The Role of Conformational Dynamics in abacavir-Induced Hypersensitivity Syndrome
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Abstract Abacavir is an antiretroviral drug used to reduce human immunodeficiency virus (HIV) replication and decrease the risk of developing acquired immune deficiency syndrome (AIDS). However, its therapeutic value is diminished by the fact that it is associated with drug hypersensitivity reactions in up to 8% of treated patients. This hypersensitivity is strongly associated with patients carrying human leukocyte antigen (HLA)-B*57:01, but not patients carrying closely related alleles. Abacavir’s specificity to HLA-B*57:01 is attributed to its binding site within the peptide-binding cleft and subsequent influence of the repertoire of peptides that can bind HLA-B*57:01. To further our understanding of abacavir-induced hypersensitivity we used molecular dynamics (MD) to analyze the dynamics of three different peptides bound to HLA-B*57:01 in the presence and absence of abacavir or abacavir analogues. We found that abacavir and associated peptides bind to HLA-B*57:01 in a highly diverse range of conformations that are not apparent from static crystallographic snapshots. Further, the presence of abacavir has a direct impact on the dynamics and the conformational space available to peptides bound to HLA-B*57:01, likely influencing abacavir-induced immune self-reactivity. Our results support hypersensitivity models in which abacavir-binding alters the equilibrium proportions of neopeptide conformations in a manner favourable to TCR binding. Our findings highlight the need to also consider the role of dynamics in understanding drug-induced hypersensitivities at the molecular and mechanistic level. This additional insight can help inform the chemical modification of abacavir to prevent hypersensitivity reactions in HLA-B*57:01+ HIV patients whilst retaining potent antiretroviral activity.Keywords:
Abacavir
Antiretroviral drug
Efavirenz
Abacavir
Antiretroviral drug
ANTIRETROVIRAL AGENTS
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Abstract Abacavir is an antiretroviral drug used to reduce human immunodeficiency virus (HIV) replication and decrease the risk of developing acquired immune deficiency syndrome (AIDS). However, its therapeutic value is diminished by the fact that it is associated with drug hypersensitivity reactions in up to 8% of treated patients. This hypersensitivity is strongly associated with patients carrying human leukocyte antigen (HLA)-B*57:01, but not patients carrying closely related alleles. Abacavir’s specificity to HLA-B*57:01 is attributed to its binding site within the peptide-binding cleft and subsequent influence of the repertoire of peptides that can bind HLA-B*57:01. To further our understanding of abacavir-induced hypersensitivity we used molecular dynamics (MD) to analyze the dynamics of three different peptides bound to HLA-B*57:01 in the presence and absence of abacavir or abacavir analogues. We found that abacavir and associated peptides bind to HLA-B*57:01 in a highly diverse range of conformations that are not apparent from static crystallographic snapshots. Further, the presence of abacavir has a direct impact on the dynamics and the conformational space available to peptides bound to HLA-B*57:01, likely influencing abacavir-induced immune self-reactivity. Our results support hypersensitivity models in which abacavir-binding alters the equilibrium proportions of neopeptide conformations in a manner favourable to TCR binding. Our findings highlight the need to also consider the role of dynamics in understanding drug-induced hypersensitivities at the molecular and mechanistic level. This additional insight can help inform the chemical modification of abacavir to prevent hypersensitivity reactions in HLA-B*57:01+ HIV patients whilst retaining potent antiretroviral activity.
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BackgroundAntiretroviral combinations that reduce the number of pills and dosing frequency have the potential to simplify therapy. We compared 2 regimens dosed as 2 pills once daily
Abacavir
Tenofovir
Antiretroviral drug
Antiretroviral treatment
Reverse-transcriptase inhibitor
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As a new drug of anti-AIDS,Abacavir has a good effect in anti-AIDS,and the market requirement is great.Based on of the foreign literatures,this paper summarizes the effect,routes of synthesis and market foreground of abacavir,and sums up the routes of synthesising its carbocyclic ring.
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Bariatric surgery is increasingly performed in morbidly obese HIV patients. Limited data exist regarding antiretroviral drug exposure after bariatric surgery. We report a case of a morbidly obese HIV patient who underwent sleeve gastrectomy. Abacavir, lamivudine, and dolutegravir therapeutic drug monitoring was performed at several time points pre- and postsurgery. Significantly increased levels were measured, particularly for abacavir, whose levels increased ∼12-fold. Several mechanistic explanations for these findings are discussed.
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Sleeve gastrectomy
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Antiretroviral drug
Morbidly obese
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Stavudine
Abacavir
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Antiretroviral drug
Antiretroviral treatment
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Clinicians are eagerly anticipating approval of the HIV reverse transcriptase inhibitor abacavir. These two early phase II studies highlight the
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To the Editors: A large observational study found an association between the use of the nucleoside reverse transcriptase inhibitor abacavir and an increase of cardiovascular risk in HIV-1–infected patients.1–3 Since then, different studies have reported controversial results: some cohort studies seemed to confirm the observation,4,5 whereas other more recent analyses and a meta-analysis seem to6–9 contradict this hypothesis. Currently, the major treatment guidelines warrant caution in the prescription of this drug in patients already showing a high cardiovascular risk based on traditional parameters.10–13 Nonetheless, a biological mechanism explaining the reasons for this finding has never been elucidated. Despite an initial observation of higher levels of inflammatory markers in a cross-sectional analysis of samples from 2 observational cohorts,4 subsequent longitudinal studies failed to detect significant associations between the use of abacavir and changes in the levels of cardiovascular risk biomarkers.14–16 In this longitudinal observation, we compared groups of patients with different patterns of exposure to abacavir to evaluate the possible effects of the use of this antiretroviral on the plasma levels of several biomarkers associated with cardiovascular risk. From the biological repository of the ICoNA Foundation study (for more details17), we collected longitudinal sample pairs from HIV-infected patients aged >18 years, treated with combination antiretroviral therapy and with a stable viral load below 400 copies per milliliter at the time of and between the 2 sampling dates. Patients with hypersensitivity reaction to abacavir, active opportunistic infections in the last year, those with chronic inflammatory diseases or treated with any corticosteroid or anti-inflammatory therapy, pregnant women, and patients with previous myocardial infarction were excluded. The longitudinal sample pairs were classified in 4 different groups according to the timing of their collection as follows: patients starting abacavir (group A); patients continuously receiving abacavir (group B); patients discontinuing abacavir (group C); and patients never exposed to abacavir (group D). In some cases, 3 longitudinal samples were collected from the same patient. There were patients contributing sample pairs to different groups. High sensitivity CRP was measured by nephelometry using an automatic analyzer (ILab 350, Instrumentation Laboratory, Milan, Italy). D-Dimer was evaluated employing a latex particle-enhanced immunoturbidimetric assay (IL ACL9000, Instrumentation Laboratory, Milan, Italy). The other biomarkers were measured in plasma samples by commercially available immunoenzymatic assays: P-selectin, sICAM-1, and sVCAM-1 (Bender MedSystems Europe, Vienna, Austria), IL-6 (R&D System Europe, Abington, United Kingdom), tissue plasminogen activator (t-PA), and plasminogen activator inhibitor (PAI)-1 (American Diagnostica Inc. Gmbh, Pfungstadt, Germany). The detection limits were 2.2 ng/mL for ICAM-1, 1.06 ng/mL for P-selectin, 0.6 ng/mL for VCAM-1, 1.0 ng/mL for t-PA, 1.0 ng/mL for PAI-1, 0.70 pg/mL for IL-6, and 1.6 pg/ml for tumor necrosis factor-alpha. We collected 161 samples from 60 patients. Considering that 1 patient and also 1 single sample could contribute to more than 1 pair, these samples contributed to 86 pairs. The main baseline characteristics of patients according to their current exposure to abacavir and those of patients according to the 4 groups of exposure to the drug are shown in the online Table (see Supplemental Digital Content, https://links.lww.com/QAI/A326). In a first cross-sectional analysis, higher levels of PAI-1 were observed in patients currently exposed versus those not currently exposed to abacavir (+0.18 log10 ng/mL, 95% confidence interval: 0.07 to 0.30, P = 0.002, Wilcoxon test). The difference was larger (+0.31 log) after adjusting for age, gender, duration of HIV RNA suppression, a diagnosis of AIDS before sampling, viral load and CD4 count at sampling, smoking status, lipids, systolic blood pressure, and concomitant use of other antiretrovirals, but it did not reach statistical significance (P = 0.18). No differences were observed in the levels of the other biomarkers between these 2 groups of samples. The longitudinal analysis did not show significant changes of the levels of biomarkers between paired samples within the 4 study groups (not shown). Given the high proportion of IL6 measures below the detection limit, we compared the percentage of patients with detectable IL6: this tended to increase upon initiation of abacavir in group A with 6 of 35 (17%) in the first sample versus 12 of 34 (35%) in the second (P = 0.09), but when the changes between proportions with detectable and undetectable were compared between groups, no significant difference was detected (χ2P = 0.34). Table 1 shows the unadjusted and adjusted covariance analysis of the changes of biomarkers between the 4 study groups, directly comparing the A, C, and D groups with the B group (patients kept on abacavir) used as reference. At multivariable analysis, as compared with the reference group, t-PA showed a trend toward a positive difference in the mean yearly change (P = 0.06) in group A (patients starting abacavir), a significant negative difference in the mean yearly change (P = 0.04) in group C (patients stopping abacavir), and no significant difference in group D (patients not exposed to abacavir). Still compared with group B, mean differences in the adjusted yearly changes in D-dimer were significantly negative in patients in groups A (P = 0.05) and D (P = 0.04), and the adjusted mean difference in the yearly change of ICAM-1 was significantly negative in patients in group A (P = 0.01) as compared with group B. No significant differences were observed between the yearly changes of the other biomarkers.TABLE 1: Unadjusted and Adjusted ANCOVA Analysis of the Mean log10 Yearly Differences in Changes of Plasma Biomarker Levels between groups A, C, and D and Reference Group B (Patients Kept on Abacavir)In a secondary analysis, where the group never exposed to abacavir (group D) was used as reference, the difference of the mean adjusted yearly changes in D-dimer was significantly positive in patients kept on abacavir D (P = 0.04); in line with the main analysis, the mean difference of the adjusted yearly changes in t-PA was significantly negative in patients discontinuing abacavir (P = 0.026). The pathogenetic mechanism determining the presumed abacavir-related increase of cardiovascular risk has not been fully clarified yet. The possible induction of inflammatory reaction due to the exposure to abacavir, and the temporal association of observed cardiovascular events with the current use of the drug, brought us to analyze association of the use of abacavir with the levels of biomarkers of inflammation and cardiovascular risk. We chose patients with viral load lower than 400 copies per milliliter to reduce the influence of HIV replication on inflammatory mechanisms. We observed a positive difference in changes of t-PA in patients starting abacavir and a trend toward a negative difference in changes in patients stopping the drug, as compared with those stably continuing the drug; a negative difference in t-PA changes in patients discontinuing abacavir was also observed when compared to patients never receiving the drug. Given the relevance of t-PA in the fibrinolytic process, this could suggest an association between the initiation of abacavir and an increased activation of fibrinolysis as compared with individuals stably on the drug. In line with this observation, patients starting abacavir showed, as compared with those stably on the drug, a negative difference in the changes of d-dimer and ICAM-1 levels, showing a reduced trend of the activation of the inflammatory, pro-coagulation, and endothelial activation process in those initiating abacavir as compared with those stably on the drug. Using the patients never exposed to abacavir as comparator, the group stably on abacavir showed a positive difference in the longitudinal change of d-dimer, suggesting that an increase in d-dimer may be the consequence of continued rather than initial exposure to abacavir. Altogether, the longitudinal observations contrast with the hypothesis that abacavir may increase cardiovascular risk in patients exposed to the drug through pathways that involve the analyzed biomarkers. Given the limited time frame of observation after abacavir initiation (a median of 5 months), we cannot exclude that these biomarkers could show changes at earlier or at later time points. Against the possibility of an effect of long-term abacavir exposure on the studied biomarkers, the longitudinal observation (median 9 months) within the patients kept on abacavir did not detect significant changes in biomarkers as follows: only a modest increase in d-dimer levels was observed as compared with the patient group never exposed to abacavir. Finally, the observed results of the biomarkers showing rather an antithrombotic trend in the group of patients starting abacavir may well represent a possible compensatory mechanism of an unexplored effect increasing the risk of thrombosis. Further analyses are warranted to clarify the implications of this observation. Overall, these results are in agreement with those presented by other authors who did not find significant changes in the levels of IL-6, hsCRP, D-dimer, and VCAM-1 in patients starting abacavir14,15 and with those of a specific subanalysis of a randomized clinical trial, whereno significant changes were observed after switching to abacavir-containing combination antiretroviral therapy in the levels of relevant biomarkers.16 In conclusion, our study did not show a significant effect of the exposure to abacavir on the main biomarkers of cardiovascular risk. Although we cannot completely exclude an early acute effect on biomarkers, immediately after abacavir initiation, our findings argue against a negative effect of abacavir treatment on the analyzed biomarkers of cardiovascular risk.
Abacavir
Antiretroviral drug
Pharmacotherapy
Reverse-transcriptase inhibitor
Nevirapine
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