Efavirenz (EFV) in HIV-Infected and HIV/Tuberculosis (TB) Coinfected Children

NCT00802802 | Completed Phase 1

• 3 other identifiers: P107010633IMPAACT P1070
• Study Type: interventional
• Target: 67
• Locations: 4 countries
• Sites: 7

Brief 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.

Conditions

HIV Infections; Tuberculosis

Outcome Measures

Primary Outcomes (4)

• Any treatment-related Grade 2B rash or Grade 3 or 4 toxicity requiring permanent discontinuation of efavirenz (EFV)

  Any treatment-related Grade 2B rash or Grade 3 or 4 toxicity requiring permanent discontinuation of efavirenz (EFV)

  Measured through Week 24

• Death

  Death

  Measured through Week 24

• A safety event as defined as a Grade 4 life-threatening toxicity or Grade 4 toxicity accompanying a serious adverse event (SAE) (e.g., hospitalization) or death that is judged to be at least possibly related to EFV

  A safety event as defined as a Grade 4 life-threatening toxicity or Grade 4 toxicity accompanying a serious adverse event (SAE) (e.g., hospitalization) or death that is judged to be at least possibly related to EFV

  Measured through Week 24

• Failure to achieve the area under the curve (AUC) target range despite dose adjustment

  Failure to achieve the area under the curve (AUC) target range despite dose adjustment

  Measured through Week 24

Secondary Outcomes (1)

• A confirmed decrease (less than 1 log) from entry quantitative HIV RNA and RNA greater than 400 copies/mL

  Measured at Week 8

Study Arms (3)

Cohort I, Step 1

EXPERIMENTAL

HIV-infected children 3 months to 36 months of age, receiving EFV and two NRTIs

Drug: Efavirenz (EFV)

Cohort II

EXPERIMENTAL

HIV/TB-coinfected children 3 months to 36 months of age, receiving EFV, two NRTIs, and rifampin-containing anti-tuberculosis (anti-TB) therapy

Drug: Efavirenz (EFV); Drug: Rifampin-containing anti-TB therapy

Cohort I, Step 2

EXPERIMENTAL

HIV-infected children from Cohort I who become coinfected with TB during the study. They will receive EFV, two NRTIs, and rifampin-containing anti-TB therapy

Drug: Efavirenz (EFV); Drug: Rifampin-containing anti-TB therapy

Interventions

Efavirenz (EFV) DRUG

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).

Also known as: EFV

Cohort I, Step 1; Cohort I, Step 2; Cohort II

Rifampin-containing anti-TB therapy DRUG

Treatment with rifampin-containing anti-TB treatment regimen. Treatment will last at least 24 weeks and up to 36 weeks.

Cohort I, Step 2; Cohort II

Eligibility Criteria

• Age: 3 Months - 35 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Older than 3 months but younger than 36 months of age (up to but not including the 3rd birthday) at the time of enrollment
• Documentation of HIV-1 infection defined as positive results from two samples collected at different time points. More details on this criterion can be found in the protocol.
• Treatment-eligible as defined by country-specific guidelines, World Health Organization (WHO) treatment algorithm, or by clinician's determination that the participant should be treated on other clinical grounds and will initiate antiretroviral (ARV) therapy (ART) AND has determined that in-country access to ART will be available at study conclusion
• Able to swallow the contents of efavirenz (EFV) as opened capsules in food or liquid vehicle
• Parent, legal guardian, or designated guardian according to country-specific guidelines able and willing to provide signed informed consent and to have the participant followed at the clinical site
• Currently enrolled in Cohort I, Step 1
• Clinically diagnosed with HIV/TB co-infection and requires rifampin-containing therapy, in the clinical judgment of the site investigator
• Chemistry and hematology laboratory values drawn during Cohort I, Step 1 are all Grade 3 or lower, except for aspartate aminotransferase/alanine aminotransferase (AST/ALT), which must be Grade 2 or lower within 4 weeks of entry into Cohort I, Step 2
• Clinically diagnosed with HIV/TB coinfection and requires rifampin-containing therapy, in the clinical judgment of the site investigator
• Participant is tolerating a rifampin-containing anti-TB drug regimen for at least 1 week prior to study entry
• Participant plans to continue anti-TB and study treatment for at least 16 weeks from initiation of study treatment

You may not qualify if:

• Known hypersensitivity to any component of EFV capsule formulation.
• Participants with severe malnutrition defined in the protocol
• Infants/children who have previously been treated with EFV-based ART
• Infants/children younger than 24 months of age with documented receipt of nevirapine (NVP) therapy, including single dose NVP for prevention of mother-to-child transmission (PMTCT). More information on this criterion can be found in the protocol.
• Infants/children younger than 24 months of age whose mothers have documentation of receiving NVP as part of PMTCT unless they meet criteria under the exception detailed in the protocol. More information on this criterion can be found in the protocol.
• Grade 2 or higher AST or ALT at screening
• Any Grade 3 or higher laboratory toxicity at screening
• Higher than Grade 3 clinical toxicity at screening
• Participants with acute, serious infections requiring active treatment (e.g. pneumocystis pneumonia \[PCP\], etc.) may not enroll until judged to be clinically stable by the site investigator. Participants may enroll while completing active opportunistic infection treatment. Prophylaxis against opportunistic infections, including isoniazid, will be allowed.
• Chemotherapy for active malignancy
• Active central nervous system (CNS) infection, such as TB meningitis or cryptococcal meningitis, receiving primary therapy
• Breastfeeding infants whose mothers are receiving or plan to initiate EFV-based highly active antiretroviral therapy (HAART) before the results of the intensive pharmacokinetic (PK) studies are available will be excluded from enrollment in this study due to the potential effect on the infant's EFV PK levels that will be evaluated in the study. More information on this criterion can be found in the protocol.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (7)

Byramjee Jeejeebhoy Medical College (BJMC) CRS

Pune, Maharashtra, 411001, India

Location

Soweto IMPAACT CRS

Johannesburg, Gauteng, 1862, South Africa

Location

Shandukani Research CRS

Johannesburg, Gauteng, 2001, South Africa

Location

Durban Paediatric HIV CRS

Durban, KwaZulu-Natal, 4001, South Africa

Location

Family Clinical Research Unit (FAM-CRU) CRS

Tygerberg Hills, Western Cape, 7505, South Africa

Location

MU-JHU Research Collaboration (MUJHU CARE LTD) CRS

Kampala, Uganda

Location

Harare Family Care CRS

Harare, Zimbabwe

Location

Related Publications (3)

• ter Heine R, Scherpbier HJ, Crommentuyn KM, Bekker V, Beijnen JH, Kuijpers TW, Huitema AD. A pharmacokinetic and pharmacogenetic study of efavirenz in children: dosing guidelines can result in subtherapeutic concentrations. Antivir Ther. 2008;13(6):779-87.

  PMID: 18839779 BACKGROUND

• Kwara A, Lartey M, Sagoe KW, Xexemeku F, Kenu E, Oliver-Commey J, Boima V, Sagoe A, Boamah I, Greenblatt DJ, Court MH. Pharmacokinetics of efavirenz when co-administered with rifampin in TB/HIV co-infected patients: pharmacogenetic effect of CYP2B6 variation. J Clin Pharmacol. 2008 Sep;48(9):1032-40. doi: 10.1177/0091270008321790.

  PMID: 18728241 BACKGROUND

• Wintergerst U, Hoffmann F, Jansson A, Notheis G, Huss K, Kurowski M, Burger D. Antiviral efficacy, tolerability and pharmacokinetics of efavirenz in an unselected cohort of HIV-infected children. J Antimicrob Chemother. 2008 Jun;61(6):1336-9. doi: 10.1093/jac/dkn112. Epub 2008 Mar 13.

  PMID: 18343800 BACKGROUND

MeSH Terms

Conditions

HIV Infections; Tuberculosis

Interventions

efavirenz

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses

Study Officials

• Carolyn Bolton, MBBCh

  UAB, CIDRZ

  STUDY CHAIR

• Mutsawashe Bwakura-Dangarembizi, MD

  Univ. of Zimbabwe, AIDS Research Unit

  STUDY CHAIR

• Ellen Gould Chadwick, MD

  Northwestern Univ. Feinberg School of Medicine - Dept. of Peds, Children's Memorial Hosp.

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 4, 2008
• First Posted: December 5, 2008
• Study Start: February 10, 2010
• Primary Completion: March 18, 2016
• Study Completion: February 16, 2018
• Last Updated: November 1, 2021

Record last verified: 2021-10

Locations

IN (1); UG (1); ZA (4); ZI (1)