Risk of reactivation of tuberculosis in the course of human immunodeficiency virus infection

OBJECTIVES: To establish, in a longitudinal study, whether reactivation of latent tuberculous infection takes place below an identifiable immunological threshold in subjects with human immunodeficiency virus (HIV) infection. METHODS: We followed up for 2 years 44 subjects with HIV infection who had a positive intradermal reaction to tuberculin. All subjects were asymptomatic at enrollment. End points of the study were the development of active tuberculosis or the final evaluation (24 months since the beginning) for those who did not develop tuberculosis over the study period. Total lymphocyte count, CD4+ lymphocyte count and beta-2 microglobulin serum levels were measured at baseline, during the period of observation (every 3-6 months) and at the end point. Multiple Antigen Skin Testing and purified protein derivative (PPD) testing were also performed at baseline and end point, as well as in intermediate phases of the study (every 6 and 12 months respectively). RESULTS: Ten subjects (22.7%) developed tuberculosis during the study period. Both baseline and end point values of the parameters investigated differed significantly between subjects who developed tuberculosis and those who did not. Cox's model showed that total and CD4+ lymphocyte counts as well as beta-2 microglobulin levels had a prognostic value at a univariate analysis; CD4+ and beta-2 microglobulin retained statistical significance in a multivariate evaluation. CD4+ lymphocyte count was the parameter most strongly associated with the development of tuberculosis. CONCLUSIONS: Tuberculosis in this setting most often reactivates only when immune surveillance has fallen to an identifiable level. Planners of antituberculous chemoprophylactic policies should consider the downgrading tendency of immune function in these subjects in order to choose the most appropriate time to intervene in the course of HIV infection. Starting prophylaxis in HIV-infected subjects only when CD4+ cells have dropped below the value of 500/mm3 seems to be a more fruitful option than the currently adopted strategy, which recommends time-limited (12 months) administration of daily isoniazid to all PPD+ HIV-infected subjects regardless their immunological status.