Alcohol Drinkers' Exposure to Preventive Therapy for TB (ADEPTT)

Study Overview
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Brief Summary
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The Alcohol Drinkers' Exposure to Preventive Therapy for TB (ADEPTT) will examine the safety and tolerability of, and adherence to, 6 months of daily INH (6H) in 300 TB and HIV-infected persons (200 drinkers and 100 non-drinkers) in Uganda. The first aim is to evaluate the safety and tolerability of 6H overall and by level of alcohol use. The second aim is to estimate adherence and compare adherence by level of alcohol use and at 3 and 6 months. Self-reported measures of alcohol use will be augmented by phosphatidylethanol (PEth), an established biomarker of alcohol use. Objective measures of adherence will include electronic pill bottle monitoring and a novel measure of INH exposure, INH concentration in hair. The study will actively monitor for hepatotoxicity using the U.S. standard of care for TB preventive therapy for heavy drinkers and discontinue if any Grade 3/4 toxicities are detected. The investigators will use the safety, tolerability, and adherence results, together with the known efficacy and mortality benefit of TB preventive therapy in HIV-infected persons in SSA, and an established decision analytic model of TB preventive therapy to conduct the third aim: to determine whether the benefits of TB preventive therapy outweigh the toxicity risks for HIV-infected drinkers in resource limited settings. The study will additionally follow the cohort every 6 months after completing INH to monitor drinking and the development of active TB.

Detailed Description
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Tuberculosis (TB) is the leading cause of mortality in persons with HIV worldwide, accounting for 20-33% of HIV-related deaths, and is a high-priority area of research in HIV/AIDS by the NIH. TB preventive therapy decreases both all-cause mortality and active TB in persons with HIV by 30-50% above and beyond the benefits of antiretroviral therapy (ART) alone. Based on these findings, the World Health Organization (WHO) recommends isoniazid (INH) preventive therapy (IPT) for all persons with HIV in resource constrained settings. However, the WHO warns against the use of IPT in persons with regular and heavy alcohol use. This exclusion stems from concern for increased hepatotoxicity in heavy drinkers in settings where liver enzymes are not routinely monitored. Heavy drinking in persons with HIV is very common, approximately 25%, in sub-Saharan Africa (SSA). Heavy drinking increases the risk for active TB at least threefold; thus, HIV-infected alcohol users should be prioritized for TB prevention. However, no studies have systematically assessed the safety of TB preventive therapy in heavy drinkers with or without HIV infection. It is critical to examine the safety and tolerability of TB preventive therapy for HIV-infected drinkers, given the high rates of HIV, TB infection, and alcohol comorbidities worldwide. While the risk of toxicity exists, the risk of TB disease could outweigh the toxicity harms. Thus, it is also crucial to determine whether the mortality benefits outweigh the toxicity risks for this significant portion of the HIV-infected population. In addition, TB preventive therapy is only effective if taken consistently for the full course. Alcohol use is an established risk factor for decreased ART pill taking and active TB treatment discontinuation. Whether HIV-infected drinkers on ART can be adherent to TB preventive therapy is not known. Therefore it is essential to determine the level of adherence to TB preventive therapy by HIV-infected drinkers on ART, thus this study aims to examine adherence to TB preventative therapy as well. This is a study to examine 6 months of daily INH (6H) among N=300 persons co-infected with HIV and TB. The aims of the study are: Aim 1: To examine the safety and tolerability of 6H in HIV/TB co-infected drinkers, measured by hepatotoxicity and treatment discontinuation rates. The main aim is to estimate safety and tolerability overall among drinkers (primary) and by level of drinking (secondary). Aim 2: To determine the level of TB preventive therapy adherence overall among drinkers and by level of drinking, and at 3 and 6 months. The main goal of this aim is to estimate adherence overall among drinkers (primary). Secondarily the investigators will estimate adherence by level of drinking (heavy, current but not heavy drinkers, and non-drinkers) and compare adherence across drinking levels. The investigators hypothesize that adherence will be highest among the non-drinkers. Aim 3: To determine whether the benefits of providing TB preventive therapy to HIV-infected drinkers in resource-limited settings outweigh the risks compared to no treatment. The investigators hypothesize that providing TB preventive therapy will result in longer life expectancy and quality-adjusted life expectancy than not providing TB preventive therapy (current standard of care).

Official Title
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URBAN ARCH (3/5) Uganda Cohort TB Preventive Therapy for HIV-infected Alcohol Users in Uganda: an Evaluation of Safety Tolerability and Adherence

Conditions
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Tuberculosis, HIV/AIDS, Alcohol Abuse

Intervention / Treatment
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* Drug: Isoniazid 300 Mg ORAL TABLET
* Drug: Pyridoxine 25 Mg Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18 years old Patient of the MRRH ISS Clinic HIV-infected Consume alcohol (self-reported consumption in the prior 3 months) (2/3) OR prior year non-drinker (1/3) Live within 2 hours of travel time to the ISS Clinic Fluent in either Runyankole or English No ALT/AST elevations (< = 2X ULN) confirmed by testing On ART for at least 6 months No history of active TB, TB treatment, or TB preventive therapy No probable current active TB as determined by symptom screening and followed by chest X-ray and Xpert MTB/RIF (if symptomatic) Positive TST results confirmed by testing Exclusion Criteria: Plans to move out of the catchment area within 6 months Probable TB via symptom screen and subsequent assessments History or current or past active TB, TB treatment, or TB preventive therapy ALT or AST >2x ULN Pregnant women

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Isoniazid & pyridoxine<br>Isoniazid 300 mg oral tablet: 300 mg daily by mouth for 6 months. Pyridoxine 25 mg oral tablet: 25mg daily by mouth for 6 months. | Drug: Isoniazid 300 Mg ORAL TABLET<br>* The study intervention will include a single arm given (1) 6H: 300 mg INH daily by mouth for 6 months.<br>* Other names: INH;Drug: Pyridoxine 25 Mg Oral Tablet<br>* All participants will also receive 25 mg pyridoxine (vitamin B-6) daily by mouth for 6 months for the treatment duration to reduce the risk of INH-induced peripheral neuropathy.<br>* Other names: Vitamin B6;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Incidence of Participants Experiencing a Grade 3/4 Hepatotoxicity | Safety will be assessed by the occurrence of a Grade 3/4 hepatotoxicity at any time during the assigned treatment period. | Hepatotoxicity occurring during the six month course (180 pills) of isoniazid (INH), which may be taken over a maximum of 9 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Discontinued Treatment | Lack of tolerability will be defined as any isoniazid (INH) treatment discontinuation prior to completion of the prescribed course (6 months of INH taken over a maximum period of 9 months) due to side effects or alanine transaminase (ALT)/aspartate transaminase (AST) elevations. | Six month course (180 pills) of isoniazid (INH), which may be taken over a maximum of 9 months. | 
| Percentage of Participants With Suboptimal INH Medication Adherence | Suboptimal INH adherence was defined as <90% of days with at least 1 electronic medication management (EMM) pill cap opening in the previous 90 days, at 3- and 6-months. | Adherence will be measured over the 6 months on INH or until INH discontinuation (whichever is shorter) | 
| Self-reported INH Medication Adherence: Number of Days Taking INH in the Past 30 Days | Participants were asked In the past 30 days, how many days in total have you not taken your pill? and were presented with a visual analog scale (VAS) to indicate the percentage of INH taken in the past 30 days. We converted the VAS percentage into number of days out of 30 to match the first question. Our final self-report measure was the minimum number of the 2 self-reported measurements. | Self-reported INH medication adherence via VAS will be measured 3- and 6- months after starting INH | 
| Self-reported INH Medication Adherence by the Self Rating Single Item (SRSI) Scale | The Self Rating Single Item (SRSI) adherence scale asks participants to rate their ability to take their medications as prescribed over the past 30 days. Participants reporting INH use in the prior 30 days at the 3- or 6-month interview are included here, and reported their INH adherence in the prior 30 days as excellent, very good, good, fair, poor, or very poor. | Self-reported INH medication adherence via SRSI will be measured 3- and 6- months after starting INH | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adherence, Hepatotoxicity, Phosphatidtylethanol