Alcohol Consumption, Treatment Adverse Effect, Tuberculosis
Conditions
Keywords
tuberculosis culture, alcohol use
Brief summary
After HIV/AIDS, tuberculosis (TB) remains the second leading cause of death due to an infectious disease globally. Retrospective studies from many countries, including the United States and South Africa, have consistently reported that in addition to having a higher burden of TB disease, patients with problem alcohol use have worse TB treatment outcomes. This prospective study will attempt to clarify both behavioral and biologic causal mechanisms underlying the deleterious effects of problem alcohol use on TB treatment response.
Detailed description
A major knowledge gap is the degree to which poor treatment outcomes in alcohol-abusing patients are due to noncompliance alone. Problem alcohol use impacts on retention in care and adherence to daily TB treatment. Poor medication adherence and increased default from TB care have been documented for patients consuming alcohol regularly in several countries. Yet there has been no research to identify reasons (beyond adherence) for these poorer outcomes among patients with problem alcohol use. A key barrier to understanding the persistent biologic effect of alcohol on TB disease is inadequate data on adherence, including detailed data on daily adherence (or number of missed doses of medication). Research combining better approaches to alcohol ascertainment and adherence monitoring is needed to advance understanding of the pathways by which alcohol use and TB disease interact. Aim 1: To (i) examine the associations between problem alcohol use and TB treatment outcomes, and (ii) demonstrate that these associations persist independent of adherence to TB treatment. Aim 2: To evaluate the effect of problem alcohol use on the pharmacokinetics (PK)/pharmacodynamics (PD) of TB drugs. Aim 3: We will use existing samples and data and continue to collect samples and data to (A) evaluate Mtb diversity in host, its dynamics overtime and in a specific set of drug resistance, drug tolerance, virulence and immune regulator genes, for evidence of directional and diversifying selection. We will (B) also evaluate how Mtb diversity and genes under selection associate with time-to culture conversion (three consecutive weeks of negative growth) and negative treatment outcomes, adherence, HIV, diabetes mellitus (DM), and substance use. We will (C) leverage MIC and sequence data from TRUST. We will combine these with a large public Mtb MIC and WGS dataset enriched for high-level antibiotic resistance generated by studies that include the NIAID funded Harvard TB Centers of Excellence for Translational Research (CETR). We will train an in silico MIC predictor and probe interactions between mutations and the Mtb lineage on a genome-wide scale. The current TRUST investigators, as well as Dr. Maha Farhat, Harvard Medical School will oversee this aim. Aim 4: A) To compare rates of dysglycemia (both hyperglycemia and hypoglycemia) in people living with HIV (PLWH) and HIV-uninfected persons receiving TB treatment in order to assess changes in blood glucose levels from study enrollment by HIV status and how alcohol use mediates the relationship; and B) to assess the role stress, inflammation and alcohol consumption play in relation to blood sugar levels in PLWH and HIV-uninfected individuals and to assess epigenetic modifications at DNA sites known to be involved in TB risk and neutrophil, monocyte, T and B cell function. Culture-positive, pulmonary TB patients will be recruited in Worcester, South Africa, and followed over an 18-month period. Patients will complete an interviewer-administered questionnaire on their alcohol use and other health-related behaviors, and their recent alcohol use will be confirmed using a biomarker (phosphatidylethanol). Chest radiographs, sputum smears and culture, and blood samples will be collected to compare the biology of treatment response in patients with and without problem alcohol use. During the 6-month treatment period, smart mobile-phone technology will be used to document daily drug adherence by trained community workers. Serial measures of alcohol intake and serial sputa isolates will be collected to assess treatment response and TB drug side effects will be recorded. In addition, intensive PK/PD studies of isoniazid, rifampin, ethambutol, and pyrazinamide will be performed in 200 HIV-seronegative patients. The full cohort will be followed for 12 months post-treatment to examine long-term TB outcomes, including relapse and death.
Interventions
BEHAVIORALDOT Adherence Monitoring
Study participants will meet with a study-employed DOT worker daily during weekdays throughout the course of their TB treatment
Sponsors
Medical Research Council, South Africa
Boston University
University of Cape Town
National Institute of Allergy and Infectious Diseases (NIAID)
University of Stellenbosch
Boston Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
15 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. at least 15 years old 2. initiating TB treatment in South Africa 3. expect to remain in the local area for the next 2 years 4. agree to comply with all study requirements, including provision of contact information and attendance at all study appointments 5. provide written, informed consent to participate in the study if ≥18 years of age or written assent and parental consent if \<18 years.
Exclusion criteria
1. they have multidrug-resistant (MDR) TB (RIF resistance will be known at screening from Xpert MTB/RIF) 2. they have a contra-indication to start on standard 4-drug therapy 3. they are pregnant at study enrollment 4. they are HIV seropositive for aim 2 only
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Culture Conversion | 12 weeks | Time to sterilization/culture conversion during the first twelve weeks of treatment in patients with problem alcohol use compared to those without |
| Cmax | 4 weeks | Peak concentrations (Cmax) of isoniazid, rifampin, pyrazinamide, and ethambutol in patients with problem alcohol use compared to those without |
| Area Under Curve (AUC) | 4 weeks | Individual patient steady state 24-hour area under curve (AUC) of isoniazid, rifampin, pyrazinamide, and ethambutol |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Poor Treatment Outcome | 18 months | Number and percent of participants that had favorable (defined as cured, treatment completed) and unfavorable (defined as treatmentfailure, death, relapse) TB outcomes. The 'other' category is defined as the treatment defaulted, was extended, participant moved or was transferred). |
| Side Effects to TB Drugs | 6 months | Nember and percentage of patients who develop side effects to the TB drugs in patients with problem alcohol use compared to those without |
Countries
South Africa
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| TRUST Cohort TRUST Study Cohort | 303 |
| Total | 303 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| 12 Weeks to 6 Months | Death | 1 |
| 12 Weeks to 6 Months | Lost to Follow-up | 4 |
| 12 Weeks to 6 Months | Moved/transferred out | 1 |
| 12 Weeks to 6 Months | Treatment failure | 1 |
| 12 Weeks to 6 Months | Withdrawal by Subject | 4 |
| 6 Months to 18 Months | Death | 4 |
| 6 Months to 18 Months | Diagnosed with multi-drug resistant tuberculosis. | 1 |
| 6 Months to 18 Months | Lost to Follow-up | 24 |
| 6 Months to 18 Months | Moved/transferred out | 6 |
| 6 Months to 18 Months | Relapse/recurrence of TB | 8 |
| 6 Months to 18 Months | Still in study. | 14 |
| 6 Months to 18 Months | Treatment failure | 7 |
| 6 Months to 18 Months | Treatment stopped due to liver injury. | 1 |
| 6 Months to 18 Months | Withdrawal by Subject | 1 |
| Baseline to 12 Weeks | Changed treatment regimen, no longer on first line drugs. | 1 |
| Baseline to 12 Weeks | Death | 1 |
| Baseline to 12 Weeks | Lost to Follow-up | 2 |
| Baseline to 12 Weeks | Moved/Transferred out | 5 |
| Baseline to 12 Weeks | Treatment extended due to bacterial meningitis. | 1 |
| Baseline to 12 Weeks | Withdrawal by Subject | 11 |
Baseline characteristics
| Characteristic | TRUST Cohort |
|---|---|
| Age, Continuous | 37 years |
| Race/Ethnicity, Customized Black African | 16 Participants |
| Race/Ethnicity, Customized Coloured/Mixed Ancestry | 284 Participants |
| Race/Ethnicity, Customized Indian/Asian | 1 Participants |
| Race/Ethnicity, Customized Other | 2 Participants |
| Region of Enrollment South Africa | 303 participants |
| Sex: Female, Male Female | 121 Participants |
| Sex: Female, Male Male | 182 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 8 / 303 |
| other Total, other adverse events | 0 / 303 |
| serious Total, serious adverse events | 10 / 303 |
Outcome results
Primary
Area Under Curve (AUC)
Individual patient steady state 24-hour area under curve (AUC) of isoniazid, rifampin, pyrazinamide, and ethambutol
Time frame: 4 weeks
Population: AUC outcome measure data was collected for 104 study participants who were enrolled into Aim 2 for pharmacokinetic/pharmacodynamic analysis. This measure was collected for 4 first-line TB medications: rifampin, isoniazid, pyrazinamide, and ethambutol.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| TRUST Cohort | Area Under Curve (AUC) | Rifampin | 22.2 mg x h/L |
| TRUST Cohort | Area Under Curve (AUC) | Isoniazid | 6.32 mg x h/L |
| TRUST Cohort | Area Under Curve (AUC) | Pyrazinamide | 259 mg x h/L |
| TRUST Cohort | Area Under Curve (AUC) | Ethambutol | 13.2 mg x h/L |
Primary
Cmax
Peak concentrations (Cmax) of isoniazid, rifampin, pyrazinamide, and ethambutol in patients with problem alcohol use compared to those without
Time frame: 4 weeks
Population: Cmax outcome measure data was collected for 104 study participants who were enrolled into Aim 2 for pharmacokinetic/pharmacodynamic analysis. This measure was collected for 4 first-line TB medications: rifampicin, isoniazid, pyrazinamide, and ethambutol.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| TRUST Cohort | Cmax | Rifampicin | 5.29 mg/L |
| TRUST Cohort | Cmax | Isoniazid | 1.63 mg/L |
| TRUST Cohort | Cmax | Pyrazinamide | 28.5 mg/L |
| TRUST Cohort | Cmax | Ethambutol | 1.98 mg/L |
Primary
Time to Culture Conversion
Time to sterilization/culture conversion during the first twelve weeks of treatment in patients with problem alcohol use compared to those without
Time frame: 12 weeks
Population: Individuals newly diagnosed with tuberculosis and initiating treatment were classified at baseline into either Low Alcohol Use (n=102), Moderate Alcohol Use (n=133), and High Alcohol Use (n=65). 3 participants were missing data on alcohol use as their baseline PEth tests were water damaged. Therefore the overall number of participants analyzed was 300 and the respective number of participants for each of the 3 levels of alcohol use are provided as just described.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TRUST Cohort | Time to Culture Conversion | Low Alcohol Use | 5.6 weeks | Standard Deviation 2.5 |
| TRUST Cohort | Time to Culture Conversion | Moderate Alcohol Use | 5.4 weeks | Standard Deviation 2.5 |
| TRUST Cohort | Time to Culture Conversion | High Alcohol Use | 5.5 weeks | Standard Deviation 2.6 |
Secondary
Poor Treatment Outcome
Number and percent of participants that had favorable (defined as cured, treatment completed) and unfavorable (defined as treatmentfailure, death, relapse) TB outcomes. The 'other' category is defined as the treatment defaulted, was extended, participant moved or was transferred).
Time frame: 18 months
Population: 3 individuals were excluded from overall numbers (total N=303) because they didn't have baseline Peth collected, so there did not have alcohol use data.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| TRUST Cohort | Poor Treatment Outcome | Favorable | 246 Participants |
| TRUST Cohort | Poor Treatment Outcome | Unfavorable | 24 Participants |
| TRUST Cohort | Poor Treatment Outcome | Other | 19 Participants |
| TRUST Cohort | Poor Treatment Outcome | Missing | 11 Participants |
Secondary
Side Effects to TB Drugs
Nember and percentage of patients who develop side effects to the TB drugs in patients with problem alcohol use compared to those without
Time frame: 6 months
Population: 3 individuals were excluded from overall numbers (total N=303) because they didn't have baseline Peth collected, so they did not have alcohol use data
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| TRUST Cohort | Side Effects to TB Drugs | Side effects | 154 Participants |
| TRUST Cohort | Side Effects to TB Drugs | No side effects | 146 Participants |