Abacavir Use Research Articles

Drug-induced liver injury: what was new in 2008?

Background: Given the number of publications appearing annually regarding drug-induced liver injury (DILI), there remains a need to concisely summarize each year's new crop of case series and reports as well as the advances in mechanisms of liver injury and in the field of pharmacogenomics relating to DILI. Objective: To present an up-to-date review of the past year's most important clinical studies and reports of DILI, placing them into context of previous publications. Methods: A Medline search was conducted of all manuscripts appearing in the fields “hepatotoxicity” and “drug-induced liver injury” during the calendar year 2008. The most clinically relevant English language case reports and studies exploring mechanisms and risk factors for DILI were then chosen for review, and supplemented with older literature where appropriate. Conclusions: As in past years, 2008 was replete with publications dealing with virtually all facets of DILI, including updated incidence and prevalence data, as well as the latest information regarding mechanisms of liver injury. Data from the first 300 patients in the National Institute of Health-sponsored DILI Network registry of > 100 non-acetaminophen causes were presented. Antimicrobials and CNS drugs were responsible for > 60% of cases, with herbals and dietary supplements being increasingly reported. Identification of genetic predispositions to DILI is coming of age with the FDA calling for the testing of human leukocyte antigen B*5701 before the use of abacavir to reduce the risk of hypersensitivity reactions. Several groups emphasized the pitfalls in utilizing Roussel Uclaf Causality Assessment Method and other causality assessment methodologies, and an updated review appeared on the use of potentially hepatotoxic medications in patients with underlying liver disease.

A1C Underestimates Glycemia in HIV Infection

OBJECTIVEThe objective of this study was to determine the relationship between A1C and glycemia in HIV infection.RESEARCH DESIGN AND METHODSWe completed a prospective cross-sectional study of 100 HIV-infected adults with type 2 diabetes (77%) or fasting hyperglycemia (23%) with measured glucose, A1C, mean corpuscular volume (MCV), and fructosamine. A total of 200 HIV-uninfected type 2 diabetic subjects matched for key demographic characteristics served as control subjects.RESULTSRelative to the control subjects, A1C underestimated glucose by 29 ± 4 mg/dl in the HIV-infected subjects. Current nucleoside reverse transcriptase inhibitors (NRTIs), higher MCV and hemoglobin, and lower HIV RNA and haptoglobin were associated with greater A1C-glucose discordance. However, only MCV and current NTRI use, in particular abacavir, remained significant predictors in multivariate analyses. Fructosamine more closely reflected glycemia in the HIV-infected subjects.CONCLUSIONSA1C underestimates glycemia in HIV-infected patients and is related to NRTI use. Use of abacavir and increased MCV were key correlates in multivariate analyses. Fructosamine may be more appropriate in this setting.

Glycated Haemoglobin in Diabetic Women with and without HIV Infection: Data from the Women's Interagency HIV Study

Limited data suggest that glycated haemoglobin (haemoglobin A1c; A1C) values might not reflect glycaemic control accurately in HIV-infected individuals with diabetes. We evaluated repeated measures of paired fasting glucose and A1C values in 315 HIV-infected and 109 HIV-uninfected diabetic participants in the Women's Interagency HIV Study. Generalized estimating equations used log A1C as the outcome variable, with adjustment for log fasting glucose concentration in all models. An HIV-infected woman on average had 0.9868 times as much A1C (that is, 1.32% lower; 95% confidence interval 0.9734-0.9904) as an HIV-uninfected woman with the same log fasting glucose concentration. In multivariate analyses, HIV serostatus was not associated, but White, other non-Black race, and higher red blood cell mean corpuscular volume (MCV) were statistically associated with lower A1C values. Use of diabetic medication was associated with higher A1C values. In multivariate analyses restricted to HIV-infected women, White and other race, higher MCV, and HCV viraemia were associated with lower A1C values, whereas older age, use of diabetic medications and higher CD4(+) T-cell count were associated with higher A1C values. Use of combination antiretroviral therapy, protease inhibitors, zidovudine, stavudine or abacavir was not associated with A1C values. A1C values were modestly lower in HIV-infected diabetic women relative to HIV-uninfected diabetic women after adjustment for fasting glucose concentration. The difference was abrogated by adjustment for MCV, race and diabetic medication use. Our data suggest that in clinical practice A1C gives a reasonably accurate refection of glycaemic control in HIV-infected diabetic women.

Proinflammatory Cytokine Changes in Clinically Stable, Virologically Suppressed, HIV-Infected Patients Switching From Protease Inhibitors to Abacavir

To the Editor: Excess cardiovascular risk has been observed in HIV-infected patients,1 driven by traditional risk factors such as smoking, hypertension, diabetes, and aging, although therapy-induced hyperlipidemia and HIV-induced proinflammatory state and immune activation seem to play a role.2-4 A recent report from the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study, one of the largest cohorts evaluating cardiovascular risk in HIV-infected patients, assessed the associations between nucleoside analogues and myocardial infarction. Contrary to the hypothesis expecting a role for thymidine analogues because of their negative effects on plasma lipids, insulin sensitivity, and limb fat loss, DAD investigators unexpectedly found that the recent use of didanosine and abacavir increased the risk of myocardial infarction by 50% and 90%, respectively.5 These findings were even more surprising as abacavir has a neutral lipid profile, does not interfere with insulin sensitivity, is not associated with limb fat loss in naive patients, and even promotes a fat increase in patients with lipoatrophy switching to abacavir from thymidine analogues.6,7 Although the DAD investigators adjusted the effect of abacavir as much as possible, the possibility of bias cannot definitively be ruled out. However, if abacavir really plays a role in promoting cardiovascular disease, other mechanisms apart from lipid changes, insulin sensitivity, and body fat alterations would have to be involved. Several studies have shown that changes in inflammatory cytokines such as adiponectin and tumor necrosis factor (TNF)-alpha may be related to increased cardiovascular risk in the general population.8-10 More recently, this association has been suggested in HIV-infected patients, mainly those with uncontrolled viral replication before initiating or after discontinuing antiretroviral therapy.1-3 The Nevirapine, Efavirenz and Abacavir (NEFA) trial assessed the relative merits of abacavir, efavirenz, or nevirapine as substitutes for the protease inhibitor (PI) component in stable virologically suppressed patients treated with a first-generation, unboosted PI and willing to simplify their regimen.11 In an intensive metabolic substudy of NEFA,12 we found favorable lipid changes in patients switching to any of the 3 options, namely a decrease in total cholesterol in the abacavir group, an increase in HDL cholesterol, and a decrease in the ratio of total cholesterol (TC) and high-density lipoprotein (HDL) cholesterol (TC:HDL) in the nonnucleoside reverse transcriptase inhibitor (NNRTI) groups.12 In addition, adiponectin and soluble tumor necrosis factor alpha receptor type 2 (sTNFR2) were assessed in baseline and 96-week serum samples adequately stored at −80°C for further laboratory analysis, contemplated in the initial design before the substudy. Plasma adiponectin was determined by radioimmunoassay (Linco Research, St. Charles, MO) with a detection threshold of 1 ng/mL and plasma sTNFR2 by a solid-phase enzyme immunoassay with amplified reactivity (Biosource Europe, Fleurus, Belgium) and a detection threshold of 0.1 ng/mL. In samples from 54 of 90 patients included in the metabolic substudy who continued with the assigned drug up to the end of follow-up (18 abacavir, 19 nevirapine, and 17 efavirenz), an increase in adiponectin levels and a decrease in sTNFR2 were observed in the overall population 96 weeks after the PI switch.12 We now present an analysis of the changes observed in these adipokines according to the antiretroviral regimen received in the NEFA metabolic substudy.

Continued Concern About Abacavir and Cardiovascular Risk

Last year, data were published from both the DAD study and the SMART trial showing an association between abacavir use and increased risk for

Longitudinal evaluation of cardiovascular disease-associated biomarkers in relation to abacavir therapy

Objectives: data from the D:A:D study indicate that recent use of abacavir, but not stavudine or zidovudine, is associated with increased risk of myocardial infarction (MI). The aim of this study was to evaluate longitudinal biomarkers of cardiovascular relevance in abacavir therapy and test whether risk profiles were higher with abacavir treatment compared with untreaated HIV, or with stavudine or zidovudine treatment. Methods: Samples were obtained retrospectively from the West Australian HIV observational cohort, and there was no MI in the study population. The longitudinal effect of abacavir treatment was considered in three study groups: (1) antiretroviral therapy (ART)-naive patients initiating abacavir but not stavudine or zidovudine (n=15), (2) previously abacavir-naive patients switching from thymidine nucleoside reverse transcriptase inhibitor (tNRTI) therapy (n=13) or (3) ongoing abacavir use in patients switching tNRTI treatment (n=13). D-dimer and Hs-CRP were measured by latex immunoiassay and latex-enhanced nephelometry, respectively. All other analytes interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-a, monocyte chemotactic protein (MCP)-1, hepatocyte growth factor (HGF), leptin and adiponectin were determined using the LINCOplex kits (Luminex xMAP Technology). Mixed effects models were used for statistical analyses to accomodate multiple measures per person, with all data log-transformed to satisfy distributional assumptions. Results: Within 1 year of initiating abacavir from ART-naive baseline, D-dimer levels and CRP were unchanged (P=0.6 and 0.3 respectively), and adiponectine increased (p=0.004). After >1 year from baseline, D-dimer decreased, adiponectin and HGF were unchanged from baseline (P=0.03, 0.9, 0.8, respectively), whereas leptin incresed (P=0.003) and IL-8, TNF and MCP-1 were decreased (all P-values <0.03). IL-6 increased marginally from baseline (P=0.05). The initial rise in adiponectin levels as compared with baseline was not observed in samples beyond 1 year post-initiation of abacavir. Initiating abacavir after switching from thymidine-based regimens was associated with no changes in the above analytes (all P-values >0.4), except that leptin increased (P=0.002) and TNF marginally increased (P=0.04). Continuing abacavir after switching from thymidines was also associated with no changes in analytes (all P-values >0.1). Conclusions: No significant change in biomarker profile known to be related to cardiovascular risk was detected in association with abacavir use. In fact, all significant changes from baseline appeared beneficial, possibly attributable to either anti-HIV effects or cessation of thymidines.

HLA-B*5701 Screening for Hypersensitivity to Abacavir

Mallal S, Phillips E, Carosi G, et al. N Engl J Med. 2008;358(6):568–579 PURPOSE OF THE STUDY. Abacavir is associated with severe and potentially life-threatening hypersensitivity reactions in up to 8% of the white population. In 2002, HLA-B*5701 was noted to be highly associated with this hypersensitivity reaction. The purpose of this study was to evaluate the effectiveness of prospective HLA-B*5701 screening to avoid these reactions. STUDY POPULATION. A total of 1956 HIV-infected patients from 19 countries who had not previously received abacavir were enrolled. METHODS. Individual patients were randomly assigned to undergo prospective HLA-B*5701 screening, with exclusion of previously known HLA-B*5701 positive patients from abacavir treatment, or to undergo a standard approach of abacavir use without screening. All subjects who started abacavir were observed for 6 weeks, the time frame in which a large majority of hypersensitivity reactions occur. The clinical diagnosis of hypersensitivity reaction to abacavir was assessed further by epicutaneous patch testing. RESULTS. The prevalence of HLA-B*5701 was 5.76% (109 of 1956 subjects) of the subjects assigned to receive abacavir. Seventy-two percent were men, 84% were white, and 18% had not received antiretroviral therapy previously. Screening effectively eliminated patch-test–confirmed hypersensitivity. None of the subjects in the prospectively screened group had reactions, compared with 2.7% in the control group. This yielded a negative predictive value of 100% and a positive predictive value of 47.9%. Hypersensitivity reactions to antiretroviral therapy were clinically diagnosed in 93 patients, with a significantly lower incidence in the prospectively screened group (3.4%) than in the control group (7.8%) (P &amp;lt; .001). CONCLUSIONS. HLA-B*5701 screening dramatically reduced the risk of immunologically confirmed hypersensitivity to abacavir. This pharmacogenetic test is useful for reducing the incidence of immunologically mediated hypersensitivity reactions to abacavir. REVIEWER COMMENTS. This expansive study demonstrated the clinical usefulness of pharmacogenomics testing for immunologically mediated hypersensitivity to a particular drug. This is the first such demonstration for reactions to antiretroviral agents. A major limitation in the use of abacavir has been the concern for a severe hypersensitivity reaction. The availability of this inexpensive test (approximately $80 at our institution) substantially reduces that potential and allows antiretroviral therapy selection to be based on the drug's merit as an effective antiretroviral agent. A unique feature of hypersensitivity to this particular drug is that it is a true T-cell–mediated reaction. Patch testing has been used for many decades to identify offending contact hypersensitivity allergens (eg, nickel). The search for additional biomarkers that would reflect a potential for adverse reactions to other drugs is ongoing. This type of study leads the way in demonstrating clinical effectiveness of such an approach

Increased regimen durability in the era of once-daily fixed-dose combination antiretroviral therapy

Data on initial antiretroviral regimen longevity predates the arrival of newer nucleoside reverse transcriptase inhibitor backbones and once-daily regimens. Modern regimens are thought to possess greater tolerability and convenience. We hypothesized this would translate into greater durability. Retrospective study of antiretroviral-naive patients starting treatment at the University of Alabama at Birmingham 1917 HIV/AIDS Clinic 1 January 2000-31 July 2007. Two periods of antiretroviral initiation were identified, prior and after August 2004 (arrival of once-daily fixed-dose regimens). Kaplan-Meier survival analyses of regimen durability by time period and regimen characteristics were performed. Staged Cox proportional hazards models evaluated the roles of dosing complexity and composition in explaining differences in regimen durability between study periods. Overall 542 patients started antiretroviral drugs (n = 309, January 2000-July 2004; n = 233, August 2004-July 2007). Median durability was 263 days longer in after August 2004 regimens. Regimens started before August 2004 had increased hazards for discontinuation relative to after August 2004 regimens [hazard ratio (HR) = 1.44; 95% confidence interval (CI) = 1.03-2.02]. Time period of initiation lost statistical significance when the model included dosing frequency (HR = 1.92 for at least twice daily vs. daily; 95% CI = 1.29-2.88). As regimen composition variables were added, time period and dosing frequency lost significance. Increased hazards of discontinuation were observed with didanosine or stavudine relative to abacavir or tenofovir use (HR = 1.92; 95% CI = 1.29-2.88) and all third drugs compared with non-nucleoside reverse transcriptase inhibitor-based regimens (triple-nucleoside reverse transcriptase inhibitor HR = 1.76; 95% CI = 1.14-2.73; unboosted-protease inhibitor HR = 1.58; 95% CI = 1.02-2.46; boosted-protease inhibitor HR = 1.57; 95% CI = 1.02-2.41). Affective mental health disorders increased the hazard of discontinuation in all models. Durability of contemporary once-daily fixed-dose antiretroviral regimens has significantly eclipsed the duration of earlier antiretroviral drug options. Our results indicate this is due to both more convenient dosing and improved tolerability of modern antiretroviral regimens.

Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients

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.

SMART Study: Abacavir Use Associated with Increased Risk for CVD

Earlier this year, researchers reported data from the DAD study linking abacavir and ddI to an increased risk for myocardial infarction (MI; AIDS Clin

Efficacy of pegylated interferon plus ribavirin treatment in HIV/hepatitis C virus co-infected patients receiving abacavir plus lamivudine or tenofovir plus either lamivudine or emtricitabine as nucleoside analogue backbone

To compare the response to hepatitis C virus (HCV) therapy among human immunodeficiency virus (HIV)/HCV co-infected patients receiving a nucleos(t)ide reverse transcriptase inhibitor [N(t)RTI] backbone consisting of abacavir plus lamivudine with that observed in subjects who receive tenofovir plus lamivudine or emtricitabine. A total of 256 subjects, enrolled in a cohort of 948 HIV-infected patients who received pegylated interferon and ribavirin from October 2001 to January 2006, were included in this study. All patients were taking one protease inhibitor or one non-nucleoside reverse transcriptase inhibitor and abacavir plus lamivudine or tenofovir plus lamivudine or emtricitabine as N(t)RTI backbone during HCV therapy. Sustained virological response (SVR) rates in both backbone groups were compared. In an intention-to-treat analysis, 20 out of 70 (29%) individuals under abacavir and 83 out of 186 (45%) under tenofovir showed SVR (P = 0.02). N(t)RTI backbone containing tenofovir was an independent predictor of SVR in the multivariate analysis [adjusted odds ratio (95% CI), 2.6 (1.05-6.9); P = 0.03]. The association between abacavir use and lower SVR was chiefly seen in patients with plasma HCV-RNA load higher than 600 000 IU/mL and genotype 1 or 4. Among patients treated with ribavirin dose <13.2 mg/kg/day, 3 (20%) of those under abacavir versus 22 (52%) under tenofovir reached SVR (P = 0.03), whereas the rates were 31% and 38% (P = 0.4), respectively, in those receiving >/=13.2 mg/kg/day. HIV-infected patients who receive abacavir plus lamivudine respond worse to pegylated interferon plus ribavirin than those who are given tenofovir plus lamivudine or emtricitabine as N(t)RTI backbone, especially in those receiving lower ribavirin doses.

First large, multicenter, open-label study utilizing HLA-B*5701 screening for abacavir hypersensitivity in North America

A hypersensitivity reaction is associated with abacavir in approximately 2-8% of exposed patients. The frequency of the HLA-B*5701 allele varies across racial groups and significantly correlates with risk of hypersensitivity. Studies in Europe and Western Australia demonstrated that prospective screening can significantly reduce the rate of hypersensitivity by avoiding the use of abacavir in patients carrying the HLA-B*5701 allele. Prospective HLA-B*5701 screening in a large, racially diverse North American population resulted in less than 1% of individuals diagnosed with a suspected abacavir hypersensitivity reaction (ABC HSR) and no positive skin patch test through 30 weeks among HLA-B*5701-negative individuals.

Abacavir Use May Decrease Response to HCV Therapy in Coinfected Patients

In patients coinfected with HIV and hepatitis C virus (HCV), the likelihood of achieving a sustained virologic response (SVR) to pegylated interferon

Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration

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.

Low Response to Pegylated Interferon plus Ribavirin in HIV-Infected Patients with Chronic Hepatitis C Treated with Abacavir

There is little information about the influence of antiretroviral drugs on the antiviral activity of pegylated interferon (PEG-IFN) plus ribavirin (RBV) against hepatitis C virus (HCV). All HIV-infected patients with chronic hepatitis C who received first-line PEG-IFN plus RBV were retrospectively analyzed. Only patients in whom virological stopping rules were applied and who did not change their antiretrovirals were chosen. Plasma RBV concentrations were measured at week 4. A total of 493 patients (78% males, mean age 41 years, 78% on antiretroviral therapy, mean CD4+ T-cell count 561 cells/microl) fit the study inclusion criteria. Mean baseline serum HCV RNA was 5.89 log10 IU/ml, 65% were infected by genotypes 1 or 4 and 40% had advanced liver fibrosis (Metavir F3F4). The overall rate of sustained virological response (SVR) was 38%. Factors associated with lack of SVR in the multivariate analyses (odds ratio [95% confidence interval], P-value) were higher baseline serum HCV RNA (2.42 per log10 IU/ml [1.31-4.46], 0.005), HCV genotypes 1 or 4 (5.95 [2.50-14.29], < 0.001) and lower RBV plasma trough concentrations (1.74 per microg/ml [1.15-2.63], 0.009). Interestingly, a trend was noticed for abacavir use (2.22 [0.91-5.40], 0.08), which become significant when only considering the subset of patients with RBV plasma levels < 2.3 microg/ml (7.63 [1.39-41.67], 0.02). The use of abacavir might interfere with the anti-HCV activity of PEG-IFN plus RBV. As both antivirals are guanosine analogues, an inhibitory competition between abacavir and RBV might explain this observation, which is more prominent in patients with lower RBV exposure.

Abacavir Hypersensitivity Reaction: an Update

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.

HLA-B*5701 Screening for Hypersensitivity to Abacavir

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. 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. 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). 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.)

MI risk heightened after recent use of abacavir, didanosine

MI risk heightened after recent use of abacavir, didanosine

MI risk heightened after recent use of abacavir, didanosine

MI risk heightened after recent use of abacavir, didanosine

824 ABACAVIR HAS A NEGATIVE IMPACT ON RAPID VIROLOGIC RESPONSE TO PEGYLATED INTERFERON AND RIBAVIRRIN COMBINATION TREATMENT OF HEPATITIS C IN HIV-1 COINFECTED PATIENTS

Ribavirin use and higher ribavirin doses are associated with accelerated viral decay during the very early phase of ant-HCV therapy. An interference of abacavir with ribavirin intracellular phosphorilation has been hypothesized. Thus, concurrent abacavir use should impair the early phases of viral decay during anti HCV treatment. A negative interaction seem to be confirmed by preliminary data from retrospective studies showing a negative impact of abacavir use on the sustained response to pegylated interferon and ribavirin combination treatment in HIV infected patients with chronic hepatitis C. However this association could be biased by confounders and not due to a reduced potency of anti HCV treatment.