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

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.

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.