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

The over-arching purpose of this project is to improve TB diagnostic and care services at 22 HIV care and treatment clinics through phased rollout of (1) strengthened ICF systems, and (2) 13 Xpert devices, while simultaneously answering important implementation science questions, concerning Xpert operationalization and impact.

The stepped-wedge study design was chosen for a number of reasons related to ethical, operational, and analytic needs, as described in the method’s section. During the course of study implementation, the operational advantages of the phased implementation approach have been particularly notable. In our RLS of Botswana, the phased implementation approach has allowed the limited human and financial resources to be focused on smaller, more manageable pieces of the whole project, one step at a time, rather than be spread thinly across study sites, as would be required in a parallel group CRT [19]. Analytically, the stepped-wedge design allows multiple opportunities for controlling trends over time [26]. Potential disadvantages, when compared with a parallel group CRT, include: (1) moderately lower ability to assign causality to the intervention, and (2) higher sample size requirements in most circumstances, because of unequal allocation ratios for most of the duration of stepped-wedge trials [19]. The ethical, operational, and analytic advantages may help explain the increasing popularity of the stepped-wedge evaluation design, especially in RLS [24].

During trial conduct, several operational challenges were experienced, mainly related to lower than expected clinic enrolment rates, human resource constraints that reduced ability to enroll all study-eligible patients in the prospective cohort, and lower than expected prevalence of culture-positive TB at clinic enrollment. The declining HIV clinic enrolment rates probably reflect success of the HIV treatment program in reaching HIV-infected persons in prior years (i.e., during 2002–2011) [49], declining HIV incidence rates [52], and expanding numbers of alternate HIV clinics at which patients can receive care [49]. The study team probably over-estimated the willingness of patients to wait at the clinic for their turn to enroll in the study. However, in response to the observation that 28 % of potentially study-eligible patients were not being enrolled in the prospective cohort, the study team wrote a protocol amendment that allowed retrospective chart abstraction for the missed prospective patients, which will allow investigators to quantify any potential selection bias incurred by non-response. The lower than expected prevalence of culture-positive TB at HIV clinic enrollment needs further investigation once all study data are available for analysis. Fueled by the HIV epidemic, TB case notification rates in Botswana increased from about 202/100,000 population in 1990 to about 600/100,000 in 1998, plateaued at this level during 1998 through 2007, and have since declined to about 470/100,000 in recent years [36]. Increased ART coverage among HIV-infected persons might again explain declining national TB incidence and the lower-than-expected TB prevalence among HIV clinic enrollees in this study [53]. In retrospect, the protocol-specified large sample sizes and resulting high pre-study power to answer the first two primary study questions, were important precautions in place to ensure any sample size shortfalls did not result in trial futility.

Although, several Xpert impact studies have been published after this trial started, the two key study questions have not yet been answered. Firstly, data validating the Botswana Xpert diagnostic algorithm have not yet been reported, and this is an important program evaluation activity [54]. Secondly, among six trials that have compared all-cause mortality outcomes of study enrollees between microscopy and Xpert arms [17, 21, 54–57], none have observed Xpert impact on either morbidity or mortality outcomes, and only one was conducted exclusively among ART enrollees (Mupfumi et al) [21]. Certain study limitations of the trial by Mupfumi et al, including small sample size (N?=?424) and powering the study to detect differences in a composite outcome (death or TB) between study arms, mean that XPRES, with its larger sample size (N?=?16,267) and powered to detect Xpert impact on 6-month mortality rates specifically, is still positioned to provide a valuable scientific contribution. In addition, the intervention in XPRES is different from interventions employed in previous Xpert impact trials [17, 21, 54–59]—it represents a package of strengthened ICF interventions, activation of the Xpert device, and improved tracing for patients late for ART clinic appointments. In real-world settings, ICF interventions are often implemented at a sub-optimal level of quality and consistency due to health system weakness [9], and strengthening health systems to improve ICF compliance is arguably as important as the rollout of a new TB diagnostic device [17]. In addition, preventing treatment interruptions or LTFU during early ART through the tracing intervention, could contribute to reductions in all-cause, 6-month ART mortality rates [42, 43].