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

Abstract

BackgroundIn 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”.MethodsThe 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.DiscussionOnly 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.Trial registrationRetrospectively registered at ClinicalTrials.gov: NCT02538952.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-016-1905-4) contains supplementary material, which is available to authorized users.

Effect of tuberculosis screening and retention interventions on early antiretroviral therapy mortality in Botswana: a stepped-wedge cluster randomized trial

“…We conducted a multi-center, stepped-wedge cluster randomized trial (CRT) with a retrospective baseline component called the Xpert Package Rollout Evaluation using a Stepped-wedge design (XPRES) trial. A stepped-wedge rather than parallel group design was chosen because the Xpert, ICF, and retention package was expected to be beneficial for patients and the trial was part of a national rollout [6].…”

“…1). For this predefined protocol analysis, only those study enrollees who newly started ART at or after study enrollment and were ≥ 12 years old at ART initiation were included [6].…”

“…1). After obtaining ethical approvals and agreement to participate in the study from MOH at a central level and MOH management at the selected facilities, the study statistician randomly selected one of the rollout permutations [6].…”

“…In 2011, following World Health Organization (WHO) endorsement of Xpert MTB/RIF® (Xpert) as the first-line TB diagnostic test for symptomatic PLHIV [5], the Botswana Ministry of Health (MOH) and partners initiated planning for a phased national Xpert rollout [6]. Review of available program data for new HIV care enrollees showed that many components of the intensified TB case finding (ICF) cascade, especially compliance with the WHO-recommended 4-symptom TB screening rule, and early retention in HIV care, should be strengthened in order for Xpert to have maximum benefit [7].…”

“…Weaknesses in the health system that have resulted in poor completion of the TB diagnostic and treatment cascade and sub-optimal retention in HIV care, have been cited as important reasons for lack of observed Xpert impact on PLHIV mortality in similar settings [8,9]. Therefore, Botswana used the Xpert rollout as an opportunity to strengthen ICF and retention in early HIV care through rollout of a package of services [6]. The intervention package has three components: (1) additional support for ICF, (2) intensified tracing for patients missing clinic appointments to return them to care, and (3) Xpert replacing sputum-smear microscopy.…”