Pharmacokinetic-Pharmacodynamic Determinants of Clinical Outcomes for Rifampin-Resistant Tuberculosis: A Multisite Prospective Cohort Study.

BACKGROUND: Rifampin-resistant and/or multidrug-resistant tuberculosis (RR/MDR-TB) treatment requires multiple drugs, and outcomes remain suboptimal. Some drugs are associated with improved outcome. It is unknown whether particular pharmacokinetic-pharmacodynamic relationships predict outcome. METHODS: Adults with pulmonary RR/MDR-TB in Tanzania, Bangladesh, and the Russian Federation receiving local regimens were enrolled from June 2016 to July 2018. Serum was collected after 2, 4, and 8 weeks for each drug's area under the concentration-time curve over 24 hours (AUC0-24). Quantitative susceptibility of the M. tuberculosis isolate was measured by minimum inhibitory concentrations (MICs). Individual drug AUC0-24/MIC targets were assessed by adjusted odds ratios (ORs) for favorable treatment outcome, and hazard ratios (HRs) for time to sputum culture conversion. K-means clustering algorithm separated the cohort of the most common multidrug regimen into 4 clusters by AUC0-24/MIC exposures. RESULTS: Among 290 patients, 62 (21%) experienced treatment failure, including 30 deaths. Moxifloxacin AUC0-24/MIC target of 58 was associated with favorable treatment outcome (OR, 3.75; 95% confidence interval, 1.21-11.56; P = .022); levofloxacin AUC0-24/MIC of 118.3, clofazimine AUC0-24/MIC of 50.5, and pyrazinamide AUC0-24 of 379 mg × h/L were associated with faster culture conversion (HR >1.0, P < .05). Other individual drug exposures were not predictive. Clustering by AUC0-24/MIC revealed that those with the lowest multidrug exposures had the slowest culture conversion. CONCLUSIONS: Amidst multidrug regimens for RR/MDR-TB, serum pharmacokinetics and M. tuberculosis MICs were variable, yet defined parameters to certain drugs-fluoroquinolones, pyrazinamide, clofazimine-were predictive and should be optimized to improve clinical outcome. CLINICAL TRIALS REGISTRATION: NCT03559582.

Process evaluation for the adaptation, testing and dissemination of a mobile health platform to support people with HIV and tuberculosis in Irkutsk, Siberia.

OBJECTIVES: We developed and tested a mobile health-based programme to enhance integration of HIV and tuberculosis (TB) care and to promote a patient-centred approach in a region of high coinfection burden. Phases of programme development included planning, stakeholder interviews and platform re-build, testing and iteration. SETTING: In Irkutsk, Siberia, HIV/TB coinfection prevalence is high relative to the rest of the Russian Federation. PARTICIPANTS: Pilot testing occurred for a cohort of 60 people with HIV and TB. RESULTS: Key steps emerged to ensure the mobile health-based programme could be operational and adequately adapted for the context, including platform language adaptation, optimisation of server management, iteration of platform features, and organisational practice integration. Pilot testing of the platform rebuild yielded favourable patient perceptions of usability and acceptability at 6 months (n=47 surveyed), with 18 of 20 items showing scores above 4 (on a scale from 1 to 5) on average. Development of this mobile health-based programme for integrated care of infections highlighted the importance of several considerations for tailoring these interventions contextually, including language adaptation and technological capacity, but also, importantly, contextualised patient preferences related to privacy and communication with peers and/or providers, existing regional capacity for care coordination of different comorbidities, and infection severity and treatment requirements. CONCLUSIONS: Our experience demonstrated that integration of care for TB and HIV can be well served by using multimodal mobile health-based programmes, which can enhance communication and streamline workflow between providers across multiple collaborating institutions and improve continuity between inpatient and outpatient care settings. Further study of programme impact on contextual disease-related stigma and social isolation as well as evaluation of implementation on a broader scale for HIV care is currently under way. TRIAL REGISTRATION NUMBER: NCT03819374.

Implementation of a Mobile Health Strategy to Improve Linkage to and Engagement with HIV Care for People Living with HIV, Tuberculosis, and Substance Use in Irkutsk, Siberia.

In Irkutsk, Siberia, there is a high prevalence of HIV and tuberculosis (TB) coinfection. Mobile health (mHealth) strategies have shown promise for increasing linkage to and engagement in care for people living with HIV (PLWH) in other contexts. We evaluated outcomes for a cohort of PLWH, TB, and substance use in Irkutsk after participation in a multi-feature mHealth intervention called MOCT. Sixty patients were enrolled during hospitalization for TB. We evaluated participant app usage, linkage to HIV care postdischarge, perception of self-efficacy related to HIV care, and HIV-related clinical outcomes at 6 months. We also performed an exploratory analysis to compare a subset of 49 patients with a pre-intervention cohort matched for age and gender. Participants demonstrated engagement with app features examined at 6 months. The majority linked to HIV care by 6 months (83%). Self-scoring of confidence in ability to communicate with HIV providers improved from baseline (median score 8, scale 1-10) to 6 months (10, p = 0.004). A higher proportion of the MOCT subset refilled antiretroviral therapy (69% vs. 43% in pre-intervention cohort, p = 0.01), with fewer deaths in the MOCT subset at 6 months (1 death vs. 10 deaths in pre-intervention cohort, p = 0.02) and a decreased likelihood of developing the composite outcome of death/failure to achieve viral suppression at 6 months (adjusted odds ratio = 0.33, p = 0.029). This study demonstrates preliminary intervention uptake and improvement in short-term outcomes for an urban cohort of PLWH, TB, and substance use enrolled in a multi-feature mHealth intervention, a novel strategy for the context. Clinical Trial Registration Number: NCT03819374.

Urine colorimetry for levofloxacin pharmacokinetics and personalized dosing in people with drug-resistant tuberculosis.

Background: Levofloxacin is a preferred drug for multidrug-resistant (MDR)-tuberculosis (TB) with bactericidal activity that correlates with the pharmacokinetic exposures of serum peak concentration (Cmax) and total area under the concentration time curve (AUC0-24). Pharmacokinetic exposures can be measured to personalize dosing to reach targets, but this practice requires venepuncture, chromatographic or mass spectrometry equipment, and technical expertise. We sought to demonstrate the accuracy of using urine colorimetry as a more feasible estimation of levofloxacin exposure. Method: A colorimetric method using bromocresol green was tested on spiked urine samples with levofloxacin measured using a spectrophotometer. This method was tested in urine samples of healthy volunteers given one 750 mg dose of levofloxacin with urine collected at 0-4 h, 4-8 h, and 8-24 h intervals, and concomitant serum samples were collected and analyzed by high-performance liquid chromatography. Validation of this assay was done in a cohort of people living with human immunodeficiency virus (PLWH), initiating a levofloxacin containing MDR-TB regimen. Results: Urine colorimetry was reproducible in spiked samples and the calibration was curve linear for levofloxacin concentrations ranging from 7.8 µg/ml to 250 µg/ml, with r = 0.98. In healthy volunteers, correlation between urine absorbance values and serum AUC0-24 was highest in urine collected between 4 and 8 h (r = 0.91, P = 0.01), yet in PLWH, urine collected between 0 and 4 h had highest correlation (r = 0.66, P = 0.05). The area under the receiver operating characteristics curve was >0.8 in the derivation, as well as the validation cohort for the urine absorbance values identifying people with total serum exposure below target. Conclusion: Urine colorimetry was highly sensitive in predicting target serum concentrations. Colorimetric methods to determine levofloxacin in urine may improve the feasibility of therapeutic drug monitoring and personalized dose adjustment in TB endemic settings.