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.