Understanding the impact of pandemics on long-term medication adherence: directly observed therapy in a tuberculosis treatment cohort pre- and post-COVID-19 lockdowns.

BACKGROUND: The COVID-19 pandemic negatively impacted tuberculosis (TB) treatment services, including directly observed therapy (DOT) programs used to promote medication adherence. We compared DOT adherence embedded in a research study before and after COVID-19 lockdowns in South Africa. METHODS: We analyzed data from 263 observational study participants undergoing drug susceptible (DS)-TB DOT between May 2017 to March 2022. Participants enrolled before October 2019 were considered 'pre-COVID-19' and those enrolled after September 2020 were considered 'post-COVID-19 lockdown groups. Negative binomial regression models were used to compare DOT non-adherence rates between the two lockdown groups. We then conducted a sensitivity analysis which only included participants enrolled in the immediate period following the first COVID-19 lockdown. RESULTS: DOT non-adherence rate was higher in the post-COVID-19 lockdown group (aIRR = 1.42, 95% CI = 1.04-1.96; p = 0.028) compared to pre-COVID-19 lockdown period, adjusting for age, sex, employment status, household hunger, depression risk, and smoked substance use. DOT non-adherence was highest immediately following the initial lockdown (aIRR = 1.74, 95% CI = 1.17-2.67; p = 0.006). CONCLUSION: The COVID-19 lockdowns adversely effected adherence to TB DOT in the period after lockdowns were lifted. The change in DOT adherence persisted even after adjusting for socioeconomic and behavioral variables. We need a better understanding of what treatment adherence barriers were exacerbated by COVID-19 lockdowns to improve outcomes in post-pandemic times. TRIAL REGISTRATION: ClinicalTrials.gov Registration Number: NCT02840877. Registered on 19 July 2016.

Patient and provider perceptions of the relationship between alcohol use and TB and readiness for treatment: a qualitative study in South Africa.

BACKGROUND: Unhealthy alcohol use is widespread in South Africa and has been linked to tuberculosis (TB) disease and poor treatment outcomes. This study used qualitative methods to explore the relationship between TB and alcohol use during TB treatment. METHODS: Focus group discussions (FGDs) were conducted with 34 participants who had previous or current drug-susceptible TB and self-reported current alcohol use. Eight interviews were conducted with healthcare workers who provide TB services in Worcester, South Africa. RESULTS: In this rural setting, heavy episodic drinking is normalized and perceived to be related to TB transmission and decreased adherence to TB medication. Both healthcare workers and FGD participants recommended the introduction of universal screening, brief interventions, and referral to specialized care for unhealthy alcohol use. However, participants also discussed barriers to the provision of these services, such as limited awareness of the link between alcohol and TB. Healthcare workers also specified resource constraints, while FGD participants or patients mentioned widespread stigma towards people with alcohol concerns. Both FGD participants and health providers would benefit from education on the relationship between TB and unhealthy alcohol use and had specific recommendations about interventions for alcohol use reduction. Healthcare workers also suggested that community health worker-delivered interventions could support access to and engagement in both TB and alcohol-related services. CONCLUSION: Findings support strengthening accessible, specialized services for the identification and provision of interventions and psychosocial services for unhealthy alcohol use among those with TB.

Patient and provider perceptions of the relationship between alcohol use and TB and readiness for treatment: a qualitative study in South Africa.

Background: Unhealthy alcohol use is widespread in South Africa and has been linked to tuberculosis (TB) disease and poor treatment outcomes. This study used qualitative methods to explore the relationship between TB and alcohol use during TB treatment. Methods: Focus groups (FGs) were conducted with 34 participants who had previous or current drugsusceptible TB and self-reported current alcohol use. Eight interviews were conducted with healthcare workers who provide TB services in Worcester, South Africa. Results: In this rural setting, heavy episodic drinking is normalized and perceived to be related to TB transmission and decreased adherence to TB medication. Both healthcare workers and FG participants recommended the introduction of universal screening, brief interventions, and referral to specialized care for unhealthy alcohol use. However, participants also discussed barriers to the provision of these services, such as limited awareness of the link between alcohol and TB. Healthcare workers also specified resource constraints while FG participants or patients mentioned widespread stigma towards people with alcohol concerns. Both FG participants and health providers would benefit from education on the relationship between TB and unhealthy alcohol use as well and had specific recommendations about interventions for alcohol use reduction. Healthcare workers also suggested that community health worker-delivered interventions could support access to and engagement in both TB and alcohol-related services. Conclusion: Findings support strengthening accessible, specialized services for the identification and provision of interventions and psychosocial services for unhealthy alcohol use among those with TB.

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.

Transmission Of Tuberculosis Among illicit drug use Linkages (TOTAL): A cross-sectional observational study protocol using respondent driven sampling.

People who use illicit drugs (PWUDs) have been identified as a key at-risk group for tuberculosis (TB). Examination of illicit drug use networks has potential to assess the risk of TB exposure and disease progression. Research also is needed to assess mechanisms for accelerated TB transmission in this population. This study aims to 1) assess the rate of TB exposure, risk of disease progression, and disease burden among PWUD; 2) estimate the proportion of active TB cases resulting from recent transmission within this network; and 3) evaluate whether PWUD with TB disease have physiologic characteristics associated with more efficient TB transmission. Our cross-sectional, observational study aims to assess TB transmission through illicit drug use networks, focusing on methamphetamine and Mandrax (methaqualone) use, in a high TB burden setting and identify mechanisms underlying accelerated transmission. We will recruit and enroll 750 PWUD (living with and without HIV) through respondent driven sampling in Worcester, South Africa. Drug use will be measured through self-report and biological measures, with sputum specimens collected to identify TB disease by Xpert Ultra (Cepheid) and mycobacterial culture. We will co-enroll those with microbiologic evidence of TB disease in Aim 2 for molecular and social network study. Whole genome sequencing of Mycobacteria tuberculosis (Mtb) specimens and social contact surveys will be done for those diagnosed with TB. For Aim 3, aerosolized Mtb will be compared in individuals with newly diagnosed TB who do and do not smoke illicit drug. Knowledge from this study will provide the basis for a strategy to interrupt TB transmission in PWUD and provide insight into how this fuels overall community transmission. Results have potential for informing interventions to reduce TB spread applicable to high TB and HIV burden settings. Trial registration: Clinicaltrials.gov Registration Number: NCT041515602. Date of Registration: 5 November 2019.

Switching to bedaquiline for treatment of rifampicin-resistant tuberculosis in South Africa: A retrospective cohort analysis.

South Africa led the world with guidelines on bedaquiline (BDQ) use as a single drug substitution to manage rifampin resistant tuberculosis regimen toxicity. We examined reasons for giving BDQ in a retrospective cohort: >75% of patients were switched to BDQ for toxicity (ototoxicity or renal dysfunction) rather than drug resistance.

Impact of alcohol consumption on tuberculosis treatment outcomes: a prospective longitudinal cohort study protocol.

BACKGROUND: An estimated 10% of tuberculosis (TB) deaths are attributable to problematic alcohol use globally, however the causal pathways through which problem alcohol use has an impact on TB treatment outcome is not clear. This study aims to improve understanding of these mechanisms. Specifically, we aim to 1) assess whether poor TB treatment outcomes, measured as delayed time-to-culture conversion, are associated with problem alcohol use after controlling for non-adherence to TB pharmacotherapy; and 2) to determine whether pharmacokinetic (PK) changes in those with problem alcohol use are associated with delayed culture conversion, higher treatment failure/relapse rates or with increased toxicity. METHODS: Our longitudinal, repeated measures, prospective cohort study aims to examine the associations between problem alcohol use and TB treatment outcomes and to evaluate the effect of alcohol on the PK and pharmacodynamics (PD) of TB drugs. We will recruit 438 microbiologically confirmed, pulmonary TB patients with evidence of rifampicin susceptibility in Worcester, South Africa with 200 HIV uninfected patients co-enrolled in the PK aim. Participants are followed for the six months of TB treatment and an additional 12 months thereafter, with sputum collected weekly for the first 12 weeks of treatment, alcohol consumption measures repeated monthly in concert with an alcohol biomarker (phosphatidylethanol) measurement at baseline, and in person directly observed therapy (DOT) using real-time mobile phone-based adherence monitoring. The primary outcome is based on time to culture conversion with the second objective to compare PK of first line TB therapy in those with and without problem alcohol use. DISCUSSION: Globally, an urgent need exists to identify modifiable drivers of poor TB treatment outcomes. There is a critical need for more effective TB treatment strategies for patients with a history of problem alcohol use. However, it is not known whether poor treatment outcomes in alcohol using patients are solely attributable to noncompliance. This study will attempt to answer this question and provide guidance for future TB intervention trials. TRIAL REGISTRATION: Clinicaltrials.gov Registration Number: NCT02840877 . Registered on 19 July 2016.

Alcohol, hospital discharge, and socioeconomic risk factors for default from multidrug resistant tuberculosis treatment in rural South Africa: a retrospective cohort study.

BACKGROUND: Default from multidrug-resistant tuberculosis (MDR-TB) treatment remains a major barrier to cure and epidemic control. We sought to identify patient risk factors for default from MDR-TB treatment and high-risk time periods for default in relation to hospitalization and transition to outpatient care. METHODS: We retrospectively analyzed a cohort of 225 patients who initiated MDR-TB treatment between 2007 through 2010 at a rural TB hospital in the Western Cape Province, South Africa. RESULTS: Fifty percent of patients were cured or completed treatment, 27% defaulted, 14% died, 4% failed treatment, and 5% transferred out. Recent alcohol use was common (63% of patients). In multivariable proportional hazards regression, older age (hazard ratio [HR]= 0.97 [95% confidence interval 0.94-0.99] per year of greater age), formal housing (HR=0.38 [0.19-0.78]), and steady employment (HR=0.41 [0.19-0.90]) were associated with decreased risk of default, while recent alcohol use (HR=2.1 [1.1-4.0]), recent drug use (HR=2.0 [1.0-3.6]), and Coloured (mixed ancestry) ethnicity (HR=2.3 [1.1-5.0]) were associated with increased risk of default (P<0.05). Defaults occurred throughout the first 18 months of the two-year treatment course but were especially frequent among alcohol users after discharge from the initial four-to-five-month in-hospital phase of treatment, with the highest default rates occurring among alcohol users within two months of discharge. Default rates during the first two months after discharge were also elevated for patients who received care from mobile clinics. CONCLUSIONS: Among patients who were not cured or did not complete MDR-TB treatment, the majority defaulted from treatment. Younger, economically-unstable patients and alcohol and drug users were particularly at risk. For alcohol users as well as mobile-clinic patients, the early outpatient treatment phase is a high-risk period for default that could be targeted in efforts to increase treatment completion rates.

Implementation of genotype MTBDRplus reduces time to multidrug-resistant tuberculosis therapy initiation in South Africa.

BACKGROUND: Diagnosis of drug resistance and timely initiation of multidrug-resistant (MDR) tuberculosis therapy are essential to reduce transmission and improve patient outcomes. We sought to determine whether implementation of the rapid MTBDRplus diagnostic shortened the time from specimen collection to patient MDR tuberculosis therapy initiation. METHODS: We conducted a retrospective cohort analysis of 197 MDR tuberculosis patients treated at Brewelskloof, a rural tuberculosis hospital in Western Cape Province, South Africa, between 2007 and 2011. RESULTS: Eighty-nine patients (45%) were tested using conventional liquid culture and drug susceptibility testing (DST) on solid medium and 108 (55%) were tested using the MTBDRplus assay after positive acid-fast bacilli or culture. Median time from sample taken to therapy initiation was reduced from 80 days (interquartile range [IQR] 62-100) for conventional DST to 55 days (IQR 37.5-78) with the MTBDRplus. Although the laboratory processing time declined significantly, operational delays persisted both in the laboratory and the clinical infrastructure for getting patients started on treatment. In multivariate analysis, patients tested using the MTBDRplus test had a reduced risk of starting treatment 60 days or more after sputum collection of 0.52 (P < .0001) compared with patients tested with culture-based DST, after adjustment for smear status and site of disease. CONCLUSIONS: Use of MTBDRplus significantly reduced time to MDR tuberculosis treatment initiation. However, DST reporting to clinics was delayed by more than 1 week due, in part, to laboratory operational delays, including dependence on smear and culture positivity prior to MTBDRplus performance. In addition, once MDR tuberculosis was reported, delays in contacting patients and initiating therapy require improvements in clinical infrastructure.

Treatment outcomes of isoniazid-resistant tuberculosis patients, Western Cape Province, South Africa.

We report treatment outcomes from a retrospective cohort of patients with isoniazid-monoresistant tuberculosis in rural South Africa. Sixteen percent of patients had poor outcomes, 61% of whom progressed to multidrug-resistant tuberculosis. These data reveal the need for early identification and aggressive follow-up of isoniazid monoresistance to increase treatment success.