Baseline Resistance and Virological Outcome in Patients with Virological Failure who Start a Regimen Containing Abacavir: Eurosida Study
Cecilia CabreraAlessandro Cozzi‐LepriAndrew PhillipsClive LovedayOle KirkMounir Ait‐KhaledPeter ReissJesper KjærBruno LedergerberJens LundgrenBonaventura ClotetLı́dia RuizM LossoAdriana DuránN. VetterNathan ClumeckP. HermansBernadette SommereijnsRobert ColebundersLadislav MachalaH RozsypalJens NielsenJens LundgrenThomas BenfieldOle KirkJan GerstoftTerese L. KatzensteinBirgit Thorup RøgePeter SkinhøjC PedersenKai ZilmerChristine KatlamaM DeJ-P ViardT Saint-MarcPhilippe VanhemsChristian PradierM. DietrichC. ManegoldJan van LunzenHJ StellbrinkVeronica MillerSchlomo StaszewskiF-D GoebelBernd SalzbergerJ RockstrohJ. KosmidisPanagiotis GargalianosH SambatakouJ. PerdiosGeorge PanosIoannis KarydisA. FilandrasDénes BánhegyiF MulcahyIsrael YustMichael BurkeS PollackZ Ben‐IshaiZvi BentwichShlomo MaayanStefano VellaAntonio ChiesiClaudio AriciR. PristeràFrancesco MazzottaAndrea GabbutiRoberto EspositoAndrea BediniAntonio ChirianniE. MontesarchioVincenzo VulloP SantopadrePhilipp NarcisoAndrea AntinoriPaolo FranciMaria Carla ReAdriano LazzarinRenato FinazziAntonella d’Arminio MonforteLudmila VīksnaSaulius ChaplinskasR HemmerT StaubPeter ReißJN BruunA MælandVidar OrmaasenBrygida KnyszJacek GąsiorowskiAndrzej HorbanD ProkopowiczAlicja Wiercińska–DrapałoAnna Boroń‐KaczmarskaM. PynkaMarek BeniowskiH TrochaFrancisco AntunesKamal MansinhoRui ProençaDan DuiculescuAdrian Streinu‐CercelM MikrasJuan González‐LahozBeatriz Díaz‐PollánTeresa García-BenayasLuz Martín‐CarboneroVincent SorianoB ClotetA. JouJ. Alberto ConejeroC. TuralJM GatellJM MiróAnders BlaxhultAnna KarlssonP PehrsonBruno LedergerberRainer WeberP FrancioliAmalio TelentiBernard HirschelV Soravia-DunandHansjakob FurrerNelly ChentsovaSimon BartonMargaret JohnsonD MerceyAndrew PhillipsClive LovedayMA JohnsonAmanda MocroftA J PinchingJacqueline ParkinJonathan WeberG ScullardMartin FisherR P Brettle
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Objectives To investigate the ability of several HIV-1 drug-resistance interpretation systems, as well as the number of pre-specified combinations of abacavir-related mutations, to predict virological response to abacavir-containing regimens in antiretroviral therapy-experienced, abacavir-naive patients starting an abacavir-containing regimen in the EuroSIDA cohort. Patients and methods A total of 100 HIV-infected patients with viral load (VL) >500 copies/ml who had a plasma sample available at the time of starting abacavir (baseline) were included. Resistance to abacavir was interpreted by using eight different commonly used systems that consisted of rules-based algorithms or tables of mutations. Correlation between baseline abacavir-resistance mutations and month 6 virological response was performed on this population using a multivariable linear regression model accounting for censored data. Results The baseline VL was 4.36 log 10 RNA copies/ml [interquartile range (IQR): 3.65–4.99 log 10 RNA copies/ml] and the median CD4 cell count was 210 cells/μl (IQR: 67–305 cells/μl). Our patients were pre-exposed to a median of seven antiretrovirals (2–12) before starting abacavir therapy. The median (range) number of abacavir mutations (according to the International AIDS Society-USA) detected at baseline was 3.5 (0–8). Overall, the Kaplan–Meier estimate of the median month 6 VL decline was 0.86 log 10 RNA copies/ml [95% confidence intervals (95% CI): 0.45–1.24]. The VL in those patients ( n=31) who intensified treatment by adding only abacavir decreased by a median 0.20 log 10 RNA copies/ml (95% CI: -0.18; +0.94). The proportion of patients who harboured viruses fully resistant to abacavir among the eight genotypic resistance interpretation algorithms ranged from 12% [Agence Nationale de Recherches sur le SIDA (ANRS)] to 79% [Stanford HIV RT and PR Sequence Database (HIVdb)]. Some interpretation systems showed statistically significant associations between the predicted resistance status and the virological response while others showed no consistent association. The number of active drugs in the regimen was associated with greater virological suppression (additional month 6 VL reduction per additional sensitive drug=0.51, 95% CI: 0.15–0.88, P=0.006); baseline VL was also weakly associated (additional month 6 VL reduction per log 10 higher=0.30, 95% CI: -0.02; +0.62, P=0.06). In contrast, the number of drugs previously received was associated with diminished viral reduction (additional month 6 VL reduction per additional drug=-0.14, 95% CI: -0.28; 0.00, P=0.05). Conclusions Our results revealed a high degree of variability among several genotypic resistance interpretation algorithms currently in use for abacavir. Therefore, the interpretation of genotypic resistance for predicting response to regimens containing abacavir remains a major challenge.Keywords:
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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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This chapter provides basic characteristics, FDA-approved indications, side effects/toxicity, dosage information, drug/food interactions and antimicrobial therapy art of Ziagen (abacavir). Abacavir is approved to be used in combination with other antiretrovirals for the treatment of HIV infection. Serious and sometimes fatal hypersensitivity reactions, with multiple organ involvement, have occurred with abacavir tablets (abacavir). Abacavir tablets are contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients. All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with abacavir tablets or reinitiation of therapy with abacavir tablets, unless patients have a previously documented HLA-B*5701 allele assessment. Abacavir is administered in a 300 mg tablet or in a strawberry-banana flavored liquid, which contains 20 mg/cc. The recommended adult dose is 300 mg twice daily or 600 mg once daily.
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HIV-infected patients have accelerated atherosclerosis. Abacavir has been associated with increased risk of cardiovascular events, for reasons that remain to be elucidated. As endothelial dysfunction is central to the pathogenesis of atherosclerosis, we tested the hypothesis that current treatment with abacavir is associated with impaired endothelial function.We studied a cohort of 61 antiretroviral-treated patients who had undetectable plasma HIV RNA levels. Endothelial function was assessed by measuring flow-mediated dilation (FMD) of the brachial artery. We compared FMD in patients treated with or without abacavir, while adjusting for traditional risk factors and HIV-specific characteristics.The median age was 50 years (interquartile range 45-57). The median duration of HIV infection was 18 years, and the median CD4 cell count was 369 cells/microl. Thirty patients (49%) were receiving abacavir. Overall, the median FMD in the HIV-infected patients was low (3.5%; interquartile range 2.3-5.6%). The FMD was lower in the abacavir-treated patients than those not on abacavir (2.8 vs. 4.9%, P = 0.01). After adjustment for traditional risk factors, HIV-specific factors, and baseline brachial artery diameter, current abacavir use was independently associated with lower FMD (P = 0.017). Duration of therapy and CD4 cell count were not associated with reduced FMD.Endothelial function, a central mechanism in atherosclerosis and a marker of cardiovascular risk, is impaired among antiretroviral-treated patients with undetectable viral loads. Current use of abacavir was independently associated with impaired endothelial function. This finding suggests that abnormal endothelial function may underlie the clinically observed increased risk in myocardial infarction among abacavir-treated patients.
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Abacavir is a nucleoside reverse transcriptase inhibitor used for combination antiretroviral therapy for treating human immunodeficiency virus (HIV) infection. An adverse effect from abacavir is a treatment-limiting hypersensitivity reaction, which can be severe and potentially life-threatening. Abacavir-induced hypersensitivity reaction has been associated with the presence of the major histocompatibility complex class I allele HLA-B*5701. A screening test for the HLA-B*5701 allele can assist clinicians to identify patients who are at risk of developing a hypersensitivity reaction to abacavir.
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HIV patients, understandably, are sometimes unenthusiastic about taking their protease inhibitor (PI) drug therapies because of the numerous pills, the side effects, and chronic problems such as lipodystrophy. To address these problems, researchers have been studying non-PI drug therapies that are potent against HIV. Research has demonstrated successful viral suppression for at least 24 weeks when patients were switched from a PI regimen to an abacavir regimen.
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Abacavirë ë¶ìì©ì´ ì ì´ ìµê·¼ ë§ì´ ì¬ì©íë íë°ì´ë¬ì¤ì ì´ì§ë§ ëë¬¼ê² ì¹ëª ì ì¸ ê³¼ë¯¼ë°ìì ì¼ì¼í¬ ì ìë¤. ì ìë¤ì abacavir í¬ì¬ í í¼ë¶ë°ì§, ë¶ì¢ , í¸í¡ê³¤ëì ì¦ìì ë³´ì¸ íììì HLA-B*5701 ì ì íì íì¸íì¬ abacavirì ìí 과민ë°ììì ì§ë¨íìì¼ë©°, 본 ì¦ë¡ë 조기ì ì½ë¬¼ì ì¤ë¨íì¬ ì¹ì ë êµë´ 첫 íìì ëí ë³´ê³ ì´ë¤. Abacavirì ìí 과민ë°ìì´ ë문 ë¶ìì©ì´ì§ë§ ìëª ì ìíì´ ë ì ìì¼ë¯ë¡ 주ì ê¹ì ê´ì°°ì´ íìíë©°, ì½ë¬¼ ì¤ë¨ ë± ì¡°ê¸°ì ì ì í ëì²ê° ì¤ìíë¤. ì¤ì¬ ë¨ì´: Abacavir; 과민ë°ì; HLA-B íì
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To review the clinical features, risk factors, diagnosis, and management of abacavir hypersensitivity reaction (HSR).A MEDLINE (1950-October 2007) and EMBASE (1980-October 2007) search using key words abacavir, HIV, human immunodeficiency virus, hypersensitivity reaction, HLA-B(*)5701, and patch tests was conducted. Conference abstracts and article bibliographies were reviewed to identify relevant studies.Studies that investigated the clinical and immunogenetic risk factors for abacavir hypersensitivity and the benefit of genetic screening, as well as articles that focused on the clinical presentation, assessment, and management of abacavir HSR, were considered for this review.Abacavir hypersensitivity is an immune-mediated reaction that typically occurs within the first 6 weeks of therapy. Signs and symptoms of abacavir HSR are nonspecific, which makes the diagnosis challenging, particularly in medically complex patients. Patch testing may improve the diagnosis and confirmation of abacavir HSR, but it remains experimental. Clinical management is aimed at supportive therapy and discontinuation of abacavir. Rechallenge with abacavir is contraindicated due to the risk of precipitating a life-threatening reaction. Appropriate patient education and a clear communication plan are essential for the safe use of this medication. Identification of patients at risk of developing abacavir hypersensitivity through routine genetic screening for human leukocyte antigen (HLA) HLA-B(*)5701 represents a significant advance in the field of pharmacogenomics, with an apparent 100% negative predictive value when used to screen for abacavir HSR. Preliminary data suggest that pharmacogenetic testing for HLA-B(*)5701 is cost effective. However, until routine testing is available, pharmacovigilance is necessary for the safe and effective use of abacavir.Serious adverse events associated with the use of abacavir can be avoided by appropriate recognition and management of the HSR. Screening patients for HLA-B(*)5701 prior to initiation of abacavir represents a tool to further decrease the risk of HSRs as well as unnecessary discontinuation of this drug.
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Patients with a baseline viral load >100,000 copies/mL receiving abacavir (ABC) as part of the nucleoside-backbone component of their first highly active antiretroviral therapy (HAART) regimen have been reported to have a greater failure rate than those receiving tenofovir (TDF). We analyzed short-term outcomes of the use of HAART combinations that included ABC or TDF. The mean 2-8-week change in viral load was calculated using linear regression. In total, 1136 patients started ABC, and 412 started TDF. After adjustment for baseline viral load and other factors, there was no difference in the change in viral load between the patients who started ABC and those who started TDF (0.03 [95% confidence interval, -0.07 to 0.12]) log copies/mL; P = .59). Furthermore, there was no evidence that this effect differed according to baseline viral load (P = .88 for the interaction between pre-HAART viral load and nucleoside started). Likewise, there was no difference in rates of virological failure between the 2 drugs at 24-48 weeks after starting HAART.
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Regimens containing abacavir (ABC), tenofovir (TDF), and lamivudine (3TC) have recently been demonstrated to have high failure rates. This poses a clinical dilemma of how to manage patients currently being treated with other regimens containing tenofovir/abacavir. We evaluated the outcomes of tenofovir/abacavir regimens in our clinical practice through a retrospective review of 2655 charts. Two hundred patients (7%) were on a tenofovir/abacavir-containing regimen. Fifty-nine patients met the criteria for analysis and were grouped into three groups: (1) antiretroviral naïve, (2) virally suppressed patients switched to TDF/ABC, and (3) patients with failure of their first antiretroviral regimen. Rates of viral suppression in the naïve, switch, and first-failure groups were 95%, 86%, and 46%, respectively. In the first-failure group, viral suppression was 66% without and 18% with a preexisting M184V. A composite analysis of the groups revealed a success rate of 86% when the regimen contained zidovudine (ZDV) and 62% when it did not. No K65R mutations were noted. These findings support continued caution in the use of TDF/ABC in combination. However, these data suggest that this combination may be successfully used in selected situations such as in combination with ZDV. In patients already virally suppressed on a TDF/ABC-containing regimen, considerations include continuing the regimen or adding zidovudine, in the attempt to protect against the development of a K65R mutation and/or virologic failure, versus changing a stable regimen.
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