Elsevier

The Lancet

Volume 383, Issue 9915, 1–7 February 2014, Pages 424-435
The Lancet

Articles
Feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF testing for tuberculosis in primary-care settings in Africa: a multicentre, randomised, controlled trial

https://doi.org/10.1016/S0140-6736(13)62073-5Get rights and content

Summary

Background

The Xpert MTB/RIF test for tuberculosis is being rolled out in many countries, but evidence is lacking regarding its implementation outside laboratories, ability to inform same-day treatment decisions at the point of care, and clinical effect on tuberculosis-related morbidity. We aimed to assess the feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF testing at primary-care health-care facilities in southern Africa.

Methods

In this pragmatic, randomised, parallel-group, multicentre trial, we recruited adults with symptoms suggestive of active tuberculosis from five primary-care health-care facilities in South Africa, Zimbabwe, Zambia, and Tanzania. Eligible patients were randomly assigned using pregenerated tables to nurse-performed Xpert MTB/RIF at the clinic or sputum smear microscopy. Participants with a negative test result were empirically managed according to local WHO-compliant guidelines. Our primary outcome was tuberculosis-related morbidity (measured with the TBscore and Karnofsky performance score [KPS]) in culture-positive patients who had begun anti-tuberculosis treatment, measured at 2 months and 6 months after randomisation, analysed by intention to treat. This trial is registered with Clinicaltrials.gov, number NCT01554384.

Findings

Between April 12, 2011, and March 30, 2012, we randomly assigned 758 patients to smear microscopy (182 culture positive) and 744 to Xpert MTB/RIF (185 culture positive). Median TBscore in culture-positive patients did not differ between groups at 2 months (2 [IQR 0–3] in the smear microscopy group vs 2 [0·25–3] in the MTB/RIF group; p=0·85) or 6 months (1 [0–3] vs 1 [0–3]; p=0·35), nor did median KPS at 2 months (80 [70–90] vs 90 [80–90]; p=0·23) or 6 months (100 [90–100] vs 100 [90–100]; p=0·85). Point-of-care MTB/RIF had higher sensitivity than microscopy (154 [83%] of 185 vs 91 [50%] of 182; p=0·0001) but similar specificity (517 [95%] 544 vs 540 [96%] of 560; p=0·25), and had similar sensitivity to laboratory-based MTB/RIF (292 [83%] of 351; p=0·99) but higher specificity (952 [92%] of 1037; p=0·0173). 34 (5%) of 744 tests with point-of-care MTB/RIF and 82 (6%) of 1411 with laboratory-based MTB/RIF failed (p=0·22). Compared with the microscopy group, more patients in the MTB/RIF group had a same-day diagnosis (178 [24%] of 744 vs 99 [13%] of 758; p<0·0001) and same-day treatment initiation (168 [23%] of 744 vs 115 [15%] of 758; p=0·0002). Although, by end of the study, more culture-positive patients in the MTB/RIF group were on treatment due to reduced dropout (15 [8%] of 185 in the MTB/RIF group did not receive treatment vs 28 [15%] of 182 in the microscopy group; p=0·0302), the proportions of all patients on treatment in each group by day 56 were similar (320 [43%] of 744 in the MTB/RIF group vs 317 [42%] of 758 in the microscopy group; p=0·6408).

Interpretation

Xpert MTB/RIF can be accurately administered by a nurse in primary-care clinics, resulting in more patients starting same-day treatment, more culture-positive patients starting therapy, and a shorter time to treatment. However, the benefits did not translate into lower tuberculosis-related morbidity, partly because of high levels of empirical-evidence-based treatment in smear-negative patients.

Funding

European and Developing Countries Clinical Trials Partnership, National Research Foundation, and Claude Leon Foundation.

Introduction

A reversal in the incidence of tuberculosis is a key component of the UN Millennium Development Goals for 2015.1 Although substantial progress has been made worldwide,2 tuberculosis remains a major cause of morbidity and mortality in sub-Saharan Africa,3 and several high-burden countries are not on track to substantively reduce their burden of tuberculosis.4 Smear microscopy, which is often done in primary-care clinics in such settings, is frequently used for the diagnosis of tuberculosis, and it can rapidly affect treatment decisions. However, it misses 40–60% of cases, and does least well in people with advanced immunosuppression.5 Tests that are rapid, accurate, and deployable at the point of care are projected to substantially reduce tuberculosis-related morbidity and mortality,6, 7 although empirical evidence is in very short supply.

The Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA, USA) is a US Food and Drug Administration-approved, automated nucleic-acid amplification test that can detect both Mycobacterium tuberculosis (MTB) complex DNA and rifampicin (RIF) resistance within 2 h.8 In 2011, it was endorsed by WHO,9 and is being piloted or integrated into the national algorithms of a growing number of high-burden countries, where it will be based at subdistrict or district level.10

The accuracy of Xpert MTB/RIF is well validated: one test detects about 88% of culture-confirmed cases of pulmonary tuberculosis, correctly identifies about 98% of patients without tuberculosis, and can detect up to 67% of cases missed by smear microscopy.11 It can detect 94% of rifampicin-resistant tuberculosis cases and correctly classify 98% of rifampicin-susceptible cases.11 Preliminary data suggest Xpert MTB/RIF could accelerate and improve tuberculosis case detection,8, 12, 13, 14 and modelling studies project it to be cost effective15 and have a substantial effect on patient health in HIV-endemic regions.16

Despite the continuing roll out and piloting of Xpert MTB/RIF, no randomised empirical data exist to show whether its improved accuracy relative to smear microscopy improves patient-important outcomes and endpoints such as morbidity and mortality. Although small observational studies in South Africa13, 17, 18 have described the feasibility of Xpert MTB/RIF implementation at the point of care, whether their findings can be generalised to other countries is uncertain, as is whether point-of-care Xpert MTB/RIF improves same-day clinical decision making. The latter question is crucial because up to 40% of patients who test positive do not return for their results in tuberculosis-endemic settings.8, 19, 20 To better understand these important issues, which inform policy decisions relevant to the scale-up of Xpert MTB/RIF, we did a randomised controlled trial to examine the feasibility, accuracy, and clinical effect of Xpert MTB/RIF deployed at the point of care compared with smear microscopy in five primary-care health-care facilities in areas of southern Africa with a high HIV prevalence.

Section snippets

Study design and participants

We did a pragmatic, randomised, parallel-group, multicentre trial. After obtaining written informed consent, we consecutively enrolled patients aged 18 years or older who presented to periurban primary-care tuberculosis clinics with attached treatment facilities and microscopy laboratories in Cape Town (South Africa; here the microscopy laboratory was close by rather than attached to the facility), Durban (South Africa), Harare (Zimbabwe), Lusaka (Zambia), and Mbeya (Tanzania). We enrolled

Results

Between April 12, 2011, and March 30, 2012, we randomly assigned 758 patients to the smear microscopy group and 744 to the Xpert MTB/RIF group (figure 1), 182 and 185 of whom were culture positive, respectively (p=0·70). Six (2%) of the 345 culture-positive patients who were tested for multidrug resistance had multidrug-resistant tuberculosis. 439 (58%) of 758 patients in the smear microscopy group were infected with HIV compared with 456 (61%) of 744 in the Xpert MTB/RIF group (p=0·18).

Discussion

This multicentre study is the first randomised controlled trial of Xpert MTB/RIF, and the first to compare its feasibility at the point of care to that in the laboratory and the effect on clinically important outcomes (panel). Xpert MTB/RIF did not reduce overall tuberculosis-related morbidity (our primary outcome), but our results do show that Xpert MTB/RIF undertaken by a minimally trained nurse in a primary-care setting is feasible, and has similar sensitivity, better specificity, and

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