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

Sponsor

University of Florida (Other)

Overall Status

Recruiting

CT.gov ID

NCT03800407

Collaborator

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)

382

Enrollment

Location

55.1

Anticipated Duration (Months)

6.9

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Tuberculosis Human Immunodeficiency Virus Coinfection	Other: Observational study

Detailed 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.

Study Design

Study Type:

Observational

Anticipated Enrollment :

382 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

Pharmacokinetics of Anti-tuberculosis and Antiretroviral Drugs in Children

Actual Study Start Date :

Jan 28, 2019

Anticipated Primary Completion Date :

Jan 31, 2023

Anticipated Study Completion Date :

Aug 31, 2023

Arms and Interventions

Arm	Intervention/Treatment
EFV-based ART ART-naïve HIV-infected children aged 3 - 14 years who initiate EFV-based ART	Other: Observational study Outcome of EFV-based ART in children with TB/HIV coinfection compared to those with HIV only on EFV-based ART
Concurrent EFV-based ART plus anti-TB therapy ART-naïve HIV-infected children aged 3 - 14 years with TB coinfection who initiate EFV-based ART while receiving first-line anti-TB therapy	Other: Observational study Outcome of EFV-based ART in children with TB/HIV coinfection compared to those with HIV only on EFV-based ART

Arm

Intervention/Treatment

EFV-based ART

ART-naïve HIV-infected children aged 3 - 14 years who initiate EFV-based ART

Other: Observational study

Outcome of EFV-based ART in children with TB/HIV coinfection compared to those with HIV only on EFV-based ART

Concurrent EFV-based ART plus anti-TB therapy

ART-naïve HIV-infected children aged 3 - 14 years with TB coinfection who initiate EFV-based ART while receiving first-line anti-TB therapy

Other: Observational study

Outcome of EFV-based ART in children with TB/HIV coinfection compared to those with HIV only on EFV-based ART

Outcome Measures

Primary Outcome Measures

TB coinfection status and HIV RNA < 200 copies/mL on EFV-based ART in HIV-infected children. [At week 24 of HIV therapy.]
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.

Secondary Outcome Measures

Efavirenz plasma mid-dose concentration and HIV RNA suppression < 200 copies/mL. [Up to week 24 of HIV therapy.]
Relationship between EFV mid-dose concentration and HIV RNA suppression rate in the combined population of HIV-infected children with and without TB coinfection.
Random efavirenz concentration below the limit of detection (poor ART adherence) and HIV RNA suppression rate. [Up to week 24 of HIV therapy.]
Relationship poor ART adherence and EFV-based ART response in the combined population of HIV-infected children with and without TB coinfection.
CYP2B6 516G>T genotype status and random efavirenz concentration below the limit of detection (poor ART adherence). [Up to week 24 of HIV therapy.]
Relationship between CYP2B6 516G>T genotype status and likelihood of poor EFV-based ART adherence.
CYP2B6 516G>T genotype status and HIV RNA suppression < 200 copies/mL. [Up to week 24 of HIV therapy.]
Relationship between CYP2B6 516G>T genotype status and likelihood of HIV RNA suppression.
TB coinfection status and risk of virological failure on EFV-based ART. [Up to week 48 of HIV therapy.]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

3 Years to 14 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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