Clinical Predictors of weekly Rifapentine/isoniazid related adverse drug reactions during national roll-out of tuberculosis preventive therapy

Infectious Diseases Institute, Kampala

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Abstract

Project Summary The WHO approved 3 months weekly rifapentine plus isoniazid (3HP) has been found non-inferior to 6H in preventing TB reactivation and achieves higher completion rates. The National TB program in Uganda is currently transitioning from 6HP to 3HP which will be scaled up starting in Jan 2021. Rifapentine has not been widely used in Uganda outside clinical trials and therefore its safety profile in programmatic setting in adults and children is still uncertain. Accurate profiling of patients likely to experience 3HP related adverse drug reactions (ADRs) has the potential to improve TPT completion rates, and in turn improve TB control. Our proposal seeks to describe safety profiles of 3HP, completion rates and the clinical, pharmacokinetic and pharmacogenomic determinants of 3HP-related ADRs for people receiving TPT at programmatic level. This study will take place in five health facilities in Uganda in collaboration with the National TB program and the National Drug Authority. We will conduct a cohort study where 614 adults and children >2 years, who have been initiated on 3HP for TPT by the facility clinician according to standard of care will be enrolled. Participants will be both HIV-infected and HIV-uninfected. Participants will be followed up monthly for evaluation for ADRs using a standardized questionnaires, clinical evaluation and laboratory tests (liver function testing). For a subset of 300 patients (150 cases who develop grade 2 and above ADRs and 150 controls who do not experience ADRs), we will conduct pharmacokinetic sampling to measure rifapentine and isoniazid concentrations and selected genotyping (for examples N-Acetyl Transferase, Cytochrome 2E1) and Human leukocyte antigen (HLA) typing. We will use pharmacokinetic/pharmacogenetic-pharmacodynamic models and stochastic gradient boosted machine learning together with conventional statistical methods to determine factors associated with ADRs and simple prediction rules for the identification of patients at high risk for ADR. We will also determine the effect of the ADRs on TPT completion rates. Patients will subsequently be followed up for up to 3 years and assessed for TB reactivation according to standard of care to determine the incidence of TB reactivation in patients who have received 3HP and the risk factors for this. This study will provide data on the safety of 3HP during national roll-out and provide information on who is likely to develop ADRs which can affect treatment completion and therefore may benefit from alternative regimens.