abacavir and Myocardial-Infarction

Most HIV-infected subjects will receive a treatment regimen including abacavir or tenofovir. Therefore, clarifying if there is an increased risk of acute myocardial infarction (AMI) among those exposed to abacavir is of the utmost importance. Due to the low frequency of AMI in this young population (2-5 per 1000 patients/year), efforts to clarify this have been quite controversial. While some observational cohorts have found a statistically significant association, others have not. Meta-analysis of randomized clinical trials offering the highest scientific evidence found no association at all, but with a limited statistical power to definitely rule out a small effect. A channelling or selection bias has been demonstrated in cohort studies, favouring the prescription of abacavir to subjects with or at risk for chronic kidney disease, and therefore, with an intrinsic increased cardiovascular risk. The recent NA-ACCORD cohort study does not identify an increased risk for AMI associated with recent abacavir use in a fully adjusted model (HR 1.33; 95%CI:0.96, 1.88). However, it does find an association in a second analysis restricted to treatment-naïve persons, with higher differences in baseline characteristics among compared arms. A critical review of the compiled available evidence is therefore mandatory, particularly in light of the first single-tablet regimen to receive approval that does contain abacavir.

Topics: Anti-HIV Agents; Cardiovascular Diseases; Clinical Trials as Topic; Dideoxynucleosides; HIV Infections; Humans; Meta-Analysis as Topic; Myocardial Infarction; Risk

Several studies have reported an association between abacavir (ABC) exposure and increased risk of myocardial infarction (MI) among HIV-infected individuals. Randomized controlled trials (RCTs) and a pooled analysis by GlaxoSmithKline, however, do not support this association. To better estimate the effect of ABC use on risk of MI, the US Food and Drug Administration (FDA) conducted a trial-level meta-analysis of RCTs in which ABC use was randomized as part of a combined antiretroviral regimen.. From a literature search conducted among 4 databases, 26 RCTs were selected that met the following criteria: conducted in adults, sample size more than 50 subjects, status completed, not a pharmacokinetic trial, and not conducted in Africa. The Mantel-Haenszel method, with risk difference and 95% confidence interval, was used for the primary analysis, along with additional alternative analyses, based on FDA-requested adverse event reports of MI provided by each investigator.. The 26 RCTs were conducted from 1996 to 2010, and included 9868 subjects (5028 ABC and 4840 non-ABC). Mean follow-up was 1.43 person-years in the ABC group and 1.49 person-years in the non-ABC group. Forty-six (0.47%) MI events were reported [24 (0.48%) ABC and 22 (0.46%) non-ABC], with no significant difference noted between the 2 groups (risk difference of 0.008% with 95% confidence interval: -0.26% to 0.27%).. To the best of our knowledge, our study represents the largest trial-level meta-analysis to date of clinical trials in which ABC use was randomized. Our analysis found no association between ABC use and MI risk.

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Female; HIV Infections; Humans; Male; Middle Aged; Myocardial Infarction; Randomized Controlled Trials as Topic; United States; United States Food and Drug Administration

The use of abacavir (ABC) has been associated with an increased risk of cardiovascular disease in some cohort studies. However, no excess risk of myocardial infarction (MI) with ABC therapy has been observed in individual randomized clinical trials (RCTs) and in the aggregated clinical trials database maintained by the manufacturer of ABC.. To combine all the evidence from RCTs by means of meta-analysis to estimate the effect of combined antiretroviral therapy (cART) containing ABC on MI and overall major cardiovascular events (CVEs).. Primary outcomes included MI, CVE, adverse events requiring discontinuation of treatment, and overall mortality. We used a conventional Mantel-Haenszel method, with risk ratio and 95% confidence intervals (CIs) or, in the presence of heterogeneity, a random-effect model.. Data were from 28 primary RCTs (9233 participants) comparing ABC-containing cART (4376 participants) to other regimens not containing ABC (4857 controls). MI data were available from 18 trials (31 episodes in 7054 patients) and CVE data from 20 trials (79 episodes in 7899 patients). Compared to the controls, ABC use did not increase significantly the occurrence of MI (risk ratio 0.73, 95% CI 0.39-1.35; P = 0.31), CVE (risk ratio 0.95, 95% CI 0.62-1.44; P = 0.80), overall mortality (risk ratio 1.20, 95% CI 0.63-2.27; P = 0.58), and adverse events requiring discontinuation of treatment (risk ratio 0.82, 95% CI 0.67-1.00; P = 0.05).. This meta-analysis of RCTs does not support the hypothesis that ABC-containing cART regimens carry a greater risk of MI or major cardiovascular events relative to comparator cART.

Topics: Anti-HIV Agents; Cardiovascular Diseases; Dideoxynucleosides; Female; HIV Infections; Humans; Male; Myocardial Infarction; Odds Ratio; Randomized Controlled Trials as Topic; Risk Factors

This review focuses on current studies addressing the association of abacavir (ABC) therapy and myocardial risk in HIV-infected patients, discusses potential pathogenetic mechanisms, and suggests a preliminary algorithm for decision making regarding ABC therapy in daily clinical practise.. The D:A:D study was the first to reveal an increased rate of myocardial infarction in patients recently treated with ABC. Subsequent analyses of both cohort studies as well as prospective randomized clinical trials largely confirmed this association. Although these studies varied considerably by design and their ability to control for confounders, they provide early support that ABC therapy can increase the risk for cardiovascular disease. The pathogenesis of this association remains elusive. Preliminary cross-sectional studies suggest the involvement of inflammation associated with ABC.. Prospective studies are required to provide additional evidence for the association of ABC therapy and cardiovascular events. In individual patients with underlying high cardiovascular risk, replacement of ABC may be considered, if it can be substituted by alternative equally effective treatment.

Topics: Algorithms; Anti-HIV Agents; Dideoxynucleosides; HIV Infections; Humans; Myocardial Infarction; Prospective Studies; Risk Factors

Topics: Antiretroviral Therapy, Highly Active; Dideoxynucleosides; HIV Infections; Humans; Myocardial Infarction; Reverse Transcriptase Inhibitors; Risk Factors

Since the presentation of the D:A:D study results at the Conference on Retroviruses and Opportunistic Infections in February 2008, 10 studies have explored the association between exposure to abacavir and the risk of myocardial infarction. Among the five larger studies, three conclude that there is an association and two that the association is not robust. Based on these studies, it is impossible to refute or confirm a causal relationship, as it is not possible to exclude remaining confounding (smoking in two of the studies, kidney function in two of the studies, cocaine and/or intravenous drug use) and selection bias in studies that report a robust association. In addition, no convincing mechanism has been described.

Topics: Anti-HIV Agents; Cardiovascular Diseases; Cohort Studies; Dideoxynucleosides; HIV Infections; Humans; Myocardial Infarction; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Risk Assessment

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.. 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.. 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.. 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.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Female; HIV Infections; Humans; Male; Middle Aged; Myocardial Infarction; Risk Assessment

Two nucleos(t)ide reverse transcriptase inhibitors (NRTIs)--abacavir and didanosine--may each be associated with excess risk of myocardial infarction. The reproducibility of this finding in an independent dataset was explored and plausible biological mechanisms were sought.. Biomarkers, ischemic changes on the electrocardiogram, and rates of various predefined types of cardiovascular disease (CVD) events according to NRTIs used were explored in the Strategies for Management of Anti-Retroviral Therapy (SMART) study. Patients receiving abacavir and not didanosine were compared with those receiving didanosine, and to those receiving NRTIs other than abacavir or didanosine (other NRTIs). Patients randomly assigned to the continuous antiretroviral therapy arm of SMART were included in all analyses (N = 2752); for the study of biomarkers, patients from the antiretroviral therapy interruption arm were also included.. Current use of abacavir was associated with an excess risk of CVD compared with other NRTIs. Adjusted hazard ratios for clinical myocardial infarction (n = 19), major CVD (myocardial infarction, stroke, surgery for coronary artery disease, and CVD death; n = 70), expanded CVD (major CVD plus congestive heart failure, peripheral vascular disease, coronary artery disease requiring drug treatment, and unwitnessed deaths; n = 112) were 4.3 [95% confidence interval (CI): 1.4-13.0], 1.8 (1.0-3.1), and 1.9 (1.3-2.9). At baseline in a subset of patients with biomarker data, high sensitivity-C-reactive protein and interleukin-6 were 27% (P = 0.02) and 16% (P = 0.02) higher for patients receiving abacavir (N = 175) compared with those receiving other NRTIs (N = 500). Didanosine was associated neither with altered risk of CVD nor with altered levels of biomarkers.. Abacavir was associated with an increased risk of CVD. The drug may cause vascular inflammation, which may precipitate a CVD event.

Topics: Adult; Anti-Retroviral Agents; Biomarkers; C-Reactive Protein; Didanosine; Dideoxynucleosides; Electrocardiography; Female; HIV Infections; HIV-1; Humans; Interleukin-6; Male; Middle Aged; Myocardial Infarction; Proportional Hazards Models; Reverse Transcriptase Inhibitors; Risk; Serum Amyloid A Protein; Serum Amyloid P-Component

Although individual antiretroviral drugs have been shown to be associated with elevated cardiovascular disease (CVD) risk, data are limited on the role of antiretroviral drug combinations. Therefore, we sought to investigate CVD risk associated with antiretroviral drug combinations.. Using an administrative health-plan dataset, risk of acute myocardial infarction (AMI) associated with current exposure to antiretroviral drug combinations was assessed among persons living with HIV receiving antiretroviral therapy (ART) across the U.S. from October 2009 through December 2014. To account for confounding-by-indication and for factors simultaneously acting as causal mediators and confounders, we applied inverse probability of treatment weighted marginal structural models to longitudinal data of patients.. Over 114,417 person-years (n = 73,071 persons) of ART exposure, 602 cases of AMI occurred at an event rate of 5.26 (95% CI: 4.86, 5.70)/1000 person-years. Of the 14 antiretroviral drug combinations studied, persons taking abacavir-lamivudine-darunavir had the highest incidence rate (IR: 11/1000; 95% CI: 7.4-16.0) of AMI. Risk (HR; 95% CI) of AMI was elevated for current exposure to abacavir-lamivudine-darunavir (1.91; 1.27-2.88), abacavir-lamivudine-atazanavir (1.58; 1.08-2.31), and tenofovir-emtricitabine-raltegravir (1.35; 1.07-1.71). Tenofovir-emtricitabine-efavirenz was associated with reduced risk (0.65; 0.54-0.78). Abacavir-lamivudine-darunavir was associated with increased risk of AMI beyond that expected of abacavir alone, likely attributable to darunavir co-administration. We did not find an elevated risk of AMI when abacavir-lamivudine was combined with efavirenz or raltegravir.. The antiretroviral drug combinations abacavir-lamivudine-darunavir, abacavir-lamivudine-atazanavir and tenofovir-emtricitabine-raltegravir were found to be associated with elevated risk of AMI, while tenofovir-emtricitabine-efavirenz was associated with a lower risk. The AMI risk associated with abacavir-lamivudine-darunavir was greater than what was previously described for abacavir, which could suggest an added risk from darunavir. The results should be confirmed in additional studies.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Combinations; HIV Infections; HIV-1; Humans; Lamivudine; Myocardial Infarction; Tenofovir; United States

To investigate the association between abacavir (ABC) use and recurrent myocardial infarction (MI) among HIV-positive people with a prior MI.. International multicohort collaboration with follow-up from 1999 to 2016.. The rate of recurrent MI was described among D:A:D participants who experienced an index MI whilst in the study, and who remained under follow-up beyond 28 days after this MI. Follow-up was considered to the date of next MI, death, 1 February 2016 or 6 months after last clinic visit. Poisson regression models considered associations between recurrent MI and exposure to ABC (use at index MI, current post-MI exposure and cumulative exposure), before and after adjusting for calendar year.. The 984 individuals who experienced an index MI during the study (91.3% male, median age 51 at index MI) were followed for 5312 person-years, over which time there were 136 recurrent MIs (rate 2.56/100 person-years, 95% confidence interval 2.13-2.99). Rates were 2.40 (1.71-3.09) and 2.65 (2.10-3.21)/100 person-years in those who were and were not on ABC, respectively, at the index MI, and 2.90 (2.01-3.78) and 2.44 (1.95-2.93)/100 person-years in those who were and were not currently receiving ABC, respectively, post-MI. No association was seen with recurrent MI and either cumulative exposure to ABC [relative rate 0.86 (0.68-1.10)/5 years], receipt of ABC at index MI [0.90 (0.63-1.29)] nor recent post-MI exposure to ABC [1.19 (0.82-1.71)].. Among people with a previous MI, there was no evidence for an association between use of ABC post-MI and an elevated risk of a recurrent MI.

Topics: Anti-HIV Agents; Dideoxynucleosides; Female; HIV Infections; Humans; Male; Middle Aged; Myocardial Infarction; Recurrence; Risk Assessment

There is persistent confusion as to whether abacavir (ABC) increases the risk of myocardial infarction (MI), and whether such risk differs by type 1 (T1MI) or 2 (T2MI) MI in adults with HIV.. Incident MIs in North American Cohort Collaboration on Research and Design participants were identified from 2001 to 2013. Discrete time marginal structural models addressed channeling biases and time-dependent confounding to estimate crude hazard ratio (HR) and adjusted hazard ratio (aHR) and 95% confidence intervals; analyses were performed for T1MI and T2MI separately. A sensitivity analysis evaluated whether Framingham risk score (FRS) modified the effect of ABC on MI occurrence.. Eight thousand two hundred sixty-five adults who initiated antiretroviral therapy contributed 29,077 person-years and 123 MI events (65 T1MI and 58 T2MI). Median follow-up time was 2.9 (interquartile range 1.4-5.1) years. ABC initiators were more likely to have a history of injection drug use, hepatitis C virus infection, hypertension, diabetes, impaired kidney function, hyperlipidemia, low (<200 cells/mm) CD4 counts, and a history of AIDS. The risk of the combined MI outcome was greater for persons who used ABC in the previous 6 months [aHR = 1.84 (1.17-2.91)]; and persisted for T1MI (aHR = 1.62 [1.01]) and T2MI [aHR = 2.11 (1.08-4.29)]. FRS did not modify the effect of ABC on MI (P = 0.14) and inclusion of FRS in the MSM did not diminish the effect of recent ABC use on the combined outcome.. Recent ABC use was associated with MI after adjustment for known risk factors and for FRS. However, screening for T1MI risks may not identify all or even most persons at risk of ABC use-associated MIs.

Topics: Adult; Aged; Antirheumatic Agents; CD4 Lymphocyte Count; Cohort Studies; Dideoxynucleosides; Female; HIV Infections; Humans; Male; Middle Aged; Myocardial Infarction; North America; Risk Assessment; Risk Factors

There is ongoing controversy regarding abacavir use in the treatment of HIV infection and the risk of subsequent development of cardiovascular disease. It is unclear how the risk varies as exposure accumulates.. Using an administrative health-plan dataset, risk of cardiovascular disease events (CVDe), defined as the first episode of an acute myocardial infarction or a coronary intervention procedure, associated with abacavir exposure was assessed among HIV-infected individuals receiving antiretroviral therapy across the U.S. from October 2009 through December 2014. The data were longitudinal, and analyzed using marginal structural models.. Over 114,470 person-years (n = 72,733) of ART exposure, 714 CVDe occurred at an incidence rate (IR) (95% CI) of 6·23 (5·80, 6·71)/1000 person-years. Individuals exposed to abacavir had a higher IR of CVDe of 9·74 (8·24, 11·52)/1000 person-years as compared to 5·75 (5·30, 6·24)/1000 person-years for those exposed to other antiretroviral agents. The hazard (HR; 95% CI) of CVDe was increased for current (1·43; 1·18, 1·73), recent (1·41; 1·16, 1·70), and cumulative [(1·18; 1·06, 1·31) per year] exposure to abacavir. The risk for cumulative exposure followed a bell-shaped dose-response curve peaking at 24-months of exposure. Risk was similarly elevated among participants free of pre-existing heart disease or history of illicit substance use at baseline.. Current, recent, and cumulative use of abacavir was associated with an increased risk of CVDe. The findings were consistent irrespective of underlying cardiovascular risk factors.

Topics: Acute Disease; Adult; Anti-Retroviral Agents; Cohort Studies; Databases, Factual; Dideoxynucleosides; Female; HIV Infections; Humans; Longitudinal Studies; Male; Middle Aged; Myocardial Infarction; Proportional Hazards Models; Reverse Transcriptase Inhibitors; Risk Factors; United States

In March 2008, the D:A:D study published results demonstrating an increased risk of myocardial infarction (MI) for patients on abacavir (ABC). We describe changes to the use of ABC since this date, and investigate changes to the association between ABC and MI with subsequent follow-up.. A total of 49,717 D:A:D participants were followed from study entry until the first of an MI, death, 1 February 2013 or 6 months after last visit. Associations between a person's 10-year cardiovascular disease (CVD) risk and the likelihood of initiating or discontinuing ABC were assessed using multivariable logistic/Poisson regression. Poisson regression was used to assess the association between current ABC use and MI risk, adjusting for potential confounders, and a test of interaction was performed to assess whether the association had changed in the post-March 2008 period.. Use of ABC increased from 10 % of the cohort in 2000 to 20 % in 2008, before stabilising at 18-19 %. Increases in use pre-March 2008, and subsequent decreases, were greatest in those at moderate and high CVD risk. Post-March 2008, those on ABC at moderate/high CVD risk were more likely to discontinue ABC than those at low/unknown CVD risk, regardless of viral load (≤1,000 copies/ml: relative rate 1.49 [95 % confidence interval 1.34-1.65]; >1,000 copies/ml: 1.23 [1.02-1.48]); no such associations were seen pre-March 2008. There was some evidence that antiretroviral therapy (ART)-naïve persons at moderate/high CVD risk post-March 2008 were less likely to initiate ABC than those at low/unknown CVD risk (odds ratio 0.74 [0.48-1.13]). By 1 February 2013, 941 MI events had occurred in 367,559 person-years. Current ABC use was associated with a 98 % increase in MI rate (RR 1.98 [1.72-2.29]) with no difference in the pre- (1.97 [1.68-2.33]) or post- (1.97 [1.43-2.72]) March 2008 periods (interaction P = 0.74).. Despite a reduction in the channelling of ABC for patients at higher CVD risk since 2008, we continue to observe an association between ABC use and MI risk. Whilst confounding cannot be fully ruled out, this further diminishes channelling bias as an explanation for our findings.

Topics: Adult; Anti-HIV Agents; Australia; Dideoxynucleosides; Europe; Female; HIV Infections; Humans; Logistic Models; Male; Medication Therapy Management; Middle Aged; Myocardial Infarction; Odds Ratio; Pharmacovigilance; Practice Patterns, Physicians'; Risk Assessment; Risk Factors; United States

The authors had for objective to describe HIV-infected patients treated with ABC (Ziagen(®), ABC), and the immune, virological, and clinical treatment outcome between 2003 and 2008.. We performed a retrospective analysis of the Dat'AIDS database on patients who were treated with ABC for the first time between 2003 and 2008.. Eight hundred and thirty-six patients were included. Before initiation of ABC, 26.3% has stopped the previous treatment because of immuno-virological failure, 30.5% because of adverse events, and 29.8% for other reasons. Thirteen percent were antiretroviral naive. One third of patients were ranked as CDC class C, and more than 2/3 had a viral load<5 log copies/mL or a CD4 count≥200mm(3). ABC was mainly included in a combination containing 2 NRTI and 1 PI (63%), or 1 non-NRTI (16%). Thirty-two percent of patients were still treated with ABC after 2years of treatment and the median of ABC treatment was 11months (IQ 84days-2years). The main causes for stopping ABC were therapeutic simplification (47.4% of patients), intolerance (19.0%), and immuno-virological failure (9.8%). Suspected hypersensitivity reactions were the main cause of discontinuation due to intolerance (27.6%); the rate was 3.8% when ABC had been introduced before the routine use of the screening test HLA-B*5701. The incidence of myocardial infarction was 3.8 per 1000 patient-years; 70.6% of patients received a fixed combination including ABC after discontinuation of ABC as a single agent (Ziagen(®)).. This retrospective analysis confirmed the effectiveness and the good tolerance of ABC in the therapeutic strategy, between 2003 and 2008.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Hypersensitivity; Drug Therapy, Combination; Drug Utilization; Electronic Health Records; Female; France; Genetic Predisposition to Disease; HIV Infections; HIV-1; HLA-B Antigens; Humans; Male; Middle Aged; Myocardial Infarction; Retrospective Studies; Reverse Transcriptase Inhibitors; Treatment Outcome; Viral Load; Viremia

Topics: Dideoxynucleosides; Drug Approval; HIV Infections; Humans; Myocardial Infarction; Reverse Transcriptase Inhibitors; United States; United States Food and Drug Administration

Some studies have suggested that exposure to antiretroviral therapy (ART) with abacavir is associated with an increased risk of acute myocardial infarction (AMI).. Using the Veterans Health Administration's Clinical Case Registry we calculated the risk of AMI and cerebrovascular events (CVA) associated with the cumulative use of abacavir and other nucleoside combinations. We also evaluated the impact of pre-existing chronic kidney disease on the selection of abacavir versus tenofovir in the last recorded ART regimen, and on highly active antiretroviral therapy-associated AMI and CVA risks.. A total of 19,424 human immunodeficiency virus-infected patients contributed 76,376 patient-years of follow. After adjusting for age, hypercholesterolemia, hypertension, type 2 diabetes, and smoking, the hazard ratio (HR) for each year of abacavir use was 1.18 (95% confidence interval [CI], .92-1.50; P=.191) for AMI and 1.16 (95% CI, .98-1.37; P=.096) for CVA. Abacavir use was more common among patients with prior chronic kidney disease than was tenofovir use (12.46% versus 7.15%; P=.0001), and chronic kidney disease was associated with a significantly higher risk of AMI (HR, 2.41; 95% CI, 1.73-3.36), and CVA (HR, 1.80; 95% CI, 1.44-2.24). Compared with patients who received neither tenofovir nor abacavir, patients who received tenofovir had lower risk of AMI (HR, 0.16; 95% CI, .08-.33; P=.0001) and CVA (HR, 0.22; 95% CI, .15-.32; P=.001). Use of abacavir was associated with lower risk of CVA (HR, 0.60; 95% CI, .45-.79).. We observed no association between cumulative or current abacavir use and AMI or CVA. Abacavir use was more common than was tenofovir use among patients with prior chronic kidney disease, and chronic kidney disease independently predicted higher rates of AMI and CVA.

Topics: Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Female; HIV Infections; Humans; Ischemic Attack, Transient; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Organophosphonates; Proportional Hazards Models; Renal Insufficiency, Chronic; Risk Factors; Stroke; Tenofovir; United States; United States Department of Veterans Affairs

Topics: Anti-HIV Agents; Dideoxynucleosides; Female; HIV Infections; Humans; Male; Myocardial Infarction; Stroke

To provide a molecular mechanism that explains the association of the antiretroviral guanosine analogue, abacavir, with an increased risk of myocardial infarction.. Drug effects were studied with biochemical and cellular assays.. Human platelets were incubated with nucleoside analogue drugs ex vivo. Platelet activation stimulated by ADP was studied by measuring surface P-selectin with flow cytometry. Inhibition of purified soluble guanylyl cyclase was quantified using an ELISA to measure cGMP production.. Pre-incubation of platelets in abacavir significantly increased activation in response to ADP in a time and dose-dependent manner. The active anabolite of abacavir, carbovir triphosphate, competitively inhibited soluble guanylyl cyclase activity with a K(i) of 55 μmol/l.. Abacavir competitively inhibits guanylyl cyclase, leading to platelet hyperreactivity. This may explain the observed increased risk of myocardial infarction in HIV patients taking abacavir.

Topics: Blood Platelets; Dideoxynucleosides; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Guanylate Cyclase; Humans; Myocardial Infarction; P-Selectin; Platelet Activation; Receptors, Cytoplasmic and Nuclear; Reverse Transcriptase Inhibitors; Soluble Guanylyl Cyclase

The aim of the study was to examine whether exposure to abacavir increases the risk for myocardial infarction (MI).. 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.. Relative risk of hospitalization with MI in abacavir users compared with abacavir nonusers.. 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.. 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.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Comorbidity; Denmark; Dideoxynucleosides; Epidemiologic Methods; Female; HIV Infections; Hospitalization; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Proportional Hazards Models; Time Factors

The D:A:D study group reported a 1.9-fold increased relative risk (RR) of myocardial infarction (MI) associated with current or recent use of abacavir. The number needed to harm (NNH) incorporates information about the underlying risk of MI and the increased RR of MI in patients taking abacavir.. NNH was calculated as the reciprocal of the difference between the underlying risks of MI with and without abacavir use. A parametric statistical model was used to calculate the underlying risk of MI over 5 years.. The relationship between NNH and underlying risk of MI is reciprocal, resulting in wide variation in the NNH with small changes in underlying risk of MI. The smallest changes in NNH are in the medium- and high-risk groups of MI. The NNH changes as risk components are modified; for example, for a patient who smokes and has a systolic blood pressure (sBP) of 160 mmHg and a 5-year risk of MI of 1.3% the NNH is 85, but the NNH increases to 277 if the patient is a nonsmoker and to 370 if sBP is within the normal range (120 mmHg).. We have illustrated that the impact of abacavir use on risk of MI varies according to the underlying risk and it may be possible to increase considerably the NNH by decreasing the underlying risk of MI using standard of care interventions, such as smoking cessation or control of hypertension.

Topics: Adult; Age Factors; Aged; Blood Pressure; Cholesterol, HDL; Diabetes Mellitus; Dideoxynucleosides; HIV Infections; HIV-1; Humans; Male; Middle Aged; Models, Statistical; Myocardial Infarction; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Risk; Smoking; Uncertainty

The role of exposure to specific antiretroviral drugs on risk of myocardial infarction in human immunodeficiency virus (HIV)-infected patients is debated in the literature.. To assess whether we confirmed the association between exposure to abacavir and risk of myocardial infarction (MI) and to estimate the impact of exposure to other nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs), and non-NRTIs on risk of MI, we conducted a case-control study nested within the French Hospital Database on HIV. Cases (n = 289) were patients who, between January 2000 and December 2006, had a prospectively recorded first definite or probable MI. Up to 5 controls (n = 884), matched for age, sex, and clinical center, were selected at random with replacement among patients with no history of MI already enrolled in the database when MI was diagnosed in the corresponding case. Conditional logistic regression models were used to adjust for potential confounders.. Short-term/recent exposure to abacavir was associated with an increased risk of MI in the overall sample (odds ratios [ORs], 2.01; 95% confidence interval [CI], 1.11-3.64) but not in the subset of matched cases and controls (81%) who did not use cocaine or intravenous drugs (1.27; 0.64-2.49). Cumulative exposure to all PIs except saquinavir was associated with an increased risk of MI significant for amprenavir/fosamprenavir with or without ritonavir (OR, 1.53; 95% CI, 1.21-1.94 per year) and lopinavir with ritonavir (1.33; 1.09-1.61 per year). Exposure to all non-NRTIs was not associated with risk of MI.. The risk of MI was increased by cumulative exposure to all the studied PIs except saquinavir and particularly to amprenavir/fosamprenavir with or without ritonavir and lopinavir with ritonavir, whereas the association with abacavir cannot be considered causal.

Topics: Adult; Anti-HIV Agents; Carbamates; Case-Control Studies; Cohort Studies; Confidence Intervals; Dideoxynucleosides; Female; France; Furans; HIV Infections; Hospitals, Isolation; Humans; Logistic Models; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Organophosphates; Regression Analysis; Risk; Ritonavir; Sulfonamides

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.. We compiled data from GlaxoSmithKline-sponsored clinical trials with > or = 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).. 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).. 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.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Anti-HIV Agents; Clinical Trials as Topic; Coronary Artery Disease; Data Interpretation, Statistical; Dideoxynucleosides; Female; HIV Infections; Humans; Male; Middle Aged; Myocardial Infarction; Risk Factors; Young Adult

Topics: Adenine; Algorithms; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Clinical Trials as Topic; Dideoxynucleosides; Humans; Myocardial Infarction; Organophosphonates; Tenofovir; Treatment Outcome

Topics: Didanosine; Dideoxynucleosides; HIV Infections; Humans; Myocardial Infarction; Reverse Transcriptase Inhibitors; Risk Factors; United States; United States Food and Drug Administration

Topics: Dideoxynucleosides; Female; HIV Infections; Humans; Male; Middle Aged; Myocardial Infarction; Reverse Transcriptase Inhibitors; Risk Factors

Topics: Anti-HIV Agents; Didanosine; Dideoxynucleosides; Endothelium, Vascular; HIV Infections; Humans; Myocardial Infarction; Nucleotidases

Topics: Anti-HIV Agents; Databases, Factual; Dideoxynucleosides; Humans; Myocardial Infarction; Risk; World Health Organization

Topics: Biomarkers, Pharmacological; Dideoxynucleosides; Female; HIV Infections; HIV-1; Humans; Longitudinal Studies; Male; Myocardial Infarction; Reverse Transcriptase Inhibitors

Topics: Dideoxynucleosides; Humans; Myocardial Infarction; Reverse Transcriptase Inhibitors; Risk Factors

Topics: Dideoxynucleosides; Humans; Myocardial Infarction; Reverse Transcriptase Inhibitors

Topics: Anti-HIV Agents; Clinical Trials as Topic; Dideoxynucleosides; HIV Infections; Humans; Myocardial Infarction; Risk Factors

Whether nucleoside reverse transcriptase inhibitors increase the risk of myocardial infarction in HIV-infected individuals is unclear. Our aim was to explore whether exposure to such drugs was associated with an excess risk of myocardial infarction in a large, prospective observational cohort of HIV-infected patients.. We used Poisson regression models to quantify the relation between cumulative, recent (currently or within the preceding 6 months), and past use of zidovudine, didanosine, stavudine, lamivudine, and abacavir and development of myocardial infarction in 33 347 patients enrolled in the D:A:D study. We adjusted for cardiovascular risk factors that are unlikely to be affected by antiretroviral therapy, cohort, calendar year, and use of other antiretrovirals.. Over 157,912 person-years, 517 patients had a myocardial infarction. We found no associations between the rate of myocardial infarction and cumulative or recent use of zidovudine, stavudine, or lamivudine. By contrast, recent-but not cumulative-use of abacavir or didanosine was associated with an increased rate of myocardial infarction (compared with those with no recent use of the drugs, relative rate 1.90, 95% CI 1.47-2.45 [p=0.0001] with abacavir and 1.49, 1.14-1.95 [p=0.003] with didanosine); rates were not significantly increased in those who stopped these drugs more than 6 months previously compared with those who had never received these drugs. After adjustment for predicted 10-year risk of coronary heart disease, recent use of both didanosine and abacavir remained associated with increased rates of myocardial infarction (1.49, 1.14-1.95 [p=0.004] with didanosine; 1.89, 1.47-2.45 [p=0.0001] with abacavir).. There exists an increased risk of myocardial infarction in patients exposed to abacavir and didanosine within the preceding 6 months. The excess risk does not seem to be explained by underlying established cardiovascular risk factors and was not present beyond 6 months after drug cessation.

Topics: Adult; Aged; Aged, 80 and over; Didanosine; Dideoxynucleosides; Female; HIV Infections; Humans; Male; Middle Aged; Myocardial Infarction; Poisson Distribution; Reverse Transcriptase Inhibitors; Risk Factors

Topics: Anti-HIV Agents; Australia; Didanosine; Dideoxynucleosides; Europe; Heart Diseases; HIV Infections; HIV-1; Humans; Myocardial Infarction; North America; Prospective Studies; Reverse Transcriptase Inhibitors; Risk Factors; Time Factors