College Hospital, Bangalore, India
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13
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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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14
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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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15
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Pavlos R, White KD, Wanjalla C, Mallal SA, Phillips EJ. Severe Delayed Drug Reactions: Role of Genetics and Viral Infections. Immunol Allergy Clin North Am 2017; 37:785-815. [PMID: 28965641 PMCID: PMC5702581 DOI: 10.1016/j.iac.2017.07.007] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Adverse drug reactions (ADRs) are a significant source of patient morbidity and mortality and represent a major burden to health care systems and drug development. Up to 50% of such reactions are preventable. Although many ADRs can be predicted based on the on-target pharmacologic activity, ADRs arising from drug interactions with off-target receptors are recognized. Off-target ADRs include the immune-mediated ADRs (IM-ADRs) and pharmacologic drug effects. In this review, we discuss what is known about the immunogenetics and pathogenesis of IM-ADRs and the hypothesized role of heterologous immunity in the development of IM-ADRs.
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Affiliation(s)
- Rebecca Pavlos
- Institute for Immunology and Infectious Diseases, Murdoch University, 6150 Murdoch, Western Australia, Australia
| | - Katie D White
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Celestine Wanjalla
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Simon A Mallal
- Institute for Immunology and Infectious Diseases, Murdoch University, 6150 Murdoch, Western Australia, Australia; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Elizabeth J Phillips
- Institute for Immunology and Infectious Diseases, Murdoch University, 6150 Murdoch, Western Australia, Australia; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
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16
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Carr DF, Bourgeois S, Chaponda M, Takeshita LY, Morris AP, Castro EMC, Alfirevic A, Jones AR, Rigden DJ, Haldenby S, Khoo S, Lalloo DG, Heyderman RS, Dandara C, Kampira E, van Oosterhout JJ, Ssali F, Munderi P, Novelli G, Borgiani P, Nelson MR, Holden A, Deloukas P, Pirmohamed M. Genome-wide association study of nevirapine hypersensitivity in a sub-Saharan African HIV-infected population. J Antimicrob Chemother 2017; 72:1152-1162. [PMID: 28062682 PMCID: PMC5400091 DOI: 10.1093/jac/dkw545] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Accepted: 11/20/2016] [Indexed: 01/11/2023] Open
Abstract
Background The antiretroviral nevirapine is associated with hypersensitivity reactions in 6%-10% of patients, including hepatotoxicity, maculopapular exanthema, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Objectives To undertake a genome-wide association study (GWAS) to identify genetic predisposing factors for the different clinical phenotypes associated with nevirapine hypersensitivity. Methods A GWAS was undertaken in a discovery cohort of 151 nevirapine-hypersensitive and 182 tolerant, HIV-infected Malawian adults. Replication of signals was determined in a cohort of 116 cases and 68 controls obtained from Malawi, Uganda and Mozambique. Interaction with ERAP genes was determined in patients positive for HLA-C*04:01 . In silico docking studies were also performed for HLA-C*04:01 . Results Fifteen SNPs demonstrated nominal significance ( P < 1 × 10 -5 ) with one or more of the hypersensitivity phenotypes. The most promising signal was seen in SJS/TEN, where rs5010528 ( HLA-C locus) approached genome-wide significance ( P < 8.5 × 10 -8 ) and was below HLA -wide significance ( P < 2.5 × 10 -4 ) in the meta-analysis of discovery and replication cohorts [OR 4.84 (95% CI 2.71-8.61)]. rs5010528 is a strong proxy for HLA-C*04:01 carriage: in silico docking showed that two residues (33 and 123) in the B pocket were the most likely nevirapine interactors. There was no interaction between HLA-C*04:01 and ERAP1 , but there is a potential protective effect with ERAP2 [ P = 0.019, OR 0.43 (95% CI 0.21-0.87)]. Conclusions HLA-C*04:01 predisposes to nevirapine-induced SJS/TEN in sub-Saharan Africans, but not to other hypersensitivity phenotypes. This is likely to be mediated via binding to the B pocket of the HLA-C peptide. Whether this risk is modulated by ERAP2 variants requires further study.
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Affiliation(s)
- Daniel F Carr
- Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
| | - Stephane Bourgeois
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Mas Chaponda
- Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.,Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Malawi
| | - Louise Y Takeshita
- Institute of Integrative Biology, University of Liverpool, Liverpool, UK
| | - Andrew P Morris
- Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.,Department of Biostatistics, University of Liverpool, Liverpool, UK
| | - Elena M Cornejo Castro
- Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
| | - Ana Alfirevic
- Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
| | - Andrew R Jones
- Institute of Integrative Biology, University of Liverpool, Liverpool, UK
| | - Daniel J Rigden
- Institute of Integrative Biology, University of Liverpool, Liverpool, UK
| | - Sam Haldenby
- Centre for Genomic Research, University of Liverpool, Liverpool, UK
| | - Saye Khoo
- Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
| | | | - Robert S Heyderman
- Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Malawi.,Division of Infection and Immunity, University College London, London, UK
| | - Collet Dandara
- Division of Human Genetics, University of Cape Town, Cape Town, South Africa
| | - Elizabeth Kampira
- Division of Human Genetics, University of Cape Town, Cape Town, South Africa
| | - Joep J van Oosterhout
- Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Malawi.,Dignitas International, Zomba, Malawi
| | - Francis Ssali
- Joint Clinical Research Centre, Headquarters, Kampala, Uganda
| | - Paula Munderi
- UVRI/MRC Uganda Research Unit on AIDS, Entebbe, Uganda
| | - Giuseppe Novelli
- Department of Biomedicine and Prevention, University of Rome 'Tor Vergata', Rome, Italy
| | - Paola Borgiani
- Department of Biomedicine and Prevention, University of Rome 'Tor Vergata', Rome, Italy
| | | | | | - Panos Deloukas
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.,Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.,Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, 21589, Saudi Arabia
| | - Munir Pirmohamed
- Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
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17
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Brandariz D, Smithson A, Anton-Vazquez V. Drug reaction with eosinophilia and systemic symptoms related to antiretroviral treatment in human immunodeficiency virus patients. Indian J Sex Transm Dis AIDS 2017; 38:163-170. [PMID: 30148271 PMCID: PMC6085929 DOI: 10.4103/ijstd.ijstd_70_17] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND The drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a life-threatening condition caused by different medications. The objective of this study was to analyze DRESS cases related to antiretroviral therapy in human immunodeficiency virus (HIV) patients. MATERIALS AND METHODS Systematic review of DRESS suspected cases in HIV patients associated to antiretrovirals published between January 1998 and April 2017. The registry of the severe cutaneous adverse reactions score was used to classify each report as a "definitive," "probable," "possible," or "no" DRESS case. Clinical characteristics, management, and outcomes were evaluated. RESULTS Thirty-five case reports were analyzed involving 5 antiretrovirals: Abacavir in 10 (28.6%) cases, efavirenz in 6 (17.1%), nevirapine in 12 (34.3%), raltegravir in 6 (17.1%), and tenofovir in 1 (2.9%). Mean age of the patients was 40 ± 13 years, 65% of which were male. A total of 57.1% reports were classified as having a "definitive-probable" DRESS case. Management was based on withdrawal of the causal antiretroviral and corticosteroids in 68.6% of the cases. None of the patients died. Treatment with nevirapine or raltegravir, the longer onset of symptoms and the presence of lymphadenopathy, eosinophilia, liver involvement, and a longer time for clinical resolution were more frequent among "definitive-probable" DRESS cases. CONCLUSIONS A DRESS syndrome has to be suspected in HIV patients with lymphadenopathy, eosinophilia, and liver involvement developing weeks after the initiation of nevirapine or raltegravir. Suspension of the causal antiretroviral and in most cases treatment with corticosteroids allowed adequate clinical control.
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Affiliation(s)
- David Brandariz
- Department of Hospital Pharmacy, Hospital de l'Esperit Sant, Santa Coloma Gramenet, Spain
| | - Alex Smithson
- Infectious Disease Unit, Hospital de l'Esperit Sant, Santa Coloma de Gramenet, Spain
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18
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Fricke-Galindo I, LLerena A, López-López M. An update on HLA alleles associated with adverse drug reactions. Drug Metab Pers Ther 2017; 32:73-87. [PMID: 28315856 DOI: 10.1515/dmpt-2016-0025] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Accepted: 02/07/2017] [Indexed: 06/06/2023]
Abstract
Adverse drug reactions (ADRs) are considered as an important cause of morbidity and mortality. The hypersensitivity reactions are immune-mediated ADRs, which are dose-independent, unpredictable and have been associated with several HLA alleles. The present review aimed to describe HLA alleles that have been associated with different ADRs in populations worldwide, the recommendations of regulatory agencies and pharmacoeconomic information and databases for the study of HLA alleles in pharmacogenetics. A systematic search was performed in June 2016 of articles relevant to this issue in indexed journals and in scientific databases (PubMed and PharmGKB). The information of 95 association studies found was summarized. Several HLA alleles and haplotypes have been associated with ADRs induced mainly by carbamazepine, allopurinol, abacavir and nevirapine, among other drugs. Years with the highest numbers of publications were 2013 and 2014. The majority of the reports have been performed on Asians and Caucasians, and carbamazepine was the most studied ADR drug inducer. Two HLA alleles' databases are described, as well as the recommendations of the U.S. Food and Drug Administration, the European Medicine Agency and the Clinical Pharmacogenetics Implementation Consortium. Pharmacoeconomic studies on this issue are also mentioned. The strongest associations remain for HLA-B*58:01, HLA-B*57:01, HLA-B*15:02 and HLA-A*31:01 but only in certain populations; therefore, studies on different ethnic groups would be useful. Due to the improvement of drug therapy and the economic benefit that HLA screening represents, investigations on HLA alleles associated with ADR should continue.
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19
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Garon SL, Pavlos RK, White KD, Brown NJ, Stone CA, Phillips EJ. Pharmacogenomics of off-target adverse drug reactions. Br J Clin Pharmacol 2017; 83:1896-1911. [PMID: 28345177 DOI: 10.1111/bcp.13294] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Revised: 03/14/2017] [Accepted: 03/19/2017] [Indexed: 12/15/2022] Open
Abstract
Off-target adverse drug reactions (ADRs) are associated with significant morbidity and costs to the healthcare system, and their occurrence is not predictable based on the known pharmacological action of the drug's therapeutic effect. Off-target ADRs may or may not be associated with immunological memory, although they can manifest with a variety of shared clinical features, including maculopapular exanthema, severe cutaneous adverse reactions (SCARs), angioedema, pruritus and bronchospasm. Discovery of specific genes associated with a particular ADR phenotype is a foundational component of clinical translation into screening programmes for their prevention. In this review, genetic associations of off-target drug-induced ADRs that have a clinical phenotype suggestive of an immunologically mediated process and their mechanisms are highlighted. A significant proportion of these reactions lack immunological memory and current data are informative for these ADRs with regard to disease pathophysiology, therapeutic targets and biomarkers which may identify patients at greatest risk. Although many serious delayed immune-mediated (IM)-ADRs show strong human leukocyte antigen associations, only a small subset have successfully been implemented in screening programmes. More recently, other factors, such as drug metabolism, have been shown to contribute to the risk of the IM-ADR. In the future, pharmacogenomic targets and an understanding of how they interact with drugs to cause ADRs will be applied to drug design and preclinical testing, and this will allow selection of optimal therapy to improve patient safety.
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Affiliation(s)
- Sarah L Garon
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Rebecca K Pavlos
- Institute for Immunology & Infectious Diseases, Murdoch University, Murdoch, WA, 6150, Australia
| | - Katie D White
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Nancy J Brown
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Cosby A Stone
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Elizabeth J Phillips
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.,Institute for Immunology & Infectious Diseases, Murdoch University, Murdoch, WA, 6150, Australia.,Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
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20
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Pichler WJ, Hausmann O. Classification of Drug Hypersensitivity into Allergic, p-i, and Pseudo-Allergic Forms. Int Arch Allergy Immunol 2016; 171:166-179. [PMID: 27960170 DOI: 10.1159/000453265] [Citation(s) in RCA: 105] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Drug hypersensitivity reactions (DHR) are clinically and functionally heterogeneous. Different subclassifications based on timing of symptom appearance or type of immune mechanism have been proposed. Here, we show that the mode of action of drugs leading to immune/inflammatory cell stimulation is a further decisive factor in understanding and managing DHR. Three mechanisms can be delineated: (a) some drugs have or gain the ability to bind covalently to proteins, form new antigens, and thus elicit immune reactions to hapten-carrier complexes (allergic/immune reaction); (b) a substantial part of immune-mediated DHR is due to a typical off-target activity of drugs on immune receptors like HLA and TCR (pharmacological interaction with immune receptors, p-i reactions); such p-i reactions are linked to severe DHR; and (c) symptoms of DHR can also appear if the drug stimulates or inhibits receptors or enzymes of inflammatory cells (pseudo-allergy). These three distinct ways of stimulations of immune or inflammatory cells differ substantially in clinical manifestations, time of appearance, dose dependence, predictability, and cross-reactivity, and thus need to be differentiated.
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21
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Konvinse KC, Phillips EJ, White KD, Trubiano JA. Old dog begging for new tricks: current practices and future directions in the diagnosis of delayed antimicrobial hypersensitivity. Curr Opin Infect Dis 2016; 29:561-576. [PMID: 27753687 PMCID: PMC5113146 DOI: 10.1097/qco.0000000000000323] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW Antimicrobials are a leading cause of severe T cell-mediated adverse drug reactions (ADRs). The purpose of this review is to address the current understanding of antimicrobial cross-reactivity and the ready availability of and evidence for in-vitro, in-vivo, and ex-vivo diagnostics for T cell-mediated ADRs. RECENT FINDINGS Recent literature has evaluated the efficacy of traditional antibiotic allergy management, including patch testing, skin prick testing, intradermal testing, and oral challenge. Although patch and intradermal testing are specific for the diagnosis of immune-mediated ADRs, they suffer from drug-specific limitations in sensitivity. The use of ex-vivo diagnostics, especially enzyme-linked immunospot, has been highlighted as a promising new approach to assigning causality. Knowledge of true rates of antimicrobial cross-reactivity aids empirical antibiotic choice in the setting of previous immune-mediated ADRs. SUMMARY In an era of increasing antimicrobial resistance and use of broad-spectrum antimicrobial therapy, ensuring patients are assigned the correct 'allergy label' is essential. Re-exposure to implicated antimicrobials, especially in the setting of severe adverse cutaneous reaction, is associated with significant morbidity and mortality. The process through which an antibiotic label gets assigned, acted on and maintained is still imprecise. Predicting T cell-mediated ADRs via personalized approaches, including human leukocyte antigen-typing, may pave future pathways to safer antimicrobial prescribing guidelines.
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Affiliation(s)
- Katherine C Konvinse
- aDepartment of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA bInstitute for Immunology and Infectious Diseases, Murdoch University, Western Australia, Australia cDepartment of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA dDepartment of Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, USA eDepartment of Infectious Diseases, Austin Hospital, Victoria, Australia fDepartment of Infectious Diseases, Alfred Hospital, Victoria, Australia gDepartment of Infectious Diseases, Peter MacCallum Cancer Centre, Victoria, Australia hDepartment of Medicine, University of Melbourne, Victoria, Australia
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22
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Li YY, Jin YM, He LP, Bai JS, Liu J, Yu M, Chen JH, Wen J, Kuang YQ. Clinical analysis of HIV/AIDS patients with drug eruption in Yunnan, China. Sci Rep 2016; 6:35938. [PMID: 27796328 PMCID: PMC5086857 DOI: 10.1038/srep35938] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Accepted: 10/07/2016] [Indexed: 01/11/2023] Open
Abstract
Drug eruption is the most common clinical presentation in patients with HIV/AIDS. The systemic clinical and risk factors associated with drug eruption remain unknown. A retrospective analysis in HIV/AIDS patients with drug eruption was carried out with demographic data, epidemiological data, clinical characteristics, laboratory data and follow-up data. The risk factors correlated with prognosis were assessed by case control analysis. A total of 134 out of 1817 HIV/AIDS patients (7.4%) presented drug eruptions. The major class of sensitizing drug was HAART drugs (47.7%), followed by antibiotics (47.0%). Nevirapine (39.6%) was the most common sensitizing drug in the HAART regimens. The patients received HAART or had allergic history were prone to develop drug eruption. The alanine aminotransferase, albumin, globulin, creatinine, blood urea nitrogen (BUN), lymphocytes, red blood cells (RBC) and eosinophils of the drug eruption patients were significantly different the control patients. The allergic history, opportunistic infection, viral load, CD4 cell count, high globulin and low albumin were the risk factors correlated with death in HIV/AIDS patients with drug eruption. It is proposed that patients with higher viral loads, higher globulin levels and lower white blood cells (WBC) should be given special attention for the prevention of complications and death.
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Affiliation(s)
- Yu-Ye Li
- Department of Dermatology and Venerology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, P. R. China
| | - Yong-Mei Jin
- Department of Dermatology and Venerology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, P. R. China.,Department of HIV/AIDS, The Third People's Hospital of Kunming, Kunming 650041, P. R. China
| | - Li-Ping He
- School of Public Health, Kunming Medical University, Kunming 650500, P. R. China
| | - Jin-Song Bai
- Department of HIV/AIDS, The Third People's Hospital of Kunming, Kunming 650041, P. R. China
| | - Jun Liu
- Department of HIV/AIDS, The Third People's Hospital of Kunming, Kunming 650041, P. R. China
| | - Min Yu
- Department of HIV/AIDS, The Third People's Hospital of Kunming, Kunming 650041, P. R. China
| | - Jian-Hua Chen
- Department of HIV/AIDS, The Third People's Hospital of Kunming, Kunming 650041, P. R. China
| | - Jing Wen
- Center for Translational Medicine, Huaihe Clinical College, Henan University, Kaifeng 475000, P. R. China.,Pharmaceutical College, Henan University, Kaifeng 475001, P. R. China
| | - Yi-Qun Kuang
- Center for Translational Medicine, Huaihe Clinical College, Henan University, Kaifeng 475000, P. R. China
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Dalal B, Shankarkumar A, Ghosh K. Individualization of antiretroviral therapy--pharmacogenomic aspect. Indian J Med Res 2016; 142:663-74. [PMID: 26831415 PMCID: PMC4774063 DOI: 10.4103/0971-5916.174549] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Combination therapy with three drug regimens for human immunodeficiency virus (HIV) infection significantly suppresses the viral replication. However, this therapeutic impact is restricted by adverse drug events and response in terms of short and long term efficacy. There are multiple factors involved in different responses to antiretrovirals (ARVs) such as age, body weight, disease status, diet and heredity. Pharmacogenomics deals with individual genetic make-up and its role in drug efficacy and toxicity. In depth genetic research has provided evidence to predict the risk of developing certain toxicities for which personalized screening and surveillance protocols may be developed to prevent side effects. Here we describe the use of pharmacogenomics for optimal use of HAART (highly active antiretroviral therapy).
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Affiliation(s)
| | - Aruna Shankarkumar
- Department of Transfusion Transmitted Disease, National Institute of Immunohaematology (ICMR), Mumbai, India
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Sousa-Pinto B, Correia C, Gomes L, Gil-Mata S, Araújo L, Correia O, Delgado L. HLA and Delayed Drug-Induced Hypersensitivity. Int Arch Allergy Immunol 2016; 170:163-179. [PMID: 27576480 DOI: 10.1159/000448217] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Indexed: 01/05/2025] Open
Abstract
Delayed drug allergy reactions (DDAR) are potentially fatal. Certain human leukocyte antigen (HLA) alleles have been associated with delayed allergy reactions following the administration of particular drugs. Examples are HLA-B*57:01 (abacavir), HLA-B*15:02/HLA-A*31:01 (carbamazepine), and HLA-B*58:01 (allopurinol). Based on the identification of these associations, it may now be possible to prevent certain allergy reactions that were, until recently, considered unpredictable. In this review, we will focus on the pharmacogenetics of the best-studied associations between specific HLA alleles and delayed allergy reactions and describe the pathogenesis models proposed so far. Finally, we will evaluate the genetic screening strategies available and discuss the clinical relevance of a better understanding of the immunogenetics and mechanisms involved in DDAR.
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Affiliation(s)
- Bernardo Sousa-Pinto
- Laboratory of Immunology, Basic and Clinical Immunology Unit, Faculty of Medicine, University of Porto, Porto, Portugal
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Arab-Alameddine M, Décosterd LA, Buclin T, Telenti A, Csajka C. Antiretroviral drug toxicity in relation to pharmacokinetics, metabolic profile and pharmacogenetics. Expert Opin Drug Metab Toxicol 2016; 7:609-22. [PMID: 21500966 DOI: 10.1517/17425255.2011.562891] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Besides therapeutic effectiveness, drug tolerability is a key issue for treatments that must be taken indefinitely. Given the high prevalence of toxicity in HIV therapy, the factors implicated in drug-induced morbidities should be identified in order to improve the safety, tolerability and adherence to the treatments. Current approaches have focused almost exclusively on parent drug concentrations; whereas recent evidence suggests that drug metabolites resulting from complex genetic and environmental influences can also contribute to treatment outcome. Pharmacogenetic variations have shown to play a relevant role in the variability observed in antiretroviral drug exposure, clinical response and sometimes toxicity. The integration of pharmacokinetic, pharmacogenetic and metabolic determinants will more probably address current therapeutic needs in patients. AREAS COVERED This review offers a concise description of three classes of antiretroviral drugs. The review looks at the metabolic profile of these drugs and gives a comprehensive summary of the existing literature on the influence of pharmacogenetics on their pharmacokinetics and metabolic pathways, and the associated drug or metabolite toxicity. EXPERT OPINION Due to the high prevalence of toxicity and the related risk of low adherence to the treatments, association of kinetic, genetic and metabolic markers predictive of therapeutic or toxicity outcomes could represent a more complete approach for optimizing antiretroviral therapy.
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Affiliation(s)
- Mona Arab-Alameddine
- Department of Clinical Pharmacology and Toxicology, University Hospital and University of Lausanne, Beaumont, Lausanne, Switzerland
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Hernández Arroyo MJ, Cabrera Figueroa SE, Valverde Merino MP, Hurlé ADG. A pharmacist’s role in the individualization of treatment of HIV patients. Per Med 2016; 13:169-188. [DOI: 10.2217/pme.15.54] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The pharmacological treatment of HIV is complex and varies considerably among patients, as does the response of patients to therapy, requiring treatment plans that are closely tailored to individual needs. Pharmacists can take an active role in individualizing care by employing their knowledge of pharmacokinetics and pharmacogenetics and by interacting directly with patients in counseling sessions. These strategies promote the following: maintenance of plasma concentrations of antiretroviral agents within therapeutic ranges, prediction of pharmacological response of patients with certain genetic characteristics, and clinical control of HIV through the correct use of antiretroviral treatments. Together, these strategies can be used to tailor antiretroviral therapy to individual patients, thus improving treatment efficacy and safety.
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Affiliation(s)
| | - Salvador Enrique Cabrera Figueroa
- Pharmacy Institute, University Austral of Chile, Valdivia, Chile
- Pharmacy Service, University Hospital of Salamanca, Paseo de San Vicente 58, 37007 Salamanca, Spain
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Pichler WJ, Adam J, Watkins S, Wuillemin N, Yun J, Yerly D. Drug Hypersensitivity: How Drugs Stimulate T Cells via Pharmacological Interaction with Immune Receptors. Int Arch Allergy Immunol 2015; 168:13-24. [DOI: 10.1159/000441280] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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Pawar MP, Pore SM, Pradhan SN, Burute SR, Bhoi UY, Ramanand SJ. Nevirapine: Most Common Cause of Cutaneous Adverse Drug Reactions in an Outpatient Department of a Tertiary Care Hospital. J Clin Diagn Res 2015; 9:FC17-20. [PMID: 26672558 DOI: 10.7860/jcdr/2015/13672.6768] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Accepted: 09/05/2015] [Indexed: 01/11/2023]
Abstract
INTRODUCTION Skin is the most commonly involved organ in adverse drug reactions. Most of the cutaneous adverse drug reactions (CADRs) being of mild to moderate severity are likely to be diagnosed and treated in an outpatient setting. Consequently, knowledge regarding morphological pattern, severity and drugs implicated in causation of these CADRs has important implications for healthcare personnel. AIM To determine the current clinical pattern of CADRs and to assess their causality and severity with the help of standard scales. STUDY DESIGN AND SETTING A prospective, observational study was conducted in the outpatient department of skin and venereal disease in a tertiary care hospital. MATERIALS AND METHODS Patients with suspected CADR after consumption of systemic drug(s) were enrolled in the study. Data regarding demographics, clinical manifestations of CADR, drug history preceding the reaction, concomitant illness, relevant laboratory investigations etc was obtained. This data was then analysed for morphological pattern, causality and severity. CADRs with causality assessment possible and above on the basis of World Health Organization-Uppsala Monitoring Centre causality assessment system were considered for analysis. STATISTICS Descriptive statistics were used to express results of pattern, severity and causality of CADRs. RESULTS Ninety patients were enrolled in the study. Male to female ratio for CADRs was 1:2.33. Maculopapular rash was most commonly encountered CADR in 76.67% cases followed by urticaria (8.89%), Stevens-Johnson syndrome (4.4%) and fixed dose eruptions (3.33%). Antiretrovirals were implicated in 75.56% (68/90) of CADRs. Nevirapine was suspected in 52 out of 90 (57.77%) cases of CADRs which included 39 cases of maculopapular rash, five cases of urticaria, four cases of Stevens-Johnson syndrome, and two cases each of pustular rash and angioedema respectively. Antimicrobials, antiepileptics and Non-steroidal Anti-inflammatory Drugs (NSAIDs) were other suspected drugs. CONCLUSION Antiretrovirals especially nevirapine was implicated in variety of CADRs ranging from maculopapular rash to life-threatening reactions like Stevens-Johnson syndrome in an outpatient setting. Women were twice as susceptible as men for CADRs.
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Affiliation(s)
| | - Shraddha Milind Pore
- Associate Professor, Department of Pharmacology, Government Medical College , Miraj, India
| | - Shekhar Nana Pradhan
- Associate Professor, Department of Dermatology, Government Medical College , Miraj, India
| | | | - Umesh Yedu Bhoi
- Associate Professor, Department of Dermatology, RCSM , Kholapur, India
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New approaches for predicting T cell-mediated drug reactions: A role for inducible and potentially preventable autoimmunity. J Allergy Clin Immunol 2015; 136:252-7. [PMID: 26254052 DOI: 10.1016/j.jaci.2015.06.024] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Revised: 06/23/2015] [Accepted: 06/25/2015] [Indexed: 12/20/2022]
Abstract
Adverse drug reactions (ADRs) are commonplace and occur when a drug binds to its intended pharmacologic target (type A ADR) or an unintended target (type B ADR). Immunologically mediated type B ADRs, such as drug hypersensitivity syndrome, drug reaction with eosinophilia and systemic symptoms syndrome, and Stevens-Johnson syndrome/toxic epidermal necrolysis, can be severe and result in a diverse set of clinical manifestations that include fever and rash, as well as multiple organ failure (liver, kidney, lungs, and/or heart) in the case of drug hypersensitivity syndrome. There is increasing evidence that specific HLA alleles influence the risk of drug reactions. Several features of T cell-mediated ADRs are strikingly similar to those displayed by patients with autoimmune diseases like type I diabetes, such as strong HLA association, organ-specific adaptive immune responses, viral involvement, and activation of innate immunity. There is a need to better predict patient populations at risk for immunologically mediated type B ADRs. Because methods to predict type 1 diabetes by using genetic and immunologic biomarkers have been developed to a high level of accuracy (predicting 100% of subjects likely to progress), new research strategies based on these methods might also improve the ability to predict drug hypersensitivity.
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White KD, Chung WH, Hung SI, Mallal S, Phillips EJ. Evolving models of the immunopathogenesis of T cell-mediated drug allergy: The role of host, pathogens, and drug response. J Allergy Clin Immunol 2015; 136:219-34; quiz 235. [PMID: 26254049 DOI: 10.1016/j.jaci.2015.05.050] [Citation(s) in RCA: 174] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2015] [Revised: 05/11/2015] [Accepted: 05/12/2015] [Indexed: 12/12/2022]
Abstract
Immune-mediated (IM) adverse drug reactions (ADRs) are an underrecognized source of preventable morbidity, mortality, and cost. Increasingly, genetic variation in the HLA loci is associated with risk of severe reactions, highlighting the importance of T-cell immune responses in the mechanisms of both B cell-mediated and primary T cell-mediated IM-ADRs. In this review we summarize the role of host genetics, microbes, and drugs in IM-ADR development; expand on the existing models of IM-ADR pathogenesis to address multiple unexplained observations; discuss the implications of this work in clinical practice today; and describe future applications for preclinical drug toxicity screening, drug design, and development.
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Affiliation(s)
- Katie D White
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn
| | - Wen-Hung Chung
- Department of Dermatology, Chang Gung Memorial Hospital, Keelung, Taiwan; Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Shuen-Iu Hung
- Program in Molecular Medicine, Institute of Pharmacology, School of Medicine, Infection and Immunity Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Simon Mallal
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn; Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia
| | - Elizabeth J Phillips
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn; Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia.
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Asensi V, Collazos J, Valle-Garay E. Can antiretroviral therapy be tailored to each human immunodeficiency virus-infected individual? Role of pharmacogenomics. World J Virol 2015; 4:169-177. [PMID: 26279978 PMCID: PMC4534808 DOI: 10.5501/wjv.v4.i3.169] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Revised: 05/07/2015] [Accepted: 06/11/2015] [Indexed: 02/05/2023] Open
Abstract
Pharmacogenetics refers to the effect of single nucleotide polymorphisms (SNPs) within human genes on drug therapy outcome. Its study might help clinicians to increase the efficacy of antiretroviral drugs by improving their pharmacokinetics and pharmacodynamics and by decreasing their side effects. HLAB*5701 genotyping to avoid the abacavir-associated hypersensitivity reaction (HSR) is a cost-effective diagnostic tool, with a 100% of negative predictive value, and, therefore, it has been included in the guidelines for treatment of human immunodeficiency virus (HIV) infection. HALDRB*0101 associates with nevirapine-induced HSR. CYP2B6 SNPs modify efavirenz plasma levels and their genotyping help decreasing its central nervous system, hepatic and HSR toxicities. Cytokines SNPs might influence the development of drug-associated lipodystrophy. APOA5, APOB, APOC3 and APOE SNPs modify lipids plasma levels and might influence the coronary artery disease risk of HIV-infected individuals receiving antiretroviral therapy. UGT1A1*28 and ABCB1 (MDR1) 3435C > T SNPs modify atazanavir plasma levels and enhance hyperbilirubinemia. Much more effort needs to be still devoted to complete large prospective studies with multiple SNPs genotyping in order to reveal more clues about the role played by host genetics in antiretroviral drug efficacy and toxicity.
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Aceti A, Gianserra L, Lambiase L, Pennica A, Teti E. Pharmacogenetics as a tool to tailor antiretroviral therapy: A review. World J Virol 2015; 4:198-208. [PMID: 26279982 PMCID: PMC4534812 DOI: 10.5501/wjv.v4.i3.198] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2014] [Revised: 01/20/2015] [Accepted: 07/27/2015] [Indexed: 02/05/2023] Open
Abstract
Highly active antiretroviral therapy (HAART) has substantially changed human immunodeficiency virus (HIV) infection from an inexorably fatal condition into a chronic disease with a longer life expectancy. This means that HIV patients should receive antiretroviral drugs lifelong, and the problems concerning with a chronic treatment (tolerability, side effects, adherence to treatment) have now become dominant. In this context, strategies for the treatment personalization have taken a central role in optimizing the therapeutic response and prevention of adverse drug reactions. In this setting, the study of pharmacogenetics features could be a very useful tool in clinical practice; moreover, nowadays the study of genetic profiles allows optimizations in the therapeutic management of People Living With HIV (PLWH) through the use of test introduced into clinical practice and approved by international guidelines for the adverse effects prevention such as the genetic test HLA-B*5701 to detect hypersensitivity to Abacavir. For other tests further studies are needed: CYP2B6 516 G > T testing may be able to identify patients at higher risk of Central Nervous System side effects following standard dosing of Efavirenz, UGT1A1*28 testing before initiation of antiretroviral therapy containing Atazanavir may aid in identifying individuals at risk of hyperbilirubinaemia. Pharmacogenetics represents a research area with great growth potential which may be useful to guide the rational use of antiretrovirals.
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Dao RL, Su SC, Chung WH. Recent advances of pharmacogenomics in severe cutaneous adverse reactions: immune and nonimmune mechanisms. Asia Pac Allergy 2015; 5:59-67. [PMID: 25938070 PMCID: PMC4415181 DOI: 10.5415/apallergy.2015.5.2.59] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Accepted: 03/22/2015] [Indexed: 01/11/2023] Open
Abstract
Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) are severe cutaneous adverse reactions (SCAR) which are majorly caused by drugs. Though the incidence rate is low, SCAR sometimes can be life-threatening and leads to lifelong sequelae. Many pharmacogenomic associations in immune and nonimmune related genes with the development of SCAR have been discovered recently and the pharmacogenetic tests have been applied to prevent specific drug-induced SCAR. In this review, we discuss the recent advances of pharmacogenomics in SCAR.
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Affiliation(s)
- Ro-Lan Dao
- Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospitals, Taipei, Linkou, and Keelung, Taiwan. ; College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Shih-Chi Su
- Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospitals, Taipei, Linkou, and Keelung, Taiwan. ; College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Wen-Hung Chung
- Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospitals, Taipei, Linkou, and Keelung, Taiwan. ; College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
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HLA-allelotype associations with nevirapine-induced hypersensitivity reactions and hepatotoxicity. Pharmacogenet Genomics 2015; 25:186-98. [DOI: 10.1097/fpc.0000000000000124] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Borroni RG. Role of dermatology in pharmacogenomics: drug-induced skin injury. Pharmacogenomics 2015; 16:401-12. [PMID: 25823788 DOI: 10.2217/pgs.15.4] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Different individuals may respond diversely to the same drug, in terms of efficacy and toxicity. Adverse drug reactions cause about 6% of all hospital admissions and account for up to 9% of hospitalization costs. Drug-induced skin injury (DISI) is the most common presentation of adverse drug reactions, ranging from maculopapular eruptions to severe adverse cutaneous drug reactions (SCARs) with mortality of up to 40%. Specific genetic polymorphisms confer susceptibility to different types of DISI. Identifying patients genetically at risk for SCARs is one of the goals of pharmacogenomics. In this article, the aspects of clinical dermatology relevant to the pharmacogenetics of DISI are reviewed. Many SCARs are now preventable, with consequent reduction of morbidity, mortality and healthcare costs.
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Abstract
Antiviral drugs used to treat HIV and hepatitis C are common causes of delayed drug hypersensitivities for which many of the more severe reactions have been recently shown to be immunogenetically mediated such as abacavir hypersensitivity where HLA-B(∗)57:01 is now used routinely as a screening test to exclude patients carrying this allele from abacavir prescription. Most antiviral drug allergies consist of mild to moderate delayed rash without other serious features (eg, fever, mucosal involvement, blistering rash, organ impairment. In these cases treatment can be continued with careful observation and symptomatic management and the discontinuation rate is low.
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Affiliation(s)
| | - Ellen M Moran
- Division of infectious diseases, Institute of Immunology and Infectious Disease, Murdoch University, Murdoch, Western Australia
| | - Elizabeth J Phillips
- Division of infectious diseases, Institute of Immunology and Infectious Disease, Murdoch University, Murdoch, Western Australia; Division of Infectious Diseases, Vanderbilt University Medical Center, 1161 21st Avenue South, A-2200, Medical Center North, Nashville, TN 37232-2582, USA.
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Fourie J, Flamm J, Rodriguez-French A, Kilby D, Domingo P, Lazzarin A, Ballesteros J, Sosa N, Van De Casteele T, DeMasi R, Spinosa-Guzman S, Lavreys L. Effect of Baseline Characteristics on the Efficacy and Safety of Once-Daily Darunavir/ Ritonavir in HIV-1–Infected, Treatment-Naïve ARTEMIS Patients at Week 96. HIV CLINICAL TRIALS 2015; 12:313-22. [DOI: 10.1310/hct1206-313] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Tsuchiya N, Pathipvanich P, Wichukchinda N, Rojanawiwat A, Auwanit W, Ariyoshi K, Sawanpanyalert P. Incidence and predictors of regimen-modification from first-line antiretroviral therapy in Thailand: a cohort study. BMC Infect Dis 2014; 14:565. [PMID: 25361850 PMCID: PMC4226857 DOI: 10.1186/s12879-014-0565-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Accepted: 10/16/2014] [Indexed: 01/11/2023] Open
Abstract
Background Antiretroviral therapy markedly reduced mortality in HIV-infected individuals. However, in the previous studies, up to 50% of patients are compelled to modify their regimen in middle and low-income countries where salvage drug is still limited. This cohort study aimed to investigate the incidence and predictors of regimen modification from the first-line antiretroviral regimen in northern Thailand. Methods All HIV-infected patients starting antiretroviral therapy (ART) with generic drug (GPOvir®; stavudine, lamivudine and nevirapine) at a governmental hospital in northern Thailand from 2002 to 2007 were recruited. Baseline characteristics and detailed information of regimen modification until the end of 2010 were ascertained from cohort database and medical charts. As a potential genetic predictor of regimen modification, HLA B allele was determined by bead-based array hybridization (WAKFlow® HLA typing kit). We investigated predictors of the regimen modification using Cox’s proportional hazard models. Results Of 979 patients, 914 were eligible for the analysis. The observed events of regimen modification was 377, corresponding to an incidence 13.8/100 person-year-observation (95% CI:12.5-15.3) over 2,728 person years (PY) follow up. The main reasons for regimen modification were adverse effects (73.5%), especially lipodystrophy (63.2%) followed by rash (17.7%). Sixty three patients (17.1%) changed the regimen due to treatment failure. 2% and 19% of patients had HLA-B*35:05 and B*4001, respectively. HLA-B*35:05 was independently associated with rash-related regimen modification (aHR 7.73, 95% CI:3.16-18.9) while female gender was associated with lipodystrophy (aHR 2.11, 95% CI:1.51-2.95). Female gender (aHR 0.54, 95% CI: 0.30-0.96), elder age (aHR 0.56, 95% CI: 0.32-0.99) and having HLA-B*40:01 (aHR 0.29, 95% CI: 0.10-0.82) were protective for treatment failure related modification. Conclusion HLA-B*35:05 and female gender were strong predictors of regimen modification due to rash and lipodystrophy, respectively. Female gender, elder age, and having HLA-B*40:01 had protective effects on treatment failure-related regimen modification. This study provides further information of regimen modification for future tailored ART in Asia. Electronic supplementary material The online version of this article (doi:10.1186/s12879-014-0565-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Naho Tsuchiya
- Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, 1-12-4, Sakamoto, Nagasaki, 852-8523, Japan. .,Global COE program, Nagasaki University, 1-12-4, Sakamoto, Nagasaki, 852-8523, Japan.
| | - Panita Pathipvanich
- Day Care Center, Lampang Hospital, 280 Paholyothin Road, Muang Lampang, Lampang, 52000, Thailand.
| | - Nuanjun Wichukchinda
- National Institute of Health, Ministry of Public Health, 88/7 Tiwanon road, Ampur Muang, Nonthaburi, 11000, Thailand.
| | - Archawin Rojanawiwat
- National Institute of Health, Ministry of Public Health, 88/7 Tiwanon road, Ampur Muang, Nonthaburi, 11000, Thailand.
| | - Wattana Auwanit
- National Institute of Health, Ministry of Public Health, 88/7 Tiwanon road, Ampur Muang, Nonthaburi, 11000, Thailand.
| | - Koya Ariyoshi
- Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, 1-12-4, Sakamoto, Nagasaki, 852-8523, Japan. .,Global COE program, Nagasaki University, 1-12-4, Sakamoto, Nagasaki, 852-8523, Japan.
| | - Pathom Sawanpanyalert
- Food and Drug Administration, Ministry of Public Health, 88/7 Tiwanon road, Ampur Muang, Nonthaburi, 11000, Thailand.
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Loubser S, Paximadis M, Gentle N, Puren A, Gray CM, Tiemessen CT. Frequencies of immune hypersensitivity reaction-associated HLA class I alleles in healthy South African Indian and mixed ancestry populations determined by a novel real-time PCR assay. ACTA ACUST UNITED AC 2014; 84:389-97. [PMID: 25154892 DOI: 10.1111/tan.12414] [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] [Received: 12/09/2013] [Revised: 06/12/2014] [Accepted: 07/09/2014] [Indexed: 11/28/2022]
Abstract
We have determined the frequencies of human leucocyte antigen (HLA)-B*57:01, HLA-B*35:05, HLA-C*04 and HLA-C*08 in healthy individuals of South African Indian (SAI) ethnicity (n = 50) and South African mixed (SAM) ancestry (n = 50) using real-time allele-specific polymerase chain reaction (AS-PCR) assay. HLA-B*57:01 associates with immune hypersensitivity reaction (IHR) in individuals exposed to abacavir (ABC), while nevirapine (NVP) IHR associates with HLA-B*35:05, HLA-C*04 and HLA-C*08. Real-time AS-PCR assays typically use less DNA, are more cost-effective and rapid compared with conventional genotyping methods, such as sequence-based typing (SBT). The assay was developed using samples of known HLA class I genotype and subsequently applied to the SAI and SAM samples. HLA-B*57:01 was detected in SAM and SAI populations at frequencies of 8.0% and 12.0%, respectively, while HLA-B*35:05 was not found in SAI individuals, but was present in 6.0% of SAM individuals. HLA-C*04 was detected in 22.0% and 24.0% of SAM and SAI individuals, respectively, while 10.0% and 8.0% of SAM and SAI individuals, respectively, were HLA-C*08 positive. This study reports the development of a novel real-time AS-PCR assay to identify HLA class I alleles associated with ABC and NVP IHR and has established the frequencies of these alleles present in healthy SAI and SAM populations. Using South African demographic data, our hypothetical analysis suggests that a substantial number of individuals would benefit from the assay.
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Affiliation(s)
- S Loubser
- Centre for HIV and STIs, National Institute for Communicable Diseases, the National Health Laboratory Service and Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
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Keane NM, Pavlos RK, McKinnon E, Lucas A, Rive C, Blyth CC, Dunn D, Lucas M, Mallal S, Phillips E. HLA Class I restricted CD8+ and Class II restricted CD4+ T cells are implicated in the pathogenesis of nevirapine hypersensitivity. AIDS 2014; 28:1891-901. [PMID: 24911354 DOI: 10.1097/qad.0000000000000345] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES This study sought to examine nevirapine hypersensitivity (NVP HSR) phenotypes and their relationship with differing major histocompatibility complex (MHC) Class I and Class II alleles and the associated CD4 and CD8 T-cell NVP-specific responses and their durability over time. METHODS A retrospective cohort study compared HIV-positive patients with NVP HSR, defined by fever and hepatitis and/or rash, with those tolerant of NVP for more than 3 months. Covariates included class I (HLA-A, B, C) and class II (HLA-DR) alleles. Cellular studies examined NVP-specific CD4 and CD8 T-cell responses by interferon-gamma (IFNγ) ELISpot assay and intracellular cytokine staining (ICS). RESULTS NVP HSR occurred in 19 out of 451 (4%) NVP-exposed individuals between March 1993 and December 2011. HLA associations were phenotype dependent with HLA-DRB1*01 : 01 associated with hepatitis (P = 0.02); HLA-B*35 : 01 and HLA-Cw4 associated with cutaneous NVP HSR (P = 0.001, P = 0.01), and HLA-Cw*08 was associated with NVP HSR with eosinophilia (P = 0.04) and multisystemic NVP HSR (P = 0.02). NVP-specific INFγ responses waned significantly more than 3 months from the original reaction and were diminished or completely abrogated when either CD4 or CD8 T cells were depleted from the peripheral blood mononuclear cells culture. CONCLUSION The association of specific class I and II allele pairings with specific phenotypes of NVP HSR, and cellular studies showing both CD4 and CD8 T-cell NVP-specific responses suggest that specific combinations of NVP reactive class I restricted CD8 and class II restricted CD4 T cells contribute to the immunopathogenesis of NVP HSR.
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Carr DF, Chaponda M, Cornejo Castro EM, Jorgensen AL, Khoo S, Van Oosterhout JJ, Dandara C, Kampira E, Ssali F, Munderi P, Lalloo DG, Heyderman RS, Pirmohamed M. CYP2B6 c.983T>C polymorphism is associated with nevirapine hypersensitivity in Malawian and Ugandan HIV populations. J Antimicrob Chemother 2014; 69:3329-34. [PMID: 25147095 PMCID: PMC4228781 DOI: 10.1093/jac/dku315] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Background Nevirapine, an NNRTI used in HIV treatment, can cause hypersensitivity reactions in 6%–10% of patients. In the most serious cases (1.3%) this can manifest as Stevens–Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). Methods DNA samples were obtained and analysed from a total of 209 adult patients with nevirapine hypersensitivity (57 from a prospective cohort and 152 routine clinic patients) and compared with 463 control patients on nevirapine without any hypersensitivity. The case group included 70 patients with SJS/TEN. All individuals were genotyped for two SNPs in the CYP2B6 gene [c.516G>T (CYP2B6*9) and c.983T>C (CYP2B6*18)] using the TaqMan real-time genotyping platform. The replication cohort comprised 29 controls and 55 nevirapine hypersensitive patients, including 8 SJS/TEN cases. Results An association between the CYP2B6 c.983T>C polymorphism and nevirapine-induced SJS/TEN was observed. In the SJS/TEN group, 30% of individuals possessed at least one c.983T>C versus 16% in the tolerant group [P = 0.006; OR (95% CI) 2.24 (1.27–3.94)]. This association was not significant in the replication cohort [P = 0.075; OR (95% CI) 4.33 (0.80–23.57)]. Combined analysis resulted in an OR of 2.52 (95% CI 1.48–4.20; P = 0.0005) for the association of c.983T>C with SJS/TEN. No association was observed for c.983T>C with other hypersensitivity phenotypes and for CYP2B6 c.516G>T with any hypersensitivity phenotypes. Conclusions Our data show an association between the c.983T>C polymorphism and nevirapine-induced SJS/TEN. CYP2B6 c.983T>C has a frequency of 5%–10% in a variety of African populations, but is not observed in Caucasians, thus representing an ethnic-specific predisposing factor.
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Affiliation(s)
- Daniel F Carr
- Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
| | - Mas Chaponda
- Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Malawi
| | - Elena M Cornejo Castro
- Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
| | | | - Saye Khoo
- Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
| | - Joep J Van Oosterhout
- Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Malawi Dignitas International, Zomba, Malawi
| | - Collet Dandara
- Division of Human Genetics, University of Cape Town, Cape Town, South Africa
| | - Elizabeth Kampira
- Division of Human Genetics, University of Cape Town, Cape Town, South Africa Department of Pathology, College of Medicine, Blantyre, Malawi
| | | | - Paula Munderi
- UVRI/MRC Uganda Research Unit on AIDS, Entebbe, Uganda
| | | | - Robert S Heyderman
- Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Malawi Liverpool School of Tropical Medicine, Liverpool, UK
| | - Munir Pirmohamed
- Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
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Barreiro P, Fernández-Montero JV, de Mendoza C, Labarga P, Soriano V. Pharmacogenetics of antiretroviral therapy. Expert Opin Drug Metab Toxicol 2014; 10:1119-30. [DOI: 10.1517/17425255.2014.930128] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Lin KY, Cheng CY, Yang CJ, Tsai MS, Hsieh SM, Sun HY, Sheng WH, Chen MY, Chang SY, Cheng SH, Hung CC. Skin rash related to once-daily boosted darunavir-containing antiretroviral therapy in HIV-infected Taiwanese: incidence and associated factor. J Infect Chemother 2014; 20:465-70. [PMID: 24855915 DOI: 10.1016/j.jiac.2014.04.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Revised: 04/11/2014] [Accepted: 04/14/2014] [Indexed: 10/25/2022]
Abstract
OBJECTIVES The study aimed to investigate the incidence of and associated factors with skin rashes among HIV-infected Taiwanese patients who received once-daily darunavir (DRV) boosted by ritonavir (RTV) (800/100 mg) plus 2 nucleoside reverse-transcriptase inhibitors (NRTIs). METHODS We reviewed the medical records of HIV-infected patients who switched to once-daily DRV/RTV-containing regimens between January 2012 and November 2013. Patients who switched from 2 NRTIs plus non-NRTI (nNRTI) or other protease inhibitor (PI) to 2 NRTIs plus PIs other than DRV were chosen as comparators. RESULTS During the study period, 238 patients who switched to once-daily DRV/RTV-containing regimens (Group A) and 178 patients who switched from 2 NRTIs plus nNRTI or other PI to 2 NRTIs plus PI other than DRV/RTV (Group B) were included. There were no differences between Groups A and B in most of the baseline characteristics. Compared with Group B in which 7 (3.9%) developed rashes after switch to PI other than DRV, 26 patients (10.9%) in Group A developed rashes after a median interval of 14 days of starting DRV/RTV-containing regimens (P = 0.009). In multivariate analysis, patients with a history of rashes related to the previous nNRTI-containing regimens before starting DRV/RTV-containing regimens were more likely to develop rashes with an adjusted odds ratio of 3.53 (95% confidence interval, 1.45-8.62). CONCLUSIONS Once-daily regimens containing DRV/RTV is associated with a higher rate of adverse cutaneous reactions than other PI-containing regimens in HIV-infected Taiwanese, especially in those who have a history of rashes to nNRTI-containing regimens before switch to DRV/RTV-containing regimens.
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Affiliation(s)
- Kuan-Yin Lin
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chien-Yu Cheng
- Department of Infectious Diseases, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan
| | - Chia-Jui Yang
- Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan
| | - Mao-Song Tsai
- Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan
| | - Szu-Min Hsieh
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Hsin-Yun Sun
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Wang-Huei Sheng
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Mao-Yuan Chen
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Sui-Yuan Chang
- Department of Laboratory Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Shu-Hsing Cheng
- Department of Infectious Diseases, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan; School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan.
| | - Chien-Ching Hung
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Department of Medical Research, China Medical University Hospital, Taichung, Taiwan; China Medical University, Taichung, Taiwan.
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Trubiano J, Phillips E. Antimicrobial stewardship's new weapon? A review of antibiotic allergy and pathways to 'de-labeling'. Curr Opin Infect Dis 2014; 26:526-37. [PMID: 24126717 DOI: 10.1097/qco.0000000000000006] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
PURPOSE OF REVIEW The continued emergence of multiresistant pathogens and widespread antimicrobial use has led to a greater emphasis on antimicrobial stewardship programs. Concurrently, an increased awareness of the rising number of antibiotic allergy labels and impact on antimicrobial use has surfaced. The integration of antibiotic allergy de-labeling and antimicrobial stewardship programs may be a pathway worthy of further focus and investigation. RECENT FINDINGS Recent literature has evaluated the efficacy of antibiotic allergy management (historical de-labeling, in-vitro testing, skin prick testing, intradermal testing, and oral challenges) and impact of antibiotic allergy labels on patient outcome. The importance of true and perceived antibiotic allergy cross-reactivity in the setting of β-lactam allergies has been highlighted. The impact of dedicated antibiotic allergy de-labeling clinics, inpatient antibiotic allergy testing, and integrated antimicrobial stewardship programs has been recently appraised. SUMMARY More recent literature supports that appropriate antibiotic allergy in-vitro and in-vivo testing and subsequent antibiotic allergy de-labeling, particularly in regard to β-lactams, can decrease broad-spectrum antibiotic use, costs, patient length of stay, and mortality. Integration of antibiotic allergy management into the decision support systems of inpatient and outpatient antimicrobial stewardship programs represents an important opportunity to further improve measured outcomes from antibiotic utilization.
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Affiliation(s)
- Jason Trubiano
- aDepartment of Infectious Diseases, Peter MacCallum Cancer Centre, East Melbourne, Victoria bThe Institute for Immunology & Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia cDepartments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
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Genetics of Immune-Mediated Adverse Drug Reactions: a Comprehensive and Clinical Review. Clin Rev Allergy Immunol 2014; 48:165-75. [DOI: 10.1007/s12016-014-8418-y] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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Pavlos R, Mallal S, Ostrov D, Pompeu Y, Phillips E. Fever, rash, and systemic symptoms: understanding the role of virus and HLA in severe cutaneous drug allergy. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2014; 2:21-33. [PMID: 24565765 DOI: 10.1016/j.jaip.2013.11.005] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Revised: 11/21/2013] [Accepted: 11/21/2013] [Indexed: 12/17/2022]
Abstract
Drug hypersensitivity syndromes such as abacavir hypersensitivity and the severe cutaneous adverse drug reactions have been associated with significant short- and long-term morbidity and mortality. More recently, these immunologically mediated and previously unpredictable diseases have been shown to be associated with primarily class I but also class II HLA alleles. The case of the association of HLA-B*57:01 and abacavir hypersensitivity has created a translational roadmap for how this knowledge can be used in the clinic to prevent severe reactions. Although many hurdles exist to the widespread translation of such HLA screening approaches, our understanding of how drugs interact with the major histocompatibility complex has contributed to the discovery of new models that have provided considerable insights into the immunopathogenesis of severe cutaneous adverse drug reactions and other T-cell-mediated drug hypersensitivity syndromes. Future translation of this knowledge will facilitate the development of preclinical toxicity screening to significantly improve efficacy and safety of drug development and design.
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Affiliation(s)
- Rebecca Pavlos
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia
| | - Simon Mallal
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia; Vanderbilt University School of Medicine, Nashville, Tenn
| | - David Ostrov
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, College of Medicine, Gainsville, Fla
| | - Yuri Pompeu
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, College of Medicine, Gainsville, Fla
| | - Elizabeth Phillips
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia; Vanderbilt University School of Medicine, Nashville, Tenn.
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Digging up the human genome: current progress in deciphering adverse drug reactions. BIOMED RESEARCH INTERNATIONAL 2014; 2014:824343. [PMID: 24734245 PMCID: PMC3966344 DOI: 10.1155/2014/824343] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Accepted: 02/03/2014] [Indexed: 12/29/2022]
Abstract
Adverse drug reactions (ADRs) are a major clinical problem. In addition to their clinical impact on human health, there is an enormous cost associated with ADRs in health care and pharmaceutical industry. Increasing studies revealed that genetic variants can determine the susceptibility of individuals to ADRs. The development of modern genomic technologies has led to a tremendous advancement of improving the drug safety and efficacy and minimizing the ADRs. This review will discuss the pharmacogenomic techniques used to unveil the determinants of ADRs and summarize the current progresses concerning the identification of biomarkers for ADRs, with a focus on genetic variants for genes encoding drug-metabolizing enzymes, drug-transporter proteins, and human leukocyte antigen (HLA). The knowledge gained from these cutting-edge findings will form the basis for better prediction and management for ADRs, ultimately making the medicine personalized.
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Abstract
Over the past decade, there have been significant advances in our understanding of the immunopathogenesis and pharmacogenomics of severe immunologically-mediated adverse drug reactions. Such T-cell-mediated adverse drug reactions such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug-induced liver disease (DILI) and other drug hypersensitivity syndromes have more recently been shown to be mediated through interactions with various class I and II HLA alleles. Key examples have included the associations of HLA-B*15:02 and carbamazepine induced SJS/TEN in Southeast Asian populations and HLA-B*57:01 and abacavir hypersensitivity. HLA-B*57:01 screening to prevent abacavir hypersensitivity exemplifies a successful translational roadmap from pharmacogenomic discovery through to widespread clinical implementation. Ultimately, our increased understanding of the interaction between drugs and the MHC could be used to inform drug design and drive pre-clinical toxicity programs to improve drug safety.
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Affiliation(s)
- Eric Karlin
- Vanderbilt University School of Medicine, 1161-21 St Avenue South, A-2200 Medical Center North, Nashville, TN, 37232-2582, USA
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Alfirevic A, Pirmohamed M, Marinovic B, Jorgensen AL, Harcourt-Smith L. Genetic testing for prevention of severe drug-induced skin rash. THE COCHRANE DATABASE OF SYSTEMATIC REVIEWS 2013. [DOI: 10.1002/14651858.cd010891] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Ana Alfirevic
- Institute of Translational Medicine, University of Liverpool; Department of Molecular and Clinical Pharmacology; Centre for Personalised Medicine, Block A: Waterhouse Building 1-5 Brownlow Street Liverpool UK L69 3GE
| | - Munir Pirmohamed
- Institute of Translational Medicine, University of Liverpool; Department of Molecular and Clinical Pharmacology; Centre for Personalised Medicine, Block A: Waterhouse Building 1-5 Brownlow Street Liverpool UK L69 3GE
| | - Branka Marinovic
- University Hospital Center Zagreb, School of Medicine University of Zagreb; Department of Dermatology and Venereology; Salata 4 Zagreb Croatia 10000
| | - Andrea L Jorgensen
- University of Liverpool; Centre for Medical Statistics and Health Evaluation; Shelley's Cottage Brownlow Street Liverpool UK L69 3 GS
| | - Linda Harcourt-Smith
- The University of Nottingham; c/o Cochrane Skin Group; A103, King's Meadow Campus Lenton Lane Nottingham UK NG7 2NR
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Saxon CJ, Helbert MR, Komolafe AJ, Higgins SP. Rash and hepatitis within days of starting a new antiretroviral regimen: nevirapine hypersensitivity, secondary syphilis or both? Int J STD AIDS 2013; 25:228-30. [PMID: 23970648 DOI: 10.1177/0956462413497703] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
We report a case in which an HIV-positive man developed general malaise, skin rash and biochemical hepatitis within days of starting a nevirapine-based antiretroviral treatment regimen. At the same time, his syphilis serology proved positive. We discuss the diagnostic dilemma: was this a nevirapine hypersensitivity reaction, secondary syphilis or both?
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Affiliation(s)
- Cara J Saxon
- Department of Genitourinary Medicine, North Manchester General Hospital, Pennine Acute Hospital NHS Trust, Manchester, UK
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