The long-term goal of the project is to improve the health of children with drug-resistant tuberculosis (DR-TB) in need of second-line anti-tuberculosis (anti-TB) drugs, through studying the pharmacokinetics (PK), safety profile and toxicity of commonly used second-line anti-TB drugs in children with and without HIV co-infection.
The specific aims are: 1) to compare the PK of second-line anti-tuberculosis drugs in children (<15 years) by age;2) to compare the plasma concentrations of antiretroviral (ARV) drugs in HIV-infected children (<15 years) on second-line anti-TB drugs to those not on anti-TB therapy;and 3) to characterize the tolerability and toxicity of second-line anti-TB drugs in HIV-infected and uninfected children. Childhood TB represents 15-20% of the disease burden in settings where TB and HIV infection is prevalent. Multidrug-resistant TB (MDR-TB;i.e. resistance to both rifampin and isoniazid) is an emerging epidemic, with an estimated 489 000 global cases annually. MDR-TB patients often experience prolonged diagnostic delay, resulting in transmission of these strains especially to young children with a sharp increase in the numbers of children on treatment and prophylaxis for MDR-TB. This hospital-based study will be implemented in Cape Town, Western Cape Province, South Africa at 2 referral hospitals - Brooklyn Hospital for Chest Diseases and Tygerberg Children's Hospital. The prevalence of MDR-TB amongst children with culture-confirmed TB was 8.6% and the prevalence of HIV infection in children with TB was 25-30% during 2009. The most frequently used second-line anti-TB drugs in children in the PIs'setting are ethionamide, fluoroquinolones, amikacin and terizidone. Capreomycin, linezolid and PAS are typically used for treatment of extensively drug-resistant TB. Although second-line anti-TB drugs are routinely given and recommended in children, there is limited information available to inform the accurate dosing in young and in HIV-infected children, who may have altered drug metabolism and drug-drug interactions. There are limited data on toxicity of these anti-TB drugs in children, who are typically treated for 18-24 months for DR-TB. The PIs will complete a prospective, longitudinal, hospital-based, observational PK study in HIV-infected and uninfected children aged 0-15 years who are receiving routine chemotherapy or chemoprophylaxis for the treatment or prevention of DR-TB. They will enroll 310 total children consecutively over 3.5 years for intensive PK sampling of second-line anti-TB drugs at baseline. HIV-infected children will have ARV PK sampling done at baseline. Approximately 30% of the PIs'sample will be HIV-infected. An equal number of HIV-infected children with and without anti-TB therapy (concurrent controls;42 on efavirenz and 22 on lopinavir) will be enrolled based on the required age strata to allow for comparison of the effect of second-line TB drugs on ARV levels in HIV-infected children with and without TB treatment. The PIs will follow children on treatment for DR disease until treatment completion for clinical outcomes including TB treatment response and drug adverse effects. Enrolment will be balanced by HIV status and age to ensure adequate number of the children 0-2 years of age and HIV-infected children.

Public Health Relevance

Although childhood TB can be treated by taking medicines, some strains of TB are resistant to commonly used TB medications (drug-resistant TB). These children need medications that are less effective, have more side effects, of which little is known which dosage (amount) children should receive and how to check whether these medications are safe in young and HIV-infected children. Knowledge gained through this study will help find out how to best give the correct amount of medication to safely treat and prevent drug-resistant TB in young and HIV-infected children.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Special Emphasis Panel (ZHD1-RRG-K (15))
Program Officer
Worrell, Carol
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Stellenbosch University Tygerberg Campus
South Africa
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Garcia-Prats, Anthony J; Rose, Penelope C; Draper, Heather R et al. (2018) Effect of Coadministration of Lidocaine on the Pain and Pharmacokinetics of Intramuscular Amikacin in Children With Multidrug-Resistant Tuberculosis: A Randomized Crossover Trial. Pediatr Infect Dis J 37:1199-1203
Garcia-Prats, Anthony J; Draper, Heather R; Thee, Stephanie et al. (2015) Pharmacokinetics and Safety of Ofloxacin in Children with Drug-Resistant Tuberculosis. Antimicrob Agents Chemother 59:6073-9
Thee, Stephanie; Garcia-Prats, Anthony J; Draper, Heather R et al. (2015) Pharmacokinetics and safety of moxifloxacin in children with multidrug-resistant tuberculosis. Clin Infect Dis 60:549-56
Sy, Sherwin K B; Malmberg, Ruben; Matsushima, Aoi et al. (2015) Effect of reducing the paediatric stavudine dose by half: a physiologically-based pharmacokinetic model. Int J Antimicrob Agents 45:413-9
Schaaf, H Simon; Garcia-Prats, Anthony J; Hesseling, Anneke C et al. (2014) Managing multidrug-resistant tuberculosis in children: review of recent developments. Curr Opin Infect Dis 27:211-9
Thee, S; Garcia-Prats, A J; McIlleron, H M et al. (2014) Pharmacokinetics of ofloxacin and levofloxacin for prevention and treatment of multidrug-resistant tuberculosis in children. Antimicrob Agents Chemother 58:2948-51
Sy, Sherwin K B; Innes, Steve; Derendorf, Hartmut et al. (2014) Estimation of intracellular concentration of stavudine triphosphate in HIV-infected children given a reduced dose of 0.5 milligrams per kilogram twice daily. Antimicrob Agents Chemother 58:1084-91
Seddon, James A; Garcia-Prats, Anthony J; Kampmann, Beate et al. (2014) Toxicity and tolerability of fluoroquinolone-based preventive therapy for childhood contacts of multidrug-resistant tuberculosis. Pediatr Infect Dis J 33:1098-9