Drinkers' Intervention to Prevent Tuberculosis (DIPT Study)

Study Overview
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Brief Summary
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There is an urgent global need to decrease the high mortality of tuberculosis (TB) in persons with HIV as TB is the leading cause of death among persons with HIV worldwide. The DIPT (Drinkers' Intervention to Prevent TB) study is a randomized, 2x2 factorial trial among HIV/TB co-infected adults in Uganda with heavy alcohol use (n=680 persons, 340 each U01). The goal of the study is to determine whether economic incentive interventions can promote both reduced alcohol use and isoniazid (INH) pill taking among HIV/TB co-infected adult heavy drinkers, during isoniazid preventive therapy (IPT: a six-month course of INH) at HIV clinics in southwestern Uganda. Participants will be randomized to one of four arms: Arm 1: no incentives (control); Arm 2: economic incentives for decreasing alcohol use only; Arm 3: economic incentives for IPT adherence only; Arm 4: economic incentives for decreasing alcohol use and for IPT adherence (rewarded independently).

Detailed Description
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TB is the leading cause of death among persons with HIV worldwide, and HIV-infected drinkers are at very high risk for TB disease and mortality. Globally, an estimated 25% of persons with HIV are heavy drinkers, and the risk of TB disease is 3-fold higher among heavy drinkers compared to non-drinkers. Six months of isoniazid (INH) preventive therapy (IPT) reduces TB morbidity and mortality by 30-50% above the benefit of antiretroviral therapy (ART). However, INH can be toxic to the liver, and as a result in many high TB/HIV prevalence settings, such as east Africa, heavy drinkers are not offered IPT. Thus interventions to reduce alcohol use are needed to decrease INH toxicity during IPT among HIV/TB infected drinkers. It is also well established that heavy drinkers have poorer ART adherence, and there is growing evidence of reduced IPT adherence in drinkers. However, interventions to reduce drinking have had limited impact on ART adherence, and further interventions to increase IPT adherence among HIV/TB infected drinkers are likely needed. The use of incentives to promote healthy behavior is a highly effective approach for reducing substance use and for improving adherence to HIV and TB regimens in resource-rich settings. Economic incentives to reduce alcohol use may create a window for safe and effective IPT use over six months by decreasing hepatotoxicity. Decreases in alcohol use may also improve IPT adherence, or additional incentives for IPT adherence may be needed. Such strategies to reduce alcohol use have not been studied in low-income countries and the effectiveness of incentives to optimize IPT in HIV/TB co-infected drinkers is unknown. OBJECTIVES Aim 1: Alcohol Reduction Intervention: Determine the effectiveness of economic incentives contingent on point-of-care (POC) urine ethyl glucuronide (EtG) <300 ng/mL (Arms 2 & 4) versus no alcohol incentives (Arms 1 & 3) to reduce heavy drinking over 6 months, among HIV/TB co-infected adult drinkers receiving IPT. The investigators will randomize participants to low-cost escalating prize incentives for EtG negative urine tests at IPT refill visits (Arms 2+4), versus no incentives (Arms 1+3). Aim 2: INH Adherence Intervention: Determine the effectiveness of economic incentives contingent on POC (IsoScreen) INH urine positive tests (Arms 3 & 4) versus no INH incentives (Arms 1 & 2) on INH adherence among HIV/TB co-infected adult drinkers. The investigators will randomize participants to low-cost escalating prize incentives for INH positive urine tests at IPT refill visits (Arms 3+4), versus no incentives (Arms 1+2). Aim 3: Impact Assessment of Intervention: Assess the impact of economic incentives on HIV virologic suppression and explore their mechanisms of action, six months after trial completion. The investigators will follow all study participants for six months after trial completion. Assess the impact of the 3 separate incentive interventions (Arms 2, 3, 4) vs. no incentives (Arm 1) on HIV virologic suppression. Explore the mechanisms that may drive the economic incentives to increase virologic suppression. Potential mediators will be reductions in alcohol use and level of IPT adherence. This study will leverage new low-cost POC tests for alcohol use and INH pill-taking for the first study of incentive-based alcohol and adherence interventions in low-resource settings; these interventions may improve the safety and effectiveness of life-saving medications for heavy alcohol users in many settings.

Official Title
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Drinkers' Intervention to Prevent Tuberculosis (DIPT Study)

Conditions
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HIV/AIDS, Tuberculosis

Intervention / Treatment
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* Behavioral: Incentives for negative EtG test
* Behavioral: Incentives for positive IsoScreen test


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-infected adult (≥18 years) prescribed antiretroviral therapy (ART) for at least 6 months; Current heavy alcohol use (AUDIT-C positive for prior 3 month drinking and positive EtG urine test); Positive tuberculin skin test (TST) (≥5 mm induration); AST and ALT <2x the upper limit of normal (ULN); Fluent in Runyankole or English; No history of active TB, TB treatment, or TB preventive therapy; Lives within 2-hour travel time or 60 km of the study site. Exclusion Criteria: Prescribed nevirapine (NVP, an ART drug that is declining in usage due to high risk for hepatotoxicity); Plans to move out of the catchment area within 6 months; Prescribed anti-convulsion medications or history of recurring seizures; ALT or AST elevations (>2X ULN); Suspected or confirmed active TB as determined by symptom screening and followed by chest X-ray and sputum testing; History of prior active TB treatment or prior IPT. Pregnant at time of screening

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: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Control<br>All participants will receive brief alcohol and adherence counseling according to Uganda Ministry of Health guidelines. | |
| Experimental: Escalating incentives (EtG tests)<br>Escalating incentives for EtG negative urine test (Intervention: Incentives for negative EtG test). | Behavioral: Incentives for negative EtG test<br>* Economic incentives are given to the study participant contingent on point-of-care (POC) urine ethyl glucuronide (EtG) <300 ng/mL with the amount of the incentive escalating with each subsequent negative EtG test.<br>|
| Experimental: Escalating incentives (IsoScreen tests)<br>Escalating incentives for IsoScreen positive urine tests (Intervention: Incentives for positive IsoScreen test). | Behavioral: Incentives for positive IsoScreen test<br>* Economic incentives contingent on POC (IsoScreen) INH urine positive tests with the amount of the incentive escalating with each subsequent positive IsoScreen test.<br>|
| Experimental: Escalating incentives (EtG + IsoScreen)<br>Escalating incentives for EtG negative tests and for IsoScreen positive urine tests with the incentives rewarded separately (Interventions: Incentives for negative EtG test and Incentives for positive IsoScreen test). | Behavioral: Incentives for negative EtG test<br>* Economic incentives are given to the study participant contingent on point-of-care (POC) urine ethyl glucuronide (EtG) <300 ng/mL with the amount of the incentive escalating with each subsequent negative EtG test.<br>Behavioral: Incentives for positive IsoScreen test<br>* Economic incentives contingent on POC (IsoScreen) INH urine positive tests with the amount of the incentive escalating with each subsequent positive IsoScreen test.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Non-heavy drinking determined by self-report (Alcohol Use Disorders Identification Test - Consumption [AUDIT-C], prior 3 months, negative) and phosphatidylethanol (PEth) <35 ng/mL | Aim 1: Primary Outcome 1. Non-heavy drinking is a composite outcome, measured at both 3 and 6 months. I.e. an individual must meet non-heavy drinking criteria at both time-points in order to achieve the outcome. | Both 3 months and 6 months (composite measure) | 
| INH Adherence determined by proportion of participants that achieve >90% MEMS adherence to INH during prescribed IPT | Aim 2: Primary Outcome. MEMS adherence determined by the number of pill bottle openings (no more than 1 per day counted) divided by the number of prescribed doses. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hepatotoxicity | Aim 1: Secondary Outcome. Treatment discontinuation due to a Grade 3/4 hepatotoxicity at any time during the treatment period. Grade 3/4 hepatotoxicity is defined as in previous trials as alanine transaminase (ALT) or aspartate aminotransferase (AST) >3-5x upper limit of normal (ULN) and symptoms (nausea, vomiting, jaundice, or fatigue) or ALT or AST >5x ULN, regardless of symptoms. Study clinicians, blinded to intervention arm, will determine treatment discontinuation. | up to 9 months | 
| INH concentration in hair | Aim 2: Secondary Outcome. INH concentration in hair captures INH adherence over a period of weeks to months. Hair samples will analyzed using liquid chromatography/tandem mass spectrometry. | 3 and 6 months | 
| HIV viral suppression | Aim 3: Secondary Outcome. The proportion of study participants with undetectable HIV viral load measurements at 6 and 12 months post-enrollment, measured through plasma HIV viral load measurements. | 6 and 12 months | 
| Active TB rates | Aim 3: Secondary Outcome. Rate of active TB which will be defined as confirmed (if Xpert MTB/RIF assay positive) or suspected (based on chest x-ray findings or response to anti-TB treatment in symptomatic, Xpert assay negative persons). | 12 months |