Efavirenz in HIV-Infected and HIV/TB Co-Infected Children - Full Text View

Sponsors and Collaborators:	National Institute of Allergy and Infectious Diseases (NIAID) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by:	National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:	NCT00802802

Purpose

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.

Condition	Intervention	Phase
HIV Infections Tuberculosis Coinfection	Drug: EFV and two NRTIs Drug: Rifampin-containing anti-tuberculosis therapy	Phase I

MedlinePlus related topics: AIDS Tuberculosis

Drug Information available for: Efavirenz Rifampin

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized, Open Label, Parallel Assignment, Safety/Efficacy Study
Official Title:	Dose-Finding and Pharmacogenetic Study of Efavirenz in HIV-Infected and HIV/TB Co-Infected Infants and Children 3 Months to Less Than 36 Months of Age

Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:

Determination of dose requirement of EFV administered as opened capsules for Cohort I [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
24-week safety and tolerance of EFV-based ART in Cohort I [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
Exploration of genetic polymorphisms in Cohort I [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Determination of dose requirement of EFV administered as opened capsules in Cohort II [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Safety and tolerance of EFV-based ART during concomitant rifampin-containing anti-TB therapy in Cohort II [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
Understand the influence of CYP 2B6 genetic polymorphisms on EFV clearance in the presence of rifampin in Cohort II [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Any treatment-related Grade 3 or Grade 4 toxicity requiring permanent discontinuation of EFV [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
Death [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
Failure to achieve the minimum target area under the curve (AUC) despite dose adjustment [ Time Frame: Throughout study ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Estimation of pharmacokinetic parameters of EFV in Cohort I [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Determination of correlation between dried blood spots (DBS) and plasma EFV concentrations in Cohort I [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Ability of 8-hydroxy-/EFV ratios in plasma and urine to predict EFV clearance phenotype in Cohort I [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Impact of pharmacokinetics and pharmacogenetics on virologic response and immunologic response in Cohort I [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Impact of concomitant rifampin-containing anti-TB therapy on EFV pharmacokinetics in Cohort II [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Pharmacokinetics of rifampin when administered with EFV in Cohort II [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Impact of pharmacokinetics and pharmacogenetics on virologic response and immunologic response in Cohort II [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Virologic endpoint, defined as less than 1 log10 decrease from entry in quantitative HIV RNA and RNA more than 400 copies/l at week 8 [ Time Frame: entry to Week 8 ] [ Designated as safety issue: No ]
Primary response variables: Pharmacokinetic parameters of EFV [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Secondary response variable, including, 8-hydroxy-EFV pharmacokinetic parameters, pharmacokinetic parameters of rifampin (Cohort II only), HIV-RNA, CD4% and CD4 count [ Time Frame: Throughout study ] [ Designated as safety issue: No ]

Estimated Enrollment:	100
Study Start Date:	December 2009
Estimated Primary Completion Date:	December 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Cohort I: Experimental HIV infected children 3 months to 36 months of age, receiving EFV and two NRTIs	Drug: EFV and two NRTIs Participants will be administered EFV at a dose ranging from 200 mg to 800 mg once daily, based on weight. Two NRTIs will also be part of the normal study treatment regimen. Treatment will last for 24 weeks.
Cohort II: Experimental HIV/TB coinfected children 3 months to 36 months of age, receiving EFV, two NRTIs, and rifampin-containing anti-tuberculosis therapy	Drug: EFV and two NRTIs Participants will be administered EFV at a dose ranging from 200 mg to 800 mg once daily, based on weight. Two NRTIs will also be part of the normal study treatment regimen. Treatment will last for 24 weeks. Drug: Rifampin-containing anti-tuberculosis therapy Treatment with rifampin-containing anti-tuberculosis treatment regimen. Treatment will last at least 24 weeks and up to 36 weeks.

Arms

Assigned Interventions

Cohort I: Experimental

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

Drug: EFV and two NRTIs

Participants will be administered EFV at a dose ranging from 200 mg to 800 mg once daily, based on weight. Two NRTIs will also be part of the normal study treatment regimen. Treatment will last for 24 weeks.

Cohort II: Experimental

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

Drug: EFV and two NRTIs

Participants will be administered EFV at a dose ranging from 200 mg to 800 mg once daily, based on weight. Two NRTIs will also be part of the normal study treatment regimen. Treatment will last for 24 weeks.

Drug: Rifampin-containing anti-tuberculosis therapy

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

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 efavirenz (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 is designed to provide necessary Phase I and II data on the safety, tolerance, and pharmacokinetics 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 have two study cohorts, which will enroll at the same time. Participants in Cohort I will be HIV infected infants without TB coinfection who are eligible for initiation of ART. Cohort I will be administered EFV and two NRTIs. EFV dosage will range from 200 mg to 600 mg once daily, based on weight. Treatment and study will last for 24 weeks.

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 2 weeks prior to enrollment. Participants in Cohort II will be followed while taking both rifampin-containing anti-TB and EFV therapy for up to 24 weeks; participants unable to obtain EFV capsules from in-country sources at the conclusion of the study may remain on the study longer than 24 weeks until discontinuing anti-TB therapy. An estimated 12 to 15 of these participants from Cohort II will be followed every 4 weeks on study and provided study drug (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. All participants will be treated with an EFV-based ART regimen using the capsule formulation of EFV and two NRTIs. 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).

Two weeks after the start of study treatment, intensive pharmacokinetic sampling prior to the observed dose at 2, 4, 8, 12, and 24 hours post-dose will be performed. Dried blood spots (DBS) will be prepared from each sample and subsequently analyzed; plasma samples will be stored as well. A urine specimen will also be obtained 3 to 5 hours post-dose.

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 when it is given as a capsule that is opened and sprinkled in food. This information will help recommend the best doses of EFV for children younger than 3 years of age.

Eligibility

Ages Eligible for Study:	3 Months to 35 Months
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

HIV infected
Treatment eligible as defined by country-specific guidelines
Able to swallow the contents of EFV as opened capsules in food or liquid vehicle
Parent or guardian able and willing to provide informed consent as designated by country-specific guidelines and (participant) willing to be followed at clinical site

Inclusion Criteria -- Cohort II only

Clinically diagnosed with HIV/TB coinfection and requiring rifampin-containing therapy, in the clinical judgment of the site investigator
Participant is tolerating a rifampin-containing antituberculosis drug regimen for at least 2 weeks prior to study entry
Participant plans to continue antituberculosis and study treatment for at least 16 weeks from initiation of study treatment

Exclusion Criteria:

Known hypersensitivity to any component of EFV capsule formulation
Severe malnutrition. More information on this criterion can be found in the study protocol.
Documented receipt of nevirapine (NVP) or EFV therapy within the previous 6 months, including single-dose NVP for prevention of mother-to-child transmission of HIV (PMTCT)
Infants younger than or equal to 6 months of age whose mothers have documentation of receiving NVP or EFV as part of PMTCT. More information on this criterion can be found in the study protocol.
Grade 2 or higher aspartate aminotransferase (AST) or alanine aminotransferase (ALT) at screening
Grade 3 or higher laboratory toxicity at screening
Higher than Grade 3 clinical toxicity at screening
Acute, serious infections requiring active treatment, such as Pneumocystis jiroveci pneumonia (PCP), cryptococcal meningitis, and tuberculosis (applicable to Cohort I only). 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, and receiving primary therapy
Use of abacavir as a background NRTI during the first 6 weeks on study treatment

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00802802

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

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

Investigators

Study Chair:	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.

More Information

Click here for more information on Efavirenz This link exits the ClinicalTrials.gov site

Publications:

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.

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.

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. Epub 2008 Mar 13.

Responsible Party:	DAIDS ( Rona Siskind )
Study ID Numbers:	IMPAACT P1070
Study First Received:	December 4, 2008
Last Updated:	December 12, 2008
ClinicalTrials.gov Identifier:	NCT00802802
Health Authority:	United States: Food and Drug Administration

Study placed in the following topic categories:

Bacterial Infections
Efavirenz
Sexually Transmitted Diseases, Viral
Acquired Immunodeficiency Syndrome
Immunologic Deficiency Syndromes
Virus Diseases
Rifampin

Signs and Symptoms
Gram-Positive Bacterial Infections
HIV Infections
Sexually Transmitted Diseases
Mycobacterium Infections
Tuberculosis
Retroviridae Infections

Additional relevant MeSH terms:

Anti-Infective Agents
RNA Virus Infections
Slow Virus Diseases
Molecular Mechanisms of Pharmacological Action
Immune System Diseases
Enzyme Inhibitors
Infection
Actinomycetales Infections

Pharmacologic Actions
Antibiotics, Antitubercular
Anti-Bacterial Agents
Therapeutic Uses
Lentivirus Infections
Antitubercular Agents
Nucleic Acid Synthesis Inhibitors
Leprostatic Agents

ClinicalTrials.gov processed this record on January 16, 2009