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

Abstract

Background: Undiagnosed tuberculosis (TB) remains the most common cause of HIV-related mortality. Xpert MTB/ RIF (Xpert) is being rolled out globally to improve TB diagnostic capacity. However, previous Xpert impact trials have reported that health system weaknesses blunted impact of this improved diagnostic tool. During phased Xpert rollout in Botswana, we evaluated the impact of a package of interventions comprising (1) additional support for intensified TB case finding (ICF), (2) active tracing for patients missing clinic appointments to support retention, and (3) Xpert replacing sputum-smear microscopy, on early (6-month) antiretroviral therapy (ART) mortality. Methods: At 22 clinics, ART enrollees > 12 years old were eligible for inclusion in three phases: a retrospective standard of care (SOC), prospective enhanced care (EC), and prospective EC plus Xpert (EC+X) phase. EC and EC+X phases were implemented as a stepped-wedge trial. Participants in the EC phase received SOC plus components 1 (strengthened ICF) and 2 (active tracing) of the intervention package, and participants in the EC+X phase received SOC plus all three intervention package components. Primary and secondary objectives were to compare all-cause 6-month ART mortality between SOC and EC+X and between EC and EC+X phases, respectively. We used adjusted analyses, appropriate for study design, to control for baseline differences in individual-level factors and intra-facility correlation. Results: We enrolled 14,963 eligible patients: 8980 in SOC, 1768 in EC, and 4215 in EC+X phases. Median age of ART enrollees was 35 and 64% were female. Median CD4 cell count was lower in SOC than subsequent phases (184/μL in SOC, 246/μL in EC, and 241/μL in EC+X). By 6 months of ART, 461 (5.3%) of SOC, 54 (3.2%) of EC, and 121 (3.0%) of EC+X enrollees had died. Compared with SOC, 6-month mortality was lower in the EC+X phase (adjusted hazard ratio, 0.77; 95% confidence interval, 0.61-0.97, p = 0.029). Compared with EC enrollees, 6-month mortality was similar among EC+X enrollees.

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

“…Strengths of this study include the use of data from prospective cohorts nested within clinical trials, meaning there was minimal missing covariate data and strong ascertainment of the primary outcome of interest (6-month ART mortality) (e.g., only one patient was LTFU from the XPRES cohort and was excluded from this analysis [ 16 ]). Additional strengths include the relatively high screening accuracy in both the XPRES and TBFT cohorts, from two geographically separate cohorts, with very different cohort characteristics (e.g., XPRES enrollees represent general outpatient ART enrollees while TBFT enrollees had homogenously low CD4 counts (< 150/μL)).…”

“…In the second phase, the Xpert® MTB/RIF assay (Cepheid; Sunnyvale, CA) (Xpert) was initiated in place of sputum smear microscopy for TB diagnosis. Details of these interventions have been previously published [ 16 ] and are provided in a supplementary appendix (see Additional file 2 , text describing enrollment and enhanced care interventions). We have previously shown that there was no significant difference in 6-month ART mortality between the two prospective phases of XPRES [ 16 ].…”

“…Details of these interventions have been previously published [ 16 ] and are provided in a supplementary appendix (see Additional file 2 , text describing enrollment and enhanced care interventions). We have previously shown that there was no significant difference in 6-month ART mortality between the two prospective phases of XPRES [ 16 ]. Enrollment and follow-up procedures are described in the supplementary appendix (see Additional file 2 , text).…”

“…By law, since 1969, all deaths need to be registered in the Death Registry, which is maintained by the Botswana Civil and National Registration Office. Available data shows Death Registry data completeness to be high [ 16 ].…”

“…Within the derivation dataset, we performed univariable analyses assessing the association of each variable with risk of mortality using logistic regression. Because follow-up of all XPRES and TBFT enrollees was complete with true ascertainment of 6-month mortality outcomes, 6-month risk was preferred to rate [ 16 ]. Continuous variables were assessed for non-linearity with log odds of death using fractional polynomials, as well as by comparing Akaike’s Information Criteria and Bayesian Information Criteria between models with linear or fractional polynomial terms.…”