Incidence of abacavir hypersensitivity reactions in euroSIDA

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.     

Risk factor analysis of hypersensitivity reactions to abacavir

BACKGROUND: A hypersensitivity reaction to abacavir has been known to occur in approximately 4% of patients treated with the drug. OBJECTIVE: The goal of this study was to determine risk factors associated with the development of hypersensitivity reactions to abacavir. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.     

HLA-B*5701 screening for susceptibility to abacavir hypersensitivity

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.     

Incidence of abacavir hypersensitivity and its relationship with HLA-B*5701 in HIV-infected patients in Taiwan

OBJECTIVES: To describe the incidence of hypersensitivity to abacavir and frequency of human leucocyte antigen (HLA)-B*5701 in HIV-infected Taiwanese persons. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Reasons for early abacavir discontinuation in HIV-infected patients

OBJECTIVE: To determine incidence of and reasons for discontinuation of abacavir within the first 6 months of therapy. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Cytokine profiling in human colostrum and milk by protein array

BACKGROUND: Human colostrum and milk contain components that influence development. Our aim was to use a protein array to determine the cytokine profile of human lacteal secretions and changes that occur during the early postpartum period. METHODS: We collected 17 samples of colostrum during the first 2 days postpartum and a 2nd group of 5 sets of 2 to 3 sequential colostrum or milk samples (at 20- to 30-h intervals). We analyzed the samples with array membranes consisting of 42 or 79 antibodies directed against cytokines. RESULTS: In most samples, we detected the previously described cytokines interleukin-8 (IL-8)/CXCL8, epidermal growth factor (EGF), growth-related oncoprotein (GRO)/CXCL1-3, angiogenin, transforming growth factor beta-2, and monocyte chemotactic protein 1 (MCP-1/CCL2). In addition, we found 32 cytokines that have not been described before in colostrum. Cytokine concentrations differed among mothers, and the spectrum of cytokines changed with time after delivery. A significant decrease occurred in IL-12 and macrophage inflammatory protein-1delta/CCL15 and a significant increase in MCP-1/CCL2. The production of angiogenin, vascular endothelial growth factor, GRO/CXCL1-3, EGF, and IL-8/CXCL8 remained high throughout. The concentrations of 2 selected cytokines measured with the array technique and ELISA showed moderate to strong correlation (r = 0.63 for EGF and r = 0.84 for IL-8/CXCL8). CONCLUSION: Despite the lack of precise quantification, the protein array might be suitable for cytokine screening. It allows simultaneous detection of a broad spectrum of cytokines (including those not described before) in lacteal secretions.     

Cytokine imbalance in patients with chronic obstructive bronchitis

A reactive ability of immunocompetent cells was assessed by the level of cytokines TNF alpha and IL-8 estimated by enzyme immunoassay ("Genzyme diagnostics" kit) in 18 patients with chronic obstructive bronchitis (mean age 58 +/- 4.2 years, mean duration of the disease 11.2 +/- 5.2 years) and 15 control patients matched for age, with normal external respiration function, free of chronic bronchopulmonary pathology and allergic diseases. The greatest differences in cytokine levels were registered between the control group and patients with moderate generalized irreversible obstruction. These patients had similar basal and E. coli LPS induced synthesis of the above cytokines showing the lack of cell reserves, adequate immune response to exogenic antigen.     

Cytokine production in patients with monoclonal gammapathies.

Increased interleukin-6 levels in culture media of mitogen-driven non adherent peripheral blood mononuclear cells were measurable in patients with monoclonal gammapathies of unknown significance but not in patients with multiple myeloma, indicating that in the former circulating mononuclear cells other than monocytes are involved in producing interleukin-6. Increased interleukin-4 levels were detected in supernatants of mitogen-driven peripheral blood mononuclear cells from patients with monoclonal gammapathies of unknown significance and from patients with multiple myeloma. The further increased interleukin-4 content in supernatants of non adherent cell cultures of multiple myeloma patients only suggests a somewhat inhibitory role of monocytes on interleukin-4 production, at least in multiple myeloma. Undetectable interleukin-2 levels in culture media were found in patients with monoclonal gammapathies of unknown significance and in patients with multiple myeloma. Serum levels of interleukin-6 and interleukin-2 were not measurable in either group, and interleukin-4 was detected only in a few patients. Our study suggests that in monoclonal gammapathies peripheral blood mononuclear cells could participate in producing cytokines involved in the regulation of B lymphocyte proliferation and differentiation. However, the pathophysiologic role in these patients of IL-6 and IL-4 in vitro, and possibly in vivo, produced by circulating lymphocytes remains to be established.     

Cytokine promoter polymorphisms in Taiwanese patients with Graves' disease

OBJECTIVES: This study aimed to examine the association between promoter polymorphisms of Th1 and Th2 cytokine genes [interleukin-4 (IL-4 T-34C, A-81G, C-285T and T-589C), IL-6 (G-174C), IL-10 (A-592C and T-819C) and tumour necrosis factor-alpha (TNF-alpha G-238A and G-308A)] and Graves' disease (GD) in Taiwanese population. DESIGN AND METHODS: Genomic DNA was extracted from peripheral blood cells of 137 GD patients and 189 control subjects. Cytokine gene polymorphisms were analyzed by polymerase chain reaction and restriction fragment length polymorphism. RESULTS: Genotype frequencies of TNF-alpha G-238A or G-308A between control and GD subjects were significantly different. Frequencies of the high TNF-alpha secreting alleles (-238*A and -308*A) and IL-10 -819*C allele were significantly increased in GD patients. No significant differences regarding IL-4 or IL-6 gene polymorphisms between GD patients and control subjects were found. CONCLUSIONS: Our data demonstrated that TNF-alpha G-238A and G-308A genotypes were strongly associated with GD incidence.     

Cytokine regulation of immune response in patients with acute HCV-infection

AIM: To study the cytokine spectrum (IL-1beta, IL-2, IL-4, IL-6, TNF-alpha, interferon-alpha, interferon gamma) in patients with acute hepatitis C (AHC). MATERIAL AND METHODS: Peripheral blood from 70 AHC patients was studied for cytokines using enzyme immunoassay (kits made by Protein contur, St-Petersburg). RESULTS. A primary examination in all the patients who finally recovered detected high levels of IL-2, IL-6, interferon-gamma, normal levels of IL-4. This evidenced for marked activity of Th1-lymphocytes, depressed synthesis of Th2-mediators stimulating immune response and elimination of the virus. AHC patients who later developed chronic disease had less frequent rise of proinflammatory mediators, but more frequent high IL-4 levels. Such features of immune response reflected higher activity of Th2-lymphocytes inhibiting Th1-effector mechanisms. This promoted active virus replication and formation of chronic hepatitis C. CONCLUSION: Determination of cytokine spectrum in AHC has a prognostic implication.     

Cytokine expression profile over time in severely burned pediatric patients

A severe burn leads to hypermetabolism and catabolism resulting in compromised function and structure of essential organs. The massive release of cytokines is implicated in this hypermetabolic response. The aim of the present study was to compare cytokine expression profiles from severely burned children without signs of infections or inhalation injury (n = 19) to the cytokine profiles from normal, noninfected, nonburned children (n = 14). The Bio-Plex suspension array system was used to measure the concentration of 17 cytokines. The expression of proinflammatory and anti-inflammatory cytokines was maximal during the first week after thermal injury. Significant increases were measured for 15 mediators during the first week after thermal injury: interleukin (IL) 1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 p70, IL-13, IL-17, interferon gamma, monocyte chemoattractant protein 1, macrophage inflammatory protein 1beta, and granulocyte colony-stimulating factor (P < 0.05). Granulocyte-macrophage colony-stimulating factor was significantly increased during the second week after burn (P < 0.05). Within 5 weeks, the serum concentrations of most cytokines decreased, approaching normal levels. When compared with the cytokine levels measured in normal children, a total of 16 cytokines were significantly altered (P < 0.05). After severe burn, a specific cytokine expression profile is observed in patients without complications such as inhalation injury or sepsis. The cytokine concentrations decrease during 5 weeks after burn but remain elevated over nonburned values. Furthermore, the elevation in most serum cytokine levels during the first week after burn may indicate a potential window of opportunity for therapeutic intervention.