Directly observed therapy to measure adherence to tuberculosis medication in observational research: Protocol for a prospective cohort study

Background: A major challenge for prospective, clinical tuberculosis (TB) research is accurately defining a metric for measuring medication adherence. Objective: We aimed to design a method to capture directly observed therapy (DOT) via mobile health carried out by community workers. The program was created specifically to measure TB medication adherence for a prospective TB cohort in Western Cape Province, South Africa. Methods: Community workers collect daily adherence data on mobile smartphones. Participant-level adherence, program-level adherence, and program function are systematically monitored to assess DOT program implementation. A data dashboard allows for regular visualization of indicators. Numerous design elements aim to prevent or limit data falsification and ensure study data integrity. Results: The cohort study is ongoing and data collection is in progress. Enrollment began on May 16, 2017, and as of January 12, 2021, a total of 236 participants were enrolled. Adherence data will be used to analyze the study’s primary aims and to investigate adherence as a primary outcome. Conclusions: The DOT program includes a mobile health application for data collection as well as a monitoring framework and dashboard. This approach has potential to be adapted for other settings to improve the capture of medication adherence in clinical TB research

Methods for handling missing data in serially sampled sputum specimens for mycobacterial culture conversion calculation

Background: The occurrence and timing of mycobacterial culture conversion is used as a proxy for tuberculosis treatment response. When researchers serially sample sputum during tuberculosis studies, contamination or missed visits leads to missing data points. Traditionally, this is managed by ignoring missing data or simple carry-forward techniques. Statistically advanced multiple imputation methods potentially decrease bias and retain sample size and statistical power. Methods: We analyzed data from 261 participants who provided weekly sputa for the first 12 weeks of tuberculosis treatment. We compared methods for handling missing data points in a longitudinal study with a time-to-event outcome. Our primary outcome was time to culture conversion, defined as two consecutive weeks with no Mycobacterium tuberculosis growth. Methods used to address missing data included: 1) available case analysis, 2) last observation carried forward, and 3) multiple imputation by fully conditional specification. For each method, we calculated the proportion culture converted and used survival analysis to estimate Kaplan-Meier curves, hazard ratios, and restricted mean survival times. We compared methods based on point estimates, confidence intervals, and conclusions to specific research questions. Results: The three missing data methods lead to differences in the number of participants achieving conversion; 78 (32.8%) participants converted with available case analysis, 154 (64.7%) converted with last observation carried forward, and 184 (77.1%) converted with multiple imputation. Multiple imputation resulted in smaller point estimates than simple approaches with narrower confidence intervals. The adjusted hazard ratio for smear negative participants was 3.4 (95% CI 2.3, 5.1) using multiple imputation compared to 5.2 (95% CI 3.1, 8.7) using last observation carried forward and 5.0 (95% CI 2.4, 10.6) using available case analysis. Conclusion: We showed that accounting for missing sputum data through multiple imputation, a statistically valid approach under certain conditions, can lead to different conclusions than naïve methods. Careful consideration for how to handle missing data must be taken and be pre-specified prior to analysis. We used data from a TB study to demonstrate these concepts, however, the methods we described are broadly applicable to longitudinal missing data. We provide valuable statistical guidance and code for researchers to appropriately handle missing data in longitudinal studies

Alcohol and tobacco use in a tuberculosis treatment cohort during South Africa’s covid-19 sales bans: A case series

Background: South Africa temporarily banned alcohol and tobacco sales for about 20 weeks during the COVID-19 lockdown. We described changes in alcohol and tobacco consumption after implementation of these restrictions among a small number of participants in a tuberculosis treatment cohort. Method: The timeline follow-back procedure and Fägerstrom test for nicotine dependence was used to collect monthly alcohol and tobacco use information. We report changes in heavy drinking days (HDD), average amount of absolute alcohol (AA) consumed per drinking day, and cigarettes smoked daily during the alcohol and tobacco ban compared to use prior to the ban. Results: Of the 61 participants for whom we have pre-ban and within-ban alcohol use information, 17 (27.9%) reported within-ban alcohol use. On average, participants reported one less HDD per fortnight (interquartile range (IQR): −4, 1), but their amount of AA consumed increased by 37.4 g per drinking occasion (IQR: −65.9 g, 71.0 g). Of 53 participants who reported pre-ban tobacco use, 17 (32.1%) stopped smoking during the ban. The number of participants smoking >10 cigarettes per day decreased from 8 to 1. Conclusions: From these observations, we hypothesize that policies restricting alcohol and tobacco availability seem to enable some individuals to reduce their consumption. However, these appear to have little effect on the volume of AA consumed among individuals with more harmful patterns of drinking in the absence of additional behavior change interventions

Clinical and laboratory findings of disseminated Mycobacterium avium complex infection (DMAC) in a pair matched case-control study Manifestações clínicas e laboratoriais da infecção disseminada pelo complexo Mycobacterium avium (DMAC) em um estudo caso/controle pareado

A pair matched case/control study was conducted from January 1991 to 30 June 1992 in order to define clinical and laboratory findings associated with DMAC infection in AIDS patients. Since DMAC infection is usually associated with advanced immunodeficiency, and therefore also with other opportunistic illnesses, in addition to the number of CD4+ lymphocytes, cases and controls were matched using the following criteria: date of AIDS diagnosis and antiretroviral therapy, number and severity of associated opportunistic infections and, whenever possible, type of Pneumocystis carinii prophylaxis, age and gender, in this order of relevance. Cases (defined as patients presenting at least one positive culture for MAC at a normally sterile site) and controls presented CD4+ lymphocyte counts below 50 cel/mm3. A significantly higher prevalence of general, digestive and respiratory signs, increased LDH levels, low hemoglobin levels and CD4+ cell counts were recorded for cases when compared to controls. Increases in <FONT FACE="Symbol">g</font>GT and alkaline phosphatase levels seen in cases were also recorded for controls. In conclusion, the strategy we used for selecting controls allowed us to detect laboratory findings associated to DMAC infection not found in other advanced immunossupressed AIDS patients without DMAC.<br>Um estudo caso/controle pareado foi realizado no período compreendido entre janeiro de 1991 e junho de 1992, a fim de determinar a associação de manifestações clínicas e laboratoriais com a DMAC em pacientes com AIDS. Como a DMAC é habitualmente associada com imunodeficiência avançada e portanto também com outras doenças oportunistas, além do número de linfócitos CD4+, casos e controles foram pareados utilizando-se os seguintes critérios: data do diagnóstico de AIDS e terapêutica anti-retroviral, número e gravidade das infecções oportunistas associadas e quando possível, tipo de profilaxia para Pneumocystis carinii, idade e sexo, nesta ordem de importância. Os casos (definidos como pacientes que apresentaram ao menos uma cultura positiva para MAC em sítio normalmente estéril) e controles apresentaram contagem de linfócitos CD4+ abaixo de 50/mm3. Uma prevalência significativamente alta de sinais gerais digestivos e respiratórios, elevação nos níveis de DHL, níveis baixos de hemoglobina e células CD4+ foi observada nos casos comparados aos controles. A elevação da <FONT FACE="Symbol">g</font>GT e fosfatase alcalina observada nos casos foram também observadas nos controles. Em conclusão, a estratégia utilizada por nós para selecionar os controles nos permitiu detectar exames laboratoriais associados à DMAC não observadas em outros pacientes com AIDS e imunossupressão avançada sem DMAC