A study of the safety, immunology, virology, and microbiology of adjunctive etanercept in HIV-1- associated tuberculosis Robert S. Wallis a,b , Peter Kyambadde c , John L. Johnson a , Libby Horter a , Rodney Kittle a,d , Monika Pohle a , Constance Ducar e , Monica Millard a , Harriet Mayanja-Kizza c , Christopher Whalen a and Alphonse Okwera c 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 tubercu- losis infection by the impairment of mycobacterial immunity. This phase 1 study examined the safety, microbiology, immunology, andvirology 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/ìl. 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 log 10 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 ¼ 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. & 2004 Lippincott Williams & Wilkins AIDS 2004, 18:1–8 From the a Department of Medicine, Case Western Reserve University, Cleveland, OH, USA; b Department of Medicine, University of Medicine and Dentistry – New Jersey Medical School, Newark, NJ, USA; c Departments of Medicine and Microbiology, Makerere University, Kampala, Uganda; d Joint Clinical Research Center, Kampala, Uganda; e Department 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. DOI: 10.1097/01.aids.0000104367.21567.d8 Article number = 348 ISSN 0269-9370 & 2004 Lippincott Williams & Wilkins 1