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Simon Mallal - One of the best experts on this subject based on the ideXlab platform.
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hla b 5701 screening for hypersensitivity to Abacavir
The New England Journal of Medicine, 2008Co-Authors: Simon Mallal, S. Rugina, Oleg Kozyrev, Eva Jagelguedes, Cassy Workman, Giampiero Carosi, Jean Michel Molina, Janez Tomažic, David NolanAbstract:Hypersensitivity reaction to Abacavir is strongly associated with the presence of the HLA-B*5701 allele. This study was designed to establish the effectiveness of prospective HLA-B*5701 screening to prevent the hypersensitivity reaction to Abacavir. Methods This double-blind, prospective, randomized study involved 1956 patients from 19 countries, who were infected with human immunodeficiency virus type 1 and who had not previously received Abacavir. We randomly assigned patients to undergo prospective HLA-B*5701 screening, with exclusion of HLA-B*5701–positive patients from Abacavir treatment (prospective-screening group), or to undergo a standard-of-care approach of Abacavir use without prospective HLA-B*5701 screening (control group). All patients who started Abacavir were observed for 6 weeks. To immunologically confirm, and enhance the specificity of, the clinical diagnosis of hypersensitivity reaction to Abacavir, we performed epicutaneous patch testing with the use of Abacavir. Results The prevalence of HLA-B*5701 was 5.6% (109 of 1956 patients). Of the patients receiving Abacavir, 72% were men, 84% were white, and 18% had not previously received antiretroviral therapy. Screening eliminated immunologically confirmed hypersensitivity reaction (0% in the prospective-screening group vs. 2.7% in the control group, P<0.001), with a negative predictive value of 100% and a positive predictive value of 47.9%. Hypersensitivity reaction was clinically diagnosed in 93 patients, with a significantly lower incidence in the prospective-screening group (3.4%) than in the control group (7.8%) (P<0.001). Conclusions HLA-B*5701 screening reduced the risk of hypersensitivity reaction to Abacavir. In predominantly white populations, similar to the one in this study, 94% of patients do not carry the HLA-B*5701 allele and are at low risk for hypersensitivity reaction to Abacavir. Our results show that a pharmacogenetic test can be used to prevent a specific toxic effect of a drug. (ClinicalTrials.gov number, NCT00340080.)
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prospective genetic screening decreases the incidence of Abacavir hypersensitivity reactions in the western australian hiv cohort study
Clinical Infectious Diseases, 2006Co-Authors: Andri Rauch, David Nolan, E Mckinnon, C. Almeida, A. Martin, Simon MallalAbstract:Abacavir therapy is associated with significant drug hypersensitivity in ∼8% of recipients, with retrospective studies indicating a strong genetic association with the HLA-B*5701 allelle. In this prospective study, involving 260 Abacavir-naive individuals (7.7% of whom were positive for HLA-B*5701), we confirm the usefulness of genetic risk stratification, with no cases of Abacavir hypersensitivity among 148 HLA-B*5701–negative recipients.
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prospective genetic screening decreases the incidence of Abacavir hypersensitivity reactions in the western australian hiv cohort study
Clinical Infectious Diseases, 2006Co-Authors: Andri Rauch, David Nolan, E Mckinnon, C. Almeida, A. Martin, Simon MallalAbstract:Abacavir therapy is associated with significant drug hypersensitivity in approximately 8% of recipients, with retrospective studies indicating a strong genetic association with the HLA-B*5701 allele. In this prospective study, involving 260 Abacavir-naive individuals (7.7% of whom were positive for HLA-B*5701), we confirm the usefulness of genetic risk stratification, with no cases of Abacavir hypersensitivity among 148 HLA-B*5701-negative recipients.
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clinical and immunogenetic correlates of Abacavir hypersensitivity
AIDS, 2005Co-Authors: Gavin A Wong, Kamnoosh Shahabi, Rupert Kaul, David Nolan, Simon Mallal, Sandra R. Knowles, A. Martin, Neil H ShearAbstract:A patch test (PT) may be useful in defining true Abacavir hypersensitivity syndrome (AHS). Seven previously PT-positive patients remote from the original AHS were shown to have robust 24 h responses, supporting PT durability. HLA-B*5701 was present in all seven PT-positive versus one of 11 controls tolerating Abacavir (P < 0.001). Five of seven PT (71%) versus one of 11 controls (9%) (P = 0.005) showed significant Abacavir-specific CD8 proliferation, suggesting a direct role for HLA-B*5701-restricted CD8 cells in the pathophysiology of AHS.
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randomized controlled 48 week study of switching stavudine and or protease inhibitors to combivir Abacavir to prevent or reverse lipoatrophy in hiv infected patients
Journal of Acquired Immune Deficiency Syndromes, 2003Co-Authors: M John, I James, E Mckinnon, C Moore, D Nolan, S Herrmann, Alex J White, Simon MallalAbstract:Objective: HIV-1 protease inhibitors (versus no protease inhibitors) and stavudine (versus zidovudine) are independently associated with a higher risk of lipoatrophy in HIV-infected patients. We sought to determine whether the revision of stavudine and/or protease inhibitor-containing regimens to combivir/Abacavir would result in prevention and/or reversibility of lipoatrophy in HIV-1-infected patients. Design: The investigation was a prospective, randomized, controlled, open-label study. Subjects: The subjects included 37 HIV-1-infected individuals with stable undetectable HIV-1 loads who were taking a regimen containing either stavudine or zidovudine with lamivudine and a protease inhibitor. Intervention: Subjects were randomized to continue therapy or switch stavudine to zidovudine and protease inhibitor to Abacavir, such that the universal switch regimen was combivir (zidovudine/lamivudine) and Abacavir. Main Outcome Measures: Total body, leg, and arm fat mass was measured at baseline, 24 weeks, and 48 weeks using whole-body dual-energy x-ray absorptiometry. Single-cut L4 computed tomography and assays of multiple metabolic parameters were also performed. Results: There was an average gain in fat mass of 0.009 kg/(leg.mo) in switch patients versus a loss of 0.010 kg/(leg.mo) in controls (p =.04, on-treatment analysis) over 48 weeks. Significant arm fat restoration was observed in patients who switched regimens, with an average gain of 0.014 kg/(arm.mo) (p =.004), whereas controls did not have a significant change from baseline. Analyses of percentage changes in arm and leg fat masses showed similar findings. No significant effects on intraabdominal fat, blood lipid levels, glycemic indices, and lactate levels were detected, although most baseline mean values were normal in study subjects. Combivir/Abacavir maintained virological control in all but one case, and three (13.6%) of 22 individuals had adverse reactions to Abacavir therapy. Conclusions: A switch to combivir/Abacavir therapy was associated with objective evidence of limb fat-sparing and fat restoration compared with continued treatment with stavudine and/or protease inhibitor.
Daniel Podzamczer - One of the best experts on this subject based on the ideXlab platform.
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switching to fixed dose bictegravir emtricitabine and tenofovir alafenamide from dolutegravir plus Abacavir and lamivudine in virologically suppressed adults with hiv 1 48 week results of a randomised double blind multicentre active controlled phase
The Lancet HIV, 2018Co-Authors: Jean Michel Molina, Luis F Lopezcortes, Peter Ruane, Daniel Podzamczer, Cynthia Brinson, Anthony Mills, Douglas J. Ward, Indira Brar, Joseph CustodioAbstract:Summary Background Bictegravir, co-formulated with emtricitabine and tenofovir alafenamide, has shown good efficacy and tolerability, and similar bone, renal, and lipid profiles to dolutegravir, Abacavir, and lamivudine, in treatment-naive adults with HIV-1 infection, without development of treatment-emergent resistance. Here, we report 48-week results of a phase 3 study investigating switching to bictegravir, emtricitabine, and tenofovir alafenamide from dolutegravir, Abacavir, and lamivudine in virologically suppressed adults with HIV-1 infection. Methods In this multicentre, randomised, double-blind, active-controlled, non-inferiority, phase 3 trial, HIV-1-infected adults were enrolled at 96 outpatient centres in nine countries. Eligible participants were aged 18 years or older and on a regimen of 50 mg dolutegravir, 600 mg Abacavir, and 300 mg lamivudine (fixed-dose combination or multi-tablet regimen); had an estimated glomerular filtration rate of 50 mL/min or higher; and had been virologically suppressed (plasma HIV-1 RNA Findings Between Nov 11, 2015, and July 6, 2016, 567 participants were randomly assigned and 563 were treated (282 received bictegravir, emtricitabine, and tenofovir alafenamide, and 281 received dolutegravir, Abacavir, and lamivudine). Switching to the bictegravir regimen was non-inferior to remaining on dolutegravir, Abacavir, and lamivudine for the primary outcome: three (1%) of 282 in the bictegravir group had HIV-1 RNA of 50 copies per mL or higher at week 48 versus one ( Interpretation The fixed-dose combination of bictegravir, emtricitabine, and tenofovir alafenamide might provide a safe and efficacious option for ongoing treatment of HIV-1 infection. Funding Gilead Sciences.
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tenofovir alafenamide plus emtricitabine versus Abacavir plus lamivudine for treatment of virologically suppressed hiv 1 infected adults a randomised double blind active controlled non inferiority phase 3 trial
The Lancet HIV, 2018Co-Authors: Alan Winston, Frank A Post, Vicente Estrada, Paula Peyrani, Francois Raffi, Peter Ruane, Giovanni Di Perri, E Dejesus, Daniel Podzamczer, Gordon CrofootAbstract:Summary Background Abacavir and tenofovir alafenamide offer reduced bone toxicity compared with tenofovir disoproxil fumarate. We aimed to compare safety and efficacy of tenofovir alafenamide plus emtricitabine with that of Abacavir plus lamivudine. Methods In this randomised, double-blind, active-controlled, non-inferiority phase 3 trial, HIV-1-positive adults (≥18 years) were screened at 79 sites in 11 countries in North America and Europe. Eligible participants were virologically suppressed (HIV-1 RNA vs other drug) at screening. Investigators, participants, and study staff giving treatment, assessing outcomes, and collecting data were masked to treatment group. The primary endpoint was the proportion of participants with virological suppression (HIV-1 RNA Findings Study enrolment began on June 29, 2015, and the cutoff enrolment date for the week 48 primary endpoint analysis was May 23, 2016. 501 participants were randomly assigned and treated. At week 48, virological suppression was maintained in 227 (90%) of 253 participants receiving tenofovir alafenamide plus emtricitabine compared with 230 (93%) of 248 receiving Abacavir plus lamivudine (difference −3·0%, 95% CI −8·2 to 2·0), showing non-inferiority. Few participants discontinued treatment because of adverse events: 12 (4%) of 280 participants in the tenofovir alafenimide plus emtricitabine group and nine (3%) of 276 in the Abacavir plus lamivudine group. Three participants had serious, treatment-related adverse events: one each with renal colic and neutropenia in the tenofovir alafenamide plus emtricitabine group, and one myocardial infarction in the Abacavir plus lamivudine group. There were no treatment-related deaths. Interpretation Tenofovir alafenamide, in combination with emtricitabine and various third drugs, maintained high efficacy with a renal and bone safety profile similar to that of Abacavir. In virologically suppressed patients, a regimen containing tenofovir alafenamide could be an alternative to those containing Abacavir, without concern for new onset of renal or bone toxicities or hyperlipidaemia. Funding Gilead Sciences Inc.
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bictegravir emtricitabine and tenofovir alafenamide versus dolutegravir Abacavir and lamivudine for initial treatment of hiv 1 infection gs us 380 1489 a double blind multicentre phase 3 randomised controlled non inferiority trial
The Lancet, 2017Co-Authors: Joel E Gallant, Pablo Tebas, Chloe Orkin, Daniel Podzamczer, Anthony Mills, Adriano Lazzarin, Eric S. Daar, Pierre Marie Girard, Indira Brar, David A WohlAbstract:Summary Background Integrase strand transfer inhibitors (INSTIs) are recommended components of initial antiretroviral therapy with two nucleoside reverse transcriptase inhibitors. Bictegravir is a novel, potent INSTI with a high in-vitro barrier to resistance and low potential as a perpetrator or victim of clinically relevant drug–drug interactions. We aimed to assess the efficacy and safety of bictegravir coformulated with emtricitabine and tenofovir alafenamide as a fixed-dose combination versus coformulated dolutegravir, Abacavir, and lamivudine. Methods We did this double-blind, multicentre, active-controlled, randomised controlled non-inferiority trial at 122 outpatient centres in nine countries in Europe, Latin America, and North America. We enrolled HIV-1 infected adults (aged ≥18 years) who were previously untreated (HIV-1 RNA ≥500 copies per mL); HLA-B*5701 -negative; had no hepatitis B virus infection; screening genotypes showing sensitivity to emtricitabine, tenofovir, lamivudine, and Abacavir; and an estimated glomerular filtration rate of 50 mL/min or more. Participants were randomly assigned (1:1), via a computer-generated allocation sequence (block size of four), to receive coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg or coformulated dolutegravir 50 mg, Abacavir 600 mg, and lamivudine 300 mg, with matching placebo, once daily for 144 weeks. Randomisation was stratified by HIV-1 RNA (≤100 000 copies per mL, >100 000 to ≤400 000 copies per mL, or >400 000 copies per mL), CD4 count ( Findings Between Nov 13, 2015, and July 14, 2016, we randomly assigned 631 participants to receive coformulated bictegravir, emtricitabine, and tenofovir alafenamide (n=316) or coformulated dolutegravir, Abacavir, and lamivudine (n=315), of whom 314 and 315 patients, respectively, received at least one dose of study drug. At week 48, HIV-1 RNA less than 50 copies per mL was achieved in 92·4% of patients (n=290 of 314) in the bictegravir, emtricitabine, and tenofovir alafenamide group and 93·0% of patients (n=293 of 315) in the dolutegravir, Abacavir, and lamivudine group (difference −0·6%, 95·002% CI −4·8 to 3·6; p=0·78), demonstrating non-inferiority of bictegravir, emtricitabine, and tenofovir alafenamide to dolutegravir, Abacavir, and lamivudine. No individual developed treatment-emergent resistance to any study drug. Incidence and severity of adverse events was mostly similar between groups except for nausea, which occurred less frequently in patients given bictegravir, emtricitabine, and tenofovir alafenamide than in those given dolutegravir, Abacavir, and lamivudine (10% [n=32] vs 23% [n=72]; p vs 40% [n=127]), the difference being driven by a higher incidence of drug-related nausea in the dolutegravir, Abacavir, and lamivudine group (5% [n=17] vs 17% [n=55]; p Interpretation At 48 weeks, coformulated bictegravir, emtricitabine, and tenofovir alafenamide achieved virological suppression in 92% of previously untreated adults and was non-inferior to coformulated dolutegravir, Abacavir, and lamivudine, with no treatment-emergent resistance. Bictegravir, emtricitabine, and tenofovir alafenamide was safe and well tolerated with better gastrointestinal tolerability than dolutegravir, Abacavir, and lamivudine. Because coformulated bictegravir, emtricitabine, and tenofovir alafenamide does not require HLA B*5701 testing and provides guideline-recommended treatment for individuals co-infected with HIV and hepatitis B, this regimen might lend itself to rapid or same-day initiation of therapy in the clinical setting. Funding Gilead Sciences.
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brief report dolutegravir plus Abacavir lamivudine for the treatment of hiv 1 infection in antiretroviral therapy naive patients week 96 and week 144 results from the single randomized clinical trial
Journal of Acquired Immune Deficiency Syndromes, 2015Co-Authors: Sharon Walmsley, Daniel Podzamczer, Axel Baumgarten, Juan Berenguer, Franco Felizarta, Eric Florence, Marieaude Khuongjosses, Michael J Kilby, Thomas A Lutz, Joaquin PortillaAbstract:The SINGLE study was a randomized, double-blind, noninferiority study that evaluated the safety and efficacy of 50 mg dolutegravir + Abacavir/lamivudine versus efavirenz/tenofovir/emtricitabine in 833 ART-naive HIV-1 + participants. Of 833 randomized participants, 71% in the dolutegravir + Abacavir/lamivudine arm and 63% in the efavirenz/tenofovir/emtricitabine arm maintained viral loads of <50 copies per milliliter through W144 (P = 0.01). Superior efficacy was primarily driven by fewer discontinuations due to adverse events in the dolutegravir + Abacavir/lamivudine arm [dolutegravir + Abacavir/lamivudine arm, 16 (4%); efavirenz/tenofovir/emtricitabine arm, 58 (14%)] through W144 [corrected]. No treatment-emergent integrase or nucleoside resistance was observed in dolutegravir + Abacavir/lamivudine recipients through W144.
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randomized comparison of renal effects efficacy and safety with once daily Abacavir lamivudine versus tenofovir emtricitabine administered with efavirenz in antiretroviral naive hiv 1 infected adults 48 week results from the assert study
Journal of Acquired Immune Deficiency Syndromes, 2010Co-Authors: Frank A Post, Hj Stellbrink, Daniel Podzamczer, Matthias Cavassini, Graeme Moyle, Pere Domingo, Martin Fisher, Anthony G Norden, A Rieger, Marieaude KhuongjossesAbstract:Background: Abacavir/lamivudine and tenofovir/emtricitabine fixed-dose combinations are commonly used first-line antiretroviral therapies, yet few studies have comprehensively compared their safety profiles. Methods: Forty-eight-week data are presented from this multicenter, randomized, open-label study comparing the safety profiles of Abacavir/lamivudine and tenofovir/emtricitabine, both administered with efavirenz, in HLA-B*5701-negative HIV-1-infected adults. Results: Three hundred eighty-five subjects were enrolled in the study. The overall rate of withdrawal was high (28%). Changes in estimated glomerular filtration rate from baseline were similar between arms [difference 0.953 mL·min -1 ·1.73 m- 2 (95% confidence interval: —1.445 to 3.351), P = 0.435]. Urinary excretion of retinol-binding protein and β-2 microglobulin increased significantly more in the tenofovir/emtricitabine arm (+50%; +24%) compared with the Abacavir/lamivudine arm (no change; -47%) (P < 0.0001). A lower proportion achieved viral load <50 copies per milliliter in the Abacavir/lamivudine arm (114 of 192, 59%) compared with the tenofovir/emtricitabine arm (137 of 193, 71%) [difference 11.6% (95% confidence interval: 2.2 to 21.1)]. The overall virological failure rate was low. The adverse event rate was similar between arms (except drug hypersensitivity, reported more in the Abacavir/lamivudine arm). Conclusions: The study showed no difference in estimated glomerular filtration rate between the arms, however, increases in markers of tubular dysfunction were observed in the tenofovir/emtricitabine arm, the long-term consequence of which is unclear. A significant difference in efficacy favoring tenofovir/emtricitabine was observed.
David Nolan - One of the best experts on this subject based on the ideXlab platform.
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hla b 5701 screening for hypersensitivity to Abacavir
The New England Journal of Medicine, 2008Co-Authors: Simon Mallal, S. Rugina, Oleg Kozyrev, Eva Jagelguedes, Cassy Workman, Giampiero Carosi, Jean Michel Molina, Janez Tomažic, David NolanAbstract:Hypersensitivity reaction to Abacavir is strongly associated with the presence of the HLA-B*5701 allele. This study was designed to establish the effectiveness of prospective HLA-B*5701 screening to prevent the hypersensitivity reaction to Abacavir. Methods This double-blind, prospective, randomized study involved 1956 patients from 19 countries, who were infected with human immunodeficiency virus type 1 and who had not previously received Abacavir. We randomly assigned patients to undergo prospective HLA-B*5701 screening, with exclusion of HLA-B*5701–positive patients from Abacavir treatment (prospective-screening group), or to undergo a standard-of-care approach of Abacavir use without prospective HLA-B*5701 screening (control group). All patients who started Abacavir were observed for 6 weeks. To immunologically confirm, and enhance the specificity of, the clinical diagnosis of hypersensitivity reaction to Abacavir, we performed epicutaneous patch testing with the use of Abacavir. Results The prevalence of HLA-B*5701 was 5.6% (109 of 1956 patients). Of the patients receiving Abacavir, 72% were men, 84% were white, and 18% had not previously received antiretroviral therapy. Screening eliminated immunologically confirmed hypersensitivity reaction (0% in the prospective-screening group vs. 2.7% in the control group, P<0.001), with a negative predictive value of 100% and a positive predictive value of 47.9%. Hypersensitivity reaction was clinically diagnosed in 93 patients, with a significantly lower incidence in the prospective-screening group (3.4%) than in the control group (7.8%) (P<0.001). Conclusions HLA-B*5701 screening reduced the risk of hypersensitivity reaction to Abacavir. In predominantly white populations, similar to the one in this study, 94% of patients do not carry the HLA-B*5701 allele and are at low risk for hypersensitivity reaction to Abacavir. Our results show that a pharmacogenetic test can be used to prevent a specific toxic effect of a drug. (ClinicalTrials.gov number, NCT00340080.)
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prospective genetic screening decreases the incidence of Abacavir hypersensitivity reactions in the western australian hiv cohort study
Clinical Infectious Diseases, 2006Co-Authors: Andri Rauch, David Nolan, E Mckinnon, C. Almeida, A. Martin, Simon MallalAbstract:Abacavir therapy is associated with significant drug hypersensitivity in ∼8% of recipients, with retrospective studies indicating a strong genetic association with the HLA-B*5701 allelle. In this prospective study, involving 260 Abacavir-naive individuals (7.7% of whom were positive for HLA-B*5701), we confirm the usefulness of genetic risk stratification, with no cases of Abacavir hypersensitivity among 148 HLA-B*5701–negative recipients.
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prospective genetic screening decreases the incidence of Abacavir hypersensitivity reactions in the western australian hiv cohort study
Clinical Infectious Diseases, 2006Co-Authors: Andri Rauch, David Nolan, E Mckinnon, C. Almeida, A. Martin, Simon MallalAbstract:Abacavir therapy is associated with significant drug hypersensitivity in approximately 8% of recipients, with retrospective studies indicating a strong genetic association with the HLA-B*5701 allele. In this prospective study, involving 260 Abacavir-naive individuals (7.7% of whom were positive for HLA-B*5701), we confirm the usefulness of genetic risk stratification, with no cases of Abacavir hypersensitivity among 148 HLA-B*5701-negative recipients.
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clinical and immunogenetic correlates of Abacavir hypersensitivity
AIDS, 2005Co-Authors: Gavin A Wong, Kamnoosh Shahabi, Rupert Kaul, David Nolan, Simon Mallal, Sandra R. Knowles, A. Martin, Neil H ShearAbstract:A patch test (PT) may be useful in defining true Abacavir hypersensitivity syndrome (AHS). Seven previously PT-positive patients remote from the original AHS were shown to have robust 24 h responses, supporting PT durability. HLA-B*5701 was present in all seven PT-positive versus one of 11 controls tolerating Abacavir (P < 0.001). Five of seven PT (71%) versus one of 11 controls (9%) (P = 0.005) showed significant Abacavir-specific CD8 proliferation, suggesting a direct role for HLA-B*5701-restricted CD8 cells in the pathophysiology of AHS.
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predisposition to Abacavir hypersensitivity conferred by hla b 5701 and a haplotypic hsp70 hom variant
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: A. Martin, Silvana Gaudieri, Coral Ann Almeida, Richard C Nolan, Filipa Carvalho, I James, Frank Christiansen, David Nolan, Anthony W PurcellAbstract:Susceptibility to a clinically significant drug hypersensitivity syndrome associated with Abacavir use seems to have a strong genetic component. We have previously shown that the presence of HLA-B*5701 strongly predicts Abacavir hypersensitivity and have identified a potential susceptibility locus within a 300-kb region between the MEGT1 and C4A6 loci in the central MHC. We now report the results of fine recombinant genetic mapping in an expanded patient population of 248 consecutive, fully ascertained, Abacavir-exposed individuals in the Western Australian HIV Cohort Study, in which 18 cases of definite Abacavir hypersensitivity (7.3%) and 230 tolerant controls were identified. Haplotype mapping within patients with allelic markers of the 57.1 ancestral haplotype suggests a susceptibility locus within the 14-kb Hsp70 gene cluster. HLA-B*5701 was present in 94.4% of hypersensitive cases compared with 1.7% of controls (odds ratio, 960; P < 0.00001). A haplotypic nonsynonymous polymorphism of Hsp70-Hom (HspA1L, resulting from the substitution of residue M493T in the peptide-binding subunit) was found in combination with HLA-B*5701 in 94.4% of hypersensitive cases and 0.4% of controls (odds ratio, 3,893; P < 0.00001). Individuals with Abacavir hypersensitivity demonstrated increased monocyte tumor necrosis factor expression in response to ex vivo Abacavir stimulation, which was abrogated with CD8+ T cell depletion. These data indicate that the concurrence of HLA-B*5701 and Hsp70-Hom M493T alleles is necessary for the development of Abacavir hypersensitivity, which is likely to be mediated by an HLA-B*5701-restricted immune response to Abacavir.
A. Martin - One of the best experts on this subject based on the ideXlab platform.
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prospective genetic screening decreases the incidence of Abacavir hypersensitivity reactions in the western australian hiv cohort study
Clinical Infectious Diseases, 2006Co-Authors: Andri Rauch, David Nolan, E Mckinnon, C. Almeida, A. Martin, Simon MallalAbstract:Abacavir therapy is associated with significant drug hypersensitivity in ∼8% of recipients, with retrospective studies indicating a strong genetic association with the HLA-B*5701 allelle. In this prospective study, involving 260 Abacavir-naive individuals (7.7% of whom were positive for HLA-B*5701), we confirm the usefulness of genetic risk stratification, with no cases of Abacavir hypersensitivity among 148 HLA-B*5701–negative recipients.
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prospective genetic screening decreases the incidence of Abacavir hypersensitivity reactions in the western australian hiv cohort study
Clinical Infectious Diseases, 2006Co-Authors: Andri Rauch, David Nolan, E Mckinnon, C. Almeida, A. Martin, Simon MallalAbstract:Abacavir therapy is associated with significant drug hypersensitivity in approximately 8% of recipients, with retrospective studies indicating a strong genetic association with the HLA-B*5701 allele. In this prospective study, involving 260 Abacavir-naive individuals (7.7% of whom were positive for HLA-B*5701), we confirm the usefulness of genetic risk stratification, with no cases of Abacavir hypersensitivity among 148 HLA-B*5701-negative recipients.
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clinical and immunogenetic correlates of Abacavir hypersensitivity
AIDS, 2005Co-Authors: Gavin A Wong, Kamnoosh Shahabi, Rupert Kaul, David Nolan, Simon Mallal, Sandra R. Knowles, A. Martin, Neil H ShearAbstract:A patch test (PT) may be useful in defining true Abacavir hypersensitivity syndrome (AHS). Seven previously PT-positive patients remote from the original AHS were shown to have robust 24 h responses, supporting PT durability. HLA-B*5701 was present in all seven PT-positive versus one of 11 controls tolerating Abacavir (P < 0.001). Five of seven PT (71%) versus one of 11 controls (9%) (P = 0.005) showed significant Abacavir-specific CD8 proliferation, suggesting a direct role for HLA-B*5701-restricted CD8 cells in the pathophysiology of AHS.
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predisposition to Abacavir hypersensitivity conferred by hla b 5701 and a haplotypic hsp70 hom variant
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: A. Martin, Silvana Gaudieri, Coral Ann Almeida, Richard C Nolan, Filipa Carvalho, I James, Frank Christiansen, David Nolan, Anthony W PurcellAbstract:Susceptibility to a clinically significant drug hypersensitivity syndrome associated with Abacavir use seems to have a strong genetic component. We have previously shown that the presence of HLA-B*5701 strongly predicts Abacavir hypersensitivity and have identified a potential susceptibility locus within a 300-kb region between the MEGT1 and C4A6 loci in the central MHC. We now report the results of fine recombinant genetic mapping in an expanded patient population of 248 consecutive, fully ascertained, Abacavir-exposed individuals in the Western Australian HIV Cohort Study, in which 18 cases of definite Abacavir hypersensitivity (7.3%) and 230 tolerant controls were identified. Haplotype mapping within patients with allelic markers of the 57.1 ancestral haplotype suggests a susceptibility locus within the 14-kb Hsp70 gene cluster. HLA-B*5701 was present in 94.4% of hypersensitive cases compared with 1.7% of controls (odds ratio, 960; P < 0.00001). A haplotypic nonsynonymous polymorphism of Hsp70-Hom (HspA1L, resulting from the substitution of residue M493T in the peptide-binding subunit) was found in combination with HLA-B*5701 in 94.4% of hypersensitive cases and 0.4% of controls (odds ratio, 3,893; P < 0.00001). Individuals with Abacavir hypersensitivity demonstrated increased monocyte tumor necrosis factor expression in response to ex vivo Abacavir stimulation, which was abrogated with CD8+ T cell depletion. These data indicate that the concurrence of HLA-B*5701 and Hsp70-Hom M493T alleles is necessary for the development of Abacavir hypersensitivity, which is likely to be mediated by an HLA-B*5701-restricted immune response to Abacavir.
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predisposition to Abacavir hypersensitivity conferred by hla b 5701 and a haplotypic hsp70 hom variant
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: A. Martin, Silvana Gaudieri, Coral Ann Almeida, Richard C Nolan, Filipa Carvalho, I James, Frank Christiansen, D Nolan, Elizabeth J Phillips, Anthony W PurcellAbstract:Susceptibility to a clinically significant drug hypersensitivity syndrome associated with Abacavir use seems to have a strong genetic component. We have previously shown that the presence of HLA-B*5701 strongly predicts Abacavir hypersensitivity and have identified a potential susceptibility locus within a 300-kb region between the MEGT1 and C4A6 loci in the central MHC. We now report the results of fine recombinant genetic mapping in an expanded patient population of 248 consecutive, fully ascertained, Abacavir-exposed individuals in the Western Australian HIV Cohort Study, in which 18 cases of definite Abacavir hypersensitivity (7.3%) and 230 tolerant controls were identified. Haplotype mapping within patients with allelic markers of the 57.1 ancestral haplotype suggests a susceptibility locus within the 14-kb Hsp70 gene cluster. HLA-B*5701 was present in 94.4% of hypersensitive cases compared with 1.7% of controls (odds ratio, 960; P < 0.00001). A haplotypic nonsynonymous polymorphism of Hsp70-Hom (HspA1L, resulting from the substitution of residue M493T in the peptide-binding subunit) was found in combination with HLA-B*5701 in 94.4% of hypersensitive cases and 0.4% of controls (odds ratio, 3,893; P < 0.00001). Individuals with Abacavir hypersensitivity demonstrated increased monocyte tumor necrosis factor expression in response to ex vivo Abacavir stimulation, which was abrogated with CD8+ T cell depletion. These data indicate that the concurrence of HLA-B*5701 and Hsp70-Hom M493T alleles is necessary for the development of Abacavir hypersensitivity, which is likely to be mediated by an HLA-B*5701-restricted immune response to Abacavir.
Anthony W Purcell - One of the best experts on this subject based on the ideXlab platform.
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allotype specific interactions of drugs and hla molecules in hypersensitivity reactions
Current Opinion in Immunology, 2016Co-Authors: Patricia T Illing, Nicole A Mifsud, Anthony W PurcellAbstract:It is hypothesised that associations between adverse drug reactions and specific alleles of the human leukocyte antigens arise due to specific interactions between the human leukocyte antigen molecules and the causative drug that stimulate immune responses targeting drug exposed tissues. To date this has only been definitively demonstrated for Abacavir, an antiretroviral that causes a systemic adverse drug reaction, Abacavir hypersensitivity syndrome, solely in HLA-B*57:01+ individuals. Whilst this has informed the modification of Abacavir to remove immunogenicity, there remains an imperative to define other interactions between drugs and specific HLA in order to understand the scope of interactions that can drive T cell mediated drug hypersensitivity. Here we review the current state of understanding of these interactions.
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human leukocyte antigen class i restricted activation of cd8 t cells provides the immunogenetic basis of a systemic drug hypersensitivity
Immunity, 2008Co-Authors: Diana Chessman, Anthony W Purcell, Lyudmila Kostenko, Lars Kjernielsen, B D Tait, Tessa Lethborg, Nicholas A Williamson, Zhenjun Chen, Nicole A Mifsud, Rhonda HoldsworthAbstract:The basis for strong immunogenetic associations between particular human leukocyte antigen (HLA) class I allotypes and inflammatory conditions like Behcet's disease (HLA-B51) and ankylosing spondylitis (HLA-B27) remain mysterious. Recently, however, even stronger HLA associations are reported in drug hypersensitivities to the reverse-transcriptase inhibitor Abacavir (HLA-B57), the gout prophylactic allopurinol (HLA-B58), and the antiepileptic carbamazepine (HLA-B∗1502), providing a defined disease trigger and suggesting a general mechanism for these associations. We show that systemic reactions to Abacavir were driven by drug-specific activation of cytokine-producing, cytotoxic CD8+ T cells. Recognition of Abacavir required the transporter associated with antigen presentation and tapasin, was fixation sensitive, and was uniquely restricted by HLA-B∗5701 and not closely related HLA allotypes with polymorphisms in the antigen-binding cleft. Hence, the strong association of HLA-B∗5701 with Abacavir hypersensitivity reflects specificity through creation of a unique ligand as well as HLA-restricted antigen presentation, suggesting a basis for the strong HLA class I-association with certain inflammatory disorders.
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predisposition to Abacavir hypersensitivity conferred by hla b 5701 and a haplotypic hsp70 hom variant
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: A. Martin, Silvana Gaudieri, Coral Ann Almeida, Richard C Nolan, Filipa Carvalho, I James, Frank Christiansen, David Nolan, Anthony W PurcellAbstract:Susceptibility to a clinically significant drug hypersensitivity syndrome associated with Abacavir use seems to have a strong genetic component. We have previously shown that the presence of HLA-B*5701 strongly predicts Abacavir hypersensitivity and have identified a potential susceptibility locus within a 300-kb region between the MEGT1 and C4A6 loci in the central MHC. We now report the results of fine recombinant genetic mapping in an expanded patient population of 248 consecutive, fully ascertained, Abacavir-exposed individuals in the Western Australian HIV Cohort Study, in which 18 cases of definite Abacavir hypersensitivity (7.3%) and 230 tolerant controls were identified. Haplotype mapping within patients with allelic markers of the 57.1 ancestral haplotype suggests a susceptibility locus within the 14-kb Hsp70 gene cluster. HLA-B*5701 was present in 94.4% of hypersensitive cases compared with 1.7% of controls (odds ratio, 960; P < 0.00001). A haplotypic nonsynonymous polymorphism of Hsp70-Hom (HspA1L, resulting from the substitution of residue M493T in the peptide-binding subunit) was found in combination with HLA-B*5701 in 94.4% of hypersensitive cases and 0.4% of controls (odds ratio, 3,893; P < 0.00001). Individuals with Abacavir hypersensitivity demonstrated increased monocyte tumor necrosis factor expression in response to ex vivo Abacavir stimulation, which was abrogated with CD8+ T cell depletion. These data indicate that the concurrence of HLA-B*5701 and Hsp70-Hom M493T alleles is necessary for the development of Abacavir hypersensitivity, which is likely to be mediated by an HLA-B*5701-restricted immune response to Abacavir.
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predisposition to Abacavir hypersensitivity conferred by hla b 5701 and a haplotypic hsp70 hom variant
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: A. Martin, Silvana Gaudieri, Coral Ann Almeida, Richard C Nolan, Filipa Carvalho, I James, Frank Christiansen, D Nolan, Elizabeth J Phillips, Anthony W PurcellAbstract:Susceptibility to a clinically significant drug hypersensitivity syndrome associated with Abacavir use seems to have a strong genetic component. We have previously shown that the presence of HLA-B*5701 strongly predicts Abacavir hypersensitivity and have identified a potential susceptibility locus within a 300-kb region between the MEGT1 and C4A6 loci in the central MHC. We now report the results of fine recombinant genetic mapping in an expanded patient population of 248 consecutive, fully ascertained, Abacavir-exposed individuals in the Western Australian HIV Cohort Study, in which 18 cases of definite Abacavir hypersensitivity (7.3%) and 230 tolerant controls were identified. Haplotype mapping within patients with allelic markers of the 57.1 ancestral haplotype suggests a susceptibility locus within the 14-kb Hsp70 gene cluster. HLA-B*5701 was present in 94.4% of hypersensitive cases compared with 1.7% of controls (odds ratio, 960; P < 0.00001). A haplotypic nonsynonymous polymorphism of Hsp70-Hom (HspA1L, resulting from the substitution of residue M493T in the peptide-binding subunit) was found in combination with HLA-B*5701 in 94.4% of hypersensitive cases and 0.4% of controls (odds ratio, 3,893; P < 0.00001). Individuals with Abacavir hypersensitivity demonstrated increased monocyte tumor necrosis factor expression in response to ex vivo Abacavir stimulation, which was abrogated with CD8+ T cell depletion. These data indicate that the concurrence of HLA-B*5701 and Hsp70-Hom M493T alleles is necessary for the development of Abacavir hypersensitivity, which is likely to be mediated by an HLA-B*5701-restricted immune response to Abacavir.
