Reducing the Burden of Tuberculosis Presenting during the Initial Months of Antiretroviral Therapy in Resource‐Limited Settings

Abstract

SIR-The high burden of tuberculosis (TB) within antiretroviral treatment (ART) programs in resource-limited settings is challenging [1,2]. We read with interest the article by Koenig and colleagues from Haiti in which they reported a very high mortality rate (27% at one year) among patients with TB diagnosed during the first 3 months of ART [3]. This observation is important and entirely consistent with other data from sub-Saharan Africa [1, 2]. It was also reported, however, that in both adjusted and unadjusted analyses, the mortality in this patient group was substantially greater than that of patients with either prevalent TB diagnosed pre-ART or incident TB diagnosed at some time beyond 3 months of ART [3]. Data from the latter two groups were pooled to form a combined comparator group with low overall TB risk. The much higher mortality risk of patients with TB presenting in early ART compared to that of patients with TB at baseline differs from the findings of previous studies [1,2] and we are concerned that this observation could be misinterpreted as showing a deleterious impact of ART on survival. We wonder whether this may be the result of patient selection. The mortality rate of patients with advanced immunodeficiency just prior to starting ART in resource limited settings is extremely high and TB in this period is difficult and time-consuming to diagnose [4–7]. Thus, many deaths occur in this period among patients with either diagnosed TB or unrecognised TB. Only selected patients in whom TB diagnosis was possible and who survived long enough to start ART could form the pre-ART group. Such patient selection may have substantially diminished the observed mortality risk of the pre-ART group. This would be consistent with the Kaplan Meier plot, which shows an unusually low frequency of deaths in the first 6 weeks of TB treatment in the comparator arm containing this patient group. Notwithstanding this potential limitation, we agree that TB is very likely to be an important contributor to early mortality in ART services [4]. The key question is how to tackle this problem. Koenig and colleagues suggested that many patients with incident TB during early ART are likely to have active TB that was present at baseline but remained undiagnosed. In agreement with this, we recently estimated that in our South African ART cohort, approximately 40% of the TB cases presenting in this period is due to ‘unmasking’ of asymptomatic or minimally symptomatic disease present at baseline [8]. Moreover, in a more recent study, all patients entering our program without a pre-existing TB diagnosis were (regardless of symptoms) systematically screened by culturing induced sputum samples. The yield of culture-confirmed TB diagnoses in these patients at baseline was extremely high (25%) [9] and was more that 2-fold higher than had been diagnosed during routine program screening in preceding years [1]. Of note, during the period of this study, the proportion of patients who presented with TB in the first 3 months of ART was correspondingly more than two-fold lower than previously observed. Thus, following the observation by Koenig and colleagues of the very high mortality rate among patients presenting with TB in the first 3 months of ART, we have found that effective baseline screening substantially reduces incident TB during this period. This suggests a need for routine pre-ART TB screening using high sensitivity tests, such automated liquid culture of sputum, and highlights an urgent need for much more rapid and sensitive diagnostics for use in this clinical setting. It remains to be demonstrated, however, whether this strategy would reduce mortality risk.