Publications
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Marais S, Wilkinson RJ, 2015, Are the Present Doses of Anti Tubercular Drugs Adequate for Severe Disease?, EBioMedicine, Vol: 2, Pages: 1572-1573, ISSN: 2352-3964
Pepper DJ, Schomaker M, Wilkinson RJ, et al., 2015, Independent predictors of tuberculosis mortality in a high HIV prevalence setting: a retrospective cohort study, AIDS Research and Therapy, Vol: 12, ISSN: 1742-6405
BackgroundIdentifying those at increased risk of death during TB treatment is a priority in resource-constrained settings. We performed this study to determine predictors of mortality during TB treatment.MethodsWe performed a retrospective analysis of a TB surveillance population in a high HIV prevalence area that was recorded in ETR.net (Electronic Tuberculosis Register). Adult TB cases initiated TB treatment from 2007 through 2009 in Khayelitsha, South Africa. Cox proportional hazards models were used to identify risk factors for death (after multiple imputations for missing data). Model selection was performed using Akaike’s Information Criterion to obtain the most relevant predictors of death.ResultsOf 16,209 adult TB cases, 851 (5.3 %) died during TB treatment. In all TB cases, advancing age, co-infection with HIV, a prior history of TB and the presence of both pulmonary and extra-pulmonary TB were independently associated with an increasing hazard of death. In HIV-infected TB cases, advancing age and female gender were independently associated with an increasing hazard of death. Increasing CD4 counts and antiretroviral treatment during TB treatment were protective against death. In HIV-uninfected TB cases, advancing age was independently associated with death, whereas smear-positive disease was protective.ConclusionWe identified several independent predictors of death during TB treatment in resource-constrained settings. Our findings inform resource-constrained settings about certain subgroups of TB patients that should be targeted to improve mortality during TB treatment.
Lai RP, Meintjes G, Wilkinson RJ, 2015, HIV-1 tuberculosis-associated immune reconstitution inflammatory syndrome., Seminars in Immunopathology, Vol: 38, Pages: 185-198, ISSN: 1863-2300
Patients co-infected with HIV-1 and tuberculosis (TB) are at risk of developing TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) following commencement of antiretroviral therapy (ART). TB-IRIS is characterized by transient but severe localized or systemic inflammatory reactions against Mycobacterium tuberculosis antigens. Here, we review the risk factors and clinical management of TB-IRIS, as well as the roles played by different aspects of the immune response in contributing to TB-IRIS pathogenesis.
Rockwood N, Abdullahi LH, Wilkinson RJ, et al., 2015, Risk Factors for Acquired Rifamycin and Isoniazid Resistance: A Systematic Review and Meta-Analysis, PLOS ONE, Vol: 10, ISSN: 1932-6203
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- Citations: 12
Getahun H, Matteelli A, Abubakar I, et al., 2015, Management of latent Mycobacterium tuberculosis infection: WHO guidelines for low tuberculosis burden countries., European Respiratory Journal, ISSN: 1399-3003
Latent tuberculosis infection (LTBI) is characterised by the presence of immune responses to previously acquired Mycobacterium tuberculosis infection without clinical evidence of active tuberculosis (TB). Here we report evidence-based guidelines from the World Health Organization for a public health approach to the management of LTBI in high risk individuals in countries with high or middle upper income and TB incidence of <100 per 100 000 per year. The guidelines strongly recommend systematic testing and treatment of LTBI in people living with HIV, adult and child contacts of pulmonary TB cases, patients initiating anti-tumour necrosis factor treatment, patients receiving dialysis, patients preparing for organ or haematological transplantation, and patients with silicosis. In prisoners, healthcare workers, immigrants from high TB burden countries, homeless persons and illicit drug users, systematic testing and treatment of LTBI is conditionally recommended, according to TB epidemiology and resource availability. Either commercial interferon-gamma release assays or Mantoux tuberculin skin testing could be used to test for LTBI. Chest radiography should be performed before LTBI treatment to rule out active TB disease. Recommended treatment regimens for LTBI include: 6 or 9 month isoniazid; 12 week rifapentine plus isoniazid; 3-4 month isoniazid plus rifampicin; or 3-4 month rifampicin alone.
Lai RPJ, Meintjes G, Wilkinson KA, et al., 2015, HIV-tuberculosis-associated immune reconstitution inflammatory syndrome is characterized by Toll-like receptor and inflammasome signalling, Nature Communications, Vol: 6, ISSN: 2041-1723
Patients with HIV-associated tuberculosis (TB) initiating antiretroviral therapy (ART) may develop immune reconstitution inflammatory syndrome (TB-IRIS). No biomarkers for TB-IRIS have been identified and the underlying mechanisms are unclear. Here we perform transcriptomic profiling of the blood samples of patients with HIV-associated TB. We identify differentially abundant transcripts as early as week 0.5 post ART initiation that predict downstream activation of proinflammatory cytokines in patients who progress to TB-IRIS. At the characteristic time of TB-IRIS onset (week 2), the signature is characterized by over-representation of innate immune mediators including TLR signalling and TREM-1 activation of the inflammasome. In keeping with the transcriptional data, concentrations of plasma cytokines and caspase-1/5 are elevated in TB-IRIS. Inhibition of MyD88 adaptor and group 1 caspases reduces secretion of cytokines including IL-1 in TB-IRIS patients. These data provide insight on the pathogenesis of TB-IRIS and may assist the development of specific therapies.
Torrado E, Fountain JJ, Liao M, et al., 2015, Interleukin 27R regulates CD4<SUP>+</SUP> T cell phenotype and impacts protective immunity during <i>Mycobacterium tuberculosis</i> infection, JOURNAL OF EXPERIMENTAL MEDICINE, Vol: 212, Pages: 1449-1463, ISSN: 0022-1007
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- Citations: 53
Zumla A, Maeurer M, Host-Directed Therapies Network, et al., 2015, Towards host-directed therapies for tuberculosis., Nature reviews. Drug discovery, Vol: 14, Pages: 511-512, ISSN: 1474-1776
The treatment of tuberculosis is based on combinations of drugs that directly target Mycobacterium tuberculosis. A new global initiative is now focusing on a complementary approach of developing adjunct host-directed therapies.
Offerman K, Deffur A, Carulei O, et al., 2015, Six host-range restricted poxviruses from three genera induce distinct gene expression profiles in an in vivo mouse model, BMC Genomics, Vol: 16, ISSN: 1471-2164
© 2015 Offerman et al.Background: Host-range restricted poxviruses make promising vaccine vectors due to their safety profile and immunogenicity. An understanding of the host innate immune responses produced by different poxvirus vectors would aid in the assessment, selection and rational design of improved vaccines for human and veterinary applications. Novel avipoxviruses are being assessed to determine if they are different from other poxvirus vectors. Analysis of the transcriptome induced in a mouse model would aid in determining if there were significant differences between different poxvirus vectors which may reflect different adjuvant potential as well as establish if they should be further evaluated as vaccine vectors. Results: We compared host transcript abundance in the spleens of BALB/c mice twenty four hours after intravenous infection (10<sup>5</sup> pfu/mouse) with six host-restricted poxvirus species from three genera, namely Lumpy Skin Disease virus (LSDV), Canarypox virus (CNPV), Fowlpox virus (FWPV), modified vaccinia Ankara (MVA) and two novel South African avipoxviruses, Feral Pigeonpox virus (FeP2) and Penguinpox virus (PEPV). These six viruses produced qualitatively and quantitatively distinct host responses with LSDV, followed by MVA, inducing the greatest interferon (IFN) response. FeP2 and PEPV caused very little change to host transcript abundance compared to the other 4 viruses tested. CNPV and FWPV induced the up regulation of two immunoglobulin genes (Ighg and Ighg3 (IgG3)) with CNPV inducing a third, Ighm (IgM). HIV-1-specific IgG3 antibodies have been correlated with decreased risk of HIV-1 infection in the RV144 trial, which included a CNPV-based vector (Yates et al. (Sci Transl Med, 6(228) p228, 2014). Up regulation of IgG3 by CNPV and FWPV but not the other poxviruses tested in vivo, implies that these two avipoxvirus-vector backbones may be involved in stimulation of the clinically important IgG3 antibody subclass.
Coussens AK, Wilkinson RJ, Martineau AR, 2015, Phenylbutyrate Is Bacteriostatic against Mycobacterium tuberculosis and Regulates the Macrophage Response to Infection, Synergistically with 25-Hydroxy-Vitamin D-3, PLOS Pathogens, Vol: 11, ISSN: 1553-7366
Adjunctive vitamin D treatment for pulmonary tuberculosis enhances resolution of inflammationbut has modest effects on bacterial clearance. Sodium 4-phenylbutyrate (PBA) is inclinical use for a range of conditions and has been shown to synergise with vitamin Dmetabolites to upregulate cathelicidin antimicrobial peptide (CAMP) expression. We investigatedwhether clinically attainable plasma concentrations of PBA (0.4-4mM) directly affectMycobacterium tuberculosis (Mtb) growth and human macrophage and PBMC response toinfection. We also tested the ability of PBA to enhance the immunomodulatory actions ofthe vitamin D metabolite 25(OH)D3 during infection and synergistically inhibit intracellularMtb growth. PBA inhibited Mtb growth in broth with an MIC99 of 1mM, which was reduced to0.25mM by lowering pH. During human macrophage infection, PBA treatment restrictedMtb uptake, phagocytic receptor expression and intracellular growth in a dose-dependentmanner. PBA independently regulated CCL chemokine secretion and induced expressionof the antimicrobial LTF (lactoferrin), the anti-inflammatory PROC (protein C) and multiplegenes within the NLRP3 inflammasome pathway. PBA co-treatment with 25(OH)D3 synergisticallymodulated expression of numerous vitamin D-response genes, including CAMP,CYP24A1, CXCL10 and IL-37. This synergistic effect was dependent on MAPK signalling,while the effect of PBA on LTF, PROC and NLRP3 was MAPK-independent. During PBAand 25(OH)D3 co-treatment of human macrophages, in the absence of exogenous proteinase3 (PR3) to activate cathelicidin, Mtb growth restriction was dominated by the effect ofPBA, while the addition of PR3 enhanced growth restriction by 25(OH)D3 and PBA co-treatment.This suggests that PBA augments vitamin D–mediated cathelicidin-dependent Mtbgrowth restriction by human macrophages and independently induces antimicrobial andanti-inflammatory action. Therefore through both host-directed and bacterial-directed mechanisms PBA and vitamin
Coussens AK, Naude CE, Goliath R, et al., 2015, High-dose vitamin D3 reduces deficiency caused by low UVB exposure and limits HIV-1 replication in urban Southern Africans., Proceedings of the National Academy of Sciences of the United States of America, Vol: 112, Pages: 8052-8057, ISSN: 1091-6490
Cape Town, South Africa, has a seasonal pattern of UVB radiation and a predominantly dark-skinned urban population who suffer high HIV-1 prevalence. This coexistent environmental and phenotypic scenario puts residents at risk for vitamin D deficiency, which may potentiate HIV-1 disease progression. We conducted a longitudinal study in two ethnically distinct groups of healthy young adults in Cape Town, supplemented with vitamin D3 in winter, to determine whether vitamin D status modifies the response to HIV-1 infection and to identify the major determinants of vitamin D status (UVB exposure, diet, pigmentation, and genetics). Vitamin D deficiency was observed in the majority of subjects in winter and in a proportion of individuals in summer, was highly correlated with UVB exposure, and was associated with greater HIV-1 replication in peripheral blood cells. High-dosage oral vitamin D3 supplementation attenuated HIV-1 replication, increased circulating leukocytes, and reversed winter-associated anemia. Vitamin D3 therefore presents as a low-cost supplementation to improve HIV-associated immunity.
Friedland JS, Sathyamoorthy T, Tezera L, et al., 2015, Membrane Type 1 Matrix Metalloproteinase Regulates Monocyte Migration and Collagen Destruction in Tuberculosis, Journal of Immunology, Vol: 195, Pages: 822-891, ISSN: 0022-1767
Tuberculosis (TB) remains a global pandemic and drug resistance is rising. Multicellular granulomaformation is the pathological hallmark of Mycobacterium tuberculosis (Mtb) infection. The membranetype1 MMP (MT1-MMP or MMP-14) is a collagenase that is key in leukocyte migration and collagendestruction. In patients with TB, induced sputum MT1-MMP mRNA levels were increased 5.1-foldcompared to matched controls and correlated positively with extent of lung infiltration on chestradiographs (r=0.483; p<0.05). Mtb infection of primary human monocytes increased MT1-MMPsurface expression 31.7-fold and gene expression 24.5-fold. Mtb-infected monocytes degradedcollagen matrix in an MT1-MMP-dependent manner, and MT1-MMP neutralisation decreased collagendegradation by 73%. In human TB granulomas, MT1-MMP immunoreactivity was observed inmacrophages throughout the granuloma. Monocyte-monocyte networks caused a 17.5-fold increase inMT1-MMP surface expression dependent on p38 MAP kinase and GPCR-dependent signalling.Monocytes migrating towards agarose beads impregnated with conditioned media from Mtb-infectedmonocytes expressed MT1-MMP. Neutralization of MT1-MMP activity decreased this Mtb networkdependentmonocyte migration by 44%. Taken together, we demonstrate that MT1-MMP is central totwo key elements of TB pathogenesis, causing collagen degradation and regulating monocyte migration.
Namale PE, Abdullahi LH, Fine S, et al., 2015, Paradoxical TB-IRIS in HIV-infected adults: a systematic review and meta-analysis., Future Microbiology, Vol: 10, Pages: 1077-1099, ISSN: 1746-0921
ABSTRACT Paradoxical tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS) was first described almost two decades ago. We undertook this systematic review and meta-analysis to collate findings across studies that have reported the incidence, clinical features, management and outcomes of paradoxical TB-IRIS. Forty studies that cumulatively reported 1048 paradoxical TB-IRIS cases were included. The pooled estimated incidence among patients with HIV-associated TB initiating antiretroviral therapy was 18% (95% CI: 16-21%). Frequent features were pulmonary and lymph node involvement. Hospitalization occurred in 25% (95% CI: 19-30%). In studies that reported treatment, corticosteroids were prescribed more frequently (38%; 95% CI: 27-48%) than nonsteroidal anti-inflammatory drugs (28%; 95% CI: 2-53%). Case fatality was 7% (95% CI: 4-11%), but death attributed to TB-IRIS occurred in 2% of cases (95% CI: 1-3%).
Lawn SD, Wilkinson RJ, 2015, ART and prevention of HIV-associated tuberculosis., The lancet. HIV, Vol: 2, Pages: e221-e222, ISSN: 2405-4704
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Mzinza DT, Sloan DJ, Jambo KC, et al., 2015, Kinetics of Mycobacterium tuberculosis-specific IFN-γ responses and sputum bacillary clearance in HIV-infected adults during treatment of pulmonary tuberculosis., Tuberculosis, Vol: 95, Pages: 463-469, ISSN: 1873-281X
In HIV-uninfected adults with pulmonary tuberculosis (TB), anti-TB treatment is associated with changes in Mycobacterium tuberculosis (Mtb)-specific immune responses, which correlate with sputum bacillary load. It is unclear if this occurs in HIV-infected TB patients. We investigated changes in Mtb-specific immune responses and sputum bacillary clearance during anti-TB treatment in HIV-infected and HIV-uninfected adults with pulmonary TB. Sputum bacillary load was assessed by smear microscopy and culture. Mtb-specific IFN-γ secreting peripheral blood mononuclear cells were enumerated using an ELISPOT assay following stimulation with PPD, ESAT-6 and CFP-10. The baseline frequency of Mtb-specific IFN-γ secreting cells was lower in HIV-infected than HIV-uninfected patients (median PPD 32 vs. 104 Spot Forming Units (SFU), p = 0.05; CFP-10 19 vs. 74 SFU, p = 0.01). ESAT-6-specific IFN-γ secreting cells and sputum bacillary load declined progressively during treatment in both HIV-infected and HIV-uninfected patients. HIV infection did not influence the 2-month sputum culture conversion rate (Odds Ratio 0.89, p = 0.95). These findings suggest that changes in ESAT-6-specific immune responses during anti-TB treatment correspond with changes in sputum bacillary load irrespective of host HIV infection status. The utility of Mtb-specific IFN-γ responses as a proxy measure of treatment response in HIV-infected TB patients warrants further evaluation in other settings.
Deffur A, Wilkinson RJ, Coussens AK, 2015, Tricks to translating TB transcriptomics., Annals of translational medicine, Vol: 3, ISSN: 2305-5847
Transcriptomics and other high-throughput methods are increasingly applied to questions relating to tuberculosis (TB) pathogenesis. Whole blood transcriptomics has repeatedly been applied to define correlates of TB risk and has produced new insight into the late stage of disease pathogenesis. In a novel approach, authors of a recently published study in Science Translational Medicine applied complex data analysis of existing TB transcriptomic datasets, and in vitro models, in an attempt to identify correlates of protection in TB, which are crucially required for the development of novel TB diagnostics and therapeutics to halt this global epidemic. Utilizing latent TB infection (LTBI) as a surrogate of protection, they identified IL-32 as a mediator of interferon gamma (IFNγ)-vitamin D dependent antimicrobial immunity and a marker of LTBI. Here, we provide a review of all TB whole-blood transcriptomic studies to date in the context of identifying correlates of protection, discuss potential pitfalls of combining complex analyses originating from such studies, the importance of detailed metadata to interpret differential patient classification algorithms, the effect of differing circulating cell populations between patient groups on the interpretation of resulting biomarkers and we decipher weighted gene co-expression network analysis (WGCNA), a recently developed systems biology tool which holds promise of identifying novel pathway interactions in disease pathogenesis. In conclusion, we propose the development of an integrated OMICS platform and open access to detailed metadata, in order for the TB research community to leverage the vast array of OMICS data being generated with the aim of unraveling the holy grail of TB research: correlates of protection.
Jacobs A, Wilkinson RJ, 2015, Humoral immunity in tuberculosis, European Journal of Immunology, Vol: 45, Pages: 647-649, ISSN: 1521-4141
Ndiaye BP, Thienemann F, Ota M, et al., 2015, Safety, immunogenicity, and efficacy of the candidate tuberculosis vaccine MVA85A in healthy adults infected with HIV-1: a randomised, placebo-controlled, phase 2 trial, The Lancet Respiratory Medicine, Vol: 3, Pages: 190-200, ISSN: 2213-2600
Wilkinson KA, Walker NF, Meintjes G, et al., 2015, Cytotoxic Mediators in Paradoxical HIV-Tuberculosis Immune Reconstitution Inflammatory Syndrome, JOURNAL OF IMMUNOLOGY, Vol: 194, Pages: 1748-1754, ISSN: 0022-1767
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- Citations: 22
Walker NF, Scriven J, Meintjes G, et al., 2015, Immune reconstitution inflammatory syndrome in HIV-infected patients, HIV/AIDS - Research and Palliative Care, Vol: 7, Pages: 49-64, ISSN: 1179-1373
Access to antiretroviral therapy (ART) is improving worldwide. Immune reconstitution inflammatory syndrome (IRIS) is a common complication of ART initiation. In this review, we provide an overview of clinical and epidemiological features of HIV-associated IRIS, current understanding of pathophysiological mechanisms, available therapy, and preventive strategies. The spectrum of HIV-associated IRIS is described, with a particular focus on three important pathogen-associated forms: tuberculosis-associated IRIS, cryptococcal IRIS, and Kaposi's sarcoma IRIS. While the clinical features and epidemiology are well described, there are major gaps in our understanding of pathophysiology and as a result therapeutic and preventative strategies are suboptimal. Timing of ART initiation is critical to reduce IRIS-associated morbidity. Improved understanding of the pathophysiology of IRIS will hopefully enable improved diagnostic modalities and better targeted treatments to be developed.
Torres M, Garcia-Garcia L, Cruz-Hervert P, et al., 2015, Effect of isoniazid on antigen-specific interferon-γ secretion in latent tuberculosis, EUROPEAN RESPIRATORY JOURNAL, Vol: 45, Pages: 473-482, ISSN: 0903-1936
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Oni T, Youngblood E, Boulle A, et al., 2015, Patterns of HIV, TB, and non-communicable disease multi-morbidity in peri-urban South Africa- a cross sectional study, BMC Infectious Diseases, Vol: 15, ISSN: 1471-2334
BackgroundMany low and middle-income countries are experiencing colliding epidemics of chronic infectious (ID) and non-communicable diseases (NCD). As a result, the prevalence of multiple morbidities (MM) is rising.MethodsWe conducted a study to describe the epidemiology of MM in a primary care clinic in Khayelitsha. Adults with at least one of HIV, tuberculosis (TB), diabetes (DM), and hypertension (HPT) were identified between Sept 2012-May 2013 on electronic databases. Using unique patient identifiers, drugs prescribed across all facilities in the province were linked to each patient and each drug class assigned a condition.ResultsThese 4 diseases accounted for 45% of all prescription visits. Among 14364 chronic disease patients, HPT was the most common morbidity (65%). 22.6% of patients had MM, with an increasing prevalence with age; and a high prevalence among younger antiretroviral therapy (ART) patients (26% and 30% in 18-35 yr and 36–45 year age groups respectively). Among these younger ART patients with MM, HPT and DM prevalence was higher than in those not on ART.ConclusionsWe highlight the co-existence of multiple ID and NCD. This presents both challenges (increasing complexity and the impact on health services, providers and patients), and opportunities for chronic diseases screening in a population linked to care. It also necessitates re-thinking of models of health care delivery and requires policy interventions to integrate and coordinate management of co-morbid chronic diseases.
Jones CE, Hesseling AC, Tena-Coki NG, et al., 2015, The impact of HIV exposure and maternal <i>Mycobacterium tuberculosis</i> infection on infant immune responses to bacille Calmette-Guerin vaccination, AIDS, Vol: 29, Pages: 155-165, ISSN: 0269-9370
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- Citations: 29
Marais S, Wilkinson RJ, 2014, The diagnosis and medical management of tuberculous meningitis in adults, SAMJ South African Medical Journal, Vol: 104, Pages: 895-895, ISSN: 0256-9574
Marais S, Wilkinson KA, Lesosky M, et al., 2014, Neutrophil-Associated Central Nervous System Inflammation in Tuberculous Meningitis Immune Reconstitution Inflammatory Syndrome, CLINICAL INFECTIOUS DISEASES, Vol: 59, Pages: 1638-1647, ISSN: 1058-4838
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- Citations: 51
Mandala WL, Cowan FM, Lalloo DG, et al., 2014, Southern Africa Consortium for Research Excellence (SACORE): successes and challenges, LANCET GLOBAL HEALTH, Vol: 2, Pages: E691-E692, ISSN: 2214-109X
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- Citations: 9
Andrade BB, Singh A, Narendran G, et al., 2014, Mycobacterial Antigen Driven Activation of CD14<SUP>++</SUP> CD16<SUP>-</SUP> Monocytes Is a Predictor of Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome, PLOS PATHOGENS, Vol: 10, ISSN: 1553-7366
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- Citations: 89
Rangaka MX, Wilkinson RJ, Boulle A, et al., 2014, Isoniazid plus antiretroviral therapy to prevent tuberculosis: a randomised double-blind, placebo-controlled trial, The Lancet, Vol: 384, Pages: 682-690, ISSN: 0140-6736
BackgroundAntiretroviral therapy reduces the risk of tuberculosis, but tuberculosis is more common in people with HIV than in people without HIV. We aimed to assess the effect of isoniazid preventive therapy on the risk of tuberculosis in people infected with HIV-1 concurrently receiving antiretroviral therapy.MethodsFor this pragmatic randomised double-blind, placebo-controlled trial in Khayelitsha, South Africa, we randomly assigned (1:1) patients to receive either isoniazid preventive therapy or a placebo for 12 months (could be completed during 15 months). Randomisation was done with random number generator software. Participants, physicians, and pharmacy staff were masked to group assignment. The primary endpoint was time to development of incident tuberculosis (definite, probable, or possible). We excluded tuberculosis at screening by sputum culture. We did a modified intention-to-treat analysis and excluded all patients randomly assigned to groups who withdrew before receiving study drug or whose baseline sputum culture results suggested prevalent tuberculosis. This study is registered with ClinicalTrials.gov, number NCT00463086.Findings1329 participants were randomly assigned to receive isoniazid preventive therapy (n=662) or placebo (n=667) between Jan 31, 2008, and Sept 31, 2011, and contributed 3227 person-years of follow-up to the analysis. We recorded 95 incident cases of tuberculosis; 37 were in the isoniazid preventive therapy group (2·3 per 100 person-years, 95% CI 1·6–3·1), and 58 in the placebo group (3·6 per 100 person-years, 2·8–4·7; hazard ratio [HR] 0·63, 95% CI 0·41–0·94). Study drug was discontinued because of grade 3 or 4 raised alanine transaminase concentrations in 19 of 662 individuals in the isoniazid preventive therapy group and ten of the 667 individuals in the placebo group (risk ratio 1·9, 95% CI 0·90–4·09). We noted no evidenc
Coussens AK, Martineau AR, Wilkinson RJ, 2014, Anti-Inflammatory and Antimicrobial Actions of Vitamin D in Combating TB/HIV., Scientifica (Cairo), Vol: 2014, Pages: 903680-903680, ISSN: 2090-908X
TUBERCULOSIS (TB) DISEASE ACTIVATION IS NOW BELIEVED TO ARISE DUE TO A LACK OF INFLAMMATORY HOMEOSTATIC CONTROL AT EITHER END OF THE SPECTRUM OF INFLAMMATION: either due to immunosuppression (decreased antimicrobial activity) or due to immune activation (excess/aberrant inflammation). Vitamin D metabolites can increase antimicrobial activity in innate immune cells, which, in the context of HIV-1 coinfection, have insufficient T cell-mediated help to combat Mycobacterium tuberculosis (MTB) infection. Moreover, maintaining vitamin D sufficiency prior to MTB infection enhances the innate antimicrobial response to T cell-mediated interferon-γ. Conversely, vitamin D can act to inhibit expression and secretion of a broad range of inflammatory mediators and matrix degrading enzymes driving immunopathology during active TB and antiretroviral- (ARV-) mediated immune reconstitution inflammatory syndrome (IRIS). Adjunct vitamin D therapy during treatment of active TB may therefore reduce lung pathology and TB morbidity, accelerate resolution of cavitation and thereby decrease the chance of transmission, improve lung function following therapy, prevent relapse, and prevent IRIS in those initiating ARVs. Future clinical trials of vitamin D for TB prevention and treatment must be designed to detect the most appropriate primary endpoint, which in some cases should be anti-inflammatory and not antimicrobial.
Esmail H, Barry CE, Young DB, et al., 2014, The ongoing challenge of latent tuberculosis, PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, Vol: 369, ISSN: 0962-8436
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- Citations: 196
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