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Abacavir hypersensitivity syndrome (ABC HSS) is strongly associated with carriage of human leukocyte antigen (HLA)-B*57:01, which has a 100% negative predictive value for the development of ABC HSS. However, 45% of individuals who carry HLA-B*57:01 can tolerate ABC. We investigated immune and non-immune related genes in ABC HSS (n = 95) and ABC tolerant (n = 43) HLA-B*57:01 + patients to determine other factors required for the development of ABC HSS. Assignment of phenotype showed that ABC HSS subjects were significantly less likely than tolerants to carry only ERAP1 hypoactive trimming allotypes (p = 0.02). An altered self-peptide repertoire model by which abacavir activates T cells is in keeping with observation that endoplasmic reticulum aminopeptidase 1 (ERAP1) allotypes that favour efficient peptide trimming are more common in ABC HSS patients compared to patients who tolerate ABC. Independently, non-specific immune activation via soluble cluster of differentiation antigen 14 (sCD14) may also influence susceptibility to ABC HSS.
Copyright © 2020 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.
Genomic medicine, which uses DNA variation to individualise and improve human health, is the subject of this Series of papers. The idea that genetic variation can be used to individualise drug therapy-the topic addressed here-is often viewed as within reach for genomic medicine. We have reviewed general mechanisms underlying variability in drug action, the role of genetic variation in mediating beneficial and adverse effects through variable drug concentrations (pharmacokinetics) and drug actions (pharmacodynamics), available data from clinical trials, and ongoing efforts to implement pharmacogenetics in clinical practice.
Copyright © 2019 Elsevier Ltd. All rights reserved.
BACKGROUND - Immune checkpoint inhibitors (ICI) produce durable antitumor responses but provoke autoimmune toxicities, including uncommon but potentially devastating neurologic toxicities. The clinical features, including the spectrum, timing, and outcomes, of ICI-induced neurologic toxicities are not well characterized.
METHODS - We performed disproportionality analysis using Vigibase, the World Health Organization pharmacovigilance database, comparing neurologic adverse event (AE) reporting in patients receiving ICIs vs. the full database. Neurologic AEs were classified by group queries using Medical Dictionary for Regulatory Activities, between database inception to September 28, 2018. Associations between ICIs and neurologic AEs were assessed using reporting odds ratios (ROR) and information component (IC). IC compares observed and expected values to find associations between drugs and AEs using disproportionate Bayesian reporting; IC (lower end of the IC 95% credibility interval) > 0 is considered statistically significant.
RESULTS - Among the full database, 18,518,994 AEs were reported, including 48,653 with ICIs. ICIs were associated with higher incidence of myasthenia gravis (0.47% of ICI reports vs. 0.04% of the full database, ROR 16.5 [95% CI 14.5-18.9]; IC 3.31), encephalitis (0.51% vs. 0.05%, ROR 10.4 [95% CI 9.2-11.8]; IC 3.15), peripheral neuropathy (1.16% vs. 0.67%, IC 0.68), and meningitis (0.15% vs. 0.06%, ROR 3.1 [95% CI 2.5-3.9]; IC 1.01). Myasthenia gravis and encephalitis were associated with anti-PD-1 whereas other neurologic AEs were associated with anti-CTLA-4. Myasthenia gravis was characterized by high fatality rates (~ 20%), early onset (median 29 days), and frequent concurrent myocarditis and myositis; whereas other neurologic AEs had lower fatality rates (6-12%), later onset (median 61-80 days), and were non-overlapping.
CONCLUSIONS - ICIs produce a spectrum of distinct classes of neurologic AEs that can cause significant morbidity and mortality and tend to occur early and with class-specific associations.
BACKGROUND - There is the need to identify new prognostic markers to refine risk stratification for HER2-positive early breast cancer patients. The aim of this study was to evaluate the association of tumor-infiltrating lymphocytes (TILs) with distant disease-free survival (DDFS) in patients with HER2-positive early breast cancer enrolled in the ShortHER adjuvant trial which compared 9 weeks versus 1-year trastuzumab in addition to chemotherapy, and to test the interaction between TILs and treatment arm.
PATIENTS AND METHODS - Stromal TILs were assessed for 866 cases on centralized hematoxylin and eosin-stained tumor slides. The association of TILs as 10% increments with DDFS was assessed with Cox models. Kaplan-Meier curves were estimated for patients with TILs ≥20% and TILs <20%. Median follow-up was 6.1 years.
RESULTS - Median TILs was 5% (Q1-Q3 1%-15%). Increased TILs were independently associated with better DDFS in multivariable model [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.59-0.89, P = 0.006, for each 10% TILs increment]. Five years DDFS rates were 91.1% for patients with TILs <20% and 95.7% for patients with TILs ≥20% (P = 0.025). The association between 10% TILs increments and DDFS was significant for patients randomized to 9 weeks of trastuzumab (HR 0.60, 95% CI 0.41-0.88) but not for patients treated with 1 year of trastuzumab (HR 0.89, 95% CI 0.71-1.12; test for interaction P = 0.088). For patients with TILs <20%, the HR for the comparison between the short versus the long arm was 1.75 (95% CI 1.09-2.80, P=0.021); whereas, for patients with TILs ≥20% the HR for the comparison of short versus long arm was 0.23 (95% CI 0.05-1.09, P = 0.064), resulting in a significant interaction (P = 0.015).
CONCLUSIONS - TILs are an independent prognostic factor for HER2-positive early breast cancer patients treated with adjuvant chemotherapy and trastuzumab and may refine the ability to identify patients at low risk of relapse eligible for de-escalated adjuvant therapy.
© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
Importance - Immune checkpoint inhibitors (ICIs) are now a mainstay of cancer treatment. Although rare, fulminant and fatal toxic effects may complicate these otherwise transformative therapies; characterizing these events requires integration of global data.
Objective - To determine the spectrum, timing, and clinical features of fatal ICI-associated toxic effects.
Design, Setting, and Participants - We retrospectively queried a World Health Organization (WHO) pharmacovigilance database (Vigilyze) comprising more than 16 000 000 adverse drug reactions, and records from 7 academic centers. We performed a meta-analysis of published trials of anti-programmed death-1/ligand-1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) to evaluate their incidence using data from large academic medical centers, global WHO pharmacovigilance data, and all published ICI clinical trials of patients with cancer treated with ICIs internationally.
Exposures - Anti-CTLA-4 (ipilimumab or tremelimumab), anti-PD-1 (nivolumab, pembrolizumab), or anti-PD-L1 (atezolizumab, avelumab, durvalumab).
Main Outcomes and Measures - Timing, spectrum, outcomes, and incidence of ICI-associated toxic effects.
Results - Internationally, 613 fatal ICI toxic events were reported from 2009 through January 2018 in Vigilyze. The spectrum differed widely between regimens: in a total of 193 anti-CTLA-4 deaths, most were usually from colitis (135 [70%]), whereas anti-PD-1/PD-L1-related fatalities were often from pneumonitis (333 [35%]), hepatitis (115 [22%]), and neurotoxic effects (50 [15%]). Combination PD-1/CTLA-4 deaths were frequently from colitis (32 [37%]) and myocarditis (22 [25%]). Fatal toxic effects typically occurred early after therapy initiation for combination therapy, anti-PD-1, and ipilimumab monotherapy (median 14.5, 40, and 40 days, respectively). Myocarditis had the highest fatality rate (52 [39.7%] of 131 reported cases), whereas endocrine events and colitis had only 2% to 5% reported fatalities; 10% to 17% of other organ-system toxic effects reported had fatal outcomes. Retrospective review of 3545 patients treated with ICIs from 7 academic centers revealed 0.6% fatality rates; cardiac and neurologic events were especially prominent (43%). Median time from symptom onset to death was 32 days. A meta-analysis of 112 trials involving 19 217 patients showed toxicity-related fatality rates of 0.36% (anti-PD-1), 0.38% (anti-PD-L1), 1.08% (anti-CTLA-4), and 1.23% (PD-1/PD-L1 plus CTLA-4).
Conclusions and Relevance - In the largest evaluation of fatal ICI-associated toxic effects published to date to our knowledge, we observed early onset of death with varied causes and frequencies depending on therapeutic regimen. Clinicians across disciplines should be aware of these uncommon lethal complications.
Preventive efforts for serious immunologically mediated adverse drug reactions (IM-ADRs) have been fueled by discovery of strong class I human leukocyte antigen (HLA) associations; however, the low positive predictive value of HLA for IM-ADRs has limited translation. Studies were undertaken to explain why most patients carrying an HLA risk allele do not develop IM-ADR on exposure to the risk drug. Tissue-specific approaches defined the T-cell receptor (TCR) repertoire and phenotype of the pathogenic T cells found in the skin and blister fluid of IM-ADRs. Dominant CD8+ T cell clonotypes representing >50% of total TCRαβ sequences among CD8+ CD137+ T cells were identified in tissue to identify the pathogenic activated T cells. Identification of the specific molecular and cellular signatures of the antigen-driven pathogenic T cells will facilitate more specific mechanisms to determine the small percentage of individuals carrying an HLA risk allele who are likely to develop an IM-ADR before drug exposure.
Adverse drug reactions (ADRs) are a significant health care burden. Immune-mediated adverse drug reactions (IM-ADRs) are responsible for one-fifth of ADRs but contribute a disproportionately high amount of that burden due to their severity. Variation in human leukocyte antigen ( HLA) genes has emerged as a potential preprescription screening strategy for the prevention of previously unpredictable IM-ADRs. Immunopharmacogenomics combines the disciplines of immunogenomics and pharmacogenomics and focuses on the effects of immune-specific variation on drug disposition and IM-ADRs. In this review, we present the latest evidence for HLA associations with IM-ADRs, ongoing research into biological mechanisms of IM-ADRs, and the translation of clinical actionable biomarkers for IM-ADRs, with a focus on T cell-mediated ADRs.
Motivation - Phenome-wide association studies (PheWAS) have been used to discover many genotype-phenotype relationships and have the potential to identify therapeutic and adverse drug outcomes using longitudinal data within electronic health records (EHRs). However, the statistical methods for PheWAS applied to longitudinal EHR medication data have not been established.
Results - In this study, we developed methods to address two challenges faced with reuse of EHR for this purpose: confounding by indication, and low exposure and event rates. We used Monte Carlo simulation to assess propensity score (PS) methods, focusing on two of the most commonly used methods, PS matching and PS adjustment, to address confounding by indication. We also compared two logistic regression approaches (the default of Wald versus Firth's penalized maximum likelihood, PML) to address complete separation due to sparse data with low exposure and event rates. PS adjustment resulted in greater power than PS matching, while controlling Type I error at 0.05. The PML method provided reasonable P-values, even in cases with complete separation, with well controlled Type I error rates. Using PS adjustment and the PML method, we identify novel latent drug effects in pediatric patients exposed to two common antibiotic drugs, ampicillin and gentamicin.
Availability and implementation - R packages PheWAS and EHR are available at https://github.com/PheWAS/PheWAS and at CRAN (https://www.r-project.org/), respectively. The R script for data processing and the main analysis is available at https://github.com/choileena/EHR.
Supplementary information - Supplementary data are available at Bioinformatics online.