Neuropsychiatric Side Effects of Efavirenz in Children Living With HIV

Neuropsychiatric Adverse Effects of Efavirenz in Children Living With HIV in Kilimanjaro, Tanzania

Efavirenz is among the preferred antiretroviral drugs for HIV-infected children. Increasing evidence shows that central nervous system side-effects in adults are more common than previously thought. Still, reliable data in children are lacking. As HIV-infected children nowadays have a prospect of reaching adulthood, there is an urgent need to identify potential long-term central nervous system side-effects, interfering with neurodevelopment and psychosocial maturation. Using validated tools, we assessed (1) competence (social/activities/school) and psychopathology (internalizing/externalizing problems), (2) cognitive performance (intelligence and working memory), and (3) adherence in Tanzanian children on an efavirenz or non-efavirenz based regimen

In this cross-sectional observational study the investigators will examine neuropsychiatric and neurocognitive functioning in 126 children (aged 6-11 years) on long-term combination antiretroviral therapy (cART) with or without efavirenz.

Study Overview

• Status: Completed
• Conditions: Medication Adherence; Drug-Related Side Effects and Adverse Reactions; Child Behavior; Cognitive Symptom; Efavirenz
• Intervention / Treatment: Drug: Efavirenz; Drug: Nevirapine; Drug: Lopinavir-Ritonavir Drug Combination

Detailed Description

In this cross-sectional observational study, we include HIV-infected children (6-12 years) on cART for ≥ 6 months, with viral loads ≤ 1000 copies/ml in Kilimanjaro Region, Tanzania. Psychopathology and competence will be assessed using the Child Behaviour Checklist. Cognitive performance will be assessed using the Raven's Coloured Progressive Matrices and the digit span test. Non-adherence is defined as any reported missed doses over the previous 3 days or <100% adherence since the last clinical visit. Analysis of covariance and logistic regression models will be used to assess differences between groups. .

• Study Type: Observational
• Enrollment (Actual): 144

Contacts and Locations

Study Locations

• Tanzania
  • Kibosho, Tanzania
    • Kibosho Hospital
  • Moshi, Tanzania
    • Kiboroloni Dispensary
  • Moshi, Tanzania
    • Majengo Health Centre
  • Moshi, Tanzania
    • Pasua Health Centre
  • Kilimanjaro Region
    • Moshi, Kilimanjaro Region, Tanzania, 3010
      • Kilimanjaro Christian Medical Centre
    • Moshi, Kilimanjaro Region, Tanzania, 3054
      • Mawenzi Regional Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 12 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Tanzanian children (6-12 years) living with HIV and receiving cART

Description

Inclusion Criteria:

• Aged 6 until 12 years
• HIV seropositive
• Using cART, with or without efavirenz, for at least 6 months
• Registered patient at one of the participating centres
• In the presence of at least one parent or caregiver who is part if the child's life/upbringing

Exclusion Criteria:

• Switch of cART regimen in the last 6 months
• History of brain injury, mental health and cognitive impairment before starting cART
• HIV RNA >1000 copies/mL within the past year
• Any AIDS-defining illness or acute illness (e.g. fever, lowered consciousness, dehydration) at time of inclusion
• Children with parent(s) or caregiver(s) not wanting or not able to give informed consent

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Efavirenz; Children using efavirenz-based cART for at least 6 months	Drug: Efavirenz; Weight-based dosing according to the National Guidelines for the Management of HIV and AIDS; Other Names: Efavirenz-group
Non-efavirenz; Children using non-efavirenz-based cART (nevirapine or Lopinavir-Ritonavir Drug Combination) for at least 6 months.	Drug: Nevirapine; Weight-based dosing according to the National Guidelines for the Management of HIV and AIDS; Other Names: Non-efavirenz group; Drug: Lopinavir-Ritonavir Drug Combination; Weight-based dosing according to the National Guidelines for the Management of HIV and AIDS; Other Names: Non-efavirenz group

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neuropsychological symptoms: competence and psychopathology (internalizing/externalizing symptoms)	Neuropsychological symptoms will be assessed using the Swahili version of the Child Behavior Checklist for 6-18 years (CBCL6-18)	At day of inclusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cognitive functioning - non-verbal cognitive ability (general intelligence)	Non-verbal cognitive ability will be assessed using the Raven's Progressive Matrices	At day of inclusion
Cognitive functioning - working memory	Working memory will be assessed using the Wechsler Intelligence Scale for Children (WISC-III) Digit Span Test	At day of inclusion
Treatment adherence	Treatment adherence will be measured using an adherence questionnaire, adapted from the PENTA 16 trial (permission obtained from the author prof. Giaquinto)	At day of inclusion

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Central nervous system symptoms	The presence of central nervous system symptoms (yes/no) in the week prior to study visit will be assessed using a checklist composed of symptoms that have been linked to efavirenz in literature.	At day of inclusion

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: Kilimanjaro Christian Medical Centre, Tanzania; Kilimanjaro Clinical Research Institute
• Investigators: Principal Investigator: Grace Kinabo, MD, PhD, Kilimanjaro Christian Medical Centre; Principal Investigator: André van der Ven, MD, PhD, Radboud University Medical Center

Publications and helpful links

General Publications

• Van de Wijer L, Schellekens AFA, Burger DM, Homberg JR, de Mast Q, van der Ven AJAM. Rethinking the risk-benefit ratio of efavirenz in HIV-infected children. Lancet Infect Dis. 2016 May;16(5):e76-e81. doi: 10.1016/S1473-3099(16)00117-1. Epub 2016 Apr 18.
• Mothapo KM, Schellekens A, van Crevel R, Keuter M, Grintjes-Huisman K, Koopmans P, van der Ven A. Improvement of Depression and Anxiety After Discontinuation of Long- Term Efavirenz Treatment. CNS Neurol Disord Drug Targets. 2015;14(6):811-8. doi: 10.2174/1871527314666150325235847.
• Van de Wijer L, Kinabo GD, Mchaile DN, de Mast Q, Schellekens AFA, van der Ven AJAM. Safety Evaluation of Efavirenz in Children: Don't Forget the Central Nervous System. Clin Infect Dis. 2018 Mar 19;66(7):1150. doi: 10.1093/cid/cix926. No abstract available.
• Van de Wijer L, Mchaile DN, de Mast Q, Mmbaga BT, Rommelse NNJ, Duinmaijer A, van der Ven AJAM, Schellekens AFA, Kinabo GD. Neuropsychiatric symptoms in Tanzanian HIV-infected children receiving long-term efavirenz treatment: a multicentre, cross-sectional, observational study. Lancet HIV. 2019 Apr;6(4):e250-e258. doi: 10.1016/S2352-3018(18)30329-1. Epub 2019 Feb 12.

Study record dates

Study Major Dates

• Study Start (Actual): June 19, 2017
• Primary Completion (Actual): December 31, 2017
• Study Completion (Actual): December 31, 2017

Study Registration Dates

• First Submitted: July 18, 2017
• First Submitted That Met QC Criteria: July 20, 2017
• First Posted (Actual): July 24, 2017

Study Record Updates

• Last Update Posted (Actual): July 10, 2018
• Last Update Submitted That Met QC Criteria: July 9, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: Efavirenz; Cognition; Medication Adherence; Child Behavior; Drug-Related Side Effects
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Drug-Related Side Effects and Adverse Reactions; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; HIV Protease Inhibitors; Viral Protease Inhibitors; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Nevirapine; Ritonavir; Lopinavir; Efavirenz
• Other Study ID Numbers: EFV Kids

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No