The impact of Xpert MTB/RIF—do we have a final answer?
Authors: Samuel G Schumacher, Claudia M Denkinger
Journal: The Lancet Global Health (2019)

In 2010, Xpert MTB/RIF (Cepheid, USA) was recommended by WHO as a test for tuberculosis diagnosis with superior accuracy to sputum smear microscopy and increased capacity to diagnose rifampicin resistance. Improvements in important intermediate outcomes relating to quality of care (eg, time to diagnosis, time to effective therapy, loss to follow-up) were subsequently reported.1Schumacher SG Sohn H Qin ZZ et al.Impact of molecular diagnostics for tuberculosis on patient-important outcomes: a systematic review of study methodologies.PLoS One. 2016; 11: e0151073Crossref PubMed Scopus (34) Google Scholar Eight randomised trials (registration numbers: NCT01530568, DOH-27-1011-3849, PACTR201010000255244, ISRCTN 18642314, PACTR201303000505764, NCT01450085, NCT01554384, and NCT01363765) measuring the effect of Xpert MTB/RIF on patient-important outcomes, such as mortality, have been completed thus far. Five of these trials, which included 8567 adult clinic attendees (63·5% HIV-positive [4490 of 7074]; 399 deaths) and assessed the use of Xpert MTB/RIF versus sputum smear microscopy for tuberculosis diagnosis, have now been summarised in an individual patient data (IPD) meta-analysis, published in The Lancet Global Health, by Gian Luca Di Tanna and colleagues.2Di Tanna GL Khaki AR Theron G et al.Effect of Xpert MTB/RIF on clinical outcomes in routine care settings: individual patient data meta-analysis.Lancet Glob Health. 2019; 7: e191-e199Summary Full Text Full Text PDF PubMed Scopus (40) Google Scholar This study makes an important contribution by providing the best available estimate of the effect of the introduction of Xpert MTB/RIF on mortality; nevertheless, some important questions remain unanswered. Across the studies included in the IPD meta-analysis,2Di Tanna GL Khaki AR Theron G et al.Effect of Xpert MTB/RIF on clinical outcomes in routine care settings: individual patient data meta-analysis.Lancet Glob Health. 2019; 7: e191-e199Summary Full Text Full Text PDF PubMed Scopus (40) Google Scholar Xpert MTB/RIF reduced the odds of death by 12% (odds ratio 0·88, 95% CI 0·68–1·14; p=0·34), with equivalent estimates for HIV-positive and HIV-negative patients (both 17%). Although this effect is smaller than anticipated, it is of similar magnitude to other widely adopted global-health interventions (eg, the use of insecticide-treated bednets for malaria prevention reduced mortality by 17%, according to a Cochrane review3Lengeler C Insecticide-treated bed nets and curtains for preventing malaria.Cochrane Database Syst Rev. 2004; 2 (CD000363.)Google Scholar that included 68 829 children). However, despite the use of rigorous methodology and pulling together the data from five large trials, the effect estimate of this IPD meta-analysis is uncertain, with the 95% CI including a mortality reduction as large as 32% but also a potential increase up to 14%. In this Comment, we discuss the multiple reasons why conclusive results were not reached despite the substantial amount of work. First, standard of care in the settings of the individual trials was largely superior to what is available to most tuberculosis patients nowadays. Although valid reasons exist for including additional procedures in trials (eg, having culture results or chest radiography available can improve interpretability of trial data, and maximising follow-up ensures outcome ascertainment in settings where vital registration systems cannot be used for this purpose), these procedures are also likely to result in artificially reduced pretreatment loss to follow-up and increased amount of empirical therapy given. Increased delivery of empirical therapy and reduced pre-treatment loss to follow-up, in turn, could result in reduced mortality and reduced intervention effect. These issues, along with the Hawthorne effect (ie, providers might be more likely to consider empirical treatment as a result of being under observation as part of a study), could lead to an underestimation of the effect that a novel diagnostic test could have in routine practice.1Schumacher SG Sohn H Qin ZZ et al.Impact of molecular diagnostics for tuberculosis on patient-important outcomes: a systematic review of study methodologies.PLoS One. 2016; 11: e0151073Crossref PubMed Scopus (34) Google Scholar, 4Lawn SD Nicol MP Corbett EL Effect of empirical treatment on outcomes of clinical trials of diagnostic assays for tuberculosis.Lancet Infect Dis. 2015; 15: 17-18Summary Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 5Auld AF Fielding KL Gupta-Wright A Lawn SD Xpert MTB/RIF—why the lack of morbidity and mortality impact in intervention trials?.Trans R Soc Trop Med Hyg. 2016; 110: 432-444Crossref PubMed Scopus (44) Google Scholar Second, the expected magnitude of the intervention effect depends on the quality of care at baseline and on the patient population tested: the better the baseline, the lower the chances of significantly improving the outcomes. Most data in the included trials came from settings in which the standard of care—in terms of available tests and human resources—is probably superior to what tuberculosis patients experience on average worldwide, thus limiting the generalisability of the findings. Furthermore, patient populations that would gain particular benefit from Xpert MTB/RIF, such as children6Raizada N Khaparde SD Salhotra VS et al.Accelerating access to quality TB care for pediatric TB cases through better diagnostic strategy in four major cities of India.PLoS One. 2018; 13: e0193194Crossref PubMed Scopus (16) Google Scholar and patients with advanced illness7Ngwira LG Corbett EL Khundi M et al.Screening for tuberculosis with Xpert MTB/RIF versus fluorescent microscopy among adults newly diagnosed with HIV in rural Malawi: a cluster randomized trial (CHEPETSA).Clin Infect Dis. 2018; (published online July 27.) (preprint)DOI:10.1093/cid/ciy590Crossref PubMed Scopus (18) Google Scholar or drug-resistant tuberculosis,8Cox HS Daniels JF Muller O et al.Impact of decentralized care and the Xpert MTB/RIF test on rifampicin-resistant tuberculosis treatment initiation in Khayelitsha, South Africa.Open Forum Infect Dis. 2015; 2: ofv014Crossref PubMed Scopus (61) Google Scholar were either excluded or uncommon in all trials. Finally, despite combining multiple trials, the IPD meta-analysis2Di Tanna GL Khaki AR Theron G et al.Effect of Xpert MTB/RIF on clinical outcomes in routine care settings: individual patient data meta-analysis.Lancet Glob Health. 2019; 7: e191-e199Summary Full Text Full Text PDF PubMed Scopus (40) Google Scholar had low statistical power. Insufficient sample size is a common problem for randomised trials of diagnostic interventions (also called test-treatment trials) that assess the effect of introducing a new diagnostic on the incidence of rare events.9di Ruffano LF Dinnes J Sitch AJ Hyde C Deeks JJ Test-treatment RCTs are susceptible to bias: a review of the methodological quality of randomized trials that evaluate diagnostic tests.BMC Med Res Methodol. 2017; 17: 35Crossref PubMed Scopus (16) Google Scholar If one were to plan a new cluster randomised trial with the baseline mortality and effect size observed in the IPD meta-analysis2Di Tanna GL Khaki AR Theron G et al.Effect of Xpert MTB/RIF on clinical outcomes in routine care settings: individual patient data meta-analysis.Lancet Glob Health. 2019; 7: e191-e199Summary Full Text Full Text PDF PubMed Scopus (40) Google Scholar (mortality reduction from 5·3% in the sputum smear microscopy group to 4·5% in the Xpert MTB/RIF group), 31 000 participants across 100 clusters would be necessary to achieve 90% power (at α 0·05 and with a coefficient of variation of 0·25). So how can we learn from, and improve upon, the important work completed thus far? We suggest two complementary avenues. First, pragmatic test-treatment trials have an important role to play in generating data beyond accuracy. However, trials that assess the implementation of new diagnostic tests pose special challenges and are subject to more variation than drug trials because of the effect of contextual factors on the various elements in the chain of causal events that lie between application of a test and patient health outcomes.1Schumacher SG Sohn H Qin ZZ et al.Impact of molecular diagnostics for tuberculosis on patient-important outcomes: a systematic review of study methodologies.PLoS One. 2016; 11: e0151073Crossref PubMed Scopus (34) Google Scholar, 10Pai MP Schumacher SG Abimbola S Surrogate endpoints in global health research: still searching for killer apps and silver bullets?.BMJ Glob Health. 2018; 3: e000755Crossref PubMed Scopus (27) Google Scholar, 11Moore GF Audrey S Barker M et al.Process evaluation of complex interventions: Medical Research Council guidance.BMJ. 2015; 350: h1258Crossref PubMed Scopus (2684) Google Scholar Incorporating process evaluation into such trials is therefore important to maximise generalisability.11Moore GF Audrey S Barker M et al.Process evaluation of complex interventions: Medical Research Council guidance.BMJ. 2015; 350: h1258Crossref PubMed Scopus (2684) Google Scholar Future trials that build on existing tools,12Loudon K Treweek S Sullivan F Donnan P Thorpe KE Zwarenstein MF The PRECIS-2 tool: designing trials that are fit for purpose.BMJ. 2015; 350: h2147Crossref PubMed Scopus (895) Google Scholar while minimising changes in the existing standard of care, can provide important knowledge. Furthermore, improved use of programmatic data, qualitative research, and modelling are crucial to complementing pragmatic trials. Countries must strengthen the reliability of programmatic data collection such that the effect of new tools can be monitored, high-quality operational research can be done,13Theron G Jenkins HE Cobelens F et al.Data for action: collection and use of local data to end tuberculosis.Lancet. 2015; 386: 2324-2333Summary Full Text Full Text PDF PubMed Scopus (81) Google Scholar and the effects that only occur with time after implementation can be assessed.14Hermans S Caldwell J Kaplan R Cobelens FG Wood R The impact of the roll-out of rapid molecular diagnostic testing for tuberculosis on empirical treatment in Cape Town, South Africa.Bull World Health Organ. 2017; 95: 554-563Crossref PubMed Scopus (22) Google Scholar The scientific community needs to use implementation science and qualitative research to understand the barriers to the uptake of new diagnostic tools and determine optimal implementation strategies.15Handley MA Gorukanti A Cattamanchi A Strategies for implementing implementation science: a methodological overview.Emerg Med J. 2016; 33: 660-664Crossref PubMed Scopus (55) Google Scholar Lastly, data from such research should inform mathematical models, which can also serve as a way to apply trial results to other settings and populations.16Lin H-H Dowdy D Dye C Murray M Cohen T The impact of new tuberculosis diagnostics on transmission: why context matters.Bull World Health Organ. 2012; 90: 739-747Crossref PubMed Scopus (43) Google Scholar We believe that this approach would allow rigorous evaluation of diagnostics beyond accuracy and beyond trials, while also ensuring that potentially impactful tools reach patients without undue delays. FIND works closely with the private and public sectors and receives funding from some of its industry partners. It has organisational firewalls to protect it against any undue influences in its work or the publication of its findings. Effect of Xpert MTB/RIF on clinical outcomes in routine care settings: individual patient data meta-analysisDespite individual patient data analysis from five RCTs, we were unable to confidently rule in nor rule out an Xpert MTB/RIF-associated reduction in mortality among outpatients tested for tuberculosis. Reduction in mortality among HIV-positive patients in a secondary analysis suggests the possibility of population-level impact. Full-Text PDF Open Access