BACKGROUND:

Recently, the Data collection of Adverse events of Anti-HIV Drugs Group (D:A:D) described results from their international observational cohort of 33,347 HIV-1-infected individuals, suggesting unexpected increased risk of myocardial infarction (MI) associated with abacavir (ABC) therapy [relative rate 1.9, 95% confidence interval (CI): 1.47 to 2.45; P = 0.0001]. To contribute to the scientific question, we summarized GlaxoSmithKline HIV clinical trial data to determine if a similar signal emerged.

METHODS:

We compiled data from GlaxoSmithKline-sponsored clinical trials with ≤24 weeks of combination antiretroviral therapy comprising 14,174 HIV-infected adults who received ABC (n = 9502; 7641 person-years) or not (n = 4672; 4267 person-years).

FINDINGS:

Baseline demographics and HIV disease characteristics, including lipids and glucose values, were similar. MI rates were comparable among subjects exposed [n = 16 (0.168%; CI.: 0.096 to 0.273; 2.09 per 1000 person-years)] or not [n = 11 (0.235%; CI.: 0.118 to 0.421; 2.57 per 1000 person-years)] to ABC-containing therapy. Results of 12 trials with randomization to ABC or not were consistent (2.15 per 1000 person-years vs. 4.10 per 1000 person-years).

INTERPRETATIONS:

In this pooled summary, we observed few MI events overall and no excess risk of MI with ABC therapy. It is unclear why results from this data set seem discrepant to the Data collection of Adverse events of Anti-HIV Drugs data set, particularly, as the non-ABC MI event rate is similar. Further data are needed to evaluate any association between ABC and increased risk of MI. Copyright © 2009 by Lippincott Williams & Wilkins.

OBJECTIVE:

The aim of the study was to examine whether exposure to abacavir increases the risk for myocardial infarction (MI).

DESIGN, SETTING AND SUBJECTS:

This was a prospective nationwide cohort study which included all Danish HIV-infected patients on highly active antiretroviral therapy (HAART) from 1995 to 2005 (N = 2952). Data on hospitalization for MI and comorbidity were obtained from Danish medical databases. Hospitalization rates for MI after HAART initiation were calculated for patients who used abacavir and those who did not. We used Cox's regression to compute incidence rate ratios (IRR) as a measure of relative risk for MI, while controlling for potential confounders (as separate variables and via propensity score) including comorbidity.

MAIN OUTCOME:

Relative risk of hospitalization with MI in abacavir users compared with abacavir nonusers.

RESULTS:

Hospitalization rates for MI were 2.4/1000 person-years (PYR) [95% confidence interval (CI) 1.7-3.4] for abacavir nonusers and 5.7/1000 PYR (95% CI 4.1-7.9) for abacavir users. The risk of MI increased after initiation of abacavir [unadjusted IRR = 2.22 (95% CI 1.31-3.76); IRR adjusted for confounders = 2.00 (95% CI 1.10-3.64); IRR adjusted for propensity score = 2.00 (95% CI 1.07-3.76)]. This effect was also observed among patients initiating abacavir within 2 years after the start of HAART and among patients who started abacavir as part of a triple nucleoside reverse transcriptase inhibitor (NRTI) regimen.

CONCLUSIONS:

We confirmed the association between abacavir use and increased risk of MI. Further studies are needed to control for potential confounding not measured in research to date.

Background: Hyperlipidemia secondary to protease inhibitors (PI) may abate by switching to anti-HIV medications without lipid effects. Method: An open-label, randomized pilot study compared changes in fasting lipids and HIV-1 RNA in 104 HIV-infected adults with PI-associated hyperlipidemia (fasting serum total cholesterol >200 mg/dL) who were randomized either to a regimen in which their PI was replaced by abacavir 300 mg twice daily (n = 52) or a regimen in which their PI was continued (n = 52) for 28 weeks. All patients had undetectable viral loads (HIV-1 RNA <50 copies/mL) at baseline and were naïve to abacavir and non-nucleoside reverse transcriptase inhibitors. Results: At baseline, the mean total cholesterol was 243 mg/dL, low density lipoprotein (LDL)-cholesterol 149 mg/dL, high density lipoprotein (HDL)-cholesterol 41 mg/dL, and triglycerides 310 mg/dL. Mean CD4+ cell counts were 551 and 531 cells/mm3 in the abacavir-switch and PI-continuation arms, respectively. At week 28, the abacavir-switch arm had significantly greater least square mean reduction from baseline in total cholesterol (-42 vs -10 mg/dL, P < 0.001), LDL-cholesterol (-14 vs +5 mg/dL, P = 0.016), and triglycerides (-134 vs -36 mg/dL, P = 0.019) than the PI-continuation arm, with no differences in HDL-cholesterol (+0.2 vs +1.3 mg/dL, P = 0.583). A higher proportion of patients in the abacavir-switch arm had decreases in protocol-defined total cholesterol and triglyceride toxicity grades, whereas a smaller proportion had increases in these toxicity grades. At week 28, an intent-to treat: missing = failure analysis showed that the abacavir-switch and PI-continuation arms did not differ significantly with respect to proportion of patients maintaining HIV-1 RNA <400 or <50 copies/mL or adjusted mean change from baseline in CD4+ cell count. Two possible abacavir-related hypersensitivity reactions were reported. No significant changes in glucose, insulin, insulin resistance, C-peptide, or waist-to-hip ratios were observed in either treatment arm, nor were differences in these parameters noted between treatments. Conclusion: In hyperlipidemic, antiretroviral-experienced patients with HIV-1 RNA levels <50 copies/mL and CD4+ cell counts >500 cells/mm3, substituting abacavir for hyperlipidemiaassociated PIs in combination antiretroviral regimens improves lipid profiles and maintains virologic suppression over a 28-week period, and it simplifies treatment. © 2005 Keiser et al; licensee BioMed Central Ltd.

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Abacavir sulfate is a nucleoside analogue and reverse transcriptase inhibitor which is used in combination with other agents in the therapy of the human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS). Abacavir is a rare cause of clinically apparent drug induced liver injury.

BACKGROUND:

Observational and retrospective clinical trial cohorts have reported conflicting results for the association of abacavir use with risk of myocardial infarction (MI), possibly related to issues that may bias estimation of treatment effects, such as time-varying confounders, informative dropout, and cohort loss due to competing events.

METHODS:

We analyzed data from 5056 individuals initiating randomized antiretroviral treatment (ART) in AIDS Clinical Trials Group studies; 1704 started abacavir therapy. An intent-to-treat analysis adjusted for pretreatment covariates and weighting for informative censoring was used to estimate the hazard ratio (HR) of MIs after initiation of a regimen with or without abacavir.

RESULTS:

Through 6 years after ART initiation, 36 MI events were observed in 17,404 person-years of follow-up. No evidence of an increased hazard of MI in subjects using abacavir versus no abacavir was seen (over a 1-year period: P=.50; HR, 0.7 [95% confidence interval {CI}, 0.2-2.4]); over a 6-year period: P=.24; HR, 0.6 [95% CI, 0.3-1.4]); these results were robust over as-treated and sensitivity analyses. Although the risk of MI decreased over time, there was no evidence to suggest a time-dependent abacavir effect. Classic cardiovascular disease (CVD) risk factors were the strongest predictors of MI.

CONCLUSION:

We find no evidence to suggest that initial ART containing abacavir increases MI risk over short-term and long-term periods in this population with relatively low MI risk. Traditional CVD risk factors should be the main focus in assessing CVD risk in individuals with human immunodeficiency virus infection.

A 24-week open-label clinical trial was conducted in 195 HIV-infected adults commonly underrepresented in research (35% female, 71% African American, 21% Hispanic, and 20% injection drug users [IDUs]) to evaluate the effect of an HIV educational program on efficacy and adherence with a simple, compact, twice-daily triple nucleoside regimen containing a lamivudine (150 mg)/zidovudine (300 mg) combination (COM) tablet plus abacavir (ABC), 300 mg. At baseline, the patients' median plasma HIV-1 RNA level was 4.18 log10 copies/mL and the median CD4+ cell count was 379 cells/mm3. Patients were randomized 1:1 to 4 modules of the Tools for Health and Empowerment HIV education intervention plus routine counseling (EI + RC; n = 96) or to routine counseling alone (RC; n = 99). No differences between the EI + RC and RC treatment arms were observed with respect to the proportion of patients achieving plasma HIV-1 RNA levels <40 copies/mL (60% [33/55] vs. 55% [38/69]; P = 0.529) or <400 copies/mL (80% [44/55] vs. 80% [55/69]; P = 0.689) at week 24 (intent-to-treat observed analysis), increase in median CD4 cell count above baseline at week 24 (78.3 vs. 104.8 cells/mm3; P = 0.498), or mean overall adherence rates as measured by the Medication Event Monitoring System (MEMS) (70% vs. 74%). COM + ABC was generally well tolerated, and no association was observed between interruptions in treatment and the development of ABC hypersensitivity (5 suspected cases). In conclusion, in underrepresented patients, the EI used in this study did not affect the efficacy and adherence results with ABC + COM to any greater degree than did RC.

OBJECTIVE:

To review the clinical features, risk factors, diagnosis, and management of abacavir hypersensitivity reaction (HSR).

DATA SOURCES:

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.

STUDY SELECTION AND DATA EXTRACTION:

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.

DATA SYNTHESIS:

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.

CONCLUSIONS:

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.

OBJECTIVES:

To compare dosing convenience and adherence with abacavir (ABC) 300 mg plus a fixed-dose lamivudine 150 mg/zidovudine 300 mg combination tablet (COM) twice daily versus indinavir (IDV) plus COM twice daily in treatment-naïve, HIV-1-infected adults; and to evaluate the association among difficulty taking antiretroviral regimens, adherence, and virologic efficacy.

METHODS:

An open-label, randomized, multicenter, international study compared the COM/ABC and IDV/COM regimens with respect to self-reported adherence and regimen convenience over 48 weeks. Logistic regression analysis (LRA) was done on a patient sub-sample from both groups to evaluate predictors of adherence and virologic response at last time-point on randomized therapy (LTORT).

RESULTS:

The study population was diverse with respect to ethnicity (38% Asian, 27% Hispanic, 28% white, 3% black, 4% other) and gender (39% women, 61% men). Baseline median HIV-1 RNA was 4.80 log(10) copies/mL and CD4+ cell count was 315 cells/mm(3). Of 329 patients who were randomized and received treatment, 315 (96%) provided adherence data. Significantly more patients in the ABC/COM group than in the IDV/COM group reported > or = 95% adherence to therapy (76 vs 58%, p < 0.001) and no difficulty in taking their regimen (91 vs 61%, p < 0.001). In both groups, the highest probability of HIV-1 RNA < 400 copies/mL occurred when median adherence was > or = 95%. The probability of HIV-1 RNA < 400 copies/mL declined more rapidly in the IDV/COM group as adherence rates decreased. LRA showed that no difficulty taking any of the drugs in the regimen, ABC/COM treatment group, and male gender were independent significant predictors of > or = 95% adherence (p < 0.05). Median adherence and baseline HIV-1 RNA were significant predictors of HIV-1 RNA < 400 copies/mL (p < 0.05).

CONCLUSIONS:

Patients reported greater ease of use and superior adherence to ABC/COM than IDV/COM. Patient-reported difficulty taking drugs in a regimen was predictive of reduced adherence, and both of the latter factors were predictive of poorer virologic outcome. Adherence levels of > or = 95% in both treatment groups maximized the probability of patients achieving an HIV-1 RNA < 400 copies/mL.

Detection of drug resistance is critical for determining antiretroviral treatment options. Ultradeep pyrosequencing (UDPS; 454 Life Sciences) is capable of detecting virus variant subpopulations with much greater sensitivity than population sequencing, which typically has a detection limit around 20%. UDPS of the HIV-1 reverse transcriptase (RT) (amino acids 56-120) was performed to detect the key mutations K65R and L74V associated with tenofovir and abacavir use. Plasma specimens from subjects with persistent rebound viremia following suppression on tenofovir (n = 8) or abacavir (n = 9)-based therapy were studied. Samples from a subject treated with zidovudine/lamivudine/efavirenz with a similar loss of virologic response served as a control. HIV-1 plasma RNA was ≥3.68 log(10) copies/ml at all time points sequenced. The median number of UDPS sequences analyzed/time point was 33,246. Among the eight tenofovir-treated subjects, three showed high-frequency (>20%) RT K65R at the time of failure, whereas one showed low-frequency (<20%) L74V; no low-frequency K65R was detected in these subjects. Among the nine abacavir-treated subjects, three showed low-frequency K65R; no L74V was detected in these patients. No K65R or L74V was detected in the samples from the control subject. At failure, other RT mutations were detected, including low-frequency NNRTI-resistant species detected at ≥1 time point in nine subjects; the key NNRTI mutation K103N, however, was always observed at >20% frequency. Although UDPS is useful in the detection of low-frequency subpopulations with transmitted resistance in antiviral-naive patients, it may have less utility in treatment-experienced patients with persistent viremia on therapy.