Mind the Gaps: Pharmacokinetic Research to Advance Pediatric HIV/TB Cotreatment and TB Prevention
Trial Snapshot
- Phase
- Phase 1
- Status
- Recruiting
- Sponsor
- Brigham and Women's Hospital
- Enrollment
- 20
- Locations
- 1
- Primary Endpoint
- Dolutegravir AUC during high-dose rifampicin
Study Overview
Brief Summary
Tuberculosis (TB) is the leading cause of death among children with HIV, yet insufficient data are available on the pharmacokinetics of newer HIV/TB cotreatment strategies in children. Current WHO-recommended rifampicin dosages result in low concentrations in most children, and high-dose rifampicin may improve outcomes and shorten treatment duration. Yet the impact of high-dose rifampicin on dolutegravir exposures has not been examined in children. This study aims to evaluate the safety and pharmacokinetics of dolutegravir twice daily among HIV/TB coinfected children receiving standard-dose and high-dose rifampicin.
Detailed Description
This study is a prospective, single-arm, open-label, intensive and sparse pharmacokinetic (PK) and safety study to evaluate steady-state dolutegravir (DTG) concentrations among 20 HIV/TB coinfected children 4 weeks to <6 years of age requiring concurrent TB treatment. Ten patients will be recruited into each of two age cohorts: 4 weeks to <2 years and ≥2 years to <6 years.
Children will be recruited from two large pediatric HIV clinics in Nigeria. Children in this study will receive HIV/TB cotreatment that is considered standard of care consisting of DTG twice daily during rifampicin (RIF)-containing TB treatment. For this portion of the study, the primary intervention is additional blood sampling for drug concentration determination and biomarker assessment. Additionally, during a two week period (study weeks 20-21), the RIF dose will be increased from standard-dose to high-dose RIF, during which two-way PK and toxicity monitoring will occur. Clinical and laboratory monitoring for toxicity during HIV/TB cotreatment is consistent with routine care.
PK sampling for drug concentration determination will occur at three time points during the 48-week study. Specifically, PK sampling will occur at week-20 to evaluate DTG twice daily during standard-dose RIF, week-22 to evaluate DTG twice daily during high-dose RIF, and at week-30 to evaluate DTG once daily after TB treatment is complete.
Additionally, the endogenous biomarker of CYP3A4 activity, 4-beta-hydroxycholesterol to cholesterol ratio, will be evaluated to advance understanding of underlying mechanisms of drug action. Blood sampling to quantify this biomarker will occur at either 4 (among ART-experienced children) or 5 (ART-naive) time points during the 48-week study.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 4 Weeks to 5 Years (Child)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •ART-naïve or ART-experienced HIV-infected children between 4 weeks and <6 years of age
- •Active TB diagnosis
- •Weight of at least 3 kilograms
- •Consent of the parent or legal guardian
Exclusion Criteria
- •Baseline labs with evidence of ≥grade 3 abnormalities: ALT, total bilirubin, absolute neutrophil count (ANC), platelets, or creatinine
- •Suspected TB meningitis or presenting with acute respiratory distress or decompensation
- •Receipt of a medication that has drug-drug interactions with dolutegravir or rifampicin
Arms & Interventions
Dolutegravir PK during standard and high-dose rifampicin
This is a single arm study: all patients are started on HIV/TB cotreatment considered standard of care and then for two weeks (study weeks 20-21) high-dose rifampicin is given during which safety and pharmacokinetics are examined.
Intervention: rifampicin (Drug)
Outcomes
Primary Outcomes
Dolutegravir AUC during high-dose rifampicin
Time Frame: week 22
Dolutegravir AUC will be compared against therapeutic ranges established in the literature and during standard-dose rifampicin
Dolutegravir AUC during standard-dose rifampicin
Time Frame: week 20
Dolutegravir area under the concentration time curve (AUC) will be compared to therapeutic ranges established in the adult and pediatric literature
Secondary Outcomes
- Rifampicin maximum concentration (Cmax) during standard-dose rifampicin(week 20)
- Rifampicin Cmax during high-dose rifampicin(week 22)
- Proportion of participants experiencing severe (grade 3 or 4) clinical or laboratory adverse events(Week 48)
Investigators
Holly Rawizza, M.D., M.P.H.
Assistant Professor of Medicine
Brigham and Women's Hospital