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Immune Reconstitution and "Unmasking" of Tuberculosis during Antiretroviral Therapy

¹ The Desmond Tutu HIV Centre, Institute for Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa; ² Clinical Research Unit, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom; ³ Mycobacterial Immunology, Institute of Infectious Disease and Molecular Medicine, and Department of Medicine, University of Cape Town, Cape Town, South Africa; ⁴ Division of Medicine, Imperial College London, London, United Kingdom; ⁵ National Institute for Medical Research, London, United Kingdom; and ⁶ Department of HIV Medicine, Royal Free Hospital, London, United Kingdom

Correspondence and requests for reprints should be addressed to Stephen D. Lawn, M.D., Desmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory 7925, Cape Town, South Africa. E-mail: stevelawn{at}yahoo.co.uk

ABSTRACT

Tuberculosis (TB) is the most common opportunistic disease in HIV-infected patients during the initial months of antiretroviral therapy (ART) and presents a great challenge to ART programs in resource-limited settings. The mechanisms underlying development of TB in this period are complex. Some cases may represent progression of undiagnosed subclinical disease present before starting ART, emphasizing the importance of careful screening strategies for TB. It has been suggested that progression in such cases is due to immune reconstitution disease—a phenomenon in which dysregulated restoration of pathogen-specific immune responses triggers the presentation of subclinical disease. However, whereas some cases have exaggerated or overtly inflammatory manifestations consistent with existing case definitions for IRD, many others do not. Moreover, since ART-induced immune recovery is a time-dependent process, active TB may develop as a consequence of persisting immunodeficiency. All these mechanisms are likely to be important, representing a spectrum of complex interactions between mycobacterial burden and changing host immune response. We propose that the potential range of effects of ART includes (1) shortening of the time for subclinical TB to become symptomatic (a phenomenon often referred to as "unmasking"), (2) increased rapidity of initial onset of TB symptoms, and (3) heightened intensity of clinical manifestations. We suggest that the term "ART-associated TB" be used to refer collectively to all cases of TB presenting during ART and that "immune reconstitution disease" be used to refer to the subset of ART-associated TB cases in which the effect on disease severity results in exaggerated and overtly inflammatory disease.

Key Words: HIV • tuberculosis • antiretroviral • immune reconstitution • IRIS

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