There were 57 deaths in this cohort with an overall mortality rate of 4.3 per 100 py (95% CI: 3.3 to 5.6). There were 7 deaths among patients with baseline prevalent TB, mortality rate of 2.7 (95% CI: 1.1 to 5.6) per 100 py compared with 50 deaths among 796 patients with no baseline prevalent TB, mortality rate of 4.7 (95% CI: 3.5 to 6.3) per 100 py (P = 0.20) of follow-up. Patients with at least 1 episode of TB (either history, prevalent or incident TB) had a lower mortality rate 3.4 (95% CI: 2.0 to 5.4) compared with patients with no TB, 4.5 (95% CI: 3.1 to 6.3) per 100 py (IRR, 0.8; 95% CI: 0.5 to 1.4; P = 0.42) of follow-up. There was 1 death each in the early and late incident TB groups. The causes of death for 29 of 57 patients was known, and this included PTB (n = 4), EPTB (n = 5), complications from severe gastroenteritis (n = 6), trauma (n = 2), natural causes (n = 5), meningitis-unknown cause (n = 2), lower respiratory tract infection (n = 2), cerebrovascular accident (n = 1), intracranial lesion (n = 1), and complications from hyperlactatemia (n = 1). Causes of death were not available in 28 patients as many of them died at home.
In contrast to our study, published literature demonstrates a far more substantial time-dependant reduction in TB incidence among patients on HAART.28–37 These studies report highest TB incidence during the first 3 months of HAART10 with a progressive reduction of all forms of TB during the first year of follow-up from 5.77/100 to 2.23/100 py.38 Published meta-analysis data from developed country cohorts estimate a comparable effect of HAART on TB incidence despite differences in background risk of Mycobacterium tuberculosis infection. These data provide an estimated TB incidence of 3 cases per 1000 py among patients accessing HAART, 10-fold lower compared with the TB incidence rates we found.10 Findings similar to ours were reported in only 1 other study, conducted in a densely populated urban informal settlement with an HIV seroprevalence of 28% and TB notification rate of >1000/100,000 population. In this study, TB incidence was reduced from 22.1 to 4.5/100 py among patients with a median baseline CD4+ count of 96 cells per cubic millimeter (IQR, 46–156), after approximately 3 years of HAART.39
Unsurprisingly, there was no statistically significant difference in mortality rates among cases with known TB at baseline compared with those without. Mortality studies among HIV-infected patients conducted in this setting have repeatedly demonstrated high rates of undiagnosed TB responsible for as much as 79% of all deaths in HIV-infected patients.43,44 Mortality rates were similar among patients with new episodes of EPTB as compared with those with new episodes of PTB; 2.3 (95% CI: 0.1 to 13.1) versus 2.1 (95% CI: 0 to 11.6) per 100 py of follow-up. Interestingly, the mortality rate at 24 months in this study among patients with and without prevalent TB at baseline was very different to 5-year mortality rates of 4.84 and 2.62 per 100 py of follow-up among prevalent TB and TB-free patients initiating antiretroviral therapy in Cape Town, South Africa.45
We acknowledge several limitations. This study was conducted in a hyper-endemic HIV and TB setting, which limits the generalizability of these findings to similar settings. Limited access to chest x-rays in this primary health care setting, especially for asymptomatic patients with low CD4+ counts may have led to significant underreporting of TB, which potentially limits the validity, and to a lesser extent the generalizability of the study. The reliance on TB clinical symptom screening, lack of use of a standardized algorithm for TB screening and diagnosis, together with limited access to TB microscopy services, further contributed to TB cases being missed. The findings from this study highlight the need for enhanced screening and the use of a diagnostic algorithm for TB in a setting with generalized TB and HIV co-epidemics. High rates of smear-negative TB and long delays in TB diagnosis may have led to the misclassification of prevalent TB cases as incident TB, especially for episodes that occurred in the first 3 months post-HAART initiation. Data used were routinely collected programmatic data, and missing data elements may have led to an underestimation of the actual burden of TB in this setting. Additionally, TB outcome data were not always readily available for complicated patients referred for hospitalization or for those who were lost to follow-up. In contrast to published literature, we report low IRIS estimates, which may be because of the retrospective nature of this study and to the lack of standardized clinical tools for diagnosing IRIS. Molecular strain typing would have been extremely useful in determining if cases of recurrent TB in this cohort were due to relapse or reinfection, particularly in patients with early incident TB and in the 3 cases with incident and recurrent TB, but given the lack of cost-effective but unavailable tools such as chest x-rays in this setting, such endeavors were unfortunately unrealistic. It is important to note that our health care facility implemented standard WHO TB infection control measures, and data for this study were collected before the programmatic implementation of IPT. The impact of IPT on TB prevalence and incidence in community-based HAART programmes remains to be explored, however, in this cohort it is important to note that starting patients on IPT with HAART may result in many patients with active TB disease having initiated IPT.
The authors gratefully acknowledge the contributions of the CAPRISA AIDS Treatment team for providing clinical care of study patients. The authors thank the KwaZulu-Natal Department of Health, the staff of the Umgungundlovu district health office, and the nurses at the Mafakhathini Primary Care Clinic for their professional support and for clinical care of patients. The mentorship and oversight provided by Professor Salim Abdool Karim and Quarraisha Abdool Karim of CAPRISA was invaluable, without which this project would not have been possible.
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