Testing novel strategies for patients hospitalised with HIV-associated disseminated tuberculosis (NewStrat-TB): protocol for a randomised controlled trial.

BACKGROUND: HIV-associated tuberculosis (TB) contributes disproportionately to global tuberculosis mortality. Patients hospitalised at the time of the diagnosis of HIV-associated disseminated TB are typically severely ill and have a high mortality risk despite initiation of tuberculosis treatment. The objective of the study is to assess the safety and efficacy of both intensified TB treatment (high dose rifampicin plus levofloxacin) and immunomodulation with corticosteroids as interventions to reduce early mortality in hospitalised patients with HIV-associated disseminated TB. METHODS: This is a phase III randomised controlled superiority trial, evaluating two interventions in a 2 × 2 factorial design: (1) high dose rifampicin (35 mg/kg/day) plus levofloxacin added to standard TB treatment for the first 14 days versus standard tuberculosis treatment and (2) adjunctive corticosteroids (prednisone 1.5 mg/kg/day) versus identical placebo for the first 14 days of TB treatment. The study population is HIV-positive patients diagnosed with disseminated TB (defined as being positive by at least one of the following assays: urine Alere LAM, urine Xpert MTB/RIF Ultra or blood Xpert MTB/RIF Ultra) during a hospital admission. The primary endpoint is all-cause mortality at 12 weeks comparing, first, patients receiving intensified TB treatment to standard of care and, second, patients receiving corticosteroids to those receiving placebo. Analysis of the primary endpoint will be by intention to treat. Secondary endpoints include all-cause mortality at 2 and 24 weeks. Safety and tolerability endpoints include hepatoxicity evaluations and corticosteroid-related adverse events. DISCUSSION: Disseminated TB is characterised by a high mycobacterial load and patients are often critically ill at presentation, with features of sepsis, which carries a high mortality risk. Interventions that reduce this high mycobacterial load or modulate associated immune activation could potentially reduce mortality. If found to be safe and effective, the interventions being evaluated in this trial could be easily implemented in clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT04951986. Registered on 7 July 2021 https://clinicaltrials.gov/study/NCT04951986.

Tuberculosis Diagnosis and Preventive Monotherapy Among Children and Adolescents Exposed to Rifampicin-Resistant Tuberculosis in the Household.

Background: Children and adolescents with household exposure to multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB) are at high risk of developing TB disease. Tuberculosis preventive therapy (TPT) is recommended, but programmatic experience is limited, particularly for adolescents. Methods: We conducted a prospective cohort study to describe MDR/RR-TB diagnosis and TPT provision for individuals aged <18 years with MDR/RR-TB exposure. Participants were assessed for TB either in homes or health facilities, with referral for chest x-ray or specimen collection at clinician discretion. The TPT regimens included levofloxacin, isoniazid, or delamanid monotherapy for 6 months, based on source patient drug-resistance profile. Results: Between March 1, 2020 and July 31, 2021, 112 participants were enrolled; median age was 8.5 years, 57 (51%) were female, and 6 (5%) had human immunodeficiency virus. On screening, 11 (10%) were diagnosed with TB: 10 presumptive MDR/RR-TB and 1 drug-susceptible TB. Overall, 95 (94% of 101) participants started TPT: 79 with levofloxacin, 9 with isoniazid, and 7 with delamanid. Seventy-six (80%) completed TPT, 12 (13%) were lost to follow up, and 7 (7%) stopped TPT early due to adverse events. Potential adverse events were reported for 12 (13%) participants; none were serious. There were no further TB diagnoses (200 days median follow up). Conclusions: Post-MDR/RR-TB exposure management for children and adolescents resulted in significant MDR/RR-TB detection and both high TPT initiation and completion. Tuberculosis preventive monotherapy was well tolerated and there were no further TB diagnoses after initial assessment. Key factors supporting these outcomes included use of pediatric formulations for young children, monotherapy, and community-based options for assessment and follow up.