Evaluating Accuracy, Impact, and Operational Challenges of GeneXpert Use for TB Case Finding Among HIV-infected Persons

NCT02538952 | Completed Phase 4

• 1 other identifier: CDC-CGH-6294
• Study Type: interventional
• Target: 18,696
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Tuberculosis; Human Immunodeficiency Virus

Keywords

GeneXpert; Tuberculosis; Human immunodeficiency virus; Diagnostic accuracy; Impact

Outcome Measures

Primary Outcomes (2)

• TB diagnostic sensitivity among adults (>12 years old). Sensitivity proportions will be estimated using laboratory data on TB diagnoses (see "Description" below).

  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.

  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.

• All-cause mortality

  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.

  Patients will be followed for an average of about 6 months each, with vital status assessed across the 6 month follow-up period.

Secondary Outcomes (12)

• 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 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.

• 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 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.

• 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.

Study Arms (3)

Xpert package

EXPERIMENTAL

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.

Device: Xpert device; Other: Intensified TB Case Finding (ICF)

Active comparator

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.

Other: Intensified TB Case Finding (ICF)

Standard of Care

NO INTERVENTION

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.

Interventions

Xpert device DEVICE

Interventions in the "Experimental phase" of this stepped-wedge trial include: (a) ensuring WHO-recommended TB screening adopted, (b) situating trained TB case finding nurses in the clinics, (c) training clinic personnel in the TB diagnostic algorithms, and (d) activation of the Xpert diagnostic device.

Xpert package

Intensified TB Case Finding (ICF) OTHER

Interventions in the active comparator phase of this stepped wedge trial only include: (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 the standard of care microscopy algorithm (smear microscopy and chest x-ray) are available during this phase.

Active comparator; Xpert package

Eligibility Criteria

• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• All new HIV clinic enrollees who meet consent requirements.

You may not qualify if:

• Prisoners
• Retrospective cohort:
• All patients starting antiretroviral therapy at a study clinic in the 24 months before study start.
• Prisoners

Sponsors & Collaborators

• Centers for Disease Control and Prevention: lead
• Botswana Ministry of Health: collaborator
• University of Pennsylvania: collaborator

Study Sites (1)

22 HIV care and Treatment clinics in Botswana

Multiple Locations, Multiple, Botswana

Location

Related Publications (4)

• Auld AF, Fielding K, Agizew T, Maida A, Mathoma A, Boyd R, Date A, Pals SL, Bicego G, Liu Y, Shiraishi RW, Ehrenkranz P, Serumola C, Mathebula U, Alexander H, Charalambous S, Emerson C, Rankgoane-Pono G, Pono P, Finlay A, Shepherd JC, Holmes C, Ellerbrock TV, Grant AD. Risk scores for predicting early antiretroviral therapy mortality in sub-Saharan Africa to inform who needs intensification of care: a derivation and external validation cohort study. BMC Med. 2020 Nov 9;18(1):311. doi: 10.1186/s12916-020-01775-8.

  PMID: 33161899 DERIVED

• Auld AF, Agizew T, Mathoma A, Boyd R, Date A, Pals SL, Serumola C, Mathebula U, Alexander H, Ellerbrock TV, Rankgoane-Pono G, Pono P, Shepherd JC, Fielding K, Grant AD, Finlay A. Effect of tuberculosis screening and retention interventions on early antiretroviral therapy mortality in Botswana: a stepped-wedge cluster randomized trial. BMC Med. 2020 Feb 11;18(1):19. doi: 10.1186/s12916-019-1489-0.

  PMID: 32041583 DERIVED

• Agizew T, Chihota V, Nyirenda S, Tedla Z, Auld AF, Mathebula U, Mathoma A, Boyd R, Date A, Pals SL, Lekone P, Finlay A. Tuberculosis treatment outcomes among people living with HIV diagnosed using Xpert MTB/RIF versus sputum-smear microscopy in Botswana: a stepped-wedge cluster randomised trial. BMC Infect Dis. 2019 Dec 16;19(1):1058. doi: 10.1186/s12879-019-4697-5.

  PMID: 31842773 DERIVED

• Auld AF, Agizew T, Pals S, Finlay A, Ndwapi N, Boyd R, Alexander H, Mathoma A, Basotli J, Gwebe-Nyirenda S, Shepherd J, Ellerbrock TV, Date A. Implementation of a pragmatic, stepped-wedge cluster randomized trial to evaluate impact of Botswana's Xpert MTB/RIF diagnostic algorithm on TB diagnostic sensitivity and early antiretroviral therapy mortality. BMC Infect Dis. 2016 Oct 26;16(1):606. doi: 10.1186/s12879-016-1905-4.

  PMID: 27782821 DERIVED

Related Links

• Trial findings reported at the Conference on Retroviruses and Opportunistic Infections (CROI) 2018.

MeSH Terms

Conditions

Tuberculosis; Acquired Immunodeficiency Syndrome; Tooth, Impacted

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; HIV Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Tooth Diseases; Stomatognathic Diseases

Study Officials

• Alyssa Finlay, MD

  CDC Botswana

  PRINCIPAL INVESTIGATOR

• Tedd V Ellerbrock, MD

  CDC Atlanta

  PRINCIPAL INVESTIGATOR

• Andrew F Auld, MBChB, MSc

  CDC Atlanta

  PRINCIPAL INVESTIGATOR

• Tefera Agizew, MD, MPhil

  CDC Botswana

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: CROSSOVER
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 20, 2015
• First Posted: September 2, 2015
• Study Start: August 1, 2012
• Primary Completion: July 1, 2017
• Study Completion: July 1, 2017
• Last Updated: June 25, 2019

Record last verified: 2017-07

Locations

BO (1)