REMEMBER: Reducing Early Mortality & Morbidity by Empiric Tuberculosis (TB) Treatment

Study Overview
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Brief Summary
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People with HIV have a high chance of becoming infected with TB, especially when they live in areas where TB infection is common. It can be difficult to diagnose TB in people who need to start HIV treatment right away. Within about 6 months after starting HIV treatment, some of these people can become very sick with TB and can even die from it. This study was being done in people who were starting HIV treatment and who lived in areas where the TB infection rate is high. The purpose of this study was to test an experimental approach to TB treatment to see if it is better than the usual approach. The experimental approach was to start TB treatment at the same time as HIV treatment, even when TB infection had not been found. The usual approach was to start TB treatment only if TB infection was found. In this study, half of the people started TB treatment at the same time as they started their HIV treatment. The other half started TB treatment only if TB infection was found. The study also tested how safe and effective it was to start TB treatment at about the same time as HIV treatment even when TB infection had not been found. The study collected information about diet, whether (and when) people in the study became sicker or died, how well their HIV was controlled, how they were feeling, how they were taking their medications, whether it mattered where they lived or what kind of HIV and TB care was standard, how many people were diagnosed with TB while in the study, and how the cost of the two treatment options on a national level could be compared.

Detailed Description
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This was a randomized, open-label, phase IV strategy trial for participants from resource-limited settings (RLS) who presented with advanced HIV disease and no probable or confirmed tuberculosis (TB), and who were initiating antiretroviral treatment (ART). Participants were randomized to one of two strategy arms: immediate, empiric TB treatment (Empiric arm) or local standard of care TB treatment (IPT arm). Randomization was balanced by clinical trial unit and stratified according to CD4+ T cell count (<25 vs. ≥25 cells/mm^3) and presence of any of the following prognostic factors: reportable hospitalization within the past 30 days, BMI <18.5 kg/m^2, or anemia (hemoglobin <8 g/dl). Participants were followed for 96 weeks. Participants attended study visits at screening, enrollment, and weeks 1, 2, 4, 8, 12, 16, 20, 24 and 48. Signs and symptoms, ART modifications, concomitant medications, and clinical events as defined by AIDS Clinical Trials Group (ACTG) Appendix 60 were collected at each visit. Blood was collected for CD4 and HIV-1 RNA at study entry, weeks 4, 24 and 48, and blood for safety laboratories (liver function, hematology, and renal function) was collected at all visits except week 1. A sputum sample was collected and stored at study entry. Phone contact was conducted at weeks 60, 72, 84 and 96 to obtain information about vital status, reportable hospitalization, TB status (including screening and follow-up), TB and HIV treatment modifications, and quality of life.

Official Title
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Reducing Early Mortality and Early Morbidity by Empiric Tuberculosis Treatment Regimens (REMEMBER)

Conditions
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HIV Infection

Intervention / Treatment
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* Drug: Atripla (r)
* Drug: Efavirenz
* Drug: Truvada
* Drug: Rifampin/isoniazid/pyrazinamide/ethambutol FDC
* Drug: Rifampin/isoniazid FDC
* Drug: Isoniazid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 infection Willingness to start efavirenz-based ART as soon as possible and within no more than 3 days following randomization. CD4+ cell count <50 cells/mm^3 obtained within 45 days prior to study entry Aspartate aminotransferase (AST) (SGOT), alanine aminotransferase (ALT) (SGPT), and total bilirubin ≤ 2.5 X ULN within 30 days prior to study entry. Creatinine clearance ≥30 mL/min either measured or estimated using values obtained within 30 days prior to study entry. Results from a hepatitis B surface antigen test performed within 30 days prior to study entry. Agreement not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, donate sperm, in vitro fertilization). Female candidates of reproductive potential must have a negative serum or urine (15-25 mIU/mL) pregnancy test result within 7 days prior to study entry. Female candidates of reproductive potential who are participating in sexual activity that could lead to pregnancy must use two reliable methods of contraception while on study. Karnofsky performance score >/= 30 at time of study entry. Ability to swallow medications. Ability and willingness of participant or legal guardian/representative to provide informed consent. Intention to remain in the same general geographic region for the duration of study participation. Exclusion Criteria: Presence of any confirmed or probable TB based on criteria listed in the current ACTG diagnosis appendix within 30 days prior to study entry and following completion of study-specific screening algorithm. Use of single-dose NVP for prevention of mother-to-child transmission (pMTCT) within 24 months prior to study entry. Use of prohibited medications within 30 days prior to study entry. Known allergy/sensitivity or any hypersensitivity to components of study-required ART or TB treatment. Current receipt of treatment for active TB or receipt of >14 days cumulative treatment for active TB within 96 weeks prior to study entry. Receipt of >30 days cumulative of INH prophylaxis within 48 weeks prior to study entry. Receipt at any time prior to study entry of >7 days cumulative treatment with any ARV or combination of ARVs (except for ARVs taken for any length of time during pregnancy for pMTCT, or ARVs taken for occupational exposure). Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements. Current Grade ≥2 neuropathy. History of multi-drug-resistant (MDR) TB. Within 12 weeks prior to entry, exposure to a household member or co-worker with known MDR TB.

Ages Eligible for Study
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Minimum Age: 13 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Empiric<br>Study treatment for Arm A participants is the strategy of initiating study-provided or other FDA-approved or tentatively approved antiretroviral treatment as soon as possible following randomization and within no more than 3 days following randomization plus a 4-drug anti-tuberculosis treatment (ATT) regimen (defined as rifampin/isoniazid/ethambutol/pyrazinamide) as soon as possible following randomization and within no more than 7 days following initiation of antiretroviral therapy. After 2 months (or 8 weeks), the 4-drug ATT will be followed with 4 months (or 16 weeks) of 2-drug ATT (defined as rifampin/isoniazid). All participants will be followed through week 96. Drug provision by or through the study will be through week 48 only | Drug: Atripla (r)<br>* Patients are administered one tablet of Efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg (EFV/FTC/TDF, Atripla) to taken be taken orally once daily at bedtime without food.<br>Drug: Efavirenz<br>* Participants will take one 600 mg tablet administered orally once daily without food.<br>* Other names: EFV;Drug: Truvada<br>* Participants will take one tablet of Emtricitabine 200mg/tenofovir disoproxil fumarate 300mg (FTC/TDF, Truvada) administered orally once daily with or without food.<br>Drug: Rifampin/isoniazid/pyrazinamide/ethambutol FDC<br>* Participants will be administered Rifampin/isoniazid/pyrazinamide/ethambutol FDC tablets orally, once daily; dose by weight as determined in Table 5.1-1 of the protocol, for the first 8 weeks.<br>Drug: Rifampin/isoniazid FDC<br>* Participants will be administered rifampin/isoniazid FDC tablets orally, once daily; dose by weight as determined in Table 5.1-1 in the protocol, for 16 weeks following the first 8 weeks.<br>|
| Experimental: Arm B: IPT<br>Study treatment for Arm B participants is the strategy of initiating study-provided or other FDA-approved or tentatively approved antiretroviral therapy as soon as possible following randomization and within no more than 3 days following randomization and of initiating anti-TB treatment (ATT) only when indicated according to local standard practice and at the discretion of the site investigator. All participants will be followed through week 96. Drug provision by or through the study will be through week 48 only. Pyridoxine is provided by the sites to all participants while they are receiving isoniazid (INH). | Drug: Atripla (r)<br>* Patients are administered one tablet of Efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg (EFV/FTC/TDF, Atripla) to taken be taken orally once daily at bedtime without food.<br>Drug: Efavirenz<br>* Participants will take one 600 mg tablet administered orally once daily without food.<br>* Other names: EFV;Drug: Truvada<br>* Participants will take one tablet of Emtricitabine 200mg/tenofovir disoproxil fumarate 300mg (FTC/TDF, Truvada) administered orally once daily with or without food.<br>Drug: Isoniazid<br>* INH 300 mg orally once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Probability of Death or Unknown Vital Status by Week 24 | The Kaplan-Meier estimate of the cumulative probability of death or unknown vital status by week 24. The vital status was considered unknown at week 24 if a participant prematurely discontinued from the study before week 24 and no vital status was obtained at week 48. | From study entry to week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Probability of Death by Week 24 | The Kaplan-Meier estimate of cumulative probability of death by week 24 | From study entry to week 24 | 
| Cumulative Probability of First AIDS Progression by Week 96 | The Kaplan-Meier estimate of the cumulative probability of first AIDS progression which was defined as the identification of a new World Health Organization (WHO) stage 3 or 4 condition | From study entry to week 96 | 
| Cumulative Probability of Death or AIDS Progression by Week 24 | The Kaplan-Meier estimate of the cumulative probability of death or AIDS progression by week 24. AIDS progression was defined as new WHO stage 3 or 4 conditions occurred after study entry. | From study entry to week 24 | 
| Proportion of Participants With HIV-1 RNA Level <400 Copies/mL | Proportion of participants with HIV-1 RNA level <400 copies/mL. | At weeks 0, 4, 24, and 48 | 
| CD4+ T-cell Count | The absolute levels of CD4+ T-cell counts (cells/mm^3) | At weeks 0, 4, 24, and 48 | 
| CD4+ T-cell Count Change From Baseline | Change was calculated as the CD4+ T-cell count at the later weeks (4, 24 and 48) minus the baseline (week 0) CD4+ T-cell count. | Weeks 0, 4, 24 and 48 | 
| Time to Initiation of TB Treatment by Week 96 | Median time to TB treatment initiation since study entry | From study entry to week 96 | 
| Proportion of Participants With TB Diagnosis by Week 96 | Proportion of participants with TB diagnosis per current ACTG Diagnosis Appendix 60 by week 96 | From study entry to week 96 | 
| Proportion of Participants With at Least One New Grade 3 or 4 Adverse Event That is at Least a One-grade Increase From Baseline by Week 48 | Proportion of participants with at least one new Grade 3 or 4 laboratory or sign or symptom that is at least a one-grade increase from baseline by Week 48. Grade 3=Severe, Grade 4=Life-Threatening according to DAIDS AE Grading Table (see references). | From study entry to week 48 | 
| Proportion of Participants With at Least One New Grade 3 or 4 Targeted Laboratory Value That is at Least a One-grade Increase From Baseline by Week 48 | Proportion of participants with at least one new Grade 3 or 4 that is at least a one-grade increase from baseline for the following targeted laboratory values by Week 48 The targeted laboratory events include hemoglobin, serum creatinine, ALT and AST | From study entry to week 48. The lab events were collected at study entry, weeks 2, 4, 8, 12, 16, 20, 24, and 48. | 
| Proportion of Participants With Immune Reconstitution Inflammatory Syndrome (IRIS) by Week 48 | Proportion of participants with IRIS (using current ACTG definition Appendix 60, see References) by Week 48. IRIS in participants with TB and other opportunistic infections may occur shortly after the initiation of potent combination ART, particularly in participants with advanced HIV disease. | From study entry to week 48 | 
| Proportion of Participants With Reportable Hospitalization by Week 48 | Proportion of participants with reportable hospitalization reported by Week 48 | From study entry to week 48 | 
| Proportion of Participants Who Prematurely Discontinued Any Component of TB Treatment by Week 48 | Proportion of participants with premature discontinuation of any component of TB treatment by Week 48 | From study entry to week 48 | 
| Proportion of Participants Who Prematurely Discontinued Antiretroviral Therapy by Week 48 | Proportion of participants with premature discontinuation of antiretroviral therapy (ART) by Week 48 | From study entry to week 48 | 
| Cumulative Probability of Death or AIDS Progression by Week 48 | The Kaplan-Meier estimate of the cumulative probability of death or AIDS progression by week 48. AIDS progression was defined as new WHO stage 3 or 4 conditions occurred after study entry. | From study entry to week 48 |