Project Title

Safety and Efficacy of High Dose Rifampicin in TB-HIV co-infected patients on Efavirenz-based Antiretroviral therapy

EDCTP Project Call

Career Development Fellowship (CDF)

Project Objectives

Primary objective 1. To determine the effect of a high dose of rifampicin (35 mg/kg orally) on the pharmacokinetics of first-line antiretroviral drugs (efavirenz and dolutegravir) in TB-HIV co-infected patients on TB treatment. Secondary objectives 1. To investigate the safety/tolerability of a high dose of rifampicin in TB-HIV co-infected patients on TB treatment and first-line antiretroviral therapies. 2. To determine if TB-HIV co-infected patients on a high dose of rifampicin are more likely to have negative sputum cultures by the end of the intensive phase of TB treatment than patients on standard-dose rifampicin. 3. To explore the relationships between exposure to rifampicin, efavirenz and dolutegravir and the tolerability and efficacy of these drugs.

Study Design

Randomized four-arm open label clinical trial (Phase IIb) High dose rifampicin will be administered for the first 8 weeks (intensive phase) of TB treatment. All other anti-TB drugs will be administered at the standard dose using fixed-dose combinations (FDC). All participants will receive standard dose rifampicin during the continuation phase (weeks 9 -24)

Project Summary

We will enrol 120 TB-HIV co-infected patients initiating TB treatment. Participants will be randomized to either high dose (35mg/kg) or standard dose (10mg/kg) rifampicin in addition to either dolutegravir (DTG) or efavirenz (EFV), for those who are antiretroviral therapy (ART) naïve. Patients who are already on ART will remain on their current ART regimen. The randomization groups (30 participants in each arm) include: Arm 1A: R35mg/kg HEZ + DTG Arm 1B: R10mg/kg HEZ + DTG (Control 1) Arm 2A: R35mg/kg HEZ + EFV Arm 2B: R10mg/kg HEZ + EFV (Control 2) Pharmacokinetic blood sampling will be performed after 6 weeks (±2 weeks) of TB treatment. PK sampling will occur pre-dose and at 1, 2, 4 and 8 hours after observed dose for rifampicin and DTG concentrations and approximately 12-14 hours post-dose for EFV (to measure mid-dose interval (MDI) concentration). The EFV MDI and rifampicin pre-dose samples will be collected concurrently in the EFV arms. Safety laboratory tests including liver and renal function tests will be measured every two weeks or when patients present with symptoms suggestive of toxicity such as abdominal pain, jaundice and malaise. In patients with culture positive TB at baseline, sputum cultures will be performed after 8 weeks of anti-TB treatment. We will use population pharmacokinetic modelling to determine the rifampicin and DTG exposure in each arm. Using these models we will evaluate for drug-drug interactions between ART and the standard and high dose of rifampicin. We will compare the mid-dose concentrations of EFV and trough concentrations of DTG in each intervention and control arm using Wilcoxon rank-sum test. We will also compare the proportion of participants with grade 3 or 4 adverse events in each arm using the chi-squared test. We will compare the proportion of patients who are sputum culture negative after 8 weeks of treatment among those in the high dose and standard dose arms using the chi-squared test.

Host Organisation

Results & Outcomes

Current Organisation

Infectious Diseases Institute

Current Job Title

Post-doc researcher

Biography

Publications