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

Wallis, Robert Sa,b; Kyambadde, Peterc; Johnson, John La; Horter, Libbya; Kittle, Rodneya,d; Pohle, Monikaa; Ducar, Constancee; Millard, Monicaa; Mayanja-Kizza, Harrietc; Whalen, Christophera; Okwera, Alphonsec

Clinical Science

Objective: Tumor necrosis factor (TNF), an important inflammatory mediator in tuberculosis, has been implicated in causing accelerated HIV disease progression in HIV-associated tuberculosis. However, TNF blockade, particularly by monoclonal antibody, has been associated with the reactivation of latent Mycobacterium tuberculosis infection by the impairment of mycobacterial immunity. This phase 1 study examined the safety, microbiology, immunology, and virology of TNF blockade using etanercept (soluble TNF receptor, Enbrel) during the initial treatment of HIV-associated tuberculosis.

Design: A single-arm trial, with key endpoints compared with historical controls, conducted in Mulago Hospital, Kampala, Uganda.

Subjects: Sixteen HIV-1-infected patients and 42 CD4-frequency-matched controls with sputum smear-positive tuberculosis and CD4 cell counts > 200 cells/μl.

Intervention: Etanercept 25 mg, eight doses administered subcutaneously twice weekly beginning on day 4 of tuberculosis therapy.

Main outcome measures: Serial examination, radiography, sputum culture, CD4 T-cell counts, plasma log10 HIV-RNA copy numbers.

Results: Trends towards superior responses to tuberculosis treatment were evident in etanercept-treated subjects in body mass, performance score, number of involved lung zones, cavitary closure, and time to sputum culture conversion. Etanercept treatment resulted in a 25% increase in CD4 cells by week 4 (P = 0.1 compared with controls). The change in CD4 cell count was inversely related to the change in serum neopterin, a marker of macrophage activation. There was no effect on plasma HIV RNA.

Conclusion: 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.

From the aDepartment of Medicine, Case Western Reserve University, Cleveland, OH, USA; bDepartment of Medicine, University of Medicine and Dentistry – New Jersey Medical School, Newark, NJ, USA; cDepartments of Medicine and Microbiology, Makerere University, Kampala, Uganda; dJoint Clinical Research Center, Kampala, Uganda; eDepartment of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Correspondence to Robert S. Wallis, Department of Medicine, UMDNJ-NJMS, 185 South Orange Avenue, MSB I-503, Newark, NJ 07103, USA.

Tel: +1 973 972 8778; fax: +1 973 972 8878; e-mail: r.wallis@umdnj.edu

Received: 6 February 2003; revised: 2 June 2003; accepted: 25 June 2003.

© 2004 Lippincott Williams & Wilkins, Inc.