Contributing Factors for Poor HIV Treatment Response in Children With TB/HIV Coinfection

Tuberculosis Clinical Trial

Official title:

Pharmacokinetics of Anti-tuberculosis and Antiretroviral Drugs in Children

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03800407
• Other study ID #: IRB201801820 TB/HIV - N
• Secondary ID: 2R01HD0717795R01
• Status: Recruiting
• Start date: January 28, 2019
• Est. completion date: November 30, 2024

Study information

• Verified date: May 2024
• Source: University of Florida
• Contact: Awewura Kwara, MD
• Phone: 3522739501
• Email: awewura.kwara[@]medicine.ufl.edu
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Efavirenz (EFV)-based antiretroviral therapy (ART) remains the preferred regimen in human immunodeficiency virus (HIV)-infected children aged 3 years or older on rifampin-containing antituberculosis (anti-TB) therapy. This is because drug interactions between first-line anti-TB therapy with protease inhibitors (PIs) are more severe to adjust for, and interactions with integrase strand transfer inhibitors (INSTIs) are not well studied in that age group. Although, current weight-based EFV dosing recommendation is not optimal in some children, pharmacokinetic-treatment response (PK-PD) data to guide optimal dosing of EFV during concurrent rifampin-containing therapy in children is very limited. The study team propose that EFV concentrations outside the optimal therapeutic range in children will be associated with virologic failure due to lack of efficacy because of low concentrations or increased central nervous system (CNS) toxicities from high concentrations leading to poor medication adherence. The study will determine virological suppression rates in HIV-infected children with and without TB coinfection treated with standard efavirenz-based therapy and examine the factors contributing to poor virologic response.

Description:

In a previous study, the study team found that first-line anti-TB therapy had minimal effect on EFV pharmacokinetics (PK) at the population level, but children with TB/HIV coinfection on anti-TB therapy had a trend towards worse virologic outcome compared to those with only HIV infection. Due to the small sample size, the study team were unable to examined the patient factors contributing to the poor virologic response. The study team hypothesized that virologic suppression rates on EFV-based therapy is significantly lower in children with TB/HIV coinfection compared to those with HIV alone. In addition, virologic response will be dependent EFV plasma concentrations, CYP2B6 516 G>T genotype and/or adherence level. This hypothesis is based on the premise that extremes (low and high EFV concentration, respectively) could lead to virologic failure because of lack of efficacy or intolerable side effects leading to poor adherence. The current study will investigate the effect of anti-TB therapy, CYP2B6 genotype and pharmacokinetically determined adherence level on virologic response in children with TB/HIV coinfection treated with EFV-based ART.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 382
• Est. completion date: November 30, 2024
• Est. primary completion date: May 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Years to 14 Years

Eligibility

Inclusion Criteria:

• HIV seropositive children with or without active TB

• Antiretroviral-naïve to efavirenz and meet criteria for initiation or switch to efavirenz-based ART

• Are available for follow-up until achievement of a study endpoint like completion of study at 6 months or discontinuation of ART.

Exclusion Criteria:

• Unable to obtain informed signed consent parent(s) or legal guardian

• Have AIDS-related opportunistic infections other than TB

• History of acute hepatitis within 30 days of study entry

• Persistent vomiting or diarrhea at time of enrolment

• Hemoglobin < 6 g/dl, white blood cells < 2500/mm3, serum creatinine > 1.5 mg/dl, aspartate transaminase (AST) and alanine transaminase (ALT) > 2 times upper limit of normal

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• Coinfection
• HIV Infections
• Human Immunodeficiency Virus
• Tuberculosis

Intervention

Other:
• Observational study
Outcome of EFV-based ART in children with TB/HIV coinfection compared to those with HIV only on EFV-based ART

Locations

Country	Name	City	State
Ghana	Kwame Nkrumah University of Science and Technology	Kumasi

Sponsors (2)

Lead Sponsor	Collaborator
University of Florida	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Country where clinical trial is conducted

Ghana, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	TB coinfection status and HIV RNA < 200 copies/mL on EFV-based ART in HIV-infected children.	The proportion of children with TB/HIV coinfection with virological suppression (HIV RNA < 200 copies/mL) on EFV-based ART and anti-TB therapy compared to that in children with only HIV infection on EFV-based therapy.	At week 24 of HIV therapy.
Secondary	Efavirenz plasma mid-dose concentration and HIV RNA suppression < 200 copies/mL.	Relationship between EFV mid-dose concentration and HIV RNA suppression rate in the combined population of HIV-infected children with and without TB coinfection.	Up to week 24 of HIV therapy.
Secondary	Random efavirenz concentration below the limit of detection (poor ART adherence) and HIV RNA suppression rate.	Relationship poor ART adherence and EFV-based ART response in the combined population of HIV-infected children with and without TB coinfection.	Up to week 24 of HIV therapy.
Secondary	CYP2B6 516G>T genotype status and random efavirenz concentration below the limit of detection (poor ART adherence).	Relationship between CYP2B6 516G>T genotype status and likelihood of poor EFV-based ART adherence.	Up to week 24 of HIV therapy.
Secondary	CYP2B6 516G>T genotype status and HIV RNA suppression < 200 copies/mL.	Relationship between CYP2B6 516G>T genotype status and likelihood of HIV RNA suppression.	Up to week 24 of HIV therapy.
Secondary	TB coinfection status and risk of virological failure on EFV-based ART.	Proportion of children with TB/HIV coinfection compared to those with only HIV infection with virological failure (HIV RNA > 1000 copies/mL) at 12 months of EFV-based ART.	Up to week 48 of HIV therapy.