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Coverage of antiretroviral therapy (ART) in low- and middle-income countries remains limited, reaching approximately 30% of those needing it by the end of 2007.[1] There has, however, been rapid progress in increasing access in developing countries with nearly 3 million people on treatment by the end of 2007, representing a 7.5 fold increase since 2003.[1] However, early mortality rates among adults in ART programmes in resource limited settings are high, and considerably exceed those in high-income settings, even after adjustment for immunodeficiency.[2,3] While knowledge of common causes of death is crucial to understanding this higher mortality, such data to date is limited with no systematic postmortem studies having been reported.[2]  A review of 5 observational cohort studies that reported on mortality in developing country ART cohorts suggested that tuberculosis (TB), cryptococcal meningitis and Kaposi’s sarcoma are leading causes of death in these settings.[2] Given that immune restoration is a time-dependant process, patients who initiate ART when profoundly immunosuppressed remain at risk for opportunistic infections for the first few months, and sometimes 1–2 years, on ART even if virologically suppressed. Opportunistic infections occurring during early ART largely reflect persistent immunodeficiency, but in a subset the immune reconstitution inflammatory syndrome (IRIS), which results from dysregulated and excessive inflammatory responses directed at the antigens of opportunistic infections, influences the clinical presentation and course.[4] More advanced immunodeficiency at ART initiation has been identified as a risk factor for IRIS. IRIS is thus a frequent early complication of ART in resource-limited settings where patients often initiate ART late with low CD4 counts and after having been diagnosed with opportunistic infections.[4–6] It has been suggested that IRIS may be an important contributor to the higher mortality rates reported from cohorts in these settings.[7]  The study by Castelnuovo et al provides important data regarding the causes of death on ART in the context of a busy ART clinic from a developing country.[8] Mortality in the first 36 months on ART is indeed high (17%) and similar to that of other resource-limited settings with the leading causes concurring with those of previous studies.[2,8] Almost 60% of these deaths occurred within the first 3 months of ART. The contribution of IRIS to this mortality was relatively small with only 4 of 54 HIV-related deaths occurring in the first 3 months on ART (7%) attributed to IRIS. No cases of death were attributed to paradoxical TB-IRIS, confirming other reports that this is a condition that infrequently results in death.[5,9]  These findings need to be interpreted with two important caveats. Firstly, our understanding of IRIS, and particularly unmasking IRIS, is currently incomplete, and secondly, the retrospective design of this study may have resulted in the contribution of IRIS being underestimated. Furthermore, as the authors indicate, not all the findings may be generalisable to other low-income settings.

Assessing the Contribution of the Immune Reconstitution Inflammatory Syndrome to Mortality in Developing Country Antiretroviral Therapy Programs