Hair isoniazid levels predict TB sputum culture conversion.

Sputum culture is the gold standard for diagnosing TB disease and confirming treatment outcomes. However, the turnaround time is 6-8 weeks, which leads to delays in decision-making regarding the care of TB patients.To evaluate isoniazid hair drug levels as a predictor of sputum culture conversion at 8 weeks of TB treatment.

Risk-stratified treatment for drug-susceptible pulmonary tuberculosis.

The Phase 3 randomized controlled trial, TBTC Study 31/ACTG A5349 (NCT02410772) demonstrated that a 4-month rifapentine-moxifloxacin regimen for drug-susceptible pulmonary tuberculosis was safe and effective. The primary efficacy outcome was 12-month tuberculosis disease free survival, while the primary safety outcome was the proportion of grade 3 or higher adverse events during the treatment period. We conducted an analysis of demographic, clinical, microbiologic, radiographic, and pharmacokinetic data and identified risk factors for unfavorable outcomes and adverse events.

Pyrazinamide Safety, Efficacy, and Dosing for Treating Drug-Susceptible Pulmonary Tuberculosis: A Phase 3, Randomized Controlled Clinical Trial.

Optimizing pyrazinamide dosing is critical to improve treatment efficacy while minimizing toxicity during tuberculosis treatment. Study 31/AIDS Clinical Trials Group A5349 represents the largest phase 3 randomized controlled therapeutic trial to date for such an investigation. We sought to report pyrazinamide pharmacokinetic parameters, risk factors for lower pyrazinamide exposure, and relationships between pyrazinamide exposure and efficacy and safety outcomes.

Isoniazid hair drug levels among TB patients as a tool to monitor adherence, exposure, and TB treatment outcomes and its acceptability in a multicultural setting. A narrative review.

Background: Accumulation of chemicals including drugs in hair has been used in forensic investigations. Studies have reported isoniazid drug levels in the hair of TB patients.

Objective: To review literature for evidence on isoniazid hair drug levels as a tool to monitor adherence, exposure, and TB treatment outcomes and the acceptability of using human hair for medical testing.

Preferred techniques of hair harvest for medical testing among adult pulmonary TB patients.

Background: Antiretroviral hair drug levels are currently being used to monitor adherence to HIV treatment. There is currently a dearth of literature on the preferred technique(s) of hair harvest for medical testing in the context of African multicultural settings.

Objective: To explore the preferred techniques(s) of hair harvest for medical testing among TB patients.

Acceptability of hair harvest as a method of tuberculosis therapeutic drug monitoring among adult pulmonary TB patients: a qualitative study.

Background: The current six months regimen for drug-susceptible tuberculosis (TB) is long, complex, and requires adherence monitoring. TB hair drug level assay is one innovative approach to monitor TB treatment adherence however, its acceptability in the context of African multi-cultural settings is not known.

Objective: To determine the acceptability of hair harvest and testing as a TB therapeutic drug monitoring method.

Facilitators and barriers to adolescent participation in a TB clinical trial.

The inclusion of adolescents in TB drug trials is essential for the development of safe, child-friendly regimens for the prevention and treatment of TB. TB Trials Consortium Study 31/AIDS Clinical Trials Group A5349 (S31/A5349) enrolled adolescents as young as 12 years old. We assessed investigator and coordinator described facilitators and barriers to adolescent recruitment, enrollment, and retention.

Childhood growth during recovery from acute illness in Africa and South Asia: a secondary analysis of the childhood acute illness and nutrition (CHAIN) prospective cohort.

Background: Growth faltering is well-recognized during acute childhood illness and growth acceleration during convalescence, with or without nutritional therapy, may occur. However, there are limited recent data on growth after hospitalization in low- and middle-income countries.

Methods: We evaluated growth following hospitalization among children aged 2-23 months in sub-Saharan Africa and South Asia.

Pharmacokinetic-Pharmacodynamic Evidence From a Phase 3 Trial to Support Flat-Dosing of Rifampicin for Tuberculosis.

Background: The optimal dosing strategy for rifampicin in treating drug-susceptible tuberculosis (TB) is still highly debated. In the phase 3 clinical trial Study 31/ACTG 5349 (NCT02410772), all participants in the control regimen arm received 600 mg rifampicin daily as a flat dose. Here, we evaluated relationships between rifampicin exposure and efficacy and safety outcomes.

Perceptions about and reasons for participation in research bronchoscopy in Uganda: A qualitative analysis.

This study sought to assess perceptions towards and reasons for participation in research bronchoscopy studies in a high TB burden urban setting. Additionally, the study aimed to identify areas of pre- and post-procedural concern among healthy adults approached to participate in research bronchoscopy. A cross sectional qualitative study was undertaken at the Uganda-Case Western Reserve University Collaboration Tuberculosis Research Project Clinic at Mulago National Referral Hospital in Kampala, Uganda.

Neurodevelopment and Recovery From Wasting.

Background And Objectives: Acute illness with malnutrition is a common indication for hospitalization among children in low- and middle-income countries. We investigated the association between wasting recovery trajectories and neurodevelopmental outcomes in young children 6 months after hospitalization for an acute illness.

Methods: Children aged 2 to 23 months were enrolled in a prospective observational cohort of the Childhood Acute Illness & Nutrition Network, in Uganda, Malawi, and Pakistan between January 2017 and January 2019.

Rifapentine With and Without Moxifloxacin for Pulmonary Tuberculosis in People With Human Immunodeficiency Virus (S31/A5349).

Background: Tuberculosis (TB) Trials Consortium Study 31/AIDS Clinical Trials Group A5349, an international randomized open-label phase 3 noninferiority trial showed that a 4-month daily regimen substituting rifapentine for rifampin and moxifloxacin for ethambutol had noninferior efficacy and was safe for the treatment of drug-susceptible pulmonary TB (DS-PTB) compared with the standard 6-month regimen. We explored results among the prespecified subgroup of people with human immunodeficiency virus (HIV) (PWH).

Methods: PWH and CD4+ counts ≥100 cells/μL were eligible if they were receiving or about to initiate efavirenz-based antiretroviral therapy (ART).

Toll-Like Receptor-Induced Immune Responses During Early Childhood and Their Associations With Clinical Outcomes Following Acute Illness Among Infants in Sub-Saharan Africa.

Severely ill children in low- and middle-income countries (LMICs) experience high rates of mortality from a broad range of infectious diseases, with the risk of infection-related death compounded by co-existing undernutrition. How undernutrition and acute illness impact immune responses in young children in LMICs remains understudied, and it is unclear what aspects of immunity are compromised in this highly vulnerable population. To address this knowledge gap, we profiled longitudinal whole blood cytokine responses to Toll-like receptor (TLR) ligands among severely ill children (n=63; 2-23 months old) with varied nutritional backgrounds, enrolled in the CHAIN Network cohort from Kampala, Uganda, and Kilifi, Kenya, and compared these responses to similar-aged well children in local communities (n=41).

Efavirenz Pharmacokinetics and Human Immunodeficiency Virus Type 1 (HIV-1) Viral Suppression Among Patients Receiving Tuberculosis Treatment Containing Daily High-Dose Rifapentine.

Background: A 4-month regimen containing rifapentine and moxifloxacin has noninferior efficacy compared to the standard 6-month regimen for drug-sensitive tuberculosis. We evaluated the effect of regimens containing daily, high-dose rifapentine on efavirenz pharmacokinetics and viral suppression in patients with human immunodeficiency virus (HIV)-associated tuberculosis (TB).

Methods: In the context of a Phase 3 randomized controlled trial, HIV-positive individuals already virally suppressed on efavirenz--containing antiretroviral therapy (ART) (EFV1), or newly initiating efavirenz (EFV2) received TB treatment containing rifapentine (1200 mg), isoniazid, pyrazinamide, and either ethambutol or moxifloxacin.

Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis.

Background: Rifapentine-based regimens have potent antimycobacterial activity that may allow for a shorter course in patients with drug-susceptible pulmonary tuberculosis.

Methods: In an open-label, phase 3, randomized, controlled trial involving persons with newly diagnosed pulmonary tuberculosis from 13 countries, we compared two 4-month rifapentine-based regimens with a standard 6-month regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (control) using a noninferiority margin of 6.6 percentage points.

Immune cells in bronchoalveolar lavage fluid of Ugandan adults who resist versus those who develop latent Mycobacterium tuberculosis infection.

Background: The search for immune correlates of protection against Mycobacterium tuberculosis (MTB) infection in humans is limited by the focus on peripheral blood measures. Bronchoalveolar lavage (BAL) can safely be done and provides insight into cellular function in the lung where infection is first established. In this study, blood and lung samples were assayed to determine if heavily MTB exposed persons who resist development of latent MTB infection (RSTR) vs those who develop latent MTB infection (LTBI), differ in the make-up of resident BAL innate and adaptive immune cells.

Optimizing drug inventory management with a web-based information system: The TBTC Study 31/ACTG A5349 experience.

Introduction: Efficient management of study drug inventory shipments is critical to keep research sites enrolling into multisite clinical treatment trials. A standard manual drug-management process used by the Tuberculosis Trials Consortium (TBTC), did not accommodate import permit approval timelines, shipment transit-times and time-zone differences. We compared a new web-based solution with the manual process, during an international 34-site clinical trial conducted by the TBTC and the AIDS Clinical Trials Group (ACTG); TBTC Study 31/ACTG A5349.

Central monitoring in a randomized, open-label, controlled phase 3 clinical trial for a treatment-shortening regimen for pulmonary tuberculosis.

Introduction: With the growing use of online study management systems and rapid availability of data, timely data review and quality assessments are necessary to ensure proper clinical trial implementation. In this report we describe central monitoring used to ensure protocol compliance and accurate data reporting, implemented during a large phase 3 clinical trial.

Material And Methods: The Tuberculosis Trials Consortium (TBTC) Study 31/AIDS Clinical Trials Group (ACTG) study A5349 (S31) is an international, multi-site, randomized, open-label, controlled, non-inferiority phase 3 clinical trial comparing two 4-month regimens to a standard 6 month regimen for treatment of drug-susceptible tuberculosis (TB) among adolescents and adults with a sample size of 2500 participants.

Hyperglycemia in severe traumatic brain injury patients and its association with thirty-day mortality: a prospective observational cohort study in Uganda.

Background: Traumatic brain injury (TBI) is a growing public health concern that can be complicated with an acute stress response. This response may be assessed by monitoring blood glucose levels but this is not routine in remote settings. There is a paucity of data on the prevalence of hyperglycemia and variables associated with mortality after severe TBI in Uganda.

Decreased plasma rifapentine concentrations associated with AADAC single nucleotide polymorphism in adults with tuberculosis.

Background: Rifapentine exposure is associated with bactericidal activity against Mycobacterium tuberculosis, but high interindividual variation in plasma concentrations is encountered.

Objectives: To investigate a genomic association with interindividual variation of rifapentine exposure, SNPs of six human genes involving rifamycin metabolism (AADAC, CES2), drug transport (SLCO1B1, SLCO1B3) and gene regulation (HNF4A, PXR) were evaluated.

Methods: We characterized these genes in 173 adult participants in treatment trials of the Tuberculosis Trials Consortium.