Immune reconstitution and "unmasking" of tuberculosis during antiretroviral therapy

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.

Figure 1.

Graphs showing the high incidence of tuberculosis (TB) during first 3 months of antiretroviral treatment (ART) and the subsequent rapid decrease. Data are from (A) cohorts in low-TB-burden countries in Europe and North America (data are from Reference 12) and (B) a community-based ART program in Cape Town, South Africa, where the burden of TB is very high (data are from Reference 9). Power trend lines are shown. PY = person-years.

Figure 2.

(A) A hypothetical graph showing the rising burden of Mycobacterium tuberculosis over time at a given anatomic site in an HIV-infected patient with advanced immunodeficiency (shown as a linear rise over time for simplicity). Symptom onset occurs when the mycobacterial load rises to a level at which the host inflammatory responses are triggered (symptom threshold). With poor immune function, the symptom threshold is reached at time t₁. (B) If the patient were to have started antiretroviral therapy (ART), tuberculosis-specific immune function would increase rapidly and the threshold for development of symptoms would correspondingly decrease. As a result, symptoms would develop much earlier soon after the initiation of ART (time t₂).

Figure 3.

Progression of subclinical disease to symptomatic tuberculosis (TB) during early antiretroviral therapy (ART). This hypothetical conceptual diagram shows the interrelationship between Mycobacterium tuberculosis antigen load, rate, and intensity of immune recovery during early ART and the resulting clinical presentation of TB (plot area) in patients with subclinical TB at the time of ART initiation. Most cases of incident TB present with relatively “normal” clinical features, and TB immune reconstitution disease (TB IRD) forms only a subset of incident TB cases. TB IRD is most likely in patients with high antigen burden and dysregulated immune recovery, leading to development of exaggerated and overtly inflammatory manifestations of TB.