Estimated clinical impact of the Xpert MTB/RIF Ultra cartridge for diagnosis of pulmonary tuberculosis: A modeling study

Abstract

Background

The Xpert MTB/RIF (Xpert) assay offers rapid and accurate diagnosis of tuberculosis (TB) but still suffers from imperfect sensitivity. The newer Xpert MTB/RIF Ultra cartridge has shown improved sensitivity in recent field trials, but at the expense of reduced specificity. The clinical implications of switching from the existing Xpert cartridge to the Xpert Ultra cartridge in different populations remain uncertain.

Methods and findings

We developed a Markov microsimulation model of hypothetical cohorts of 100,000 individuals undergoing diagnostic sputum evaluation with Xpert for suspected pulmonary TB, in each of 3 emblematic settings: an HIV clinic in South Africa, a public TB center in India, and an adult primary care setting in China. In each setting, we used existing data to project likely diagnostic results, treatment decisions, and ultimate clinical outcomes, assuming use of the standard Xpert versus Xpert Ultra cartridge. Our primary outcomes were the projected number of additional unnecessary treatments generated, the projected number of TB deaths averted, and the projected number of unnecessary treatments generated per TB death averted, if standard Xpert were switched to Xpert Ultra. We also simulated alternative approaches to interpreting positive results of the Ultra cartridge’s semi-quantitative trace call. Extensive sensitivity and uncertainty analyses were performed to evaluate the drivers and generalizability of projected results. In the Indian TB center setting, replacing the standard Xpert cartridge with the Xpert Ultra cartridge was projected to avert 0.5 TB deaths (95% uncertainty range [UR]: 0, 1.3) and generate 18 unnecessary treatments (95% UR: 10, 29) per 1,000 individuals evaluated—resulting in a median ratio of 38 incremental unnecessary treatments added by Ultra per incremental death averted by Ultra compared to outcomes using standard Xpert (95% UR: 12, indefinite upper bound). In the South African HIV care setting—where TB mortality rates are higher and Ultra’s improved sensitivity has greater absolute benefit—this ratio improved to 7 unnecessary treatments per TB death averted (95% UR: 2, 43). By contrast, in the Chinese primary care setting, this ratio was much less favorable, at 372 unnecessary treatments per TB death averted (95% UR: 75, indefinite upper bound), although the projected number of unnecessary treatments using Xpert Ultra was lower (with a possibility of no increased overtreatment) when using specificity data only from lower-burden settings. Alternative interpretations of the trace call had little effect on these ratios. Limitations include uncertainty in key parameters (including the clinical implications of false-negative results), the exclusion of transmission effects, and restriction of this analysis to adult pulmonary TB.

Conclusions

Switching from the standard Xpert cartridge to the Xpert Ultra cartridge for diagnosis of adult pulmonary TB may have different consequences in different clinical settings. In settings with high TB and HIV prevalence, Xpert Ultra is likely to offer considerable mortality benefit, whereas in lower-prevalence settings, Xpert Ultra will likely result in considerable overtreatment unless the possibility of higher specificity of Ultra in lower-prevalence settings in confirmed. The ideal use of the Ultra cartridge may therefore involve a more nuanced, setting-specific approach to implementation, with priority given to populations in which the anticipated prevalence of TB (and HIV) is the highest.

Abstract

In this modelling study, Emily Kendall and colleagues estimate the potential for increased tuberculosis case-finding as well as unnecessary treatments when adopting the more sensitive Xpert Ultra cartridges for detecting TB in settings of high and low prevalence.

Author summary

Why was this study done?

• Xpert Ultra is a new version of a widely used molecular test for tuberculosis (TB) that has a better ability to detect TB (higher sensitivity) but also more frequently gives false-positive results (lower specificity).

• These differences in sensitivity and specificity will have different clinical implications in settings with different characteristics such as higher or lower TB and HIV prevalence among the people being tested.

• The relative advantages and disadvantages of adopting Xpert Ultra are therefore likely to differ across different clinical contexts.

What did the researchers do and find?

• We modeled and compared the likely clinical outcomes, including number of TB deaths and number of unnecessary treatments, when using Xpert Ultra versus the standard Xpert assay.

• We performed this comparison for 3 different hypothetical patient populations in different medium- to high-TB-burden settings (a South African HIV clinic, an Indian TB center, and a Chinese primary care clinic).

• We found that the estimated clinical impact of switching from standard Xpert to Xpert Ultra differed dramatically between settings: Ultra yielded fewer than 10 additional unnecessary TB treatments per TB death prevented in the HIV clinic setting in South Africa, in contrast to more than 300 additional unnecessary TB treatments per TB death prevented in the general primary care setting in China.

What do these findings mean?

• Xpert Ultra is likely to provide a large clinical benefit over standard Xpert in patient populations with high TB prevalence, high HIV prevalence, and high case fatality ratios for untreated TB.

• In populations with low TB prevalence or small proportions of HIV-associated or smear-negative TB, Xpert Ultra will require more cautious implementation and interpretation to avoid costly and harmful overdiagnosis of TB.