Mind the gaps: Pharmacokinetic research to advance pediatric HIV/TB cotreatment and TB prevention

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PROJECT SUMMARY Tuberculosis (TB) is the leading cause of death among children with HIV, yet insufficient data are available on the pharmacokinetics (PK) of newer HIV/TB cotreatment and TB prevention strategies in children. Global expansion of dolutegravir use for young children has the potential to significantly improve HIV treatment outcomes, but there are no PK data to inform use of double-dose dolutegravir during rifampicin-containing HIV/TB cotreatment for children under 6 years of age. Further, multiple studies have shown that current WHO-recommended rifampicin dosages result in low concentrations in most children, and high-dose rifampicin may improve outcomes and shorten treatment duration in adults and children. Yet the impact of high-dose rifampicin on dolutegravir exposures has not been examined. Finally, it is well-established that treatment of latent TB infection (LTBI) significantly reduces incident TB among HIV-infected persons, yet this strategy is vastly underused in endemic settings. Short-course LTBI treatment regimens increase completion rates, but have not been studied among HIV-infected children receiving dolutegravir. To address these gaps in knowledge and provide needed PK and safety data to extend use of these promising strategies from adults to children, we will carry out two prospective PK studies to examine: (1) twice daily dolutegravir during both standard- and high-dose rifampicin, and (2) PK of dolutegravir during weekly rifapentine/isoniazid for TB prevention/LTBI treatment. To advance our understanding of underlying mechanisms of drug action we will also examine the impact of standard- and high-dose daily rifampicin and weekly rifapentine on the 4β-hydroxy-cholesterol to cholesterol ratio, an endogenous biomarker of CYP3A4 activity. This will provide critical pharmacodynamic (PD) data for use in population PK/PD models to quantify variability and inform optimal drug dosing in this vulnerable population of children. Nigeria is home to more children living with HIV than any other country in the world, and also bears one of the greatest burdens of incident TB. Since 2004, APIN Public Health Initiatives has provided HIV care and treatment to over 20,000 children in Nigeria and thus is uniquely positioned to support this vital PK research. This combination of studies addresses critical gaps in knowledge regarding PK and safety of newer drug combinations for HIV/TB cotreatment and TB prevention, findings that may inform WHO guidance on use in children, toward the goal of curbing TB’s devastating toll in this vulnerable population.