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

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ClinicalTrials.gov Identifier: NCT03800407
Recruitment Status : Recruiting
First Posted : January 11, 2019
Last Update Posted : February 2, 2021
Sponsor:
Collaborator:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
University of Florida

Study Description
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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
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
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Study Type : Observational
Estimated Enrollment : 236 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Pharmacokinetics of Anti-tuberculosis and Antiretroviral Drugs in Children
Actual Study Start Date : January 28, 2019
Estimated Primary Completion Date : January 31, 2023
Estimated Study Completion Date : August 31, 2023

Resource links provided by the National Library of Medicine


Groups and Cohorts
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Group/Cohort 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
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Primary Outcome Measures :
  1. TB coinfection status and HIV RNA < 200 copies/mL on EFV-based ART in HIV-infected children. [ Time Frame: 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 :
  1. Efavirenz plasma mid-dose concentration and HIV RNA suppression < 200 copies/mL. [ Time Frame: 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.

  2. Random efavirenz concentration below the limit of detection (poor ART adherence) and HIV RNA suppression rate. [ Time Frame: 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.

  3. CYP2B6 516G>T genotype status and random efavirenz concentration below the limit of detection (poor ART adherence). [ Time Frame: Up to week 24 of HIV therapy. ]
    Relationship between CYP2B6 516G>T genotype status and likelihood of poor EFV-based ART adherence.

  4. CYP2B6 516G>T genotype status and HIV RNA suppression < 200 copies/mL. [ Time Frame: Up to week 24 of HIV therapy. ]
    Relationship between CYP2B6 516G>T genotype status and likelihood of HIV RNA suppression.

  5. TB coinfection status and risk of virological failure on EFV-based ART. [ Time Frame: 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.


Biospecimen Retention:   Samples With DNA
Ethylenediaminetetraacetic acid (EDTA) plasma and whole blood DNA

Eligibility Criteria
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Ages Eligible for Study:   3 Years to 14 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Children aged 3 to 14 years old with HIV infection with or without active TB
Criteria

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03800407


Contacts
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Contact: Awewura Kwara, MD 3522739501 awewura.kwara@medicine.ufl.edu
Contact: Oluwayemisi Ojewale, MBChB, MPH 3522739446 Oluwayemisi.Ojewale@medicine.ufl.edu

Locations
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Ghana
Kwame Nkrumah University of Science and Technology Recruiting
Kumasi, Ghana
Contact: Sampson Antwi, MBChB    +233265812061    kantwi@gmail.com   
Contact: Anthony Enimil, MBChB    +233208164433    tenimil@live.com   
Sponsors and Collaborators
University of Florida
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators
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Principal Investigator: Awewura Kwara, MD University of Florida
More Information
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Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT03800407    
Other Study ID Numbers: IRB201801820 TB/HIV - N
2R01HD071779 ( U.S. NIH Grant/Contract )
First Posted: January 11, 2019    Key Record Dates
Last Update Posted: February 2, 2021
Last Verified: February 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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.: Yes
Keywords provided by University of Florida:
Pharmacokinetic
Concurrent antituberculosis therapy
Efavirenz
Virologic response
Children
Additional relevant MeSH terms:
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Tuberculosis
Acquired Immunodeficiency Syndrome
HIV Infections
Coinfection
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Bacterial Infections and Mycoses
Infections
Immunologic Deficiency Syndromes
 Immune System Diseases
Blood-Borne Infections
Communicable Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Slow Virus Diseases