Inpatient initiation of tuberculosis preventive therapy with 1 month of isoniazid and rifapentine for adults with advanced HIV disease and cryptococcal meningitis (IMPROVE): a non-inferiority, randomised controlled trial

Abstract

Background: Tuberculosis preventive therapy coverage for people with advanced HIV disease (AHD) is poor. Innovative delivery strategies to increase tuberculosis preventive therapy uptake are needed; we sought to evaluate the safety and feasibility of two strategies for ultra-short course tuberculosis preventive therapy with 1 month of daily rifapentine plus isoniazid (1HP). Methods: In this phase-3, open-label, non-inferiority, randomised controlled strategy trial (ISRCTN 18437550), we recruited consecutive adults (aged ≥18 years) admitted to hospital with AHD receiving treatment for cryptococcal meningitis who were screened for active tuberculosis during their hospitalisation from three tertiary referral hospitals in Uganda (Mulago National Specialised Hospital, Kiruddu National Referral Hospital in Kampala, and Mbarara Regional Referral Hospital). Adults without evidence of tuberculosis disease and meeting all eligibility criteria were approached for consent and inclusion. Patients were excluded if they had evidence of active hepatitis B infection, abnormal liver function tests, had known chronic liver disease, were jaundiced, were pregnant or breastfeeding, or presented with a clinical syndrome which, in the opinion of the attending clinician, put the patient at significant risk if they were to participate in the trial. After providing informed consent, we randomly assigned participants (1:1) to inpatient initiation of 1HP before hospital discharge or outpatient initiation at 6 weeks after time of cryptococcal meningitis diagnosis. 1HP was standardised across treatment groups, a 28-day course of 600 mg rifapentine plus 300 mg isoniazid daily with adjunctive pyridoxine (25 mg per day). The 1HP regimen was not dose adjusted on the basis of weight. The primary endpoint was tuberculosis disease-free survival and 1HP treatment completion at 18 weeks, powered for a 15% non-inferiority margin; analysis was by intention to treat. Findings: From Jan 24, 2022, to Nov 13, 2024, 419 adults were screened after 210 were found ineligible and four died before random allocation, 205 were randomly allocated (171 in Kampala and 34 in Mbarara, Uganda): 103 to the inpatient group and 102 to the outpatient group. 119 participants (58%) were male and 86 (42%) were female. In the primary adjusted intention-to-treat analysis, 72 participants in the inpatient 1HP group (70%) had tuberculosis disease-free survival and 1HP treatment completion at 18 weeks compared with 63 (62%) in the outpatient 1HP group (adjusted risk difference 7·1%, 90% CI –3·8 to 17·9) confirming non-inferiority. Treatment completion was achieved in 78 (76%) of 103 in the inpatient 1HP group compared to 67 (66%) of 102 in the outpatient 1HP group (site-adjusted risk difference 9·7%, 95% CI –2·4 to 21·8). 170 grade 3 or 4 adverse events occurred in 99 (48%) of 205 participants. Among participants who had taken at least one dose of 1HP the frequency of adverse events across trial groups was similar apart from grade 4 anaemia, which occurred in a higher proportion of participants in the outpatient group (9% vs 2%, p=0·045). Interpretation: 1HP initiation before hospital discharge was non-inferior to outpatient initiation among adults with AHD and cryptococcosis. These data suggest that following exclusion of active tuberculosis disease, inpatient 1HP initiation is feasible and comparably safe compared with outpatient initiation.