D. Nolan

HLA-B*5701 Screening for Hypersensitivity to Abacavir

BACKGROUND 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. METHODS 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. RESULTS 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). CONCLUSIONS 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.)

Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant

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.

Predisposition to nevirapine hypersensitivity associated with HLA-DRB1*0101 and abrogated by low CD4 T-cell counts

Genetic (human leukocyte antigen), disease-related and demographic risk factors for nevirapine reactions were examined in a nevirapine-exposed cohort. Cases involving combinations of hepatitis, fever or rash were associated with an interaction between HLA-DRB1*0101 and the percentage of CD4, whereas no associations were detected for isolated rash. These data suggest that HLA-DRB1*0101 and the CD4 status may determine susceptibility to nevirapine hypersensitivity, consistent with a CD4 T-cell-dependent immune response to nevirapine-specific antigens.

Apolipoprotein E, cholesterol metabolism, diabetes, and the convergence of risk factors for Alzheimer's disease and cardiovascular disease

High fat diets and sedentary lifestyles are becoming major concerns for Western countries. They have led to a growing incidence of obesity, dyslipidemia, high blood pressure, and a condition known as the insulin-resistance syndrome or metabolic syndrome. These health conditions are well known to develop along with, or be precursors to atherosclerosis, cardiovascular disease, and diabetes. Recent studies have found that most of these disorders can also be linked to an increased risk of Alzheimers disease (AD). To complicate matters, possession of one or more apolipoprotein E ɛ4 (APOE ɛ4) alleles further increases the risk or severity of many of these conditions, including AD. ApoE has roles in cholesterol metabolism and Aβ clearance, both of which are thought to be significant in AD pathogenesis. The apparent inadequacies of ApoE ɛ4 in these roles may explain the increased risk of AD in subjects carrying one or more APOE ɛ4 alleles. This review describes some of the physiological and biochemical changes that the above conditions cause, and how they are related to the risk of AD. A diversity of topics is covered, including cholesterol metabolism, glucose regulation, diabetes, insulin, ApoE function, amyloid precursor protein metabolism, and in particular their relevance to AD. It can be seen that abnormal lipid, cholesterol and glucose metabolism are consistently indicated as central in the pathophysiology, and possibly the pathogenesis of AD. As diagnosis of mild cognitive impairment and early AD are becoming more reliable, and as evidence is accumulating that health conditions such as diabetes, obesity, and coronary artery disease are risk factors for AD, appropriate changes to diets and lifestyles will likely reduce AD risk, and also improve the prognosis for people already suffering from such conditions.

Prospective Genetic Screening Decreases the Incidence of Abacavir Hypersensitivity Reactions in the Western Australian HIV Cohort Study

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.

Chronic hyperlactatemia in HIV-infected patients taking antiretroviral therapy.

ObjectiveTo determine the prevalence, course and risk factors for hyperlactatemia in HIV-infected patients. DesignA prospective, longitudinal study of venous lactate concentrations over an 18-month period in 349 participants of the Western Australian HIV Cohort Study. ResultsIn 516 patient-years of observation, two patients experienced severe fulminant lactic acidosis (lactate > 5 mmol/l) and hepatic steatosis attributable to nucleoside analogue reverse transcriptase inhibitors (NRTI). A further five patients with lesser elevations of lactate (2.8–4.1 mmol/l) but with symptoms of nausea or abdominal discomfort and evidence of hepatic steatosis had NRTI therapy revised, with relief of symptoms and a fall in lactate levels. Most remaining patients on highly active antiretroviral therapy (HAART) had mild, chronic, asymptomatic hyperlactatemia, with mean lactate level between 1.5 mmol/l and 3.5 mmol/l most commonly. Longitudinal data was analysed in a non-linear mixed effects growth model which indicated that average lactate levels rose after the start of HAART but tended to stabilise at low-grade elevation, with an average 0.23 mmol/l greater long term level in stavudine users compared with zidovudine users (p < 0.01). A multiple linear regression model showed that the association between stavudine and higher lactate level was not confounded by longer duration of total NRTI exposure. Risk of hyperlactatemia was not significantly associated with use of other NRTIs, protease inhibitors, non-nucleoside analogue reverse transcriptase inhibitors or multiple immunological and virological factors in multivariate analyses. ConclusionsChronic, compensated, asymptomatic hyperlactatemia is common in patients taking HAART. Decompensated, life-threatening lactic acidosis/hepatic steatosis is rare. Treatment with stavudine appears to be the predominant risk factor for development of chronic hyperlactatemia.

Human Leukocyte Antigen Class I-Restricted Activation of CD8+ T Cells Provides the Immunogenetic Basis of a Systemic Drug Hypersensitivity

The basis for strong immunogenetic associations between particular human leukocyte antigen (HLA) class I allotypes and inflammatory conditions like Behçets 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.

Clinical and immunogenetic correlates of abacavir hypersensitivity

A patch test (PT) may be useful in defining true abacavir hypersensitivity syndrome (AHS). Seven previously PT-positive patients remote from the original AHS were shown to have robust 24 h responses, supporting PT durability. HLA-B*5701 was present in all seven PT-positive versus one of 11 controls tolerating abacavir (P < 0.001). Five of seven PT (71%) versus one of 11 controls (9%) (P = 0.005) showed significant abacavir-specific CD8 proliferation, suggesting a direct role for HLA-B*5701-restricted CD8 cells in the pathophysiology of AHS.

Stable or increasing bone mineral density in HIV-infected patients treated with nelfinavir or indinavir.

Background and objectivesTo determine the factors contributing to changes in bone mineral density (BMD) over time in HIV-infected patients receiving highly active antiretroviral therapy (HAART). MethodsAnalyses of lumbar spine BMD in 183 male Caucasian participants in the Western Australian HIV Cohort study, comprising a longitudinal analysis of data from 54 patients on stable HAART regimens, and a cross-sectional analysis comparing data from 131 protease inhibitor (PI)-treated patients and 52 PI-naive (including 28 antiretroviral treatment-naive) patients. ResultsAverage lumbar spine BMD remained stable or increased over the time frame considered. Although there was no evidence of a change of average BMD over time in patients receiving nelfinavir (P = 0.92), there was evidence of increasing bone density in the indinavir group (average increase, 0.31 z-score per year;P < 0.001). Lower initial z-scores in the longitudinal analysis were significantly associated with lower pre-HAART BMI (P = 0.003), consistent with results of the cross-sectional analysis in which lowest BMI prior to initial dual X-ray absorptiometry scan was associated with decreased BMD (P = 0.02, overall group). Although PI therapy was also associated with decreased BMD in a univariate analysis of the cross-sectional data (P = 0.04), this effect was abrogated in a multiple linear regression analysis (P = 0.11) with lowest BMI remaining significant (P = 0.04). ConclusionsWe found no evidence, overall, of accelerated bone loss in patients treated with nelfinavir- or indinavir-containing HAART regimens, and propose that indinavir therapy may be associated with an increase in bone mineral density over time. Pre-HAART BMI was an independent and powerful determinant of an individuals initial z-score in the longitudinal analysis, and adjustment for this effect in a cross-sectional analysis abrogated the association between PI therapy and decreased lumbar spine z-score.

Population Level Analysis of Human Immunodeficiency Virus Type 1 Hypermutation and Its Relationship with APOBEC3G and vif Genetic Variation

ABSTRACT APOBEC3G and APOBEC3F restrict human immunodeficiency virus type 1 (HIV-1) replication in vitro through the induction of G→A hypermutation; however, the relevance of this host antiviral strategy to clinical HIV-1 is currently not known. Here, we describe a population level analysis of HIV-1 hypermutation in near-full-length clade B proviral DNA sequences (n = 127). G→A hypermutation conforming to expected APOBEC3G polynucleotide sequence preferences was inferred in 9.4% (n = 12) of the HIV-1 sequences, with a further 2.4% (n = 3) conforming to APOBEC3F, and was independently associated with reduced pretreatment viremia (reduction of 0.7 log10 copies/ml; P = 0.001). Defective vif was strongly associated with HIV-1 hypermutation, with additional evidence for a contribution of vif amino acid polymorphism at residues important for APOBEC3G-vif interactions. A concurrent analysis of APOBEC3G polymorphism revealed this gene to be highly conserved at the amino acid level, although an intronic allele (6,892 C) was marginally associated with HIV-1 hypermutation. These data indicate that APOBEC3G-induced HIV-1 hypermutation represents a potent host antiviral factor in vivo and that the APOBEC3G-vif interaction may represent a valuable therapeutic target.