Feasibility and acceptability of the smart pillbox and medication label with differentiated care to support person-centered tuberculosis care among ASCENT trial participants - A multicountry study.

Introduction: Digital adherence technologies (DATs) can offer alternative approaches to support tuberculosis treatment medication adherence. Evidence on their feasibility and acceptability in high TB burden settings is limited. We conducted a cross-sectional survey among adults with drug-sensitive tuberculosis (DS-TB), participating in pragmatic cluster-randomized trials for the Adherence Support Coalition to End TB project in Ethiopia (PACTR202008776694999), the Philippines, South Africa and Tanzania (ISRCTN 17706019). Methods: From each country we selected 10 health facilities implementing the DAT intervention (smart pillbox or medication labels, with differentiated care support), ensuring inclusion of urban/rural and public/private facilities. Adults on DS-TB regimen using a DAT were randomly selected from each facility. Feasibility of the DATs was assessed using a standardized tool. Acceptability was measured using a 5-point Likert-scale, using the Capability, Opportunity, Motivation, Behavior (COM-B) model. Mean scores of Likert-scale responses within each COM-B category were estimated, adjusted for facility-level clustering. Data were summarized by country and DAT type. Results: Participants using either the pillbox (n = 210) or labels (n = 169) were surveyed. Among pillbox users, phone ownership (79%), use of pillbox reminders (87%) and taking treatment without the pillbox (22%) varied by country. Among label users, phone ownership (81%), paying extra to use the labels (8%) and taking treatment without using labels (41%) varied by country. Poor network, problems with phone charging and access, not having the pillbox and forgetting to send text were reasons for not using DATs. Overall, people with TB had a favorable impression of both DATs, with mean composite scores between 4·21 to 4·42 across COM-B categories. Some disclosure concerns were reported. Conclusion: From client-perspective, pillboxes and medication labels with differentiated care support were feasible to implement and acceptable in variety of settings. However, implementation challenges related to network, phone access, stigma, additional costs to people with TB to use DATs need to be addressed.

Effectiveness of digital adherence technologies in improving tuberculosis treatment outcomes in four countries: a pragmatic cluster randomised trial protocol.

INTRODUCTION: Successful treatment of tuberculosis depends to a large extent on good adherence to treatment regimens, which relies on directly observed treatment (DOT). This in turn requires frequent visits to health facilities. High costs to patients, stigma and burden to the health system challenged the DOT approach. Digital adherence technologies (DATs) have emerged as possibly more feasible alternatives to DOT but there is conflicting evidence on their effectiveness and feasibility. Our primary objective is to evaluate whether the implementation of DATs with daily monitoring and a differentiated response to patient adherence would reduce poor treatment outcomes compared with the standard of care (SOC). Our secondary objectives include: to evaluate the proportion of patients lost to follow-up; to compare effectiveness by DAT type; to evaluate the feasibility and acceptability of DATs; to describe factors affecting the longitudinal engagement of patients with the intervention and to use a simple model to estimate the epidemiological impact and cost-effectiveness of the intervention from a health system perspective. METHODS AND ANALYSIS: This is a pragmatic two-arm cluster-randomised trial in the Philippines, South Africa, Tanzania and Ukraine, with health facilities as the unit of randomisation. Facilities will first be randomised to either the DAT or SOC arm, and then the DAT arm will be further randomised into medication sleeve/labels or smart pill box in a 1:1:2 ratio for the smart pill box, medication sleeve/label or the SOC respectively. We will use data from the digital adherence platform and routine health facility records for analysis. In the main analysis, we will employ an intention-to-treat approach to evaluate treatment outcomes. ETHICS AND DISSEMINATION: The study has been approved by the WHO Research Ethics Review Committee (0003296), and by country-specific committees. The results will be shared at national and international meetings and will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN17706019.

Shorter regimens improved treatment outcomes of multidrug-resistant tuberculosis patients in Tanzania in 2018 cohort.

OBJECTIVE: In 2018, shorter treatment regimens (STR) for people with drug-resistant tuberculosis (DR-TB) were introduced in Tanzania and included kanamycin, high-dose moxifloxacin, prothionamide, high-dose isoniazid, clofazimine, ethambutol and pyrazinamide. We describe treatment outcomes of people diagnosed with DR-TB in a cohort initiating treatment in 2018 in Tanzania. METHODS: This was a retrospective cohort study conducted at the National Centre of Excellence and decentralised DR-TB treatment sites for the 2018 cohort followed from January 2018 to August 2020. We reviewed data from the National Tuberculosis and Leprosy Program DR-TB database to assess clinical and demographic information. The association between different DR-TB regimens and treatment outcome was assessed using logistic regression analysis. Treatment outcomes were described as treatment complete, cure, death, failure or lost to follow-up. A successful treatment outcome was assigned when the patient achieved treatment completion or cure. RESULTS: A total of 449 people were diagnosed with DR-TB of whom 382 had final treatment outcomes: 268 (70%) cured; 36 (9%) treatment completed; 16 (4%) lost to follow-up; 62 (16%) died. There was no treatment failure. The treatment success rate was 79% (304 patients). The 2018 DR-TB treatment cohort was initiated on the following regimens: 140 (46%) received STR, 90 (30%) received the standard longer regimen (SLR), 74 (24%) received a new drug regimen. Normal nutritional status at baseline [adjusted odds ratio (aOR) = 6.57, 95% CI (3.33-12.94), p < 0.001] and the STR [aOR = 2.67, 95% CI (1.38-5.18), p = 0.004] were independently associated with successful DR-TB treatment outcome. CONCLUSION: The majority of DR-TB patients on STR in Tanzania achieved a better treatment outcome than on SLR. The acceptance and implementation of STR at decentralised sites promises greater treatment success. Assessing and improving nutritional status at baseline and introducing new shorter DR-TB treatment regimens may strengthen favourable treatment outcomes.

Implementation of the 'Removed Injectable modified Short-course regimens for EXpert Multidrug Resistant Tuberculosis' (RISE study) in Tanzania: a protocol for a mixed-methods process evaluation.

INTRODUCTION: Tanzania is adapting a shortened injectable-free multidrug resistant tuberculosis (MDR-TB) regimen, comprising new drugs such as bedaquiline and delamanid and repurposed drugs such as clofazimine and linezolid. The regimen is implemented using a pragmatic prospective cohort study within the National TB and Leprosy Programme and is accompanied by a process evaluation. The process evaluation aims to unpack the implementation processes, their outcomes and the moderating factors in order to understand the clinical effectiveness of the regimen. This protocol describes the methods employed in understanding the implementation processes of the new MDR-TB regimen in 15 regions of Tanzania. METHODS: This study adopts a concurrent mixed-methods design. Using multiple data collection tools, we capture information on: implementation outcomes, stakeholder response to the intervention and the influence of contextual factors. Data will be collected from the 22 health facilities categorised as dispensaries, health centres, district hospitals and referral hospitals. Health workers (n=132) and patients (n=220) will fill a structured questionnaire. For each category of health facility, we will conduct five focus group discussions and in-depth interviews (n=45) for health workers. Participant observations (n=9) and review documents (n=22) will be conducted using structured checklists. Data will be collected at two points over a period of 1 year. We will analyse quantitative data using descriptive and inferential statistical methods. Thematic analysis will be used for qualitative data. ETHICS AND DISSEMINATION: This study received ethical approval from National Institute of Medical research (NIMR), Ref. NIMR/HQ/R.8a/Vol.IX/3269 and from the Mbeya Medical Research and Ethics Review Committee, Ref. SZEC-2439/R.A/V.I/38. Our findings are expected to inform the wider implementation of the new MDR-TB regimen as it is rolled out countrywide. Dissemination of findings will be through publications, conferences, workshops and implementation manuals for scaling up MDR-TB treatments.

Successful treatment of XDR-TB patient in Tanzania: report of the first XDR-TB patient.

Drug-resistant tuberculosis (TB) is emerging as a new and serious public health challenge. We present the first case with confirmed extensive drug-resistant TB in Tanzania in a patient who had prior exposure to anti-TB drugs and a history of imprisonment in South Africa. The addition of bedaquiline to the treatment regime resulted in positive to negative sputum conversion. After a total of 30 months on treatment he was declared cured, remaining clinically stable and culture-negative throughout the follow-up. Close monitoring is important in managing drug-resistant TB cases, and good surveillance is required to detect drug-resistant TB to prevent further transmission.

Gridlock from Diagnosis to Treatment of Multidrug-Resistant Tuberculosis (MDR-TB) in Tanzania: Illuminating Potential Factors for Possible Intervention.

SETTINGS: Kibong'oto Infectious Diseases Hospital, Kilimanjaro, Tanzania. OBJECTIVE: Characterise multidrug-resistant tuberculosis (MDR-TB)-treated cases during the scaling up of molecular diagnostics using Xpert MTB/RIF and GenoType MTBDRplus. DESIGN: Retrospective cohort study. RESULTS: A total of 223 MDR-TB patients were referred to the Kibong'oto Infectious Disease Hospital from January 2013 through December 2014. Four cities-Dar es Salaam, Mbeya, Mwanza, and Tanga-contributed 144 (65%) of referrals. Of the total referred patients, HIV coinfection was found in 92 (41%) and 180 (81%) had history of previous TB treatment. Molecular drug susceptibility testing (DST) contributed 201 (91%) of referrals and resulted in a shorter time from diagnosis to start of treatment, 30 days (95% confidence interval [CI], 26-37), compared to conventional phenotypic DST, 212 days (95% CI, 151-272; P<.001). Molecular DST found higher proportions of MDR-TB children and people living with HIV without prior treatment, 5 (12%) and 24 (56%), respectively, compared to those with previous treatment for TB, 4 (2%) and 68 (38%), respectively. The median CD4 count correspondingly was 131 cells/µl (IQR, 109-131) and 200 cells/µl (IQR, 94-337) for MDR-TB diagnosed by phenotypic and molecular diagnostics (P=.70). Despite the more rapid time to treatment initiation among patients diagnosed by molecular DST, treatment outcomes, including time to sputum culture conversion, did not differ compared to those diagnosed with conventional phenotypic DST. Regardless of the method of diagnosis, MDR-TB/HIV coinfected patients who died had lower CD4 counts (mean 86 ± 87 cells/µl) than survivors (mean 274 ± 224 cells/µl; P=.02). CONCLUSION: Molecular diagnostics appear to speedup the time to treatment initiation, but may not improve other treatment outcomes.

Efavirenz, tenofovir and emtricitabine combined with first-line tuberculosis treatment in tuberculosis-HIV-coinfected Tanzanian patients: a pharmacokinetic and safety study.

BACKGROUND: To evaluate the effect of rifampicin-based tuberculosis (TB) treatment on the pharmacokinetics of efavirenz/tenofovir/emtricitabine in a fixed-dose combination tablet, and vice versa, in Tanzanian TB-HIV-coinfected patients. METHODS: This was a Phase II open-label multiple dose pharmacokinetic and safety study. This study was conducted in TB-HIV-coinfected Tanzanian patients who started TB treatment (rifampicin/isoniazid/pyrazinamide/ethambutol) at week 1 to week 8 and continued with rifampicin and isoniazid for another 16 weeks. Antiretroviral treatment (ART) of efavirenz/tenofovir/emtricitabine in a fixed-dose combination tablet was started at week 4 after initiation of TB treatment. A 24-h pharmacokinetic sampling curve was recorded at week 8 (with TB treatment) and week 28 (ART alone). For TB drugs, blood samples at 2 and 5 h post-dose were taken at week 3 (TB treatment alone) and week 8 (with ART). RESULTS: A total of 25 patients (56% male) completed the study; 21 had evaluable pharmacokinetic profiles. The area under the concentration-time curve 0-24 h post-dose of efavirenz, tenofovir and emtricitabine were slightly higher when these drugs were coadministered with TB drugs; geometric mean ratios (90% CI) were 1.08 (0.90, 1.30), 1.13 (0.93, 1.38) and 1.05 (0.85, 1.29), respectively. For TB drugs, equivalence was suggested for peak plasma concentrations when administered with and without efavirenz/tenofovir/emtricitabine. Adverse events were mostly mild and no serious adverse events or drug discontinuations were reported. CONCLUSIONS: Coadministration of efavirenz, tenofovir and emtricitabine with a standard first-line TB treatment regimen did not significantly alter the pharmacokinetic parameters of these drugs and was tolerated well by Tanzanian TB patients who are coinfected with HIV.

Comparison of overnight pooled and standard sputum collection method for patients with suspected pulmonary tuberculosis in northern Tanzania.

In Tanzania sputum culture for tuberculosis (TB) is resource intensive and available only at zonal facilities. In this study overnight pooled sputum collection technique was compared with standard spot morning collection among pulmonary TB suspects at Kibong'oto National TB Hospital in Tanzania. A spot sputum specimen performed at enrollment, an overnight pooled sputum, and single morning specimen were collected from 50 subjects and analyzed for quality, quantity, and time to detection in Bactec MGIT system. Forty-six (92%) subjects' overnight pooled specimens had a volume ≥5 mls compared to 37 (37%) for the combination of spot and single morning specimens (P < 0.001). Median time to detection was 96 hours (IQR 87-131) for the overnight pooled specimens compared to 110.5 hours (IQR is 137 right 137-180) for the combination of both spot and single morning specimens (P = 0.001). In our setting of limited TB culture capacity, we recommend a single pooled sputum to maximize yield and speed time to diagnosis.