Evaluating Performance, Impact, and Operational Challenges of GeneXpert Use for TB Case Finding Among HIV-infected Persons in Botswana During 2012-2013: The Xpert Package Rollout Evaluation Study (XPRES)
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- 入组人数
- 18,696
- 试验地点
- 1
- 主要终点
- TB diagnostic sensitivity among adults (>12 years old). Sensitivity proportions will be estimated using laboratory data on TB diagnoses (see "Description" below).
研究概览
简要总结
Background: In Botswana, as in the rest of sub-Saharan Africa, undiagnosed TB or TB diagnosed late in the course of disease is thought to be the most common cause of death among HIV-infected persons.
Interventions for Evaluation: The Xpert MTB/RIF assay for the GeneXpert platform (Xpert) has a TB diagnostic sensitivity of 82.4%, significantly superior to that of smear microscopy (44.6%). In line with WHO guidelines, the Botswana Ministry of Health (MOH) and CDC rapidly rolled out the Xpert device and a new Xpert-based diagnostic algorithm in service of 22 HIV care and treatment clinics. To maximize impact of the Xpert device in improving detection of active TB, Xpert rollout was preceded by strengthening of TB screening procedures by: (1) adopting the WHO-recommended 4-symptom TB screen for adults; (2) situating trained TB case-finding nurses in facilities; and (3) training health facility personnel in TB diagnostic algorithms. The combination of these strengthened TB screening procedures and rollout of the Xpert device is referred to as the "Xpert package" in this protocol.
Key Evaluation Objectives: The protocol has two key objectives: (1) to evaluate whether the new MOH-recommended Xpert-based TB diagnostic algorithm for new adult HIV clinic enrollees is more sensitive than the pre-Xpert smear-microscopy-based algorithm in diagnosing culture-positive TB disease; and (2) to evaluate the impact of the whole "Xpert package" on all-cause mortality during the first 6 months of ART, among adult patients.
Design: Stepped-wedge cluster randomized trial. Sample Size: 6,136 patients were prospectively enrolled to meet the first primary objective. A retrospective cohort of 10,131 persons was also enrolled to meet the second objective. Projected power to meet both objectives is >80%.
Time line: Prospective cohort enrollment started in July 2012 and was complete by March 2014. Retrospective cohort enrollment was complete by March 2015. Patient follow-up and data entry will be complete in March 2016 at which time analysis to answer the first two primary study questions will be possible.
详细描述
Background: In Botswana, as in the rest of sub-Saharan Africa, undiagnosed tuberculosis (TB) or TB diagnosed late in the course of disease is thought to be the most common cause of death among HIV-infected persons receiving antiretroviral therapy (ART) as well as those not yet on ART. Common reasons for failure to diagnose TB early, include: (1) failure to appropriately screen HIV-infected patients for TB; and (2) difficulty in diagnosing TB with traditional diagnostic methods.
Public Health Intervention: The recent development of the Xpert MTB/RIF assay for the GeneXpert platform (Xpert) has revolutionized TB diagnostic capability for clinicians managing HIV-infected patients. Among HIV-infected adults, TB diagnostic sensitivity of Xpert (82.4%) has been proven superior to that of smear microscopy (44.6%). In line with World Health organization (WHO) guidelines, the Botswana Ministry of Health (MOH) and the United States Centers for Disease Control and Prevention (CDC), initiated a project in July 2012 to rapidly rollout 13 Xpert devices in service of 22 HIV care and treatment clinics while simultaneously initiating an evaluation to answer important operational research questions that can inform future national scale-up. To maximize the impact of the Xpert device in improving detection of active TB, the Xpert rollout was preceded by strengthening of TB screening procedures by: (1) ensuring the 22 HIV care and treatment clinics adopted the WHO-recommended four-symptom TB screen for adults; (2) situating trained TB case-finding nurses in all 22 facilities; and (3) training health facility personnel in both smear-microscopy-based and Xpert-based TB diagnostic algorithms. The combination of these strengthened TB screening procedures and rollout of the Xpert device is referred to as the "Xpert package" in this proposal.
Key Evaluation Objectives: The evaluation component of this project has two key objectives: (1) to evaluate whether the new MOH-recommended Xpert-based pulmonary TB diagnostic algorithm (including Xpert testing of sputum samples for all TB suspects and chest x-ray for Xpert-negative TB suspects) is more sensitive than the pre-Xpert smear-microscopy-based algorithm (smear microscopy and chest x-ray for smear-negative TB suspects) in diagnosing culture-positive TB disease; and (2) to evaluate the impact of the whole "Xpert package" on all-cause mortality during the first six months of ART, among adult patients.
Rationale for the First Evaluation Objective: Although it is expected that the Xpert-based TB diagnostic algorithm will be both more sensitive and more specific than the pre-Xpert algorithm, superiority of the Xpert- over the microscopy-based algorithm in Botswana has not yet been evaluated.
Rationale for the Second Evaluation Objective: In Botswana, undiagnosed TB or TB diagnosed late in the course of disease is thought to be the most common cause of death among HIV-infected persons receiving antiretroviral therapy (ART). The Xpert package could conceivably reduce TB-related mortality by ensuring all patients are screened for TB and ensuring TB suspects have access to a sensitive TB test (Xpert). Since the start of our Botswana stepped wedge trial in 2012, two separate but related randomized trials in Africa, the TB-NEAT study and the XTEND trial, have fallen short of demonstrating an association between use of Xpert for patients with symptoms of TB and reduced TB mortality. However, limitations in both these trials mean that the question of whether Xpert can reduce early ART mortality has not been definitively answered.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Diagnostic
- 盲法
- None
入排标准
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Prospective cohorts:
- •Inclusion Criteria:
- •All new HIV clinic enrollees who meet consent requirements.
排除标准
- •Prisoners
- •Retrospective cohort:
- •Inclusion Criteria:
- •All patients starting antiretroviral therapy at a study clinic in the 24 months before study start.
- •Exclusion Criteria:
- •Prisoners
研究组 & 干预措施
Xpert package
There are three phases to this stepped-wedge trial: (1) the retrospective cohort (standard of care) phase, (2) the active comparator phase, where intensified TB case finding (ICF) interventions are in place but no Xpert device, and (3) the "experimental phase" of full Xpert package implementation that includes both ICF interventions and Xpert device activation. Interventions in the experimental phase therefore include: (a) adoption of the WHO-recommended 4-symptom TB screen for adults; (b) situating trained TB case-finding nurses in the 22 facilities; (c) training health facility personnel in TB diagnostic algorithms; and (d) Xpert device activation. The combination of the ICF interventions and rollout of the Xpert device is referred to as the "Xpert package" in this protocol.
干预措施: Xpert device (Device)
Xpert package
There are three phases to this stepped-wedge trial: (1) the retrospective cohort (standard of care) phase, (2) the active comparator phase, where intensified TB case finding (ICF) interventions are in place but no Xpert device, and (3) the "experimental phase" of full Xpert package implementation that includes both ICF interventions and Xpert device activation. Interventions in the experimental phase therefore include: (a) adoption of the WHO-recommended 4-symptom TB screen for adults; (b) situating trained TB case-finding nurses in the 22 facilities; (c) training health facility personnel in TB diagnostic algorithms; and (d) Xpert device activation. The combination of the ICF interventions and rollout of the Xpert device is referred to as the "Xpert package" in this protocol.
干预措施: Intensified TB Case Finding (ICF) (Other)
Active comparator
There are three phases to this stepped-wedge trial: (1) the retrospective cohort (standard of care) phase, (2) the active comparator phase, where intensified TB case finding (ICF) interventions are in place but no Xpert device, and (3) the "experimental phase" of full Xpert package implementation that includes both ICF interventions and Xpert device activation. Interventions in the active comparator phase therefore include only: (a) adoption of the WHO-recommended 4-symptom TB screen for adults; (b) situating trained TB case-finding nurses in the 22 facilities; and (c) training health facility personnel in TB diagnostic algorithms. There is no Xpert device activation in this phase. Only standard of care microscopy-based TB diagnostic algorithms are available during this phase.
干预措施: Intensified TB Case Finding (ICF) (Other)
Standard of Care
There are three phases to this stepped-wedge trial: (1) the retrospective cohort (standard of care) phase, (2) the active comparator phase, where intensified TB case finding (ICF) interventions are in place but no Xpert device, and (3) the "experimental phase" of full Xpert package implementation that includes both ICF interventions and Xpert device activation. There are no interventions in the standard of care arm (retrospective cohort). There are no ICF interventions and no Xpert device activations in this phase. Only the standard of care TB case finding procedures and microscopy-based TB diagnostic algorithm are available during this phase.
结局指标
主要结局
TB diagnostic sensitivity among adults (>12 years old). Sensitivity proportions will be estimated using laboratory data on TB diagnoses (see "Description" below).
时间窗: Patients will be followed for an average of about 6 months each, and TB diagnostic sensitivity will be estimated at each clinical visit where the patient tests culture-positive for TB, with clinic visits occuring every one to 3 months.
TB diagnostic algorithm sensitivity will be estimated in the pre-Xpert and post-Xpert time periods of this stepped wedge design, among adults (\>12 years old). Sensitivity is the proportion of culture-positive TB cases correctly diagnosed with TB using the relevant diagnostic algorithm. The denominator is all culture-confirmed TB cases and the numerator the number of culture-confirmed TB cases that were correctly identified as positive by the relevant TB diagnostic algorithm.
All-cause mortality
时间窗: Patients will be followed for an average of about 6 months each, with vital status assessed across the 6 month follow-up period.
All-cause 6-month mortality among adult antiretroviral therapy enrollees will be compared between the pre-Xpert retrospective cohort and the post-Xpert package cohorts.
次要结局
- Xpert diagnostic sensitivity. Sensitivity proportions will be estimated using laboratory data on TB diagnoses (see "Description" below).(Patients will be followed for an average of about 6 months each, and TB diagnostic sensitivity will be estimated at each clinical visit where the patient tests culture-positive for TB, with clinic visits occuring every one to 3 months.)
- The proportion of attempts to use Xpert where Xpert was considered inoperable. These data will be obtained from study questionnaires.(Patients will be followed for an average of about 6 months each, and Xpert fuctionality be estimated at each clinical visit where the patient screens positive for TB and provides a sputum sample, with clinic visits occuring every one to 3 months.)
- TB diagnostic sensitivity among children (<=12 years old). Sensitivity proportions will be estimated using laboratory data on TB diagnoses (see "Description" below).(Patients will be followed for an average of about 6 months each, and TB diagnostic sensitivity will be estimated at each clinical visit where the patient tests culture-positive for TB, with clinic visits occuring every one to 3 months.)
- Median turnaround time for sputum samples from the time of sample collection to the time the patient was initiated on TB treatment. These data will be obtained from study questionnaires.(Patients will be followed for an average of about 6 months each, and turnaround times for sputum samples will be estimated at each clinical visit where the patient provides a sputum sample, with clinic visits occuring every one to 3 months.)
- Clinician TB screening compliance. Compliance proportions will be estimated using data from study questionnaires (see "Description" below).(Patients will be followed for an average of about 6 months each, with clinician TB screening compliance assessed at each clinic visit, which should occur every one to 3 months.)
- The proportion of patients diagnosed with TB at HIV clinic enrollment. Proportions diagnosed with TB will be estimated using data from study questionnaires and laboratory tests.(Patients will be followed for an average of about 6 months each, and the proportion diagnosed with TB will be estimated at each clinical visit, with clinic visits occuring every one to 3 months.)
- TB screening algorithm sensitivity among children (<=12 years old). Sensitivity proportions will be estimated using laboratory data on TB diagnoses and questionnaire data on the screening algorithm (see "Description" below).(Patients will be followed for an average of about 6 months each, and TB diagnostic sensitivity will be estimated at each clinical visit where the patient tests culture-positive for TB, with clinic visits occuring every one to 3 months.)
- Diagnostic sensitivity of Xpert in diagnosing culture-positive drug resistant TB.(Patients will be followed for an average of about 6 months each, and TB diagnostic sensitivity will be estimated at each clinical visit where the patient tests culture-positive for drug resistant TB, with clinic visits occuring every one to 3 months.)
- TB treatment outcomes. The incidence rate will be estimated using data from study questionnaires (see "Description" below).(Patients will be followed for an average of about 6 months each, and TB treatment outcomes will be estimated at each clinical visit, with clinic visits occuring every one to 3 months.)
- Hospitalization rates. Incidence of hospitalization rates will be estimated from study questionnaires.(Patients will be followed for an average of about 6 months each, and the hospitalization outcome will be measured at each clinical visit, with clinic visits occuring every one to 3 months.)
- The proportion of patients screening positive for TB at the HIV clinic enrollment visit. Proportions screening positive will be estimated using data from study questionnaires (see "Description" below).(Patients will be followed for an average of about 6 months each, and the proportion screening positive for TB will be estimated at each clinical visit, including the first clinic visit, with clinic visits occuring every one to 3 months.)
- TB incidence(Patients will be followed for an average of about 6 months each, and TB incidence will be estimated at each clinical visit, with clinic visits occuring every one to 3 months.)