Measuring mortality due to HIV-associated tuberculosis among adults in South Africa: Comparing verbal autopsy, minimally-invasive autopsy, and research data

Abstract

BackgroundThe 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).Methods and findingsDecedents 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).ConclusionsCurrent 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.

Performance of verbal autopsy methods in estimating HIV-associated mortality among adults in South Africa

“…Only one study, conducted by our group in South Africa, has compared VA to CoD derived from pathological autopsy in HIV-positive individuals and found that VA methods likely underestimated HIV-associated CoD. 29 In part because of difficulties faced with ICD coding, there are few direct (autopsy or clinical) estimates of the HIV-associated mortality fraction among HIV-positive adults. A recent systematic review, which included only studies of HIV-positive individuals entirely or mostly on ART (n=19 studies), estimated that 18.5% (95% CI 13 to 24) of deaths in HIV-positive individuals on ART in sub-Saharan countries were due to ‘non-AIDS’ causes (ie, 76%–83% due to AIDS).…”

Socio-anthropological methods to study the feasibility and acceptability of the minimally invasive autopsy from the perspective of local communities: lessons learnt from a large multi-centre study

“…The MIA is a protocolized and systematic post-mortem methodology targeting key organs (brain, lungs, heart, liver, spleen, kidneys, bone marrow, uterus) and bodily fluids (blood and cerebrospinal fluid), and aiming to provide sufficiently good quality samples for pathological and microbiological investigations so as to substitute the complete pathological autopsy. The MIA has been validated for CoD investigation in all age groups [11][12][13][14] and has been used in different settings [15,16]. CoD results derived from the use of the MIA tool could also contribute in the future to modify and improve current analytical approaches utilized for VA data interpretation.…”

Mortality and risk of tuberculosis among people living with HIV in whom TB was initially ruled out

“…Another prospective study in Zambia found that in those inpatients without presumptive TB (i.e. without presence of cough of 2 or more weeks at admission) but who were able to provide a sputum sample, 19/133 (14.3%) were HIV-positive and 7/118 (5.9%) had culture-confirmed TB 10 . Thus, given the low case detection rate in the Mozambique and the lack of active case finding strategies during the study period, misdiagnosis could have been due to poor diagnostic work-up and the intrinsic challenges to diagnose TB in HIV-positive patients, who are frequently paucibacillary and often asymptomatic.…”

“…Several studies have shown the increased mortality associated with TB misdiagnosis, in particular, with TB underdiagnosis 8 , 9 . Although TB is a common cause of death in post-mortem studies conducted in high HIV prevalence settings 10 – 13 , ascertainment of TB as a cause of death is challenging in most low income countries 14 – 16 . In addition, PLHIV with clinically diagnosed TB have a higher mortality risk than those with laboratory-confirmed TB 17 highlighting the importance of improving laboratory-based TB diagnosis in this population.…”