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

Acronym	SAEFRIF (Reference Number: TMA2016CDF-1580)
Duration	01/06/2018 - 30/05/2021
Project Topic	Background: Tuberculosis (TB) is a public health burden that causes substantial morbidity and mortality particularly in sub- Saharan Africa. Although there have been considerable advances in TB control since 1990, the current WHO goal of ending the global TB epidemic by 2035 will not be achieved without considerable new advances in TB treatment. A growing body of evidence has indicated that the current dose of rifampicin (10mg/kg) is inadequate. Several studies have suggested that dose escalation (to 20-35mg/kg) is safe, and that higher doses (35mg/kg) may accelerate clearance of TB bacteria from the sputum of infected individuals. However, these studies have almost entirely been completed on HIV negative TB patients, or TB-HIV co-infected patients without severe immunosuppression who are not yet receiving antiretroviral therapy (ART). As we move towards early initiation of ART in Uganda, drug-drug interactions between rifampicin and efavirenz (which is one of the most widely used ART regimen) need to assessed. It is also not clear if high dose rifampicin is safe in patients on efavirenz-based ART. Aim: We propose to determine the effect of higher doses of rifampicin (20mg/kg and 35mg/kg) on efavirenz concentrations and the safety of TB regimens containing high dose rifampicin in TB-HIV infected patients also receiving efavirenz-based ART. Methods: We will enrol 160 TB-HIV co-infected patients at the Infectious Diseases Institute. This will be a randomized open label Phase IIb clinical trial. Patients diagnosed with TB will be consecutively enrolled into this study and randomized to one of three rifampicin doses (10 (control), 20 or 35mg/kg) for the first 8 weeks of TB treatment. Isoniazid, pyrazinamide and ethambutol will be given in their standard doses. Patients who are not on ART will be initiated on efavirenz-based ART after two weeks of TB treatment. Alanine transaminase will be done two weekly and sputum culture performed after 8 weeks of treatment. We will determine whether TB-HIV infected patients on efavirenz-based ART and higher doses of rifampicin (20mg/kg and 35mg/kg) have lower concentrations of efavirenz, develop liver toxicity more frequently compared to patients on standard dose (10mg/kg). We will also determine the proportion of patients who remain sputum culture positive after 8 weeks of treatment in each treatment arm. Expected results: The results of this study will inform Phase III clinical trials which can be performed in a larger group of TB-HIV coinfected patients to determine the utility of higher doses of rifampicin in this population. Through this fellowship, I will enhance my capabilities in patient oriented research by strengthening my skills in performing pharmacokineticfocused clinical trials, and learn new model-based approaches for the analysis of pharmacokinetic data therefore enriching my knowledge in drug development, dose optimization and drug-drug interaction studies.
Network	EDCTP2
Call	Career Development Fellowships 2016

Project partner

Number	Name	Role	Country
1	Infectious Diseases Institute Limited	Coordinator	Uganda