Electronic pillbox-enabled self-administered therapy versus standard directly observed therapy for tuberculosis medication adherence and treatment outcomes in Ethiopia (SELFTB): protocol for a multicenter randomized controlled trial.

BACKGROUND: To address the multifaceted challenges associated with tuberculosis (TB) in-person directly observed therapy (DOT), the World Health Organization recently recommended that countries maximize the use of digital adherence technologies. Sub-Saharan Africa needs to investigate the effectiveness of such technologies in local contexts and proactively contribute to global decisions around patient-centered TB care. This study aims to evaluate the effectiveness of pillbox-enabled self-administered therapy (SAT) compared to standard DOT on adherence to TB medication and treatment outcomes in Ethiopia. It also aims to assess the usability, acceptability, and cost-effectiveness of the intervention from the patient and provider perspectives. METHODS: This is a multicenter, randomized, controlled, open-label, superiority, effectiveness-implementation hybrid, mixed-methods, two-arm trial. The study is designed to enroll 144 outpatients with new or previously treated, bacteriologically confirmed, drug-sensitive pulmonary TB who are eligible to start the standard 6-month first-line anti-TB regimen. Participants in the intervention arm (n = 72) will receive 15 days of HRZE-isoniazid, rifampicin, pyrazinamide, and ethambutol-fixed-dose combination therapy in the evriMED500 medication event reminder monitor device for self-administration. When returned, providers will count any remaining tablets in the device, download the pill-taking data, and refill based on preset criteria. Participants can consult the provider in cases of illness or adverse events outside of scheduled visits. Providers will handle participants in the control arm (n = 72) according to the standard in-person DOT. Both arms will be followed up throughout the 2-month intensive phase. The primary outcomes will be medication adherence and sputum conversion. Adherence to medication will be calculated as the proportion of patients who missed doses in the intervention (pill count) versus DOT (direct observation) arms, confirmed further by IsoScreen urine isoniazid test and a self-report of adherence on eight-item Morisky Medication Adherence Scale. Sputum conversion is defined as the proportion of patients with smear conversion following the intensive phase in intervention versus DOT arms, confirmed further by pre-post intensive phase BACTEC MGIT TB liquid culture. Pre-post treatment MGIT drug susceptibility testing will determine whether resistance to anti-TB drugs could have impacted culture conversion. Secondary outcomes will include other clinical outcomes (treatment not completed, death, or loss to follow-up), cost-effectiveness-individual and societal costs with quality-adjusted life years-and acceptability and usability of the intervention by patients and providers. DISCUSSION: This study will be the first in Ethiopia, and of the first three in sub-Saharan Africa, to determine whether electronic pillbox-enabled SAT improves adherence to TB medication and treatment outcomes, all without affecting the inherent dignity and economic wellbeing of patients with TB. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04216420. Registered on 2 January 2020.

Mentoring in Global Health: Formative Evaluation of Tuberculosis Research Training Programs in Ethiopia and Georgia.

Mentoring is a critical component of career development for research scientists and is related to mentee success both in terms of career selection and advancement. However, there are limited data on the role of mentoring in low- and middle-income countries (LMICs). Cross-cultural mentorship programs have the potential to foster the transfer of knowledge and the development of capacity to resource-poor settings. This formative evaluation explores the cultural context of mentoring in the countries of Georgia and Ethiopia. Results were used to build culturally relevant mentor training programs for two Global Infectious Disease Research Training Programs focused on tuberculosis funded by the Fogarty International Center at the US National Institutes of Health. Four focus group discussions were conducted with research trainees and mentors to explore the perceptions of mentorship, identify obstacles for successful mentoring, and generate recommendations to strengthen mentoring in each program situated in a LMIC. Data revealed the barriers to mentoring in Ethiopia and Georgia included gaps in knowledge about mentoring roles and responsibilities, lack of knowledge about the responsibilities of the trainee in a mentoring relationship, and the need to set clear expectations between mentors and trainees. All of the focus group participants desired formal mentor training. These data informed six key components of the development and implementation of the mentor training programs in both countries. The topics included the following: a foundation in mentoring, establishing expectations between mentees and mentors, increasing interactions between mentees and mentors, additional mentor training, a case study curriculum, and methods of evaluating mentoring relationships.

Cost-effectiveness of WHO-Recommended Algorithms for TB Case Finding at Ethiopian HIV Clinics.

BACKGROUND: The World Health Organization (WHO) recommends active tuberculosis (TB) case finding and a rapid molecular diagnostic test (Xpert MTB/RIF) to detect TB among people living with HIV (PLHIV) in high-burden settings. Information on the cost-effectiveness of these recommended strategies is crucial for their implementation. METHODS: We conducted a model-based cost-effectiveness analysis comparing 2 algorithms for TB screening and diagnosis at Ethiopian HIV clinics: (1) WHO-recommended symptom screen combined with Xpert for PLHIV with a positive symptom screen and (2) current recommended practice algorithm (CRPA; based on symptom screening, smear microscopy, and clinical TB diagnosis). Our primary outcome was US$ per disability-adjusted life-year (DALY) averted. Secondary outcomes were additional true-positive diagnoses, and false-negative and false-positive diagnoses averted. RESULTS: Compared with CRPA, combining a WHO-recommended symptom screen with Xpert was highly cost-effective (incremental cost of $5 per DALY averted). Among a cohort of 15 000 PLHIV with a TB prevalence of 6% (900 TB cases), this algorithm detected 8 more true-positive cases than CRPA, and averted 2045 false-positive and 8 false-negative diagnoses compared with CRPA. The WHO-recommended algorithm was marginally costlier ($240 000) than CRPA ($239 000). In sensitivity analysis, the symptom screen/Xpert algorithm was dominated at low Xpert sensitivity (66%). CONCLUSIONS: In this model-based analysis, combining a WHO-recommended symptom screen with Xpert for TB diagnosis among PLHIV was highly cost-effective ($5 per DALY averted) and more sensitive than CRPA in a high-burden, resource-limited setting.

Improving clinical and translational research training: a qualitative evaluation of the Atlanta Clinical and Translational Science Institute KL2-mentored research scholars program.

A major impediment to improving the health of communities is the lack of qualified clinical and translational research (CTR) investigators. To address this workforce shortage, the National Institutes of Health (NIH) developed mechanisms to enhance the career development of CTR physician, PhD, and other doctoral junior faculty scientists including the CTR-focused K12 program and, subsequently, the KL2-mentored CTR career development program supported through the Clinical and Translational Science Awards (CTSAs). Our evaluation explores the impact of the K12/KL2 program embedded within the Atlanta Clinical and Translational Science Institute (ACTSI), a consortium linking Emory University, Morehouse School of Medicine and the Georgia Institute of Technology. We conducted qualitative interviews with program participants to evaluate the impact of the program on career development and collected data on traditional metrics (number of grants, publications). 46 combined K12/KL2 scholars were supported between 2002 and 2016. 30 (65%) of the 46 K12/KL2 scholars are women; 24 (52%) of the trainees are minorities, including 10 (22%) scholars who are members of an underrepresented minority group. Scholars reported increased research skills, strong mentorship experiences, and positive impact on their career trajectory. Among the 43 scholars who have completed the program, 39 (91%) remain engaged in CTR and received over $89 000 000 as principal investigators on federally funded awards. The K12/KL2 funding provided the training and protected time for successful career development of CTR scientists. These data highlight the need for continued support for CTR training programs for junior faculty.

Cost analysis of a nucleic acid amplification test in the diagnosis of pulmonary tuberculosis at an urban hospital with a high prevalence of TB/HIV.

INTRODUCTION: The Centers for Disease Control and Prevention has recommended using a nucleic acid amplification test (NAAT) for diagnosing pulmonary tuberculosis (TB) but there is a lack of data on NAAT cost-effectiveness. METHODS: We conducted a prospective cohort study that included all patients with an AFB smear-positive respiratory specimen at Grady Memorial Hospital in Atlanta, GA, USA between January 2002 and June 2008. We determined the sensitivity, specificity, and positive and negative predictive value of a commercially available and FDA-approved NAAT (amplified MTD, Gen-Probe) compared to the gold standard of culture. A cost analysis was performed and included costs related to laboratory tests, hospital charges, anti-TB medications, and contact investigations. Average cost per patient was calculated under two conditions: (1) using a NAAT on all AFB smear-postive respiratory specimens and (2) not using a NAAT. One-way sensitivity analyses were conducted to determine sensitivity of cost difference to reasonable ranges of model inputs. RESULTS: During a 6 1/2 year study period, there were 1,009 patients with an AFB smear-positive respiratory specimen at our public urban hospital. We found the NAAT to be highly sensitive (99.6%) and specific (99.1%) on AFB smear-positive specimens compared to culture. Overall, the positive predictive value (PPV) of an AFB smear-positive respiratory specimen for culture-confirmed TB was 27%. The PPV of an AFB smear-positive respiratory specimen for culture-confirmed TB was significantly higher for HIV-uninfected persons compared to those who were HIV-seropositive (152/271 [56%] vs. 85/445 [19%]; RR = 2.94, 95% CI 2.36-3.65, p<0.001). The cost savings of using the NAAT was $2,003 per AFB smear-positive case. CONCLUSIONS: Routine use of the NAAT on AFB smear-positive respiratory specimens was highly cost-saving in our setting at a U.S. urban public hospital with a high prevalence of TB and HIV because of the low PPV of an AFB smear for culture-confirmed TB.

The health-system benefits and cost-effectiveness of using Mycobacterium tuberculosis direct nucleic acid amplification testing to diagnose tuberculosis disease in the United States.

BACKGROUND: The utility of Mycobacterium tuberculosis direct nucleic acid amplification testing (MTD) for pulmonary tuberculosis disease diagnosis in the United States has not been well described. METHODS: We analyzed a retrospective cohort of reported patients with suspected active pulmonary tuberculosis in 2008-2010 from Georgia, Hawaii, Maryland, and Massachusetts to assess MTD use, effectiveness, health-system benefits, and cost-effectiveness. RESULTS: Among 2140 patients in whom pulmonary tuberculosis was suspected, 799 (37%) were M. tuberculosis-culture-positive. Eighty percent (680/848) of patients having acid-fast-bacilli-smear-positive specimens had MTD performed; MTD positive-predictive value (PPV) was 98% and negative-predictive value (NPV) was 94%. Nineteen percent (240/1292) of patients having smear-negative specimens had MTD; MTD PPV was 90% and NPV was 88%. Among patients suspected of tuberculosis but not having MTD, smear PPV for lab-confirmed tuberculosis was 77% and NPV 78%. Compared with no MTD, MTD significantly decreased time to diagnosis in patients with smear-positive/MTD-positive specimens, decreased respiratory isolation for patients having smear-positive/MTD-negative/culture-negative specimens, decreased outpatient days of unnecessary tuberculosis medications, and reduced resources expended on contact investigation. While MTD generally cost more than no MTD, incremental cost savings occurred in patients with human immunodeficiency virus (HIV) or homelessness to diagnose or to exclude tuberculosis, and in patients with substance abuse having smear-negative specimens to exclude tuberculosis. CONCLUSIONS: MTD improved diagnostic accuracy and timeliness and reduced unnecessary respiratory isolation, treatment, and contact investigations. It was cost saving in patients with HIV, homelessness, or substance abuse, but not in others.

A culture-specific nutrient intake assessment instrument in patients with pulmonary tuberculosis.

BACKGROUND & AIM: To develop and evaluate a culture-specific nutrient intake assessment tool for use in adults with pulmonary tuberculosis (TB) in Tbilisi, Georgia. METHODS: We developed an instrument to measure food intake over 3 consecutive days using a questionnaire format. The tool was then compared to 24 h food recalls. Food intake data from 31 subjects with TB were analyzed using the Nutrient Database System for Research (NDS-R) dietary analysis program. Paired t-tests, Pearson correlations and intraclass correlation coefficients (ICC) were used to assess the agreement between the two methods of dietary intake for calculated nutrient intakes. RESULTS: The Pearson correlation coefficient for mean daily caloric intake between the 2 methods was 0.37 (P = 0.04) with a mean difference of 171 kcals/day (p = 0.34). The ICC was 0.38 (95% CI: 0.03-0.64) suggesting the within-patient variability may be larger than between-patient variability. Results for mean daily intake of total fat, total carbohydrate, total protein, retinol, vitamins D and E, thiamine, calcium, sodium, iron, selenium, copper, and zinc between the two assessment methods were also similar. CONCLUSIONS: This novel nutrient intake assessment tool provided quantitative nutrient intake data from TB patients. These pilot data can inform larger studies in similar populations.

Exposure to tuberculosis among newborns in a nursery: decision analysis for initiation of prophylaxis.

OBJECTIVE: Newborns in a hospital nursery were exposed to a mother whose sputum was direct-smear negative for acid-fast bacilli but culture positive for Mycobacterium tuberculosis. Given the low risk for exposure, the high susceptibility of infants to M. tuberculosis infection, and the possibility of hepatotoxicity due to isoniazid therapy, a decision analysis model was used to determine whether administration of isoniazid prophylaxis against tuberculosis is preferable to no administration of prophylaxis. DESIGN: A decision analysis tree was constructed with software, using probabilities from the literature and costs from local health facilities. The expected values for each strategy were obtained, and sensitivity analyses were performed. RESULTS: For the strategy in which prophylaxis was administered under direct observation (DO), the probability for survival was 0.999980. For the strategy in which no prophylaxis was administered, the probability of survival was 0.999950, which corresponds to 3 more deaths per 100,000 patients than with the DO prophylaxis strategy. The incremental cost-effectiveness of the DO prophylaxis strategy was 21,710,000 US dollars per death prevented. Sensitivity analysis for survival showed that the DO prophylaxis strategy was preferable to the strategy in which no prophylaxis is given if the probability of infection was >0.0002, the probability of tuberculous disease in an infected infant who did not receive prophylaxis was greater than 0.12, the probability of dying from tuberculosis was greater than 0.025, the probability of hepatotoxicity was less than 0.004, and the probability of dying from hepatotoxicity was less than 0.04. For the strategy in which prophylaxis was administered under non-DO conditions (ie, by parents), the incremental cost-effectiveness was 929,500 US dollars per death prevented, which is approximately 5% of the incremental cost-effectiveness of the DO prophylaxis strategy. CONCLUSION: This model provides a structure for determining the preferable prophylaxis strategies for different risks of exposure to tuberculosis in a nursery. Administration of prophylaxis is preferable to no administration of prophylaxis, unless the probability of infection is extremely low.

Pre-event willingness to receive smallpox vaccine among physicians and public safety personnel.

BACKGROUND: Planning for voluntary smallpox vaccination of health and safety officials began in December 2002. MATERIALS AND METHODS: Surveys were conducted among physicians and fire and police department personnel in Atlanta, Georgia. Information on demographics, willingness to receive smallpox vaccine, self-reported knowledge level, and potential vaccine contraindications was analyzed. RESULTS: Forty-one percent of physicians (n = 199) were undecided on vaccination (32% would receive vaccine and 27% would not). Forty-eight percent of firefighters (n = 343) and 41% of police (n = 466) were undecided; 23% and 41% would receive vaccine, whereas 28% and 18% would not (fire and police, respectively). Absence of contraindications was associated with physicians' willingness to be vaccinated (P = 0.006). Many physicians (66%) and most public safety personnel (88%) considered themselves inadequately informed on smallpox vaccine. In a multivariate analysis, inadequately informed respondents were more likely to be undecided (OR = 2.23, CI = 1.39 to 3.56). CONCLUSIONS: Before implementation of the smallpox vaccination program, self-assessed knowledge about smallpox disease and vaccine were poor.