Dolutegravir Pharmacokinetics Among HIV/TB Coinfected Children Receiving Standard and High-dose Rifampicin

Mind the Gaps: Pharmacokinetic Research to Advance Pediatric HIV/TB Cotreatment and TB Prevention

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.

Study Overview

• Status: Recruiting
• Conditions: Tuberculosis Infection; Pediatric HIV Infection
• Intervention / Treatment: Drug: 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 Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Holly Rawizza, MD, MPH; Phone Number: 617-432-4686; Email: hrawizza@bwh.harvard.edu

Study Locations

• Nigeria
  • Oyo State
    • Ibadan, Oyo State, Nigeria
      • Recruiting
      • University College Hospital/ University of Ibadan
      • Contact: Regina Oladokun, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 weeks to 5 years (Child)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: rifampicin; Patients will receive standard TB and HIV treatment, however, for two weeks (study weeks 20-21) the dose of rifampicin will be increased from standard-dose to high-dose to assess pharmacokinetics and safety

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dolutegravir AUC during standard-dose rifampicin	Dolutegravir area under the concentration time curve (AUC) will be compared to therapeutic ranges established in the adult and pediatric literature	week 20
Dolutegravir AUC during high-dose rifampicin	Dolutegravir AUC will be compared against therapeutic ranges established in the literature and during standard-dose rifampicin	week 22

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rifampicin maximum concentration (Cmax) during standard-dose rifampicin	Rifampicin Cmax will be determined during standard rifampicin	week 20
Rifampicin Cmax during high-dose rifampicin	Rifampicin Cmax will be determined during high-dose rifampicin and compared to that observed during standard-dose rifampicin	week 22
Proportion of participants experiencing severe (grade 3 or 4) clinical or laboratory adverse events	Laboratory and clinical toxicities are monitored at 8 time points throughout the study and the proportion of children experiencing severe adverse events will be determined	Week 48

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: University of Cape Town; APIN Public Health Initiatives
• Investigators: Principal Investigator: Holly Rawizza, MD, MPH, Brigham and Women's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): July 7, 2023
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: September 16, 2021
• First Submitted That Met QC Criteria: September 26, 2021
• First Posted (Actual): October 6, 2021

Study Record Updates

• Last Update Posted (Actual): December 2, 2025
• Last Update Submitted That Met QC Criteria: November 25, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: pharmacokinetic; dolutegravir; rifampicin
• Additional Relevant MeSH Terms: Latent Infection; Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Latent Tuberculosis; Heterocyclic Compounds; Heterocyclic Compounds, Fused-Ring; Polycyclic Compounds; Heterocyclic Compounds, 4 or More Rings; Rifamycins; Lactams, Macrocyclic; Macrocyclic Compounds; Rifampin
• Other Study ID Numbers: 2021P002401

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: At the request of researchers de-identified data may be shared.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No