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Journal of Immunology Research 2017Adverse drug reactions (ADRs) remain a common and major problem in healthcare. Severe cutaneous adverse drug reactions (SCARs), such as Stevens-Johnson syndrome... (Review)
Review
Adverse drug reactions (ADRs) remain a common and major problem in healthcare. Severe cutaneous adverse drug reactions (SCARs), such as Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) with mortality rate ranges from 10% to more than 30%, can be life threatening. A number of recent studies demonstrated that ADRs possess strong genetic predisposition. ADRs induced by several drugs have been shown to have significant associations with specific alleles of human leukocyte antigen (HLA) genes. For example, hypersensitivity to abacavir, a drug used for treating of human immunodeficiency virus (HIV) infection, has been proposed to be associated with allele 57:01 of gene (terms ). The incidences of abacavir hypersensitivity are much higher in Caucasians compared to other populations due to various allele frequencies in different ethnic populations. The antithyroid drug- (ATDs- ) induced agranulocytosis are strongly associated with two alleles: and . In addition, allele was reported to be related to carbamazepine-induced SJS/TEN, and in abacavir hypersensitivity and flucloxacillin induced drug-induced liver injury (DILI). In this review, we summarized the alleles of HLA genes which have been proposed to have association with ADRs caused by different drugs.
Topics: Alleles; Drug-Related Side Effects and Adverse Reactions; Ethnicity; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; HLA Antigens; Humans; Polymorphism, Genetic
PubMed: 29333460
DOI: 10.1155/2017/3186328 -
Immunology and Allergy Clinics of North... Aug 2014Antiviral 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... (Review)
Review
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.
Topics: Antiviral Agents; Disease Management; Drug Hypersensitivity; Humans
PubMed: 25017682
DOI: 10.1016/j.iac.2014.04.011 -
Pharmacogenomics 2014Antimicrobial efficacy and toxicity varies between individuals owing to multiple factors. Genetic variants that affect drug-metabolizing enzymes may influence... (Review)
Review
Antimicrobial efficacy and toxicity varies between individuals owing to multiple factors. Genetic variants that affect drug-metabolizing enzymes may influence antimicrobial pharmacokinetics and pharmacodynamics, thereby determining efficacy and/or toxicity. In addition, many severe immune-mediated reactions have been associated with HLA class I and class II genes. In the last two decades, understanding of pharmacogenomic factors that influence antimicrobial efficacy and toxicity has rapidly evolved, leading to translational success such as the routine use of HLA-B*57:01 screening to prevent abacavir hypersensitivity reactions. This article examines recent advances in the field of antimicrobial pharmacogenomics that potentially affect treatment efficacy and toxicity, and challenges that exist between pharmacogenomic discovery and translation into clinical use.
Topics: Anti-Infective Agents; Dideoxynucleosides; Drug Hypersensitivity; Genetic Variation; HLA-B Antigens; Humans; Pharmacogenetics
PubMed: 25495412
DOI: 10.2217/pgs.14.147 -
Current Allergy and Asthma Reports Mar 2014Over the past decade, there have been significant advances in our understanding of the immunopathogenesis and pharmacogenomics of severe immunologically-mediated adverse... (Review)
Review
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.
Topics: Allopurinol; Amoxicillin-Potassium Clavulanate Combination; Carbamazepine; Dideoxynucleosides; Drug Hypersensitivity; Genotype; HLA-B Antigens; Humans; Nevirapine; Pharmacogenetics; Protein Conformation; Stevens-Johnson Syndrome
PubMed: 24429903
DOI: 10.1007/s11882-013-0418-0 -
Current Opinion in Allergy and Clinical... Aug 2019Immune-mediated adverse drug reactions (IM-ADRs) are many times more common in HIV-infected patients. Usual offending drugs include antiretroviral and antiinfectives,... (Review)
Review
PURPOSE OF REVIEW
Immune-mediated adverse drug reactions (IM-ADRs) are many times more common in HIV-infected patients. Usual offending drugs include antiretroviral and antiinfectives, but the burden of specific drug IM-ADRs is population-specific; changing as new and fixed dose combinations enter the market, and drug-resistance patterns demand. This review considers recent literature on epidemiology, mechanisms, clinical management and prevention of IM-ADRs amongst persons living with HIV/AIDS.
RECENT FINDINGS
Epidemiological studies continue to describe high rates of delayed hypersensitivity to known offenders, as well as similar reactions in preexposure prophylaxis. IM-ADRs to oral and injectable integrase strand transfer inhibitors are reported with expanding use. The clinical spectrum and management of IM-ADRs occurring in HIV-infected populations is similar to uninfected; with exceptions such as a recently described severe delayed efavirenz DILI with high mortality. Furthermore, the context can be unique, such as the lower than expected mortality in a Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) cohort from a HIV/TB high burden setting. Programmatic data showing the near complete elimination of Abacavir drug hypersensitivity syndrome following implementation of HLA-B57:01 screening is a stellar example of how prevention is possible with mechanistic insight.
SUMMARY
IM-ADRs remain a challenge in persons living with HIV. The complexities posed by polypharmacy, overlapping drug toxicities, drug interactions, overlap of IM-ADRs with other diseases, limited alternative drugs, and vulnerable patients with advanced immunosuppression with high mortality, necessitate increased use of drug provocation testing, treat-through and desensitization strategies. There is an urgent need for improved diagnostics and predictive biomarkers for prevention, or to guide treat-through, rechallenge and desensitization approaches.
Topics: Allergens; Anti-Infective Agents; Anti-Retroviral Agents; Biomarkers; Dideoxynucleosides; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Genetic Predisposition to Disease; Genetic Testing; HIV Infections; HIV-1; HLA-B Antigens; Humans; Immunization
PubMed: 31145192
DOI: 10.1097/ACI.0000000000000545 -
Journal of Acquired Immune Deficiency... Mar 2022Antiretroviral options for neonates (younger than 28 days) should be expanded. We evaluated the pharmacokinetics, safety, and acceptability of the "4-in-1" fixed-dose...
BACKGROUND
Antiretroviral options for neonates (younger than 28 days) should be expanded. We evaluated the pharmacokinetics, safety, and acceptability of the "4-in-1" fixed-dose pediatric granule formulation of abacavir/lamivudine/lopinavir/ritonavir (30/15/40/10 mg) in neonates.
METHODS
The PETITE study is an ongoing phase I/II, open-label, single-arm, 2-stage trial conducted in South Africa. In stage 1, term neonates exposed to HIV on standard antiretroviral prophylaxis (nevirapine ± zidovudine) received single dose(s) of the 4-in-1 formulation, followed by intensive pharmacokinetic sampling and safety assessments. At each PK visit, blood was drawn after an observed dose at 1, 2, 4, 8, and 12 hours postdose. In this study, we have reported the planned interim pharmacokinetic and safety analysis after completion of the single-dose administration.
RESULTS
Sixteen neonates, with a median (range) birth weight of 3130 g (2790-3590 g), completed 24 pharmacokinetic visits. The 4-in-1 formulation imposed relatively high doses of abacavir [8.6 mg/kg (6.6-11.4)] and lamivudine [4.3 mg/kg (3.3-5.7)] but lower doses of lopinavir [11.5 mg/kg (8.8-15.2)]. The geometric means (GM, 90% CI) AUC0-12 of abacavir, lamivudine, and lopinavir were 29.87 (26.29-33.93), 12.61 (10.72-14.83), and 3.49 (2.13-5.72) µg.h/mL, respectively. Lopinavir GM AUC0-12 was below the predefined target (20-100 µg.h/mL), and ritonavir concentrations were only detectable in 4 of the 120 (3%) samples. No adverse events were related to study drugs. No neonate had difficulty swallowing the 4-in-1 formulation.
CONCLUSIONS
The high doses of abacavir and lamivudine (in mg/kg) and AUCs were safe, and the formulation was well tolerated; however, lopinavir/ritonavir exposures were extremely low, preventing its use in neonates use in neonates. Alternative pediatric solid antiretroviral formulations must be studied in neonates.
Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Therapy, Combination; HIV Infections; Humans; Infant, Newborn; Lamivudine; Lopinavir; Ritonavir
PubMed: 34855626
DOI: 10.1097/QAI.0000000000002871