Date Published: March 23, 2017
Publisher: Public Library of Science
Author(s): Aaron S. Karat, Mpho Tlali, Katherine L. Fielding, Salome Charalambous, Violet N. Chihota, Gavin J. Churchyard, Yasmeen Hanifa, Suzanne Johnson, Kerrigan McCarthy, Neil A. Martinson, Tanvier Omar, Kathleen Kahn, Daniel Chandramohan, Alison D. Grant, Petros Isaakidis.
The World Health Organization (WHO) aims to reduce tuberculosis (TB) deaths by 95% by 2035; tracking progress requires accurate measurement of TB mortality. International Classification of Diseases (ICD) codes do not differentiate between HIV-associated TB and HIV more generally. Verbal autopsy (VA) is used to estimate cause of death (CoD) patterns but has mostly been validated against a suboptimal gold standard for HIV and TB. This study, conducted among HIV-positive adults, aimed to estimate the accuracy of VA in ascertaining TB and HIV CoD when compared to a reference standard derived from a variety of clinical sources including, in some, minimally-invasive autopsy (MIA).
Decedents were enrolled into a trial of empirical TB treatment or a cohort exploring diagnostic algorithms for TB in South Africa. The WHO 2012 instrument was used; VA CoD were assigned using physician-certified VA (PCVA), InterVA-4, and SmartVA-Analyze. Reference CoD were assigned using MIA, research, and health facility data, as available. 259 VAs were completed: 147 (57%) decedents were female; median age was 39 (interquartile range [IQR] 33–47) years and CD4 count 51 (IQR 22–102) cells/μL. Compared to reference CoD that included MIA (n = 34), VA underestimated mortality due to HIV/AIDS (94% reference, 74% PCVA, 47% InterVA-4, and 41% SmartVA-Analyze; chance-corrected concordance [CCC] 0.71, 0.42, and 0.31, respectively) and HIV-associated TB (41% reference, 32% PCVA; CCC 0.23). For individual decedents, all VA methods agreed poorly with reference CoD that did not include MIA (n = 259; overall CCC 0.14, 0.06, and 0.15 for PCVA, InterVA-4, and SmartVA-Analyze); agreement was better at population level (cause-specific mortality fraction accuracy 0.78, 0.61, and 0.57, for the three methods, respectively).
Current VA methods underestimate mortality due to HIV-associated TB. ICD and VA methods need modifications that allow for more specific evaluation of HIV-related deaths and direct estimation of mortality due to HIV-associated TB.
Data on causes of death (CoD) are essential in guiding public health strategy and research agendas. In South Africa in 2014, HIV prevalence was 18.9% among individuals aged 15–49 years  and there were an estimated 72,000 deaths due to HIV-associated tuberculosis (TB) . However, methods to measure CoD, particularly HIV-associated TB, do not provide sufficiently accurate estimates . Autopsy studies have typically investigated small numbers of deaths and mostly included individuals dying in hospitals [4–6]; death certification has consistently been shown to correspond poorly with retrospective clinical and autopsy diagnoses [7–9]; and verbal autopsy (VA), used to estimate CoD at a population level in many areas with poor civil registration systems, differentiates poorly between deaths due to HIV-associated TB and other HIV-associated causes [10–12]. These difficulties are compounded by the way deaths due to HIV-associated TB are coded by the International Classification of Diseases (ICD), which counts them as ‘HIV-related’ . The World Health Organization (WHO) presents TB mortality data separately for HIV-negative and HIV-positive individuals. However, due to the coding issues described above, all estimates of mortality due to HIV-associated TB are generated indirectly through mathematical modelling that uses country-level data on TB incidence and case-fatality ratios [14,15]; WHO itself states the ‘urgent need’ for direct measurement of HIV-associated TB mortality . An aim of the WHO ‘End TB’ strategy is to reduce TB deaths by 95% by 2035 .
This study, conducted among HIV-positive adults in a setting of high TB prevalence, compared CoD assigned by VA to a robust gold standard, including MIA, and found the proportion of deaths attributable to TB was underestimated by methods that did not include data from pathological autopsy. Overall HIV-associated mortality was also underestimated by all VA methods when compared to the L3 (autopsy) reference standard, with poor agreement at an individual level; all methods performed better at a population level.
Current VA methods underestimate mortality due to HIV-associated TB. At present, VA does not assign individual CoD in areas of high HIV prevalence with sufficient accuracy and, in part due to the limitations of ICD-10, does not distinguish between deaths due to HIV-associated TB and advanced HIV disease. More accurate methods are needed that allow for direct estimation of deaths due to HIV-associated TB; unless TB mortality is more accurately measured, it will be extremely difficult to track progress towards the goals set by the post-2015 global strategy.