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Shared peptide binding of HLA Class I and II alleles associate with cutaneous nevirapine hypersensitivity and identify novel risk alleles.
Pavlos R, McKinnon EJ, Ostrov DA, Peters B, Buus S, Koelle D, Chopra A, Schutte R, Rive C, Redwood A, Restrepo S, Bracey A, Kaever T, Myers P, Speers E, Malaker SA, Shabanowitz J, Jing Y, Gaudieri S, Hunt DF, Carrington M, Haas DW, Mallal S, Phillips EJ
(2017) Sci Rep 7: 8653
MeSH Terms: Alleles, Anti-HIV Agents, Case-Control Studies, Disease Susceptibility, Drug Hypersensitivity, Histocompatibility Antigens Class I, Histocompatibility Antigens Class II, Humans, Nevirapine, Odds Ratio, Peptides, Protein Binding, Risk Assessment, T-Lymphocytes
Show Abstract · Added March 30, 2020
Genes of the human leukocyte antigen (HLA) system encode cell-surface proteins involved in regulation of immune responses, and the way drugs interact with the HLA peptide binding groove is important in the immunopathogenesis of T-cell mediated drug hypersensitivity syndromes. Nevirapine (NVP), is an HIV-1 antiretroviral with treatment-limiting hypersensitivity reactions (HSRs) associated with multiple class I and II HLA alleles. Here we utilize a novel analytical approach to explore these multi-allelic associations by systematically examining HLA molecules for similarities in peptide binding specificities and binding pocket structure. We demonstrate that primary predisposition to cutaneous NVP HSR, seen across ancestral groups, can be attributed to a cluster of HLA-C alleles sharing a common binding groove F pocket with HLA-C*04:01. An independent association with a group of class II alleles which share the HLA-DRB1-P4 pocket is also observed. In contrast, NVP HSR protection is afforded by a cluster of HLA-B alleles defined by a characteristic peptide binding groove B pocket. The results suggest drug-specific interactions within the antigen binding cleft can be shared across HLA molecules with similar binding pockets. We thereby provide an explanation for multiple HLA associations with cutaneous NVP HSR and advance insight into its pathogenic mechanisms.
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Genotyping for severe drug hypersensitivity.
Karlin E, Phillips E
(2014) Curr Allergy Asthma Rep 14: 418
MeSH Terms: Allopurinol, Amoxicillin-Potassium Clavulanate Combination, Carbamazepine, Dideoxynucleosides, Drug Hypersensitivity, Genotype, HLA-B Antigens, Humans, Nevirapine, Pharmacogenetics, Protein Conformation, Stevens-Johnson Syndrome
Show Abstract · Added March 30, 2020
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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Durability of first ART regimen and risk factors for modification, interruption or death in HIV-positive patients starting ART in Europe and North America 2002-2009.
Abgrall S, Ingle SM, May MT, Costagliola D, Mercie P, Cavassini M, Reekie J, Samji H, Gill MJ, Crane HM, Tate J, Sterling TR, Antinori A, Reiss P, Saag MS, Mugavero MJ, Phillips A, Manzardo C, Wasmuth JC, Stephan C, Guest JL, Gomez Sirvent JL, Sterne JA, Antiretroviral Therapy Cohort Collaboration (ART-CC)
(2013) AIDS 27: 803-13
MeSH Terms: Adenine, Alkynes, Anti-HIV Agents, Antiretroviral Therapy, Highly Active, Benzoxazines, Cohort Studies, Cyclopropanes, Deoxycytidine, Dideoxynucleosides, Drug Combinations, Emtricitabine, Europe, HIV Infections, HIV Protease Inhibitors, HIV Seropositivity, HIV-1, Humans, Lamivudine, Lopinavir, Nevirapine, Organophosphonates, Reverse Transcriptase Inhibitors, Risk Factors, Tenofovir, Time Factors, United States
Show Abstract · Added February 17, 2016
OBJECTIVES - To estimate the incidence of and risk factors for modifications to first antiretroviral therapy (ART) regimen, treatment interruption and death.
METHODS - A total of 21 801 patients from 18 cohorts in Europe and North America starting ART on regimens including at least two nucleoside reverse transcriptase inhibitors and boosted protease inhibitor or non-nucleoside reverse transcriptase inhibitor during 2002-2009 were included. Incidence of modifications (change of drug class, substitution/addition within class, or switch to nonstandard regimen), interruption or death and associations with patient characteristics were estimated using competing-risks methods.
RESULTS - During median 28 months follow-up, 8786 (40.3%) patients modified first ART, 2346 (10.8%) interrupted and 427 (2.0%) died before changing regimen. Three-year cumulative percentages of modification, interruption and death were 47, 12 and 2%, respectively. After adjustment, rates of interruption were highest for IDUs and lowest for MSM, and higher for patients starting ART with CD4 cell count above 350 cells/μl than other patients. Compared to efavirenz, patients on lopinavir and other protease inhibitors had higher rates of modification and interruption, on atazanavir had lower rates of class change, and on nevirapine higher rates of interruption. Those on tenofovir/emtricitabine backbone had lowest rates of substitutions and switches to nonstandard regimen, and on abacavir/lamivudine lowest rates of interruption. Rates of substitution and switches to nonstandard regimen were lower in 2006-2009.
CONCLUSION - Rates of modification and interruption were high, particularly in the first year of ART. Decreased rates of substitutions or switches to nonstandard regimen in recent years may be linked to greater use of well tolerated once-daily drugs.
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26 MeSH Terms
Clinical and genetic determinants of plasma nevirapine exposure following an intrapartum dose to prevent mother-to-child HIV transmission.
Vardhanabhuti S, Acosta EP, Ribaudo HJ, Severe P, Lalloo U, Kumarasamy N, Taulo F, Kabanda J, Oneko O, Ive P, Sambarey P, Chan ES, Hitti J, Hong F, McMahon D, Haas DW, A5207 ACTG Study Team
(2013) J Infect Dis 208: 662-71
MeSH Terms: Adult, Anti-HIV Agents, Aryl Hydrocarbon Hydroxylases, Chemoprevention, Cytochrome P-450 CYP2B6, Female, HIV Infections, Humans, Infant, Newborn, Infectious Disease Transmission, Vertical, Inhibitory Concentration 50, Male, Metabolic Clearance Rate, Nevirapine, Oxidoreductases, N-Demethylating, Plasma, Polymorphism, Genetic, Pregnancy, Time Factors, Young Adult
Show Abstract · Added March 13, 2015
OBJECTIVE - Nevirapine is metabolized by cytochrome P450 (CYP) 2B6 and CYP3A4. We characterized relationships between clinical parameters, human genetics, pharmacokinetics, and human immunodeficiency virus type 1 (HIV-1) drug resistance mutations in pregnant women following single-dose intrapartum nevirapine.
METHODS - In AIDS Clinical Trials Group study A5207, women received nevirapine at onset of labor and were randomly assigned to receive lamivudine/zidovudine, emtricitabine/tenofovir, or lopinavir/ritonavir for 7 or 21 days. Plasma nevirapine level was quantified on postpartum day 1 and on weeks 1, 3, and 5. We assayed 214 polymorphisms in CYP2B6 and other genes and evaluated associations with pharmacokinetic parameters, including elimination constant, time to protein-adjusted 50% inhibitory concentration (IC50), and week 5 nevirapine level below the quantification limit.
RESULTS - Among 301 women with evaluable pharmacokinetic and genotype data, lower body mass index and random assignment to receive lopinavir/ritonavir were associated with more rapid nevirapine elimination. Among those of African ancestry, longer time to IC50 was associated with CYP2B6 983T → C (P = .004) but not with CYP2B6 516G → T (P = .8). Among Indians, slower nevirapine elimination was associated with CYP2B6 516G → T (P = .04). Emergent resistance was infrequent and not associated with pharmacokinetics or CYP2B6 genotype.
CONCLUSIONS - The effects on plasma drug exposure following single-dose nevirapine may be greater for CYP2B6 983T → C than for 516G → T and are less pronounced than at steady state.
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20 MeSH Terms
Cardiometabolic risk factors among HIV patients on antiretroviral therapy.
Kiage JN, Heimburger DC, Nyirenda CK, Wellons MF, Bagchi S, Chi BH, Koethe JR, Arnett DK, Kabagambe EK
(2013) Lipids Health Dis 12: 50
MeSH Terms: Adenine, Adolescent, Adult, Alkynes, Anti-HIV Agents, Antiretroviral Therapy, Highly Active, Benzoxazines, Cardiovascular Diseases, Cholesterol, HDL, Cholesterol, LDL, Cyclopropanes, Female, HIV, HIV Infections, Humans, Insulin Resistance, Lamivudine, Male, Middle Aged, Nevirapine, Organophosphonates, Risk Factors, Stavudine, Tenofovir, Triglycerides, Zambia, Zidovudine
Show Abstract · Added February 28, 2014
BACKGROUND - HIV and combination antiretroviral therapy (cART) may increase cardiovascular disease (CVD) risk. We assessed the early effects of cART on CVD risk markers in a population with presumed low CVD risk.
METHODS - Adult patients (n=118) in Lusaka, Zambia were recruited at the time of initiation of cART for HIV/AIDS. Cardiometabolic risk factors were measured before and 90 days after starting cART. Participants were grouped according to cART regimens: Zidovudine + Lamivudine + Nevirapine (n=58); Stavudine + Lamivudine + Nevirapine (n=43); and 'other' (Zidovudine + Lamivudine + Efavirenz, Stavudine + Lamivudine + Efavirenz, Tenofovir + Emtricitabine + Efavirenz or Tenofovir + Emtricitabine + Nevirapine, n=17). ANOVA was used to test whether changes in cardiometabolic risk markers varied by cART regimen.
RESULTS - From baseline to 90 days after initiation of cART, the prevalence of low levels of high-density lipoprotein cholesterol (<1.04 mmol/L for men and <1.30 mmol/L for women) significantly decreased (78.8% vs. 34.8%, P<0.001) while elevated total cholesterol (TC ≥5.18 mmol/L, 5.1% vs. 11.9%, P=0.03) and the homeostasis model assessment of insulin resistance ≥3.0 (1.7% vs. 17.0%, P<0.001) significantly increased. The prevalence of TC:HDL-c ratio ≥5.0 significantly decreased (44.9% vs. 6.8%, P<0.001). These changes in cardiometabolic risk markers were independent of the cART regimen.
CONCLUSION - Our results suggest that short-term cART is associated with a cardioprotective lipid profile in Zambia and a tendency towards insulin resistance regardless of the cART regimen.
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27 MeSH Terms
Pharmacokinetics of phase I nevirapine metabolites following a single dose and at steady state.
Fan-Havard P, Liu Z, Chou M, Ling Y, Barrail-Tran A, Haas DW, Taburet AM, ANRS12154 Study Group
(2013) Antimicrob Agents Chemother 57: 2154-60
MeSH Terms: Adult, African Americans, Anti-HIV Agents, Area Under Curve, Aryl Hydrocarbon Hydroxylases, Asian Continental Ancestry Group, Biotransformation, Case-Control Studies, Chromatography, Liquid, Cytochrome P-450 CYP2B6, Drug Administration Schedule, Female, HIV Infections, HIV-1, Humans, Male, Nevirapine, Oxidoreductases, N-Demethylating, Polymorphism, Genetic, Tandem Mass Spectrometry
Show Abstract · Added March 13, 2015
Nevirapine is one of the most extensively prescribed antiretrovirals worldwide. The present analyses used data and specimens from two prior studies to characterize and compare plasma nevirapine phase I metabolite profiles following a single 200-mg oral dose of nevirapine in 10 HIV-negative African Americans and a steady-state 200-mg twice-daily dose in 10 HIV-infected Cambodians. Nevirapine was assayed by high-performance liquid chromatography (HPLC). The 2-, 3-, 8- and 12-hydroxy and 4-carboxy metabolites of nevirapine were assayed by liquid chromatography-tandem mass spectrometry (LC/MS/MS). Pharmacokinetic parameters were calculated by noncompartmental analysis. The metabolic index for each metabolite was defined as the ratio of the metabolite area under the concentration-time curve (AUC) to the nevirapine AUC. Every metabolite concentration was much less than the corresponding nevirapine concentration. The predominant metabolite after single dose and at steady state was 12-hydroxynevirapine. From single dose to steady state, the metabolic index increased for 3-hydroxynevirapine (P < 0.01) but decreased for 2-hydroxynevirapine (P < 0.001). The 3-hydroxynevirapine metabolic index was correlated with nevirapine apparent clearance (P < 0.001). These findings are consistent with induction of CYP2B6 (3-hydroxy metabolite) and a possible inhibition of CYP3A (2-hydroxy metabolite), although these are preliminary data. There were no such changes in metabolic indexes for 12-hydroxynevirapine or 4-carboxynevirapine. Two subjects with the CYP2B6 *6*6 genetic polymorphism had metabolic indexes in the same range as other subjects. These results suggest that nevirapine metabolite profiles change over time under the influence of enzyme induction, enzyme inhibition, and host genetics. Further work is warranted to elucidate nevirapine biotransformation pathways and implications for drug efficacy and toxicity.
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Associations between HLA-DRB1*0102, HLA-B*5801, and hepatotoxicity during initiation of nevirapine-containing regimens in South Africa.
Phillips E, Bartlett JA, Sanne I, Lederman MM, Hinkle J, Rousseau F, Dunn D, Pavlos R, James I, Mallal SA, Haas DW
(2013) J Acquir Immune Defic Syndr 62: e55-7
MeSH Terms: Adult, Alanine Transaminase, Anti-HIV Agents, Aryl Hydrocarbon Hydroxylases, Aspartate Aminotransferases, Chemical and Drug Induced Liver Injury, Cytochrome P-450 CYP2B6, Double-Blind Method, Female, Genotype, HIV Infections, HLA-B Antigens, HLA-DRB1 Chains, Humans, Male, Multivariate Analysis, Nevirapine, Oxidoreductases, N-Demethylating, Phenotype, Reverse Transcriptase Inhibitors, South Africa
Added March 13, 2015
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21 MeSH Terms
Multiple genetic variants predict steady-state nevirapine clearance in HIV-infected Cambodians.
Bertrand J, Chou M, Richardson DM, Verstuyft C, Leger PD, Mentré F, Taburet AM, Haas DW, ANRS 12154 Study Group
(2012) Pharmacogenet Genomics 22: 868-76
MeSH Terms: Adult, Anti-HIV Agents, Asian Continental Ancestry Group, Cohort Studies, Female, Genetic Variation, Genotype, HIV Infections, Humans, Linear Models, Male, Middle Aged, Nevirapine, Polymorphism, Single Nucleotide
Show Abstract · Added March 13, 2015
OBJECTIVE - In a previous analysis involving protocol ANRS 12154, interindividual variability in steady-state nevirapine clearance among HIV-infected Cambodians was partially explained by CYP2B6 516G→T (CYP2B6*6). Here, we examine whether additional genetic variants predict nevirapine clearance in this cohort.
METHODS - Analyses included Phnom Penh ESTHER (Ensemble pour une Solidarité Thérapeutique Hospitalière en Réseau) cohort participants who had consented for genetic testing. All participants were receiving nevirapine plus two nucleoside analogs. The mean individual nevirapine clearance estimates were derived from a population model developed on nevirapine concentrations at 18 and 36 months of therapy. Polymorphisms were assayed in ABCB1, CYP2A6, CYP2B6, CYP2C19, CYP3A4, CYP3A5, and NR1I2.
RESULTS - Of 198 assayed loci, 130 were polymorphic. Among 129 individuals with evaluable genetic data, nevirapine clearance ranged from 1.06 to 5.00 l/h in 128 individuals and was 7.81 l/h in one individual. In bivariate linear regression, CYP2B6 516G→T (CYP2B6*6) was associated with lower nevirapine clearances (P=3.5×10). In a multivariate linear regression model conditioned on CYP2B6 516G→T, independent associations were identified with CYP2B6 rs7251950, CYP2B6 rs2279343, and CYP3A4 rs2687116. The CYP3A4 association disappeared after censoring the outlier clearance value. A model that included CYP2B6 516G→T (P=1.0×10), rs7251950 (P=4.8×10), and rs2279343 (P=7.1×10) explained 11% of interindividual variability in nevirapine clearance.
CONCLUSION - Among HIV-infected Cambodians, several CYP2B6 polymorphisms were associated independently with steady-state nevirapine clearance. The prediction of nevirapine clearance was improved by considering several polymorphisms in combination.
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14 MeSH Terms
Improving retention in the early infant diagnosis of HIV program in rural Mozambique by better service integration.
Ciampa PJ, Burlison JR, Blevins M, Sidat M, Moon TD, Rothman RL, Vermund SH
(2011) J Acquir Immune Defic Syndr 58: 115-9
MeSH Terms: Adult, Anti-HIV Agents, Delivery of Health Care, Drug Therapy, Combination, Female, HIV Infections, Humans, Infant, Newborn, Infectious Disease Transmission, Vertical, Lamivudine, Mozambique, Nevirapine, Pregnancy, Retrospective Studies, Rural Population, Young Adult, Zidovudine
Show Abstract · Added December 10, 2013
Low mother/infant retention has impeded early infant diagnosis of HIV in rural Mozambique. We enhanced the referral process for postpartum HIV-infected women by offering direct accompaniment to the location of exposed infant testing before discharge. Retrospective record review for 395 women/infants (September 2009 to June 2010) found enhanced referral was associated with higher odds of follow-up (adjusted odds ratio = 3.18, 95% confidence interval: 1.76 to 5.73, P < 0.001); and among those followed-up, earlier infant testing (median follow-up: 33 days vs. 59 days, P = 0.01) compared with women receiving standard referral. This simple intervention demonstrates benefits gleaned from attention to system improvement through service integration without increasing staff.
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17 MeSH Terms
Toxicogenomics of nevirapine-associated cutaneous and hepatic adverse events among populations of African, Asian, and European descent.
Yuan J, Guo S, Hall D, Cammett AM, Jayadev S, Distel M, Storfer S, Huang Z, Mootsikapun P, Ruxrungtham K, Podzamczer D, Haas DW, Nevirapine Toxicogenomics Study Team
(2011) AIDS 25: 1271-80
MeSH Terms: Adolescent, Adult, African Continental Ancestry Group, Asian Continental Ancestry Group, CD4-Positive T-Lymphocytes, European Continental Ancestry Group, Female, Genetic Variation, HIV Infections, Humans, Liver Diseases, Male, Middle Aged, Nevirapine, Skin Diseases, Viral, Toxicogenetics, Young Adult
Show Abstract · Added March 13, 2015
OBJECTIVE - Nevirapine is widely prescribed for HIV-1 infection. We characterized relationships between nevirapine-associated cutaneous and hepatic adverse events and genetic variants among HIV-infected adults.
DESIGN - We retrospectively identified cases and controls. Cases experienced symptomatic nevirapine-associated severe (grade III/IV) cutaneous and/or hepatic adverse events within 8 weeks of initiating nevirapine. Controls did not experience adverse events during more than 18 weeks of nevirapine therapy.
METHODS - Cases and controls were matched 1: 2 on baseline CD4 T-cell count, sex, and race. Individuals with 150 or less CD4 T cells/μl at baseline were excluded. We characterized 123 human leukocyte antigen (HLA) alleles and 2744 single-nucleotide polymorphisms in major histocompatibility complex (MHC) and drug metabolism and transport genes.
RESULTS - We studied 276 evaluable cases (175 cutaneous adverse events, 101 hepatic adverse events) and 587 controls. Cutaneous adverse events were associated with CYP2B6 516G→T (OR 1.66, all), HLA-Cw*04 (OR 2.51, all), and HLA-B*35 (OR 3.47, Asians; 5.65, Thais). Risk for cutaneous adverse events was particularly high among Blacks with CYP2B6 516TT and HLA-Cw*04 (OR 18.90) and Asians with HLA-B*35 and HLA-Cw*04 (OR 18.34). Hepatic adverse events were associated with HLA-DRB*01 (OR 3.02, Whites), but not CYP2B6 genotypes. Associations differed by population, at least in part reflecting allele frequencies.
CONCLUSION - Among patients with at least 150 CD4 T cells/μl, polymorphisms in drug metabolism and immune response pathways were associated with greater likelihood of risk for nevirapine-related adverse events. Results suggest fundamentally different mechanisms of adverse events: cutaneous, most likely MHC class I-mediated, influenced by nevirapine CYP2B6 metabolism; hepatic, most likely MHC class II-mediated and unaffected by such metabolism. These risk variants are insensitive for routine clinical screening.
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17 MeSH Terms