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Background 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. Methods 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 ≥2), uncertain (mean score ≥-1 and ≤1) and unlikely (mean score ≤-2). HLA typing was performed using sequence-based methods. Results 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 ( PConclusions 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.

Objectives 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. Design and methods 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. Results 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. Conclusions 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.

ObjectivesIt has been proposed that the contribution of nucleoside-analogue reverse transcriptase inhibitor (NRTI) therapy to subcutaneous fat wasting involves adipose tissue-specific mitochondrial DNA toxicity. We have investigated the relationships between NRTI therapy, adipocyte mitochondrial DNA content, evidence of toxicity in adipose tissue and fat wasting in Caucasian male Western Australian HIV Cohort study participants. Methods: Longitudinal mixed effects analysis of fat wasting was undertaken in individuals receiving initial stavudine- or zidovudine-containing highly active anti-retroviral therapy (HAART) ( n=49, 149 DEXA measurements). Adipocyte mitochondrial DNA (mtDNA) depletion was also assessed according to current NRTI therapy in 92 subcutaneous fat biopsies from 69 HIV-positive individuals and seven healthy controls, and results were correlated with fat wasting among a subset of patients with biopsy data receiving initial stavudine-or zidovudine-containing HAART ( n=22, 103 DEXA measurements). Confocal microscopy was performed in 22 biopsy samples obtained before and after initiating/switching NRTI therapy.ResultsStavudine therapy was associated with more severe adipocyte mitochondrial DNA depletion ( PConclusionsSeverity of subcutaneous fat wasting is primarily determined by choice of NRTI therapy (stavudine versus zidovudine) and by duration of exposure to the relevant NRTI. At the cellular level, evidence is provided that this effect manifests through NRTI-induced mitochondrial DNA depletion.

The aim of this study was to evaluate the effect of CD4+ T-cell counts and other characteristics of HIV-infected individuals on hepatitis C virus (HCV) RNA levels.All HIV-HCV-coinfected Swiss HIV Cohort Study participants with available HCV RNA levels and concurrent CD4+ T-cell counts before starting HCV therapy were included. Potential predictors of HCV RNA levels were assessed by multivariate censored linear regression models that adjust for censored values.The study included 1,031 individuals. Low current and nadir CD4+ T-cell counts were significantly associated with higher HCV RNA levels (P = 0.004 and 0.001, respectively). In individuals with current CD4+ T-cell counts200/microl, median HCV RNA levels (6.22 log10 IU/ml) were +0.14 and +0.24 log10 IU/ml higher than those with CD4+ T-cell counts of 200-500/microl and500/microl. Based on nadir CD4+ T-cell counts, median HCV RNA levels (6.12 log10 IU/ml) in individuals with200/microl CD4+ T-cells were +0.06 and +0.44 log10 IU/ml higher than those with nadir T-cell counts of 200-500/microl and500/microl. Median HCV RNA levels were also significantly associated with HCV genotype: lower values were associated with genotype 4 and higher values with genotype 2, as compared with genotype 1. Additional significant predictors of lower HCV RNA levels were female gender and HIV transmission through male homosexual contacts. In multivariate analyses, only CD4+ T-cell counts and HCV genotype remained significant predictors of HCV RNA levels.Higher HCV RNA levels were associated with CD4+ T-cell depletion. This finding is in line with the crucial role of CD4+ T-cells in the control of HCV infection.

The availability of durable, effective antiretroviral therapy for HIV-infected patients has fundamentally altered the prognosis of this disease and has also increased awareness that long-term drug toxicities have the potential to cause significant morbidity and even mortality in this patient population. The long-term use of nucleoside analogue reverse transcriptase inhibitor (NRTI) drugs has been associated with a number of clinically relevant toxicities including hyperlactataemia and lactic acidosis, neuropathy, pancreatitis and, more recently, a syndrome of pathological loss of subcutaneous fat tissue (lipoatrophy). Importantly, the toxicity profile of each NRTI drug within this class is unique in terms of the overall risk of long-term complications, as well as the tissue specificity of its toxic effects. In this review, the clinical manifestations, risk factors and pathological basis for NRTI-associated toxicity syndromes are explored, with an emphasis on clinical assessment and management.