Interventions for the prevention of mycobacterium avium complex in adults and children with HIV
ABSTRACT Mycobacterium avium complex (MAC) infection is a common complication of advanced acquired immunodeficiency syndrome (AIDS) disease and is an independent predictor of mortality and shortened survival.
To determine the effectiveness and safety of interventions aimed at preventing MAC infection in adults and children with HIV infection.
We searched MEDLINE, EMBASE, and The Cochrane Library (search date December 2012).
Randomised controlled trials comparing different strategies for preventing MAC infection in HIV-infected individuals.
Two reviewers independently assessed trial eligibility and quality, and extracted data. Where data were incomplete or unclear, a third reviewer resolved conflicts and/or trial authors were contacted for further details. Development of MAC infection and survival were compared using risk ratios (RR) and 95% confidence intervals (CI). The quality of evidence has been assessed using the GRADE methodology.
Eight studies met the inclusion criteria.Placebo-controlled trialsThere was no statistically significant difference between clofazimine and no treatment groups in the number of patients that developed MAC infection (RR 1.01; 95% CI 0.37 to 2.80). Rifabutin (one study; RR 0.48; 95% CI 0.35 to 0.67), azithromycin (three studies; RR 0.37; 95% CI 0.19 to 0.74) and clarithromycin (one study; RR 0.35; 95% CI 0.21 to 0.58) were more effective than placebo in preventing the development of MAC infection. There was no statistically significant difference between those treated with clofazimine (one study; RR 0.98; 95% CI 0.41 to 2.32), rifabutin (one study RR 0.91; 95% CI 0.78 to 1.05), azithromycin (three studies, pooled RR 0.96; 95% CI 0.69 to 1.32) and placebo in number of reported deaths. One study found that the risk of death was reduced by 22% in patients treated with clarithromycin compared to those treated with placebo (RR 0.78; 95% CI 0.64 to 0.96). Monotherapy vs. monotherapyPatients treated with clarithromycin (RR 0.60; 95% CI 0.41 to 0.89) and azithromycin (RR 0.60; 95% CI 0.40 to 0.89) were 40% less likely to develop MAC infection than those treated with rifabutin. There was no statistically significant difference between those treated with clarithromycin (RR 0.98; 95% CI 0.83 to 1.15), azithromycin (RR 0.98; 95% CI 0.77 to 1.24) and rifabutin in the number of reported deathsCombination therapy versus monotherapyThere was no statistically significant difference between patients treated with a combination of rifabutin and clarithromycin and those treated with clarithromycin alone (RR 0.74; 95% CI 0.46 to 1.20); and those treated with combination of rifabutin and azithromycin and those treated with azithromycin alone (RR 0.59; 95% CI 1.03). Patients treated with a combination of rifabutin plus clarithromycin were 56% less likely to develop MAC infection than those treated with rifabutin alone (RR 0.44; 95% CI 0.29 to 0.69). Patients treated with a combination of rifabutin plus azithromycin were 65% less likely to develop MAC infection than those treated with rifabutin alone (RR 0.35; 95% CI 0.21 to 0.59). There was no statistically significant difference in the number of reported deaths in all the four different comparisons of prophylactic agents.
Based on limited data, azithromycin or clarithromycin appeared to be a prophylactic agent of choice for MAC infection. Further studies are needed, especially direct comparison of clarithromycin and azithromycin. In additions, studies that will compare different doses and regimens are needed.
5th Annual Meeting of the Austrian Society for Laboratory Medicine and Clinical Chemistry (ÖGLMKC); 11/2014
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ABSTRACT: Advanced macrolides, such as azithromycin (AZM) or clarithromycin (CLM), are antibiotics with immunomodulatory properties. Here we have sought to evaluate their in vitro influence on the activation of CD4 1 T-cells. Isolated CD4 1 T-cells were stimulated with agonistic anti-CD3/anti-CD28 monoclonal antibodies in the presence of 0.6 mg/L, 2.5 mg/L, 10 mg/L or 40 mg/L AZM or CLM. Cell proliferation, cytokine level in supernatants and cell viability was assessed. Intracellular signaling pathways were evaluated using reporter cell lines, FACS analysis, immunoblotting and in vitro kinase assays. AZM inhibited cell proliferation rate and cytokine secretion of CD4 1 T-cells in a dose-dependent manner. Similarly, high concentrations of CLM (40 mg/L) also suppressed these T-cell functions. Analysis of molecular signaling pathways revealed that exposure to AZM reduced the phosphorylation of the S6 ribosomal protein, a downstream target of mTOR. This effect was also observed at 40 mg/L CLM. In vitro kinase studies using recombinant mTOR showed that AZM inhibited mTOR activity. In contrast to rapamycin, this inhibition was independent of FKBP12. We show for the first time that AZM and to a lesser extent CLM act as immunosuppressive agents on CD4 1 T-cells by inhibiting mTOR activity. Our results might have implications for the clinical use of macrolides. M acrolides are a group of antimicrobial substances with well-described immunomodulatory properties 1,2 . They inhibit bacterial protein synthesis by reversibly binding to the prokaryotic 50S ribosomal subunit 3 , whereas effects on eukaryotic ribosomes are not described. Due to their beneficial pharmacokinetics, advanced macrolides, including azithromycin (AZM) and clarithromycin (CLM), are widely used to medicate respiration tract infections, sexually transmitted diseases and Helicobacter pylori-associated peptic ulcer diseases 4 . Due to a high degree of cellular penetration, AZM and CLM reach 10 to 100 fold higher concentrations in body tissues, and enrich in leukocytes at more than 100 fold higher concentrations compared serum levels 5–7 . The penetration efficacy depends on environmental factors, such as pH, extracellular calcium concentrations, tem-perature and inflammatory stimuli, as well as on the cell type 8–10 . In contrast to CLM and other macrolides, AZM has unique characteristics, being an azalide derivate which does not inhibit the human CYP3A4 oxidases 1 . Particularly, in patients suffering from lung diseases and chronic diseases with an auto-immune component, beneficial therapeutic effects of macrolide treatment have been observed. Clinical efficacy of AZM and CLM has been shown for the prevention of exacerbation in patients with chronic obstructive pulmonary disease (COPD) 11,12 , cystic fibrosis 13,14 and non-cystic fibrosis bronchiectasis 15 . Similarly, in patients suffering from diffuse panbronchiolitis 16 , bronchiolitis obliterans syndrome after lung transplantation 17,18 and patients with asthma 19–21 , clinical improvements have been demonstrated following administration of AZM or CLM. Obviously, immunomodulatory effects might also occur in patients without the need of any immunotherapy, e.g. patients during the immunodepressed phase of a severe sepsis 22 or HIV positive patients with a low CD4Scientific Reports 12/2014; 4:7438. DOI:10.1038/srep07438 · 5.08 Impact Factor