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Randomized clinical trial to identify optimal pediatric efavirenz dosage to treat HIV infected infant and children in Africa

More than 90% of the estimated 3.3 million HIV infected children worldwide live in Sub Saharan Africa. Efavirenz (EFV) is approved recently by US-FDA and WHO as part of first line combination ART for HIV infected children >3 years of age. Based on results from few clinical studies, the US-FDA approved the use of EFV in infant and children aged ≥3 months weighing >3.5 kg. Due to lack of efficacy, safety and pharmacokinetic data WHO continues to limit the use of EFV in children under <3 years of age. The current body weight-based EFV dose recommended (FDA and WHO) to treat HIV in infant and children is scaled-down prediction from population pharmacokinetic modeling of data obtained from adult subjects treated with the standard maximum EFV dose. Biochemical and physiological processes between children and adults such as metabolism are disproportionate to their body weight differences. Although adult data is helpful to decide a first-in-children dose to initiate a safety, efficacy and PK study, the appropriate way to determine pharmacokinetic and pharmacodynamic parameters in children for a given age group is to conduct a dose optimization studies in specific age groups. Our extensive EFV dose optimization studies in Sub Saharan Africa patients indicate the importance of pharmacogenetic variations for efavirenz plasma exposure and treatment outcome. Based on population PK modeling of observational data, we demonstrated that standard 600 mg daily adult dose is unnecessarily high and recommended a dose reduction to 400 mg daily for adults in black African populations, which is confirmed by recent randomized clinical trials. In the present study we aim to perform a similar EFV dose optimization study specific for pediatrics population in Africa. EFV crosses the blood brain barrier and high plasma EFV concentration is associated with CNS toxicity, which may result in untoward effect for the developing child brain. We hypothesize that with the current recommended EFV dose, the risk of under- or overdosing of EFV is eminent among black African children who exhibit significant nutritional, comorbidity and host-genetic diversity from populations where pharmacokinetic and safety studies are performed and data extrapolated with “one-dose-fit-all” principle. We aim to identify safe and effective efavirenz dosage recommendations specific for pediatric use to treat HIV infected infants and children in Sub Saharan Africa. A three-phase extensive efavirenz pharmacokinetics, pharmacogenetics and pharmacodynamics based EFV dose optimization study will be conducted in HIV and HIV-TB co-infected infant and children from two genetically diverse African populations (Uganda and Ethiopia) during 2016 – 2020. First (Phase-1): observational study will be conducted to evaluate EFV plasma exposure, safety (skin rash, liver and CNS toxicity) and efficacy (immunologic and virological outcomes) of EFV based ART using the current EFV dose approved by FDA (< 3 years of age) and WHO (> 3 years of age) treatment guidelines. Patients will be enrolled prospectively and followed for one year. Application and feasibility of bedside genotype testing for patient care to aid EFV dose adjustment in HIV pediatric clinic will be developed and evaluated. Secondly (Phase-2): Population pharmacokinetic, pharmacogenetic and pharmacodynamics modeling and simulation of the data we will be performed to identify the normal efavirenz therapeutic range and optimal predictive EFV dose recommendation for the various age group. Thirdly (Phase-3): In a randomized clinical trial, we will evaluate the safety and efficacy of the predicted optimal EFV dose and compare it against the current FDA/WHO approved EFV dose recommendations. The study, to be conducted through a well-established multidisciplinary collaboration, will provide evidence-based recommendation for policy makers to develop safe and effective HIV treatment guidelines for the most vulnerable pediatric population in

Project ID

SE-0-SE-29-2015-03295_1-285-12182

Activity status

2 - Implementation

Aid type

D02 - Other technical assistance

% to Uganda

100.00

Organisations

Funding

Sweden

Extending

The Swedish Research Council

Implementing

Karolinska Institutet

CRS code	%
Medical research (12182)	100.0