abacavir and Drug-Hypersensitivity

Individuals vary in their susceptibility to adverse reactions to medications, some of which can be potentially life-threatening. Idiosyncratic drug toxicity (IDT) has been shown to be strongly associated to specific polymorphisms in genes encoding human leukocyte antigens (HLAs) by recent genome-wide association studies. However, the pathogenic mechanisms governing such reactions remain unclarified, at least in part because of a lack of suitable experimental animal models to assess IDT. This review describes our work on the specific allele/drug combination of HLA-B*57:01 and abacavir, an antiretroviral drug targeting the human immunodeficiency virus. As abacavir is known to trigger an HLA-dependent immune response, we engineered a transgenic mouse model-HLA-Tg-by partially substituting the mouse HLA sequence for the corresponding human sequence. Local abacavir exposure was found to trigger a significant immune response in an HLA-dependent manner, and oral administration induced liver injury partially via concurrent activation of the innate immune system. Additionally, we developed a technique for evaluating structural alterations in HLA complexes resulting from drug exposure based on phage display to ensure specificity. Further scrutiny of the mechanism(s) underlying drug-induced immune reactions using the HLA-Tg model, as well as enhanced methods for predicting adverse event incidence, are anticipated to help resolve issues surrounding HLA-associated drug hypersensitivity.

Topics: Alleles; Animals; Anti-HIV Agents; Dideoxynucleosides; Disease Models, Animal; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Genome-Wide Association Study; HLA Antigens; HLA-B Antigens; Humans; Individuality; Mice; Polymorphism, Genetic

Human leukocyte antigen (HLA)-B*5701 screening identifies patients at increased risk for abacavir (ABC) hypersensitivity reaction (HSR). Screening was adopted in GlaxoSmithKline and ViiV Healthcare clinical trials in 2007 and human immunodeficiency virus treatment guidelines in 2008. Company meta-analyses of trials pre-HLA-B*5701 screening reported HSR rates of 4-8%. We analyzed the effectiveness of HLA-B*5701 screening on reducing HSR rates using clinical trial, Observational Pharmaco-Epidemiology Research & Analysis (OPERA) cohort, and spontaneous reporting data.. A meta-analysis examined 12 trials in 3063 HLA-B*5701-negative patients receiving an ABC-containing regimen from April 9, 2007, to September 22, 2015. Potential cases were identified using prespecified Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (drug hypersensitivity, hypersensitivity, anaphylactic reaction, anaphylaxis) and adjudicated against a Company ABC HSR case definition. Investigator-diagnosed cases were identified and rates were calculated. In the OPERA cohort, 9619 patients initiating their first ABC-containing regimen from January 1, 1999, to January 1, 2016, were identified. Patients were observed from regimen start until the earliest-following censoring event: ABC discontinuation, loss to follow-up, death, or study end (July 31, 2016). OPERA physicians evaluated events against OPERA definitions for definite/probable cases of ABC HSR; rates were calculated pre- and post-2008. The Company case definition was used to identify spontaneously reported cases for four marketed ABC-containing products; reporting rates were calculated using estimated exposure from sales data, through December 31, 2016.. Suspected ABC HSR rates were 1.3% or less in the meta-analysis. In the OPERA cohort, the rate was 0.4% among patients initiating ABC post-2008 versus 1.3% pre-2008 (p<0.0001). Spontaneous reporting rates were low post-2008 (54 to 22 cases per 100,000 patient-years exposure [PYE]) versus pre-2008 (618 to 55 cases per 100,000 PYE).. Clinically suspected ABC HSR rates were 1.3% or less in HLA-B*5701-negative patients. Recognizing their limitations, data from the OPERA cohort and spontaneous reporting indicate that HLA-B*5701 screening has reduced reporting rates of suspected HSR in clinical practice. Where screening for HLA-B*5701 is standard care, patients should be confirmed negative for this allele before starting ABC treatment.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HLA-B Antigens; Humans; Mass Screening

Immune-mediated adverse drug reactions (IM-ADRs) are many times more common in HIV-infected patients. Usual offending drugs include antiretroviral and antiinfectives, but the burden of specific drug IM-ADRs is population-specific; changing as new and fixed dose combinations enter the market, and drug-resistance patterns demand. This review considers recent literature on epidemiology, mechanisms, clinical management and prevention of IM-ADRs amongst persons living with HIV/AIDS.. Epidemiological studies continue to describe high rates of delayed hypersensitivity to known offenders, as well as similar reactions in preexposure prophylaxis. IM-ADRs to oral and injectable integrase strand transfer inhibitors are reported with expanding use. The clinical spectrum and management of IM-ADRs occurring in HIV-infected populations is similar to uninfected; with exceptions such as a recently described severe delayed efavirenz DILI with high mortality. Furthermore, the context can be unique, such as the lower than expected mortality in a Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) cohort from a HIV/TB high burden setting. Programmatic data showing the near complete elimination of Abacavir drug hypersensitivity syndrome following implementation of HLA-B57:01 screening is a stellar example of how prevention is possible with mechanistic insight.. IM-ADRs remain a challenge in persons living with HIV. The complexities posed by polypharmacy, overlapping drug toxicities, drug interactions, overlap of IM-ADRs with other diseases, limited alternative drugs, and vulnerable patients with advanced immunosuppression with high mortality, necessitate increased use of drug provocation testing, treat-through and desensitization strategies. There is an urgent need for improved diagnostics and predictive biomarkers for prevention, or to guide treat-through, rechallenge and desensitization approaches.

Topics: Allergens; Anti-Infective Agents; Anti-Retroviral Agents; Biomarkers; Dideoxynucleosides; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Genetic Predisposition to Disease; Genetic Testing; HIV Infections; HIV-1; HLA-B Antigens; Humans; Immunization

Human leukocyte antigen (HLA) alleles are implicated in drug-induced hypersensitivity, including by nevirapine and abacavir. The purpose of this meta-analysis was to evaluate the relationship between HLA polymorphisms and hypersensitivity to antiretroviral therapy in human immunodeficiency virus (HIV)-infected patients.. We conducted a systematic search of PubMed, Embase, Web of Science, and the Cochrane Library for studies that evaluated the associations of HLA polymorphisms with antiretroviral therapy-induced hypersensitivity published in April 2019. The summary odds ratios (ORs) with 95% confidence intervals (CIs) were considered as estimates of the effect.. The meta-analysis included 17 studies that assessed a total of 4273 patients. First, carriers of HLA-A *24 were associated with an increased risk of hypersensitivity among patients with HIV who received antiretroviral therapy (OR: 12.12; P = 0.018). Second, five SNPs of HLA-B genotypes, including *18 (OR: 1.63; P = 0.028), *35 (OR: 2.31; P = 0.002), *39 (OR: 11.85; P = 0.040), *51 (OR: 1.66; P = 0.028), and *81 (OR: 8.11; P = 0.021), were associated with an increased risk of hypersensitivity. Conversely, carriers of HLA-B *15 were associated with a reduced risk of hypersensitivity (OR: 0.43; P < 0.001). Third, HLA-C *04 was associated with an increased risk of hypersensitivity (OR: 3.09; P < 0.001), whereas a lower risk for hypersensitivity was observed in patients who were carriers of HLA-C *02 (OR: 0.22; P = 0.030), *03 (OR: 0.53; P = 0.049), and *07 (OR: 0.61; P = 0.044). Finally, carriers of HLA-DRB1 *05 (OR: 0.18; P = 0.006) and *15 (OR: 0.23; P = 0.013) were associated with a reduced risk of hypersensitivity among patients receiving antiretroviral therapy.. The findings of this meta-analysis indicated patients carrying HLA-A *24, HLA-B *18, *35, *39, *51, *81, HLA-C *04 were associated with a higher risk of hypersensitivity. Conversely, subjects carrying HLA-B *15, HLA-C *02, *03, *07, HLA-DRB1 *05, *15 were associated with a reduced risk of hypersensitivity.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Female; HIV Infections; HLA Antigens; Humans; Male; Nevirapine; Odds Ratio; Polymorphism, Single Nucleotide

Adverse drug reactions (ADR) can be broadly categorised as either on-target or off-target. On-target ADRs arise as a direct consequence of the pharmacological properties of the drug and are therefore predictable and dose-dependent. On-target ADRs comprise the majority (>80%) of ADRs, relate to the drug's interaction with its known pharmacological target and are a result of a complex interplay of genetic and ecologic factors. In contrast, off-target ADRs, including immune-mediated ADRs (IM-ADRs), are due to unintended pharmacological interactions such as inadvertent ligation of host cell receptors or non-pharmacological interactions mediated through an adaptive immune response. IM-ADRs can be classified according to the primary immune cell involved and include B-cell-mediated (Gell-Coombs type I-III reactions) and T-cell-mediated (Gell-Coombs type IV or delayed hypersensitivity) reactions. IM-ADRs mediated by T cells are associated with phenotypically distinct clinical diagnoses and can vary from a mild delayed rash to a life-threatening cutaneous, systemic or organ disease, such as Stephen Johnson syndrome/toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms and drug-induced liver disease. T-cell-mediated ADRs are strongly linked to the carriage of particular HLA risk alleles which are in the case of abacavir hypersensitivity and HLA-B*57:01 has led to translation into the clinic as a routine screening test. In this review, we will discuss the immunogenetics and pathogenesis of IM-ADRs and how HLA associations inform both pre-drug screening strategies and mechanistic understanding.

Topics: B-Lymphocytes; Dideoxynucleosides; Drug Hypersensitivity; HLA-B Antigens; Humans; Immunity, Cellular; Risk Factors; T-Lymphocytes

Adverse drug reactions (ADRs) affect many patients and remain a major public health problem, as they are a common cause of morbidity and mortality. It is estimated that ADRs are responsible for about 6% of hospital admissions and about 9% of hospitalization costs. Skin is the organ that is most frequently involved in ADRs. Drug-induced skin injuries vary from mild maculopapular eruptions (MPE) to severe cutaneous adverse reactions (SCARs) that are potentially life threatening. Genetic factors have been suggested to contribute to these SCARs, and most significant genetic associations have been identified in the major histocompatibility complex (MHC) genes. Common drugs associated with SCARs connected with strong genetic risk factors include antiepileptic drugs (AEDs), allopurinol, abacavir, nevirapine, sulfonamides, dapsone, non-steroidal anti-inflammatory drugs (NSAIDs), and analgesic drugs. However, genetic associations vary between different ethnic populations. Differences may in part be explained by the different prevalence of HLA (human leukocyte antigen) alleles among ethnic groups. In this review, we present and discuss the recent advances in genetic associations with ADRs in the skin. Many of these ADRs are now preventable with pharmacogenetic screening.

Topics: Alleles; Allopurinol; Anti-HIV Agents; Anti-Inflammatory Agents, Non-Steroidal; Anticonvulsants; Carbamazepine; Dideoxynucleosides; Drug Hypersensitivity; Gene Expression; Genetic Testing; Gout Suppressants; HLA-B Antigens; Humans; Pharmacogenetics; Skin

Adverse drug reactions are a significant cause of morbidity and mortality and represent a major burden on the healthcare system. Some of those reactions are immunologically mediated (hypersensitivity reactions) and can be clinically subdivided into two categories: immediate reactions (IgE-related) and delayed reactions (T-cell-mediated). Delayed hypersensitivity reactions include both systemic syndromes and organ-specific toxicities and can be triggered by a wide range of chemically diverse drugs. Recent studies have demonstrated a strong genetic association between human leukocyte antigen alleles and susceptibility to delayed drug hypersensitivity. Most notable examples include human leukocyte antigen (HLA)-B*57:01 allele and abacavir hypersensitivity syndrome or HLA-B*15:02 and HLA-B*58:01 alleles related to severe cutaneous reactions induced by carbamazepine and allopurinol, respectively. This review aims to explore our current understanding in the field of pharmacogenomics of HLA-associated drug hypersensitivities and its translation into clinical practice for predicting adverse drug reactions.

Topics: Allopurinol; Anticonvulsants; Carbamazepine; Dideoxynucleosides; Drug Hypersensitivity; Enzyme Inhibitors; Genetic Predisposition to Disease; HLA Antigens; Humans; Pharmacogenetics; Reverse Transcriptase Inhibitors

It is hypothesised that associations between adverse drug reactions and specific alleles of the human leukocyte antigens arise due to specific interactions between the human leukocyte antigen molecules and the causative drug that stimulate immune responses targeting drug exposed tissues. To date this has only been definitively demonstrated for abacavir, an antiretroviral that causes a systemic adverse drug reaction, abacavir hypersensitivity syndrome, solely in HLA-B*57:01

Topics: Alleles; Dideoxynucleosides; Drug Hypersensitivity; Genetic Predisposition to Disease; HLA Antigens; HLA-B Antigens; Humans; Hypersensitivity, Delayed; Polymorphism, Genetic; T-Lymphocytes

This study aimed to systematically review and quantitatively synthesize the association between HLA-B*5701 and abacavir-induced hypersensitivity reaction (ABC-HSR).. We searched for studies that investigated the association between HLA-B genotype and ABC-HSR and provided information about the frequency of carriers of HLA-B genotypes among cases and controls. We then performed a meta-analysis with a random-effects model to pool the data and to investigate the sources of heterogeneity.. From 1,026 articles identified, ten studies were included. Five using clinical manifestation as their diagnostic criteria, 409 and 1,883 subjects were included as cases and controls. Overall OR was 23.6 (95% CI = 15.4 - 36.3). Whereas, the another five studies using confirmed immunologic test as their diagnostic criteria, 110 and 1,968 subjects were included as cases and controls, respectively. The association of ABC-HSR was strong in this populations with HLA-B*5701. Overall OR was 1,056.2 (95% CI = 345.0 - 3,233.3).. Using meta-analysis technique, the association between HLA-B*5701 and ABC-HSR is strong in the studies using immunologic confirmation to identify ABC-HSR. These results support the US FDA recommendations for screening HLA-B*5701 allele before initiating abacavir therapy.

Topics: Alleles; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Genotype; HLA-B Antigens; Humans

Topics: Dideoxynucleosides; Drug Hypersensitivity; Female; HLA-B Antigens; Humans; Male; Pharmacogenetics

Drug hypersensitivity reactions are an important clinical problem for both health care and industry. Recent advances in genetics have identified a number of HLA alleles associated with a range of these adverse reactions predominantly affecting the skin but also other organs, such as the liver. The associations between abacavir hypersensitivity and HLA-B*57:01 and carbamazepine-induced Stevens-Johnson syndrome and HLA-B*15:02 have been implemented in clinical practice. There are many different mechanisms proposed in the pathogenesis of drug hypersensitivity reactions, including the hapten hypothesis, direct binding to T-cell receptors (the pharmacologic interaction hypothesis), and peptide-binding displacement. A problem with all the hypotheses is that they are largely based on in vitro findings, with little direct in vivo evidence. Although most studies have focused on individual mechanisms, it is perhaps more important to consider them all as being complementary, potentially occurring at the same time with the same drug in the same patient. This might at least partly account for the heterogeneity of the immune response seen in different patients. There is a need to develop novel methodologies to evaluate how the in vitro mechanisms relate to the in vivo situation and how the highly consistent genetic findings with different HLA alleles can be more consistently used for both prediction and prevention of these serious adverse reactions.

Topics: Carbamazepine; Dideoxynucleosides; Drug Hypersensitivity; Gene Expression Regulation; Genetic Heterogeneity; HIV Infections; HLA Antigens; Humans; Models, Immunological; Pharmacogenetics; Receptors, Antigen, T-Cell; Stevens-Johnson Syndrome; T-Lymphocytes

Immune-mediated (IM) adverse drug reactions (ADRs) are an underrecognized source of preventable morbidity, mortality, and cost. Increasingly, genetic variation in the HLA loci is associated with risk of severe reactions, highlighting the importance of T-cell immune responses in the mechanisms of both B cell-mediated and primary T cell-mediated IM-ADRs. In this review we summarize the role of host genetics, microbes, and drugs in IM-ADR development; expand on the existing models of IM-ADR pathogenesis to address multiple unexplained observations; discuss the implications of this work in clinical practice today; and describe future applications for preclinical drug toxicity screening, drug design, and development.

Topics: Allopurinol; B-Lymphocytes; Carbamazepine; Dideoxynucleosides; Drug Hypersensitivity; Gene Expression Regulation; Genetic Loci; HLA Antigens; Humans; Models, Immunological; Pharmacogenetics; Stevens-Johnson Syndrome; T-Lymphocytes; Virus Diseases

Adverse drug reactions (ADRs) are commonplace and occur when a drug binds to its intended pharmacologic target (type A ADR) or an unintended target (type B ADR). Immunologically mediated type B ADRs, such as drug hypersensitivity syndrome, drug reaction with eosinophilia and systemic symptoms syndrome, and Stevens-Johnson syndrome/toxic epidermal necrolysis, can be severe and result in a diverse set of clinical manifestations that include fever and rash, as well as multiple organ failure (liver, kidney, lungs, and/or heart) in the case of drug hypersensitivity syndrome. There is increasing evidence that specific HLA alleles influence the risk of drug reactions. Several features of T cell-mediated ADRs are strikingly similar to those displayed by patients with autoimmune diseases like type I diabetes, such as strong HLA association, organ-specific adaptive immune responses, viral involvement, and activation of innate immunity. There is a need to better predict patient populations at risk for immunologically mediated type B ADRs. Because methods to predict type 1 diabetes by using genetic and immunologic biomarkers have been developed to a high level of accuracy (predicting 100% of subjects likely to progress), new research strategies based on these methods might also improve the ability to predict drug hypersensitivity.

Topics: Autoimmunity; Carbamazepine; Diabetes Mellitus, Type 1; Dideoxynucleosides; Drug Hypersensitivity; Gene Expression Regulation; HLA Antigens; Humans; Models, Molecular; Pharmacogenetics; Prognosis; Receptors, Antigen, T-Cell; Stevens-Johnson Syndrome; T-Lymphocytes; Virus Diseases

Aldehydes are highly reactive molecules, which can be generated during numerous physiological processes, including the biotransformation of drugs. Several non-P450 enzymes participate in their metabolism albeit alcohol dehydrogenase and aldehyde dehydrogenase are the ones most frequently involved in this process. Endogenous and exogenous aldehydes have been strongly implicated in multiple human pathologies. Their ability to react with biomacromolecules (e.g. proteins) yielding covalent adducts is suggested to be the common primary mechanism underlying the toxicity of these reactive species. Abacavir is one of the options for combined anti-HIV therapy. Although individual susceptibilities to adverse effects differ among patients, abacavir is associated with idiosyncratic hypersensitivity drug reactions and an increased risk of cardiac dysfunction. This review highlights the current knowledge on abacavir metabolism and discusses the potential role of bioactivation to an aldehyde metabolite, capable of forming protein adducts, in the onset of abacavir-induced toxic outcomes.

Topics: Aldehydes; Animals; Anti-HIV Agents; Biotransformation; Dideoxynucleosides; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Heart Diseases; Humans

Over the past decade, there have been significant advances in our understanding of the immunopathogenesis and pharmacogenomics of severe immunologically-mediated adverse drug reactions. Such T-cell-mediated adverse drug reactions such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug-induced liver disease (DILI) and other drug hypersensitivity syndromes have more recently been shown to be mediated through interactions with various class I and II HLA alleles. Key examples have included the associations of HLA-B*15:02 and carbamazepine induced SJS/TEN in Southeast Asian populations and HLA-B*57:01 and abacavir hypersensitivity. HLA-B*57:01 screening to prevent abacavir hypersensitivity exemplifies a successful translational roadmap from pharmacogenomic discovery through to widespread clinical implementation. Ultimately, our increased understanding of the interaction between drugs and the MHC could be used to inform drug design and drive pre-clinical toxicity programs to improve drug safety.

Topics: Allopurinol; Amoxicillin-Potassium Clavulanate Combination; Carbamazepine; Dideoxynucleosides; Drug Hypersensitivity; Genotype; HLA-B Antigens; Humans; Nevirapine; Pharmacogenetics; Protein Conformation; Stevens-Johnson Syndrome

Drug allergy is an adverse drug reaction that is immune-mediated. Immune activation can occur when drugs or haptens bind covalently to proteins and then act as antigens. The purpose of this review is to summarize the recent data on the formation of hapten-protein complexes and to assess the importance of these complexes in the generation of drug allergy.. The formation of hapten-protein complexes by drugs and their reactive metabolites has largely been investigated using model proteins such as human serum albumin. Precise identification of the structure of the hapten and the resulting modified residue(s) in the protein has been undertaken for a small number of drugs, such as p-phenylenediamine, nevirapine, carbamazepine, β-lactams and abacavir. Some progress has also been made in identifying hapten-protein complexes in the serum of patients with allergy.. Drug-specific T cells have been isolated from different patients with allergy. Formation of hapten-protein complexes, their processing and antigen presentation have been implicated in the development of drug allergy to p-phenylenediamine, sulfonamides and β-lactams. However, evidence also supports the pi mechanism of immune activation wherein drugs interact directly with immune receptors. Thus, multiple mechanisms of immune activation may occur for the same drug.

Topics: Antigen Presentation; beta-Lactams; Dideoxynucleosides; Drug Hypersensitivity; Haptens; Humans; Phenylenediamines; Sulfonamides; T-Lymphocytes

To determine diagnostic accuracy of HLA-B*57:01 testing for prediction of abacavir-induced hypersensitivity and to quantify the clinical benefit of pretreatment screening through a meta-analytic review of published studies.. A comprehensive search was performed up to June 2013. The methodological quality of relevant studies was assessed by the QUADAS-2 tool. The pooled diagnostic estimates were calculated using a random effect model.. Despite the presence of heterogeneity in sensitivity or specificity estimates, the pooled diagnostic odds ratio to detect abacavir-induced hypersensitivity on the basis of clinical criteria was 33.07 (95% CI: 22.33-48.97, I(2): 13.9%), while diagnostic odds ratio for detection of immunologically confirmed abacavir hypersensitivity was 1141 (95% CI: 409-3181, I(2): 0%). Pooled analysis of risk ratio showed that prospective HLA-B*57:01 testing significantly reduced the incidence of abacavir-induced hypersensitivity.. This meta-analysis demonstrates an excellent diagnostic accuracy of HLA-B*57:01 testing to detect immunologically confirmed abacavir hypersensitivity and corroborates existing recommendations.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Genetic Testing; HIV Infections; HLA-B Antigens; Humans; Pharmacogenetics

Antimicrobial efficacy and toxicity varies between individuals owing to multiple factors. Genetic variants that affect drug-metabolizing enzymes may influence antimicrobial pharmacokinetics and pharmacodynamics, thereby determining efficacy and/or toxicity. In addition, many severe immune-mediated reactions have been associated with HLA class I and class II genes. In the last two decades, understanding of pharmacogenomic factors that influence antimicrobial efficacy and toxicity has rapidly evolved, leading to translational success such as the routine use of HLA-B*57:01 screening to prevent abacavir hypersensitivity reactions. This article examines recent advances in the field of antimicrobial pharmacogenomics that potentially affect treatment efficacy and toxicity, and challenges that exist between pharmacogenomic discovery and translation into clinical use.

Topics: Anti-Infective Agents; Dideoxynucleosides; Drug Hypersensitivity; Genetic Variation; HLA-B Antigens; Humans; Pharmacogenetics

Rare but severe adverse drug reactions (ADRs) are an important issue in drug development and in the proper usage of drugs during the post-approval phase. The ability to predict patient susceptibility to severe ADRs would prevent drug administration to high-risk patients. This would save lives and ensure the quality of life for these patients, but occurrence of idiosyncratic severe ADRs had been very difficult to predict for a long time. However, in this decade, genetic markers have been found for several ADRs, especially for severe cutaneous adverse reactions (SCARs) and drug-induced liver injury (DILI). In this review, we summarize recent progress in identifying genetic markers for SCARS and DILI, and discuss issues that remain unresolved. As for SCARs, associations of HLA-B*15:02 or HLA-A*31:01 and HLA-B*58:01 have been revealed for carbamazepine- and allopurinol-related Stevens-Johnson syndrome and toxic epidermal neclolysis, respectively. HLA-B*57:01 is strongly associated with abacavir-induced hypersensitivity syndrome. Several HLA alleles also demonstrate drug-specific associations with DILI, such as HLA-A*33:03 for ticlopidine, HLA-B*57:01 for flucloxacillin and HLA-DQA1*02:01 for lapatinib. Efforts should be continued to find other genetic markers to achieve high predictability for ADRs, with the goal being development of genetic tests for use in clinical settings.

Topics: Alleles; Allopurinol; Amoxicillin-Potassium Clavulanate Combination; Azetidines; Benzylamines; Carbamazepine; Chemical and Drug Induced Liver Injury; Diclofenac; Dideoxynucleosides; Drug Hypersensitivity; Floxacillin; Genetic Markers; HLA Antigens; HLA-A Antigens; HLA-B Antigens; HLA-DQ alpha-Chains; Humans; Lapatinib; Pharmacogenetics; Quinazolines; Skin; Stevens-Johnson Syndrome; Ticlopidine

Abacavir is a nucleoside analogue reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus infection as part of a multidrug, highly active antiretroviral therapy regimen. Despite its efficacy, approximately 5% of individuals who receive abacavir develop an immune-mediated hypersensitivity reaction (HSR) that warrants immediate discontinuation of abacavir and switching to an alternative antiretroviral regimen. Abacavir HSR is associated with individuals who carry the *57:01 variant in the human leukocyte antigen B (HLA-B) gene. There is a large volume of evidence to show that those who carry HLA-B*57:01 are at significantly increased risk of developing HSR and should not receive abacavir. Pharmacogenetic screening to ensure individuals who carry HLA-B*57:01 do not receive abacavir can reduce the incidence of HSR and is now considered the standard of care before prescribing abacavir. Genetic testing to prevent abacavir HSR is currently one of the best examples of integrating pharmacogenetic testing into clinical practice.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HLA-B Antigens; Humans; Pharmacogenetics; Reverse Transcriptase Inhibitors; Standard of Care

A growing number of associations between adverse drug reactions and alleles of the human leukocyte antigen (HLA) genes are now known. Although several models have been proposed to explain these associations, an underlying molecular basis has only recently been described. The associations between HLA-B*57:01 and abacavir hypersensitivity syndrome, and HLA-B*15:02 and carbamazepine-induced bullous skin disease have provided new insights into the mechanism associated with hypersensitivity reactions to these drugs. Here we discuss recent evidence that small molecules can interact with specific HLA to distort self-peptide presentation leading to autoimmune-like drug hypersensitivities that potentially provide clues to the mechanisms underlying other immunopathologies.

Topics: Animals; Anti-HIV Agents; Anticonvulsants; Antigen Presentation; Autoantigens; Carbamazepine; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HLA Antigens; Humans; Peptide Fragments; Protein Binding; Seizures; Skin

Abacavir is an effective nucleoside analog reverse transcriptase inhibitor used to treat human immunodeficiency virus (HIV) infected patients. Its main side effect is hypersensitivity reaction (HSR). The incidence of the HSR is associated with ethnicity among patients exposed to abacavir, and retrospective and prospective studies show a significantly increased risk of abacavir-induced HSR in human leukocyte antigen (HLA)-B*57:01-carrying patients. Immunological studies indicated that abacavir interacts specifically with HLA-B*57:01 and changed the binding specificity between the HLA molecule and the HLA-presented endogenous peptide repertoire, leading to a systemic autoimmune reaction. HLA-B*57:01 screening, combined with patch testing, had clinically predictive value and cost-effective impact in reducing the incidence of abacavir-induced HSR regardless of the HLA-B*57:01 prevalence in the population. Therefore, the US Food and Drug Administration (FDA) and international HIV treatment guidelines recommend a routine HLA-B*57:01 screening prior to abacavir treatment to decrease false positive diagnosis and prevent abacavir-induced HSR. The studies of abacavir-induced HSR and the implementation of the HLA-B*57:01 screening in the clinic represent a successful example of the use of pharmacogenetics for personalized diagnosis and therapy.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Gene Frequency; Genetic Testing; Histocompatibility Testing; HIV Infections; HLA-B Antigens; Humans; Pharmacogenetics; Precision Medicine; Translational Research, Biomedical

The human leukocyte antigen (HLA) genes are the most polymorphic in the human genome and are critical in regulating specific immunity, hence their historical discovery as "immune response" genes. HLA allotypes are also implicated in unwanted immune reactions, including drug hypersensitivity syndrome, in which small therapeutic drugs interact with antigenic peptides to drive T cell responses restricted by host HLA. Abacavir, allo-purinol, and carbamazepine are three commonly used drugs that cause a T cell-mediated hypersensitivity that is HLA linked, with each drug exhibiting striking specificity for presentation by defined HLA allotypes. Recent findings have begun to unearth the mechanistic basis for these HLA associations, and here we review recent advances in the field of HLA-associated drug hypersensitivities.

Topics: Alleles; Allopurinol; Carbamazepine; Dideoxynucleosides; Drug Hypersensitivity; HLA Antigens; Humans; Major Histocompatibility Complex; Pharmacogenetics; Polymorphism, Genetic; T-Lymphocytes

The human leucocyte antigen (HLA) system is well known for its association with certain diseases such as ankylosing spondylitis, celiac disease and many others. More recently, severe and even fatal drug hypersensitivity reactions linked to particular HLA alleles have been discovered. The significance of these discoveries has led the European Medicines Agency (EMA) and its member state agencies to recommend HLA gene testing before initiation of drug treatment. To date, the following drugs have been identified as causing significant drug hypersensitivity reactions in patients who have the following HLA alleles: abacavir and HLA-B*57:01, carbamazepine and HLA-B*15:02/A*31:01 and finally allopurinol and HLA-B*58:01. This review will outline and discuss these three drugs and their associated HLA alleles as well as examine the pathogenesis of the drug hypersensitivity reactions.

Topics: Alleles; Allopurinol; Anti-HIV Agents; Carbamazepine; Dideoxynucleosides; Drug Hypersensitivity; Gene Frequency; Genetic Testing; HLA-B Antigens; HLA-B15 Antigen; Humans; Pharmacogenetics; Stevens-Johnson Syndrome

The most important factor limiting the success of an antiretroviral therapy regimes is toxicity. Toxicity can depend on a number of factors; some of these are intrinsic to the host and may not only affect the latter's outward appearance, but also determine the intensity these toxic effects may reach. The former is exemplified by idiosyncratic or hypersensitivity reactions, whereas the latter is usually appreciated in metabolic disturbances or fat redistribution syndromes. Some of the determinants of antiretroviral toxicity are genetic in origin and have been the subject of intense study in recent years. Some of these are linked to a single nucleotide polymorphism (SNP), whereas others depend on a complex interaction between multiple genes variations. One of these tests (HLA B*5701) is now being applied in clinical practice and widely used to prevent the risk of hypersensitivity reactions to abacavir. Many other genetic determinants of antiretroviral drug toxicity have been suggested as an explanation for nucleoside analogue toxicity; these include lactic acidosis, peripheral neuropathy and pancreatitis, and have also been suggested as a potential basis for the non-nucleoside toxicity derived from immunogenetic factors involved in nevirapine hypersensitivity to SNPs in efavirenz enzyme metabolism, amongst other things. Metabolic toxicity, mainly due to protease inhibitors (PIs) is far more complex and depends on the interaction of various genes. The same seems to be true for fat redistribution syndromes and atherosclerosis, although a clear picture of the genetic factors operating in these syndromes is yet to emerge. The ultimate goal of pharmacogenetics is to customize antiretroviral therapy by identifying the genes that can maximize efficacy whilst helping avoid known side effects of antiretroviral drugs.

Topics: Alkynes; Anti-Retroviral Agents; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Hypersensitivity; Genetic Variation; Humans; Nevirapine; Oligopeptides; Polymorphism, Single Nucleotide; Pyridines; Reverse Transcriptase Inhibitors; Toxicogenetics

Many drugs used for the treatment of HIV disease (including the associated opportunistic infections) can cause drug hypersensitivity reactions, which vary in severity, clinical manifestations and frequency. These reactions are not only seen with the older compounds, but also with the newer more recently introduced drugs. The pathogenesis is unclear in most cases, but there is increasing evidence to support that many of these are mediated through a combination of immunologic and genetic factors through the major histocompatibility complex (MHC). Genetic predisposition to the occurrence of these allergic reactions has been shown for some of the drugs, notably abacavir hypersensitivity which is strongly associated with the class I MHC allele, HLA-B*5701. Testing before the prescription of abacavir has been shown to be of clinical utility, has resulted in a change in the drug label, is now recommended in clinical guidelines and is practiced in most Western countries. For most other drugs, however, there are no good methods of prevention, and clinical monitoring with appropriate (usually supportive and symptomatic) treatment is required. There is a need to undertake further research in this area to increase our understanding of the mechanisms, which may lead to better preventive strategies through the development of predictive genetic biomarkers or through guiding the design of drugs less likely to cause these types of adverse drug reactions.

Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Anti-Infective Agents; Dideoxynucleosides; Drug Hypersensitivity; Genetic Predisposition to Disease; HIV Protease Inhibitors; Humans; Reverse Transcriptase Inhibitors

Drug hypersensitivity reactions and severe cutaneous adverse drug reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, are examples of serious adverse drug reactions mediated through a combination of metabolic and immunological mechanisms that could traditionally not have been predicted based on the pharmacological characteristics of the drug alone. The discovery of new associations between these syndromes and specific HLA has created the promise that risk for these reactions could be predicted through pharmacogenetic screening, thereby avoiding serious morbidity and mortality associated with these types of drug reactions. Despite this, several hurdles exist in the translation of these associations into pharmacogenetic tests that could be routinely used in the clinical setting. HLA-B*5701 screening to prevent abacavir hypersensitivity syndrome is an example of a test now in widespread routine clinical use in the developed world.

Topics: Diagnostic Uses of Chemicals; Dideoxynucleosides; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Forecasting; HLA-B Antigens; Humans; Pharmaceutical Preparations; Pharmacogenetics; Stevens-Johnson Syndrome

Pharmacogenetics (PGX) is the study of drug response as a function of an individual's DNA. PGX is often viewed as an extension of disease association genetics, and although this information may be related, it is not the study of drug response. Although medicines are used to treat diseases, the value of strategies that identify and incorporate DNA biomarkers associated with clinical efficacy, or DNA biomarkers for untoward clinical responses, can be applied directly to pharmaceutical pipelines. The growth of adverse event PGX studies involving marketed medicines generally uses relatively large numbers of affected patients, but has been productive. However, the two critical strategies for pipeline genetics must make use of fewer patients: (1) the early identification of efficacy signals so that they can be applied early in development for targeted therapies and (2) identification of safety signals that can subsequently be validated prospectively during development using the least number of patients with adverse responses. Assumptions are often made that large numbers of patients are necessary to recognize PGX hypotheses and to validate DNA biomarkers. In some ways, pipeline pharmacogenetics may be viewed as the opposite of current genome-wide scanning designs. The goal is to obtain PGX signals in as few patients as possible, and then validate PGX hypotheses for specificity and sensitivity as development trials go forward--not using hundreds of thousand of markers to detect strong linkage disequilibrium signals in thousands of patients and their controls. Drug development takes 5-7 years for a drug candidate to traverse to registration--and this is similar to the timeframe for validating genetic biomarkers using sequential clinical trials. Two important examples are discussed, the association of APOE genotypes to the demonstration of actionable efficacy signals for the use of rosiglitazone for Alzheimer's disease; and the identification of HLA-B(*)5701 as a highly sensitive and specific predictive marker for abacavir treated patients who will develop hypersensitivity syndrome (HSS). The rosiglitazone study prevented pipeline attrition by changing the interpretation of a critical Phase IIB proof of concept study (2005) from a failed study, to a positive efficacy response in a genetically predictable proportion of patients. Now, three years later, a Phase III program of clinical trials using pharmacogenetic designs is months away from completion (late08). If s

Topics: Alzheimer Disease; Apolipoprotein E4; Apolipoproteins E; Biomarkers, Pharmacological; Clinical Trials as Topic; Cost-Benefit Analysis; Dideoxynucleosides; Drug Discovery; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Genome-Wide Association Study; Genotype; HLA-B Antigens; Humans; Models, Biological; Pharmacogenetics; Rosiglitazone; Sample Size; Thiazolidinediones

Abacavir hypersensitivity (ABC HSR) is a treatment-limiting adverse event associated with the use of the antiretroviral medicine, abacavir. The objective of the ABC HSR pharmacogenetics program was to identify clinically useful genetic risk factors to predict an individual patient's risk for ABC HSR. The major histocompatibility complex allele, HLA-B*5701, was identified retrospectively and confirmed with independent sample sets. The clinical utility of prospective HLA-B*5701 screening was demonstrated in a blinded randomized clinical trial and in open-label cohorts. Screening has been incorporated into clinical practice and the ABC HSR pharmacogenetics program has been highlighted as a success by pharmacogenetics researchers. Important lessons from this pharmacogenetics program will be discussed in this paper.

Topics: Dideoxynucleosides; Drug Hypersensitivity; HLA-B Antigens; Humans; Phenotype; Prospective Studies; Research Design; Retrospective Studies; Reverse Transcriptase Inhibitors

Abacavir hypersensitivity syndrome (AHS) is a potentially life-threatening illness occurring in 4-8% of those initiating the drug. Early studies identified a strong association between the MHC class I allele HLA-B*5701 and AHS. These studies suggested that HLA-B*5701 holds promise as a screening test to prevent AHS, but concern arose from HLA-B*5701-negative cases with a clinical diagnosis of AHS, and particularly from early reports of apparently low sensitivities of HLA-B*5701 for AHS in patients of non-White race. However, open screening studies suggested that HLA-B*5701 screening can largely eliminate AHS. Furthermore, skin-patch testing was used in later-generation studies to separate those patients with true immunologically mediated AHS from those with false-positive clinical diagnoses. Currently, high-level evidence suggests that HLA-B*5701 has a negative predictive value of 100% for patch-test-confirmed AHS, which is generalizable across White and Black populations. Current HIV treatment guidelines have been revised to reflect the recommendation that HLA-B*5701 screening be incorporated into routine care for patients who may require abacavir. New laboratory techniques such as PCR and flow cytometric methods, as well as an international quality assurance program, have evolved to ensure the availability of cost-effective screening methods whose consistency and standard can be maintained over time. An elegant body of basic science has evolved, which supports and complements the clinical research in suggesting that AHS is specifically and exquisitely restricted by HLA-B*5701 and mediated by CD8+ lymphocytes. Abrogating factors explaining why 45% of those carrying HLA-B*5701 can tolerate abacavir remain to be defined. The research approach applied to AHS has led to a genetic screening test being successfully implemented globally in primary HIV clinical practice. The abacavir 'example' can be applied to other drugs to facilitate the development and operationalization of genetic tests that may be useful to predict and prevent otherwise unpredictable drug reactions.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Genetic Predisposition to Disease; Genetic Testing; HIV Infections; HLA-B Antigens; Humans; Patch Tests; Pharmacogenetics; Syndrome

This review focuses on the development of HLA-B*5701 genetic screening as a means of preventing drug hypersensitivity reactions caused by a commonly prescribed antiretroviral drug, abacavir. This strongly predictive genetic association, which in many respects represents a test case for the clinical application of pharmacogenetics, highlights the fine specificity of HLA-restricted immunity, here directed against a drug-specific antigen rather than an allogeneic molecule (as occurs in transplantation) or a pathogenic organism (as in viral infection). However, this example also demonstrates that successful implementation of pharmacogenetic screening requires that a range of criteria be adequately addressed. These include pharmaceutical factors (e.g. lack of alternative treatments with similar or improved cost effectiveness, safety, and efficacy), clinical factors (e.g. accurate diagnosis of the adverse event, in this case provided by clinical diagnostic criteria and adjunctive epicutaneous patch testing), sufficient objective evidence of the test's predictive value and generalizability (in this case provided by the first large-scale randomized trial of a pharmacogenetic test), as well as availability of quality-assured laboratory services that are responsive to the needs of targeted genetic screening. This example is intended to serve as a precedent for other pharmacogenetic screening strategies, particularly those aimed at reducing rates of serious drug hypersensitivity reactions in clinical practice.

Topics: Dideoxynucleosides; Drug Hypersensitivity; Genetic Testing; HLA-B Antigens; Humans; Pharmacogenetics

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; Humans; Nevirapine; Patch Tests

HIV infection is a serious but treatable disease, yet current treatment is limited by development of resistance and high rates of adverse drug reactions. Antiretroviral therapy is especially suitable for pharmacogenomic investigation as both drug exposure and treatment response can be reliably measured. Increasing knowledge about genes implicated in pharmacokinetics, mode of action, efficacy, and toxicity of drugs has already provided relevant results for clinical practice, for example: The strong association of the abacavir hypersensitivity reaction with HLA-B*5701 permits testing patients for the allele, and if present avoiding the drug and therefore preventing the reaction. Persons with the allele CYP2B6*6 present higher efavirenz "area under the curve" and have increased risk of neuropsychological toxicity. Additional gene variants are being discovered that influence the action of antiretroviral drugs. And, moreover, it is expected that larger-scale comprehensive genome approaches will profoundly improve the landscape of knowledge of HIV therapy in the future. The present article shows some recent patents related to the treatment of viral infections.

Topics: Alkynes; Anti-Retroviral Agents; Aryl Hydrocarbon Hydroxylases; Atazanavir Sulfate; Benzoxazines; Central Nervous System Diseases; Cyclopropanes; Cytochrome P-450 CYP2B6; Dideoxynucleosides; Drug Hypersensitivity; Drug Resistance, Viral; Dyslipidemias; Genetic Predisposition to Disease; Genetic Testing; Glucuronosyltransferase; HLA Antigens; Humans; Hyperbilirubinemia; Nevirapine; Oligopeptides; Oxidoreductases, N-Demethylating; Patents as Topic; Patient Selection; Pharmacogenetics; Pyridines; Ritonavir

A pharmacogenetic marker for abacavir hypersensitivity is rapidly being incorporated into routine medical practice following demonstration of strong clinical utility in pivotal clinical studies. As one of the few pharmacogenetic markers that have crossed from research tools to clinical adoption and utilization, the abacavir hypersensitivity pharmacogenetic marker provides a great model for demonstration of factors that are critical to successful pharmacogenetic test adoption. Several examples of novel diagnostic test implementation are reviewed with focus on factors that are critical to translation into clinical practice. Other pharmacogenetic markers that have not yet been integrated into routine clinical care are discussed and reasons for their lack of acceptance are suggested.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HLA-B Antigens; Models, Biological; Pharmacogenetics

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.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HLA-B Antigens; Humans

The hypersensitivity (HSR) to abacavir (ABC) pharmacogenetics (PGx) program represents the progression from an exploratory discovery to a validated biomarker. Within the program, two retrospective PGx studies were conducted to identify HIV-1 patients at increased risk for ABC HSR, a treatment-limiting and potentially life-threatening adverse event. A strong statistical association between the major histocompatibility complex allele, HLA-B*5701, and clinically diagnosed ABC HSR was identified but varied between racial populations. Subsequently, ABC skin patch testing was introduced as a research tool to supplement clinical case ascertainment. In a randomized, prospective study evaluating the clinical utility of HLA-B*5701 screening, avoidance of ABC in HLA-B*5701-positive patients significantly reduced clinically diagnosed ABC HSR and eliminated patch test-positive ABC HSR. Finally, a retrospective PGx study supports the generalizability of the association across races. Prospective HLA-B*5701 screening should greatly reduce the incidence of ABC HSR by identifying patients at high risk for ABC HSR before they are treated.

Topics: Dideoxynucleosides; Drug Hypersensitivity; HLA-B Antigens; Humans; Patch Tests; Pharmacogenetics; Reverse Transcriptase Inhibitors

A large amount of pharmacogenetic information has, in particular, accumulated on the association between human leukocyte antigen (HLA) alleles and hypersensitivity to certain drugs. Prospective HLA typing has dramatically reduced the risk of abacavir hypersensitivity because of its strong association with HLA-B*5701. Significant predisposition to nevirapine hypersensitivity has been reported in Caucasian Australians harboring HLA-DRB1*0101 with high CD4+ T-cell counts, and Sardinians and Japanese harboring HLA-Cw8. A strong association between carbamazepine hypersensitivity and HLA-B*1502 has been reported in Han Chinese. Most Han Chinese individuals with allopurinol-induced severe cutaneous adverse reactions are positive for HLA-B*5801. HLA typing can stratify risk of hypersensitivity to certain drugs and allow personalized treatment, although the patients should be monitored closely even if they are negative for HLA alleles associated with hypersensitivity.

Topics: Alleles; Animals; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; HLA Antigens; Humans; Nevirapine; Pharmacogenetics

The present article reviews the recent literature on the identification of human leukocyte antigen (HLA) alleles as major susceptible genes for drug hypersensitivity and discusses the clinical implications.. Several recent studies have reported strong genetic associations between HLA alleles and susceptibility to drug hypersensitivity. The genetic associations can be drug specific, such as HLA-B*1502 being associated with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), HLA-B*5701 with abacavir hypersensitivity and HLA-B*5801 with allopurinol-induced severe cutaneous adverse reactions. A genetic association can also be phenotype-specific, as B*1502 is associated solely with carbamazepine-SJS/TEN, and not with either maculopapular eruption or hypersensitivity syndrome. Furthermore, a genetic association can also be ethnicity specific; carbamazepine-SJS/TEN associated with B*1502 is seen in south-east Asians but not in whites, which may be explained by the different allele frequencies.. The strong genetic association suggests a direct involvement of HLA in the pathogenesis of drug hypersensitivity when the HLA molecule presents an antigenic drug for T cell activation. The high sensitivity/specificity of some markers provides a plausible basis for developing tests to identify individuals at risk for drug hypersensitivity. Application of HLA-B*1502 genotyping as a screening tool before prescribing carbamazepine could be a valuable tool in preventing carbamazepine-induced SJS/TEN in south-east Asian countries.

Topics: Allopurinol; Carbamazepine; Dideoxynucleosides; Drug Eruptions; Drug Hypersensitivity; Genetic Predisposition to Disease; HLA Antigens; HLA-B Antigens; Humans; Pharmacogenetics; Stevens-Johnson Syndrome

Drug hypersensitivity has been reported to occur 100 times more commonly in those living with HIV. In the first decade of HIV treatment, this mainly involved drugs used to treat HIV-related infections but now primarily includes drugs used to treat HIV. This review focuses on the current knowledge of the epidemiology, pathophysiology and clinical features of drug hypersensitivity reactions of drugs used in the management of the HIV-infected patient.. Our understanding of the immunogenetics and host predisposition to drug hypersensitivity has been advanced considerably by the antiretroviral drugs abacavir and nevirapine. The association of abacavir hypersensitivity reaction with HLA-B*5701 has been particularly important and provides a basis for genetic screening in the clinic setting.. The increased predisposition of drug hypersensitivity disease in HIV will continue to provide a fertile ground for study of the diverse and complex processes that drive its pathophysiology. Our knowledge of drug hypersensitivity will also increase as the expanding armentarium of antiretroviral therapy is applied to more diverse populations in the developing world. The potential for widespread implementation of HLA-B*5701 screening for abacavir hypersensitivity will set an important precedent for bringing individualized medicine to the clinic and the use of genetic testing to improve drug safety.

Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Anti-Infective Agents; Dideoxynucleosides; Drug Hypersensitivity; Genetic Predisposition to Disease; HIV Infections; HLA-B Antigens; Humans; Reverse Transcriptase Inhibitors; Trimethoprim, Sulfamethoxazole Drug Combination

There is a growing discussion surrounding the issue of personalized approaches to drug prescription based on an individual's genetic makeup. This field of investigation has focused primarily on identifying genetic factors that influence drug metabolism and cellular disposition, thereby contributing to dose-dependent toxicities and/or variable drug efficacy. However, pharmacogenetic approaches have also proved valuable in predicting drug hypersensitivity reactions in selected patient populations, including HIV-infected patients receiving long-term antiretroviral therapy. In this instance, susceptibility has been strongly linked to genetic loci involved in antigen recognition and presentation to the immune system--most notably within the major histocompatibility complex (MHC) region--consistent with the notion that hypersensitivity reactions represent drug-specific immune responses that are largely dose independent. Here the authors describe their experiences with the development of pharmacogenetic approaches to hypersensitivity reactions associated with abacavir and nevirapine, two commonly prescribed antiretroviral drugs. It is demonstrated that prospective screening tests to identify and exclude individuals with a certain genetic makeup may be largely successful in decreasing or eliminating incidence of these adverse drug reactions in certain populations. This review also explores the broader implications of these findings.

Topics: Animals; Anti-HIV Agents; Biomarkers; Dideoxynucleosides; Drug Hypersensitivity; HIV-1; Humans; Nevirapine

Drug hypersensitivity reactions can occur with most drugs, although the frequency, severity, and clinical manifestations vary. Case reports have suggested that there may be familial clustering of drug hypersensitivity suggesting a genetic predisposition. As with most other forms of drug response, predisposition to drug hypersensitivity reactions is likely to be multifactorial and multigenic. Given the immune pathogenesis of these reactions, it is perhaps not surprising that the most significant genetic associations have been identified in the major histocompatibility complex for drugs such as abacavir, carbamazepine, and allopurinol. For abacavir, it has been suggested that preprescription genotyping for HLA-B*5701 in whites may reduce the incidence of hypersensitivity. It is likely that as our knowledge of variation in the human genome improves, coupled with improvements in technology, many more significant genetic predisposing factors for drug hypersensitivity are likely to be identified in the next decade. However, as we search for these genetic factors, it is important that we do not forget environmental predisposition, and to bear in mind that a genetic marker for drug hypersensitivity in one population may not necessarily be relevant for another population. Notwithstanding the advances in genetic technologies, the ultimate determinant of success in this area of research will be the identification and careful phenotyping of patients with drug hypersensitivity reactions. As we progress to whole genome scanning, in order to satisfy the requirements for adequate statistical power, the identification of large numbers of carefully phenotyped patients will be feasible only through international collaborations.

Topics: Dideoxynucleosides; Drug Hypersensitivity; Genetic Markers; Genetic Predisposition to Disease; Humans

Heterogeneity exists in the effectiveness and toxic effects of antiretroviral agents between individuals and populations. Although patient-related clinical variables such as age, sex and ethnic origin have been associated with drug response, inherited predispositions may have a significant effect on treatment outcome. The role of host and pathogen pharmacogenomics is gaining increasing interest in the field of both antiretrovirals in development, such as the chemokine (C-C motif) receptor 5 (CCR5) inhibitors, and in established therapies where toxicity and efficacy may be predicted. Despite numerous studies available in the literature, the interpretation of the relationship between genetic polymorphisms and clinical outcomes is often posed with many confounding variables, making clinical interpretations of these results difficult. This review summarizes the key findings in the growing knowledge between human genetics and response to antiretroviral drugs and how these findings may be effectively applied in a clinical context.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CCR5 Receptor Antagonists; Dideoxynucleosides; Drug Hypersensitivity; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Male; Pharmacogenetics; Reverse Transcriptase Inhibitors

Drug hypersensitivity is a major problem in HIV medicine. These reactions limit the choice of antiretrovirals that can be used in a patient and, at times, can lead to failure to administer an adequate regimen. Hypersensitivity reactions occur in a minority of patients, but represent a high cost both to the patient and to health services. Our current understanding of these reactions is based on the hapten and the danger hypotheses, which state that a drug signal by itself is insufficient to induce an immune response but must be accompanied by co-stimulatory or danger signals. Furthermore, individual susceptibility to a hypersensitivity reaction may be determined by genetic factors. In this review, we explore our understanding of the immunological mechanisms of hypersensitivity to drugs used in HIV-positive patients, by using sulphamethoxazole and abacavir as paradigms. A deeper understanding of the mechanism(s) of these reactions will help us in their prevention, diagnosis and treatment.

Topics: Anti-Bacterial Agents; Dideoxynucleosides; Drug Hypersensitivity; Female; HIV Infections; HIV-1; Humans; Male; Reverse Transcriptase Inhibitors; Trimethoprim, Sulfamethoxazole Drug Combination

CIRCUMSTANCES AND CHARACTERISTICS: The risk of toxiderma is greater in patients infected by the human immunodeficiency virus (HIV). The most common toxidermas are maculopapular exanthema and drug hypersensitivity reactions. These toxidermas are predominantly observed with non-nucleoside reverse transcriptase analogs (nevirapine, efavirenz) and abacavir. Toxiderma has also been observed with other nucleoside reverse transcriptase analogs (zalcitabine) and protease inhibitors. REGARDING SEVERITY: The toxidermas observed are usually benign (maculopapular exanthema) and do not always require suspension of the treatment. However, certain toxidermas (Stevens-Johnson syndrome, Lyell syndrome and drug hypersensitivity syndrome) may be life-threatening and therefore contraindicate the continuation of treatment and also its sudden reintroduction. PREVENTION AND PRACTICAL APPROACH: Several studies have assessed the risk factors for toxiderma induced by nevirapine and hypersensitivity reactions to abacavir. The practical approach varies depending on the drug responsible, the clinical form of the toxiderma and the possible alternatives.

Topics: Alkynes; Anti-HIV Agents; Anti-Inflammatory Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Hypersensitivity; Exanthema; Histamine H1 Antagonists; HIV Infections; HIV Protease Inhibitors; Humans; Nevirapine; Oxazines; Reverse Transcriptase Inhibitors; Risk Factors; Steroids; Stevens-Johnson Syndrome

Abacavir sulfate is a recent addition to the nucleoside reverse-transcriptase inhibitor class of antiretroviral agents used in the treatment of HIV infection. It is approved for use in combination with other antiretroviral agents. Its tolerability has been studied, but the overall clinical relevance of the findings has yet to be determined.. This review investigates available data on the abacavir hypersensitivity reaction (HSR) and provides a clinical perspective on maximizing this agent's tolerability and effective incorporation into antiretroviral regimens.. Relevant data were identified through MEDLINE and AIDSLINE searches of the English-language literature from 1966 through 2002 using the terms abacavir and 1592U89, the investigational new drug designation for abacavir. The reference lists of identified articles were searched for additional documents. Additional information was obtained from the US Food and Drug Administration and the drug's manufacturer.. The abacavir HSR occurs in <5% of all patients started on therapy; the incidence appears to be unaffected by specific demographic characteristics or disease stage. Accurate diagnosis and appropriate patient education are essential, because reintroduction of abacavir in a patient with a history of possible HSR has been shown to result in a profound worsening of symptoms, including acute, severe hypersensitivity syndrome and possible death-even with aggressive treatment. Careful evaluation is necessary to distinguish an HSR from other manifestations of antiretroviral therapy. Despite the risk of HSR, compared with other anti-HIV medications, abacavir has demonstrated an overall favorable adverse-event profile.. The risk of abacavir HSR must be taken into consideration when selecting initial antiretroviral therapy for patients with HIV infection. Careful, appropriate evaluation is necessary to rule out an HSR and determine whether the medication can be continued.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Clinical Trials as Topic; Dideoxynucleosides; Drug Hypersensitivity; Humans; Reverse Transcriptase Inhibitors

A near-fatal hypersensitivity reaction to abacavir developed in a 62-year-old HIV-seropositive man who had been sensitized 17 months before presentation. Six days after he was rechallenged, acute respiratory distress developed, requiring mechanical ventilation for 2 weeks. Four days after extubation, he was again rechallenged. Hours later, the patient experienced anaphylactic shock, requiring mechanical ventilation for 3 weeks, aggressive volume resuscitation, and vasopressor support. Recovery was complicated by acute tubular necrosis, digital necrosis, and a GI bleed. This report reviews the mechanisms of action, efficacy, and adverse reactions of abacavir and illustrates the danger of serially rechallenging patients with this agent.

Topics: Anaphylaxis; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; Humans; Male; Middle Aged; Reverse Transcriptase Inhibitors

To develop an abacavir hypersensitivity reaction management protocol for the University of Oklahoma Health Sciences Center.. Conference abstracts, published literature, and manufacturer-provided materials were reviewed to define the syndrome and manifestations and to recommend steps to take when a patient develops abacavir-related reactions.. Initial education, formalized contact and response mechanism, and intervention levels were incorporated into a protocol for clinicians.. Abacavir, a newly approved agent for the treatment of HIV, has been associated with a fatal hypersensitivity reaction. Our protocol provides a mechanism to minimize progression of abacavir hypersensitivity reaction by providing a formalized management procedure.

Topics: Anti-HIV Agents; Contraindications; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; Humans

To determine the frequencies of HLA-B alleles in Ugandan patients in the NORA substudy of the DART trial and to compare HLA-B allele frequencies in those with and without clinically diagnosed hypersensitivity reaction (HSR).. DNA-based HLA-B genotyping was used to determine HLA alleles in 247 participants who received abacavir, including all six participants ('cases') with clinically diagnosed abacavir HSR.. The incidence of clinical abacavir HSR in this double-blinded study was 2.0% (6/300) in the abacavir group. As HLA-B*5701 was absent throughout the entire cohort, including the six HSR 'cases', an association could not be established between HLA-B*5701 and clinically diagnosed abacavir HSR. No other HLA-B*57 alleles were present among the six 'cases'. HLA-B*5703 was the most frequent HLA-B*57 allele among the abacavir-tolerant participants.. The rate of clinical HSR was low, which may reflect the expected 2-3% clinical false-positive rate seen in previous double-blind randomized studies. The presumption that these cases may be false-positive abacavir HSR is supported by the fact that no HLA-B*5701 alleles were found in the abacavir group. Implementation of prospective HLA-B*5701 screening must be based on benefit/risk considerations within local practice. Clinical risk management remains paramount.

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Double-Blind Method; Drug Hypersensitivity; Gene Frequency; Genetic Predisposition to Disease; Genotype; HIV Infections; HLA-B Antigens; Humans; Nevirapine; Uganda

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.

Topics: Adult; Alleles; Anti-Retroviral Agents; Dideoxynucleosides; Drug Hypersensitivity; Female; Genetic Testing; HIV Infections; HLA-B Antigens; Humans; Male; North America

The aim of the PREDICT-1 study was to determine the clinical utility of the pharmacogenetic test identifying HLA-B*5701 to reduce the incidence of hypersensitivity reaction to abacavir, diagnosed clinically and with immunological confirmation, as well as to reduce unwarranted withdrawal of this drug. In the PREDICT-1 study, 1,956 patients were randomized to be screened for HLA-B*5701 before starting abacavir treatment (excluding participants who were HLA-B*5701-positive) or to receive abacavir without knowing their HLA-B*5701 status under conventional clinical monitoring. The prevalence of HLA-B*5701-positivity was 5.7%. In the group that underwent prospective screening, no hypersensitivity tests with immunological confirmation (by positive epicutaneous patch testing) were observed compared with an incidence of 2.7% in the group undergoing standard follow-up. The sensitivity of prospective screening in predicting immunologically confirmed hypersensitivity reaction to abacavir was 100% and its negative predictive value was 100%. The number of clinically suspected hypersensitivity reactions to abacavir was also lower in the screened group (3.4% versus 7.8% in the group undergoing conventional follow-up). The sensitivity of epicutaneous patch testing for immunological confirmation was 100%.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Genetic Predisposition to Disease; HIV Infections; HLA-B Antigens; Humans; Mass Screening; Pharmacogenetics; Prospective Studies; Sensitivity and Specificity

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.)

Topics: Adolescent; Adult; Aged; Dideoxynucleosides; Double-Blind Method; Drug Hypersensitivity; Female; Genetic Markers; Genetic Testing; Genotype; HIV Infections; HIV-1; HLA-B Antigens; Humans; Male; Middle Aged; Patch Tests; Reverse Transcriptase Inhibitors

Abacavir hypersensitivity is strongly associated with the human leukocyte antigen (HLA)-B*5701 allele; however, the cost of routine high-resolution HLA typing before initiation of therapy remains prohibitive. We propose a simple approach to reduce B*5701-associated abacavir hypersensitivity based on the screening of human immunodeficiency virus (HIV) reverse transcriptase (RT) for a signature B*5701-associated cytotoxic T lymphocyte escape mutation at RT codon 245.. The correlation between HLA-B*5701 and RT codon 245 variation was investigated in 392 HIV-infected, antiretroviral-naive adults who were initiating highly active antiretroviral therapy. The relationship between codon 245 variation and premature abacavir discontinuation was investigated in a larger cohort of treated individuals (n=982). Associations between HLA-B*5701 and codon 245 variants were determined using Fisher's exact test or the chi (2) test.. A very strong association between HLA-B*5701 and RT codon 245 variation was observed. Only 1 (4.2%) of 24 subjects with B*5701 harbored virus with the clade B "wild-type" amino acid 245V, compared with 278 (75.5%) of 368 who did not have B*5701 (P<.001). The sensitivity and specificity of codon 245 substitutions for predicting HLA-B*5701 were 96% and 75%, respectively, and the positive and negative predictive values were 20% and 99.6%, respectively. This association remained robust even after antiretroviral treatment was administered (negative predictive value, 100%; n=269). In abacavir-treated individuals (n=982), codon 245 substitutions were predictive of premature abacavir discontinuation (P=.02).. As HIV RT sequence is incidentally obtained as a part of routine drug-resistance testing, the examination of sequence variation at RT codon 245 could be adopted as a simple, low-cost screening method to identify individuals who could be safely treated with abacavir and/or who could benefit from HLA characterization.

Topics: Adult; Alleles; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Contraindications; Dideoxynucleosides; Drug Hypersensitivity; Female; Genetic Testing; Genotype; HIV Reverse Transcriptase; HLA-B Antigens; Humans; Male; Mutation; Prevalence; Reverse Transcriptase Inhibitors; Sensitivity and Specificity; Sequence Analysis, RNA

Suspected hypersensitivity is the main reason for the early discontinuation of abacavir. After the observation that the risk of hypersensitivity correlated with ethnicity, the presence of the HLA allele B5701 was found to be the strongest retrospective predictor of hypersensitivity. Two prospective cohorts have since demonstrated a significant reduction in abacavir hypersensitivity rates with the use of prospective human leukocyte antigen screening. We describe our experience of prospective HLA-B5701 testing and the impact on rates of abacavir hypersensitivity.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Drug Hypersensitivity; Female; Genetic Predisposition to Disease; Histocompatibility Testing; HIV Infections; HIV Reverse Transcriptase; HLA-B Antigens; Humans; Male; Prospective Studies; Reverse Transcriptase Inhibitors

HIV-associated encephalopathy (HIV-AE) is a severe neurologic condition that affects HIV-infected children. The potential benefit of antiretroviral (ARV) agents with good cerebrospinal fluid (CSF) penetration remains to be defined. Abacavir (ABC) achieves good CSF concentrations and studies of high-dose ABC showed benefit in adults with HIV dementia. The present study evaluated the safety and virologic, immunologic and neuropsychological responses of an ARV regimen including high-dose ABC in children with HIV-AE.. Children between 3 months and 18 years old and abacavir-naive with HIV-AE and virologic failure were eligible.. : Seventeen children (16 ARV-experienced) were enrolled and 14 children completed 48 weeks of therapy. The overall tolerability was good; 2 children had a possible hypersensitivity reaction. At week 48, 53% and 59% of the children achieved HIV RNA levels below the limit of quantitation in plasma and CSF, respectively. The median (25%-75% range) change of HIV RNA from baseline to week 48 was -2.29 (-0.81 to -2.47) log10 copies/mL in plasma and -0.94 (0 to -1.13) log10 copies/mL in CSF. The mean increases in CD4 (+/-standard error of mean) cell count and CD4% were 427 (+/-169) cells/mm and 8% (+/-2), respectively. Concentrations of soluble tumor necrosis factor receptor II were reduced in plasma and CSF. Children less than 6 years of age demonstrated significant neuropsychological improvement at week 48.. In the present study with a limited number of children, highly active ARV therapy including high-dose ABC showed a safety profile similar to standard dose ABC and provided clinical, immunologic and virologic response in children with HIV-AE at week 48. Children less than 6 years of age also demonstrated significant neuropsychological improvement.

Topics: Adolescent; AIDS Dementia Complex; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; CD4-CD8 Ratio; Child; Child, Preschool; Dideoxynucleosides; Drug Hypersensitivity; Female; HIV; Humans; Infant; Male; Pilot Projects; Receptors, Tumor Necrosis Factor, Type II; Reverse Transcriptase Inhibitors; RNA, Viral; Salvage Therapy

Expanded access programs (EAPs) provide medication to patients with life-threatening, treatment-refractory illnesses before regulatory approval and allow the acquisition of safety information. A 2-part, multisite EAP to evaluate abacavir, a carbocyclic nucleoside reverse-transcriptase inhibitor for use in combination antiretroviral therapy, was conducted. The EAP involved >13,000 adults infected with human immunodeficiency virus type 1 (HIV-1) who no longer responded to commercially available treatment regimens. Part A (open-label trials) examined the efficacy, safety, and tolerance of abacavir, and part B (provision of abacavir through expanded access) assessed only the occurrence of serious adverse events. By month 2 of abacavir-containing treatment, plasma HIV-1 RNA levels decreased by > or =0.5 log(10) in 31.4% of patients, and 5.6% of the patients had HIV-1 RNA levels decrease to <400 copies/mL. Drug-related serious adverse events were reported by 7.7% of patients, the most common of which were nausea, skin rash, diarrhea, malaise or fatigue, and fever. Approximately 4.6% of patients experienced a hypersensitivity reaction that was possibly drug related. Overall, the types and incidences of adverse events reported in the abacavir EAP were similar to those reported in phase 2 and 3 clinical trials evaluating abacavir.

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Drug Therapy, Combination; Female; Health Services Accessibility; HIV Infections; HIV-1; Humans; Male; Treatment Outcome

A hypersensitivity reaction to abacavir has been known to occur in approximately 4% of patients treated with the drug.. The goal of this study was to determine risk factors associated with the development of hypersensitivity reactions to abacavir.. We constructed an analysis population from all protocols conducted by GlaxoSmithKline that involved at least 24 weeks of abacavir exposure with a quality-assured or validated clinical database by June 30, 2000. Demographic, clinical, and laboratory characteristics of patients who developed a hypersensitivity reaction to abacavir were compared with those of patients who did not. Univariate and multivariate logistic regression models were fit to understand the predictive ability of each potential risk factor. Odds ratios (ORs) and 95% Wald CIs were computed.. A total of 5332 patients exposed to abacavir were included in this analysis; 197 cases of hypersensitivity reaction were reported (3.7%). In univariate models, several associations were noted, but most subgroups produced rates within the expected range of 3% to 6%. The multivariate model using all demographic data available (Model 1) indicated that the risk of hypersensitivity reaction among black patients (3% hypersensitivity reaction) was lower (OR = 0.59; 95% CI, 0.38-0.91) compared with other ethnic groups. In addition, a lower rate of hypersensitivity reaction was observed in patients who received previous therapy for HIV-1 infection with other antiretroviral agents (3% hypersensitivity reaction) compared with those receiving therapy for the first time (OR = 0.58; 95% CI, 0.44-0.78).. The only characteristics identified as prognostic factors for hypersensitivity reaction to abacavir were antiretroviral treatment status (ie, treatment experience) and black race, each resulting in a lower rate compared with the expected incidence.

Topics: Adult; Analysis of Variance; Anti-HIV Agents; Black People; Dideoxynucleosides; Drug Hypersensitivity; Female; Humans; Logistic Models; Male; Odds Ratio; Prognosis; Regression Analysis; Risk Factors

Topics: Adult; Dideoxynucleosides; Drug Hypersensitivity; Female; HIV Infections; Humans; Male

To determine the effect of adjuvant prednisolone use on the development of abacavir (ABC)- and nevirapine (NVP)-associated hypersensitivity reactions (HSR).. Randomized open-label study in antiretroviral-naive adult HIV-1 infected patients using a factorial design in which NVP and/or hydroxyurea (HU) and/or prednisolone are added to a regimen of ABC, zidovudine and lamivudine. Prednisolone (40 mg once daily) was added for the first 2 weeks of treatment. As it was difficult to distinguish ABC-associated HSR from NVP-associated HSR, these events were treated as a composite endpoint. The odds ratio (OR) of developing HSR for prednisolone-use was calculated with and without stratification by NVP and/or HU. Logistic regression was performed to identify risk factors for developing HSR.. Of the 229 patients 115 were randomized to prednisolone and 114 to no-prednisolone; 19 (17%) and 11 (10%) patients, respectively, developed HSR. The expected prevention of HSR by prednisolone use was not observed. In fact use of prednisolone showed an increased risk for HSR although this did not reach statistical significance [OR, 1.82; 95% confidence interval (CI), 0.82-4.03]. There was a higher incidence of HSR in the NVP group than in the non-NVP group (20% versus 6%; P = 0.002). An additional risk factor identified in a multivariate logistic model was a high baseline CD4 cell count (OR, 1.26 per 100 x 10(6) cells/l increase; 95% CI, 1.06-1.51).. The simultaneous start of ABC and NVP in first-line antiretroviral regimens should be avoided because of a high (20%) incidence of HSR. Short-term therapy with prednisolone did not prevent HSR in patients using ABC with or without NVP.

Topics: Adult; Anti-HIV Agents; Anti-Inflammatory Agents; Dideoxynucleosides; Drug Hypersensitivity; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Nevirapine; Prednisolone; Reverse Transcriptase Inhibitors

Abacavir is a nucleoside reverse transcriptase inhibitor that is used as a component of the antiretroviral treatment regimen in the management of the human immunodeficiency virus for both adults and children. It is efficacious, but its use may be limited by a hypersensitivity reaction linked with the HLA-B*57:01 genotype. HLA-B*57:01 has been reported to be rare in African populations. Because of the nature of its presentation, abacavir hypersensitivity is prone to late diagnosis and treatment, especially in settings where HLA-B*57:01 genotyping is not routinely done.. We report a case of a severe hypersensitivity reaction in a 44-year-old Kenyan female living with the human immunodeficiency virus and on abacavir-containing antiretroviral therapy. The patient presented to the hospital after recurrent treatment for a throat infection with complaints of fever, headache, throat ache, vomiting, and a generalized rash. Laboratory results evidenced raised aminotransferases, for which she was advised to stop the antiretrovirals that she had recently been started on. The regimen consisted of abacavir, lamivudine, and dolutegravir. She responded well to treatment but was readmitted a day after discharge with vomiting, severe abdominal pains, diarrhea, and hypotension. Her symptoms disappeared upon admission, but she was readmitted again a few hours after discharge in a hysterical state with burning chest pain and chills. Suspecting abacavir hypersensitivity, upon interrogation she reported that she had taken the abacavir-containing antiretrovirals shortly before she was taken ill. A sample for HLA-B*57:01 was taken and tested positive. Her antiretroviral regimen was substituted to tenofovir, lamivudine, and dolutegravir, and on subsequent follow-up she has been well.. Clinicians should always be cognizant of this adverse reaction whenever they initiate an abacavir-containing therapy. We would recommend that studies be done in our setting to verify the prevalence of HLA-B*57:01.

Topics: Adult; Anti-HIV Agents; Anti-Retroviral Agents; Child; Dideoxynucleosides; Drug Hypersensitivity; Female; HIV Infections; Humans; Kenya; Lamivudine; Vomiting

Based on recent genome-wide association studies, abacavir-induced hypersensitivity is highly associated with human leukocyte antigen (HLA)-B*57:01 allele. However, the underlying mechanism of this occurrence is unclear. To investigate the underlying mechanism, we developed HLA-B*57:01 transgenic mice and found that application of abacavir could cause CD8 T cell activation with elevation in PD1 expression; however, severe skin hypersensitivity was not observed. To eliminate the immunosuppressive effect of PD1, HLA-B*57:01 transgenic/PD1 knockout (01Tg/PD1) mice were generated by mating HLA-B*57:01 transgenic mice and PD1 knockout mice. Thereafter, 01Tg/PD1 mice were treated with abacavir. Similar to the above results, severe skin hypersensitivity was not observed. Therefore, we treated 01Tg/PD1 mice with an anti-CD4 antibody to deplete CD4 T cells, followed by abacavir topically and orally. Severe abacavir-induced skin hypersensitivity was observed in 01Tg/PD1 mice after depletion of CD4 T cells, in addition to significant CD8 T cell activation and dendritic cell maturation. Taken together, we succeeded in reproducing severe skin hypersensitivity in a mouse model. And we found that through the combined depletion of PD1 and CD4 T cells, CD8 T cells could be activated and could proceed to clonal proliferation, which is promoted by mature dendritic cells, thereby eventually inducing severe skin hypersensitivity.

Topics: Animals; Anti-HIV Agents; CD8-Positive T-Lymphocytes; Dendritic Cells; Dideoxynucleosides; Disease Models, Animal; Drug Eruptions; Drug Hypersensitivity; HLA-B Antigens; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Programmed Cell Death 1 Receptor

Immune-mediated drug hypersensitivity reactions are an important source of iatrogenic morbidity and mortality. Human leukocyte antigen (HLA)-B*57:01, HLA-B*15:02, HLA-A*31:01, and HLA-B*58:01 constitute established risk factors and preemptive genotyping of these HLA alleles in patients prior to the initiation of abacavir, carbamazepine, and allopurinol-based therapies can prevent toxicity and improve patient outcomes. However, the cost-effectiveness of preemptive HLA testing has only been evaluated in the United States and few countries in Europe and Asia. In this study, we consolidated HLA genotypes from 3.5-6.4 million individuals across up to 74 countries and modeled the country-specific cost-effectiveness of genetic testing. We find major ethnogeographic differences in risk allele prevalence, which translated into pronounced differences in the number of patients needed to test to prevent one case of severe hypersensitivity reactions between countries and populations. At incremental cost-effectiveness ratio thresholds of $40,000, testing of HLA-B*57:01 in patients initiating abacavir was cost-effective in the majority of countries with potential exceptions of East Asia, Saudi Arabia, Ghana, and Zimbabwe. For carbamazepine, preemptive genotyping of HLA-B*15:02 is only cost-effective across most of East and South Asia, whereas HLA-A*31:01 testing is likely to be cost-effective globally. Testing of HLA-B*58:01 is more likely to be cost-effective throughout Africa and Asia compared with Europe and the Americas. We anticipate that this data set can serve as an important resource for clinicians and health economists to guide clinical decision making and inform public healthcare strategies.

Topics: Alleles; Allopurinol; Asia; Carbamazepine; Cost-Benefit Analysis; Dideoxynucleosides; Drug Hypersensitivity; Europe; Genetic Testing; Genotype; HLA Antigens; Humans; Pharmacogenetics; Pharmacogenomic Testing

Abacavir (ABC) is an HIV nucleotide-analogue reverse transcriptase inhibitor that can produce a severe hypersensitivity reaction (ABC-HSR) in about 5% of the patients. The HLA-B*57:01 allele is associated with the development of ABC-HSR. Therefore, HLA-B*57:01 genotyping is required prior to the prescription of ABC. The technique routinely used in our laboratory is the sequence-specific oligonucleotide probes (SSOP) reverse hybridization method followed by Sanger sequencing. This technique is time-consuming and expensive. The single-nucleotide polymorphism (SNP) HCP5 rs2395029 was described to be in complete linkage disequilibrium with HLA-B*57:01. In this study, we aimed to assess the linkage disequilibrium between HCP5 rs2395029 and HLA-B*57:01 in patients receiving medical assistance at our hospital. We selected 226 HIV-infected patients from our hospital who had been routinely genotyped since 2009 with the SSOP and Sanger sequencing method: 49 HLA-B*57:01 positives and 177 negatives. We genotyped them for HCP5 rs2395019 by real time PCR (qPCR). We exploratory performed two copy number variation assays flanking HCP5 rs2395019 to explore possible deletions that could break the linkage disequilibrium with HLA-B*57:01. The concordance between HLA-B*57:01 and the HCP5 rs2395029 G allele was absolute, with a specificity and sensitivity of 100% (95% confidence interval: 93.0-100.0% and 98.0-100.0%, respectively) and estimated positive and negative predictive values of 84.4% (48.1-93.9%) and 99.9% (99.4-100.0%), respectively. No deletions were found at HCP5 flanking regions. The duration and cost of the SSOP-based method was considerably higher than the SNP-based method. Therefore, the HCP5 rs2395029 genotyping method may be alternatively used in the clinical practice.

Topics: Alleles; Anti-HIV Agents; Dideoxynucleosides; DNA Copy Number Variations; Drug Hypersensitivity; Genotype; HIV Infections; HLA-B Antigens; Humans; Linkage Disequilibrium; Polymorphism, Single Nucleotide; RNA, Long Noncoding

Abacavir hypersensitivity syndrome can occur in individuals expressing the HLA-B*57:01 major histocompatibility complex class I allotype when utilising the drug abacavir as a part of their anti-retroviral regimen. The drug is known to bind within the HLA-B*57:01 antigen binding cleft, leading to the selection of novel self-peptide ligands, thus provoking life-threatening immune responses. However, the sub-cellular location of abacavir binding and the mechanics of altered peptide selection are not well understood. Here, we probed the impact of abacavir on the assembly of HLA-B*57:01 peptide complexes. We show that whilst abacavir had minimal impact on the maturation or average stability of HLA-B*57:01 molecules, abacavir was able to differentially enhance the formation, selectively decrease the dissociation, and alter tapasin loading dependency of certain HLA-B*57:01-peptide complexes. Our data reveals a spectrum of abacavir mediated effects on the immunopeptidome which reconciles the heterogeneous functional T cell data reported in the literature.

Topics: Anti-HIV Agents; Cell Line; Dideoxynucleosides; Drug Hypersensitivity; HLA-B Antigens; Humans; Kinetics; Lymphocyte Activation; T-Lymphocytes

The presence of the human leukocyte antigen HLA-B*57:01 is associated with the development of a hypersensitivity reaction to abacavir (ABC). Limited data exist on HLA-B*57:01 prevalence in individuals with HIV-1 in Africa. This study aimed to estimate HLA-B*57:01 prevalence in individuals with HIV-1 in West and Central Africa.. A cross-sectional study was conducted in four countries in West and central Africa (Burkina-Faso, Côte d'Ivoire, Gabon, and Togo) from January 2016 to February 2020 to determine the status of HLA-B*57:01 in adults with HIV-1. The presence of HLA-B*57:01 was determined by using Single Specific Primer-Polymerase Chain Reaction (SSP-PCR) in blood samples. Prevalence rates were stratified based on country.. A total of 4016 (69.8% women) individuals with HIV were enrolled. Their median age was 45, and the interquartile range was 38-52. We included 500 (12.4%) patients in Burkina-Faso, 1453 (36.2%) in Côte d'Ivoire, 951 (23.7%) in Gabon, and 1112 (27.7%) in Togo. The overall HLA-B*57:01 prevalence was 0.1% [95% CI: 0.0-0.2%]. The prevalence of HLA-B*57:01 was similar according to the four countries. Only one case was reported in each country except Togo, with no cases.. HLA-B*57:01 prevalence is low in individuals with HIV in West and central Africa, and there is no difference among countries. This study does not confirm the utility of HLA-B*57:01 allele testing for abacavir use in this region.

Topics: Adult; Africa, Central; Africa, Western; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; HIV Infections; HIV-1; HLA-B Antigens; Humans; Middle Aged; Prevalence

Abacavir is associated with hypersensitivity reactions in individuals positive for the HLA-B*57:01 allele. The drug binds within the peptide binding groove of HLA-B*57:01 altering peptides displayed on the cell surface. Presentation of these HLA-abacavir-peptide complexes to T-cells is hypothesized to trigger a CD8. Seventeen abacavir analogues were synthesized and cytokine secretion from abacavir/abacavir analogue-responsive CD8. Abacavir and ten analogues stimulated CD8. Alteration of the chemical constitution of abacavir generates analogues that retain a degree of pharmacological activity, but have variable ability to activate T-cells. Modelling and immunopeptidome analysis delineate how drug HLA-B*57:01 binding and peptide display by antigen presenting cells relate to the activation of CD8

Topics: CD8-Positive T-Lymphocytes; Dideoxynucleosides; Drug Hypersensitivity; HLA-B Antigens; Humans; Molecular Docking Simulation; Structure-Activity Relationship

Carriage of human leukocyte antigen (HLA)-B*57:01 allele increases the risk of abacavir hypersensitivity reaction. Therefore, since 2008 HIV treatment guidelines recommend HLA-B*57:01 screening before abacavir administration, greatly reducing hypersensitivity reaction rate. However, clinically suspected abacavir-related hypersensitivity reactions are described in allele non-carriers. Major aim of this study was to evaluate the relationship between HLA-B*57:01 pattern and abacavir-related hypersensitivity reaction, focusing on hypersensitivity reaction prevalence in allele non-carriers.. We included all outpatients aged >18 years old with HIV infection and known HLA-B*57:01 pattern, followed at our Department from January 2000 until December 2017. Patients were divided according to HLA-B*57:01 pattern and first antiretroviral treatment prescribed (containing or not abacavir) as follows: HLA-B*57:01 allele carriers treated with abacavir and HLA-B*57:01 allele non-carriers treated with abacavir. We considered all adverse events reported during first abacavir administration, differentiating between confirmed hypersensitivity reactions and non-hypersensitivity reactions, according to abacavir hypersensitivity reaction definition included in the abacavir EU Summary of Product Characteristics and the US Prescribing Information.. A total of 3144 patients had a known HLA-B*57:01 pattern. About 5.4% of them showed allele polymorphism; Caucasian ethnicity was the most represented. In this cohort, 1801 patients were treated with a first abacavir-containing regimen (98.2% of them was represented by allele non-carriers). 191 out of 1801 patients discontinued abacavir because of toxicity/intolerance; among them 107 described adverse events fulfilled the criteria of confirmed abacavir hypersensitivity reaction (22/32 allele-positive patients and 85/1769 allele-negative patients). After having experienced a confirmed abacavir hypersensitivity reaction, abacavir was re-administered to eight HLA-B*57:01 negative patients. Seven of them re-experienced a syndrome consistent with hypersensitivity reaction, finally leading to drug discontinuation. Overall, no fatal reactions were described.. Not all abacavir-related side effects occur as a result of classic HLA-B*57:01-mediated hypersensitivity reaction, as they can develop irrespective of HLA-B*57:01 status. Clinical vigilance must be an essential part of the management of individuals starting abacavir, at any time during treatment. In a 'real-life' setting, clinical diagnosis of suspected abacavir hypersensitivity reaction in allele non-carriers remains crucial for further clinical decision making.

Topics: Adult; Anti-HIV Agents; Clinical Decision-Making; Dideoxynucleosides; Drug Hypersensitivity; Female; Genetic Predisposition to Disease; Haplotypes; HIV Infections; HLA-B Antigens; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide

Hypersensitivity drug reactions (HDRs) are common among drugs, despite this, there are no validated in vitro or in vivo methods for screening the sensitizing potential of drugs in the preclinical phase. We previously developed the THP-1 activation assay, based on CD86 upregulation and IL-8 production, for the in vitro identification of drugs able to induce selective dendritic cell activation. In this paper, we investigated the predictive capacity of the method toward drugs associated with HDRs for which a correlation with specific human leukocyte antigens (HLA) have been demonstrated. For that purpose, abacavir, carbamazepine and clozapine were used. Metformin was used as negative control. Dose- and time-course experiments were conducted. The surface markers CD86, CD54 and HLA-DR were evaluated by flow cytometry analysis, whereas IL-8 release by ELISA. Abacavir, carbamazepine and clozapine gave positive results with CD86 upregulation and/or IL-8 release, with abacavir also inducing HLA-DR. The test reveals the ability of drugs to induce dendritic cell activation (signals 1/2), that preceded the adaptive immune response, which will be manifested only in a minority of patients carrying the specific HLA genotypes. The idea is to integrate this simple method during drug development to identify the potential of drugs to induce hypersensitivity reactions in the pre-clinical phase.

Topics: B7-2 Antigen; Carbamazepine; Cell Survival; Clozapine; Dideoxynucleosides; Drug Hypersensitivity; Genotype; HLA Antigens; Humans; Intercellular Adhesion Molecule-1; Interleukin-8; Metformin; THP-1 Cells

Pre-treatment screening of individuals for human leukocyte antigens (HLA) HLA-B*57:01 is recommended for the prevention of life-threatening hypersensitivity reactions to abacavir, a drug widely prescribed for HIV treatment. However, the implementation of screening in clinical practice is hindered by the slow turnaround time and high cost of conventional HLA genotyping methods. We have developed a biosensor platform using interdigitated electrode (IDE) functionalized with a monoclonal antibody to detect cells expressing HLA-B*57:01. This platform was evaluated using cell lines and peripheral blood mononuclear cells expressing different HLA-B alleles. The functionalized IDE sensor was able to specifically capture HLA-B*57:01 cells, resulting in a significant change in the impedance magnitude in 20 min. This IDE platform has the potential to be further developed to enable point-of-care HLA-B*57:01 screening.

Topics: Alleles; Antibodies, Immobilized; Antibodies, Monoclonal; Biosensing Techniques; Dideoxynucleosides; Drug Hypersensitivity; Electrochemical Techniques; Electrodes; HIV Infections; HLA-B Antigens; Humans; Leukocytes, Mononuclear

Topics: Aged; Anti-HIV Agents; Arthralgia; CD8-Positive T-Lymphocytes; Dideoxynucleosides; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Gene Expression Profiling; Headache; HLA-B Antigens; Humans; Immunologic Memory; Lymphocyte Activation; Male; Myalgia; Patch Tests; Single-Cell Analysis; Skin

HLA-B*57:01 screening was added to clinical care guidelines in 2008 to reduce the risk of hypersensitivity reaction from abacavir. The uptake of HLA-B*57:01 screening and incidence of hypersensitivity reaction were assessed in a prospective clinical cohort in the United States to evaluate the effectiveness of this intervention.. We included all patients initiating an abacavir-containing regimen for the first time in the pre-HLA-B*57:01 screening period (January 1, 1999 to June 14, 2008) or the post-HLA-B*57:01 screening period (June 15, 2008 to January 1, 2016). Yearly incidence of both HLA-B*57:01 screening and physician panel-adjudicated hypersensitivity reactions were calculated and compared.. Of the 9619 patients eligible for the study, 33% initiated abacavir in the pre-screening period and 67% in the post-screening period. Incidence of HLA-B*57:01 screening prior to abacavir initiation increased from 43% in 2009 to 84% in 2015. The incidence of definite or probable hypersensitivity reactions decreased from 1.3% in the pre-screening period to 0.8% in 2009 and further to 0.2% in 2015 in the post-screening period.. Frequency of HLA-B*57:01 screening increased steadily since its first inclusion in treatment guidelines in the United States. This increase in screening was accompanied by a decreasing incidence of definite or probable hypersensitivity reactions over the same period. However, a considerable proportion of patients initiating abacavir were not screened, representing a failed opportunity to prevent hypersensitivity reactions. Where HLA-B*57:01 screening is standard of care, patients should be confirmed negative for this allele before starting abacavir treatment.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Drug Hypersensitivity; Electronic Health Records; Female; HIV Infections; HLA-B Antigens; Humans; Male; Mass Screening; Middle Aged; Practice Guidelines as Topic; Prospective Studies

Topics: Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HIV-1; Humans; Immunologic Memory

Abacavir administration is associated with drug-induced hypersensitivity reactions in HIV+ individuals expressing the HLA-B*57:01 allele. However, the immunological effects of abacavir administration in an HLA-B57 mismatched transplantation setting have not been studied. We hypothesized that abacavir exposure could induce de novo HLA-B57-specific allorecognition. HIV-specific CD8 T cell clones were generated from HIV+ individuals, using single cell sorting based on HIV peptide/HLA tetramer staining. The T cell clones were assayed for alloreactivity against a panel of single HLA-expressing cell lines, in the presence or absence of abacavir. Cytokine assay, CD137 upregulation, and cytotoxicity were used as readout. Abacavir exposure can induce de novo HLA-B57 allorecognition by HIV-specific T cells. A HIV Gag RK9/HLA-A3-specific T cell did exhibit interferon-γ production, CD137 upregulation, and cytolytic effector function against allogeneic HLA-B57, but only in the presence of abacavir. Allorecognition was specific to the virus specificity, HLA restriction, and T cell receptor TRBV use of the T cell. We provide proof-of-principle evidence that administration of a drug could induce specific allorecognition of mismatched HLA molecules in the transplant setting. We suggest that HIV-seropositive recipients of an HLA-B57 mismatched graft should not receive abacavir until further studies are completed.

Topics: Alleles; Anti-HIV Agents; CD8-Positive T-Lymphocytes; Cytokines; Dideoxynucleosides; Drug Hypersensitivity; gag Gene Products, Human Immunodeficiency Virus; Histocompatibility Testing; HIV Infections; HIV Seropositivity; HLA-B Antigens; Humans; Interferon-gamma; Leukocytes, Mononuclear; Receptors, Antigen, T-Cell; T-Lymphocytes; Tumor Necrosis Factor Receptor Superfamily, Member 9

Topics: Cost-Benefit Analysis; Dideoxynucleosides; Drug Hypersensitivity; Genetic Markers; Genetic Testing; Genotype; Genotyping Techniques; HIV Infections; HLA-B Antigens; Humans; Polymorphism, Genetic; Reverse Transcriptase Inhibitors; Risk Assessment; Singapore

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, but observed no difference in either the conformations, nor degree of flexibility when compared to abacavir-unbound systems. Our results support hypersensitivity models in which abacavir-binding alters the conformational ensemble of neopeptides, so as to favour exposed peptide surfaces that are no longer recognized as self by circulating CD8+ T cells, and are conducive 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.

Topics: Amino Acid Sequence; Anti-HIV Agents; Binding Sites; Crystallography, X-Ray; Dideoxynucleosides; Drug Hypersensitivity; Genetic Predisposition to Disease; HLA-B Antigens; Humans; Models, Molecular; Molecular Dynamics Simulation; Oligopeptides; Protein Binding; Protein Conformation

To determine the prevalence of HLA-B*5701 allele in HIV-infected children, and to find its association with Abacavir hypersensitivity.. Children (2 to 18 y) already on, or to be initiated on Abacavir were included for PCR sequencing to detect HLA-B*5701.. proportion with HLA B*5701 allele and hypersensitivity with Abacavir. Abacavir was stopped if patient tested positive for HLA-B*5701 allele.. 100 children (median age 11 y) were enrolled; 10 were already on Abacavir. HLA-B*5701 positivity was observed in 11 (11%) children. Two of these 11 children developed hypersensitivity after initiation of Abacavir. Abacavir was thereafter stopped in all who tested HLA-B*5701 positive, irrespective of the development of hypersensitivity reaction.. HLA-B*5701 allele was present in 11 (11%) of HIV-infected children, of which two developed Abacavir hypersensitivity. None of the patients without the allele developed hypersensitivity.

Topics: Anti-HIV Agents; Child; Child, Preschool; Dideoxynucleosides; Drug Hypersensitivity; Female; HIV Infections; HLA-B Antigens; Humans; India; Male; Prospective Studies

Five to eight per cent of HIV-positive individuals initiating abacavir (ABC) experience potentially fatal hypersensitivity reactions (HSRs). We sought to describe the proportion of individuals initiating ABC and to describe the incidence and factors associated with HSR among those prescribed ABC.. We calculated the proportion of EuroSIDA individuals receiving ABC-based combination antiretroviral therapy (cART) among those receiving cART after 1 January 2009. Poisson regression was used to identify demographic, and current clinical and laboratory factors associated with ABC utilization and discontinuation.. Between 2009 and 2016, of 10 076 individuals receiving cART, 3472 (34%) had ever received ABC-based cART. Temporal trends of ABC utilization were also heterogeneous, with 28% using ABC in 2009, dropping to 26% in 2010 and increasing to 31% in 2016, and varied across regions and over time. Poisson models showed lower ABC utilization in older individuals, and in those with higher CD4 cell counts, higher cART lines, and prior AIDS. Higher ABC utilization was associated with higher HIV RNA and poor renal function, and was more common in Central-East and Eastern Europe and lowest during 2014. During 779 person-years of follow-up (PYFU) in 2139 individuals starting ABC after 1 January 2009, 113 discontinued ABC within 6 weeks of initiation for any reason [incidence rate (IR) 14.5 (95% confidence interval (CI) 12.1, 17.5) per 100 PYFU], 13 because of reported HSR [IR 0.3 (95% CI 0.1, 1.0) per 100 PYFU] and 35 because of reported HSR/any toxicity [IR 4.5 (95% CI 3.2, 6.3) per 100 PYFU]. There were no factors significantly associated with ABC discontinuation because of reported HSR/any toxicity.. ABC remains commonly used across Europe and the incidence of discontinuation because of reported HSR was low in our study population.

Topics: Adult; Anti-HIV Agents; Cohort Studies; Dideoxynucleosides; Drug Hypersensitivity; Drug Utilization; Europe; Female; HIV Infections; Humans; Incidence; Longitudinal Studies; Male; Middle Aged; Poisson Distribution

Topics: Anti-HIV Agents; Cardiovascular Diseases; Dideoxynucleosides; Drug Hypersensitivity; Forecasting; Genome-Wide Association Study; Humans; Pharmacogenetics

The discovery of HLA-B*57:01-associated abacavir hypersensitivity is a translational success story that eliminated adverse reactions to abacavir through pretreatment screening and defined a mechanistic model of an altered peptide repertoire. In this issue of the JCI, Cardone et al. have developed an HLA-B*57:01-transgenic mouse model and demonstrated that CD4+ T cells play a key role in mediating tolerance to the dramatically altered endogenous peptide repertoire induced by abacavir and postulate a known mechanism by which CD4+ T cells suppress DC maturation. This report potentially explains why 45% of HLA-B*57:01 carriers tolerate abacavir and provides a framework for future studies of HLA-restricted, T cell-mediated drug tolerance and hypersensitivity.

Topics: Animals; Dideoxynucleosides; Drug Hypersensitivity; Drug Tolerance; HLA-B Antigens; Mice; Mice, Transgenic; Peptides

Adverse drug reactions (ADRs) are a major obstacle to drug development, and some of these, including hypersensitivity reactions to the HIV reverse transcriptase inhibitor abacavir (ABC), are associated with HLA alleles, particularly HLA-B*57:01. However, not all HLA-B*57:01+ patients develop ADRs, suggesting that in addition to the HLA genetic risk, other factors may influence the outcome of the response to the drug. To study HLA-linked ADRs in vivo, we generated HLA-B*57:01-Tg mice and show that, although ABC activated Tg mouse CD8+ T cells in vitro in a HLA-B*57:01-dependent manner, the drug was tolerated in vivo. In immunocompetent Tg animals, ABC induced CD8+ T cells with an anergy-like phenotype that did not lead to ADRs. In contrast, in vivo depletion of CD4+ T cells prior to ABC administration enhanced DC maturation to induce systemic ABC-reactive CD8+ T cells with an effector-like and skin-homing phenotype along with CD8+ infiltration and inflammation in drug-sensitized skin. B7 costimulatory molecule blockade prevented CD8+ T cell activation. These Tg mice provide a model for ABC tolerance and for the generation of HLA-B*57:01-restricted, ABC-reactive CD8+ T cells dependent on both HLA genetic risk and immunoregulatory host factors.

Topics: Animals; Anti-HIV Agents; CD8-Positive T-Lymphocytes; Dideoxynucleosides; Disease Models, Animal; Drug Hypersensitivity; Drug Tolerance; Drug-Related Side Effects and Adverse Reactions; Female; HLA-B Antigens; Humans; In Vitro Techniques; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Reverse Transcriptase Inhibitors

The presence of the HLA-B*57:01 allele in HIV-infected subjects is associated with a higher risk of abacavir-associated hypersensitivity reaction (ABC HSR). HLA-B*57:01 allele prevalence varies in different populations, but HLA-B*57:01 testing with immunological confirmation has had a negative predictive value for ABC HSR between 97 and 100%.. In the ASSURE study (EPZ113734), the HLA-B*57:01 prevalence in virologically suppressed, antiretroviral treatment-experienced, HIV-infected subjects from the United States, including Puerto Rico, was assessed.. Three hundred eighty-five subjects were screened; 13 were HLA-B*57:01 positive and 372 were negative. Only HLA-B*57:01-negative, abacavir-naive subjects were eligible to enroll into the ASSURE trial. Eleven of the 13 subjects who possessed the HLA-B*57:01 allele were white, the other 2 were African-American. There was no geographic clustering of HLA-B*57:01-positive subjects, and the incidence correlated roughly with those states with the greatest numbers of subjects screened. Similarly, there was no statistically significant correlation between subjects who possessed or lacked the allele and age, gender, ethnicity or CD4+ T-cell numbers. The incidence of ABC HSR following abacavir initiation was also evaluated. Only 1 of 199 HLA-B*57:01-negative subjects (an African-American male) randomized to receive abacavir-containing treatment developed symptoms consistent with suspected ABC HSR; ABC HSR was not immunologically confirmed.. These findings confirm the utility of HLA-B*57:01 allele testing to reduce the frequency of ABC HSR. The prevalence of HLA-B*57:01 positivity was higher in white than in African-American subjects. In HLA-B*57:01-negative subjects, suspected ABC HSR is very rare, but should lead to discontinuation of abacavir when ABC HSR cannot be definitively excluded from the differential diagnosis.. The ASSURE (EPZ113734) study was registered on ClinicalTrials.gov registration on April 8th 2010 and the registration number is NCT01102972.

Topics: Adult; Anti-HIV Agents; Black or African American; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Hypersensitivity; Female; Gene Frequency; HIV Infections; HLA-B Antigens; Humans; Male; Middle Aged; United States; White People

Abacavir is an effective antiretroviral drug and one of the most commonly used nucleoside reverse transcriptase inhibitors in Serbia. А percentage of the treated patients experience a potentially life-threatening hypersensitivity reaction, which was shown to be associated with the presence of the class I MHC allele, HLA-B*57:01; hence genotyping for HLA-B*57:01 prior to starting abacavir is nowadays recommended in international HIV treatment guidelines. In Serbia, this testing became available in 2013. This study was designed to estimate the prevalence of the HLA-B*57:01 allele in Serbian HIV-1-infected patients. The presence of the HLA-B*57:01 allele was analyzed in 273 HIV-1-infected patients aged 18 years or more, who were abacavir naïve. Buccal swab samples were obtained from all participants and assayed for the presence of HLA-B*57:01 using a commercially available HLA-B*57:01 real-time PCR kit. The presence of the HLA-B*57:01 allele was found in 22 of 273 tested individuals (8%; 95% CI 5.4-11.9%). This is the first study that estimated the HLA-B*57:01 prevalence among HIV-infected patients in Serbia. The very high prevalence of HLA-B*57:01 found in our study strongly supports HLA-B*57:01 genotyping, which should be implemented prior to the initiation of an abacavir-containing therapy to reduce the risk of potentially life-threatening hypersensitivity reactions.

Topics: Adult; Alleles; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Female; Genotype; Genotyping Techniques; HIV Infections; HIV-1; HLA-B Antigens; Humans; Male; Middle Aged; Reverse Transcriptase Inhibitors; Serbia; Young Adult

Antiretroviral drug hypersensitivity in HIV patients is common. Publications have shown that Abacavir (ABC) patch testing is useful in confirming ABC hypersensitivity in 24-50% of cases with a 100% sensitivity of HLA-B*5701 in patch test positive cases. However, Nevirapine (NVP) patch testing has not been reported.. (1) To evaluate the usefulness and safety of NVP patch testing in Thai HIV patients with NVP hypersensitivity. (2) To assess the correlation of positive patch tests with HLA-B*3505.. Patients were classified into two groups: (1) study group of 20 HIV NVP hypersensitivity patients and (2) control group of 15 volunteers without NVP hypersensitivity. Both groups were patch tested with purified and commercialized form of NVP in various vehicles.. Two HIV patients with NVP hypersensitivity were patch test positive. All controls tested negative. Three HIV patients were positive for HLA-B*3505 and the two patients with positive patch testing were both HLA-B*3505 positive.. NVP patch testing in Thai HIV patients is safe and can be used to help confirm the association between NVP and hypersensitivity skin reactions. NVP patch test results significantly correlated with HLA-B*3505. The sensitivity of HLA-B*3505 for positive patch test was 100%.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; HIV; Humans; Nevirapine; Patch Tests; Predictive Value of Tests; Thailand

The progressing discovery of genetic variants associated with drug-related adverse events has raised expectations for pharmacogenetic tests to improve drug efficacy and safety. To further the use of pharmacogenetics in health care, tests with sufficient potential to improve efficacy and safety, as reflected by good clinical validity and population impact, need to be identified. The potential benefit of pharmacogenetic tests is often concluded from the strength of the association between the variant and the adverse event; measures of clinical validity are generally not reported. This paper describes measures of clinical validity and potential population health impact that can be calculated from association studies. We explain how these measures are influenced by the strength of the association and by the frequencies of the variant and the adverse event. The measures are illustrated using examples of testing for HLA-B*5701 associated with abacavir-induced hypersensitivity and SLCO1B1 c.521T>C (*5) associated with simvastatin-induced adverse events.

Topics: Dideoxynucleosides; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Genetic Testing; Genetic Variation; HLA-B Antigens; Humans; Pharmacogenetics; Simvastatin

We report this case to highlight the possibility of a severe hypersensitivity reaction as an important potential consequence of couples, living with HIV, sharing anti-retroviral treatment. An HIV-1 positive and carrier of HLA-B*57:01 allele, treatment experienced man was commenced one pill Regimen Stribild (tenofovir, emtricitabine, elvitegravir and cobicistat) in July 2015. On running short of medication, he admitted to sharing his partner's treatment (Triumeq; abacavir, lamivudine and dolutegravir). On the second occasion, re-introduction resulted in whole body rash 4 h post dose and was associated with fever, respiratory symptoms, headache and vomiting. On examination, he was pyrexic, tachyponeic, tachycardiac and hypotensive. Hypersensitivity to abacavir can cause significant morbidity. Re-challenge can result in a more rapid, severe and potentially life-threatening reaction. This potentially could become an increasing problem with more couples, living with HIV, sharing medication.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Combinations; Drug Hypersensitivity; Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; HLA-B Antigens; Humans; Lamivudine; Oxazines; Piperazines; Pyridones

Abacavir is currently recommended as a part of first line regimen by National AIDS Control Organization. The objective of this study was to observe the incidence of clinically diagnosed abacavir Hypersensitivity reaction (HSR) among children on abacavir based therapy in the National program. In this observational study, all children started on abacavir were included and HSR reaction was diagnosed clinically as per National guidelines. HLA- B*5701 testing was done in children diagnosed with clinical abacavir HSR. Among 101 children started on abacavir during the study period, 8 [7.9 % (95 % CI 3.5-15.0 %)] children developed clinically diagnosed abacavir HSR. All children with concomitant illness (4/8) were HLA-B*5701 negative. Only 2 (25 %, 2/8) carried HLA-B*5701 allele. Fever with abdominal symptoms as compared to respiratory symptoms were more common in HLA-B*5701 positive cases. Overdiagnosis of clinically diagnosed abacavir HSR is common and could be decreased by treating concomitant illness before starting abacavir.

Topics: Anti-HIV Agents; Child; Child, Preschool; Dideoxynucleosides; Drug Hypersensitivity; Female; HIV Infections; Humans; India; Male

Since the HLA-B*57:01 allele is strongly associated with abacavir hypersensitivity reaction, testing for the presence of HLA-B*57:01 is mandatory before administration of abacavir. While HLA-B*57:01 testing is usually provided by pharmacogenetics, genetics or blood transfusion services, clinical virology laboratories can be an optimal opportunity for HLA-B*57:01 testing since they receive blood samples for routine HIV monitoring and have the expertise for convenient and less expensive PCR-based point mutation assays.. The Italian HLA-B*57:01 Network gathers accredited clinical virology laboratories offering HLA-B*57:01 testing in Italy with the aim to share protocols, test new methods, develop and maintain external quality assurance (EQA) programs.. A panel of 9HLA-B*57:01-positive and 16HLA-B*57:01-negative frozen blood samples were blindly distributed to 10 units including 9 clinical virology laboratories and one reference pharmacology laboratory. Each laboratory was free to use its own routine method for DNA extraction and HLA-B*57:01 testing.. DNA was extracted by automated workstations in 6 units and by manual spin columns in 4. Eight units used the Duplicα Real Time HLA-B*57:01 kit by Euroclone and two units used two different PCR homemade protocols. All the 10 units correctly identified all the 25 samples.. The first HLA-B*57:01 EQA program run in Italy showed that clinical virology units are equipped and proficient for providing HLA-B*57:01 testing by inexpensive assays easy to integrate into their routine.

Topics: Anti-HIV Agents; Clinical Laboratory Techniques; Dideoxynucleosides; Drug Hypersensitivity; Genotyping Techniques; HLA-B Antigens; Humans; Italy; Laboratory Proficiency Testing; Quality Assurance, Health Care

Since the beginning of this century, information on pharmacogenetics appears in the summary of product characteristics (SPC) of drugs. Pharmacogenetic tests particularly concern the enzymes involved in the metabolism of drugs, among which P450 cytochromes. Some patients known as poor metabolisers eliminate some drugs more slowly, causing overdoses and adverse drug reactions (ADRs). The best-known examples are AVK and VKORC1-CYP2C9 or clopidogrel and CYP2C19. In the USA, the tests are recommended before the introduction of these drugs to prevent the occurrence of ADRs. Other tests are also commonly performed to address the toxicity of certain anticancer drugs (DPYD-capecitabine, UGT1A1-irinotecan, TPMT 6-mercaptopurine). Pharmacogenetic testing is also available to identify HLA loci that are very strongly associated with the occurrence of immuno-allergic reactions to a specific drug. The best-known example is HLA-B*5701, strongly associated with hypersensitivity to abacavir, and this test is now always prescribed before the instatement of this drug.

Topics: Antineoplastic Agents; Cytochrome P-450 Enzyme System; Dideoxynucleosides; Drug Hypersensitivity; Drug Overdose; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmacogenetics; Pharmacovigilance

Most of the cost-effectiveness analyses are based on estimations to make decisions on the future implementation of a test. However, the model should be verified with real data to prove that previous estimations have been successfully fulfilled.. To study the economic impact of the systematic HLA-B*57:01 genotyping in preventing hypersensitivity reactions (HSRs) in the patient population of a tertiary-care hospital treated with abacavir (ABC) using retrospective data of 5 years of experience.. A retrospective study was carried out with two cohorts including 780 and 473 patients before and after the implementation of the systematic HLA-B*57:01 genotyping before ABC treatment. Cost-effectiveness analysis was carried out by the parameter 'cost per HSR avoided'. The clinical utility of the test was verified by evaluating the differences in HSR incidence between both cohorts. Finally, a sensitivity analysis including all variables was carried out.. In the population studied, systematic genotyping represents an additional cost of &OV0556;306 per HSR avoided. In the sensitivity analysis, pharmacological therapy cost is the major influencing factor found in the estimation of the 'cost per HSR avoided'. In terms of clinical utility, the incidence ratio was 0.040 (95% confidence interval 0.0009-0.2399) and statistically significant differences were found between both groups (P=1.40×10).. Retrospective data from 5 years of experience have confirmed the cost-effectiveness of the systematic genotyping in candidate patients for ABC therapy, and have shown that cost-effectiveness is a dynamic parameter closely linked to allele prevalence and pharmacological therapy costs.

Topics: Adult; Anti-HIV Agents; Cost-Benefit Analysis; Dideoxynucleosides; Drug Hypersensitivity; Female; Genotype; HIV Seropositivity; HIV-1; HLA-B Antigens; Humans; Male; Pharmacogenetics; Retrospective Studies

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Combinations; Drug Hypersensitivity; Drug Interactions; Drug Resistance, Viral; Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Emtricitabine, Rilpivirine, Tenofovir Drug Combination; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Lamivudine; Mental Disorders; Oxazines; Piperazines; Pyridones; Viral Load

Topics: Antidepressive Agents; Child; Dideoxynucleosides; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Evidence-Based Medicine; Genetic Testing; HIV Infections; HLA-B Antigens; Humans; Male; Mercaptopurine; Pharmacogenetics; Precision Medicine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Primaquine; Purine-Pyrimidine Metabolism, Inborn Errors; Succinylcholine; Warfarin

One of the most successful applications of pharmacogenetics research is the genetic screening for HLA-B*57:01, strongly associated with an increased risk to develop hypersensitivity reaction in HIV-positive patients following abacavir administration. Taking into consideration the limits of current genotyping methodologies, we have developed and validated (150 buccal swabs) an inexpensive pharmacogenetic approach for HLA-B*57:01 typing. In our assay DNA extraction and amplification are combined in one single step (direct PCR protocol), which is performed directly on the biological sample without the need of extraction and sequencing passages. The amplicons obtained by direct PCR can be easily separated on the agarose gel under ultraviolet. As per our results, the direct PCR represents a good alternative to the traditional methods of HLA-B*57:01 pharmacogenetic test, especially for those laboratories or countries where currently available approaches are often not available or not affordable. Furthermore it is an innovative approach, promoting a personalized, safer and cost-effective therapy.

Topics: Cost-Benefit Analysis; Dideoxynucleosides; Drug Hypersensitivity; Genetic Testing; Genotype; HIV Infections; HLA-B Antigens; Humans; Pharmacogenetics; Polymerase Chain Reaction; Reverse Transcriptase Inhibitors

Abacavir (ABC) is one of the more affordable antiretroviral drugs used for controlling HIV. Although with similar efficacy to current first-line drugs, its limited usage in Singapore can be attributed to its possible side effect of adverse hypersensitivity reactions (HSRs). HLA-B*5701 genotyping is a clinically relevant procedure for avoiding abacavir-induced HSRs. As patients who do not carry the risk allele are unlikely to develop HSRs, a simple rule can be developed to allow abacavir prescription for patients who are B*5701 negative. Here, we carry out a cost-effectiveness analysis of HLA-B*5701 genotyping before abacavir prescription in the context of the Singapore healthcare system, which caters predominantly to Han Chinese, Southeast-asian Malays, and South-asian Indians. In addition, we aim to identify the most cost-effective treatment regimen for HIV patients.. A decision tree model was developed in TreeAge. The model considers medical treatment and genotyping costs, genotyping test characteristics, the prevalence of the risk allele, reduction in the quality of life, and increased expenditure due to side effects and other factors, evaluating independently over early-stage and late-stage HIV patients segmented by drug contraindications.. The study indicates that genotyping is not cost-effective for any ethnicity irrespective of the disease stage, except for Indian patients with early-stage HIV who are contraindicated to tenofovir.. Abacavir (as first-line) without genotyping is the cheapest and most cost-effective treatment for all ethnicities except for early-stage Indian HIV patients contraindicated to tenofovir. The HLA-B*5701 frequency, the mortality rate from abacavir-induced HSRs, and genotyping costs are among the major factors influencing the cost-effectiveness.

Topics: Adult; Aged; Anti-HIV Agents; Cost-Benefit Analysis; Decision Support Techniques; Decision Trees; Dideoxynucleosides; Drug Hypersensitivity; Drug Prescriptions; Genotyping Techniques; Health Care Costs; HIV Infections; HIV-1; HLA-B Antigens; Humans; Life Expectancy; Middle Aged; Practice Patterns, Physicians'; Singapore

Fifty-five percent of individuals with HLA-B*57:01 exposed to the antiretroviral drug abacavir develop a hypersensitivity reaction (HSR) that has been attributed to naïve T-cell responses to neo-antigen generated by the drug. Immunologically confirmed abacavir HSR can manifest clinically in less than 48 hours following first exposure suggesting that, at least in some cases, abacavir HSR is due to re-stimulation of a pre-existing memory T-cell population rather than priming of a high frequency naïve T-cell population.. To determine whether a pre-existing abacavir reactive memory T-cell population contributes to early abacavir HSR symptoms, we studied the abacavir specific naïve or memory T-cell response using HLA-B*57:01 positive HSR patients or healthy controls using ELISpot assay, intra-cellular cytokine staining and tetramer labelling.. Abacavir reactive CD8+ T-cell responses were detected in vitro in one hundred percent of abacavir unexposed HLA-B*57:01 positive healthy donors. Abacavir-specific CD8+ T cells from such donors can be expanded from sorted memory, and sorted naïve, CD8+ T cells without need for autologous CD4+ T cells.. We propose that these pre-existing abacavir-reactive memory CD8+ T-cell responses must have been primed by earlier exposure to another foreign antigen and that these T cells cross-react with an abacavir-HLA-B*57:01-endogenous peptide ligand complex, in keeping with the model of heterologous immunity proposed in transplant rejection.

Topics: Anti-HIV Agents; Cross Reactions; Dideoxynucleosides; Drug Hypersensitivity; Epitopes, T-Lymphocyte; HIV Infections; HLA-B Antigens; Humans; Immunologic Memory; Immunophenotyping; Leukocytes, Mononuclear; Lymphocyte Count; Phenotype; T-Lymphocyte Subsets; Time Factors; Vaccination; Yellow Fever Vaccine

Abacavir is a nucleoside reverse transcriptase inhibitor used as part of combination antiretroviral therapy in HIV-1-infected patients. Because this drug can cause a hypersensitivity reaction that is correlated with the presence of the HLA-B*57:01 allotype, screening for the presence of HLA-B*57:01 is recommended before abacavir initiation. Different genetic assays have been developed for HLA-B*57:01 screening, each with specific sensitivity, turnaround time and assay costs. Here, a new real-time PCR (qPCR) based analysis is described and compared to sequence specific primer PCR with capillary electrophoresis (SSP PCR CE) on 149 patient-derived samples, using sequence specific oligonucleotide hybridization combined with high resolution SSP PCR as gold standard. In addition to these PCR based methods, a complementary approach was developed using flow cytometry with an HLA-B17 specific monoclonal antibody as a pre-screening assay to diminish the number of samples for genetic testing. All three assays had a maximum sensitivity of >99. However, differences in specificity were recorded, i.e. 84.3%, 97.2% and >99% for flow cytometry, qPCR and SSP PCR CE respectively. Our data indicate that the most specific and sensitive of the compared methods is the SSP PCR CE. Flow cytometry pre-screening can substantially decrease the number of genetic tests for HLA-B*57:01 typing in a clinical setting.

Topics: Alleles; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; DNA Primers; Drug Hypersensitivity; Electrophoresis, Capillary; Flow Cytometry; Gene Expression; Genetic Testing; HIV Infections; HIV-1; HLA-B Antigens; Humans; Nucleic Acid Hybridization; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Inhibitors; Sensitivity and Specificity

Hypersensitivity reaction to abacavir (ABC hypersensitivity syndrome, AHS) is strongly associated with the presence of the HLA-B*57:01 allele. This study was designed to estimate the prevalence of HLA-B*57:01 allele in Argentinean HIV-1 infected patients. We analyzed the presence of HLA-B*57:01 allele in 1646 HIV-1 infected patients from different regions of Argentina. This allele was detected in 81 patients; most of them corresponded to patients living in the central region of the country. The prevalence of HLA-B*57:01 was 4.9%, similar to other Caucasian populations and higher than other data reported for South American populations. This strongly supports screening for the presence of HLA-B*57:01 in abacavir treatment of HIV-1 in our country.

Topics: Adult; Alleles; Anti-HIV Agents; Argentina; Dideoxynucleosides; Drug Hypersensitivity; Female; Gene Expression; Gene Frequency; Genetic Testing; HIV Infections; HIV-1; HLA-B Antigens; Humans; Male; Middle Aged

Allergic reactions to drugs are a serious public health concern. In 2013, the Division of Allergy, Immunology, and Transplantation of the National Institute of Allergy and Infectious Diseases sponsored a workshop on drug allergy. International experts in the field of drug allergy with backgrounds in allergy, immunology, infectious diseases, dermatology, clinical pharmacology, and pharmacogenomics discussed the current state of drug allergy research. These experts were joined by representatives from several National Institutes of Health institutes and the US Food and Drug Administration. The participants identified important advances that make new research directions feasible and made suggestions for research priorities and for development of infrastructure to advance our knowledge of the mechanisms, diagnosis, management, and prevention of drug allergy. The workshop summary and recommendations are presented herein.

Topics: Carbamazepine; Dideoxynucleosides; Drug Hypersensitivity; Gene Expression; Haptens; HLA Antigens; Humans; Immunoglobulin E; National Institute of Allergy and Infectious Diseases (U.S.); Practice Guidelines as Topic; Receptors, Antigen, T-Cell; Stevens-Johnson Syndrome; Terminology as Topic; Translational Research, Biomedical; United States; Virus Diseases

Exposure to abacavir is associated with T-cell-mediated hypersensitivity reactions in individuals carrying human leukocyte antigen (HLA)-B57 : 01. To activate T cells, abacavir interacts directly with endogenous HLA-B57 : 01 and HLA-B57 : 01 expressed on the surface of antigen presenting cells. We have investigated whether chemical modification of abacavir can produce a molecule with antiviral activity that does not bind to HLA-B57 : 01 and activate T cells.. An interdisciplinary laboratory study using samples from human donors expressing HLA-B57 : 01. Researchers were blinded to the analogue structures and modelling data.. Sixteen 6-amino substituted abacavir analogues were synthesized. Computational docking studies were completed to predict capacity for analogue binding within HLA-B57 : 01. Abacavir-responsive CD8 clones were generated to study the association between HLA-B57 : 01 analogue binding and T-cell activation. Antiviral activity and the direct inhibitory effect of analogues on proliferation were assessed.. Major histocompatibility complex class I-restricted CD8 clones proliferated and secreted IFNγ following abacavir binding to surface and endogenous HLA-B57 : 01. Several analogues retained antiviral activity and showed no overt inhibitory effect on proliferation, but displayed highly divergent antigen-driven T-cell responses. For example, abacavir and N-propyl abacavir were equally potent at activating clones, whereas the closely related analogues N-isopropyl and N-methyl isopropyl abacavir were devoid of T-cell activity. Docking abacavir analogues to HLA-B57 : 01 revealed a quantitative relationship between drug-protein binding and the T-cell response.. These studies demonstrate that the unwanted T-cell activity of abacavir can be eliminated whilst maintaining the favourable antiviral profile. The in-silico model provides a tool to aid the design of safer antiviral agents that may not require a personalized medicines approach to therapy.

Topics: Anti-HIV Agents; CD8-Positive T-Lymphocytes; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HLA-B Antigens; Humans; Microbial Sensitivity Tests; Molecular Docking Simulation; Protein Binding

HLA-B*57:01 status needs to be determined before initiating abacavir therapy. We developed a pharmacogenetic real-time (Q)-PCR screening test using two sets of sequence specific primers. This test has been implemented into routine clinical practice.. HIV-infected patients admitted at our University Hospital were thus genotyped using the above mentioned test. A panel of 80 DNA samples with a known genotype were used to characterize Q-PCR conditions using different master mixes.. A total of 353 patients were genotyped, detecting 15 (4.25%) HLA-B*57:01 positive carriers. Among the negative patients, 17.2% were treated with abacavir without any hypersensitivity reaction. Using different Q-PCR master mixes, significantly lower cutoff Ct values were found, thus new analytical settings are provided.. The pharmacogenetic test developed in our laboratory for the fast screening of HLA-B*57:01 can be successfully implemented into routine clinical practice. All 16 sequences (including an additional six) currently known for the HLA-B*57:01 allele are detected by sequence specific primers used in this test. The Brilliant II SYBR(®) Green QPCR MM (Stratagene) can safely replace the master mix originally used to develop the test.

Topics: Adult; Dideoxynucleosides; Drug Hypersensitivity; Female; Genotype; HIV Infections; HLA-B Antigens; Humans; Male; Pharmacogenetics; Real-Time Polymerase Chain Reaction

A strong association between the human leucocyte antigen (HLA)-B*58:01 allele and allopurinol-associated severe cutaneous adverse reactions (SCAR) has been reported. A screening for HLA-B*58:01 before allopurinol has been suggested in guidelines for management of gout. HLA-B*58:01 screening is generally based on molecular biology methods that may be not suitable for wide application. We have retrospectively evaluated the performance on a rapid flow cytometry (FCM) test, based on the use of a monoclonal antibody specific for HLA-B17, an antigen that can be split into HLA-B*57 and -B*58 alleles by molecular biology testing, which is used to screen for HLA-B*57:01 before prescription of the antiretroviral agent abacavir in HIV-positive patients. Among 475 samples that were analysed by FCM and by molecular biology test as gold standard, 2 out of 89 false negative tests for HLA-B*58:01 were found. The sensitivity was 97.8% and the negative predictive value was 98.9%. We have shown that a FCM test can identify almost all HLA-B*58:01 positive individuals. As FCM laboratories are more widely available than molecular biology ones, this approach could be used to reduce the risk for allopurinol-induced SCAR. Where both facilities are available, a two-step strategy (FCM as screening, molecular biology for confirmation) may reduce the cost of the screening.

Topics: Alleles; Allopurinol; Antibodies, Monoclonal; Dideoxynucleosides; Drug Hypersensitivity; False Negative Reactions; Flow Cytometry; HLA-B Antigens; Humans; Predictive Value of Tests; Reproducibility of Results; Retrospective Studies; Sensitivity and Specificity; Skin Diseases

Hypersensitivity reactions to the drug abacavir are strongly associated with possession of HLA-B*57:01. Hence, patients with HIV/AIDS who may be prescribed abacavir should be tested for this HLA allele and the drug withheld from those that possess B*57:01. The UK National External Quality Assessment Service for Histocompatibility and Immunogenetics has operated a scheme for B*57:01 testing since 2008 which, in 2013, involved 47 participants from 12 countries. A total of 24 B*57:01-positive, 2 B*57:03-positive and 22 B*57-negative blood samples (including 2 B*58 samples) were distributed to between 28 and 47 laboratories each year over 6 years. Participants, who were unaware of the samples' HLA types, tested and reported on their B*57/B*57:01 status. A total of 1868 reports were assessed over the 6 years. Of the 880 reports on B*57:01 samples, 93.4% were correctly assigned as B*57:01, 2.8% were assigned as groups of B*57 alleles including B*57:01, and 3.3% were reported as B*57 positive only. Over the 6 years, there were four (0.46%) false B*57:01 negative reports. All the B*57:03-positive and B*57-negative samples, involving 72 and 916 assignments, respectively, were essentially reported as B*57:01 negative. Thus, there were no false B57:01 positive assignments. The reporting of B*57:01 status over the last 3 years of the scheme was 99.8% sensitive and 100% specific. Over the last year, it was 100% sensitive and 100% specific.

Topics: Alleles; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Genetic Testing; Histocompatibility Testing; HLA-B Antigens; Humans; Polymerase Chain Reaction; Quality Control; Reproducibility of Results; Sensitivity and Specificity

Abacavir (ABC) is a commonly used nucleoside reverse-transcriptase inhibitor with potent antiviral activity against HIV-1. The US Food and Drug Administration and international HIV treatment guidelines recommend HLA-B*57:01 screening before initiating treatment with ABC. The current standard method for HLA-B*57:01 screening is limited by its high-cost, time-consuming and labour-intensive procedure with the requirement of a specialized laboratory. Our study aims to develop a more reliable screening test by selecting rs3093726 as an additional single nucleotide polymorphism (SNP) to combine with rs2395029 for multiplex pyrosequencing development. It offers high-accuracy, cost-effective and rapid detection.. Multiplex pyrosequencing was developed for HLA-B*57:01 screening using rs2395029 and rs3093726 as a surrogate marker and tested in 130 Thai subjects in parallel with singleplex pyrosequencing of each SNP and the standard sequence-based method.. Multiplex pyrosequencing showed 100% concordance when compared with both singleplex pyrosequencing and standard sequence-based method. This method showed 100% of negative predictive value (NPV), positive predictive value (PPV), specificity and sensitivity.. Multiplex pyrosequencing is a powerful tool for HLA-B*57:01 screening using the rs2395029 and rs3093726 haplotype genotyping as surrogate marker for this HLA-B. The assay provides accurate, cost-effective and rapid detection of this haplotype. It can be applied for ABC hypersensitivity screening of the Thai population before initiating treatment with ABC.

Topics: Anti-HIV Agents; Asian People; Dideoxynucleosides; DNA Primers; Drug Hypersensitivity; Haplotypes; HLA-B Antigens; Humans; Multiplex Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Predictive Value of Tests; Thailand

HLA-B(∗)57:01 is a well-known and cost-effective pharmacogenetic marker for abacavir hypersensitivity. As with other HLA alleles, there is widespread variation in its frequency across populations. The Costa Rica Central Valley Population (CCVP) is the major population in this country. The frequency of HLA-B(∗)57:01 in this population has not been described yet. Thus, our aim was to determine the frequency of this allele in the CCVP. 200 unrelated healthy volunteer donors born in the CCVP were typed. HLA-B(∗)57-positive samples identified by HLA intermediate resolution typing methods were further typed by SBT to high resolution. An HLA-B(∗)57:01 carrier frequency of 5.00% was determined in this sample. This frequency is relatively high in comparison to reports from other populations in Latin America. These results suggest that there is a considerable frequency of HLA-B(∗)57:01 in the CCVP and that pharmacogenetic testing for HIV+ patients who are going to receive abacavir-based treatment should be considered in this country.

Topics: Alleles; Anti-HIV Agents; Costa Rica; Dideoxynucleosides; Drug Hypersensitivity; Female; Gene Expression; Gene Frequency; Genetic Markers; Heterozygote; HIV Infections; HLA-B Antigens; Humans; Male; Risk Factors

Topics: Dideoxynucleosides; Drug Hypersensitivity; Genetic Predisposition to Disease; HLA-B Antigens; Humans; Pharmacogenetics; Reverse Transcriptase Inhibitors; Risk Assessment

Topics: Adenine; Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Asthenia; Benzoxazines; Cyclopropanes; Deoxycytidine; Dideoxynucleosides; Drug Eruptions; Drug Hypersensitivity; Drug Substitution; Emtricitabine; Female; Fever; HIV Infections; Humans; Lamivudine; Nevirapine; Organophosphonates; Reverse Transcriptase Inhibitors; Syndrome; Tenofovir

Abacavir hypersensitivity is associated with the presence of human leukocyte antigen (HLA)-allele B*5701. However, the cost and workload of routine HLA-B*5701 pretreatment screening is relatively heavy. This study aimed to determine the prevalence of the HLA-B*5701 allele in the HIV-positive population under care in Hong Kong. Blood samples from 1264 HIV-1 infected patients in Hong Kong were collected between 2007 and 2011 for this study. HLA-B*5701 screening of the study group was determined by in-house polymerase chain reaction (PCR) followed by confirmation using the AlleleSEQR(®) HLA-B PCR/Sequencing Kit (Celera Corporation for Abbott, San Francisco, USA). HLA-B*5701 carriers were identified among 3% of Caucasians, 1% of non-Chinese Asians and 0.5% of Han-Chinese in Hong Kong. Our findings revealed that HLA-B*5701 pretreatment screening might not be necessary for the local Han-Chinese population due to its low prevalence.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alleles; Asian People; Dideoxynucleosides; Drug Hypersensitivity; Female; Genetic Markers; Genetic Testing; Genotype; HIV Infections; HIV-1; HLA-B Antigens; Hong Kong; Humans; Male; Middle Aged; Molecular Sequence Data; Polymerase Chain Reaction; Reverse Transcriptase Inhibitors; Young Adult

Topics: Adolescent; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Female; HIV Infections; HLA-B Antigens; Humans; Male; Patch Tests; T-Lymphocytes

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

Human leukocyte antigen (HLA)-B*5701 allele is associated with abacavir hypersensitivity. Limited data among Asians showed lower rates of HLA-B*5701 compared with Caucasians. In 296 children with HIV in Thailand and Cambodia, the prevalence of HLA-B*5701 was 4.0% (95% confidence interval: 1.6-8.0%) among Thai and 3.4% (95% confidence interval: 0.9-8.5%) among Cambodian children. HLA-B*5701 carriage is not uncommon among Thai and Cambodian children; it is close to the prevalence found in European and higher than the prevalence found in East Asian and African studies.

Topics: Cambodia; Child; Child, Preschool; Dideoxynucleosides; Drug Hypersensitivity; Female; Gene Frequency; HIV Infections; HLA-B Antigens; Humans; Infant; Male; Prevalence; Thailand

Hypersensitivity reactions to the drug abacavir, used to treat HIV/AIDS patients, is associated with possession of HLA-B*57:01. We have carefully assessed two commercially available HLA-B57/B58 murine monoclonal antibodies [0196HA and BIH0243 (One Lambda Inc.)] in a simple flow cytometry-based assay. The evaluation involved tests on 228 reference and random samples covering 91% of all WHO recognized HLA-A, B and C specificities. These involved donors with six different HLA-B*57 alleles and included 19 examples of B*57:01. Both antibodies unambiguously detected B57, but there were small difference in their reactivity against B57-positive non-B*57:01 samples. Importantly, there was no reactivity against B57/B58-negative samples. The possible amino acid motifs involved in the reactivity of these antibodies with B57/B58 were delineated. Thus, HLA-B57/B58, normally present in <10% of patients, can be easily recognized using these two antibodies and further tested by a DNA-based typing method to identify B*57:01.

Topics: Alleles; Anti-HIV Agents; Antibodies, Monoclonal; Dideoxynucleosides; Drug Hypersensitivity; Drug Prescriptions; Epitopes; Flow Cytometry; Genetic Variation; HLA-B Antigens; Humans

The field of pharmacogenetics is witnessing a growing interest in the role of the human leukocyte antigen (HLA) in manifestation of adverse drug reactions (ADR). Here we report a retrospective analysis of the association of HLA-B*5701 with abacavir hypersensitivity syndrome (AHS) in a large Canadian cohort of 489 human immunodeficiency virus-1-positive patients exposed to abacavir. A total of 3.7% of abacavir-exposed patients had developed AHS. Using polymerase chain reaction sequence-specific primer-based genotyping, the HLA-B*5701 allele was observed in 20 patients (4.1%). Of the 20 HLA-B*5701(+) abacavir-treated patients, 18 (90%) had developed AHS. Carriage of the HLA-B*5701 allele indicated a strong association with abacavir hypersensitivity (p < 0.0001; odds ratio = 6,934; 95% confidence interval = 321-149,735). HLA-B*5701 genotyping demonstrated high sensitivity, specificity, and positive and negative predictive values. The data derived from the study highlight the importance of engaging histocompatibility and immunogenetics laboratories in taking a lead in mapping other less characterized HLA and immunogenetic markers associated with ADRs.

Topics: Adult; Aged; Aged, 80 and over; Alberta; Anti-HIV Agents; Biomarkers; Dideoxynucleosides; Drug Hypersensitivity; Female; Genetic Testing; HIV Infections; HLA-B Antigens; Humans; Male; Middle Aged; Pharmacogenetics; Retrospective Studies

The antiretroviral agent abacavir can cause hypersensitivity reaction (HSR) and the presence of HLA-B*57:01 is predictive of abacavir-HSR in Caucasian HIV-infected patients. However, abacavir-HSR also occurs in HLA-B*57:01 negative patients. In these patients, a safe diagnostic tool to dissect clinically suspected HSR against abacavir from adverse reactions against co-administered drugs is mandatory, and abacavir-ELISpot was evaluated. Peripheral blood mononuclear cells from 87 HIV patients were stimulated by abacavir and the production of interferon-γ to the ELISpot was determined. Abacavir treated patients with HSR [confirmed (n=5) or suspected (n=12)] vs without HSR (n=42) displayed significantly higher numbers of abacavir-specific cells (82.3±23.0 or 10.5±4.5 vs -0.5±1.0 spot forming cells per million PBMC, p < .005 each). In conclusion, we established the first abacavir-specific ELISpot. According to our preliminary data, a negative abacavir-ELISpot nearly excludes HSR against abacavir. Thereby the ELISpot may facilitate the decision to continue or withdraw abacavir treatment.

Topics: Adult; Aged; Anti-HIV Agents; Canada; Dideoxynucleosides; Drug Hypersensitivity; Enzyme-Linked Immunospot Assay; Female; HIV Infections; HLA-B Antigens; Humans; Interferon-gamma; Leukocytes, Mononuclear; Male; Middle Aged; Young Adult

The antiretroviral drug abacavir (abc) elicits severe drug hypersensitivity reactions in HLA-B*5701(+) individuals. To understand the abc-specific activation of CD8(+) T cells, we generated abc-specific T-cell clones (abc-TCCs). Abc reactivity could not be linked to the metabolism and/or processing of the drug, since abc metabolizing enzymes were not expressed in immune cells and inhibition of the proteasome in APCs did not affect TCC reactivity. Ca(2+) influx assays revealed different reactivity patterns of abc-TCCs. While all TCCs reacted to abc presented on HLA-B*5701 molecules, a minority also reacted immediately to abc in solution. Titration experiments showed that the ability to react immediately to abc correlated significantly with the TCR avidity of the T cells. Modifications of soluble abc concentrations revealed that the reactivity patterns of abc-TCCs were not fixed but dynamic. When TCCs with an intermediate TCR avidity were stimulated with increasing abc concentrations, they showed an accelerated activation kinetic. Thus, they reacted immediately to the drug, similar to the reaction of TCCs of high avidity. The observed immediate activation and the noninvolvement of the proteasome suggest that, in contrast to haptens, abc-specific T-cell stimulation does not require the formation of covalent bonds to produce a neo-antigenic determinant.

Topics: Anti-HIV Agents; Antibody Affinity; Calcium; CD8-Positive T-Lymphocytes; Clone Cells; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Hypersensitivity; HLA-B Antigens; Humans; Kinetics; Leukocytes, Mononuclear; Lymphocyte Activation; Proteome; Statistics, Nonparametric

Drug hypersensitivity reactions are an immune-mediated reaction to otherwise innocuous antigens derived from drugs. These reactions can affect many different organs, with the skin being the commonest. Skin involvement can range in severity with hypersensitivity syndrome (or DRESS) and the blistering reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), also termed serious cutaneous adverse drug reactions, being the most severe and most feared. There is increasing evidence for the role of the immune system in the pathogenesis of these reactions, with drug-specific T cells having been identified in many patients. Until recently, very little was known about the predisposition to these reactions. However, the availability of more accurate molecular typing methods, and the ability to analyse the whole genome in an unbiased fashion, has led to some remarkable findings of the role of the HLA genes as genomic biomarkers of predisposition. The 'revolution' started with abacavir where the predisposition to hypersensitivity was linked to HLA-B*57:01, which was confirmed in a clinical trial, and where its implementation has shown to reduce the incidence of hypersensitivity in a cost-effective manner. Since then, associations have also been shown for allopurinol (HLA-B*58:01)- and carbamazepine (HLA-B*1502 and HLA-A*3101)-induced serious cutaneous adverse drug reactions. The latter is interesting since the association with HLA-B*1502 is present in certain South-Eastern Asian populations, and the predisposition is phenotype specific (only for SJS/TEN). The utility of this biomarker has been shown in a prospective cohort study performed in Taiwan. By contrast, the association with HLA-A*3101 is seen in more diverse ethnic groups, and predisposes to mild as well more severe cutaneous reactions associated with carbamazepine. It is important to note that strong HLA associations have also been shown with a number of drugs that cause liver injury including flucloxacillin, lumiracoxib, lapatinib and ximelagatran, indicating that the immune system is also important in the pathogenesis of other forms of drug-induced organ toxicity. The crucial question as to whether these HLA alleles are truly causative or acting as surrogate markers of predisposition, however, is still unclear, and will require further investigations in larger patient cohorts, through the use of bioinformatic techniques, fine mapping using next generation sequencing technologies and functional stud

Topics: Allopurinol; Anti-Bacterial Agents; Anti-HIV Agents; Anticonvulsants; Antimetabolites; Biomarkers; Carbamazepine; Chemical and Drug Induced Liver Injury; Dideoxynucleosides; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Genome-Wide Association Study; HLA Antigens; HLA-A Antigens; HLA-B Antigens; Humans; Immune System; Predictive Value of Tests; Stevens-Johnson Syndrome

Abacavir drug hypersensitivity in HIV-treated patients is associated with HLA-B57:01 expression. To understand the immunochemistry of abacavir drug reactions, we investigated the effects of abacavir on HLA-B57:01 epitope-binding in vitro and the quality and quantity of self-peptides presented by HLA-B57:01 from abacavir-treated cells.. An HLA-B57:01-specific epitope-binding assay was developed to test for effects of abacavir, didanosine or flucloxacillin on self-peptide binding. To examine whether abacavir alters the peptide repertoire in HLA-B57:01, a B-cell line secreting soluble human leucocyte antigen (sHLA) was cultured in the presence or absence of abacavir, peptides were eluted from purified human leucocyte antigen (HLA), and the peptide epitopes comparatively mapped by mass spectroscopy to identify drug-unique peptides.. Abacavir, but not didansosine or flucloxacillin, enhanced binding of the FITC-labeled self-peptide LF9 to HLA-B57:01 in a dose-dependent manner. Endogenous peptides isolated from abacavir-treated HLA-B57:01 B cells showed amino acid sequence differences compared with peptides from untreated cells. Novel drug-induced peptides lacked typical carboxyl (C) terminal amino acids characteristic of the HLA-B57:01 peptide motif and instead contained predominantly isoleucine or leucine residues. Drug-induced peptides bind to soluble HLA-B57:01 with high affinity that was not altered by abacavir addition.. Our results support a model of drug-induced autoimmunity in which abacavir alters the quantity and quality of self-peptide loading into HLA-B57:01. Drug-induced loading of novel self-peptides into HLA, possibly by abacavir either altering the binding cleft or modifying the peptide-loading complex, generates an array of neo-antigen peptides that drive polyclonal T-cell autoimmune responses and multiorgan systemic toxicity.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Autoimmunity; Cells, Cultured; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Hypersensitivity; Histocompatibility Testing; HLA-B Antigens; Humans; Models, Immunological; Peptide Fragments; Self Tolerance; Spectrum Analysis

Human leukocyte antigens (HLAs) are highly polymorphic proteins that initiate immunity by presenting pathogen-derived peptides to T cells. HLA polymorphisms mostly map to the antigen-binding cleft, thereby diversifying the repertoire of self-derived and pathogen-derived peptide antigens selected by different HLA allotypes. A growing number of immunologically based drug reactions, including abacavir hypersensitivity syndrome (AHS) and carbamazepine-induced Stevens-Johnson syndrome (SJS), are associated with specific HLA alleles. However, little is known about the underlying mechanisms of these associations, including AHS, a prototypical HLA-associated drug reaction occurring exclusively in individuals with the common histocompatibility allele HLA-B*57:01, and with a relative risk of more than 1,000 (refs 6, 7). We show that unmodified abacavir binds non-covalently to HLA-B*57:01, lying across the bottom of the antigen-binding cleft and reaching into the F-pocket, where a carboxy-terminal tryptophan typically anchors peptides bound to HLA-B*57:01. Abacavir binds with exquisite specificity to HLA-B*57:01, changing the shape and chemistry of the antigen-binding cleft, thereby altering the repertoire of endogenous peptides that can bind HLA-B*57:01. In this way, abacavir guides the selection of new endogenous peptides, inducing a marked alteration in 'immunological self'. The resultant peptide-centric 'altered self' activates abacavir-specific T-cells, thereby driving polyclonal CD8 T-cell activation and a systemic reaction manifesting as AHS. We also show that carbamazepine, a widely used anti-epileptic drug associated with hypersensitivity reactions in HLA-B*15:02 individuals, binds to this allotype, producing alterations in the repertoire of presented self peptides. Our findings simultaneously highlight the importance of HLA polymorphism in the evolution of pharmacogenomics and provide a general mechanism for some of the growing number of HLA-linked hypersensitivities that involve small-molecule drugs.

Topics: Antigen Presentation; Autoimmunity; Binding Sites; Blood Donors; Carbamazepine; CD8-Positive T-Lymphocytes; Dideoxynucleosides; Drug Hypersensitivity; HLA-B Antigens; Humans; Models, Molecular; Protein Conformation; Syndrome; T-Lymphocytes

The potentially life-threatening adverse reactions to Abavacir (ABC), a nucleoside analog reverse transcriptase inhibitor for the treatment of HIV infection, have been known for several years to be limited to individuals expressing the HLA-B57:01 gene. Why the ABC hypersensitivity syndrome is only seen in HLA-B57:01-expressing subjects and what the precise mechanisms underlying this intolerance are remain however controversial. A series of recent studies, particularly a study by Illing et al. recently published in Nature, now answer some of these questions and offer new opportunities to better understand autoimmune disorders and prevent adverse reactions to other drugs.

Topics: Alleles; Anti-HIV Agents; Autoimmunity; Carbamazepine; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HLA-B Antigens; Humans; Syndrome

Carriers of HLA-B*57:01 are at risk for Abacavir hypersensitivity reaction (ABC-HSR). In Caucasians, a SNP (rs2395029) in the HCP5 gene is reported to be in linkage disequilibrium (LD) with HLA-B*57:01. Genotyping the HCP5 SNP has increasingly been adopted as a simple method to screen for susceptibility to ABC-HSR. We genotyped both the HCP5 SNP and HLA-B*57:01 in a set of 1888 samples and found a good correlation; significantly, however, one HLA-B*57:01-positive sample tested negative for the HCP5 SNP. In addition, HCP5 could not be amplified in two samples, both negative for HLA-B*57:01. Further investigation demonstrated both samples were homozygous for deletion of the HCP5 gene. The fact HCP5 occurs within a region of copy number variation and the fact LD is incomplete and may vary between ethnicities should be considered when using the HCP5 SNP as a surrogate marker for HLA-B*57:01.

Topics: Dideoxynucleosides; DNA Copy Number Variations; Drug Hypersensitivity; Genotype; HLA-B Antigens; Humans; Linkage Disequilibrium; Major Histocompatibility Complex; Polymorphism, Single Nucleotide; RNA, Long Noncoding; RNA, Untranslated

Recently, genome wide association studies showed that there is a strong association between abacavir-induced serious, idiosyncratic, adverse drug reactions (ADRs) and human leukocyte antigen-B*5701 (HLA-B*5701). Studies also found that abacavir-induced ADRs were seldom observed in patients carrying the HLA-B*5801 subtype. HLA-B*5801 of the same serotype (B17) as B*5701 differs by only 4 amino acids from B*5701. It is believed that because of these sequence differences, HLA-B*5801 cannot bind the specific peptides which are required for HLA-B*5701 to stimulate the T cell immune response. Thus, the difference in peptide binding profiles between HLA-B*5701 and B*5801 is an important clue for exploring the mechanisms of abacavir-induced ADRs. VHSE (principal component score vector of hydrophobic, steric, and electronic properties), a set of amino acid structural descriptors, was employed to establish QSAR models of peptide-binding affinities of HLA-B*5701 and B*5801. Optimal linear SVM (support vector machine) models with high predictive capabilities were obtained for both B*5701 and B*5801. The R(2) (coefficient of determination), Q(2) (cross-validated R(2)), and R(PRE)(2) (R(2) of test set) of two optimal models were 0.7530, 0.7037, 0.6153 (B*5701) and 0.6074, 0.5966, 0.5762 (B*5801), respectively. For B*5701 and B*5801, the mutations in positions 45 (MET-THR) and 46 (ALA-GLU) have little influence on the selection specificity of the P2 position of the bound peptide. However, the mutation in position 97 (VAL-ARG) greatly influences the selection specificity of the P7 position. HLA-B*5701 prefers the bulky and positively charged amino acids at the P7 position. In contrast, HLA-B*5801 prefers the non-polar hydrophobic amino acids at the P7 position while positively charged amino acids are unfavored.

Topics: Amino Acid Sequence; Amino Acids; Binding Sites; Binding, Competitive; Dideoxynucleosides; Drug Hypersensitivity; HLA-B Antigens; Humans; Hydrophobic and Hydrophilic Interactions; Linear Models; Models, Molecular; Mutation; Peptides; Protein Binding; Protein Structure, Secondary; Protein Structure, Tertiary; Quantitative Structure-Activity Relationship; Reverse Transcriptase Inhibitors; Support Vector Machine

The availability of high-resolution genetic profiling raises the possibility, during the course of a drug development program, of discovering a subset of patients at particular risk of an adverse drug reaction who might be excluded from subsequent randomization into studies and identified as unsuitable for post-licensing use. Such methods depend on the estimation of the risk of adverse drug reactions for patients with differing genetic profiles followed by an assessment of the risks and benefits of their exposure to the drug. In this paper we explore the performance of a number alternative statistical methods for the estimation of risk in terms of the success of the subsequent exclusion rules. The approaches were evaluated using a single-nucleotide polymorphism dataset concerning HIV patients at risk of hypersensitivity to the drug abacavir. Overall we found that a method based on LASSO performed better than the alternatives that we studied, which included a decision-theoretic Bayesian approach, and that its performance suggested suitability for its prospective implementation.

Topics: Anti-HIV Agents; Bayes Theorem; Clinical Trials as Topic; Dideoxynucleosides; Drug Design; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Gene Expression Profiling; Genome, Human; HIV Infections; Humans; Models, Statistical; Polymorphism, Single Nucleotide; Reproducibility of Results; Risk Assessment

Prospective screening for HLA-B*5701 decreases or abolishes abacavir hypersensitivity reaction. In Caucasians, the HLA complex protein 5 gene (HCP5) rs2395029(G) allele is in complete linkage disequilibrium (LD) with HLA-B*5701 (r(2) = 1).. To assess the frequency of HLA-B*5701 and its LD with HCP5 rs2395029(G) allele, to extend our knowledge of genetic variants that are of critical relevance for the development of pharmacogenetics in Mexico.. We genotyped 300 Mexican Mestizos from the Mexican Genome Diversity Project. HLA-B*5701 genotyping was performed using a DNA sequencing method. HCP5 rs2395029 was genotyped using a custom TaqMan(®) SNP genotyping assay and confirmed by direct sequencing. Genotypes for 14 SNPs in the HCP5 region were retrieved from the Mexican Genome Diversity Project database for LD analysis.. HLA-B*5701 carrier frequency was 2% and the allelic frequency was 0.010. Haplotype analysis revealed that HLA-B*5701 and the HCP5 rs2395029(G) allele are in complete LD (r(2) = 1) in this Mexican Mestizos sample.. It is feasible to have a pharmacogenetic program based on HCP5 rs2395029 genotyping as a screening tool with confirmation of HLA-B*5701 carriage by sequenciation, to prevent abacavir hypersensitivity reaction in Mexican patients before initiating abacavir therapy.

Topics: Alleles; Dideoxynucleosides; Drug Hypersensitivity; Gene Frequency; Genetic Markers; Genetic Predisposition to Disease; Haplotypes; HLA-B Antigens; Humans; Linkage Disequilibrium; Major Histocompatibility Complex; Mexico; Pharmacogenetics; Reverse Transcriptase Inhibitors; RNA, Long Noncoding; RNA, Untranslated

The most important factor limiting the success of an antiretroviral therapy is toxicity. The HLA-B*5701 allele is predictive of hypersensitivity reaction to Abacavir, and this gene is in a perfect linkage disequilibrium with the rs2395029 SNP present in the HCP5 gene.. Genomic DNA was extracted from blood obtained from 201 unrelated healthy Argentinean volunteers. The DNA was subjected to an allele-specific PCR method. Sequencing was performed to validate the test results.. We were successful to amplify specific fragment of interest from the DNA samples. The method is easy, specific and reproducible.. The application of this methodology is a rapid and simple method to detect the HCP5 polymorphism (rs2395029) previous to administration of Abacavir in patients with HIV infection.

Topics: Adolescent; Adult; Aged; Alleles; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Female; Genotype; Humans; Major Histocompatibility Complex; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Predictive Value of Tests; Reference Values; Reproducibility of Results; RNA, Long Noncoding; RNA, Untranslated; Sensitivity and Specificity; Young Adult

International HIV treatment guidelines recommend HLA-B*57:01 typing before abacavir administration, in order to reduce the incidence of abacavir hypersensitivity reactions, the major cause of early therapy discontinuation. A fast, sensitive and specific test for HLA-B*57:01 detection has been developed in the present study.. Two sets of sequence-specific primers were designed, and amplification rapidly detected by real-time PCR.. A total of 108 samples were analyzed in a single-blind fashion, and 41 samples were identified as positive. Complete agreement, with κ = 1 (standard error = 0.0962, p < 0.0001), was found, with a validated methodology used in the EPI109367 clinical trial funded by GlaxoSmithKline, and consisting of low-resolution sequence-specific oligonucleotide PCR, followed by high-resolution sequence-specific oligonucleotide PCR carried out on the HLA-B*57-positive samples.. We provided a detailed characterization of a novel HLA-B*57:01 screening test, which can be easily implemented by those laboratories already involved in the detection of viral load and virus genotyping. Original submitted 26 October 2010; Revision submitted 13 December 2010.

Topics: Anti-HIV Agents; Base Sequence; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HLA-B Antigens; Humans; Molecular Sequence Data; Pharmacogenetics; Polymerase Chain Reaction

Topics: Adolescent; Adult; Anti-HIV Agents; Brazil; Case-Control Studies; Dideoxynucleosides; Drug Hypersensitivity; Female; Gene Frequency; Genotype; HIV Infections; HLA-B Antigens; Humans; Male; Middle Aged; Real-Time Polymerase Chain Reaction; Young Adult

The HLA-B*57:01 allele is associated with a hypersensitivity reaction to abacavir, and its prevalence varies in different populations. The aim of the study was to investigate HLA-B*57:01 prevalence in the Czech HIV-infected population. HLA-B*57:01 prevalence in our cohort was 5.33%, which is similar to the situation in other Central European countries.

Topics: Anti-HIV Agents; Cross-Sectional Studies; Czech Republic; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HLA-B Antigens; Humans; Prevalence

A potentially life-threatening hypersensitive reaction occurs in association with initiation of HIV nucleoside analogue abacavir therapy in 4 to 8% of patients. Preliminary studies appear to confirm the role of the immune system in abacavir hypersensitivity. The reaction is possibly the result of presentation of drug peptides onto HLA, that may induce a pathogenic T-cell response. Hypersensitivity reaction to abacavir is strongly associated with the presence of the HLA-B*5701 allele and prospective HLA-B*5701 genetic screening has now been instituted in clinical practice to reduce the risk of hypersensitivity reaction.

Topics: Alleles; Anti-HIV Agents; Antigen Presentation; Dideoxynucleosides; Drug Hypersensitivity; Gene Frequency; Genes, MHC Class I; Genetic Predisposition to Disease; Genetic Testing; HIV Reverse Transcriptase; HLA-B Antigens; Humans; Peptide Fragments; Polymerase Chain Reaction; Reverse Transcriptase Inhibitors; Sequence Analysis, DNA; T-Lymphocytes, Cytotoxic

Human leukocyte antigen (HLA)-B(*)5701 is strongly associated with developing a hypersensitivity reaction to abacavir (ABC) in White and Hispanic subjects. Across the UK, limited data exist on HLA-B(*)5701 prevalence in HIV-1-infected subjects. We determined HLA-B(*)5701 prevalence in the general HIV-1-infected population and in specific ethnic groups, particularly Black Africans who, in general, exhibit greater genetic diversity. We also compared HLA-B(*)5701 results obtained from local laboratories with those from a central provider.. Multi-centre, observational study. All HIV-1-infected adult individuals receiving care at participating centres were eligible, irrespective of treatment status or prior exposure to ABC. Subjects provided samples for HLA-B(*)5701 assessment by both local (blood) and central laboratories (buccal swabs). HLA-B(*)5701 prevalence was adjusted to represent the ethnic group composition of the general UK population, and by main ethnic group. RESULTS; From eight UK centres, 1494 subjects [618 (41%) White, 770 (52%) Black] were recruited. Eighty-nine per cent of Black subjects reported an immediate country of origin in Africa. Overall adjusted HLA-B(*)5701 prevalence was 4.55% [95% confidence interval (CI) 3.49% to 5.60%]. Among White subjects, prevalence was 7.93% (CI 5.80% to 10.06%). Among Black subjects, only two (both Ugandan) were HLA-B(*)5701 positive giving a rate of 0.26% (CI 0.07% to 0.94%).. HLA-B(*)5701 prevalence was similar to previously reported rates in White HIV-infected subjects but considerably lower than that reported in Black HIV-1-infected subjects, as a result of the large proportion of Black African subjects.

Topics: Adult; Africa; Aged; Anti-HIV Agents; Black People; Dideoxynucleosides; Drug Hypersensitivity; Epidemiologic Studies; Female; Genetic Markers; Genetic Testing; Genotype; HIV Infections; HLA-B Antigens; Humans; Male; Middle Aged; Prospective Studies; United Kingdom; White People; Young Adult

Abacavir is a nucleoside reverse transcriptase inhibitor (NRTI) that is used in combination antiretroviral therapy in HIV-infected patients. It is currently recommended as a preferred or an alternative NRTI in antiretroviral-naïve patients. The major toxicity of abacavir is a hypersensitivity reaction (HSR), which occurs in approximately 5% of treated patients. There is a strong association between the human leukocyte antigen (HLA)-B*5701 allele and abacavir HSR, which has allowed for rapid acceptance of genetic screening for HLA-B*5701 in clinical use. Canadian clinicians working in hospital centers with HLA typing capacity opted to launch a pilot project in 2006 to offer the screening test as standard of care to HIV-infected patients. Currently, more than 11,000 HLA-B*5701 tests have been performed, among which 6.3% are positive. Continued efforts have been made to ensure that testing is available to all HIV-infected patients to widen the patients' therapeutic options. HLA-B*5701 screening shows clinical use and preliminary data suggest cost-effectiveness.

Topics: Alleles; Anti-HIV Agents; Canada; Cost-Benefit Analysis; Dideoxynucleosides; Drug Hypersensitivity; Genetic Testing; HIV Infections; HLA-B Antigens; Humans; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors

Prospective pharmacogenetic screening for the human leucocyte antigen (HLA) B*5701 allele can significantly reduce the number of cases of abacavir-related hypersensitivity among HIV-infected patients treated with this drug. The aim of this study was to establish the frequency of the HLA B*5701 variant in HIV-infected Poles.. The sequence-specific primer (SSP) test was used to assess the feasibility of the introduction of such testing in clinical practice. For this purpose, 234 randomly selected HIV-positive patients were screened using a low-resolution SSP assay, with HLA B*5701-positive results confirmed using a high-resolution test.. The HLA B*5701 variant was found in 11 of 234 subjects (4.7%). Testing with the selected method proved quick and reliable.

Topics: Adult; Alleles; Dideoxynucleosides; Drug Hypersensitivity; Feasibility Studies; Female; Gene Frequency; Genetic Testing; Genotype; HIV Infections; HLA-B Antigens; Humans; Male; Middle Aged; Mutation; Poland; Polymerase Chain Reaction; Predictive Value of Tests; Reverse Transcriptase Inhibitors; Skin Tests

Approximately 4% to 8% of patients with HIV-1 treated with abacavir present a hypersensitivity reaction (HSR). Various studies have shown a direct association between human leukocyte antigen (HLA)-B*5701 and HSR to abacavir. The objective of this study was to analyze whether systematic HLA-B*5701 testing to prevent HSR in patients treated with abacavir is a cost-effective option for the Spanish National Health System.. An analytical decision-making model was constructed as a decision tree model for a simulated cohort of 1000 HIV patients to evaluate whether HLA-B*5701 testing to prevent HSR to abacavir was cost effective compared with not performing the test. The parameters included in the model and the use of healthcare resources should the patient develop HSR were taken from the PREDICT-1 study and the opinion of clinical experts. The principal result obtained was the incremental cost per HSR avoided. The time horizon of the analysis was to 2 months [corrected] . All costs were expressed in 2008 Euros.. The analysis showed that the total direct healthcare costs per patient were €1344 and €1322 with and without HLA-B*5701 testing respectively, and that 36 cases of HSR were prevented per 1000 screened patients. These results yielded a cost per HSR avoided of €630. The sensitivity analysis showed that the results were sensitive to the cost of the test, with an economic saving of €102 or a cost-effectiveness ratio of €4234.. The model predicts that generalized use of the HLA-B*5701 test before prescribing abacavir in HIV+ patients could represent an economic saving or a limited additional cost for the National Health System which may be counterbalanced by the benefits in terms of a lower incidence of HSR.

Topics: Anti-HIV Agents; Cost-Benefit Analysis; Dideoxynucleosides; Drug Hypersensitivity; HIV Seropositivity; HLA-B Antigens; Humans; Models, Economic; Spain

Drug-induced hypersensitivity reactions represent a major concern for clinicians, patients, regulators and drug developers. Severe hypersensitivity is associated with high morbidity and mortality, it cannot be predicted from the known pharmacology of the drug and it is usually detected post-marketing when a large number of patients have been exposed to a particular drug. Recent success in developing clinically useful genetic tests that have allowed us to predict the risk of abacavir-induced hypersensitivity has helped to pave the path for a pharmacogenetic approach. However, the loop from identifying a genetic association to improving clinical outcome is still lacking for many drugs. In this commentary, we discuss the progress of hypersensitivity pharmacogenomics over the last decade and point out what remains to be done in the future. The current efforts of the international community are focused on the development of consortia, which aim to standardize disease phenotypes, but also to collect larger numbers of well-phenotyped patients and to pool biological samples through these collaborations. In addition, it is necessary to advance our knowledge of hypersensitivity mechanisms through functional studies, which will lead to the development of predictive and diagnostic tests.

Topics: Dideoxynucleosides; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; HLA Antigens; Humans; Pharmaceutical Preparations; Pharmacogenetics; Polymorphism, Genetic

Topics: Adult; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HLA-B Antigens; Humans; Male; Reverse Transcriptase Inhibitors; Taiwan

To study the correlation between the HLA-B*5701 allele and the single nucleotide polymorphism in HCP5 (rs2395029).. All HIV patients naive for abacavir seen at our institution between September 2007 and December 2008 were prospectively screened for HLA-B*5701. HCP5 rs2395029 genotyping was carried out by allelic discrimination using the TaqMan 5'-nuclease assay. High-resolution HLA class I typing was undertaken using sequence-specific primers.. A total of 245 HIV patients were included in the study. A good correlation between HLA-B*5701 and HCP5 was observed (negative and positive predictive values of 100% and 93%, respectively).. The use of HCP5 rs2395029 testing could be as useful as HLA-B*5701 typing to prevent the abacavir hypersensitivity reaction. Given that HCP5 testing is cheaper, less time-consuming and easier to perform than HLA typing, it may confidently replace the latter in clinical settings.

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Female; HIV Infections; HLA-B Antigens; Humans; Major Histocompatibility Complex; Male; Middle Aged; Polymorphism, Single Nucleotide; Predictive Value of Tests; Prospective Studies; RNA, Long Noncoding; RNA, Untranslated

Avoiding abacavir in HIV-infected patients tested positive for HLA-B*5701 reduces the risk of abacavir hypersensitivity reaction (ABC-HSR). Our aim was to assess the costs of clinically suspected HSR and to estimate potential cost savings of implementing prospective HLA-B*5701-screening for HIV-infected patients initiating abacavir/lamivudine fixed-dose combination (ABC/3TC FDC) compared to initiating respective treatment without screening.. Employing a decision tree model the expected HSR-related costs of screening vs. no screening were estimated from the societal and healthcare payer perspective (reference year 2007). A retrospective standardized assessment of all clinically suspected ABC-HSR cases without screening at 5 German HIV-centres was performed to measure resource consumption. In- and outpatient care, discarded ABC/3TC FDC and concomitant medication were considered. Direct resource utilization was valued using German fees (EBM, G-DRGs). Indirect costs were measured with the human capital approach. Estimates for the HLA-B*5701-prevalence, HSR-incidence, and hospitalization rate were based on clinical trials and cohorts and it was assumed that screening reduces the incidence of clinically suspected ABC-HSR from 10% to 0.5%.. Thirty-two ABC-HSR cases were identified from 1998 to 2007. Mean direct and total costs per clinically suspected HSR case were Euro 1,362 and Euro 2,235, respectively. Hospital costs contributed 63.3% to direct costs. Potential cost savings when implementing genetic screening were estimated at Euro 44 and Euro 127 per screened patient, from a healthcare payer or societal perspective.. HLA-B*5701 screening prior to ABC/3TC FDC initiation prevents significant HSR-related costs per screened patient and is likely to lead to overall net savings.

Topics: Anti-HIV Agents; Costs and Cost Analysis; Dideoxynucleosides; Drug Hypersensitivity; Drug Therapy, Combination; Germany; HLA-B Antigens; Hospitalization; Humans; Lamivudine; Mass Screening; Retrospective Studies; Reverse Transcriptase Inhibitors

Abacavir sulfate (abacavir) is associated with a hypersensitivity reaction (HSR) that affects 5-8% of patients. While serious complications are rare, failure to identify it, or abacavir re-challenge following HSR, can be fatal. Genetic screening for HLA-B*5701 can identify patients who are likely to experience an HSR and reduces the incidence of the reaction.. We assessed the intrinsic and practical value, from the US healthcare system perspective, of prospective HLA-B*5701 screening among a population of antiretroviral-naive patients without elevated risk factors for cardiovascular disease, plasma HIV RNA >100,000 copies/mL, or pre-existing renal insufficiency.. Two approaches were used to evaluate the costs and benefits of prospective screening. First, the efficiency of HLA-B*5701 screening compared with no screening prior to abacavir initiation (intrinsic value of screening) was evaluated using a 60-day decision-tree model. Next, the practical value of screening was assessed using a lifetime discrete-event simulation model that compared HLA-B*5701 screening prior to abacavir use versus initiation with a tenofovir-containing regimen. Screening-effectiveness parameters were taken from an open-label trial that incorporated screening prior to abacavir initiation and other published studies. Treatment efficacy was derived from clinical trials. Modelling assumptions, costs ($US, year 2007 values) and other parameters were derived from published sources, primary data analysis and expert opinion. Multiple one-way sensitivity and scenario analyses were performed to assess parameter uncertainty. The primary outcome measure for the short-term screening versus no screening analysis was cost per patient. For the long-term analysis, outcomes were presented as QALYs. Costs and effects were discounted at 3% per year.. Over the first 60 days of treatment, prospective screening prior to abacavir initiation cost an additional $US17 per patient and avoided 537 HSRs per 10,000 patients. The per-patient cost of screening was sensitive to the cost of the genetic test, HSR costs and screening performance. In the lifetime model, screening-informed abacavir use was more effective and less costly than initiation with a tenofovir-containing regimen in the base case and in sensitivity analyses.. Our results suggest that prospective HLA-B*5701 screening prior to abacavir initiation produces cost savings and should become a standard component of HIV care.

Topics: Adenine; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Computer Simulation; Cost-Benefit Analysis; Decision Trees; Dideoxynucleosides; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Genetic Testing; HIV Infections; HLA-B Antigens; Humans; Middle Aged; Models, Economic; Organophosphonates; Quality-Adjusted Life Years; Tenofovir; United States

Abacavir (ABC) is an antiretroviral drug highly effective in the treatment of HIV, but its intake can cause severe hypersensitivity reaction (HSR). A strong association between HLA-B(*)57:01 and ABC HSRs was reported by several studies, which demonstrated that HLA-B(*)57:01 screening had a 100% negative predictive value and that it could accurately identify patients at high risk of ABC HSRs. We propose a new sequence-specific primer PCR assay based on fluorescence detection through CE which is highly sensitive, allowing the use of non-infective sources of DNA such as saliva and buccal swabs, in addition to blood and reproducible, allowing automation of the analytical process. The results of our study were first compared with a standard sequence-specific primer PCR technique and reported a concordance of 100%, and then a blind external validation further confirmed the accuracy of our method.

Topics: Blood Chemical Analysis; Cheek; Dideoxynucleosides; DNA; DNA Primers; Drug Hypersensitivity; Electrophoresis, Capillary; Genetic Predisposition to Disease; Genetic Testing; HIV Infections; HLA-B Antigens; Humans; Mouth Mucosa; Polymerase Chain Reaction; Reproducibility of Results; Sensitivity and Specificity; Spectrometry, Fluorescence

A hypersensitivity reaction to abacavir develops in approximately 2-8% of HIV patients receiving this drug and is strongly associated with presence of the human leukocyte antigen (HLA)-B*5701. Screening for HLA-B*5701 reduces the risk of developing an abacavir hypersensitivity reaction. The carriage rate of HLA-B*5701 has not been studied in Georgia before 2009. Objective of the study was to determine HLA-B*5701 prevalence in HIV-infected patients in Georgia. One hundred and sixty HIV positive patients attending Georgian Infectious Diseases, AIDS and Clinical Immunology Research Center in 2009 were recruited for the study. None of the patients had previously been treated with abacavir. Blood samples were collected and screened for HLA-B*5701 prior to abacavir prescription. Of 160 patients recruited 9 tested HLA B*5701 positive - 5.6% (95% CI: 2.6-10.4%). Of these nine patients 7 were males (male prevalence: 6.5%, 95% CI: 2.6-12.9 %) and 2 females (female prevalence: 4.8%, 95% CI: 0.6-16.2%). The first prospective study of HLA-B*5701 prevalence in Georgia show similar results to the results of other studies. Abacavir still remains one of the key drugs of antiretroviral regimens in Georgia and other countries. Therefore, prospective HLA-B*5701 screening should be implemented in all settings where abacavir is widely used to guide selection of ART regimens and to reduce the risk of potentially life threatening hypersensitivity reaction.

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Female; Genetic Markers; Genetic Testing; Georgia (Republic); HIV; HIV Infections; HLA-B Antigens; Humans; Male; Prospective Studies; Reverse Transcriptase Inhibitors

Human leukocyte antigen allele (HLA)-B*5701 is associated with abacavir hypersensitivity. However, the carriage rate of HLA-B*5701 has rarely been studied in Asians. In 534 Korean patients with human immunodeficiency virus infection, HLA-B*5701 status was determined by polymerase chain reaction with HLA-B*5701-specific primers. No patients had the HLA-B*5701 allele (95% confidence interval, 0%-0.7%). This explains the paucity of immunologically confirmed cases of abacavir hypersensitivity in Koreans.

Topics: Adult; Dideoxynucleosides; Drug Hypersensitivity; Ethnicity; Female; Genetic Testing; HIV Infections; HLA-B Antigens; Humans; Korea; Male; Middle Aged; Polymerase Chain Reaction

HLA-B*5701 is strongly related to abacavir hypersensitivity reactions (HSRs). Polymorphisms at position 245 of HIV type-1 (HIV-1) reverse transcriptase (RT) show an association with HLA-B*5701 suggesting that viral genotyping performed for antiretroviral drug resistance testing could reduce human leukocyte antigen (HLA) screening necessity to prevent abacavir HSR.. To further test the validity of 245 codon analysis results for predicting HSR, we analysed 1,179 sequences from 752 HIV-1-infected patients.. Mutant amino acid residues in RT 245 were found in 30.6% of sequences. Among 239 patients with multiple longitudinal genotypes, 245 residues varied in 37 (15.5%) from wild type to mutant and/or vice versa. All these changes appeared during antiretroviral treatment. A total of 15 out of 229 (6.5%) abacavir-treated patients developed a clinically confirmed HSR: all carried B subtypes. There was no significant difference in the prevalence of 245 mutants between abacavir-treated patients with HSR (27%) and those without (29%), even after limiting the analysis to subtype B carriers.. The significant intraindividual variability of 245 residues and the lack of their association with clinically confirmed HSR argue against their use as viral genetic markers to exclude patients at risk for HSR.

Topics: Biomarkers; Dideoxynucleosides; Drug Hypersensitivity; Drug Resistance, Viral; Genotype; HIV Infections; HIV Reverse Transcriptase; HIV-1; HLA-B Antigens; Humans; Mutation; Polymorphism, Genetic; Reverse Transcriptase Inhibitors; RNA, Viral; Sequence Analysis, DNA; Sequence Analysis, RNA

The discovery of new associations between drug toxicities and specific HLA alleles has been facilitated by the use of DNA-based molecular techniques and the introduction of higher-resolution HLA typing, which have replaced serological typing in this field of study. Drug toxicity/HLA associations have been best documented for immunologically mediated reactions, such as drug hypersensitivity reactions associated with the use of abacavir, and severe cutaneous adverse drug reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis induced by carbamazepine and allopurinol use, respectively. The implementation of HLA-B*5701 screening for the prevention of abacavir hypersensitivity syndrome (ABC HSR) has provided a model approach that can be applied to the screening of other drugs. High-level clinical evidence supporting HLA-B*5701 screening for ABC HSR has converged with experimental findings characterizing the CD8+T-cell HLA-B*5701-restricted immune response triggered by abacavir. This has been followed by the successful development of simplified inexpensive and quality-assured laboratory tests for HLA-B*5701 and ongoing quality assurance programs, resulting in a paradigm both for the implementation of HLA-B*5701 screening for HIV providers as well as for the broader successful implementation of pharmacogenetic screening in the clinic.

Topics: Dideoxynucleosides; Drug Hypersensitivity; Genetic Testing; Histocompatibility Antigens; HIV Infections; Humans; Pharmacogenetics

Topics: Dideoxynucleosides; Drug Hypersensitivity; Flow Cytometry; Genetic Predisposition to Disease; HIV Infections; HLA-B Antigens; Humans; Mass Screening; Pharmacogenetics; Reverse Transcriptase Inhibitors; Sensitivity and Specificity

Screening for HLA-B 5701 reduces the risk of developing an abacavir hypersensitivity reaction (ABC HSR) and is recommended in all patients before initiating highly active antiretroviral therapy (HAART) with abacavir. Between September 2007 and March 2008 we conducted a study of the attitudes and practice patterns of HIV providers in the United States to identify barriers to HLA-B 5701 testing in clinical practice. Study participants who completed an educational program could receive HLA-B 5701 test kits for use in their clinical practice. Surveys were administered before and after the educational program. A total of 477 HIV providers registered to participate in the survey, and 134 providers tested a total of 874 HIV-infected subjects, of which 6% (49/874) were HLA-B 5701 positive. Of 433 providers who completed the preeducation survey, 97% indicated that the test provided clinical value and 77% anticipated barriers to testing, with cost/reimbursement the most frequently cited. Among 202 providers who completed the posteducation survey, perceptions of the test's value remained largely unchanged while the proportion of providers who anticipated or encountered barriers to testing decreased. Of providers who used HLA-B 5701 test kits, 86% (115/134) found it "very easy" or "easy" to obtain test results, 95% (127/134) found it "very easy" or "easy" to interpret results, and 89% (119/134) indicated that they planned to continue HLA-B 5701 testing after the study. The results of this study suggest that HLA-B 5701 testing is easy to use in clinical practice and is a valuable tool to help reduce the risk of developing ABC HSR.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Attitude of Health Personnel; Case-Control Studies; Dideoxynucleosides; Drug Hypersensitivity; Histocompatibility Testing; HIV Infections; HIV-1; HLA-B Antigens; Humans; Reverse Transcriptase Inhibitors; United States

Adverse drug reactions (ADRs) have a major impact on patients, physicians, health care providers, regulatory agencies and pharmaceutical companies. Identifying the genetic contributions to ADR risk may lead to a better understanding of the underlying mechanisms, identification of patients at risk and a decrease in the number of events. Technological advances have made the routine monitoring and investigation of the genetic basis of ADRs during clinical trials possible. We demonstrate through simulation that genome-wide genotyping, coupled with the use of clinically matched or population controls, can yield sufficient statistical power to permit the identification of strong genetic predictors of ADR risk in a prospective manner with modest numbers of ADR cases. The results of a 500,000 single nucleotide polymorphism analysis of abacavir-associated hypersensitivity reaction suggest that the known HLA-B gene region could be identified with as few as 15 cases and 200 population controls in a sequential analysis.

Topics: Clinical Trials as Topic; Dideoxynucleosides; DNA; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Genome, Human; HLA-B Antigens; Humans; Pharmacogenetics; Polymorphism, Single Nucleotide

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Brachial Plexus Neuritis; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HIV-1; Humans; Male; Reverse Transcriptase Inhibitors

Topics: Dideoxynucleosides; Drug Hypersensitivity; Genetic Testing; HIV Infections; HLA-B Antigens; Humans; Patch Tests; Reverse Transcriptase Inhibitors

Topics: Black People; Dideoxynucleosides; Drug Hypersensitivity; Genetic Testing; Genotype; HIV Infections; HLA-B Antigens; Humans; Reverse Transcriptase Inhibitors

The basis for strong immunogenetic associations between particular human leukocyte antigen (HLA) class I allotypes and inflammatory conditions like Behçet's disease (HLA-B51) and ankylosing spondylitis (HLA-B27) remain mysterious. Recently, however, even stronger HLA associations are reported in drug hypersensitivities to the reverse-transcriptase inhibitor abacavir (HLA-B57), the gout prophylactic allopurinol (HLA-B58), and the antiepileptic carbamazepine (HLA-B*1502), providing a defined disease trigger and suggesting a general mechanism for these associations. We show that systemic reactions to abacavir were driven by drug-specific activation of cytokine-producing, cytotoxic CD8+ T cells. Recognition of abacavir required the transporter associated with antigen presentation and tapasin, was fixation sensitive, and was uniquely restricted by HLA-B*5701 and not closely related HLA allotypes with polymorphisms in the antigen-binding cleft. Hence, the strong association of HLA-B*5701 with abacavir hypersensitivity reflects specificity through creation of a unique ligand as well as HLA-restricted antigen presentation, suggesting a basis for the strong HLA class I-association with certain inflammatory disorders.

Topics: Anti-HIV Agents; Antigen Presentation; CD8-Positive T-Lymphocytes; Dideoxynucleosides; Drug Hypersensitivity; HLA-B Antigens; Humans; Lymphocyte Activation; Reverse Transcriptase Inhibitors

Hypersensitivity reactions to abacavir occur in 5-8% of patients starting treatment with this drug and limits future treatment. Some host genetic factors, especially the HLA-B*5701 allele, have been identified as risk factors for hypersensitivity reaction in Caucasians. Consequently, the possibility of routine implementation of a genetic test to rule out the presence of this allele has been proposed to achieve a personalized therapeutic profile. The present article discusses all the information related to hypersensitivity to abacavir and its genetic and immunological markers, as well as the distinct techniques for HLA-B*5701 allele detection. The various studies performed to date in distinct population are also discussed.

Topics: Alleles; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Genetic Markers; Genetic Predisposition to Disease; HIV Infections; HLA-B Antigens; Humans

Topics: Anti-HIV Agents; Case-Control Studies; Dideoxynucleosides; Drug Hypersensitivity; Drug Labeling; Genetic Testing; HIV Infections; HLA-B Antigens; Humans; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; United States; United States Food and Drug Administration

Technological and scientific advances, stemming in large part from the Human Genome and HapMap projects, have made large-scale, genome-wide investigations feasible and cost effective. These advances have the potential to dramatically impact drug discovery and development by identifying genetic factors that contribute to variation in disease risk as well as drug pharmacokinetics, treatment efficacy, and adverse drug reactions. In spite of the technological advancements, successful application in biomedical research would be limited without access to suitable sample collections. To facilitate exploratory genetics research, we have assembled a DNA resource from a large number of subjects participating in multiple studies throughout the world. This growing resource was initially genotyped with a commercially available genome-wide 500,000 single-nucleotide polymorphism panel. This project includes nearly 6,000 subjects of African-American, East Asian, South Asian, Mexican, and European origin. Seven informative axes of variation identified via principal-component analysis (PCA) of these data confirm the overall integrity of the data and highlight important features of the genetic structure of diverse populations. The potential value of such extensively genotyped collections is illustrated by selection of genetically matched population controls in a genome-wide analysis of abacavir-associated hypersensitivity reaction. We find that matching based on country of origin, identity-by-state distance, and multidimensional PCA do similarly well to control the type I error rate. The genotype and demographic data from this reference sample are freely available through the NCBI database of Genotypes and Phenotypes (dbGaP).

Topics: Case-Control Studies; Databases, Genetic; Dideoxynucleosides; Drug Hypersensitivity; Female; Genetics, Population; Genome, Human; Genotype; Humans; Male; Pharmacogenetics; Polymorphism, Single Nucleotide; Population Groups; White People

The aim of the study was to investigate the incidence of abacavir-related hypersensitivity reaction (HSR) and associated deaths in EuroSIDA HIV-1-infected patients.. Poisson regression models were developed to compare incidence of abacavir discontinuation according to the line of therapy within which abacavir was received, geographical regions, calendar time and drug formulation (abacavir/lamivudine combination tablet versus abacavir as a single drug or abacavir/zidovudine/lamivudine combination).. Of 3,278 patients that started abacavir, 2,101 (64.1%) discontinued. Of these, 167 (5.1%) discontinued abacavir within 3 months due to HSR with an incidence of 22.1 (95% confidence interval [CI] 18.7-25.4) per 100 person-years of follow-up. After adjustment for gender, prior AIDS, hepatitis C serostatus, baseline CD4+ T-cell count, region and calendar time, HSR incidence was significantly higher in those starting abacavir in a first-line regimen compared with second-line (incidence rate ratio [IRR] 2.04 [95% CI 1.24-3.38]; P=0.005). There was no significant difference between regions. HSR incidence from 2005 onwards was significantly lower compared with 1999-2000 (IRR 0.54 [95% CI 0.32-0.92]; P=0.024). There was a lower observed incidence in patients starting abacavir/lamivudine compared with other formulations (IRR 0.33 [95% CI 0.13-0.88]; P=0.027), however, available data were limited.. Incidence of abacavir-related HSR is higher in patients starting abacavir in first-line therapy, which could indicate increased over-diagnosis. HSR incidence has decreased in recent years, which might reflect the wider availability of genetic screening and improved awareness of symptoms. There were no reported deaths due to abacavir HSR.

Topics: Adult; Anti-HIV Agents; Cohort Studies; Dideoxynucleosides; Drug Administration Schedule; Drug Hypersensitivity; Drug Therapy, Combination; Europe; Female; HIV Infections; HIV-1; Humans; Incidence; Lamivudine; Male; Middle Aged; Poisson Distribution; Reverse Transcriptase Inhibitors; Treatment Outcome; Zidovudine

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Gene Expression Regulation; Genetic Predisposition to Disease; HIV Infections; HLA-B Antigens; Humans

Topics: Algorithms; Anti-HIV Agents; Clinical Trials as Topic; Dideoxynucleosides; Drug Hypersensitivity; HLA-B Antigens; Humans; Patch Tests

To evaluate the clinical impact and cost-effectiveness of HLA-B*5701 testing to guide selection of first-line HIV regimens in the United States.. Cost-effectiveness analysis using a simulation model of HIV disease. The prevalence of HLA-B*5701 and the probabilities of confirmed and unconfirmed severe systemic hypersensitivity reaction among patients taking abacavir testing HLA-B*5701 positive and negative were from the Prospective Randomized Evaluation of DNA Screening in a Clinical Trial study. The monthly costs of abacavir-based and tenofovir-based regimens were $1135 and $1139, respectively; similar virologic efficacy was assumed and this assumption was varied in sensitivity analysis.. Simulated cohort of patients initiating HIV therapy.. The interventions are first-line abacavir, lamivudine, and efavirenz without pretreatment HLA-B*5701 testing; the same regimen with HLA-B*5701 testing; and first-line tenofovir, emtricitabine, and efavirenz.. Quality-adjusted life years and lifetime medical costs discounted at 3% per annum, cost-effectiveness ratios ($/QALY).. Abacavir-based treatment without HLA-B*5701 testing resulted in a projected 30.93 years life expectancy, 16.23 discounted quality-adjusted life years, and $472,200 discounted lifetime cost per person. HLA-B*5701 testing added 0.04 quality-adjusted months at an incremental cost of $110, resulting in a cost-effectiveness ratio of $36,700/QALY compared with no testing. Initiating treatment with a tenofovir-based regimen increased costs without improving quality-adjusted life expectancy. HLA-B*5701 testing remained the preferred strategy only if abacavir-based treatment had equal efficacy and cost less per month than tenofovir-based treatment. Results were also sensitive to the cost of HLA-B*5701 testing and the prevalence of HLA-B*5701.. Pharmacogenetic testing for HLA-B*5701 is cost-effective only if abacavir-based treatment is as effective and costs less than tenofovir-based treatment.

Topics: Adenine; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cost-Benefit Analysis; Dideoxynucleosides; Drug Costs; Drug Hypersensitivity; Female; Genetic Testing; Health Care Costs; HIV Infections; HLA-B Antigens; Humans; Male; Middle Aged; Models, Biological; Organophosphonates; Pharmacogenetics; Quality-Adjusted Life Years; Reverse Transcriptase Inhibitors; Sensitivity and Specificity; Tenofovir; Treatment Outcome

Abacavir is a potent nucleoside analog reverse transcriptase inhibitor approved for the treatment of HIV infection. Approximately 5-8% of Caucasian patients receiving abacavir develop a hypersensitivity reaction, characterized by rash, fever and, occasionally, multisystemic involvement. Rechallenge with the drug can be fatal. The discovery of the mechanisms involved in this hypersensitivity reaction and the identification of tools for its prediction are the subject of this review. The most relevant finding is the recognition of a strong association between one specific haplotype at the HLA complex type I, HLA-B*5701, and the abacavir hypersensitivity reaction. The heterogeneity in the prevalence of HLA-B*5701 across distinct ethnicities accounts for differences in the risk of abacavir hypersensitivity reactions in distinct populations.

Topics: Alleles; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Forecasting; Genetic Testing; Haplotypes; HIV Infections; HLA-B Antigens; Humans; Models, Immunological; Reverse Transcriptase Inhibitors; Risk Factors; Sensitivity and Specificity

Topics: Dideoxynucleosides; Drug Hypersensitivity; Drug Labeling; Humans; Reverse Transcriptase Inhibitors; United States; United States Food and Drug Administration

We aimed to assess the value of a structured clinical assessment and genetic testing for refining the diagnosis of abacavir hypersensitivity reactions (ABC-HSRs) in a routine clinical setting.. We performed a diagnostic reassessment using a structured patient chart review in individuals who had stopped ABC because of suspected HSR. Two HIV physicians blinded to the human leukocyte antigen (HLA) typing results independently classified these individuals on a scale between 3 (ABC-HSR highly likely) and -3 (ABC-HSR highly unlikely). Scoring was based on symptoms, onset of symptoms and comedication use. Patients were classified as clinically likely (mean score > or =2), uncertain (mean score > or = -1 and < or = 1) and unlikely (mean score < or = -2). HLA typing was performed using sequence-based methods.. From 131 reassessed individuals, 27 (21%) were classified as likely, 43 (33%) as unlikely and 61 (47%) as uncertain ABC-HSR. Of the 131 individuals with suspected ABC-HSR, 31% were HLA-B*5701-positive compared with 1% of 140 ABC-tolerant controls (P < 0.001). HLA-B*5701 carriage rate was higher in individuals with likely ABC-HSR compared with those with uncertain or unlikely ABC-HSR (78%, 30% and 5%, respectively, P < 0.001). Only six (7%) HLA-B*5701-negative individuals were classified as likely HSR after reassessment.. HLA-B*5701 carriage is highly predictive of clinically diagnosed ABC-HSR. The high proportion of HLA-B*5701-negative individuals with minor symptoms among individuals with suspected HSR indicates overdiagnosis of ABC-HSR in the era preceding genetic screening. A structured clinical assessment and genetic testing could reduce the rate of inappropriate ABC discontinuation and identify individuals at high risk for ABC-HSR.

Topics: Anti-HIV Agents; Cohort Studies; Dideoxynucleosides; Drug Hypersensitivity; Genetic Predisposition to Disease; Genetic Variation; HIV Infections; HLA-B Antigens; Humans; Patch Tests; Switzerland

Topics: Dideoxynucleosides; Drug Hypersensitivity; Genetic Markers; Genetic Testing; HLA-B Antigens; Humans; Patch Tests; Pharmacogenetics; Reverse Transcriptase Inhibitors

Although the human leukocyte antigen (HLA)-B*5701 is highly associated with a hypersensitivity reaction (HSR) to abacavir (ABC), variable sensitivities have been reported when clinical data alone have been used to define an ABC HSR. This study evaluated the sensitivity of detection of the HLA-B*5701 allele as a marker of ABC HSRs in both white and black patients, using skin patch testing to supplement clinical diagnosis.. White and black patients, identified through chart review, were classified as having received a diagnosis of an ABC HSR based on clinical findings only (a clinically suspected ABC HSR) or based on clinical findings and a positive skin patch test result (an immunologically confirmed [IC] ABC HSR). Control subjects were racially matched subjects who tolerated ABC for >/=12 weeks without experiencing an ABC HSR. Patients and control subjects were tested for the presence of HLA-B*5701. Sensitivity, specificity, and odds ratios for the detection of HLA-B*5701 as a marker for an ABC HSR were calculated for white and black participants.. Forty-two (32.3%) of 130 white patients and 5 (7.2%) of 69 black patients who met the criteria for clinically suspected HSRs had IC HSRs. All 42 white patients with IC HSRs were HLA-B*5701 positive (sensitivity, 100%; odds ratio, 1945; 95% confidence interval, 110-34,352). Among all white patients with clinically suspected HSRs, sensitivity was 44% (57 of 130 patients tested positive for HLA-B*5701); specificity among white control subjects was 96%. Five of 5 black patients with IC HSRs were HLA-B*5701 positive (sensitivity, 100%; odds ratio, 900; 95% confidence interval, 38-21,045). Among black patients with clinically suspected HSRs, the sensitivity was 14% (10 of 69 tested positive for HLA-B*5701); specificity among black control subjects was 99%.. Although IC ABC HSRs are uncommon in black persons, the 100% sensitivity of HLA-B*5701 as a marker for IC ABC HSRs in both US white and black patients suggests similar implications of the association between HLA-B*5701 positivity and risk of ABC HSRs in both races.

Topics: Adolescent; Adult; Aged; Anti-HIV Agents; Black People; Dideoxynucleosides; Drug Hypersensitivity; Female; Gene Frequency; HLA-B Antigens; Humans; Male; Middle Aged; Pharmacogenetics; Sensitivity and Specificity; Skin Tests; United States; White People

Abacavir hypersensitivity in genetically susceptible individuals implicates an abacavir-specific T-cell response to either the parent drug or a metabolite generated in vivo. We have analysed the cytokine profile in antigen-presenting cells and the T-lymphocytes that are involved in the pathological immune response to abacavir.. In this study, we compared abacavir-specific cytokine responses in cultured peripheral blood mononuclear cells (PBMCs) from HIV-infected abacavir hypersensitive, tolerant and naive individuals. Cells were cultured in the presence or absence of abacavir. Cytokine expression was determined by microarray analysis, enzyme-linked immunosorbent assays and flow cytometry.. We demonstrated using in vitro models of immune activation that the production of interferon-gamma was specifically induced by abacavir treatment in PBMCs obtained from hypersensitive patients carrying the HLA-B*5701 allele (median 123.86 compared with -30.83 for tolerant controls, P=0.001).. These results provide further insight into the immunological and metabolic basis of abacavir hypersensitivity syndrome. In vitro assays could assist in the identification of susceptible loci by providing a surrogate marker for the hypersensitivity reaction. Such a marker could be studied in unexposed individuals to shed further light on the immunopathogenesis of the abacavir hypersensitivity syndrome.

Topics: Anti-HIV Agents; Cells, Cultured; Cytokines; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HLA-B Antigens; Humans; Interferon-gamma; Leukocytes, Mononuclear; Reverse Transcriptase Inhibitors

Topics: Anti-HIV Agents; Black People; Cohort Studies; Dideoxynucleosides; Drug Hypersensitivity; England; HIV Infections; HLA-B Antigens; HLA-B52 Antigen; Humans

Abacavir is associated with an infrequent but potentially serious hypersensitivity reaction (HSR) that can include a wide range of signs and symptoms. Identification of this reaction through medical insurance claims could provide a simple and efficient means of monitoring the incidence of abacavir hypersensitivity in large populations of patients.. Using data from a safety study of 948 abacavir users with 22 hypersensitivity events identified from claims and validated through medical record review, we used a recursive partitioning analysis to construct an algorithm to differentiate between patients with and without validated adverse events. Bootstrap resampling techniques provided validation for the analysis.. The analysis produced a classification tree with three decision nodes that comprised the best indicators of HSRs. The predictors included any one of several specific symptoms commonly found with this reaction, a claims diagnosis of adverse effect of drug, anaphylactic shock or unspecified allergy, and a discontinuation in abacavir prior to completing a 90-day course of therapy. The algorithm demonstrated 95% sensitivity and 90% specificity when tested using a bootstrap resampling approach with the current data.. A sensitive and specific algorithm for identifying abacavir hypersensitivity from claims was created. This algorithm would permit efficient identification of charts for medical review. Further testing of the algorithm with additional medical claims data for abacavir users will be required to ascertain its validity across databases.

Topics: Algorithms; Anti-HIV Agents; Decision Trees; Dideoxynucleosides; Drug Hypersensitivity; Female; HIV Infections; Humans; Insurance Claim Reporting; Male; Regression Analysis; Sensitivity and Specificity

A 36-year-old man with HIV infection developed a reaction compatible with an abacavir hypersensitivity reaction after switching from the twice-daily to the once-daily formulation. The switch was determined by a more convenient intake. The patient was treated with abacavir twice-daily plus lamivudine and efavirenz for more than 5 years with no side effects. At the time of this change, his CD4 count was 1069 cell/mm(3) and HIV-RNA undetectable. Our case suggests that patients should be carefully monitored after switching, and warned about the potential effects.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Dideoxynucleosides; Drug Administration Schedule; Drug Hypersensitivity; HIV Infections; Humans; Lamivudine; Male; Oxazines; RNA, Viral

The introduction of highly active antiretroviral therapy (also known as combination therapy) has transformed the nature of HIV infection from a severe and ultimately fatal disease to that of a manageable chronic condition. HIV drugs are highly efficacious, but their use comes at the cost of a range of drug-related adverse events, including severe drug hypersensitivity reactions (HSRs) that have been most notably associated with abacavir and nevirapine therapy. This article discusses the issues of pharmacogenetic screening, in the light of the strong genetic association of the HLA-B*5701 allele and the susceptibility to developing abacavir HSRs. It also presents the screening's impact on clinical practice and discusses the practical considerations that influence the introduction and cost-effectiveness of such screening.

Topics: Alleles; Anti-HIV Agents; Dideoxynucleosides; Drug Evaluation, Preclinical; Drug Hypersensitivity; Genetic Testing; HIV Infections; HIV-1; HLA-B Antigens; Humans; Pharmacogenetics; Predictive Value of Tests

A potentially life-threatening hypersensitive reaction accompanies the use of HIV nucleoside analogue abacavir (ABC) in 4-8% of Caucasian individuals. HLA-B*5701 and Hsp70 493T alleles have been shown to predict susceptibility to this hypersensitivity.. This study was undertaken to provide a mechanistic understanding of the highly significant genetic association of HLA Class I and Hsp70 alleles with ABC hypersensitivity.. In this study an ABC-induced localization of intracellular HSP70 to endosomal vesicles of antigen-presenting cells was demonstrated. This ABC-stimulated redistribution of endogenous HSP70 was substantially higher in the genetically homogenous HLA-B*5701, Hsp70 493T ABC-hypersensitive individuals and ABC-naive individuals in comparison with the heterogeneous tolerant patients (P = 0.023). Increased expression of HSP70 was also detected in the hypersensitive group as measured by flow cytometry (P = 0.032). Blocking of HSP70 and HSP70 cell surface receptors CD14 and TLR2 abrogated ABC-stimulated HSP70 redistribution in sensitized individuals to basal levels (P < 0.004). In addition, the use of TcRalphabeta and HLA-B57/58 antibodies also ablated the expression of HSP70. Cells expressing the activation markers CD40 were increased after ABC stimulation in the hypersensitive patients (P = 0.006). ABC-stimulated interferon-gamma levels were higher in hypersensitive patients in comparison with ABC-tolerant individuals with a mean of 123.54 versus 0 pg/ml (P = 0.001).. The present data indicates that ABC stimulates an innate immune response and activates antigen-presenting cells via the endogenous HSP70-mediated Toll-like receptor pathway in genetically susceptible individuals potentially initiating the immuno-pathological hypersensitive response.

Topics: Antigen-Presenting Cells; CD40 Antigens; Cells, Cultured; Dideoxynucleosides; Drug Hypersensitivity; Endoplasmic Reticulum; Endosomes; Fluorescent Antibody Technique; Histocompatibility Antigens Class I; HIV Seropositivity; HLA-B Antigens; HSP70 Heat-Shock Proteins; Humans; Immunophenotyping; Interferon-gamma; Microscopy, Confocal; Monocytes; Receptors, Cell Surface; Reverse Transcriptase Inhibitors

Inheritance of HLA-B*5701 is a strong predictor of a hypersensitivity reaction to the anti-HIV drug abacavir. The identification of susceptible individuals prior to the institution of abacavir therapy is therefore of clinical importance and has generated demand for a simple and rapid diagnostic test for carriage of HLA-B*5701. In this study, we describe the development of such a method based on allele-specific polymerase chain reaction (AS-PCR) and melting curve analysis. Ninety-six patient samples including 36 HLA-B*5701-positive samples and 60 HLA-B*5701-negative samples were analysed. Compared with sequence-based typing, this method had 100% sensitivity and specificity for the HLA-B*5701 allele. In conclusion, the AS-PCR/melting curve approach minimises post-polymerase chain reaction handling processing and provides an attractive alternative to currently described AS-PCR methods.

Topics: Alleles; Anti-HIV Agents; Base Sequence; Biological Assay; Dideoxynucleosides; Drug Hypersensitivity; Genetic Testing; Histocompatibility Testing; HLA-B Antigens; Hot Temperature; Humans; Molecular Sequence Data; Polymerase Chain Reaction; Reverse Transcriptase Inhibitors; Sensitivity and Specificity

To describe the incidence of hypersensitivity to abacavir and frequency of human leucocyte antigen (HLA)-B*5701 in HIV-infected Taiwanese persons.. Medical records of 337 HIV-infected Taiwanese in whom abacavir-containing combination antiretroviral therapy (CART) was prescribed from 1 May 2001 to 31 December 2006 were reviewed, and HLA typing of the patients was performed in 320 patients (232 receiving abacavir and 88 not receiving abacavir) with available blood samples. HLA class I and II polymorphisms were determined by PCR with specific primers. HLA-B*5701 was further confirmed by sequence-based typing.. Of the 337 patients, median CD4 count was 166.5 cells/mm3 (range, 1.0-1914.0) and 83 patients (24.6%) had AIDS-defining opportunistic infections. Thirty-eight patients (11.3%) discontinued abacavir within 6 weeks of starting abacavir-containing CART. Among them, 10 patients had successful abacavir re-challenge and another 11 patients had other specific reasons for abacavir discontinuation. Therefore, 14 patients (4.2%) were classified as cases in whom abacavir hypersensitivity could not be excluded, and 3 patients (0.9%) met the criteria of abacavir hypersensitivity. Of the 320 patients undergoing HLA typing, HLA-A02 was the most common allele and only one individual (0.3%) expressed HLA-B*5701. Along with some differences in allele distributions, there was a significant difference in the genetic frequency of HLA-B57 in our patients compared with those of previous studies in other Chinese populations.. Abacavir hypersensitivity was less frequently encountered in HIV-infected Taiwanese initiating abacavir-containing CART than in Caucasians, which might be explained by the low frequency of the HLA-B*5701 allele.

Topics: Adult; Alleles; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Drug Hypersensitivity; Female; Gene Frequency; HIV Infections; HLA Antigens; HLA-B Antigens; Humans; Male; Polymorphism, Genetic; Taiwan; Terminology as Topic

The aim of this study was to determine the incidence of abacavir discontinuation within the first two months of treatment and the link with a true hypersensitivity reaction (HSR).. A retrospective study was made between January 1998 and January 2006 on a cohort of HIV positive patients treated by abacavir delivered by the Bordeaux Saint-André University Hospital pharmacy.. Six hundred (and) twenty-eight patients were included. The reasons for non-renewal of abacavir prescription within the first three months of treatment were investigated. Early discontinuation for adverse effects was reported in 32 patients (5.1%): proved diagnosis of HSR (N=10), uncertain diagnosis of HSR (N=8), and no HSR (N=14). The decision for discontinuation was taken by physician after consultation in 76% of cases.

Topics: Dideoxynucleosides; Drug Hypersensitivity; Fever; France; Gastrointestinal Diseases; HIV Infections; Hospitals, University; Humans; Musculoskeletal Diseases; Retrospective Studies

Triple nucleoside reverse transcriptase inhibitors are recommended as an alternative regimen for HIV-infected patients undergoing tuberculosis treatment in resource-limited settings. Few data exist on the efficacy of such regimens in tuberculosis patients. In 34 tuberculosis/HIV-co-infected patients treated with zidovudine/lamivudine/abacavir, 76% achieved HIV RNA less than 50 copies/ml at 24 weeks. No cases of hypersensitivity or immune reconstitution syndrome were observed. These data support the continuing evaluation of nucleoside-based antiretroviral regimens as an alternative treatment for this population.

Topics: Adult; Antitubercular Agents; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Hypersensitivity; Drug Therapy, Combination; Female; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Neutropenia; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome; Tuberculosis, Pulmonary; Zidovudine

Topics: Dideoxynucleosides; Drug Hypersensitivity; Female; Fibrin; HIV Infections; Humans; Lung; Middle Aged; Pneumonia; Reverse Transcriptase Inhibitors

Topics: Alleles; Anti-HIV Agents; Cohort Studies; Dideoxynucleosides; Drug Hypersensitivity; Genetic Markers; Genetic Testing; HIV Reverse Transcriptase; HLA-B Antigens; Humans; Incidence; Polymorphism, Genetic; Sensitivity and Specificity

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; Humans; Reverse Transcriptase Inhibitors

HLA-B*5701 strongly predicts abacavir hypersensitivity (HSR), but implementation of effective routine screening into clinical practice requires testing be practical and accurate. We tested the proficiency of HLA-B*5701 typing among laboratories using sequence-specific primer PCR.. DNA panels (1 and 2) were distributed to seven laboratories (A to G) for blinded typing of the HLA-B*5701 allele. Panel 1 (n = 10 samples; n = 7 laboratories) included 3 positives and other closely related B17 subtypes (B*5702, B*5703, B*5704 and B*5801). Panel 2 (n = 96 samples; n = 4 laboratories) included 36 positives among a broad spectrum of other B alleles. Two laboratories (A and B) also submitted 96 routine samples, typed by the same methodology, to the reference centre for additional analysis by sequence-based typing.. All laboratories correctly typed panel 1 for HLA-B*5701 carriage. Laboratories A, B and C identified HLA-B*5701 alleles in panel 2 with 100% sensitivity and 100% specificity. Laboratory D reported one false negative, reportedly due to a sampling error. The results obtained for routine samples typed by laboratories A and B and those generated by the reference laboratory using sequencing were fully concordant.. Detection of HLA-B*5701 alleles among laboratories was 100% specific and 99.4% sensitive, indicating that participating HIV testing laboratories were currently offering effective primary screening to identify individuals at high risk of abacavir HSR. Accurate reporting of HLA-B*5701 status is critical for the safe administration of this drug and participation in quality assurance programmes by all sites who report HLA-B*5701 status should be promoted.

Topics: Alleles; Anti-HIV Agents; Dideoxynucleosides; DNA Primers; DNA Probes, HLA; Drug Hypersensitivity; Genetic Testing; HLA-B Antigens; Humans; Polymerase Chain Reaction; Quality Control; Reproducibility of Results; Sensitivity and Specificity

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; Humans; Male; Middle Aged

The use of abacavir (ABC) may be associated with a hypersensitivity reaction (HSR) that requires discontinuation of the drug. The HLA-B*5701 allele has been linked to this HSR. Information on the strength of this association across distinct geographic regions and ethnicities is scarce. We tested HLA-B*5701 in 53 Spaniards infected with HIV who received ABC treatment. The presence of HLA-B5701 had strong positive and negative predictive values for ABC HSR, 92% and 63%, respectively.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Genetic Testing; HLA-B Antigens; Humans; Predictive Value of Tests; Spain

Topics: Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HLA-B Antigens; Humans; Reverse Transcriptase Inhibitors

Abacavir hypersensitivity reaction (ABC HSR) is a potentially life-threatening adverse reaction that affects approximately 8% of patients that initiate this antiretroviral drug. Independent groups have shown a strong predictive association between ABC HSR and HLA-B*5701, indicating that exclusion of HLA-B*5701 positive individuals from abacavir treatment would largely prevent ABC HSR. However, the limited availability and relatively high cost of human leukocyte antigen (HLA) typing represent barriers to the widespread implementation of this pharmacogenetic approach to abacavir prescribing. To facilitate routine screening, we have developed a rapid flow cytometry method for HLA-B57 phenotyping using commercially available B17 monoclonal antibodies.. Whole blood samples from 84 human immunodeficiency virus (HIV) patients were examined by standard flow cytometry methods, using a two-colour B17-specific immunofluorescence assay in the CD45 lymphocyte population.. All eight HLA-B57 individuals examined tested positive, while HLA-B57/58 negative individuals (n=74) tested negative for this flow cytometry test. Two non-HLA-B57 individuals showed weak cross-reactivity.. In our predominantly Caucasian population, B17/CD45 dual staining was sufficient to identify individuals carrying B17 cell surface antigens. This approach, utilizing flow cytometry methods that are widely available in HIV laboratories, therefore offers a sensitive, rapid and cost-effective screening assay prior to abacavir prescription. Following risk stratification with this assay, it would be anticipated that identification of HLA-B*5701 using molecular HLA typing methods would be required in <10% of the screened population.

Topics: Alleles; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Flow Cytometry; Genetic Testing; Histocompatibility Testing; HIV Seropositivity; HLA-B Antigens; Humans; Sensitivity and Specificity

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; Humans; Reverse Transcriptase Inhibitors

Abacavir therapy is associated with significant drug hypersensitivity in approximately 8% of recipients, with retrospective studies indicating a strong genetic association with the HLA-B*5701 allele. In this prospective study, involving 260 abacavir-naive individuals (7.7% of whom were positive for HLA-B*5701), we confirm the usefulness of genetic risk stratification, with no cases of abacavir hypersensitivity among 148 HLA-B*5701-negative recipients.

Topics: Adult; Anti-HIV Agents; Australia; Cohort Studies; Dideoxynucleosides; Drug Hypersensitivity; Female; Genetic Testing; HIV Infections; HLA-B Antigens; Humans; Incidence; Male; Middle Aged

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Genetic Testing; HLA-B Antigens; Humans; Pharmacogenetics

To evaluate risk factors associated with the abacavir hypersensitivity reaction during primary HIV infection (PHI).. Acute HIV Infection and Early Disease Research Program protocol (AIEDRP) AI-02-001 provided antiretroviral therapy including abacavir. This retrospective analysis evaluated variables potentially associated with hypersensitivity in the cohort enrolled in AI-02-001 at the University of Washington Primary Infection Clinic.. Cases of suspected hypersensitivity were identified prospectively and reviewed retrospectively using a standardized case definition. Controls were the remaining cohort without hypersensitivity. Univariate analyses were performed by linear logistic regression.. Nine (18%) of 50 individuals treated with abacavir developed suspected hypersensitivity. Two of nine cases and no controls were HLA-B5701 positive. When antiretroviral medications were started, cases had lower mean CD8 T-cell percentage and plasma HIV RNA value. After 2 weeks on abacavir, cases had a lower mean HIV RNA value and a trend towards greater decrease in RNA. Cases began abacavir a median of 103 days after HIV acquisition compared to 48 days for controls. There was no significant in vitro abacavir-specific lymphoproliferation or IFN-gamma production in peripheral blood mononuclear cells from individuals following the suspected hypersensitivity reaction.. Abacavir use during PHI may be associated with increased risk of hypersensitivity. As in chronic infection, HLA-B5701 is associated with the abacavir hypersensitivity reaction in PHI. Although levels of CD8 T cells and HIV RNA may be risk factors for hypersensitivity, the observed association may be due to correlation with HLA-B5701. The interesting temporal association of hypersensitivity with initiation of abacavir later in PHI merits future investigation.

Topics: Adult; Case-Control Studies; Dideoxynucleosides; Drug Hypersensitivity; Flow Cytometry; HIV Infections; HIV-1; HLA-B Antigens; Humans; Logistic Models; Male; Prospective Studies; Retrospective Studies; Risk; Statistics, Nonparametric

Numerous large, long-term clinical trials have assessed the safety and efficacy of the two antiretroviral nucleoside analogs lamivudine and abacavir as components of highly active antiretroviral therapy for the treatment of patients with HIV-1 infection. This analysis pools the safety data on multi-drug regimens containing lamivudine/abacavir in combination with a protease inhibitor, non-nucleoside reverse transcriptase inhibitor, or nucleoside reverse transcriptase inhibitor.. Data are presented from 2279 treatment-naive HIV-1-infected patients who were enrolled in one of five clinical trials that assessed the safety and tolerability of lamivudine/abacavir in combination with a third antiretroviral agent. The well characterised combination of lamivudine/zidovudine plus efavirenz was used as the comparator arm. All available safety data (including data beyond 48 weeks) were used in all analyses, which included calculation of treatment emergent laboratory values, adverse events (AEs), serious AEs, fatalities, drug discontinuations and any summaries by study week of safety data.. In the total lamivudine/abacavir group, 1585 of 2229 (71%) patients experienced at least one drug-related AE during the study compared with 247 of 325 (76%) patients in the lamivudine/zidovudine/efavirenz treatment group. The most common drug-related AEs reported during the study were diarrhoea (19%), nausea (18%) and dizziness (12%) in patients treated with lamivudine/abacavir plus a third agent, and nausea (31%), dizziness (27%) and headache (16%) in the comparator group. Overall, in the total lamivudine/abacavir group there were only three severe (Division of AIDS 1992 toxicity table grade 3 or 4) AEs that were reported in >1% of subjects: drug hypersensitivity, elevated ALT levels and elevated AST levels. In the lamivudine/zidovudine/efavirenz group, six severe AEs that occurred in >1% of the safety population were reported. The abacavir hypersensitivity reaction rate reported in these five studies was comparable with the previously reported rate. In addition, there were no patient fatalities attributed by investigators to the study drugs.. This analysis indicates that the combination of lamivudine/abacavir is generally safe for the majority of patients when used as part of combination therapy.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Controlled Clinical Trials as Topic; Cyclopropanes; Dideoxynucleosides; Drug Hypersensitivity; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Incidence; Lamivudine; Male; Oxazines; Prospective Studies; Time Factors; Treatment Outcome; Zidovudine

Topics: Anti-HIV Agents; Clofibric Acid; Dideoxynucleosides; Drug Hypersensitivity; Drug Interactions; Drug Therapy, Combination; Fibric Acids; HIV Infections; Humans; Hyperlipidemias; Hypolipidemic Agents; Male; Middle Aged; Rhabdomyolysis

Abacavir is an effective antiretroviral drug used to treat HIV-1 infection. Approximately 5% of patients treated with abacavir develop a hypersensitivity reaction that requires discontinuation of the drug. In an initial pharmacogenetic study conducted in a predominantly White male population, multiple markers in the human leukocyte antigen (HLA)-B chromosomal region were associated with hypersensitivity to abacavir. The HLA-B*5701 association has now been confirmed in White males in a subsequent, larger study (n=293, p=4.7 x 10(-18)) and is also observed in White females (n=56, p=6.8 x 10(-6)) and Hispanics (n=104, p=2.1 x 10(-4)). HLA-B*5701 was not associated with hypersensitivity in Blacks (n=78, p=0.27). HLA-B*5701 alone lacks sufficient predictive value to identify patients at risk for hypersensitivity to abacavir across diverse patient populations. Efforts are ongoing to identify markers with sufficient sensitivity and specificity to be clinically useful. Even after a marker set is identified, appropriate clinical identification and management of hypersensitivity to abacavir must remain the cornerstone of clinical practice.

Topics: Anti-HIV Agents; Black People; Case-Control Studies; Dideoxynucleosides; Drug Hypersensitivity; Female; Genetic Markers; Genetic Variation; Genotype; HLA-B Antigens; Humans; Male; Polymorphism, Single Nucleotide; Retrospective Studies; Tumor Necrosis Factor-alpha; White People

Susceptibility to a clinically significant drug hypersensitivity syndrome associated with abacavir use seems to have a strong genetic component. We have previously shown that the presence of HLA-B*5701 strongly predicts abacavir hypersensitivity and have identified a potential susceptibility locus within a 300-kb region between the MEGT1 and C4A6 loci in the central MHC. We now report the results of fine recombinant genetic mapping in an expanded patient population of 248 consecutive, fully ascertained, abacavir-exposed individuals in the Western Australian HIV Cohort Study, in which 18 cases of definite abacavir hypersensitivity (7.3%) and 230 tolerant controls were identified. Haplotype mapping within patients with allelic markers of the 57.1 ancestral haplotype suggests a susceptibility locus within the 14-kb Hsp70 gene cluster. HLA-B*5701 was present in 94.4% of hypersensitive cases compared with 1.7% of controls (odds ratio, 960; P < 0.00001). A haplotypic nonsynonymous polymorphism of Hsp70-Hom (HspA1L, resulting from the substitution of residue M493T in the peptide-binding subunit) was found in combination with HLA-B*5701 in 94.4% of hypersensitive cases and 0.4% of controls (odds ratio, 3,893; P < 0.00001). Individuals with abacavir hypersensitivity demonstrated increased monocyte tumor necrosis factor expression in response to ex vivo abacavir stimulation, which was abrogated with CD8(+) T cell depletion. These data indicate that the concurrence of HLA-B*5701 and Hsp70-Hom M493T alleles is necessary for the development of abacavir hypersensitivity, which is likely to be mediated by an HLA-B*5701-restricted immune response to abacavir.

Topics: Chromosome Mapping; Dideoxynucleosides; Drug Hypersensitivity; Genetic Markers; Haplotypes; HLA-B Antigens; HSP70 Heat-Shock Proteins; Humans; Major Histocompatibility Complex; Molecular Sequence Data; Prevalence; T-Lymphocytes; Tumor Necrosis Factor-alpha

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Female; HIV Infections; Humans

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HIV-1; Humans; Male; Middle Aged

Researchers in Australia found an accurate test to predict who cannot tolerate Ziagen (abacavir). This is still a research test, not in general use.

Topics: Cohort Studies; Dideoxynucleosides; Drug Hypersensitivity; HLA-B Antigens; Humans; Pharmacogenetics; Reverse Transcriptase Inhibitors

Although the ever-expanding armamentarium of antiretroviral drugs has significantly decreased the morbidity and mortality due to human immunodeficiency virus infection, patients and clinicians are increasingly faced with the problems of inadequate or toxic response to therapy that may be genetically mediated. Significant evidence now exists that interindividual differences, such as efficacy of therapy, hypersensitivity reactions, and metabolic complications as a result of antiretroviral therapy, are in part genetically determined. This article reviews the significant studies published to date in the area of the pharmacogenetics of antiretroviral therapy and summarizes current trends, as well as areas where further research is needed.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cytokines; Dideoxynucleosides; Drug Hypersensitivity; Haplotypes; HIV Infections; HLA Antigens; Humans; Hyperbilirubinemia; Pharmacogenetics; Receptors, Chemokine

Abacavir, a human immunodeficiency virus-1 (HIV-1) nucleoside-analogue reverse transcriptase inhibitor, causes severe hypersensitivity in 4-8% of patients. HLA B*5701 is a known genetic risk factor for abacavir hypersensitivity in Caucasians. Our aim was to confirm the presence of this genetic factor in our patients, and to determine whether genotyping for HLA B*5701 would be a cost-effective use of healthcare resources.. Patients with and without abacavir hypersensitivity were identified from a UK HIV clinic. Patients were genotyped for HLA B*5701, and pooled data used for calculation of test characteristics. The cost-effectiveness analysis incorporated the cost of testing, cost of treating abacavir hypersensitivity, and the cost and selection of alternative antiretroviral regimens. A probabilistic decision analytic model (comparing testing versus no testing) was formulated and Monte Carlo simulations performed.. Of the abacavir hypersensitive patients, six (46%) were HLA B*5701 positive, compared to five (10%) of the non-hypersensitive patients (odds ratio 7.9 [95% confidence intervals 1.5-41.4], P = 0.006). Pooling of our data on HLA B*5701 with published data resulted in a pooled odds ratio of 29 (95% CI 6.4-132.3; P < 0.0001). The cost-effectiveness model demonstrated that depending on the choice of comparator, routine testing for HLA B*5701 ranged from being a dominant strategy (less expensive and more beneficial than not testing) to an incremental cost-effectiveness ratio (versus no testing) of Euro 22,811 per hypersensitivity reaction avoided.. Abacavir hypersensitivity is associated with HLA B*5701, and pre-prescription pharmacogenetic testing for this appears to be a cost-effective use of healthcare resources.

Topics: Adult; Cost-Benefit Analysis; Dideoxynucleosides; Drug Hypersensitivity; Female; Genotype; HIV Infections; HIV-1; HLA-B Antigens; Humans; Male; Middle Aged; Molecular Diagnostic Techniques; Monte Carlo Method; Odds Ratio; Pharmacogenetics; Point-of-Care Systems; Reverse Transcriptase Inhibitors; Risk Factors

Abacavir (ABC) is a generally well-tolerated NRTI. However, up to 5% of patients may develop hypersensitivity syndrome (HSS) within the first weeks of treatment. The objectives of this study were to describe the side effects of ABC, to evaluate the incidence of the ABC-HSS, and to identify the risk factors of HSS after first exposure to ABC in a cohort of patients followed up in a university HIV clinic.. The charts of all HIV-infected patients who started ABC between February 1998 and May 2002 were reviewed. HSS was defined as the onset, within 8 weeks of ABC initiation, of either a skin rash associated with at least one of the following symptoms (fever, gastrointestinal symptoms, respiratory symptoms, myalgia, malaise) or at least three of the above symptoms in the absence of rash. A multivariate logistic regression analysis was performed to identify risk factors of HSS.. Of the 191 patients studied (134 M, 57 F, mean age 39 years), 53 (27.8%) presented with manifestations that were regarded as potential side-effects of ABC. Ten (5.2%) developed HSS, none of whom died. Two factors were independently associated with an increased risk of HSS: history of allergy to nevirapine (OR 8.1, 95% CI 1.6-40.5, p = 0.02), and being naïve to ART (OR 5.8, 95% CI 1.2-28.5, p = 0.04).. This study "in the real world" confirms that the incidence of ABC-induced HSS is of about 5%. It also confirms that HSS occurs more frequently in patients with a history of allergy to nevirapine and in ART-naïve patients.

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Female; Humans; Incidence; Male; Retrospective Studies; Reverse Transcriptase Inhibitors; Risk Factors; Syndrome

Topics: Anti-HIV Agents; Black People; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; Humans; Retrospective Studies; Risk Factors

Topics: Dideoxynucleosides; Drug Hypersensitivity; HLA-B Antigens; Humans; Reverse Transcriptase Inhibitors

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Drug Labeling; Humans

Topics: Dideoxynucleosides; Drug Hypersensitivity; Humans; Lipodystrophy; Protease Inhibitors; Reverse Transcriptase Inhibitors; Skin Diseases

Differentiation between abacavir hypersensitivity and viral respiratory infections is problematic. Fifteen cases of abacavir hypersensitivity were matched to 30 controls with culture proven influenza A with no abacavir exposure. Rash was associated with hypersensitivity (odds ratio [OR] = 13.1, P = 0.02) as was the presence of nausea (OR = 30, P < 0.001), vomiting (OR = 17.1, P = 0.001) or diarrhoea (OR = 22, P < 0.001). The number of gastrointestinal symptoms was also predictive of hypersensitivity reaction (P < 0.001). Respiratory symptoms (cough, sore throat, or dyspnoea) were not associated with abacavir hypersensitivity (OR = 0.08, P = 0.001). Multivariate analysis confirmed the following associations for abacavir hypersensitivity: the number of gastrointestinal symptoms (OR = 8.6, P = 0.0032), cough (OR = 0.039, P = 0.02) and rash (OR = 16.9, P = 0.07). Abacavir hypersensitivity is strongly associated with gastrointestinal (GI) symptoms. Cough without GI symptoms is associated with influenza.

Topics: Anti-HIV Agents; Case-Control Studies; Cough; Diagnosis, Differential; Dideoxynucleosides; Drug Eruptions; Drug Hypersensitivity; Female; Gastrointestinal Diseases; HIV Infections; Humans; Influenza A virus; Influenza, Human; Logistic Models; Male; Multivariate Analysis; Retrospective Studies

To determine incidence of and reasons for discontinuation of abacavir within the first 6 months of therapy.. Retrospective study performed in the cohort of HIV-infected adults who started abacavir in a medical unit between 1997 and December 2000. All adverse drug reactions (ADRs) (especially hypersensitivity) observed in this cohort were reported. The association between drugs and complications were evaluated, using the French method to assess unexpected and toxic drug reactions. According to the variables studied, statistical analysis was performed using the chi2 test, Fisher's exact test, Mann-Whitney, Wilcoxon, or Kruskal-Wallis tests.. All 331 patients treated with abacavir during this time period were included in this study. Early discontinuation of abacavir was observed in 34.1% of patients, the main reasons being adverse effects (20.8%), virologic failure (3.3%), drug holidays (2.7%), poor adherence (2.7%), and death (1.8%). Adverse effects were mostly represented by hypersensitivity reactions. After retrospective analysis, abacavir was stopped for likely hypersensitivity in 8.5% of patients, for doubtful hypersensitivity in 4.2%, and for other adverse effects in 8.1% of patients.. This study shows that abacavir is mainly stopped during the first 6 months of therapy for ADRs. The rate of likely hypersensitivity reaction observed in this study (8.5%) is higher than that observed in clinical trials (5%). After retrospective evaluation, the causality assessment of abacavir is not always certain.

Topics: Adult; Adverse Drug Reaction Reporting Systems; Dideoxynucleosides; Drug Hypersensitivity; Female; France; HIV Infections; Humans; Male; Middle Aged; Retrospective Studies; Risk Factors; Time Factors

We investigated risk factors for hypersensitivity reactions (HSR) to abacavir in a case-control study. In a multivariate analysis, white race [odds ratio (OR), 5.16; 95% confidence interval (CI), 1.16-22.97] and a higher CD8 cell count at initiation of abacavir (>850 vs. < or =850 cells: OR, 3.74; 95% CI, 1.19-11.77) were found to be significantly associated with the development of HSR. Age, gender, stage of disease, prior antiretroviral exposure and type of concurrent antiretroviral therapy were not associated with HSR. Differences in predisposition to HSR according to ethnicity and baseline CD8 cell count may be explained by the reported MHC genetic associations with HSR.

Topics: Adult; Anti-HIV Agents; Case-Control Studies; CD8-Positive T-Lymphocytes; Dideoxynucleosides; Drug Hypersensitivity; Europe; Female; HIV Infections; Humans; Lymphocyte Count; Male; Multivariate Analysis; Odds Ratio; Risk Factors; White People

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Female; HIV Infections; Humans; Reverse Transcriptase Inhibitors

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; Humans; Hypersensitivity, Delayed; Male; Syndrome

Topics: Dideoxynucleosides; Drug Hypersensitivity; Female; Humans; Male; Reverse Transcriptase Inhibitors

Topics: Anti-HIV Agents; Biopsy; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; Humans; Immunohistochemistry; Prospective Studies; Skin Tests

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Humans; Mucocutaneous Lymph Node Syndrome

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Genetic Testing; Haplotypes; HIV Infections; Humans; Major Histocompatibility Complex; Reverse Transcriptase Inhibitors

The use of abacavir--a potent HIV-1 nucleoside-analogue reverse-transcriptase inhibitor--is complicated by a potentially life-threatening hypersensitivity syndrome in about 5% of cases. Genetic factors influencing the immune response to abacavir might confer susceptibility. We aimed to find associations between MHC alleles and abacavir hypersensitivity in HIV-1-positive individuals treated with abacavir.. MHC region typing was done in the first 200 Western Australian HIV Cohort Study participants exposed to abacavir. Definite abacavir hypersensitivity was identified in 18 cases, and was excluded in 167 individuals with more than 6 weeks' exposure to the drug (abacavir tolerant). 15 individuals experienced some symptoms but did not meet criteria for abacavir hypersensitivity. p values were corrected for comparisons of multiple HLA alleles (p(c)) by multiplication of the raw p value by the estimated number of HLA alleles present within the loci examined.. HLA-B*5701 was present in 14 (78%) of the 18 patients with abacavir hypersensitivity, and in four (2%) of the 167 abacavir tolerant patients (odds ratio 117 [95% CI 29-481], p(c)<0.0001), and the HLA-DR7 and HLA-DQ3 combination was found in 13 (72%) of hypersensitive and five (3%) of tolerant patients (73 [20-268], p(c)<0.0001 ). HLA-B*5701, HLA-DR7, and HLA-DQ3 were present in combination in 13 (72%) hypersensitive patients and none of the tolerant patients (822 [43-15 675], p(c)<0.0001). Other MHC markers also present on the 57.1 ancestral haplotype to which the three markers above belong confirmed the presence of haplotype-specific linkage disequilibrium, and mapped potential susceptibility loci to a region bounded by C4A6 and HLA-C. Within the entire abacavir-exposed cohort (n=200), presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 had a positive predictive value for hypersensitivity of 100%, and a negative predictive value of 97%.. Genetic susceptibility to abacavir hypersensitivity is carried on the 57.1 ancestral haplotype. In our population, withholding abacavir in those with HLA-B*5701, HLA-DR7, and HLA-DQ3 should reduce the prevalence of hypersensitivity from 9% to 2.5% without inappropriately denying abacavir to any patient.

Topics: Adult; Alleles; Anti-HIV Agents; Cohort Studies; Dideoxynucleosides; Drug Hypersensitivity; Female; Gene Frequency; Genetic Markers; Haplotypes; HIV Infections; HIV-1; HLA-B Antigens; HLA-DQ Antigens; HLA-DR7 Antigen; Humans; Male; Middle Aged; Reverse Transcriptase Inhibitors

A hypersensitivity reaction occurs in association with initiation of abacavir therapy as part of combination antiretroviral therapy in approximately 3.7% of patients. The reaction is possibly the result of a combination of altered drug metabolism and immune dysfunction, which is poorly understood. White patients appear to be at higher risk and patients of African descent at lower risk of abacavir hypersensitivity. Clinical management involves supportive measures and discontinuation of abacavir therapy. Rechallenge with abacavir in a hypersensitive patient should be avoided because it might precipitate a life-threatening reaction.

Topics: Anti-HIV Agents; Contraindications; Dideoxynucleosides; Drug Hypersensitivity; Humans; Risk Factors

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HLA Antigens; Humans; Reverse Transcriptase Inhibitors

Hypersensitivity to abacavir affects about 4% of patients who receive the drug for HIV-1 infection. We did a retrospective, case-control study to identify multiple markers in the vicinity of HLA-B associated with hypersensitivity reactions. HLA-B57 was present in 39 (46%) of 84 patients versus four (4%) of 113 controls (p<0 small middle dot0001). However, because of low numbers of women and other ethnic groups enrolled, these findings relate largely to white men. The lower sensitivity of HLA-B57 for predicting hypersensitivity to abacavir identified in this study compared with a previous report highlights that predictive values for markers will vary across populations. Clinical monitoring and management of hypersensitivity reactions among patients receiving abacavir must remain unchanged.

Topics: Adult; Aged; Anti-HIV Agents; Case-Control Studies; Dideoxynucleosides; Drug Hypersensitivity; Female; Genetic Markers; Genetic Variation; HIV Infections; HIV-1; HLA-B Antigens; Humans; Male; Middle Aged; Polymorphism, Genetic; Predictive Value of Tests; Racial Groups; Retrospective Studies; Reverse Transcriptase Inhibitors; Sensitivity and Specificity; Tumor Necrosis Factor-alpha

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Genetic Variation; HIV Infections; HLA-B Antigens; Humans; Risk Factors

Topics: Acquired Immunodeficiency Syndrome; Adult; Anaphylaxis; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Humans; Male; Reverse Transcriptase Inhibitors

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Administration Schedule; Drug Hypersensitivity; HIV Infections; Humans; Liver Function Tests; Reverse Transcriptase Inhibitors

Topics: Adult; Anti-HIV Agents; Child; Dideoxynucleosides; Drug Hypersensitivity; Female; Humans; Male

Hypersensitivity reactions consist of a variable group of clinical findings and have been described for a wide variety of chemical compounds.. This review characterizes the clinical profile of hypersensitivity to the nucleoside reverse transcriptase inhibitor abacavir sulfate.. We performed a retrospective medical review of pooled adverse events data from approximately 200,000 patients who received abacavir in clinical trials, through expanded-access programs, or by prescription from 1996 through 2000. Screened cases of hypersensitivity were classified as either definitive or probable. Definitive cases were identified when initial symptoms resolved on interruption of abacavir therapy and returned on reintroduction of abacavir therapy.. A total of 1803 cases were identified, 1302 in the 30,595 patients participating in clinical trials or the expanded-access program and 501 in patients from the post-marketing experience. On review, 176 (9.8%) of these cases were considered definitive and the remainder probable. Based on the 1302 cases identified in clinical trials or the expanded-access program, the calculated incidence of hypersensitivity was 4.3%. Symptoms reported in > or = 20% of cases of this multiorgan reaction included fever, rash, malaise/fatigue, and gastrointestinal symptoms such as nausea, vomiting, and diarrhea, among others. Respiratory symptoms occurred in 30% of cases and included dyspnea (12%), cough (10%), and pharyngitis (6%). In 90% of cases, hypersensitivity reactions occurred within the first 6 weeks after initiation of abacavir (median time, 11 days); after an initial reaction, rechallenge with abacavir resulted in the reappearance of symptoms within hours of reexposure. Hypotension was present in 25% of these rechallenge reactions. Among patients who received abacavir in clinical trials, the mortality rate was 0.03% (3 per 10,000 patients).. Hypersensitivity to abacavir is an idiosyncratic reaction and a distinct clinical syndrome characterized predominantly by systemic involvement. It can be expected to appear as a treatment-limiting event in approximately 5% of patients. The appearance of clinical symptoms consistent with this syndrome mandates immediate discontinuation of abacavir. Hypersensitivity to abacavir is an absolute contraindication to subsequent treatment with any formulation that includes this agent.

Topics: Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dideoxynucleosides; Drug Hypersensitivity; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Incidence; Product Surveillance, Postmarketing; Randomized Controlled Trials as Topic; Retrospective Studies; Reverse Transcriptase Inhibitors; Survival Rate

Topics: Adult; Agranulocytosis; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Drug Therapy, Combination; Fever; HIV Infections; Humans; Male; Reverse Transcriptase Inhibitors

Abacavir sulfate is an inhibitor of HIV-1 reverse transcriptase. Approximately 5% of patients given abacavir develop a hypersensitivity reaction, a clinical syndrome thought to be immune-mediated and described previously with many different drugs, including other antiretroviral agents. Although rare, fatal reactions have occurred. Actions aimed at reducing morbidity and risk of fatality with hypersensitivity reactions include patient education, early identification and evaluation of symptoms suggestive of hypersensitivity, and prompt discontinuation of abacavir once the diagnosis has been established.

Topics: Dideoxynucleosides; Drug Hypersensitivity; Humans; Reverse Transcriptase Inhibitors

Topics: Dideoxynucleosides; Drug Hypersensitivity; Humans; Reverse Transcriptase Inhibitors

It has long been known that this drug must never be restarted after it has been discontinued because of a hypersensitivity reaction. Now the manufacturer, Glaxo Wellcome, has warned physicians that serious complications have developed in some cases where the drug had been discontinued for other reasons, but where a hypersensitivity reaction may have occurred without being recognized. The letter, reproduced below, outlines precautions for physicians. Patients who have missed more than one or two doses should always check with their physician before restarting this drug.

Topics: Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; Humans; Reverse Transcriptase Inhibitors

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Drug Therapy, Combination; Drug Tolerance; HIV Infections; Humans; Male

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Humans; Reverse Transcriptase Inhibitors

Topics: Adverse Drug Reaction Reporting Systems; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Drug Information Services; Humans; Internet; Reverse Transcriptase Inhibitors; United States; United States Food and Drug Administration

Abacavir (Ziagen), a nucleoside analog used in combination therapy, can cause a hypersensitivity reaction in as many as five percent of patients. When this reaction occurs, the drug must be stopped immediately and never restarted. The hypersensitivity can cause fever, rash, gastrointestinal symptoms, fatigue, and life-threatening hypotension. The reaction generally occurs in the first six weeks of treatment. The risk of hypersensitivity has long been recognized, but it is often misdiagnosed as a respiratory ailment. Glaxo Wellcome sent out a letter in January 2000 to warn health care providers about the reaction and how to diagnose it; the full text of that letter is included. The manufacturer has also relabeled the drug with stronger warnings; the Web site address is provided for further information on the change in labeling.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Drug Therapy, Combination; HIV Infections; Humans

Topics: Anaphylaxis; Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Drug Therapy, Combination; HIV Infections; Humans; Male; Middle Aged; Reverse Transcriptase Inhibitors

Topics: Anaphylaxis; Dideoxynucleosides; Drug Hypersensitivity; Drug Therapy, Combination; Fatal Outcome; HIV Infections; HIV Protease Inhibitors; Humans; Male; Middle Aged; Nelfinavir; Reverse Transcriptase Inhibitors

Topics: Adult; Agranulocytosis; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; Humans; Male; Reverse Transcriptase Inhibitors

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Approval; Drug Hypersensitivity; Drug Resistance, Microbial; HIV; HIV Infections; Humans; Mutation; Reverse Transcriptase Inhibitors; United States; United States Food and Drug Administration

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Humans

The Food and Drug Administration (FDA) announced accelerated approval of Glaxo-Wellcome's abacavir (Ziagen, 1592) in combination with other antiretrovirals. Abacavir is in the same nucleoside analog class as AZT, but abacavir has stronger effects against HIV. Use of the drug requires caution, because it can cause a serious hypersensitivity or allergic reaction in 5 percent of patients. If abacavir is stopped and restarted, the hypersensitivity can be more fatal. Little is known about long-term use of the drug or its effects when in combination with other anti-HIV medications other than AZT plus 3TC.

Topics: Adult; Anti-HIV Agents; Child; Dideoxynucleosides; Drug Approval; Drug Hypersensitivity; Drug Therapy, Combination; HIV Infections; Humans; United States Food and Drug Administration

Ribavirin (Rebetol) is Schering Corporation's newly approved drug. It is used in combination with interferon for treatment of chronic hepatitis C in patients whose compensated liver disease has not been treated or who have relapsed after interferon monotherapy. Results of clinical trials are summarized, and dosing options and side effects are detailed. Similar information is provided for abacavir (Ziagen), Glaxo-Wellcome's new nucleoside analog reverse transcriptase inhibitor (NRTI) that is used in combination therapy to treat HIV.

Topics: Anti-HIV Agents; Antiviral Agents; Clinical Trials as Topic; Dideoxynucleosides; Drug Combinations; Drug Hypersensitivity; Drug Resistance, Microbial; Hepatitis C; HIV Infections; Humans; Ribavirin

Federal HIV treatment guidelines will soon include recommendations about selecting salvage therapy and will provide advice on understanding the increasingly complex science of cross-resistance and HIV mutations. The increasing number of HIV drugs makes selecting a salvage therapy more difficult. The guidelines will upgrade the nucleoside analog reverse transcriptase inhibitor abacavir (Ziagen) to an alternative treatment. In addition, hypersensitivity to abacavir and the differences in progression of HIV disease between women and men are described.

Topics: Adolescent; Adult; Anti-HIV Agents; Dideoxynucleosides; Disease Progression; Drug Hypersensitivity; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Practice Guidelines as Topic; Salvage Therapy; United States

Topics: Anti-HIV Agents; Clinical Trials as Topic; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; Humans

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Humans

Glaxo Wellcome has expanded its access program for its experimental drug abacavir (Ziagen, formerly known as 1592). The program already includes 1900 patients since its start last summer and the newly expanded program is less restrictive. Patients over 13 years of age who have already failed standard treatments are eligible. These patients must take Ziagen as part of a combination antiretroviral treatment including at least one other antiretroviral the patient has never taken before. Pregnant or nursing women, and patients with medical conditions who cannot use the drug safely are excluded. Children under 13 years old may participate in a pediatric program. Presently it is not clear who would benefit from taking abacavir. An estimated three percent of patients taking Ziagen experienced hypersensitivity reaction, characterized by a fever in conjunction with nausea, malaise and possibly a rash. If hypersensitivity occurs, the patient must discontinue use indefinitely; symptoms will disappear within one to two days of termination. More information is available from the Abacavir Coordinating Center.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Drug Therapy, Combination; HIV Infections; Humans

Glaxo Wellcome is offering an expanded access program for abacavir (Ziagen, formerly 1592) to HIV-positive patients who are not benefiting from their current combination therapy. In a dramatic departure from the usual entry criteria, the abacavir eligibility criteria require no specific CD4 cell count or viral load. To qualify, volunteers must be on a failing regimen, unable to tolerate standard therapies, and a physician must verify that another drug combination would not be viable. Patients are urged to switch to a regimen of at least two new drugs based on U.S. government treatment guidelines. Similar programs are available for the anti-HIV drugs efavirenz (Sustiva) and adefovir dipivoxil (Preveon). People using abacavir, a nucleoside analog, may experience side effects such as headache, nausea, and vomiting. If a hypersensitivity reaction develops, patients must stop the treatment. Taking the drug after experiencing an adverse reaction can be life threatening.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Drug Therapy, Combination; Drugs, Investigational; Health Services Accessibility; HIV Infections; Humans; United States

The 5th Conference on Retroviruses and Opportunistic Infections included 837 abstracts and oral presentations on clinical and basic science aspects of HIV. A major theme of the conference was the effectiveness of newer anti-HIV therapies, and there were many sessions dealing with combination treatments, including six-drug treatments. Results of studies with several drugs, including abacavir, efavirenz, amprenavir, PMPA Prodrug, adefovir dipivoxil, hydroxyurea, and protease inhibitors in several combinations are summarized. Treatments for opportunistic infections, including MAC, CMV retinitis, herpesvirus, and tuberculosis, are also presented.

Topics: AIDS-Related Opportunistic Infections; Alkynes; Anti-HIV Agents; Antiviral Agents; Benzoxazines; Carbamates; Chicago; Clinical Trials as Topic; Congresses as Topic; Cyclopropanes; Dideoxynucleosides; Drug Hypersensitivity; Drug Interactions; Drug Therapy, Combination; Drugs, Investigational; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Hydroxyurea; Oxazines; Reverse Transcriptase Inhibitors; Sulfonamides

Glaxo Wellcome has expanded its access program for the nucleoside analog abacavir (Ziagen). Currently there are no CD4 count or viral load requirements and the program is open to patients over age 13 who have failed standard treatments. Pregnant and breastfeeding women are excluded from the study. Patients must take Ziagen with at least one other new anti-HIV drug. In a previous trial, approximately three percent of people taking abacavir developed a severe hypersensitivity reaction that forced interruption of treatment. After suspension of treatment, initial symptoms subside, however, the syndrome could reappear in life-threatening proportions should treatment be resumed. Physicians have a limited window to enroll patients in the expanded program because abacavir is anticipated to get clearance from the Food and Drug Administration (FDA) in the fall.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Hypersensitivity; Drug Resistance, Microbial; Drug Therapy, Combination; Health Services Accessibility; HIV Infections; Humans

Abacavir (ABC), an experimental nucleoside reverse transcriptase inhibitor created by Glaxo Wellcome, appears as effective in combination therapy as protease inhibitors, when ABC is combined with Combivir. Combivir is a two-drugs-in-one combination comprised of AZT and 3TC. ABC was developed as an investigational treatment for HIV and is currently in Phase III trials for adults and children. This is the first time that three drugs in the same class have effectively reduced the viral load of treatment-naive patients to levels usually only seen with protease inhibitors. Trial results are nearly identical to those where AZT, 3TC, and a protease inhibitor have been combined. ABC can potentially change the way treatment is initiated because it involves a simple regimen. Due to its potency, fewer pills are necessary. There are also very few side effects or serious drug interactions associated with ABC.

Topics: Adipose Tissue; Anti-HIV Agents; Clinical Trials, Phase III as Topic; Dideoxynucleosides; Drug Combinations; Drug Hypersensitivity; Drug Therapy, Combination; Drugs, Investigational; HIV Infections; HIV Protease Inhibitors; Humans; Patient Compliance; Patient Education as Topic; RNA, Viral; Viral Load

Glaxo Wellcome reports that 2-3 percent of patients in their clinical trial of the nucleoside analog abacavir (1592) have a hypersensitivity to the drug. Patients experience fever, severe nausea, and a generalized rash, usually occurring an average of 11 days after treatment begins. Symptoms subside when the drug is discontinued and return immediately when the drug is restarted.

Topics: Anti-HIV Agents; Clinical Trials as Topic; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; Humans

Caution is advised when using the experimental antiretroviral abacavir (1592U89) in the event of a systemic hypersensitivity reaction because continued use may be life-threatening. Glaxo is planning research to determine the cause of the hypersensitivity and is educating physicians, researchers, and volunteers in clinical trials about abacavir hypersensitivity. The Food and Drug Administration (FDA) has been informed as well.

Topics: Anti-HIV Agents; Clinical Trials as Topic; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; Humans; Reverse Transcriptase Inhibitors