Dataset Information

Impact on Patients' Treatment Outcomes of XpertMTB/RIF Implementation for the Diagnosis of Tuberculosis: Follow-Up of a Stepped-Wedge Randomized Clinical Trial.

ABSTRACT:

Introduction

The impact on treatment outcomes of XpertMTB/RIF, a molecular-based test that provides rapid diagnosis of tuberculosis (TB) and rifampicin resistance with high accuracy, has not been reported despite its adoption in a few countries. We here report treatment outcomes in a step-wedged cluster randomized trial for patients diagnosed with XpertMTB/RIF compared to patients diagnosed with sputum smear examination in public health facilities in Brazil.

Methods

Treatment outcome data were added to the trial database of patients diagnosed from 4 February to 4 October 2012, and crosschecked with data from the national mortality and the drug-resistant TB registers. Treatment outcomes in the intervention (n=2232) and baseline (n=1856) arms were compared using a multilevel regression model.

Results

Unfavourable outcomes were frequent in both arms, mainly due to loss to follow-up (16%). Overall unfavourable outcomes were not reduced in the intervention arm (29.6% versus 31.7%, OR=0.93; 95%CI=0.79-1.08). However, the overall TB-attributed death rate was lower in the intervention arm (2.3% vs. 3.8%). Adjusted for HIV status, age group and city, the intervention resulted in a 35% decrease in TB-attributed deaths (OR=0.65, 95%CI=0.44-0.97).

Conclusions

The proportion of patients successfully treated did not increase with Xpert MTB/RIF implementation, with high loss to follow-up rates in both arms. We did observe a 35% reduction in TB-related mortality, which we hypothesize may be explained by less advanced disease among the smear-negative patients diagnosed by Xpert. In conclusion, XpertMTB/RIF introduction did not improve TB treatment outcomes in Brazil.

Trial registration

clinicaltrials.gov NCT01363765.

SUBMITTER: Trajman A

PROVIDER: S-EPMC4411054 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Publications

Impact on Patients' Treatment Outcomes of XpertMTB/RIF Implementation for the Diagnosis of Tuberculosis: Follow-Up of a Stepped-Wedge Randomized Clinical Trial.

Trajman Anete A Durovni Betina B Saraceni Valeria V Menezes Alexandre A Cordeiro-Santos Marcelo M Cobelens Frank F Van den Hof Susan S

PloS one 20150427 4

<h4>Introduction</h4>The impact on treatment outcomes of XpertMTB/RIF, a molecular-based test that provides rapid diagnosis of tuberculosis (TB) and rifampicin resistance with high accuracy, has not been reported despite its adoption in a few countries. We here report treatment outcomes in a step-wedged cluster randomized trial for patients diagnosed with XpertMTB/RIF compared to patients diagnosed with sputum smear examination in public health facilities in Brazil.<h4>Methods</h4>Treatment outc ...[more]

PMID: 25915745

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Project description:BackgroundAbundant evidence on Xpert MTB/RIF accuracy for diagnosing tuberculosis (TB) and rifampicin resistance has been produced, yet there are few data on the population benefit of its programmatic use. We assessed whether the implementation of Xpert MTB/RIF in routine conditions would (1) increase the notification rate of laboratory-confirmed pulmonary TB to the national notification system and (2) reduce the time to TB treatment initiation (primary endpoints).Methods and findingsWe conducted a stepped-wedge cluster-randomized trial from 4 February to 4 October 2012 in 14 primary care laboratories in two Brazilian cities. Diagnostic specimens were included for 11,705 baseline (smear microscopy) and 12,522 intervention (Xpert MTB/RIF) patients presumed to have TB. Single-sputum-sample Xpert MTB/RIF replaced two-sputum-sample smear microscopy for routine diagnosis of pulmonary TB. In total, 1,137 (9.7%) tests in the baseline arm and 1,777 (14.2%) in the intervention arm were positive (p<0.001), resulting in an increased bacteriologically confirmed notification rate of 59% (95% CI = 31%, 88%). However, the overall notification rate did not increase (15%, 95% CI = -6%, 37%), and we observed no change in the notification rate for those without a test result (-3%, 95% CI = -37%, 30%). Median time to treatment decreased from 11.4 d (interquartile range [IQR] = 8.5-14.5) to 8.1 d (IQR = 5.4-9.3) (p = 0.04), although not among confirmed cases (median 7.5 [IQR = 4.9-10.0] versus 7.3 [IQR = 3.4-9.0], p = 0.51). Prevalence of rifampicin resistance detected by Xpert was 3.3% (95% CI = 2.4%, 4.3%) among new patients and 7.4% (95% CI = 4.3%, 11.7%) among retreatment patients, with a 98% (95% CI = 87%, 99%) positive predictive value compared to phenotypic drug susceptibility testing. Missing data in the information systems may have biased our primary endpoints. However, sensitivity analyses assessing the effects of missing data did not affect our results.ConclusionsReplacing smear microscopy with Xpert MTB/RIF in Brazil increased confirmation of pulmonary TB. An additional benefit was the accurate detection of rifampicin resistance. However, no increase on overall notification rates was observed, possibly because of high rates of empirical TB treatment.Trial registrationClinicalTrials.gov NCT01363765. Please see later in the article for the Editors' Summary.

Project description:BACKGROUND:Xpert® MTB/RIF (Xpert) has high sensitivity for diagnosing tuberculosis (TB) compared to sputum-smear microscopy (smear) and can reduce time-to-diagnosis, time-to-treatment and potentially unfavorable patient-level treatment outcome. METHODS:People living with HIV (PLHIV) initiating antiretroviral therapy at 22 HIV clinics were enrolled and underwent systematic screening for TB (August 2012-November 2014). GeneXpert instruments were deployed following a stepped-wedge design at 13 centers from October 2012-June 2013. Treatment outcomes classified as an unfavorable outcome (died, treatment failure or loss-to-follow-up) or favorable outcome (cured and treatment completed). To determine outcome, smear was performed at month 5 or 6. Empiric treatment was defined as initiating treatment without/before receiving TB-positive results. Adjusting for intra-facility correlation, we compared patient-level treatment outcomes between patients screened using smear (smear arm)- and Xpert-based algorithms (Xpert arm). RESULTS:Among 6041 patients enrolled (smear arm, 1816; Xpert arm, 4225), 256 (199 per 2985 and 57 per 1582 person-years of follow-up in Xpert and smear arms, respectively; adjusted incidence rate ratio, 9.07; 95% confidence interval [CI]: 4.70-17.48; p?<?0.001) received TB diagnosis and were treated. TB treatment outcomes were available for 203 patients (79.3%; Xpert, 157; smear, 46). Unfavorable outcomes were reported for 21.7% (10/46) in the smear and 13.4% (21/157) in Xpert arm (adjusted hazard ratio, 1.40; 95% CI: 0.75-2.26; p?=?0.268). Compared to smear, in Xpert arm median days from sputum collection to TB treatment was 6?days (interquartile range [IQR] 2-17 versus 22?days [IQR] 3-51), p?=?0.005; patients with available sputum test result had microbiologically confirmed TB in 59.0% (102/173) versus 41.9% (18/43), adjusted Odds Ratio [aOR], 2.00, 95% CI: 1.01-3.96, p?=?0.048). In smear arm empiric treatment was 68.4% (39/57) versus 48.7% (97/199), aOR, 2.28, 95% CI: 1.24-4.20, p?=?0.011), compared to Xpert arm. CONCLUSIONS:TB treatment outcomes were similar between the smear and Xpert arms. However, compared to the smear arm, more patients in the Xpert arm received a TB diagnosis, had a microbiologically confirmed TB, and had a shorter time-to-treatment, and had a lower empiric treatment. Further research is recommended to identify potential gaps in the Botswana health system and similar settings. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT02538952. Retrospectively registered on 2 September 2015.

Project description:BackgroundIn high tuberculosis (TB) burden settings, there is growing evidence that TB is common in children with pneumonia, the leading cause of death in children under 5 years worldwide. The current WHO standard of care (SOC) for young children with pneumonia considers a diagnosis of TB only if the child has a history of prolonged symptoms or fails to respond to antibiotic treatments. As a result, many children with TB-associated severe pneumonia are currently missed or diagnosed too late. We therefore propose a diagnostic trial to assess the impact on mortality of adding the systematic early detection of TB using Xpert MTB/RIF Ultra (Ultra) performed on nasopharyngeal aspirates (NPA) and stool samples to the WHO SOC for children with severe pneumonia, followed by immediate initiation of anti-TB treatment in children testing positive on any of the samples.MethodsTB-Speed Pneumonia is a pragmatic stepped-wedge cluster randomized controlled trial conducted in six countries with high TB incidence rate (Côte d'Ivoire, Cameroon, Uganda, Mozambique, Zambia and Cambodia). We will enrol 3780 children under 5 years presenting with WHO-defined severe pneumonia across 15 hospitals over 18 months. All hospitals will start managing children using the WHO SOC for severe pneumonia; one hospital will be randomly selected to switch to the intervention every 5 weeks. The intervention consists of the WHO SOC plus rapid TB detection on the day of admission using Ultra performed on 1 nasopharyngeal aspirate and 1 stool sample. All children will be followed for 3 months, with systematic trial visits at day 3, discharge, 2 weeks post-discharge, and week 12. The primary endpoint is all-cause mortality 12 weeks after inclusion. Qualitative and health economic evaluations are embedded in the trial.DiscussionIn addition to testing the main hypothesis that molecular detection and early treatment will reduce TB mortality in children, the strength of such pragmatic research is that it provides some evidence regarding the feasibility of the intervention as part of routine care. Should this intervention be successful, safe and well tolerated, it could be systematically implemented at district hospital level where children with severe pneumonia are referred.Trial registrationClinicalTrials.gov, NCT03831906 . Registered 6 February 2019.

Project description:In 2012, as a pilot for Botswana's national Xpert MTB/RIF (Xpert) rollout plans, intensified tuberculosis (TB) case finding (ICF) activities were strengthened at 22 HIV treatment clinics prior to phased activation of 13 Xpert instruments. Together, the strengthened ICF intervention and Xpert activation are referred to as the "Xpert package".The evaluation, called the Xpert Package Rollout Evaluation using a Stepped-wedge design (XPRES), has two key objectives: (1) to compare sensitivity of microscopy-based and Xpert-based pulmonary TB diagnostic algorithms in diagnosing sputum culture-positive TB; and (2) to evaluate impact of the "Xpert package" on all-cause, 6-month, adult antiretroviral therapy (ART) mortality. A pragmatic, stepped-wedge cluster-randomized trial design was chosen. The design involves enrollment of three cohorts: (1) cohort R, a retrospective cohort of all study clinic ART enrollees in the 24 months before study initiation (July 31, 2012); (2) cohort A, a prospective cohort of all consenting patients presenting to study clinics after study initiation, who received the ICF intervention and the microscopy-based TB diagnostic algorithm; and (3) cohort B, a prospective cohort of all consenting patients presenting to study clinics after Xpert activation, who received the ICF intervention and the Xpert-based TB diagnostic algorithm. TB diagnostic sensitivity will be compared between TB culture-positive enrollees in cohorts A and B. All-cause, 6-month ART-mortality will be compared between cohorts R and B. With anticipated cohort R, A, and B sample sizes of about 10,131, 1,878, and 4,258, respectively, the study is estimated to have >80 % power to detect differences in pre-versus post-Xpert TB diagnostic sensitivity if pre-Xpert sensitivity is ?52.5 % and post-Xpert sensitivity ?82.5 %, and >80 % power to detect a 40 % reduction in all-cause, 6-month, ART mortality between cohorts R and B if cohort R mortality is ?13/100 person-years.Only one small previous trial (N?=?424) among ART enrolees in Zimbabwe evaluated, in a secondary analysis, Xpert impact on all-cause 6-month ART mortality. No mortality impact was observed. This Botswana trial, with its larger sample size and powered specifically to detect differences in all-cause 6-month ART mortality, remains well-positioned to contribute understanding of Xpert impact.Retrospectively registered at ClinicalTrials.gov: NCT02538952 .

Project description:BackgroundSouth Africa has a large burden of rifampicin-resistant tuberculosis (RR-TB), with 18,734 patients diagnosed in 2014. The number of diagnosed patients has increased substantially with the introduction of the Xpert MTB/RIF test, used for tuberculosis (TB) diagnosis for all patients with presumptive TB. Routine aggregate data suggest a large treatment gap (pre-treatment loss to follow-up) between the numbers of patients with laboratory-confirmed RR-TB and those reported to have started second-line treatment. We aimed to assess the impact of Xpert MTB/RIF implementation on the delay to treatment initiation and loss to follow-up before second-line treatment for RR-TB across South Africa.Methods and findingsA nationwide retrospective cohort study was conducted to assess second-line treatment initiation and treatment delay among laboratory-diagnosed RR-TB patients. Cohorts, including approximately 300 sequentially diagnosed RR-TB patients per South African province, were drawn from the years 2011 and 2013, i.e., before and after Xpert implementation. Patients with prior laboratory RR-TB diagnoses within 6 mo and currently treated patients were excluded. Treatment initiation was determined through data linkage with national and local treatment registers, medical record review, interviews with health care staff, and direct contact with patients or household members. Additional laboratory data were used to track cases. National estimates of the percentage of patients who initiated treatment and time to treatment were weighted to account for the sampling design. There were 2,508 and 2,528 eligible patients in the 2011 and 2013 cohorts, respectively; 92% were newly diagnosed with RR-TB (no prior RR-TB diagnoses). Nationally, among the 2,340 and 2,311 new RR-TB patients in the 2011 and 2013 cohorts, 55% (95% CI 53%-57%) and 63% (95% CI 61%-65%), respectively, started treatment within 6 mo of laboratory receipt of their diagnostic specimen (p < 0.001). However, in 2013, there was no difference in the percentage of patients who initiated treatment at 6 mo between the 1,368 new RR-TB patients diagnosed by Xpert (62%, 95% CI 59%-65%) and the 943 diagnosed by other methods (64%, 95% CI 61%-67%) (p = 0.39). The median time to treatment decreased from 44 d (interquartile range [IQR] 20-69) in 2011 to 22 d (IQR 2-43) in 2013 (p < 0.001). In 2013, across the nine provinces, there were substantial variations in both treatment initiation (range 51%-73% by 6 mo) and median time to treatment (range 15-36 d, n = 1,450), and only 53% of the 1,448 new RR-TB patients who received treatment were recorded in the national RR-TB register. This retrospective study is limited by the lack of information to assess reasons for non-initiation of treatment, particularly pre-treatment mortality data. Other limitations include the use of names and dates of birth to locate patient-level data, potentially resulting in missed treatment initiation among some patients.ConclusionsIn 2013, there was a large treatment gap for RR-TB in South Africa that varied significantly across provinces. Xpert implementation, while reducing treatment delay, had not contributed substantially to reducing the treatment gap in 2013. However, given improved case detection with Xpert, a larger proportion of RR-TB patients overall have received treatment, with reduced delays. Nonetheless, strategies to further improve linkage to treatment for all diagnosed RR-TB patients are urgently required.

Project description:BackgroundIndia has announced a goal of universal access to quality tuberculosis (TB) diagnosis and treatment. A number of novel diagnostics could help meet this important goal. The rollout of one such diagnostic, Xpert MTB/RIF (Xpert) is being considered, but if Xpert is used mainly for people with HIV or high risk of multidrug-resistant TB (MDR-TB) in the public sector, population-level impact may be limited.Methods and findingsWe developed a model of TB transmission, care-seeking behavior, and diagnostic/treatment practices in India and explored the impact of six different rollout strategies. Providing Xpert to 40% of public-sector patients with HIV or prior TB treatment (similar to current national strategy) reduced TB incidence by 0.2% (95% uncertainty range [UR]: -1.4%, 1.7%) and MDR-TB incidence by 2.4% (95% UR: -5.2%, 9.1%) relative to existing practice but required 2,500 additional MDR-TB treatments and 60 four-module GeneXpert systems at maximum capacity. Further including 20% of unselected symptomatic individuals in the public sector required 700 systems and reduced incidence by 2.1% (95% UR: 0.5%, 3.9%); a similar approach involving qualified private providers (providers who have received at least some training in allopathic or non-allopathic medicine) reduced incidence by 6.0% (95% UR: 3.9%, 7.9%) with similar resource outlay, but only if high treatment success was assured. Engaging 20% of all private-sector providers (qualified and informal [providers with no formal medical training]) had the greatest impact (14.1% reduction, 95% UR: 10.6%, 16.9%), but required >2,200 systems and reliable treatment referral. Improving referrals from informal providers for smear-based diagnosis in the public sector (without Xpert rollout) had substantially greater impact (6.3% reduction) than Xpert scale-up within the public sector. These findings are subject to substantial uncertainty regarding private-sector treatment patterns, patient care-seeking behavior, symptoms, and infectiousness over time; these uncertainties should be addressed by future research.ConclusionsThe impact of new diagnostics for TB control in India depends on implementation within the complex, fragmented health-care system. Transformative strategies will require private/informal-sector engagement, adequate referral systems, improved treatment quality, and substantial resources. Please see later in the article for the Editors' Summary.

Project description:Background Tuberculosis (TB) is among the leading causes of infectious death worldwide. Contact investigation is an evidence-based, World Health Organisation-endorsed intervention for timely TB diagnosis, treatment, and prevention but has not been widely and effectively implemented. Methods We are conducting a stepped-wedge, cluster-randomised, hybrid Type III implementation-effectiveness trial comparing a user-centred to a standard strategy for implementing TB contact investigation in 12 healthcare facilities in Uganda. The user-centred strategy consists of several client-focused components including 1) a TB-education booklet, 2) a contact-identification algorithm, 3) an instructional sputum-collection video, and 4) a community-health-rider service to transport clients, CHWs, and sputum samples, along with several healthcare-worker-focused components, including 1) collaborative improvement meetings, 2) regular audit-and-feedback reports, and 3) a digital group-chat application designed to develop a community of practice. Sites will cross from the standard to the user-centred strategy in six, eight-week transition steps following a randomly determined site-pairing scheme and timeline. The primary implementation outcome is the proportion of symptomatic close contacts completing TB evaluation within 60 days of TB treatment initiation by the index person with TB. The primary clinical effectiveness outcomes are the proportion of contacts diagnosed with and initiating active TB disease treatment and the proportion initiating TB preventative therapy within 60 days. We will assess outcomes from routine source documents using intention-to-treat analyses. We will also conduct nested mixed-methods studies of implementation fidelity and context and perform cost-effectiveness and impact modelling. The Makerere School of Public Health IRB (#554), the Uganda National Council for Science and Technology (#HS1720ES), and the Yale Institutional Review Board (#2000023199) approved the study with a waiver of informed consent for the main trial implementation-effectiveness outcomes. We will submit trial results for publication in a peer-reviewed journal and disseminate findings to local shareholders, including policymakers and representatives of affected communities. Discussion This pragmatic, quasi-experimental implementation trial will inform efforts to find and prevent undiagnosed persons with TB in high-burden setting using contact investigation. It will help assess the suitability of human-centred design and communities of practice for tailoring implementation strategies and sustain evidence-based interventions in low-and-middle-income countries. Trial registration number ClinicalTrials.gov Identifier: NCT05640648.

Project description:BackgroundTuberculosis(TB) is among the leading causes of infectious death worldwide. Contact investigation is an evidence-based, World Health Organisation-endorsed intervention for timely TB diagnosis, treatment, and prevention but has not been widely and effectively implemented.MethodsWe are conducting a stepped-wedge, cluster-randomised, hybrid Type III implementation-effectiveness trial comparing a user-centred to a standard strategy for implementing TB contact investigation in 12 healthcare facilities in Uganda. The user-centred strategy consists of several client-focused components including (1) a TB-education booklet, (2) a contact-identification algorithm, (3) an instructional sputum-collection video, and (4) a community-health-rider service to transport clients, CHWs, and sputum samples, along with several healthcare-worker-focused components, including (1) collaborative improvement meetings, (2) regular audit-and-feedback reports, and (3) a digital group-chat application designed to develop a community of practice. Sites will cross-over from the standard to the user-centred strategy in six, eight-week transition steps following a randomly determined site-pairing scheme and timeline. The primary implementation outcome is the proportion of symptomatic close contacts completing TB evaluation within 60 days of TB treatment initiation by the index person with TB. The primary clinical effectiveness outcomes are the proportion of contacts diagnosed with and initiating active TB disease treatment and the proportion initiating TB preventative therapy within 60 days. We will assess outcomes from routine source documents using intention-to-treat analyses. We will also conduct nested mixed-methods studies of implementation fidelity and context and perform cost-effectiveness and impact modelling. The Makerere School of Public Health IRB(#554), the Uganda National Council for Science and Technology(#HS1720ES), and the Yale Institutional Review Board(#2000023199) approved the study and waived informed consent for the main trial implementation-effectiveness outcomes. We will submit results for publication in peer-reviewed journals and disseminate findings to local policymakers and representatives of affected communities.DiscussionThis pragmatic, quasi-experimental implementation trial will inform efforts to find and prevent undiagnosed persons with TB in high-burden settings using contact investigation. It will also help assess the suitability of human-centred design and communities of practice for tailoring implementation strategies and sustaining evidence-based interventions in low-and-middle-income countries.Trial registrationThe trial was registered(ClinicalTrials.gov Identifier NCT05640648) on 16 November 2022, after the trial launch on 7 March 2022.

Dataset Information

Impact on Patients' Treatment Outcomes of XpertMTB/RIF Implementation for the Diagnosis of Tuberculosis: Follow-Up of a Stepped-Wedge Randomized Clinical Trial.

Introduction

Methods

Results

Conclusions

Trial registration

Publications

Impact on Patients' Treatment Outcomes of XpertMTB/RIF Implementation for the Diagnosis of Tuberculosis: Follow-Up of a Stepped-Wedge Randomized Clinical Trial.

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