Efavirenz (EFV) in HIV-Infected and HIV/Tuberculosis (TB) Coinfected Children
Condition: HIV Infections; Tuberculosis
MeSH terms: Tuberculosis
Study type: Interventional
Phase: Phase 1

Summary: 
      Efavirenz (EFV) is an anti-HIV medicine that is commonly used to treat HIV infection in
      adults and children older than 3 years of age. This study is being conducted to look at the
      safety of EFV, blood levels of EFV, genetic factors that may affect blood levels of EFV, and
      how easy it is for infants and young children to take and tolerate EFV. This information will
      help recommend the best doses of EFV for children younger than 3 years of age.
    

Detailed description: 
      An increasing number of children in resource-limited countries require treatment for both HIV
      and tuberculosis (TB); however, the options for antiretroviral therapy (ART) that is
      compatible with concurrent rifampin-containing anti-TB therapy are limited. As a result,
      treatment of HIV/TB-coinfected patients remains difficult with multiple drug interactions,
      very high pill burdens, overlapping toxicities, and possible immune reconstitution affecting
      treatment outcomes.

      The use of EFV in adults and older children has allowed them to maintain their non-nucleoside
      reverse transcriptase inhibitor (NNRTI) backbone while receiving TB therapy including
      rifampin. In younger children with TB/HIV coinfection, the first-line treatment
      recommendation has been the triple-nucleoside reverse transcriptase inhibitor (NRTI) regimen.
      However, this regimen has been shown to be less effective than an EFV plus NNRTI-based
      regimen. In addition, triple-NRTI regimens in resource-limited settings are costly and have
      limited data in patients with TB, and monitoring for drug-related hypersensitivity reactions
      is difficult. All of these factors make EFV an attractive agent for use in HIV-infected
      pediatric patients with and without TB coinfection. This study will evaluate the safety,
      tolerance, and pharmacokinetics (PKs) of EFV when administered as opened capsules to
      pediatric patients younger than 3 years of age, with and without concomitant
      rifampin-containing anti-TB therapy. This study will also investigate genetic polymorphisms,
      including CYP 2B6, to help establish dosing guidelines.

      This study will have two cohorts that will enroll at the same time. Cohort I, Step 1 will
      enroll HIV-infected infants without TB coinfection who are eligible for initiation of ART.
      Cohort I, Step 1 will be administered EFV for up to 24 weeks. EFV dosage, in Cohort I, Step
      1, will range from 50 mg to 600 mg once daily, based on weight and CYP 2B6 genotype.

      Participants in Cohort I Step 1 who develop TB or TB immune reconstitution inflammatory
      syndrome (IRIS) and require anti-TB medications will be allowed to enroll into Cohort I, Step
      2, in which they will receive rifampin-containing anti-TB therapy and a higher dose of EFV
      (50 mg to 800 mg) to account for the anticipated impact of rifampin on EFV PKs. If
      participants in Cohort I, Step 2 require more than 24 weeks of anti-TB therapy and are unable
      to obtain EFV capsules from in-country sources, they may remain on the study longer than 24
      weeks until discontinuing anti-TB therapy, up to 36 weeks study duration.

      Participants in Cohort II will be HIV/TB coinfected infants who are eligible for ART and have
      been treated with and tolerated a rifampin-containing anti-TB treatment regimen for at least
      1 week prior to enrollment. Participants in Cohort II will be followed while taking both
      rifampin-containing anti-TB and EFV therapy for 24 weeks; participants unable to obtain EFV
      capsules from in-country sources at the conclusion of the study may remain on the study until
      discontinuing anti-TB therapy, up to 36 weeks study duration. An estimated 10 to 20 of these
      participants from Cohort II will be followed every 4 weeks on study and provided EFV until
      completion of TB treatment (for up to 36 weeks study duration).

      Participants in both cohorts will be stratified based on age. One stratification will include
      children 3 months to younger than 24 months of age, and the second stratification will
      include children 24 months to younger than 36 months of age. Participants will then be
      further stratified by cytochrome P450 genotype polymorphisms, including CYP 2B6. All
      participants will receive an EFV-based ART regimen using the capsule formulation of EFV and
      two NRTIs (chosen by site investigator). EFV capsules will be opened into a small amount of
      compatible, familiar, and locally available food or liquid (e.g., formula, expressed breast
      milk, mashed banana).

      Study visits will occur at screening, entry, and at Weeks 2, 4, 6, 8, 12, 16, 20, and 24;
      some participants may continue to have a visit every 4 weeks after Week 24 until Week 36. At
      most visits, participants will undergo a physical exam, give a medical history, and have
      blood and urine collected. At some visits, dried blood spots (DBS) will be prepared and
      plasma samples will be stored. The Week 2 visit will also consist of intensive PK samplings
      where blood will be collected prior to taking the EFV dose and at 2, 4, 8, 12, and 24 hours
      post-dose. Individual dose adjustments may be made based on the results from the Week 2
      visit.
    

Intervention name(s): Efavirenz (EFV); Rifampin-containing anti-TB therapy
Intervention type(s): Drug; Drug
Intervention description(s): Participants will be administered oral EFV at a dose ranging from 50 mg to 800 mg once daily, based on weight and CYP 2B6 genotype. EFV capsules will be opened into a small amount of a compatible food or liquid vehicle; the smallest amount of food or liquid that will enable the child to swallow the capsule contents should be used (i.e., EFV should not be taken with a meal).; Treatment with rifampin-containing anti-TB treatment regimen. Treatment will last at least 24 weeks and up to 36 weeks.
Other intervention name(s): EFV
Intervention MeSH terms: Efavirenz; Rifampin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment