Alcohol Abuse, HIV/AIDS, Tuberculosis
Conditions
Keywords
Adherence, Hepatotoxicity, Phosphatidtylethanol
Brief summary
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
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).
Interventions
The study intervention will include a single arm given (1) 6H: 300 mg INH daily by mouth for 6 months.
DRUGPyridoxine 25 Mg Oral Tablet
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.
Sponsors
Boston University
Boston Medical Center
Mbarara University of Science and Technology
University of California, San Francisco
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age \> 18 years old 2. Patient of the MRRH ISS Clinic 3. HIV-infected 4. Consume alcohol (self-reported consumption in the prior 3 months) (2/3) OR prior year non-drinker (1/3) 5. Live within 2 hours of travel time to the ISS Clinic 6. Fluent in either Runyankole or English 7. No ALT/AST elevations (\< = 2X ULN) confirmed by testing 8. On ART for at least 6 months 9. No history of active TB, TB treatment, or TB preventive therapy 10. No probable current active TB as determined by symptom screening and followed by chest X-ray and Xpert MTB/RIF (if symptomatic) 11. Positive TST results confirmed by testing
Exclusion criteria
1. Plans to move out of the catchment area within 6 months 2. Probable TB via symptom screen and subsequent assessments 3. History or current or past active TB, TB treatment, or TB preventive therapy 4. ALT or AST \>2x ULN 5. Pregnant women
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Incidence of Participants Experiencing a Grade 3/4 Hepatotoxicity | Hepatotoxicity occurring during the six month course (180 pills) of isoniazid (INH), which may be taken over a maximum of 9 months. | Safety will be assessed by the occurrence of a Grade 3/4 hepatotoxicity at any time during the assigned treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Suboptimal INH Medication Adherence | Adherence will be measured over the 6 months on INH or until INH discontinuation (whichever is shorter) | 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. |
| Number of Participants Who Discontinued Treatment | Six month course (180 pills) of isoniazid (INH), which may be taken over a maximum of 9 months. | 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. |
| Self-reported INH Medication Adherence: Number of Days Taking INH in the Past 30 Days | Self-reported INH medication adherence via VAS will be measured 3- and 6- months after starting INH | 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 by the Self Rating Single Item (SRSI) Scale | Self-reported INH medication adherence via SRSI will be measured 3- and 6- months after starting INH | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Latent Tuberculosis at Study Screening. | Study screening visit | Latent tuberculosis assessed at screening via tuberculin skin testing (TST). A TST induration \>=5mm was considered positive for latent tuberculosis. |
| Number of Participants With Alanine Transaminase (ALT) or Aspartate Transaminase (AST) Elevations at Study Screening | Study screening visit | Alanine transaminase (ALT) or aspartate transaminase (AST) elevations (\>2x the upper limit of normal) at study screening |
| INH Concentration in Hair: (INH Pmol + Acetyl INH Pmol) Per mg of Hair | Measured at 3- and 6- months after INH initiation | INH concentration in hair (pmol/mg) will be measured at 3- and 6- months during INH therapy. |
Countries
Uganda
Participant flow
Recruitment details
Participants were recruited from an HIV clinic from April 2017 through December 2019.
Participants by arm
| Arm | Count |
|---|---|
| INH and Vitamin B6 This was a single arm trial; participants were given 300 mg INH daily by mouth for 6 months, and 25 mg pyridoxine (vitamin B-6) daily by mouth for 6 months. | 301 |
| Total | 301 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Protocol Violation | 1 |
Baseline characteristics
| Characteristic | INH and Vitamin B6 | — |
|---|---|---|
| Age, Continuous | 40 year | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment Uganda | 301 participants | — |
| Sex: Female, Male Female | 154 Participants | — |
| Sex: Female, Male Male | 147 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 301 |
| other Total, other adverse events | 88 / 301 |
| serious Total, serious adverse events | 11 / 301 |
Outcome results
Primary
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.
Time frame: Hepatotoxicity occurring during the six month course (180 pills) of isoniazid (INH), which may be taken over a maximum of 9 months.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| INH and Vitamin B6 | Cumulative Incidence of Participants Experiencing a Grade 3/4 Hepatotoxicity | 8.3 percent |
Secondary
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.
Time frame: Six month course (180 pills) of isoniazid (INH), which may be taken over a maximum of 9 months.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| INH and Vitamin B6 | Number of Participants Who Discontinued Treatment | 32 Participants |
Secondary
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.
Time frame: Adherence will be measured over the 6 months on INH or until INH discontinuation (whichever is shorter)
Population: 279/301 participants completed at least 1 study visit at either 3 or 6 months while on INH and are included here. 275 participants were included at 3 months; 264 participants were included at 6 months.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| INH and Vitamin B6 | Percentage of Participants With Suboptimal INH Medication Adherence | at 3 months | 31.3 percentage of participants |
| INH and Vitamin B6 | Percentage of Participants With Suboptimal INH Medication Adherence | at 6 months | 43.9 percentage of participants |
p-value: <0.0195% CI: [0.94, 2.71]Regression, Logistic
p-value: <0.0195% CI: [1.62, 4.76]Regression, Logistic
Secondary
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.
Time frame: Self-reported INH medication adherence via SRSI will be measured 3- and 6- months after starting INH
Population: 280 unique participants are included here. 279 individuals are included at 3 months; 260 individuals are included at 6 months. Participants who reported no INH use in the prior 30 days were excluded.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| INH and Vitamin B6 | Self-reported INH Medication Adherence by the Self Rating Single Item (SRSI) Scale | At 6 months | Good | 41 Participants |
| INH and Vitamin B6 | Self-reported INH Medication Adherence by the Self Rating Single Item (SRSI) Scale | At 3 months | Excellent | 160 Participants |
| INH and Vitamin B6 | Self-reported INH Medication Adherence by the Self Rating Single Item (SRSI) Scale | At 3 months | Very good | 79 Participants |
| INH and Vitamin B6 | Self-reported INH Medication Adherence by the Self Rating Single Item (SRSI) Scale | At 3 months | Good | 38 Participants |
| INH and Vitamin B6 | Self-reported INH Medication Adherence by the Self Rating Single Item (SRSI) Scale | At 3 months | Fair | 0 Participants |
| INH and Vitamin B6 | Self-reported INH Medication Adherence by the Self Rating Single Item (SRSI) Scale | At 3 months | Poor | 2 Participants |
| INH and Vitamin B6 | Self-reported INH Medication Adherence by the Self Rating Single Item (SRSI) Scale | At 3 months | Very poor | 0 Participants |
| INH and Vitamin B6 | Self-reported INH Medication Adherence by the Self Rating Single Item (SRSI) Scale | At 6 months | Excellent | 124 Participants |
| INH and Vitamin B6 | Self-reported INH Medication Adherence by the Self Rating Single Item (SRSI) Scale | At 6 months | Very good | 90 Participants |
| INH and Vitamin B6 | Self-reported INH Medication Adherence by the Self Rating Single Item (SRSI) Scale | At 6 months | Fair | 4 Participants |
| INH and Vitamin B6 | Self-reported INH Medication Adherence by the Self Rating Single Item (SRSI) Scale | At 6 months | Poor | 0 Participants |
| INH and Vitamin B6 | Self-reported INH Medication Adherence by the Self Rating Single Item (SRSI) Scale | At 6 months | Very poor | 1 Participants |
Secondary
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.
Time frame: Self-reported INH medication adherence via VAS will be measured 3- and 6- months after starting INH
Population: 290 unique participants are included here. 285 individuals are included at 3 months; 268 individuals are included at 6 months. Participants with missed visits or who were not taking INH (ie. due to either a temporary pause due to the COVID lockdown in Uganda, or because they were discontinued) were excluded.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| INH and Vitamin B6 | Self-reported INH Medication Adherence: Number of Days Taking INH in the Past 30 Days | at 3 months | 30 days |
| INH and Vitamin B6 | Self-reported INH Medication Adherence: Number of Days Taking INH in the Past 30 Days | at 6 months | 30 days |
Other Pre-specified
INH Concentration in Hair: (INH Pmol + Acetyl INH Pmol) Per mg of Hair
INH concentration in hair (pmol/mg) will be measured at 3- and 6- months during INH therapy.
Time frame: Measured at 3- and 6- months after INH initiation
Population: We had funding to analyze the first shipped batch of hair (n=161 total visits, representing 97 unique participants) for INH.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| INH and Vitamin B6 | INH Concentration in Hair: (INH Pmol + Acetyl INH Pmol) Per mg of Hair | at 3 months | 36.0 pmol/mg |
| INH and Vitamin B6 | INH Concentration in Hair: (INH Pmol + Acetyl INH Pmol) Per mg of Hair | at 6 months | 37.8 pmol/mg |
Other Pre-specified
Number of Participants With Alanine Transaminase (ALT) or Aspartate Transaminase (AST) Elevations at Study Screening
Alanine transaminase (ALT) or aspartate transaminase (AST) elevations (\>2x the upper limit of normal) at study screening
Time frame: Study screening visit
Population: People who completed liver transaminase testing as part of the screening for this study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| INH and Vitamin B6 | Number of Participants With Alanine Transaminase (ALT) or Aspartate Transaminase (AST) Elevations at Study Screening | 80 Participants |
Other Pre-specified
Number of Participants With Latent Tuberculosis at Study Screening.
Latent tuberculosis assessed at screening via tuberculin skin testing (TST). A TST induration \>=5mm was considered positive for latent tuberculosis.
Time frame: Study screening visit
Population: People who completed tuberculin skin testing (TST) as part of the study screening. People who did not return for the TST reading within the required window of 48-72 hours are excluded here.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| INH and Vitamin B6 | Number of Participants With Latent Tuberculosis at Study Screening. | 308 Participants |