Antiretroviral therapy and tuberculosis: what's the connection and what's the way forward?

The articles by Nicholas et al 1 and Petit et al in this issue of the Journal of Acquired Immune Deficiency Syndromes report on the incidence of tuberculosis (TB) before and after the initiation of highly active antiretroviral therapy in high and low-TB-prevalence settings. The TB incidence rate reported by Nicholas et al was high (13 per 100 person-years) during the first 3 months of antiretroviral therapy (ART) in a multicountry African cohort. Petit et al also found high TB incidence (4 per 1000 person-years) during the first 6 months of ART in a low-TB-prevalence setting cohort in the United States. Multiple studies in countries with a high TB burden have consistently documented high rates of TB during the very early months of ART. This high TB incidence during the early phase of ART is, at least in part, the result of unmasking of subclinical TB during the initial rapid restoration of immune response. However, suboptimal TB case finding due to the use of poorly sensitive TB screening and diagnostic tools before the initiation of ART is also a contributory factor for this reported high TB incidence. Nicholas et al used respiratory symptoms lasting for a duration of $2 weeks as the sole screening criterion to identify TB suspects. This TB screening approach has been shown to have a low sensitivity and likely to miss a large proportion of prevalent cases at the time of ART initiation. Many of the cases identified as incident TB cases during the first 3 months of ART could have been identified before the initiation of ART with the use of a more sensitive TB-screening tool. The World Health Organization (WHO) recommends that people living with HIV (PLHIV) in resource-constrained settings should be actively screened for TB using an evidence-based symptom screening tool (any one of current cough, fever, night sweats, or weight loss) and that the identified TB suspect should be further evaluated. In addition to using a less sensitive TB-screening tool, Nicholas et al used sputum smear microscopy and chest radiography for the diagnosis of TB. These diagnostic tests have a low sensitivity to detect culture-positive TB among HIV-infected individuals and might have missed some prevalent TB cases at the initiation of ART. A study in South Africa found that when using routine liquid culture to identify persons with active TB before initiating ART, the TB incidence rates after the initiation of ART were 2-fold lower than previously reported and that the rates during the first 3 months of ART were comparable with the rates during months 4–12. This study by Lawn et al suggests that approximately half of incident TB cases during the first 3 months of ART under routine program conditions might have been diagnosed before the initiation of ART by using sensitive screening methods and diagnostic tests such as sputum TB culture. Although there are international efforts to scale up culture-based TB diagnosis, the availability of qualified laboratory facilities that can reliably perform this test remains limited. Moreover, despite the high sensitivity, automated liquid culture takes a median