The Impact of Alcohol Consumption on Tuberculosis Treatment Outcomes

Tuberculosis Clinical Trial

Official title:

The Impact of Alcohol Consumption on Tuberculosis Treatment Outcomes

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02840877
• Other study ID #: H-34970
• Secondary ID: 1R01AI119037-01A
• Status: Completed
• Phase: N/A
• Start date: May 16, 2017
• Est. completion date: October 12, 2023

Study information

• Verified date: October 2023
• Source: Boston Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 303
• Est. completion date: October 12, 2023
• Est. primary completion date: June 28, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 15 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Alcohol Consumption
• Alcohol Drinking
• Treatment Adverse Effect
• Tuberculosis

Intervention

Behavioral:
• DOT Adherence Monitoring
Study participants will meet with a study-employed DOT worker daily during weekdays throughout the course of their TB treatment

Locations

Country	Name	City	State
South Africa	Worcester Community Day Centre	Worcester	Western Cape Province

Sponsors (6)

Lead Sponsor	Collaborator
Boston Medical Center	Boston University, Medical Research Council, South Africa, National Institute of Allergy and Infectious Diseases (NIAID), University of Cape Town, University of Stellenbosch

Country where clinical trial is conducted

South Africa, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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	12 weeks
Primary	Cmax	Peak concentrations (Cmax) of isoniazid, rifampin, pyrazinamide, and ethambutol in patients with problem alcohol use compared to those without	4 weeks
Primary	Area Under Curve (AUC)	Individual patient steady state 24-hour area under curve (AUC) of isoniazid, rifampin, pyrazinamide, and ethambutol	4 weeks
Secondary	Poor Treatment Outcome	Risk of poor final TB outcomes (defined as treatment failure, death, or relapse) in patients with problem alcohol use compared to those without	18 months
Secondary	Side Effects to TB Drugs	Percentage of patients who develop side effects to the TB drugs in patients with problem alcohol use compared to those without	6 months