A study of the safety, immunology, virology, and microbiology of adjunctive etanercept in HIV-1-associated tuberculosis

Wallis, Robert S.; Kyambadde, Peter; Johnson, John L.; Horter, Libby; Kittle, Rodney; Pohle, M.; Ducar, Constance; Millard, Monica; Mayanja‐Kizza, Harriet; Whalen, Christopher C.; Okwera, Alphonse

doi:10.1097/00002030-200401230-00015

Cited by 201 publications

(137 citation statements)

References 33 publications

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“…In a phase I study, 16 HIV-infected patients with TB were treated safely with etanercept as a therapeutic adjunct to standard chemotherapy. These patients had an increase in CD4ϩ lymphocytes and a slightly shorter time to sputum culture conversion when compared with a retrospective control group of patients who had not received etanercept (28).…”

Section: Interim Recommendations For the Prevention And Management Ofmentioning

confidence: 85%

Tuberculosis associated with therapy against tumor necrosis factor α

Winthrop¹,

Siegel²,

Jereb³

et al. 2005

Arthritis & Rheumatism

103

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Section: Interim Recommendations For the Prevention And Management Ofmentioning

confidence: 85%

Tuberculosis associated with therapy against tumor necrosis factor α

Winthrop¹,

Siegel²,

Jereb³

et al. 2005

Arthritis & Rheumatism

103

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“…Elevated TNFα levels are seen throughout all stages of HIV infection. Several case reports and controlled trials have examined anti-TNF therapy in patients with underlying HIV infection [85,86]. One of seventeen patients given single doses of ETA or INF had an adverse event (elevated creatinine) and 13 patients with HIV and active TB given 4 weeks of ETA had no adverse events.…”

Section: Adverse Consequences Of Tnfα Blockade Therapies Infectionsmentioning

confidence: 99%

TNFα blockade in human diseases: An overview of efficacy and safety

Lin

Ziring

Desai

et al. 2008

Clinical Immunology

233

188

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“…A bias in cell death towards activated T cells in TB patients might explain the anergy seen in advanced TB patients, which appears to be TNF-a related [68,69]. Finally, if TNF-a-driven apoptosis of T cells plays a role in M. tuberculosis pathogenesis, it would also provide an interesting explanation for why blocking TNF-a with Etanercept (soluble TNF receptor) in TB patients undergoing treatment, led to an increase in CD4T cell numbers [70].We have tested some aspects of this hypothesis by infecting human THP-1 cells with virulent M. tuberculosis or avirulent M. tuberculosis and BCG in vitro and measuring expression of the same genes as we have tested here. These experiments have confirmed both the overall anti-apoptotic effect of virulent M. tuberculosis infection of monocytes, at the same time as it drives activation of many of the genes we see upregulated in patients -including the TNF-a/TNFR axis (Abebe et al, submitted).…”

mentioning

confidence: 99%

Expression of apoptosis‐related genes in an Ethiopian cohort study correlates with tuberculosis clinical status

et al. 2009

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Mycobacterium tuberculosis remains one of the world's deadliest pathogens in part because of its ability to persist in the face of an active immune response. It has been suggested that apoptosis of infected macrophages is one way in which the host deals with intracellular pathogens and that M. tuberculosis can inhibit this process. To assess the relevance of this process for human disease, we compared the expression of multiple genes involved in the activation of the extrinsic (''death receptor initiated'') pathway of apoptosis in 29 tuberculosis patients, 70 tuberculosis contacts and 27 community controls from Ethiopia. We found that there is a strong upregulation of genes for factors that promote apoptosis in PBMC from individuals with active disease, including TNF-a and its receptors, Fas and FasL and proCaspase 8. The anti-apoptotic factor FLIP, however, was also upregulated. A possible explanation for this dichotomy was given by fractionation of PBMC using CD14, which suggests that macrophage/monocytes may regulate several key molecules differently from non-monocytic cells (especially TNF-a and its receptors, a finding confirmed by protein ELISA) potentially reducing the sensitivity to apoptotic death of monocyte/macrophages -the primary host cell for M. tuberculosis. This may represent an important survival strategy for the pathogen. IntroductionDespite vaccination and drug treatment campaigns, tuberculosis (TB) causes an estimated 8-9 million new cases and mortality of 2-3 million deaths annually [1]. The TB epidemic is largely confined to developing countries, and is particularly serious in Sub-Saharan Africa [2], where it is fanned by the HIV epidemic. Despite the high mortality, most infected people do not immediately develop active disease, but become latently infected -though they may later reactivate their disease, if they become immunocompromised [3]. It is thought that perhaps as much as a third of the world's population is latently infected, [4] Eur. J. Immunol. 2010. 40: 291-301 DOI 10.1002 Clinical immunology 291 complicating control efforts by providing a reservoir from which new cases continually arise. Understanding immunity to Mycobacterium tuberculosis, so that more effective vaccines can be developed, is thus an international priority. The response to infection with M. tuberculosis is characterized by a strong inflammatory cell-mediated immune response, with elevated expression of both and . These two cytokines are essential for controlling mycobacterial infections [11][12][13] but in most cases, M. tuberculosis survives to establish a latent infection -which can rapidly reactivate if TNF-a production is blocked [14]. The precise mechanisms involved in this process are still only poorly known. We and others have previously shown that a bias towards IL-4 expression is associated with elevated risk of disease [15] while a bias towards the IL-4 antagonist IL-4d2, or towards IFN-g, is associated with reduced pathology, a better prognosis after infection, recovery after treatment and with ...

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A study of the safety, immunology, virology, and microbiology of adjunctive etanercept in HIV-1-associated tuberculosis

Abstract: Etanercept can be safely administered during the initial treatment of pulmonary tuberculosis. Further studies are warranted to examine the effects of etanercept on T-cell numbers, activation and apoptosis in AIDS and tuberculosis.

Cited by 201 publications

References 33 publications

Tuberculosis associated with therapy against tumor necrosis factor α

Tuberculosis associated with therapy against tumor necrosis factor α

TNFα blockade in human diseases: An overview of efficacy and safety

Expression of apoptosis‐related genes in an Ethiopian cohort study correlates with tuberculosis clinical status

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