Helen Cox and colleagues investigate the impact Xpert MTB/RIF for diagnosing patients with presumptive tuberculosis in a large primary care clinic in Khayelitsha, Cape Town.
Please see later in the article for the Editors' Summary
Xpert MTB/RIF is approved for use in tuberculosis (TB) and rifampicin-resistance diagnosis. However, data are limited on the impact of Xpert under routine conditions in settings with high TB burden.
Methods and Findings
A pragmatic prospective cluster-randomised trial of Xpert for all individuals with presumptive (symptomatic) TB compared to the routine diagnostic algorithm of sputum microscopy and limited use of culture was conducted in a large TB/HIV primary care clinic. The primary outcome was the proportion of bacteriologically confirmed TB cases not initiating TB treatment by 3 mo after presentation. Secondary outcomes included time to TB treatment and mortality. Unblinded randomisation occurred on a weekly basis. Xpert and smear microscopy were performed on site. Analysis was both by intention to treat (ITT) and per protocol.
Between 7 September 2010 and 28 October 2011, 1,985 participants were assigned to the Xpert (n = 982) and routine (n = 1,003) diagnostic algorithms (ITT analysis); 882 received Xpert and 1,063 routine (per protocol analysis). 13% (32/257) of individuals with bacteriologically confirmed TB (smear, culture, or Xpert) did not initiate treatment by 3 mo after presentation in the Xpert arm, compared to 25% (41/167) in the routine arm (ITT analysis, risk ratio 0.51, 95% CI 0.33–0.77, p = 0.0052).
The yield of bacteriologically confirmed TB cases among patients with presumptive TB was 17% (167/1,003) with routine diagnosis and 26% (257/982) with Xpert diagnosis (ITT analysis, risk ratio 1.57, 95% CI 1.32–1.87, p<0.001). This difference in diagnosis rates resulted in a higher rate of treatment initiation in the Xpert arm: 23% (229/1,003) and 28% (277/982) in the routine and Xpert arms, respectively (ITT analysis, risk ratio 1.24, 95% CI 1.06–1.44, p = 0.013). Time to treatment initiation was improved overall (ITT analysis, hazard ratio 0.76, 95% CI 0.63–0.92, p = 0.005) and among HIV-infected participants (ITT analysis, hazard ratio 0.67, 95% CI 0.53–0.85, p = 0.001). There was no difference in 6-mo mortality with Xpert versus routine diagnosis. Study limitations included incorrect intervention allocation for a high proportion of participants and that the study was conducted in a single clinic.
These data suggest that in this routine primary care setting, use of Xpert to diagnose TB increased the number of individuals with bacteriologically confirmed TB who were treated by 3 mo and reduced time to treatment initiation, particularly among HIV-infected participants.
Pan African Clinical Trials Registry PACTR201010000255244
Please see later in the article for the Editors' Summary
In 2012, about 8.6 million people developed active tuberculosis (TB)—a contagious mycobacterial disease that usually affects the lungs—and at least 1.3 million people died from the disease. Most of these deaths were in low- and middle-income countries, and a fifth were in HIV-positive individuals, who are particularly susceptible to TB. Mycobacterium tuberculosis, the bacterium that causes TB, is spread in airborne droplets when people with active disease cough or sneeze. The characteristic symptoms of TB include a cough, weight loss, and night sweats. Diagnostic tests for TB include microscopic examination of sputum (mucus coughed up from the lungs), growth (culture) of M. tuberculosis from sputum, and molecular tests (for example, the automated Xpert MTB/RIF test) that rapidly and accurately detect M. tuberculosis in sputum and determine its antibiotic resistance. TB can be cured by taking several antibiotics daily for at least six months, although the emergence of multidrug-resistant TB is making the disease harder to treat.
Why Was This Study Done?
To improve TB control, active disease needs to be diagnosed and treated quickly. However, sputum microscopy, the mainstay of TB diagnosis in many high-burden settings, fails to identify up to half of infected people, and mycobacterial culture (the “gold standard” of TB diagnosis) is slow and often unavailable in resource-limited settings. In late 2010, the World Health Organization recommended the routine use of the Xpert MTB/RIF test (Xpert) for TB diagnosis, and several low- and middle-income countries are now scaling up access to Xpert in their national TB control programs. But although Xpert performs well in ideal conditions, little is known about the impact of its implementation in routine (real-life) settings. In this pragmatic cluster-randomized trial, the researchers assess the health impacts of Xpert in a large TB/HIV primary health care clinic in South Africa, an upper-middle-income country that began to scale up access to Xpert for individuals showing symptoms of TB (individuals with presumptive TB) in 2011. A pragmatic trial asks whether an intervention works under real-life conditions; a cluster-randomized trial randomly assigns groups of people to receive alternative interventions and compares outcomes in the differently treated “clusters.”
What Did the Researchers Do and Find?
The researchers assigned everyone with presumptive TB attending a TB/HIV primary health care clinic in Cape Town to receive either Xpert for TB diagnosis or routine sputum microscopy and limited culture. Specifically, Xpert was requested on the routine laboratory request forms for individuals attending the clinic during randomly designated Xpert weeks but not during randomly designated routine testing weeks. During the 51-week trial, 982 individuals were assigned to the Xpert arm, and 1,003 were assigned to the routine testing arm, but because clinic staff sometimes failed to request Xpert during Xpert weeks, only 882 participants in the Xpert arm received the intervention. In an “intention to treat” analysis (an analysis that considers the outcomes of all the participants in a trial whether or not they received their assigned intervention), 13% of bacteriologically confirmed TB cases in the Xpert arm did not initiate TB treatment by three months after enrollment (the trial's primary outcome) compared to 25% in the routine testing arm. The proportion of participants with microbiologically confirmed TB and the proportion initiating TB treatment were higher in the Xpert arm than in the routine testing arm. Finally, the time to treatment initiation was lower in the Xpert arm than in the routine testing arm, particularly among HIV-infected participants.
What Do These Findings Mean?
These findings show that, in this primary health care setting, the provision of Xpert for TB diagnosis in individuals with presumptive TB provided benefits over testing that relied primarily on sputum microscopy. Notably, these benefits were seen even though a substantial proportion of individuals assigned to the Xpert intervention did not actually receive an Xpert test. The pragmatic nature of this trial, which aimed to minimize clinic disruption, and other aspects of the trial design may limit the accuracy and generalizability of these findings. Moreover, further studies are needed to discover whether the use of Xpert in real-life settings reduces the burden of TB illness and death over the long term. Nevertheless, these findings suggest that the implementation of Xpert has the potential to improve the outcomes of TB control programs and may also improve outcomes for individuals.
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001760.
The World Health Organization provides information (in several languages) on all aspects of tuberculosis, including general information on tuberculosis diagnostics and specific information on the roll-out of the Xpert MTB/RIF test; further information about the World Health Organization's endorsement of Xpert MTB/RIF is included in a Strategic and Technical Advisory Group for Tuberculosis report; the “Global Tuberculosis Report 2013” provides information about tuberculosis around the world, including in South Africa
The Stop TB Partnership is working towards tuberculosis elimination and provides patient stories about tuberculosis (in English and Spanish); the Tuberculosis Vaccine Initiative (a not-for-profit organization) also provides personal stories about tuberculosis
The US Centers for Disease Control and Prevention has information about tuberculosis and its diagnosis (in English and Spanish)
The US National Institute of Allergy and Infectious Diseases also has detailed information on all aspects of tuberculosis
The South African National Tuberculosis Management Guidelines 2014 are available
The Foundation for Innovative New Diagnostics, a not-for-profit organization that helps to develop and introduce new diagnostic tests for tuberculosis, malaria, and neglected tropical diseases, has detailed information about the Xpert MTB/RIF test
More information about TB, HIV, and drug-resistant TB treatment in Khayelitsha, Cape Town, South Africa are provided by Médecins sans Frontières, South Africa