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| Name | Class |
|---|---|
| APIN Public Health Initiatives | UNKNOWN |
| University of Cape Town | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Dolutegravir PK during standard and high-dose rifampicin | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| rifampicin | Drug | 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 |
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Holly Rawizza, MD, MPH | Contact | 617-432-4686 | hrawizza@bwh.harvard.edu |
| Name | Affiliation | Role |
|---|---|---|
| Holly Rawizza, MD, MPH | Brigham and Women's Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University College Hospital/ University of Ibadan | Recruiting | Ibadan | Oyo State | Nigeria |
At the request of researchers de-identified data may be shared.
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| ID | Term |
|---|---|
| D055985 | Latent Tuberculosis |
| ID | Term |
|---|---|
| D014376 | Tuberculosis |
| D009164 | Mycobacterium Infections |
| D000193 | Actinomycetales Infections |
| D016908 | Gram-Positive Bacterial Infections |
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| ID | Term |
|---|---|
| D012293 | Rifampin |
| ID | Term |
|---|---|
| D012294 | Rifamycins |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
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Prospective single-arm, open-label, pharmacokinetic and safety study
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| 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 |
| D001424 | Bacterial Infections |
| D001423 | Bacterial Infections and Mycoses |
| D007239 | Infections |
| D000085343 | Latent Infection |
| D047029 | Lactams, Macrocyclic |
| D047028 | Macrocyclic Compounds |
| D011083 | Polycyclic Compounds |