Study protocol: a cluster randomized trial to evaluate the effectiveness and implementation of onsite GeneXpert testing at community health centers in Uganda (XPEL-TB).

BACKGROUND: Delays in diagnosis and treatment of tuberculosis (TB) remain common in high-burden countries. To improve case detection, substantial investments have been made to scale-up Xpert MTB/RIF (Xpert), a cartridge-based nucleic acid amplification test that can detect TB within 2 hours, as a replacement for sputum smear microscopy. However, the optimal strategy for implementation of Xpert testing remains unclear. METHODS: The Xpert Performance Evaluation for Linkage to Tuberculosis Care (XPEL-TB) trial uses an ultra-pragmatic, hybrid type II effectiveness-implementation design to assess the effectiveness and implementation of a streamlined strategy for delivery of Xpert testing in real-world settings. Twenty health centers with TB microscopy units were selected to participate in the trial, with ten health centers randomized to the intervention strategy (onsite molecular testing using GeneXpert Edge, process redesign to facilitate same-day TB diagnosis and treatment, and performance feedback) or routine care (onsite sputum smear microscopy plus referral of sputum samples to Xpert testing sites). The primary outcome is the number of patients with microbiologically confirmed TB who were initiated on treatment within 14 days of presentation to the health center, which reflects successful completion of the TB diagnostic evaluation process. Secondary outcomes include health outcomes (6-month vital status), as well as measures of the reach, adoption, and implementation of the intervention strategy. DISCUSSION: The design elements and implementation approach for the XPEL-TB trial were intentionally selected to minimize disruptions to routine care procedures, with the goal of limiting their influence on key primary and secondary outcomes. Trial findings may result in increased support and funding for rapid, onsite molecular testing as the standard-of-care for all patients being evaluated for TB. TRIAL REGISTRATION: US National Institutes of Health's ClinicalTrials.gov, NCT03044158. Registered 06 February 2017. Pan African Clinical Trials Registry, PACTR201610001763265. Registered 03 September 2016

Quality of care for patients evaluated for tuberculosis in the context of Xpert MTB/RIF scale-up.

RATIONALE: Many high-burden countries are scaling-up Xpert MTB/RIF using a hub-and-spoke model. We evaluated the quality of care for patients undergoing TB evaluation at microscopy centers (spokes) linked to Xpert testing sites (hubs) in Uganda. OBJECTIVES: To characterize the extent to which patients were receiving care in accordance with international and national guidelines. METHODS: We conducted a prospective cohort study of all adults with presumptive pulmonary TB at 24 health centers linked to Xpert testing sites. Health center staff photographed TB registers, and uploaded photos to a secure server bi-weekly. We assessed the proportion of patients (1) initiating testing; (2) completing testing; and (3) treated for confirmed TB within 14 days. MEASUREMENTS AND MAIN RESULTS: Between January to December 2017, 6744 patients underwent evaluation for pulmonary TB. Only 1316 patients had sputum referred for Xpert testing, including 1075/3229 (33.3%) people living with HIV and 241/3515 (6.9%) without HIV. Of 119 patients confirmed to have TB by Xpert testing, 44 (36%) did not initiate treatment. There were significant losses along the entire diagnostic cascade of care, with only 5330/6744 (79.0%) patients having samples referred for sputum-based testing, 2978/5330 (55.9%) patients completing recommended testing if referred, and 313/418 (74.9%) patients initiating treatment within 14 days if confirmed to have TB. CONCLUSIONS: Although coverage of Xpert testing services across Uganda is high, the quality of care delivered to patients undergoing TB evaluation remains poor. Further research is needed to identify health system interventions to facilitate uptake of Xpert testing and high-quality care

Design and execution of a public randomization ceremony to enhance stakeholder engagement within a cluster randomized trial to improve tuberculosis diagnosis in Uganda.

Public randomization ceremonies have been proposed as a strategy to strengthen stakeholder engagement and address concerns and misconceptions associated with trial randomization. However, there are few published examples that describe how to conduct a public randomization ceremony with meaningful stakeholder engagement or how such ceremonies impact stakeholder perceptions about randomization and the randomization process. Cluster randomization for the GeneXpert Performance Evaluation for Linkage to Tuberculosis Care (XPEL-TB) trial was conducted at a public randomization ceremony attended by 70 stakeholders in Kampala, Uganda. Presentations given by the Acting Assistant Commissioner from the Uganda National Tuberculosis and Leprosy Programme and trial investigators emphasized how the trial aimed to further national TB goals, as well as how stakeholders contributed to the intervention design. The purpose and process of randomization were described using simple text and visuals. Randomization was an interactive activity that required participation of stakeholders from each trial site. A survey administered to stakeholders at the end of the ceremony suggested high comprehension of randomization (98%), trust in the randomization process (96%), and satisfaction with randomization outcomes (96%). Public randomization ceremonies should be considered more routinely to engage stakeholders in and address potential concerns about the fairness and impartiality of the randomization process for community-based trials

Multicomponent Strategy with Decentralized Molecular Testing for Tuberculosis.

BACKGROUND: Effective strategies are needed to facilitate the prompt diagnosis and treatment of tuberculosis in countries with a high burden of the disease. METHODS: We conducted a cluster-randomized trial in which Ugandan community health centers were assigned to a multicomponent diagnostic strategy (on-site molecular testing for tuberculosis, guided restructuring of clinic workflows, and monthly feedback of quality metrics) or routine care (on-site sputum-smear microscopy and referral-based molecular testing). The primary outcome was the number of adults treated for confirmed tuberculosis within 14 days after presenting to the health center for evaluation during the 16-month intervention period. Secondary outcomes included completion of tuberculosis testing, same-day diagnosis, and same-day treatment. Outcomes were also assessed on the basis of proportions. RESULTS: A total of 20 health centers underwent randomization, with 10 assigned to each group. Of 10,644 eligible adults (median age, 40 years) whose data were evaluated, 60.1% were women and 43.8% had human immunodeficiency virus infection. The intervention strategy led to a greater number of patients being treated for confirmed tuberculosis within 14 days after presentation (342 patients across 10 intervention health centers vs. 220 across 10 control health centers; adjusted rate ratio, 1.56; 95% confidence interval [CI], 1.21 to 2.01). More patients at intervention centers than at control centers completed tuberculosis testing (adjusted rate ratio, 1.85; 95% CI, 1.21 to 2.82), received a same-day diagnosis (adjusted rate ratio, 1.89; 95% CI, 1.39 to 2.56), and received same-day treatment for confirmed tuberculosis (adjusted rate ratio, 2.38; 95% CI, 1.57 to 3.61). Among 706 patients with confirmed tuberculosis, a higher proportion in the intervention group than in the control group were treated on the same day (adjusted rate ratio, 2.29; 95% CI, 1.23 to 4.25) or within 14 days after presentation (adjusted rate ratio, 1.22; 95% CI, 1.06 to 1.40). CONCLUSIONS: A multicomponent diagnostic strategy that included on-site molecular testing plus implementation supports to address barriers to delivery of high-quality tuberculosis evaluation services led to greater numbers of patients being tested, receiving a diagnosis, and being treated for confirmed tuberculosis. (Funded by the National Heart, Lung, and Blood Institute; XPEL-TB ClinicalTrials.gov number, NCT03044158.)

Evaluating the impact of cash transfers on tuberculosis (ExaCT TB): a stepped wedge cluster randomised controlled trial

BackgroundMitigating financial barriers to tuberculosis (TB) diagnosis and treatment is a core priority of the global TB agenda. We evaluated the impact of a cash transfer intervention on completion of TB testing and treatment initiation in Uganda.MethodsWe conducted a pragmatic complete stepped wedge randomised trial of a one-time unconditional cash transfer at 10 health centres between September 2019 and March 2020. People referred for sputum-based TB testing were enrolled to receive UGX 20 000 (∼USD 5.39) upon sputum submission. The primary outcome was the number initiating treatment for micro-bacteriologically confirmed TB within 2 weeks of initial evaluation. The primary analysis included cluster-level intent-to-treat and per-protocol analyses using negative binomial regression.Results4288 people were eligible. The number diagnosed with TB initiating treatment was higher in the intervention period versus the pre-intervention period (adjusted rate ratio (aRR)=1.34) with a 95% CI of 0.62-2.91 (p=0.46), indicating a wide range of plausible true intervention effects. More were referred for TB testing (aRR=2.60, 95% CI 1.86-3.62; p<0.001) and completed TB testing (aRR=3.22, 95% CI 1.37-7.60; p=0.007) per National Guidelines. Results were similar but attenuated in per-protocol analyses. Surveys revealed that while the cash transfer supported testing completion, it was insufficient to address long-term underlying social/economic barriers.InterpretationWhile it is uncertain whether a single unconditional cash transfer increased the number of people diagnosed and treated for TB, it did support higher completion of diagnostic evaluation in a programmatic setting. A one-time cash transfer may offset some but not all of the social/economic barriers to improving TB diagnosis outcomes

Evaluating the impact of cash transfers on tuberculosis (ExaCT TB): a stepped wedge cluster randomised controlled trial

Background Mitigating financial barriers to tuberculosis (TB) diagnosis and treatment is a core priority of the global TB agenda. We evaluated the impact of a cash transfer intervention on completion of TB testing and treatment initiation in Uganda. Methods We conducted a pragmatic complete stepped wedge randomised trial of a one-time unconditional cash transfer at 10 health centres between September 2019 and March 2020. People referred for sputum-based TB testing were enrolled to receive UGX 20 000 (∼USD 5.39) upon sputum submission. The primary outcome was the number initiating treatment for micro-bacteriologically confirmed TB within 2 weeks of initial evaluation. The primary analysis included cluster-level intent-to-treat and per-protocol analyses using negative binomial regression. Results 4288 people were eligible. The number diagnosed with TB initiating treatment was higher in the intervention period versus the pre-intervention period (adjusted rate ratio (aRR)=1.34) with a 95% CI of 0.62–2.91 (p=0.46), indicating a wide range of plausible true intervention effects. More were referred for TB testing (aRR=2.60, 95% CI 1.86–3.62; p<0.001) and completed TB testing (aRR=3.22, 95% CI 1.37–7.60; p=0.007) per National Guidelines. Results were similar but attenuated in per-protocol analyses. Surveys revealed that while the cash transfer supported testing completion, it was insufficient to address long-term underlying social/economic barriers. Interpretation While it is uncertain whether a single unconditional cash transfer increased the number of people diagnosed and treated for TB, it did support higher completion of diagnostic evaluation in a programmatic setting. A one-time cash transfer may offset some but not all of the social/economic barriers to improving TB diagnosis outcomes

Variation in tuberculosis treatment outcomes and treatment supervision practices in Uganda.

BackgroundVariation in healthcare delivery is increasingly recognized as an important metric of healthcare quality. Directly observed therapy (DOT) has been the standard of care for tuberculosis (TB) treatment supervision for decades based on World Health Organization (WHO) guidelines. However, variation in implementation of DOT and associated TB treatment supervision practices remains poorly defined.MethodsWe collected individual patient data from TB treatment registers at 18 TB treatment units in Uganda including District Health Centers, District Hospitals, and Regional Referral Hospitals. We also administered a survey and did observations of TB treatment supervision practices by health workers at each site. We describe variation in TB treatment outcomes and TB treatment supervision practices.ResultsOf 2767 patients treated for TB across the 18 clinical sites between January 1 and December 31, 2017, 1740 (62.9%) were men, most were of working age (median 35 years, interquartile range [IQR] 27 - 46), 2546 (92.0%) had a new TB diagnosis, and nearly half (45.9%, n = 1283) were HIV positive. The pooled treatment success proportion was 69.4% (95% confidence interval [CI] 67.8 - 71.1) but there was substantial variation across sites (range 42.6 - 87.6%, I-squared 92.7%, p &lt; 0.001). The survey and observation of TB treatment practices revealed that the majority of sites practice community-based DOT (66.7%, n = 12) and request a family member, who receives no additional training or supervision, to serve as a treatment supporter (77.8%, n = 14). At TB medication refill visits, all sites screen for side effects and most assess adherence via self-report (83.3%, n = 15). Only 7 (38.9%) sites followed-up patients who missed appointments using either phone calls (22.2%, n = 4/7) or community health workers (16.7%, n = 3/7). All 18 sites counseled patients at treatment initiation, but none provided additional counseling at refill visits other than addressing poor adherence or missed appointments.ConclusionThere was substantial variation in implementation of DOT, including observation and documentation of daily dosing, training and supervision of treatment supporters, and follow-up for missed clinic visits. Identifying best practices and reducing uncontrolled variation in the delivery of TB treatment is critical to improving treatment outcomes

Variation in tuberculosis treatment outcomes and treatment supervision practices in Uganda.

BackgroundVariation in healthcare delivery is increasingly recognized as an important metric of healthcare quality. Directly observed therapy (DOT) has been the standard of care for tuberculosis (TB) treatment supervision for decades based on World Health Organization (WHO) guidelines. However, variation in implementation of DOT and associated TB treatment supervision practices remains poorly defined.MethodsWe collected individual patient data from TB treatment registers at 18 TB treatment units in Uganda including District Health Centers, District Hospitals, and Regional Referral Hospitals. We also administered a survey and did observations of TB treatment supervision practices by health workers at each site. We describe variation in TB treatment outcomes and TB treatment supervision practices.ResultsOf 2767 patients treated for TB across the 18 clinical sites between January 1 and December 31, 2017, 1740 (62.9%) were men, most were of working age (median 35 years, interquartile range [IQR] 27 - 46), 2546 (92.0%) had a new TB diagnosis, and nearly half (45.9%, n = 1283) were HIV positive. The pooled treatment success proportion was 69.4% (95% confidence interval [CI] 67.8 - 71.1) but there was substantial variation across sites (range 42.6 - 87.6%, I-squared 92.7%, p &lt; 0.001). The survey and observation of TB treatment practices revealed that the majority of sites practice community-based DOT (66.7%, n = 12) and request a family member, who receives no additional training or supervision, to serve as a treatment supporter (77.8%, n = 14). At TB medication refill visits, all sites screen for side effects and most assess adherence via self-report (83.3%, n = 15). Only 7 (38.9%) sites followed-up patients who missed appointments using either phone calls (22.2%, n = 4/7) or community health workers (16.7%, n = 3/7). All 18 sites counseled patients at treatment initiation, but none provided additional counseling at refill visits other than addressing poor adherence or missed appointments.ConclusionThere was substantial variation in implementation of DOT, including observation and documentation of daily dosing, training and supervision of treatment supporters, and follow-up for missed clinic visits. Identifying best practices and reducing uncontrolled variation in the delivery of TB treatment is critical to improving treatment outcomes

Feasibility of a short message service (SMS) intervention to deliver tuberculosis testing results in peri-urban and rural Uganda.

BackgroundPre-treatment loss to follow-up is common for patients diagnosed with tuberculosis (TB) in high-burden countries. Delivering test results by Short-Messaging-Service (SMS) is increasingly being considered as a solution, but there is limited information about its feasibility as a public health tool in low resourced settings.ObjectiveWe sought to assess the feasibility of utilizing SMS technology to deliver TB test results during routine TB diagnostic evaluation in Uganda.MethodsWe conducted a single arm interventional pilot study at four community health centers in Uganda that referred sputum samples to a district hospital for GeneXpert-MTB/RIF (Xpert) testing (Cepheid, USA). Using existing GxAlert-software (SystemOne,USA), we set up an automated SMS platform to send Xpert results to patients and referring health centers. We assessed each step of the SMS delivery cascade for consecutive patients who presented to these four community health centers between December 2015 and March 2016 and underwent Xpert testing.ResultsOf 233 patients enrolled, 161 (69%) had phone numbers recorded on individual Xpert referral forms. Phone numbers were entered into Xpert device software in the correct format for 152 (94%) patients. GxAlert-software generated an automated SMS reporting Xpert results for 151 (99%) patients and delivered it successfully to mobile phone service providers for 145/151 (96%). Of the 123 patients reached by phone to determine receipt of test results, 114 (93%) confirmed SMS receipt. SMS-based delivery of Xpert results was verified for 114/233 (49%) patients overall. In contrast, phone calls to health centers confirmed that health centers received messages for 222/233 (95%) patients.ConclusionReporting Xpert results via automated SMS is technically feasible and results in approximately half of patients receiving their test results immediately. Additional research should be done to address process inefficiencies in order to maximize impact of this technology and link its successful utilization to improved patient outcomes